Centre for Youth Mental Health - Research Publications
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ItemRemote Control in Formation of 3D Multicellular Assemblies Using Magnetic Forces(AMER CHEMICAL SOC, 2019-05)Cell constructs have been utilized as building blocks in tissue engineering to closely mimic the natural tissue and also overcome some of the limitations caused by two-dimensional cultures or using scaffolds. External forces can be used to enhance the cells' adhesion and interaction and thus provide better control over production of these structures compared to methods like cell seeding and migration. In this paper, we demonstrate an efficient method to generate uniform, three-dimensional cell constructs using magnetic forces. This method produced spheroids with higher densities and more symmetrical structures than the commonly used centrifugation method for production of cell spheroids. It was also shown that shape of the cell constructs could be changed readily by using different patterns of magnetic field. The application of magnetic fields to impart forces on the cells enhanced the fusion of these spheroids, which could be used to produce larger and more complicated structures for future tissue engineering applications.
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ItemThe operational environment and rotational acceleration of asteroid (101955) Bennu from OSIRIS-REx observations(NATURE PUBLISHING GROUP, 2019-03-19)During its approach to asteroid (101955) Bennu, NASA's Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) spacecraft surveyed Bennu's immediate environment, photometric properties, and rotation state. Discovery of a dusty environment, a natural satellite, or unexpected asteroid characteristics would have had consequences for the mission's safety and observation strategy. Here we show that spacecraft observations during this period were highly sensitive to satellites (sub-meter scale) but reveal none, although later navigational images indicate that further investigation is needed. We constrain average dust production in September 2018 from Bennu's surface to an upper limit of 150 g s-1 averaged over 34 min. Bennu's disk-integrated photometric phase function validates measurements from the pre-encounter astronomical campaign. We demonstrate that Bennu's rotation rate is accelerating continuously at 3.63 ± 0.52 × 10-6 degrees day-2, likely due to the Yarkovsky-O'Keefe-Radzievskii-Paddack (YORP) effect, with evolutionary implications.
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ItemAn investigation into the association of pre- and post-migration experiences on the self-rated health status among new resettled adult humanitarian refugees to Australia: a protocol for a mixed methods study.(Springer Science and Business Media LLC, 2019-04-30)BACKGROUND: Refugees are one of the most vulnerable groups in our society. They are at risk of poor physical and mental health outcomes, much of this attributed to traumatic events prior to migration and the additional risk factors refugees face in the host nations. However, how migration factors shape the health of resettling refugees is not well understood. This study uses a mixed methods approach to examine how pre- and post-migration factors shape the self-rated health of resettling adult refugees in an effort to address the current knowledge gap. METHODS: This study will use a sequential explanatory mixed method study design. We begin by analyzing resettlement and health data from the 'Building a New Life In Australia' longitudinal study of humanitarian refugees resettled in Australia to identify significant associations between migration factors and refugee health. Then, a series of semi-structured interviews with resettled refugees will further explore the lived experiences of refugees with respect to the relationship between migration and refugee health. Finally, we will integrate both sets of findings to develop a detailed understanding of how and why migratory factors contribute to refugee health during resettlement. DISCUSSION: There is a paucity of studies that examine the multidimensional nature of refugee health during resettlement and as a result, little is understood about their resettlement health needs. This information is required to inform existing or new resettlement interventions to help promote or improve refugee health. To overcome these limitations in the research knowledge, this study will use a mixture of study methods to illustrate the complex and multifaceted determinants of refugee health during resettlement in Australia.
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ItemImproving access to primary healthcare for vulnerable populations in Australia and Canada: protocol for a mixed-method evaluation of six complex interventions.(BMJ, 2019-07-27)INTRODUCTION: Access to primary healthcare (PHC) has a fundamental influence on health outcomes, particularly for members of vulnerable populations. Innovative Models Promoting Access-to-Care Transformation (IMPACT) is a 5-year research programme built on community-academic partnerships. IMPACT aims to design, implement and evaluate organisational innovations to improve access to appropriate PHC for vulnerable populations. Six Local Innovation Partnerships (LIPs) in three Australian states (New South Wales, Victoria and South Australia) and three Canadian provinces (Ontario, Quebec and Alberta) used a common approach to implement six different interventions. This paper describes the protocol to evaluate the processes, outcomes and scalability of these organisational innovations. METHODS AND ANALYSIS: The evaluation will use a convergent mixed-methods design involving longitudinal (pre and post) analysis of the six interventions. Study participants include vulnerable populations, PHC practices, their clinicians and administrative staff, service providers in other health or social service organisations, intervention staff and members of the LIP teams. Data were collected prior to and 3-6 months after the interventions and included interviews with members of the LIPs, organisational process data, document analysis and tools collecting the cost of components of the intervention. Assessment of impacts on individuals and organisations will rely on surveys and semistructured interviews (and, in some settings, direct observation) of participating patients, providers and PHC practices. ETHICS AND DISSEMINATION: The IMPACT research programme received initial ethics approval from St Mary's Hospital (Montreal) SMHC #13-30. The interventions received a range of other ethics approvals across the six jurisdictions. Dissemination of the findings should generate a deeper understanding of the ways in which system-level organisational innovations can improve access to PHC for vulnerable populations and new knowledge concerning improvements in PHC delivery in health service utilisation.
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ItemThe association of migration experiences on the self-rated health status among adult humanitarian refugees to Australia: an analysis of a longitudinal cohort study.(Springer Science and Business Media LLC, 2019-08-22)BACKGROUND: Refugees are potentially at an increased risk for health problems due to their past and current migration experiences. How migration factors shape refugee health is not well understood. We examined the association between migration factors and the self-rated general health of adult humanitarian refugees living in Australia. METHODS: We analyzed the first three waves of data from the 'Building A New Life In Australia' longitudinal survey of 2399 humanitarian refugees resettled in Australia. The study outcome was self-rated health measured by the 36-Item Short Form Health Survey. Predictors were migration process and resettlement factors. We used generalized linear mixed models to investigate the relationship between predictor and outcome variables. RESULTS: Poor general health persisted among this refugee population at high levels throughout the three-year follow-up. At baseline, 35.7% (95% CI: 33.8-37.7%) of the study population reported poorer general health. Female gender, increasing age and post-migration financial stressors were positively associated with poorer general health. Having a university degree and absence of chronic health conditions were seemingly protective against declining general health (OR: 0.50; 95% CI: 0.65-1.81 and OR: 0.15, 95% CI: 0.09-1.04, respectively). CONCLUSION: Our results show that there is persisting high prevalence of poorer general health among adult refugees across the initial years of resettlement in Australia. This finding suggests unmet health needs which may be compounded by the challenges of resettlement in a new society, highlighting the need for increased clinical awareness of this sustained health burden to help inform and prepare refugee health care and settlement service providers.
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ItemNeurocognitive and neuroanatomical maturation in the clinical high-risk states for psychosis: A pattern recognition study(ELSEVIER SCI LTD, 2019)BACKGROUND: Findings from neurodevelopmental studies indicate that adolescents with psychosis spectrum disorders have delayed neurocognitive performance relative to the maturational state of their healthy peers. Using machine learning, we generated a model of neurocognitive age in healthy adults and investigated whether individuals in clinical high risk (CHR) for psychosis showed systematic neurocognitive age deviations that were accompanied by specific structural brain alterations. METHODS: First, a Support Vector Regression-based age prediction model was trained and cross-validated on the neurocognitive data of 36 healthy controls (HC). This produced Cognitive Age Gap Estimates (CogAGE) that measured each participant's deviation from the normal cognitive maturation as the difference between estimated neurocognitive and chronological age. Second, we employed voxel-based morphometry to explore the neuroanatomical gray and white matter correlates of CogAGE in HC, in CHR individuals with early (CHR-E) and late (CHR-L) high risk states. RESULTS: The age prediction model estimated age in HC subjects with a mean absolute error of ±2.2 years (SD = 3.3; R2 = 0.33, P < .001). Mean (SD) CogAGE measured +4.3 (8.1) years in CHR individuals compared to HC (-0.1 (5.5) years, P = .006). CHR-L individuals differed significantly from HC subjects while this was not the case for the CHR-E group. CogAGE was associated with a distributed bilateral pattern of increased GM volume in the temporal and frontal areas and diffuse pattern of WM reductions. CONCLUSION: Although the generalizability of our findings might be limited due to the relatively small number of participants, CHR individuals exhibit a disturbed neurocognitive development as compared to healthy peers, which may be independent of conversion to psychosis and paralleled by an altered structural maturation process.
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ItemNo Preview AvailableBrain Aging in Major Depressive Disorder: Results From the ENIGMA MDD Consortium(ELSEVIER SCIENCE INC, 2018-05-01)Background: Major Depressive Disorder has been associated with accelerated biological aging. From a brain perspective, normal aging is associated with significant loss of grey matter and depression may have an accelerating effect on age-related brain atrophy. Here, data on brain aging in MDD from the ENIGMA MDD Working Group will be presented. Methods: A normative model of brain-based age was devel- oped in 4708 healthy controls by applying a Gaussian Process Regression analysis with 10-fold cross-validation to estimate chronological age from structural MRI scans, separately for males and females. This model was then applied to 2924 MDD individuals to predict their brain-based age. Accelerated brain aging was measured as the difference between predicted brain-based age and actual chronological age (brain age gap). Results: The brain age model explained 92% and 93% of the age variance in female and male healthy controls, respectively. The mean absolute error (MAE) was 6.79 years in females and 6.60 in males. Application of the model to MDD patients showed a mean brain age gap of 0.75 years in females (MAE¼6.82) and 0.64 in males (MAE¼6.68), which were significantly lower than brain age gap estimates in healthy controls in both females (F(1,4379)¼6.10,P¼0.01) and males (F(1,3166)¼4.07,P¼0.04). Our preliminary analysis also showed greater brain age gap associations with various clinical characteristics. Conclusions: We found preliminary evidence for accelerated brain aging in MDD, however, the brains of patients were estimated to be only <1 years older than healthy controls. The impact of different methods, feature selection and potential confounding effects will also be discussed.
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ItemNo Preview AvailableMETHYLOME-WIDE ASSOCIATION STUDIES FOR MAJOR DEPRESSIVE DISORDER IN BLOOD OVERLAP WITH METHYLATION RESULTS FROM BRAIN AND LARGE-SCALE GWAS(ELSEVIER SCIENCE BV, 2019-01-01)Background: Epigenetic modifications such as DNA methy- lation provide stability and diversity to the cellular phenotype and aberrant methylation has been implicated in processes underlying psychiatric disorders. Therefore, studies combining DNA methylation and genotype information provide a promis- ing approach to study disorders where genotype information alone has failed to reveal the full etiology. Methods: We applied an optimized MBD-seq protocol to assay the complete CpG methylome in cases with Major Depressive Disorder (MDD) and controls using blood samples (N=1,132) from Netherlands Study of Depression and Anxiety and brain samples (N=64) from the Victorian Brain Bank Network. Data were analyzed with RaMWAS, a novel Biocon- ductor package specifically designed for Methylome-Wide Association Studies (MWAS). To study the overlap between top MWAS findings in blood and brain, we used a permutation based enrichment test (shiftR) that accounted for the depen- dency between adjacent CpG sites. Furthermore, we utilized the methylation data in combination with existing genotype information from the same individuals in a MWAS of CpGs created or destroyed by SNPs. Next, we tested whether top results from this CpG-SNP MWAS overlapped with recent large- scale GWAS to identify robust associations with genomic loci of importance for MDD etiology Results: The MWAS in blood identified five methylome- wide significant sites (P o 5 10-8) from three distinct loci and 472 nominally significant (P o 1 10-5) CpG sites. To study the robustness of the overall MWAS signal, we used an “in-sample” replication based on k-fold cross validation. Results showed that the findings replicated (P = 4.0 10- 10). When we compared blood and brain we found that top blood MWAS findings were significantly enriched for top CpGs in the brain MWAS (P = 5.4 10-3). The MWAS of CpG-SNPs identified 32 nominally significant sites and in- sample replication showed that the signal replicated (P = 2.2 10-8). Finally, the top CpG-SNP MWAS showed a consistent trend towards enrichment in all tested large- scale GWAS, with the most significant enrichment observed for the 23andMe study (P = 4.9 10-3). This overlap involved 55 genes that were overrepresented (P o 0.01) in 12 level-5 gene ontology terms, of which a major portion was related to neuronal regulation, function and development. Discussion: This work involves the largest MWAS for MDD performed to date. Our integrated analysis with brain tissue, genotype information and GWAS results highlighted biological functions of potential value for MDD etiology. Part of the associated methylation marks in blood overlapped with MWAS finding in brain. As blood can easily be collected in a clinical setting, these loci may be of direct value as potential diagnostic biomarkers for MDD.
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ItemNo Preview AvailableDeviations From Normative Age-Brain Associations in Over 3,000 Individuals With Major Depressive Disorder(ELSEVIER SCIENCE INC, 2019-05-15)Background: Major depressive disorder (MDD) is a complex heterogeneous disorder. Identifying brain alterations as indi- vidual deviations from normative patterns of brain-age asso- ciations, instead of patient group mean differences, can provide important insights into heterogeneous patterns of brain abnormalities observed in MDD. Methods: We estimated normative models of (1) age pre- dicting individual structural brain measures, and (2) structural brain measures predicting age (Brain Age model) using ma- chine learning in healthy individuals (N¼2,515) from the ENIGMA MDD consortium. We applied model parameters to independent samples of healthy individuals (N¼2,513) and MDD patients (N¼3,433) to obtain predicted values of brain structure (model 1) and age (model 2). Z-scores quantifying differences between predictive and true values were calcu- lated, representing individual deviations from the normative range. Results: The estimated normative models showed good model fit in the training sample; e.g. a correlation of R¼0.86 between actual and predicted age for the Brain Age Model, and good generalization to independent healthy and MDD samples. We identified heterogeneous patterns of brain deviations in MDD patients (model 1). Patients with more extreme deviations showed different clinical characteristics compared to patients residing within the normative range. Additionally, patients were estimated on average w1 year older than controls (model 2), but we also observed large between-person variation in brain age gaps. Further ana- lyses showed associations between brain age gap and clinical symptoms. Conclusions: Our work shows substantial heterogeneity in deviations from normal age-related variation in brain structure in individuals with MDD. The impact of and solutions for con- founding effects of scan site will also be discussed.
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ItemNo Preview AvailableEpigenetic aging in major depressive disorder(ELSEVIER, 2019-01-01)Major depressive disorder (MDD) is associated with increased risk of mortality and aging-related diseases [1–3]. The authors examined whether MDD is associated with higher epigenetic aging (EA) [4] in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of MDD have a further impact on these patterns, and whether findings replicate in brain tissue. DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate EA. MDD diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying EA in blood and brain. Significantly higher EA was observed in MDD patients compared with control subjects, with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, EA was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent dataset of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes. As compared with control subjects, MDD patients exhibited higher EA in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.