Early-Mid Career Fellowships

Sudden death or cardiac arrest occurs when the heart goes into a fatal heart rhythm called ventricular tachycardia (VT). These fatal rhythms almost invariable occur due to underlying scar tissue in the heart from a variety of heart diseases. Cardiac arrest survivors receive a specialised form of pacemaker, called an implanted cardiac defibrillator (ICD) placed under the skin that automatically delivers an internal shock if VT recurs, thereby aborting otherwise inevitable sudden death. However, ICDs do not prevent VT from occurring in the first place, they only treat VT when it occurs. Cardiac arrest survivors will experience recurrent VT at an annual rate of 30-50 per cent/year. Recurrent shocks are painful, cause tremendous psychological trauma and lead to increased risk of death. They also lead to frequent hospital visits, and exponential health care utilisation.

Recurrent VT can be treated with strong doses of anti-arrhythmic (AAD) medications but these tend to be minimally effective, and with potent side effects. An alternative is to perform a cardiac ablation (CA) procedure that entails electrical wires navigated up through the veins to the heart, to identify, cauterise and thus destroy the electrical short circuits causing VT. Some studies have shown that CA is highly effective in curing VT, reducing VT burden and improving quality of life in patients with scar tissue due to coronary heart disease (blocked arteries). It is unknown if CA is just as effective for a large population of patients who have scar related to genetic (familial) disease, or infection or inflammation of the heart (termed non-ischemic cardiomyopathy). This group is important as the incidence of non-ischemic cardiomyopathy is rising; such patients tend to be young (30-60 years), and are very likely to experience toxic side effects from AAD and thus stand to gain the most benefit from CA. This research proposal is for a randomised trial that will examine if CA is superior to AAD in the treatment of VT in patients with non-ischemic cardiomyopathy.

Results of this study will be disseminated through clinicians at scientific meetings/publication in journals (and via their social media channels), and by engagement of Sydney Health Partners, NSW Agency for Clinical Innovation and major national/international cardiac societies. Findings will lead to major practice and policy change nationally and globally. Engagement with patients and the general public will be via novel e-health social media channels such as Facebook and Twitter, as well as involvement of charitable foundations.

Atherosclerosis and related complications are a major cause of death and disability in NSW. This project will use see-through zebrafish to literally shed new light on what happens in atherosclerotic plaques using microscopy of the disease inside living zebrafish. We will be able to ask fundamental questions about how plaques form, mature, and harm us by observing the course of disease in zebrafish embryos.

To find new cures of atherosclerosis and it’s complications, the project will take two arms. The first arm will investigate a treatment that may prevent the blood vessel damage necessary for atherosclerosis to get a foothold in our blood vessels while a second arm of the project will set up a zebrafish system to discover new drugs to prevent or reverse the build up of bad fats in atherosclerotic plaques.

Death and disability from stroke is a massive burden on the healthcare system and society. In Australia, it is estimated that one million people will be living with the effects of stroke by 2050 - more than double the number of strokes in 2017. Ischaemic stroke is caused by a blocked artery, leading to a lack of blood flow and oxygen supply to a specific region of the brain supplied by that artery, resulting in brain cell death (infarction). Up to 38 per cent of ischaemic stroke patients present to hospital with mild or rapidly improving symptoms, yet final outcomes are poor, >50 per cent require assistance with self-care at three months post stroke. This delayed progression of stroke due to early neurological deterioration (END) within the first 24hrs post-stroke remains a clinically significant, yet unresolved problem - the number of patients totalling more than the annual number of new cases of multiple sclerosis, Huntington’s disease and motor neuron disease combined. However, its cause and the underlying mechanisms are poorly understood. Currently there are no guidelines or diagnostic tests that can predict the outcome of these patients. Understanding the true pathophysiology and recognising those at risk are key first steps.

Dr Patabendige and her team will use advanced medical imaging analysis and a novel non-invasive method to measure the pressure within the skull, intracranial pressure (ICP) to provide definitive evidence to confirm that ICP elevation causes infarct expansion, and that it is associated with neurological deterioration. In addition, their previous studies confirm that oedema (swelling of the brain) was not the primary cause for this ICP rise. Therefore, Dr Patabendige will investigate whether cerebrospinal fluid (CSF, the fluid that bathes the brain and spinal cord) volume increase is responsible, and if confirmed, show that short-duration hypothermia reverses this.

These findings will provide evidence to confirm the cause for END, and provide for the first time a clear pathological explanation for why these patients, who seem to be improving when initially presenting to the hospital progress to neurological deterioration.

Expected key outcomes:
1. Provide significant fundamental knowledge about a highly clinically relevant, yet unresolved problem of END
2. Help future diagnosis, prevention and management of stroke patients that are at risk of developing END, thereby making a significant reduction in stroke morbidity in the longer term
3. Prove the effectiveness of a potential treatment that is safe, easy to apply and generalizable .

Chest pain is one of the most common presentations to adult emergency departments. Its management requires specialist assessment and tests, which places a significant burden on hospital resources and patients. To address this, Royal North Shore Hospital has implemented a rapid access Chest Pain Clinic (CPC) – a new model of care, for which I am director. As part of this, there is the need for cardiac investigations that are feasible, diagnostic, and cost-effective. Two advanced cardiac diagnostic techniques have untapped potential in this setting in Australia – cardiovascular magnetic resonance (CMR) and advanced electrocardiography (A-ECG). This fellowship seeks to develop new insights into health service of acute chest pain by the application and development of these state-of-the-art investigations to create a paradigm shift in chest pain management and improve healthcare costs.

CMR is the future of non-invasive cardiology, and is utilised widely in clinical practice and research worldwide but less so in Australia because of slow adoption and restrictions with Medicare rebate. In European and UK healthcare models, CMR with stress testing (‘stress CMR’) has been shown to be cost-effective in the management of suspected coronary disease with high diagnostic and prognostic performance. There is a lack of evidence of stress CMR in the Australian healthcare setting. Part 1 of this study will assess the cost-effectiveness of stress CMR in the CPC, in order to optimise its use in Australia.

The traditional ECG is a fundamental cardiac test. Standard analysis depends on visual assessment. Novel methods for computerised ECG measurement permit the application of advanced digital analysis techniques collectively known as A-ECG, which have dramatically higher diagnostic accuracy for detecting disease. Currently, A-ECG is only available in a handful of international centres outside Australia. Part 2 of this study will assess A-ECG in the CPC to show its diagnostic performance, ability to influence downstream tests, and power to predict cardiovascular outcomes. A-ECG could be the much needed paradigm shift in chest pain management – to allow patients to be managed safely as outpatients, thus avoiding hospital admission and unnecessary tests, and improving healthcare costs.

The overarching goals are aligned with Sydney Health Partners’ Cardiovascular Stream and the Northern Sydney Local Health District. Collaboration with international centres of excellence will support the science and the technology. Translation of findings and implementation into clinical practice will be led by the research team, which includes engagement with key stakeholders and hospital administration.

The proposed projects will study new mechanisms that may be involved in a disease that results in increase in blood pressure in the lungs, which is called pulmonary hypertension. This disease is very deadly and despite the progress made, the survival rates within five years of diagnosis remain unacceptably low (up to 50 per cent of patients may die or require heart-lung transplantation). Therefore, research in this area is of high priority.

We will study two different drugs both in the basic science lab, and if these studies support our theories; and as suggested by the safety of the target drugs that are already in use in patients for other diseases; we believe that the second part of the project where we will test these drugs in patients is practically feasible, promising to add two new drugs for treatment of pulmonary hypertension.

I have studied new intricate methods in my post-doctoral studies In the United States which I am excited to establish back in my lab in Australia. This has also provided the team with the opportunity for collaboration with centres of excellence internationally, which will be key in conducting a multi-centre clinical study. The proposed team consist of clinician-scientist who can lead both the basic science project and the human trial.

Cardiovascular diseases, including heart attack and stroke, are a leading cause of disease and death. In patients who have experienced a cardiovascular event such as a heart attack, smoking increases the risk of future events and death. Programs supporting cardiac patients to quit smoking improve survival and quality of life, and reduce the burden on the hospital system. However, smoking remains undertreated in cardiac patients. Prescribed medicines, including Zyban, Champix and Nicotine Replacement Therapy, are the most effective strategies available to help smokers quit, but there have been highly publicised concerns regarding their safety among cardiac patients, contributing to reluctance to prescribe and use these treatments.

This project will examine whether these safety concerns are supported by Australian data. It will also determine which of the three medicines is most likely to have the greatest long term benefit for cardiac patients, and the extent to which each of these medicines are currently used by cardiac patients after discharge from NSW hospitals. It will achieve this by linking records of filled prescriptions with other data from health services in NSW. This will be the largest study of the safety and effectiveness of prescribed medicines for smoking cessation conducted to date, and the first conducted in Australia. It will use sophisticated statistical techniques that allow data to be analysed in a way that closely replicates the characteristics of a clinical trial.

This project will provide clinically useful information about the risks and benefits of prescribed quit aids when used by cardiac patients. This will allow cardiac patients and health care providers to make informed decisions about whether a smoking cessation medicine and which one(s), should be used. This evidence, together with statistics on how many patients receive these quit aids after they leave hospital, will indicate whether efforts to promote or discourage use of any of these treatments among cardiac patients are needed. The research team will communicate the findings to staff of NSW Health services, cardiology units in particular, so that protocols and guidelines for the discharge of cardiac patients can be updated. Likewise, the findings will be shared with general practitioners to guide the in-community prescribing of smoking cessation aids to patients with cardiovascular disease. By informing changes to the care of cardiac patients who smoke, this project has the potential to improve the survival of patients with cardiovascular disease and reduce healthcare costs.

Atrial fibrillation (AF), the most common abnormal heart rhythm (arrhythmia), is a major risk factor for both stroke and heart failure. With an ageing population tackling the problem of arrhythmias, in particular AF, will be a major challenge for healthcare in the coming decades. At present, we lack good drugs to treat AF. As a result there is a pressing need for new strategies to study and better understand the molecular basis of these arrhythmias. This is the best way to identify and develop novel therapeutic avenues.

While clinically we accept that altered mechanical load in the chambers of the heart leads to structural and electrical changes, the molecular mechanisms of how these mechanical forces underpin arrhythmias are not understood. This project aims to identify novel mechanical pathways that underlie arrhythmias in conditions like AF.

This project will identify these new cellular pathways underlying arrhythmia generation by evaluating how mechanical stress affects the cells that line the chambers of the heart. We have access to a unique cell type mimicking the single cell layer that lines the inner wall of the heart chambers. Using state-of-the-art technology to simulate blood flow this project will assess how these cells may provide mechanically-regulated signals to the underlying heart muscle cells and assess how this may contribute to arrhythmias. This crucially acknowledges the inseparable function of the specialized cells that line the heart chambers and the muscle cells in the overall performance of the heart. Understanding these molecular pathways and their effect on the underlying heart muscle will likely identify novel therapeutic targets for prevention but also for management of arrhythmias.

Aside from unearthing targets for therapy, these pathways are also likely to contain candidate genes for genetic studies in patients with inherited heart arrhythmias and atrial fibrillation. Thus data generated in this study will be used to look for disease causing gene variants in studies already ongoing such as a NSW Health funded project aimed at sequencing the genomes of a large cohort of patients with cardiomyopathies, many of whom will develop AF and associated arrhythmias. As a result this project is likely to provide tangible outcomes for patient and family management and counselling.

Cancer and heart disease are the two most common disease conditions and the leading causes of death. Chemotherapy is more effective than ever at treating cancer, but has a price. There are over 400,000 cancer survivors in Australia and this figure is expected to increase due to a continuous decline in cancer death rates: there is a 70 per cent chance of survival from cancer in Australia. However, up to 25 per cent of these cancer survivors die from chemotherapy-induced cardiotoxicity (CIC) within 7 years, making it the leading cause of death in cancer survivors.

Cardio-oncology, an under-recognised area in Australia, is the intersection of heart conditions in cancer patients, an emerging field with immense potential to improve quality of life and cardiovascular burden in a growing number of cancer survivors.

The main reason for long-term cardiovascular and healthcare burden is delay in early detection of CIC due to imperfect diagnostic techniques. This is a major limitation, as early detection and treatment of CIC can lead to prevention of heart failure, and recovery of heart function. In addition, lack of an integrated, patient centred approach in Australia results in the fact that most cancer patients are still largely unaware of this adverse drug reaction and tend to neglect care for risk factors that may precipitate cardiotoxicity.

Thus, our program aims to address poor outcomes for the many cancer survivors who go on to develop CIC by discovering simple blood test(s) that could detect early onset of CIC as well as providing better education and facilitating self-care and empowerment for cancer patients/survivors.

Specifically, I will utilise state-of-the-art high through-put techniques that can gather a large amount of data to identify:
1) proteins in blood that change with early onset of CIC
2) genetic markers
3) chemotherapy-induced changes in genetic dispositions (epigenetics).

This data will be combined with latest imaging modalities to develop an individualised risk prediction tool for our patients. As risk assessment and early detection are cornerstones of early treatment and improved outcomes, this could in future lead to change in clinical practice/guidelines and translate in earlier discontinuation/change in chemotherapeutic regimen and initiation of cardioprotective therapy. I will also establish and facilitate a dedicated cardio-oncology nurse-led program of patient education and empowerment. This would achieve both improved interdisciplinary communication related to the diagnosis, monitoring and therapy of cancer treatment related cardiovascular complications and improved patients’ journey and outcomes through improved and dedicated cardiovascular care.

Blood clots blocking the blood supply to the heart and the brain, known as arterial thrombosis, cause heart attack and stroke – the leading cause of death and disability in the Australia. Platelets are the cells that form these blood clot, thus drugs targeting platelets such as aspirin are the mainstay of heart attack and stroke prevention. Yet current treatment has limited effectiveness with optimal therapy – up to 30 per cent of patients will have a recurrent event within three years, and more effective therapies often lead to bleeding side effects.

Our work has identified a particular sub-set of platelets within people with cardiovascular disease that increase blood clots, but are not turned-off by aspirin. These are called procoagulant platelets. Measurement of procoagulant platelets in patients has initially been very difficult due to the lack of sensitive and specific tests. We have recently developed a way to measure procoagulant platelets in people at risk of heart attack and stroke, and have shown that more procoagulant platelets are indeed formed during stroke and heart attacks. It is therefore this sub-set of platelets in people with cardiovascular disease that we would like to target more specifically when designing new drugs, in order to increase the beneficial effect and at the same time reduce the bleeding side effect when treating patients.

Interestingly, a simple non-invasive process called remote ischaemic preconditioning (RIPC), which is performed by inflating and deflating a blood pressure cuff three times, was able to reduce procoagulant platelets in people with heart disease when aspirin and other anti-platelet drugs could not. Others have previously shown that RIPC can protect the heart muscle and brain from damage during heart attack and stroke, but the mechanism by which it does this is unknown.

My studies indicate that RIPC affects procoagulant platelets by affecting the platelet mitochondria. Mitochondria are organelles inside the platelet that converts glucose to energy. My project investigates the link between procoagulant platelets, platelet mitochondrial function and cardiovascular disease. In addition to providing the rationale for RIPC, these studies aim to identify platelet mitochondrial pathways as a novel target for cardiovascular disease that will work in addition to existing cardiovascular drugs without causing bleeding. Ultimately, our work would be able to provide more tailored therapies for patients, reduce our patients’ waiting time, pain and risk of receiving treatments, improve their disease outcome, and reduce medical cost for the NSW health system.

Heart failure rates are increasing exponentially in Australia and worldwide. One in two people diagnosed with severe heart failure will die within one year of diagnosis. This burden of heart failure is underpinned by the heart’s limited capacity for self-repair after injury. This limitation could be overcome by stimulating newly discovered stem cell populations residing within the adult heart itself. We recently discovered a cardiac colony-forming stem cell population and have found that the molecule Platelet Derived Growth Factor (PDGF) can improve the heart function of mice and pigs after induced heart attack. PDGF does this by activating and rejuvenating resident heart stem and stromal cells. Before this promising therapy can be considered for clinical trials in humans, further testing to validate its safety is required.

This project will build on over a decade of preliminary work in mice and pigs, validating our results in a preclinical large animal model. In the second phase of this work, new materials such as nanoparticles will be used to more selectively deliver PDGF therapy to the heart. Outcomes of this project include expedited progression of this promising therapy, from the laboratory into the clinic, where thousands of heart failure patients could one day benefit.

Note: This project received project funding only. This project did not received full Fellowship funding.

Heart defects are the most common form of birth defects, occurring in ~1 per cent of live born babies. In 80 per cent of families it is not known why they occur. We use the latest technologies to study the genetic code of families with children that are born with heart defects. We aim to identify mutations, i.e. changes in the genetic code that are the cause of these defects.

The genetic code of each individual is stored in large datasets. Our goal is limited by the current methodologies to analyse such large datasets to identify causal mutations. Currently, a large percentage (~70 per cent) of families we study cannot receive a personalised genetic diagnosis. We propose to develop new quantitative and analytical approaches to improve our ability to identify mutations that are the cause of heart defects in every family.

Our research has specific and immediate clinical benefit for the families affected with heart defects that have been recruited. Increasing the genetic diagnosis of heart defects will help more families receive an accurate genetic diagnosis, personalised advice concerning the disease in their family and a better estimate of the risk of having a subsequent child with a heart defect.

Identifying the genetic causes of heart defects not only has benefits for the patient and the family but also for the community. Currently, efforts to identify causes of disease require large costs, and it can include multiple medical screens and procedures. We expect that systematic adoption of genetic testing in clinical practise will improve the financial sustainability of the health system.

Note: This project received project funding only. This project did not received full Fellowship funding.

Hypertrophic cardiomyopathy (HCM) is a clinically variable disease, ranging from asymptomatic diagnoses, to heart failure and sudden cardiac death. It occurs in 1 in 200-500 of the general population, and given it is an inherited disease close family members are recommended to undergo lifetime clinical surveillance. Due to the wide variability in disease presentation and features, there is little ability to predict who will develop the worst outcomes, despite decades of research.

Recent advances in genetic technologies have allowed an opportunity to better understand the underlying genetic causes of HCM, but have also challenged the prevailing view that HCM is primarily an inherited disease. My recent paper in Circulation: Cardiovascular Genetics proposed for the first time that a non-familial sub-group of HCM exists and that it occurs in approximately 40 per cent of cases. Non-familial HCM patients have a less severe disease and while current clinical guidelines recommend lifetime clinical screening of their first-degree relatives, our finding suggests this is not necessary.

No study to date has focused exclusively on the familial HCM sub-group. Reassessment of risk algorithms in a more homogeneous patient population will allow development of accurate risk prediction scores. Until now, risk scores have been developed in populations including both nonfamilial and sarcomere positive HCM and not surprisingly show poor predictive ability. To date, no scores have incorporated genetic variables, and based on my recent work there is a strong likelihood that genotype can impact outcomes.

For the first time, genetic testing could offer a clearer way to understand the disease, allowing us to make more precise recommendations for family screening and better predict those more likely to have poor outcomes. This will reduce uncertainty, but also minimise unnecessary health care resources from clinical screening family members who are not at increased risk of disease.

Note: This project received project funding only. This project did not received full Fellowship funding.

The purpose of this research project is to develop and validate a blood test that can be widely used, e.g. hospital outpatients, and general practitioner offices, to detect a new molecule in blood that we discovered. It will indicate whether a patient has liver fat and whether they are at risk of developing diabetes, which frequently leads to heart disease and stroke.

We are facing a global epidemic of obesity and related diseases. Almost three-quarters of Australians are now overweight or obese, and childhood obesity is at an all-time high. Overweight and obese people have a high risk of developing fatty liver disease and/or type 2 diabetes. Fatty liver disease is often the first stage leading to type 2 diabetes, and puts patients at increased risk of fat deposits in their blood vessels that may cause heart attacks and strokes, which are the most common causes of death in these patients.

We are failing to prevent the catastrophic obesity epidemic. It is a global challenge. The numbers are far greater in developing countries. In China, for example, 114 million people have type 2 diabetes and half a BILLION have prediabetes. These staggering numbers underscore the enormity of this healthcare challenge globally.Although obese people with diabetes most commonly die from heart attacks and strokes, the rate at which this occurs is highly variable, and until now, we cannot predict who is most at risk and who will have an event.

Our results indicate that the new blood molecule discovered by us can predict, more than a decade in advance, who will develop diabetes. This is tremendously important, as it will allow us to target those most at risk with interventions to prevent them from developing diabetes, thereby reducing complications such as heart attacks and strokes. It has been repeatedly shown that the best way to prevent diabetes and its complications is early intervention – by the time of diagnosis a lot of damage has been done, most of it irrevocably.

The way we currently measure this molecule is not widely accessible, limiting its availability to populations that need it most. In this project, we aim to develop a test that can be used everywhere -- even at the bedside, outpatients, general practitioner offices -- and will be fast, precise, and reliable. We will ensure that the public, patients, and clinicians are fully aware of all aspects of this assay.

Note: This project received project funding only. This project did not received full Fellowship funding.

Increasing life expectancy has resulted in a higher proportion of older individuals (≥65 years) in the population compared to a decade ago. As the population ages, demand will increase for hospital and aged care services, including permanent residential aged care (RAC), respite RAC, and transitional care (TC). The number of injury-related hospitalisations for older individuals are growing, accounting for 27 per cent of hospitalised injury.

Following an injury, older individuals may require assistance to perform activities of daily living (ADL), either transitionally as they return to their prior ability, or on a more permanent basis. Prior research has identified that age, functional ability, cognitive impairment, depression, multimorbidity and falls are commonly associated with aged care placements. However, individual and psychosocial characteristics associated with admission/return to RAC have not been examined following a hospitalised injury at a population-level, nor have factors associated with entry into supplementary care programs, such as TC or respite RAC, been identified. For older individuals, there is limited information available regarding their care transitions between the home, hospital, RAC, respite RAC and TC following a hospitalised injury in NSW. Suboptimal care transitions may result in diminished ADL and increased costs, including through re-hospitalisation.

This research will examine factors that influence older individuals transitioning between services and will advance the understanding of the influence of individual and psychosocial characteristics on post-acute care placement of individuals who are hospitalised following an injury. Ultimately, this information will be invaluable in influencing policy, driving change, and informing planning of the post-acute phase healthcare for older individuals in NSW and to identify future priority areas for research.

The promise of e-health interventions as a solution to overcome current healthcare challenges such as accessibility and cost have been hampered by poor translation into the community. Despite major advances in the availability of evidence-based mental health programs there is a serious shortfall in the delivery of such programs in practice, with an estimated 17-year delay between the identification of an effective program and its integration into practice and policy domains (IOM, 2001; Westfall, 2007). A significant contributor to this problem is the lack of available skills and knowledge to conduct rigorous interdisciplinary implementation science research.

The goal of this project is to inform the implementation of an evidence-based e-health intervention to prevent the onset of depression in youth. The intervention, SPARX, is a six-session online ‘serious game’, based on the principles of Cognitive Behaviour Therapy, which we have adapted into a prevention program (SPARX-R) for adolescents. In an randomised-controlled trial conducted across 10 Sydney high schools we showed that SPARX-R prevents the onset of depression, with gains maintained at 6-month follow up (Perry et al., 2005; the trial is ongoing and 18-month outcomes are expected in August 2016). SPARX-R does not require extensive training to support its delivery, making ideal for the school context.

A better approach to bridging the gap between ‘what we know’ and ‘what we do’ in health could make a substantial contribution to improving health outcomes and efficiencies. Increasingly it has been recognised that research to bridge this gap (implementation research) requires the expertise of researchers, policy makers and practitioners to be combined; implementation projects require both a deep understanding of the real world and how it operates, along with the often sophisticated research skills necessary for complex research designs. This is commonly referred to as partnership or co-production research.

Co-production, where researchers and research users work together throughout the research process from question formation through to interpretation and dissemination of findings, appears likely to be the most effective model for partnership. Such partnerships are a relatively recent phenomenon, however, and there is much to be learnt about how best to bring the diffuse skills, needs and priorities of these groups together to drive more effective implementation research and reduce research wastage. In Australia, the promise of co-produced research has led to the creation of funding schemes designed to foster collaboration (e.g. NHMRC partnership grant, NSW Health Translational Grant Scheme) but it is unknown how effective these partnerships are or how they operate in practice.

The specific aims are to:
1. Understand how research/end user partnerships are currently enacted in New South Wales, what works and what does not: and
2. Evaluate, for the first time internationally, a suite of tools to strengthen coproduction in implementation research:
a. A training course for early career researchers to build their capacity to develop and sustain effective research partnerships with policy agencies;
b. A tool for research users to help them navigate the process of working with researchers, from the initial agreement to partner through to dissemination.

This project is a joint collaboration between the Northern Sydney Primary Health Network (PHN), Healthdirect Australia, Hornsby General Practice (GP) Unit (a NSW Health entity), Macquarie University Health Services, and the Australian Institute of Health Innovation. It is designed specifically to realise the vision of “a digitally enabled and integrated health system delivering patient-centred health experiences and quality health outcomes”, set by NSW Health in its recently released eHealth Strategy (2016-2026).

General Practitioners (GPs) tend to refer patients to the Emergency Department (ED) in order to ensure their patients receive affordable specialist care without extensive delays. They may not be aware of outpatient services available at their local hospital. This contributes to unnecessary ED access block and increased waiting times. Patients are frustrated by months of waiting for outpatient appointments, and they lack skills in self-management in the interim.

To address this, health pathways (a collaborative initiative between primary and secondary health providers to improve the referral and management of patients) have aimed to build capacity in general practice to help patients navigate the health system. Supported by the NSW Agency of Clinical Innovation (ACI), health pathways are implemented and evaluated across NSW.

This research will make use of the unique opportunity at the NHMRC Centre of Research Excellence in eHealth which is co-located within the Northern Sydney PHN. The PHN will develop its first 20 local health pathways over the next six months. We will work closely with the PHN to select two high-priority health pathways and conduct studies to 1) understand the pain points experienced by consumers in their journey through the current service landscape (e.g. inability to get timely access to specialist care; lack of self-management skills due to limited health literacy); 2) co-design a consumer portal to address these challenges with input from consumers, GPs, clinicians and health service practitioners; and 3) evaluate the acceptance of the portal from consumer, GP and health service practitioner perspectives.

Burn injury can be a traumatic event for both the child and their carer, requiring extensive, specialised care and protracted hospitalisations. For paediatric burn injuries, optimal outcomes are associated with good multidisciplinary care, consistent follow-up with high quality burns units, functioning family units, and early return to pre-burns activities. In Australia, Aboriginal and Torres Strait Islander children are over-represented in burn-related hospitalisations yet, no research until now has examined the outcomes of these children nor their access to care either immediately after the burn injury or following discharge from hospital.

In addition to being more likely to be hospitalised following a burn injury, unpublished data suggest Aboriginal and Torres Strait Islander children are less likely to be treated in a specialist tertiary burn service.(Moller, unpublished). The NSW ACI Statewide Burn Injury Service, NSW Burn Transfer Guidelines provides clear guidelines for paediatric burn referral to tertiary burn services. However, there is evidence to suggest these guidelines are inconsistently applied. The proportion of Aboriginal and Torres Strait Islander children treated at specialist tertiary burn services in NSW is lower than population expectations. Further, numbers treated in regional centres appear to be higher, suggesting children are not referred as per the guidelines.

PIDs result from monogenic mutations in genes crucial to the functioning of an intact immune system. Currently, mutations in ~290 genes have been identified that cause PID. However, there are many more cases where the genetic lesion is unknown. This project will perform WGS on these PIDs to reveal the underlying gene mutation.

This “from bedside to bench and back” approach incorporating genomics and bioinformatics will identify novel gene mutations in PID patients and provide an explanation for disease pathogenesis. While PIDs are rare, they have played an instrumental role in pinpointing the essential and non-redundant roles of genes in the development and function of immune cells. Furthermore, some of the complications affecting PID patients are prevalent in the healthy population; for example, the incidence of thrush due to chronic fungal infections. In addition to having direct affects on clinical policy/practice ie treatment regimens for affected patients, results will be disseminated via the publication of manuscripts, presentations at national/international conferences and via media outlets through the work of the Garvan Research Foundation.

The top causes of disease burden among Australians (15–44yrs) are dominated by mental health and substance use disorders. Of particular concern is the common co-occurrence (i.e. comorbidity) of disorders, with up to 50 per cent of people presenting to services with more than one disorder. Despite increased awareness and public concern leading to a major government initiative (National Comorbidity Initiative), comorbid mental health and substance use remains a major cause of disability, poor quality of life, early mortality and poses a significant challenge for the Australian health system.

Evidence suggests that integration of substance use and mental health treatment is ideal for optimal patient outcomes and to avoid patients falling through the gaps. Individuals with comorbidity however, continue to receive disparate care targeting either the mental health or substance use disorder. NSW Health is well placed to be the leader in responding to this crisis by translating high quality comorbidity research evidence to practice. The improved clinical management of comorbidity is a priority for NSW Health and is consistent with the NSW State Health Plan: Towards 2021 which aims to deliver truly integrated care by providing right care in the right place at the right time.

The purpose of this project is to directly address this priority by implementing effective models of translation to increase the capacity for NSW treatment services to respond to comorbidity. The specific objectives are to:
1. Employ standardised US toolkits for assessing comorbidity competency (DDCAT and DDCMHT) and adapt them for adolescent and adult treatment services in NSW and Australia
2. Implement these adapted toolkits and evidence-based recommendations in NSW treatment services to examine utility in assessing comorbidity competency and enhancing capacity to respond to comorbidity.

A transient Ischemic Attack (TIA) is a major warning sign for stroke. There is a 15 per cent risk of stroke ≤ 90 days following initial event and the risk of cardiovascular events remains high 10-15 years post-TIA. It is best practice for TIA patients to receive secondary medical care to determine TIA cause and to commence preventative pharmacological therapy early post-event.

Behaviour change programs which include education and group exercise (ie. advice and support to address modifiable cardiovascular disease risk factors including hypertension, inactivity, poor diet etc.) significantly reduce the odds of further cardiovascular events. These programs significantly increase the time TIA patients spend in moderately vigorous physical activity (ie. brisk walking) (5). The latter extremely important as increasing physical activity independently contributes to significant reductions in cardiovascular risk, with an inverse relationship between time spent in moderately vigorous physical activity and risk of cardiovascular events and all-cause mortality.

This project aims to :
1. Develop and implement a new service- a behaviour change program for people who have had a recent TIA (Study 1: Implementation Study)
2. Increase the minutes/week people who have had a recent TIA spend in moderately vigorous physical activity (Study 2: Outcomes Study).

Antibodies are the effector molecules of the immune system and are responsible for neutralising pathogens with remarkable specificity and memory. However, 5 per cent of Australians suffer from autoimmune diseases, such that their antibodies recognise their own cells, tissues and organs (autoantibodies). Autoantibody-mediated disorders account for a large burden of chronic disease and can be difficult to diagnose and treat due to heterogeneous symptoms ranging from arthritis, dry eyes/mouth to kidney failure and giving birth to a child with cardiac abnormalities. The unpredictability of disease outcomes reduces patient quality-of-life, while posing significant costs to healthcare systems for ongoing monitoring and treating symptoms as they occur. Treatment options are limited to non-specific steroids and expensive biologics that are only effective in a subset of patients.

The objective of this research is to use cutting-edge genomic technology to characterise human autoantibodies to improve diagnosis and monitoring of disease. This approach traces the cellular source of autoantibodies revealing novel and specific therapeutic targets.

There are two ways to characterise an antibody: i) antigen specificity - what the antibody interacts with; ii) the genes that form the antigen binding site on the antibody (variable (V), diversity (D) and joining (J) genes). For the last 40 years, the former method has been employed by clinical diagnostics to detect autoantibodies but has limited value for predicting disease outcome. For example, maternal autoantibodies binding the Ro self-antigens are associated with foetal cardiac abnormalities such that weekly echocardiograms from 12-22 weeks gestation are recommended for all Ro autoantibody-positive pregnancies. However only 2 per cent of these pregnancies result in this disease. A more specific biomarker would identify patients at highest risk, allowing for early intervention and improved disease management.

Advances in genomic technologies for sequencing antibody genes now make it possible to evaluate VDJ-genes for diagnostic purposes. Specific VDJ-genes have become useful diagnostic and prognostic indicators of lymphoma. Extending this approach to autoimmunity creates the exciting possibility of stratifying autoantibodies according to VDJ-gene usage and clinical symptoms. Previous research by others and myself has revealed distinct subsets of Ro autoantibodies that cause disease pathology. These “pathogenic” Ro autoantibodies cannot be distinguished from “quiescent” Ro autoantibodies by routine diagnostic assays. Genetic analysis of Ro autoantibodies is limited but has revealed biases in VDJ-gene usage across multiple patients. This research will extend these promising preliminary studies to evaluate the diagnostic utility of sequencing VDJ-genes and reveal where autoantibodies come from.

Mental and substance use disorders account for more years of life lost due to disability than any other disorders and are second only to cardiovascular disease and cancer as leading causes of disease burden. Comorbidity of mental and substance use disorders pose a significant challenge for the Australian health system. The silo structure of the healthcare system has historically treated clients in parallel by different treatment providers. Typically, treatment is incomplete and outcomes are poor.

The NHMRC Centre of Research Excellence in Mental Health and Substance Use (CREMS) leads the way in new research examining innovative treatments for comorbidity. NSW health services provide a unique context into which new approaches to comorbidity treatment can be embedded. Our research has demonstrated that an integrated, stepped care (ISC) approach is ideal for optimal client outcomes and to avoid clients falling through the gaps.

Integrated care involves both substance use and the mental health condition being addressed by the same provider. This can be facilitated by a stepped approach where additional care is provided for a mental health diagnosis after stabilisation from substance use, enabling the distinction between substance-related mental health symptoms versus symptoms remaining or emerging once use has resolved.

This project aims to:
i) Evaluate the impact of a Multi-modal Translation Intervention Package (MTP) to (a) increase ISC proficiency and uptake; (b) enhance clinician knowledge and attitudes; (c) improve substance use and mental health outcomes.
ii) Examine barriers and facilitators of ISC implementation using the MTP.
iii) Deliver MTP resources and sustainability recommendations to NSW Health for future rollout.
Promote identification, assessment and clinical management of comorbidity within the drug and alcohol services of NSW local health districts.

Genomic technologies, including targeted sequencing, and more recently, whole genome sequencing (WGS) have generated unprecedented insights into the molecular basis of disease. The application of WGS to patients with rare Monogenic Disorders is now identifying a molecular diagnosis in approximately 50 per cent of patients. The ability for WGS to characterise structural variants (SV) has redefined the genomic landscape of many cancers, providing treatment insights that were not possible from targeted sequencing approaches alone. One of the greatest challenges for precision medicine is the translation of bioinformatic methods developed in the research setting, often to study cohorts, into the clinic. Methods must be accurate, fast, comprehensive, interpretable by a multidisciplinary team, and must apply to the n-of-1 patient-centred situation.

The purpose of this proposal is to improve the clinical management of patients with inherited genetic disease, through increasing the diagnostic yield in rare disease, or improved tumour characterisation. The objectives of the proposal are to continue to develop a suite of bioinformatic approaches to uncover different aspects of genome biology and assess how these influence disease, and ultimately to translate these methodologies into clinically accredited tests. Many of these aspects of genome biology can only be uncovered by WGS. As we have already developed Australia’s first clinically accredited^ WGS-based diagnostic test for investigating single nucleotide variants (SNVs) and small insertions and deletions, we are uniquely positioned to achieve these objectives.

This proposal will develop critical bioinformatic and translational capability to improve patient care in NSW, and beyond.

This screening and secondary prevention project could help reduce the burden of stroke worldwide by introducing a novel, scalable, cost-effective technology to screen for post-operative atrial fibrillation (POAF) following cardiac surgery discharge. This project could influence policy and AF management guidelines to include routine monitoring for POAF recurrence.

POAF occurs in 25-40 per cent of cardiac surgery patients, and is associated with increased mortality and stroke risk. POAF is thought to be transient and self-correcting, thus patients discharged in stable sinus rhythm are rarely followed up. POAF recurrence is often missed as it is largely asymptomatic or has non-specific symptoms. Additionally, patient knowledge of the extent of AF symptoms is poor despite inpatient education. In my systematic review (n=6 studies) active monitoring post-discharge identified POAF recurrence in 33 per cent of patients with transient in-hospital POAF, and late-onset POAF in ~4 per cent with no prior POAF. I have shown self-monitoring for POAF recurrence is feasible using a smartphone handheld ECG (iECG).

The outcomes from this study will assist development of a risk score to better identify patients at highest risk of devastating complications, such as stroke, allowing clinicians to better target effective preventative therapy. The project aims to:
1. Determine the incidence and predictors, and explore the prognostic significance of recurrent POAF and late-onset POAF
2. Determine if education using a 'graphic app' improves patient knowledge, particularly awareness of POAF symptoms
3. Determine scalability of self-monitoring using an iECG.

Cardiovascular disease is the leading cause of premature death among Aboriginal Australians and there is increasing disparity in rates of cardiovascular-related deaths between Aboriginal and non-Aboriginal Australians. From 2008-2012, non-communicable diseases, such as cardiovascular disease and diabetes, accounted for 81 per cent of the gap in mortality rates. Obesity (16 per cent) and physical inactivity (12 per cent) are leading risk factors in the development of chronic disease and the overall health gap in Aboriginal Australians.

Obesity is responsible for 1-3yrs of the 10-yr gap in life expectancy. Higher levels of these modifiable risk factors that contribute to this health disparity among Aboriginal adults are already present in Aboriginal children. Compared with their non-Aboriginal peers, Aboriginal children are 1.4 times more likely to be overweight or obese, 1.8 times more likely to exceed screen time guidelines and 1.6 times more likely to have unhealthy eating habits. The risk of type 2 diabetes in Aboriginal children is 8 times higher than in their non-Aboriginal counterparts.

As cardiovascular disease is one of the leading contributors to the life expectancy gap, there is a need to better understand the key modifiable behaviours of cardiovascular disease, such as physical activity (PA) and sedentary behaviour (SB), and better understand culturally acceptable ways to promote healthy levels of these behaviours among Aboriginal children. This evidence is currently lacking for Aboriginal children and is critical to improving cardiovascular health behaviours in Aboriginal Australians.

Conducting research with Aboriginal communities is a long-term commitment, requiring respectful negotiations within the research partnership, which can only occur through continuous and consistent relationship building. This fellowship will build on a 2-year partnership with three Aboriginal communities in NSW. A priority identified by these communities is to raise healthy children and provide their children with opportunities to connect with Country and culture. This fellowship will use a behavioural epidemiology framework to understand PA and SB behaviours among Aboriginal children and how these health behaviours relate to cultural connectedness.

Specifically, this project aims to:
1. Determine the prevalence and patterns of PA and SB and their associations with cardiovascular health.
2. Identify the cultural determinants of PA and SB;
3. Design, implement and evaluate an afterschool Aboriginal cultural program to promote healthy lifestyle behaviours; and
4. Translate the evidence into dissemination strategies of Australia’s Physical Activity Guidelines to 5-12 year-old Aboriginal children.

This project will address an internationally-important healthcare problem in hospital emergency departments: with a surging demand for services, how can we ensure a safe environment for patients while still maintaining throughput?

In the first quarter of 2016 there were 672,483 presentations to NSW emergency departments (EDs) – a 9 per cent increase in triage Category 1 patients, and a 4 per cent increase in presentations overall compared with 2015. Despite introduction of National Emergency Access Targets across Australia in 2010, 25 per cent of patients were not ‘seen on time’ in accordance with Australasian Triage Scale standards, and 26 per cent of visits were not concluded within 4 hours. Increasing numbers of patient presentations, coupled with limited in-patient bed capacity, can result in long waiting times and prolonged lengths of stay in the ED. Overcrowding is becoming more prevalent, and has been associated with an increase in medical errors and poor patient outcomes, including death.

When EDs get overloaded, things are more likely to go wrong (e.g diagnostic errors, medication errors, delayed treatment). The processes we put in place to prevent errors from occurring often add to workload in the ED, paradoxically making it even more likely that things will go wrong. A new way to solve this dilemma is to shift our focus from preventing things going wrong, to increasing the number of things that go right. We call this ‘productive safety’. The purpose of this project is to design and implement ED processes to improve productive safety in NSW public hospitals. This project will seek to identify key quantitative and qualitative measures that are predictive of productive safety in response to unexpected events and periods of peak patient demand in the ED. Based on these measures, processes will be developed for assessing and improving productive safety. By doing so, we will assist ED leaders and clinicians to evaluate their organisation, and implement action to improve the number of things that go right when faced with challenging or unanticipated conditions. Such a proactive effort is likely to strengthen ED responses to threats and crises, and thereby save money and lives.

The project aims are to:
1. establish baseline measurement of productive safety in EDs in NSW public hospitals
2. refine productive safety processes, following an in-depth study of two NSW ED cases
3. develop a suite of context-dependent and generic tools to support re-design of processes to improve productive safety in EDs in NSW public hospitals.

Mitochondrial diseases are the commonest group of inherited metabolic disorders. Children often present with severe disease that is fatal in two thirds of patients before the age of 16. Adults tend to endure chronic and progressive disease that is often be severely debilitating and precludes them from employment. Mitochondrial diseases are notoriously difficult to diagnose due to the diversity of genetic causes (>300 mutations in mitochondrial DNA and >150 known nuclear disease genes), the extreme variability in clinical presentation (the same mutation in a family can manifest very differently) and a lack of comprehensive and definitive diagnostic tools.

The current diagnostic pathway involves invasive, expensive and inaccurate testing that often results in patients going undiagnosed or being misdiagnosed and spending years trying to access appropriate healthcare. This project will evaluate two new diagnostic tools, metabolomic biomarker profiling and genomic sequencing, in order to define a rapid, cost-effective, comprehensive and accurate diagnostic pathway that will improve the diagnosis of mitochondrial diseases.

Accurate diagnosis enables specialist clinicians to encourage disease modifying lifestyle changes, to administer appropriate treatments, identify and avoid contraindicated pharmacological agents (e.g. the common antiepileptic sodium valproate can cause death in mitochondrial disease patients presenting with seizures) and to provide informed family planning. The accurate diagnosis of mitochondrial diseases would also have a significant impact on the cost to NSW Health associated with undiagnosed or misdiagnosed patients, would enable treatment development through better understanding of disease pathophysiology in defined disease-specific cohorts, would define patient cohorts for genotype-specific clinical trials and enable appropriate treatment administration to those who will benefit most.

As genomic sequencing and bioinformatic analysis costs are still considerable, the first objective of this project is to develop metabolite signatures (combinations of small molecules that can be used to define a disease discriminatory test) of the mitochondrial disease group and individual mitochondrial diseases. This frontline indication of disease will inform clinical decision-making on whether to progress to other diagnostic testing, including comprehensive genomic sequencing.

As a result of recent technological advances, it is now possible to simultaneously and comprehensively sequence both mitochondrial and nuclear genomes. However, the very recent introduction of this technique means that objective research evidence for its applicability to genomic healthcare and how best to integrate it into clinical practice is lacking. Therefore, the second objective of this project is to develop a robust bioinformatic approach for the identification of causative mitochondrial disease mutations.

Inflammation is central to the pathogenesis of atherosclerotic plaque progression and athero-thrombotic vascular events with systemic inflammatory markers correlating strongly with prognosis in acute coronary syndrome (ACS) patients. Indeed, these patients are particularly vulnerable to recurrent ischaemic events in the early post-ACS period, likely driven by pan-coronary inflammation, resulting in a higher prevalence of vulnerable non-culprit plaque.

Moreover, percutaneous coronary intervention (PCI) to treat culprit coronary stenoses in the setting of ACS, is strongly associated with a relatively high rate of peri-procedural myocardial infarction and adverse cardiovascular outcomes, due in part, to distal embolisation of inflamed plaque fragments with microvascular obstruction. Therefore, suppression of atherosclerosis-associated inflammation is of critical importance to stabilise vulnerable plaque (AIM 1); to decrease inflammatory mediator release after PCI of vulnerable lesions (AIM 2); and to reduce plaque progression/instability, which itself is strongly linked with adverse cardiovascular outcomes (AIM 3).

The principle aim of this project is to investigate a new, innovative, and cost-effective approach to reduce the deleterious effects of atherosclerosis-associated inflammation, based on our discovery that oral colchicine, a safe and well established drug, widely used in non-vascular inflammatory disorders, has marked anti-inflammatory properties in ACS patients. Notably, SP’s recent published studies have elucidated that colchicine, within hours of ingestion, markedly reduces (1) secretion of the pro-inflammatory cytokine IL-1β by circulating monocytes and (2) local coronary levels of the inflammatory cytokines IL-1β and IL-18, together with downstream IL-6, a cytokine strongly linked with future coronary events.

Based on these findings, colchicine’s acute effects on plaque stability will be studied, as well as its more long term effects on plaque volume/inflammatory content. Such studies have enormous clinical relevance as they have the potential to directly improve outcomes in patients presenting with unstable coronary syndromes, particular in the context of PCI, as well as ‘stable” patients with established atherosclerosis. Moreover, as colchicine is safe, readily available and cost-effective, it can be rapidly included as part of the standard therapy for both ACS and stable coronary disease patients.

Delirium, a transient confusional state, is an increasing problem for Australia’s ageing inpatient demographic. Incidence rates from international studies range between 3-29 per cent for patients over 65 years, equivalent to 116,731 – 1,128,400 inpatients using Australian 2013-14 admissions data.

Higher rates of 47-63 per cent have been observed in surgical patients over 65 years, and critically ill patients with delirium have substantially higher prevalence rates (up to 70 per cent) and longer hospital stays (by 6.5 days). Delirium has a significant health impact as inpatients developing delirium are 2.6 times more likely to die during admission, and have a higher risk of developing dementia (adjusted relative risk of 5.7, CI 1.3-24.0). The presence of pre-existing dementia increases the risk of developing delirium two to five times.

A key factor for this research is that delirium is largely preventable, using evidence based guidelines for implementing pharmaceutical, physical, and care delivery changes to inpatient care. The Australian Commission for Safety and Quality in Health Care is releasing a new Delirium Clinical Care Standard (Standard) in 2016 which incorporates this multi-component approach. This is therefore a critical time to investigate and evaluate the impact and effect size of implementing the new Standard, whether the Standard is being implemented as planned, and whether the Standard is effectively addressing the need to identify, prevent and treat delirium.

This study will provide critical data for assessing the benefits to patients and cost-savings gained through preventing and treating delirium in a rapidly ageing population, using a novel combination of applied health economic and implementation science principles. Delirium incidence rates in study hospitals will be measured before, and after, the implementation of the multi-component intervention that forms the basis of the Standard. In addition to standardised clinical outcomes, the study will assess barriers and enablers to the implementation and provide vital feedback to policy makers to understand and improve translation of the evidence based guidelines into practice. Despite existing research on the design of the multi-component interventions, the financial impact of delirium to the health system, and effectiveness of interventions for clinical outcomes, the unique contribution of this study is in determining the cost-effectiveness of these multi-component interventions in Australian acute care and the factors that ensure success.