Medicine & Health

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  • (2023) Green, Nicole
    Thesis
    The onset of psychiatric disorders, such as autism spectrum disorder, schizophrenia, anxiety, and major depressive disorder, can be associated with both genetic and environmental factors. This thesis examines transcriptional changes caused by either genetic or environmental factors linked to psychiatric disorders. We investigated regulatory regions which harbour mutations associated with psychiatric disorders, and the effects of early life stress on the developing brain and its consequent adverse mental health outcomes. Here, we assessed the function of active enhancers in the brain to understand their regulatory roles, and their link to mutations associated with psychiatric disorders. This was achieved using a CRISPR interference (CRISPRi) screen to repress almost one thousand enhancers in primary human astrocyte cells. The effect of enhancer repression on transcription was measured using single cell mRNA sequencing (scRNA-seq), a which measures gene expression from individual cells. This thesis describes the first CRISPRi screen to be performed in brain cells, and the first to be performed in primary cells. Active enhancers targeted in this screen were characterised based on their chromatin state and through analysing enhancer marks from relevant published data. Regions of open chromatin are a marker for enhancers and were determined in primary human astrocytes using ATAC-seq, a method which transposes DNA in an open chromatin state, before using sequencing to determine regions of open chromatin. Candidate enhancers were filtered based on the ability to detect potential target genes of the enhancer by scRNA-seq, to which gene expression was required to be above an expression threshold. The expression of potential target genes was determined by mRNA-seq, and candidate enhancers were required to be in the same topologically associated domain as a detectable target gene expressed above the threshold. The CRISPRi screen was optimised with a pilot screen to determine the degree of silencing due to CRISPRi and the detectability of the transcriptional effect of silencing enhancers by CRISPRi using scRNA-seq. A large-scale CRISPRi screen was then performed to investigate and validate candidate enhancers in primary human astrocytes. This identified almost one hundred enhancers active in the human brain that have disease-associated variants, and 140 enhancer target genes associated with disease. We also investigated the transcriptional effect of early life stress using murine models. A limited nesting (LN) model was used, as this emulates human maternal neglect and has been previously shown to increase measures of anxiety like-behaviours in rats. We performed RNA sequencing on the prefrontal cortex (PFC) of rats that underwent an LN paradigm as a model for early life stress. Our results indicated that this primarily led to transcriptional repression in the PFC. We further identified a molecular signature of LN in rat PFC that, when compared with other studies, is observed across ELS protocols and replicable in other murine models.

  • (2023) Tesema, Azeb Gebresilassie
    Thesis
    Mortality from non-communicable diseases (NCDs) in Africa will overtake combined mortality from communicable, maternal, neonatal and nutritional diseases by 2030. Despite global declarations on the need for comprehensive primary health care (PHC) to address NCDs, the policy responses of African nations have been limited. In this thesis, I conduct a mixed methods study to assess the capacity of PHC systems to improve the prevention and management of NCDs in Africa, with a focus on Ethiopia. Section 1 summarises the NCD burden in Africa and provides an overview of the Ethiopian health system. Section 2 comprises Chapters 1 and 2. Chapter 1 maps progress against World Health Organization (WHO) targets for NCD care in the 47 countries of the WHO African Region. No country has met all recommended targets, and seven have met no targets. In Chapter 2, I propose priority areas to address these gaps, including (i) enhanced political commitment; (ii) service redesign; (iii) workforce capacity strengthening; (iv) improved treatment protocols; (v) comprehensive resource gap analysis; (vi) large-scale implementation; and (vii) support from multilateral institutions. In Section 3, which comprises Chapters 3–5, I focus on Ethiopia. Chapter 3 presents an in-depth qualitative study that corroborates the Chapter 1 findings, highlighting health system governance challenges to strengthening PHC (limited political commitment, inter-sectoral coordination and funding) combined with operational constraints (an insufficiently skilled and supported PHC workforce, fragmented information systems, and inadequate equipment and medicines). Chapter 4 presents a multi-level analysis of the National Ethiopia Health Extension Program (HEP) Survey. The analysis showed that provision of essential non-NCD HEP services was both positively and negatively associated with NCD service provision. In Chapter 5, I assess NCD training, supervision and performance appraisal for health extension workers (HEWs). I found variable quality in NCD training for HEWs and supervisors; inconsistent and somewhat punitive supervision practices; and non-transparent performance appraisal, which has led to HEW de-motivation. In Section 4, I synthesise all study findings and discuss the policy implications for Ethiopia and Africa more broadly. I also appraise the opportunities to strengthen NCD service delivery in the context of the COVID-19 coronavirus disease pandemic and the ongoing civil war in Ethiopia. I conclude with recommendations for future research and policy to increase Ethiopia’s capacity to provide comprehensive PHC that includes NCD care.

  • (2023) Afzal, Hafiz
    Thesis
    Sensory signals informing about frictional properties of a surface are used both for perception to experience material properties and for motor control to be able to handle objects using adequate manipulative forces. There are fundamental differences between these two purposes and scenarios, how sensory information typically is obtained. This thesis aims to explore the mechanisms involved in the perception of frictional properties of the touched surfaces under conditions relevant for object manipulation. Firstly, I show that in the passive touch condition, when the surface is brought in contact with immobilised finger, humans are unable to use existing friction-related mechanical cues and perceptually associate them with frictional properties. However, a submillimeter range lateral movement significantly improved the subject's ability to evaluate the frictional properties of two otherwise identical surfaces. It is demonstrated that partial slips within the contact area and fingertip tissue deformation create very potent sensory stimuli, enabling tactile afferents to signal friction-dependent mechanical effects translating into slipperiness (friction) perception. Further, I demonstrate that natural movement kinematics facilitate the development of such small skin displacements within the contact area and may play a central role in enabling the perception of surface slipperiness and adjusting grip force to friction when manipulating objects. This demonstrates intimate interdependence between the motor and sensory systems. This work significantly extends our understanding of fundamental tactile sensory processes involved in friction signaling in the context of motor control and dexterous object manipulation tasks. This knowledge and discovered friction sensing principles may assist in designing haptic rendering devices and artificial tactile sensors as well as associated control algorithms to be used in robotic grippers and hand prostheses.

  • (2023) Rosewarne, Emalie
    Thesis
    Non-communicable diseases (NCDs) are the leading cause of death and disability globally. NCDs are largely preventable, with the majority attributable to four behavioural risk factors: physical inactivity, harmful use of alcohol, tobacco use and exposure to tobacco smoke, and unhealthy diets. Dietary risks are a leading mortality risk factor: eight million deaths and 188 million disability-adjusted life years each year can be attributed to dietary risks worldwide. Intervention strategies to reduce dietary risks can be broadly grouped into environmental, behavioural, or multi-component strategies. Food environment policies focus on changing the physical, social, political, or economic environment that individuals and groups live in. Policies that directly impact the food environment include food reformulation targets and nutrition standards for publicly-funded institutions. Such interventions alter food access, availability, and affordability, and can create environments that support individuals to make healthier choices. The aim of this thesis is to evaluate the design, implementation and impact of nutrition policies and advocacy strategies to improve the food environment in Australia and globally. Formative research included two secondary analyses of a global review of salt reduction programs to understand the extent and scope of national reformulation strategies and nutrition standards for publicly funded institutions, including whether these policies are designed in line with current evidence. This was followed by comprehensive policy analyses of the Australian Government’s Healthy Food Partnership reformulation strategy and state- and territory-based nutrition standards for publicly funded institutions to evaluate policy design, potential impact, and scope for strengthening policies. Finally, a five-study, mixed methods evaluation of the Victorian Salt Reduction Partnership’s (VSRP) advocacy program was undertaken to evaluate the program’s design and implementation, and the impact on the food environment. This work found that one-third of countries globally had sodium reformulation programs and a similar number had institutional nutrition standards. Most policies were in high-income countries, and Europe was the region with the highest number of policies. Policy design was highly variable and substantial opportunity to better align policies with best practice evidence and global guidance was highlighted. These opportunities include applying sodium reduction targets to a wider range of foods using the World Health Organization’s global sodium benchmarks and applying school nutrition standards to all types of publicly funded institutions. There is ample opportunity to increase the public health impact of Australian food environment policies through alignment with evidence of best practice globally. The majority of government-led reformulation targets were determined to be too conservative, and therefore likely to have limited impact on the food supply. For most food categories, more than 43% of products were already meeting the reformulation targets prior to implementation, a greater than 10% difference from the government-proposed criteria of one-third. There were also no plans for implementation, monitoring, or evaluation. The design of institutional nutrition policies may be a barrier to implementation and prevent the policies from having their intended impact: policy designs were complex, many lacked key components such as accountability mechanisms, and there were differences within and between institution types and jurisdictions. The five-study evaluation of the VSRP advocacy strategy demonstrated the multi-faceted sodium reduction program had no impact on reducing sodium levels in the food supply or government policy; however, short-term objectives (e.g., project outputs) were achieved and important lessons were generated that will be useful for future public health partnerships and interventions. The establishment of a Partnership or guiding coalition with diverse skills and experience facilitated collaborative action, capacity building and execution of the intervention. Continual monitoring and evaluation of implementation informed strategy adaptations that allowed optimisation of the Partnership strategy. The political advocacy strategy, which involved advocating for stringent government-led sodium reformulation targets, enabled the dissemination of VSRP resources to food manufacturers, although had little impact on strengthening the draft targets. The media advocacy strategy, which involved the dissemination of sodium-monitoring data through media releases, was a useful tool to gain access to the media and reach consumers with salt reduction messages, and to engage food manufacturers in discussions about salt reduction. However, in the absence of an established government reformulation policy, this food industry engagement did not translate into meaningful reductions in sodium in the packaged food supply. More effective communication between strategic and implementation partners could have improved program implementation and outcomes. Greater emphasis on developing and maintaining relationships with policymakers could have increased influence on government policy and public health impact. Existing institutional nutrition policies in Victoria also require strengthening through improvements to policy design, governance, and support services, and overcoming barriers within and external to implementing organisations, to propel state-wide progress. Overall, this thesis identified substantial scope to accelerate the local and global impact of food environment policies. In addition to improving the design of food environment policies in line with best practice evidence and global guidance, implementation of food environment policies could be strengthened through the provision of support services, step-by-step guidance, and additional tools/resources. Further, performance measurement methods need to be integrated into policy monitoring systems to enhance evaluation approaches and facilitate policy enforcement. Strong government leadership and regular monitoring of measurable goals are essential elements of successful policies. Three step-wise frameworks were developed from the evidence generated and lessons learnt in this thesis to support i) governments to design impactful food environment policies and monitor them, ii) end-users to effectively implement food environment policies and iii) public health professionals to persuasively advocate for food environment policies. Thus, this thesis will be useful for informing future public health partnerships, interventions, and government policies to reduce the global burden of diet-related NCDs.

  • (2023) Wu, Verena
    Thesis
    Background: Chinese-Australian immigrant patients with cancer report poorer psychosocial outcomes compared to Anglo-Australians. Additionally, Chinese immigrant caregivers experience burden and anxiety associated with caregiving. Presently, there are limited resources available that can support them in coping with these challenges. This thesis aims to address this gap by developing and evaluating the acceptability and feasibility of a culturally appropriate self-management (SM) resource, WeCope, for Chinese-Australian immigrant patients and caregivers affected by cancer. Methods: A systematic review was conducted to identify the unmet supportive care needs of Chinese patients and caregivers with cancer to identify areas of concern requiring support (Chapter 2). An overview of self-management interventions, including theoretical underpinnings and evidence for effectiveness on psychological outcomes and unmet needs was provided (Chapter 3). The cultural sensitivity framework and community participatory approach were explored to guide the methods for developing WeCope with content based on a previous dyadic resource, Coping-Together (Chapter 4). Acceptability among patients, caregivers and community members was explored in a qualitative study (Chapter 5), and feasibility of WeCope as an intervention and the study methods employed were assessed in a mixed methods study (Chapter 6). Results: The systematic review (Chapter 2) showed that health system and information needs was the predominant domain of unmet need frequently reported by Chinese patients and caregivers. The qualitative study (Chapter 4) indicated overall acceptability with suggestions for additional information which informed modifications to the WeCope booklets. The feasibility study (Chapter 5) indicated barriers to the feasibility of WeCope as an intervention across several aspects: demand, acceptability, practicality, and implementation. Preliminary efficacy of WeCope could not be assessed due to low recruitment and response rates, and the study methods were deemed unfeasible for a larger trial. Conclusion: This thesis reports the acceptability and preliminary feasibility of a SM intervention for Chinese-Australian immigrants affected by cancer. While WeCope demonstrated some degree of acceptability, feasibility of the intervention and study methods were limited. Considerable additional resources and refinement of the study methods are needed if a large-scale study is undertaken.

  • (2023) Chiang, Jeremy Chung Bo
    Thesis
    Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition affecting up to 80% of treated patients with severe impact on their quality of life. While some patients experience improvement in signs and symptoms after dose reduction or cessation of treatment, many develop chronic neuropathy which can last for years leading to high economic and disease burden. Assessment of CIPN currently relies on crude severity grading by clinicians, subjective patient questionnaires and nerve conduction studies limited to large nerve fibre assessment. Unfortunately, there is still an absence of reliable and efficient methods which can provide sensitive endpoint measures particularly with small nerve fibre assessments. While ocular surface neural changes have been well established as potential diagnostic and prognostic markers in other aetiologies of peripheral neuropathy particularly diabetes, there have been limited studies in CIPN. Hence, the overall aim of this thesis was to investigate whether neural changes on the ocular surface occurred with neurotoxic chemotherapy along with CIPN development. This was explored across several studies primarily with in-vivo corneal confocal microscopy (CCM). The first series, comprised of five cross-sectional studies, assessed patients who have already completed neurotoxic chemotherapy treatment for cancer and may have persistent CIPN. Neurotoxic chemotherapeutic drugs including taxanes or platinum compounds were the focus as these were the most commonly associated with CIPN. Chapter 2 analysed the reproducibility of corneal nerve image selection and analysis outcomes from the central cornea and inferior whorl region, a distinct landmark of the sub-basal nerve plexus. Analysis of both regions produced reliable and reproducible findings, although the inferior whorl region had slightly higher variability compared to the central cornea. This study also demonstrated that complex inferior whorl patterns, more commonly found in patients with CIPN compared to healthy individuals, may reduce reproducibility of image selection and analysis. Chapter 3 assessed whether corneal nerve damage occurred in patients who have already completed treatment with neurotoxic chemotherapy prior to assessment. This study established that there was corneal nerve reduction particularly in patients treated with paclitaxel who still had peripheral neuropathy post-treatment cessation, and this reduction was associated with worse fine hand dexterity. Chapter 4 then investigated whether the loss of nerves described in the previous study contributed to ocular surface discomfort associated with dry eye disease, which is a widespread and overlooked condition severely impacting quality of life analogous to CIPN. In this study, paclitaxel-treated patients with CIPN who had more severe corneal nerve fibre reduction, also had higher risk of suffering from ocular surface discomfort and worse visual function compared to patients without neuropathy and healthy controls. The study highlighted the need for eye care clinicians and medical oncologists to be aware of such ocular surface symptoms even in those who have completed neurotoxic chemotherapy treatment. Chapter 5 investigated corneal dendritic cells which are antigen-presenting cells and potent initiators of inflammatory responses residing in the sub-basal corneal nerve plexus. This study was conducted as these immune cells can also be observed with CCM, and neuroinflammation and immune cell infiltration have been implicated in the pathophysiology of CIPN. The findings indicated that there was an elevated presence of immature dendritic cell density in oxaliplatin-treated patients well after treatment cessation, but not in paclitaxel-treated patients. Chapter 6 evaluated the concentration of substance P, a sensory neuropeptide primarily expressed by small nerve fibres in the cornea and essential for maintenance of ocular surface health, in the tears. While the previous study demonstrated elevated dendritic cell density in oxaliplatin-treated patients, this study showed reduced substance P concentration in paclitaxel-treated patients instead. These two studies further emphasise potential differences in pathophysiological mechanisms underlying CIPN associated with these two drugs. Chapter 7 involved a longitudinal study which observed ocular surface and peripheral neuropathic changes during the treatment period, and monitoring patients up to twelve months post-treatment cessation. The study found a progressive loss in corneal nerve parameters with increasing cumulative dose from baseline to end of treatment particularly with taxane treatment, while other ocular surface measures including corneal dendritic cells and tear film substance P levels did not have significant changes. The findings indicated a potential mixed pattern of small and large nerve fibre involvement with taxane treatment, while oxaliplatin affects predominantly large nerve fibres. Corneal nerve fibre length measured during the treatment period was also lower in patients who continued to have persistent CIPN after treatment cessation compared to patients who did not, indicating the potential for early detection of corneal nerve fibre loss as an indicator of CIPN progression. Future studies investigating corneal nerve changes at multiple timepoints in larger studies involving taxane-treated patients may provide greater insight into the diagnostic and predictive utility of CCM in CIPN. Improvements in CCM instrumentation and methodology may also contribute to better assessment of the state of the sub-basal corneal nerve plexus. The discussion section further explores these issues in relation to the clinical applicability or scalability of CCM and potential solutions to improve imaging capabilities in the future.

  • (2023) Samir, Jerome
    Thesis
    The adaptive immune response is responsible for recognising, containing and eliminating viral infection, and protecting from further reinfection. This antigen-specific response is driven by T and B cells, which recognise antigenic epitopes via highly specific heterodimeric surface receptors, termed T-cell receptors (TCRs) and B cell receptors (BCRs). The theoretical diversity of the receptor repertoire that can be generated via homologous recombination of V, D and J genes is large enough (>1015 unique sequences) that virtually any antigen can be recognised. However, only a subset of these are generated within the human body, and how they succeed in specifically recognising any pathogen(s) and distinguishing these from self-proteins remains largely unresolved. The recent advances in applying single-cell genomics technologies to simultaneously measure the clonality, surface phenotype and transcriptomic signature of pathogen- specific immune cells have significantly improved understanding of these questions. Single-cell multi-omics permits the accurate identification of clonally expanded populations, their differentiation trajectories, the level of immune receptor repertoire diversity involved in the response and the phenotypic and molecular heterogeneity. This thesis aims to develop a bioinformatic workflow utilising single-cell multi-omics data to explore, quantify and predict the clonal and transcriptomic signatures of the human T-cell response during and following viral infection. In the first aim, a web application, VDJView, was developed to facilitate the simultaneous analysis and visualisation of clonal, transcriptomic and clinical metadata of T and B cell multi-omics data. The application permits non-bioinformaticians to perform quality control and common analyses of single-cell genomics data integrated with other metadata, thus permitting the identification of biologically and clinically relevant parameters. The second aim pertains to analysing the functional, molecular and immune receptor profiles of CD8+ T cells in the acute phase of primary hepatitis C virus (HCV) infection. This analysis identified a novel population of progenitors of exhausted T cells, and lineage tracing revealed distinct trajectories with multiple fates and evolutionary plasticity. Furthermore, it was observed that high-magnitude IFN-γ CD8+ T-cell response is associated with the increased probability of viral escape and chronic infection. Finally, in the third aim, a novel analysis is presented based on the topological characteristics of a network generated on pathogen-specific, paired-chain, CD8+ TCRs. This analysis revealed how some cross-reactivity between TCRs can be explained via the sequence similarity between TCRs and that this property is not uniformly distributed across all pathogen-specific TCR repertoires. Strong correlations between the topological properties of the network and the biological properties of the TCR sequences were identified and highlighted. The suite of workflows and methods presented in this thesis are designed to be adaptable to various T and B cell multi-omic datasets. The associated analyses contribute to understanding the role of T and B cells in the adaptive immune response to viral-infection and cancer.

  • (2023) Ajisegiri, Whenayon
    Thesis
    Non-communicable diseases (NCDs) account for 71% of deaths globally, and 77% of NCD-related deaths occur in low-income and middle-income countries. In Nigeria, 29% of deaths in 2016 were attributed to NCDs. However this proportion is expected to substantially increase in the next decade. In response to the growing NCD burden, Nigeria has launched health reform policies with a focus on integrating NCD management with primary health care (PHC) services. This includes enhanced workforce capacity, particularly through training non-physician health workers. Despite the emphasis on PHC strengthening, there is a lack of timely and relevant evidence to inform policy and service delivery. This poses major challenges for the development of effective NCD prevention and control programs. In this thesis, I appraise policy, health service and workforce factors contributing to NCD prevention and control programs in Nigeria. Chapter 1 describes the NCD burden and provides an overview of the country’s health system structure. Chapters 2 and 3 include a document analysis of NCD prevention and control policies, clinical guidelines and subnational policies implemented at regional levels. Key findings include a lack of consideration for decentralisation and ineffective coordination mechanisms for the implementation of NCD programs. Chapter 4 includes mixed methods research to understand the organisational context of NCD service delivery in PHC facilities. Several systemic enablers and barriers to implementing NCD interventions were identified: physicians working at PHC services played a critical enabling role, and negative perceptions of PHC as inferior care acted as a major barrier. Chapter 5 includes further mixed methods research to understand the practices of community health workers (CHWs) in relation to NCD care. It was observed that many CHWs are conducting informal task-shifting, performing the work of physicians for NCD care in PHC facilities. Chapter 6 includes a discrete choice experiment with 300 CHWs to understand CHW motivational preferences for service delivery. Policy scenario modelling predicted that an employment package comprising educational opportunities, career progression opportunities and an additional 10% of salary as incentives would be most appealing to CHWs. In the final chapter (Chapter 7), I synthesise findings from all studies to identify the priority policy issues for improving NCD integration with PHC services in Nigeria. Recommendations focus on physical, workforce and organisational resource mobilisation via several ‘motive forces’, including improved goal alignment, harnessing of team action, enhanced organisational support, local and national policy responsiveness, and continuous learning.

  • (2023) Stirling, Robert
    Thesis
    In Australia, there is no standardised approach to measuring performance of alcohol and other drug (AOD) treatment services. Non-government organisations (NGOs) that provide AOD treatment in Australia manage contracts from multiple funding sources, with performance measures varying between funders. They have reported a high reporting burden and inconsistent expectations from different funders to demonstrate accountability. The primary aim of this thesis was to establish a list of performance measures that are acceptable to service users, treatment providers, and funders; explore approaches to improve implementation of performance measures; and make recommendations to funders of non-government AOD treatment. The research approach involved three phases: 1) an assessment by three independent raters of existing measures used in contracts against best practice; 2) focus groups with service users, treatment providers, and funders (n=10 focus groups) to identify the most important performance measures among diverse stakeholders and explore the challenges associated with implementation; 3) a Delphi process with a purposeful sample of service users, treatment providers, and funders to prioritise a core set of performance measures. Phase One found over 500 unique measures used in contracts for AOD treatment services, with most not adhering to best practice. Further, the majority were output and process measures. In Phase Two, focus groups identified that access, outcome, and experience measures were the most important measurement types across all stakeholder groups, with structural measures also important to service users. In Phase Three, 17 performance measures reached consensus. In contrast to Phase One, the final set were mostly outcome, access, and structural measures (n= 11/17) with only one measure each for output and process. Further, key findings from the focus groups highlighted that identification of measures is only part of a robust performance measurement system. Support systems for collecting, analysing, interpreting, and reporting performance data are also needed. At the policy-level, implementation of the final set of measures can improve accountability of public funds, and support the collection of standardised performance-related data to inform funding decisions and treatment planning. At the practice-level, the measures have the potential to reduce reporting burden, improve organisational efficiency, and inform quality improvement initiatives.

  • (2023) Mulligan, Christopher
    Thesis
    Background Powered off-road vehicles, such as quad-bikes and two-wheeled motorcycles, are popularly used recreationally by children, and are also used in a variety of farming and agricultural contexts. However, crashes can result in serious injuries and deaths, and as such are an important public health concern for Australian children. Compared to adults, children have different riding patterns, injury causes and risk factors relating to their level of development, as well as different patterns of injury outcomes and severity. Aims This work aims to investigate paediatric quad-bike and motorcycle riding patterns and behaviours, along with risk factors, injury severity, outcomes and potential avenues for injury prevention counter-measures. The work consists of five related studies. Methods and Results The first study was a survey of paediatric off-road vehicle riders, which was undertaken to characterise patterns of use, rider behaviours, experience and attitudes. Recreational motorcycle riding was most common, with children having high rates of previous riding experience and often participating in ‘structured’ riding within organised motorsports competitions and events. There was a small proportion of ‘unstructured’ riding in the context of agriculture or on private properties. Riders generally rode frequently and used helmets and other protective gear. The second study examined a group of children admitted to a paediatric hospital as a result of injury sustained from an off-road vehicle crash. In-depth crash investigation techniques examined injury mechanisms and related them to injury outcomes, along with rider, environmental and vehicular risk factors. A variety of recurring mechanisms emerged, particularly loss-of-control events leading to impacts with the ground or vehicle. A wide range of injuries were also observed, particularly to the extremities. A case-control component of the study identified a lower rider to vehicle weight ratio as a factor associated with higher crash risk. The third and fourth studies used large, linked population-level hospital admission and mortality datasets. The first of these examined injury epidemiology and outcomes for paediatric off-road vehicle crashes across New South Wales over a 17-year time period. The outcomes for different vehicle types were compared. The findings demonstrated the large burden of injury caused by ORV crashes in terms of hospital admissions and operative interventions. Furthermore, although on an individual level, quad-bike injuries were associated with higher injury severity, the far greater number of two-wheeled off-road motorcycle crash admissions suggest that motorcycles should be an injury prevention priority. The second linked data study examined the subset of children who have multiple hospital admissions following off-road vehicle crashes. Children who re-present to hospital repeatedly are a particularly vulnerable group, prone to more serious injury, and higher overall costs to the healthcare system. ‘Recidivist’ riders were compared to non-recidivists across various demographic, vehicle and injury outcome factors, highlighting the areas in which potential recidivists may be identified or targeted for injury prevention interventions. The fifth study was a systematic review of injury prevention countermeasures delivered through clinical environments such as hospitals and Emergency Departments, centred around the concept of the ‘Teachable Moment’: that children may be more receptive or amenable to behaviour change after sustaining an injury. The strengths and weaknesses of interventions that apply this model were identified, which may inform potential interventions pertaining to off-road crashes. The review found that multi-modal approaches combining face-to-face counselling or teaching, supplemented with other forms of written or visual communication, often paired with the provision of safety equipment and accurate monitoring as the most effective means of intervention. However, injury prevention programs are often limited by short-term and largely self-reported outcome measures, so research and programs applying these findings to off-road vehicle riders should be designed with robust design methods and appropriate measures of behaviour change, knowledge gain or injury reduction. Conclusion The results of the project overall demonstrate that off-road vehicle injuries are a large and important cause of injury, disability and death for Australian children. An overarching theme of this project is to demonstrate that children who participate in off-road riding are a unique and vulnerable population. Riding patterns are largely recreational, and the resultant injuries are common, spanning the spectrum of severity. Factors associated with worse injury outcomes and recidivism are explored, which, along with the review of injury prevention countermeasures delivered in clinical settings, may help re-prioritise and target injury prevention resources and research. Ultimately the goal of this project, as with any injury research, is to try to prevent or mitigate the severity off-road crashes. The studies investigate various aspects of paediatric off-road riding and provide important foundational knowledge for researchers and clinicians to work towards real-world applications and interventions.