Volume 176 Issue 4

The biology of colorectal cancer provides an important opportunity for cancer prevention, as most cancers in the lower bowel evolve from polyps (adenomas). Removal of adenomas markedly reduces the subsequent risk of disease. Consequently, the rational aim of any prevention program should be not only to detect early cancer but also the precursor adenoma. The strategies to reduce mortality include: investigation of high-risk symptoms such as rectal bleeding — often by colonoscopy; colonoscopic surveillance for those with a personal or family history of colorectal cancer or polyps; and screening, beginning at age 50 years, of individuals of average risk, who account for 85% of sporadic cancers. The practice of colorectal cancer prevention in Australia has been largely influenced by recent National Health and Medical Research Council (NHMRC) guidelines.1 An attempt to finalise these guidelines began in 1997 and their slow gestation may have rendered them insensitive to more recent data and not typical of practice worldwide. Three of the major NHMRC recommendations remain controversial. Patients with a single first-degree relative with colorectal cancer diagnosed over the age of 55 do not have a sufficiently increased risk to warrant colonoscopic surveillance. The NHMRC guidelines quote a twofold increase in risk in this group. A recent analysis of 27 case–control and cohort studies indicates that the relative risk is 2.25 and that this risk doubles with more than one relative affected.2 We believe that a doubling of lifetime expected risk of colorectal cancer in men from 1 in 18 to 1 in 9 (only slightly lower in women) is sufficient to advocate colonoscopic surveillance on a five-yearly basis starting at the age of 40, irrespective of the age of the relative. Patients with a single adenoma < 1 cm in size not showing any villous component need colonoscopic follow-up only at 4–6-yearly intervals. This recommendation is mainly based on the US National Polyp Study.3 It is difficult to reconcile these data with other reports. For example, Rex et al3 showed "miss-rates" of 5% for colorectal cancer, and polyp "miss-rates" ranging from 6% to 15%, even in experienced hands. Therefore, there needs to be considerable flexibility in planning postpolypectomy surveillance. Two articles in this issue of the Journal, by

Terry Bolin MD, FRCP · Alistair E Cowen MD, FRACP · Melvyn G Korman PhD, FRACP

Sedation is a difficult concept to define, as it includes a continuum from anxiolysis to anaesthesia. The point at which sedation becomes anaesthesia is generally accepted as occurring when the patient becomes unresponsive to verbal commands.1-3 Sedation is a depression of, rather than a loss of, consciousness, and may be combined with analgesia and amnesia to facilitate otherwise unpleasant and painful procedures. There is a large demand for sedation with endoscopy in Australia, although this is not universal practice.4 For instance, most colonoscopies in Germany are performed without sedation. There has been serious concern as to the safety of sedation for endoscopy following a prospective audit of gastroscopy and sedation in the United Kingdom in 1994. This audit found a 0.05% (1 in 2000) 30-day mortality.5 Although arguable, a third of these deaths were attributed to complications of sedation. There have been no comparable large-scale audits reported since, but anecdotal reports of mortality persist. The concern becomes more apparent when the comparison is made to the Australian anaesthesia-related death rate of less than 1 in 63 000.6 There are no reliable Australian data on deaths related to sedation. Consequently, professional documents have been formulated in the UK, the United States, Australia and New Zealand based on first principles and consensus, rather than on substantial evidence. In this issue of the Journal (page 158), the audit by Clarke et al on sedation for endoscopy7 primarily demonstrates how effective these professional guidelines have been. With the universal use of dedicated trained sedationists, supplemental oxygen, monitoring of pulse oximetry, blood pressure and respiration, patient selection and an accredited facility, there was no mortality reported in 28 472 endoscopies. The only caveat to this mortality rate is that postdischarge follow-up was limited to one telephone call. Notwithstanding this good news, most of the interest generated in this report will be because it describes general practitioner sedationists using propofol. The GPs in this audit had selection criteria, training and a maintenance-of-standards program that was entirely consistent with the current guidelines.1 Furthermore, complex or high-risk patients were transferred to hospitals (numbers unknown) or to the care of an anaesthetist (21.4%), which again is in keeping with the guidelines.1 The departure from the guidelines occurs with the use of propofol — the guidelines do not allow medical practitioners other than anaesthetists to use this agent. This applies to all intravenous anaesthetic agents (eg, methohexitane and ketamine), largely because of the rapidity with which sedation becomes anaesthesia. Sedation is achieved with propofol at about a third of the anaesthetic blood concentration or dose. Problems arise with propofol because of the individual variation of the anaesthetic concentration or dose, which in itself can vary by a factor of three, and the synergistic effects of narcotics and benzodiazepines, which may reduce the anaesthetic concentration or dose by as much as 50%. Propofol is further complicated by having its peak effect at about four minutes, making titration difficult. However, propofol is redeemed by the short redistribution half-life of 2–8 minutes and the failure of blood concentrations to achieve significant levels during its long elimination half-life (3–8 hours), owing to its extremely high clearance rate. Propofol is approved in Australia for conscious sedation. The real issue is what is the intent of the propofol administration. If the intent is loss of consciousness, then it is anaesthesia, and the drug should be administered by an anaesthetist in an institution equipped and licensed for anaesthesia. In New South Wales, institutions have been prosecuted after adverse patient outcomes for administering anaesthesia with such agents while not licensed. It is difficult in this audit, because of the failure to differentiate the propofol doses used by the GPs (78.6% of cases) and the anaesthetists (21.4% of cases), to determine the doses used by the GPs. However, the doses appear consistent with planned sedation. Nevertheless, GPs had a higher incidence of adverse events (not reaching statistical significance) and, significantly, a higher intervention rate for respiratory adverse events than the anaesthetists, even though complex patients and procedures were allocated to anaesthetists. In summary, the audit by Clarke et al supports the effectiveness of the current guidelines for sedation. The use of propofol in circumstances defined by current guidelines may be sufficiently safe when the agent is administered by such appropriately trained medical practitioners. Propofol and other intravenous anaesthetic agents should not otherwise be used by medical practitioners, except those who are trained in anaesthesia.

Greg E Knoblanche

Few events are harder to deal with than sudden death in young people. Each year in the United States, about one in 200 000 high school or college athletes will die suddenly, the vast majority without any prior symptoms,1 and these devastating events are often the first clinical manifestation of an underlying cardiovascular disorder. Indeed, about 90% of sudden deaths, defined as death occurring within one hour of the onset of symptoms, are found to be caused by cardiac structural pathology in autopsy-based series. The remaining 10% relate to other cardiac electrical disorders, such as long-QT syndrome and Wolf–Parkinson–White syndrome, or commotio cordis (the result of sudden sharp chest blows), as well as complications of asthma, substance misuse, and sudden infant death syndrome (SIDS).2 The single most common disorder causing sudden cardiac death in people aged less than 35 years, including competitive athletes, is the genetically inherited cardiac disorder hypertrophic cardiomyopathy (HCM).1 HCM is characterised by cardiac hypertrophy, usually of the left ventricle, in the absence of other loading conditions such as hypertension or hyperthyroidism. This disease occurs in approximately one in 500 people. It is clinically heterogeneous, with most affected individuals having few or no symptoms, while others develop serious complications, including heart failure, arrhythmias, and sudden death.3 In a series of 158 sudden deaths in young competitive athletes (median age, 17 years), 36% were found to have HCM and an additional 10% had evidence of increased cardiac mass suggestive of HCM.1 In Australia, 34 sudden deaths in people with HCM were reported to the HCM clinic at Sydney's Royal Prince Alfred Hospital over a five-year study period.4 A substantial proportion of patients with HCM die during or immediately after vigorous physical activity, but sudden death during rest or sleep is also common. The mechanism of death relates to ventricular arrhythmias in over 90% of known cases. Over the past decade, major advances have been made in understanding the genetic basis of many of the disorders which cause sudden death. DNA defects in disease-causing genes have been identified in HCM, as well as the long-QT syndrome, Marfan syndrome, dilated cardiomyopathy and arrhythmogenic right ventricular dysplasia. Over 200 mutations in at least 10 genes, all encoding proteins of the sarcomere (the basic contractile element of the heart), have been identified.5 Not only have such discoveries thrown light on the molecular pathogenesis of this disorder, but they have also enabled us to predict an apparently favourable or unfavourable clinical course.6,7 For example, many people in families with the Arg403Gln mutation in the beta-myosin heavy chain gene develop severe symptoms and even die by age 45 years. In contrast, individuals with the Val606Met mutation in the same gene usually appear to experience minimal symptoms and have a normal life expectancy.7 Clearly, understanding the molecular mechanisms by which gene defects lead to the clinical phenotype is important. To this end, the recent sequencing of the human genome8 offers the potential to identify more causative genes in HCM and other medical disorders. It also provides the possibility of understanding the mechanisms and signalling processes with which these genes regulate and modify gene expression (either by second disease-causing or modifying genes or environmental factors), leading to recognition of therapeutic targets important in the pathogenesis of sudden death (eg, ion-channel genes and genes regulating cardiac collagen formation). Pharmacological agents ranging from β-blockers to amiodarone, while frequently used, have not been shown to be effective in preventing sudden death in HCM. However, the implantable cardioverter-defibrillator has emerged as a proven therapy.9 Patients should be selected for implantable cardioverter-defibrillator implantation based on risk-stratification parameters. Proven predictors of sudden death which should identify patients who would most benefit from an implantable cardioverter-defibrillator are shown in the Box. Further, providing automatic external defibrillators in public places where crowds are present and where people may be at higher risk (eg, sporting venues) might be of significant benefit in reducing sudden cardiac death in this setting. In HCM, sudden death has been the most visible and devastating consequence of the disease since the original report by Teare over 40 years ago.10 Accurately identifying individuals at highest risk and initiating the most effective therapy to prevent this complication are clearly the ultimate goals. Understanding the genetic basis and molecular mechanisms underlying the cardiovascular disorders that cause sudden death, using this knowledge to identify potential new therapeutic targets, coupled with the use of established therapies such as implantable defibrillators, will go a long way to achieving these goals. Risk stratification and screening in sudden cardiac death Risk factors for sudden cardiac death Family history of premature sudden death Individuals with a family history of an inherited disorder associated with sudden death (eg, hypertrophic cardiomyopathy, long-QT syndrome) Previous cardiac arrest Previous episodes of documented ventricular tachycardia Recurrent syncope A known "malignant" gene mutation Specific risk factors for a disease (eg, left ventricular wall thickness greater than 30 mm in hypertrophic cardiomyopathy) Screening tests for family members at risk of sudden cardiac death History Physical examination 12-lead electrocardiogram Echocardiogram Other tests, such as Holter monitoring and exercise testing

Christopher Semsarian MB BS, PhD · Barry J Maron MD

Objectives: To assess whether referrals for surveillance colonoscopy and subsequent follow-up recommendations for patients with a family history of colorectal cancer concurred with the published National Health and Medical Research Council (NHMRC) guidelines.Design: A prospective audit of patients with a family history of colorectal cancer referred for surveillance colonoscopy. Follow-up recommendations were assessed retrospectively.Setting and subjects: All patients referred to a major teaching hospital for surveillance colonoscopy on the basis of a family history of colorectal cancer from 2 January 2000 – 15 April 2001.Main outcome measures: Concurrence of referrals and recommendations with NHMRC guidelines.Results: Of 340 patients referred because of a family history of colorectal cancer, 202 (83 men, 119 women) were asymptomatic. Their mean age was 50 years (95% CI, 48.3–51.6 years). The family history of 95 (47%) of these patients satisfied the NHMRC criteria for colonoscopic surveillance. Another 20 patients (17%) satisfied the criteria, but were referred before the recommended age to commence surveillance. Analysis by referral source showed that the proportion of referrals meeting NHMRC guidelines was higher from specialists than from general practitioners (75% v 45%), and this difference was significant. Follow-up recommendations, when made, concurred with NHMRC guidelines in 81% of cases.Conclusions: Further education of the medical community is required to increase understanding of colorectal screening strategies and ensure appropriate resource allocation.

Ian F Yusoff MB BS, FRACP · Neville E Hoffman PhD, FRACP · Hooi C Ee PhD, FRACP

Objectives: To determine whether applying National Health and Medical Research Council (NHMRC) guidelines for colorectal cancer prevention would reduce the number of follow-up colonoscopies.Design: A prospective audit of colonoscopic surveillance decisions before and after the intervention.Setting: The endoscopy suite at a metropolitan tertiary hospital three months before and after January 2000. Intervention: Dissemination of NHMRC guidelines, and supervision of application of the guidelines by a nurse coordinator.Subjects: We compared colonoscopic surveillance decisions before and after the intervention in two groups of 100 consecutive patients after polypectomy and in two groups of 50 consecutive patients with a family history of colorectal cancer after a normal colonoscopy. Main outcome measures: Change in concordance of decisions with NHMRC guidelines; and effect on number of follow-up colonoscopies.Results: After the intervention, the proportion of postpolypectomy surveillance decisions matching the guidelines increased from 37% to 96% (P < 0.05). The mean time to repeat colonoscopy after polypectomy increased from 2.7 to 3.5 years (P < 0.005) (ie, a 23% reduction in the number of postpolypectomy surveillance colonoscopies performed per year). Likewise, the proportion of family-history surveillance decisions matching the guidelines increased from 63% to 96%. Adhering to the guidelines resulted in a 17% reduction in colonoscopies performed on the basis of a family history of colorectal cancer.Conclusions: Supervised application of evidence-based guidelines to a colorectal cancer surveillance program significantly reduces the number of surveillance colonoscopies performed.

Peter A Bampton FRACP · Jayne J Sandford BN · Graeme P Young MD, FRACP

Objective: To determine the incidence of adverse events related to an endoscopy sedation regimen that included propofol, delivered by general practitioner (GP) sedationists.Design: Audit of reports of sedation-related adverse events in patients undergoing endoscopy. A sample of 1000 patients' medical records was also reviewed to determine the drugs and dosages used and the proportion of sedations delivered by GPs.Setting and participants: All patients undergoing gastroscopy and/or colonoscopy from January 1996 to December 2000 in two private endoscopy centres in Canberra. Sedation was provided by GPs or a specialist anaesthetist, in most cases using a drug regimen that included propofol.Main outcome measures: Incidences of respiratory arrest, airway obstruction, hypoxia requiring intervention, hypotension, and death; number of interventions to correct these events, including extra airway management, bag-mask ventilation, intravenous fluid infusion, endotracheal intubation and the use of reversal agents, and admission to hospital.Results: 28 472 procedures were performed in the five years. There were 185 sedation-related adverse events (6.5/1000 procedures; 95% CI, 5.6–7.4): 107 for airway or ventilation problems (3.8/1000) and 77 hypotensive episodes (2.7/1000). Respiratory-related adverse events were more common in patients managed by GPs than anaesthetists, but this was not significant (P = 0.1). Interventions were recorded in 234 patients (8.2/1000; 95% CI, 7.2–9.3): 123 to maintain ventilation, and 111 intravenous infusions. GPs were more likely than anaesthetists to intervene to manage respiratory-related adverse events (P = 0.03). Four patients required transfer or admission to hospital. No patients required endotracheal intubation, and there were no deaths.Conclusions: The GP sedationists encountered a low incidence of adverse events, which they managed effectively. It appears that appropriately selected and trained GPs can safely use propofol for sedation during endoscopy.

Anthony C Clarke FRCP, FRACP · Louise Chiragakis MA · Lybus C Hillman MD, FRACP · Graham L Kaye FRACP

Objectives: To determine whether the occurrence of paracetamol and non-paracetamol analgesic deliberate self-poisoning (DSP) and accidental paediatric poisoning was affected by two periods of recall of paracetamol products.Design: Retrospective, observational audit of proportions of poisonings with tablet and capsule formulations of paracetamol, ibuprofen and aspirin products during two recall periods compared with the number of poisonings during the same periods of the previous three years.Setting: A national poisons information centre and a regional toxicology service.Main outcome measures: Rates of DSP and accidental paediatric poisoning with paracetamol, ibuprofen and aspirin.Results: During the two recall periods, there was a significant increase in ibuprofen DSP calls to the poisons information centre (RR, 1.86; 95% CI, 1.41–2.44; P = 0.001). There was no significant change in paracetamol or aspirin DSP calls over the two recall periods. However, there was a non-significant reduction in DSP calls with paracetamol in the first recall period alone (P = 0.057). There was a significant increase in the proportion of aspirin DSP presentations for the toxicology service (RR, 3.33; 95% CI, 0.97–11.4; P = 0.043), but no significant changes in paracetamol and ibuprofen DSP presentations. For accidental paediatric ingestions there was a significant increase in the proportion of ibuprofen calls (RR, 2.35; 95% CI, 1.85–2.98; P = 0.001), but no significant change in paracetamol or aspirin calls.Conclusions: Reduced paracetamol availability increased poisoning with alternative analgesics, but had little effect on the incidence of paracetamol poisoning. Restriction of paracetamol-containing products may inadvertently increase poisoning with potentially more toxic agents.

Corrine R Balit BPharm · Geoffrey K Isbister BSc, MB BS · Andrew H Dawson FRCP(Ed), FRACP · Ian M Whyte MB BS, FRACP · Jennifer Peat PhD

Preventive treatment Inhaled corticosteroids are indicated in children with asthma who have more than mild persistent asthma or are unresponsive to non-steroidal medications after 2–4 weeks. Initial administration of 400 µg/day of chlorofluorocarbon-beclomethasone dipropionate, or budesonide, or 200 µg/day of fluticasone propionate or hydrofluoroalkane-beclomethasone dipropionate, is suggested, with subsequent titration of the dose to achieve ongoing control with the lowest dose possible. In situations where asthma control cannot be achieved with the above doses of inhaled corticosteroids, the addition of a long-acting β2-agonist, theophylline or a leukotriene antagonist should be considered. Specialist referral is recommended in children requiring high doses of inhaled steroids, regular oral steroids or in whom there is concern about possible steroid side effects. Treatment of acute asthma Systemic corticosteroid therapy is recommended for children with moderate to severe acute asthma or if there is incomplete response to β2-agonists. Initial administration of 1 mg/kg prednisolone (maximum, 50 mg) orally is suggested, and this may be repeated every 12–24 hours, depending on response. While a course of up to three days is generally sufficient, in more severe cases a prolonged course (with tapering) may occasionally be indicated. The need for recurrent systemic corticosteroid therapy for acute episodes is an indication for reassessment of the child's interval therapy.

Peter P van Asperen MD, FRACP · Craig M Mellis MD, MPH, FRACP · Peter D Sly MD, FRACP

"Culture" can be understood as the way in which people make sense of the world by deploying shared meanings, attitudes, assumptions and values. Doctors will frequently encounter patients whose lives are guided by ethical systems and values that are different from their own. Individuals may differ in their beliefs about decision-making, regardless of their cultural background. Doctors should be willing to examine and test their own moral systems and cultural assumptions and be open to alternative traditions and beliefs. Engaging with other cultures does not imply that all cultural norms should be accepted uncritically, as there may not always be room for compromise. Failure to engage with issues of culture can erode the trust on which the doctor–patient relationship depends. Tensions can only be resolved through rigorous attention to a person's story.

Rob Irvine BA (Hons), PhD · John McPhee BCom(Hons)(LegStud) · Ian Kerridge MPhil, FRACP, FRCPA

The Story of Penicillin that we were taught as children was a simple story of how Alexander Fleming searched in vain for antibacterial agents until Penicillium mould spores drifted through his open laboratory window onto a plate of bacteria and killed them. Realising immediately the potential, he spent many years fighting against a resistant medical establishment and then guided Howard Florey and Ernst Chain to refine and test his great discovery. This myth meets the specifications of the archetypal "quest story", as described by the Russian anthropologist Vladimir Propp.1 The basic quest story seems to be a template in every human culture. It involves heroes who undergo trials or answer riddles, usually with the help of magical or divine intervention (in this case, mould spores drifting through windows). It has been argued2 that the quest story's structure (along with other story structures) is "hardwired" into the human brain, and that such structures evolved, like poetry and music, in human brains as mnemonic aids to help preliterate people store and remember vast quantities of words. Of course, we also have a tendency to rewrite history in a manner that renders it more momentous or more pleasing to the reader or listener. For example, Captain Robert Lewis, copilot of the plane that carried the first atomic bomb, records in his published account of the flight that his words immediately following the explosion were "My God, what have we done?". His exact words, as recalled by the rest of the crew, were "My God, look at that son-of-a-bitch go!".3 Among numerous inconvenient details missing from the penicillin myth is exactly how long the son-of-a-bitch took to get going, who was responsible, and why.4,5 The fact that Florey eschewed publicity while Fleming actively sought it did not help reveal the true story. A BBC film about Fleming, made as late as 1970, still perpetuated the myth, at least in popular culture. Alexander Fleming (1881–1955) in Edinburgh, where he had just been appointed Vice-Chancellor of the University, was received with just cause as a benefactor of humanity. Reproduced with permission from The Illustrated History of Medicine, by Jean-Charles Sournia. Published by Harold Starke. The search for non-toxic antimicrobial chemical agents"We can see further because we stand on the shoulders of giants", Albert Einstein said of Isaac Newton. The "giant" Louis Pasteur allowed the world to see the power of microbes in disease and the ability of the body's antibodies to combat these microbes. The search was then on for antimicrobial chemical agents — but antiseptics were too toxic for anything but surface use on wounds. In Frankfurt, Paul Ehrlich6 (who later won a Nobel Prize for his work on the theory of immunity) began to systematically test substances, searching for the "magic bullet" that could be taken internally, but ended up with little more than a high-risk arsenic-based treatment for syphilis. The resulting mindset was fixed — chemical agents were too toxic for internal use in the human body. Fleming, working in London, had been looking for antibacterial agents in human secretions. His discovery of the enzyme lysozyme (which he regarded as much more important than penicillin) came from an accidental sneeze onto a Petri dish (another divine intervention). He noticed that the area on which he had sneezed subsequently did not grow bacteria. "Noticed" is a key word — Fleming had a genius for taking notice of small, superficially inconsequential effects. Contrary to the myth, Penicillium spores did not fly in through an open window, as the windows of his laboratory were fixed shut. Luckily, Fleming's laboratory work practices were substandard. After stacking uncleaned plates in a corner while he was on holidays, he noticed (that word again) on his return that Penicillium mould had inhibited the growth of staphylococcal cultures. Fleming had little idea what to do with his mould apart from dabbing it on infected wounds. It seems astonishing now that he went so far as to inject his early "mould-broth" into a healthy rabbit, discovering it to be non-toxic, yet failed to take the further step of injecting it into infected rabbits to investigate its therapeutic effect. He then effectively forgot about it for 13 years. What was he thinking? And why, in this instance, did he not take notice? It's easy to see his mistake in retrospect, easy (in the words of author Julian Barnes) "to make the past suck up to the present".7 Fleming was of his time, a victim of the pessimistic mindset against toxic chemical antimicrobials. Ernst Chain at work in his laboratory at Oxford. Keystone (London) The contribution of Howard FloreyHoward Florey, the abrasive Australian who, Robert Menzies said, had more effect upon the welfare of the world than any other Australian, had also been working on lysozyme with his team at Oxford.8 He was a more methodical scientist than Fleming — methodical to the point of obsession — but the psychological imperatives behind this (the "madness in his method") had various origins. Florey suffered from a range of gastrointestinal symptoms, on which he blamed his irritable personality.8 He investigated his own condition by — among other tests — regularly swallowing a rubber tube to extract his stomach contents. The diagnosis was achlorhydria. His famous pinched smile was to hide the erosion of his teeth that resulted from drinking hydrochloric acid. The tests also sparked his interest in saliva and mucus and the antibacterial qualities of lysozyme. An important driving force in the quest for penicillin was Florey's idiosyncratic temperament, with its elements of idealism and obsession. His absorption with his work, and his rather unusual relationship with his wife Ethel, illustrate the power of an idea, or ideal, to sustain passion in the absence of reward. His relationship with Ethel began in his final year of medicine and was continued, in idealised form, by correspondence for five years of separation after he left for England. Even when she later joined him, the couple sometimes preferred to communicate via notes left on the hallway table. Florey worked seven days a week in his laboratory, seldom eating at home, and family holidays were generally spent visiting overseas laboratories. Ethel's involvement in his research was perhaps the one facet of the relationship that worked. She administered and recorded the clinical progress of the first large-scale trial of 187 cases of sepsis. Florey continued to work on lysozyme long after Fleming had abandoned it. Florey had the advantage of the services of a great biochemist, Ernst Chain (a refugee of the Hitler regime), on his team. Chain had purified lysozyme and understood its antibacterial function. Florey and Chain searched the medical literature for other antibacterial substances, and in so doing they rediscovered Fleming's finding of many years before. This was around the time of the discovery of sulfonamides and their minimal toxicity. To Florey, as to many others, this meant the end of the earlier mindset against toxic "magic bullets". He was interested in the fact that staphylococci, while resistant to sulfonamides and lysozyme, were apparently sensitive to the Penicillium mould. Chain was intrigued by the failure of Fleming and others to identify the active ingredient in the penicillin "mould-broth". The background of war in 1939 was a crucial spur to research on antimicrobial agents. Delayed infection (especially staphylococcal infection and gas gangrene) was killing more men than the immediate organ damage caused by shell and bullet wounds. Florey's awareness of this was not without an emotional resonance, as he felt some guilt about not having enlisted in the First World War. World War II provided an impetuous and risk-taking research environment. Resources normally denied could be commandeered, money was freed up, and Florey was able to persuade breweries to ferment mould for the conduct of trials on the battlefields of North Africa. Florey did many things that a modern researcher would be admonished for. He did not patent his work, despite being implored to do so by Chain. The United Kingdom was forced to buy back the technology from the United States for the mass production of penicillin. Florey shunned the media for fear of creating false expectations and had nothing but contempt for their intrusions into his life. He believed that sensational stories about penicillin would create a demand that could not possibly be met. He always stressed the team effort involved (teamwork was an unusual feature of medical research in those days), and claimed that he got more credit than he deserved. As a consequence, he almost left Fleming — seldom out of the limelight by then — to receive the Nobel Prize alone. Howard Florey. Photograph courtesy Dr Joan Gardner, AO. The moral of the storyThe philosopher Richard Rorty has written that "inquiry is never pure ... It is always a matter of getting us something we want".9 The story of the quest for penicillin contains too many complicated semi-heroes to allow itself to be twisted into a myth of the usual impoverished Hollywood dimensions. If there are mythical heroes in scientific research they work in teams — sometimes in teams that are not even aware they are teams, being disconnected in time and place. If a relay team is the closest analogy, the baton is more often tossed into the air in the hope that someone — anyone — will grab it than passed on directly. But, like most archetypal stories, the story of penicillin doesn't lack simple moral lessons. Perhaps the most lasting is the recurring theme of human creativity: how to see what has been hidden in full view all along. The great clinician Sir William Osler wrote of an earlier mindset in 1905: "We may have become more plastic and receptive, but I doubt it; even our generation . . . had a practical demonstration of the slowness of the acceptance of an obvious truth in the long fight for the aseptic treatment of wounds. . . . [It was] a long and grievous battle, as many of us well know who had to contend in hospitals with the opposition of men who could not — not who would not — see the truth . . . "In making knowledge effective we have succeeded where our masters failed. But this last and final stage, always of slow and painful consummation, is evolved directly from truths which cannot be translated into terms intelligible to ordinary minds."10 As the philosopher John Locke wrote, "Truth scarce ever yet carried by vote anywhere at its first appearance. . . . The final struggle for acceptance is the real challenge in achieving knowledge".10 The narrative impulse always seeks to personify that struggle, to dramatise it as a battle between individuals, in black and white — but the truth is much more messy and complex.

Peter D Goldsworthy MB BS · Alexander C McFarlane MB BS (Hons), MD, Dip Psychother, FRANZCP

Mycobacterium ulcerans is an environmental bacterium causing skin ulcers. An endemic area of M. ulcerans disease in temperate south-east Victoria, where the disease is known as "Bairnsdale ulcer", has been extensively studied, and continues to involve new geographic areas.1 A less well known endemic area exists in tropical far north Queensland between Mossman and the Daintree River (Douglas Shire) (Box 1), where it is called "Daintree ulcer".2 Our patient presented with diffuse limb swelling of acute onset without ulceration and associated with systemic symptoms, which is unusual for M. ulcerans disease in Australia; only two previous cases from far north Queensland have presented in this way.2 Most patients in Australia initially note a papular lesion, which subsequently ulcerates after weeks to months without associated systemic symptoms.3 The classic ulcer is painless, with a sharp, undermined edge and surrounding induration, indicating the extent of necrotic subcutaneous tissue. Histopathological examination of excised tissue from patients with M. ulcerans disease shows large numbers of extracellular mycobacteria, a poorly developed immune response and widespread necrosis of subcutaneous tissue,4 which may be mediated by a recently described lipid toxin (mycolactone) produced by M. ulcerans.5 The accepted treatment of M. ulcerans disease remains complete surgical excision of all necrotic tissue, often extending well beyond the visible margins of the ulcer, with primary closure of small lesions and immediate or delayed skin grafting to larger lesions. Antimycobacterial therapy appears ineffective,2 despite in-vitro sensitivity of the organisms to several antimycobacterial agents, possibly because of clustering of the organisms in necrotic fat, where penetration of antimicrobials is likely to be poor. We have used adjunctive therapy in addition to surgical excision in patients with locally extensive or disseminated disease, and/or incomplete surgical excision. In these situations, relapse and residual functional impairment are more common. The combination of rifampicin, ethambutol and clarithromycin, although not established in the treatment of M. ulcerans infection, has shown good activity against other non-tuberculous mycobacteria, and M. ulcerans is sensitive in vivo to rifampicin6 and in vitro to clarithromycin.7 Early diagnosis can reduce the extent of surgical excision required, and therefore the residual scarring and deformity, and may also minimise the risk of relapse. Increased awareness of the disease in endemic areas is important in early diagnosis. A diagnostic polymerase chain reaction (PCR) test,8 developed at the Royal Children's Hospital (Melbourne), has 96% sensitivity and 100% specificity for M. ulcerans and is available from the Victorian Infectious Diseases Reference Laboratory, Melbourne. It can be performed within one day from a dry swab of the ulcer, and allows clinicians to make a rapid decision about whether or not surgical excision is required. Laboratory culture confirmation remains important and provides isolates for further analysis, but it may take more than six weeks. Microscopy for acid-fast bacilli from ulcer swabs, although sensitive, is non-specific — it cannot distinguish M. ulcerans from other non-tuberculous mycobacteria. The high specificity of the diagnostic PCR is important, as, in contrast to M. ulcerans infection, other non-tuberculous mycobacteria usually respond to antimycobacterial therapy. Clinical record A 45-year-old farmer from near Mossman, Queensland, presented with fevers and severe pain, swelling and redness of the left forearm. He recalled striking his forearm on a tree branch two weeks previously, with resulting bruising and soreness, but had not noticed any skin break. Treatment with oral cephalexin for presumed cellulitis was commenced five days before admission, with no improvement. Examination showed an erythematous, tender swelling of his whole left forearm, with pitting oedema and indistinct margins from 10 cm above the elbow to 5 cm above the wrist (Box 2). M. ulcerans infection was considered in the differential diagnosis because of an awareness of the disease among healthcare workers in this area. Microscopic examination of Ziehl–Neelsen-stained skin biopsies revealed acid-fast bacilli, and a swab taken from the base of a punch biopsy site was positive for M. ulcerans by polymerase chain reaction (PCR), confirming the diagnosis of oedematous M. ulcerans disease. M. ulcerans was subsequently cultured from the skin biopsy. Excision of skin and necrotic tissue was performed to the approximate margin of the lesion and split-skin grafts were applied. Histological examination showed typical changes of M. ulcerans disease, with extensive necrosis of the deep dermis and subcutis undermining intact epidermis. Numerous acid-fast bacilli were seen to the margins of the excised tissue. Because the disease was present to the excision margins, antimycobacterial therapy with rifampicin 600 mg daily, ethambutol 1200 mg daily and clarithromycin 500 mg twice a day was commenced. Three weeks after surgery, recurrent redness, swelling and pain developed at the proximal and distal margins of the wound. Re-excision of these necrotic areas at the wrist and upper arm was performed and further split-skin grafts applied. Histopathological examination of these specimens showed no acid-fast bacilli and cultures were negative. Antimycobacterial therapy was continued for two months after surgery. There has been no evidence of subsequent recurrence of disease and the patient has regained normal function in the affected arm. 1 : Mycobacterium ulcerans-endemic area The location of the M. ulcerans-endemic area, Douglas Shire, far north Queensland, Australia. 2 : Mycobacterium ulcerans disease The patient's left arm before operation, showing extensive oedema and erythema. Lessons from practice Increased awareness of Mycobacterium ulcerans infection in the endemic areas (south-east Victoria and far north Queensland) is important in early diagnosis. The disease may present with an acute onset and oedema, without ulceration. Early diagnosis can reduce the extent of surgical excision and minimise the risk of relapse. A diagnostic polymerase chain reaction (PCR) test with 96% sensitivity and 100% specificity for M. ulcerans is available from the Victorian Infectious Diseases Reference Laboratory (Melbourne).

Grant A Jenkin FRACP · May Smith MSc, BA · Mark Fairley FRACGP · Paul D R Johnson PhD, FRACP

Clinical question A 68-year-old woman diagnosed with osteoporosis attended a naturopath, who advised (a) exercise in the gym 2–3 times a week, because "walking wasn't good enough"; (b) natural progesterone cream applied to the skin; (c) oral boron supplements; (d) codliver oil 1000 mg daily; (e) chelated calcium (instead of her current calcium carbonate); and recommended that she stop drinking tea. The patient challenged her general practitioner for not giving the same advice as the naturopath, suggesting he was remiss. Her GP wondered if there was any empirical basis for these recommendations in osteoporotic patients. Search question The revised question was: Is there empirical evidence that the following interventions reduce fracture rates and improve bone mineral density (BMD) in postmenopausal women with osteoporosis?: exercise in the gym 2–3 times a week; natural progesterone cream; boron; codliver oil; chelated calcium supplement; abstaining from tea. The ideal studies for this would be randomised controlled trials (RCTs) comparing each of the recommendations with either placebo or no treatment (or, in the case of the last recommendation, drinking tea) for the outcomes of interest: fracture rate and BMD. Search We searched three online databases: PubMed Clinical Queries (<http://www.ncbi.nlm.nih.gov/entrez/query/static/clinical.html>), SUMSearch (<http://sumsearch.uthscsa.edu>) and the Cochrane Library, using the search terms "osteoporosis", "weight-bearing exercise", "walking", "progest", "natural progesterone cream", "boron", "bone", "cod liver oil", "caltrate", "calcium carbonate", "tea", "tannin" and "vitamin D". Summary of findings We identified a number of studies that used the primary outcome measure of BMD, but none that assessed fracture rate as the primary outcome. →Exercise Five meta-analyses were identified that demonstrated the effectiveness of aerobic and/or strength-training exercise in increasing BMD in different body regions,1 the lumbar spine,2-4 the hip,5 and femoral neck.4 The meta-analyses applied adequate eligibility criteria for the trials analysed and included either RCTs only1,3,5 or RCTs and non-randomised controlled trials.2,4 Four RCTs specifically evaluated the benefits of walking on BMD. The sample sizes were small in two of these trials but adequate in the other two. In a seven-month trial of 33 postmenopausal women, walking above (but not below) the anaerobic threshold (ie, sufficient to leave the subject panting) was found to significantly increase lumbar spine BMD in the walking women compared with controls, in whom BMD decreased.6 In a trial assessing the effects of walking and calcium supplementation on 36 postmenopausal women, those involved in a supervised one-year walking program showed a significant increase in trabecular BMD of the lumbar spine compared with sedentary women.7 In another trial,8 165 postmenopausal women with a history of fracture of an upper limb in the previous two years were randomly assigned to do upper-limb exercises or brisk walking: after two years, there was significantly greater loss of BMD in the femoral neck for women in the former group than the latter group, but no difference in lumbar spine BMD between the two groups. The dropout rate was high in this trial at 41%. In the largest trial assessing the benefits of walking, 255 women were randomly allocated to a walking group or a control group: after 3 years BMD changes in the cross-sectional dimensions of the radius did not differ significantly between the two groups.9 →Progesterone One controlled clinical trial assessed the efficacy of natural progesterone cream as an adjunct to percutaneous oestradiol in reducing postmenopausal bone loss in 57 women.10 Progesterone cream did not influence BMD. →Boron One RCT assessed the effect of boron supplements over one year on BMD.11 Subjects were grouped according to whether they were athletes (n = 17) or sedentary (n = 11). It was not possible to tell whether boron had an effect on BMD, as no results were reported that compared those who received supplements with those who did not. Moreover, this trial was conducted in female college students rather than postmenopausal women. →Codliver oil No trials were identified that examined the benefits of codliver oil for BMD. →Calcium In a randomised crossover controlled trial, three calcium supplements were assessed for their absorption ability.12 Thirty-five osteoporotic women received the three preparations on successive evenings: 1 g effervescent calcium, 1 g calcium carbonate or 1.2 g calcium carbonate. Urinary calcium excretion rose significantly and similarly for all three preparations, indicating similar levels of absorption. The effect that this had on BMD was not measured. Comment There is good evidence that exercise increases BMD in postmenopausal women with osteoporosis. Despite slight variations in the way different analyses defined each outcome measure, all five meta-analyses supported this conclusion. Although no trials specifically compared "just walking" with "exercise in the gym", there was reasonable evidence supporting the beneficial role of walking in this patient group, particularly above the anaerobic threshold. There is little good-quality empirical evidence to support the use of natural progesterone cream. One non-randomised controlled trial reported that its use had no effect on BMD. There is insufficient empirical evidence to support the use of boron, codliver oil or chelated calcium supplements (as opposed to calcium carbonate), or to suggest that drinking tea should be avoided. Outcome The GP discussed the available evidence with the patient, who then understood why he had not made the same recommendations as her naturopath. She was pleased to have avoided the unnecessary expense that she would have incurred if she had followed the alternative advice.

Christopher B Del Mar MD, FRACGP, FAFPHM · Paul P Glasziou MB BS, PhD, FRACGP, FAFPHM · Anneliese B Spinks BSc/Arts (Hons) · Sharon L Sanders BSc (Pod)

To the Editor: We wish to report the identification of a novel virus causing lower respiratory tract disease in Australian children. The presence of this virus was recently described in Dutch children and tentatively called human metapneumovirus (hMPV).1 Clinical symptoms of infection are reported to resemble those of human respiratory syncytial virus (hRSV) infection. We therefore investigated whether the virus was present in Australian children. Three isolates were identified from a random selection of 200 nasopharyngeal aspirate (NPA) specimens collected throughout 2001 from children presenting to the Royal Children's Hospital, Brisbane, or the Logan Hospital, a public hospital to the south of Brisbane, with clinical respiratory tract disease. All NPA specimens were initially negative for hRSV, influenza A and B, parainfluenza 1, 2 and 3 and adenovirus by direct fluorescent antigen testing and subsequent viral culture. These negative NPA specimens were then screened by polymerase chain reaction (PCR) for hMPV, based on the known sequence of the virus.2 Sequencing of the PCR product in all three positive samples was 100% homologous with the known hMPV sequence. Viral growth was subsequently detected in culture from two of these samples, and confirmed as hMPV, using the method of van den Hoogen et al.1 Co-existent infection with coronavirus, rhinovirus, Bordetella pertussis, Chlamydia pneumoniae and Mycoplasma pneumoniae was excluded by PCR screening of the three hMPV isolates using validated in-house methods based on established protocols. Clinical features of the infected children are summarised in the Box. This is the first report of the presence of hMPV infection in Australian children and describes a new viral respiratory syndrome. It also adds to the clinical spectrum and understanding of respiratory viruses causing acute bronchiolitis in children. Only 25%–33% of NPA specimens collected from our population with suspected respiratory tract disease yield a positive result for a known viral or bacterial pathogen. Clinical features in this small cohort are difficult to separate retrospectively from hRSV. Based on the findings of this limited preliminary study of children presenting to hospital with respiratory tract symptoms, we would predict that hMPV is also relatively common in the Australian community. We are currently undertaking further characterisation of the hMPV isolates, a more detailed study of the epidemiology of hMPV disease, as well as developing improved diagnostic assays to rapidly identify clinical cases and assess seroprevalence of immunity to hMPV. Clinical features of human metapneumovirus in three Australian children Case 1 (Girl, 12 months) Case 2 (Boy, 5 years 11 months) Case 3 (Boy, 20 months) Date of nasopharyngeal aspirate collection 17/2/01 21/3/01 11/5/01 Presenting symptoms Rhinorrhoea, cough, tachypnoea, wheeze, vomiting Rhinorrhoea, cough, pharyngitis, conjunctivitis Rhinorrhoea, cough, fever Symptom duration before presentation (days) 4 3 4 Clinical signs Respiratory distress with hypoxia, rhinorrhoea, pharyngitis, chest wheeze with crackles Pharyngitis, chest wheeze Rhinorrhoea, pharyngitis, chest wheeze, cervical lymphadenopathy Chest X-ray Not performed Bilateral parahilar pneumonic infiltrates Bilateral parahilar pneumonic infiltrates Clinical diagnosis Bronchiolitis Viral lower respiratory tract infection Viral lower respiratory tract infection Outcome Admitted for oxygen therapy and nasal suctioning for three days Symptomatic treatment at home Symptomatic treatment at home

Michael D Nissen · Ian M Mackay · Stephen J Withers · David J Siebert · Theo P Sloots

To the Editor: I write to offer a re-analysis of the data presented by Whitby and colleagues.1 They reported a meta-analysis of crude estimates and relative risk of death derived from nine published studies for Staphylococcus aureus bacteraemia. They concluded that bacteraemia caused by methicillin-resistant S. aureus (MRSA) is associated with a "real increase in risk of death" compared with bacteraemia caused by methicillin-sensitive S. aureus (MSSA), with a relative risk of 2.12. However, they failed to explore fully the possible confounding effect of the patients' underlying diseases and treatment in their analysis. With this in mind, I offer a re-analysis of their data using regression analysis. Mortality rates versus median length of stay in hospital before bacteraemia (LOS) are shown in the Box (next page) for the five studies for which these data were presented by Whitby et al (in Boxes 1 and 2). The four studies without LOS data were combined, using the median LOS from the other five studies in the figure and the regression model. The regression analysis was performed with and without the weights provided by Whitby et al (Box 2), and also with and without the four studies for which LOS data were not available. Regression analysis revealed a significant association between mortality rate and LOS (P < 0.005). However, the addition of group status (MRSA or MSSA) failed to achieve significance in any iteration of the regression, while LOS remained a significant predictor of mortality risk. This suggests that, with S. aureus bacteraemia, mortality rate increases with length of time in hospital before the bacteraemia. The likely explanation is that patients residing in hospital for longer periods are sicker. Moreover, they are more likely to have been exposed to antibiotics, leading to increased risk of acquiring an S. aureus strain that is methicillin-resistant. The mortality risk is no different for MRSA versus MSSA bacteraemia if LOS, a surrogate marker for severity of patient illness, is taken into account. The difference that Whitby et al observed between the groups of patients with MRSA and MSSA bacteraemia could be accounted for by the difference in LOS between these groups. Mortality rate versus hospital length of stay before bacteraemia (LOS) in patients with MRSA or MSSA bacteraemia

James C Hurley MB BS, PhD, FRACP

In Reply: We thank Hurley for his comments on our meta-analysis.1 However, we strongly dispute that our analytical technique is flawed, and argue that we have been extremely cautious in drawing our conclusions. Hurley's contention is that hospital length of stay before bacteraemia (LOS) is a surrogate for severity of underlying disease and risk for colonisation with methicillin-resistant Staphylococcus aureus (MRSA), and that these factors explain the higher mortality in patients with MRSA. We agree that LOS may be a confounder. It may be an effect modifier, whereby patients in hospital for longer may be more ill, and therefore more susceptible to infection with and death from MRSA. Both are intuitive and biologically plausible conclusions. In fact, we referred to these possibilities in our Discussion, writing that "patients who ultimately become infected with MRSA are more seriously ill than those who become infected with MSSA [methicillin-sensitive S. aureus]" and "separating the effect of the bacteraemia per se from the effects of patients' underlying disease and treatment is a major problem when comparing outcomes". We also cautioned readers that available published data on mortality made it impossible for us to adjust for numerous potential confounders, including LOS, as the information given did not link these potential confounders with the outcome in individual patients. Hurley has not, as he suggests, undertaken an analysis that would allow him to control correctly for the potential confounder, LOS. He, like us, used "group-as-a-unit" data, but, although the groups are homogeneous for MRSA or MSSA, they are heterogeneous for LOS. Adequate examination of and control for potential confounders requires either individual patient data or data from homogeneous groups. Hurley has attempted to use analysis normally reserved for individual data.4 His analysis was analogous to treating the data as though from an ecological study, a design in which control of confounding is difficult,5 and thus does not permit him to draw his conclusions. Our analysis (not presented in our original article) of only those studies where the authors attributed mortality to bacteraemia6-8 found that the magnitude of effect remained (fixed-effect relative risk, 2.27; 95% CI, 1.75–2.96; P < 0.001; test for heterogeneity, χ2 = 6.14, df = 4, P = 0.19). As MRSA bacteraemia is a rare event and published studies are small, the statistical ability to control for confounding and effect modification is limited. Until sufficient suitable data for individual patients are available for analysis, we have remained restrained in our assessment. Mindful that MRSA bacteraemia is associated with increased mortality, regardless of the cause, we hold with our original conclusion that "our findings justify ongoing surveillance and proactive management of MRSA in healthcare facilities".

Michael Whitby · Mary-Louise McLaws · Geoffrey Berry

To the Editor: The article by Nelson et al1 estimates Pharmaceutical Benefits Scheme and Repatriation Pharmaceutical Benefits Scheme (PBS/RPBS) savings if hypertensive patients on monotherapy were prescribed the agents recommended in guidelines; however, the analysis contains algebraic errors and insufficient sensitivity analyses. The question of excessive costs through the use of expensive agents for which there is no evidence of increased benefit for most patients is an important one, but the estimates of extent of overuse should be methodologically sound. The three main concerns we have with the paper's estimates are as follows: The total number of patients on monotherapy in Box 3 of the article adds to 1.1 million, whereas elsewhere the authors state that 60% of all 1.2 million Australian patients treated for hypertension are on monotherapy, giving an estimate of 0.72 million. (These estimates of 60% and 1.2 million are not referenced in the article.) One reason for this discrepancy is that the authors have treated the sum of column 4 in Box 2 as patients, not patient-years of treatment (some patients are on dual or triple therapy), leading to a 40% overestimate of numbers of patients on monotherapy reported in Box 3. Utilisation of prescription drugs is recorded by PBS/RPBS only if the cost to patient is subsidised. Therefore, PBS/RPBS expenditure divided by total patient numbers (Box 2) underestimates consumer cost for diuretics and β-blockers, both of which cost less than the non-concessional co-payment. Of total PBS/RPBS scripts, 16% are for non-cardholders,2 and the cost per script to these patients is about three to four times the prevailing 1998 cardholder co-payment. As a rough estimate, total consumer cost for these agents may need to be doubled, and their omission is therefore material. Although non-concessional patients still have a saving, it is less than that estimated in the article. Sensitivity analysis should have been performed on the following critical assumptions: (1) proportion of use for hypertension for each class of drugs, (2) the number of unsubsidised users of diuretics and β-blockers, and (3) the proportion of patients on each agent who are on monotherapy. It is vital that the current scrutiny by all stakeholders of PBS/RPBS expenditure be informed by reasonable estimates of inappropriate utilisation. The contribution made by the authors in developing a technique to estimate appropriate use for this group of drugs is valuable. However, use of unreferenced estimates of key variables, insufficient application of sensitivity analyses, algebraic errors and inappropriately combining PBS with non-PBS data may cloud rather than shed light on this issue.

Ben D Ewald · Brita A Pekarsky

In reply: We thank Pekarsky and Ewald for their comments. It is difficult to estimate the percentage of patients on monotherapy from any source. We used data from IMS Health (http: //www.ims-global.com/) to determine the number of person-years of exposure to drugs prescribed with a principal indication of hypertension. Some of these drugs were prescribed as a sole agent if the script was for this single drug alone. Exposure for such agents was expressed as a percentage of the total exposure of this drug. For example, angiotensin-converting enzyme (ACE) inhibitors were sole agents in 63.9%. In the other 36.1%, the co-prescribed drugs may have been another antihypertensive drug or another type of drug altogether. Corresponding figures for calcium-channel blockers were 61.3%, for diuretics 53.6%, and for β-blockers 60.0%. As an approximation, we used the estimation that 60% of patients were likely to have been on monotherapy for hypertension. Adding the number on monotherapy for each drug gives an estimate of 1.2 million for the total population on monotherapy for hypertension. Therefore, the total number on drugs is likely to be greater than the 1.2 million as estimated in our article. However, the essential figure is that of 1.2 million for monotherapy, which we stand by. It is true that a minority of prescriptions (16%) are written for people without a concession card and that these are more likely to pay the full cost of a cheaper drug. Our economic perspective was that of the PBS/RPBS. Hence, consumer costs were only included where the government made a copayment. It is acknowledged in the Methods section that "with some drugs, the patient copayment covers the total cost; in these instances the Commonwealth makes no contribution to the cost and these prescriptions are not recorded in the PBS/RPBS data" (page 566). It is also stated in the Discussion that the PBS/RPBS captures "much more of the cost of the newer, more expensive agents than thiazide diuretics or β-blockers" (page 567). We chose to limit our sensitivity analysis to the key issue of redistribution of agents after initiation of monotherapy. The data we presented allow interested parties to conduct their own further sensitivity analyses, such as those suggested by Pekarsky and Ewald.

Mark R Nelson MFM, FRACGP · John J McNeil PhD, FRACP · Anna Peeters BSc(Hons), PhD · Henry Krum PhD, FRACP · Christopher M Reid MSc, PhD

To the Editor: In his recent Commentary on hastening death in terminally ill patients,1 Hunt may not have fully appreciated a very cogent point made in the research by Douglas and colleagues.2 The surgeons surveyed clearly reported the intent of their prescribing. This is contrary to Hunt's assertion that "Intention is inherently subjective . . . complex [and] ambiguous". Some surgeons gave a dose appropriate to the symptoms, others deliberately increased the dose beyond direct symptomatic control, and a few deliberately ended life, at times with no explicit request. As Douglas points out, the dose of a medication given will be an important clue in this. Good clinical practice is about minimum effective dose (MED), not maximum administrable dose (MAD). This is the case for all patients, whether they are near the end of life or not. Hunt also states that "The duty of doctors is to strive to satisfy the wishes and interests of their patients and their patients' loved ones".1 This is a disturbing comment if left unqualified. There is a broader accountability for doctors to the community through the registration process, quality assurance and continuing education, and the criminal code. If the article by Douglas et al highlights nothing else, it should be clear that there are certain members of the medical profession who believe that they are above the law and have control over the life and death of their patients, with no external review.2 It is frightening that such paternalism still exists. Unfortunately, the Dutch experience of tolerating euthanasia does not appear to have decreased unilateral decision-making on the part of some doctors.3,4 If the premise that the interests of the patients' loved ones is a consideration in the duty of care,1 then we are risking the loss of patient autonomy in an unprecedented way. As a practising clinician, the majority of requests that I receive to hasten death are from relatives, not patients. These relatives ask that they be put out of their own misery by ending the patient's life prematurely. To do something to a patient for a third party, however concerned or distressed, is an unacceptable action for clinicians. For the profession to credibly engage in the debate about end-of-life care, we must accept that we are part of the community and hence governed by its laws. There are reference points external to the profession by which we will be judged.

David C Currow

In reply: The survey by Douglas et al1 indicated that, under the current criminal code, about one in three Australian general surgeons are at risk of prosecution for murder because of the way they treat their dying patients. It is likely that many other Australian doctors are similarly at risk of prosecution. This is a serious problem that raises important questions: Why are so many doctors breaking the law? Should these practices be kept covert or brought out into the open for audit and discussion? Is the law serving the needs and interests of dying patients, those who care for them, and the wider community? Rather than argue that doctors are above the law, I have argued that the practice of medicine should be congruent with the law.2 Laws have been established and refined over time so doctors can help their patients (eg, with procedures and the administration of drugs) in ways that are illegal for others. An integral part of the medical role involves the negotiation of life–death decisions. I believe murder laws should be refined to reflect the reality that some terminally ill patients want death as a release from suffering and seek the help of their doctor to provide this. Just as there are differences between rape and making love, I see obvious differences between common murder and the hastening of death that doctors provide for terminally ill patients out of compassion, mercy, and respect for their wishes. Unfortunately, the ethics of current practices are difficult to elucidate because the existing law makes investigations problematic. The current crude law does not reflect community values — Morgan Gallup polls indicate about 80% of Australians are in favour of allowing voluntary euthanasia in certain circumstances.3 As Currow observes, these widely held values are sometimes expressed by the relatives of dying patients. In my experience, however, these relatives are usually advocating for the patient's wishes and interests, rather than undermining patient autonomy. I support the established hospice tenet that "the family is the unit of care" and there is a duty to address the concerns not only of patients but also of their loved ones. I think it is only a matter of time before politicians introduce the reforms that render the legal framework for terminal care more congruent with community values, the wishes of patients and their families, and current medical practices. These reforms should enable research, audit and the better regulation of end-of-life care.

Roger W Hunt BM BS, GDPH, FAChPM

To the Editor: Australia has been successful so far in maintaining a low prevalence of HIV infection among injecting drug users (IDUs). This has been achieved by adopting a harm-reduction approach to the prevention of bloodborne virus transmission, including needle and syringe programs, methadone maintenance and peer-education. Sharing of needles and syringes has declined markedly: cross-sectional surveys among users of needle and syringe programs across Australia have shown a decrease in the prevalence of reported sharing from 31% in 1995 to 15% in 1997.1 However, there is evidence that among some subpopulations, especially those of Indo-Chinese origin, unsafe injecting practices remain common. In a survey of Indo-Chinese IDUs in Sydney and Melbourne, Maher et al reported that 22% of those surveyed had shared needles and syringes in the preceding month.1 Although the Indo-Chinese community is becoming increasingly aware of issues related to drug use, IDUs are under-represented in drug treatment programs.3 There is also evidence that parents send their children back to their country of origin to escape the Australian heroin scene. In a Melbourne survey of Vietnamese IDUs, Kelsall et al reported that 19% of their sample (38 of 200) had returned to Vietnam during the previous five years for drug-related reasons. Of these, 24 reported using heroin in Vietnam, a disturbing finding given that HIV prevalence among IDUs in parts of Vietnam is greater than 50%.4 We analysed HIV surveillance data in Victoria to investigate whether there was an over-representation of Indo-Chinese-born IDUs. Country of birth has been collected as part of HIV notification in Victoria since January 1996. Since then, there have been 38 notifications of HIV infection in individuals reporting intravenous drug use as a risk factor. Of these 38, 11 (29%; 95% CI, 15%–46%) reported an Indo-Chinese country of birth — a higher proportion than expected given the 1996 census finding that 1.5% of Victoria's population was born in an Indo-Chinese country.5 These 11, all men, were significantly younger than other IDUs notified in this time (mean, 23.3 years v 31.3 years, respectively; P < 0.05). Although these numbers are small, they highlight a group at increased risk of HIV who are not currently being effectively reached by prevention services. These data also suggest a hidden route for spread of HIV from Asia into the Australian community. There is an urgent need to provide culturally relevant education and harm-reduction programs to prevent transmission of HIV within this group. The Victorian Department of Human Services is allocating additional resources to working with culturally and linguistically diverse communities on prevention activities to address this issue.

Jane S Hocking · Peter G Higgs · Cathy M Keenan · Nick Crofts

To the Editor: On reviewing the results of the Wimmera clinical risk management program,1 we are prompted to ask whether the model can be generalised to a tertiary hospital. The program outlined by Wolff and colleagues is a good model for local quality improvement and provides a foundation for developing a model for tertiary hospitals. However, in considering its applicability to tertiary hospitals, a number of issues must be addressed. The number of separations and emergency department presentations at tertiary hospitals does not lend itself to review of all medical records. Such review is time- and resource-intensive and probably unrealistic in a tertiary setting. A sampling strategy might be more suitable, but would introduce the possibility of sampling error and missing adverse events. The availability of medical staff to review records is also limited, with clinicians often having public, private and teaching commitments. It would also not be feasible for a medical director to be involved regularly in the day-to-day tasks of the process. Nevertheless, these issues could be addressed by allocating the review process to a dedicated, trained team. Development of a review pathway would ensure participation of senior medical or management staff when necessary. The interface between tertiary hospitals and local general practitioners is broader and less defined than in rural areas, making the involvement of GPs difficult. The clinical mix and complexity of patients requiring tertiary care differ significantly from those at a rural base hospital, and restricting screening criteria for adverse events to eight items, as in the Wimmera program, would likely result in adverse events being missed. In addition, the clinical structure of tertiary hospitals is not uniform, and specific criteria may need to be developed to address the clinical specialties of the hospital. Lastly, in this era of cost containment in healthcare, Wolff et al did not address the cost of its clinical risk management program. While this is not a fault in the study, cost would be an essential consideration in generalising the program to a tertiary hospital. The model used in the Wimmera program has limitations when considering adaptability to tertiary hospitals, because of issues of scale and day-to-day practicalities. Further examination of the costs involved in ongoing operation of the program and a cost–benefit analysis are required. In addition, investigation is needed into feasible options that deliver useful results in a tertiary setting before a quality improvement model can be developed that is relevant, appropriate and cost-effective for tertiary hospitals.

Kathy M Brown · Humsha Naidoo · Arona E Offenberger

In reply: The model developed in the Wimmera hospital for clinical quality improvement has formed the basis for quality improvement systems in several regional and tertiary hospitals in Australia. The resources required to implement the model have been costed, and the Victorian Department of Human Services has allocated $4.8 million to establish clinical risk management programs based on the Wimmera model in every Victorian public hospital in 2001–2002.1 Whichever programs are implemented, some adverse events will be missed. However, not all medical records need to be reviewed, nor all adverse events found. Regular identification of some events provides significant opportunities to improve care. As clinician time is limited, some hospitals that have implemented the Wimmera model have paid clinicians with existing appointments for extra hours to participate in risk-management programs. Although feedback to general practitioners is logistically more difficult in a tertiary centre, it can still provide valuable information if limited to only a sample of inpatients. We agree that some departments in tertiary hospitals, because of their specialised nature, would need to develop additional screening criteria. The actual cost of running a clinical risk-management program based on the Wimmera model depends on how many components of the model are implemented, but in our experience should not exceed 0.5% of a hospital's total budget. Cost–benefit analyses are difficult to undertake, as some adverse events arise through underuse of available evidence, and additional resources would be needed for full implementation of the evidence (eg, giving prophylactic antibiotics immediately before surgery to prevent postoperative infection,2 or low molecular weight heparin postoperatively to prevent thromboembolism3). We believe that in any institution, whatever its size, the initiation of effective programs for clinical quality improvement needs both enthusiastic support from the highest level of management and champions at the "coalface" of patient care. If these two elements are present, adequate resources will often be found. However, providing resources without appropriate clinical and administrative support is unlikely to improve patient care.

Alan M Wolff · Jo Bourke · lan A Campbell · David W Leembruggen

To the Editor: The recent supplement by Hickie et al looking at the mental health of Australians attending general practice1 would have us believe that we are quite a mentally unwell nation indeed! The authors propose a broad concept of "mental disorder" which they found in 49% of general practice attenders based on 12 questionnaire items (the SPHERE-12). These 12 items include six relating to psychiatric symptoms (PSYCH-6) and six relating to somatic symptoms (SOMA-6).2 The SOMA-6 items are muscle pain after activity, needing to sleep longer, prolonged tiredness after activity, poor sleep, poor concentration, and tired muscles after activity. Patients with a total score of two or more in PSYCH-6 and/or three or more on SOMA-6 were classified as having a "mental disorder". Firstly, the SPHERE-12 is grossly oversensitive, as the six somatic items detect many medical conditions, glandular fever being just one example. Other validity issues include the two-week cut-off for symptoms (further adding to the overinclusiveness because of temporary distress and minor illnesses), and the lack of discussion regarding transcultural and inter-rater reliability, particularly with so many general practitioners involved. Secondly, the authors' interchangeable use of neurasthenia and chronic fatigue syndrome and somatisation needs discussion. Ten years ago, Hickie and several New South Wales physicians were dismissive of an article linking chronic fatigue syndrome and neurasthenia: "We have demonstrated immunological abnormalities in patients with chronic fatigue syndrome as compared with both normal controls and patients with major depression. Further, the demonstration of abnormal cytokine production in patients with chronic fatigue syndrome may underpin 'acquired neurasthenia'."3 All the SOMA-6 items are key symptoms of chronic fatigue syndrome. With the overwhelming amount of biological data now available, purely psychological theories about chronic fatigue syndrome (as opposed to chronic fatigue) are totally untenable, as is the use of the term neurasthenia, introduced into medicine in 1869 and discarded by the American Psychiatric Association's Diagnostic and statistical manual of mental disorders4 as invalid.5 A recent study from the Fatigue Clinic, King's College Hospital, UK,6 found that an astonishing 68% of patients had been inappropriately misdiagnosed with a psychiatric illness. This is surely a warning for overzealous psychiatrists. Thirdly, treatment implications are a concern. The authors comment that "only 27% of patients with Level 1 disorders received pharmacological interventions" (Level 1 implying positivity for PSYCH and SOMA items). They say that general practitioners mostly used "relatively ineffective non-pharmacological strategies", and that they had responded to missing all this "unmet need" by "criticising the oversensitivity of the screening instrument and inappropriateness of diagnostic systems used", implying an underprescribing of antidepressants. The recent National Survey of Mental Health and Well-being7 showed that somewhere between two-thirds and a half of the 23% of the population diagnosed with psychiatric disorders did not visit their general practitioner. How does this fit in with the 49% found by Hickie et al? In summary, the authors' broad and idiosyncratic conceptualisation of "mental disorder" and their use of a screening tool which labels many physically ill people with or without concurrent distress as cases of "mental disorder" implies that general practitioners need to prescribe more antidepressants — at what cost and for whose benefit?

Nicole Phillips MB ChB, FRANZCP · Michael J Oldmeadow MB BS, FRACP · Natalie Krapivensky MB BS, FRANZCP

In reply: It is with great pleasure that we resume our ongoing correspondence with Phillips concerning the medical and psychological status of patients who present with non-specific somatic complaints such as chronic fatigue.1 As we have reported previously,2 we have been strong advocates of both the need to develop appropriate instruments for measuring neuropsychiatric states characterised by non-specific somatic symptoms and to promote effective medical and psychological management of patients with these disabling conditions.3 In their letter, Phillips and colleagues fail to grasp the essential issue. To describe a condition as a neuropsychiatric state (or mental disorder) does not necessarily lead to simplistic and entirely unhelpful assumptions about "medical" versus "psychological" causes or treatments. Phillips et al attempt to promote once again the notion of "biological" (ie, acceptable) versus "psychological" (ie, unacceptable) theories of the causation of chronic fatigue syndrome. Such an approach is not only intellectually sterile and inconsistent with the past decade of intensive research by a wide range of medical and psychological research teams,4 but also profoundly unhelpful to people affected by these disabling disorders.3 In recent years, the very significant health burden of common mental disorders such as depression, anxiety, alcohol or other substance misuse, and neurasthenia (prolonged fatigue states lasting longer than three months) has been well documented in the Australian community5 and in the primary care setting.6 Phillips and colleagues appear to have no knowledge of the basic epidemiological fact that mental disorders are two to three times more common in primary and other medical care settings than in community studies (hence the total rate of disorder in our study is about twice that detected in the Australian National Survey of Mental Health and Well-being). Contrary to their implications, the total rates reported in our general practice study are entirely consistent with the largest multinational study of primary care ever conducted.7 That study indicated that a third of all primary care patients have mental disorders and another third have mental health difficulties (with or without concurrent medical disorders) requiring specific psychological assessment. The significance of our study is that it has brought the extent of common mental health needs (including depression, anxiety, alcohol or other substance-misuse and somatoform disorders) to the attention of the Australian medical profession. What is now required is a concerted and integrated response — not a return to dualistic notions of illness that have for so long hampered the provision of effective pharmacological and non-pharmacological treatments to patients with mental disorders who present for medical care.

Ian B Hickie MD, FRANZCP · Tracey A Davenport BA(Hons) · Elizabeth M Scott FRANZCP · Sharon L Naismith BA(Hons)

To the Editor: The EBM in Action article on laser treatment by Del Mar et al1 raises my anxiety about the reliability of evidence-based medicine (EBM) in general and, at the very least, the authors' assessment of the question they set out to answer. One is seldom, if ever, in a position to understand the breadth and depth of an issue unless it is the subject of particular study. Most of us can not challenge statements made in such articles without an intimate knowledge of the literature. As laser therapy is the topic of my PhD thesis, I am in a unique position to have much of the literature on the subject at my fingertips. The authors state in their conclusions that "low power laser therapy appears to be no more efficacious than placebo in relieving musculoskeletal pain". Several aspects of the analysis on which they base this conclusion cause me great concern. Firstly, they state that "The search report highlighted the high quality of evidence supporting the refined question". Quite the contrary. One of the two systematic reviews they cite2 has been criticised in the literature for its many inadequacies, not the least being that laser acupuncture and laser therapy are included in that review as if they were the same, which they are certainly not.3 In addition, the review by Beckerman et al concludes, with regard to musculoskeletal pain, that "the efficacy of laser therapy for musculoskeletal disorders seems, on average, to be larger than the efficacy of placebo treatment. More specifically, for rheumatoid arthritis, post-traumatic joint disorders and myofascial pain, laser therapy seems to have a substantial specific therapeutic effect".4 How can this fit with the conclusion of Del Mar et al? Furthermore, Gross et al state in their review, which consisted of three trials of laser therapy, that "In general, all therapies have not been studied in enough detail to adequately assess either efficacy or effectiveness".5 The choice of other articles by Del Mar et al is also somewhat mystifying in that, out of the nine references cited, one is in Russian and two in Danish. There are many other relevant articles in English that they have not cited.6,7 There is no doubt, as I myself have found, that it is difficult to search for this topic in the literature, as there are many terms used for laser therapy and the information comes from a broad range of sources. However, this is no excuse for a group that holds itself out to be "expert" in a field. It is very disappointing to see such an incomplete review with such an inappropriate conclusion based on such a poor sample of the literature. If this is an example of EBM in action, then I think we should be very concerned.

Roberta Chow MB BS (Hons), FRACGP, FAMAC, MApplSci(MedAcu)

In reply: Chow criticises us for not identifying all relevant trials. But is she willing to help others in the process of reviewing? We could not identify a systematic review of the area with her involvement, nor does she appear to have registered an appropriate protocol with the Cochrane Collaboration (instructions for which are available at <http://www.cochrane.de>). Systematic reviews are important to help clinicians make sense of a diversity of trials. If experts such as she, devoting years to the area, do not help us, who should? We were not attempting such a systematic review (which would probably take several months of work). Rather, we were trying to provide clinicians with the best obtainable answer in a 24–48-hour turnaround time.2 Given that clinicians might have one question per patient,1 attempting a systematic review with each question would give us a lifetime of work after only a fortnight of clinical work! We needed to balance the timely requirements of clinicians with the quality of the evidence obtained. As Chow points out, tracking down every last trial is difficult. Therefore, we first aimed to identify systematic reviews rather than attempting to find all trials ourselves. These reviews missed some relevant material — as indeed did Chow, who did not cite several recent studies,3,4 which makes us wonder if she has a strong prior belief that may bias her views. Would these missed trials have made any difference to the conclusions we reached previously? A systematic review published since our original literature report (January 2000) suggests not, although there may be some specific subgroups of patients and conditions for which laser therapy is effective.5 All of this highlights the need for a collective effort to sort out the mess of medical information. In seven years the Cochrane Collaboration has systematically reviewed less than 5% of more than 300 000 trials on the clinical trials registry. They are difficult to perform and maintain. Millions of dollars continue to pour into primary research that still remains inaccessible to us at the clinical frontline, the "great criticism" with which Archie Cochrane pricked the profession into action.6 Please, Dr Chow, abandon throwing bricks from the sidelines, and join us in trying to help clinicians access research evidence in the timely fashion needed for day-to-day practice!

Chris B Del Mar MD, FRACGP · Paul P Glasziou MB BS, PhD, FAFPHM

To the Editor: With respect to the article by Ferson in the Christmas issue of the Journal, a personal experience of an unwanted side effect which occurred in 1927 may be of interest. I was a boarder at school, and four weeks before sitting for the Leaving Certificate examination I contracted a violent sore throat associated with a bodywide erythema similar to sunburn, but without any associated burning sensation. The doctor had no hesitation in diagnosing scarlet fever, and I was transferred to the Coast (now Prince Henry) Hospital, which was the infectious diseases hospital for leprosy, scarlet fever, diphtheria and the like. I had asked if I could take my textbooks to the hospital, but was told that if I did they would be destroyed when I was discharged. I left the books at school, spent four weeks in isolation and returned to school with one weekend to prepare for the examinations — the results were quite disappointing!

Sir Keith Jones

Chris Silagy was born on 14 September 1960 and educated in Melbourne. He graduated in medicine from the University of Melbourne in 1983 and completed a PhD in epidemiology at Monash University in 1992. After spending two years in Oxford as the Sir Robert Menzies Scholar in Medicine, Chris returned to Australia in 1993, at the age of only 33, to take up the foundation Chair of General Practice at Flinders University. He was actively involved in supporting the development of the Cochrane Collaboration, both in Australia (as Director of the Australasian Cochrane Centre from 1994 to 2001) and internationally (as Chair of the international Steering Group from 1996 to 1998). In February 1999, Chris moved to Melbourne to take up the position of Professor of Public Health and Foundation Director of the Monash Institute of Health Services Research. He had a passionate belief in the need for an evidence-based approach to healthcare and the important role that consumers have within that process. He was a strong public advocate for this approach, reinforced by his personal need for reliable information after he was diagnosed with non-Hodgkin's lymphoma in 1997. Chris spent the last few years of his all-too-short life cramming in as much as he had always done. He was fully involved with his national and international committee work, speaking engagements, and research activities. In 2000, he was appointed to chair the board of the newly established National Institute of Clinical Studies. He was also Deputy Chair of the National Health and Medical Research Council (Health Advisory Committee). Chris also found time to serve the community. For almost 20 years he was actively involved in scouting, holding the posts of Branch Commissioner for Scouts in Victoria and National Commissioner for Youth Program. He managed to combine all these activities with a strong and devoted commitment to his family. He was immensely proud of the achievements of his wife Jane and sons Andrew, Michael, Nicholas and Benjamin. In 2000, he was made an Officer of the Order of Australia for services to medicine, an award of which he was extremely proud. In the end, his battle with lymphoma was lost, but his vision and legacy will live on in many ways. Chris A Silagy* [Postscript: Chris Silagy died on 13 December 2001, at the age of 41. It was his wish that a fund be established in his memory to help continue the work of the Cochrane Collaboration. Donations to the "Monash University Medical Foundation — Chris Silagy Fund" can be forwarded to Monash Institute of Health Services Research, Locked Bag 29, Monash Medical Centre, Clayton, VIC, 3168.] *Self-written obituary.

Christopher A Silagy AO, MB BS, PhD, FRACGP, FAFPHM

Heart attack and the pill It remains unclear whether second-generation oral contraceptives, containing levonorgestrel, or third-generation formulations, containing desogestrel or gestodene, have a more favourable risk profile with regard to myocardial infarction. Third-generation preparations are associated with at least a doubling of the risk of venous thrombosis; however, it has been suggested that they may protect against myocardial infarction by having a more favourable effect on lipid profile. A recent Dutch nationwide, population-based, case–control study enrolled 248 women aged 18–49 years who had a first myocardial infarction (MI) between 1990 and 1995, and 925 matched controls. Use of the OCP was associated with a doubling in MI rates, but the results suggested that second-generation formulations produced a higher risk than the third-generation preparations (OR, 2.5 [95% CI, 1.5–4.1] v 1.3 [95% CI, 0.7– 2.0]). However, the authors note that a previous study suggested the reverse, and that neither study was conclusive due to wide confidence intervals. Among women who had used the OCP, the risk of MI was highest among those who smoked (OR, 13.6), had diabetes (OR, 17.4) or hypercholesterolaemia (OR, 24.7). N Engl J Med 2001; 345: 1787-1793 One lonely phone An analysis of the telephone book from the World Health Organization headquarters in Geneva, confirmed by specific enquiry, has revealed that only one of 2184 telephone numbers is dedicated to staff dealing with prevention of road injuries. The British researchers note that every day about 3000 people die and about 30000 people are seriously injured in road crashes worldwide. Most casualties occur in low- and middle-income countries, and most are vulnerable road users: pedestrians, cyclists and motorcyclists. BMJ 2001; 323: 1485 Prayer: results of RCTs Intercessory prayer (IP) is focused, committed and organised prayer on behalf of another person. A recent Cochrane Review1 concluded that data are too inconclusive to guide those wishing to uphold or refute the effect of IP on healthcare outcomes. Doctors from the Mayo Clinic2 have reported on a double-blind, randomised-controlled trial (RCT) of IP on 799 consenting patients, 18 years and older, discharged from a coronary care unit with a cardiovascular diagnosis. Intercessors were asked to pray for each person in the intervention group at least once a week for 26 weeks. They had no contact with subjects, just first names and minimal details. Primary endpoints in the study were significant cardiac events, such as rehospitalisation or death. As delivered in this study, IP had no significant effect on medical outcomes. In its Christmas 2001 edition, the BMJ published an RCT from Israel3 on “remote, retroactive” prayer involving 3393 patients with bloodstream infections, treated between 1990 and 1996. As the authors were not prepared to assume that time is linear, the intervention was carried out four to 10 years later. A list of the first names of the patients in the intervention group was given to a person who said a short prayer for the well being and full recovery of the group as a whole. There was no difference in mortality between the two groups. However, length of stay in hospital and duration of fever were significantly shorter in the intervention group than in the control group (P=0.01 and P=0.04, respectively). A few dozen BMJ readers lodged “rapid responses”. Treatment of the control group was recommended. 1. The Cochrane Library, Issue 4, 2001 2. Mayo Clin Proc 2001; 76: 1192-1198 3. BMJ 2001; 323: 1450-1451 MRI and the heart Invasive x-ray coronary artery angiography remains the gold standard diagnostic procedure for coronary artery disease. However, a substantial minority of patients referred electively for this test do not have clinically significant disease, so non-invasive alternatives are being investigated. A prospective study conducted at seven institutions in the United States and Europe concluded that three-dimensional coronary magnetic resonance angiography (MRA) reliably identifies (or rules out) left main coronary artery or three-vessel disease. A standard protocol was used to image 109 patients with suspected coronary artery disease, who were scheduled for their first elective x-ray coronary angiography. The results of the two procedures were then compared. The overall accuracy of coronary MRA in diagnosing coronary artery disease was 72% (95% CI, 63% – 81%). However, for patients with disease of the left main coronary artery or three-vessel disease, sensitivity was 100%, specificity 85%, and accuracy 87%. Surgical revascularisation in patients with such disease is associated with a more favourable long-term survival benefit. N Engl J Med 2001; 345: 1863-1869