Though vaccination has had a major impact on the number of persons becoming infected, chronic infection with the hepatitis B virus (HBV) still remains a major worldwide problem, with 350 million people chronically infected. The existence of HBV vaccine escape mutants and the fact that 5% of vaccinees fail to respond implies that HBV will remain a significant public health problem for the foreseeable future. Current treatments for chronic HBV infection have a low success rate (~20%) and patients ....Though vaccination has had a major impact on the number of persons becoming infected, chronic infection with the hepatitis B virus (HBV) still remains a major worldwide problem, with 350 million people chronically infected. The existence of HBV vaccine escape mutants and the fact that 5% of vaccinees fail to respond implies that HBV will remain a significant public health problem for the foreseeable future. Current treatments for chronic HBV infection have a low success rate (~20%) and patients with chronic infection are expected to die prematurely due to chronic liver disease or primary liver cancer. Interestingly, exposure to HBV can lead to either acute resolving or chronic HBV infection. Like chronic infections, acute infections involve spread of virus to virtually every hepatocyte, followed by rapid clearance of the virus mediated by the host immune response. Our immediate aim is to study the resolution of acute HBV infections to determine how the stable intracellular viral genome, covalently closed circular DNA (cccDNA), is cleared from the nucleus of infected hepatocytes. Our broad long-term aim is to develop new and effective treatments for chronic HBV infection based on a better understanding of how acute HBV infections are resolved by the host. Based on our previous work we believe that clearance of cccDNA requires hepatocyte death, together with compensatory proliferation of other infected hepatocytes. We will perform detailed studies in duck hepatitis B virus (DHBV) infected ducks to determine if hepatocyte death and compensatory proliferation are essential to clear the infection, or if mechanisms exist for clearance that do not involve cell destruction.Read moreRead less
Understanding How Sepsis Causes Kidney Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$471,770.00
Summary
Acute renal failure is a serious condition that affects up to 20% of patients in Intensive Care Units. Sepsis and septic shock remain the most important causes of acute renal failure in critically ill patients. Despite our ability to support vital organs and resuscitate patients, the incidence and mortality of septic acute renal failure remain unacceptably high at up to 55%. There have been no major advances in our understanding of its pathogenesis and in its prevention or treatment over the las ....Acute renal failure is a serious condition that affects up to 20% of patients in Intensive Care Units. Sepsis and septic shock remain the most important causes of acute renal failure in critically ill patients. Despite our ability to support vital organs and resuscitate patients, the incidence and mortality of septic acute renal failure remain unacceptably high at up to 55%. There have been no major advances in our understanding of its pathogenesis and in its prevention or treatment over the last 50 years. The traditional view is that sepsis-induced renal failure results from reduced perfusion of the kidney secondary to the low blood pressure. In a model of sepsis in sheep with renal failure, we demonstrated, however, that renal blood vessels dilated and blood flow increased. Furthermore, renal function improved following treatment with vasoconstrictor drugs that raised blood pressure and renal blood flow. These findings indicate that renal ischaemia is not the cause of the renal dysfunction in sepsis. We hypothesise that sepsis causes renal vasodilatation, which reduces glomerular filtration rate and renal function, and induces a delayed development of apopotosis. We will study in sepsis 1) the effects of a treatment to increase glomerular filtration rate 2) the development of apoptosis and the effect of an anti-apoptotic drug, and 3) whether there is bioenergetic failure in the kidney in sepsis and the effects of treatments on this. Finally, in septic patients we will measure renal blood flow and determine the effects of our novel treatment on this and renal function. These studies will significantly increase our understanding of the factors causing acute renal failure in sepsis. They are likely to lead to the development of new therapies to improve renal function in sepsis and their effectiveness will be examined in septic animals and patients.Read moreRead less
Consumer Information Materials And A Communication Aid For Diagnostic Tests For Breast Disease
Funder
National Health and Medical Research Council
Funding Amount
$105,863.00
Summary
Many studies have now shown that the majority of patients want to participate in clinical decisions about medical treatments they might receive. As a result, information materials are being developed to help consumers and doctors work together to reach satisfying treatment decisions which are based on the best available evidence and also reflect the individual patient's needs and preferences about the treatment options. Very little is known, however, about whether consumers also want to particip ....Many studies have now shown that the majority of patients want to participate in clinical decisions about medical treatments they might receive. As a result, information materials are being developed to help consumers and doctors work together to reach satisfying treatment decisions which are based on the best available evidence and also reflect the individual patient's needs and preferences about the treatment options. Very little is known, however, about whether consumers also want to participate in decisions about whether to have a medical test. Tests can be trivial, such as a blood or urine test, or quite major and invasive, such as a biopsy or a colonoscopy. People considering a medical test might want to know the answers to the following questions: What is my chance of having the disease being tested for? If the test result is positive what is the chance I have the disease? If the test result is negative what is the chance I have the disease anyway? How will the test result influence treatment of my condition? What are possible side-effects of the test? Generally information materials about medical tests only describe the test itself, and do not contain the information people need to answer these questions. Even doctors may not have to hand the data needed to answer these questions. Yet without this information, consumers cannot make truly informed and rational choices about whether to have the test. This project aims to find out whether consumers want to participate in decisions about medical tests, what information they would want to do this, and to develop and trial information materials and a communication aid for a small number of breast cancer tests. We will use tests for diagnosing breast cancer as our model but we anticipate the work will be applicable across a wide range of medical tests.Read moreRead less
Cancer Trials Australia-OnLine: A Tool For Cancer Patients To Find Open Clinical Trials And Consider Trial Participation
Funder
National Health and Medical Research Council
Funding Amount
$525,604.00
Summary
We will develop and evaluate a website for consumers which will interface with the ACTR to provide up to date information on currently recruiting cancer trials. Aims are: a) to increase awareness of cancer trials, and facilitate discussion between doctors and patients about participation in a clinical trial, and b) to support cancer consumers to make an informed decision about enrolling in a trial. A randomized trial will assess the effectiveness of the site in achieving these aims.
Single-Beat Preload Recruitable Stroke Work Measurement Of Cardiac Contractility In Three Mammalian Models.
Funder
National Health and Medical Research Council
Funding Amount
$241,980.00
Summary
The accurate measurement of the inherent pumping capacity of the heart muscle is difficult because (i) most measurements currently in use cannot accurately discriminate between the contribution of the heart muscle and that of the vascular system to the results obtained, and (ii) the measurements which can discriminate currently require invasive measurements and procedures that frequently restrict their use. The overall purpose of this proposal is to more rigorously validate a promising method we ....The accurate measurement of the inherent pumping capacity of the heart muscle is difficult because (i) most measurements currently in use cannot accurately discriminate between the contribution of the heart muscle and that of the vascular system to the results obtained, and (ii) the measurements which can discriminate currently require invasive measurements and procedures that frequently restrict their use. The overall purpose of this proposal is to more rigorously validate a promising method we have developed that will (i) make accurate assessment possible from a single cardiac beat in both experimental animals and human subjects; (ii) reduce the number of experimental animals required for such measurements by permitting sequential measurements in the same animals; (iii) make it possible to perform such measurements non-invasively in human subjects.Read moreRead less
Development And Evaluation Of A Decision Aid For Women With A Breech-presenting Baby.
Funder
National Health and Medical Research Council
Funding Amount
$156,890.00
Summary
Many studies have shown that women want to participate in clinical decisions about the treatments they receive during pregnancy and that involvement in decision making increases satisfaction with maternity care. Decision aids are interventions to help people make specific and deliberative decisions by providing information on the options and outcomes relevant to the person's health. This project aims to develop and evaluate the world's first decision aid for women with a breech presenting baby ( ....Many studies have shown that women want to participate in clinical decisions about the treatments they receive during pregnancy and that involvement in decision making increases satisfaction with maternity care. Decision aids are interventions to help people make specific and deliberative decisions by providing information on the options and outcomes relevant to the person's health. This project aims to develop and evaluate the world's first decision aid for women with a breech presenting baby (bottom rather than head first) in late pregnancy. A decision aid for breech presentation is timely because recent results of an international trial have dramatically altered women's options in the management of breech presentation. The trial of vaginal breech birth versus planned caesarean section (CS) found overwhelming evidence of reduced infant death and disability for women with a planned CS. Planned CS is now considered best practice for delivery of a breech presentation at birth. However, another treatment option for women with a breech presentation is turning the breech to head first before birth (called external cephalic version, ECV). Each of these options (ECV or planned CS) has benefits and risks, and the relative importance of these benefits and risks varies for individual women, a scenario where a decision aid produces the greatest benefit. The breech decision aid developed in this project will be based on the best and most recently available evidence and outcomes. It will incorporate a workbook, audiotape-CD and worksheet that will guide (but not direct) women to a treatment option that best suits them, taking ~20 minutes to complete. The decision aid will be evaluated to assess the impact on women's satisfaction with decision making, knowledge, anxiety and pregnancy outcomes. If successful, the results could be applied to improve consumer information and participation in clinical decisions across a wide spectrum of pregnancy care issues.Read moreRead less
An Ethical Analysis Of The Disclosure Of Surgeons' Performance Data To Patients Within The Informed Consent Process
Funder
National Health and Medical Research Council
Funding Amount
$148,937.00
Summary
For over a decade, hospitals in the American state of New York have been collecting information about the mortality rates of surgeons conducting Coronary Artery Bypass Grafts, and making this information available to patients. The United Kingdom is set to make these and other performance indicators on the ability of surgeons ('report cards') available from 2004. There are good reasons to think a similar system may be introduced in Australia in the near future. Patients can use the information co ....For over a decade, hospitals in the American state of New York have been collecting information about the mortality rates of surgeons conducting Coronary Artery Bypass Grafts, and making this information available to patients. The United Kingdom is set to make these and other performance indicators on the ability of surgeons ('report cards') available from 2004. There are good reasons to think a similar system may be introduced in Australia in the near future. Patients can use the information contained in report cards when deciding whether or not to consent to have a particular surgeon conduct an operation on them. Contemporary bioethicists stress the importance of a proper informed consent process in medicine. This is a process in which a doctor advises a patient of relevant information and ensures that the patient comprehends that information, before the patient consents to an operation. Currently report cards in America are publicly disseminated on the internet, however there is no systematic attempt to incorporate the information contained in report cards into the informed consent process. We do not know if patients understand the information they are given, or if they incorporate it into their decision making procedures appropriately. In our study we will consider how information that is contained in report cards could best be used in the informed consent process. We will keep in mind the importance of helping patients to make their own informed decisions to consent to operations, the importance of respecting the professional integrity of surgeons and the importance of providing the best possible standard of care for patients. The result of our study will be a revised model of the informed consent process that incorporates report cards in an ethically acceptable way.Read moreRead less
Factors Controlling Lipid Accumulation In Non-adipose Tissues
Funder
National Health and Medical Research Council
Funding Amount
$463,500.00
Summary
The fat cells of the body are designed to store excess fuel for use when supply from the diet is low, or in situations like exercise, demand is high. Fat also accumulates to some extent in the cells of other tissues types, but in some people the accumulation is excessive. This can have a number of serious effects. In the liver and muscle it can interfere with the ability of insulin to properly regulate the amount of glucose present in the blood, contributing to the development of diabetes. In th ....The fat cells of the body are designed to store excess fuel for use when supply from the diet is low, or in situations like exercise, demand is high. Fat also accumulates to some extent in the cells of other tissues types, but in some people the accumulation is excessive. This can have a number of serious effects. In the liver and muscle it can interfere with the ability of insulin to properly regulate the amount of glucose present in the blood, contributing to the development of diabetes. In the liver, fat accumulation can also lead to cirrhosis and liver failure. Cardiovascular complications, resulting in premature death, are also likely. However despite these devastating consequences it is not clear what the underlying cause of the over-accumulation of fat is not known. In this project we will investigate in detail several aspects of fat metabolism that we think are important in controlling how tissues take up fat from the circulation and whether it is subsequently stored or burnt for energy. We will study the amount of fat that is taken up by different tissues of the body under a range of conditions including fed, and short- and long-term fasting. We will also use drugs to inhibit or promote the amount of fat that is burnt, to see if this changes the rate at which fat is taken up by different tissues. In addition we will accelerate, by genetic manipulation, the rate at which some key enzymes of fat metabolism are produced, to determine their effect on the amount of fat that is stored by different tissue types. Our aim is to determine the metabolic processes that influence fat accumulation in those adversely affected tissues such as liver, heart and skeletal muscle. The identification of the most important processes will contribute significantly to the targeting of therapies aimed at preventing excess fat accumulation and its associated diseases.Read moreRead less
A Randomised Trial Of A Decision Aid For Women At Increased Risk For Ovarian Cancer
Funder
National Health and Medical Research Council
Funding Amount
$115,110.00
Summary
Epithelial ovarian cancer is the leading cause of death from gynaecological malignancy in Australia. The majority of women with ovarian cancer are diagnosed with advanced disease, and the chance of cure is low. The strongest risk factor for ovarian cancer identified to date is a family history of ovarian cancer, and up to 5% of all ovarian cancers are thought to be due to dominantly inherited mutations in a small number of ovarian-cancer-related genes. National guidelines on surveillance and pro ....Epithelial ovarian cancer is the leading cause of death from gynaecological malignancy in Australia. The majority of women with ovarian cancer are diagnosed with advanced disease, and the chance of cure is low. The strongest risk factor for ovarian cancer identified to date is a family history of ovarian cancer, and up to 5% of all ovarian cancers are thought to be due to dominantly inherited mutations in a small number of ovarian-cancer-related genes. National guidelines on surveillance and prophylactic strategies have recently been ratified. These are largely based on expert opinion. Because of the uncertain efficacy of ovarian cancer screening and the high mortality associated with ovarian cancer, prophylactic oophorectomy is considered an option for women at high risk. Decisions about optimal care are difficult for both women and their doctors. Efforts to improve services for women who are trying to make informed decisions about screening and prophylactic strategies under conditions of uncertainty must be informed by sound knowledge of the efficacy of educational interventions. Decision aids have been developed as adjuncts to practitioners' counselling to prepare patients for decision-making. The proposed randomised controlled trial will compare the efficacy of a general educational pamphlet and that of a tailored decision aid. A total of 120 women at risk for ovarian cancer who are attending one of five familial cancer clinics will be included in the trial to determine the efficacy of different educational interventions in preparing women for decision-making about screening and prophylactic options.Read moreRead less
Alternatives To Homologous Blood Transfusion - Development Of Evidence- Based Decision Aids.
Funder
National Health and Medical Research Council
Funding Amount
$213,697.00
Summary
Transfusion of donor blood is the traditional means of treating blood loss resulting from injury or during surgery. Donor blood is in short supply and in the past there have been episodes of contamination by viruses that have led to hepatitis and AIDS. Consequently there is much interest in a range of techniques designed to reduce the need for transfusion of donor blood. One of the most popular is transfusion of patients' own blood (autologous transfusion). Despite the popularity of some of thes ....Transfusion of donor blood is the traditional means of treating blood loss resulting from injury or during surgery. Donor blood is in short supply and in the past there have been episodes of contamination by viruses that have led to hepatitis and AIDS. Consequently there is much interest in a range of techniques designed to reduce the need for transfusion of donor blood. One of the most popular is transfusion of patients' own blood (autologous transfusion). Despite the popularity of some of these techniques their true value is not really proven. They may be capable of diminishing the need for a transfusion of donor blood, but the long-term effects of this are not clear. In addition the preparation of autologous blood is a burden for overworked blood banks, and autologous blood may itself be associated with its own problems. The main aims of this study are to carry out reviews of the best quality trials of the various alternatives to transfusion of donor blood and to carry out surveys to find out what patients and doctors think. In a third phase of the project we will use the information gathered in the first two phases to design decision aids. These are comprehensive structured summaries of the available evidence to enable patients and their physicians to collaborate in making informed decisions that are likely to lead to the best outcomes for patients. The products of the research will be a number of reviews of 'best evidence' that appear in the International Cochrane Library, available to health professionals around the world. In addition, the decision aids, if successful, will be made available in a form that can be used by all Australian patients who are facing surgery that is likely to require a blood transfusion.Read moreRead less