Volume 186 Issue 7

A giant step forward, but more needs to be done To have lived through a revolution, to have seen a new birth of science, a new dispensation of health, reorganized medical schools, remodeled hospitals, a new outlook for humanity, is not given to every generation.1 An enduring feature of modern medicine is the constancy of challenges and change — and no more so than in medical education and training. In the 1980s and 90s, the Australian medical workforce was deemed to be adequate for the requirements of health services and the community,2 and for more than 20 years there was no political pressure to expand the capacity of our medical schools.3,4 More recently, Australia, along with the rest of the world, has found itself in the grip of a serious medical workforce shortage. This has moved the Australian Government to establish six new medical schools since 2004, in addition to the 11 existing schools. A further five are in the pipeline.5 With this unprecedented expansion, the number of medical graduates is set to rise from around 1600 in 2005 to about 3000 in 2012.5,6 In short, in less than a decade, the number of medical schools in Australia — and their graduate output — will have doubled. Despite the claim that with medical school plurality comes diversity,7 the purpose of our medical schools is decidedly uniform: to produce a graduate who has the attributes and commitment for lifelong learning and a solid foundation on which to build a clinical and professional career. The Australian Medical Council details this foundation in medical knowledge and understanding, skills, and professional behaviour, and notes: “The goal of medical education is to develop junior doctors who possess attributes that will ensure that they are initially competent to practise safely and effectively as interns in Australia or New Zealand, and that they have an appropriate foundation for lifelong learning and for further training in any branch of medicine.”8 Medical education is a continuum from medical school to independent practice, but the prevocational years (PGY1 and PGY2) interposed between undergraduate and vocational training are crucial in the quest for good medical practice and good doctors. And herein lies the rub — the prevocational years have been labelled as a lost opportunity for medical education.9 The factors responsible for this are many and include the apprenticeship nature of training;10-12 an ill-defined curriculum;10 training by time-poor and variably competent teachers;10 variable teacher training;13 the clash between the priorities of service delivery and education;10,12 and variable resourcing of teachers, program supervisors, and the state or territory postgraduate medical education councils.12,14 But at the core of the lost opportunity has been the lack of a relevant and rigorous national curriculum. The supplement “Australian Curriculum Framework for Junior Doctors” published with this issue of the Journal is a giant step forward in bringing much-needed national guidance for Australian prevocational medical training, and celebrates the launching of the Framework by the Confederation of Postgraduate Medical Education Councils in October 2006. The Framework is the outcome of wide consultation with relevant stakeholders and is built on initiatives pioneered by the Postgraduate Medical Education Councils of New South Wales (now part of the NSW Institute of Medical Education and Training), South Australia and Western Australia, and was funded by the Medical Training Review Panel of the Australian Government Department of Health and Ageing. It also draws from the experience of the recently introduced “Modernising Medical Careers” Foundation Programme in the United Kingdom15 and the Royal College of Physicians and Surgeons of Canada’s CanMEDS 2000 Project.16 The Framework, in essence, is a template for education and assessment of performance of junior doctors in the major areas of clinical management, communication, and professionalism (see Box). The Confederation of Postgraduate Medical Education Councils and other relevant players are to be congratulated for making this defining document a reality. It shows what can be achieved with purposeful leadership and effective communication between key stakeholders. But there is more to do! The Framework has to be implemented Australia-wide in hospitals and in general practice. This will require commitment and support from the federal, state and territory departments of health, public hospitals, and general practice. Without this, nothing will change. These agencies need to acknowledge that investment in prevocational medical training now will yield dividends in health care safety and quality in the future. Prevocational education must be a separate entity, not another health service add-on. The need to assess the utility and impact of the Framework is self-evident: will it make a difference? Answers to this vital question will require the elaboration of discerning and measurable outcomes and processes for assessment. The article by Grant in the supplement (→ Changing postgraduate medical education: a commentary from the United Kingdom) outlining initial experience in the UK with Foundation Years 1 and 2 of the Modernising Medical Careers Programme (the equivalent of our PGY1 and PGY2) provides a valuable insight into what not to do: introduce a detailed determination of clinical competence based on multiple observed activities, in the face of insufficient resources and poorly informed and prepared participants.18 Edmonds and Everett (→ Prevocational medical education at the coalface: report from the 2006 notional junior medical officer and director of clinical training/registrar forums) outline the views of junior medical officers, registrars, and directors of clinical training on the Framework.19 Junior doctors caution against failing to include affected stakeholders in its implementation, request that training positions be accredited, and believe that the Framework should be a promoter of teaching and not a barrier to vocational training or another checklist to complete.12 Registrars and directors of clinical training believe that the Framework will add value and resources to current training systems, and improve support for international medical graduates entering the workforce. We continually hear the descriptors “coordinated”, “integrated”, “assessment” and “accredited” applied to the medical training continuum, and to the casual observer it does appear to be a linked and orderly process. But with the expansion of our medical schools, current cracks in the continuum will become wide gaps. Questions now asked sotto voce will become fortissimo; questions such as: Will the medical education and training infrastructure be able to cope with increasing throughput? Despite teaching alternatives such as simulation, the experience garnered by extensive clinical exposure still remains crucial in medical training.9 What are the core competencies of the new medical graduate? How are these to be tested? Should undergraduate and prevocational medical education and training be outcome-focused? With differing medical school curricula and assessments, should there be a common yardstick? Is a national qualifying examination overdue? Are current postgraduate training programs too long and inflexible? Should there be early vocational streaming? Should there be common basic training modules that are transferable between colleges? Should there be part-time and flexible tracks to cater for the lifestyle expectations of modern doctors, especially younger doctors and women? Should there be different competence ceilings for differing levels of specialist training? And there are more. Several experts have poignantly drawn attention to how the Australian medical training sector is fragmented and plagued by limited collaboration and coordination between relevant groups.11,14 Underscoring this is the current situation: the medical schools have their representative body, Medical Deans Australia and New Zealand; the clinical colleges have an overarching body in the Committee of Presidents of Medical Colleges; and the postgraduate medical councils have the Confederation of Postgraduate Medical Education Councils. But despite their good intentions, all are virtual silos with limited interaction beyond their immediate spheres of interest. Is it not time that this insularity is broken down? If not, the drive for reform of Australian medical education and training may come from outside the profession in the form of an overarching government-regulated body.20 As a profession, do we really want this? The Australian Curriculum Framework for Junior Doctors12,17 The Framework is an educational template that identifies the core competencies and capabilities necessary to provide quality health care. It will enable individual doctors to assess their education and training needs. It outlines the general knowledge, skills and behaviour that prevocational doctors should acquire, regardless of their planned specialisation or training location. It bridges undergraduate curricula and college training requirements, and is intended to assist education providers, clinical teachers and employers to provide a structured and planned program of education for junior doctors. It is built around three learning areas — Clinical Management, Communication, and Professionalism — which are divided into varying numbers of categories and topics. Each category comprises a number of learning topics, each of which details the associated capabilities expected. It is envisaged that learning and assessment resources will be made available to support each learning topic.

Martin B Van Der Weyden MD, FRACP, FRCPA

Crystalline methamphetamine usage can wreak havoc in emergency departments “Ice”, or crystalline methamphetamine, is a relatively new drug in Australia. It may be injected intravenously or swallowed, but is increasingly consumed by smoking. With about 1.8 million Australians (9%) reporting ever using methamphetamine and about half a million Australians aged 14 years and older (3.2%) reporting current use of the drug,1 Australia is among the top dozen countries in the world in terms of prevalence of methamphetamine use.2 However, its use varies considerably across the country, being higher in some states — such as Queensland (especially the Gold Coast region), South Australia and Western Australia3 — than others. Reported methamphetamine use increased in surveys of the general population in Australia in the 1990s, but has since declined slightly.4 However, in recent years, indicators of harm (such as psychosis, emergency department presentations, and methamphetamine-related crime) have increased considerably. There was a 59% increase in amphetamine-related psychosis nationally between 1999–00 and 2003–04.5 In New South Wales, methamphetamine-related arrests rose from 18 per 100 000 population in 1995 to 46 per 100 000 population in 2005 (an increase of 253%).4 Why is the consumption of methamphetamine apparently relatively stable, while harms seem to be increasing markedly? Possible explanations for this anomaly include the problems of conducting and interpreting surveys of illicit drug consumption, the increasing purity of street methamphetamine, and the increasing availability and use of more readily absorbed forms of methamphetamine, including ice, which have a far greater psychoactive effect on the brain. Methamphetamine has diverse health and social impacts. These include effects on hospitals, crime, personal relationships, employment and private debt. The nature and extent of these adverse effects have not yet been fully determined. The report by Gray et al6 in this issue (→ Amphetamine-related presentations to an inner-city tertiary emergency department: a prospective evaluation) represents one of the first attempts in Australia to estimate the impact of amphetamine use on a hospital. The authors found that amphetamine-related presentations account for over 1% of all admissions. They involve high-acuity patients who often present with aggressive behaviour, require prolonged emergency department admission and consume considerable resources. They concluded that increasing amphetamine use has had a substantial impact on the hospital emergency department studied. Amphetamine-related presentations are a great burden on the health care system. It can take days before amphetamine-related psychosis can be distinguished from other serious mental health conditions, such as schizophrenia. Knowledge of the full nature and extent of medium- to long-term physical and mental health impairment from street amphetamine use is still evolving. Although we should be wary of predictions that illicit drug problems are destined to deteriorate inexorably and indefinitely, it is likely that amphetamine-related problems will continue to worsen in Australia for some time. In part, the increase in amphetamine production and use may reflect a shift from plant-based drugs (such as heroin or cocaine) to chemical-based drugs, which allow producers to evade law enforcement detection using aerial and satellite surveillance and to avoid the vagaries of the weather. The value of the global market in all illicit drugs for the year 2003 was estimated at US$322 billion at the retail level,7 with the lucrative profits of drug trafficking estimated to account for 26%–58% of turnover.8 Existing alcohol and drug treatment services attract and retain few methamphetamine users, but services that specialise in patients with stimulant problems seem more successful in attracting a higher proportion. The processes of amphetamine withdrawal and detoxification are still poorly understood. Psychosocial interventions (such as cognitive behavioural therapy, contingency management and motivational interviewing) may be sufficient for the many patients with milder problems. But these interventions are unlikely to be sufficient for those who consume substantial quantities of methamphetamine and have severe problems. While many pharmacotherapeutic agents have been tried without success, amphetamine substitution treatment9 appears to be an effective and safe treatment for carefully selected, treatment-refractory patients with severe problems. Drug law enforcement is often touted as a panacea for the problem of illicit drug use, but, as a recent review noted, There is strikingly little evidence that tougher law enforcement can materially reduce drug use. By contrast, drug treatment services remain in short supply, even though research indicates that treatment expenditures easily pay for themselves in terms of reduced crime and improved productivity.10 Accordingly, authorities would be wise to invest more in health and social interventions. New drugs appear frequently in the constantly changing illicit drug industry and are often hailed as “the most dangerous drug yet”. In the politicised and highly charged environment surrounding illicit drugs, it is difficult, but all the more important, to maintain a balanced and evidence-based approach to policy and practice. For many decades, tackling the illicit drug problem around the world has been considered primarily a matter for the criminal justice system. Funding has flowed accordingly, with health and social interventions usually treated as the poor cousins of law enforcement. Yet, in most countries, illicit drug use and consequent problems have continued to increase. The evidence for effectiveness and cost-effectiveness of health interventions for illicit drug use is far more impressive than the evidence for drug law enforcement. It is time that Australia regarded illicit drugs in general, and methamphetamine in particular, as primarily a matter for health and social interventions, although drug law enforcement should continue to play an important role.

Gordian W O Fulde FRACS, FRCS, FACEM · Alex Wodak FRACP, FAChAM, FAFPHM

Objective: To describe the prevalence, characteristics and outcomes of amphetamine-related presentations to a tertiary hospital emergency department (ED).Design, setting and participants: Prospective observational study of amphetamine-related presentations to the ED of the Royal Perth Hospital (RPH), an adult, inner-city, tertiary referral hospital, between 3 August and 2 November 2005. For all patients presenting to the ED, the treating doctors were automatically prompted by the computerised data entry system to consider amphetamine use.Main outcome measures: Proportion of ED presentations related to amphetamine use; demographic features and usage practices of amphetamine users; characteristics of presentations and admissions; associated psychiatric illnesses and use of other drugs.Results: Over the study period, there were 13 125 presentations, of which 156 (1.2%) were judged to be causally related to amphetamine use. Of those 156 patients, over half were habitual drug users (89 [57.1%] used amphetamines at least weekly), and the majority were men (111 [71.2%]). The mean age was 28 years (range, 16–55 years). Presentations were of high acuity: 104 patients [66.7%] were rated 1, 2 or 3 on the Australasian Triage Scale; 50 (32.1%) arrived by ambulance; and 25 (16.0%) arrived with police. The mean time spent in the ED was 6 h (range, 0.5–24 h). Fifty patients (32.1%) required sedation, and the likelihood of requiring sedation increased almost threefold if the heart rate was over 100 beats/min on presentation. Sixty-two patients (39.7%) were admitted and 58 (37.2%) required psychiatric evaluation. Repeat attendance was common, with 71 patients (45.5%) having previous amphetamine-related presentations to the RPH ED.Conclusions: Amphetamine-related presentations comprise 1.2% of all ED attendances and have a major impact on hospital EDs. Patients are often agitated and aggressive, require extensive resources, and frequently re-attend. The burden of amphetamine-related illnesses on EDs is likely to increase in the future.

Suzanne D Gray MB BS · Daniel M Fatovich MB BS, FACEM · David L McCoubrie MB BS, FACEM · Frank F Daly MB BS, FACEM

Objective: To examine trends in hospital separations related to “drug-induced” psychosis for cannabis and methamphetamine, in the context of patterns of cannabis and methamphetamine use in the Australian population.Design and setting: Analysis of prospectively collected data from the National Hospital Morbidity Database on hospital separations primarily attributed to drug-induced psychosis (July 1993 – June 2004), and specifically for cannabis and amphetamines (1999–2004). Calculation of Australian population-adjusted rates of drug-induced psychosis hospital separations using estimated resident population data from the Australian Bureau of Statistics (at 30 June each year) and data on cannabis and methamphetamine use from the 2004 National Drug Strategy Household Survey.Main outcome measures: Number of hospital separations due to drug-induced psychosis, and standardised (age-specific) rates per million population and per million users.Results: There have been notable increases in hospital separations due to drug-induced psychosis, which appear to have been driven by amphetamine-related rather than cannabis-related episodes. The rate of hospital separations was higher for amphetamine users than for cannabis users in all age groups, and the rate increased among older amphetamine users.Conclusions: The risk of hospitalisation for a drug-induced psychotic episode associated with amphetamine use appears to be greater than that for cannabis use in all age groups.

Louisa Degenhardt PhD, MPsych(Clinical) · Amanda Roxburgh BA(Hons)Psych, MCrim · Rebecca McKetin PhD

Objective: To examine pre-registration junior doctors’ perceptions of the value of a general practice term in their training program.Design, setting and participants: Semi-structured interviews, in five teaching hospitals in South Australia in 2005, with 20 pre-registration junior doctors (interns) who had completed a general practice term and at least one core term of intern training.Main outcome measure: Comparisons between general practice and teaching hospital core training terms with respect to the domains of junior doctor education.Results: Interns perceived general practice and teaching hospital terms to be complementary in their overall training program. The general practice term provided them with knowledge and skills they would not have acquired in the teaching hospital terms alone. One-on-one consulting, initiating patient management, and the opportunity to practise a range of practical and procedural skills were seen to be of particular value.Conclusions: The general practice and teaching hospital terms both contribute to the training of interns, offering contrasting environments and experiences which enhance interns’ professional and personal growth. General practice terms should be considered for inclusion in intern training programs across Australia.

Anne A Martin BSc(Hons), PhD · Caroline O Laurence BA(Hons), MHlthServMt · Linda E Black BA(Psych), DipApplPsych, MAPS · Bruce V Mugford BM BS, FRACGP, FACRRM

Objective: To assess the prevalence of obesity in patients undergoing coronary artery bypass grafting, heart valve surgery, or both procedures, and its association with postoperative outcomes.Design and setting: Retrospective analysis of data, collected by the Australasian Society of Cardiac and Thoracic Surgeons Victorian Cardiac Surgery Database Project, on patients undergoing coronary artery bypass grafting, heart valve surgery, or both procedures, between 1 June 2001 and 31 January 2006.Participants: 11 736 patients divided into four groups: underweight (body mass index [BMI], < 20), normal weight (BMI, 20–30), obese (BMI, > 30 to < 40), and morbidly obese (BMI, ≥ 40).Main outcome measures: Prevalence of obesity (compared with the age- and sex-matched adult Australian population); associations between obesity and morbid obesity in cardiac patients and adverse postoperative outcomes.Results: 30.4% of patients had a BMI > 30 (28.6% obese, 1.8% morbidly obese) compared with an expected prevalence of 21.2%. Morbid obesity was associated with prolonged ventilation (adjusted odds ratio [OR], 2.4; 95% CI, 1.6–3.7), readmission to intensive care (adjusted OR, 2.2; 95% CI, 1.2–4.1), and length of stay > 14 days (adjusted OR, 2.1; 95% CI, 1.4–3.3). Both obesity and morbid obesity were associated with renal failure (adjusted ORs, 1.4 [95% CI, 1.1–1.7] and 2.9 [95% CI, 1.7–4.9], respectively) and deep sternal wound infection (adjusted ORs, 2.4 [95% CI, 1.5–3.8] and 7.2 [95% CI, 2.8–18.7], respectively).Conclusions: Obesity is 1.4 times more prevalent in patients having coronary artery bypass grafting or heart valve surgery in Victoria compared with the general adult Australian population. Both obesity and morbid obesity are associated with early morbidity, but not mortality, after operation.

Cheng-Hon Yap MB BS, MS · Morteza Mohajeri FRACS · Michael Yii FRACS, MS

Alexander (“Alec”) Gonski, a pioneer of neurosurgery in Australia, died on 25 September 2006 after developing progressive multi-organ failure. When the news of Alec’s death reached the executives of the Coast Golf Club in Little Bay, Sydney, small black flags were attached to the poles of all 18 holes as a sign of respect for its first president. His effort in establishing the golf course exemplified the pioneering spirit that was a feature of his life. Born in Łódź, Poland, on 7 July 1919, Alec later migrated to South Africa, where he completed his medical degree in 1944, briefly interrupted by serving in the Allied Army in Egypt. From 1947 to 1951, he trained in neurosurgery in Edinburgh, then returned to Capetown to resume his career. Christiaan Barnard was one of his registrars. In 1961, Alec was recruited to establish a neurosurgical unit at Prince Henry Hospital at Little Bay as part of the new teaching hospital of a very young University of New South Wales. Together with James Lance, the newly appointed Head of the Department of Neurology, Alec established a world-class unit of combined neurology and neurosurgery at Prince Henry Hospital. By the time of his retirement in 1985, the unit was the largest in the state, with six neurosurgeons — all but one trained by him personally. Alec was a very skilful surgeon. He began his career at the very infancy of neurosurgery. Despite the rudimentary diagnostic and operating equipment (computed tomography and magnetic resonance imaging were not available until the 1970s and 1980s, respectively), his patients’ outcomes were excellent. He was also a great teacher. His quiet, gentle manner and humour, interspersed with interesting vignettes, made ward rounds and operating sessions enjoyable as well as educational. Alec was closely involved with the University of NSW, where he taught anatomy for 16 years. Many of the specimens he dissected are still kept in the University’s Anatomy Museum and are tagged with his name. Alec remained active as a clinician for many years after retiring from Prince Henry Hospital. He continued to publish articles on the investigation and management of spinal and cerebral conditions. His monograph, A beginner’s guide to neuroanatomy, published only a month before his death, is freely available on the Internet at http://www.amsa.org.au/docs/GonskiNeuroanatomypdf.pdf. In his leisure time, Alec thoroughly enjoyed the outdoor life. Besides being a keen golfer, he enjoyed watching cricket and was passionate about sailing. With the help of his neurosurgical and carpentry skills, he built his first boat in the backyard. He also loved spending time with his children and grandchildren. Alec’s remarkable contribution to his adopted country was recognised by the award of Member of the Order of Australia in 2003. He will be remembered for his clinical skill, humility and commitment to medical education. He is survived by his wife of 54 years, Hélène, and children David, Peter, Stephen and Lisa.

Bernard C T Kwok · David Gonski · Peter N Gonski

To minimise the health impact of pandemic influenza, general practice will need to provide influenza-related and non-influenza primary health care, as well as contribute to the public health goal of disease control. Through interviews and workshops with general practitioners, nurses and policy leaders between March and July 2006, and literature analysis, we identified potential models of general practice in an established pandemic, and assessed their strengths and weaknesses. Three possible clinical models were identified: a default model of no change to service delivery; a streamed services model, where general practices reorganise themselves to take on either influenza-specific care or other clinical services; and a staff-determined mixed model, where staff move between different types of services. No single model or set of strategies meets the needs of all general practices to deliver and sustain the essential functions of primary health care during an established pandemic. Governments, general practice and the relevant peak professional bodies should decide before a pandemic on the suite of measures needed to support the models most suitable in their regions. Effective participation by general practice in a pandemic requires supplementary infrastructure support, changes to financial and staffing patterns, a review of legislation on medicolegal implications during an emergency, and intensive collaboration between general practices.

Christine B Phillips MPH, MA, FRACGP · Mahomed S Patel MB BCh, FRACP, FAFPHM · Nicholas Glasgow FRNZGP, FRACGP, FAChPM · Christopher Pearce MFM, FRACGP, FACRRM · Paul Dugdale MPH, PhD, FAFPHM · Alison Davies MPubPol, BPhty · Sally Hall RN, GradCertClinMan · Marjan Kljakovic FRNZCGP, FRACGP, PhD

In 2001, the Medical Practitioners Board of Victoria received a complaint from an Australian Government Senator regarding a late-term abortion carried out in February 2000 at the Royal Women’s Hospital, Melbourne. Five years later, the complaint of professional misconduct was finally dismissed by the Board as being frivolous and vexatious. The action highlights a number of deficiencies in the way medical practitioner boards deal with complaints against medical practitioners; in particular, the Board’s lack of discretion to deal with complaints lacking substance. Early mediation of the dispute between the Royal Women’s Hospital and the Medical Practitioners Board could have avoided a great deal of suffering and expense. As a result of this case, it is likely that the Victorian Medical Practitioners Board will be given additional powers in the future to deal with complaints without merit.

Paul Gerber LLB, DJur

Maternal mortality associated with psychiatric illness in the perinatal period (pregnancy to the end of the first year postpartum) has until recently been under-reported in Australia due to limitations in the scope of the data collection and methods of detection. The recent United Kingdom report Why mothers die 2000–2002 identified psychiatric illness as the leading cause of maternal death in the UK. Findings from the last three reports on maternal deaths in Australia (covering the period 1994–2002) suggest that maternal psychiatric illness is one of the leading causes of maternal death, with the majority of suicides occurring by violent means. Such findings strengthen the case for routine perinatal psychosocial screening programs, with clear referral guidelines and assertive perinatal treatment of significant maternal psychiatric morbidity. Data linkage studies are needed to measure the full extent of maternal mortality associated with psychiatric illness in Australia.

Marie-Paule Austin MB BS, MD, FRANZCP · Susan Kildea RM, BHSc(Hons), PhD · Elizabeth Sullivan MB BS, MPH, MMed(Sexual Health)

A 50-year-old woman presented to her dermatologist in 1999 with a 6-month history of recurrent pruritic scaly plaques on the abdomen, arms and hairline. The rash, which was presumed to be seborrhoeic dermatitis, improved after treatment with systemic prednisolone. No skin biopsies were taken at the time. In 2004, she developed a leonine facies (Box, A), widespread erythroderma, alopecia, generalised peripheral lymphadenopathy, hyperkeratosis of the palms, and bilateral swollen pinnae with otorrhoea (Box, B). Punch biopsies revealed Pautrier microabscesses containing atypical CD4+ lymphocytes. A peripheral blood film showed Sézary cells, confirming Sézary syndrome. The patient’s condition deteriorated despite treatment with methotrexate, prednisone, bexarotene, interferon, psoralen and ultraviolet A, as well as extracorporeal photopheresis. Radical palliative radiotherapy to the head and neck improved her leonine facies and otitis externa (Box, C). The patient died in 2006, 8 years after initial presentation. Sézary syndrome is a rare, aggressive, cutaneous T-cell lymphoma characterised by widespread erythroderma, atypical peripheral lymphocytes (Sézary cells) and lymphadenopathy. Cutaneous T-cell lymphomas typically present as indolent cutaneous eruptions and are often misdiagnosed at initial presentation, as the skin lesions mimic common dermatological disorders such as eczema or psoriasis. A: Leonine facies. B: Oedematous right pinna. C: Left pinna after radiotherapy.

David R Waterhouse MB ChB · Subhaschandra Shetty MB BS, MS(ENT) · Jeremy S Gathercole MRCS, LRCP, FRACS · Christopher J Seeley MB ChB, FRACS

Authors of articles reporting clinical trials should discuss the results of their trial in the context of existing evidence. This approach is encouraged by the CONSORT statement (Box 1).1 A trial’s contribution to the evidence can be pinpointed by seeking answers to questions such as: How do the results apply in a broader clinical context and patient population? Do they confirm or contradict the existing evidence? Do they confirm current clinical practice or suggest that a change may be needed? Do they point to the next question that should be studied? A complete picture of the trial results includes how the findings apply to other patients, how they guide or change practice, how they relate to prior knowledge (possibly by a systematic review of the evidence), and any new questions raised. What do the results mean in real-world clinical practice?Are the trial participants representative of the patients being considered for treatment?Trials usually focus on single interventions, but clinical practice is complex, and the features of the clinical practice environment — intercurrent illnesses, use of other drugs, mood, compliance, and access to services — need to be taken into account. This can limit our understanding of how widely the results can be safely applied. For example, trials aiming to prevent stroke using antithrombotic therapies among patients with atrial fibrillation have recruited as few as 20% of eligible patients — often excluding older patients, women and people with previous cerebrovascular disease,2 leading to uncertainty about the net benefit of such treatment in these groups. Does the study question relate to the patients being considered for treatment?It is worth reflecting on the question addressed by the study, as results may be misconstrued. One of the Women’s Health Initiative (WHI) group’s large studies of hormone replacement therapy (HRT) for postmenopausal women serves as an example.3 The study was undertaken to determine whether, compared with placebo, long-term combined oestrogen and progestin would reduce cardiovascular events. It was already known that short-term HRT relieves symptoms of menopause, such as hot flushes. It was also known that long-term HRT increases the risk of breast cancer, but it was hoped that this risk might be offset by better cardiovascular outcomes. However, the trial of combined HRT, over an average of 5.2 years (the trial was stopped early), showed an increase in breast cancer and cardiovascular events with HRT use.3 When the WHI reported the results,3 widespread confusion followed, because many people interpreted these findings as relating to short-term use of HRT to relieve menopausal symptoms. Many women stopped using short-term and long-term HRT. The WHI trial was well designed and might, of itself, be regarded as sufficient evidence for clinicians to no longer consider HRT to prevent cardiovascular disease. The research question was not “What are the effects of short-term use of HRT in newly menopausal women with significant symptoms?”; the safety of short-term HRT for control of menopausal symptoms is still unresolved.4 Randomised trial or systematic review?Individual randomised trials and systematic reviews (including meta-analyses) are similar but not identical means of arriving at health care evidence, and each has its place. They have different strengths within the broad common purpose of establishing the efficacy (or otherwise) of interventions. Thus, a highly specific clinical question (Is X mg of a therapy better than Y mg after a heart attack?) would probably best be answered by a single appropriately powered study. But even where relatively large trials have been done, treatment effects can be modest, and a meta-analysis of several trial results may be a useful way of showing that there is statistically robust evidence to support a change in clinical practice. For example, before a large-scale review of early breast cancer trials,5 it was known that postoperative tamoxifen is effective in preventing recurrence of cancer in postmenopausal women, but it was unclear whether this applied to premenopausal women. The review, which included an updated meta-analysis of all available trials, was able to show a clear benefit (2P < 0.00001) in the premenopausal group. The same dataset definitively answered a subsidiary question: survival was longer after 5 years of treatment than 2 years of treatment. These two observations changed clinical practice, and thousands of lives were potentially saved. Meta-analyses may further refine conclusions by also considering variation in the treatment dosages.6,7 Randomised trial with a meta-analysisPresenting a meta-analysis as part of the study report helps to show the consistency of the new results with other existing evidence. A forest plot of the results with the published trial evidence will help readers judge the consistency of the results of individual trials and the reliability of the accumulated evidence (Box 2).8 Do the results confirm current clinical practice or suggest a change?Trial results that confirm results of previous studies (particularly in a different patient population) might justify a change in clinical practice or even discontinuing further trials of the same clinical question. For example, lipid-lowering statins given to patients after myocardial infarction are known (from trial evidence) to reduce subsequent cardiovascular events in a general, predominantly male population. A trial substudy testing statins in women also shows possible efficacy.9 Given what was known previously, the burden of proof may be lower, such that this trial may be sufficient to affect clinical practice. On the other hand, if the findings of the current study contradict those of previous studies, possible explanations for the discrepancy should be acknowledged and discussed. A change in clinical practice would only be advocated if the results of the new trial significantly outweighed previous evidence in terms of design, adequacy of follow-up, and statistical strength (Box 3). There will always be some legitimate disagreement about the overall significance of individual trial results; one person’s “definitive” results will be another’s “interesting”, “thought-provoking” or “hypothesis-generating” results. Extensive extrapolation may lead to erroneous conclusions; too little or slow extrapolation may retard improvements in clinical practice. However, there are some helpful guidelines, illustrated by the following examples. Look for biological plausibility: A randomised placebo-controlled trial of folate supplementation during pregnancy confirmed benefits in neonatal outcomes. After decades of follow-up, an unexpected increase in mortality from breast cancer was found. This could be related to the folate therapy, but the result may be a chance finding, and would not be considered biologically plausible at our current level of understanding. In this scenario, women should probably be advised to maintain adequate folate intake around the time of conception, unless further evidence about breast cancer risk emerges.10 Interpret the statistical findings for clinical relevance: If multiple outcomes in a single trial are similarly affected by the treatment, some effects may be significant and some non-significant simply because of the differing numbers of events and by the play of chance. For example, a trial in early breast cancer reported that treatment with an aromatase inhibitor resulted in fewer recurrences of the cancer (measured as the disease-free survival period) than treatment with tamoxifen (P = 0.003).11 There was no statistically significant treatment effect for overall survival (P = 0.16). At first glance, this might be interpreted as statistical inconsistency across the two outcomes (Box 4). However, the confidence interval for the effect of treatment on mortality extends to plausible worthwhile clinical benefits, so it would be incorrect to rule out a useful survival benefit. Given that that there were relatively few cancer recurrences, a significant survival advantage might still emerge with longer follow-up. A reasonable conclusion would be that “there were fewer deaths in the aromatase inhibitor arm of the trial, but this difference was not beyond the play of chance”. Efficacy is not the only issue: Adverse effects are always important, but take on added significance when efficacy is modest or when we are treating essentially well patients to modify the risk of some future adverse event. Lipid-lowering drugs to prevent heart attacks, blood pressure drugs to prevent strokes, adjuvant chemotherapy to reduce the risk of cancer recurrence, and tamoxifen to prevent a first breast cancer are all examples where large trials have shown modest efficacy. Drug efficacy is usually more carefully measured and reported than toxicity or quality of life and, perhaps understandably, is more readily trumpeted. Nevertheless, once we have established the biological effect of a drug and how confident we are about this, we should then consider at what cost this was achieved. This might involve formal and complex analyses, such as health economics studies and synthesis of quality-of-life data, but in the shorter term we should also be prepared to make a rough and ready judgement. Financial cost, extra time spent in hospital or doctors’ rooms, extra blood tests and x-rays, as well as adverse effects, all count as costs against which to judge any improvements in clinical outcomes. The patient may also have strong views that need to be taken into account. Cancer patients, when asked, will often accept significant inconvenience and drug toxicity for surprisingly small benefits.12 Do the results point to the future or new questions that should be studied?Randomised trials are the critical units of evidence when the average benefits and harms of interventions are considered. In addition to a statement of the generalisability of the findings,13 the overall context of the trial results must be incorporated into the discussion. The authors’ pragmatic conclusions on the immediate implications for everyday clinical practice (or regulatory decisions), as well as what might constitute the next scientific or clinical question to arise from the current findings, are integral to a report of new evidence. 1 CONSORT checklist of items to include when reporting a randomised trial1 Section and topic Item no. Descriptor Discussion Overall evidence 22 General interpretation of the results in the context of current evidence 2 Forest plot of a meta-analysis of a new study (LIPID) with previous studies (4S, CARE) of statin therapy for preventing further cardiovascular events in people with diabetes and existing coronary heart disease8 Combining results from these trials leads to a statistically significant finding of a beneficial treatment effect for statins. For stroke, statin therapy has no significant treatment effect in the individual trials; when data for all patients are combined, a reduction in risk with statin therapy is seen. The black squares are proportional to the number of events (here, CHD events or strokes) in the analysis. CHD event = death from coronary heart disease or non-fatal myocardial infarction. 4S = Scandinavian Simvastatin Survival Study (Arch Intern Med 1999; 159: 2661-2667). CARE = Cholesterol and Recurrent Events (Circulation 1998; 98: 2513-2519). LIPID = Long-Term Intervention with Pravastatin in Ischemic Disease (N Engl J Med 1998; 339: 1349-1357). 3 Various trial result scenarios and possible implications for clinical practice Trial outcome Population studied Implications of the results in clinical practice Benefit First studied Is there sufficient evidence to change practice or are confirmatory trials needed? The trial report should propose and discuss these questions. Confirms previous results Same as previous population Change practice (if therapy is cost-effective) Confirms previous results New population Is there enough evidence or are more data needed to extend the treatment indication to the new population? Apparently contradictory results, compared with previous studies Same as previous population Is there an explanation for the result? Is there evidence of significant heterogeneity between the trials? Does not confirm previous results New population Is the difference in effect of treatment between populations biologically plausible? How strong is the evidence from the trials? Are more trials needed before the evidence is enough to support different guidelines in different populations? 4 Forest plot showing hazard ratios for disease-free survival (time to recurrence of breast cancer) and overall survival for an aromatase inhibitor, letrozole (4003 patients), compared with tamoxifen treatment (4007 patients)11 The median follow-up was about 2 years. The graph shows that disease-free survival was better in the letrozole group. Fewer women died in the letrozole group, but overall survival appears not to differ between the treatment groups. The black squares are proportional to the number of events (here, recurrences and deaths) in the trial.

Nicholas R Wilcken MB BS, PhD, FRACP · Val J Gebski BA, MStat · Rhana Pike MA, ELS · Anthony C Keech MB BS, FRACP, MSc(Epi)

Clinical record A 45-year-old woman was referred to the Victorian Liver Transplant Unit with acute liver failure following the use of paracetamol at a therapeutic dose during prolonged fasting. Eight weeks previously, the patient had undergone total abdominal hysterectomy for symptomatic uterine fibroids. Seven weeks after surgery, she was readmitted to hospital with subacute bowel obstruction secondary to adhesions. She had lost 10 kg in weight since the surgery, which was attributed to poor food intake as a result of recurrent abdominal pain and intermittent vomiting. Conservative treatment failed, and the patient subsequently underwent laparoscopic division of adhesions on the fifth day after admission. She had remained nil-by-mouth throughout this period. From the time of admission, and for the following 8 days, the patient was prescribed paracetamol 1 g “QID strict” for her abdominal pain (total cumulative dose, 32 g). Four days after surgery (ninth day after admission), the patient developed haematuria and was noted to be displaying odd behaviour. The following morning, she became increasingly confused and drowsy. She was admitted to the intensive care unit, where her conscious state deteriorated rapidly and she required intubation. She was found to have acute hepatic failure, renal failure, and profound metabolic acidosis (Table). Paracetamol levels were in the toxic range (238 μmol/L; therapeutic range, 66–132 μmol/L). The patient was commenced on an N-acetylcysteine intravenous infusion and transferred to the Victorian Liver Transplant Unit for consideration for urgent liver transplantation. The patient was subsequently listed for liver transplantation, but died before a suitable donor became available. Postmortem examination confirmed that the cause of death was multisystem organ failure secondary to acute liver failure associated with paracetamol toxicity. The liver weighed 0.786 kg (normal weight in women, 1.2–1.4 kg), and the capsule appeared wrinkled. Histological assessment of the liver revealed a pattern of massive panlobular necrosis, with some mild fatty changes associated with preserved hepatocytes adjacent to portal tracts. The sinusoids contained increased numbers of inflammatory cells (Box 1). Blood test results for the patient Test Result Reference range Sodium 148 mmol/L 135–145 mmol/L Potassium 3.3 mmol/L 3.5–5.0 mmol/L Urea 4.3 mmol/L 2.5–7.7 mmol/L Creatinine 271 μmol/L 30–110 μmol/L Albumin 28 g/L 36–48 g/L Bilirubin 57 μmol/L < 18 μmol/L ALP 247 U/L 35–104 U/L ALT 5859 U/L < 55 U/L GGT 141 U/L < 45 U/L Lactate 14.6 mmol/L 0.5–2.2 mmol/L pH(arterial) 7.01 7.35–7.45 INR 8.4 0.9–1.2 Paracetamol 238 μmol/L 66–132 μmol/L Parameters in italic are of prognostic use in paracetamol overdose.1,2 ALP = alkaline phosphatase. ALT = alanine aminotransferase. GGT = γ-glutamyl transferase. INR = international normalised ratio. Paracetamol toxicity is the most common cause of acute liver failure in Australia.3 A recent study of 662 patients from 22 tertiary care centres in the United States found that 48% of patients presenting with severe paracetamol hepatotoxicity had not intended to poison themselves, and took the drug for therapeutic purposes only. These patients tended to be older than patients who intentionally poison themselves.4 Paracetamol hepatotoxicity in those older than 40 years is associated with an increased risk of fulminant hepatic failure, death or liver transplantation.4,5 An analysis of 67 cases of “therapeutic misadventure” with paracetamol found that 60% of patients with accidental paracetamol poisoning had taken no more than 6 g paracetamol per day, and 40% had not exceeded the recommended maximum dose of 4 g per day.6 Risk factors for developing hepatic toxicity under these circumstances include prolonged fasting,7 regular excessive alcohol intake,6 or concurrent use of drugs that induce cytochrome P450 (CYP450), especially CYP450 2E1. Elderly patients with renal and cardiopulmonary insufficiency may also be at increased risk.8 Interestingly, there is little evidence that pre-existing liver disease increases the risk.1 Lessons from practice Paracetamol poisoning at recommended therapeutic doses can occur. Accidental paracetamol poisoning should be suspected in any patient with acute liver failure. Prolonged starvation can increase susceptibility to paracetamol poisoning by depleting hepatic glutathione stores. Reduce the daily dose of paracetamol in people who are fasting, in heavy users of alcohol, or in those taking medications that induce cytochrome P450. Paracetamol poisoning is typically associated with large rises in serum transaminase levels. Patients with hepatic failure due to paracetamol poisoning should be referred early to a liver transplant unit for further management. The link between fasting or CYP450 induction and increased susceptibility to paracetamol toxicity can be readily explained by reviewing the metabolism of this drug. When paracetamol is taken in standard doses in healthy individuals, more than 90% is conjugated to form inactive metabolites, which are then excreted in the urine. A small proportion of the paracetamol is metabolised by the CYP450 system to N-acetyl-p-benzoquinone imine (NAPQI), which, if allowed to accumulate, is toxic to the liver. Normally, NAPQI is conjugated with glutathione and the harmless products excreted in the urine (Box 2). Prolonged starvation can severely deplete the cosubstrates required for paracetamol conjugation and reduce glutathione stores, so that even therapeutic doses of the drug can result in the accumulation of toxic amounts of NAPQI (Box 2). Regular and prolonged treatment with paracetamol may be particularly dangerous in fasting patients, as ongoing metabolism of the drug leads to further consumption of already depleted glutathione stores. Alcohol and other drugs capable of inducing CYP450 predispose patients to paracetamol toxicity by increasing the production of NAPQI. In addition, chronic alcohol misuse leads to depletion of glutathione. Between 1989 and 2004, 42 patients were referred to the Victorian Liver Transplant Unit with paracetamol-induced acute liver failure.9 In 11 of these (26%), the poisoning was clearly accidental. Eight patients recovered spontaneously, one survived after undergoing liver transplantation, and two died — including the patient described in this report. Thus, in Australia, severe life-threatening liver injury from accidental paracetamol poisoning appears to be quite uncommon. Nevertheless, this is a readily preventable syndrome of which both patients and the medical profession should be made more aware. In particular, clinicians should be cautious about prescribing regular doses of paracetamol for pain control in malnourished or fasting patients, and need to appropriately counsel patients who are regular users of the drug. Although many cases of accidental paracetamol poisoning at therapeutic dosage have been described, controversy surrounds the actual incidence and mechanism. Unfortunately, as with our patient, it is impossible to determine whether larger quantities of paracetamol had been ingested either accidentally or intentionally.2,10 1 Photomicrograph of the liver at autopsy Massive panlobular necrosis with relative preservation of portal tracts (4 × objective). Inset: Hepatic necrosis with mild fatty changes (20 × objective). 2 Metabolism of paracetamol A: In a healthy individual, about 95% of paracetamol is conjugated with glucuronide and excreted in the urine. Most of the remainder is conjugated with glutathione. B: In starvation, impaired conjugation and depletion of glutathione result in accumulation of hepatotoxic N-acetyl-p-benzoquinone imine (NAPQI).

John S Lubel MRCP, FRACP · Peter W Angus MD, FRACP · Paul J Gow MD, FRACP

A woman presenting with recurrent purpura fulminans was eventually found to have inflammatory bowel disease. We suggest the inflammatory state resulted in a deficiency of functional protein C. Clinical recordFirst admissionA 28-year-old woman presented to hospital with a 1-week history of diarrhoea (three soft, non-bloody stools daily), 2 days of vomiting, and a 12-hour history of a purpuric truncal rash. Five years previously, she had experienced a 1-month diarrhoeal illness, managed as an outpatient. At that time, the full blood count and erythrocyte sedimentation rate were within the normal range. Faecal microscopy had shown scanty leukocytes. Colonoscopy was scheduled; however, the symptoms disappeared and investigation did not proceed. The patient subsequently suffered from mild, intermittent diarrhoea. Her uncle had a history of inflammatory bowel disease, although the patient was not aware of this when she first presented to us. On presentation, her vital signs were normal. There was mild right upper quadrant abdominal tenderness, and multiple large, purpuric lesions over the trunk. Blood tests suggested a systemic inflammatory response and mild disseminated intravascular coagulation (Box 1). Faecal microscopy was positive for leukocytes and erythrocytes. The differential diagnosis was broad, and included systemic infection (such as meningococcaemia), Henoch Schönlein purpura, the antiphospholipid syndrome, thrombotic thrombocytopenic purpura, and purpura fulminans associated with protein C deficiency. Ceftriaxone and enoxaparin were commenced as empirical treatment for infection and/or purpura fulminans. Over the next day, the skin lesions became larger and confluent, with new lesions on the legs and perineum. A morphine infusion was required for analgesia. Four units of fresh frozen plasma were infused for suspected protein C deficiency, while awaiting laboratory test results. These confirmed a slightly reduced functional protein C level (63%). This was considered most likely an acquired deficiency, as seen in inflammatory states. Further fresh frozen plasma or protein C replacement was regarded as unnecessary. Additional tests for prothrombotic (Box 1) and autoimmune diseases (antinuclear, extractable nuclear antigen, and double-stranded DNA antibodies) revealed no abnormality. Thrombocytopenic purpura was excluded by the finding of a normal haptoglobin level. There was no significant bacterial growth from blood, urine or faeces. Ceftriaxone was ceased on Day 3. Purpura fulminans was confirmed on skin biopsy by the finding of dermal venous and capillary thrombosis, without evidence of vasculitis (Box 2). There was no further progression in the number or size of the skin lesions. However, on Day 5, the lesions formed bullae and ulcerated (Box 3). Metronidazole and dicloxacillin were added to treat secondary infection of the ulcers. The morphine infusion was ceased on Day 14, and oral oxycodone was substituted. The results of blood tests taken on Day 22 (Box 1) reflected an ongoing intense systemic inflammatory response. At the time of discharge on Day 23, the patient continued to pass three soft stools daily and had multiple ulcers over the trunk and perineum, which required daily nursing care for wound management. The discharge diagnosis was purpura fulminans, possibly precipitated by an enteric infection. After dischargeBy Day 36 of the illness, the diarrhoea had resolved. However, the patient remained fatigued, and the blood tests (Box 1) indicated persistent systemic inflammation and rising serum liver enzyme concentrations. Abdominal ultrasound was normal. The liver abnormalities were considered secondary to the oxycodone. Over the ensuing weeks, the analgesia was reduced and stopped, the blood parameters normalised, and the patient returned to her normal level of function. The skin lesions had healed by Week 15, but left significant scarring. Twenty-five weeks following the onset of the illness, the patient re-presented as an outpatient with a 1-week history of diarrhoea (six watery stools daily). There was one mouth ulcer, but no new skin lesions. A faecal specimen showed only erythrocytes. The erythrocyte sedimentation rate, C-reactive protein, and platelets were slightly elevated (Box 1). The symptoms and abnormal blood parameters resolved completely over the following week. Referral was made for colonoscopy to investigate for inflammatory bowel disease. Second admissionThe patient presented again, 46 weeks after her original hospitalisation, with a 1-week history of bloody diarrhoea and colicky abdominal pain. The colonoscopy was due the following week. Her vital signs were normal. She had left lower quadrant tenderness. Laboratory tests indicated inflammation and mild coagulation abnormalities (Box 1). She was admitted to hospital. Over the next 24 hours, a purpuric rash consistent with purpura fulminans developed on her abdomen, sacrum and vulva (Box 4). Colonoscopy revealed widespread inflammation involving the entire colon, with multiple deep ulcers, but relative rectal sparing. The histology showed active chronic pancolitis, most suggestive of ulcerative colitis (Box 5). The consensus diagnosis was inflammatory bowel disease (colitis, unspecified). Methylprednisolone 60 mg intravenously was administered daily for 1 week. The skin lesions regressed, without ulceration, and the diarrhoea ceased. She was discharged on a reducing dose of prednisolone. Five months after ceasing prednisolone, she has remained asymptomatic. DiscussionPurpura fulminans is an uncommon condition characterised by rapidly progressive dermal vascular thrombosis leading to haemorrhagic necrosis of the skin, which may extend to the muscle and bone, resulting in severe scarring.1,2 It has been described in three settings: (1) hereditary or acquired abnormalities in the protein C anticoagulant pathway; (2) infections, especially meningococcaemia; and (3) idiopathic.3 Purpura fulminans is associated with high mortality and morbidity rates, reflecting the seriousness of the underlying disease, such as bacterial sepsis, and the complications of tissue necrosis, such as secondary infection and limb loss.4,5 Therapy should be primarily aimed at treating the underlying cause and providing supportive care. Surgical intervention such as fasciotomy, skin grafting and amputation may be required.2,4,6 However, because of its rarity, there are few data to support specific treatments for purpura fulminans. Fresh frozen plasma is recommended for idiopathic purpura fulminans or protein C or S deficiencies.1,2,7 Idiopathic purpura fulminans has also been reported to respond to heparin.2 Protein C replacement has been most widely used for purpura fulminans as a result of severe sepsis or congenital protein C deficiency.2,5,7,8 The use of corticosteroids in treating purpura fulminans remains controversial.1,5 There has been one other report of purpura fulminans associated with ulcerative colitis, involving a 60-year-old man who was deficient in protein S, protein C and antithrombin III.9 There was no improvement with heparin or methylprednisolone. Fresh frozen plasma was administered and he underwent total colectomy. No further skin lesions developed, but he died as a consequence of nosocomial infections. In retrospect, our patient had symptoms of inflammatory bowel disease for several years. Purpura fulminans, a rare manifestation of inflammatory bowel disease, had dominated the initial clinical presentation, distracting clinicians from the underlying condition. We believe that a possible pathophysiological explanation for this case is that the inflammation associated with the colitis led to a deficiency in protein C, thus precipitating purpura fulminans. Methylprednisolone appeared most effective in halting the progression of purpura fulminans, although this may have been secondary to treatment of the colitis, rather than of the purpura fulminans per se. What remains to be seen is whether future exacerbations of her colitis will be associated with recurrent purpura fulminans. 1 Results of laboratory tests Test, unit (reference range) First admission Recovery period Recurrent symptoms Second admission Day 1 Day 2 Day 22 Day 36 Week 15 Week 25 Week 46 Haemoglobin, g/L (115–160) 129 123 84 93 126 122 126 White cell count, 109/L (4–11) 5.4 4.8 7.9 8.5 8.0 9.1 11.6 Platelet count, 109/L (150–400) 150 56 888 948 395 510 414 ESR, mm/h (1–20) — 16 106 112 14 44 36 Total bilirubin, μmol/L (2–20) 15 10 4 7 2 6 12 ALT, U/L (< 55) 52 29 7 67 16 31 51 ALP, U/L (20–110) 204 209 157 1039 99 108 129 GGT, U/L (12–43) 34 48 48 293 56 33 50 Albumin, g/L (33–50) 34 31 24 30 42 39 42 C-reactive protein, mg/L (0–10) — 197 97 31 <5 25 239 Haptoglobin, g/L (0.6–2.7) — 2.1 — — — — 2.9 Prothrombin time, s (9–15) 17 18 15 — — — 17 APTT, s (23–34) 31 33 40 — — — 32 Fibrinogen, g/L (1.5–4.0) 4.6 2.9 4.4 — — — 5.9 XDP, mg/L (0–0.19) 3.24 4.30 0.22 — — — 0.75 Functional protein C (70%–130%) — 63% — — — — 65% Free protein S Ag (50%–130%) — 106% — — — — 116% Antithrombin III (70%–145%) — 95% — — — — 63% Lupus anticoagulant, factor V Leiden, and prothrombin mutations — Not detected — — — — — ACA IgG (< 8) — 2 — — — — — Bold indicates abnormal results. — = not measured. ACA = anti-cardiolipin antibody. ALP = serum alkaline phosphatase level. ALT = serum alanine transaminase level. APTT = activated partial thromboplastin time. ESR = erythrocyte sedimentation rate. GGT = serum γ-glutamyl transferase level. XDP = cross-linked fibrin degradation products. 2 Skin lesions: histopathology A: Thrombosis of venules and capillaries is visible in both superficial and deep dermis (arrows) with intact overlying epidermis (haematoxylin and eosin [H&E]; ×50). B: Higher power view of thrombosed venule showing some apoptotic debris (arrows) but no inflammation (H&E; ×200). 3 Skin lesions: first hospital admission Three bullous lesions (arrows) involving the abdomen, with mild surrounding erythema and diffuse purpura. The largest lesion involves the umbilicus. 4 Skin lesions: second hospital admission Within 24 hours of presentation, multiple purpuric lesions developed over the patient’s abdomen and perineum. Two of these early lesions (black arrows) can be seen adjacent to the large scar involving the umbilicus and three smaller scars (white arrows) from the previous episode. 5 Colonic mucosa: histopathology A: There was some crypt shortening and architectural distortion, and the lamina propria contained a brisk mixed inflammatory infiltrate, which extended into the submucosa (haematoxylin and eosin [H&E]; ×100). B: Eosinophils and neutrophils were prominent in the lamina propria, and there was patchy cryptitis (arrow) (H&E; ×400).

Karina J Kennedy MB BS · Sarah Walker MB BS, BSc(Hons) · Paul Pavli MB BS(Hons), PhD, FRACP · Lavinia Hallam BSc(Hons), FRCPath, FRCPA · Chris Hemmings BHB, MB ChB, FRCPA

To the Editor: Cryopreservation has been an integral tool in the development of modern assisted reproductive technologies, beginning with sperm cryopreservation in 1953 and extending to embryo cryopreservation in 1983, with the evolution of in-vitro fertilisation (IVF) and embryo transfer as a major tool in the treatment of infertility.1 Until recent times, however, there has been a lack of reliable cryopreservation methods for human oocytes. The world’s first recorded pregnancy arising from frozen oocytes occurred in Australia in 1984,2 and although occasional live births following oocyte cryopreservation were subsequently announced,3 it was another 11 years before more reliable protocols were developed4 — hundreds of live births have since been reported.5 The most common protocol follows that of embryo cryopreservation, using slow freezing with propanediol as the cryoprotectant, although rapid vitrification methods are also being developed. Reliable oocyte cryopreservation protocols are important for patients for whom embryo cryopreservation is unacceptable under some national laws or religions, and in whom there may be sperm collection problems or unexplained azoospermia during IVF procedures. We report four live births, one ongoing pregnancy, and an ectopic pregnancy following oocyte cryopreservation. Three of these cases involved religious opposition to embryo freezing. In each case, only two oocytes were fertilised fresh and the remainder frozen. No pregnancies resulted from the fresh embryo transfers, and the frozen oocytes were subsequently thawed, fertilised, and transferred, to produce the pregnancies. Two cases involved idiopathic azoospermia on the day of IVF, while in another, no sperm could be obtained from testicular aspiration on the day. Oocytes from these men’s partners were frozen until the sperm supply problems were resolved. As these cases demonstrate, oocyte cryopreservation can serve as a valuable adjunct to assisted reproduction programs, by providing a solution to the occasional logistical problems caused by unavailable spermatozoa. It also provides another option for patients with ethical or religious objections to the cryopreservation of embryos, and for fertility preservation in women with cancer facing chemotherapy or for women who may wish to insure against age-related fertility decline. The six pregnancies described here arose from embryo transfers in 13 women who had oocytes cryopreserved. The results, combined with others achieved worldwide, suggest that oocyte cryopreservation may at last be coming of age.

Keith L Harrison · Michelle T Lane · Jeremy C Osborn · Christine A Kirby · Regan Jeffrey · John H Esler · David Molloy

To the Editor: We write in response to recently published consensus recommendations for the off-label use of pharmaceuticals, which provide a common-sense, evidence-based approach to a commonly encountered clinical problem.1 The recommendations indicate that, other than for exceptional or research indications, off-label use of a medicine is generally not recommended unless there is high-quality evidence supporting such use. However, for some older pharmaceuticals, there is little incentive to perform additional trials to generate good evidence to support off-label use. An example is rifampicin, which is commonly used in combination with fusidic acid to treat methicillin-resistant Staphylococcus aureus (MRSA) infection, but is not licensed or subsidised by the Pharmaceutical Benefits Scheme (PBS) for this indication. Rifampicin has a well defined toxicity profile, with a long history of use in treating tuberculosis and preventing meningococcal disease. Rifampicin-based combinations for staphylococcal infection are recommended by Australian and international guidelines,2,3 and supported by small clinical trials.4 For rifampicin, a generic drug, there is no financial incentive for the manufacturers to apply for an additional indication for treating MRSA infection. Since 1998, an orphan drugs policy has encouraged sponsors of patented pharmaceuticals to apply for indications that may only involve small numbers of patients and has waived Therapeutic Goods Administration (TGA) fees for such marketing applications. A “rule of rescue” has also operated, lowering the regulatory bar for serious diseases that are otherwise untreatable. Despite these initiatives, no application to add the treatment of MRSA infection as an indication for rifampicin (in combination with another active agent) has been received by the TGA.5 A solution would be for the National Health and Medical Research Council (NHMRC) to commission clinical trials where further evidence is required. This proposal could see an expanded role for the National Institute of Clinical Studies (NICS), which will soon be incorporated into the NHMRC. The NICS/NHMRC could also make applications to the TGA for the approval of pharmaceuticals for particular indications, particularly for orphan diseases and generic drugs. Reviews of evidence could be generated from within the NHMRC or from external bodies such as professional Colleges and societies, or groups of experts such as those appointed by the Board of Therapeutic Guidelines Limited. Clinical trials could be performed in conjunction with overseas research agencies and draw from within the existing budget of the NHMRC. This initiative would improve prescribing through the generation of appropriate evidence and may also redefine the utility of some established off-label indications. It could reduce out-of-pocket expenses for patients by facilitating PBS listing. As this initiative would focus on relatively low-cost generic drugs and/or uncommon orphan indications, it would be unlikely to have a significant impact on the cost of the PBS. It would also help focus the clinical research agenda on clinical practice and encourage the use of appropriate generic pharmaceuticals.

Allen C Cheng · Priscilla M Robinson · Ken Harvey

To the Editor: The human costs of the war in Iraq are mounting. The war has already claimed the lives of about 3000 Coalition service men and women1 and well over half a million Iraqi men, women and children.2 Reports by the United Nations Assistance Mission for Iraq indicate that hundreds of thousands of civilians have been displaced, and that military operations in the country are limiting civilian access to health and education services, food, electricity and water supplies.3 Furthermore, the reports describe a generalised breakdown of law and order in the country, continued growth of militias and organised gangs, and abhorrent human rights violations such as torture in the form of electrical and chemical burns, injury inflicted to eyes and genitals, and wounds from power drills and nails.3 Currently, the Iraqi health system is unable to cope with the health care needs of its population. Iraqi health infrastructure has not escaped the damage or destruction of war. Hospitals lack basic medical supplies such as intravenous fluids, antibiotics, oxygen, disinfectants and bed sheets.4 The precarious security situation in the country has also contributed to a severe shortage of medical personnel. About 25% of Iraq’s physicians have left since the beginning of the war, while those remaining are the targets of violence, intimidation and kidnappings.4 Such an exodus of health personnel has required many of the remaining medical staff to undertake procedures for which they are not qualified.4 Recognising the need for action in Iraq, a workshop was arranged by the International Committee of the Faculty of Public Health, Royal Colleges of Physicians of the United Kingdom, in 2003. The workshop, which included representation from the World Health Organization and the Iraqi Ministry of Health, called for health organisations to be active advocates for improving the health of Iraqis and to provide technical support and assistance to their Iraqi health colleagues.5 Training and professional development opportunities for health staff and the provision of up-to-date health information were identified as specific areas of need in the Iraqi health sector to which health organisations could make a meaningful contribution. In Australia, there has been a small move in this direction, with the federal government providing in-principle support for an initiative to train three Iraqi physicians in emergency surgery. Australian health associations, agencies and professionals need to do more to respond to the humanitarian crisis in Iraq. Carefully coordinated training programs, particularly in the areas of medicine and public health, and the provision of medical aid, resources and information by Australian health organisations, would enhance the capacity of the Iraqi health system to alleviate the effects of war on its citizens. Furthermore, health organisations and professionals need to advocate on behalf of Iraqis, raise awareness of the inadequacies of Coalition government aid, and demand a more effective humanitarian relief effort for victims of the 2003 invasion.

Luke Wolfenden · John Wiggers

To the Editor: I was surprised by Wong’s letter on the role of history-taking and examination in the diagnostic process.1 I would suggest that Wong, as a surgical registrar, receives the majority of his abdominal pain referrals from the medical staff of the emergency department. Although he advocates the liberal use of abdominal computed tomography (CT) scanning, I believe he ignores the fact that another medical practitioner has already taken a history and performed an examination that has suggested a surgical cause of pain for which a surgical opinion is then requested. Wong would thus remain unaware of other cases in which patients present with abdominal pain but the case is ruled non-surgical on the basis of history, examination and limited investigation not involving abdominal CT scanning. History, examination and even appropriately targeted investigations remain imperfect diagnostic tools, but I agree with Schattner2 that history-taking and examination are very important adjuncts in the diagnostic process.

Andrew P Wright

To the Editor: Like Schattner, I am appalled by the attitude to diagnosis displayed by Wong regarding the use of computed tomography (CT) scanning in preference to initial history-taking and physical examination in abdominal pain.1 Unfortunately, this approach is becoming increasingly more prevalent among junior staff (and even among some senior staff). Wong poses the question, “[W]hy do some clinicians continue to routinely promulgate the sacred and arcane ritual of taking a history and doing an examination, which, as diagnostic tools, are clearly second-rate?” There are several reasons why I continue to promulgate the classical paradigm. Firstly, I would remind him of Bayes’ theorem: post-test probability equals pre-test probability multiplied by the likelihood ratio of the test. Put simply, this means that, for a test that is not 100% accurate (ie, effectively, all imaging tests), you cannot interpret the meaning of the result without having some idea of the pre-test probability of a diagnosis. And how can you satisfactorily arrive at a pre-test probability without having clinically assessed the patient? In addition, the radiologist is able to interpret the images more accurately when there are clinical details provided.2 Secondly, is Wong seriously suggesting that all patients with abdominal pain, including young adults and children, undergo CT scanning without any kind of clinical filtering or assessment? This is wrong and potentially negligent. The radiation dose received by the patient from an abdominal CT scan is a serious consideration. Assuming a total effective body dose of 10 mSv, there is an excess risk of a radiation-induced fatal cancer of about 1 in 2000.3 Apart from the risk to the individual, the number of iatrogenic cancers potentially induced in the community by indiscriminate use of CT would be a major concern.4 Thirdly, the implication of Wong’s letter is that clinical assessment and imaging are somehow in competition with each other, whereas nothing could be further from the truth. Of course, modern imaging has contributed to making diagnosis far more accurate than in the time of Hippocrates, but a complementary approach is far more rewarding for patients and doctors. Lastly, in patients with abdominal pain, there are many occasions when no imaging is required and others when ultrasonography is more appropriate than CT, because it avoids ionising radiation in young patients and is more accurate for diagnosing gynaecological causes of pain.5

Richard M Mendelson

To the Editor: It is clear Dr Wong1 has a practice rather different from mine. He is not used to the truly undifferentiated patients that present in their thousands to emergency departments and general practices every day. There, the art of history and examination is truly alive. No one questions the value of complex imaging. It has its place after a detailed history has been taken and focused examination and relevant investigations have been carried out, leading to a risk assessment and management plan. One does not order computed tomography (CT) scans willy-nilly. For example, the Canadian CT Head Rule2 for patients with minor head injury sets out which patients should have a head CT scan, based on a simple set of historical and examination findings. Moreover, CT scans are wasted on conditions for which CT imaging is inappropriate — it is rare that I order a CT scan for a child with abdominal pain. When I ask surgical registrars for their opinion, I am actually asking for their consultant’s opinion. Nothing guides like an experienced hand, whether it be feeling a belly or writing a CT request form. On many occasions, I have concluded that all the imaging performed on a patient with abdominal pain did not contribute to the diagnosis and the patient simply needed a laparotomy. At my insistence, the consultant is called, appropriate treatment commences, and the patient boards the experience express on the track to recovery. As Shem quips, in his satirical book on medical training and hospital life — nothing heals like cold steel.3 CT is not the be-all and end-all of medicine. Hopefully, by the end of his training, Wong will have developed the hand of experience and be able to continue the art of medicine through the ages. In the words of William Osler: The practice of medicine is an art, not a trade; a calling, not a business; a calling in which your heart will be exercised equally with your head. Often the best part of your work will have nothing to do with potions and powders, but with the exercise of an influence of the strong upon the weak, of the righteous upon the wicked, of the wise upon the foolish.4

James L Mallows

To the Editor: Apropos the letter by Wong entitled “Clinical paradigms revisited” in the Christmas issue,1 declaring fossilisation of the very pillars on which medicine stands, we would like to express a contrary opinion. To be adept physicians, clinicians must hone their skills at taking a lucid and informative history and conducting a thorough physical examination. It would be a crying shame if young doctors, having slaved for 5 or more years to obtain a medical degree, had to rely solely on expensive investigations when they have the God-given tools of the five senses. To confirm a clinical diagnosis and assess the extent of disease, doctors should order specific and appropriate investigations, rather than ordering tests that may be irrelevant and financially bleeding the patient. The issues of cost, radiation hazard, availability of trained personnel, and need for expensive equipment have been trivialised. In a country like India, where the majority of the population cannot afford even minimal hospital fees, to even contemplate using a computed tomography scan as a first-line diagnostic tool for something as basic as abdominal pain is absurd. Moreover, the use of advanced technology does not guarantee a correct diagnosis. A recent case of aortic dissection was misdiagnosed as acute coronary syndrome on the basis of electrocardiography.2 If due emphasis had been given to pulse and blood pressures in both limbs, this mistake could have been avoided. In another case, involving recurrent loss of consciousness, investigations were non-contributory, but a history of substance misuse at home pointed to the correct diagnosis.3 In another study, clinical judgement regarding the severity of pneumonia was found to be a more reliable predictor than a standardised scoring system based on clinical signs and laboratory findings.4 Doctors ought to be able to make a clinical judgement in the first instance, rather than resorting blindly to expensive investigatory tools. We do not deny the usefulness of modern technological devices for confirming or ruling out clinical possibilities, but they must be used judiciously. Such investigations cannot take precedence over physicians’ reliance on their clinical skills, lest we become helpless without technology.

Sandeep Chauhan · Ruth D’Cruz · Sanjay D’Cruz · Ram Singh · Atul Sachdev

To the Editor: Schattner1,2 and Wong3 raise issues that examine what has been the core of medical practice since antiquity. Grasping antiquity for its own sake is problematic, at best, and possibly heralds the extinction of long held practices, at worst. As technology improves, we are witnesses to improved imaging modalities that provide higher diagnostic yields, with improved sensitivity and specificity, at increasingly reduced costs. Refusal to even acknowledge the possibility that the history and examination may be terminal is not prudent. Instead, we need to examine carefully our mantra(s) with respect for the temporal nature of medicine. History and examination evolved in their current form because previous generations could not see inside the body, or examine physiological and pathological processes in real time. Our predecessors amassed a series of verbal cues and physical rules that generally conformed to the presentation of a particular disease. The future of medicine heralds dramatic departure from the world view that preceded computed tomography and magnetic resonance imaging. Wong raises an important issue with regard to diagnosing emergency abdominal conditions in busy hospital practice. He does not discount a role for the history or physical examination. He does, however, challenge their pre-eminence in “conditions that require emergency surgical treatment”. Is it really in the best interests of patients and the health care system for the emergency department intern/resident, then the registrar/consultant, then the surgical fellow, to all take the history and perform a physical examination? In essence, doesn’t Wong’s “scan first approach” reflect a prudent reliance on, and respect for, the information already gathered? Schattner4 states that “all imaging studies combined (computed tomography, magnetic resonance imaging, ultrasound, and echocardiography) were decisive in only 10.5% of cases” whereas “the patient’s history and the evolution of the condition proved to be the decisive diagnostic method in 23% of cases”. Doesn’t this show that Wong’s approach provides a heuristic that increases the diagnostic yield, reduces delays and guesswork, and streamlines the processing of patients presenting with acute abdominal pain — or is it acceptable to miss the significant percentage of diagnoses that are decided by imaging alone?!

Stuart Kostalas

To the Editor: In his message From the Editor’s Desk,1 Van Der Weyden laments what he perceives to be “the absence of many voices in protest” against the current Council of Australian Governments’ (COAG) proposals2 for national systems of registration and accreditation of the Australian health workforce. The absence of an “overwhelming public response” to the proposals can surely be attributed to the general public’s lack of awareness of the proposals. It cannot be said, however, that the medical profession has been idle. By the time this letter is published, the situation in regard to the proposals is likely to be much clearer. To date, all elements of the medical profession have been very active in seeking to achieve the best possible outcomes from the COAG proposals for our patients and for the profession. These efforts were impeded initially by the lack of specificity available from the COAG Health Working Group. Clear evidence of the effectiveness of the efforts of the Australian Medical Council, the Australian Medical Association, and the Committee of Presidents of Medical Colleges (CPMC) and its individual member Colleges was the abandonment of the second consultation paper after the profession’s analysis and evaluation of the proposals presented. As I write, government officials are meeting to develop a new model which recognises the profession’s criticisms and views. The profession’s message clearly has reached the federal Minister for Health, who asserted recently that it appeared that “the best way forward is to have separate national registration boards for medicine and for each of the other health professions”.3 This is a significant departure from the original COAG proposal. The CPMC and its member Colleges are well aware of the undesirable developments in other countries where governments are attempting to take control of regulation of the medical profession, as mentioned by Van Der Weyden.1 At their meeting on 15 February, the College presidents endorsed a two-page statement of key issues in regard to the COAG proposals. This statement has been sent to the premiers, chief ministers and health ministers in each state and territory, as well as to the relevant federal government agencies. At the same time, it is appropriate for the Colleges to cooperate responsibly with government initiatives, provided those initiatives do not diminish in any way the safety and quality of health services provided in Australia or threaten the sovereignty of the Colleges in the determination and maintenance of standards for their respective disciplines.

Michael J Cousins

To the Editor: Your statement that the present “grab for control [of Australian medicine] by governments” is unprecedented is not correct.1 Between 1946 and 1949, the federal government came close to nationalising the medical profession.2 The lines were drawn earlier. In 1941, the Federal Council of the British Medical Association (BMA) in Australia (now the Australian Medical Association) made recommendations about the provision of medical services. Two years later, in response to a report by the National Health and Medical Research Council, Outline of a possible scheme for a salaried medical service, the BMA laid down a more detailed policy, with retention of the existing (largely private) general practitioner and specialist services. The government responded by proposing a scheme under which patients would pay nothing directly for medical care, with costs to be met from general revenue.3 Asking the doctors to cooperate, the government indicated that it would if necessary seek other means to achieve its object.4 The referendum of 1946, one of the few to be passed, gave the federal government power to provide a range of social services, including pharmaceutical and hospital benefits and medical and dental services. There were, however, a few words of critical importance in the question put to the people — “but not so as to authorise any form of civil conscription”. It was the Leader of the Opposition, Mr (later Sir) Robert Menzies (acting on a request from Sir Henry Newland, President of the BMA Federal Council and a surgeon of great distinction), who moved the amendment, which the government accepted. The referendum enabled the government in 1948 to pass the National Health Service Act 1948–49 (Cwlth). Resistance by the BMA to what it regarded as objectionable features led to an attempt to coerce the profession by enforcing the Pharmaceutical Benefits Act 1947 (Cwlth), which required compulsory use of a Formulary issued to all doctors. (In the event, only 2% of doctors ever used it.) The BMA took the issue to the High Court of Australia, which decided in August 1949 that a section of the Act amounted to civil conscription and was invalid. Later in the year, the heavy defeat of the government, the result of its attempt to nationalise the banks, sealed the doctors’ victory.5 Over the next few years, the coalition led by Menzies introduced a health service based on the principle of voluntary insurance for hospital and medical benefits, which is still in force. There are clear lessons to be learned from this history.

Derek H Meyers

Verbal medicine. Twenty-one contemporary clinician–poets of Australia and New Zealand Tim Metcalf, editor. Canberra: Ginninderra Press, 2006 (148 pp). ISBN 1 74027 369 9 When I sit on medical curriculum advisory committees, I hear that the subjects studied and examined to gain entry to medical courses, and the courses themselves, have become too focused, too narrow, too mechanistic, too concentrated on sciences and biology. I hear that our students lack sufficient exposure to literature and philosophy to cope with the intense emotional impact of the blessing and the curse that is the life of a doctor. I worry that so many colleagues are at risk of emotional burnout. It has been said that there is no greater tragedy than an unexamined life. This book of poems by 21 contemporary Australasian clinician–poets is a delight, but it is no light read. I could not read it all in one sitting as each poem is strong and powerful. Verbal medicine goes a long way towards examining what it means to be a doctor, and how it feels to deal with the joys and sorrows, frustrations and successes of practice. It does not stop there; painfully, ruthlessly, thoroughly, it examines the role of doctor as patient and mortal human being. I believe that more doctors should be encouraged to write poems as a way of examining their own lives, and this book is a great example. The MJA editor took a chance on asking me, as a poet, to review a book on poetry. So I cannot let the opportunity pass without a poem of my own. Why? Why do we write, why do we dare? Do we think that there’s someone there? Have we a message, have we a thought? On a piece of our lives that fortune brought? Why do we write? Do we want to be heard? Or just carve order from the great absurd? To tear a pain from our inside? Or see a terror that no more can hide? To release our anger and give it vent? Until our passion and frustration’s spent? Or play with words and toy with sound? And admire the pretty game we’ve found.

Christopher D Hogan

Watercress best? Daily consumption of watercress, a cruciferous vegetable, may have significant antioxidant effects and reduce damage to lymphocyte DNA, according to a study from Northern Ireland. In the single-blind, randomised study, subjects consumed 85 g of raw watercress daily in addition to their normal diet during the intervention phase. The control group maintained their normal diet. Blood was taken from each group before and after the intervention period. Researchers performed screening of peripheral blood lymphocytes and measured levels of antioxidants for each specimen, and found a significant increase in the plasma concentration of the anti-oxidant β-carotene. They also demonstrated a reduction in basal DNA damage in lymphocytes after challenge with hydrogen peroxide. The effects of watercress consumption appeared to be greater in smokers than in non-smokers. Am J Clin Nutr 2007; 85: 504-510 Stages of Sadness The five stages of grief after bereavement — disbelief, yearning, anger, depression, and acceptance — are well described and accepted in medical teaching on death and grief. The Yale Bereavement Study set out to test the five-stage theory empirically, and to determine if the stages were relevant and useful in a clinical sense. Researchers interviewed over 200 recently bereaved people, using scales to assess the frequency and timing of each of the grief indicators. In the circumstances of a natural (non-traumatic) death, the authors found that the normal grief response initially involves acceptance and yearning for the deceased. The stages indicated by the theory then peak in order as previously described. It appears that all the negative grief indicators are declining by 6 months after the loss. The authors comment that the persistence of such negative emotions after 6 months may suggest the need for further assessment and possible intervention for the bereaved survivor. JAMA 2007; 297: 716-723 Faecal occult blood tests Detecting occult blood in faeces is a widely used method of screening for colorectal cancer. Commonly used guaiac-based faecal occult blood tests (FOBTs) are not specific for human haemoglobin and have low sensitivity, despite their use being shown to reduce mortality from colorectal neoplasia. An alternative quantitative immunochemical FOBT has been put to the test by Israeli researchers in a prospective study of 1000 colonoscopy patients.1 The haemoglobin content of faecal samples from each patient was measured and correlated with findings at colonoscopy. Patients who had neoplasia (advanced adenoma or carcinoma) showed significantly higher levels of faecal haemoglobin than those who were free of disease or had only small polyps. Thus, the authors were able to determine a threshold for the detection of clinically significant amounts of faecal haemoglobin. Despite some limitations of the study, including the use of patients selected for colonoscopy, and an effect of variable faecal consistency on sampling, an accompanying editorial comments on the clinical usefulness of a quantitative immunochemical FOBT in allowing the clinician to choose the positivity threshold for the test.2 1. Ann Intern Med 2007; 146: 244-255 2. Ann Intern Med 2007; 146: 309-311 Babycino Reducing caffeine intake in the second half of pregnancy does not have an effect on birthweight or length of gestation, according to Danish researchers. In a randomised, double-blind controlled trial involving more than 1100 pregnant women, one group was supplied with decaffeinated coffee from 20 weeks’ gestation, and a second group with caffeinated coffee. All the participants were coffee drinkers in the first 20 weeks of pregnancy. After adjusting for other factors, including smoking status and alcohol consumption, a difference in caffeine intake of three cups of instant coffee a day during the second half of pregnancy did not have an effect on birthweight or the length of gestation. Women who smoked more than 10 cigarettes a day and were in the caffeinated coffee group had babies with a lower mean birthweight than smokers in the decaffeinated coffee group. The authors comment that the results seem to contradict some earlier studies, which indicated a relationship between higher caffeine intake in pregnancy and preterm birth. BMJ 2007; 334: 409 Circumcision short circuits AIDS in Africa Male circumcision can significantly reduce the risk of HIV acquisition in young African men, according to the results of two randomised controlled trials.1,2 HIV-negative men in the Ugandan and Kenyan studies were randomised to an intervention group (circumcision) or a control group (delayed circumcision after 2 years). Both trials showed a positive effect of circumcision, with the intervention groups having a significantly lower incidence of HIV in all sociodemographic and behavioural categories. An accompanying editorial3 comments that wide-scale implementation of circumcision has the potential to significantly decrease the transmission of HIV in sub-Saharan Africa, but points out that a fresh approach to HIV prevention in women is urgently required. 1. Lancet 2007; 369: 643-656 2. Lancet 2007; 369: 657-666 3. Lancet 2007; 369: 615 Dr Tanya Grassi, MJA

Tanya Grassi

Med J Aust 2007; 186 (7 Suppl).