Volume 178 Issue 7

The identification of specific causal genes and the development of animal models of MND offer realistic hope of new treatments Since Charcot's first description, motor neurone disease (or amyotrophic lateral sclerosis) has remained an enigma.1 Without a clear understanding of the pathogenesis, and with relatively little therapy to offer other than symptomatic and palliative intervention, clinicians have faced the difficult task of effectively managing patients with this relentlessly progressive disease. However, advances in understanding over the past decade have reignited research interest, renewing hope that a curative approach may be forthcoming. Motor neurone disease (MND) is characterised by progressive deterioration involving the corticospinal tract, brainstem and anterior horn cells of the spinal cord. Extraocular and sphincter muscles innervated by motor neurones not receiving direct projections from the motor cortex are characteristically spared. The term MND is used to encompass all forms of the disease, whatever the combination of upper and lower motor neurone involvement, while Americans still call it Lou Gehrig's disease, after the New York Yankees baseballer diagnosed with MND towards the end of his playing career. The aetiology of MND is unknown but appears heterogeneous. Environmental factors may trigger a genetic susceptibility — toxins, chemicals, metals, previous infections, and trauma have all been proposed. Uncertainty about the aetiology often creates added concern in MND patients with regard to heritability, as highlighted by the Personal Perspective article in this issue of the Journal (page 344).2 Most aetiologies have been linked to a cascade involving the glutamatergic neurotransmitter system, with excessive activation of glutamate receptors at the synaptic cleft (excitotoxicity) eventually triggering destruction of motor neurones. In the rarer, familial type of MND, the breakthrough finding of a mutation involving the copper/zinc superoxide dismutase-1 (SOD1) gene3 (encoded on chromosome 21q22.1) has provided an impetus for MND research and suggested new therapeutic strategies. Mutations have subsequently been documented in a fifth of the approximately 5% of patients with familial MND. However, while SOD1 mutation screening is now clinically available, genetic counselling is critical before predictive testing is undertaken. While MND is usually relentlessly progressive, with 50% of patients surviving fewer than three years from diagnosis, a smaller proportion of patients (about 20%) may survive between 5 and 10 years.4 Predominantly lower motor involvement tends to predict longer survival. In contrast, bulbar onset and respiratory compromise suggest a worse prognosis. How is MND diagnosed?There remains no pathognomonic test for the diagnosis of MND. Physicians continue to rely on clinical criteria for diagnosis, specifically the presence of both upper motor neurone (spasticity, weakness and hyperreflexia) and lower motor neurone (fasciculation, wasting, weakness and hyporeflexia) signs. Fasciculations, an almost inevitable feature of MND, reflect spontaneous nerve activity, probably generated through upregulation of persistent sodium channels in dying motor axons.5 Clinical features, in combination with neurophysiological investigation, can confirm the diagnosis. Nerve conduction studies and electromyography may also be used to identify alternative, but potentially treatable, lower motor neurone disorders confined to motor fibres, particularly immune-mediated demyelinating neuropathies and multifocal motor neuropathy.6 While research criteria exist for diagnosis,7 these are rigorous and still rely on clinical findings to stratify the likelihood of diagnosis, with most patients considered as "possibly" or "probably" having MND before the diagnosis becomes "definite" with time. Although newer imaging techniques have shown promise in aiding diagnosis, the primary role of imaging is to exclude other conditions. Despite this clinically oriented approach, the reliability of diagnosis is high, demonstrated to be 90% when compared with autopsy findings.8 Confirming the diagnosis is devastating for the patient and family members and must be handled sensitively. Patients often complain that the diagnosis was conveyed in a hurried and inappropriate manner, with some told off-handedly "to go home and write their will". A follow-up appointment a few weeks later may be beneficial to answer questions not addressed at the initial consultation, and to provide further information about support networks, particularly the Motor Neurone Disease Association. MND management and disease-modifying treatmentManagement needs to be multidisciplinary, involving physiotherapists (mobility and prevention of contractures), speech therapists (communication aids and swallowing assessment), occupational therapists (maintaining function), social workers (counselling and organising home support), and dietitians (particularly with percutaneous endoscopic gastrostomy feeding), all coordinated by the supervising neurologist or physician, with the aim of collectively maximising function and alleviating symptoms.9 Involvement of palliative care services should occur early, anticipating patient needs (eg, implementation of home services) well in advance of deterioration, and later assisting with disease-related symptoms and psychosocial issues. The role of ventilatory support remains controversial: non-invasive ventilation may improve symptoms related to respiratory insufficiency without extending survival, while invasive support may extend survival in MND patients with severe disability.10 Riluzole, an inhibitor of glutamate release, is the first medication found to increase survival in MND patients (by 3–6 months in two large randomised trials).11 Recent retrospective analyses suggest greater benefit, but these data have been confounded by general improvements in the care of MND patients. Although licensed worldwide, riluzole was only recently made available in Australia, and is currently being reconsidered for listing by the Pharmaceutical Benefits Advisory Committee. Many MND patients take a range of over-the-counter antioxidants, particularly vitamins C and E, based on promising experimental data, although there remains no sound clinical evidence concerning efficacy. Neurotrophic and immunomodulatory treatments likewise have shown little clinical benefit, while preliminary studies focusing on neuroprotective approaches (eg, with minocycline12) suggest promise. "Alternative" therapies, some offering unrealistic hope of cure, are universally unproven for MND, are often expensive, and carry the risk of potentially harmful effects. New preventive and restorative approaches are being intensively explored, including the role of stem cells as vehicles to regenerate functional connections in motor pathways. After a century of limited progress, the identification of specific causal genes and the development of animal MND models offer realistic hope that new treatments will emerge.

Matthew C Kiernan PhD, FRACP

The anti-smoking crusade in Australia is in a sorry state, say the leaders of California's Tobacco Control Program Fear comes in many forms. At the turn of the 20th century, our grandparents were terrified by tuberculosis and polio (to mention only a few of the hideous communicable diseases that plagued the human race). We pulled out all the stops and gladly spent millions to "conquer" the responsible infective agents, at least in the resource-rich nations. As a result, the "plagues" which now terrorise the industrialised world are cardiovascular disease and cancer. These two categories of disease alone are responsible for a majority of all deaths, illnesses, disabilities and the lion's share of medical care costs. The leading responsible agent for these is tobacco. Yet, we tolerate this agent, subsidise it with government funds, and passively accept the tobacco industry argument that our societal ethos accepts its use (that is, it's "normal" and "expected"), and those who oppose its use are, by implication, "intolerant" and "puritanical". There are few examples of so deadly an error in human history. We need to recognise that this problem is caused by an agent (tobacco) as virulent as the tubercule bacillus or the poliovirus. Furthermore, this agent is being skilfully marketed by an industry which is, sans hyperbole, an immensely profitable organisation that has grown by strategically buying social and political influence. An egregious example of this is the relationship between the big tobacco lobbyists and most of the major political parties in Australia.1 Tobacco use remains the single largest underlying preventable cause of death in Australia. The tragic irony is that these deaths are so very preventable. Yet tobacco control measures in Australia have stalled, primarily due to a monumental paucity of funds and political will. Sadly, the Australian crusade is actually a non-crusade. Because of complacency, you are falling far short of what could be achieved if you were once again to become global leaders in tobacco control. Needless to say, tobacco companies are constantly and very effectively working behind the scenes to diminish the gains that have been made to date. Tobacco use in Australia will probably fail to decline, and could even increase, unless a proactive campaign to regenerate your flagging efforts is undertaken. To that end the Cancer Council of New South Wales invited us to visit in November 2002 to transfer some of the California Tobacco Control Program's expertise, irreverence, passion and technology to our Australian counterparts. From 1988 (the year before the California program was launched) to 2001, annual per capita consumption of cigarettes in California declined by 60% to 50 packs per capita. During the same period, annual per capita consumption in the entire nation (including California) declined by only 34%, to just over 100 packets per capita (twice the rate in California).2 The comparable statistic for Australia is currently derived to be about 75 packs per capita annually. From 1988 to 1997, the decline in lung and bronchial cancer rates in California was five times the rate of the decline in the rest of the nation.3 Furthermore, prevalence rates of youth tobacco use in California declined 47% (from 11.2% in 1997 to 5.9% in 2001).4 What worked in California will also work in Australia. The California experience demonstrates that a comprehensive approach designed to change social norms and expectations around tobacco use will reduce both its use and tobacco-related morbidity and mortality. This approach involves media-supported advocacy for laws and voluntary policies that discourage tobacco use, especially at the community level. The objective of this approach is to change the social environment in such a way as to make tobacco use less desirable, less acceptable, and less accessible to adults and youth. The four broad priority areas, or policy themes, of the California program are: Protecting people from exposure to secondhand tobacco smoke; Exposing and countering tobacco industry influences in Californian communities; Reducing the availability of tobacco by regulating tobacco retailers; and Providing support for smoking cessation services. Having studied the dynamics of your political and governmental system, we identified four areas for Australia to work on. Firstly, the insidious influence of the tobacco industry on both sides of your parliamentary aisle is a huge drawback. The fact that a former premier of New South Wales is currently the chairman of your biggest tobacco company says it all. Secondly, your allocation of funds to tobacco control is ludicrous. Our largest State, California, has spent over US$1 billion in 12 years to achieve these results. In your largest State, New South Wales, you spent less than US$2 million last year. Thirdly, your governmental bureaucracy needs to be infinitely more agile and aggressive. Throughout our trip, we were complacently assured by government officials that some of these interventions "would not work" in Australia. We used to hear the same arguments in California. We just ignored them and pushed ahead aggressively to become the first major governmental organisation to take this "legally constituted tobacco industry" head on, by publicly ridiculing them for their falsehoods (as to the addictive, atherogenic, mutagenic and carcinogenic properties of tobacco smoke) and questioning their amoral marketing practices. You must give the leaders of your tobacco control program permission to be caustically critical of the tobacco industry and its surrogates as an official government policy. Lastly, your constituency of anti-tobacco control advocates is too civil by far. Even as we enjoyed success after success, we were continuously and usefully criticised, prodded and even pilloried by an ever-vigilant anti-tobacco constituency to do more and more, to good avail. In expressing these criticisms, we speak as respectful co-labourers in the field of tobacco control. Our own efforts were inspired by Australia's pioneering initiatives in tobacco control 20 years ago. Australia has had phenomenal success in the implementation of certain measures like advertising bans and point-of-sale restrictions (price and pack warnings being good examples of these), but none of these is a fundamental threat to the operation of the industry. Thus, having seen your once-proud effort diminished considerably, we have ventured to speak frankly in the hope that this may contribute to restoring your tobacco control efforts to their former glory. Our best advice? The allocation of funds to tobacco control in Australia is negligent, bordering on the farcical. At a minimum, you have to spend $50 million per year in New South Wales and well over twice that for all of Australia. This could fund an aggressive tobacco control program capable of producing a sea change in community norms around tobacco use. Your focus should be on increasing the tax on all tobacco products, as well as promulgating a total ban on smoking in all indoor venues, including bars, pubs and clubs. Smoking bans are, contrary to the tobacco industry's propaganda, good for health reasons, good for business, and good politics, as has been amply illustrated in California.5-7 A key point to remember is that a good adult campaign is also a good youth campaign. There is a clear divide between your political leaders "cosying up to" the tobacco industry and the preferences of your population, as expressed by polling and survey data.8-10 During our visit, we were repeatedly confronted with the question as to why your political leaders were not responding to these expressed needs. In conclusion, we do not delude ourselves that this will be easy to achieve given the organised opposition of the monolithic tobacco industry behemoth and its front groups and political influence in Australia. However, there is no shortage of anti-tobacco control expertise in Australia, where some of the world's leading tobacco control experts reside. You have the talent and technical expertise for an effective program. So, why are Australian authorities emulating the ostrich and sticking their heads in the sand? The anti-tobacco constituency needs to sound the clarion call: "In tobacco control in Australia: what aren't we doing and why aren't we doing it?".

Dileep G Bal MD, MS, MPH · Donald O Lyman MD, DT, DTPH · David F Veneziano MPA

The International Clinical Trials Symposium, held in Sydney in October 2002, brought together over 700 people to explore the issues and future directions for clinical trials. The support from government as well as industry and the diversity of people attending the symposium indicated the importance of clinical trials research in Australia. Established principles and new challengesAfter about 50 years of developing and refining the design and conduct of clinical trials, researchers have established the fundamentals. Randomisation, blinding, informed consent, adequate sample size and a prospectively stated study design are well accepted as means of producing unbiased evidence of the effectiveness of therapies. However, the symposium brought to light various issues that continue to challenge clinical trials researchers. Prominent among these were: how to make the conduct of trials more relevant to clinical practice (and, conversely, how to draw more of "real-world" care into the context of trials); the importance of consumers participating (not just as patients, but by voicing research questions); how to ensure that trials research concentrates on the clinical questions most needing answers (rather than on, for example, comparable products jostling for market share); and how success in these areas can practicably be achieved (not least by using technology to run trials efficiently). Some of these themes have been aired in the Journal.1 Bridging the gap between researchers and practitioners and patientsStephen Blamey (Chairman, Medical Services Advisory Committee, Commonwealth Department of Health and Ageing, Canberra) set the agenda in his opening address by stressing the importance of evidence-based medicine in allocating government funding. On behalf of the users of trial evidence, David Henry (Professor of Pharmacology, University of Newcastle) recommended that purchasers of services be represented when trials are being designed (and possibly share the cost of trials). Sue Lockwood (Chair, Breast Cancer Action Group, Melbourne), using the example of the Australian Sentinel Node Biopsy Trial (Royal Australasian College of Surgeons),2 showed that involving consumers ensures that recruitment is fast and that the outcome is evidence that matters to patients. Bob Temple (Director, Office of Medical Policy, US Food and Drug Administration, Rockville, Md, USA) raised the issue of the need for regulatory bodies to have a say in trial design to ensure that trials meet their objectives for rigour and new indications. Researchers can reach out to consumers by publicising the results of trials. Although journals have traditionally been the providers of this information, Richard Horton (Editor, Lancet) thought that promoting the results of research in other ways, such as communications aimed directly at consumers, is what really changes practice. Evidence may become known only from discussion in other journals and the mass media. As noted by Sally Redman (Chief Executive Officer, Institute for Health Research, University of Sydney), results published in specialised journals are often translated into practice by way of guidelines. "I carry a card that says, 'Invite me to participate in all randomized controlled trials for which I am potentially eligible'," said Iain Chalmers (Founder of the UK Cochrane Centre). He added that participation in controlled trials should become a widely available treatment option within routine healthcare. It was pointed out early in the symposium by Paul Glasziou (Professor of Evidence-based Practice, School of Population Health, University of Queensland), and others, that patients participating in clinical trials appear to do better than those receiving standard care outside of trials.3 Refinements in trial design, such as recruitment of clusters of patients rather than individuals (Judy Simpson, Associate Professor, Department of Public Health and Community Medicine, University of Sydney), and more control of confounders to widen entry criteria, can mean that more patients will be able to take advantage of participating in a trial. When commercial confidentiality is not an issue, trials can be advertised on web sites or public trials registers so that patients themselves can take the initiative in enlisting. Which diseases and treatments need evidence?Various speakers identified the many areas where more trials research is needed. Richard Horton championed an international perspective and the need for trials research in developing countries, focusing on diseases affecting people in these regions. In terms of the numbers of trials and the numbers of patients recruited, cardiovascular disease and cancer are way ahead. This is partly because of the large number of people with these diseases and the number of new treatments being developed. A challenge for researchers is to diversify to other areas. An innovative afternoon session comprised 12 concurrent forums in different clinical specialties. The objective was to identify current research priorities for particular clinical areas, and to develop new trial proposals or address concerns about trial methodology, such as measurement of outcomes, methods of randomisation and recruitment of patients. Besides cardiovascular disease and cancer, the forums embraced complementary medicine, diabetes, general practice, HIV medicine, perinatal medicine, reproductive and gynaecological medicine, rheumatology and surgery, as well as health technology assessment and information technology in research. The symposium also included speakers whose work focused on laboratory rather than human research. Some urged that the need for increased support of clinical studies should not compromise basic science research. A vision of the possibility of selecting the right drug for an individual patient is becoming a driving force in drug development (Peter Shaw, Director, Human Genetics and Pharmacogenomics, Bristol-Myers Squibb, Pennington, NJ, USA), particularly in oncology, where some drugs are especially effective for patients with certain genetic profiles. In HIV research, characterisation of viral gene sequences is affecting all aspects of trial design and analysis, adding to their complexity (Victor DeGruttola, Professor of Biostatistics, Harvard School of Public Health, Boston, Mass, USA). Systems for conducting trials more efficientlyMike Conlon (Chief Information Officer, University of Florida Health Science Center, Gainesville, Fla, USA) related that internet-based systems can reduce overall operational costs by a factor of three and significantly reduce workloads. Several groups in Australia are also working toward eliminating paper in the day-to-day running of trials. In view of the need for more and better trials in more areas of healthcare, these efficiencies will be essential. The necessity for an Australian trials registryPerforming trials is an expensive business. Researchers need to know about every trial in their field so as not to duplicate what is already being done (John Simes, Director, NHMRC Clinical Trials Centre, University of Sydney). Most of the trials in Australia are still unregistered (Paul Glasziou). Patients and their doctors want to know which trials are available and suitable. Ensuring that everyone can find out which trials are under way requires central coordination. The way forward would be an Australian register of clinical trials. A national register is essential for planning, for maximising patient participation, and for identifying relevant randomised trials for studies compiling the available evidence. Tony Keech (Deputy Director, NHMRC Clinical Trials Centre, University of Sydney) stressed that such a register would also facilitate meta-analyses, which ideally should be planned prospectively. Panel sessions — debates and hypotheticalsWhether (subject to consent and safety) every patient should be in a clinical trial was savagely contested by Richard Horton and Harvey White (Director, Coronary Care and Cardiovascular Research, Green Lane Hospital, Auckland) and David Celermajer (Professor of Cardiology, University of Sydney) and Martin Tattersall (Professor of Cancer Medicine, University of Sydney). Horton and White asserted that the key to better patient recruitment lay with doctors — they must offer more trial opportunities to their patients. And simpler inclusion criteria would allow typical patients with multiple morbidities to participate. Celermajer and Tattersall insisted that proof-of-concept trials do not require typical patients and that entry criteria do not require broadening. A hypothetical, moderated by David Celermajer, took a make-believe hospital ethics committee through an evolving scenario. The committee members agreed on the principles of justice, equity and non-maleficence, and that the trial research must be of adequate quality and not harmful to patients. However, when trials researchers want to extend the protocol to reuse data and analyse blood samples, a green light from the ethics committee may come only after strong debate. If blood analysis reveals a risk of disease, should the risk be disclosed to individual patients? If so, should it also be disclosed to their relatives? Some of the ethical dilemmas showed how closely the conduct of trials reflects usual medical practice, in that many ethical issues are the same. The ultimate panel session was moderated by Norman Swan (Producer and Presenter of the Health Report, Australian Broadcasting Corporation, Sydney), who examined the main themes emerging from the symposium with a broad-based panel. The panel recommended the following areas of action. More trials, especially prospectively designed trials in resource-poor countries; AIDS and malaria should have priority. Registration of trials. Trials in everyday practice. Development of funding mechanisms for trials. Guidelines as a means of translating trial evidence into practice. Trials of treatments (other than drugs) and technologies, to build on the work done by the pharmaceutical industry. Advancing alliances of triallists and government, particularly the NHMRC. ConclusionClinical trials have come of age. Researchers are now critically evaluating their methods to improve the precision of trial results and reduce bias. At the same time, a widening of inclusion criteria for patients entering trials is allowing more patients to take part. Therefore, the trial environment is becoming more like standard clinical practice; indeed, the next step may take us toward integrating trials with medical care so that research is part of the healthcare system.

Rhana Pike MA · Anthony C Keech FRACP, MScEpid · R John Simes FRACP, SM

Objectives: To assess the use of evidence-based investigations and treatments in patients with acute stroke in selected Australian hospitals and to compare management and outcomes between stroke and other types of hospital specialty unit.Design: Retrospective, multicentre audit of hospital case files.Setting: Eight metropolitan tertiary-care hospitals from five Australian States.Subjects: 300 consecutive patients from each hospital admitted between 17 September 1999 and 23 May 2001 and having a discharge diagnosis of stroke or transient ischaemic attack.Main outcome measures: Use of investigations and treatments supported by best available evidence; comparison of management and outcomes between stroke, neurology, general medical and geriatric units.Results: 2383 patients were audited (median age, 72.7 years; 52% men); 72% had ischaemic events, and 28% haemorrhagic events. Use of investigations and treatments varied between hospitals and types of unit. Stroke units or teams cared directly for 23% of patients (range across hospitals, 0–100%). Although 47% of patients with ischaemic events presented within 3 hours of symptom onset (when thrombolysis might provide benefit), only nine (2%) received thrombolysis. Angiotensin-converting enzyme (ACE) inhibitors were given to 28% of survivors at discharge (range, 14%–38%). Stroke units were more likely to use diagnostic tests, while neurology units were more likely to prescribe heparin acutely for patients with ischaemic stroke (not recommended for patients in general), and geriatric units were less likely to discharge patients with atrial fibrillation on anticoagulation therapy. Outcomes also varied significantly between types of unit. In-hospital survival rates were 90% (stroke units), 91% (neurological units), 82% (general medical units) and 79% (geriatric units) (P < 0.001). Stroke units and neurological units sent more patients home than the other units. Stroke units also sent fewer patients to rehabilitation and had longer mean length of stay.Conclusions: Acute stroke care varies between Australian tertiary-care hospitals and types of specialty unit, with suboptimal use of many evidence-based interventions.

Brendan K Duffy MD · Paddy A Phillips DPhil, FRACP, FACP · Stephen M Davis MD, FRACP · Geoffrey A Donnan MD, FRACP · Miriam E Vedadhaghi BSc, PGDipNutrDiet

Objective: To report initial experience with the use of intravenous tissue plasminogen activator (tPA) to treat acute ischaemic stroke at an Australian tertiary-care hospital.Design: Retrospective audit of computerised hospital stroke database.Participants and setting: All patients with acute ischaemic stroke treated with intravenous tPA between April 1999 and July 2002 at the Royal Melbourne Hospital, VIC.Main outcome measures: Times from stroke onset to arrival at the emergency department (ED) and treatment; rates of symptomatic intracerebral haemorrhage (ICH); clinical outcome at three months; and violations of treatment protocol.Results: Of 932 patients admitted with ischaemic stroke, 30 were treated with intravenous tPA. Median time from stroke onset to tPA treatment was 2 h 48 min, and median door-to-needle time was 1 h 49 min. Door-to-needle time improved in the last 12 months of the audit, with four of 15 patients achieving the recommended 60 min. Eleven patients (37%) had excellent clinical outcomes at three-month follow-up (modified Rankin score, 0–1), and 15 (50%) were functionally independent (score, 0–2). Mortality rate was 10%, similar to that of all ischaemic stroke patients during the audit period. Two patients (7%) had symptomatic ICH. Treatment deviated from protocol in seven patients (23%), five of whom received tPA over three hours after stroke onset.Conclusion: Rates of favourable outcomes and symptomatic ICH at our hospital were similar to those achieved in international phase III and IV trials in specialised centres.

Cassandra E I Szoeke MB BS · Mark W Parsons FRACP · Kenneth S Butcher MD, PhD, FRCP(C) · Tracey A Baird MRCP · Peter J Mitchell FRACR · Sonya E Fox RN · Stephen M Davis MD, FRACP

Objectives: To determine the time from symptom onset to hospital admission of patients with suspected acute stroke, final diagnoses and patient eligibility for thrombolytic therapy.Design: Hospital-based, prospective, observational study.Setting: Royal Adelaide Hospital Stroke Unit, South Australia.Patients: All patients admitted to the unit with suspected acute stroke over 11 months (11 April to 10 October 2000 and 20 August 2001 to 19 January 2002).Main outcome measures: Time from symptom onset to admission; final diagnosis.Results: Of 284 patients admitted, 39 (14%) had diagnoses other than stroke (including eight with transient ischaemic attacks), 42 (15%) had haemorrhagic stroke and 203 (71%) had ischaemic stroke. Median time to admission after symptom onset was 6 hours (range, 30 min to 13 days), with 100 patients admitted within 3 hours of symptom onset (35%), and 80 within 2 hours (28%). Thirty-seven patients (13%) could have been considered for thrombolysis (diagnosis of non-severe but disabling ischaemic stroke and admission time < 3 hours). Location at stroke onset was the only independent predictor of time to admission.Conclusions: Most patients with stroke do not present urgently to the emergency department, rendering them less likely to be considered for thrombolytic therapy.

Simon A Broadley PhD, MRCP · Philip D Thompson PhD, FRACP

Objectives: To compare hospital length of stay (LOS) and outcome after stroke between patients in a stroke unit offering combined acute and rehabilitation services and patients treated elsewhere in New South Wales.Design: Retrospective audit of two hospital databases (Diagnosis-Related Groups [DRG] database and Australian National Subacute Non-Acute Patient Classification System [AN-SNAP] database), with comparison with DRG and AN-SNAP data for NSW.Setting and participants: 242 episodes of acute stroke in patients admitted to the stroke unit of a metropolitan teaching hospital between July 1999 and November 2000, 113 of whom also underwent rehabilitation in the unit; 9777 episodes of acute stroke in the NSW DRG database, and 2350 in the NSW AN-SNAP database.Main outcome measures: Acute and rehabilitation LOS; mortality in acute care; FIM (Functional Independence Measure) score at discharge and change in FIM score; and discharge destination.Results: Patients in the combined stroke unit had shorter LOS and better functional outcome in all DRG and AN-SNAP groups, with both higher discharge FIM scores and greater gain in FIM scores than NSW patients. Acute stroke mortality of 12% and nursing home admission rate of 15.5% in the combined stroke unit were not significantly different from rates for NSW (15.7% and 11.2%, respectively).Conclusions: Combining acute and rehabilitation services in a stroke unit may reduce LOS and improve functional outcome of patients with acute stroke.

Yan H Ang MRCP · Daniel K Y Chan MD, FRACP · Qing Shen MB BS, MSc · Derrick M K Heng MB BS, MPhil

Medical rosters are not free of trade practices problems, notwithstanding assurances by the Australian Competition and Consumer Commission (ACCC). Neither the ACCC nor the recently convened Wilkinson Committee has applied rigorous legal principles in interpreting the Trade Practices Act 1974 (Cwlth) to reach its conclusions. The Australian law should be changed to bring it into line with that of the United States and New Zealand.

Warren Pengilley LLB, DSc

Pengilley has neatly summarised the long and ongoing disputation between the Australian Medical Association (AMA) and the Australian Competition and Consumer Commission (ACCC).1 The AMA claims that medical roster arrangements are likely to constitute a breach of the primary boycott provisions of the Trade Practices Act 1974 (Cwlth), a proposition vehemently denied by the ACCC (and by the Wilkinson Committee, which came into being as the result of vocal representations made to the federal government by the AMA). Pengilley claims to be on the side of the angels (ie, the AMA) with wings; I prefer to be the devil's advocate. Central to the dispute is to ask what is the meaning of the word "purpose" in any arrangement set out in section 4D(1) of the Trade Practices Act. Is it, as claimed by the ACCC, aimed at — and limited to — an anticompetitive purpose, or, as Pengilley maintains (because the word "purpose" is unqualified), does the section render illegal any roster that has the incidental effect of limiting medical services? The kind of literal reading of the Trade Practices Act applied by Pengilley had already fallen into disuse by the end of the 16th century. In what is now known as the "Mischief Rule", the Court, in Heydon's Case,2 asked itself "what was the mischief for which the common law did not provide and what has Parliament done to remedy it?". Thus, regarding rosters, the mischief for which the common law did not provide was the "combinations" that resulted in public harm. The incidental effect of section 4D is to give an imprimatur to all medical roster arrangements, save those whose "substantial purpose" is to deprive the community of competition. It follows that the roster arrangements entered into in compliance with the AMA's trade practices compliance program are immune from legal challenge. Thus, an arrangement whereby Dr X and Dr Y agree on a roster service which may incidentally deprive a community of 24-hour medical cover (eg, because of a medical manpower shortage) is clearly legal, provided no member of the roster deliberately agrees to withhold his or her services. I am puzzled by Pengilley's statement that "Indeed, no roster could function unless Doctor Y agreed not to provide services during the hours during which Doctor X is rostered on duty". Indeed, any attempt by Dr Y to keep himself or herself "out of service" is not only illegal, but unethical, and deliberately "caught" by the Act, and so it ought to be. In the end, the argument comes down to how many angels can dance on the head of a pin. I am satisfied that Pengilley's argument in support of an amendment to the Trade Practices Act is a counsel of perfection, if only because any attempt by the ACCC to prosecute a bona fide medical roster arrangement would face insurmountable legal and evidentiary hurdles.

Paul Gerber LLB DJur

Rural doctors, like their colleagues elsewhere, are thinking individuals whose main aim is to provide timely, appropriate care to the patients living in their local communities. More often than not, they are small-business operators running a practice which is becoming more complex, both in the clinical sphere and in the myriad requirements associated with accreditation, indemnity, practice incentive payments, vocational registration, the Pharmaceutical Benefits Scheme and Medicare, credentialling at the local hospital, the Privacy Act 1988 (Cwlth), and the Trade Practices Act 1974 (Cwlth). Non-compliance with any of these regulations and requirements can lead to severe penalties — in the case of breaches of the Trade Practices Act, exposure to $500 000 fines for individuals. The Productivity Commission's recent enquiry into red tape in general practice1 and the Wilkinson Review of the impact of Part IV of the Trade Practices Act on the recruitment and retention of medical practitioners in regional Australia are two demonstrable consequences of the general concern. In rural Australia, the medical workforce faces a special subset of challenges in providing a broad range of medical services to small communities with limited resources and support facilities. This is in an environment where there is a relative shortage of medical practitioners and an increased workload.2,3 Administrative and bureaucratic requirements can make the difference between staying in and leaving rural practice.4,5 The size of isolated rural practices does not allow for the management processes, information technology, and support staff required to meet the bureaucratic requirements. Pengilley's article6 is a timely reminder that government reviews may not solve the questions faced by doctors in their everyday work in their efforts to comply with the law. Grey areas of the law will only be resolved by changes in the law itself, not by reviews. Pengilley has given an example of rostering for 16 hours out of 24, which would almost certainly be in contravention of the law and bring the full force of the Australian Competition and Consumer Commission (ACCC) down on those doctors. There are real examples happening in Australia today of doctors struggling to provide services in a sustainable manner so that they do not become exhausted, which may lead to disruption of their family, social and professional life and ultimate cessation of practice in that community. For example, a consensus of opinion is that rural doctors require a one-in-four roster to ensure sustainability. How is this to be achieved in a three-doctor town where it recently took three years to replace a doctor? The doctors may choose to advise their communities that, if they are to have sustainable medical services, it may be necessary for the community to have no doctor available one weekend in four. The trade-off for the community is that their doctors will stay longer. The ACCC has never given a clear opinion in relation to such an arrangement, but, if consumers complained, then almost certainly the ACCC could take the view that the arrangement breaches section 4D(1)(ii) of the Trade Practices Act: "The provision has the purpose of preventing, restricting or limiting the supply of services to particular persons or classes of persons." Similarly, a cluster of four small towns, perhaps 50 km apart, with one doctor each, may not be able to form an after-hours roster, because services would be reduced to three of the communities after hours on any particular night. The result may be that no doctors service such towns. Authorisation under the Act is both costly and complex — from the doctors' viewpoint, why bother when there is work at the larger town 100 km away? Yet, Pengilley argues that even more straightforward rosters may in fact breach section 4D. The rural doctor's job is difficult enough without continued uncertainty over whether the Trade Practices Act will be brought to bear on well-meaning practitioners doing the best for their local communities in difficult circumstances. The persisting uncertainties are likely to hinder further recruitment and may lead to exhausted doctors leaving their communities.

David Mildenhall

Clinical record A 65-year-old woman had recurrent generalised tonic–clonic seizures. She was being treated with peritoneal dialysis for chronic renal failure caused by a combination of agenesis of the left kidney and focal sclerosing glomerulonephritis. Other medical problems included mixed connective tissue disease, ischaemic heart disease, Raynaud's phenomenon, anaemia of chronic disease, asthma, hypertension and chronic bilateral serous otitis media (treated with tympanostomy tubes). Her regular medications included atorvastatin, alendronate, perindopril, aspirin, allopurinol, ranitidine, doxepin, controlled release morphine sulfate, ferrous sulfate, calcium carbonate, frusemide, prednisolone, and diltiazem. Intermittently she had been given erythropoietin (a seizure precipitant)1 for her anaemia. She developed a rash when taking cephalosporins, and had a sister who had primary generalised epilepsy. The seizures continued despite cessation of the erythropoietin therapy and administration of sodium valproate. Magnetic resonance imaging of the brain and electroencephalography gave normal results. Meticulous medication review eventually revealed the coincidence of seizures with the intermittent prescription of ciprofloxacin eardrops. Eight of the nine seizures occurred while taking Ciproxin HC Ear Drops (ciprofloxacin 2 mg, hydrocortisone 10 mg; Alcon Laboratories, Sydney) for otitis media (Box). The ciprofloxacin eardrops were neither recorded on admission nor listed by the patient on direct questioning about medications she was taking. She has had a seizure-free period of 9 months after cessation of the eardrops, despite tapering of the dose of sodium valproate. The ciprofloxacin eardrops are considered the probable cause of the seizures in this case, according to the Naranjo algorithm for estimating causality of an adverse drug reaction (score, 8).2 Polypharmacy in complex medical patients frequently causes adverse effects.3 Up to 26% of prescription drugs are not recorded at the time of hospital admission,4 and eardrops are a common omission from medication lists. Ciprofloxacin is a fluoroquinolone antibiotic that inhibits bacterial replication. It is thought to lower seizure threshold by reducing γ-aminobutyric acid (GABA) transmission. Ciprofloxacin is excreted renally and has a half-life of 2.9–4.3 hours, which doubles in end-stage renal failure. Dose reduction is advised when patients not receiving dialysis have a creatinine clearance of less than 30 mL/min.5 There are reports of seizures after enteral and intravenous administration of ciprofloxacin,6 but, to our knowledge, this is the first report of seizures with ciprofloxacin eardrops. The recurrent seizures were believed to be due to the combination of an epileptogenic predisposition, renal failure, and intermittent ciprofloxacin use, with absorption facilitated by the bilateral tympanostomy tubes. Topical medications can produce systemic effects and this should be considered, particularly when other factors favour systemic absorption. A thorough drug history is necessary in assessing patients with complex medical problems taking multiple medications. Lessons from practice Topical medications can produce systemic effects. Fluoroquinolones may trigger seizures by any route of administration. A thorough drug history is necessary in assessing patients with complex medical problems. Eardrops are a frequent omission from medication histories. Chronological sequence of seizures and medication The period during which the patient had seizures () related to receiving ciprofloxacin eardrops (dropper), erythropoietin (EPO) for anaemia in chronic renal failure, and increasing doses of sodium valproate. (We thank Heidi Cartwright for preparing the diagram.)

Carolyn F Orr MRCP · Dominic B Rowe PhD, FRACP

"Rod, are you sure it's MND?" It was James Lance, my former Professor of Neurology (now Professor Emeritus, University of New South Wales), on the telephone. He had just received the letter I sent to all my close friends and colleagues when the diagnosis was confirmed. Jim had always emphasised the importance of leaving no stone unturned before accepting a diagnosis of incurable disease, both in his book on headache — which inspired me to do neurology — and during my subsequent clinical training. However, I had to tell him there was no doubt. Four months previously, I had experienced the sudden dramatic onset of widespread muscle fasciculation, without definite weakness, and, after four weeks of rising anxiety, I took my concerns to a colleague. Although at that stage he reassured me that he had found no definite abnormality, I was concerned that during the examination I had not been able to support my weight on my left leg. I then entered a period of uncertainty, during which I could not discuss my fears with family or friends. Three weeks later my colleague found measurable muscle atrophy and hyperreflexia, and electromyography documented fasciculation and early muscle denervation. Magnetic resonance imaging and a second opinion finally confirmed the diagnosis of MND. When I went to see David Burke, my then Professor of Neurology (Institute of Neurological Sciences, Prince of Wales Medical Research Unit, Sydney, NSW), to tell him my news, he tried to focus his mind on practicalities. As a young registrar he had supervised my research for an MD thesis and now, as my Chief of Neurology, he would have to arrange my replacement as Visiting Medical Officer and Director of the Comprehensive Epilepsy Service at Prince of Wales Hospital. However, for some moments all he could say was, "Rod, we go back a long way . . . ". It is now 16 months since the onset and there has been significant progression of weakness and spasticity. I can look back on my experience of MND thus far and make some observations. DiagnosisThe final confirmation of the diagnosis came almost as a relief after the period of uncertainty and false hopes — certainly the worst four months of my life. Once the diagnosis was confirmed, it was as if a great weight had been lifted from my shoulders and I was able to face the challenges ahead. The hardest task was breaking the news to my wife and each of my four children, but then they were able to provide much-needed emotional support. I was also able to begin the complicated process of selling my practice and disengaging myself from all my medical commitments. A lot of friends and colleagues were surprised by the speed and completeness with which this was achieved and still ask me if I miss medicine. On looking back, I can honestly say I have no regrets about this course of action. Freeing myself from the day-to-day concerns of clinical practice has allowed me to make up for lost time, especially with my family, and to "smell the roses". It has also made easier the transition from doctor to patient. This experience has reinforced my long-held view that one must be completely frank with patients about the diagnosis and prognosis of terminal illness. The neurologist who has assessed the patient and confirmed the diagnosis of MND is in the best position to break the news, and then to discuss the myriad issues that will come up. These include a frank discussion of prognosis, the manner of progression, symptoms to be experienced, the role of exercise and drugs and the possible need for assisted breathing and feeding in the future. AetiologyAlthough most cases of MND are sporadic, up to 10% are familial and may be associated with a mutation on the superoxide dismutase gene.1 I was relieved to find that this test was negative in my case, reducing the chances of other family members being affected. MND patients have a higher than normal incidence of previous paralytic poliovirus infection. In 1951, when aged 5 years, I suffered a febrile illness which was associated with diplopia, recurrent seizures and coma and followed by three weeks of limb weakness. Although I made a complete recovery without ventilatory support being needed, this was thought to be poliovirus encephalomyelitis and I suspect that this illness may have played a role in my MND. Ongoing careThe general practitioner should, as always, coordinate care, but the possibility of this diagnosis should always lead to a referral to a neurologist. One or both of these practitioners might feel that one of the specialist MND clinics, now available at several of the teaching hospitals, is the best place for making the definitive diagnosis and providing the ongoing care. These clinics provide an expert diagnostic service, and they can monitor progress and arrange referral to a number of ancillary services. When necessary, they arrange provision of aids and can refer patients for advice on respiratory support and gastrostomy feeding at the appropriate time. My GP put me in touch with the MND Society of New South Wales, a registered charitable, not-for-profit organisation which provides information, outreach support and access to disability aids and equipment. I have had a home visit from my designated outreach worker to discuss the diagnosis and prognosis, and my current and future needs and those of my wife as future carer. I have since become a board member of the society to assist them in their admirable work. Role of exerciseAs a neurologist I had always advised my patients to exercise only to the onset of muscle pain or weakness and then to cease, as exercise beyond this point was thought to be unhelpful and possibly harmful. However, as a patient, I found that, if I continued to exercise despite these symptoms, over the next few days the muscle pain and stiffness resolved and the weakness improved, even though it did not recover to previous levels. I was able to maintain a program of exercise with weights, stair-climbing and walking for two to three hours a day for 12 months before increasing weakness and spasticity forced a gradual reduction and finally cessation of these activities. This program was so successful that it is spasticity rather than weakness that is now forcing me off my feet. Role of drugsThe American Academy of Neurology (AAN) Practice Parameters for ALS2 represent a significant advance in formulating evidence-based guidelines for the care of people with MND and should be consulted when treatment options are being considered. Riluzole is the only drug which has been shown to prolong survival in MND. Two large randomised trials3 suggest that it improves survival of MND patients by at least three months. I began taking the drug as soon as the diagnosis was confirmed and have had no side effects. It costs $700 per month on private script, but it is currently being considered for listing on the Pharmaceutical Benefits Scheme. Baclofen is essentially the only muscle relaxant available, as the alternative, dantrolene sodium, is associated with unacceptable side effects (asthenia and muscle weakness). I have been taking baclofen with only modest benefit, but no side effects. Oxandrolone is a synthetic anabolic steroid, and a pilot trial of this drug over 12 months involving 12 MND patients found that the most severely affected muscles underwent little or no further deterioration, while less affected muscles continued to deteriorate.4 I began taking this drug (cost, $1400 per month) three months ago, but unfortunately this has not prevented progression of weakness of my left leg, nor of other, less affected muscles. I have therefore ceased taking the drug. Minocycline, a semi-synthetic tetracycline derivative, has been found to improve survival in a mouse model of MND,5 and I have been taking it with no side effects. ProgressionIn MND, respiratory muscle strength is a strong predictor of survival, and death usually results from respiratory failure. Non-invasive ventilation improves quality of life and possibly survival.6 The AAN recommends commencing non-invasive ventilation when vital capacity is less than 50% predicted. Recent work7 suggests that measurement of sniff nasal inspiratory pressure is more predictive of benefit, and that non-invasive ventilation should begin when sniff nasal inspiratory pressure is less than 60% predicted. I am monitoring both vital capacity and sniff nasal inspiratory pressure and will make a decision about non-invasive ventilation, and the option of gastrostomy feeding, closer to the time these may be necessary. Meanwhile, I am content to take one day at a time. As someone said, "Every day you're breathing is a good day". Life issuesI now realise that the most important entities of my life are my family and friendships sustained over many years. Although my medical career defined my day-to-day existence and most others' perception of me, its significance pales in comparison. However, my knowledge of medical issues, such as those with which I am now personally faced, will hopefully help me cope with what lies ahead.

Roderick A Mackenzie MB BS, MD, FRACP

Trial: Pan XR, Li GW, Hu YH, et al. Effect of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and diabetes study. Diabetes Care 1997; 20: 537-544. QuestionCan changes in diet and/or physical activity levels reduce the progression to type 2 diabetes in people with impaired glucose tolerance (IGT)? Trial details Design: A cluster-randomised controlled trial with four arms. Setting: 33 health clinics in Da Qing, China. Patients: 557 people (mean age, 46.5 years; mean body mass index [BMI], 25.8 kg/m2; 46.6% female) of more than 110 000 screened for diabetes who were found to have impaired glucose tolerance (IGT) on the basis of a two-hour glucose tolerance test (GTT) and who agreed to participate. Interventions: The arms were control, diet only, physical activity only, and diet plus physical activity. For people who were not overweight (BMI < 25 kg/m2), the diet was much the same as the Australian dietary guidelines (10%–15% energy from protein, 25%–30% energy from fat, 55%–60% energy from carbohydrate, reduce simple sugar intake, eat more vegetables, control alcohol intake). People in the diet groups (BMI > 25 kg/m2) who were overweight were encouraged to lose weight gradually but details of the diet were not specified. Patients received individual counselling and also attended group sessions. The exercise intervention was to increase physical activity by one unit, and preferably two units, per day (eg, one unit was 30 minutes of slow walking or five minutes of swimming). The control group was given general information about diabetes and IGT and a pamphlet about diet and exercise. Main outcome measure: Diabetes (glucose level > 11.1 mmol/L), determined by biennial two-hour GTT and confirmed by a repeat GTT. Patients also had three-monthly urine tests; if results were positive, plasma glucose was tested after a standard breakfast (100 g steamed bread). If plasma glucose was > 11.1 mmol/dL, or if the doctor suspected diabetes, a 75 g GTT was performed. Subjects also received a GTT if they had signs of diabetes at any time. Main results: Compared with the control group (six-year incidence, 15.7/100 person-years [py]) the incidence of diabetes was significantly reduced in all three intervention groups: 10.0/100 py in the diet group, 8.3/100 py in the exercise group and 9.6/100 py in the combined group. The interventions also reduced the incidence of diabetes within subgroups of those who were overweight and not overweight at baseline. Among those who were not overweight, all groups gained a small amount of weight, whereas among those overweight at baseline all groups lost weight, with the control and exercise groups both losing an average of 0.9 kg/m2. There was no significant difference in the proportion of dietary energy derived from fat between the groups at follow-up. The two exercise groups significantly increased their exercise by 0.6 units/day (exercise only) and 0.8 units/day (exercise and diet), compared with 0.1 units/day in the control group. Conclusion: The authors concluded that increasing physical activity or altering the diet reduced the incidence of conversion from impaired glucose tolerance to diabetes. Combining physical activity with dietary modification was not more efficacious than altering one component alone. CommentaryRationale for the trialBefore this trial, there had been only a small number of non-randomised studies investigating the value of lifestyle change in reducing the conversion of IGT to diabetes. Trial methodsThe losses to follow-up were small, with only seven people declining follow-up, 11 dying and 29 moving to another location. Techniques to allow for clustering in the design appear to have been used. There are two main methodological questions in this trial. The first relates to assessing endpoints and the second to the lifestyle modifications actually achieved. The decision about who reached an endpoint at the three-monthly visits was made by the chairman of the committee using the single GTT; whether the chairman was blinded to the randomisation code is not stated. Diagnoses made at the biennial visits were based on two consecutive GTTs. However, people diagnosed with diabetes between biennial visits were retested at the next biennial exam. Why this was done if they had already reached an endpoint is unclear. The article does not state whether the 21% diagnosed between scheduled visits were evenly distributed across the four groups, or whether the date of the interim or biennial exam was used when calculating person-time. Hence, it is unclear whether all endpoints were assessed using the same criteria and whether there was differential bias in outcome assessment between the groups. The diet-related information presented does not show that any dietary differences were achieved between the four groups, and overweight people in the control group lost nearly as much weight as those in the diet group. Hence, it is not clear what the dietary intervention actually was. Dietary quality may have improved in the diet groups (eg, a higher intake of micronutrients), but this is not described. The change in incidence of conversion to diabetes in the combined group was no better than that in either of the single intervention groups, although it should have been greater under a no-interaction assumption. This suggests a negative interaction between the two interventions which would be unexpected. New informationThis was the first study to have a control group that was randomly allocated concurrently with the intervention groups to test the theory that lifestyle modification could alter the conversion to diabetes. It is still the only trial to examine the effects of diet and physical activity separately. Implications for clinical practiceIf this were the only trial available, it would be hard to recommend the interventions to delay the onset of diabetes in patients with IGT (although the intervention could be recommended for general health) owing to the methodological uncertainties. However, two subsequent, much larger and well-conducted studies have examined the combined effect of dietary and physical activity change.1,2 Both have documented the intervention that was achieved, and this provides a basis for identifying the level of change in diet and physical activity needed for effect. However, neither of these trials had separate arms examining the effect of diet alone or physical activity alone. As the relative effects of the two interventions are still unknown, patients should be advised to change both dietary and physical activity.

Dorothy EM Mackerras MPH, PhD

In judging the results of randomised trials it is important to know from where and how participants were recruited, to what extent they received the intended interventions, whether they were followed up as planned, and whether their data were analysed as stated. These details are to ensure that readers of trial reports can appreciate both how closely participants reflect those more generally suffering from the condition under investigation, and how reliably the trial's results test its hypothesis. Participant flow diagramEnrolmentItem 13 of the CONSORT statement recommends a flow diagram to aid in the reporting of participant flow (see Box 1).1 Box 2 provides a checklist for tracking subject participation throughout the trial. In this scheme Part A refers to the number of participants with the condition of interest screened for eligibility criteria as specified in the trial protocol. For a recent example see the Second Australian National Blood Pressure trial.2 This study clearly details the process resulting in the final 6083 participants recruited. With 54 288 people screened to participate, 31 255 had the condition of interest (hypertension). Of these, 8273 were found to be ineligible and 16 899 refused to participate. The remaining 6083 were randomly allocated, corresponding to Part C of the flowchart in Box 2. The ratio of participants randomly allocated to those initially assessed helps determine how generalisable the results of the trial will be, and consequently may also affect the extent to which the results of the trial might influence health policy. Part B of Box 2 indicates assessed participants who do not subsequently participate, with reasons for non-participation given. Enough information should be given to identify separately the numbers who were deemed ineligible, refused to participate and those not randomly allocated to an intervention for other reasons. The ratio of the number of participants to the number of people initially assessed for eligibility may also provide an insight into the acceptability and practicability of the intervention. For example, if 2000 people were assessed and only 300 recruited, such a low ratio might be the result of highly restrictive eligibility criteria, participant requirements that are too complicated or impractical, or an intervention too intrusive for participants to readily accept over standard care. AllocationOf the total number of participants randomly allocated, the number assigned to each of the study arms should be separately presented (Box 2, Part D). A breakdown of the number of participants who actually received the allocated treatment and those who did not (with reasons given) should be included. This information, together with details of participant follow-up (see below), helps determine how well the intentions of the protocol were met. Follow-up detailsDuring the trial, participants' status in terms of outcomes (both efficacy and safety) is usually ascertained at predefined time intervals. However, some participants may withdraw from the study before completion; these participants are classified as "lost to follow-up" from that point onwards. Details of the number of participants who are lost to follow-up in each of the study arms are essential (Box 2, Part E), as this provides information on the reliability of the study's conclusions. When participants cannot be accounted for at the end of the study, their outcome status cannot be determined. If substantial numbers of participants are lost to follow-up, concerns may arise about the integrity of any observed effect of an intervention. A common approach to evaluating the potential influence of losses to follow-up is to use a sensitivity analysis, where worst-case and best-case scenarios relating to these losses are examined. For example, at one extreme, it could be assumed that all the control-arm and none of the intervention-arm participants who were lost to follow-up suffered the outcome of interest. At the other extreme, the opposite (ie, all intervention-arm participants lost to follow-up and none of the control participants lost to follow-up have suffered the outcome of interest) could be assumed. This provides bounds for the maximum possible influence of such losses on the observed treatment effect. Less extreme (more plausible) scenarios can also be examined. If this results in the effect of treatment disappearing or reversing direction, the robustness of the results should be questioned. Box 3 provides an example. Compliance lossesA further issue in interpreting study results is the degree to which participants adhered to their allocated treatment during the study period. Participants who stop or never take their allocated treatment are usually called "drop-outs", and those who begin active treatment when they have been allocated to the control group are called "drop-ins"; all are considered compliance losses. Compliance losses reduce the study power and dilute the observed effects of treatment, and should be documented in the participant flow (Box 2, Part E). Where such non-compliance can be predicted in advance, its potential effect on the power of the study may be reduced by increasing the study sample size.3 Differential compliance rates may offer clues as to the real side-effects of an intervention, or about the success of methods used to blind participants or clinicians to treatments.4 AnalysisPart F of Box 2 relates to the number of participants who were included in the statistical analyses. If any other than those lost to follow-up have been excluded from analysis, both the number in each treatment arm and the reasons should be detailed. As excluding patients from analysis can potentially undermine the effectiveness of the randomisation4 and produce comparisons which may no longer conform to the intention-to-treat principle,5 the nature of, and justification for, any such exclusions should also be provided. ConclusionsDifferent study types may slightly alter the participant flow diagram. For example, a cluster-randomised study will enumerate the clusters of randomised subjects (ie, the units of randomisation, such as whole communities, schools, hospital departments) rather than the number of individuals. Participant flow diagrams are an effective method of summarising all stages of key trial processes. They suggest how these processes should be reported in the trial, specifying separately trial enrolment, treatment allocation, subject follow-up and statistical analysis. In reporting the results of randomised studies, all individuals originally considered for participation in the study should be accounted for in the participant flow diagram. The diagram also provides an overview of many aspects of study quality that can have a major influence on the generalisability and reliability of the conclusions. 1: CONSORT checklist of items to report when reporting a trial Section and topic Item no. Descriptor Participant flow 13 Flow of participants through each stage of a clinical study (a diagram is strongly recommended). Specifically, for each group, report the numbers of participants randomly assigned, receiving intended treatment, completing the study protocol, and with data analysed for the primary outcome. Describe deviations from the planned study protocol, together with reasons. 2: Checklist: flow diagram of the process through key stages of a randomised trial1 3: Sensitivity analysis for a hypothetical study of 1000 participants with 300 events observed, but 84 participants lost to follow-up Patient no. Basis of analysis Intervention Control Odds 95% CI P Observed events only (lost subjects excluded) 130/440 170/476 0.76 0.57–0.996 0.047 All lost participants in placebo group, but none in intervention group assumed to have suffered an event 130/500 194/500 0.55 0.42–0.73 < 0.001 All lost participants in intervention group, but none in placebo group assumed to have suffered an event 190/500 170/500 1.19 0.92–1.54 0.19 Comment: The study had lost enough participants to follow-up to potentially nullify any conclusion of a significant treatment benefit based on the most extreme assumptions about event occurrence in lost subjects. A more plausible scenario might be to assume that the event rate among lost subjects was twice that seen in those with full follow-up. In this instance, up to 35 of the 60 lost subjects in the intervention arm and 17 of the 24 in the placebo arm could be anticipated to have experienced the event. The boundaries this yields (odds, 0.59; 95% CI, 0.45–0.77; P < 0.001 to odds, 0.96; 95% CI, 0.74–1.24; P = 0.74) again calls into question whether a definite effect of treatment can be concluded.

Burcu Cakir MPH · Val J Gebski MStat · Anthony C Keech FRACP, MSc(Epid)

To the Editor: Methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to glycopeptides (vancomycin-intermediate S. aureus, or VISA) was initially described in Japan,1 then the United States,2 and subsequently other regions of the world. Recently, Ward and colleagues reported the initial Australian isolate — a heteroresistant VISA (hVISA) strain — in Melbourne, Victoria.3 We report the first isolation of hVISA in Sydney, New South Wales. A 79-year-old man underwent mitral valve annuloplasty in April 2002. Post-operative complications included MRSA bacteraemia, which resolved. He was discharged at the end of July 2002, but 12 days later was admitted to a second hospital with endocarditis caused by Streptococcus viridans. A month later, he developed a third episode of septicaemia, and MRSA was isolated from blood cultures. Despite two weeks' treatment with intravenous vancomycin, blood cultures again yielded MRSA. A transoesophageal echocardiogram confirmed endocarditis. Resistance screening of the MRSA isolate by E test (AB Biodisk, Solna, Sweden)4 gave minimum inhibitory concentrations of 16 mg/L for vancomycin and 32 mg/L for teicoplanin, suggesting resistance to glycopeptides. The patient was then treated with intravenous linezolid and underwent vegetectomy. Subsequent blood cultures were negative for MRSA, but the patient died seven days after surgery from nosocomial pneumonia caused by Escherichia coli. Population analysis of the MRSA isolate showed that it was heterogeneously resistant to vancomycin (hVISA). The emergence of hVISA in Sydney is a sentinel event, with ramifications for clinicians, laboratories and infection control. Routine susceptibility testing will not detect this resistance. Hence, clinicians and laboratories should consider VISA and hVISA if a patient with a proven MRSA infection fails to respond to vancomycin or teicoplanin, or has had several courses of vancomycin/teicoplanin and continuing positive cultures. If alerted that specimens could contain VISA or hVISA, the laboratory should perform glycopeptide resistance screening using E tests or other methods. Isolates that screen positive should be confirmed with population analysis profile testing.4 Treatment of hVISA and VISA infections, particularly bacteraemia and endocarditis, with vancomycin and/or teicoplanin is likely to fail. Alternative antibiotics include linezolid and quinupristin–dalfopristin, which are both very expensive. There is limited information on the success or otherwise of these agents in treating serious staphylococcal infections, especially bacteraemia and endocarditis.5 As a number of outbreaks of VISA and hVISA infection have already been described in other countries, we must ensure that these organisms do not become established in Australian institutions. Strict attention to infection control must be observed, particularly handwashing and use of alcohol hand rubs before and after patient contact. Attention to rational prescribing of antibiotics is required, avoiding broad-spectrum agents whenever possible. Vancomycin and teicoplanin should be used only when necessary: when there is resistance to other agents, and only when infection is present. Colonisation is not an indication to use glycopeptides, nor is minor allergy to β-lactams.

Iain B Gosbell · David H Mitchell · Helen Ziochos · Peter B Ward

To the Editor: In their systematic review of clinicians' attitudes to clinical practice guidelines, Farquhar et al1 found that, although healthcare providers reported high satisfaction with guidelines, a significant number also expressed concerns about their practicality, their role in cost-cutting and their potential for increasing litigation. The review, however, did not address other potentially significant concerns of clinicians regarding the perceived validity of guidelines and the influence of external agencies (such as the pharmaceutical industry) on treatment recommendations. In April 2002, I conducted a survey of 155 full-time nephrologists and renal medicine trainees practising in Australia and New Zealand about their attitudes to the Caring for Australians with Renal Insufficiency (CARI) clinical practice guidelines (www.kidney.org.au/cari). The response rate was high (90.3%), with the majority (89%) of doctors agreeing or strongly agreeing that CARI provided a useful evidence summary. However, only 39% indicated that their practice had been significantly influenced by these guidelines, and just 14% felt that patient outcomes were improved as a result of CARI. While a minority expressed concern about the applicability of guidelines to individual patients (16%) and the potential for augmenting litigation (44%), the most significant worry was that 49% did not agree that the treatment recommendations matched the available evidence. Of those who felt that the recommendations were not justified, most believed that erroneous conclusions had been drawn from the evidence and that working parties had been affected by external influences, principally the pharmaceutical industry (74%). This view was significantly more common among nephrologists who were guideline authors (odds ratio, 3.6; 95% CI, 1.5–8.5; P < 0.01). Choudhry et al2 similarly reported that guideline authors frequently felt that their coauthors' recommendations were influenced by financial relationships with the pharmaceutical industry, despite the fact that only 7% believed that their own recommendations had been influenced by such factors, and that conflicts of interest were disclosed in only a minority (< 5%) of instances. In fact, 47 (59%) of the 80 guideline authors surveyed had financial relationships with companies whose drugs were considered in the guideline they authored. Other studies have further demonstrated that most clinical practice guidelines published in the peer-reviewed literature in the past decade did not adhere well to established methodological standards of identifying, evaluating and synthesising scientific evidence.3,4 Any review or survey of clinicians' attitudes to clinical practice guidelines should therefore include an assessment of their opinion as to the quality of those guidelines and the extent to which outside agencies (such as drug companies) may have influenced them.

David W Johnson

In reply: Johnson's letter raises an important point about the influence of external agencies such as pharmaceutical companies in the development of clinical practice guidelines. Although our systematic review1 of 30 studies of clinician attitudes to clinical practice guidelines did not identify this issue as a major barrier, it is possible that the surveys used overlooked this concern. Conflict-of-interest statements and the source of funding for clinical practice guidelines and their development teams are not always published. In the AGREE2 questionnaire (a measurement instrument developed for clinical practice guidelines), reporting conflict of interest and source of funding is encouraged. The New Zealand Guideline Group has a policy of declaring conflicts of interest, and pharmaceutical industry representatives are not included in guideline development teams.3 Choudhry et al4 reported that 59% of guideline authors had financial relationships with companies whose drugs were considered in the guideline they authored. Although these figures are not surprising given the role of the industry in research and educational activities, they do present a challenge to guideline development teams. The New Zealand Guideline Group approach (apart from declaring conflicts of interest and not including industry representatives on guideline development teams) is to take an evidence-based strategy. This involves considering all available evidence, publishing search strategies, linking evidence tables to evidence statements and recommendations, developing the recommendations by using a "considered judgement form" (which takes into account evidence, cost, generalisability and applicability), and drawing on representatives from a broad range of stakeholders (including consumer and allied health groups). By taking such an approach, it is hoped that the influence of external agencies can be minimised.

Cynthia M Farquhar

In reply: The fundamental purpose of clinical practice guidelines is to improve patient outcomes. Thus, as members of the CARI (Caring for Australians with Renal Insufficiency) Guidelines Steering Committee, we welcome Johnson's letter, which gives us reassurance and renewed enthusiasm to move forward with improving and refining the CARI clinical practice guideline process. The most gratifying revelation in Johnson's survey was the near-90% endorsement of the CARI guidelines as a document providing a useful evidence summary — clearly very reassuring in those areas in which that evidence relates to treatment interventions for patients with renal disease. Of additional interest was the range of responses to questions about matching the recommendations with available evidence. This seems to reflect both an awareness among renal medicine health workers of the importance of evidence-based medicine and a maturing understanding of the need for the evidence to be of high quality. The CARI guideline process has a relatively short history (just over three years), and before Johnson's survey the CARI Steering Committee had adopted a number of strategies that anticipated some of the issues his survey raises. These strategies included: establishing a formal link with the Renal Cochrane Organisation (to produce the best possible search outcomes of all the available evidence); adopting the National Health and Medical Research Council (NHMRC) evidence levels I (systematic reviews) and II (randomised controlled trials) as the minimum requirement to justify definitive guidelines (to assess the quality of evidence available and match appropriate guidelines with that evidence); adopting a peer-review process to evaluate draft guidelines to complement newly revised requirements for guideline writers' conflict-of-interest declarations (to assess perceptions of guideline validity and the influence of external agencies); broadening the multidisciplinary nature of guideline working parties. In addition, the Australian Kidney Foundation has moved to further disseminate the guidelines, and the CARI guideline process has been reformed with the aim of meeting the standards required to achieve NHMRC endorsement. Furthermore, feedback obtained from legal advisers suggests that the CARI guidelines and the process of establishing them are far more likely to obviate litigation than to promote it. The next important phase for the CARI guidelines will be the development of an implementation process. As the acceptance of evidence-based medicine increases and the knowledge base among healthcare workers of the nature, quality and relevance of evidence in patient care expands, the CARI guideline process is likely to be enhanced. The results of future surveys of the type carried out by Johnson will be keenly anticipated.

Rowan G Walker

To the Editor: In concluding that health policy research in Australia is a virtual desert,1 Van Der Weyden failed to acknowledge several recent developments. The Health Services Research Association of Australia and New Zealand, formed in late 2001 (www.chere.uts.edu.au/hsraanz/), and its biennial conferences (the next to be held in Melbourne in November 2003), are evidence of good quality research across a range of topics. Particularly Australian contributions include economic evaluation as a basis for funding decisions in both pharmaceuticals and medical services; the Coordinated Care Trials; and the adaptation of casemix funding to Australian cost structures and payment mechanisms. Health policy development around the world borrows freely from other countries, but, unlike the generalisability of biomedical and clinical research, health services research can only be transferred after taking into account the characteristics of each country's unique system. Nonetheless, health services and policy research are underfunded and underdeveloped in Australia. Is the answer an internationally acclaimed Australian Institute for Health Policy? Not entirely. A well-funded institute would overcome some of the lack of security of tenure faced by health services researchers — and would certainly be a welcome advance over the usual Australian practice of spreading the available funds so that a paltry amount goes to each State or Territory. However, according to the Wills Review,2 Australia requires not one but several research centres with the necessary critical mass. We need a multifaceted strategy that goes beyond the organisational base. Funding is needed for investigator-initiated long term research to address underlying theory and methods, as well as contemporary policy issues. Researchers need to be able to build sustained inquiry into a specific area, instead of moving rapidly from topic to topic just to maintain their funding. Recognised avenues for training, education and further professional development are needed to build a critical mass of researchers. Only then will the success rate of National Health and Medical Research Council (NHMRC) project grants for health services research move from its current 5% or less to the success rate for public health of around 20%, or even the overall success rate of 25%–30%. Finally, the US-based Harkness Fellowships in Health Policy and Practice are important,3 but support only two Fellows each year. This program needs to be complemented by an Australian-based program of training and international exchange on a similar scale to the various public health training programs.

Jane P Hall

To the Editor: Keech and Gebski recently discussed some strategies for answering randomised clinical trial (RCT) questions with fewer subjects.1 We would like to point out another alternative for addressing this important topic — adjustment for baseline characteristics.2-4 Heterogeneity among patients participating in RCTs is common. Prognosis may vary according to important baseline characteristics, which are commonly recorded in RCTs. Heterogeneity may lead to imbalanced treatment arms, even after proper randomisation.3 Covariate adjustment for baseline characteristics is a statistically efficient procedure. It leads to more individualised treatment-effect estimates, corrects for imbalance and improves statistical power.2,3 Hence, it may potentially reduce the necessary sample size of an RCT for the same power as unadjusted analyses. Nevertheless, covariate adjustment is not commonly performed in the RCTs reported in major medical journals.5 We recently performed a simulation study using logistic regression models in the context of RCTs with dichotomous outcomes and one simple dichotomous baseline characteristic in addition to the treatment indicator variable. Covariate adjustment was found to potentially reduce the sample size between 3% and 46%, in direct relation to the strength of the baseline characteristic (odds ratio, 2 to 30). Results of a simulation study in RCTs with survival outcomes, using Cox proportional hazards models, yielded similar results. Covariate adjustment for well-known and important predictors of patient prognosis is a useful tool for potentially reducing the sample size of RCTs, and should be considered more often in their design and analysis.

Adrián V Hernández · Ewout W Steyerberg

In reply: While we agree that covariate adjustment during analysis can be a potential mechanism for reducing sample size (even when there is no imbalance in the important covariate levels between the treatment groups), unless such analyses are prospectively planned then they will not allow valid statistical inference. This is because post-hoc adjustment is an exploratory procedure and may have involved examining any number of potential covariates. Further, to quantify any anticipated sample-size gains would depend on specifying likely maximum covariate imbalances, overall covariate distributions and plausible effects of treatment within the covariate levels during study design. In practice, the study would then have to meet these assumptions for the calculated sample-size gain to be achieved. Covariate adjustment is an accepted practice for subsidiary analysis in clinical trials, and can take account of differential effects in imbalanced subgroups. For example, see the case of an apparent chance imbalance in numbers of women in the treatment arms of the HERO-2 trial, where investigators presented both unadjusted and adjusted results.1 Where important predictors of the clinical outcomes are expected to be variable for the population under study, a particularly useful approach is to stratify the randomisation by those predictors.2 Such stratification allows for valid adjusted analyses.3

Anthony C Keech · Val J Gebski

To the Editor: Evidence-based medicine should be supported by randomised controlled trials (RCTs) that show the efficacy of interventions in producing clinically relevant outcomes, not by those that show statistically significant, but clinically irrelevant, differences. RCTs are designed to investigate whether an intervention in one homogeneous group results in a different outcome compared with no intervention, or a different intervention in an otherwise identical group. Statistical analyses are performed to estimate the probability that any difference in outcome has arisen as the result of chance alone, and sample size is determined to control the probability of a real difference in outcome being overlooked by chance alone. However, statistical analyses provide no information about the clinical relevance of any difference in outcome. There is no validated method for determining a minimum clinically relevant difference in outcome (minimum important difference). Kirby and colleagues suggest that, wherever possible, the minimum important difference in response should be determined from Phase II or pilot studies and expert opinion from colleagues.1 It is ironic that the clinical relevance of Level I evidence2 depends on determining the minimum important difference based on Level IV or Level V evidence. Although the original CONSORT statement recommended describing the minimum important difference and indicating how the target sample size was projected,3 the most recent statement is less specific and only recommends describing how the sample size was determined.4 Neither statement requires investigators to specifically describe the method by which the minimum important difference was determined. The minimum important difference must be justified so others can determine if the study has the power to detect a clinically relevant difference in outcome as the result of a particular intervention. Similarly, the minimum important difference must be stated so that any statistically significant difference in outcome can be judged for clinical relevance. If the minimum important difference cannot be justified as being clinically relevant, the result of the study will be of statistical interest only, and valuable resources will have been wasted. While it is reasonable to suggest that sample size must be planned to ensure that research time, patient effort and support costs invested in any clinical trial are not wasted,5 manipulating the minimum important difference to allow an RCT to conform to these constraints cannot be justified unless the RCT can still detect a clinically relevant difference in outcome.

Owen D Williamson

In reply: A key message of our article is that the minimum possible difference that would render the intervention clinically worthwhile needs to be determined in the design phase of the study.1 This potential clinical difference (net advantage over standard care) must, of necessity, incorporate the potential trade-offs between any outcome advantages and associated toxicities and/or cost disadvantages. In determining the minimum clinically worthwhile difference, the intention is not to ignore Level I evidence (phase III studies and meta-analyses) when such evidence exists. However, in most cases of designing a phase III study, such evidence is not available. In this instance, the use of phase II information (which can often provide good estimates of potential side effects and toxicities) can help to inform the estimated advantage in clinical outcome which would be needed to justify widespread use of the intervention. Tools have been developed to help clinicians determine worthwhile benefit against toxicity trade-offs for individual patients.2 While there are instances of study results reliably showing statistical significance without the measured effect being sufficiently large to be considered clinically relevant, this occurs rarely. Far more commonly, statistically non-significant results may obscure clinically relevant outcomes because studies have been seriously underpowered.3 For example, 17 of the first 22 small trials of thrombolytic therapy compared with placebo for acute myocardial infarction reported non-significant results, although they showed a 19% reduction in early mortality (2P < 0.01) in subsequent meta-analysis.4 Individual doctors treating their patients ultimately determine whether net differences are sufficiently worthwhile to change their clinical practice. The fundamental principle is that clinical trials should be designed with sufficient power (through having appropriate sample sizes) to detect differences that doctors would consider clinically worthwhile to improve health outcomes.

Adrienne Kirby · Val Gebski · Anthony C Keech

To the Editor: The motivating article by Bent and colleagues1 is a most welcome addition to the literature of what works in the movement for performance improvement. We can hardly overemphasise the need to share knowledge on innovations (ie, what works and what does not work) in the quest for best quality and safety practices. However, to aid efficient lesson-drawing, we are inclined to look for more contextual information and levers in any quality-of-care interventions. For a safety research discussion, the report by Bent and others has at least three important elements: the use of a technology (personal digital assistants [PDAs]), the clinical performance of healthcare professionals (here, anaesthetists), and the permissive culture (to want to learn and improve). Nevertheless, what such innovative pilot practices should also incorporate and report are the contextual factors responsible for successful acceptance,2 application and appraisal of quality interventions. Bearing continuity and sustainability in mind, one should be interested in the "characteristics" of anaesthetists who would voluntarily engage in personal monitoring and feedback. Initial technology use is seen among the "technologically proficient few" before becoming widespread.3 The introduction of PDAs for incident monitoring calls for the evaluation of the sociotechnical meta-system4 in which it will ultimately exist. Therefore, it is important for us to add a qualitative assessment to such a pilot study to identify personal motivating factors, climate for action, and the personal performance effects. Failure to evaluate technology "deployment" in healthcare results in lack of commitment, slow technology adoption, and perhaps decreased patient safety.5 The application of PDAs in reporting adverse events will increase within and across clinical disciplines and borders, but so must the rigorous appraisal to aid transference of knowledge. The global stage for international comparative research is widening, necessitating the need for integrated study designs, contextual analysis and robust reporting. It is often desirable to look for cost-effective means of improving patient care, with a dual learning carriage between institutions and nations. Patient safety and quality care studies will therefore continue to enjoy inputs from epidemiology, health services research, health economics, health policy, cognitive engineering, and information and communication technology. However, the main challenge remains: where is the patient in "patient safety"?.

Onyebuchi A Arah

In reply: I thank Arah for pointing out the importance of the "context" into which any quality and safety program will be deployed. Success or failure of innovative pilot programs will always depend upon the willingness of the end-user to embrace change. In the case of performance monitoring using electronic logbooks, this will first require an easily workable and reliable tool, not just for the technologically proficient few, but for all users. In addition, users must also be motivated to monitor their professional performance. In today's world, where medicolegal issues are increasingly significant, there is pressure to prove accountability and reduce one's risk exposure. In carrying out a pilot project only, we aimed to demonstrate the technological feasibility of such a tool. We believe that this has been successful, and that now is the time to embrace the use of such tools. Ultimately, cultural change will only occur when the "early adopters" and enthusiasts demonstrate the usefulness of a concept, leading the way and pulling the rest of the population behind them.

Paul D Bent

To the Editor: A recent MJA article by Kjellstrom et al1 correctly lists home heating using wood as a major cause of air pollution in Australia. It is therefore surprising to read in their optimistic view of "Circa 2100" that, whereas coal will be burnt in superefficient and clean-burning electric power stations, more wood will be burnt to heat houses. When the Irish government banned the sale of coal in Dublin, there were substantial decreases in smoke pollution and mortality from respiratory and cardiovascular causes.2 If any evidence is needed that similar benefits can be expected from banning domestic wood heaters, it is to be found in recent research on the emission of fine particles and a wide range of toxic compounds by wood heaters, old and modern.3 The reason given by Kjellstrom et al for regarding wood-burning for home heating as desirable is that it would cause less global warming. But this reason is not convincing, as the potential "benefit" would be outweighed by the immediate harm inflicted by wood smoke on public health. People are unlikely to agree that we have to accept death and disease now in order to save the planet a few decades hence. It is commonly claimed that the burning of wood is "greenhouse-neutral". This is not true if the burning takes place in home heaters, which emit methane and soot particles — both powerful greenhouse agents. When global emission rates and global warming potentials are both taken into account, the probable ranking of the three most important greenhouse agents is (first) carbon dioxide, (second) soot particles, and (third) methane.4 As almost everything in greenhouse science is fraught with high uncertainty, it is not possible to say what percentage of the potential greenhouse advantage of wood heaters is cancelled by their emission of soot particles and methane. What can be said is that firing superefficient and clean-burning electric power stations with plantation timber is the best way to burn wood, using the greenhouse advantage without the toxic hazard.

Louis A du Plessis

Photograph courtesy Ray Sherman To the Editor: I read with interest the entry in "In other Journals" entitled "Beware the zebra".1 It described a study in the United States (reported in JAMA)2 which found that elderly people were more likely to be struck by a motor vehicle when crossing at a marked crossing than at an unmarked site! Personal observation after a year of living and working in the States has led me to be no longer surprised by such a report. There is what I believe to be a culturally different attitude to road safety here. There seems to be a general belief by pedestrians that cars will stop if they walk out on to the road — often without looking. This is more so at marked crossings, where I can attest to the findings of the article that "nearly 40% of pedestrians incorrectly believed that traffic must stop for a pedestrian who is on the curb waiting to cross at a marked crosswalk." I believe that this perception may have been ingrained from an early age — US school buses have stop signs which appear when the bus stops, so that traffic behind the bus, alongside and in the opposing lanes has to stop while children are getting on or off the bus and then crossing the road. There is little attempt by the schoolchildren to "look both ways", as we were taught when growing up. This, I think, leads to a misperception that traffic will stop for all pedestrians, who may feel even more entitled at a marked crossing to cross without looking. Since the report may have horrified some readers, I thought it might be worth providing a little local experience on the subject!

Pedita S Rowe

Re: "Lymphoedema in breast cancer patients", the letter to the editor by Graeme N Brodie in the 3 March issue of the Journal (Med J Aust 2003; 178: 244), in which washing soda, used in a simple dialysis treatment for lymphoedema, was mistakenly called crystalline calcium carbonate. Washing soda is, in fact, sodium carbonate. The web version of the article was corrected on 4 March 2003.

Graeme N Brodie

Handbook of sports medicine and science. Strength training for sport. William J Kraemer, Keijo Hakkinen (editors). Oxford: Blackwell Science, 2002 (x + 186 pp). ISBN 0 632 05568 5. Few areas of sports medicine are as plagued by mythology and unscientific jingoism as the area of strength training. Methods used vary according to the environment in which the training is conducted. Different sporting codes have different traditions, and coaches tend to have their own set of beliefs or bias, often the result of their own sporting experiences. This book provides a very readable overview of the principles and practical applications of strength training. Its most impressive feature is that each chapter is heavily referenced from peer-reviewed journals, providing credibility in an area renowned for quackery. The authors begin with a history of strength training and a thorough explanation of the underlying scientific principles. The chapter on neuromuscular adaptions provides fascinating reading. For those who work with sporting teams, the authors provide practical advice on how to develop a strength training program. Issues such as periodisation of training programs are covered, as well as examples of strength training programs for various specific sports. Special considerations, such as differences between the sexes, junior athletes, the aged and overtraining, have all been addressed. The information is presented in a format suited for practical application. There are plenty of illustrations, point form summaries and graphical representation of data. This is an excellent book for those involved with athletes or those wishing to understand the science behind strength training. My only criticism is its failure to deal with the controversial and difficult area of nutrition for strength training. Sports supplementation is one of the boom areas of athlete exploitation, with aggressive marketing of substances that are often unproven and potentially dangerous. A chapter on nutritional aspects would have rounded off what is otherwise an excellent publication. David C HughesSports Physician Deakin, ACT

David C Hughes

Pattern recognition in diagnostic imaging. Peter Corr. Geneva: World Health Organization, 2001 (x + 205 pp). Here is another useful WHO publication. It stays close to the topic of pattern recognition through most of its 205 pages, but it does enter the field of radiography to emphasise issues of quality and safety — a relevant reminder, since many in its target audience would be involved closely in taking x-rays. In this era of CT and MRI, plain x-rays are often overlooked in favour of high technology solutions, but in rural areas they remain the mainstays of diagnosis. Many readers will enjoy having access to a book that addresses this topic, without having to pay for a tome which also describes how to interpret digitised images. For the generalist doctor who has to interpret his or her own x-rays, it provides a useful primer. The book is organised into sections on the chest, musculoskeletal and gastrointestinal/urinary systems. Each chapter is well set out, with learning points providing a succinct summary at the end. This systematic approach provides a good collation of standard approaches to the assessment of such areas as the cervical spine. The patterns alluded to in the title are patterns of disease rather than radiographic patterns. The disease-based approach provides a practical compromise for the clinician. There is an emphasis on tuberculous disease which reflects the South African origins of many of the authors, and this means that the book has practical applications in many developing countries where the disease is rife. The lack of an index is a deficiency, although the systematic approach of the book allows the reader to find the relevant area reasonably easily. The photographs and line drawings are generally of a high standard but some, especially in the musculoskeletal section, lack sufficient annotation. The inclusion of renal ultrasound seems out of place. The book would be a useful text for those entering rural or remote practice, or practice in the developing world. This is especially true for those in training or early in their career as it provides a useful framework of patterns of disease, which will augment their knowledge base and help them organise their experience. Alan B ChaterRadiological Advisory Council of Queensland

Alan B Chater

Re: "Experimental human infection with the dog hookworm, Ancylostoma caninum", the Research article by Juergen K Landmann and Paul Prociv in the 20 January issue of the Journal (Med J Aust 2003; 178: 69-71). The labels for the second oral infection and cutaneous infection in the Figure in Box 2 were accidentally reversed. The corrected Figure is reproduced here. 2: Peripheral blood eosinophil levels after exposure to infective larvae of Ancylostoma caninum * The three separate experiments were run consecutively over a period of one year.

Juergen K Landmann BSc(Hons) · Paul Prociv MB BS, PhD, FRACP, FRCPA