Volume 189 Issue 6

The Journal has a permanent home On 31 July, the new AMPCo House was officially opened by Dr Rosanna Capolingua, President of the Australian Medical Association, in the presence of AMPCo staff, AMA officials, and distinguished guests including past Editors of the Journal and Chairs of the company. AMPCo (the Australasian Medical Publishing Company) was established in 1913, with the express purpose of publishing the Medical Journal of Australia, the first issue of which appeared on 4 July 1914. At its inception, the Journal was subtitled “The Journal of the Australian branches of the British Medical Association”, reflecting our colonial heritage, and its one editor, one manager and one typist resided at the old BMA building in Elizabeth Street, Sydney. In 1925, the Journal moved to its own purpose-built premises, “The Printing House”, in Arundel Street in Glebe, a triangular building across the road from the University of Sydney. Here, everything was done on the premises, from copyediting and typesetting in hot metal, to printing and binding. The company expanded to include printing tradesmen as well as editorial and administrative staff. In 1962, the AMA was founded, taking over all state branches of the BMA and the publishing company. The Journal thus became “The Journal of the Australian Medical Association”. In 1990, the AMA sold The Printing House to help fund its new headquarters in Canberra, and the Journal moved into rented premises, first in Kingsgrove, then North Sydney, and then Pyrmont. Last year, faced with ever-spiralling Sydney rental prices, AMPCo bought the new building at 277 Clarence Street, a stone’s throw from the Sydney Town Hall. The new AMPCo House is about the same age as the Journal and, at five storeys, is a relative dwarf among the more modern giants of the city. But it has character, with original timber floors and solid beams, and arched windows that look out to the Town Hall clock. AMPCo staff now number over 50, comprising the Editorial department, staff who manage and maintain the database for the Medical Directory of Australia, sales and marketing staff, information technology staff, coordinators of medical book sales, and administrative staff. All printing is outsourced, but the Journal is otherwise “desktop published” in-house. We have our own medical library and now have space to display the books and accessories available through our online medical bookshop. The Journal is now 94 years old, and remains Australia’s premier peer-reviewed general medical journal. With a home of our own once more, we look forward to many productive years at AMPCo House. A: AMPCo House B: AMPCo staff and distinguished guests at the official opening C: AMPCo board members Dr John Kessell, Dr Sam Lees, Mr Ben Armstrong, Mr Francis Sullivan, Dr Ross Glasson and Dr Peter Garcia-Webb, with AMA President Dr Rosanna Capolingua (centre) D: MJA Editor Dr Martin Van Der Weyden with Deputy Editors Dr Bronwyn Gaut, Dr Tatiana Janusic, Dr Ruth Armstrong, and (inset) Dr Tanya Grassi and Dr Ann Gregory.

Bronwyn Gaut

Now that we can predict risk accurately, we need to reconsider screening strategies The recent completion of the Human Genome Project offered great promise that medical genetics would have a population-based impact on the prevention and treatment of inherited conditions. A common inherited condition, hereditary haemochromatosis, was initially touted as a “poster child” for population genetic screening. Most cases are due to homozygosity for a single mutation of the HFE gene, leading to iron overload. Hereditary haemochromatosis is considered an ideal candidate for population genetic screening as genetic susceptibility is common, testing is inexpensive, and iron studies can detect early stages of the disease.1 Most importantly, venesection is a simple and effective way to both prevent and manage the potential sequelae of iron overload,2 which include severe fatigue, arthritis, impotence, cirrhosis, diabetes, and cardiomyopathy.3 However, even for an inherited condition as apparently straightforward as haemochromatosis, justifying population genetic screening has proven more complicated than initially expected.4 After the gene linked with hereditary haemochromatosis was identified in 1996,5 a flurry of publications called for the consideration of population genetic screening, as it was thought that most people who were homozygous for the C282Y mutation would eventually develop the disease. Although more than 90% of cases are due to C282Y homozygosity,3 there is now good evidence that not all those who are homozygous will progress through all stages of the disease. These stages comprise genetic predisposition without abnormality; iron overload (raised serum ferritin in the presence of a raised fasting transferrin saturation) without symptoms; iron overload with haemochromatosis-associated symptoms, such as arthritis and fatigue; and iron overload with organ damage, particularly cirrhosis.6 Although most of those who are homozygous appear to develop raised serum ferritin and raised transferrin saturation by the fifth decade of life,7 until now there have been few reliable data on the number of homozygous individuals who develop disease as a result of iron overload. Population estimates of the prevalence of non-specific signs and symptoms of haemochromatosis (eg, arthritis and fatigue) and disease due to documented iron overload (eg, cirrhosis) in C282Y homozygous individuals have been hindered by either the failure to clinically assess individuals before knowledge of their genetic status or an inability to account for the long lead time of preclinical iron-overload status. A cross-sectional population study of participants aged 20–80 years suggested that disease attributable to haemochromatosis occurs in fewer than 1% of those who are homozygous, regardless of sex.8 However, this study did not conduct clinical examinations or liver biopsies, and a quarter of the homozygous patients were excluded on the basis that they had been previously diagnosed. This exclusion would be expected to reduce the estimate of clinical penetrance of C282Y homozygosity. Furthermore, the study included homozygous patients of ages at which disease would not be expected to have developed. Until recently, there had been only two longitudinal studies of hereditary haemochromatosis designed to accurately estimate the proportion of homozygous patients who will develop disease secondary to iron overload.9,10 However, with a combined total of 23 patients, they were substantially underpowered to assess disease prevalence. In the largest longitudinal prospective study to date, my colleagues and I assessed 203 homozygous individuals among a healthy population of 31 192, followed up over 12 years.11 Data were collected by physicians who were blinded to genotype, and liver biopsies were performed as clinically indicated (serum ferritin > 1000 μg/L, unexplained hepatomegaly or raised serum aminotransferase levels).12 We found that homozygous individuals with a serum ferritin level higher than 1000 μg/L were at increased risk of haemochromatosis-associated signs and symptoms, when compared with either those who were homozygous with a serum ferritin level of 1000 μg/L or less, or individuals with other HFE genotypes. In particular, homozygous men with a serum ferritin level higher than 1000 μg/L reported greater fatigue, use of arthritis medication and history of liver disease than men without the C282Y mutation. We also assessed the proportion of homozygous individuals with disease that was directly attributable to iron overload using the combined definition of documented iron overload13 and one or more of the following: cirrhosis, liver fibrosis, hepatocellular carcinoma, raised aminotransferase concentration, physician-diagnosed symptomatic hereditary haemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. Iron overload-related disease developed in 28% of homozygous men, but only 1% of homozygous women.11 Our study is important because it enables us, for the first time, to make accurate predictions about the proportion of those at genetic risk of haemochromatosis who will develop symptoms that could otherwise be prevented. Furthermore, we confirmed that homozygous individuals with a serum ferritin level higher than 1000 μg/L were not only at increased risk of cirrhosis, but also of non-specific signs and symptoms of haemochromatosis. This has implications for a cost-effectiveness analysis of population genetic screening for hereditary haemochromatosis. Other criticisms of such screening,14 including concerns over insurance implications and creating a cohort of “worried well” among those at genetic risk of haemochromatosis, have proved unfounded.15,16 It appears that cost is the last barrier to screening. The questions that remain regarding population screening include: Would it be more cost-effective to simply offer screening to men? What is the most cost-effective age to screen at? What is the most pragmatic way to access a population before an age at which disease is likely to develop? Hereditary haemochromotosis may yet offer a prototype for population genetic screening programs, but the journey of justification has offered unexpected challenges.

Katrina J Allen BMedSc, FRACP, PhD

A decade of research has led to more precise guidelines for a complex health problem It has long been considered that all patients with heart conditions that predispose to infective endocarditis should receive antibiotic prophylaxis when undergoing procedures that can lead to bacteraemia with organisms known to cause endocarditis. However, the evidence for such action is surprisingly poor.1 It is based on isolated case reports of endocarditis following dental or other procedures, and on theoretical considerations, rather than the results of randomised controlled trials. The American Heart Association (AHA) has published guidelines for endocarditis prophylaxis since 1955. In Australia, all editions of the Antibiotic guidelines (now Therapeutic guidelines: antibiotic, version 132) have also included recommendations for antibiotic prophylaxis against endocarditis. Of necessity, these guidelines have been complex, as three major variables were considered — the lifetime risk of endocarditis due to the underlying heart condition, the likelihood and nature of bacteraemia following the procedure, and the risk of adverse effects from antibiotic therapy.2 The lifetime risk associated with the cardiac condition was divided into three risk categories (high, medium and low), and the likelihood of bacteraemia from a procedure was similarly divided into risk categories. Thus, prophylaxis has been firmly recommended for patients with an underlying heart condition who are at high risk of endocarditis and are undergoing a procedure that has a high risk of leading to significant bacteraemia. Conversely, it has not been recommended for patients with conditions who are at low risk of endocarditis and are undergoing procedures with a low risk of leading to significant bacteraemia. Prophylaxis has been “possibly” and “probably” recommended for various intermediate-risk combinations. Over the past 10 years, thinking has changed for three main reasons. First, there is now strong evidence that bacteraemia with endocarditis-causing organisms frequently occurs following everyday activities, such as tooth brushing.3-6 Second, it has been recognised that very few cases of endocarditis can reasonably be attributed to a preceding procedure and are more likely to have resulted from everyday activities. Third, it has been realised that we should be more concerned about patients who are likely to have a poor outcome if they develop endocarditis than those who are at high risk of developing endocarditis at all.1 In the context of this change in thinking, organisations around the world (including the AHA) have published new guidelines for endocarditis prophylaxis that differ considerably from the previous versions.1,7,8 In Australasia, at the request of the Heart Foundation (formerly, the National Heart Foundation of Australia) and The Cardiac Society of Australia and New Zealand, Therapeutic Guidelines Limited convened an expert group to reconsider its guidelines. This expert group updated the Australian guidelines largely along the lines of the new AHA guidelines, continuing a trend to reduce the categories of patients for whom prophylaxis is recommended, while still specifying procedures for which it is required. In summary, the changes are: The list of heart conditions for which endocarditis prophylaxis is recommended is much shorter and is largely limited to conditions in which foreign material is implanted in the heart. In this setting, endocarditis is very difficult to eradicate, so an adverse outcome is more likely. Of note, the list does not include rheumatic valvular heart disease in non-Indigenous patients or mitral valve prolapse. The list of dental and respiratory procedures for which endocarditis prophylaxis should be given is more precise. For some dental procedures, the guidelines emphasise that the need for prophylaxis relates more to the circumstances of the procedure and the patient’s periodontal condition than to the procedure itself. The list of gastrointestinal and genitourinary procedures is similarly precise, and includes procedures that also have a requirement for surgical antibiotic prophylaxis, or which are being carried out in the presence of a related infection. The only significant difference between the new Australian guidelines and the AHA guidelines is that rheumatic valvular heart disease in Indigenous Australians has been retained in the list of cardiac conditions for which prophylaxis should be given. Experienced clinicians have the strong impression that the outcome of endocarditis in Indigenous Australians is poorer than in non-Indigenous Australians, possibly in part because of delays in diagnosis and therapy. Studies are currently being undertaken to determine whether this clinical impression is correct, but until the results are available, it was thought wise to retain this indication. These new guidelines might cause confusion at first, particularly when patients who previously received prophylaxis are advised that it is no longer necessary. To help ease this confusion, the new guidelines state that it is reasonable to give prophylaxis to patients who have previously received it and would prefer to be given it again. The new Australian guidelines are available free of charge on the Therapeutic Guidelines website (http://www.tg.com.au) and in its electronic publications (eTG complete and miniTG). The print versions of Therapeutic guidelines: antibiotic and Therapeutic guidelines: oral and dental will be updated as the new editions are published. We recommend these guidelines to Australian practitioners and trust they will find them useful and decide to follow them.

Robert F W Moulds BMedSc, PhD, FRACP · Melanie S Jeyasingham BPharm, MPS

Trials measuring major cardiovascular events as an endpoint are the best evidence to determine if an intervention such as ezetimibe conveys benefit At an American College of Cardiology meeting in Chicago earlier this year, the long-awaited results of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial were finally presented, with simultaneous publication in the New England Journal of Medicine.1 ENHANCE was a double-blind, randomised controlled trial comparing 80 mg of simvastatin plus placebo daily with 80 mg of simvastatin plus 10 mg of ezetimibe daily in patients with familial hypercholesterolaemia. The primary trial endpoint was change in mean carotid and femoral intima-media thickness (IMT) over a 24-month period (Box). Although the trial finished in mid 2006, the results were not forthcoming from the United States sponsors (Merck and Schering-Plough) until a US Congressional Committee required the companies to reveal them, which they did in the form of a press release earlier this year.2,3 In the combined-therapy group, the benefit expected from a 17% lower level of low-density lipoprotein cholesterol (LDL-C) due to ezetimibe was not realised — mean IMT did not differ between the two groups. There was progression in mean carotid IMT (CIMT) in both groups (P = 0.02 for simvastatin-only group and P < 0.01 for combined-therapy group). Regression occurred in 44.4% of the simvastatin-only group and 45.3% of the combined-therapy group. New lesions (> 1.3 mm CIMT) occurred in 2.8% of the simvastatin-only group and 4.7% of the combined-therapy group (P = 0.20). Various possible explanations for these unexpected results were given by the study authors.1 The first was that ezetimibe is not protective for the vasculature, in spite of its significant lowering of LDL-C levels; the second was that the methodology used to measure IMT was insufficient to detect small changes in response to the therapy; and the third was that the population with familial hypercholesterolaemia had virtually normal baseline IMT due to their previous extensive treatment with statins, which may have rendered their arteries relatively unresponsive to further LDL-C reduction. The first explanation is unlikely because ezetimibe has shown no previous evidence of vascular toxicity, and a recent study in which statin–ezetimibe therapy was used as part of an aggressive management algorithm showed regression of CIMT (although this was not a randomised trial of ezetimibe use).4 The second explanation is also unlikely, although ENHANCE did not employ electrocardiogram gating of images to control for image variability during the cardiac cycle, and used single-frame technology rather than cine-loop technology to improve image quality.2 The third explanation seems the most likely, for several reasons. Previous studies of CIMT have shown either lack of progression (ie, stabilisation) or regression with lipid-modifying therapy, primarily related to changes in LDL-C levels.5 Unlike ENHANCE, these studies involved patients with increased baseline CIMT and had inclusion criteria for CIMT. Data also presented at the American College of Cardiology meeting, but yet to be published, showed that statin-naïve patients had no significant change in CIMT with either therapy.2 Baseline CIMT in this group was also near-normal — an unusual finding for true familial hypercholesterolaemia patients. However, no data were presented to confirm the presence of LDL receptor mutations. If this explanation is correct, perhaps ENHANCE could never have shown a positive result, because most patients had been treated with statins for decades before enrolment in the trial. Evidence for this theory comes from the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) extension study, in which patients in the earlier ASAP trial were continued on 80 mg of atorvastatin daily for a further 2 years.6 Patients in the original atorvastatin group (in whom there had been regression of 0.031 mm) showed no further change in CIMT, while those originally in the simvastatin 40 mg group (in whom there had been progression of 0.036 mm) showed significant regression.6 The results of the ENHANCE trial are important because ezetimibe accounts for a significant proportion of lipid-lowering medication prescriptions around the world (3% in Canada, similar to use in Australia; and 15% in the US).7 Ezetimibe was approved for marketing in the US about 5 years ago, based on its efficacy in lowering LDL-C levels rather than efficacy in reducing major adverse cardiovascular events or improving surrogate endpoints such as CIMT. This situation is the opposite for newer drugs such as torcetrapib, which, in spite of increasing high-density lipoprotein cholesterol levels by more than 50%, was withdrawn from the market because of negative results in trials investigating its effects on CIMT and major adverse cardiovascular events.8,9 So, where do we go from here? The first caveat is not to abandon the modern cholesterol hypothesis (“the lower the LDL-C, the better”) after one negative trial. Only trials measuring major adverse cardiovascular events as an endpoint can definitively answer the question of whether a given intervention conveys benefit, regardless of changes in surrogate markers like CIMT or plaque size. We must therefore await the results of a clinical endpoint trial with ezetimibe, which adds a further 15%–20% reduction in LDL-C levels to that achieved by statin therapy, and which should reduce major adverse cardiovascular events by a similar percentage. IMPROVE-IT is a trial comparing cardiovascular death, major coronary events and stroke in 18 000 patients with recent acute coronary syndromes treated with 40 mg of simvastatin either alone or in combination with 10 mg of ezetimibe.2 It is due to be reported in 2012. Until then, it seems prudent to continue clinical practice on the basis that the cholesterol hypothesis is alive and well, and to continue using ezetimibe in statin-intolerant patients and those taking maximum-tolerated doses of statins who have not yet achieved LDL-C target levels.10 Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study1 720 patients with familial hypercholesterolaemia Baseline: low-density lipoprotein (LDL) cholesterol, 8.2 mmol/L; high-density lipoprotein (HDL) cholesterol, 1.2 mmol/L Compared simvastatin 80 mg + placebo daily with simvastatin 80 mg + ezetimibe 10 mg daily Primary endpoint was mean intima-media thickness (IMT) of carotid and femoral arteries with B-mode ultrasonography End of study: mean LDL cholesterol 16.5% lower in ezetimibe group (P < 0.01); no difference in HDL cholesterol No difference between treatment groups in carotid IMT after 2 years (P = 0.29): + 0.0058 mm in simvastatin–placebo group + 0.011 mm in simvastatin–ezetimibe group Side-effect and safety profiles similar in both groups

Ian R Hamilton-Craig MB BS, PhD, FRACP

Objective: To determine whether a 5-day course of oral prednisolone is superior to a 3-day course in reducing the 2-week morbidity of children with asthma exacerbations who are not hospitalised.Design, setting and participants: Double-blind randomised controlled trial of asthma outcomes following a 5-day course of oral prednisolone (1 mg/kg) compared with a 3-day course of prednisolone plus placebo for 2 days. Participants were children aged 2–15 years who presented to the emergency departments of three Queensland hospitals between March 2004 and February 2007 with an acute exacerbation of asthma, but were not hospitalised. Sample size was defined a priori for a study power of 90%.Main outcome measures: Difference in proportion of children who were symptom-free at Day 7, as measured by intention-to-treat (ITT) and per-protocol analysis; quality of life (QOL) on Days 7 and 14.Results: 201 children were enrolled, and there was an 82% completion rate. There was no difference between groups in the proportion of children who were symptom-free (observed difference, 0.04 [95% CI, − 0.09 to 0.18] by ITT analysis; 0.04 [95% CI, − 0.17 to 0.09] by per-protocol analysis). There was also no difference between groups in QOL (P = 0.42). The difference between groups for the primary outcome was within the equivalence range calculated post priori.Conclusion: A 5-day course of oral prednisolone confers no advantage over a 3-day course for children with asthma exacerbations who are not hospitalised.Trial registration: Australian Clinical Trials Registry ACTRN012605000305628.

Anne B Chang MPHTM, PhD, FRACP · Ronald Clark PhD, FRACP · Theo P Sloots BSc, PhD · David G Stone FRACP · Helen L Petsky BN · Donna Thearle BN · Anita A Champion BPharm · Coralie Wheeler BN · Jason P Acworth FRACP

Objective: To ascertain the current level of understanding among older men about prostate cancer, including treatment options and their potential side effects.Design and setting: Questionnaires administered by general practitioners in five general practices in the Perth metropolitan and regional areas of Western Australia.Participants: Convenience sample of 503 men aged 40–80 years, with or without prostate cancer, presenting for routine consultations between January and August 2006.Main outcome measure: Knowledge and attitudes of men about prostate cancer, and predictors of knowledge.Results: Eighty per cent of men did not know the function of the prostate, and 48% failed to identify prostate cancer as the most common internal cancer in men. Thirty-five per cent had no knowledge of the treatments for prostate cancer and 53% had no knowledge of the side effects of treatments. Asked how they would arrive at a decision about treatment, 70% said they would ask the GP or specialist for information on all their options and then decide themselves.Conclusion: There is a deficit in knowledge about prostate cancer among men in the at-risk age group, encompassing areas that could delay diagnosis and treatment. Overall, the men preferred some GP or specialist involvement in treatment decision making.

Diane E Arnold-Reed BSc(Hons), PhD · Dana A Hince BSc(Hons), PhD · Max K Bulsara MSc · Hanh Ngo BSc(Hons) · Michael Eaton MB BS, FACRRM · Alan R Wright MB BS, MFM, FRACGP · Frank R Jones MB BCh, FACRRM, FRACGP · Walter Kaczmarczyk MB BS, FRACGP · Andreas G Marangou MB BS, FRACGP · Thomas D Brett MD, FRACGP, MRCGP

Objective: To describe trends in prostate-specific antigen (PSA) testing, prostate cancer incidence and mortality in New South Wales.Design and setting: Descriptive analysis using routinely collected data of observed trends in PSA testing from 1989 to 2006, and prostate cancer cases and deaths from 1972 to 2005 in NSW.Main outcome measures: Age-standardised and age-specific rates and joinpoint regression to identify changes in trends; projected trends observed before the introduction of PSA testing to quantify its impact on incidence and mortality rates.Results: The number of PSA tests per year more than doubled between 1994 and 2006. Age-standardised incidence of prostate cancer peaked in 1994, fell by 10.0% per year to 1998 and then increased by 4.9% per year from 2001 to 2005. An estimated 19 602 (43%) more men than expected from preceding trends were diagnosed with prostate cancer between 1989 and 2005 after PSA testing was introduced. The incidence of recorded advanced prostate cancer at diagnosis fell from 13.0 per 100 000 men in 1987–1991 to 7.0 per 100 000 men in 2002–2005. The age-standardised mortality from prostate cancer increased by 3.6% per year between 1984 and 1990 and then fell by 2.0% per year to 2005.Conclusions: There was a sustained increase in prostate cancer incidence in NSW after PSA testing was introduced. While falls in the incidence of advanced disease at diagnosis and mortality from prostate cancer after 1993 are consistent with a benefit from PSA testing, other explanations cannot be excluded.

David P Smith BA, MPH · Rajah Supramaniam MSc, MPH(Hons) · Villis R Marshall MD, FRACS · Bruce K Armstrong MB BS, DPhil, FRACP

Objective: To determine how well the current Pharmaceutical Benefits Scheme (PBS) eligibility criteria for subsidy of lipid-lowering drugs compare with current national guidelines for determining the population at high risk of developing cardiovascular disease (CVD).Design and participants: Analyses of the population-based, cross-sectional Australian Diabetes, Obesity and Lifestyle (AusDiab) study, conducted in 1999–2000. The 1991 Framingham risk prediction equation was used to compute 5-year risk of developing first-time CVD in 8286 participants aged 30–74 years with neither CVD nor diabetes. Based on the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand guidelines, people with either 5-year CVD risk ≥ 15% or with 5-year CVD risk of 10%–< 15% and the metabolic syndrome were defined as having estimated high absolute CVD risk.Main outcome measures: 5-year CVD risk; estimated population with high CVD risk.Results: Among participants without prevalent CVD or diabetes, 7.9% of men and 1.5% of women had a 5-year CVD risk ≥ 15%. Of the estimated residential Australian population in 2000 aged 30–74 years without CVD or diabetes, 717 000 people were considered to be at high absolute CVD risk. Among the high-risk AusDiab participants without CVD or diabetes, only 16.9% of men and 15.4% of women were being treated with lipid-lowering drugs. Of the 9.6% of participants free of CVD and diabetes who were untreated but eligible for subsidy under PBS criteria, only 27.4% had an estimated high absolute CVD risk.Conclusion: Strategies for CVD prevention using lipid-lowering medications can be improved by adoption of the absolute-risk approach.

Lei Chen MD, MMed · Sophie L Rogers MEpi · Stephen Colagiuri MD, FRACP · Dominique A Cadilhac MPubHlth, PhD · Timothy H Mathew MB BS, FRACP · Andrew N Boyden BM BS(Hons), MPH, FRACGP · Anna Peeters BSc(Hons), PhD · Dianna J Magliano MPH, PhD · Jonathan E Shaw MD, MRCP, FRACP · Paul Z Zimmet MD, PhD, FRACP · Andrew M Tonkin MB BS, MD, FRACP

Objectives: To describe all cases of staphylococcal pyomyositis in the Geelong region of Victoria over 110 months, to estimate the incidence of this disease, and to describe the clinical outcomes and identify any predisposing factors.Design, participants and setting: A prospective case series identified by clinical features (local pain and fever) and magnetic resonance imaging (MRI) findings (hyperintense signal on T2-weighted scan), among patients presenting to Geelong Hospital, Victoria between 1 April 1998 and 1 June 2007.Main outcome measures: Estimation of incidence, clinical course and identification of predisposing factors.Results: We estimate an annual incidence of 0.5 cases per 100 000 person-years, and propose a recent history of vigorous exercise (six of 11 patients) and underlying skin condition (five of 11 patients) as possible predisposing factors. MRI showed eight patients had osteomyelitis and one had septic arthritis. All patients had bacteraemia and one had mitral valve endocarditis. The duration of intravenous antibiotic therapy varied between 4 and 12 weeks, and all patients were completely cured.Conclusion: Pyomyositis should be considered in patients presenting with local pain, fever, muscle tenderness, and a recent history of vigorous exercise or underlying skin condition. MRI may guide non-surgical management.

Andrew A Block MB BS, BMedSci, FRACP · Catherine Marshall MB BS · Alison Ratcliffe MB BS, FRACP · Eugene Athan MB BS, FRACP

Earlier this year, two industry-sponsored advertising campaigns for cholesterol awareness that target the general public were launched in Australia. These campaigns aimed to alert the public to the risks associated with having high cholesterol and encouraged cholesterol testing for wider groups than those specified by the National Heart Foundation. General practitioners should be aware of the potential for the two campaigns to confuse the general public as to who should be tested, and where. The campaign sponsors (Unilever Australasia and Pfizer) each have the potential to benefit by increased market share for their products, and increased profits. These disease awareness campaigns are examples of what is increasingly being termed “condition branding” by pharmaceutical marketing experts.

Danika V Hall BA, MEd · Megan D Cobcroft · John W Ketelbey

In a now diverse range of teaching hospitals striving to excel, excellence in research should be prioritised Mention Johns Hopkins Hospital or the Massachusetts General Hospital, and most doctors will recognise these as leading teaching hospitals of the Johns Hopkins School of Medicine and the Harvard Medical School — both consistently ranked in the top 10 medical schools in the United States.1 Both hospitals are exemplars of excellence in the teaching hospital’s functions of patient care, medical education and clinical research. While Australia’s teaching hospitals may not have the same international status, the best of our teaching hospitals are recognised as providers of complex and high-quality care, suppliers of the nation’s medical and health professionals, and leaders in clinical research. Indeed, a recent review of the status of medical research in Australia acknowledged both its high quality and international standing.2 However, it appears that the standing of this research in Australia’s teaching hospitals is under threat. In this issue of the Journal, Penington, a leading academic and Chairman of the not-for-profit company Bio21, which links the University of Melbourne with its teaching hospitals and research institutes, argues that Australia’s teaching hospitals are in danger of slipping behind other nations such as the US, Canada and the United Kingdom in the calibre of their clinical research.3 The immediate concern is that the prevailing administrative emphasis in our teaching hospitals now revolves around service delivery and quantitative performance indices that ignore quality of services. Cecil Helman, general practitioner and social commentator, wrote: . . . hospitals have become factories, yet another form of industrial mass-production in our society . . . Many hospitals have become businesses, dedicated solely to production . . . but without considering the other types of cost that result from this approach . . . They have become businesses run by managers, primarily for the benefit of other managers, accountants and of other executives higher up in the food chain.4 In this environment, the importance of research and its supporting frameworks have dropped below the bureaucratic radar. Furthermore, Penington argues that support for research in teaching hospitals has fallen victim to “cost shifting” and “buck passing” of responsibilities between bureaucracies as to who is responsible for the infrastructure sustaining research and development (R&D) in teaching hospitals.3 A new channel or dedicated funding is needed. The UK has recently witnessed an orderly series of inquiries that have culminated in the UK Government corralling the National Health Service research budget of around £1 billion and forming a new funding body — the National Institute for Health Research — for translational (aiming to connect research to actual patient care) and clinical research programs. An international panel has awarded comprehensive biomedical research centre status with major funding to five major medical research centres — University College London, Imperial and Kings Colleges, and Oxford and Cambridge universities. These are the super medical research universities in the UK, and will be internationally highly competitive in translational research done in a clinical setting (Edward Byrne, Executive Dean, Faculty of Biomedical Sciences and Head of Medical School, University College London, personal communication). The overarching vision is for health research to be performed by the best people, in the best facilities, and focused on the immediate needs of patients and the public. Paramount in this vision are partnerships with industry, and the central roles of universities, granting bodies and research charities.5 An example of this vision in action is the partnership of the Medical Research Council, the Wellcome Trust and Cancer Research UK in a new institute in central London with a building cost of about US$1.5 billion. This institute will perform mainly basic research, but there is a firm requirement that there be clinical research links to the large hospitals in its proximity, particularly those affiliated with University College London (Edward Byrne, personal communication) The issues raised by Penington3 are just part of the story. With the recent increase in the number of Australian medical schools and in medical student numbers, there is also a pressing need for more teaching hospitals, ideally linked in a “hub and spoke” configuration with general practice, which has now been given a greater role in medical education.6 If this is to be achieved with the best possible outcome, it is important that there be specific guidelines and a quantifiable framework for what actually constitutes a teaching hospital, and what may be acknowledged as acceptable variability within this framework. Teaching hospitals have one common characteristic — a commitment to medical education in partnership with university medical schools and clinical colleges. But they can differ in many other ways.7 These include: the size and scope of resident staff; the number of fellowships or advanced training positions; the standing of R&D in the hospital; the facilities and infrastructure to support R&D; the level of integration of university staff in the hospital; the number of academic staff as heads of services; the mix of special clinical services offered; the extent and depth of diagnostic laboratory services; the mix and complexity of clinical care; and so on. The organisational structures of university presence in our teaching hospitals also vary, borrowing extensively from either UK or US models.8,9 It is a given that descriptors like the ones outlined above need to be refined and quantified so that teaching hospitals can be stratified, and key performance indicators can be developed and measured. These parameters might then be the basis of evidence-based and comprehensive remuneration schemes by state and federal agencies, allowing for rigorous accountability of the flow of money. The Australian community needs access to the best health care, benefiting from advances in medical science and technology. The way forward is to borrow from the UK experience of independent and focused inquiries that have resulted in clear expositions and recommendations for action. It is time to confidently answer the question of whether or not our teaching hospitals perform to the level of their international counterparts, and to prevent the deterioration in clinical research capacity signalled by Penington.3

Martin B Van Der Weyden MD, FRACP, FRCPA

Partnership between research and health services has a long history in other countries, but has been relatively recent in Australia, with several models arising in the 1960s and 1970s as research-based specialties developed. Since the implementation of Medibank, which became Medicare, Australian Health Care Agreements have been primarily crafted on the basis of transactional numbers, ignoring the need for links with teaching and research and the need to implement new developments. Education and research have been seen as the responsibility of the federal government, and hospitals are progressively less recognised or funded for these functions by the states. Australia’s teaching hospitals are in danger of falling seriously behind those in other countries and losing their capacity to monitor quality, to innovate and to branch into new strategies in partnership with primary care services. We should look at initiatives in other countries such as the United Kingdom and Canada, which are making big strides in tackling similar issues. University hospitals hold the key, if appropriately linked with other services. The current Australian Health Care Agreements are on hold. A new agency is needed to support clinical and service-related research, with a new structure and track for federal government funding, and providing oversight of research and development, of clinical governance and quality of outcomes in health care, linked with new strategies for prevention and treatment. A component of the foreshadowed additional federal government funding for health should be sequestered to set up such an agency.

David G Penington AC

Clinical record A 47-year-old woman — an Australian resident of North Indian origin — was referred to our outpatient clinic. She had a 4-year history of lethargy on a background of primary hypothyroidism that was diagnosed 2 years earlier. She reported weakness, myalgia, poor concentration and chronic diarrhoea, which had been attributed to irritable bowel syndrome after a colonoscopy found no abnormalities. Given her racial origin, coeliac disease had not previously been considered. Rather, a chronic pain syndrome was diagnosed as the cause of the myalgia, and was managed with narcotic analgesia. The patient’s medications also included thyroxine (50 μg daily). Her body mass index was 29.5 kg/m2; normal findings were obtained on physical examination, and she was clinically euthyroid on thyroxine replacement. Hashimoto’s hypothyroidism with under-replacement of thyroxine, secondary hyperparathyroidism with vitamin D deficiency, and impaired fasting glycaemia were biochemically confirmed (Table). A high vitamin B12 level was also noted, and this was attributed to recent intramuscular injection of vitamin B12. Bone density was measured using the Lunar Prodigy DXA system (GE Healthcare, Madison, Wis, USA), which revealed osteopenia with lumbar bone mineral density (BMD) of 1.02 g/cm2 (T-score, − 1.9 SD) and total femoral BMD of 1.02 g/cm2 (T-score, − 1.6 SD). Titration of thyroxine to a weekly dose of 1400 μg and vitamin D3 replacement dosage of 6000 IU daily, over a 6-month period with confirmed compliance, failed to ameliorate hypothyroidism and vitamin D deficiency. In view of her history, previous investigations and progress, serological testing for coeliac disease was carried out. Results were positive for endomysial IgA antibodies, with normal total IgA antibody titre. Also, histological analysis of a small bowel biopsy specimen was consistent with coeliac disease (Figure). A 6-month gluten-free diet resulted in complete resolution of lethargy, diarrhoea and myalgia. Hypothyroidism was corrected with a weekly dose of 750 μg thyroxine, and both secondary hyperparathyroidism and impaired fasting glycaemia resolved (Table). Histological examination of small bowel mucosa Histological examination showed focal, partial villous atrophy and crypt hyperplasia, with evidence of chronic inflammation in the lamina propria (original magnification, × 400) — consistent with coeliac disease. Results of laboratory investigations At presentation After 6 months of gluten-free diet Reference range Thyroid-stimulating hormone (mIU/L) 13.4 8.3 0.3–4.0 Thyroxine, free (pmol/L) 12 15 10–25 Thyroid antimicrosomal antibody titre 25 600 — < 100 Calculated ionised calcium (mmol/L) 1.08 — 1.00–1.25 25-hydroxyvitamin D (nmol/L) < 15 34 40–150 Parathyroid hormone (pmol/L) 6.0 4.5 1.0–5.2 Fasting glucose (mmol/L) 6.3 5.4 < 5.6 Glycated haemoglobin (%) 6.2 5.5 < 6.0 Vitamin B12 (pmol/L) > 1470 — 145–637 Ferritin (μg/L) 124 — 15–200 While the prevalence of coeliac disease in the European population has been estimated to range from 1 in 150 to 1.5 in 1000,1 the prevalence in the Indian population is unknown due to lack of population-based data,2 leading to the common misconception that coeliac disease is rare. However, recent studies using new serological screening methods have demonstrated gross underdiagnosis of coeliac disease in the past,1-3 and an unexpectedly frequent prevalence in countries populated by non-Europeans. The highest reported population prevalence is in the Saharawi people of Arab–Berber origin, who live in the Sahara desert, with a prevalence of 5.6% — almost tenfold higher than that reported from most European countries.4 Similarly, recent studies in India found a prevalence of 9%–26% in patients who presented with chronic diarrhoea or malabsorption.5,6 The pathogenesis of coeliac disease is related to intolerance of gluten that results in a T-lymphocyte-mediated, small intestinal enteropathy in genetically predisposed individuals, who commonly express the HLA-DQ2 or HLA-DQ8 haplotypes.7 Such genetic predisposition is common in Europeans, but also occurs in Indian patients, as evident from detection of the HLA-DQ2 heterodimer in 14 out of 15 North Indian patients with coeliac disease.8 The HLA-DQ2 haplotype is also found in almost 25% of the healthy North Indian population, similar to the Western population,9 which has led to speculation that some Indians share ancestral origin with “ancient Caucasians” from the Fertile Crescent.9,10 Environmental challenge from the increasingly popular Western diet, which is gluten-rich, may also contribute to observed changes in the epidemiology of coeliac disease. For example, “summer diarrhoea” has been described in communities of Punjabis and Gujaratis from India. Traditionally, wheat replaces maize during summer in India, and Punjabis and Gujaratis residing in England and Canada have been reported to develop coeliac disease when exposed to a gluten-rich diet.11,12 Another misconception about coeliac disease patients is that they are all underweight. In one study, the mean body mass index of 371 patients with coeliac disease was 24.6 kg/m2, with only 5% being underweight, while 39% and 13% were in the overweight and obese ranges, respectively.13 Our patient’s body mass index was in the overweight range, which may have contributed to the delay in diagnosis until she was referred to our clinic. Coeliac disease is also associated with a wide range of autoimmune conditions. The presence of Hashimoto’s hypothyroidism was a clue to an autoimmune cluster in our patient, and persistent hypothyroidism despite large replacement doses of thyroxine is highly suggestive of a malabsorption disorder, such as coeliac disease. The complex symptomatology of our patient illustrates the non-specific, extraintestinal manifestations of coeliac disease, including lethargy, neuropsychiatric complaints, and myalgia from vitamin D deficiency; the latter may also lead to impaired insulin secretion and result in impaired fasting glycaemia.14 A high index of suspicion is required to screen for the disease, which is associated with significant morbidity. In conclusion, screening for coeliac disease with serological testing is non-invasive and should be considered in Indian patients with suggestive symptoms or associated autoimmune conditions. It is important for clinicians to overcome historical bias and consider coeliac disease as a diagnosis in non-European patients. Early diagnosis may help to avoid unnecessary investigation and reduce the long-term risk of small bowel malignancies associated with coeliac disease. Compliance with a gluten-free diet not only reduces symptoms, but also rectifies malabsorption of micronutrients and medications, which impact on comorbidity such as, in this case, abnormalities of thyroid replacement and metabolism of bone and glucose. Lessons from practice Coeliac disease is not limited to Europeans; it has been increasingly reported in patients from non-European backgrounds. Not all patients with coeliac disease are underweight, and a significant minority are overweight or obese. Serological testing is non-invasive and should be considered in patients with suggestive symptoms or associated autoimmune conditions, regardless of racial background. Presentation of coeliac disease can be non-specific, and is not limited to gastrointestinal manifestations. A high index of suspicion is required to screen for the condition in patients with predominant extraintestinal presentation.

Paul Lee MB BS(Hons) · Katherine Samaras MB BS(Hons), FRACP, PhD

A 66-year-old, previously well man presented with colicky abdominal pain and vomiting. He was a cigarette smoker and consumed homemade spirits daily. On physical examination, the patient had poor dentition, a bluish pigment along the gingival line (Figure, arrow), and generalised abdominal tenderness with no peritonism; he was afebrile with a heart rate of 68 beats/min, blood pressure of 190/90 mmHg with no postural drop, and oxygen saturation of 99% in room air; and all other results were normal. Full blood examination revealed normocytic anaemia (haemoglobin, 90 g/L; reference range, 130–180 g/L) and basophilic stippling. The patient’s blood lead level was elevated at 7.10 μmol/L (reference range, < 0.48 μmol/L), but fell to 2.28 μmol/L after 3 weeks of treatment with the chelating agent 2,3-dimercaptosuccinic acid (DMSA). Burton’s lead line indicates lead poisoning and occurs due to deposition of lead sulfide, the result of a reaction between sulfur produced by oral flora and lead.1,2 The source of this patient’s lead exposure is unknown. Distilling equipment, especially for spirits, can be a source of lead exposure,3 but testing of this patient’s equipment ruled it out as a source.

Jayne E Camuglia · George Grigoriadis · Christopher P Gilfillan

Strategies for managing increasing health system demand have focused on the acute sector and chronic disease management in the community, with little attention on the role of rehabilitation. There were over 53 000 inpatient rehabilitation episodes in Australia in 2006. We argue that rehabilitation can improve patient flow and outcomes in acute care if engaged early. The effectiveness of rehabilitation can be enhanced by increasing the intensity of therapy and developing models of rehabilitation that provide alternatives to inpatient care. Factors that reduce the efficiency of rehabilitation services include the location of many services in small, stand-alone hospitals without acute support; the lack of options for managing younger people with acquired disability in the community; and deficiencies in government programs for the supply of aids, equipment and home modifications. Improving the organisation of rehabilitation services should improve access to acute and rehabilitation inpatient beds, improve patient outcomes and reduce costs.

Peter W New MB BS, MClinEpi, FAFRM(RACP) · Christopher J Poulos MB BS, MSc, FAFRM(RACP)

To the Editor: Growing revenue from the sale of products for nicotine-replacement therapy (NRT), such as nicotine patches, has fuelled media interest in the likelihood that “reformed smokers” are “getting hooked on nicotine replacement”.1 While there may be anecdotal evidence of long-term use, there are no current population-based data to indicate whether this is the case in Australia. Overseas data suggest long-term use of NRT is low.2,3 For example, a United States study found the median duration of patch use decreased from 30 days to 21 days following over-the-counter NRT availability.2 Another study found that more than 75% of NRT purchases were for 1 month, while only 5% of smokers purchased NRT for more than 3 consecutive months and less than 1% of purchases continued to 24 months.3 An Australian survey conducted in 2000 suggested that most NRT use (61%) was short-term, lasting less than 2 weeks.4 More recently, our 2004 telephone survey of smoking-related perceptions and practices included an item on length of NRT use. The survey involved households selected at random from the New South Wales electronic white pages, with quotas applied to the sample based on NSW census proportions. The study was approved by the University of Newcastle Human Research Ethics Committee. Of the 3503 participants (response rate, 43%), all 539 current smokers and 1013 former smokers were asked about NRT use. Those who had made their most recent quit attempt in the previous 2 years reported on their NRT use during that quit attempt. Of the 138 who had used NRT on their most recent quit attempt, only three (2%) used an NRT product for 12 weeks (the recommended length of use). Only four NRT users (3%) reported using the product for more than 3 months, and none reported using NRT for more than 6 months. It appears that fears of widespread addiction to NRT products are probably unfounded. In fact, lack of compliance with use recommendations, resulting in inappropriately short episodes of use, is probably a bigger problem, and one that may help explain the disappointing effectiveness of NRT under “real world” over-the-counter conditions.5 Data on frequent repeated short-term use of NRT products would be useful to round out the picture on NRT use in the over-the-counter environment.

Christine L Paul · Flora Tzelepis · Raoul A Walsh · Billie Bonevski

To the Editor: In the 4 February issue of the Journal, Playford and colleagues highlighted that clinical schools are encouraging interns and postgraduate year 2 (PGY2) trainees to complete some training in rural locations,1 a good strategy considering the link between living in a rural area and working there later.2 Prevocational training in New South Wales and the Australian Capital Territory is undertaken in 15 training networks administered by the NSW Institute of Medical Education and Training (IMET). Networks typically include a city tertiary referral hospital, a metropolitan district hospital and a rural hospital. Until now, all trainees were allocated to a network by an “optimised-preference” algorithm that maximises trainees’ preference for a particular network but does not guarantee their first choice. Intern and PGY2 rotations occur in the hospitals throughout the network, including rural sites. Over the past few years, IMET has received requests to expand the number of rural sites accredited to provide trainees with all or most of their prevocational training in a rural site because: graduates with an interest in rural medicine want more opportunities for rural-based training; rural hospitals associated with a rural clinical school want to “retain” their rural students after graduation; and investment in rural clinical schools and the expanding service roles of rural hospitals has increased the attractiveness and viability of rural postgraduate training. In 2006, as part of its review into the delivery of prevocational training in NSW, IMET piloted the Rural Preferential Recruitment (RPR) process: Accredited rural hospitals advertise positions under RPR. Interested trainees apply directly to these hospitals while applying for network optimised-preference allocation. These hospitals run a merit-based selection process before the main allocation process. Trainees who receive and accept an offer from a rural hospital are removed from the main allocation list. Trainees who do not gain a position from the RPR process remain in the main allocation process. In 2006, four rural hospitals were involved in RPR and recruited 15 interns for the 2007 clinical year. In 2007, 11 rural hospitals attracted 122 applications from 58 applicants, and 35 doctors began a rural internship in January 2008. IMET recently evaluated the RPR scheme, and there is clear demand for quality prevocational training in rural areas, particularly when applicants can choose their hospitals. We hope this increase in rural exposure during the prevocational years will result in more doctors spending all or part of their careers in rural practice.

Louise Rice · Marie-Louise Stokes · Mark A Brown · Kirsten A Campbell · Cassandra Smith

To the Editor: Cunningham and colleagues discussed the rationale for using a live attenuated vaccine against varicella zoster virus (VZV) in preventing herpes zoster (HZ) in an older population.1 They also noted the difficulties in using a live vaccine in immunocompromised adults. Although generally considered less immunogenic than its live counterpart, an inactivated VZV vaccine would be ideal for vaccinating immunocompromised hosts. There is little information in the medical literature on inactivated VZV vaccines. However, the studies that do exist tested inactive vaccine on adult populations and showed favourable performance when compared with a live vaccine.2,3 Despite these promising results, the inactivated vaccine seems to have gone out of favour. Furthermore, if an inactivated VZV vaccine was used in the childhood vaccination programs against varicella, then it would simultaneously solve two problems caused by the vaccine strain of the virus, namely the development of infectious varicella and the reactivation of the vaccine strain as HZ.4 Cunningham and colleagues discussed the benefits of vaccinating an older population with VZV vaccine,1 but did not raise the intriguing possibility that the vaccination program might reduce rates of listeriosis in older people.4 A recent study examined the T-cell response in mice to latent herpesvirus infection, and found that it led to activation of macrophages that, surprisingly, protected the host against subsequent infection with other pathogens such as Listeria monocytogenes.5 Given that protection from HZ through vaccination is achieved by stimulating T-cell numbers above a critical threshold for HZ,6 it could be hypothesised that VZV vaccinees may be protected against listeriosis, an infection to which older people are more susceptible. The basis of this hypothesis is that macrophage activity would be stimulated by the T-cell response to the VZV vaccine, thereby providing cross-protection against L. monocytogenes. Prospective follow-up of vaccinees in Australia over time could refute or confirm this hypothesis.

Sanjaya N Senanayake

To the Editor: Spriggs and Gillam1 recently evaluated the updated guidance on ethical conduct in human research from the National Health and Medical Research Council (NHMRC),2 with particular reference to paediatric consent. The introduction in 2007 of the National Ethics Application Form (NEAF; http://www.neaf.gov.au) represented an attempt to streamline the process of obtaining ethics approval from multiple human research ethics committees (HRECs) for multicentre research. In 2007, just prior to mandatory introduction of the NEAF, we submitted identical NEAFs to 13 HRECs, covering all Australian states and territories, for an epidemiological study into childhood empyema. All but one HREC accepted the NEAF, but, despite use of the same form by the majority, we identified a variety of inconsistencies. With regard to child consent or assent, 11 HRECs required a single child information sheet and consent form; one required two separate age-appropriate forms; and one questioned the planned involvement of children in the consent/assent process and did not require a child’s consent. This latter response arguably contravenes the United Nations Convention on the Rights of the Child, which provides for a child’s right to information in a form they can comprehend, whether or not they have the ability to make decisions.3 Other inconsistencies included the time taken to obtain approval, which ranged from 1 day to 197 days (median, 31 days). One HREC defined a child as being aged less than 18 years; the others used a cut-off of 16 years. One HREC responded that the application did not specifically address local Aboriginal and Torres Strait Islander peoples’ issues, which suggests that the NEAF may not be sufficient to cover such site-specific requirements. One HREC required plain-language translation of consent and information sheets, and another required Aboriginal translation. Also of concern, the NEAF requires justification for the inclusion of Aboriginal or Torres Strait Islander children and other groups where ethical considerations may be different, such as children with intellectual impairment or mental illness. This approach places the wrong emphasis on the desired outcome, which is to give due consideration to cultural, social, health, psychological and local issues that may introduce ethical concerns that are not the same for all children, and it risks exclusion of some children from research that is relevant to them. We suggest the NEAF should instead include a justification for exclusion of any children as a result of cultural or religious background or social or psychological problems. This would provide an alternative way of gathering information about ethically relevant issues, to ensure best practice in ethical conduct or research. Clearly, there is a lack of consistency across Australia in engaging children in research, including the consent/assent process. We believe that use of the NEAF alone is insufficient to rectify these inconsistencies, and now is the time to consider a single national ethics committee for Australia, similar to the National Research Ethics Service recently introduced in the United Kingdom (http://www.nres.npsa.nhs.uk).

Adam Jaffe · Roxanne E Strachan · Katrina J Williams

To the Editor: I read with interest the letter by Lim and colleagues on anorexia nervosa and senna misuse.1 I have seen abnormal whole body bone scans in patients with severe eating disorders of exactly the same pattern (except for the avid bilateral apical lung and gastric uptake) as the case described. However, I disagree with the interpretation of the bone scan. There was increased periarticular tracer uptake involving long bones. The pattern was not that of hypertrophic osteoarthropathy (HOA). The pattern in HOA is linear tracer uptake by the periosteum, particularly along the distal ends of long bones.2 The scan in the case reported did not show uptake of this pattern, despite radiological evidence showing periosteal reaction and new bone formation of the tibia and fibula at the ankle. The pattern exhibited in this patient was more consistent with metabolic bone disease (increased tracer uptake by the ends of long bones periarticularly, the axial skeleton, calvaria, mandible, sternum and “beading” of costochondral junctions, with faint, or absent, renal uptake),3 although not all of these features were present in this case. Metastatic calcification of the gastric wall (not mentioned by the authors) and upper lobes of the lung was present in this patient. Metastatic calcification of the lungs can be diffuse4 or localised (most commonly) to the upper lobes, as in this case.5 With regard to the bone mineral density results in this case, the authors state that the lumbar and femoral neck T scores were elevated (1.2 and 1.3, respectively). The normal range of the T scores is ± 1.0 standard deviation of young adult normal values.6 Elevated bone mineral density measurements are generally not of pathological significance and are therefore clinically not relevant. In my experience they are usually decreased, and are often osteoporotic, in patients with severe eating disorders.

Andrew F McLaughlin

To the Editor: We share the sentiments of Murphy’s article in the 7 April issue of the Journal.1 As intensive care physicians, the issue of futile care is an almost daily consideration. We agree with his assertion that “the community looks to the (senior) medical practitioners for the security they need to accept decisions of great moment, such as withholding futile treatment”.1 It is common for a referral to an intensive care unit to be made because “We asked the family, and they want everything done”. This is the least confrontational manner of “sorting out the resuscitation status” with the next of kin. Unfortunately, it shifts end-of-life decision making to others, particularly the family in crisis. This places additional stress on an already stressful situation. It often results in undignified, ultimately futile medical interventions and prolongation of dying. It is also a potential pastoral and mental health disaster for families. It is our duty of care to such patients to minimise the iatrogenic damage to their families by having senior clinicians communicate which therapies are appropriate, and thereby help families accept the likely prognosis. Ethically, we believe doctors should not harm families in crisis. Establishing when treatment is futile is difficult. The decision is often qualitative, with differing thresholds for futility. Personal and religious beliefs and anecdotal experience all affect the ability of a clinician to determine when a therapy is futile. We believe it is the duty of the clinician who performs an intervention, not the referring clinician, to determine its utility. A patient should not be referred to an intensive care unit if the intensivist believes the multitude of life-supporting therapies are not of clear benefit. If initiated, the intensivist should determine when such therapies are no longer of benefit. A framework for debate and review of contentious cases should be established within institutions as a matter of process. Sadly, intensive care units are increasingly seen as locations for palliative care. When a patient dies, it is unreasonable for referring clinicians to claim a clear conscience by saying “we did everything we could”, when the outcome is a prolonged, undignified death in an intensive care unit. Such deaths are not just wasteful of resources, but cause unnecessary distress to patients, their families and staff who care for them. We must not mistake “treating” our patients for “caring” for them. Doctors should be part of the solution, not part of the problem.

Thomas R Solano · James D Fratzia

To the Editor: Congratulations to Murphy1 for raising the important and sensitive issue of when to stop trying. This is an issue that needs to be discussed more widely in the community and in hospitals, and presented sensitively to all health students. We know that a significant proportion of the health dollar is spent on the last 12 months of life,2 but, more importantly (as Murphy points out), a clear decision, discussed openly with patients and their families, can save significant pain — both physical and emotional — to all concerned. Advance treatment orders can aid decision making in these situations, but need to be backed up with support for patients’ families when they are to be followed. This issue is with us now but will become more widespread in the future. Health professionals need to be well schooled in this important area of caring. We have to understand when to cease the desire to keep a patient alive. Modern health care has provided incredible advances but we are still not good at knowing and being “strong” in our beliefs and behaviour about when to stop.

Peter M Brooks

To the Editor: In the 7 April issue of the Journal, Murphy encouraged the medical profession to be more proactive about discussing end-of-life care options with family members (or next of kin) with a view to withholding care that may be considered futile by the clinical team.1 While we agree that it is important to offer advice about what course of action the clinical team recommends in a particular case, it is equally important that this advice be based on good evidence and sound clinical judgement. This can be difficult, even for experienced clinicians. Further, it is unwise to leave the family without any alternative but to accept that advice, because this can lead to distrust and disagreement between the family and the treating team. This is not a matter of acquiescing to a family’s unrealistic expectations — often the prognosis is not clear-cut, and there are times when a planned but limited trial of therapy is warranted. In complex situations, the prognosis often becomes obvious, and families can and do draw comfort from the fact that every effort was made, and are then more willing to accept limitation or withdrawal of therapy. In the case of withholding cardiopulmonary resuscitation, the treating team has sole responsibility for the medical opinion, but the family should be involved in the final decision and not have it enforced unilaterally.

Mathew Piercy · Graeme Duke

To the Editor: We support the conclusions reached by Parker and colleagues in their study on the attitudes of Australian medical practitioners to end-of-life decisions.1 They recommend the inclusion of decision-making theory and practice within medical ethics curricula, and highlight the need “to facilitate more discussion between specialties about medical decisions at the end of life”.1 An investigation commissioned to the Australian Institute for Suicide Research and Prevention by the Australian Government Department of Health and Ageing in 2006 aimed to verify receptivity towards, and possible ways of implementing, suicide prevention education in the medical curricula of Australian universities. This mandate also provided the opportunity to assess potential interest in and feasibility for education on end-of-life decisions.2 Our exploratory investigation included interviews of key academics in curriculum or accreditation committees of 10 out of 15 Australian medical schools, 24 general practitioners from six Australian states, and 373 medical students from the University of Queensland.2 Representatives of the medical schools considered it a “very high priority” to implement adequate education on end-of-life issues, including euthanasia, in medical curricula. Most of the interviewed GPs (21/24) and 80% of medical students agreed with this sentiment. Common themes that emerged from the study were the need for good preparedness in coping with difficult situations, and the desired capacity in competently handling decisions that are perceived to be requested with increasing frequency in clinical scenarios.2 End-of-life issues nearly always involve aspects that go beyond the treatment of somatic conditions. Moral convictions, religious beliefs, and self-identification processes (with the patient) all compound the challenge physicians face in their practice. The very complexity of the challenge should push towards more knowledge, and this should be obtained through modern medical curricula.

Diego De Leo · Jacinta L Hawgood

To the Editor: In their recent “Clinical Update” on adrenal insufficiency, Jung and Inder1 state: In patients with adrenal insufficiency who are fasting before procedures, glucocorticoid therapy must be continued, by parenteral routes if necessary. A recent case report has highlighted the adverse consequences of omitting oral steroid therapy in a patient who was fasting before a surgical procedure. The patient developed hypotension and acute renal failure. The patient described in the case report2 was admitted with septic arthritis. His usual cortisone dose of 12.5 mg had been omitted that evening, and his morning dose of 25 mg was not given the next day until after he had returned from the operating theatre. Over the next 3 days, he became overtly septic, and returned to theatre for another knee washout. Cortisone was not given during this time. When he developed acute renal failure on Day 5, dehydration and gentamicin toxicity were listed as possible causes. The article by Jung and Inder does not make it clear that the case report contains nothing of relevance to the management of patients with adrenal insufficiency who are fasting for routine surgical procedures, as this man’s hypotension and acute renal failure actually developed over 5 days in the context of sepsis, dehydration and possible gentamicin toxicity, in addition to prolonged withholding of cortisone and two operations.

Ian J Woodforth

To the Editor: The recent article by Jung and Inder1 provides sensible advice for the safe management of adults with adrenal insufficiency (AI) during illness and surgery, without risking adrenal crisis or excessive steroid dosing. However, the authors make no reference to paediatric practice and no guidelines have been provided for the body-size-related steroid doses required in paediatric patients with AI, either for routine steroid replacement or during illness and surgery. It is important that doctors be aware that the doses recommended by Jung and Inder are not suitable for children with AI. In keeping with recent studies of daily cortisol production, daily hydrocortisone replacement doses of 6–8 mg/m2/day are now recommended for children with secondary AI (eg, due to adrenocorticotropic hormone deficiency), provided the patient has no hypoglycaemia or symptoms of cortisol deficiency.2 In children with primary AI, higher hydrocortisone doses are often necessary (up to 10–15 mg/m2/day) — for example, to minimise adrenal androgen secretion in children with congenital adrenal hyperplasia.3 During minor illness (as defined in Box 3 of Jung and Inder’s article1), a child’s usual daily oral dose of glucocorticoid should be doubled or tripled until recovery.3,4 However, for children with secondary AI who are on the lower doses of daily hydrocortisone (about 6–8 mg/m2/day), these multiples may not constitute adequate doses during stress. In these patients, per-m2 dosing is more accurate (ie, 30–40 mg/m2/day for minor illnesses). During moderate-to-severe illness, for patients who are vomiting, those who have experienced trauma and those undergoing anaesthesia and surgery, the following doses of intravenous hydrocortisone are recommended: For children aged < 3 years: 25 mg initial dose then 25–30 mg/day; For children aged 3–12 years: 50 mg initial dose then 50–60 mg/day; and For adolescents and adults: 100 mg initial dose then 100 mg/day. These doses are in keeping with national4 and international3 recommendations, and equate to doses of 60–100 mg/m2/day of hydrocortisone. The more accurate per-m2 dosing should be used for children who are not within the normal weight range for their age. These recommendations for children are extrapolated from adult studies and also based on expert consensus. Attention to the specific body-size dose adjustments required in paediatric prescribing can provide safe levels of steroid cover while avoiding exposure to excessive steroid doses.

Ann M Maguire · Maria E Craig · Christopher T Cowell

To the Editor: The excellent article by Jung and Inder1 in a recent issue of the Journal contains a detailed discussion of different regimens proposed for glucocorticoid supplementation in the perioperative period and makes recommendations for the use of hydrocortisone therapy according to the degree of “surgical stress”. It is worth noting that, in many cases, these recommendations and the detailed advice of endocrinologists regarding individual patients are rendered moot by the changes in routine perioperative antiemetic therapy that have occurred in the past decade. The use of intravenous dexamethasone as an antiemetic has been the subject of much clinical research. The IMPACT study2 showed that it has an antiemetic efficacy similar to that of ondansetron or droperidol when given prophylactically. Dexamethasone is less expensive than either of these drugs and is ineffective as rescue therapy in the setting of postoperative nausea and vomiting (PONV), unlike the alternative drugs. As a result, it is used routinely on induction of anaesthesia in many cases of surgery associated with an increased risk of PONV or where PONV would pose a risk of injury or delayed discharge. A range of doses of dexamethasone for antiemetic prophylaxis has been investigated without finding superior efficacy from higher doses (of up to 1.0 mg/kg).3 The dose typically used in clinical anaesthesia practice is 0.05–0.1 mg/kg. This is equivalent in glucocorticoid activity to more than the highest dose of hydrocortisone described in the guidelines of Jung and Inder1 and should provide a self-tapering effect over 2–3 days, consistent with their recommendations for hydrocortisone dosing.

James A Mitchell

In reply: We thank Woodforth for his interest in our article.1 The cited case report2 involved a patient with panhypopituitarism who had septic arthritis following a total knee replacement, requiring knee washout. As stated by Woodforth, the patient was without glucocorticoid replacement for 5 days, during which time he underwent two surgical procedures. Symptoms of cortisol deficiency were described on Days 1 and 2 postoperatively, with overt sepsis not manifesting until Day 3. The absence of adequate glucocorticoid replacement while the patient was under a “nil oral” instruction and suffering sepsis was undoubtedly a contributory factor in his decline, given that his condition improved significantly after he had received 24 hours of intravenous hydrocortisone treatment and other supportive care. It appears that the cortisone acetate was withheld because of concerns about administering it without food, as other medications were in fact given. We stand by our assertion that patients with proven or suspected cortisol deficiency should receive adequate glucocorticoid replacement before and after surgery, according to the likely stress of the procedure. Often, for minor procedures, an oral route of administration will suffice. Doses of oral glucocorticoids given under these circumstances do not need to be taken with food. If there are sound clinical reasons for the patient not to have any medications orally, then parenteral administration is appropriate.1 Maguire and colleagues correctly point out that the glucocorticoid dosage recommendations in our article are suitable only for adults. They have made a significant contribution to the literature on the investigation and management of paediatric adrenal insufficiency and we would like to thank them for providing the appropriate glucocorticoid doses for paediatric patients under stress. We are aware of the use of dexamethasone as a perioperative antiemetic, as outlined by Mitchell, although it is not clear how widespread this practice is. He is correct in stating that in cases in which dexamethasone is used for this purpose, the glucocorticoid dose thereby provided is likely to be more than adequate for adrenal replacement. However, dexamethasone has no mineralocorticoid activity, and this must be taken into account when treating patients with primary adrenal insufficiency. Doses of hydrocortisone greater than 50–75 mg per 24 hours provide adequate mineralocorticoid replacement. If dexamethasone is used for patients with primary adrenal insufficiency undergoing surgery, it is imperative that the patient continue to take oral fludrocortisone throughout the perioperative period to provide mineralocorticoid replacement. This highlights the need for good communication between the patient’s general practitioner, endocrinologist, surgeon and anaesthetist to ensure the best patient outcome.

Caroline Jung · Warrick J Inder

To the Editor: We all privately seek statistics that enable us to put ourselves in perspective (even if we keep the results to ourselves!), but I am now unsure where my sexual performance stands.1 On the one hand, I am told premature ejaculation affects at least one, and from time to time two, of every three males (is that the < 2 minutes version?), and on the other that there is a skewed distribution with a median of 5.4 minutes and a range of 0.55–44.1 minutes. I’m impressed by the aerobic fitness, never mind the sex. It seems we have a continuously distributed, perhaps skewed, normal distribution of an apparently genetically determined variable, with which individual players (?70%) and their partners are dissatisfied at times. Is that not like height, or IQ? “Premature” ejaculation may not be caused by individual psychology, but it is defined by it: from our beginnings in the Garden of Eden we have always wanted more than we have! The early sperm may not get the bird but historically it got its share of the ovum and thus has persisted over millennia. There may be a role for medicine in some extreme cases (as for “constitutional” dwarfism and gigantism, where being very different carries a significant psychological disadvantage), but for the rest are we not colluding to some extent with an escape from the reality of our limitations? How much of this is treatment and how much is performance enhancement?

Paul T Dignam

In reply: Dignam queries the validity of treating early ejaculation that may simply be a variant of normal. However, if one in three men complain to us of premature ejaculation and how it affects their relationships, we listen. They may regard themselves as very different from other men and may become psychologically disadvantaged. In our article we detailed various presentations of premature ejaculation (PE), including that of a subjective perception of PE although the intravaginal ejaculatory time is normal.1 In such cases, reassurance is an appropriate response. However, for men with primary PE, for whom ejaculation consistently occurs within 1 minute or even before vaginal penetration, there is a problem. This problem can be treated successfully to improve a relationship that may have been foundering. And, yes, this may mean performance enhancement unrelated to aerobic fitness. If men are unsure where their sexual performance stands, they should ask their partner. After all, communication improves a loving relationship.

Neil R Palmer · Bronwyn G A Stuckey

The anatomist. A true story of Gray’s anatomy. Bill Hayes. Melbourne: Scribe Publishing, 2008 (xix + 250 pp). ISBN 978 1 921215 89 6. This is a terrific read, even if the idea of slicing into a cadaver makes you queasy. Hayes is the author of two previous books, Sleep demons, an account of insomnia, and Five quarts, on blood. If The anatomist is anything to go by, then these earlier books are certainly worth reading (I’ve already ordered them). Hayes’ book on blood is particularly poignant, as his long-term partner was HIV-positive and died shortly before the present book was completed. To write The anatomist, Hayes undertook human dissection as an active observer in the medical school at the University of California in San Francisco. I got a bit lost with the student characters, but the anatomy side of things is vivid — I learned several tips even though I’ve been teaching the subject for over 30 years. The account of Gray’s life is sketchy, but that’s because so little is known of the man. He died, horribly, of smallpox, aged only 34 (or 36 — even his birth date is uncertain). Much more interesting is the very detailed picture of Henry Vandyke Carter, Gray’s impoverished yet gifted young colleague who did the illustrations for the book for a paltry one-off sum of 150 pounds (Gray received the same sum for every thousand copies sold — a deal that would eventually benefit four generations of his descendants). Hayes managed to unearth a huge cache of Carter’s letters and diaries. The artist was a sombre man, perhaps even clinically depressed at times, but typically Victorian in his attitudes and self-criticism. He rose above the grind of illustrating Gray’s anatomy and went on to a successful career as a doctor specialising in tropical diseases in India. Although I personally find his illustrations rather gloomy, they are still hugely informative. The book is extremely well researched and has an excellent bibliography.

James M Cummins

Clinical cases in obstetrics, gynaecology and women’s health. Caroline M de Costa, Paul Howat. Sydney: McGraw-Hill, 2007 (xv + 256 pp). ISBN 978 0 07 471640 3. Clinical cases in obstetrics, gynaecology and women’s health is the kind of book I would have liked to have had when I was a medical student or junior resident. Well written and in a conversational tone, de Costa and Howat outline an approach to those common questions that arise in clinical practice. The book extends the type of cases presented to medical students as part of problem-based learning to a higher level of complexity, and pleasingly incorporates the emotional, social and psychological aspects of care that are often absent from standard obstetric and gynaecology textbooks. Each case provides an up-to-date overview of the topic area and concludes with references which, while not cited in the text, are accompanied by useful suggestions for further reading. Readers are kept engaged with highlighted boxes and clinical pearls, and for those undertaking a diploma in obstetrics and gynaecology, the multiple choice questions at the end of the book are a useful way to test your knowledge. Targeted at the level of medical student and junior doctor, general practitioners very experienced in women’s health may find the content a little simplistic, and there are some omissions, such as preconception care and counselling regarding an unplanned pregnancy. However, for those who want to know what current practice is or should be in clinical scenarios that arise in day-to-day practice, Clinical cases in obstetrics, gynaecology and women’s health will be very useful.

Danielle Mazza

Febrile seizures Many parents have experienced the worry and stress linked with a childhood febrile seizure, but the risks associated with these convulsions have been difficult to determine. A large Danish study of over 55 000 children with a history of febrile seizures has shown that long-term mortality does not appear to be increased in these children. The 28-year study identified a higher mortality rate in the first and second year after a febrile convulsion, with the rate returning to baseline for the normal population after this period. A nested case-control study examining the type and duration of seizure showed that children who experienced simple (15 minutes or less and no recurrence within 24 hours) febrile seizures had a mortality rate similar to the general population. The authors comment that the findings should serve to reassure parents of children who suffer simple febrile convulsions. Lancet 2008; 372: 457-463 Low-down on hypercalcaemia Some therapeutic practices in medicine become standard care by default, even when evidence may be lacking as to their efficacy and safety. One such exercise is the treatment of hypercalcaemia with furosemide, claim the US authors of a review on the optimal management of hypercalcaemia. Although the use of forced saline diuresis with furosemide for hypercalcaemia continues to appear in textbooks, the results of the review support that best practice is to use hydration with normal saline and immediate biphosphonate therapy. Calcitonin may be required for emergency management of patients with severe symptoms. The authors take into account potential side effects of biphosphonate therapy, but conclude that furosemide no longer has a place in the treatment of hyperclacaemia. Ann Intern Med 2008; 149: 259-263 The spoils of war Images of political violence assault our senses through the media on a daily basis. The effect on children exposed to armed conflict, and how the resulting psychological trauma may be minimised, was the subject of a recent Indonesian cluster randomised controlled trial. Researchers set out to determine the effect of a school-based mental health intervention on children affected by political violence in Poso, Indonesia. Almost 500 children (with a mean age of 9.9 years) were enrolled in the study, with one group undergoing regular group sessions including trauma-processing activities and cooperative play. Children on a waiting list were used as a control group. Outcome measures were psychiatric symptoms rated on scales assessing post-traumatic stress, depression, anxiety and hope. Results showed an improvement in post-traumatic stress disorder symptoms and maintenance of hope in the treatment group, but no apparent differences in the other outcomes. Girls benefited more from intervention than boys. The authors comment that they used non-professional community-based facilitators in their intervention, and that this reflects the resources available in such areas. In conclusion they state these results may show that psychosocial interventions alone are unable to reverse the challenges to psychosocial wellbeing presented by chronic poverty and political instability. JAMA 2008; 300: 655-662 Windows of the soul The electronic eye may be closer to reality than you think, according to ground-breaking work undertaken by US scientists.1 Previous attempts at creating an imaging device as subtle in design as the human eye have been thwarted by limitations in the fabrication of optoelectronic devices, particularly problems in developing the required technology on a curved surface. Drawing inspiration from the structure of animal eyeballs, the researchers fabricated a network of semiconductor photodetectors on a silicon wafer that can not only tolerate compression but has the ability to elastically transform from a planar to a hemispherical shape. An accompanying commentary observes that these innovations have implications for use not only as bionic implants, but as health-monitoring devices, in industrial applications, and in the development of artificial eyes structured like those of fish or even insects.2 1 Nature 2008; 454: 748-753 2 Nature 2008; 454: 703-704 Wheeze, rattle and purr Asking if a child has a history of “wheeze” is fraught with problems, as most primary care providers are aware. In a Scottish study, parents of over 1300 children completed a questionnaire about respiratory noises when the children were 2 and 5 years of age. Those reporting wheeze subsequently described the sound as rattling, purring or whistling. The different sounds appeared to be associated with varying outcomes; compared with other respiratory sounds, whistle was more likely to persist and children demonstrating whistling noises were more likely to require asthma medication in the future. The authors comment that subjective reports of respiratory noises in children may be difficult to interpret, and that further characterisations of the sounds may be clinically useful. Arch Dis Child 2008; 93: 701-704

Tanya Grassi