Editorials

Mandatory reporting and public sharing of information would likely lead to improved health care practices and save lives Staphylococcus aureus bacteraemia (SAB) is common, and it causes serious morbidity and mortality. In Australia, it is estimated that there are over 6000 episodes per year, most of which are health care-associated.1 SAB is also a major problem internationally, and this problem is compounded by antibiotic resistance. Methicillin-resistant S. aureus (MRSA) infections are common in most countries, and MRSA bacteraemia has reached epidemic proportions in some areas of the United States.2,3 The study by Turnidge and colleagues on behalf of the Australia New Zealand Cooperative on Outcomes in Staphylococcal Sepsis in this issue of the Journal4 highlights again how frequently these infections occur, their association with health care (particularly with intravascular catheters), and the high mortality rate associated with them (over 20% by 30 days). It also illustrates our rapidly growing problem with community MRSA strains, which caused over 6% of all the SABs in the period June 2007 to May 2008, during which Turnidge et al collected data. Currently, we have only very patchy measurements of this problem in Australia in comparison with New Zealand, Denmark and the United Kingdom,2 where all SABs are measured. Despite probably causing more deaths in Australia than occur on our roads, there is very little investigation into the causes and the preventable factors of individual episodes of bacteraemia. Most of these infections are preventable. Numerous interventions (such as compliance with hand hygiene and improved care of intravenous catheters) have been shown to lead to major reductions in rates of bacteraemia.2,5,6 The current National Hand Hygiene Initiative7 should also achieve a significant reduction. The Australian Commission on Safety and Quality in Health Care has noted how significant these infections are, and the importance of surveillance.2 It has also taken this matter to the Australian Health Ministers’ Conference, which then endorsed the reporting of SABs in each jurisdiction and nationally. It is time that all health care facilities started collecting and acting on information about SABs. However, this probably won’t happen effectively unless all SABs (based on pathology laboratory results) are made “reportable”. After mandatory reporting was introduced in the UK, the number of documented cases increased by 50%.2,8 It is important that we do more than just collect these data. We need to ensure that, in each hospital, every case is looked at to try to determine why it occurred. Then health care professionals need to intervene at their own local level to make sure that appropriate policies are adhered to (or, where necessary, changed). Nearly all people with SABs are either in hospital already, or will be admitted. Thus, it should be possible to see them at or near the time of their infection. This will usually mean that either a physician or an infection control practitioner would look at every case to determine whether it was the result of a health care-associated procedure, and also look into other issues, such as the likely cause (eg, intravascular catheter) and outcomes.2 This would then also allow timely feedback to the teams responsible for the patients’ current and previous medical care about potential preventable factors.9 Many episodes of SAB, even though they are health care-associated, have their onset in the community. Thus, all cases of SAB will need to be looked at, and not just those with their onset in hospitals.1,2,9 While this will seem arduous to some, at the Canberra and Austin Hospitals, it takes between 30 and 60 minutes to see each affected patient and review each case.2,9,10 Even our largest hospitals are unlikely to have more than a couple of hundred SAB episodes per year. As these episodes have a mortality of more than 20%, this is not an undue task to expect hospitals to perform. They need to devote resources to doing this, and make it part of the core duties of any infection control team. It is important that the data be analysed, reported and acted on in a timely fashion, and this process must involve those at the hospital executive level. The success and benefits of doing this at a local level are highlighted in the study reported by Dendle and colleagues in this issue of the Journal.10 The study by Turnidge et al shows how data can be analysed and reported efficiently at a national (and international) level, with relatively few extra resources being supplied, through the use of a web-based tool.4 Such a system allows summaries to be sent back to the individual hospitals so that they can look at their own data in a timely fashion. It also allows some external auditing of the data to ensure they are accurate. Importantly, it will allow hospitals of similar types to benchmark themselves nationally. This is important because we already know that hospitals in Perth have much lower rates of health care-acquired MRSA than those in the eastern states,11 and we should learn from them. Most Australian states do not have sufficiently large populations to make many comparisons internally, especially of their largest hospitals, where most cases of SAB occur. By using national comparisons, institutions with higher rates of infections should be able to learn from those that have lower rates of infections. There are always arguments that looking at these data and having them publicly available does not help. However, the experience in the UK suggests otherwise. Amid controversy, SAB rates have been published on the web for many years, and this type of benchmarking, when coupled with funded infection control interventions, has led to a 50% reduction in the number of MRSA bacteraemias.2,8 This has not only resulted in substantial monetary savings, but, more importantly, has saved many hundreds of lives each year. Internationally, we are seeing rising levels of SAB. This is principally the result of complications of health care, and most of these infections are preventable. It is time we measured these life-threatening episodes much more accurately, examined each case, and intervened to stop further cases occurring.

Peter J Collignon FASM, FRCPA, FRACP · Marilyn Cruickshank RN, PhD, FRCNA

There is still no cure, but what advances have been made in managing this disabling condition? In its more aggravated forms diffuse scleroderma is one of the most terrible of all human ills. Like Tithonus [a Greek mythological hero who was granted immortality but not eternal youth] to “wither slowly” and like him to be “beaten down and marred and wasted” until one is literally a mummy, encased in an evershrinking, slowly contracting skin of steel, is a fate not pictured in any tragedy, ancient or modern. Sir William Osler, 18981 Scleroderma encompasses the name of a disease and a clinical sign (thickened skin) that have eluded any unifying mechanism of causation. While we still await a cure, new and significant pharmacological agents are now available that can assist in the symptomatic treatment and disease modification of this condition. The disease is uncommon, with Australian estimates of prevalence per 10 000 population ranging from 0.4–0.9 (Sydney, 1974–1988)2 to 1.47 (South Australia, 1993)3 to 2.4 (Tasmania, 2007).4 Scleroderma is classified into either localised (skin alone) disease or systemic (internal organ involvement ± skin) disease, which is known as systemic sclerosis. The principal subsets of systemic sclerosis are: diffuse cutaneous systemic sclerosis, limited cutaneous systemic sclerosis, systemic sclerosis sine scleroderma (systemic disease with no skin involvement), environmentally induced scleroderma, overlap syndromes and pre-scleroderma. In limited disease, skin thickening is limited to the extremities distal to the elbows and knees, and the face. Diffuse disease, at its maximal extent, affects not only the skin of the distal extremities and face but also the skin over the proximal extremities and trunk. The disease has three pathological features: fibrosis with excessive collagen and other ground substance deposition; vasculopathy involving small and large vessels; and smooth muscle atrophy. In diffuse systemic sclerosis, inflammation and fibrosis predominate, whereas in limited disease, vascular changes predominate. While skin involvement (dermal inflammation and fibrosis) is associated with variable morbidity, it is the systemic manifestations, especially pulmonary and cardiac, and occasionally renal and gastrointestinal, that are responsible for much of the disease-related premature mortality. Therapy is classified as either “disease-modifying” or “symptomatic” and is tailored to the individual’s tolerance and need. Therapeutic decisions are determined by the pattern of organ involvement (vital or non-vital), underlying pathological features, and other comorbidities. General measures such as staying warm, using gloves and skin moisturisers, taking antireflux or bowel motility agents, modifying timing and volume of meals, brushing teeth regularly to prevent caries, using eye drops for sicca symptoms, and avoiding aggravating factors are important first steps in treating and managing the condition. In the early onset of systemic sclerosis, an activated immune system (Box 1) may be important in the pathogenesis of subsequent fibrotic and vascular lesions, so early disease-modifying drug therapy is aimed at suppressing the immune response. Immunosuppressive drugs such as methotrexate, cyclophosphamide and mycophenolate, often in conjunction with judicious use of corticosteroids (there is some controversy surrounding the causal association between high-dose corticosteroids and scleroderma renal crisis), intravenous gammaglobulin, and minocycline, have been used with varying measures of success. The levels of evidence for therapeutic intervention strategies are outlined in Box 2. “Heavier” immunosuppression, with or without haemopoietic stem cell rescue, is contemplated in patients with early inflammatory vital organ involvement of the lung or myocardium.6,7 Two large multicentre Phase III studies — the ASTIS (Autologous Stem cell Transplantation International Scleroderma) Trial in Europe, and the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) study in the United States — to determine the relative efficacy of haemopoietic stem cell transplantation compared with less rigorous immunosuppression are well underway. In Australia, we have performed autologous stem cell transplantation in seven patients with systemic sclerosis who had progressive vital organ involvement and in whom conventional immunosuppression had failed, and noted a dramatic, sustained, long-term remission in four of them that featured marked skin softening, stabilisation of interstitial lung disease and a three- to fourfold fall in antinuclear antibody titre (H J E, personal communication). These findings support the use of autologous stem cell transplantation as a disease-modifying modality. The use of mesenchymal stem cells (MSCs) in the treatment of arthritic disease is novel, and this approach has shown great potential because of the ease of isolation, rapid growth and extensive culture expansion of MSCs suitable for therapeutic use. In diseases such as scleroderma where there is excessive mesenchymal overactivity, MSCs are an ideal candidate cell type for tissue regeneration and repair of damaged structures. Trials of therapeutic uses of MSCs are currently in progress.8 Therapies directed toward modification of established fibrosis have been uniformly disappointing. D-penicillamine, previously the gold standard of scleroderma therapy, has fallen into disrepute after a US multicentre study showed no outcome difference between very low dose and usual dose D-penicillamine therapy.9 However, occasionally patients will exhibit resolution of skin fibrosis with little or no therapeutic intervention. Pulmonary arterial hypertension is a relatively common complication of systemic sclerosis and is caused by pulmonary arterial narrowing and thickening leading to increased pulmonary vascular resistance and arterial pressures (> 25 mmHg). As early diagnosis and treatment can have a profound effect on outcome, it is extremely important to screen patients for this condition. The gold-standard screening procedure is right heart catheterisation. There is level I evidence5 of efficacy of three categories of medications for pulmonary arterial hypertension: endothelin receptor antagonists, prostanoids, and phosphodiesterase inhibitors. These may be used as a single agent or in combination, with combined epoprostenol and sildenafil being more efficacious than combined bosentan and sildenafil. The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been found to favourably modify the outcome of the vascular pathological features of scleroderma renal crisis. Symptomatic therapies for microvascular hyperreactivity, upper and lower gastrointestinal dysmotility, and musculoskeletal symptoms are outlined in Box 2. Promising new approaches include the use of a protein tyrosine kinase inhibitor, imatinib mesylate (Glivec, Novartis), that interferes with the signalling of platelet-derived growth factor and transforming growth factor-β, two pivotal mediators of the fibrotic process of systemic sclerosis. However, no biological agent has shown definitive evidence of efficacy thus far. Overall, despite the obvious absence of a cure, progress is being made in the understanding and management of this chronic and disabling rheumatic condition. 1 Pathophysiology of systemic sclerosis, with possible sites for therapeutic intervention Rational therapy would be designed to (1) prevent endothelial cell damage; (2) alter communication between mononuclear cells; (3) prevent mononuclear cell stimulation of fibroblasts; (4) prevent mast cell degranulation; (5) block fibroblast production or extrusion of procollagen; or (6) increase solubilisation of preformed collagen. Diagram courtesy of Professor Thomas Medsger, University of Pittsburgh. 2 Therapeutic intervention strategies for systemic sclerosis, with levels of evidence* Organ-specific features† Therapy (level of evidence) Cardiovascular (> 95%) (i) Microvascular (> 95%) Raynaud’s syndrome (> 95%) Efficacious: calcium channel blockers (II); topical glyceryl trinitrate (I); prazosin (I); intravenous iloprost (I); losartan (I); endothelin receptor antagonists; phosphodiesterase-5 inhibitors Disappointing: cisaprost; oral iloprost Promising: autologous progenitor cell implantation (II); protein tyrosine kinase ± Rho‑kinase inhibitors Digital ulcers Efficacious: as above; statins (I); bosentan (I); sildenafil (I) (ii) Macrovascular Myocardium (5%) Efficacious: immunosuppressives (III) Pericardium Efficacious: corticosteroids ± immunosuppressives Skin/adnexae (> 95%) Sclerosis Efficacious: cyclosporin (?II); tacrolimus (?II); cyclophosphamide (III) Disappointing: methotrexate (I) Promising: intravenous gammaglobulin (III) Respiratory (40%) Interstitial lung disease‡ Efficacious: cyclophosphamide (II) Promising: azathioprine (remission) (I) Pulmonary arterial hypertension Efficacious: bosentan (I); sildenafil (I); epoprostenol (I); treprostinil (I) Promising: beraprost (II) Aspiration pneumonitis None Gastrointestinal (75%–90%) Upper Efficacious: proton-pump inhibitors; histamine H2-receptor antagonists Lower Efficacious: domperidone (II); erythromycin (II); cisapride (II); octreotide (II) Renal (10%–15%) Hypertensive renal crisis Efficacious: angiotensin-converting enzyme inhibitors (II) * United States Preventive Services Task Force levels of evidence:5 I = at least one randomised controlled trial; II = well designed trial(s) without randomisation, or well designed case–control or cohort studies, or multiple time series with/without intervention; III = opinions of respected experts based on clinical experience; ?II = probably level II, but uncertain. † Percentages represent prevalence among all patients with systemic sclerosis. ‡ Non-specific interstitial pneumonitis, usual interstitial pneumonitis, bibasilar pulmonary fibrosis.

Helen J Englert MB BS, PhD, FRACP · Nicholas Manolios MB BS, PhD, FRACP

Time to debate the recommendations of the National Health and Hospitals Reform Commission is slipping away When the history of the Rudd Labor Government is written, undoubtedly a chapter will be devoted to its penchant for summits, inquiries and reports. Health has not escaped this inquisitorial focus. There have been, among others, inquiries and reports regarding preventive health,1 primary care,2 and health care delivery in general.3 The latter was the remit of the National Health and Hospitals Reform Commission (NHHRC), and its final report, A healthier future for all Australians, was released in June this year.3 If the NHHRC’s 123 recommendations are enacted, they have the capacity to change Australian health care in a manner reminiscent of the establishment of Medibank. Despite the report’s length (292 pages) and its prolific list of recommendations, common themes emerge: shared responsibility for care; increased responsibility by the federal government for existing and new health services; consolidation and integration of services, with an emphasis on non-institutional care; shifting care towards being more patient- and person-responsive than provider-convenient; better intrasectoral communication through the use of information technology; extracting greater efficiencies from hospitals; relating remuneration to outcomes and performance targets; and, finally, fundamental changes in the provision of health insurance. In short, if implemented, the report will mean a time of uncertainty, inherent in change. Despite this, the report has not yet been widely debated within the profession. In this issue of the Journal, we commence a series of articles (National health reform: it’s time for a decision, A healthier future for all Australians: an overview of the final report of the National Health and Hospitals Reform Commission and Final report of the National Health and Hospitals Reform Commission: will we get the health care governance reform we need?) exploring the social, health and professional impact of the recommendations of A healthier future for all Australians. Prime Minister Rudd is currently engaged in a whirlwind “getting to know you” tour of selected Australian hospitals, before the federal government’s response to the report is further massaged by the Council of Australian Governments into a united policy and a possible implementation plan. If the profession seeks to influence these outcomes, now is the time to present our views and recommendations. If we do not accept this challenge, change will be imposed from on high and may well be uncomfortable or even intolerable! Although it is important to “talk the talk”, this should not excessively delay “walking the walk”.

Martin B Van Der Weyden MD, FRACP, FRCPA

We have a tool for absolute risk assessment — now we need a robust implementation program In March 2009, the National Vascular Disease Prevention Alliance (NVDPA), a consortium of Diabetes Australia, Kidney Health Australia, the National Heart Foundation of Australia, and the National Stroke Foundation, released evidence-based guidelines for assessing absolute cardiovascular risk.1 The guidelines are for use by health professionals who assess patients’ cardiovascular risk, primarily general practitioners. The risk charts that accompany the guidelines differ somewhat from the New Zealand risk charts,2 which are commonly used in Australia. Both the Australian and NZ charts are based on the Framingham Heart Study.3 The Australian cardiovascular risk charts are separated at the broader level into people with and without diabetes, rather than into men and women. In addition, systolic, but not diastolic, blood pressure is included because it is the stronger determinant of future events. The charts extend to upper cut-off points of 179 mmHg for systolic blood pressure and 7.5 mmol/L for total cholesterol level, respectively. The NVDPA guidelines also have an online risk calculator (http://www.cvdcheck.org.au). The new NVDPA guidelines and charts have the advantage of taking into account other drivers of practice in Australia, such as the Royal Australian College of General Practitioners’ Guidelines for preventive activities in general practice,4 and eligibility for Pharmaceutical Benefits Scheme subsidies for statins. Absolute risk assessment maximises the effectiveness of prediction of risk of future cardiovascular disease (CVD) events in people apparently free of such disease. This is because the underlying equations acknowledge fundamental epidemiological principles: risk depends on the range of independent risk factors and, for biomedical factors, risk typically increases in a log–linear manner above ideal levels (systolic blood pressure and total cholesterol level, 115 mmHg and 3.8 mmol/L, respectively).5 The present, somewhat arbitrary, definitions of hypertension and hypercholesterolaemia as ≥ 140/90 mmHg and ≥ 5.5 mmol/L, respectively, are fundamentally flawed, and most people who have CVD events have a clustering of risk factors with only modest abnormalities. If relative risk reduction with an intervention is relatively constant (the usual case), use of the intervention in those at higher absolute risk leads to greater absolute risk reduction and net benefit, thus also maximising cost-effectiveness. All absolute risk tools share some problems. As they are derived from large population studies, they are better at rank-ordering risk in subgroups and less precise in an individual. However, individual risk assessment may be refined (particularly in those initially assessed to be at intermediate risk) by measuring biomarkers or by imaging,6 and probably more so in the future, as more evidence becomes available. Other factors that might also be added to future algorithms include anthropometric measures (of these, waist circumference or waist : hip ratio appears more predictive than body mass index), a family history of premature atherosclerotic disease, and measures of socioeconomic deprivation.7 The NVDPA guidelines acknowledge that the Framingham risk equation may underestimate risk if these factors are present. The major determinant of CVD risk is increasing age, and it is also likely that equations specific for various age groups will become available. Particularly among younger people, this will improve identification of those with greater modifiable risk. Ideally, risk equations should be developed and validated in the local population. In Australia, algorithms for the general population have been developed from the Busselton8 and Dubbo9 studies. These are important contributions, although the relatively narrow endpoint (in Busselton) and the cohort age (in Dubbo) limit their application. How best can the NVDPA tools be used by practising clinicians? The first step is to identify high-risk groups. These include people with one or more of the following: prior CVD events, peripheral arterial disease, diabetes and age ≥ 60 years, chronic kidney disease, and familial hypercholesterolaemia. Such people should be treated accordingly and do not need absolute risk assessment. In all others, absolute risk assessments should commence at age 45 years, or 35 years for Aboriginal and Torres Strait Islander people, and be repeated at intervals reflecting the initial level of risk.1 An example of how to incorporate absolute cardiovascular risk assessment into management is given in the Box. What we now need is a robust implementation program. This makes economic sense. Recently, the National Health Service Health Check program was released in the United Kingdom.10 Everyone between 40 and 74 years, not already diagnosed with heart disease, stroke or kidney disease, will be invited, once every 5 years, to have their risk assessed using an absolute risk tool, and given support and advice to help them reduce or manage their risk. Analyses showed that this program would be very cost-effective compared with other accepted health interventions. The modelled cost-effectiveness ratio of this UK program is only £2480 per quality-adjusted life-year gained. Presently, in Australia, a Medicare item number supports a single health check for those aged 45–49 years. Although cost-effectiveness analyses are sensitive to the local health care system, the UK data strongly suggest that the current Medicare item number could be expanded, and other systems-based approaches implemented, to ensure that ongoing primary care risk assessments are supported, and that people at higher risk receive lifestyle and appropriate medical management. Implementation would be most likely to be effective if decision-support tools and recall mechanisms were used and incorporated into prescribing linked to electronic health records. Accompanying materials that appropriately communicate concepts of risk to patients would also be useful. The NVDPA is now developing a single CVD risk-management guide that will integrate the various specific risk-factor guides and make it easier to manage patients according to their absolute risk status. Absolute risk assessment does not replace the need to base all approaches to CVD prevention on lifestyle change. Studies have clearly shown the value of this, whether or not individuals are receiving blood-pressure or lipid-lowering therapies.11 However, absolute risk assessment leaves behind time-hallowed approaches based on individual risk factors, treated in silos, and often “dichotomised” to be regarded as “normal” or “abnormal”. It moves us forward to a more rational and effective paradigm for preventing our major health problem. How to incorporate absolute risk assessment into management using the Australian cardiovascular risk charts (the “People without diabetes” section of the charts is reproduced below) Example: Two women with similar risk profiles, but different ages Both women are smokers, without diabetes, with systolic blood pressure, 140 mmHg; total cholesterol : high-density lipoprotein cholesterol (TC : HDL) ratio, 7.2 mmol/L; and body mass index, 27 kg/m2. A is 46 years old and estimated to have a low risk (5%–9%) of developing cardiovascular disease (CVD) within 5 years. However, if she continues to smoke and to have a high TC : HDL ratio, she will place herself at high risk of prematurely developing CVD as she gets older. The chart can be used to demonstrate this to her. The priority intervention should be lifestyle advice, including smoking cessation, physical activity and healthy eating. B is 66 years old and estimated to be at high risk (20%–24%) of having a CVD event within 5 years. As a high priority, she should receive advice about smoking cessation and other lifestyle changes, as well as statin therapy. How to use the risk chart 1. Identify the chart relating to the person’s sex, diabetes status, smoking history and age. The charts should be used for all adults aged 45–74 years (and all Aboriginal and Torres Strait Islander adults aged 35 years or older) without known history of CVD or already known to be at high risk. 2. Within the chart, choose the cell nearest to the person’s age, systolic blood pressure (SBP) and total cholesterol (TC):HDL ratio. For example, the lower left cell contains all non-smokers without diabetes who are 35–44 years and have a TC:HDL ratio of less than 4.5 and a SBP of less than 130 mm Hg. 3. The colour of the cell that the person falls into provides their 5-year absolute cardiovascular risk level (see legend above for risk category). People who fall exactly on a threshold between cells are placed in the cell indicating higher risk. Charts are based on the NVDPA’s Guidelines for the assessment of absolute cardiovascular disease risk and adapted with permission from New Zealand Guidelines Group. New Zealand Cardiovascular Guidelines Handbook: A Summary Resource for Primary Care Practitioners. Second edition. Wellington, NZ: 2009. www.nzgg.org.nz. These charts are taken from Absolute cardiovascular disease risk assessment – quick reference guide for health professionals. © 2009 National Heart Foundation of Australia. Reproduced with permission. No further reproduction is allowed.

Andrew M Tonkin MD, FRACP, FCSANZ · Andrew N Boyden MPH, FRACGP · Stephen Colagiuri FRACP

New guidelines and a multidisciplinary approach have the potential to help patients in need while minimising inappropriate use of opioids With an estimated community prevalence of about 20%, chronic non-malignant pain represents a significant but neglected and often poorly managed problem in Australia. In 2007, the cost of chronic pain to the community was estimated at $34 billion, which included burden of disease and productivity costs, each accounting for one-third of the total, and one-fifth ($7 billion) attributed to health system costs.1 Its prevalence and associated costs will rise as the population ages. The causes of chronic non-malignant pain are many, including rheumatic disorders, injuries and musculoskeletal degenerative disorders, and vary greatly with age, sex and other demographic characteristics. Many doctors currently approach such pain from a narrow biomedical perspective. This too often defaults to the use of opioids under pressures including time constraints, patient demands, and limited access to supports such as pain clinics and physical therapies. The introduction of sustained-release prescription opioids in Australia two decades ago promised a new era in chronic pain management. These agents were preferred because they offered prolonged analgesia with a potentially lower risk of dependence and drug-seeking behaviour. Previously, short-acting opioids had often been prescribed, causing problems when peak effects of analgesia and euphoria alternated frequently with troughs marked by pain and opioid withdrawal. This created conditions conducive to dose escalation and the eventual development of dependence. The shining promise of the sustained-release prescription opioids has been dulled by two main problems. First, the long-term effectiveness and net benefit of opioids in the management of patients with chronic non-malignant pain remain uncertain, reflecting the biopsychosocial complexity of the underlying conditions and the difficulties of performing clinical trials in such heterogeneous populations.2 Second, increasing consumption of sustained-release prescription opioids has been accompanied by some disturbing developments, first reported from the United States. In 2000, drug overdose deaths from prescription opioids, especially from unsanctioned use, began to outnumber deaths from heroin and cocaine.3 Between 1997 and 2007, admissions for treatment of “abuse” rose by 456% for opioid analgesics and 5% for heroin.4 Australia may be starting to follow these US trends, with substantial increases in consumption of oral prescription opioids since 1990,5 and reports of diversion, injection and related harms.6 However, the extent of inappropriate opioid prescribing and of unsanctioned opioid use in Australia cannot currently be determined. Our information systems are not standardised across jurisdictions, are unable to capture all prescriptions (both private and funded by the Pharmaceutical Benefits Scheme), and are not available to intending prescribers and pharmacists. Three overlapping groups — patients with chronic non-malignant pain, patients with malignant pain, and illicit users (of heroin or prescription opioids) — form a potential common market for opioids, with flow-on effects if any group is inadequately managed. The idea of a continuum between opioid use for pain management and addiction underpins the idea of “universal precautions in pain medicine”.7 Inappropriate prescription can lead to problematic use and opioid dependence. The heroin shortage that started in 2000 in Australia was followed by increasing injection of prescription opioids, especially in rural areas and jurisdictions where heroin was scarcest.8 Increasing demand for prescription opioids may arise where there is unmet demand for opioid substitution treatment with methadone or buprenorphine. People on low incomes may be tempted to request and on-sell prescription drugs to the black market as demand and prices increase. These considerations underpin the desirability of a broader biopsychosocial framework for the assessment of patients with chronic non-malignant pain, and a greater role for non-pharmacological interventions. Such interventions are scarce and underfunded in primary care. Australia has the most developed training program for pain medicine worldwide, but there are too few specialists and there is great demand for pain clinics. In an effort to bring these complex issues to the fore, the Royal Australasian College of Physicians (RACP) has released a prescription opioid policy;9 the Box contains a summary of its recommendations. Reflecting the complex nature of the subject, the report was prepared by an interdisciplinary group, including representatives from the RACP, the Royal Australian College of General Practitioners, the Royal Australian and New Zealand College of Psychiatrists and the Faculty of Pain Medicine of the Australian and New Zealand College of Anaesthetists. The challenge is to provide a better balance between two, sometimes competing, objectives — encouraging more appropriate opioid prescription for patients with chronic non-malignant pain while reducing unsanctioned use of opioids, whether by patients or illicit users. No single health discipline can overcome these complex problems, but a truly multidisciplinary approach has the potential to achieve great advances. The current situation not only results in frustration for patients and families, but also undermines the good standing of the medical profession. The present unhappy cocktail includes patients with chronic, complex painful conditions; doctors who lack succinct uniform guidelines, real-time prescription monitoring information and ready access to relevant specialist advice; and a setting where authorities must minimise diversion of prescription opioids. In 2008, unmet demand for opioid substitution treatment was estimated to exceed the 39 000 patients then in such programs.10 Better tailoring of such treatment to also meet the needs of people dependent on pharmaceutical opioids, many of whom have never previously sought help, may attract and retain more patients in effective treatment. This would most likely decrease the demand for black-market prescription opioids. Australia has a unique opportunity to improve management of patients with chronic non-malignant pain and people who become dependent on opioids; to reduce inappropriate prescribing of opioids; and to avoid the problems that have bedevilled the US. The most important step required is establishing a group with sufficient authority to achieve wide consensus on an action plan and then implement and coordinate national change across jurisdictions, professions and disciplines (especially general practitioners and pharmacists). As most management of chronic non-malignant pain occurs in general practice, little will be achieved unless and until GPs are provided with more support and better linkages to critical specialties. Summary of recommendations of the Royal Australasian College of Physicians report9 1. Establish a national expert advisory group to develop a coordinated approach to implementing the recommendations below, to improve management of chronic non-malignant pain and reduce problematic use of pharmaceutical opioids. 2. Develop guidelines for management of chronic non-malignant pain appropriate for and accepted by general practitioners, integrating non-pharmacological elements of treatment with pharmacological approaches within a biopsychosocial framework, and providing widely accepted standards for audit and feedback. 3. Enhance clinical practice, with improved support for GPs and better linkages to relevant specialties, especially pain medicine and addiction medicine. 4. Improve information systems, with one national, web-based system that includes private and Pharmaceutical Benefits Scheme prescriptions and provides information for prescribers and pharmacists in real time. 5. Standardise regulation and control across jurisdictions. 6. Minimise unmet demand for opioid substitution therapy, and revise it for people dependent on pharmaceutical opioids to decrease the demand for black-market prescription opioids. 7. Improve integration of College training programs in the fields of pain medicine, addiction medicine, psychiatry and general practice. 8. Increase applied research to reduce gaps in knowledge and improve health service delivery.

Alex D Wodak FRACP, FAChAM, FAFPHM · Milton L Cohen MD, FRACP, FFPMANZCA · Malcolm D H Dobbin PhD, FAFPHM, MPH · Richard A Hallinan BMed, FAChAM · Mary Osborn MPubHlth

To provide the ongoing robust evidence needed for workforce planning, a national longitudinal study will itself need to be sustained into the future Globally, medical workforce shortages and maldistribution are major impediments to providing accessible, sustainable and safe health care.1,2 Strategic medical workforce planning is essential for resolving this problem. This requires up-to-date, robust data to predict future trends and, most importantly, give sound insights into the underlying determinants of workforce patterns and choices for workforce participation. Many countries have sought to develop appropriate medical workforce data collection mechanisms for tracking practitioners from graduation through employment, with varying degrees of success.3,4 Rural medical workforce shortages have been the impetus for several of these collections. Experience from these highlights the importance of comprehensive, systematic and ongoing quantitative data collection, and the value of establishing a minimum data collection system from the outset of a medical education program.5-9 In Australia and New Zealand, a small number of cross-sectional workforce studies have been undertaken in the past.10 A major limitation in using the disparate research outcomes of these to inform policy directions is the lack of connection between studies of students, current practitioners and past practitioners. Evaluations of government health workforce initiatives in Australia and New Zealand further emphasise the need for a uniform data collection methodology as the basis for tracking the progress of students throughout their training program and beyond.11-13 All of these approaches highlight the fundamental problem — a series of cross-sectional studies and evaluations “stitched together” to answer workforce questions will always provide less robust evidence than a well conducted, purpose-built, ongoing study. Sound medical workforce planning requires longitudinal data. Responding to this need, Medical Deans Australia and New Zealand (MDANZ) established the Medical Schools Outcomes Database (MSOD) and Longitudinal Tracking Project in 2005. This project collects reliable demographic and educational data about medical students across all Australian and New Zealand medical schools. To date, data have been collected on at least 11 200 medical students in Australia over 5 years of their training. Using an agreed national minimum dataset based on consistent definitions, the project targets critical times of medical career decision making — at the commencement of, and exit from, medical school; during the intern year; and during postgraduate training. Demographic information and data on vocational and practice location intentions are collected from surveys of students commencing medical school. Data obtained directly from the medical schools provide information on the nature of the students’ education and clinical experiences; for example, the length and nature of rural exposure, or membership of rural health clubs. Exit surveys of students again collect demographic data, vocational and practice location intentions, data on factors influencing career choices, and future contact details. Initial results from the MSOD show that length of residence in a rural area, generalist practice intention, and financially supported study (but not a bonded arrangement) are the strongest predictors of intention to take up rural medical practice. In addition, changing trends towards intended take-up of specialties are apparent — for example, a steadily increasing proportion of students intending to take up general practice was apparent between 2006 and 2008.14 In short, excellent data now exist to benchmark the impact of medical education and training activities. Success for this project requires more than a strong interest in evaluative medical education research. Other important catalysts have included champions (leading medical education researchers and medical school deans), resources (national funding provided by the Australian Government), a mandate (national auspicing by MDANZ to ensure comprehensive collection of relevant data), and timing (eg, to assess the impact and effectiveness of specific Rural Undergraduate Support and Coordination program funding designed to increase the numbers of students taking up rural practice). Importantly, the process for establishing the MSOD drew on international expertise to identify possible pitfalls and to help realise its potential. Professor Howard Rabinowitz, a rural workforce expert in the United States who played a leading role in a medical school longitudinal study in Pennsylvania, was engaged in an advisory capacity at the outset and continues to have an ongoing role. The MSOD will allow both short- and long-term monitoring and reporting on outcomes of medical education programs, and will inform national workforce policy implementation. It can contribute to evaluating the effectiveness of federally funded medical education initiatives in achieving improved medical workforce recruitment and retention. It complements activities of bodies such as the National Health Workforce Taskforce (NHWT), state and territory medical boards in Australia, and the Medical Council of New Zealand. It has the potential to link with data collected by the NHWT and other similar groups to track graduates after they leave medical school. This will allow further exploration of factors influencing career choice and destination, and continued data collection on the location and types of their clinical experience. Linking the MSOD with the forthcoming national medical registration system has the potential to identify specialty, practice location and changes in patterns of medical practice. In addition, the MSOD project offers a facility for conducting targeted substudies of specific policy or research questions, not unlike other well known longitudinal studies such as the 45 and Up Study.15 The project has access to 100% of the relevant student doctor population, and to date has achieved a student participation rate of around 95%, providing a high-quality sampling frame on which to base any empirical study. MDANZ considers MSOD an essential resource and is fully committed to its success — but is this sufficient to ensure its sustainability? Given the tyranny of distance, the process of bringing diverse groups together has required fostering trust and collegiality among all players around a shared project goal, in order to minimise competition and apprehension. Moreover, longitudinal studies have a long lead time before results become apparent, and convincing funders that outputs will justify the time and resources needed requires good ongoing communication and strong partnership arrangements. The Australian Government Department of Health and Ageing has provided crucial financial support that has produced a solid foundation without which the MSOD project would not have progressed. Several factors have been built into the project with a view to ensuring its sustainability. The database has not been produced by any one individual, university or workforce organisation. Instead, a collective approach that reflects all parties as equal partners is led by the MDANZ steering and management group. The process is underpinned by project officers who liaise with stakeholders. Project objectives, processes and desired outcomes are shared by all parties, and stakeholders are regularly engaged in full and open discussion of any likely sticking points, including ethics, ownership of data, roles and responsibilities. Agreed principles (such as simplicity, necessity, consistency, objectivity, sufficiency and relevance) guide the data collection process and support the intended outcomes. While all medical schools share a belief that the total good is more valuable than the sum of the parts, there is ample opportunity within the MSOD and Longitudinal Tracking Project to conduct rigorous substudies, either by individual medical schools or in partnership with others. Sound medical workforce policy decisions and reforms cannot be made in the absence of quality longitudinal data. The MSOD project is unique, well established and running effectively. With the continued and sustained commitment of MDANZ and the Department of Health and Ageing, the full potential of this resource as a valuable platform for informing a more coordinated approach to medical workforce planning will be realised.

John S Humphreys BA(Hons), DipEd, PhD · David Prideaux BA(Hons), MEd, PhD · Justin J Beilby MB BS, MD, FRACGP · Nicholas J Glasgow MB ChB, MD, FRACGP

Don’t just report, respond — inaction injures children Every Australian state has enacted mandatory reporting of child abuse. Child abuse is a ubiquitous problem affecting at least one in 13 children, and among Indigenous Australians, this rate is higher.1 The most important comorbidities for child abuse — poverty, domestic violence, mental ill health and substance misuse2 — are seen by all health professionals on a daily basis. Mandatory reporting of child abuse aims to achieve better outcomes for children and families where abuse is thought to have occurred or has occurred. It arose in the United States out of the correctly perceived need to allow health workers to report concerns about child abuse to statutory child protection agencies without fear of subsequent litigation for breach of confidentiality. The assumption is that the child protection agency will pick up the baton and protect the child. Current research clearly indicates that this is not the case.3 The recent Wood Inquiry into the New South Wales child protection agency (Department of Community Services) has outlined the perils of this false expectation; no child protection agency can cope with all the referrals that it receives.4 Mandatory reporting is not essential to good child protection. However, good communication between agencies and practitioners is essential; when this fails, disaster strikes. There are, sadly, many examples of these failures in Australia (where the case of Daniel Valerio is one of the best known5) and overseas (eg, the cases of Victoria Climbié6 and Baby P7). Management of child abuse does require mandatory responding. There is an obligation on each and every one of us who work in the community as a health professional to respond, and this must involve more than completing a mandatory reporting form. If we are to make a difference to children’s lives, all health professionals must respond when they suspect child abuse. The difficulty for all of us is that, unlike in other areas of medical practice, few patients are either willing or able to outline their suffering in a standard consultation. On many occasions, the parent deliberately sets out to mislead the practitioner in situations where child protection issues exist. This may be done maliciously, out of pride, or out of fear of prosecution. Thus health professionals need to have an index of suspicion, and then act on that suspicion in a way that does not jeopardise further the safety of the child. This suspicion is often outside the comfort zone of many health care practitioners. Of reports made to statutory agencies, substantiation rates vary from 2.4 to 9.3 per 1000 reports.1 Substantiation is not a cure for the child in question; all it does is confirm that the original concerns were correct and that the child needs help. The vast bulk of cases are unable to be substantiated, and this may result in the protection agencies feeling that such cases are no longer a priority; this potentially endangers children even further. The onus is thus on health practitioners, you and me, to respond.8 How can we do this? Responding can take many forms, depending on what is needed. It must never be assumed that someone else will fix it. If a particular case requires major social intervention, and if statutory agencies have not acted or have acted inappropriately, phone/write/fax/email them and alert them to your concerns. On occasion it may entail being more tenacious than you are used to being. If the issue is the mental ill health of a parent or child, ensure that the parent gets help either from you or from someone else. This may require repeated contact with mental health agencies. Mental Health Care Plans are very useful in this setting. Child abuse is a criminal matter that puts children at risk. In such cases, ensure that police are involved and are taking appropriate action. If there are medical matters affecting a parent’s ability to parent, these need to be addressed. If you are in doubt about what you see when a child presents, arrange for the child to be admitted and for the protection issues to be investigated while the child is safe. At a general practice level, responding appropriately in child protection cases may involve reviewing the patient on a number of occasions in order to obtain a clearer picture, and being in contact with your local child protection agency and other health care providers. Doctors often falsely believe that they can do better alone than by involving child protection services.9 Every capital city in Australia has at least one child protection unit at their children’s hospital, from where advice can be obtained. There is often a moral and legal fear that reporting may do more harm than good for the child and his or her family. A groundless report can cause anguish; however, inaction injures many more children than the odd report that should not have occurred. With Australia-wide mandatory reporting, the onus is now on us to provide mandatory responding. Only by responding in an appropriate manner, case by case, will we be able to facilitate better outcomes for children and, in turn, for society at large. Mandatory responding at the individual level and as a public health issue is the universal panacea for child abuse; mandatory reporting is only one tool in that response.

Peter M Winterton BA, MB BS, FRACGP

“Second-generation” clinical trials are refining the use of toxic and expensive drugs, but “silo” regulatory and funding structures prevent Australia participating The development of drugs aimed at new molecular targets exemplifies the power of translational research — “bench to bedside” translation of biomolecular science into clinical practice — to offer both significant clinical outcomes and the opportunity for commercial benefit. Classic examples are the monoclonal antibody trastuzumab for HER-2 receptor-positive breast cancer and the “designer” small-molecule inhibitor imatinib for BCR/ABL-positive chronic myeloid leukaemia.1,2 However, in Australia, there are structural constraints on funding for translational clinical research that prevent us participating fully in its clinical and financial benefits. To understand these constraints, we need to examine the roles of the various regulatory and funding bodies in Australia — the Pharmaceutical Benefits Scheme (PBS), Medical Services Advisory Committee (MSAC), Medicare, and the National Health and Medical Research Council (NHMRC). We also need to consider their different attitudes to “primary” and “second-generation” clinical trials. Pharmaceutical companies devise clinical trial strategies to register their drugs as rapidly as possible. These “primary” trials are conducted by large groups and provide high statistical power;3 the resulting data form the basis for drug marketing and reimbursement in Australia by the PBS. In contrast, “second-generation” trials apply new pathological and radiological technologies to refine treatment schedules and identify patient subgroups in whom new drugs have optimal clinical and cost-effectiveness. Second-generation trials have the potential both to improve clinical outcomes and to reduce costs. In Europe, second-generation studies refining dosage and patient subgroups are emerging through government-funded cooperative trial groups. Such studies require integrated funding of imaging, molecular analysis and pharmaceutics. This is currently not possible in Australia, reflecting “silo”-like structural barriers that prevent the PBS, MSAC and Medicare commissioning research. These regulatory bodies are unable to look beyond primary marketing data submitted by industry. They are unable to commission evaluation of the integration of diagnostic and therapeutic modalities. The optimal indications, schedules and duration of use of expensive pharmaceuticals cannot be effectively investigated in Australia — our superb collaborative clinical trial organisations are structurally limited to first-generation industry-funded studies, unless they can obtain funding through competitive grant systems that are neither pragmatically nor economically orientated. Two examples of second-generation trials that Australian groups have not accessed, reflecting the inability of the regulatory silos to fund such activity, are: Trastuzumab in HER-2 receptor-positive early breast cancer.4 Based on initial trials, current therapy is a 1-year course of the monoclonal antibody trastuzumab, at a cost to the PBS of about $50 000 per course. Separate European groups are currently investigating 3-month and 6-month versus 12-month courses with potential for dramatic cost savings and reduction in toxicity. Oxaliplatin in stage II colorectal cancer.5 Current therapy includes a 6-month course of this expensive and toxic drug at an overall cost of about $20 000. European groups are comparing 3-month versus 6-month courses, which could increase cost effectiveness and reduce toxicity. An application by an Australian group to the NHMRC to fund participation in this cost-neutral study was not ranked highly enough based on “lack of innovation” (Professor J Zalcberg, Peter MacCallum Cancer Institute, Melbourne, VIC, personal communication). A solution to the disconnection between regulation and funding could be to develop relationships between the PBS, MSAC, Medicare and others to address funding of the translation of new diagnostic and therapeutic technologies into practice. The treatment of cancer is an ideal model for this, given its interdependence on imaging, molecular pathology and targeted therapeutics.6 The stakes are high. In the 2005–06 financial year, the PBS cost7 Australia more than $6 billion, and its cost is increasing rapidly. The current Health Technology Assessment review to examine Therapeutic Goods Administration and MSAC procedures may solve some of these problems; it has noted the need to coordinate Pharmaceutical Benefits Advisory Committee and MSAC recommendations.8 One solution could be the creation of an “Emerging Technology Assessment Group”, representing the PBS, MSAC, Medicare, NHMRC and the cooperative clinical trials groups, supported by health economics input. This group could recognise emerging issues and commission appropriate second-generation trials. These would almost certainly be associated with international groups using the European model. These trials would be cost-neutral, reflecting reduced drug usage in the experimental arms. There may even be a place for a “health dollar offset trading scheme” (analogous to carbon emissions trading schemes) between the PBS, MSAC and Medicare. The second-generation trials would represent a new form of postmarketing surveillance, with the emphasis moving from assessing toxicity to optimising clinical and cost outcomes through the application of technology to translate into rational therapeutics. We should not adopt the simplistic solution of using NHMRC funding for these trials, as this would exacerbate the cost-transfer silo problem. The scheme should also recognise the need for Australian Health Care Agreements to appropriately support clinical research and infrastructure funding in teaching hospitals.

Richard M Fox MB BS, PhD, FRACP

Supporting trainees more effectively will benefit doctors and patients In this issue of the Journal, Hore and colleagues discuss clinical supervision in postgraduate medical education.1 They identify multiple difficulties and signal the need for adequate training and supervision, and for environments that support such supervision. What is meant by supervision?Previous articles have discussed the concepts of clinical supervision and educational supervision. There are a number of definitions of supervision; a useful one is “the provision of guidance and feedback on matters of personal, professional and educational development in the context of the trainee’s experience and providing safe and appropriate patient care”.2 This definition links provision of care with personal, professional and educational enrichment. It is further underpinned by the notion of provision of guidance and feedback. Supervision can be considered to have at least three discrete functions: educational, supportive, and managerial or administrative. Supervision should be regular, structured and should relate to agreed-upon learning objectives.3 Is supervision of junior doctors important for patient care?There is evidence from the Netherlands and the United States that training in teaching skills results in positive changes in the teaching and supervisory behaviour of medical doctors.4,5 Additionally, when provided effectively, supervision not only improves trainees’ performance, but also improves patient outcomes.4,5 Health authorities are increasingly recognising that support of education and supervision may lead to better health outcomes. Indeed, closer to home, the Special Commission of Inquiry into Acute Care Services in NSW Public Hospitals (the Garling inquiry) identified a number of issues in the New South Wales health service;6 for example, Recommendation 30: Benchmarks which adequately measure the extent of the delivery of postgraduate clinical education and training should be included in performance agreements between NSW Health and area health services and statutory corporations.6 Is supervisory input into our doctors’ professional development important?The educational supervisor has been considered the most critical figure in ensuring the effectiveness of postgraduate medical training.7 Appropriate supervision demonstrates evidence of commitment by educational supervisors to trainees. Critical elements of effective supervision include: providing constructive feedback; offering career advice; helping set learning objectives; listening rather than talking; taking into account trainees’ individual needs; and being encouraging. This type of supervision leads to improved professional development among trainees.8 Is the environment within the health system supportive of supervision?Hore and colleagues’ article clearly shows that the Achilles heel of supervision is the environment within Australian hospitals in which supervision is delivered. They argue for the creation of systems, environments and cultures that support high standards of conduct and effective clinical supervision.1 The Royal Australasian College of Physicians, which trains the largest number of trainees in Australian hospitals, has recently developed a new basic training program called the PREP (Physician Readiness for Expert Practice) Program. The core aspect of this program is effective educational supervision provided by consultants to help trainees construct learning goals, reflect on their learning needs, work with their developing medical professionalism, and closely link their learning experience with the curricula objectives for training. This grand design has a fundamental flaw — it requires extensive supervision in the health sector. Currently, the health sector is struggling to provide the human and financial resources required for effective supervision. Given the evidence that effective supervision not only develops the medical professionalism of a trainee, but can also lead to improved safety and better health outcomes for patients, it would seem clear that the provision of adequate supervision for our trainees is a high priority for our health system. Several comments and recommendations in the Garling report support this, such as: It is absolutely clear to me that there is a culture of service delivery in most hospitals that does not value teaching and education and that effort needs to be made to overcome this culture. The current system for education and training, which is largely opportunistic and ad hoc, will only become more difficult to sustain as hospitals become busier, and in the area of medical education, the number of medical graduates increases. (paragraph 10.12) . . . In my view, what is required is the recognition of the importance of the role of clinical teacher in the provision of facilities for and the dedication of time for teaching. (paragraph 10.102)6 There are multiple demands on our health service. Attending the sick does take priority. However, an examination of the literature around how we prepare and train our doctors during their training programs quickly demonstrates that the provision of good supervision to these trainees yields multiple benefits in that they are better equipped for the work they do, and this will be reaped many times over during that individual’s professional life. There is a need to systematically address the issues of good supervision for our trainees, with a particular emphasis on supporting them educationally and professionally.

Kevin D Forsyth MD, PhD, FRACP

Regardless of how obstructive lung disease is labelled, targeting treatment to components of the problem is the best solution Three-quarters of deaths due to asthma in Australia occur among people aged 55 years or older.1,2 Many more deaths and hospitalisations in older people are attributed to chronic obstructive pulmonary disease (COPD).2 Between 1997 and 2003, 318 deaths per year were attributed to asthma and 5581 deaths per year were attributed to COPD among Australians aged 55 and over.2 How can we do better than we are now in dealing with this problem? First, we need to consider whether we are dealing with two separate problems, or one, or several. This is the subject of some controversy. It has been argued for many years that the terms “asthma” and “COPD” are not particularly useful for clinicians in defining a disease or syndrome, particularly in older people.3 However, the terms are entrenched in clinical usage and, in the case of asthma, general usage. Furthermore, separate guidelines have been promulgated for both conditions. People who are labelled as having asthma have diverse clinical characteristics, and some people with other disease labels have clinical characteristics similar to those labelled as having asthma. There are very few features of aetiology, pathology, natural history, or management strategy that are uniquely linked to the diagnostic labels of asthma or COPD. Our view is that we are dealing with a diverse range of disorders that cannot be adequately classified simply as either “asthma” or “COPD”. The real problem we face is obstructive lung disease, whether it carries the label asthma, COPD, emphysema, or chronic bronchitis. Obstructive lung disease exists as a heterogeneous disorder affecting people of all ages. The manifestations of the disease may include episodic breathlessness (with or without cough) and progressively worsening exertional breathlessness and airflow limitation. In some individuals, this may progress to respiratory failure. Avoidance of smoking prevents one form of the disease, reduces the rate of lung function decline, and improves treatment response in more reversible disease. Rigorous attention to occupational hygiene in high-risk workplaces can prevent some cases of the disease. Reducing indoor exposure to smoke and fumes from biomass fuels may also prevent some forms of obstructive lung disease.4 However, no other preventive strategies are supported by available evidence. The range of management strategies that are available may control the disease, but do not cure it. In clinical practice, the various labels for obstructive lung disease tend to be applied in a fairly haphazard manner.5,6 This is not only because it is difficult to distinguish them clinically but also because there appears to be little point in doing so. Clinical management is most often guided by other characteristics. Among all patients with obstructive lung disease, management is targeted at person-centred problems: for example, pulmonary rehabilitation for breathlessness and loss of physical condition;7 bronchodilators for airflow obstruction and hyperinflation; inhaled corticosteroids for airway inflammation; smoking cessation for smokers; and influenza vaccinations for all those who are at risk of exacerbations. There is also increasing recognition of the need to assess and manage systemic problems and relevant comorbidities in older people with obstructive airway disease.8 In addition to addressing patients’ current problems, assessing their future risk is also important, and anticipation of exacerbations and deterioration will facilitate planning and better management. Targeting treatment to components of the problem in this way may overcome the limitations of a diagnosis-centred approach, and accords with multicomponent-based approaches to illness that are effective in older people.9 Such an approach is also well suited to primary care, where patients present with symptoms, activity limitation and concerns about the impact of the disease on their daily life. Having established that we are dealing with a heterogeneous disease entity with a range of clinical problems, and solutions specific to these problems, what are the barriers to making progress with this disorder? There is evidence of generally poor diagnostic evaluation of symptomatic patients; inadequate availability of some effective therapies, particularly in disadvantaged populations1 and those in rural and remote areas; and lack of services for severely disabled (breathless) patients. Simple interventions such as educating patients on correct use of devices, vaccinations, and prompt treatment of infective exacerbations are not universally implemented. Patients with severe, end-stage airways disease often do not receive appropriate referral for oxygen therapy and frequently miss out on appropriate guidance and discussion of end-of-life issues.10 If these are the barriers to better outcomes for patients with obstructive lung disease, how do we overcome them? Diagnosis is the doorway to effective management and hence improved clinical outcomes. However, for some breathless patients, the correct diagnosis is elusive. Cardiac failure, obesity, anaemia and general unfitness, as well as obstructive lung disease, may individually or collectively cause breathlessness in older patients. Spirometry is crucial to the diagnosis of obstructive lung disease and assessment of its severity, and yet few patients who present with breathlessness have an assessment that includes this procedure. For example, only 6% of general practice encounters for asthma among adults include an assessment of lung function.1 The optimal mechanism for improving patients’ access to spirometry is yet to be established.11 Equipping, training and remunerating general practitioners for performing the procedure is one approach that has been tried12 and may prove more effective as practice nurses are deployed more widely. The alternative is to improve accessibility of specialist pulmonary function laboratories. This latter approach has the advantage of high standards of quality control and linking the procedure to expert interpretation. We need translational research studies to identify the most effective strategy for ensuring that all patients with undiagnosed breathlessness or suspected obstructive lung disease have a valid and reliable objective assessment of their lung function. In a substantial proportion of patients with obstructive lung disease, regular use of inhaled corticosteroids has been shown to be effective in improving a diverse range of clinical outcomes. In particular, patients with reversible airflow obstruction, eosinophilic inflammation,13 severe airflow obstruction and frequent exacerbations gain significant benefits from regular inhaled corticosteroid use.14,15 Research at the Australian Centre for Asthma Monitoring has shown that people who purchase inhaled corticosteroids at the concessional Pharmaceutical Benefits Scheme price are dispensed 2.5 times more prescriptions for these medications than those who pay the full (general beneficiary) price.16 While some of this difference may indicate unnecessary or excessive use, it is clear that a scheme that makes drugs from this class available at a reduced price to those who are most likely to benefit from them and cannot currently afford them will result in substantial health gains. Breathlessness is not only a distressing symptom but also a disabling one. People who are disabled due to breathlessness are poorly served in our community. Exercise-based pulmonary rehabilitation is one intervention that has been shown to help people with this problem. Although many tertiary care hospitals have established programs to deliver pulmonary rehabilitation, their location, predominantly in major centres, means that many people who stand to benefit from these programs cannot access them. We need improved transport services to bring severely breathless patients to the services they need. Surely this is more cost-effective than trying to deliver individualised pulmonary rehabilitation in the home. People who are disabled by breathlessness, either temporarily during exacerbations or permanently, are often institutionalised because they cannot maintain their homes or perform self-care tasks unaided. Provision of enhanced home-help and self-care assistance would enable some of these people to fulfil their desire to stay at home and away from hospitals and other care institutions. As National Asthma Week (1–7 September 2009) approaches, it is time to act now to adopt policies promoting a holistic, person-centred and problem-oriented approach to the care of older people with obstructive lung disease, whether it is labelled as asthma or COPD, or not labelled at all.

Guy B Marks PhD, FRACP · Leanne M Poulos BMedSc(Hons), MPH(Hons) · Christine R Jenkins MD, FRACP · Peter G Gibson MB BS, FRACP

Large-scale randomised controlled trials in Europe and the United States are informing evidence-based clinical advice Population-wide prostate-specific antigen (PSA) screening for prostate cancer is not recommended in Australia, primarily because of the lack of large-scale randomised trial evidence of a beneficial effect on prostate cancer mortality and the known harms of overdiagnosis and unnecessary treatment that may ensue. In spite of this, PSA testing is common; the limited evidence available suggests that more than 50% of Australian men over the age of 50 years have had the test.1,2 In March 2009, the New England Journal of Medicine published the first articles from two large, randomised controlled trials to report on whether screening for PSA reduces the risk of death from prostate cancer.3,4 It was hoped that these long expected — albeit not final — reports from the European Randomized Study of Screening for Prostate Cancer and the prostate cancer component of the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (Box) would answer outstanding questions about the efficacy of prostate cancer screening. In the European trial, 162 243 men aged 55–69 years were randomly allocated to receive an invitation to undergo PSA screening about once every 4 years or usual care. After a median of 9 years of follow-up, there were 71% more cases of prostate cancer and a 20% reduction in the risk of death from prostate cancer in those allocated to screening than in those receiving usual care (relative risk [RR], 0.80; 95% CI, 0.65–0.98), but no reduction in overall mortality (RR, 0.99; 95% CI, 0.97–1.02). In the US trial, 76 693 men aged 55–74 years were randomly allocated to receive an annual PSA test for 6 years and an annual digital rectal examination for 4 years, or usual care. After a minimum of 7 years of follow-up, there were 22% more cases of prostate cancer but no reduction in the risk of death from prostate cancer in those randomly allocated to screening compared with usual care (RR, 1.13; 95% CI, 0.75–1.70). The trials have a number of notable differences, including length of follow-up, screening interval, PSA threshold for recommending biopsy, and proportion of the control group screened (Box). Although these differences prevent easy comparison of their results, it is important to note that the relative risks for prostate cancer mortality with screening do not differ significantly between the trials (χ12 = 2.19, P = 0.14), and that the 95% confidence interval about their summary relative risk, estimated using fixed-effects meta-analysis, includes unity (summary RR, 0.86; 95% CI, 0.71–1.03) (Box). These trials have important limitations. First, their combined power is low, so that a moderate beneficial effect of screening cannot be established or excluded without longer follow-up or other trials. Moreover, in the US trial, although 85% of the screening arm had a PSA test, so too did 52% of the control arm. With only a 33% difference in screening between the groups, the power of the study to detect an effect of screening was substantially reduced. Screening in the control arm of the European trial was not reported. Second, the trials are yet to report on other outcomes of PSA screening, including major treatment side effects, which are crucial to deciding whether large-scale screening is appropriate. The risk–benefit equation for PSA screening is complex. The major potential benefit is a reduction in risk of death from prostate cancer. The main risks are physical or psychological complications of screening and detection, overdiagnosis and concomitant treatment side effects, and unwarranted costs. Some elements of these risks were reported in the European trial. Overall, 16.2% of all PSA tests gave positive results and presumably led to biopsy, and 75.9% of these were found to be false-positives.4 The risk of undergoing radical prostatectomy in the screening group was nearly three times that in the control group (277 versus 100 per 10 000 men).5 To prevent one prostate cancer death, 1410 men needed to be screened, and 48 men needed to be treated.4 Although the number needed to screen compares favourably with that for breast6 and colorectal7 cancer, the issues around overdiagnosis are probably greater for prostate cancer. The cost-effectiveness of PSA screening is yet to be established. Even if it were shown to be favourable, the appropriate testing interval, target age range and PSA cut-off levels are not known. Hence, the persisting uncertainty about the effect of PSA testing on mortality is compounded by other outstanding questions. What are the implications of the trial results for men and their doctors? The findings of these studies are finely balanced. Before they were reported, we had no valid randomised trial evidence; now we have evidence, but it is inconclusive and consistent with a modest but uncertain reduction in prostate cancer mortality at 10 years. Both trials can continue to inform us with longer-term follow-up and comprehensive assessment of all treatment outcomes. What is the best advice that we can give now about PSA screening for prostate cancer? Population-wide PSA screening should not be recommended. The findings from these two studies provide important evidence but are not adequate to allow a conclusion either for or against a benefit of screening. In addition, they reveal potentially high levels of overdiagnosis and its consequent costs and harm. For individual men considering PSA screening, the potential risks and benefits should be carefully considered. Information from these trials and other studies, and data on the potential of treatments for localised prostate cancer to affect quality of life should be communicated, stating that uncertainty continues to cloud this issue. Clearly, men with a life expectancy of less than 10 years are particularly unlikely to benefit from screening, but those who wish to be tested after considering the evidence available should be given the test. Clinical practice includes treating patient concerns and worries, so that if a well informed man really wants to know whether he has prostate cancer, proceeding with PSA testing is a reasonable step. GPs play a crucial role in disclosing the uncertainties of PSA testing and in supporting men in their decision making. Research assumes even greater importance when decision making is clouded by uncertainty. There is a clear need for more evidence on all effects of PSA testing. A greater understanding of decision making around PSA testing is also needed,8 as is better information to help men and their doctors address the issue. Whether screening for prostate cancer lowers risk of death from prostate cancer remains uncertain. However, our uncertainty is increasingly based on evidence, which is far preferable to uncertainty based on ignorance. Characteristics of two published randomised controlled trials of the effect of PSA screening on prostate cancer mortality ERSPC (n = 162 243) PLCO (n = 76 693) Trial period 1991–2003 1993–2001 Age range (years) 55–69 55–74 No. of participants (S v C) 72 890 v 89 353 38 343 v 38 350 Average screening interval 4 years 1 year PSA cut-off for biopsy 3 ng/mL* 4 ng/mL Tested with PSA (S v C) 82% v not stated 85% v 52% Prostate cancers (no.) 5990 v 4307 2820 v 2322 Cumulative incidence of prostate cancer (S v C) 8.2% v 4.8% 7.4% v 6.1% RR (95% CI) of incident prostate cancer in S v C 1.71 (1.64–1.78)† 1.22 (1.16-1.29) No. of prostate cancer deaths (S v C) 214 v 326 50 v 44 Prostate cancer death rate (per 10 000 person-years) (S v C) 3.3 v 4.1 2.0 v 1.7 RR of prostate cancer death in S v C (95% CI) 0.80 (0.65–0.98) 1.13 (0.75–1.70) Summary RR of prostate cancer death in S v C (95% CI) 0.86 (0.71–1.03)‡ PSA = prostate-specific antigen. ERSPC = European Randomized Study of Screening for Prostate Cancer. PLCO = prostate cancer component of the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. S = screening group. C = control group. RR = relative risk. * Two centres had slightly different cut-offs, of around 4 ng/mL. † Calculated from data presented in the report of the ERSPC, Table 1, using a Poisson approximation for the variance. ‡ χ2 (heterogeneity) = 2.19, P = 0.14.

David P Smith BA, MPH, PhD · Emily Banks MB BS(Hons), PhD, FAFPHM · Mark S Clements BSc(Hons), PhD · Robert A Gardiner MD, FRCS, FRACS · Bruce K Armstrong MB BS(Hons), DPhil, FAFPHM

Australia is in a unique position to assess the impact of two different rotavirus vaccines In 1973, Ruth Bishop and her colleagues in Melbourne were the first to identify rotavirus gastroenteritis in infants. Rotavirus has since been recognised as the most frequent cause of severe childhood gastroenteritis worldwide. In temperate climates, infection occurs predominantly in winter and spring. The spectrum of disease ranges from severe gastroenteritis to mild or clinically inapparent infection. Reinfection is common. In Australia, the peak age of hospitalisation for rotavirus infection is 6–24 months; however, in Indigenous children, infection occurs earlier and is more severe.1 About half of the 20 000 annual hospitalisations for acute gastroenteritis in Australian children under 5 years of age are attributed to rotavirus.2 The first rotavirus vaccine licensed in the United States (RotaShield [Wyeth, Madison, NJ, USA]) was withdrawn from use in 1999, after barely 9 months, due to an increased occurrence of intussusception after vaccination (attributable risk, one case per 10 000 vaccine recipients). Two other live attenuated oral vaccines (RotaTeq [Merck, Whitehouse Station, NJ, USA], a pentavalent human–bovine reassortant vaccine; and Rotarix [GlaxoSmithKline, Rixensart, Belgium], a human monovalent vaccine) have recently been approved for use in many countries after extensive clinical trials showed them to be effective against the most common circulating strains, and found no evidence of an association with intussusception.3,4 The RotaTeq vaccine was introduced into the US vaccination schedule in February 2006. A report from a national network of sentinel laboratories, published in June 20085 and updated in October 2008,6,7 shows that the 2007–2008 US rotavirus season was significantly delayed, shortened and diminished compared with the 2000–2006 seasons. Only 4% of children aged under 3 years who were hospitalised with acute gastroenteritis had rotavirus-positive stools in 2008 compared with 56% in 2006, and only 9% of emergency room patients with acute gastroenteritis tested positive for rotavirus compared with 58% in 2006. Reductions in hospitalisation of up to 85% for rotavirus gastroenteritis and 56% for all-cause diarrhoea in young children were also reported, suggesting very large savings in hospital costs.6 Although these findings need confirmation over future seasons, this rapid vaccine impact is particularly striking given that, at the time, the estimated vaccine coverage was just 56% for one dose in infants aged 3 months and 34% for three doses by age 13 months.5 Reassuringly, preliminary data from surveillance in the US over the first 19 months of its rotavirus program, when over 9 million doses of vaccine were distributed, do not indicate any association of RotaTeq with intussusception or other serious adverse events.8 In Australia, rotavirus vaccination commenced in the Northern Territory in October 2006 and in the remaining jurisdictions in July 2007. Rotarix is used in the NT, New South Wales, Tasmania and the Australian Capital Territory, and was used in Western Australia until May 2009. RotaTeq is used in Victoria, South Australia and Queensland. This geographical split results in about half of the birth cohort receiving Rotarix (two-dose schedule) and half receiving RotaTeq (three-dose schedule). Program implementation has been faster in Australia than in the US, with an estimated coverage, by December 2008, of 87% for at least one dose of vaccine received by 4 months of age, and 84% for a full vaccine course (either two or three doses) received by 13 months of age (Mr Brynley Hull, Epidemiologist, National Centre for Immunisation Research and Surveillance, personal communication). Australia is in a unique position to assess the impact of the two vaccines because of the geographical split. However, it is important to recognise that the prevailing strains of rotavirus vary by region and change unpredictably from year to year.9 As the composition of the two licensed vaccines differs, effectiveness against certain strains, such as those not contained in the vaccines, may vary. An early study during a rotavirus outbreak in the NT showed that Rotarix was effective against the lately emerged G9 strain.10 Although Australia has an established national strain surveillance system,9 it needs to be enhanced, as samples for strain typing have not always been representative of all geographical areas or accompanied by clinical data. National disease notification using laboratory-confirmed cases needs to be implemented, and further studies of field effectiveness should be undertaken. Adverse events following vaccination in Australia are reported and reviewed nationally. The vaccines have not been associated with an excess of serious adverse events during the first 6 months of the program.11 Additionally, all cases of any-cause intussusception are reported by paediatricians to the Australian Paediatric Surveillance Unit, with enhanced active surveillance for intussusception being undertaken in a pilot program. Although efficacy of both vaccines persisted in clinical trials for 2 years,12,13 the full extent and duration of vaccine effectiveness, the degree of herd immunity, and whether a shift in disease incidence to older age groups has occurred, are yet to be determined. Identifying the emergence of new strains of rotavirus, either spontaneously or under vaccine pressure, will also be essential. Successful implementation of rotavirus vaccination in developing countries — where more than 95% of the world’s annual rotavirus deaths occur — is also much anticipated, possibly using new, less costly vaccines.7 In this issue of the Journal, Lambert and colleagues14 report on rotavirus notifications and laboratory tests performed in Queensland before and after the introduction of an infant rotavirus vaccination program. This is the first published evidence of a substantial population-based decline in rotavirus disease activity in Australia since introduction of the vaccine. Furthermore, laboratory-confirmed rotavirus infection appears to have declined not only in the cohort eligible for vaccination (infants aged under 2 years), but also in older children and in adults, suggesting a herd immunity effect, as has been observed in preliminary data from the US.7 Much points to the potential for Australia’s rotavirus vaccine program to have a substantial impact on acute childhood gastroenteritis, both in terms of health care utilisation and broader social and economic effects. It is important to document this with well targeted research and surveillance.

Kristine K Macartney MB BS, MD, FRACP · Margaret A Burgess MD, FRACP, FAFPHM

The Therapeutic Goods Administration is strengthening pharmacovigilance, but strategies to encourage the conduct of pharmacoepidemiological research in Australia are needed For four decades, spontaneous reporting has been the main mechanism by which adverse drug reactions are identified after a medicine is released onto the market, and the Australian program has been exceptionally effective. However, spontaneous reporting programs are limited in their ability to identify an association between a drug and an outcome that is common among the users independent of drug use, and they are not sufficiently sensitive to detect a small increase in the risk of certain rare events. In particular, the increasing long-term use of medication for prevention and control of chronic disease in otherwise healthy individuals presents a challenge to which current postmarketing surveillance mechanisms cannot effectively respond. For example, spontaneous reporting cannot detect an increased rate of myocardial infarction associated with hormone replacement therapy, rosiglitazone or rofecoxib; demonstration of these associations requires large, long-term randomised controlled trials. In recognition of these limitations, the Therapeutic Goods Administration (TGA) recently announced administrative changes that involve a strengthening of pharmacovigilance.1-3 As part of the pre-approval process for a medicine, sponsors will be required to present postmarketing pharmacovigilance and risk minimisation plans. In some cases, the pharmacovigilance plan may simply describe routine passive pharmacovigilance activities. In other cases, where there are important gaps in safety data (eg, groups of potential users for whom documented exposure is inadequate) or where data suggest potentially significant safety issues, the plan will propose studies that specifically address these matters. Studies may use any of the full gamut of epidemiological approaches, including randomised controlled trials, registries of new drug users, and data-linkage and case–control studies. Risk minimisation plans will outline practical steps that will be undertaken to reduce the risk of known safety hazards during the postmarketing period. Possible steps include a small pack size, second-line use only, and advice given in the product information; these measures were available options in the past, but they will now be listed in a single document. Pharmacovigilance and risk minimisation plans may be updated at any time during the postmarketing period, if a need to do so is identified. In addition, sponsors of medicines that are already registered when the new measures are implemented may also be required to draw up suitable plans on a case-by-case basis. These changes bring Australia into line with overseas initiatives, particularly those in the United States and Europe, and involve adoption of guidelines prepared by the European Medicines Agency.4,5 The result has been termed a “whole-of-lifecycle” approach, where active investigation of the safety of a medicine may continue for as long as it is in clinical use.1 A newly constituted medicines safety committee will have responsibility for providing advice on pharmacovigilance and risk minimisation plans, and overseeing the spontaneous reporting program. Medicines prescribed over a long period for disease prevention have typically been approved on the basis of a measured response to a surrogate marker for efficacy, such as improved glucose control, decreased cholesterol level or lowered blood pressure. However, the critical measures of the benefits of such responses to medicines are changes in risk of hard end points, such as myocardial infarction, renal failure and death. These end points are outcomes of the multidimensional effects of medicines — beneficial and adverse — on body systems. Marketing approval of medicines has rarely, if ever, required demonstration of such hypothesised benefits. Under the administrative changes, promising new medicines may still be approved on the basis of surrogate data, but consideration will be given to pharmacovigilance plans that include long-term studies with cohorts that are large enough to determine differences in hard clinical end points and identify any serious adverse effects that may offset benefits. In 2004, Merck Sharp and Dohme precipitately removed rofecoxib from the market worldwide, because evidence of a significantly higher rate of myocardial infarction than with placebo was an incidental outcome of a randomised controlled trial. There had been prior evidence of this association in the VIGOR (Vioxx Gastrointestinal Outcomes Research) study published in 2000.6 At that time, the manufacturer made a small protocol change to the already commenced APPROVe (Adenomatous Polyp Prevention on Vioxx) study, to allow participants to take low-dose aspirin,7 but apparently took no action to verify the association before 2002.8 Under the new procedures, it will be a routine matter for medicine regulators, including the TGA, to ensure that the sponsor conducts suitable studies to clarify safety concerns such as those raised in the VIGOR study. Of critical importance to the success of the expanded approach to pharmacovigilance is the level of resourcing at the TGA. Consideration of requirements must include capacity to: evaluate the suitability of pharmacovigilance plans that are included in applications for marketing approval of medicines; review pharmacovigilance plan updates that are submitted by sponsors; identify areas that require further investigation during the lifecycle of a medicine; and prepare reports for the medicines safety committee. It is disappointing that the initiatives do not include provisions for the TGA to fund, commission or conduct active safety investigations. The US Food and Drug Administration has received a substantial injection of funding for this purpose,4 and Medsafe, the New Zealand medicines authority, is funding product vigilance research through a joint initiative with the Health Research Council of New Zealand.9 Commissioned studies could address questions that sponsors could not reasonably be required to ask, such as those related to genetic markers for hypersensitivity reactions. They could also provide an alternative source of data in cases where the manufacturer chooses not to be transparent about safety matters, as allegedly occurred with rofecoxib10 and cerivastatin.11 As these changes in pharmacovigilance and drug regulation are occurring internationally, in general the TGA will be requiring postmarketing studies in concert with other regulators. In the absence of local initiatives or leadership from the TGA or other federal agencies that encourage the conduct of pharmacovigilance research in this country, Australia may not do much better than to achieve high-level observer status. Linkage of de-identified data from the Pharmaceutical Benefits Scheme and National Cancer Statistics Clearing House, as well as morbidity and mortality data from the Australian Institute of Health and Welfare, would provide a platform for epidemiological studies. Studies using this platform would need to be ones that do not require data on disease severity, concurrent disease, non-subsidised medication or lifestyle factors to control for confounding. While studies using more time-intensive means of data collection should also be encouraged in Australia, the years of inaction with regard to advancing this data linkage cannot be justified.12 The new approach being implemented by the TGA is welcome. Supplementing passive spontaneous reporting with evidence from active pharmacovigilance, in the form of studies designed to address important safety issues associated with medicines, will lead to more timely elucidation of adverse effects, together with reassurance for prescribers and patients. But the failure to include, as an essential part of the proposed changes, a package to ensure that active pharmacovigilance occurs in this country is baffling. This deficiency needs to be addressed urgently, and the matter would benefit from being taken up at a high level of government.

Kathlyn J Ronaldson BSc, MSc, DPhil

Results are promising but long-term safety remains uncertain Hypoactive sexual desire disorder (HSDD; loss of desire that causes personal distress)1 is common, with proposed prevalences ranging between 8% and 50% (wide variation is due to differences among populations surveyed and questionnaires used).2,3 Women with HSDD have been observed to experience poor sexual self-image, feelings of unattractiveness, fear of disappointing their partners, depression, anxiety and diminished quality of life.4,5 The effect of HSDD on quality of life has been reported as similar in magnitude to the effect of other common chronic conditions, such as diabetes and back pain.5 Furthermore, both men and women reporting a discrepancy between their own and their partner’s sexual desire have lower relationship satisfaction,6 and individuals in sexually inactive marriages report less marital happiness.7 Thus, HSDD merits recognition and intervention. In many cases, counselling and general sex education are helpful. However, the proportion of postmenopausal women who continue to experience HSDD despite good clinical care are left with few options, as there are no approved therapies presently available for this condition. APHRODITE is the most recent of a series of randomised controlled trials (RCTs) evaluating the efficacy and safety of transdermal testosterone patch therapy in postmenopausal women with HSDD.8 This large, multinational study, involving women with either natural or surgical menopause, differed from preceding studies in that participants were not receiving concurrent oestrogen therapy. The study was conducted and financed by Procter and Gamble Pharmaceuticals. However, it was instigated by the investigators, who were concerned that women may resort to off-label use of the testosterone patch Intrinsa (Procter and Gamble), when it becomes available, in the wake of the findings of the Women’s Health Initiative Studies (these findings initially raised concerns about the safety of postmenopausal oestrogen therapy). As effects of testosterone use without concurrent treatment with systemic oestrogen are unknown, the investigators believed this study would provide much-needed data. In this 52-week trial, 814 women with HSDD were randomly assigned to receive a patch delivering 150 μg or 300 μg of testosterone per day, or placebo. The primary end point was the number of self-reported sexually satisfactory events per month. The findings were interesting on several fronts. At baseline, women reported engaging in sexual activity on average 5 times per month, with half these events reported as unsatisfying. Participants had low sexual desire and a high level of personal distress measured by validated scales. By 24 weeks, women treated with the testosterone 300 μg patch reported a mean of 4.5 satisfactory events per month compared with 3.2 satisfactory events per month for women in the placebo group. Sexual desire increased and distress diminished substantially for both groups of women receiving active therapy. These findings have been interpreted by some as representing very little gain.9 However, women treated with the 300 μg testosterone patch reported enjoying nearly all of their sexual encounters, whereas those who received the placebo experienced pleasure 65% of the time. It is worth noting that women treated with testosterone did not report a significant increase in total sexual activity; this may be an effect of strongly established relationship patterns, including interest and availability of partners. In line with previous studies of transdermal testosterone therapy in postmenopausal and premenopausal women, efficacy did not manifest until after 8 weeks of therapy.10,11 Although women who received testosterone were more likely to report increased hair growth (20% of women receiving testosterone 300 μg v 10.5% of those receiving placebo), withdrawal from the study due to androgenic effects did not differ between the groups, and women treated with placebo were more likely to withdraw (19% of women receiving placebo v 14% of those receiving testosterone 300 μg). No significant adverse metabolic or endometrial effects were detected. The main concern arising from this study was the finding of breast cancer in four women treated with testosterone and none in the placebo group; the ratio of participants receiving testosterone to those receiving placebo was 2:1. The relationship between these findings and testosterone use is unclear, with two of the cancers likely to have been pre-existing (one diagnosed within 4 months of randomisation and another in a woman who recalled symptoms before randomisation when diagnosed after 7 months of treatment). A third woman diagnosed with breast cancer had previously been treated with hormone replacement therapy for 25 years and had a sister with breast cancer. The fourth was diagnosed after completion of 24 months of the study. The literature regarding the breast cancer risk of exogenous testosterone does not illuminate this issue. No other RCTs have been large enough or long enough to provide meaningful data. Observational data for oral methyltestosterone suggesting an increase in breast cancer risk12 have major limitations — the data are from the 1990s when testosterone was commonly prescribed for mastalgia in postmenopausal women receiving oestrogen therapy and the comparator group comprised non-hormone users, such that any apparent risk may have been the risk of oestrogen or oestrogen plus progestin use. A subsequent study in fact suggests the latter may well be the case.13 Two independent observational Australian studies have not found an increase in breast cancer risk with therapeutic testosterone use.14,15 Available data indicate transdermal testosterone can be useful for the treatment of HSDD in postmenopausal women. Short-term use appears to be safe, yet the effects of long-term use remain uncertain. Ideally, long-term safety should be evaluated in large longitudinal studies; however, as 70% of women who elect to use testosterone for HSDD do so for less than 3 years,15 retention of women in such studies will be a challenge.

Susan R Davis MB BS, FRACP, PhD

General practice needs resolute and united medical leadership to ensure its fitness for survival Two-hundred years after the birth of Charles Darwin and 150 years after the publication of On the origin of species, we elected to pursue a Darwinian theme in the 2009 MJA annual General Practice issue. “Survival of the fittest” relates to the ability to adapt to the immediate environment, which, for medicine and health care, has certainly undergone some changes! Indeed, the Lancet recently redefined health as the ability to adapt.1 We wanted to explore just how medicine, and general practice in particular, has adapted to changing societal, commercial and political environments. There is no denying that societal changes, coupled with advances in science and technology, have brought substantive changes in health care. Not only are Australians now living longer than ever before,2 but we also enjoy a comprehensive health system that has made us “a nation free from financial worries that go with illness and incapacity”.3 But it must be acknowledged that there are smouldering tensions both within medicine and in its relationship with society — tensions that may well bring about fundamental change in medical practice. These catalysts for change have been comprehensively explored by Lilford and his colleagues from the Department of Public Health and Epidemiology at the University of Birmingham in an essay entitled “Medical practice: where next?”4 First, there is the rise of consumerism and corporatism. These days, medicine in the developed world is practised in societies consumed by consumerism, individual rights, and a low threshold for litigation. As a consequence, we now practise “defensive medicine”. The very word “patient” is decried by some and replaced by “consumers”, “customers” and “clients”, with their inherent service connotations. In fact, medicine has moved from an environment of individual professionals to one of corporate entities, as the financial lodestones of government subsidies and guaranteed cash flows attract corporate interests. Doctors practising in such environments are no longer considered valued partners, but are regarded simply as workers in a health care team involved in the production cycle. Second, administrators and accountants now reign supreme, with an emphasis on organisational performance. One of the unforeseen consequences of this corporatisation of general practice, with its production lines accommodating discrete and circumscribed tasks,5 has been the loss of continuity of care.4 The ever-present problem of patients’ access to health care has led to an increasing displacement of doctors by other health professionals.6 Nowhere is this more evident than in general practice. Doctors might still play a very important role in managing an illness, but they no longer exclusively direct the play. The roles of other primary health care providers and coordinators are evolving, and new tensions are being generated as they become involved in decision making, diagnostic procedures, prescribing and the organisation of referrals. Indeed, the widespread unhappiness and loss of morale among doctors, particularly general practitioners,7 is usually attributed to these and other pressures, especially when accompanied by diminishing autonomy and professional control. When practice frameworks, remuneration and regulations are determined by central bureaucratic commands, disempowerment and loss of professional control will result. Lilford and colleagues are particularly bleak in their predictions for the future, arguing that medicine may well lose its hegemony: What we are arguing is that the link between the work of a health professional and specific ‘professional background’ will become increasingly tenuous. This happened some twenty years ago in chemical pathology and more recently in public health, and the trend is now apparent in subjects as diverse as anaesthesia, primary care and ophthalmology. It is increasingly difficult to define ‘doctor’ in such a way as to distinguish the practitioner unambiguously from other clinicians in the healthcare team who have decision-making responsibility and/or who administer critical interventions.4 They go on to argue that intellectual and communication skills will become the most crucial competencies in health care, and that the consultation will reassert itself as the central encounter in health practice. This special General Practice issue of the Journal contains contributions that explore such diverse topics as the reform of health care policy and general practice (Kidd, Coote, Mara and Sturmberg et al), the development of models of care (Harris et al, Wakerman et al, Phillips et al and Hartigan et al) and medical education in general practice (Laurence and Black, Sen Gupta et al and Sturman et al). Together, they offer some insight into the future direction of general practice. Coote details the reforms in Australian general practice from 1989 to 2009 (Coote).8 He describes how successive governments enacted reform revolving around remuneration, regulation and accreditation, organisational frameworks, and governance. During this process, governments capitalised on the principle of “divide and rule”. This is not particularly difficult in Australia, given the multiplicity of representative bodies and players in general practice, including such diverse organisations as the Australian Medical Association, the Divisions of General Practice, the Rural Doctors Association of Australia and the academic bodies of general practice and rural and remote medicine. Moreover, the federal government is itself a major powerbroker in the reform process, in that a considerable proportion of general practice income is derived from Medicare, and the government effectively controls both the workforce and the scope and diversity of its practitioners.9 Of even more importance, perhaps, is the federal government’s capacity to create ongoing uncertainty with its endless cavalcade of inquiries and their potentialities for change. All of this reinforces the notion that reform of general practice should be fuelled by GPs and shepherded by resolute and united medical leadership. Australian general practice has had effective leadership in the past, but if it is to develop further changes in medical care, it will need a multi-representative overarching body. Sir John Tooke’s inquiry into the United Kingdom’s Modernising Medical Careers debacle made pertinent comments on leadership of the British medical profession that may also apply in Australia: Indeed the advice derived from individual medical professional constituencies frequently reflected the particular interests of that grouping rather than the interests of medicine and medical care as a whole ... At a national level the Inquiry acknowledges that the medical profession has frequently failed to proffer coherent advice on key issues of principle, reflecting in part a very complex organizational structure, which owes more to history than necessarily function or purpose. There has been a dearth of medical professional leadership over this period.10 Here in the Antipodes, things are essentially no different. Without such a structure and courageous leadership, the Darwinian evolution of general practice may well be driven by chance alone or, at the very least, a passive or submissive response to the environments imposed by successive governments, as recounted in this issue by Coote8 and Mara.11 If GPs caring for patients 50 years ago were to return today, they would be amazed by the profound changes that have occurred. Yet one constant remains: general practice will continue to be subjected to changing professional, political and social paradigms. In this environment, unless resolute and united leadership ensures its centrality in the process of reform, general practice will no longer be deemed “the fittest” and, according to the basic principles of Darwinian evolution, will not survive.

Martin B Van Der Weyden MD, FRACP, FRCPA

A compilation of effective non-drug treatments could help increase their uptake in clinical practice In 2004, the Journal published a randomised controlled trial of graded exercise for chronic fatigue syndrome (CFS).1 As with several similar trials, this trial found that graded exercise was an effective intervention. But what is graded exercise? In response to numerous emails from both doctors and CFS patients who wanted further details of the exercise program, the authors of the study published a second article that provided the additional “how to” details and addressed different scenarios.2 I now keep the pdf file of this second article on my general practice computer to give to, and discuss with, CFS patients. The difficulties in accessing information on this simple, non-drug intervention are in stark contrast to the helpful tools available for prescribing pharmaceuticals: formularies, prescription pads, and pharmacies. The problem is not unique to graded exercise. In a review of studies selected for the journal Evidence-Based Medicine, we found that the adequacy of treatment descriptions in trials and systematic reviews appeared to be worse for non-drug treatments than drug treatments,3 with only about 30% of non-drug treatments (compared with 66% of drug treatments) being directly replicable from the information given. Fortunately, obtaining additional information from references, searches and authors increased this figure to around 65%.3 The poor descriptions and lack of easy reference may help explain the slow uptake of some effective non-drug treatments. For example, while the Epley manoeuvre for benign positional vertigo has been known as a simple effective physical treatment for over a quarter of a century, a German survey suggested that it is used in only 8% of affected patients.4 Though many general practitioners seem have heard of it, informal surveys of GPs at large educational seminars have shown that few know how to do it and fewer actually use it. Title page of a 1669 edition of Pliny’s Naturalis historiae, volume 1 For medicinal treatments, the need for an encyclopaedic collection with clear descriptions of how to prepare them was recognised long ago. Pharmacopoeias date back to at least the first century AD, when Pliny catalogued the herbal medicines in use in ancient Rome (Box).5 In the United Kingdom, the first list of approved drugs with information on preparation methods was the London pharmacopoeia, published in 1618. In 1864, the British pharmacopoeia (http://www.pharmacopoeia.gov.uk) was published to try to harmonise pharmaceutical standards through the merger of the London, Edinburgh and Dublin pharmacopoeias. Today, we cannot imagine the practice of medicine without a pharmacopoeia and a formulary. Outside pharmaceuticals, there seems to have been much less compilation and standardisation. This is not for lack of effective non-drug treatments. For example, a survey of 1464 randomised controlled trials supported by non-commercial sources in the UK between 1980 and 20026 found that more than half were for non-drug treatments, such as education, surgery, diet, exercise, and physical and psychological therapies. Although some of these are picked up by the relevant professions, many seem to fall between professional boundaries. For example, “bibliotherapy” (providing patients with informative reading material on self-management of their condition) has been used successfully in treating depression7 and irritable bowel syndrome.8 What would a formulary of non-drug therapies look like? Although an extensive compendium of all non-drug treatments would be worthwhile, for clinicians a non-drug formulary should be restricted to interventions shown to be effective by randomised controlled trials or other definitive evidence.9 As with drug formularies such as the British national formulary (http://www.bnf.org/bnf) or the Australian medicines handbook (http://www.amh.net.au), a non-drug formulary should also contain information on indications, contraindications and precise details of treatment. To be sufficient for a practitioner to replicate the treatment delivered in the trials, the treatment details will commonly need to be longer than the dosage, duration, and titration information typically given for pharmaceuticals. However, with the move to online information access, there are now minimal restrictions on space. Many journals now allow supplements, including video material, to be included with online versions of research articles. For example, the Journal of Visualized Experiments (http://www.jove.com) was established to capture the intricacies of life science research by providing online videos of experimental procedures. For non-drug interventions, it is essential that details of procedures and treatments are not copyright to a specific journal but are made freely available. Although pharmaceuticals have been central to many breakthroughs in medicine, non-pharmaceutical advances — in areas such as behavioural therapy, exercise therapy and nutrition — also offer many benefits, but their uptake has been less. For GPs, but also for the many discipline specialists, a non-drug handbook would be an important tool to foster a more balanced use of evidence-based treatments. I would like one on my clinic desk tomorrow, please.

Paul P Glasziou MB BS, FRACGP, PhD

Evidence-based therapies offer hope of prolonged survival for selected patients with this disease There is now a substantial body of published evidence of the survival benefits conferred by cytoreductive surgery (peritonectomy) and perioperative intraperitoneal chemotherapy comprising hyperthermic intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis. The technique of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is described in the Box. Here, we, the clinicians at the St George Hospital Peritoneal Surface Malignancy Program, who have had more than 12 years of experience in this treatment, provide a review of this topic. Peritoneal carcinomatosis refers to the dissemination of tumour onto the surfaces of the peritoneum. If left untreated, it is considered a terminal disease with a mean survival time for affected patients of 6 months.1 Over the past decade, the clinical view of peritoneal carcinomatosis has evolved from it being regarded as a terminal and untreatable condition that is palliated with systemic chemotherapy and bypass surgery, to a locoregional disease that is potentially curable in a defined group of patients after aggressive cytoreductive surgery and perioperative intraperitoneal chemotherapy. Unlike liver resection for colorectal liver metastases, for which there is no randomised clinical trial to justify its use, the current literature provides level I evidence to suggest the routine use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in suitable patients with colorectal cancer peritoneal carcinomatosis. Two randomised controlled trials and a multi-institutional study of 506 patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have been conducted. The body of these current results, and results from other non-randomised clinical series, as previously summarised,2 have shown a median survival time ranging from 13 to 29 months, and a 5-year survival rate ranging from 11% to 19%. To date, we have treated 60 patients with colorectal peritoneal carcinomatosis at our unit with a median survival time of 33 months and a 3-year survival rate of 38%.3 Pseudomyxoma peritonei or “jelly-belly” is a clinical syndrome characterised by the production and accumulation of mucinous ascites within the peritoneal cavity after the rupture of a mucinous tumour in the appendix. For patients treated in our unit who had favourable findings on histological examination of the tumour (disseminated peritoneal adenomucinosis), the median survival time for 73 patients was 97 months, with a 5-year survival rate of 70%. In patients with unfavourable histological findings (peritoneal mucinous carcinomatosis), the median survival time for 11 patients was 33 months, with a 3-year survival rate of 30%.4 These outcomes are similar to those published for 863 patients, who had median survival times ranging from 51 to 156 months, and a 5-year survival rate ranging from 52% to 96%.5 Long-term survival results, with a 10-year survival rate of 21%, have also been reported in a series of patients treated with debulking surgery.6 However, this treatment is associated with high rates of recurrence. The incidence of malignant mesothelioma is rising in Australia as a consequence of widespread exposure to asbestos in the 1970s. A third of malignant mesothelioma arises from the peritoneum. A recent systematic review of cytoreductive surgery and perioperative intraperitoneal chemotherapy for malignant peritoneal mesothelioma from seven observational studies reported a median survival time ranging from 34 to 92 months, with a 1-year survival rate of 60%–80% and a 3-year survival rate of 43%–65%.7 In a recent report of 20 consecutive patients from our institution, the overall median survival time was 30 months, with a 3-year survival rate of 46%. In patients who had favourable prognostic features (complete cytoreduction and epithelioid tumour), the median survival time was 87 months, with a 1-year survival rate of 90%.8 The 5-year survival rate of patients with advanced ovarian cancer is less than 25%.9 Intraperitoneal chemotherapy is the standard of care following a Gynecologic Oncology Group (GOG) Phase III trial that compared intravenous chemotherapy with intravenous plus intraperitoneal chemotherapy in Stage III ovarian cancer.10 However, the adoption of this therapy into standard practice has been slow, perhaps because of its poor tolerability.11 A systematic review of 15 studies of 512 patients with primary advanced ovarian cancer and recurrent ovarian cancer reported an overall median survival time of 29–64 months. In patients with an optimal cytoreduction, survival time ranged from 29 to 66 months, with a 3-year survival rate of 35%–63% and a 5-year survival rate of 12%–66%.12 In our unit, we have only treated patients with recurrent ovarian cancer who are not responsive to conventional treatment options. In 12 patients with recurrent ovarian cancer and peritoneal carcinomatosis whom we have treated with cytoreductive surgery and early postoperative intraperitoneal chemotherapy, the median survival was 36 months, with a 3-year survival rate of 39%. St George Hospital in Sydney is the only high-volume specialist institution offering cytoreductive surgery and hyperthermic intraperitoneal chemotherapy treatment in Australia. Despite the limited number of randomised trials of these therapies, there is strong evidence from Phase II studies of the survival benefits. The unit’s mortality rate has been 3% in the last 210 patients and we have demonstrated a learning curve effect.13 Our treatments are in accordance with the consensus statements from the Peritoneal Surface Oncology Group International.14-16 We emphasise that, in carefully selected patients, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is able to offer the hope of prolonged survival for cancer patients who are diagnosed with what many still regard as a terminal disease. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) Cytoreductive surgery and HIPEC combines surgery and intraoperative chemotherapy. This combined therapy is an aggressive approach to treating patients with diffuse and widespread intra-abdominal cancers localised to the peritoneal cavity, and is performed with the aims of cure and life prolongation. The surgery involves stripping the diseased peritoneum and performing multiple visceral organ resections to achieve maximal cytoreduction, leaving a minimal residual tumour volume within the abdomen. Following surgery, but intraoperatively, a heated chemotherapy perfusate is administered into the abdomen to cover all raw peritoneal surfaces. Intraperitoneal chemotherapy allows a high local concentration of a cytotoxic drug to be achieved for microscopic cytoreduction to target any microscopic residual tumour volume with minimal adverse systemic effects. Hyperthermia has been shown to act synergistically with the chemotherapy, and can thus enhance the cytotoxicity of the drug.

Terence C Chua BScMed(Hons) · Winston Liauw FRACP · David L Morris MD, PhD, FRACS

Could a technique using fetal DNA from the maternal circulation mean the end of invasive prenatal testing? Since the first application of ultrasound to it 50 years ago, the “black box” that is the pregnant uterus has gradually yielded to efforts to gain increasingly precise information about the condition of the fetus. Technological advances in ultrasound and, more recently, magnetic resonance imaging have seen the production of high-resolution displays of fetal anatomy and physiology. Specific information about the fetal genome, however, has until now only been available through the application of invasive techniques. Amniocentesis and chorionic villus sampling have been used to diagnose fetal aneuploidy (such as Down syndrome) and an ever-increasing range of genetic conditions. But these invasive procedures come at a cost — an associated 1% risk of pregnancy loss1 limits their application and causes significant stress for women thinking of undertaking such testing. Screening tests such as ultrasound and maternal serum screening to assess aneuploidy risk have been developed to allow more judicious application of invasive procedures, but of themselves cannot accurately diagnose the fetal condition, and false negatives and positives both occur. Now, the era of non-invasive prenatal diagnosis beckons — offering the ability to obtain specific and accurate genetic information from the fetus without the need for an invasive procedure and its associated risks. The article by Hyland and colleagues in this issue of the Journal reports on the first potential clinical application of non-invasive prenatal diagnosis in an Australian population — the determination of fetal RHD status in Rhesus (Rh) D-negative women.2 About 17% of Australian women are RhD-negative.3 These women are at risk of isoimmunisation, caused by the passage of RhD-positive fetal red blood cells across the placenta during pregnancy and childbirth. The resultant antibodies produced by the mother can cross the placenta and cause fetal anaemia due to haemolysis of fetal red blood cells. Women who are isoimmunised require intensive fetal surveillance, and are at risk for fetal death and neonatal brain injury if timely intervention is not performed. The incidence of isoimmunisation has been dramatically reduced since the introduction of preventive strategies, but these rely on administration of plasma-derived RhD immunoglobulin to all RhD-negative women. The technique employed by Hyland et al involves detecting cell-free fetal DNA (ffDNA) in maternal plasma by real-time polymerase chain reaction (PCR).2 ffDNA constitutes about 4%–6% of all cell-free DNA in the maternal circulation and can be reliably detected as early as 7 weeks after conception.4 The use of ffDNA to detect the RHD gene in RhD-negative pregnant women was first described by Lo and colleagues in 1998.5 Others have since applied the technique, and a recent meta-analysis demonstrated 96.1% sensitivity and 96.5% specificity for correctly determining fetal RHD status.6 To minimise false-negative results, internal controls are used to confirm the presence of fetal DNA. The SRY gene was initially used for this purpose, but as this only detects male fetuses, Hyland and colleagues have also utilised the RASSF1A gene to confirm the presence of fetal DNA from female fetuses.2 Where they were able to determine the fetal RHD status, their predictions showed 100% accuracy when compared with the infants’ serotype determined from cord blood after delivery. In a small number of cases, determination of fetal status could not be achieved. This technique requires further evaluation in larger studies to clarify the true performance characteristics of the test, and to allow algorithms to be developed for dealing with indeterminate results and the RHD gene variants seen in some ethnic groups. However, if these issues can be satisfactorily addressed, the potential applications are significant. In the small group of women with isoimmunised pregnancies, it will allow the determination of fetal RHD status without resorting to invasive tests. In addition to the risk of pregnancy loss, invasive procedures also have the potential to cause further sensitisation and worsen the natural history of the condition. More broadly, this testing has the potential to reduce unnecessary exposure of pregnant women to RhD immunoglobulin. Currently, RhD immunoglobulin is administered for antenatal prophylaxis, potential sensitising events, and postnatally for RhD-positive infants. This regime has been very effective, reducing the incidence of sensitisation during pregnancy by more than 90%.7 However, up to 40% of RhD-negative women receive treatment unnecessarily, as they will be carrying an RhD-negative fetus from a heterozygous partner.8 Routine introduction of non-invasive fetal DNA testing would therefore be likely to have cost implications for delivery of this preventive treatment. Non-invasive detection of fetal RHD status is already being incorporated into clinical practice in Europe, and the feasibility of using this approach to make decisions about prophylaxis has been demonstrated.9 The use of ffDNA can also be applied more broadly than determination of fetal RHD status. Already, reports exist of the non-invasive prenatal diagnosis of Huntington disease,10 cystic fibrosis11 and other conditions. Detection of the SRY gene allows determination of fetal sex in women at risk of carrying a fetus with an X-linked condition.12 The non-invasive diagnosis of Down syndrome and other aneuploidies remains challenging, but newer techniques such as methylation-dependent PCR and digital PCR hold promise.13 As with many technological advances involving reproductive choices, there are ethical concerns associated with this test. Sex determination for social rather than health reasons, for example, could result from unregulated use of such technologies. There is a pressing need for vigorous discussion of these issues. Non-invasive diagnosis of specific fetal gene status using fetal DNA from the maternal circulation without any risk to the pregnancy may be the “holy grail” of prenatal diagnosis. The determination of fetal RHD status is nearing availability as a clinical tool, and is likely to be the first of many applications of non-invasive prenatal testing over the coming decade. Is a future without amniocentesis and chorionic villus sampling dawning? Not quite yet, but at least there is some light on the horizon.

Stephen A Cole MB BS, FRANZCOG, CMFM · Helen F Savoia MB BS, FRCPA

The Australian Commission on Safety and Quality in Health Care is providing doctors with an opportunity to say what they think about safety and quality Early in 2009, the Australian Commission on Safety and Quality in Health Care (ACSQHC) developed a draft national safety and quality framework that sets out a vision for a health system that delivers safe and high-quality care (Box). At the ACSQHC, we now want to talk to Australians about how the safety and quality of the nation’s health care system can be improved. We are keen to hear from patients, consumers, clinicians, health service managers, policymakers and researchers about what aspects of safety and quality are important to them, the barriers they perceive to providing optimal care and suggestions for improving safety and quality. We have produced a detailed discussion paper as a starting point,1 and we need to know what you, the people on the ground, think about the ideas it contains. Opportunities for providing input include completing a short survey available on our website,1 providing written submissions and participating in meetings and focus groups. The result of these conversations will be a report, to be released mid 2010, that will include strategies for achieving sustainable, safe and high-quality patient care in all settings. The Journal has recently published articles by leading commentators and academics advocating health care reforms,3-7 and we have taken note of their views. A common theme was the need for a sustained focus on implementation — turning words into action — not just creating new policy. We know that safe and high-quality care requires the vigilance and cooperation of a wide range of health care staff, and that the success of initiatives to improve safety and quality requires the participation of doctors.8-11 Thus we believe it is crucial that frontline medical staff be involved in developing health policy in this area. Your participation in the conversations about safety and quality is essential to ensure that our final report is both practical and powerful. We know that it can be difficult for doctors to find time to participate in activities such as this one. However, we need to know about what you are doing to keep your patients safe, what gets in the way of this, and what changes you think are needed. We look forward to talking with you over the coming months and working with you to build a future of safe and high-quality patient care in Australia. Drop in to our website1 to read the discussion paper or fill in the survey to give us your views. Draft national framework for a health system that delivers safe and high-quality care1 Characteristics of safe, high-quality health care What it means for me as a patient or consumer Strategies for action by administrators, policymakers and providers 1. Patient-focused This means providing care that is respectful of and responsive to individual preferences, needs and values. It means a partnership between consumers, family, carers and their health care providers. Processes of care are designed to optimise the patient experience. I can access high-quality care when I need it. Develop service models which improve access to health care for patients. I can obtain and understand health information so that I can make decisions about my own care and participate in ensuring my safety. Increase health literacy. Involve patients so that they can make decisions about their care and plan their lives. Provide care that is culturally safe.* My health care is coordinated because people and systems work in partnership with me. Enhance continuity of care. Minimise risks at handover. Provide case management for complex care. Facilitate patient-centred service models. I know my health care rights.2 Promote health care rights. If I am harmed during health care, it is dealt with fairly. I will get an apology and a full explanation of what happened. Inform and support patients who are harmed during health care. 2. Driven by information This means enhancing knowledge and evidence about safety and quality. Safety and quality data are collected, analysed and fed back for improvement. Action is taken to reduce unjustified variation in standards of care and to improve patients’ experiences and clinical outcomes. My care is based on the best knowledge and evidence. Reduce unjustified variation in standards of care. Collect and use data to improve safety and quality. My clinical outcomes and experiences are used to build the evidence base for care and for strategies designed to improve care. Learn from patients’ and carers’ experiences. Encourage and apply research that will improve safety and quality. Continually monitor the effects of health care interventions. 3. Organised for safety This means that safety is a high priority in the design of health care. Organisational structures, work processes and funding models recognise and reward those who take responsibility for safety. I know that governments, health care managers and health care staff take responsibility for my safety. Clinicians, managers and governments recognise their responsibilities for safety. Our money funds a safe and efficient health system. Restructure funding models to support safe, appropriate care. Support and implement e-health. Design facilities, equipment and work processes for safety. I know that, when something goes wrong, actions are taken to prevent it happening to someone else. Take action to prevent or minimise harm resulting from health care errors. * Clinicians provide care that is culturally safe by recognising and respecting the cultural differences of the patient or consumer. Cultural safety goes beyond cultural appropriateness by creating better partnerships with people of different backgrounds.

Christopher J Baggoley FACEM, BM BS · Imogen E Curtis BComm(Hons) · Nicola J Dunbar BSc(Hons), PhD, MPS · Christine M Jorm MB, PhD, FANZCA

The risk of bleeding, as well as patient preferences, must be considered when deciding duration of warfarin therapy Venous thromboembolism (VTE) affects about 17 000 Australians each year, usually as deep vein thrombosis (DVT) of the legs or pulmonary embolism (PE).1 The sequelae of VTE include death, post-thrombotic syndrome, chronic pulmonary thromboembolic disease and recurrent VTE. Anticoagulation with an oral vitamin K antagonist (warfarin), overlapped for the first 5–7 days with unfractionated heparin, low-molecular-weight heparin or fondaparinux, prevents thrombus progression and reduces the risk of recurrent VTE and death during the acute phase.2,3 When treatment is continued beyond the acute phase, warfarin reduces the risk of recurrent VTE but increases the risk of bleeding and requires frequent laboratory monitoring, which is inconvenient for patients. Thus, decisions regarding the optimal duration of anticoagulant therapy must balance the increased risk and sequelae of recurrent VTE when warfarin is stopped against the risk of bleeding and the inconvenience of continuing treatment.3 Many randomised controlled trials have evaluated the optimal duration of anticoagulant therapy in patients with VTE, and their results can be summarised as follows: In patients with a first episode of VTE that is provoked by a reversible risk factor, 3 months of anticoagulant therapy halves the risk of recurrence compared with the level of risk achieved with 1 month of therapy.4 The risk of recurrence beyond 3 months is low.4 In patients with isolated provoked or unprovoked calf DVT, 6 weeks of anticoagulant therapy is as effective as 3 months’ therapy.5 In patients with a first episode of unprovoked VTE, 3 months of anticoagulant therapy is as effective as 6 months’ therapy,5,6 but there is a high rate of recurrence (about 10%) during the first year after stopping warfarin; in subsequent years, the recurrence rate decreases to 3%–4% per annum.7,8 Continuing warfarin treatment beyond the acute phase for 1–2 years reduces the risk of recurrence during treatment by as much as 90% compared with no warfarin, but a “catch-up” phenomenon occurs after stopping warfarin, so that after several years the risk of recurrence is similar in patients who are treated for 3 months compared with those treated for 12 months.9 Although the efficacy of long-term treatment with vitamin K antagonists for preventing recurrent VTE is impressive and consistent,7,8,10 pooled data from 10 trials involving 4833 participants provide no evidence that long-term anticoagulant therapy reduces fatal PE.8 Trial data show that continuing warfarin treatment beyond 3 months is associated with an annual risk of major bleeding of 1%–3%,11 and the incidence of major bleeding is likely to be even higher in unselected patients not enrolled in a clinical trial. Long-term warfarin therapy targeting an international normalised ratio (INR) of 1.5–2.0 is less effective for the prevention of recurrent VTE than warfarin therapy targeting an INR of 2.0–3.0; nor does the lower target ratio reduce the risk of bleeding.12 Several new oral anticoagulants (eg, rivaroxaban, apixaban, dabigatran etexilate) that selectively target coagulation factor Xa or factor IIa (thrombin) are in advanced stages of clinical development.13 These agents appear to be attractive alternatives to warfarin for long-term management of patients with VTE because they can be given in fixed daily or twice-daily doses without laboratory monitoring. However, it remains to be seen whether the new oral anticoagulants will provide a more favourable risk–benefit profile than warfarin during long-term treatment. Our recommendations for duration of anticoagulant therapy for VTE (Box) are generally consistent with those of the 2008 American College of Chest Physicians guidelines.14 The risk of bleeding and patient values and preferences must be taken into account when making treatment decisions. Patients with acute DVT or PE or both should receive warfarin for a minimum of 3 months. An exception is patients with isolated calf DVT, for whom 6 weeks of warfarin treatment is adequate. Patients whose first episode of proximal DVT or PE is provoked by a transient risk factor (eg, surgery) can stop treatment after 3 months because they have a relatively low risk of recurrence after warfarin is discontinued. Patients with a persisting reversible risk factor should continue taking warfarin until the risk is no longer present. Compared with those who experience provoked VTE, patients with a first episode of unprovoked proximal DVT or PE have a substantially higher risk of recurrence after warfarin treatment is discontinued, presumably because they have a chronic propensity to thrombus formation. However, there is little point in continuing treatment beyond 3–6 months in these patients unless a decision is made to treat indefinitely, as the benefits of extended treatment are lost when warfarin is discontinued. Long-term or indefinite warfarin therapy seems reasonable for patients with a history of limb- or life-threatening VTE, chronic pulmonary thromboembolism or severe post-thrombotic syndrome, and for patients who prefer to continue anticoagulant treatment. Indefinite treatment also seems reasonable for patients at very high risk of recurrence, such as those with a history of recurrent unprovoked VTE, high-risk thrombophilia (eg, antiphospholipid antibody syndrome, antithrombin deficiency, multiple thrombophilic defects) or active cancer (or those receiving treatment for cancer). Other tests (eg, for residual thrombus detected by compression sonography, or D-dimer) might also identify patients at increased risk of recurrence, but their utility in determining the optimal duration of anticoagulant therapy remains uncertain. Ultimately, the question of which patients will benefit from indefinite anticoagulant therapy requires evaluation in large randomised controlled trials that have sufficient power to show a worthwhile reduction in morbidity or mortality or an improvement in quality of life. Recommended duration of anticoagulant therapy Condition Recommended duration Evidence grade* Provoked VTE (transient risk factor) 3 months 1A Isolated calf DVT 6 weeks† 1B First unprovoked proximal DVT or PE Minimum 3 months Consider long-term‡ 1A 2B Recurrent unprovoked VTE Long-term 1A Cancer-related VTE Minimum 3 months§ Continue during treatment for cancer and while cancer is active 1A 1C VTE with high-risk thrombophilia¶ ** Minimum 3 months; consider long-term 2C Limb- or life-threatening VTE** Minimum 3 months; consider long-term 2C Chronic thromboembolic pulmonary disease Long-term 1C Severe post-thrombotic syndrome** Consider long-term 2C DVT = deep vein thrombosis. PE = pulmonary embolism. VTE = venous thromboembolism. * Based on the grading system used by the American College of Chest Physicians (ACCP) guidelines.13 Strong (Grade 1) recommendations can be applied uniformly to most patients. Weak (Grade 2) suggestions require more judicious application. Level A denotes high-quality evidence; Level B, moderate-quality evidence; and Level C, low-quality evidence. Risk of bleeding, as well as patient values and preferences, must be taken into account. † Unlike the ACCP guidelines, which do not provide a separate recommendation for calf vein thrombosis, we recommend 6 weeks, based on the results of the Durée Optimale du Traitement AntiVitamines K trial.5 There is no evidence to guide the treatment of calf vein thrombosis limited to muscle veins; if anticoagulants are used, we suggest that the duration of use does not exceed 6 weeks (Grade 2, Level C). ‡ Unlike the ACCP guidelines, we do not explicitly recommend long-term treatment after a first episode of unprovoked VTE. Our recommendation attaches a relatively high value to the burden of long-term anticoagulant therapy and a lower value to preventing recurrence beyond the acute phase. § Low-molecular-weight heparin is the preferred treatment. ¶ Includes patients with antiphospholipid antibody syndrome, antithrombin deficiency and multiple thrombophilic defects. ** The ACCP guidelines do not provide guidance for these categories of patients.

Nina C Raju MB BS, FRACP, FRCPA · Jack Hirsh MD, FRCPC, DSc · John W Eikelboom MB BS,MSc, FRCPC

Australia can benefit from lessons learned in the epidemic of C. difficile infection in Europe and North America It is 30 years since Clostridium difficile was shown to be the cause of pseudomembranous colitis and many cases of antibiotic-associated diarrhoea in humans. In the interim, C. difficile has risen from relative obscurity to become a major hospital pathogen. Two factors were particularly important in its emergence during the 1980s. First, increased and inappropriate use of some broad-spectrum antibiotics, particularly cephalosporins, predisposed more patients to infection with C. difficile. Second, contamination of the hospital environment with C. difficile spores was, and remains, a significant problem, as the spore is likely to be the infective particle. The epidemiology of C. difficile infection continues to evolve, and developments overseas in the past decade threaten not only parts of Australia’s vast agricultural sector but also the country’s health care system. Since 2002, rates of C. difficile infection have escalated, with outbreaks of severe infection in North America and Europe caused by an epidemic strain — polymerase chain reaction (PCR) ribotype 027 (also known as North American pulsed-field type 1 [NAP1]). This strain is characterised by the production of greater amounts of toxins A and B and an additional, binary toxin, as well as resistance to fluoroquinolone antimicrobials.1 When this editorial was submitted for publication in January 2009, there was no evidence that this epidemic strain was present in Australia. However, C. difficile PCR ribotype 027 has now been isolated for the first time in Australia, as reported in this issue of the Journal2 (Riley et al). Although the patient most probably acquired the organism while travelling in North America, this case illustrates the ease with which it could be introduced into Australia. Thought to be driving the epidemic in humans in North America and Europe are the overuse of fluoroquinolones and fluoroquinolone resistance, but the ageing population and improved case ascertainment may also be contributing to the dramatic increase in cases. Other factors may also be important, such as the increase in prescription of proton-pump inhibitors, which coincided with the emergence of epidemic C. difficile.3 Several recent observations from overseas have broad relevance for Australia. First, there has been an apparent increase in community-acquired C. difficile infection in the absence of classic risk factors such as antibiotic exposure, leading to suggestions that all patients with community-acquired diarrhoea should be tested for C. difficile.4 Assertions that community-acquired C. difficile infection is a new disease4 are not correct — it has been recognised in Australia for over 15 years but is underdiagnosed.5 Therefore, it is difficult to determine whether this increase is a true increase or rather reflects better case ascertainment. Nonetheless, the suggestion that C. difficile infection should be considered more than just a hospital problem is valid, and general practitioners need to be aware of this change in epidemiology. The prevalence of binary toxin-producing C. difficile in human disease is also increasing, and there is an association between binary toxin-producing isolates and community acquisition.6 Second, it is speculated that C. difficile is part of a zoonosis, and that transmission of infection via spores may be foodborne.7 There is compelling evidence for the former, but none for the latter. C. difficile is known to colonise many animals.8 Indeed, as in humans, it probably colonises the gastrointestinal tracts of most infant animals until weaning. There was alarm at a report that 20% of a small sample (n = 60) of retail beef in Canada contained C. difficile.9 Equally disturbing are reports that many pig herds in the United States are infected with C. difficile. The overall prevalence of C. difficile in piglets from 10 herds in North Carolina was 48%, and ranged from 0 to 97% across the herds. Mortality for piglets with C. difficile infection is 15%, and animals that survive are 10% underweight when they go to market.10 Most animal isolates of C. difficile produce binary toxin, and both pigs and cattle harbour PCR ribotype 078 — a strain that, like ribotype 027, produces increased amounts of toxins A and B, in addition to binary toxin. In the Netherlands, the prevalence of human C. difficile infection with ribotype 078 strains has increased since 2005; these infections were in a younger population and more frequently community-acquired than infections with ribotype 027 strains. In the eastern Netherlands, where more than 90% of the country’s pig farms are located, over 20% of human isolates are now ribotype 078, and human and pig strains of C. difficile are highly genetically related.11 In Australia, little is known about the prevalence of C. difficile in pigs. A small study in 2007 found C. difficile in 10 of 37 samples (27%) from piglets with diarrhoea, but none of the isolates were ribotype 078 (unpublished data). Why is C. difficile infection increasing in pigs in Europe, and what are the implications for Australia? The use of antimicrobials for growth promotion was banned from 2006 in Europe, and even earlier in Denmark, starting in 1995. However, since 2000, the use of therapeutic antimicrobials in production animals has increased in Europe in general, and specifically in Denmark, a big producer of pork. Of real concern is evidence of greater use of cephalosporins in animals. While the number of pigs in Denmark increased by 50% in the past 15 years, the amount of penicillinase-susceptible penicillins used increased by 400%, and cephalosporins by 1000%. Most of this increase was in piglets and sows.12 Although the total amount of cephalosporins used remains small, this is a worrying trend. If the situation is similar in the Netherlands, and anecdotal evidence suggests that it is, then this may be analogous to the situation in humans in the 1980s when there was a dramatic increase in C. difficile in many hospitals, driven by cephalosporin use.13 The overlap between the location of pig farms in the Netherlands and the occurrence of human ribotype 078 infections suggests a common source.11 This is likely to be the environment. The Netherlands has one of the highest population densities in the world. If infection rates in pig farms in the Netherlands are as high as those in the US,10 then it is likely that a large proportion of the Dutch population comes into contact with C. difficile spores every day. Individuals are at risk of infection if they are taking antimicrobials or any other medication that perturbs the gut flora. The good news for Australia is that, with our very low population density, a similar risk to humans is unlikely to develop. However, this is no reason for complacency. Every effort should be made to stop epidemic C. difficile from becoming established in our production animals. Unfortunately, the mere perception of C. difficile infection as a foodborne disease will damage the industry. Even before the first isolation of C. difficile PCR ribotype 027 in a patient in Australia, health care practitioners were becoming justifiably concerned. A proposal for C. difficile to be made notifiable in all states and territories of Australia was approved at the Australian Health Ministers’ Advisory Council meeting in November 2008. Australia’s conservative policies on fluoroquinolone use in humans and animals may offer some protection. However, if cephalosporin use is driving C. difficile infection in animals overseas, then additional efforts to target cephalosporin use in veterinary medicine may be needed in Australia. The solution to these problems continues to lie in surveillance for the emergence of virulent strains of C. difficile, promotion of judicious use of antimicrobials in both human and veterinary medicine, and environmental cleanliness, the latter perhaps easier said than done outside health care facilities.

Thomas V Riley MAppEpid, PhD, FRCPath

Reintroducing the alcopops tax is important, but more comprehensive reform of alcohol taxation and other broader measures are needed To those Australians who believe that alcohol consumption in this country is causing too much damage, and that a public health-focused, evidence-based alcohol policy can make a difference, the defeat of the “alcopops” legislation in the Senate in March this year was a disappointment. However, this is no reason to stop national action to reduce damage from alcohol. The thousands of Australians whose lives are damaged by alcohol, and the hundreds each year whose deaths could be prevented, are too important.1 Concerned organisations need to collaborate and advocate for a comprehensive, evidence-based approach to reducing the alcohol toll. Their ultimate goal should be to move to a more moderate and responsible drinking culture in Australia. The first question is what to do with the more than $400 million raised from the alcopops tax. Our elected representatives are to be congratulated on voting in May to retain it, rather than handing it back to the alcohol industry. Judging by past performance, had it gone to DrinkWise, it would have been spent on soft-sell advertising, which the great body of evidence suggests has no impact on alcohol consumption or consequent harms.2,3 The alcopops revenue should be directed to independent public health agencies to develop evidence-informed interventions that aim to reduce consumption and consequent harms. The Alcohol Education and Rehabilitation Foundation is one such entity, established using tax revenues generated in similar circumstances from beer sales. The national Preventative Health Taskforce has already developed a framework to prevent alcohol-related harms,4 and will soon deliver a final report and recommendations for action, including an overarching National Prevention Agency, which will need funds. With additional funding, the National Health and Medical Research Council (NHMRC) could give special priority to alcohol-related research. Funding of agencies such as VicHealth and Healthway in Western Australia, which were originally supported by tobacco revenues, could also be considered. The Royal Australasian College of Physicians welcomes the federal government’s initiative to reintroduce the alcopops tax legislation in the current sitting of Parliament, but encourages the government to go further. Although there was evidence the alcopops tax was followed by reduced overall alcohol consumption,5 if the government wishes to address the full range of alcohol-related harms — which include much more than binge drinking in young people — it should comprehensively reform alcohol taxation. Controlling price is by far the most effective, and cost-effective, single intervention available to control consumption and consequent harms.2,3,6 A comprehensive reform of alcohol tax is needed, with public health as a principal objective. Specific elements could include: taxing beverages on the basis of their alcohol content — a volumetric system; a minimum price per standard drink; and additional taxation based on evidence of harm associated with particular beverage types. A proportion of alcohol-related tax revenues should be directed towards prevention and treatment of alcohol-related problems. The Australian public will probably support such taxes.7 Taxation policy is crucial but must be part of a broader approach. There is good evidence for the effectiveness of controlling the availability of alcohol by regulating the number, nature and opening hours of alcohol venues.2,3,8 The forthcoming review of the Northern Territory’s Liquor Act provides an opportunity to encourage alcohol legislation to genuinely focus on preventing alcohol-related harms, and not just on regulating the sale of alcohol. The role and practice of alcohol promotion should also be closely examined. Loosening the link between alcohol advertising, sponsorship and sporting organisations may be an important way to encourage Australian drinking culture to evolve in a healthier direction. Some alcohol tax revenues could be directed towards replacing alcohol-industry sponsorship, as was done for tobacco in several states, or buying back alcohol advertising during sports programs, as suggested by the Australian Medical Association.9 Although prevention is essential, many people and their families are already suffering from the effects of alcohol. More treatment programs are urgently needed, particularly in rural and remote areas, where alcohol problems are even more common than in the cities, and for groups with particular needs, such as Aboriginal people, who need tailored programs. Finally, a strong vision and framework would bind all these strategies together. The National Alcohol Strategy10 expires this year, and another is needed: one that more closely follows the evidence of what really works in reducing harm. Much good work to reduce the harms from alcohol has been done in Australia by individuals and organisations such as the Public Health Association of Australia and the Australian Drug Foundation. However, much more is needed, as the level of harm is still unacceptable, especially among young people. We in the health profession need to play a greater advocacy role, in partnership with others within and beyond the health sector, such as the Cancer Councils, and social welfare and community organisations. The Royal Australasian College of Surgeons Trauma Committee, with its experience in road trauma and interpersonal violence, has indicated a strong interest in being involved. We need to be part of, and to help build, active coalitions. We should heed the lessons learned from the fight against tobacco. Although there are important differences between alcohol and tobacco, much is similar in the need to change the culture surrounding their use, and in the large and powerful industries that profit from their sale. Overcoming these obstacles will require an alliance of organisations, with a common understanding of the key issues, goals and ways to achieve them, and persistence in their pursuit. With thousands of lives lost or damaged, and billions of dollars wasted every year,1 this is our challenge and our responsibility.

on behalf of the Royal Australasian College of Physicians Alcohol Advisory Group.*

One of the dilemmas in delaying sex-assignment surgery is the increased risk of gonadal malignancy Few areas of medicine are as controversial as the management of disorders of sex development (DSD). The use of the term DSD to describe patients born with ambiguous genitalia has undergone major change from older terms with negative connotations, such as “intersex”, “testicular feminisation” and “hermaphroditism”.1 Meanwhile, international debate continues about the ethics of performing genital surgery on affected infants and children. In fact, the debate has been raging for more than a decade between the medical profession and patient advocacy groups in Western countries, and has been documented by anthropologist Katrina Karkazis in a recent book.2 A long-term outcome study of 50 patients aged 18–32 years who had been treated in Melbourne when they were children showed that mental and physical health outcomes were as good for most of the DSD patients as for those in two control groups; however, there was a small minority of patients whose gender identity as adults was a source of such profound discomfort that they felt compelled to undergo treatment to change it.3 Clearly, this is unsatisfactory, and management practices have been reviewed internationally by clinicians looking for ways of minimising the risk of making such mistakes about gender assignment. The main problem relates to feminising genitoplasty (Box), which involves the removal of phallic erectile tissues and skin that cannot be replaced. This type of operation is considered appropriate for 46,XX girls with congenital adrenal hyperplasia (Box), who rarely identify as male when they are adults if they are treated with appropriate hormones to maintain androgen suppression from soon after birth and throughout childhood.4 However, feminising genitoplasty is much more of a problem in patients with a Y chromosome. For example, in one study of 14 adult patients with genetically confirmed partial androgen insensitivity who were treated at Johns Hopkins University in the United States as children, 25% experienced gender dysphoria (Box) as adults, and a small number wanted to undergo sex change surgery.5 Although policy changes are still being discussed, it seems likely that fewer and fewer XY patients with frankly ambiguous genitalia due to DSD will have feminising genitoplasty and be raised female. The option to assign a gender but postpone surgery until the child is able to give consent has been strongly advocated in some quarters,6 but has not gained much traction because of concerns that children might suffer psychological harm if left with ambiguous genitalia. In 2008, clinicians from Melbourne’s Royal Children’s Hospital, recognised for their expertise in the management of DSD, were required to meet representatives of the Victorian state Justice Department. They were asked to respond to a proposal — advanced by an advisory committee representing the interests of the gay, lesbian, bisexual, transsexual and intersex communities — that doctors wanting to perform surgery to treat ambiguous genitalia in children too young to consent on their own behalf should have to seek approval from the Family Court of Australia on a case-by-case basis. Also in 2008, the Australian Human Rights Commission decided to initiate a public inquiry into the same question, and circulated a draft discussion paper called Genital surgery for babies born intersex to health professionals for comment. Thus, in Australia as elsewhere, the arm wrestle between medical professionals and patient advocacy groups continues. What has largely been missing from the debate is recognition of the fact that surgery forms a necessary part of the risk management strategy for preventing gonadal malignancy. In any DSD associated with a Y chromosome, there is an increased risk of germ cell cancer,7 especially when the testes are intra-abdominal (the risk of seminoma in partial androgen insensitivity is 50% for an intra-abdominal testis) or when there is gonadal dysgenesis. In this issue of the Journal, a salutary case report by Parker and colleagues8 reminds us of the need to be mindful of this risk, and also to take a long-term view of risk. If the intra-abdominal gonad in the patient described had been removed at the initial surgery, he would never have needed to fear this tumour. It had not been removed because, by today’s standards, he had been inadequately investigated in the past, and therefore the intersex condition was not recognised. The trend for surgeons to recommend male-sex rearing for greater numbers of children with DSD could also mean greater reluctance to remove testes that pose a significant risk of cancer on the grounds that physiologically useful hormone secretion might be retained. It is therefore imperative that a risk management strategy be prepared for each patient. This would mandate: educating parents and patients about risk; removing all intra-abdominal gonads that cannot be brought down into the scrotum; regular clinical and ultrasound surveillance of scrotal gonads with removal of any that contain suspicious lumps; biopsy of testes after the onset of puberty, looking for early signs of malignant change; and effective communication between paediatric and adult care-providers at the time of transition. It is also important for all children identified as having DSD to be referred to a centre of excellence where they will be seen by paediatric endocrinologists, surgeons and other health care professionals with expertise in the field and who recognise the importance of a multidisciplinary team approach.9 Case conferences about patients diagnosed as having a DSD in adult life would be enhanced if paediatric specialists in DSD were asked to comment. Of equally great importance is the need for an accurate aetiological diagnosis wherever possible. At the moment, about 40% of patients with 46,XY forms of DSD are left without a precise diagnosis.10 The application of microarray (gene chip) technology,11 which is available in Australia, is an exciting and promising step forward in identifying genetic mutations. In this technique, samples of very large numbers of genes are arranged in a regular pattern on a solid surface or membrane, which is then incubated with DNA from a patient. Alterations in known (and even unknown) genes are rapidly detected by studying patterns of matches and mismatches. The current challenge for researchers is to develop new tools, such as microarray technology, that will lead to gene discovery and to better methods of screening patients for mutations in all the known genes. Glossary of terms relating to disorders of sex development DSD: Disorders of sex development, previously known as intersex. Congenital conditions in which development of the chromosomal, gonadal or anatomical sex is atypical. Feminising genitoplasty: Surgery carried out to give genitalia that were originally ambiguous a more female appearance. Usually involves clitoral reduction (removal of erectile tissue) and surgery to create a vaginal opening separate from the urethra. Congenital adrenal hyperplasia: A genetic disorder caused by a deficiency of the enzyme 21-hydroxylase in the adrenal cortex, and the commonest adrenal disorder of childhood. Cause of virilisation in an affected female fetus. Partial androgen insensitivity: An X-linked genetic disorder causing ambiguous genitalia in 46,XY individuals. Caused by a lack of androgen receptors in androgen target tissues, such as genital skin. Gender dysphoria: Mental distress caused by unhappiness with one’s own sex and the desire to be identified as the opposite sex.

Garry L Warne MB BS, FRACP · Jacqueline K Hewitt MB BS

Robust evidence remains to be gathered Whenever possible, clinical decision making should be evidence-based. In reality, the evidence may be incomplete and the practitioner must use personal clinical judgement. This should be based on recommendations or guidelines provided by authoritative groups. An example of clinical practice reliant on guidelines with an incomplete evidence base is the use of low-dose aspirin for primary prevention of cardiovascular disease (CVD) events in people with diabetes mellitus. Diabetes Australia, the Royal Australian College of General Practitioners, and the National Health and Medical Research Council (NHMRC), as well as numerous associations in the United States and United Kingdom, have all recommended low-dose aspirin for men and women with diabetes (Box). Until very recently, there were no randomised controlled trials of aspirin use for people with diabetes to provide the evidence for these guidelines. Rather, the recommendations are based on the rationale that low-dose aspirin should benefit people with diabetes because aspirin has proven benefit for secondary prevention of CVD events, and people with diabetes have a risk of CVD events equivalent to the risk found in secondary prevention populations. However, people with diabetes represent a heterogeneous population, and an individual patient’s risk of CVD events varies according to factors such as age at diagnosis and duration of diabetes.8 Therefore, the guidelines for aspirin use in people with diabetes, based on extrapolation from secondary to primary prevention, may be flawed. Two substudies of the Bettering the Evaluation And Care of Health (BEACH) program, one undertaken in 20069 and the other in 2007,10 generated data about patients with diagnosed type 2 diabetes and allowed us to determine the compliance of Australian general practitioners with the relevant guidelines. Using the BEACH substudy data, we analysed aspirin usage by patients with and without diagnosed CVD comorbidity. The results indicated that 39% of people with type 2 diabetes were taking aspirin for primary prevention. In late 2008, two randomised controlled trials of low-dose aspirin in people with diabetes were reported.11,12 They showed no significant effect of aspirin on the primary endpoint (CVD events). These studies attracted a good deal of attention, not only in the medical press but the lay press as well (eg, Norman Swan’s The health report on Radio National13). They also left medical practitioners with a conundrum — whether or not to prescribe low-dose aspirin to their patients with diabetes but no overt CVD. In this editorial, we highlight the deficiencies in these trials; suggest that the evidence for the use of aspirin in this context is still lacking; and inform clinicians of ongoing trials that should provide adequate power to address this issue reliably. The two 2008 trials of low-dose aspirin therapy for people with diabetes were substantially underpowered to address the question of aspirin effectiveness for reducing CVD events.14,15 The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) study of low-dose aspirin (100 mg daily)11 followed 1276 participants with diabetes and asymptomatic peripheral arterial disease but no CVD events for a median of 6.7 years. The annual CVD event rate was less than 3% in those assigned placebo (lower than the expected rate of 8% per annum). There were 116 primary CVD events in subjects receiving aspirin, compared with 117 in those not receiving aspirin (hazard ratio, 0.98). In the open-label Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) study,12 2539 patients with type 2 diabetes and no history of CVD were treated either with aspirin (81 mg or 100 mg daily) or with no aspirin. The median follow-up period was 4.37 years. In both groups, actual event rates were about three times lower than anticipated rates. A 20% reduction in the primary endpoint of composite CVD events for the group assigned aspirin was not statistically significant because of wide confidence intervals. Nevertheless, the secondary endpoint of CVD mortality was significantly reduced, and, in a sub-analysis of subjects aged 65 years and over at baseline, aspirin significantly reduced CVD events. For both the POPADAD and JPAD trials, there was no significant difference in the occurrence of adverse events among subjects receiving or not receiving aspirin. As a result of the lower than expected event rates (possibly related to effects of more optimal background therapies) and the relatively low numbers of people included in the trials, results of POPADAD and JPAD have not ruled out important benefits or risks of aspirin. Larger trials are needed. A major study (A Study of Cardiovascular Events in Diabetes [ASCEND])16 is underway in Britain to determine whether low-dose aspirin has a benefit for primary prevention of CVD in people with diabetes. About half of its estimated sample size of 10 000 men and women has been recruited. In Australia, our own trial of aspirin therapy for primary prevention in 19 000 people aged 70 years and over, the Aspirin in Reducing Events in the Elderly (ASPREE) study17 (clinical trial registration number ISRCTN83772183), will also be including participants with diabetes on the basis that equipoise prevails between the benefits and risks of aspirin therapy. In the ASPREE study, a GP co-investigator will help decide whether the patient is a suitable candidate for the placebo-controlled trial. A recent editorial in the Journal of the American Medical Association concluded that [T]he decision to prescribe aspirin should be made on an individual patient basis after careful evaluation of the balance between the expected benefits and the risk of major bleeding. The issue of aspirin therapy for patients with diabetes is an example of how, in the presence of a long-lasting uncertainty, scientific organizations or governmental bodies should provide the foundation for answering this question by promoting pragmatic, large-scale clinical trials.14 We concur that an enhanced evidence base can inform a more rational approach to therapy. Guidelines for the use of aspirin for primary prevention in people with diabetes Source Recommendation Diabetes Australia and Royal Australian College of General Practitioners (guidelines updated annually)1 Prophylactic aspirin (75–325 mg/day) for people with diabetes unless contraindicated National Health and Medical Research Council2 Prophylactic aspirin (75–325 mg/day) should be considered for people with type 2 diabetes unless contraindicated United States Preventive Services Task Force3 Aspirin (75 mg/day) should be used for primary prevention in people with diabetes who have a 5-year risk ≥ 3% of a CHD event American Diabetes Association and American Heart Association4 Aspirin (75–162 mg/day) strongly recommended for people aged > 40 years with diabetes or with an additional risk factor for vascular disease British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society and British Diabetic Association5,6 Cardioprotective use of aspirin (75 mg/day) in people with diabetes or other risk factors aged > 50 years with an absolute CHD risk ≥ 15% over 10 years International Diabetes Federation7 Low-dose aspirin (75–100 mg/day) prophylaxis recommended for people with diabetes CHD = coronary heart disease.

Robyn L Woods BSc(Hons), PhD · Andrew M Tonkin MB BS, MRACP, FRACP · Mark R Nelson MB BS, MFM, PhD · Helena C Britt BA, PhD · Christopher M Reid BA, MSc, PhD

The challenge of providing a multidisciplinary response to complex health problems A developmental disability is a neurological abnormality having its onset in childhood that is associated with long-term neurological and developmental deficits (for example, spastic quadriplegic cerebral palsy). Although the degree of physical and intellectual disability varies greatly, people with a severe developmental disability often have very limited mobility, are dependent on caregivers for their daily needs, and usually have several concomitant medical problems. Because of their complex health needs, consensus is growing that multidisciplinary clinics provide the optimal setting for assessment and management of patients with a developmental disability. Life expectancy is significantly reduced in people with developmental disabilities compared with the general population.1-3 Review of the causes of death of people with a disability living in state-funded supported accommodation in New South Wales shows that respiratory disease accounts for about 40% of deaths (Kelly Savage, NSW Ombudsman, personal communication). Similar findings have been reported from Victoria and the United Kingdom.2,3 Multiple factors contribute to the increased mortality in this group. Gastro-oesophageal reflux disease is common in people with severe developmental disability,4,5 with or without intellectual disability, and is an important comorbidity in individuals with incoordinate swallowing. Respiratory disease, often secondary to recurrent aspiration, is also common and under-recognised. Malnutrition caused by reduced food intake (related to swallowing difficulties) frequently accompanies neurological impairment. Previous studies from our group6 identified profound levels of protein energy malnutrition, severe disturbance of body composition, and almost universal osteoporosis in subjects with spastic quadriplegic cerebral palsy. Seizure activity can also compromise food intake. Orthopaedic problems such as joint contractures, hip dislocation and kyphoscoliosis further contribute to limited mobility and may exacerbate lung disease. Kyphoscoliosis also poses technical challenges for surgical procedures, such as gastrostomy device insertion and fundoplication. The interrelationships of these conditions clearly require the coordinated input of several disciplines. However, there have been no clinical trials attesting to the efficacy of multidisciplinary clinics in improving patient outcomes in this group of patients. We recently reported our experience with 452 adults and children with severe developmental disability, most of whom had cerebral palsy.7 These patients were seen at tertiary referral dysphagia–nutrition multidisciplinary clinics at Westmead Hospital and the Children’s Hospital at Westmead in NSW between 2001 and 2006. The treating teams included a developmental paediatrician–physician, paediatric gastroenterologist, clinical nurse coordinator, speech pathologist, dietitian, and paediatric physiotherapist. Patients ranged in age from 7 months to 53 years; 90% were wheelchair-dependent and 60% had epilepsy. Among other things, we found that: 90% of patients had dysphagia; three-quarters of the children and half of the adults were malnourished due to inadequate food intake; 60% of the total clinic population reported respiratory symptoms; and half of the patients undergoing upper endoscopy had reflux oesophagitis, and 66% of patients undergoing computed tomography scans of the chest had chronic suppurative lung disease. In our series, simple interventions such as dietary advice, change of food consistencies, appropriate positioning during feeding and sleeping, use of proton-pump inhibitors, and implementation of a chest management plan were effective for many patients. However, a significant number of patients required gastrostomy with or without fundoplication for nutritional rehabilitation and to control gastro-oesophageal reflux and pulmonary aspiration. Improving the quality of life of the person with a developmental disability is the primary goal of management. Quality of life of the patient’s family and carers is also an important consideration when formulating management plans. Studies of children with a severe level of disability suggest that gastrostomy tube insertion has a positive impact on quality of life for both the children and their caregivers.8 However, the news is not all positive. Studies of caregivers’ attitudes to health professionals indicate that the way the health system dealt with their child with a disability was seen as a significant negative factor in the carer’s quality of life.9 Caregivers describe problems such as a lack of information, communication difficulties with health professionals, and lack of experience and expertise in managing the complex health needs of patients with a disability. Many of the medical problems described here are relatively easy to diagnose, and most respond to simple interventions, but they are often overlooked or undertreated in the general medical system. Interventions include treatment of nutrient deficiencies, management of reflux oesophagitis, saliva management, strategies to reduce episodes of aspiration pneumonia, and active management of chronic suppurative lung disease. Seizure control can also be problematic and may require regular specialist review. Coordination and provision of satisfactory health care to this population is a challenge to the health system, especially as these patients often present acutely to already overcrowded emergency departments.10 There are few specialist multidisciplinary clinical services in Australia for people with a developmental disability and complex health needs. Training opportunities in disability medicine are few outside of paediatrics, where developmental paediatrics is an essential component of paediatric training. Specific expertise and support services are often not available, and care may be significantly compromised in the adult health system. Communication barriers, lack of up-to-date medical records, difficulty doing a simple examination or routine investigations, and confusion about consent for even simple interventions all conspire to challenge the system to provide optimal care. These problems can be compounded by preconceived ideas about the quality of life of a person with a disability. Many of the problems confronting people with a developmental disability and complex health needs, and their carers attempting to access health services, need to be addressed. Increased awareness of their needs, improved education and training of health professionals, and the development of multidisciplinary clinics and support services are basic requirements to improve their health status.

Edward V O’Loughlin MD, FRACP · Helen M Somerville MB BS, MPaed · Ernest R Somerville MB BS, FRCP, FRACP