Research with Impact - 2017 Highlights

HIGHLIGHTS 2017

Research with impact

MENZIES INSTITUTE FOR MEDICAL RESEARCH BUILDING A HEALTHIER COMMUNITY

menzies.utas.edu.au

HIGHLIGHTS 2017

Research with impact The University of Tasmania’s Menzies Institute for Medical Research exists to perform internationally significant medical research leading to healthier, longer and better lives for Tasmanians.

We have been making discoveries to improve the health of our community since our establishment in 1988. Menzies is committed to seeing the investment in our research flow through to the ultimate recipients – people in our community with or at risk of disease.

Each of the Menzies research themes addresses a different group of diseases affecting the Tasmanian community. Across these themes we are developing an integrated multi-disciplinary flagship program of research in multiple sclerosis. Our research themes are: • Public Health and Primary Care • Musculoskeletal Health and Diseases • Neurodegenerative Diseases/Brain Injury • Cardio-metabolic Health and Diseases • Cancer, Genetics and Immunology

Dean Picone won the Menzies Best of the Best Award for research published in 2017.

Multiple Sclerosis (MS) Flagship Research Program Genetics of MS The onset of multiple sclerosis (MS) is caused by an interplay of environmental and genetic factors, but little is known about the role genes play in the progression and severity of MS. In our southern Tasmania MS Longitudinal (TasMSL) Study, a genome-wide association analysis found that variations in a gene known as LRP2 are associated with a twofold higher risk of relapse in early and established MS. This finding has been replicated in an independent study, making it the first confirmed finding of a genetic variation associated with the severity of MS. Future research will investigate the precise mechanism by which variations in LRP2 affect the progression of MS. Zhou et al, ‘Genetic variation in the gene LRP2 increases relapse risk in multiple sclerosis’, published in Journal of Neurology, Neurosurgery & Psychiatry. This paper was a winner of a Menzies Ten of the Best award.

Economic cost of MS For the first time in Australia, we quantified the impact of increasing severity of multiple sclerosis on quality of life among a representative sample of people with MS. The data generated will be useful in further health economic analyses of interventions that slow progression of MS. Ahmad et al, ‘The impact of multiple sclerosis severity on health state utility values: Evidence from Australia’, published in Multiple Sclerosis Journal.

Public Health and Primary Care

Dr Barbara de Graaff researched the growth of after-hours Medicare claims.

Childhood BMI and adult obesity We have found that people who avoid obesity as an adult have a lower body mass index (BMI) at age 6 and a lower yearly change in BMI in childhood compared to people who develop obesity as adults. Our study also identified a second “critical window”, beginning in adolescence for females and early adulthood for males, where BMI levels started to stabilise in overweight or obese children who were able to avoid obesity as adults. The study involved using a new statistical modelling approach to analyse the long-term BMI trajectories in a sample of more than 2,700 participants

Research with Impact THE AIRRATER PROJECT AirRater is a smartphone app that enables people to monitor and improve their health conditions and learn how they respond to specific environmental triggers.

It does this by providing real-time, location-specific information on key environmental triggers and by allowing users to log symptoms and identify which conditions impact their health.

After two years of operation in Tasmania and three months in the ACT, by December 2017 the AirRater data platform and smartphone app had reached almost 5,500 users and

had generated more than 15,000 symptom reports.

Data collected through the app shows it is reaching its target population: people who have (or are caring for someone who has) allergies, asthma or other respiratory conditions. AirRater has been incorporated into public health response strategies, contributing to a new early warning system to

alert Tasmanians to short episodes of increased smoke levels. In November 2017, the Tasmanian Department of Health and Human Services issued the first thunderstorm asthma alert in Tasmania on the basis of AirRater data and advice.

The AirRater research team were the recipients of the inaugural Menzies Research Impact Prize.

who were tracked over three decades from age 6 to 49. Our research extended the findings of earlier work by suggesting that efforts to prevent adult obesity should ideally begin before age 6 years with a second chance among teens and young adults.

after-hours services that were defined as urgent, which had increased by 170%. The findings question whether these convenient house calls are having the desired benefits for hospital emergency departments and are the best use of taxpayers’ money.

Buscot et al, ‘BMI trajectories associated with resolution of elevated youth BMI and incident adult obesity’, published in Pediatrics. This paper was a winner of a Menzies Ten of the Best award.

De Graaff et al, ‘Up, up and away: The growth of after-hours MBS claims’, published in Australian Family Physician.

Breastfeeding and healthy growth Babies who are fed only breastmilk for the first three months of life appear to be much more likely to maintain a healthy weight trajectory, with the benefits possibly lasting through to early adulthood. This study pooled weight and height data from 6,708 babies in four cohorts – three in Europe and the one we studied in Australia – who were measured either once or twice a year until they were six years old. The collection of data used in the Australian part of the study began more than 20 years ago, which enabled researchers to follow up more than 1,000 children as young adults. The observations indicate that, if full breastfeeding stops before three months of age, children are at greater risk of becoming overweight, even through to 20 years of age. This adds to the evidence behind the World Health Organization recommendation that, if possible, mothers should aim to fully breastfeed their baby beyond three months and, ideally, until six months of age.

Oddy et al, ‘Infant feeding and growth trajectory patterns in childhood and body composition in young adulthood’, published in The American Journal of Clinical Nutrition. This paper was a winner of a Menzies Ten of the Best award.

After-hours medical care The rollout of after-hours GP-type home visits, introduced to relieve pressure on hospital emergency departments, is linked with as much as a 10-fold increase in Medicare claims for after-hours consultations. Researchers reviewed 201011 data, when these after-hours services first began, and compared it with 2015-16 data. They focused in particular on

Workplace stress A broad range of childhood factors are associated with job stress in adulthood. In a unique 25-year follow-up study, we compared data on a range of childhood factors – including school enjoyment, socio-economic position, and some markers of physical and mental health – with the development of job stress later in life. The study was part of the larger Childhood Determinants of Adult Health study (CDAH). Our results show that healthy childhood experiences contribute to a healthy, productive work life into adulthood. The findings highlight that the characteristics of the job itself should not be viewed in isolation. Rather, job stress in adults is complex and multifactorial and associated with a range of individual factors across the life course.

Wang et al, ‘Association between childhood health, socioeconomic and school-related factors and effort-reward imbalance at work: a 25-year follow-up study’, published in Occupational and Environmental Medicine.

Lifestyle habits and weight gain Simple lifestyle changes are effective in reducing weight gain. We surveyed a cohort of 1,155 people at two points five years apart about four behaviours: eating breakfast, limiting takeaway food to no more than once per week, taking at least 10,000 steps per day and watching no more than two hours of television per day. We found that the healthy behaviours paid off – those who met the guidelines at both survey times had lower weight gain than those who didn’t meet the guidelines. The study also showed that it’s never too late to change – those who didn’t meet the guidelines in the first survey but did five years later had a

similar weight gain to those who met the guidelines in both surveys. Participants who met none or only one guideline gained on average 3.8 kilograms more over the five years than those who met all four guidelines.

Sharman et al, ‘Validation of non-invasive central blood pressure devices: ARTERY Society task force consensus statement on protocol standardization’, in the European Heart Journal.

Smith et al, “Lifestyle behaviours associated with 5-year weight gain in a prospective cohort of Australian adults aged 26-36 years at baseline”, published in BMC Public Health.

Understanding stroke About a third of the cases of stroke are cryptogenic, meaning that the cause is unknown. However, a known risk factor for stroke is atrial fibrillation, a type of abnormal heart rhythm, and atrial fibrillation may also be associated with recurrent strokes. Our research showed that an analysis of the mechanics of cardiac function can be used to predict which patients who have had a cryptogenic stroke will develop atrial fibrillation and thus increase their chances of having another stroke. By using cutting-edge echocardiographic imaging techniques to analyse the mechanics of the left atrium – one of the chambers of the heart – and comparing this with clinical risk scores, we were able to create a sensitive and specific algorithm which predicts atrial fibrillation following cryptogenic strokes. As well as identifying a new imaging biomarker, our research also found limitations in the imaging biomarkers that had previously been used (left atrial volume and diastolic function). These results have immediate application to clinical monitoring and could help to prevent recurrent strokes.

Cardio-metabolic Health and Diseases Blood pressure measurement This paper won the 2017 Menzies Best of the Best Award for outstanding research achievement evidenced through publication in a scholarly journal. The international study led by Menzies found that the most common method for measuring blood pressure (BP) – the upper arm cuff method – is often inaccurate. BP is the strongest risk factor for cardiovascular disease and inaccurate measurement could result in misdiagnosis and inappropriate medical intervention. It had long been uncertain whether cuff blood pressure accurately reflects the pressure in the arteries of the arm or in the major artery just outside the heart, the aorta, which is a better indicator of pressure. By analysing almost seven decades of international data on 2,500 people, the study found that cuff BP was systematically inaccurate, particularly for people with mid-range BP. The study provides the basis for work by Menzies (with industry and clinical collaborators) to improve the accuracy of cuff BP measurement.

Picone et al, “Accuracy of cuff-measured blood pressure: systematic reviews and meta-analyses”, published in Journal of the American College of Cardiology.

Menzies is involved in work by the Artery Society Task Force aimed at setting industry standards for determining the accuracy of new blood pressure devices that measure the pressure in the aorta (central blood pressure). This is the most clinically important place to measure blood pressure, but up until the publication of this paper, the approach to testing the accuracy of new devices to measure central blood pressure was unregulated. The paper provides clear guidance and recommendations on how to test device accuracy.

Pathan et al, “Use of atrial strain to predict atrial fibrillation after cerebral ischemia”, published in JACC: Cardiovascular Imaging.

This paper was a winner of a Menzies Ten of the Best award.

Women are reported to have greater mortality after stroke than men, but the reasons are uncertain. This work examined sex differences in mortality at one and five years after stroke and identified factors contributing to these differences. Greater mortality in women is mostly because of age but also stroke severity, atrial fibrillation and pre-stroke functional limitations. Lower survival after stroke among the elderly is inevitable, but there may be opportunities for intervention, including better access to evidence-based care for cardiovascular and general health.

Phan et al, ‘Sex differences in long-term mortality after stroke in the INSTRUCT (International STRoke oUtComes sTudy. A metaanalysis of individual participant data’, published in the American Journal of Clinical Nutrition. This paper was a winner of a Menzies Ten of the Best award.

Dr Liesel FitzGerald, Professor Alex Hewitt and Dr Feitong Wu all contributed to Menzies' success in 2017.

Echocardiography in reducing heart failure Stage B heart failure is an early stage of heart failure with no symptoms but evidence of cardiac impairment.

The recognition of this could be helpful because early treatment could delay or prevent progression of disease.

However, current clinical guidelines do not support using echocardiography (imaging) in asymptomatic patients.

Our world-first clinical study of advanced imaging in urban and rural areas across the State confirmed that the use of imaging screening was useful in identifying patients likely to progress to heart failure. We were unable to show that imaging guided management improved the outcome of people with Stage B heart failure, and are proceeding to study that in a new trial. The Editorial board of JACC: Cardiovascular Imaging awarded the lead author, Dr Hong Yang, the Young Author Award of 2017.

Yang et al, ‘Imaging-Guided Cardioprotective Treatment in a Community Elderly Population of Stage B Heart Failure’, published in JACC: Cardiovascular Imaging.

Cancer, Genetics and Immunology Genes involved in leukaemia Rare genetic variants are suspected to play a significant role in the development of familial haematological malignancies (HMs), which are cancers that affect the blood and lymph system like leukaemia and lymphomas. The advent of whole genome and exome sequencing is now allowing us to properly study genomes to identify the variants involved.

We applied this technology to the Tasmanian Familial Haematological Malignancy cohort to test a recent proposal that a rare genetic variant in the ITGB2 gene was associated with risk of chronic lymphocytic leukaemia (CLL). Our study was unique in that it allowed us to evaluate the contribution of the variant to different subtypes of HMs in a familial cohort. Our work found no evidence to suggest that this ITGB2 genetic mutation contributed to a risk of familial HMs in our dataset. Studies such as this are critical in this field to distinguish between true causal mutations, as opposed to statistical association.

Blackburn et al, ‘Evaluating a CLL susceptibility variant in ITGB2 in families with multiple sub-types of hematological malignancies’, published in Blood. This paper was a winner of a Menzies Ten of the Best award.

Prostate cancer We know that inherited changes in our genes help determine risk of developing many diseases, but also determines how the disease progresses and how we respond to therapies. Our study examined genetic changes associated with prostate cancer, and how one change in particular, that can be inherited by some men, contributes to development of tumours of the prostate.

Fitzgerald et al, ‘Impact of the G84E variant on HOXB13 gene and protein expression in formalin-fixed, paraffin-embedded prostate tumours’, published in Scientific Reports.

Genetic determinants of keratoconus Keratoconus is a disease of the eye in which the cornea thins out and bulges causing the vision to become blurry and distorted. The disease affects about 1 in 2,000 people and

Dr Rosemary Clark is contributing to the understanding of the most common adult-onset motor neurone disease.

has a clear genetic component. The possible role of one gene, known as ZNF469, was controversial with several conflicting reports, primarily from small, poorly designed studies. We conducted detailed genetic sequencing research and statistical analysis to thoroughly evaluate the possible role of ZNF469 in keratoconus using the largest cohort studied to date. The research clearly showed that variants in this gene are no more common in people with the disease than in the general population. This finding unequivocally shows that the gene should not be used diagnostically for keratoconus, which will allow research to focus on the possible involvement of other genes.

Lucas et al, ‘Potentially pathogenic variants in ZNF469 are not enriched in keratoconus in a large Australian cohort of European descent’, published in Investigative Ophthalmology & Visual Science.

This paper was a winner of a Menzies Ten of the Best award.

Stem cell therapies in eye disease This research used induced pluripotent stem cells from people with a variety of inherited retinal diseases to study the cells at the back of the eye (the retinal pigment epithelium), which are responsible for vitamin A cycling and removing the debris produced by light sensing cells. It was found that dysfunction of these cells alone is sufficient to cause the accumulation of drusen, a precursor for age-related macular degeneration.

Hewitt et al, ‘Drusen in patient-derived hiPSC-RPE models of macular dystrophies’, published in Proceedings of the National Academy of Sciences of The United States of America. This paper was a winner of a Menzies Ten of the Best award.

Immunotherapy for Devil Facial Tumour Disease This study showed that immunotherapy can cure Tasmanian devils of the transmissible cancer called devil facial tumour disease (DFTD). Normally, animals show no evidence of antibody or immune cell response against DFTD and usually die within a few months. We used immunotherapy on devils with tumours the size of golf balls and then observed the tumours gradually shrink and disappear over three months. This breakthrough builds on earlier work that showed the devil’s immune system was capable of mounting an immune response to DFTD. It therefore demonstrates the feasibility of a vaccine for DFTD. Tovar et al, ‘Regression of devil facial tumour disease following immunotherapy in immunised Tasmanian devils’, published in Scientific Reports.

Neurodegenerative Diseases/Brain Injury

Musculoskeletal Health and Diseases

Motor Neurone Disease Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neurone disease. It has traditionally been viewed as a disease affecting motor neurones extending from the spinal cord to the muscle. However, a growing body of evidence suggests that inhibitory circuits in the brain may be key to understanding and treating ALS, but the exact cell type/s responsible had not previously been identified. Our research has identified two distinct cell sub-types, of the inhibitory interneuronal class, that are progressively altered in the primary motor cortex of the brain even before symptoms are seen. These alterations may drive the motor neurone vulnerability typical of ALS. This work has the potential to change the way ALS is viewed and treated in the medical and scientific community. For people living with ALS, it broadens the understanding of the underlying pathology central to this devastating disease and offers potential new avenues for the effective prevention and treatment.

Age-related muscle loss Age-related muscle loss is a major cause of disability and loss of independence in the elderly. Our research has shown for the first time that, in addition to differences between individuals, changes in serum Vitamin D, physical activity, knee pain and dysfunction over time within the same individual is associated with muscle loss. The study applied new and sophisticated statistical methods to data collected from a relatively large sample of community-dwelling older adults over four time points during 10 years of follow-up. Loss of muscle mass is inevitable as a person ages. However, this study shows that some preventative measures can be taken to slow this decline.

Clark et al, ‘Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1G93A mouse model of ALS’, published in Scientific Reports. This paper was a winner of a Menzies Ten of the Best award.

Balogun et al, ‘Longitudinal associations of serum 25-hydroxyvitamin D, physical activity, and knee pain and dysfunction with muscle loss in community-dwelling older adults’, published in The Journals of Gerontology: Medical Sciences. This paper was a winner of a Menzies Ten of the Best award.

Traumatic brain injury It is clear that even mild forms of traumatic brain injury (TBI) can have lasting cognitive effects; however, the specific cellular changes responsible for the functional deficits remain poorly understood. Previous studies suggest that not all neurons respond in the same way and that changes to neuronal architecture may be subtype specific. This work characterised the response of interneurons to TBI.

Maintaining balance in middle age Poor balance is a risk factor for falls and fracture in older adults, but little is known about modifiable factors affecting balance in younger women. This study aimed to examine whether lower limb muscle strength in young women and changes in this strength are independent predictors of balance in middle age. This was an observational 10-year follow-up study of 470 women aged 25 to 44 years at baseline. The findings suggest that both improvement of muscle strength in younger age and prevention of age-related loss of muscle strength could be potentially useful strategies to improve balance and reduce falls in later life.

Brizuela et al, ‘Mild traumatic brain injury leads to decreased inhibition and a differential response of calretinin positive interneurons in the injured cortex’, published in Journal of Neurotrauma.

Wu et al, ‘Both baseline and change in lower limb muscle strength in younger women are independent predictors of balance in middle age: A 12-year population-based prospective study’.

Would you like to know more?

If you would like more information about our current research projects: www.menzies.utas.edu.au Phone: +61 (03) 6226 7700 Email: enquiries@menzies.utas.edu.au Facebook: www.facebook.com/MenziesResearch Twitter: @ResearchMenzies Cover image: Multiple sclerosis researcher Dr Yuan Zhou Photograph by Peter Mathew

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