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CONCORD HOSPITALRESEARCH REPORT
2002/2003
Concord Repatriation General Hospital
Hospital Road, Concord 2139 Australia
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Contents
Overview of Research 3
Message from the Chair of the Research Committee 4
Message from the Chair of the Ethics Committee 5
Markus Seibel 6
Robert Cumming 7
Rosemary Burke 8
Biao Zeng 9
The ANZAC Research Institute 11
The Centre for Education and Research on Ageing (CERA) 12
Cardiology 14
The Burns Unit 17
Breast Cancer 19
Brain Diseases 21
Respiratory Diseases 23
Andrology 26
Urology Research 27
Research into Pain Relief 28
Orthopaedic Research 30
The Ageing Process and the Liver 32
Palliative Care 33
Cognitive Behavioural Treatment of Panic Disorder 34
Table of Research at Concord Hospital 2002/2003 36
Funding 45
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Overview of researchResearch at Concord Hospital is diverse,spanning the spectrum from basic,laboratory-based research throughapplied clinical research to population-based studies. This reflects theenormous breadth of talent and expertiseat Concord and our close links with TheUniversity of Sydney and the ANZACResearch Institute. Furthermore,specialist services, such as the BurnsUnit, provide the opportunity for groundbreaking studies in areas of need.
The establishment of the ANZAC Research Institute hasbeen a major factor in promoting laboratory-basedresearch on this campus. The Institute has provided state-of-the-art laboratories to facilitate quality research andpromote an environment which fosters scientificexcellence. This, together with the recruitment over recentyears of a number of world class senior staff withexperience in a variety of research techniques, hasstrengthened and expanded the repertoire of conditionsand diseases investigated.
An important feature of the research at Concord Hospital,and one which sets us apart from many centres, is themultidisciplinary nature of many of the studies. By drawingon the expertise of all facets of professional health care therelevance and calibre of the research in ensured.
Furthermore, research is performed while maintaining the highest standards of clinical medicine and patient care.The combination of talented, dedicated staff and theimproved physical environment brought about by theredevelopment of the hospital suggests that the future of research at Concord Hospital will be bright.
Jillian KrilAssociate Professor (Geriatric Medicine)Editor, Research Report
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Message from theChair of the ConcordHospital ResearchCommitteeIt is a great pleasure to see theproduction of this Research Reportcome to fruition. In some ways it marksthe coming of age of research atConcord Repatriation General Hospital,which for many years has been ateaching hospital of the University ofSydney. The new millennium has seenthe commissioning of the ANZACResearch Institute – a purpose-builtmodern research facility – right here onthe Concord campus.
The ANZAC Research Institute or ARI, headed bythe inaugural Director Professor DavidHandelsman, commemorates in a very tangibleway the Hospital’s links with the veterancommunity, and has a primary theme of ageing.The ARI has initiated new directions of researchexcellence in men’s health and in bone disease, aswell as capitalising on previously establishedresearch in ageing through CERA (Centre forEducation and Research on Ageing) and geneticaspects of neurodegenerative disorders. The ARIhas already established itself as a major focus ofresearch activities at Concord.
This publication illustrates the broad depth ofresearch at Concord on many fronts, ranging fromdirect patient care to the molecular and genetic
basis of disease. It is obvious that this research ismultidisciplinary in nature, with contributions fromnurses, physiotherapists, dieticians, speechtherapists and pharmacists in addition to thosefrom physicians and surgeons and basic scienceresearchers. We have chosen not to beexhaustive, but to showcase the highlights. Wehave also featured biographies of our two newestProfessors, Markus Seibel and Robert Cumming,Rosemary Burke the director of Pharmacy, andBiao Zeng, one of our many PhD students - ourresearchers in training.
This research report would not have been possiblewithout the hard work of Associate ProfessorJillian Kril and Virginia Turner who collected,collated and edited the material. We owe themboth a debt of gratitude for a job well done.
Research in a teaching hospital has a fundamentalplace not only in improving our understanding ofdisease but in improving healthcare. It deservesrecognition and support from the community. Thiscan best be achieved by fostering anunderstanding of what is happening here atConcord. We hope this publication will go someway towards facilitating this goal.
Professor Ben FreedmanChair, Concord Hospital Research Committee
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A message from theChair of the EthicsCommitteeThe Human Research EthicsCommittee (HREC) is central to thegovernance of good research in thehospital. As a result of therecommendations of the Review ofResearch at Concord Hospital in 2000,much has occurred to improve therunning of Research and Ethics at ourhospital.
Central to this has been the reorganisation of theResearch Office with the appointment of Virginia Turner,who has worked extremely hard to bring realprofessionalism to the office and who is ably supportedby Rodger Lomberg.
The Concord HREC has 20 members, including laypeople, a Minister of Religion, two lawyers and a groupof professionals with a diverse range of expertise inresearch and clinical care.
In 2002, the HREC was fortunate to have the additionof two more lay representatives (making a total of five),Mr Rob Neurath and Mrs Elizabeth Buckpitt. Dr MattRickard (colorectal surgeon) and Mr Leo Turner (ClinicalNurse Consultant) also took up positions on theCommittee in 2002. In 2003, Professor RobertCumming (Professor of Epidemiology and GeriatricMedicine) and Dr George Lau (Department ofCardiology), joined the HREC. In 2003, the Committeewelcomed Rev Paul Weaver, and was pleased to retainthe services of retiring Minister of Religion, Rev PaulWatkins as one its lay representatives. Two other long-standing members have retired. Dr Sue Liew retired in2000 after 15 years as Chairperson and Mrs Ethel(Stalky) Lane retired as Veterans’ Representative after
serving almost the same length of time. The hospitalowes a debt of gratitude to both these dedicatedpeople.
The Concord HREC has struggled with many issuesover the last twelve months. Many of these issues arisefrom the new Information Privacy laws which have beenintroduced at both State and Commonwealth levels. Inthe light of this new legislation, the Ethics Committeehas had to look at the need to provide more stringentethical oversight of medical records research and theissue of identifiable information kept on databaseswithin the hospital.
The Committee has also developed new policies formeeting the increasingly frequent demands for genetictesting as part of large multi-centre, pharmaceuticalcompany-sponsored drug trials.
The issue of healthy volunteers taking part in researchhas also been a contentious one and the Committeehas developed guidelines for providing sufficientinformation to healthy participants about any risksinvolved in the research for which they are volunteering.
In 2001, the HREC agreed to a process involving anew committee called the Expedited Ethical ReviewPanel (EERP) to assist with some of the moremanagerial/administrative aspects of the ethical reviewprocess.
Finally, I would like to thank my colleague Dr RossBradbury, who chairs the Concord Hospital DrugCommittee, and all the clinicians who assist Ross in theprocess of assessing and reviewing Clinical Drug Trialsbefore they are seen by the Ethics Committee. Mythanks also go to the Pharmacy Department and theClinical Drug Trials Pharmacists who have worked sohard to make clinical trials of new drugs possible atConcord Hospital.
Dr Garry PearceChairmanConcord Human Research Ethics Committee
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Markus J SeibelIn late 2001, Professor Markus Seibeljoined Concord Hospital as Professorof Endocrinology and Head of the BoneResearch Program at the ANZACResearch Institute.
Markus, a native of Germany and France, graduatedfrom the Universities of Mainz, Germany, andPennsylvania, USA. He then trained in AnatomicalPathology (University of Freiburg and WHO CentreMainz, Germany), Rheumatology, Gerontology andRehabilitation Medicine (University of Basel,Switzerland), Immunobiochemistry and Endocrinology(Columbia University, USA) and Internal Medicine(University of Heidelberg, Germany). Markus completedhis PhD on the “Biochemical Assessment of BoneTurnover and Remodelling” in 1997 (University ofHeidelberg, Germany) and became an AssociateProfessor at the University’s Department of Medicineand the Director of the Department’s EndocrineDiagnostic Laboratories.
Markus is an advisor to national and internationalresearch foundations and a member of the scientificadvisory board of the International OsteoporosisFoundation. He is also a member of the editorialboards of several international journals.
Several of the current areas of research which are partof the Bone Research Program at the ANZACResearch Institute are described below.
Preventing The Spread Of Malignant Tumours To BoneDr Colin Dunstan, a world-recognised bone researcher,was awarded the prestigious BioFirst Award to supporthis work on the mechanisms that govern the spread ofmalignant tumours, such as breast and prostatecancer, to bone. This work uses a novel animal modelof metastatic bone disease developed by MarkusSeibel’s team in Germany.
Understanding the mechanisms of malignant spread tobone will help to develop more efficient strategies forthe prevention and treatment of these painful and oftenfatal complications of many cancers.
Genetic Influences on bone mass and bone turnoverin healthy and osteoporotic menDr Christian Meier from the University of Basel,Switzerland joined the laboratory to undertake researchon genetic factors in bone metabolism. This project iscarried out in collaboration with Professor John Eismanand the Dubbo Epidemiological Study. The project isexpected to shed light on the presently ill understoodmechanisms causing osteoporosis in men, and isexpected to provide opportunities for new and betterprevention and treatment.
Bone metabolismResearch is also underway into the mechanismsgoverning normal and abnormal bone metabolism.Using transgenic mouse models, the effects ofcortisone on bone will be evaluated. A frequent adverseoutcome of this widely used drug is severe bonedisease. A better understanding of why cortisone is sodamaging to bone will point the way to strategies forthe reversal or prevention of its detrimental effects onthe skeleton.
Bone markersAll bone diseases are characterised by changes inbone formation and in bone resorption, the two majorprocesses that keep bone alive, healthy and strong.Measurement of specific ‘bone markers’ in serum andurine determines the activity of these processes andcan help the clinician assess the severity, and monitorthe treatment of bone diseases such as osteoporosis.In collaboration with Clinical Associate ProfessorMichael Hooper, research is underway into thedevelopment and clinical validation of novel orimproved markers of bone turnover. Present studiesfocus on the evaluation of bone turnover rates in thevery elderly, the significance of androgens on bonehealth, the effect of anti-osteoporotic drugs on boneremodelling fracture rates in patients with osteoporosis,and the novel use of bisphosphonates on the healing ofprostheses used for total hip replacements.
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Robert CummingProfessor Robert Cumming hasrecently been appointed Professor ofEpidemiology and Geriatric Medicine atConcord Hospital. This newly createdChair is the first of its kind in Australiaand one of the few in the world toformally recognise the importantcontribution that epidemiology canmake to improving the health of olderpeople.
Robert graduated in medicine from the University ofNew South Wales in 1979. Following several years atPrince of Wales Hospital he worked in general practicein England and Australia before spending a year inGeriatric Medicine at War Memorial Hospital in Sydney.In 1986, Robert enrolled in the Master of Public HealthDegree at the University of Sydney. He subsequentlywon a scholarship to study at Columbia University inNew York, where his research work on health problemsof older people began. Since returning to Sydney in1990, he has worked in the School of Public Health atthe University of Sydney.
Most of Robert’s research has been in two areas: fallsand fractures in older people and age-related eyediseases, particularly cataract. He has more than 150publications and is well known for his work on the roleof calcium in prevention of fractures and theimportance of psychotropic drugs as causes of falls inolder people. He also has an international reputation forhis expertise in the design and conduct of randomizedtrials of non-pharmacological interventions forprevention of falls and fractures. Robert’s research oncataract resulted in the first paper to report anassociation between use of inhaled corticosteroids andrisk of cataract.
One of the research projects he is currently doing is arandomised trial of improving vision to prevent falls.
This project is based at Concord Hospital and willinvolve more than 1,000 people aged 70 years andover, recruited mainly from aged care services. He isalso involved in randomised trials of hip protectors andof the use of Tai Chi to prevent falls. Another project isthe Blue Mountains Eye Study, one of the world’slargest epidemiological studies of eye diseases.
Future plans include a randomized trial of fallsprevention in hospitals and a large observational studyof the health of older men.
Professor Cumming is a member of the Centre forEducation and Research on Ageing, as well as being amember of the University of Sydney’s School of PublicHealth.
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Rosemary BurkeRosemary Burke commenced asDirector of Pharmacy at ConcordHospital in 2001 after seven years asDirector of Pharmacy at theWollongong and Port KemblaHospitals. She has also worked atPrince Henry and St George Hospitals.Rosemary holds a Diploma ofEducation and is a fellow of TheSociety of Hospital Pharmacists ofAustralia (SHPA). She has beeninvolved for many years in this societyand was NSW Chairman for five years.Rosemary has also chaired the nationalcommittee of Specialty Practice inHospital Pharmacy Management and isthe current chairman of SHPA’sCommittee of Specialty Practice inMedication Safety. She is also areviewer for the Pharmacy Board’sgraduate review panel.
Rosemary’s major professional interests includeeducation of health professionals and patients, and thequality use of medicines and medication safety. Shehas also been involved in a number of projects aimedat improving the continuum of care and developingcommunication networks with General Practitioners.She has been an invited speaker at many meetings andhas presented on her areas of interest at a number ofconferences.
In 2001 Rosemary received the SHPA Neil NaismithBaxter grant which is awarded to a hospital pharmacymanager who is considered to have contributed to theprofession. With this support she undertook a study
tour of the United States focusing on the area ofmedication safety. The report of this visit has recentlybeen published in the Journal of Pharmacy Practiceand Research.
The pharmacy department at Concord has beeninvolved in a number of practice research projects oftenin collaboration with other hospitals through groupssuch as the NSW Therapeutic Assessment Group.These include drug utilisation review and collaborativeprograms for quality improvement. The hospital joinedthe 2001 International Round-table Adverse DrugEvents Improvement Collaborative (ADEIC). There werenumerous projects involving the pharmacy departmentincluding work designed to ensure safer use ofanticoagulants in the hospital.
The pharmacy department plays an important role inthe review of clinical trials at Concord Hospital. TheHospital’s Drug Ciommittee acts as the scientific reviewcommittee and the department is involved in themanagement of suspected adverse drug reactionsrelated to clinical trials. Apart from stock managementand the institutional review process, the department isinvolved in literature searches and the importation ofinvestigational drug material. Pharmacists are oftencalled on to provide advice on the design ofinvestigator initiated trials or randomisation methods.The department is able to offer aseptic reconstitutionfacilities for clinical trials based at the hospital. Thisservice can cover a number of aspects includingaseptic reconstitution, blinding of the investigator andthe design and formulation of placebos.
Recently, Rosemary has been successful in obtaining a$100 000 grant from the Australian Council for Qualityand Safety in Health Care to carry out a study whichaims to identify the reasons for adverse events fromhigh risk drugs in elderly hospitalised patients. Thestudy also aims to design strategies for preventingsimilar recurrences.
Rosemary hopes to facilitate more pharmacy practicebased research programs at Concord. The departmentis well placed to both initiate and assist with a widerange of research activities centred around medicationuse.
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Biao ZengDr Biao Zeng obtained his MBBS in1984 and Master’s degree inCardiology from Tongji MedicalUniversity, China. From 1984 to 1993he trained in Cardiology and worked inthe Research Institute of CardiovascularDisease, Union Hospital. From 1994 to1997 he was funded by the VictorChang Foundation to work in theDepartment of Cardiology, Royal NorthShore Hospital.
In 1998 Biao enrolled as a PhD candidate, under thesupervision of Dr David Brieger and Professor BenFreedman in the Department of Cardiology, ConcordHospital. He was awarded an NHMRC PostgraduateResearch Scholarship in 2000. In 2002 Biao wasawarded the poster prize by the Cardiac Society ofAustralia & New Zealand (CSANZ) for his presentationat the XIVth World Congress of Cardiology in Sydney.
Biao’s research interests include the investigation ofneutrophil mediators of fibrinolysis in plasminogenknockout mice. This research, which is described indetail on page 16, was published as a paper titled“Influence of plasminogen deficiency on thecontribution of polymorphonuclear leucocytes tofibrinogenolysis” in the Journal of Thrombosis andHaemostasis in 2002.
Biao has also been involved in research on the role ofmatrix metalloproteinases (MMPs) in patients withcoronary artery disease (described on page 15).Results from this study indicated that circulatingplasma levels of the gelatinolytic MMP-2 and MMP-9were elevated in patients with symptomatic coronarydisease. The strong correlation of MMP-9 levels withcirculating levels of high sensitivity C-reactive protein(hs-CRP), suggests MMP-9 is a more sensitive markerof the systemic inflammatory process that underlies thepathophysiology of acute coronary syndrome.
Biao’s research and clinical experience have given himbroad insights into cardiovascular disease. He hopes tocontinue his research in areas that lead to thediscovery and understanding of the mechanismsunderlying cardiac disorders.
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The ANZAC Research Institute
The ANZAC Research Institute wasestablished in 2000 on the ConcordHospital campus in conjunction withthe University of Sydney. Theestablishment of the Institute ensureddedicated research infrastructure so asto promote basic and applied medicalresearch on the Concord Hospitalcampus.
The main research theme of the ANZAC ResearchInstitute is ageing, with the long-term goal of prolongingenjoyable, independent living for the ageing population.As the only major independent biomedical researchinstitute with a primary focus on ageing, the ANZACResearch Institute aims to co-ordinate the highestquality innovative research at all levels - from public andpopulation health, to clinical research, molecularphysiology (animal models) as well as cell andmolecular biology.
Under the overall leadership of its Director, ProfessorDavid Handelsman, the major research groups of theANZAC Research Institute are:
The Andrology group (leader: Professor DavidHandelsman) is conducting research into malereproductive health, medicine and biology.
The Biogerontology group (leader: Professor David LeCouteur) is studying age-related changes in the liver. Itis proposed that these changes accelerate many of themajor diseases (such as cardiovascular disease andosteoporosis) that accompany ageing.
The Bone Biology group (leader: Professor MarkusSeibel) is studying bone disorders, especiallyosteoporosis and bone cancers.
The Neurobiology group (leader: Professor GarthNicholson) has as its major research focus theidentification of genes that cause neurodegenerativediseases.
The Respiratory group (leader: Dr Sam Lim) has beenstudying lung function and the effects of steroidtreatment in major respiratory diseases such as asthmaand chronic obstructive pulmonary disease. FollowingDr Lim’s recruitment by GlaxoSmithKline (UK) to headtheir respiratory clinical Research & Development, the Vascular Biology group (leader: AssociateProfessor Len Kritharides) has commenced research ina new laboratory. This group is studying the role ofinflammatory factors in cardiac and vascular injury andischemia, with the aim of improving early detection anddeveloping better treatments for heart disease.
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The Centre for Education andResearch on Ageing(CERA)CERA is a multidisciplinary centre thataims to improve the health and qualityof life of older people through researchinto ageing, diseases of old age andservice delivery. CERA is a joint facilityof the Aged and Extended CareDepartment of Concord Hospital andThe Department of Medicine of TheUniversity of Sydney and is involved ineducation of aged care workers andstudents in many professional areas.
CERA is staffed by geriatricians, nurses, psychologists,scientists and other professionals who work together inhealth care delivery and research. CERA’s director,Professor David Le Couteur, is a leading figure ingeriatric pharmacology and he serves on a number ofnational committees including the Australian DrugEvaluation Committee.
In addition to the provision of in-patient and ambulatorycare for Geriatric Medicine, CERA maintains a highprofile in geriatric and gerontological research. Thecentre’s research utilises laboratory, clinical andpopulation methodologies and covers a broadspectrum of issues of significance to ageing. Researchat CERA occurs in four main areas:
The ageing liver – Professor Le Couteur’s team, at itslaboratory in the ANZAC Research Institute, is studyingage-related changes in the blood vessels of the liver, asthese are thought to underlie a number of diseaseswhich increase in prevalence with age (see also p32).
In particular, the team is examining how structuralchanges in the ageing liver can predispose toatherosclerosis, heart disease and stroke, all commondiseases of the elderly. The ultimate aim of thisresearch is the development of therapeutic strategieswhich prevent blood vessel changes in the liver andconsequently prevent many of these debilitatingdiseases.
Neurodegenerative disease – The prevalence ofdementia rises steeply with age, yet Alzheimer’sdisease and other causes of cognitive decline remainpoorly understood. Dr Helen Creasey, AssociateProfessor Jillian Kril, Dr William Brooks and colleaguesat CERA are studying the clinical, psychological,genetic and pathological aspects of brain ageing anddementia in communities and clinic based populations.A major outcome of this research is improvedunderstanding of the risk factors for dementia andimproved diagnosis of dementia. Another major recentdiscovery was the particular genetic defect that causesa dementia syndrome in a family that has been studiedfor decades at CERA.
Population studies - The recent appointment ofProfessor Cumming as the Chair of Epidemiology andGeriatric Medicine has brought internationally renownedexpertise in research into falls, osteoporosis andmedication usage inolder people. Thiswork has shown theimportance ofcalcium inpreventingosteoporosis, andthe role ofmedications andvisual impairment infalls in older people.In addition, themajorepidemiologicalstudy of ageing, theSydney Older Person Study (SOPS), has continued incollaboration with Professor Broe and Dr Creasey. Thisstudy has identified risk factors for neurodegenerationand clarified health service delivery needs of olderpeople in the community.
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Residential and Community Care - This area has beendeveloped by Chris Shanley, (Assistant Director,Education and Information Services) to address thehealth care needs of older people in the communityand residential care. In particular, the work has focusedon the prevention of falls in residential care, advancedcare directives in older people (similar to “living wills”),and the organisational strategies for establishing bestpractices in residential care facilities.
PhD candidate Sarah Hilmer at work in the laboratory
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CardiologyThe Cardiology Department has astrong and varied research profile. TheDepartment undertakes clinical,laboratory-based and basic researchinto many aspects of cardiovasculardisease.
The GRACE RegistryAcute coronary syndromes, including the full spectrumfrom unstable angina to myocardial infarction (“heartattack”), represent a major cause of morbidity andmortality throughout the world. GRACE – the GlobalRegistry of Acute Coronary Events – is a large,multinational, observational study of patientshospitalised with acute coronary syndromes (ACS). The aim of GRACE is to improve the quality of care forpatients with ACS. The registry gathers information onthe relationships between patient characteristics,treatment practices, and in-hospital and post-dischargeoutcomes at hospitals around the world. A total of 94hospitals in 14 countries in North America, SouthAmerica, Europe, and Australia/New Zealand arecurrently collaborating in GRACE. In Australia and NewZealand, the study is being coordinated by Dr DavidBrieger.
Information on patient demographics, medical history,acute symptoms, clinical characteristics,electrocardiographic (ECG) findings, treatmentapproaches, and in-hospital outcomes is collected.Patients are followed up by telephone at 6 months afterhospital discharge. The information collected from theGRACE project has provided important and extensiveinsights into patient characteristics, current practicepatterns, and outcomes for patients with acutecoronary syndromes. Given the pressures of practicingevidence-based medicine in a cost-effective manner,the results of GRACE provide a multinationalperspective into these important outcomes, and identifyareas requiring improved patient care.
The SPORTIF 3 StudyAtrial fibrillation is a common condition affecting 5% ofthe population over the age of 65. The danger of thiscondition is that people with it are at a greater risk ofstroke, which can only be prevented by thinning theirblood with anticoagulants. The only orally activeanticoagulant available at present is warfarin. This is adifficult drug to use as it increases the risk of bleedingsignificantly. Furthermore the levels of warfarin in theblood are very sensitive to both diet and othermedications so the blood levels must be constantlymonitored, a major inconvenience for patients anddoctors alike. Recently a new anticoagulant, Exanta,has been developed which appears to be safer andcan therefore be used without monitoring. TheSPORTIF 3 study is an international trial in 4,000patients which compares treatment with warfarinversus Exanta. In Australia, this study is beingconducted out of Concord Hospital under the directionof Dr David Brieger. Promising preliminary resultssuggest that this new therapy should be available in thenear future.
EchocardiographyDr Kevin Fung, under the supervision of AssociateProfessor Len Kritharides, has investigated whethernew ultrasound techniques can detect very mild andpreviously undetectable degrees of heart muscledamage. He found that reversible and irreversibleweakness of the heart muscle can be detected usingthe technique of Tissue Doppler, and applied thistechnique to study patients undergoing electrical shockto revert abnormal heart rhythm. In addition, in acollaborative study with Clinical Associate ProfessorAlastair Corbett from the Department of Neurology, heinvestigated patients with myotonic dystrophy, adisease which causes widespread weakness of themuscles. It was found that Tissue Doppler could detecta reduction in heart muscle function well beforeweakness could be detected by conventionaltechniques.
Liver Dysfunction in Heart FailureIn this study, Dr George Lau and Associate ProfessorLen Kritharides are investigating the build up of fluid inthe liver which occurs in patients with heart failure. Theability to diagnose such build up would be improved byknowing the patterns of damage which are typical of
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fluid build up, and the cardiac factors which contributeto it. This study to date has shown that the pattern ofbiochemical damage is the same as the pattern seen inpatients with blockage of bile flow. Furthermore thebiochemical changes are directly related to the severityof leakage across one of the heart valves, the tricuspidvalve. This result may allow doctors to use liver imagingtests more sparingly and save patients inconvenienceand time.
Investigation of matrix metalloproteinases in patientswith coronary disease.Matrix metalloproteinases (MMPs) are enzymesinvolved in the breakdown of extracellular matrixcomponents and have been implicated in both thedevelopment of atherosclerosis and in plaque rupture inacute coronary syndromes. However, few studies haveexamined the association between circulating MMPsand symptomatic coronary artery disease. Dr David Brieger and colleagues measured plasmaactivities of MMP-9 and MMP-2 in healthy controls, andin patients with unstable and stable angina. In patientswith stable angina, MMP-9 levels were significantlyelevated relative to controls. In unstable anginapatients, levels of both MMPs were significantlyelevated relative to controls and patients with stableangina. This incremental elevation in patients withunstable angina may be of diagnostic utility andsupports the role of MMPs in the pathogenesis ofunstable coronary syndromes. Further studiesinvestigating the mechanism and clinical significance ofthese findings are planned.
Minimally-Invasive Detection of Coronary Artery DiseaseComputer tomography (CT) is a minimally-invasivetechnique to image coronary arteries. Recentrefinements in image acquisition and analysis arecurrently being evaluated by the research team ofAssociate Professor Len Kritharides, Dr George Lauand Dr Lloyd Ridley from the Department of Radiology.
In this study patients underwent conventional coronaryangiography followed by CT coronary angiography.The conventional angiographs and the CT angiographswere assessed to identify coronary vessels which haveblockages (stenoses). Using the new CT method,stenoses were identified with 88% accuracy, with lowerrisk and inconvenience to the patients than
conventional angiography. This technique will allow theaccurate assessment and classification of coronaryartery disease in the majority of patients.
Three-dimensional image of the heart by computertomography (CT)
A study patient having a cardiac CT scan
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Investigation of neutrophil mediated fibrinolysis inplasminogen knock out mice.When blood clots (thrombi) form they are broken downby a process called fibrinolysis which most commonlyoccurs due to a protein called plasminogen. If noplasminogen is present then clots cannot be lysed. Inorder to study alternative, non-plasminogen dependentmechanisms of fibrinolysis, mice were bred which donot make any plasminogen (Plasminogen knock-outmice). In these mice it has been found that whiteblood cells contain non-plasmin fibrinolytic proteases,however the degree to which these cells contribute toclot degradation in these animals is not known.
Thrombi were generated in carotid arteries and jugularveins of knock-out and normal (wild type) mice by theapplication of a ferric chloride solution. White bloodcells quickly accumulated in the thrombus and agreater number were retained within the thrombi ofknock-out mice compared to the wild type miceproviding the potential for more fibrinolytic enzymes tobe present. In addition the researchers, PhD studentBiao Zeng and Dr David Brieger, showed that whiteblood cells extracted from knock-out mice were able tobreak down fibrinogen to a greater extent than cellsfrom wild type mice and that the fibrinogen breakdownproducts were distinct in the knock outs. These resultssuggest that a relatively greater role for white bloodcell-initiated fibrinolysis exists in the setting ofplasminogen deficiency.
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The Burns Unit The Burns Unit at Concord Hospitalwas established as a statewide referralcentre for burns injuries by the NSWDepartment of Health in the late1980’s. The Unit provides specialisedtreatment to complex burns casesunder the directorship of Dr Peter Maitzin collaboration with Dr Peter Haertsch,Head of Plastic and ReconstructiveSurgery. The Unit will soon move into anew location on the seventh floor of theMulti building. Here it will have a 17-bed treatment centre, dedicatedOperating Theatre and a new skinlaboratory. A multi-disciplinary team ofresearchers carries out its work in theBurns Unit
The Skin Culture LaboratoryThe Burns Unit tissue culture laboratory wasestablished in 2001 to provide tissue for skinregeneration in severe burns patients. The laboratoryhas developed procedures for skin cell replacement(keratinocyte grafting), for the treatment of existingscars and the late resurfacing of burn wounds.
Keratinocyte grafts are prepared from healthy cellstaken from an unaffected area of the patient and grownin the laboratory under specialised conditions (cellculturing). These are used to form skin sheets, or putinto a liquid to spray over the surface of the wound,providing rapid healing with little scarring. Work in thislaboratory has shown that the cultured skin sheetsneeded to resurface 20-25% of the body area can beproduced in 16-18 days, and sheets to cover 90% ofthe body area can be made in 23-25 days. When cellsprays are used, it takes less than 2 weeks to culturecells to cover 25% of the body surface.
The laboratory has also prepared suspensions of cells,harvested from the patient, and sprayed themimmediately onto the patient, without culture. Thesesprays are suitable for small area injury such as harvestsites, and have the advantage of also containing othertypes of skin cells including those which produce thepigment in skin (melanocytes), so that the natural skincolour is preserved.
As well as providing this clinical service for patients inConcord Hospital, the laboratory is working atimproving both the clinical outcome of using culturedskin and the skin culture process. For the bestcosmetic outcome, the cells should be applied to thewound as soon as possible after injury and thelaboratory is working towards speeding up cellproduction time by growing islands of healthy cells onmembranes or dressings which can be applied directlyto the patient soon after injury. In this way the wound isclosed whilst new skin is developing.
Other uses for keratinocyte grafts to be explored in thefuture include their use as biological dressings for thetreatment of chronic skin disorders, such as vascularand diabetic ulcers, congenital navei and smallepidermal injuries.
Investigations into skin graft infection and graft survivalAnother focus of research interest in the Burns Unit hasbeen in the area of skin graft infection.
Currently, the key surgical intervention in severelyburned patients is the replacement of burned skin withskin grafts taken from healthy skin elsewhere on thesame patient. Early excision of deep burns andimmediate skin grafting have been shown to reducefatality rates in severely burned patients, and improvefunctional outcomes by reducing scarring. Skin graftsurvival is important for good functional and cosmeticresults and, in severely burned patients, for patientsurvival.
It is well recognised that infection is an important causeof graft failure in burn wounds. A study was undertakento examine whether there is a clinically importantassociation between biopsy evidence of infection intissues underneath burned skin that has just beensurgically removed, and subsequent skin graft survival.
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Biopsies were examined histologically and weresubmitted for microbiological cultures. Subsequently,percent skin graft survival, graft infection, episodes ofbacteraemia, and length of hospital stay were recordedfor each subject.
Only a small proportion of patients’ biopsies grew anyorganisms at all. The remainder of the biopsies showedno organisms, and only mild inflammation, consistentwith a burn injury. The culture results did not correlatewith skin grafting outcome. Of those with a positiveculture only one (which grew S.aureus) required repeatskin grafting. Meanwhile, several patients who didrequire repeat grafting had biopsies which werenegative on culture. The biopsies, therefore, do notappear to predict the risk of graft failure. Clearly thereare other factors that have more influence on graftoutcome. These may include general factors such aspatient age, and local factors such as size and locationof wounds.
Physiotherapy research in the Burns UnitOver the past five years, a number of projects havebeen conducted by the Senior Burns Physiotherapist,Dr Frank Li, to improve patient care.
It was observed that many burns patients with skingrafts to their hands showed a significant decrease inrange of hand motion and strength when reviewed inthe out-patient clinic 6 weeks after discharge. A studywas conducted to test grip strength using a hand helddynamometer. All patients with skin grafts to theirhand(s) were tested at regular intervals for 3 months. Itwas found that their grip strength improved steadilyafter surgery until about 2 weeks after discharge, thena decline occurred. Unless the patient had regular handtherapy treatment, the decline would continue for 4 to6 weeks. The results demonstrated that this group ofpatients requires regular follow-up for at least the firstthree months following their discharge.
Burns patients experience a great deal of painthroughout their recovery phase and are reluctant toexercise because movement aggravates the pain.Physiotherapy treatment targets this problem by aprogram of daily stretching exercises. In order to walkproperly, a range of movement of the knee of about120 degrees is required. A Continuous Passive Motion
machine, which is used by patients with Total KneeReplacement to improve knee range, was trialled onburn patients. Patients with lower limb burns, whorequired skin grafts to both legs, were invited toparticipate in the study. The Continuous Passive Motionmachine was used on one leg while the other legreceived passive stretches only. The results indicatedthat there was no difference in terms of rangeachieved. However, the patients felt less pain with theuse of the Continuous Passive Motion machine. Thispositive result supports the proposal to purchaseContinuous Passive Motion machines in thedevelopment of the burns service in New South Wales.
Occupational Therapy in the Burns UnitScar management is one of the major tasks in thelong-term management of burn patients. Thetherapeutic value of customised pressure garments inthe management of scarring after burn injury is welldocumented. However, most patients find pressuregarments uncomfortable to wear. Researchers, MichelleCarne and Cheree Walker, are undertaking a study toidentify the most appropriate and cost effectivepressure garment manufacturer from 3 major Australiansuppliers. Participants in the study compare twodifferent brands of pressure garment by wearing themon alternate days and completing satisfactionquestionnaires after 2 weeks and 3 months. Theoccupational therapist also makes an evaluation of theeffectiveness of the garment, and results on theoutcome will be available in 2003.
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Breast Cancer
Last year in NSW, over 4000 newcases of breast cancer werediagnosed. Concord Hospitalresearchers are involved in researchstudies which look at promising newapproaches to improve breast cancertreatment and quality of life.
Treating Cancer with ChemotherapySydney Cancer Centre at Concord Hospital is an activeparticipant in international breast cancer research trials,accruing patients from both Concord Hospital andStrathfield Private Hospital. These trials are called‘adjuvant’ therapy trials, which means that they aretesting the value of additional treatment after surgeryfor breast cancer. Giving treatment at this time canimprove the chance of cure.
In 2000-2001, 17 women were recruited toInternational Breast Cancer Study Group trial 20, whichcompared a standard adjuvant chemotherapy toadjuvant chemotherapy including the new drugdocetaxel, in women with breast cancer that hadspread to lymph nodes in the axilla (armpit). The trial is
now closed and the first results should be available inMay 2004.
Currently, Concord Hospital is involved in two BreastCancer International Research Group (BCIRG) trials.Trial 6 is examining the addition of Herceptin® tochemotherapy for women with breast cancer which ispositive for the HER2 oncogene (15 – 20% of all breastcancers). It is known that breast cancers positive forHER2 are more aggressive, and have a worseprognosis. Herceptin® is an antibody which binds withand inhibits HER2. It has been shown to be ofsignificant benefit to women with metastatic breastcancer, and the current research is examining its role inaddition to adjuvant chemotherapy in an internationalrandomized trial. Internationally, 700 women are alreadyparticipating and accrual will be complete in about 12months when just over 3000 women will be enrolled.
In 80% of women breast cancer is negative for HER2.These patients are offered participation in BCIRG trial 5,which is testing sequences of giving chemotherapydrugs. Internationally, 1,800 women are alreadyparticipating and accrual will be complete by the middleof 2003 when just over 3000 women will be enrolled.
Research into Surgery for Breast Cancer: The “SNAC” TRIALThe major morbidity from surgery for breast cancer isrelated to removal of the lymph glands in the armpit (or axilla).
The SNAC (Sentinel Node biopsy vs Axillary Clearance)trial has been set up with a view to minimising theextent of surgery in this area. The trial is being carriedout in hospitals around Australia under the auspices ofthe Royal Australasian College of Surgeons and theNational Health and Medical Research Council ClinicalTrials Centre. At Concord, the trial is being carried outby Professor David Gillett and his colleagues from theDepartment of Surgery. Approximately 5 percent of thepatients involved in the study have come from thebreast service at Concord Hospital and StrathfieldPrivate Hospital.
In 60 to 70 percent of breast cancer patients theaxillary nodes are not affected by metastatic cancerand, therefore, do not require removal. It is essential,
Appearing from left to right: Ms Lili Truong (Clinical TrialsData Manager), Mrs Sumitra Nidagal (receiving Herceptintreatment), Dr Anne Sullivan (Oncologist), Ms ChantalGebbie (Clinical Trials Nurse)
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however, to know if these glands contain cancer or notand in the past, it has been practice to remove at leasttwo thirds of them to determine the likelihood of theirinvolvement.
The SNAC trial has been set up using a technique todefine the pathways along which cancer cells will travelfrom the tumour to the lymph glands and to define themost significant lymph gland or sentinel node. It isbelieved that if this gland is free of tumour all the otherglands will be free of tumour and that removing onlythis gland will adequately determine the status of theaxillary nodes in general. It is proposed that removingone gland will produce much less morbidity thanremoving two thirds of the glands. Preliminary studieshave indicated this to be the case and the SNAC trial isa randomised prospective trial to conclusively provethat the patients are not disadvantaged by having onlythis gland removed (if it is free of tumour) and nothaving any treatment to the other glands in the axilla.
To date some 600 patients have been randomised intothis trial. It is expected that accrual of 1000 women willbe complete towards the end of 2003. The initial dataanalysis has been done and shows that the sentinelnode can be identified in 100 percent of cases and thatcancer has been detected in 30 percent of patients asexpected.
The success of this trial is dependant on cooperationbetween the surgeons, the radiologists and the NuclearMedicine personnel who inject radioactive material nextto the tumour to define and mark the sentinel node.
Quality of Life for patients with Breast CancerResearch into treatments for breast cancer involves notonly measures which improve patient’s length of life butalso their quality of life.
Minh Arvin, Clinical Nurse Consultant for BreastSurgery at Concord Hospital has been looking at thequality of life for women receiving Tamoxifen adjuvanttherapy following surgical management of breastcancer.
Patients were surveyed for sociodemographicinformation (age, marital status, level of education,employment status, number and age of children,
menopausal status) and information relating to theirbreast cancer history. At the same time, patients wereasked about their quality of life, physical symptoms,general and psychosocial well-being and dailyfunctioning. Information was collected from patientsregarding their Tamoxifen treatment (eg side effects),how they adjusted to their breast cancer diagnosis andtreatment, and the effect of both on family and friends.A majority of women with breast cancer who wereprescribed Tamoxifen did well following the completionof their surgery and chemotherapy. This informationmay be helpful for newly diagnosed women, and forwomen facing the end of treatment. However healthcarers should be alert for continuing symptoms ofdistress in follow-up care, such as symptoms ofdepression or social dysfunction. Early intervention mayhelp to reduce subsequent problems. Interventions,such as stress management, relaxation, counseling andsupport for the family can improve mood, physicalfunctioning and quality of life in breast cancer patients.
Many women complained of menopausal symptomswith Tamoxifen. These included fatigue, hot flushes,sleep disturbance and depression. Although mostwomen tolerate these symptoms and are able toremain active, others find it can have an impact ontheir quality of life or functional ability. Some womenhave considered discontinuing therapy, or have beenless compliant with their daily Tamoxifen regimen.
Many women experienced positive effects from breastcancer. Coming to some understanding of and findinga new sense of meaning in their illness experience maybe an important aspect of the recovery process. Thesewomen have developed personal resources and skills,and their positive attitudes greatly enhance their copingand adjustment. Many women reported improvedoutlook on life and stronger interpersonal relationships.
It is hoped that the results of this study can be used toinform clinicians, researchers and breast cancersurvivors about the longer-term impact of Tamoxifen onhealth and related quality of life.
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Brain Diseases Researchers from the Department ofNeurology, Molecular Medicine and theCentre for Education and Research onAgeing (CERA) are investigatingdiseases of the brain which occur morefrquently as we age.
Parkinson’s DiseaseThe Parkinson’s Disease Clinic in the Department ofNeurology offers a comprehensive multi-disciplinaryservice to patients and their carers, and provides afocus for clinical research into the disease.
The clinic’s director, Dr Michael Hayes, in collaborationwith researchers from both within the hospital andoutside, is looking at ways of measuring neuronal(nerve cell) damage in patients with Parkinson’sDisease. These studies include blood tests, magneticresonance imaging (MRI) and a smell test, since theloss of smell is an early finding in many patients withParkinson’s Disease. Early diagnosis of Parkinson’sDisease will become very important once more effectivetreatment is available.
The Parkinson’s Disease clinic is also involved in twointernational, multi-centre, Phase III, randomised,placebo-controlled trials of new drugs. Both of thesedrugs act to stimulate chemicals in the brain which aredepleted in Parkinson’s Disease (the dopamine system).One of the studies involves patients whose response tostandard therapy has become less predictable andrequires supplementation. The other is aimed at peoplewith early Parkinson’s Disease who have had little drugexposure and are being tested with a medication in theform of a patch that is only changed once daily. Bothstudies are funded by major pharmaceutical companiesand offer valuable opportunities for Parkinson’s Diseaseresearch. Patients have access to drugs that are nototherwise available in this country and they usuallylearn more about their condition; doctors get first-handexperience in assessing new medications and if thedrugs prove to be useful this local experience is likely to
assist in getting PBS approval.
The pathogenesis of Parkinson’s Disease is also beingstudied by the Molecular Medicine Laboratory, underthe direction of Professor Garth Nicholson, who isresearching the genetics of the disease. Only a fewcausative mutations for Parkinson’s Disease have beenidentified, including one in the so-called parkin gene.Researchers are screening the parkin gene fordeletions, which may cause a sporadic (or therecessive) form of Parkinson’s Disease. To date theyhave found some undescribed mutations which may bea cause of isolated cases of Parkinson’s Disease.
StrokeThe Stroke Unit and Stroke Service at ConcordHospital were established in 1996, the second of theirkind in NSW. The Stroke Unit, directed by ClinicalAssociate Professor Alastair Corbett, has facilitated thestudy of patients with stroke and has participated in anumber of national and international trials for themanagement and prevention of stroke. Currently theunit is participating in two international, multi-centredrug trials. One study is assessing the potentialbenefits of the antihypertensive drug Ramipril (a drugwhich lowers blood pressure) by itself, or incombination with another antihypertensive drugTelmisartan. Another study is investigating theusefulness of Telmisartan alone in preventing strokeand other vascular complications in patients who havealready experienced stroke or myocardial infarction(heart attack).
The Stroke Service is also assessing improvedmethods for patient management and looking at someof the outcomes of stroke, including vascular dementia.
Vascular DementiaAssociate Professor Jillian Kril from the Centre forEducation and Research on Ageing (CERA) incollaboration with Associate Professor Corbett andother neurologists and geriatricians across NSW, isstudying brain pathology in patients with vasculardementia. Professor Kril and colleagues run a braindonor program where interested individuals consent tothe use of their brain for research following their death.This program, which has been running for over tenyears, studies patients with a variety of
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neurodegenerative disorders such as Alzheimer’sdisease and Parkinson’s disease as well as those withstroke. The program also looks at the brains of normal,aged subjects.
Recently, Professor Kril and colleagues have shownthat one of the primary memory areas of the brain, thehippocampus, undergoes substantial degeneration invascular dementia. It was previously thought that thisregion, which is markedly damaged in Alzheimer’sdisease, is spared in vascular dementia. However, theresults of this study suggest that memory impairment isa feature of vascular dementia and that significantoverlap in clinical symptoms between Alzheimer’sdisease and vascular dementia might be expected.
A computer tomography (CT) scan of the brain of a patientwho has had a number of strokes.
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Respiratory DiseasesChronic Obstructive Pulmonary Disease (COPD) is a lifelonginflammatory disorder of the lungs thatis ranked third behind heart diseaseand stroke as a major cause ofdisability and early death in Australia.The prevalence, morbidity and mortalityof COPD are increasing in manywestern countries. COPD results in thedeaths of over 5000 patients per yearin Australia and serious disability occursin many more. Chronic cigarettesmoking is the main cause of COPD.Currently, there is no cure for COPDnor is there any treatment available toreverse the lung damage or the declinein lung function.COPD is one of the major focuses ofresearch carried out in RespiratoryMedicine at Concord Hospital.
Cell culture experimentation: The Expression of MatrixMetalloproteinases (MMPs), Tissue Inhibitors ofMetalloproteinases (TIMPs) and Cytokines from AlveolarMacrophages in COPD.Inflammatory cells in the lung called alveolarmacrophages are increased in number in the lungs ofthose who smoke. These cells can producesubstances called cytokines and matrixmetalloproteinases (MMPs), which can destroy the lungtissue and thus may be important in the developmentof COPD. Tissue inhibitors of metalloproteinases(TIMPs), also produced by alveolar macrophages,inhibit the action of MMPs and thus may be protectiveagainst lung damage.Dr Linda Seeto is investigating whether there is an
overproduction of pro-inflammatory cytokines andMMPs and/or an imbalance between the pro- and anti-inflammatory substances produced in the lung incigarette smokers who develop this disease (seeFigures 1 and 2).
Alveolar macrophages are harvested from two sources:lung specimens removed during surgery and lungwashings performed via fibreoptic bronchoscopy. Thecells are cultured in the laboratory and stimulated withvarious drugs including steroids, bronchodilators, andbeta-blockers which inhibit the effect ofbronchodilators. Levels and activity of MMPs andTIMPs are measured by two techniques: enzymelinked immunosorbent assay and zymography.Cytokine levels are measured by the former.
MMP-9
MMP-2
Figure 1: MATRIX METALLOPROTEINASES (MMPs) IN COPD SUBJECTZymogram showing areas of enzymatic digestion by MMPs (white bands) fromlung macrophages from a patient with COPD. The band size reflects theamount of enzymatic activity. Pro-MMP in vivo is the inactive form of MMP-2.
MMP-9
MMP-2
Figure 2: MATRIX METALLOPROTEINASES (MMPs) IN CONTROL SUBJECTZymogram showing MMP activity from lung macrophages from a subjectwithout COPD. Smaller band size reflects lower levels of enzymatic activity.
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A clinical study of theophylline as treatment for COPDTheophylline has been shown to be effective in dilatingthe airways in people with asthma. Although aninexpensive and effective drug, theophylline can beassociated with side effects such as gastrointestinalupset and abnormal heart rhythms. In cell culturestudies, theophylline has been shown to be anti-inflammatory at doses below that required for airwaydilatation in people with asthma.
Dr Seeto’s study, the first of its kind, seeks to definechanges in lung function, quality of life, and airwayinflammation due to theophylline treatment versusplacebo in subjects with COPD. If theophylline is shownto be anti-inflammatory in people with COPD, this willbe the first evidence in clinical trials that it can be usefulin the management of patients with COPD for its anti-inflammatory effect.
Laryngopharyngeal Sensitivity in COPDMembers of the Concord Hospital RespiratoryInvestigation Unit have been using a multi-disciplinaryapproach to investigating the relationship betweenswallowing function and COPD. This research is beingcarried out by Nicola Clayton (Speech Pathology) andrespiratory physicians, Clinical Associate ProfessorMatthew Peters and Dr Alvin Ing.
Preliminary studies have shown that swallowingfunction is impaired in patients with COPD, and thismay lead to increased pulmonary infection throughaspiration and inhalation of food and gastric contents.Pulmonary infection is regarded as a major cause ofCOPD exacerbation, and a major factor in the declineof lung function and increased morbidity in thesepatients.
The aims of this study were to use a newly developedtechnique to assess the degree of swallowingimpairment in patients with COPD as well as to assesslaryngeal sensitivity. The ultimate aim is to establish asimple method of assessing swallowing function andaspiration risk at the bedside.
Patients with COPD underwent the new techniqueknown as Fibreoptic Endoscopic Evaluation ofLaryngeal Sensitivity and Swallowing (FEELSS). Thisprocedure involves the delivery of a quantifiable pulseof air to the larynx via a fibreoptic nasoendoscope,which then induces the Laryngeal Adductor Reflex(LAR). The LAR is an airway protective mechanism andis assessed by the visualization of the vocal cordsadducting (drawing together). In normal subjects an airpulse of 2.5 to 4.5 mmHg is sufficient to induce theLAR. In patients with COPD, air pulses of 9.9 mmHgwere required to induce the LAR. This implies COPDpatients have impaired laryngeal sensitivity and are atrisk of aspiration and recurrent pulmonary infection.
The second part of the study involves assessment ofswallowing. Under direct visualisation of the larynx viathe nasoendoscope, COPD patients swallowed fluidand solids of varying consistency. The passage of foodand fluid into the oesophagus was directly observed.Evidence of laryngeal penetration (material entering thelaryngeal vestibule above the level of the vocal cords)and aspiration was observed and recorded. COPDpatients were found to have a higher incidence ofaspiration and swallowing difficulties than controlsubjects.
This study found that COPD patients have impairedlaryngeal sensitivity and impaired swallowing function,which places them at risk of recurrent pulmonaryinfection. The researchers also found that this newtechnique is reliable and easy to use in the wardsituation. By applying this technique to a larger groupof COPD patients, they hope to predict which patientsare at risk of recurrent infection and COPDexacerbations, and prevent this with diet modificationsand swallowing therapy.
A volunteer undergoingthe FEELSS test
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Asthma
Asthma is a major focus of respiratory research atConcord Hospital. Associate Professor Matthew Petersfrom the Department of Thoracic Medicine is co-ordinating a series of clinical trials looking at newtreatments which may lead to improvements in themanagement of this complex disease.
One such trial is investigating a new drug which acts byblocking a specific enzyme involved in the inflammatoryprocess of asthma (called phosphodiesterase 4). In asecond trial another new type of anti-inflammatorymedication (aimed at blocking specific inflammatorycells and their proteins) will be tested in people withmild to moderate asthma. Both trials will usemedication in tablet-form, and not the traditional inhaleror "puffer" form.
In a third clinical trial, also commenced in 2003, a newinhaled preventer medication will be assessed todetermine its effectiveness in asthma management. Asecond aim of this study is to examine the frequencyand occurrence of side effects from the medication incomparison to other inhaled steroids currently availableon prescription.
A nurse initiated discharge plan in the EmergencyDepartment to improve the management of patientswith asthmaAsthma is a significant problem in the community, withone in ten adults affected by the disorder. Over 20,000asthma admissions to hospital are recorded nationallyevery year. Of these, 9% will be readmitted within 28days and 34% within one year, resulting in considerableeconomic costs.A team of researchers led by Julie Munro and MargoRichardson have undertaken a study to try and reducehospital re-presentations due to asthma, following theimplementation of a nurse-initiated discharge plan inthe Emergency Department. The discharge planconsists of an education program for staff andpatients, the provision of an individualised AsthmaAction Plan, education on correct use of medicationdevices and peak flow meters, a follow up medicalappointment and a nurse follow up phone call 2-3 dayspost discharge.
A retrospective medical record audit will establish past
management practices and re-presentation rates to theemergency department, and these will be comparedwith data from those patients who have received thespecialised discharge plan. It is hoped that this will a)increase the number of patients with asthma who havean Asthma Action Plan and regular medical follow up,and b) decrease the number of patients with asthmawho re-present to the emergency department. Findingsfrom this study could also be used to influence policyand practice related to discharge planning in theEmergency Department.
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AndrologyThe Department of Andrology atConcord Hospital is the firstDepartment of its type in Australiacatering specifically to men’sreproductive health.
Therapeutic use of androgen in the older manThe Department has performed a number of novelstudies examining the therapeutic use of androgen(male hormone) in older men as a way to potentiallyreduce frailty and disability. These studies aim todetermine whether androgen therapy can improvequality of life for community-living, healthy older men by improving physical functioning (including enhancedmuscle strength) or by improving balance and walkingendurance. Importantly the safety of such treatmentwas also of prime importance in these studies.
In a series of clinical trials of 3 months duration, twonovel hormone preparations were studied: (1) the mostpowerful naturally occurring androgen(dihydrotestosterone) made into a gel to allow dailyadministration on the skin and (2) a new, geneticallyengineered, hormone (hCG), not yet available forroutine treatment, which can be conveniently self-administered twice weekly. These studies used aspecial design, called randomised placebo controlleddesign. This guarantees that they are of the highestquality and most persuasive to the peer scientificcommunity. In both studies, an increase in muscle anda reduction in fat were found. But the improvement inmuscle strength was only modest and there was nodetectable change in physical function. The studiesshowed that in the short term, these treatments causedno adverse effects on either the cardiovascular systemor the prostate.
In another important study (also a randomised placebocontrolled study) the Andrology group examined ingreater detail the potential safety of high dose standardtestosterone injections on sleep and breathing in oldermen. They showed for the first time that high dosetherapy could shorten sleep and worsen breathing in
community-living, healthy older men thereby raisingsafety concerns regarding high dose standardtestosterone injection therapy. This study was honoredby an invitation for presentation as the first of only 4oral presentations, at the prestigious Clinical TrialsSymposium of the US Endocrine Society AnnualScientific Meeting in San Francisco, California.
Male Hormonal ContraceptionThe staff of the Department of Andrology have beeninvolved in groundbreaking studies to develop ahormonal male contraceptive over the last 15 years.Currently the only male contraceptive methods arecondoms, vasectomy, abstinence and the withdrawalmethod. None are ideal: vasectomy is reliable but notreadily reversible; condom use and withdrawal are oftenunreliable and not popular among couples in stablerelationships. For these reasons, there is a pressingneed to develop a male contraceptive method which isreversible, reliable and safe. Such a method wouldallow couples to share more equally in family planningresponsibilities. Landmark studies performed under theauspices of the World Health Organisation (WHO), withthe Department of Andrology as its largest centre,proved during the 1980’s and 1990’s that a safe andreversible male hormonal contraceptive was feasible.Although successful, this early study required weeklyinjections of testosterone, and was therefore impracticalfor community use.
Since then, the researchers have pursued the idea ofusing depot combination hormonal preparations. Thesepreparations are combinations of 2 or more hormonesand are long acting. (Instead of weekly injections, onlya single visit to a clinic every 4 months for treatment isrequired).
A two-centre Australian study, led by the Department ofAndrology, has recently completed a study of thecombination hormonal preparation and establishedclearly that the approach is feasible. This new treatmentproved much more effective than condom use, and atleast as reliable as female hormonal contraception. Thisresearch is a major contribution to the development ofa practical male contraceptive. Future practicaldevelopments of contraceptive products will requirepharmaceutical company involvement, now thatacademic researchers have proved that a safe, depothormonal male contraceptive is feasible and effective.
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Urology ResearchOne in five people over 40 may sufferfrom urinary frequency, urgency orincontinence, a condition termed the‘overactive’ or ‘unstable’ bladder.Although medical disorders such asstroke, Parkinson’s Disease or spinalcord injury may cause symptoms of theoveractive bladder, in the majority ofpeople the cause is unknown.
The ultrastructural basis of voiding dysfunctionThe Detrusor Ultrastructure Group, led by Dr LewisChan and comprising members of the UrologyDepartment, the Electron Microscopy Unit, andscientists from the University of Sydney, has beeninvestigating the cause of this common and oftendebilitating disease.
The project “Ultrastructural Basis of VoidingDysfunction” has been focusing on the structure of the
The project “Ultrastructural Basis of VoidingDysfunction” has been focusing on the structure of thebladder muscle in normal and overactive bladders.Using the electron microscope, this group hasdemonstrated the presence of abnormal connectionsbetween bladder muscle cells in patients withoveractive bladder (see Figure 1).
It is postulated that these abnormal ‘gap junctions’ mayact as short circuits and allow electrical activity in amuscle to spread to its neighbours and cause aninvoluntary bladder contraction resulting in urgency orurge incontinence.
The group’s recent study using a molecular biologytechnique has demonstrated that there are higher levelsof gap junctional proteins (called connexins) in theseunstable bladders. The researchers are currently tryingto identify the exact type of connexin protein present atthese abnormal gap junctions. In future, drugstargeting these proteins may offer a novel treatment forpatients with overactive bladder.
A view of the bladder under theelectron microscope. Protrusion and Ultracloseabutment junctions arepostulated to act as lowresistance electrical pathwayswhich may play a role in thepathophysiology of detrusorinstability. (x 29900)
Types of JunctionsProtrusion ( )Ultraclose abutment ( )Normal intercellular ( )
FIGURE 1
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Research into Pain ReliefSeveral teams of investigators atConcord Hospital, from a number ofdisciplines, are undertaking researchinto pain and pain relief.
Prevalence of pain in a teaching hospital (Departmentof Palliative Care)A number of studies in the past have suggested thatmany patients in hospital experience pain. Dr GhauriAggarwal and colleagues from the Department ofPalliative Care are investigating this finding to establishhow common pain is at Concord Hospital. They areinterested in whether patients report pain to nursing ormedical staff, and if so, whether adequate pain relief(analgesia) is used.
In addition, the researchers are using an interview-stylequestionnaire called the brief pain inventory as well as aself-administered questionnaire to look at the impact ofpain on the functional ability of the patient. Medicalstudents are involved in administering part of thequestionnaire, including recording patientcharacteristics.
Early results of the study indicate that about 60% ofpatients in hospital experience pain. This pain is mild tomoderate in intensity and interferes with quality of life toa moderate degree. However, under-treatment withanalgesics or under-reporting of pain to medical staff isnot common. Studies of this type allow researchers toassess the adequacy of pain management in thehospital setting.
Continuous wound infusion with ropivacaine usingthe OnQ/Painbuster system following thoracotomy(Department of Anaesthetics and Pain Management)In 2001 Dr Janet Smith, from the Department ofAnaesthetics led a team of investigators which trialled anew pain management procedure followingthoracotomy.
Thoracotomy (an incision to the chest wall made duringsurgery) is a very painful procedure, and it is oftennecessary to use several different types of analgesia tomake patients as comfortable as possible (multimodalanalgesia). The mainstay of analgesia is morphine, oranother similar opioid, usually delivered by a patient-controlled analgesia machine, but in addition localanaesthetics (intercostal nerve blocks) are also usedwhich anaesthetise the wound for several hourspostoperatively. Once the blocks wear off, opioid drugsused alone in sufficient doses to control the pain oftenproduce unpleasant side effects such as nausea,vomiting, or drowsiness.
This study aimed to see whether the continuousinfusion of ropivacaine (a long-acting local anaesthetic)into the wound for 2-3 days would increase patientcomfort, and decrease the amount of morphineneeded. The invesigtators used a simple, commerciallyavailable infusion device, the OnQ™ device (which isnow marketed as Painbuster™). The device consists ofa distensible elastomeric balloon, which infuses drug ata constant rate through a simple restrictor tubing(Figure 1).
The investigators studied a total of 40 patients who hadcatheters placed in the posterior part of their wounds,near the intercostal nerve, before the wound wasclosed. Half the patients received ropivacaine, and halfreceived normal saline at a rate of 5mls/hour via thecatheter for 2-3 days after their operation. All patientswere able to use as much morphine as needed fromtheir patient-controlled analgesia machine. Theinvestigators collected information on how much painthe patients had (using pain scores at rest and oncoughing), how much morphine was used on each ofthe first two days, and what side effects occurred.
Mr Arthur Darnley ofAuburn received bothpatient-controlledanalgesia (opioid) andlocal anaestheticdelivered by thePainbuster device tooptimise analgesia afterhis operation.
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Physiotherapists assessed how well the patientsperformed physiotherapy, and patients were also askedto rate how easily they could do their physiotherapy,which is an important part of recovery from theprocedure.
The study found that a much higher proportion ofpatients receiving ropivacaine were able to use very lowamounts of morphine, and had far fewer side effects(Figure 2). The physiotherapists did not detect anydifference in actual performance of physiotherapy, but a higher proportion of patients receiving ropivacaine
reported finding physiotherapy easy or very easy to perform. There were no complications or side effectsattributed to the infusions.
This study has demonstrated a safe, simple andeffective way to improve patient comfort afterthoracotomy
Pain relief following back surgery (Department of Neurosurgery)The success rate for the surgical treatment of rupturedlumbar discs is directly related to the early mobilisationof the patient after surgery. This in turn is related to theeffectiveness of post-surgical analgesia. Currentmethods of pain control are generally effective, buthave less desirable side effects such as making therecipient drowsy.
It has long been known that morphine applied directlyto the spinal region (epidural space) is an effectiveanalgesic, but it is rapidly absorbed and has a shortduration of action. One of the risks of this type ofdelivery is suppression of respiration. Morphine mayinstead be delivered by a tube into the region, but thismethod introduces the risk of infection.
The present study being conducted by ClinicalAssociate Professor Noel Dan and colleagues from theDepartment of Neurosurgery, is testing a morphinepaste applied directly to the epidural space. Thisstudy, which is being conducted in collaboration withthe paste’s manufacturer, The Bard Corporation, isexamining whether the morphine paste will providesatisfactory pain relief with a lower risk ofcomplications. The success of the technique isassessed by carefully monitoring the quantity of otheranalgesics used during the six weeks immediatelyfollowing surgery.
Preliminary results indicate that the use of otherpainkillers is reduced following surgery. Furthermore,an assessment of the cost effectiveness of deliveringthe analgesia by the epidural route indicates that it iscompetitive with other methods.
Figure 2Proportions of patients with low morphine use
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1 2Days after surgery
% o
f pa
tien
ts
Ropivacaine group
Normal saline group<20mg
<10mg
Figure 1 The PainbusterTM continuous infusion device (courtesy of Smith+ Nephew)
30
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Testing new joint replacementsDr Bruce also researches new joint replacements thatare put on the market, to assess their performancebefore they are used in a patient. This involves usingpressure measurement devices to see that there arenot areas of high pressure which may lead topremature wear of a knee or hip replacement.
The investigators also carry out computer modelling tosee how the hip and knee replacements will affect boneover a long period of time. Some joint replacements areso rigid that they do not stress the patient’s boneevenly and can lead to loss of bone over many years.
Orthopaedic ResearchDr Warwick Bruce, an orthopaedicsurgeon, has major research interestsin the areas of Sports Medicine andJoint Replacement.
Sports Medicine Research – anterior cruciate ligament reconstructionA large part of Dr Bruce’s research has looked atimproving anterior cruciate ligament reconstructions ofthe knee, particularly where the tendon is in contactwith the bone. The aim of this research is to usedifferent methods to improve bony ingrowth into thetendon. If bone grows more rapidly into the tendon,then the patient is able to rehabilitate more quickly andget back to sport more quickly.
An initial study was to assess the improvement ofanterior cruciate ligament grafting in sheep by addinggrowth factors. Whole blood was taken from the sheepand concentrated using a special filter which gave aconcentrate of growth factors. An anterior cruciateligament reconstruction was then performed on thesheep and growth factors were injected into the bonytunnels. The growth factors had a positive effect on thehealing tendon bone interface with improved strengthof the graft and improvement in the radiographicappearance of the tunnel.
The next stage of the study was to use low doseultrasound (Cartogen) on sheep after cruciatereconstruction. The sheep had a standard cruciateligament reconstruction and then had an ultrasounddevice strapped to their knee for approximately 20minutes each day. There was rapid improvement inbone ingrowth into the tendon in both the femur andthe tibia. The benefit of this research is that people whohave anterior cruciate ligament reconstruction canshorten their rehabilitation time and their return to sportby attaching an ultrasound to their leg in the recoveryperiod.
0
1
2
3
4
5
GRADE
3 wks 6wks 12 wks
BONE INGROWTH AT INTERFACE
Control
Cartogen
Twenty minutes ultrasound treatment per day rapidly improved boneingrowth into the tendon after surgery to the knee in sheep.
31
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complication rate after joint replacement surgery issignificantly decreased. This has major implications forjoint replacements in the future.
Diffuse mottling is seen in both lung fields (arrows) at sites of fat embolism. The lungs would normally show no uptake and would be a uniform black colour in apatient without fat embolism.
Distinguishing fat emboli from pulmonary emboli afterjoint replacement surgeryAnother major study has examined the incidence of fatemboli and pulmonary emboli after joint replacementsurgery. After a joint replacement, fat can be releasedinto the blood vessels of the leg and travel to the lungsand cause respiratory distress to the patient(embolisation). Another possibility is that blood clotscan be released into the vessels and travel to the lungs.Until now, it has not been possible to tell the differencebetween emboli of blood or fat.
In collaboration with Dr Hans Van Der Wall, Departmentof Nuclear Medicine, the investigators have developeda test that can be performed postoperatively if patientshave respiratory complications. This test will telldoctors whether a patient has a fat embolus or a bloodclot. The advantage of knowing this is that a fatembolus does not need to be treated with bloodthinning agents, whereas the blood clot does. Doctorstherefore do not have to use blood thinning agents onpatients who have fat emboli, which means that the
32
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The Ageing Processand the LiverThis research is led by CERA DirectorProfessor Le Couteur and Dr Muller inthe ANZAC Research Institute. Theteam are interested in why ageingincreases the susceptibility to disease.Their main interest has focused on anage-related change in the bloodvessels of the liver which they recentlydiscovered and calledpseudocapillarisation.
Pseudocapillarisation involves thickening of the bloodvessels with loss of pores and these changes preventthe passage of toxins and nutrients from the blood tothe liver for processing. These changes in the liver,particularly the loss of pores, impair the ability to breakdown dietary fats and predispose to atherosclerosis,heart disease and stroke. Professor Le Couteur andcolleagues have also shown that ageing is associatedwith impaired capacity of the liver to handleneurotoxins, including pesticides. This may explain whyageing is the main risk factor for Parkinson’s disease.
Pseudocapillarisation of the ageing liver is associatedwith impaired oxygenation of the liver cells, whichprovides an explanation for the age-related impairmentof liver medication metabolism, contributing to theincreased prevalence of adverse drug reactions in olderpeople. These studies are now focusing on therapeuticstrategies to reverse or prevent age-relatedpseudocapillarisation, as a way of preventing andtreating diseases of older age. The researchers areutilising cultured liver endothelial cells to improveunderstanding of the basic biology of the pores in theliver blood cells and to screen for novel therapeuticagents.
Scanning electron micrographs of the liver endothelium. In theblood vessel from a young liver (top), there are numerouspores called fenestrations that allow the passage of fat andpossibly other large molecules. With old age (bottom), thefenestrations are reduced, thereby impeding the ability of theliver to break down fat. This may explain why hyperlipidaemiaand atherosclerosis are more common in old age.
33
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Palliative CarePalliative care is the total care ofpatients whose disease is notresponsive to curative treatment.Palliative care encompasses control ofpain and other symptoms, as well asthe psychological well-being and qualityof life of the patient.
End of life decision-making in the care of the patient.The aim of this study is to assess the care of the dyingpatient and how health care professionals’ decisionsmay play a role in this last phase of life. This will beassessed by collecting information from the medicalrecords of 150 patients who have died at ConcordHospital. Dr Ghauri Aggarwal and colleagues havedeveloped a survey form to document a number offactors believed to be of importance in the decision-making process. These factors include the use ofmedication in the last phase of life; any procedures orinterventions in that phase; the documentation of a‘Not For Resuscitation’ (NFR) order and how well this isexplained in the medical records.
Other background information about the patient’s lastillness, diagnosis and reason for admission will also becollected. Patients’ charts, nursing and physiciannotes will be examined to provide further informationabout decision-making and changes of care in the lastphases of life. It is hoped that the data will becollected over a period of 8 months. The patient’sterminal phase will be looked at in a critical manner,documenting the appropriateness of decisions, medicaland nursing care and changes to interventions andmedications during that time.
This study will provide valuable information on theneeds of dying patients by recording the adequacy ofcare in this important phase of life. It will be used tohelp develop strategies to improve the care of thedying. It is also hoped that the results will be used toprovide educational tools to better equip our medicaland nursing staff to react appropriately to changing
conditions in this last phase, and in particular, toprovide adequate palliative care and comfort measureswhen it is apparent that a patient is dying.
34
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Cognitive BehaviouralTreatment of PanicDisorder Fiona Kemp & Fiona Wilkinson, clinicalpsychologists at Concord Hospital,have undertaken research intotreatments for Panic Disorder. Theinvestigators analysed the componentsof Cognitive Behavioural Therapy (CBT)which were most successful in thetreatment of Panic Disorder.
Cognitive Behaviour Therapy (CBT) is a psychologicaltherapy that focuses on irrational thoughts (cognitions),and how these thoughts effect subsequent emotions andbehaviours. Therapy includes ‘cognitive restructuring’which involves identifying these thoughts, challengingthem and developing a different set of attributions. Thebehavioural component of CBT includes changingbehaviours so that these thoughts and emotions mayfurther be challenged. For example, a person who isanxious may be required to go into a fearful situation thatthey would normally avoid in order to challenge thethoughts and emotions that have previously beenassociated with the situation. This type of behaviouralexercise is known as exposure therapy and may be donein the situation itself, in the imagination, or interoceptively(behaviours that induce feared bodily sensations). CBTfor people who are anxious may also include ‘breathingretraining’, a technique that rectifies the shallow breathingand ensuing hyperventilation often associated with panic.
A person who experiences Panic Disorder will typicallyexperience the following symptoms: a brief episode ofintense fear with physical sensations such as heartpalpitations, dizziness, and shallow breathing. In additionthe person will be concerned about future panic ‘attacks’.For example they may fear losing control or ‘going crazy’.They may also modify their behaviour to avoid futurepanic attacks.
Substantial evidence supports the efficacy of CBT in thetreatment of panic disorder. Controversy exists as towhich components of CBT are essential for change.Standard cognitive behaviour treatment of panic disorderusually includes the following components: cognitiverestructuring, “in situation” exposure, breathing retraining,relaxation training and psychoeducation. Researchershave suggested an increasing trend towards omitting thebreathing retraining component in panic control, andincluding interoceptive exposure. To investigate this issue,the current study examined the relative efficacy of twostandard components of CBT for panic disorder, namelyinteroceptive exposure and breathing retraining. Subjectsmeeting the criteria for panic disorder were recruited andallocated to one of two treatment groups: - interoceptiveexposure and breathing retraining. Each group receivedsix one hour CBT sessions which differed only by theinclusion / exclusion of breathing retraining andinteroceptive exposure.
Findings to date suggest that, contrary to expectationsand previous research, it would appear that the groupthat received breathing retraining has attained greatertreatment benefits than the group that receivedinteroceptive exposure. This finding suggests thatbreathing retraining is an essential component in theeffective treatment of panic disorder, while the importanceof interoceptive exposure requires further investigation.
Concord
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36
Con
cord
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RE
SE
AR
CH
AT
CO
NC
OR
D H
OS
PIT
AL
2002
/200
3
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earc
her
sP
roje
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rig
in o
f F
un
din
g
Ana
esth
esio
logy
J S
mith
, A S
pral
ja a
nd P
Hen
del
A s
tudy
to in
vest
igat
e th
e ef
fect
s of
con
tinuo
us in
filtr
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men
ts, p
ain
scor
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nt m
obili
tyA
stra
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eca
John
son
&Jo
hnso
nA
nato
mic
al P
atho
logy
/Ele
ctro
n M
icro
scop
e U
nit
B L
in, R
L S
uthe
rland
et a
l.M
olec
ular
pat
holo
gy o
f pan
crea
tic c
ance
r
B L
in,C
Cha
n, E
L B
okey
et a
l.M
olec
ular
gen
etic
s an
d im
mun
ohis
toch
emic
al a
naly
sis
of S
tage
B c
olon
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arci
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ughe
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Cha
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naly
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of p
53 e
xpre
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tran
sitio
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ell c
arci
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a
L H
ughe
s, S
Lim
et a
l.A
sses
smen
t of d
isea
se c
ontr
ol in
chr
onic
airw
ays
limita
tion
by s
putu
m e
osin
ophi
l cou
nt
S B
ram
mah
, L W
right
, E D
elik
atny
et a
l.U
ltras
truc
tura
l cha
nges
indu
ced
by T
TP
-bas
ed c
atio
nic
lipop
hilic
pho
spho
nium
sal
ts (
CLP
S)
and
chlo
rpro
maz
ine
(CP
Z)
NH
MR
CLe
o &
Jen
ny L
euka
emia
and
Can
cer
Fou
ndat
ion
C H
awke
, P K
irwa,
R v
an D
riel a
ndA
Bax
ter
Myc
obac
teriu
m a
s an
env
ironm
enta
l enh
ance
r of
SLE
in a
mou
se m
odel
of S
LE
Bur
ns U
nit
T H
eath
, P
Mai
tz a
nd T
Got
tlieb
Inva
sive
bur
n w
ound
infe
ctio
n: it
s re
latio
nshi
p to
ski
n gr
aft o
utco
me
and
seps
is
P M
aitz
and
J S
harp
The
app
licat
ion
of c
ultu
red
epith
elia
l cel
ls to
gra
fts o
n bu
rns
wou
nds
P M
aitz
and
R J
ohns
onA
Pha
se Ii
a cl
inic
al e
valu
atio
n of
a to
pica
lly a
pplie
d, b
iolo
gica
lly a
ctiv
e, m
ilk-d
eriv
ed e
xtra
ct (
B60
11A
) in
the
trea
tmen
t of s
kin
graf
t don
or s
ite w
ound
sG
roP
ep L
imite
d
M C
arne
Pre
ssur
e ga
rmen
t com
paris
on
F L
i and
M C
arne
Doe
s sp
lintin
g ef
fect
the
inci
denc
e of
het
erto
pic
ossi
ficat
ion
at th
e el
bow
in b
urns
?
Car
diol
ogy
A S
indo
neC
HA
RM
(C
ande
sart
an in
pat
ient
s w
ith h
eart
failu
re)
Ast
raZ
enec
a
A S
indo
neE
PH
ES
US
(E
pler
enon
e in
the
surv
ival
from
hea
rt fa
ilure
afte
r he
art a
ttack
)S
earle
A S
indo
neO
VE
RT
UR
E (
Om
apat
rilat
vs
Ena
lapr
il in
pro
long
ing
surv
ival
and
del
ayin
g th
e pr
ogre
ssio
n of
hea
rtfa
ilure
)B
risto
l-Mye
rs S
quib
b
A S
indo
neE
NA
BLE
(B
osen
tan
in h
eart
failu
re p
atie
nts)
Act
elio
n Lt
d.
A S
indo
neC
HA
T (
Qua
lity
of li
fe o
f pat
ient
s w
ith h
eart
failu
re)
A S
indo
neI-
PR
ES
ER
VE
(Ir
besa
rtan
in h
eart
failu
re p
atie
nts
with
pre
serv
ed s
ysto
lic fu
nctio
n)B
risto
l-Mye
rs S
quib
b &
San
ofi~
synt
hela
boA
SIn
done
PE
RIN
DO
PR
IL (
Per
indo
pril
in h
eart
failu
re p
atie
nts
with
pre
serv
ed s
ysto
lic fu
nctio
n)S
ervi
er
37
G L
au, L
Krit
harid
es, L
Rid
ley
and
D B
riege
rA
ccur
acy
of C
oron
ary
CT
ang
iogr
aphy
G L
au, L
Krit
harid
es, D
Sul
livan
,L
Rid
ley,
P B
anno
n an
d D
Brie
ger
CA
BG
-Ris
k S
tudy
(R
isk
fact
ors
for
coro
nary
vei
n gr
aft d
isea
se)
G L
au, H
Tan
and
L K
ritha
rides
Live
r D
ysfu
nctio
n in
Hea
rt F
ailu
re
S C
hand
ar, R
Wal
ls a
ndS
B F
reed
man
C-R
eact
ive
Pro
tein
(C
RP
) an
d th
rom
bus
in u
nsta
ble
angi
na
G L
au, S
Rim
into
n an
dS
B F
reed
man
C-R
eact
ive
Pro
tein
(C
RP
) an
d va
scul
ar in
jury
D B
riege
r an
d M
Hay
esS
PO
RT
IF (
Stu
dy o
f a n
ew a
ntic
oagu
lant
in p
atie
nts
with
atr
ial f
ibril
latio
n)A
stra
Zen
eca
D B
riege
rG
RA
CE
(A
reg
istr
y to
def
ine
char
acte
ristic
s, m
anag
emen
t and
out
com
es o
f pat
ient
s w
ith A
cute
Cor
onar
y E
vent
s A
CE
)A
vent
is
D B
riege
rS
yner
gy (
Eno
xapr
in in
hig
h-ris
k pa
tient
s w
ith a
cute
cor
onar
y sy
ndro
mes
)A
vent
is
D B
riege
r, D
Bru
ce, B
Zen
g an
dS
B F
reed
man
Alte
rnat
e m
edia
tors
of f
ibrin
olys
is in
pla
smin
ogen
kno
ck-o
ut m
ice
NH
MR
C
CE
RA
(C
entr
e fo
r E
duca
tion
and
Res
earc
h on
Age
ing)
D L
e C
oute
ur, A
McL
ean
and
A A
nsse
linH
epat
ic o
xyge
natio
n an
d ag
eing
NH
MR
C (
proj
ect g
rant
)
D L
e C
oute
urP
atho
gene
sis
and
func
tiona
l sig
nific
ance
of a
ge-r
elat
ed p
seud
ocap
illar
isat
ion
SE
SQ
UI,
Uni
vers
ity o
fS
ydne
yD
Le
Cou
teur
, Z K
halil
, G A
ndre
ws,
J K
ril e
t al
Sco
ping
stu
dy o
n ag
eing
res
earc
hN
HM
RC
D L
e C
oute
ur, C
Sha
nley
, et a
l.F
alls
pre
vent
ion
in r
esid
entia
l car
eD
ept o
f Hea
lth a
nd A
ged
Car
e
D L
e C
oute
urP
urch
ase
of H
PLC
NH
MR
C E
quip
men
t gra
nt,
K D
oubl
e, G
Hal
liday
, D L
e C
oute
uret
al
A p
oten
tial n
ew te
st fo
r di
agno
sing
ear
ly d
opam
ine
cell
loss
Aus
tral
ian
Bra
in F
ound
atio
n
A M
cLea
n an
d D
Le
Cou
teur
Age
ing
and
the
liver
NH
MR
C/D
VA
J K
ril, P
Wal
ey, S
Pat
el a
ndF
Png
Cor
rela
tes
of b
rain
atr
ophy
in A
lzhe
imer
�s d
isea
se (
AD
)M
edic
al F
ound
atio
n of
The
Uni
vers
ity o
f Syd
ney
J K
ril, H
Cre
asey
, G H
allid
ay a
ndM
Bro
eN
on-A
lzhe
imer
dem
entia
s: P
atho
gene
sis
and
clin
icop
atho
logi
cal c
orre
latio
nsN
HM
RC
G H
allid
ay, G
A B
roe,
A H
ardi
ng a
ndW
S B
rook
sG
enet
ic fa
ctor
s an
d re
gion
al b
rain
atr
ophy
in th
e di
agno
sis
of d
emen
tia w
ith L
ewy
bodi
es.
NH
MR
C (
gran
t hel
d by
PO
WM
edic
al R
esea
rch
Inst
itute
)C
Mas
ters
, P R
Sch
ofie
ld, G
A B
roe,
H C
reas
ey a
nd W
S B
rook
sN
HM
RC
Net
wor
k of
Bra
in R
esea
rch
into
Men
tal D
isor
ders
(G
enet
ic L
inka
ge C
onso
rtiu
m, D
iagn
ostic
Ass
essm
ent C
onso
rtiu
m)
NH
MR
C
(gra
nt
held
by
th
eU
nive
rsity
of M
elbo
urne
)J
Kw
ok, P
R S
chof
ield
and
W S
Bro
oks
Clo
ning
and
bio
chem
ical
cha
ract
eris
atio
n of
a n
ew g
ene
that
cau
ses
Alz
heim
er's
dis
ease
.D
VA
(gr
ant h
eld
by th
e G
arva
nIn
stitu
te o
f Med
ical
Res
earc
h)
Con
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38
Con
cord
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lRes
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t
Clin
ical
And
rolo
gyD
Han
dels
man
, S K
elle
her
and
A C
onw
ayA
stu
dy o
f the
pro
stat
ic c
ontr
ibut
ion
of c
ircul
atin
g D
HT
(di
hydr
otes
tost
eron
e)
D H
ande
lsm
an, S
Kel
lehe
r an
dA
Con
way
Long
-ter
m p
harm
acok
inet
ics
and
clin
ical
effi
cacy
of A
ndro
men
For
te 5
% C
ream
for
andr
ogen
repl
acem
ent i
n hy
pogo
nada
l men
Law
ley
Pha
rmac
eutic
als
D H
ande
lsm
an, S
Kel
lehe
r an
dA
Con
way
Pha
rmac
okin
etic
s of
And
rom
en F
orte
5%
cre
am: A
dos
e-fin
ding
stu
dyLa
wle
y P
harm
aceu
tical
s
D H
ande
lsm
an a
nd P
And
erso
nD
evel
opm
ent o
f a s
erum
pan
el to
dev
elop
nor
mal
labo
rato
ry r
ange
s w
hen
test
ing
for
repr
oduc
tive
heal
th in
men
And
rolo
gy A
ustr
alia
D H
ande
lsm
an, L
Tur
ner
and
A C
onw
ayE
ffica
cy, s
afet
y an
d se
rvic
e fe
asib
ility
of a
n an
drog
en/p
roge
stin
dep
ot r
egim
en fo
r ho
rmon
al m
ale
cont
race
ptio
n.C
ON
RA
D
D H
ande
lsm
an a
nd M
Cou
sins
The
effe
cts
of N
andr
olon
e D
ecan
oate
on
reha
bilit
atio
n an
d qu
ality
of l
ife in
men
with
chr
onic
pai
n an
dop
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-indu
ced
andr
ogen
def
icie
ncy:
a r
ando
miz
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lace
bo-c
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olle
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oss-
over
clin
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tria
l.P
Liu
, D H
ande
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ndR
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nste
inA
dou
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blin
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lace
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ontr
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ndom
ised
cro
ssov
er s
tudy
of t
esto
ster
one
on p
hysi
cal a
ctiv
ity,
slee
p an
d co
gniti
on in
men
ove
r 60
yea
rs o
f age
.S
eron
o
D H
ande
lsm
anP
rena
tal F
acto
rs in
Mal
e R
epro
duct
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Hea
lthN
HM
RC
Col
orec
tal U
nit
L Ir
wig
, L B
okey
, P C
hapu
i et a
l.P
opul
atio
n sc
reen
ing
for
colo
rect
al c
ance
rC
omm
onw
ealth
pro
ject
gra
nt
L B
okey
, P C
hapu
is e
t al.
Mai
nten
ance
of t
he C
olor
ecta
l Can
cer
(CR
C)
Hos
pita
l Reg
istr
y
Der
mat
olog
yE
Col
lins,
M P
iggi
n, J
Feg
on a
ndC
Ong
An
open
-labe
l stu
dy to
eva
luat
e th
e sa
fety
and
long
-ter
m c
linic
al e
ffica
cy o
f Im
iqui
mod
cre
am a
pplie
don
ce d
aily
, sev
en d
ays
per
wee
k fo
r 6
wee
ks o
n th
e tr
eatm
ent o
f sup
erfic
ial b
asal
cel
l car
cino
ma
3M P
harm
aceu
tical
s
End
ocrin
olog
yM
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per
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RE
(R
aloi
fene
in lo
wer
ing
risk
of b
reas
t can
cer
in p
ostm
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ausa
l wom
en w
ith o
steo
poro
sis)
Eli
Lilly
M H
oope
rG
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TH
(N
ew c
ombi
natio
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eatm
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or o
steo
poro
sis
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omen
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li Li
lly
M H
oope
rA
lend
rona
te in
Pag
et�s
dis
ease
Mer
k, S
harp
& D
ohm
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oope
rR
io-L
ipid
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udy
(a n
ew d
rug
for
wei
ght l
oss
in o
bese
pat
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s w
ith d
yslip
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mia
s)S
anof
i
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oope
rP
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RL
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ofox
ifene
for
post
men
opau
sal w
omen
with
ost
eopo
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s)P
fizer
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oope
rLa
sofo
xife
ne in
sex
ual d
ysfu
nctio
nP
fizer
R C
hen
HM
R 1
964
(fas
t-ac
ting
insu
lin)
in T
ype1
dia
bete
sA
vent
is
M H
oope
rE
xten
sion
stu
dy: R
ised
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te in
ost
eopo
rosi
sP
roct
or a
nd G
ambl
e
M H
oope
rZ
olod
roni
c ac
id in
ost
eopo
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tens
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2N
ovar
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M H
oope
rZ
olod
roni
c A
cid
in P
aget
�s D
isea
seN
ovar
tis
M H
oope
rR
ised
rona
te fo
r os
teop
oros
is in
men
Ave
ntis
/Pro
ctor
Gam
ble
39
R C
hen,
M H
oope
r, T
Cro
mer
,C
Tin
g, N
Kor
mas
and
C S
hank
ley
HM
R19
64 V
S r
egul
ar h
uman
insu
lin in
type
2 d
iabe
tes
mel
litus
Ave
ntis
Gas
troe
nter
olog
yG
Par
k, M
Ngu
, B J
ones
, P K
atel
aris
and
D L
e C
oute
urT
he C
affe
ine
Bre
ath
test
NH
MR
C
Hyp
erte
nsio
n U
nit
R W
yndh
amF
IELD
stu
dy (
Fen
ofib
rate
in p
reve
ntin
g va
scul
ar d
isea
se in
pat
ient
s w
ith n
on-in
sulin
dep
ende
ntdi
abet
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NH
MR
C
Imm
unol
ogy
R W
alls
and
G H
uT
radi
tiona
l Chi
nese
med
icin
e in
trea
tmen
t of a
llerg
ic d
isea
ses
Tai
ji-U
nive
rsity
of S
ydne
yR
esea
rch
Fun
d fo
r T
radi
tiona
lC
hine
se M
edic
ine
Mic
robi
olog
yT
Got
tlieb
and
G F
unne
llA
ustr
alia
n G
roup
for
Ant
imic
robi
al R
esis
tanc
e (A
GA
R)
� S
taph
aur
eus
stud
y
T G
ottli
eb a
nd G
Fun
nell
Aus
tral
ian
Gro
up fo
r A
ntim
icro
bial
Res
ista
nce
(AG
AR
) �
Gra
m N
egat
ive
stud
y
T G
ottli
eb a
nd G
Fun
nell
Aus
tral
ian
Gro
up fo
r A
ntim
icro
bial
Res
ista
nce
(AG
AR
) �
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umoc
occa
l stu
dy
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ottli
ebC
omm
unity
acq
uire
d ba
cter
aem
ia
S S
iara
kas,
T G
ottli
eb e
t al.
Mul
ti-C
entr
e E
valu
atio
n of
Rap
id C
omm
erci
al T
ests
for
the
Dia
gnos
is o
f Clo
strid
ium
diff
icile
Mul
tiple
com
pany
spo
nsor
ship
S S
iara
kas,
J S
anto
s an
d H
Agu
sT
he R
ole
of C
lost
ridiu
m p
erfr
inge
ns in
Nos
ocom
ial a
nd C
omm
unity
dia
rrho
ea (
Sup
ervi
sed
Hon
ors
Pro
ject
)C
ompa
ny s
pons
orsh
ipU
nive
rsity
of S
ydne
yS
Sia
raka
s, A
. K
ew
ley,
P L
oren
tzos
and
H A
gus
Clo
strid
ium
diff
icile
: Liv
ing
in th
e V
aria
nt E
ra (
Sup
ervi
sed
Hon
ors
Pro
ject
)U
nive
rsity
of S
ydne
y.
M L
eroi
, S
Sia
raka
s an
d T
Got
tlieb
Rol
e of
Nov
el A
ntib
iotic
s ag
ains
t Clo
strid
ium
diff
icile
Pha
rmac
iaB
ayer
T G
ottli
eb a
nd M
Pet
ers
Line
zolid
vs.
Van
com
ycin
/ Oxa
cilli
n in
Gra
m P
ositi
ve C
annu
la r
elat
ed s
epsi
sP
harm
acia
T G
ottli
ebA
ustr
alia
n C
andi
dem
ia s
tudy
J M
erlin
o, R
Bra
dbur
y, T
Got
tlieb
et a
lP
heno
typi
c an
d G
enot
ypic
stu
dies
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taph
yloc
occu
s au
reus
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n-m
ultid
rug
and
mul
tidru
g re
sist
ance
MR
SA
) is
olat
es in
CS
AH
SU
nive
rsity
of S
ydne
y
J M
erlin
o, R
Bra
dbur
y, T
Got
tlieb
et a
lS
urve
illan
ce a
nd E
valu
atio
n of
New
Det
ectio
n an
d Is
olat
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Met
hods
for
Sta
phyl
ococ
cus
aure
us (
non-
mul
tidru
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d m
ultid
rug
resi
stan
ce M
RS
A)
in C
SA
HU
nive
rsity
of S
ydne
yC
ompa
ny s
pons
orsh
ipM
Poy
ten,
J M
erlin
o an
d T
Got
tlieb
Det
ectio
n of
Ext
ende
d S
pect
rum
Bet
a-La
ctam
ases
in G
ram
-neg
ativ
e B
acill
i at C
RG
HC
ompa
ny s
pons
orsh
ip
T G
ottli
eb, M
Ler
oiC
onco
rd A
nim
al H
ospi
tal
Cox
iella
bur
netii
in c
ats
in S
ydne
y �
a se
rolo
gica
l sur
vey
T G
ottli
eb a
nd G
Fun
nell
Mox
iflox
acin
sus
cept
ibili
ty in
res
pira
tory
isol
ates
� M
ultic
entr
e st
udy
Bay
er
Con
cord
Hos
pita
lRes
earc
h R
epor
t
40
Con
cord
Hos
pita
lRes
earc
h R
epor
t
Mol
ecul
ar M
edic
ine
G N
icho
lson
and
M K
enne
rson
Gen
etic
Bas
is fo
r C
harc
ot-M
arie
-Too
th a
nd H
ered
itary
Sen
sory
Neu
ropa
thy
type
IN
H&
MR
C
G N
icho
lson
and
M K
enne
rson
Fin
ding
the
gene
for
here
dita
ry s
enso
ry n
euro
path
yR
ebec
ca L
. Coo
per
G N
icho
lson
and
M K
enne
rson
Fun
ctio
nal s
tudi
es o
n th
e ge
ne c
ausi
ng h
ered
itary
sen
sory
neu
ropa
thy
Cliv
e an
d V
era
Ram
acio
ttiF
ound
atio
nG
Nic
hols
onM
appi
ng th
e m
utat
ion
for
here
dita
ry s
enso
ry n
euro
path
yU
SA
Mus
cula
r D
ystr
ophy
Ass
ocia
tion
G N
icho
lson
and
M K
enne
rson
Gen
e m
utat
ion
anal
ysis
in P
arki
nson
�s d
isea
se u
sing
rea
l tim
e P
CR
Cliv
e an
d V
era
Ram
acio
ttiF
ound
atio
nG
Nic
hols
onId
entif
ying
new
gen
e m
utat
ions
for
mot
or n
euro
ne d
isea
seT
he A
myo
trop
hic
Late
ral
Scl
eros
is A
ssoc
iatio
n U
SA
G N
icho
lson
and
M K
enne
rson
Mol
ecul
ar g
enet
ics
of s
pina
l cor
d ne
urop
athi
esD
epar
tmen
t of M
edic
ine
Uni
vers
ity o
f Syd
ney
Neu
rolo
gyA
Cor
bett
PR
OG
RE
SS
(P
erin
dopr
il an
d In
dapa
mid
e fo
r se
cond
ary
stro
ke p
reve
ntio
n)S
ervi
er a
nd M
RC
New
Zea
land
A C
orbe
ttT
RA
NS
CE
ND
and
ON
TA
RG
ET
(R
amip
ril a
nd T
elm
isar
tan
for
seco
ndar
y pr
even
tion
of c
ompl
icat
ions
inst
roke
, cor
onar
y ar
tery
dis
ease
, dia
bete
s an
d pe
riphe
ral v
ascu
lar
dise
ase)
Bo
eh
rin
ge
r In
gle
he
im/C
an
ad
ian
Ca
rdio
va
sc
ula
r C
oll
ab
ora
tio
nP
roje
ct O
ffice
M H
ayes
A m
ulti-
cent
re, m
ultin
atio
nal,
Pha
se 3
, ran
dom
ized
, dou
ble
blin
d, d
oubl
e-du
mm
y, 3
-arm
par
alle
l gro
up,
plac
ebo-
and
rop
iniro
le-c
ontr
olle
d tr
ial o
f the
effi
cacy
and
saf
ety
of r
otig
otin
e C
DS
pat
ch in
sub
ject
s w
ithea
rly s
tage
, idi
opat
hic
Par
kins
on d
isea
se
Sch
war
z P
harm
a
M H
ayes
A p
hase
3, d
oubl
e bl
ind,
pla
cebo
con
trol
led,
ran
dom
ized
stu
dy c
ompa
ring
the
effic
acy,
saf
ety
and
tole
rabi
lity
of s
uman
irole
ver
sus
plac
ebo
or r
opin
irole
, as
an a
djuv
ant t
o le
vodo
pa, i
n pa
tient
s w
ithad
vanc
ed P
arki
nson
s D
isea
se
Pha
rmac
ia
M H
ayes
Bot
ulin
um to
xin
and
low
er li
mb
spas
ticity
follo
win
g st
roke
Alle
rgon
A C
orbe
tt, J
Wat
son,
J C
ulle
n an
dS
Alle
nP
riorit
y H
ealth
Car
e P
rogr
am �
Str
oke
Dep
artm
ent o
f Hea
lth
Neu
rosu
rger
yN
Dan
and
N K
azem
iA
pro
spec
tive,
ran
dom
ized
, dou
ble-
blin
d tr
ial t
o ev
alua
te th
e ef
ficac
y of
ana
lges
ic e
pidu
ral p
aste
inlu
mba
r di
sc s
urge
ryN
ursi
ngJ
Ran
dall,
L C
heno
wet
h, C
Luc
k,C
Sm
ith a
nd C
Fen
nell
Dis
char
ge P
lann
ing
from
the
pers
pect
ive
of p
atie
nts
and
thei
r fa
mily
/car
er.
The
Ass
ocia
tion
of D
isch
arge
Pla
nnin
g N
urse
s
V S
uthe
rland
and
D L
ear
Ext
rave
ntric
ular
dra
ins
� st
erile
ver
sus
asep
tic te
chni
que
Res
earc
h C
entr
e fo
r A
dapt
atio
nin
Hea
lth a
nd Il
lnes
s, U
nive
rsity
of S
ydne
yG
Gly
nnT
he im
plem
enta
tion
of th
e F
amily
nee
ds P
roto
col t
o as
sist
nur
ses
in a
ddre
ssin
g th
e ne
eds
of th
e fa
mily
mem
bers
of c
ritic
ally
ill p
atie
nts
Res
earc
h C
entr
e fo
r A
dapt
atio
nin
Hea
lth a
nd Il
lnes
s, U
nive
rsity
of S
ydne
yJ
Mu
nro
, M
Ric
ha
rdso
n,
J O
�Co
nn
ell
and
R H
awle
yE
valu
atio
n of
a n
urse
-initi
ated
dis
char
ge p
lan
to im
prov
e th
e m
anag
emen
t of p
atie
nts
with
ast
hma
in th
eE
mer
genc
y D
epar
tmen
tR
esea
rch
Cen
tre
for
Ada
ptat
ion
in H
ealth
and
Illn
ess,
Uni
vers
ityof
Syd
ney
41
Nut
ritio
n an
d D
iete
tics
P M
acLe
nnan
, K J
ukko
la,
A T
horn
ton,
N C
zinn
er a
nd J
Rav
ens
Inve
stig
atio
n o
f th
e e
ffe
cts
of
cha
rtin
g H
igh
Pro
tein
, H
igh
En
erg
y N
utr
itio
na
l S
up
ple
me
nts
on
th
eO
utco
mes
of E
lder
ly H
ospi
talis
ed p
atie
nts
at r
isk
of M
alnu
triti
on.
Res
earc
h C
entr
e fo
r A
dapt
atio
nin
Hea
lth &
Illn
ess,
Uni
vers
ity o
fS
ydne
yN
Cro
cket
t, P
Bea
le, J
Jac
quet
and
P M
acLe
nnan
Inve
stig
atio
n in
to th
e ef
fect
of N
utrit
ion
Inte
rven
tion
in L
ong-
term
Che
mot
hera
py P
atie
nts.
Res
earc
h C
entr
e fo
r A
dapt
atio
nin
Hea
lth &
Illn
ess,
Uni
vers
ity o
fS
ydne
yL
Bay
tieh,
R J
ohns
on a
nd P
Mai
tzD
iarr
hoea
inci
den
ce in
bur
ns p
atie
nts
in th
e B
urn
s U
nit a
t Con
cord
Hos
pita
l � p
ossi
ble
aet
iolo
gic
al
me
chan
ism
s a
nd in
terv
entio
n.R
esea
rch
Cen
tre
for
Ada
ptat
ion
in H
ealth
and
Illn
ess,
Uni
vers
ityof
Syd
ney
Onc
olog
yP
Bea
le, S
Cla
rke
and
A S
ulliv
anN
SA
BP
C-0
7 tr
ial (
Clin
ical
Tria
l of c
hem
othe
rapy
follo
win
g su
rger
y fo
r bo
wel
can
cer)
Nat
iona
l Su
rgic
al A
djuv
ant B
reas
tan
d B
owel
Pro
ject
(N
SA
BP
)P
Bea
le a
nd S
Cla
rke
Cel
ecox
ib/C
PT
11 (
Clin
ical
tria
l of c
eleb
rex
with
che
mot
hera
py fo
r pa
tient
s w
ith a
dvan
ced
colo
n or
rec
tal
canc
er).
Pha
rmac
ia
M S
tock
ler,
A S
ulliv
an a
nd P
Bea
leA
NZ
0001
tria
l(Clin
ical
tria
l of c
hem
othe
rapy
for
wom
en w
ith a
dvan
ced
or m
etas
tatic
bre
ast c
ance
r)A
ustr
alia
New
Zea
land
Bre
ast
Can
cer
Tria
l Gro
up (
AN
ZB
CT
G)
A S
ulliv
an a
nd P
Bea
leB
CIR
G tr
ials
005
& 0
06 (
Clin
ical
tria
ls o
f che
mot
hera
py a
nd a
ntib
ody
trea
tmen
ts fo
r w
omen
follo
win
gsu
rger
y fo
r br
east
can
cer)
.B
reas
t Can
cer
Inte
rnat
iona
lR
esea
rch
Gro
up (
BC
IRG
)M
Sto
ckle
r, M
Boy
er, S
Cla
rke
and
P B
eale
YM
598
pro
stat
e tr
ial (
Clin
ical
tria
l of a
new
dru
g w
ith c
hem
othe
rapy
for
adv
ance
d pr
osta
te c
ance
r)Y
aman
ouch
i
P B
eale
and
S C
lark
eC
hrys
in/C
PT
11 s
tudy
(C
linic
al tr
ial o
f a d
rug
to p
reve
nt d
iarr
hoea
with
che
mot
hera
py fo
r bo
wel
can
cer)
M S
tock
ler
ZE
ST
stu
dy (
Clin
ical
tria
l of a
ntid
epre
ssan
t dru
g in
adv
ance
d ca
ncer
pat
ient
s)N
HM
RC
-CT
C
S C
lark
e, M
Mill
war
d an
d P
Bea
leJM
AT
NS
CLC
(C
linic
al tr
ial o
f che
mot
hera
py fo
r pa
tient
s w
ith a
dvan
ved
lung
can
cer)
Eli
Lilly
S C
lark
e, M
Mill
war
d, P
Bea
le a
ndM
Boy
erA
G33
40 N
SC
LC (
Clin
ical
tria
l of a
new
dru
g to
pre
vent
tum
our
spre
ad in
lung
can
cer
patie
nts)
Ago
uron
A S
ulliv
an a
nd M
Sto
ckle
rIB
CS
G S
tudy
20
(Clin
ical
tria
ls o
f che
mot
hera
py fo
r w
omen
follo
win
g su
rger
y fo
r br
east
can
cer)
.A
ustr
alia
New
Zea
land
Bre
ast
Can
cer
Tria
l Gro
up (
AN
ZB
CT
G)
S C
lark
e, M
Mill
war
d an
d P
Bea
leIR
ES
SA
NS
CLC
(C
linic
al tr
ial o
f a n
ew d
rug
with
che
mot
hera
py to
pre
vent
tum
our
grow
th in
lung
canc
er p
atie
nts)
Ast
ra Z
enec
a
M S
tock
ler,
M B
oyer
and
P B
eale
TA
X 3
27 (
Clin
ical
Tria
l of c
hem
othe
rapy
for
men
with
adv
ance
d pr
osta
te c
ance
r)A
vent
is
S C
lark
e an
d P
Bea
leC
apec
itabi
ne T
S s
tudy
(P
redi
ctin
g to
xici
ty fr
om tr
eatm
ent f
or a
dvan
ced
bow
el c
ance
r)
M S
tock
ler
and
P B
eale
Cis
plat
in in
patie
nt/o
utpa
tient
stu
dy
Ort
hopa
edic
sW
Bru
ce a
nd H
Van
der
Wal
lE
arly
Pro
spec
tive
Det
ectio
n of
Bon
e M
arro
w/F
at E
mbo
lism
afte
r Jo
int A
rthr
opla
sy
Con
cord
Hos
pita
lRes
earc
h R
epor
t
42
Con
cord
Hos
pita
lRes
earc
h R
epor
t
Oph
thal
mol
ogy
F B
ooth
, J G
eorg
e an
d A
Lee
Eva
luat
ion
of d
ry e
ye te
sts
in n
orm
al a
sym
ptom
atic
pop
ulat
ion
Pal
liativ
e C
are
G A
ggar
wal
and
M A
gar
Doc
umen
tatio
n of
the
Inci
denc
e of
Mal
igna
nt A
scite
s an
d th
e U
se o
f Par
acen
tesi
s an
d D
iure
tics
inC
urre
nt M
anag
emen
t of M
alig
nant
Asc
ites
(Pilo
t Stu
dy)
G A
ggar
wal
, N S
atha
siva
m a
ndC
Won
gE
nd o
f life
dec
isio
n-m
akin
g in
the
care
of t
he p
atie
nt
G A
ggar
wal
Dou
ble-
blin
d, D
oubl
e-du
mm
y, R
ando
mis
ed, p
aral
lel-a
rm e
quiv
alen
ce s
tudy
com
parin
g H
ydro
mor
phon
eH
ydro
chlo
ride
exte
nded
-rel
ease
cap
sule
s (H
HE
R)
with
MS
Con
tin T
able
ts, a
t a d
ose
ratio
of 1
:7.5
, in
Can
cer
or N
on-C
ance
r pa
tient
with
a h
isto
ry o
f mod
erat
e to
sev
ere
pain
Mun
diph
arm
a
P G
lare
and
G A
ggar
wal
Dat
abas
e of
pat
ient
s us
ing
stro
ng o
pioi
ds fo
r no
n-ca
ncer
pai
n
G A
ggar
wal
and
A K
outa
ntos
Pre
vale
nce
of p
ain
in a
teac
hing
hos
pita
l
J C
layt
on, P
But
ow, M
Tat
ters
all
R C
hye
and
G A
ggar
wal
Com
mun
icat
ion
of p
rogn
ostic
info
rmat
ion
in p
allia
tive
med
icin
e �
an a
naly
sis
of a
udio
tape
ddo
ctor
/pat
ient
con
sulta
tions
NH
MR
C M
edic
al/D
enta
lR
esea
rch
Sch
olar
ship
P G
lare
, J Y
ip a
nd G
Agg
arw
alP
ain
in h
ospi
talis
ed p
atie
nts
with
can
cer:
pre
vale
nce,
clin
ical
cha
ract
eris
tics,
impa
ct o
n qu
ality
of l
ifean
d ba
rrie
rs to
trea
tmen
t.J
Cla
yton
, M T
atte
rsal
l, P
But
ow a
ndG
Agg
arw
alP
ilotin
g a
ques
tion
prom
pt s
heet
for
palli
ativ
e ca
re p
atie
nts
and
subs
eque
ntly
con
duct
ing
a ra
ndom
ised
cont
rolle
d tr
ial o
f the
que
stio
n pr
ompt
she
et.
NH
MR
C m
edic
al p
ostg
radu
ate
scho
lars
hip
Phy
siot
hera
pyY
Silv
a an
d F
Li
Qua
lity
Impr
ovem
ent P
roje
ct to
rev
iew
out
com
e m
easu
res
post
upp
er a
nd lo
wer
abd
omin
al s
urge
ry
P v
an d
en D
olde
r an
d M
Kw
anA
Tria
l int
o th
e E
ffect
iven
ess
of s
oft t
issu
e m
assa
ge in
the
trea
tmen
t of S
houl
der
Pai
n
K R
efsh
auge
, C M
aher
, L B
arns
ley
and
L P
enge
lE
xerc
ise
or A
dvic
e fo
r su
bacu
te L
ow B
ack
Pai
n?N
HM
RC
Aus
tral
asia
n P
hysi
othe
rapy
low
back
tria
l con
sort
ium
F L
i and
Y S
ilva
For
ces
and
Fre
quen
cies
use
d in
per
cuss
ion
and
vibr
atio
n te
chni
ques
Y S
ilva,
F L
i and
M P
eter
sT
he e
ffect
iven
ess
of p
ulm
onar
y re
habi
litat
ion
on p
atie
nts
post
lung
res
ectio
n.
F L
i, V
Gra
ham
, N B
uckl
e,D
Del
aney
and
A. K
arko
vic
Mul
ti-ce
ntre
tria
l of a
rev
ised
ver
sion
of t
he E
lder
ly M
obili
ty S
cale
; a r
etro
spec
tive
stud
y.
Psy
chol
ogic
al M
edic
ine
I McG
rego
r an
d G
Hun
tT
he b
ehav
iour
al a
nd n
euro
toxi
c ef
fect
s of
MD
MA
(�E
csta
sy�)
NH
&M
RC
Psy
chol
ogy
F K
emp
and
F W
ilkin
son
Cog
nitiv
e be
havi
oura
l tre
atm
ent o
f pan
ic d
isor
der
Res
earc
h C
entr
e fo
r A
dapt
atio
nin
Hea
lth a
nd Il
lnes
s, U
nive
rsity
of S
ydne
yP
Man
gion
iC
ompa
rison
of p
atie
nts�
psy
chol
ogic
al s
tate
atte
ndin
g ca
rdia
c re
habi
litat
ion
with
thos
e pa
tient
s re
ceiv
ing
�nor
mal
� di
scha
rge
care
Re
sea
rch
Ce
ntr
e f
or
Ad
ap
tatio
nin
He
alth
an
d I
llne
ss,
Un
ive
rsity
of S
ydne
y
43
Rhe
umat
olog
yR
Cho
w a
nd L
Bar
nsle
yLo
w L
evel
Las
er fo
r N
eck
Pai
n
L B
arns
ley
Out
com
es o
f rad
iofr
eque
ncy
dene
rvat
ion
for
chro
nic
neck
pai
n
L B
arns
ley
Rem
icad
e fo
r R
heum
atoi
d ar
thrit
is
Spe
ech
Pat
holo
gyN
Cla
yton
, A In
g, M
Pet
ers
and
G M
ann
The
effe
ct o
f chr
onic
obs
truc
tive
pulm
onar
y di
seas
e (C
OP
D)
on la
ryng
o-ph
aryn
geal
sen
sitiv
ity (
LPS
)an
d dy
spha
gia
Tho
raci
c M
edic
ine
L S
eeto
The
rol
e of
AK
T in
the
mol
ecul
ar p
atho
gene
sis
of C
hron
ic O
bstr
uctiv
e P
ulm
onar
y D
isea
se (
CO
PD
).
L S
eeto
Alv
eola
r m
acro
phag
e ex
pres
sion
of p
21 in
Chr
onic
Obs
truc
tive
Pul
mon
ary
Dis
ease
(C
OP
D).
L S
eeto
The
exp
ress
ion
of m
atrix
met
allo
prot
eina
ses
(MM
Ps)
and
cyt
okin
es fr
om a
lveo
lar
mac
roph
ages
inC
hron
ic O
bstr
uctiv
e P
ulm
onar
y D
isea
se (
CO
PD
): T
he e
ffect
of o
ral t
heop
hylli
ne in
CO
PD
, ara
ndom
ised
dou
ble
blin
d pl
aceb
o co
ntro
lled
stud
y in
pat
ient
s w
ith C
OP
D.
Mits
ubis
hi
L S
ecco
mbe
Ris
k fa
ctor
s fo
r de
velo
ping
hyp
oxia
dur
ing
air
trav
el in
pas
seng
ers
with
lung
dis
ease
.
M C
omsa
Stu
dy o
n th
e et
iolo
gy o
f com
mun
ity-a
cqui
red
pneu
mon
ia in
pat
ient
s ad
mitt
ed to
Con
cord
Hos
pita
l.
G C
ossa
A s
tudy
to e
xam
ine
the
effe
cts
of e
nviro
nmen
t (ae
roal
lerg
ens)
on
noct
urna
l ast
hma
usin
g an
aut
omat
edw
heez
e qu
antif
icat
ion
devi
ce (
Pul
moT
rack
)K
Wad
e an
d L
Plo
wm
anM
eter
ed d
ose
inha
ler
(MD
I) a
sses
smen
t in
subj
ects
with
chr
onic
obs
truc
tive
pulm
onar
y di
seas
e(C
OP
D)
or a
sthm
a.A
Ing
and
B R
ost
The
Rol
e of
Neu
rotr
ophi
ns in
Chr
onic
Idio
path
ic C
ough
Uro
logy
V T
se, L
Cha
n, J
Yin
, C M
cLac
hlan
E W
ills
and
S B
ram
mah
Ultr
astr
uctu
ral B
asis
of V
oidi
ng D
ysfu
nctio
n (C
orre
latio
n of
Gap
Jun
ctio
nal P
rote
in E
xpre
ssio
n an
dU
ltras
truc
tura
l Fea
ture
s in
the
Uns
tabl
e H
uman
Det
ruso
rA
bbot
Aus
tral
asia
Inst
itute
of U
rolo
gy, C
SA
HS
A L
alak
, L C
han,
A M
itter
dorf
er,
D V
asila
reas
and
N H
anly
GU
OG
� A
Pha
se II
Stu
dy to
Ass
ess
the
Effe
ct o
f Int
erm
itten
t And
roge
n B
lock
ade
in th
e T
reat
men
t of
Adv
ance
d P
rost
ate
Can
cer
Sch
erin
g P
loug
h
L C
han,
D E
isin
ger,
A M
itter
dorf
erJ
Rog
ers,
D V
asila
reas
and
N H
anly
A R
ando
mis
ed, D
oubl
e-bl
ind,
Par
alle
l Gro
up, P
lace
bo a
nd A
ctiv
e C
ontr
olle
d, M
ulti-
Cen
tre
Stu
dy o
fY
M90
5 5
mg
and
10 m
g in
Pat
ient
s w
ith O
vera
ctiv
e B
ladd
erY
aman
ouch
i
L C
han,
D E
isin
ger,
A M
itter
dorf
erJ
Rog
ers.
D V
asila
reas
and
N H
anly
An
Ope
n-la
bel,
Long
-ter
m S
afet
y an
d E
ffica
cy F
ollo
w-u
p S
tudy
of Y
M90
5 5m
g an
d 10
mg
in P
atie
nts
with
Ove
ract
ive
Bla
dder
Yam
anou
chi
L C
han,
D V
asila
reas
and
N H
anly
UK
-338
,003
(S
tudy
of a
new
dru
g fo
r tr
eatin
g sy
mpt
oms
of b
enig
n pr
osta
tic o
bstr
uctio
n).
Pfiz
er
A L
alak
, A M
itter
dorf
er, P
Mah
er a
ndN
Han
lyT
RIU
MP
H S
tudy
(S
tudy
of t
he m
anag
emen
t of p
atie
nts
with
ben
ign
pros
tatic
hyp
erpl
asia
)Y
aman
ouch
i
J M
edd,
A L
alak
, L C
han,
P M
aher
and
M S
tock
ler
Pat
ient
s E
xper
ienc
e of
Uro
dyna
mic
s an
d P
rost
ate
Bio
psy
Con
cord
Hos
pita
lRes
earc
h R
epor
t
44
Con
cord
Hos
pita
lRes
earc
h R
epor
t
Funding:
The research described in this publication was supported by funding from the following sources:
● Altana Pharma● Amgen Inc.● Astra-Zeneca● Australian Brain Foundation● Aventis Pharma● Bard Corporation● BioFirst Award (NSW Government)● CONRAD● Department of Veterans’ Affairs● Eli Lilly ● Federal Department of Health and Ageing ● International Osteoporosis Foundation● Johnson and Johnson● Mitsubishi (Japan)● National Health and Medical Research Council● National Health and Medical Research Council Postgraduate Scholarship● NSW Health Department Infrastructure Grant● Pfizer Cardiovascular Lipid Research Grant● Pharmacia Australia● RACP McCaughey Research Scholarship● Research Centre for Adaptation in Health and Illness, University of Sydney● Roche Pharmaceuticals● RM Gibson Foundation of Australian Association of Gerontology● Royal Australian College of Surgeons● SchwarzBiosciences● Serono● Singapore College of Physicians● Swiss National Research Fund● The University of Heidelberg Research Foundation● The Medical Foundation of The University of Sydney● The University of Sydney● Vingmed GE Australia
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