Strengthening mental health research outcomes through genuine partnerships with young people with lived or living experience: A pilot evaluation study.

BACKGROUND: Despite increasing support for stakeholder inclusion in research, there is limited evaluative research to guide safe (i.e., youth-friendly) and meaningful (i.e., non-tokenistic) partnerships with young people with lived experience of mental ill-health in research. This paper describes a pilot evaluation and iterative design of a Youth Lived Experience Working Group (LEWG) protocol that was established by the Youth Mental Health and Technology team at The University of Sydney's Brain and Mind Centre, based on the results of two studies. METHODS: Study one consisted of a pilot evaluation of the extent to which youth partners felt empowered to contribute, to qualitatively explore how LEWG processes could be improved. Youth partners completed online surveys, and results were shared over two LEWG meetings in 2021 to empower youth partners to collectively identify actions of positive change regarding LEWG processes. These meetings were audio-recorded and transcripts were subsequently coded using thematic analysis. Study two assessed whether LEWG processes and proposed improvements were acceptable and feasible from the perspective of academic researchers via an online survey in 2022. RESULTS: Quantitative and qualitative data collected from nine youth partners and 42 academic researchers uncovered initial learnings regarding facilitators, motivators, and barriers to partnering with young people with lived experience in research. Implementing clear processes for youth partners and academic researchers on effective partnership strategies, providing training opportunities for youth partners to develop research skills, and providing regular updates on how youth partner contributions led to research outcomes were identified as key facilitators. CONCLUSIONS: This pilot study provides insight into a growing international field on how to optimise participatory processes so that researchers and young people with lived experience can be better supported and engaged to make meaningful contributions to mental health research. We argue that more transparency is needed around participatory research processes so that partnerships with young people with lived experience are not merely tokenistic. CONSUMER CONTRIBUTIONS: Our study has also been approved by and reflects the concepts and priorities of our youth lived experience partners and lived experience researchers, all of whom are authors of this paper.

[Expression and significance of PD-1 and PD-L1 in the specimens of epithelial ovarian cancer].

Objective: To examine the expression of programmed cell death 1 (PD-1) and its ligand (PD-L1) in epithelial ovarian cancer (EOC) tissues, and investigate the correlation among their expression, clinicopathological features and prognosis. Methods: The specimens of 180 patients with EOC treated in the First Affiliated Hospital of Dalian Medical University from October 2002 to December 2013 were confirmed by pathological examination. The pathological tissue specimens of subtypes ，included 120 cases of serous carcinoma, 30 cases of mucinous carcinoma, 20 cases of endometrioid carcinoma, and 20 cases of clear cell carcinoma. The normal paracancerous tissues of 50 cases randomly selected from the 180 patients as control group. Immunohistochemical SP method was used to detect the expressions of both PD-1 and PD-L1 in epithelial ovarian cancer tissues, and the relationships among their expressions,the clinicopathological parameters and prognosis were respectively analyzed. Results: （1） PD-1 was expressed in lymphocytes infiltrated in EOC tissues, and PD-L1 was expressed in the cell membranes of cancer tissues. In all EOC cases, 33 cases (18.3%, 33/180) of both PD-1 and PD-L1 were highly expressed, and only 1 (2.0%, 1/50) of control group showed high expression. There was statistically significant difference between two groups (P<0.01). (2) Among the four subtypes tissue specimens of EOC, the high expression rate of PD-1 was 25.0% (30/120) for serous carcinoma, 3/15 for endometrioid carcinoma, 0 (0/30) for mucinous carcinoma, and 0 (0/15) for clear cell carcinoma. The high expression rate of PD-L1 was 23.3% (28/120) for serous carcinoma, 3.3% (1/30) for mucinous carcinoma, 2/15 for endometrioid carcinoma, and 2/15 for clear cell carcinoma. Both PD-1 and PD-L1 expressions in the four sub-types of tissue specimens were significantly different (P<0.05). The high expression rate of both PD-1 and PD-L1 was 9.2% (8/87) in the early stage and 26.9% (25/93) in the late stage. There was a statistically significant difference between the two groups (P<0.01). Similarly, the expression of both PD-1 and PD-L1 were significantly higher in the cases of high-grade EOC （type Ⅱ） than those of low-grade （type Ⅰ） and in the cases of EOC distributed bilaterally than that distributed unilaterally, and there were statistically significant differences (P<0.05). (3) The Kaplan-Meier survival analysis showed that the survival time were respectively 35 and 36 months in the cases with high expressions of both PD-1 and PD-L1, and the survival time were the same as 61 months in the cases with low expression of both PD-1 and PD-L1, and the comparison was statistically significant (P<0.05). Conclusions: The expression levels of PD-1 and PD-L1 in EOC tissues are higher than those in adjacent tissues, especially in serous carcinomas. The expression of both PD-1 and PD-L1 is higher in specimens of the patients with advanced stages. The results showed that the high expression of both PD-1 and PD-L1 is an indicator of poor prognosis of patients suffering from EOC.

Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/ acne inversa.

The precise pathogenic mechanisms in the development, persistence and worsening of hidradenitis suppurativa (HS) remain ill-defined. This chronic inflammatory dermatosis displays a strong Th1 and Th17 inflammatory signature with elevated levels of TNF-α, IL-1ß, IL-17 and IFNγ in lesional and perilesional tissue. HS significantly differs to other chronic inflammatory dermatoses due to the development of hypertrophic scarring and dermal tunnels. The development of scarring and tunnels suggests that fibroblastic stromal cells (including myofibroblasts, fibroblasts, pericytes etc) may be involved in the development and progression of disease. Heterogeneous populations of fibroblasts have been identified in other inflammatory disorders and malignancy which contribute to inflammation and present novel therapeutic targets for fibrotic disorders. Findings in HS are consistent with these fibroblast subpopulations and may contribute to tunnel formation, aggressive squamous cell carcinoma and the phenotypic presentation of familial HS variants. We describe the existing knowledge regarding these mechanistic pathways and methods to confirm their involvement in the pathogenesis of HS.

CEP295 interacts with microtubules and is required for centriole elongation.

Centriole duplication is a tightly ordered process during which procentrioles are assembled in G1-S and elongate during S and G2. Here, we show that human CEP295 (Drosophila Ana1) is not essential for initial cartwheel assembly, but is required to build distal half centrioles during S and G2. Using super-resolution and immunogold electron microscopy, we demonstrate that CEP295 is recruited to the proximal end of procentrioles in early S phase, when it is also localized at the centriolar microtubule wall that surrounds the human SAS6 cartwheel hub. Interestingly, depletion of CEP295 not only inhibits the recruitments of POC5 and POC1B to the distal half centrioles in G2, resulting in shorter centrioles, it also blocks the post-translational modification of centriolar microtubules (e.g. acetylation and glutamylation). Importantly, our results indicate that CEP295 directly interacts with microtubules, and that excess CEP295 could induce the assembly of overly long centrioles. Furthermore, exogenous expression of the N-terminal domain of CEP295 exerts a dominant-negative effect on centriole elongation. Collectively, these findings suggest that CEP295 is essential for building the distal half centrioles and for post-translational modification of centriolar microtubules.

Effect of peer support on diabetes distress: a cluster randomized controlled trial.

AIM: To investigate whether peer support would reduce diabetes distress and improve glycaemic control when added to usual diabetes education among adults with Type 2 diabetes in China. METHODS: We conducted a cluster randomized trial involving 400 adults with Type 2 diabetes from eight communities in Nanjing. All participants received usual education for an average of 2 h each month from physicians, certified diabetes educators, dieticians, psychologists and podiatric nurses. Peer support was led by trained peer leaders and included diabetes knowledge- and skills-sharing at least once a month, as well as peer-to-peer communication. The primary outcome was diabetes distress measured using the Diabetes Distress Scale at 12 months. Secondary outcomes included fasting plasma glucose, 2-h postprandial glucose and HbA1c concentration. Outcome data were collected from all participants at baseline, 6 months and 12 months. RESULTS: From 2012 to 2013, there were 200 participants in each study arm at baseline. Compared with the usual education arm, the peer support with usual education arm had greater reductions in regimen-related distress (1.4 ± 0.6 vs 1.2 ± 0.4; P=0.004) and total distress (1.3 ± 0.4 vs 1.2 ± 0.3; P=0.038) at 6 months. At 12 months, the scores for emotional burden (1.2 ± 0.3 vs 1.4 ± 0.6; P=0.002), physician-related distress (1.1 ± 0.3 vs 1.3 ± 0.4; P=0.001) and total scores (1.2 ± 0.3 vs 1.3 ± 0.4; P=0.002) were significantly lower in the peer support with usual education arm than in the usual education arm. Fasting plasma glucose levels were lower in the peer support with usual education arm than in the usual education arm at 6 months (7.5 ± 1.95 vs 8.0 ± 2.2; P=0.044) and 12 months (7.0 ± 2.3 vs 7.6 ± 1.5; P=0.008). CONCLUSIONS: Beyond the benefits of usual education, peer support was effective in reducing diabetes distress for Type 2 diabetes mellitus. (Clinical Trials Registry no: NCT02119572).

Human microcephaly protein CEP135 binds to hSAS-6 and CPAP, and is required for centriole assembly.

Centrioles are cylindrical structures that are usually composed of nine triplets of microtubules (MTs) organized around a cartwheel-shaped structure. Recent studies have proposed a structural model of the SAS-6-based cartwheel, yet we do not know the molecular detail of how the cartwheel participates in centriolar MT assembly. In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. Furthermore, CEP135 depletion led to abnormal centriole structures with altered numbers of MT triplets and shorter centrioles. Overexpression of a CEP135 mutant lacking the proper interaction with hSAS-6 had a dominant-negative effect on centriole assembly. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation.

Neuroticism and the Overlap Between Autistic and ADHD Traits: Findings From a Population Sample of Young Adult Australian Twins.

Neuroticism, a 'Big Five' personality trait, has been associated with sub-clinical traits of both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The objective of the current study was to examine whether causal overlap between ASD and ADHD traits can be accounted for by genetic and environmental risk factors that are shared with neuroticism. We performed twin-based structural equation modeling using self-report data from 12 items of the Neo Five-Factor Inventory Neuroticism domain, 11 Social Responsiveness Scale items, and 12 Adult ADHD Self-Report Scale items obtained from 3,170 young adult Australian individual twins (1,081 complete pairs). Univariate analysis for neuroticism, ASD, and ADHD traits suggested that the most parsimonious models were those with additive genetic and unique environmental components, without sex limitation effects. Heritability of neuroticism, ASD, and ADHD traits, as measured by these methods, was moderate (between 40% and 45% for each respective trait). In a trivariate model, we observed moderate phenotypic (between 0.45 and 0.62), genetic (between 0.56 and 0.71), and unique environmental correlations (between 0.37and 0.55) among neuroticism, ASD, and ADHD traits, with the highest value for the shared genetic influence between neuroticism and self-reported ASD traits (r g = 0.71). Together, our results suggest that in young adults, genetic, and unique environmental risk factors indexed by neuroticism overlap with those that are shared by ASD and ADHD.

Pedometer intervention and weight loss in overweight and obese adults with Type 2 diabetes: a meta-analysis.

AIM: Although pedometer intervention is effective in increasing physical activity among adults with Type 2 diabetes, its impact on weight loss remains unclear. This meta-analysis was aimed to assess whether pedometer intervention promotes weight loss. METHODS: Three different databases were searched for randomized controlled trials (RCTs) published in English up to April 2015. Studies were included if they investigated the effects of pedometer intervention on weight loss, as measured by BMI or weight. Effect sizes were aggregated using a random-effects model. Subgroup and meta-regression analyses were used to identify potential moderators. Eleven RCTs with 1258 participants were included. All enrolled participants were overweight or obese. RESULTS: Pedometer intervention led to significantly decreased BMI [weighted mean difference (WMD) -0.15 kg/m(2) , 95% confidence interval (CI) -0.29 to -0.02 kg/m(2) ] and reduced weight (WMD -0.65 kg, 95% CI -1.12 to -0.17 kg). Dietary counselling seemed to be a key predictor of the observed changes. However, none of the following variables had a significant influence: step goal setting, baseline age, BMI, weight, sex distribution, disease duration, intervention duration, and baseline values or change scores for total or moderate-to-vigorous physical activity. After completion of the pedometer intervention, non-significant declines in BMI and weight were observed during the follow-up periods. CONCLUSIONS: Pedometer intervention promotes modest weight loss, but its association with physical activity requires further clarification. Future studies are also required to document dietary and sedentary behaviour changes to facilitate the use of pedometers for weight loss in overweight and obese adults with Type 2 diabetes.

Differential expression of two C-type lectins in grass carp Ctenopharyngodon idella and their response to grass carp reovirus.

The cDNAs of two C-type lectins in grass carp Ctenopharyngodon idella, galactose-binding lectin (galbl) and mannose-binding lectin (mbl), were cloned and analysed in this study. Both of them exhibited the highest expression level in liver, whereas their expression pattern differed in early phase of embryonic development. Following exposure to grass carp reovirus (GCRV), the mRNA expression level of galbl and mbl was significantly up-regulated in liver and intestine.

The human microcephaly protein STIL interacts with CPAP and is required for procentriole formation.

Centriole duplication involves the growth of a procentriole next to the parental centriole. Mutations in STIL and CPAP/CENPJ cause primary microcephaly (MCPH). Here, we show that human STIL has an asymmetric localization to the daughter centriole and is required for procentriole formation. STIL levels oscillate during the cell cycle. Interestingly, STIL interacts directly with CPAP and forms a complex with hSAS6. A natural mutation of CPAP (E1235V) that causes MCPH in humans leads to significantly lower binding to STIL. Overexpression of STIL induced the formation of multiple procentrioles around the parental centriole. STIL depletion inhibited normal centriole duplication, Plk4-induced centriole amplification, and CPAP-induced centriole elongation, and resulted in a failure to localize hSAS6 and CPAP to the base of the nascent procentriole. Furthermore, hSAS6 depletion hindered STIL targeting to the procentriole, implying that STIL and hSAS6 are mutually dependent for their centriolar localization. Together, our results indicate that the two MCPH-associated proteins STIL and CPAP interact with each other and are required for procentriole formation, implying a central role of centriole biogenesis in MCPH.

A dual-targeting antibody against EGFR-VEGF for lung and head and neck cancer treatment.

An antibody simultaneously targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), two major tumor growth-driving machineries, may provide a novel effective strategy for optimizing tumor targeting and maximizing potential clinical benefits. Human domain antibodies selected against VEGF and EGFR were formatted into a fully human dual-targeting IgG (DT-IgG) to directly target both antigens in a single molecule. We evaluated the efficacy of DT-IgG in comparison with bevacizumab and cetuximab alone and in combination in the lung cancer cell line A549 (low EGFR expression and KRAS mutant) and the head and neck squamous cell carcinoma (HNSCC) cell line Tu212 (high EGFR expression and KRAS wild type) in vitro and in vivo. DT-IgG suppressed Tu212 and A549 cell growth, inhibited EGFR activation and induced apoptosis as effectively as cetuximab, and neutralized VEGF as effectively as bevacizumab. DT-IgG induced EGFR-dependent VEGF internalization, constituting a novel antiangiogenesis mechanism. In xenograft models with lung and head and neck cancer cell lines, DT-IgG displayed efficacy equivalent to bevacizumab in diminishing tumor growth despite its short serum half-life (36 hr in rats) and both agents may constitute preferable alternatives to cetuximab in KRAS-mutant tumors. Immunofluorescence staining revealed that localization of DT-IgG was similar to that of cetuximab, largely associated with EGFR+tumor cells. Our proof of principle study suggests a DT-IgG against EGFR and VEGF as an alternative therapeutic strategy with potentially enhanced clinical benefit.

Missing in action: the right to the highest attainable standard of mental health care.

BACKGROUND: The right to the highest attainable standard of mental health remains a distant goal worldwide. The Report of the UN Special Rapporteur on the right of all people to enjoyment of the highest attainable standard of physical and mental health pleaded the urgent need for governments to act through appropriate laws and policies. We argue that Australia is in breach of international obligations, with inadequate access to mental health services, inconsistent mental health legislation across jurisdictions and ongoing structural (systematic) and individual discrimination. DISCUSSION: Inadequate access to mental health services is a worldwide phenomenon. Australia has committed to international law obligations under the Convention on the Rights of Persons with Disabilities (CRPD) to 'promote, protect and ensure the full and equal enjoyment of all human rights and fundamental freedoms by all persons with disability, with respect to their inherent dignity'. This includes people with mental health impairment and this convention includes the right to 'the highest attainable standard of mental health'. Under the Australian Constitution, ratification of this convention enables the national government to pass laws to implement the convention obligations, and such national laws would prevail over any inconsistent state (or territory) laws governing mental health service provision. The authors argue that enabling positive rights through legislation and legally binding mental health service standards may facilitate enhanced accountability and enforcement of such rights. These steps may support critical key stakeholders to improve the standards of mental health service provision supported by the implementation of international obligations, thereby accelerating mental health system reform. Improved legislation would encourage better governance and the evolution of better services, making mental health care more accessible, without structural or individual discrimination, enabling all people to enjoy the highest attainable standard of health.

A Dynamic Approach to Economic Priority Setting to Invest in Youth Mental Health and Guide Local Implementation: Economic Protocol for Eight System Dynamics Policy Models.

Background: Mental illness costs the world economy over US2.5 Bn each year, including premature mortality, morbidity, and productivity losses. Multisector approaches are required to address the systemic drivers of mental health and ensure adequate service provision. There is an important role for economics to support priority setting, identify best value investments and inform optimal implementation. Mental health can be defined as a complex dynamic system where decision makers are challenged to prospectively manage the system over time. This protocol describes the approach to equip eight system dynamics (SD) models across Australia to support priority setting and guide portfolio investment decisions, tailored to local implementation context. Methods: As part of a multidisciplinary team, three interlinked protocols are developed; (i) the participatory process to codesign the models with local stakeholders and identify interventions for implementation, (ii) the technical protocol to develop the SD models to simulate the dynamics of the local population, drivers of mental health, the service system and clinical outcomes, and (iii) the economic protocol to detail how the SD models will be equipped to undertake a suite of economic analysis, incorporating health and societal perspectives. Models will estimate the cost of mental illness, inclusive of service costs (health and other sectors, where necessary), quality-adjusted life years (QALYs) lost, productivity costs and carer costs. To assess the value of investing (disinvesting) in interventions, economic analysis will include return-on-investment, cost-utility, cost benefit, and budget impact to inform affordability. Economic metrics are expected to be dynamic, conditional upon changing population demographics, service system capacities and the mix of interventions when synergetic or antagonistic interactions. To support priority setting, a portfolio approach will identify best value combinations of interventions, relative to a defined budget(s). User friendly dashboards will guide decision makers to use the SD models to inform resource allocation and generate business cases for funding. Discussion: Equipping SD models to undertake economic analysis is intended to support local priority setting and help optimise implementation regarding the best value mix of investments, timing and scale. The objectives are to improve allocative efficiency, increase mental health and economic productivity.

Optimizing Strategies for Improving Mental Health in Victoria, Australia during the COVID-19 Era: A System Dynamics Modelling Study.

The ongoing COVID-19 pandemic has impacted the mental health of populations and highlighted the limitations of mental health care systems. As the trajectory of the pandemic and the economic recovery are still uncertain, decision tools are needed to help evaluate the best interventions to improve mental health outcomes. We developed a system dynamics model that captures causal relationships among population, demographics, post-secondary education, health services, COVID-19 impact, and mental health outcomes. The study was conducted in the Australian state of Victoria. The model was calibrated using historical data and was stratified by age group and by geographic remoteness. Findings demonstrate that the most effective intervention combination includes economic, social, and health sector initiatives. Assertive post-suicide attempt care is the most impactful health sector intervention, but delaying implementation reduces the potency of its impact. Some evidence-based interventions, such as population-wide community awareness campaigns, are projected to worsen mental health outcomes when implemented on their own. Systems modelling offers a powerful decision-support tool to test alternative strategies for improving mental health outcomes in the Victorian context.

Participatory Methods for Systems Modeling of Youth Mental Health: Implementation Protocol.

BACKGROUND: Despite significant investment, mental health issues remain a leading cause of death among young people globally. Sophisticated decision analysis methods are needed to better understand the dynamic and multisector drivers of youth mental health. System modeling can help explore complex issues such as youth mental health and inform strategies to effectively respond to local needs and achieve lasting improvements. The advantages of engaging stakeholders in model development processes have long been recognized; however, the methods for doing so are often not well-described. OBJECTIVE: This paper aims to describe the participatory procedures that will be used to support systems modeling for national multisite implementation. The Right Care, First Time, Where You Live research program will focus on regional youth mental health applications of systems modeling in 8 different sites across Australia. METHODS: The participatory model development approach involves an iterative process of engaging with a range of participants, including people with lived experience of mental health issues. Their knowledge of the local systems, pathways, and drivers is combined with the academic literature and data to populate the models and validate their structure. The process centers around 3 workshops where participants interact and actively engage in group model-building activities to define, refine, and validate the systems models. This paper provides a detailed blueprint for the implementation of this process for mental health applications. RESULTS: The participatory modeling methods described in this paper will be implemented at 2 sites per year from 2022 to 2025. The 8 selected sites have been chosen to capture variations in important factors, including determinants of mental health issues and access to services. Site engagement commenced in August 2021, and the first modeling workshops are scheduled to commence in February 2022. CONCLUSIONS: Mental health system decision makers require tools to help navigate complex environments and leverage interdisciplinary problem-solving. Systems modeling can mobilize data from diverse sources to explore a range of scenarios, including the impact of interventions in different combinations and contexts. Involving stakeholders in the model development process ensures that the model findings are context-relevant and fit-for-purpose to inform decision-making. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/32988.

Sound Decision Making in Uncertain Times: Can Systems Modelling Be Useful for Informing Policy and Planning for Suicide Prevention?

The COVID-19 pandemic demonstrated the significant value of systems modelling in supporting proactive and effective public health decision making despite the complexities and uncertainties that characterise an evolving crisis. The same approach is possible in the field of mental health. However, a commonly levelled (but misguided) criticism prevents systems modelling from being more routinely adopted, namely, that the presence of uncertainty around key model input parameters renders a model useless. This study explored whether radically different simulated trajectories of suicide would result in different advice to decision makers regarding the optimal strategy to mitigate the impacts of the pandemic on mental health. Using an existing system dynamics model developed in August 2020 for a regional catchment of Western Australia, four scenarios were simulated to model the possible effect of the COVID-19 pandemic on levels of psychological distress. The scenarios produced a range of projected impacts on suicide deaths, ranging from a relatively small to a dramatic increase. Discordance in the sets of best-performing intervention scenarios across the divergent COVID-mental health trajectories was assessed by comparing differences in projected numbers of suicides between the baseline scenario and each of 286 possible intervention scenarios calculated for two time horizons; 2026 and 2041. The best performing intervention combinations over the period 2021-2041 (i.e., post-suicide attempt assertive aftercare, community support programs to increase community connectedness, and technology enabled care coordination) were highly consistent across all four COVID-19 mental health trajectories, reducing suicide deaths by between 23.9-24.6% against the baseline. However, the ranking of best performing intervention combinations does alter depending on the time horizon under consideration due to non-linear intervention impacts. These findings suggest that systems models can retain value in informing robust decision making despite uncertainty in the trajectories of population mental health outcomes. It is recommended that the time horizon under consideration be sufficiently long to capture the full effects of interventions, and efforts should be made to achieve more timely tracking and access to key population mental health indicators to inform model refinements over time and reduce uncertainty in mental health policy and planning decisions.

Measuring, Modeling, and Forecasting the Mental Wealth of Nations.

The COVID-19 pandemic has exposed the deep links and fragility of economic, health and social systems. Discussions of reconstruction include renewed interest in moving beyond GDP and recognizing "human capital", "brain capital", "mental capital", and "wellbeing" as assets fundamental to economic reimagining, productivity, and prosperity. This paper describes how the conceptualization of Mental Wealth provides an important framing for measuring and shaping social and economic renewal to underpin healthy, productive, resilient, and thriving communities. We propose a transdisciplinary application of systems modeling to forecast a nation's Mental Wealth and understand the extent to which policy-mediated changes in economic, social, and health sectors could enhance collective mental health and wellbeing, social cohesion, and national prosperity. Specifically, simulation will allow comparison of the projected impacts of a range of cross-sector strategies (education sector, mental health system, labor market, and macroeconomic reforms) on GDP and national Mental Wealth, and provide decision support capability for future investments and actions to foster Mental Wealth. Finally, this paper introduces the Mental Wealth Initiative that is harnessing complex systems science to examine the interrelationships between social, commercial, and structural determinants of mental health and wellbeing, and working to empirically challenge the notion that fostering universal social prosperity is at odds with economic and commercial interests.

Partnering with Aboriginal and Torres Strait Islander Peoples: An Evaluation Study Protocol to Strengthen a Comprehensive Multi-Scale Evaluation Framework for Participatory Systems Modelling through Indigenous Paradigms and Methodologies.

The social and emotional wellbeing of young Aboriginal and Torres Strait Islander peoples should be supported through an Indigenous-led and community empowering approach. Applying systems thinking via participatory approaches is aligned with Aboriginal and Torres Strait Islander research paradigms and can be an effective method to deliver a decision support tool for mental health systems planning for Indigenous communities. Evaluations are necessary to understand the effectiveness and value of such methods, uncover protective and healing factors of social and emotional wellbeing, as well as to promote Aboriginal and Torres Strait Islander self-determination over allocation of funding and resources. This paper presents modifications to a published evaluation protocol for participatory systems modelling to align with critical Aboriginal and Torres Strait Islander guidelines and recommendations to support the social and emotional wellbeing of young people. This paper also presents a culturally relevant participatory systems modelling evaluation framework. Recognizing the reciprocity, strengths, and expertise Aboriginal and Torres Strait Islander methodologies can offer to broader research and evaluation practices, the amended framework presented in this paper facilitates empowering evaluation practices that should be adopted when working with Aboriginal and Torres Strait Islander peoples as well as when working with other diverse, non-Indigenous communities.

Enhanced anti-tumor activity by the combination of the natural compounds (-)-epigallocatechin-3-gallate and luteolin: potential role of p53.

Natural dietary agents have drawn a great deal of attention toward cancer prevention because of their wide safety margin. However, single agent intervention has failed to bring the expected outcome in clinical trials; therefore, combinations of chemopreventive agents are gaining increasingly popularity. In the present study, we investigated a combinatorial approach using two natural dietary polyphenols, luteolin and EGCG, and found that their combination at low doses (at which single agents induce minimal apoptosis) synergistically increased apoptosis (3-5-fold more than the additive level of apoptosis) in both head and neck and lung cancer cell lines. This combination also significantly inhibited growth of xenografted tumors in nude mice. The in vivo findings also were supported by significant inhibition of Ki-67 expression and increase in TUNEL-positive cells in xenografted tissues. Mechanistic studies revealed that the combination induced mitochondria-dependent apoptosis in some cell lines and mitochondria-independent apoptosis in others. Moreover, we found more efficient stabilization and ATM-dependent Ser(15) phosphorylation of p53 due to DNA damage by the combination, and ablation of p53 using shRNA strongly inhibited apoptosis as evidenced by decreased poly(ADP-ribose) polymerase and caspase-3 cleavage. In addition, we observed mitochondrial translocation of p53 after treatment with luteolin or the combination of EGCG and luteolin. Taken together, our results for the first time suggest that the combination of luteolin and EGCG has synergistic/additive growth inhibitory effects and provides an important rationale for future chemoprevention trials of head and neck and lung cancers.

Striatal ß-amyloid in dementia with Lewy bodies but not Parkinson's disease.

Professor Jellinger first identified that striatal Aß deposition at postmortem seemed to differentiate cases of dementia with Lewy bodies (DLB) from those with Parkinson's disease dementia (PDD), a finding subsequently questioned. Our replication study in 34 prospectively studied cases assessed the ability of striatal Aß deposition to differentiate DLB from PDD, and also assessed the relationship between striatal and cortical Aß deposition and α-synuclein-immunoreactive pathologies, using previously published protocols. Cases with DLB had significantly shorter durations and greater dementia severities compared with cases with PDD. Striatal Aß-immunoreactive plaques were only consistently found in cases with DLB and correlated with both the severity (positive correlation) and duration (negative correlation) of dementia. Striatal Aß-immunoreactive plaques also positively correlated with the severity of α-synuclein-immunoreactive pathologies as well as cortical Aß-positive plaques. Striatal Aß deposition positively predicted dementia in Lewy body cases with high specificity and had the greatest sensitivity to differentiate DLB from PDD with 100% negative predictive value. These data suggest that striatal Aß deposition in Lewy body diseases contributes to early dementia and in these cases may impact on the efficacy of treatments targeting the striatum.