Editorials

Australia is following North America, the United Kingdom and other developed countries in promoting the use of nurse-led telephone advice services. The core of these services is very similar — nurses follow computer-driven protocols to give advice about a wide range of problems, most of which relate to acute minor illness. In the UK, NHS Direct has been introduced by government to improve access to NHS services and NHS Direct advice is also available on the Internet.1 In this issue of the Journal , Turner and colleagues report for the first time the operation of a nurse-led telephone advice service in Australia, HealthDirect in Western Australia.2 The service has been widely used, with over 300 000 calls being received during the first two years of its operation. The 10 most frequently used guidelines of the service covered more than half of all calls to HealthDirect, and more than half of callers were advised to contact their general practitioners. As in other countries, most callers were young adults or parents calling on behalf of children. There is some concern that the increasing use of telephone advice may disadvantage elderly and ethnic people, who find it less easy to use the telephone. Healthcare planners are clearly interested in whether these new services will reduce the demand for existing healthcare services. Turner and colleagues found that HealthDirect has reduced telephone calls to hospital emergency departments. In the UK, a reduction in the number of calls handled by emergency department staff coincided with the introduction of NHS Direct,3 but there was no reduction in the numbers actually attending hospital emergency departments or using ambulance services.4,5 NHS Direct may, however, have stemmed the rise in demand for GP out-of-hours care. The main effect in the UK appears to have been to provide a new service that the public use, and initial evaluation suggests that satisfaction with the service is high.6 An ongoing evaluation will determine the relative extent to which HealthDirect substitutes for other contacts with health professionals or simply provides a new service. A key question is whether such services are safe. A report of the UK service identified three cases out of over 280 000 where the advice given might have resulted in an avoidable serious outcome.7 A randomised controlled trial of a computer-assisted nurse telephone consultation service found no increase in deaths or serious adverse events resulting from nurse telephone advice.8 It seems likely that, in terms of avoiding serious adverse events, nurse-led services are at least as safe as other forms of care. However, US studies of simulated patients have documented substantial variability and incorrect advice,9,10 and early evaluation of the computer programs in NHS Direct reported similar levels of variability.11 For example, the proportion of callers in the first three NHS Direct sites advised to seek immediate GP care varied nearly threefold between sites (from 10% to 29%), and there was agreement on management between sites for only 39% of 119 standardised evaluation calls. Further studies of safety and consistency of advice are clearly needed. These should include evaluating telephone advice given by both nurses and doctors. Indeed, doctors have expressed concern about safety of the increasing amount of advice which they themselves give over the telephone.12 There remains the question about the cost effectiveness of nurse-led telephone advice lines. The actual cost of calls to NHS Direct has been estimated at £15 (A$42.50) per call.7 However, as important as the actual cost is the impact of these services on overall demand for care. If the net impact is to provide additional services, we do not know whether this is the best way to spend extra healthcare resources. Further, we do not know whether telephone advice would best be given by doctors or nurses. In Denmark, doctors staff telephone advice lines, and are electronically linked to community pharmacies so that they can prescribe remotely for suitable patients.13 If the aim is to reduce demand for existing medical services, then it might be more cost effective to use doctors (who deal with minor illness more rapidly) than nurses in this type of service. Overall, nurse-led telephone advice lines should be welcomed cautiously. Patients use them, and they are probably safe, but we do not know if they will reduce demand for existing services, or if they will merely provide patients with additional, albeit valued, service.

Martin Roland

In Australia, 7.5% of the adult population has diabetes, and for every one person diagnosed with diabetes there is another undiagnosed.1 The prevalence of the most common form of diabetes, type 2, is increasing worldwide because of changing lifestyle, especially increasing weight caused by nutritional excess and decreasing physical activity. Many people with type 2 diabetes have cardiovascular and renal complications on diagnosis, and early detection of diabetes is an important strategy for reducing morbidity and premature mortality.2 The diagnostic test for diabetes is measurement of plasma glucose (PG) level. Although population PG is a continuum, PG levels diagnostic of diabetes identify a subgroup of the population at increased risk of diabetes-related complications. Risk data on these complications are based on the 2 h PG level during an oral glucose tolerance test (OGTT), with risk increasing significantly at a PG ≥ 11.1 mmol/L. It has long been recognised that this 2 h level does not equate to the fasting PG level of 7.8 mmol/L that has also been used to diagnose diabetes. Recently, both the American Diabetes Association (ADA)3 and the World Health Organization (WHO)4 lowered the diagnostic fasting PG level from 7.8 mmol/L to 7.0 mmol/L to more closely align it with a 2 h PG of 11.1 mmol/L. Despite this agreement, the ADA and WHO differ fundamentally on their recommended procedure for diagnosing diabetes, in particular the role of the OGTT in routine clinical practice. WHO continues to advocate routine use of the OGTT to maximise identification of people with increased risk of diabetes complications that may be reduced or prevented by treatment. In contrast, the ADA does not recommend routine use of the OGTT, as it believes that the new lower fasting PG level will detect most people with diabetes diagnosed by the OGTT. However, if an OGTT is performed, the ADA and WHO agree completely as to how the test should be done and interpreted. The study by Hilton and colleagues published in this issue of the Journal5 compares the prevalence of diabetes diagnosed using the ADA and WHO recommendations in a high-risk cohort from the Australian Diabetes Screening Study. It reports that about 50% fewer people are diagnosed with diabetes on the basis of the fasting PG alone (ADA recommendations) compared with the fasting and/or 2 h PG levels (WHO recommendations). Similar findings have come from other populations.6 As the ADA and WHO recommendations define different, although overlapping, cohorts, both of which are labelled with diabetes, the question arises as to when is diabetes really diabetes? There are several reasons why Australia, and indeed most of the world, has adopted the WHO recommendations.7 The diagnostic criteria for diabetes were derived from the increased risk of complications defined by the 2 h PG value, not the fasting PG.3 Clearly, the new lower fasting PG cut-off of 7.0 mmol/L does not equate to a 2 h PG of 11.1 mmol/L. Also, recent evidence confirms the importance of a raised 2 h PG as an independent risk factor for mortality and cardiovascular disease, even when the fasting PG is not raised.8,9 Therefore, failure to consider the 2 h PG ignores a subgroup at particular risk of macrovascular complications. In summary, diabetes is diagnosed by one of the following: symptoms of diabetes and a casual PG level ≥ 11.1 mmol/L; fasting PG level ≥ 7.0 mmol/L; or 2 h PG level during an OGTT ≥ 11.1 mmol/L. How should this information be used by general practitioners faced daily with many people at risk of undiagnosed type 2 diabetes? In Australia, soon-to-be-released evidence-based guidelines from the National Health and Medical Research Council advocate a staged approach for case detection of undiagnosed type 2 diabetes.6 A staged approach is similarly recommended by all national diabetes guidelines in other countries. The new Australian guidelines recommend risk assessment followed by measurement of fasting PG (Box). Those with a fasting PG < 5.5 mmol/L are considered unlikely to have diabetes but should be retested every three years, while those with a fasting PG ≥ 7.0 mmol/L are very likely to have diabetes, which should be confirmed by repeat fasting PG measurement. The remainder with an equivocal result (fasting PG, 5.5–6.9 mmol/L) should have an OGTT. Our analysis of population data from the AusDiab Study (Australian Diabetes, Obesity and Lifestyle Study) shows that, if the above recommendations were followed, about 25% of people who are at risk of undiagnosed diabetes and have a fasting PG measured would require an OGTT (unpublished analysis). The study by Hilton and colleagues confirms the important role of the OGTT in identifying people with diabetes, despite the inconvenience of the test.5 However, not all people with an equivocal PG result are in fact having an OGTT when indicated. Release and adoption of the new national guideline for case detection of undiagnosed type 2 diabetes should help correct this. Indications for measuring fasting plasma glucose levels Age 55 years or over. Age 45 years or over and one of the following: - obesity; - hypertension; - first degree relative with type 2 diabetes. Age 35 or over if Aboriginal or Torres Strait Islander. Age 35 or over if from a high-risk group from non-English-speaking background (Indian subcontinent, Pacific Islands, Chinese origin). Previous history of impaired glucose tolerance or impaired fasting glycaemia. Previous history of cardiovascular event. Women with previous history of gestational diabetes. Obese women with polycystic ovary syndrome.

Stephen Colagiuri FRACP

The Hippocratic Oath has been in a parlous state, especially in the past three decades, since the rise of contemporary bioethics. Ethicists, historians, feminists, and patients' rights activists have all, for one reason or another, disparaged it. The Oath has been called outmoded, an instrument of gender discrimination, a device for professional monopoly, out of tune with societal mores, and inadequate to meet the moral demands of modern medical practice. Critics seem to agree that the Oath must be revised, replaced by a new ethic or left to physician and patient to decide for themselves. I have dealt elsewhere with the substance of these critiques.1 Here, I wish to call to attention the curious fact that, as depreciation of the Oath has intensified, its use at commencement exercises has become virtually universal in US and Canadian medical schools.2 To be sure, with increasing usage, extensive alterations have been made to the content of the Oath. Yet, the idea of an oath persists, and indeed flourishes, almost in direct relationship to its depreciation. Clearly, medical students, faculty members and medical school deans see some lasting value in an oath at the end, and even at the beginning, of a medical education. One may ask, What is the value of so discredited an exercise? Why does it survive? Why should it survive? Should, or, given the choice, would, medical students refuse to take it? Is the idea of an oath, Hippocratic or otherwise, merely a shard of a shattered image, or is it a seed of hope against a dispiriting future? Its currently dubious state notwithstanding, there are several reasons why oath-taking persists and should persist: An oath is a solemn promise made on a solemn occasion at which medical graduates publicly declare their dedication to certain distinguishing moral commitments. This makes them de facto a moral community, a group of people united by a common ideal and together making up a single organism. Their common commitment is a reassurance to the public, a source of strength for those taking the oath and a promise that physicians will act in the interest of their patients. An oath sets the profession apart. It declares that those who take it are committed to something beyond self-interest. This is not commonly the case in a world where competition and self-interest are so strongly legitimised. Although this competitive element has already corroded the idea of a profession, there is enough awareness of the common bond of profession to provide a restraining force. An oath is also a reminder of the continuity of a profession whose roots are in antiquity. Although many medical practitioners in the past and present have violated the canons of the oath, physicians are loath to give up the ideal. They know intuitively that to do so would be to destroy the ideal and to lower the moral sights of a majority of physicians. Even those who argue strongly for the laissez faire approach to medical practice do so with the lame excuse that an oath is too "idealistic". An oath also has the seed of hope within it. Not that a golden age of the past will be resuscitated — there never has been a golden age of medical morality. But there have been times when physicians were more unequivocally committed than now to the good of those they serve. The pragmatists may call this impractical and unrealistic. But even pragmatists can not deny that there is something especially demanding, but, at the same time, satisfying, about caring for sick people. What this all adds up to is the innate recognition by conscientious physicians that they are engaged in something more than commerce, industry or mere contracts for service. They may justify their lapses in behaviour by saying that change is required by the times or that it is what society wants, and so on. But no true physician can, in good conscience, destroy the archetype of medicine as a noble profession. Yes, perhaps for many the medical oath is today a shard of a fractured ancient image. But enough of that image remains in the consciousness of the profession to remind us that to forget it entirely would be to make medicine a commercial, industrial or proletarian enterprise. We know instinctively what this would do to the care of the sick. That is why we still take oaths. Let us hope we always will.

Edmund D Pellegrino

The ability to remain continent is fundamental to our functioning as socially capable individuals. Loss of faecal continence leads to physical, psychological and social disability. Contrary to common belief, the condition is not confined to the disabled elderly. Rather, it affects people of all ages. The greatest contribution to improving the care of people with faecal incontinence would come from improved recognition by doctors. If those who experience faecal incontinence are able to overcome embarrassment, they will seek help from a doctor, usually their general practitioner. To be told that there is nothing to be done (still a common response) is disheartening — and incorrect. In this issue of the Journal (page 54), Kalantar and colleagues have published important data about the prevalence of faecal incontinence in the Australian community.1 They used a postal questionnaire to determine the prevalence of faecal incontinence over the previous 12 months. Incontinence for solid stool occurred in 2% of respondents, and of liquid stool in 9%. These figures are similar to, or somewhat higher than, data published from the USA and Europe over the last 10 years. All recent studies demonstrate that faecal incontinence is common. Current figures are much higher than estimates from the 1980s and earlier, which appear to have markedly underestimated the true prevalence, probably because of the methods of case ascertainment used and the unwillingness of sufferers to disclose the presence of such a stigmatised symptom. In the study by Kalantar et al, men and women were affected in approximately equal proportion. A perineal tear or surgical trauma were identified as associated factors, as were feelings of impaired rectal emptying, loose bowel actions, and a sense of bowel urgency. Only one in eight of those with incontinence had sought medical care. This was despite impaired quality of life and perception of poorer health. In a specialist centre, the commonest cause of faecal incontinence is structural anal sphincter damage associated with childbirth.2 The most important risk factor is instrumental delivery; other risk factors are a large baby, occipito-posterior position, and a long second stage of labour. Anal endosonography, a painless, quick and non-invasive test, has demonstrated that such damage occurs in up to a third of first vaginal deliveries.3 A third of those with damage will have new bowel symptoms after their delivery. The vast majority of these women have not had a recognised third-degree tear. It is therefore perhaps not surprising that 31% of female obstetricians, when asked about their preferred mode of delivery for their first uncomplicated pregnancy, said they would opt for a caesarean section.4 The main reason given was to prevent perineal trauma. The second-commonest cause of incontinence in a specialist referral unit is postsurgical sphincter damage.2 Some patients have anal sphincter damage as an unavoidable consequence of a necessary treatment (eg, in the care of anal fistula). Others sustain irreversible sphincter damage as a consequence of procedures which are now outdated, such as manual dilatation performed for chronic anal fissure, constipation and non-specific anal symptoms. When there is no structural damage present, the commonest cause of faecal incontinence appears to be a degenerative disorder affecting the delicate smooth muscle which keeps the anal canal closed, the internal anal sphincter.2 In patients with congenital anorectal abnormalities, it has only recently been appreciated that, despite corrective surgery in infancy or childhood, impaired continence can persist into adult life.5 Encopresis, often related to behavioural issues, can also severely affect a child's development. In the elderly, many factors can contribute to impaired continence, including co-morbidity, medications, and social circumstances. Faecal impaction is an important factor in some. Patients with a range of primary disorders, such as neurological disease, inflammatory bowel disease, and connective tissue disorders, can experience severe faecal incontinence. For many this hidden symptom causes them the greatest uncertainty and substantially impairs their quality of life. Is it worth making a diagnosis? Can anything useful be done? Emphatically, yes. Many individuals can be helped substantially, often by a combination of careful history taking, examination for sphincter damage or impaction, and correction of predisposing factors. A broad range of therapies have been applied to this condition. Selection of an appropriate therapy, after correcting simple contributory factors, should be based on the aetiology and severity of a patient's incontinence. The least invasive and safest treatments should be used first. Many patients with excessively strong bowel contractions, or sphincter weakness, can have their well-being transformed by a small dose of an antidiarrhoeal medication such as loperamide. This drug is extremely effective and safe in adults. If patients become constipated, the dose can be reduced. Behavioural techniques, such as "biofeedback" (teaching patients to improve sphincter function using physiological feedback, such as anal electromyography or pressure measurement) and sphincter exercises, help about two-thirds of patients, including some with structural sphincter damage.6 Such behavioural techniques are not simply "exercises"; rather, they involve a complex package of care that includes dietary advice, proper use of constipating drugs, teaching patients to resist urgency, decreasing their sense of panic, sphincter training and counselling. Topical pharmacological therapies have radically altered the management of anal fissure, thereby preventing the need for surgical sphincterotomy (one of the causes of incontinence). The first such topical therapy was glyceryl trinitrate (GTN), which lowers anal tone, thereby allowing fissures to heal. Topical GTN is associated with headache in two-thirds of patients, limiting compliance.7 The use of calcium-channel blockers such as diltiazem offers the same therapeutic benefit but without the side effects.8 Injectable botulinum toxin also lowers anal pressure and allows healing. Topical preparations which raise sphincter tone and prevent leakage, such as phenylephrine, are also under development.9 Only a very small proportion of patients require surgical treatment. Sphincter repair for major obstetric structural damage produces a good short term outcome, but the longer-term results are less satisfactory.10 New surgical techniques include: The artificial bowel sphincter (a circular cuff implanted around the anal canal and inflated to maintain sphincter closure).11 Sacral nerve stimulation by means of a fine electrode implanted through a sacral foramen.12 This is connected to a battery to provide continuous low level stimulation, resulting in altered rectal and sphincter motor function. Dynamic graciloplasty. The gracilis muscle is mobilised from the inner thigh and wrapped around the anal canal. Battery stimulation produces muscle contraction, which increases anal pressure.13 This procedure has limited application owing to its complexity and associated morbidity. When all else has failed, a tiny proportion of patients will be well served by a colostomy. Data such as those published in the Journal today should serve to remind doctors that faecal incontinence is a common and treatable condition. A range of treatments is required if patients with different types and severities of incontinence are to be successfully managed. Such a range of expertise is not readily available in many centres. These data should therefore also remind healthcare planners that this is a health issue which requires action in the community, in addition to multiskilled centres of expertise for the minority of patients who need more intense treatment.

Michael A Kamm

We are well aware of the excess mortality of Australian Aboriginals and Torres Strait Islanders, their higher hospital admission rates and their longer duration of hospital stay.1,2 However, despite this, relative to their need, Aboriginals and Torres Strait Islanders underutilise specialist healthcare, both as inpatients3 and outside hospitals.4 This situation is exacerbated by demonstrable underfunding of primary care services for Indigenous Australians.4 In this issue of the Journal, Cunningham (page 58)5 reports an analysis of Australian hospital separation data which documents significantly fewer diagnostic and therapeutic procedures performed on patients identified as Indigenous. Cunningham took into account variables possibly affecting use of procedures, including diagnosis, age, sex and place of residence, and acknowledged the problem of incomplete identification of hospital patients as Indigenous. The adjusted data still show fewer recorded procedures in Indigenous compared with non-Indigenous inpatients. These differences are significant within certain disease and diagnostic groups, and of a magnitude which cannot be ignored. Cunningham's study is also consistent with a large body of research from other countries showing disparities according to ethnic group and gender in the use of procedures.6,7 Are the reasons for these disparities in use of procedures related to disease characteristics (including severity), the patient (including preferences and comorbidities), the clinician or the institutional setting? Are they appropriate? And what exactly do these findings indicate? Ideally, decisions regarding medical care are based on evidence, or at least consensus opinion as reflected in a range of standard practices or options. Patient goals and values are then factored in, together with provider and institutional preferences and consideration of available resources. The end-result should be an individualised decision for each patient. Cunningham's findings suggest that, somewhere along this chain within hospitals, different decisions about use of procedures are being made that correlate with, but may not be caused by, ethnic origin. It seems implausible that such significant and Australia-wide differences could implicate large numbers of individual clinicians and result from purely personal biases based on race. The disparities are more likely a result of subtler systemic practices, not ill-intentioned but still discriminatory, and almost invisible within an individual patient–provider encounter. The challenge for clinicians is to further dissect the available information and identify the true cause from the many possible contributory factors. For example, it is likely that in some disease conditions where aetiology is well identified in a population and where the disease is endemic that fewer investigations (and therefore procedures) are needed. Renal biopsy may be performed less frequently to investigate renal disease in Indigenous patients, in whom identified antecedent chronic diseases are endemic. Iron-deficiency anaemia may be treated with anthelmintic drugs rather than first confirming the cause. Alternatively, there may be situations in which a population is genuinely underserviced relative to need (eg, some forms of elective or semi-elective surgery). Possible patient factors should also be identified and dealt with. These include stage of presentation, comorbidities, consent and anticipated postprocedural compliance. All may be reasons why a procedure is not performed, but all these factors can be ultimately overcome, in particular with greater recognition of the importance of primary care. The Royal Australasian College of Physicians has emphasised that adequate primary care is a prerequisite for effective specialist care.8 The uptake of services is more than "patient related" and cannot be separated from the provision of services; societal and institutional factors also structure the doctor–patient encounter within which decisions are made.9 Compliance is likely to improve when a patient's understanding and ownership of his or her disease is matched by a commitment (in the broadest sense) to providing high quality communication and a range of treatment options. The national underdevelopment of key services — Aboriginal Health Workers, Liaison Officers, and particularly interpreter services — shows a lack of appreciation by health institutions of the importance of involvement of Indigenous patients in decision making. Finally, could clinician factors be a major issue in this disparity in the use of procedures? Do we try hard enough and devote sufficient resources to the early diagnosis of serious conditions, to ensuring stabilisation of comorbidities, to obtaining meaningful consent, and to ensuring good postprocedural care and compliance? Do we have preconceived and incorrect perceptions of cultural appropriateness? Are the expectations we factor into our decision making, often derived from our knowledge of group outcomes, appropriate for this individual patient? It is certainly interesting that for trauma and infectious diseases, in which the decision-making process may be less subjective, Cunningham found no difference overall in the likelihood of having a procedure. However, even within these groups, large differences could be seen at an individual "principal diagnosis" level. To improve and structure our medical decision making, we need to continue to develop standardised protocols based on best evidence. Subsequent careful recording of consent processes, together with documentation of the decisions reached and the reasons behind them, will shed further light on the issues raised by Cunningham's data. Cunningham's article shows why clinicians need to contribute to the interpretation of population health information. As presented, these data do not identify the specific clinical procedures possibly denied to Aboriginal and Torres Strait Islander inpatients, and, although the findings have flagged the disparity in procedures, more information is needed for clinicians to take these concerns to the next level of analysis. Specifically, these findings should prompt us to review the decision-making processes determining use of diagnostic and therapeutic procedures in Aboriginal and Torres Strait Islander inpatients. Specialist colleges, societies, hospital units and individual clinicians now have a responsibility to review their own data and establish whether the trend in differential use of procedures applies to their area and, if so, what is driving this difference. The next chapter in this story needs to tease out the connections between healthcare need, use of procedures and health outcomes. If healthcare services are to foster equity rather than further institutionalise inequity, inappropriate reasons for different use of procedures need to be identified and the problems rectified.

Dale A Fisher FRACP, DTM · Tarun S Weeramanthri PhD, FRACP, FAFPHM

In a recent issue of the Journal, Blake and colleagues described a cluster of three cases of measles from western Sydney.1 The index patient acquired measles overseas, while the other two patients acquired the infection during a hospital visit and probably in the waiting room of a general practice, respectively. Measles is highly contagious and can spread with relative ease in healthcare settings, especially if there is a failure to diagnose the infection, to isolate the infectious patient or to notify the case so that other infection control measures can be implemented. Other recent Australian outbreaks of measles have also been associated with virus importation from overseas and subsequent nosocomial transmission.2-4 Measles was imported in nine separate incidents investigated in Western Australia between March 1999 and October 2000, and subsequently transmitted among hospital patients, visitors and healthcare workers on two separate occasions. Victoria has experienced two outbreaks in the past three years,3,4 and a third is evolving (Dr Sean Tobin, Medical Officer, Communicable Diseases Section, Department of Human Services, Victoria, personal communication). In two of the three outbreaks, the index patient had returned from overseas during the incubation period, and genotyping provided strong evidence that the viruses were imported. All three outbreaks involved predominantly young adults. Healthcare staff aged in their 20s or early 30s accounted for six of the 75 cases in the 1999 Victorian outbreak (a doctor, three nurses, a social worker and a medical student3), and for two of the 51 cases in the first of the 2001 Victorian outbreaks (a medical student [the index case] and a nurse who remained unvaccinated despite being identified as susceptible in the previous outbreak5). In the latter outbreak, an unvaccinated 11-year-old child also became infected after attending an emergency department at the same time as an infectious patient. In the current outbreak, one case was in a 36-year-old hospital orderly, and another in a 30-year-old pharmacy assistant, both almost certainly infected while at work (Dr Sean Tobin, personal communication). The hospital orderly, born in 1965, might have been expected to be immune to measles, having grown up when measles virus was circulating in the community and measles epidemics occurred every two years.6 However, people born between about 1968 (when measles vaccine was first licensed in Australia) and 1981 (when a measles–mumps combination vaccine was introduced to the Australian childhood schedule) grew up when exposure to wild measles virus was decreasing. Because of initial poor vaccine coverage, there was inadequate compensation for the subsequent decline in natural immunity in the population, leaving a proportion of this age group, now aged 20–33 years, at risk of measles infection.7 These cases of measles transmission in healthcare settings in Victoria, Western Australia and New South Wales illustrate failure to implement the published guidelines for measles control.8 These involve four key components: isolate the patient, confirm the diagnosis, identify other cases and identify and protect all susceptible persons. However, the failures may be caused by a general lack of awareness of the guidelines rather than an unwillingness to follow their recommendations. In particular, the guidelines are not useful if measles has not been diagnosed. Measles is now relatively uncommon and more likely to affect young adults than children.2 A high index of suspicion is needed, and measles should always be considered in the differential diagnosis of fever and rash in an unwell adult, especially if the person was born between 1968 and 1981. Had the four key components of outbreak control been implemented in some or all of the reported measles outbreaks, some or all of the infections in these outbreaks may have been prevented. As recommended in the guidelines for measles control,8 vaccination of some or all of the young adults involved in these outbreaks may also have prevented further cases. Australia has recently spent more than $30 million on a highly successful mass-vaccination campaign that has effectively protected school-aged children against measles.9 It seems extraordinary that measles transmission can still occur in hospitals or general practice surgeries. Case reports are very unlikely to reveal the extent of the problem. It might be said that transmission of measles — or any other vaccine-preventable disease — in a healthcare setting is a sentinel sign of system failure. Offering susceptible healthcare workers measles–mumps–rubella vaccine has been made a quality standard for all healthcare workers in the United States,10 and a similar approach may be warranted in Australia. Healthcare providers in hospitals and the wider community should record which staff members are susceptible to vaccine-preventable diseases that may be occupationally transmitted, and should provide facilities for vaccination of all those who wish to protect themselves and their patients. As recommended in the Australian guidelines for measles control, young adults intending to travel to measles-endemic countries should be advised to check and update their measles vaccination status. At a time when measles transmission has probably been interrupted in several Australian States,2,11 it is important to suspect the diagnosis of measles in young adults with rash and fever, especially those with a history of international travel, and to take pro-active infection control measures to prevent measles transmission in healthcare settings.

Heath A Kelly · Michaela A Riddell · Ross M Andrews

Percutaneous liver biopsy, a technique first accredited to Paul Ehrlich over 100 years ago, is still considered an essential component in the management of most liver diseases. However, the revolution in imaging techniques and development of serological investigations means that, at least for certain conditions, biopsy may no longer be necessary. The usual technique for obtaining liver tissue for histological evaluation of diffuse parenchymal liver diseases is percutaneous needle biopsy, which is performed either blind or guided by ultrasound or computed tomography. The attendant mortality ranges from 0.01% to 0.1%,1,2 the major cause of death being intraperitoneal haemorrhage. Controversy still exists over whether guided biopsies can reduce the complication rate and whether an increased diagnostic yield renders them more cost-effective.3,4 To maximise diagnostic yield, it is usual practice to perform liver biopsy with a 14 G or 16 G needle. Increased complications are observed when clinicians perform liver biopsy less frequently5 and when more than three passes are made.6 It is only relatively recently that guidelines have been established for performing liver biopsies on a day-case basis7,8 and these recommend subsequent observation of patients for 6–8 hours, although the majority of complications are apparent within the first three hours. In this issue of the Journal, Pokorny and Waterland (page 67)9 have examined the safety and possible cost benefits of performing liver biopsy in an out-of-hospital radiology clinic. Of 251 patients who underwent liver biopsy with an 18 G needle, 91.2% were discharged at 60 minutes and none were kept for longer than 2 hours 45 minutes. Moderate to severe pain was reported in 3.6% of patients, but no serious complications were observed. While a histological diagnosis was possible for all patients, it is not usual practice to use an 18 G needle for assessment of diffuse parenchymal liver disease, and there are no data regarding the adequacy of the biopsy (as regards number of portal tracts and number of sections). Could the low morbidity of the study simply reflect the use of a small biopsy needle rather than a positive benefit of radiological control? While a cost benefit was suggested when compared with in-hospital, day-case liver biopsies, the method of cost comparison relied upon two discrepant funding models — the Australian Medicare Benefits Schedule (for out-of-hospital biopsy) and DRG-based funding (for in-hospital biopsy). Ideally, actual resource costs should have been derived for each biopsy setting in order to determine an economic advantage. Does this mean that we should be performing all our routine liver biopsies out of hospital? Although the mortality rate after liver biopsy in Pokorny and Waterland's study was low, the study does not have the power to demonstrate a clearly comparable safety profile between out-of-hospital and in-hospital liver biopsy. However, it is unlikely that a formal study with sufficient power will ever be conducted to prove this point, and perhaps ongoing audit of in-hospital and out-of-hospital biopsy and documentation of similar outcomes is all that is required to prove the safety of shorter recovery times and out-of-hospital biopsy. Nonetheless, if a major complication such as haemorrhage did occur, it would require urgent intervention that would be easier to provide in a hospital environment. The American Gastroenterological Association recommends that biopsies be performed in a unit with blood-banking facilities and an approved laboratory.7 Apart from the logistics of where liver biopsy is carried out, there is a major issue of why biopsy should be performed. There are differing opinions on the indications for liver biopsy. Current practice has recently been reviewed2 and the British Society of Gastroenterology has published guidelines for the use of liver biopsy in the United Kingdom.8 A key factor in the decision-making process should be whether knowledge of liver histology is likely to affect patient management. Histological assessment can help either to reach a diagnosis or to grade severity of disease in patients with a known hepatic disorder. Therefore, deciding whom to biopsy can be approached in one of two ways. In patients with a known or suspected disorder, biopsy enables staging of inflammation and fibrosis, providing the clinician and patient with a well-informed and accurate prognosis. This can guide or determine eligibility for treatment regimens and, in patients with cirrhosis, determine whether they should be enrolled in screening programs for hepatocellular carcinoma. The other major role of liver biopsy is in investigating patients with abnormal liver function tests (LFTs) for whom serology and imaging have been unhelpful in reaching a diagnosis. Chronic hepatitis C is probably the most rapidly growing indication for liver biopsy in Australia. Current S100 Pharmaceutical Benefits Scheme regulations require liver biopsy before consideration of treatment of chronic hepatitis C, except in patients for whom liver biopsy is contraindicated. Should liver biopsy be performed routinely in all patients before antiviral treatment, and how does it really benefit the patient? There is growing debate on this issue within Australia10 and overseas,11 indicating that we need to re-evaluate the role of liver biopsy in hepatitis C. The commonest cause of persistently abnormal LFTs (in the absence of markers for infectious, metabolic, autoimmune or hereditary liver disease) is non-alcoholic fatty liver disease. In a study by Daniel et al of 81 marker-negative patients with abnormal LFTs who had liver biopsies, eight patients had normal liver histology, while the remaining 73 patients all had some degree of steatosis.12 Non-alcoholic steatohepatitis was found in 26 of these patients and two had cirrhosis. Although there is a risk of cirrhosis in patients with non-alcoholic steatohepatitis, this is minimal in the absence of diabetes and obesity and in patients under 45 years.13 The result of a biopsy in patients at low risk of cirrhosis is unlikely to influence management and has not been shown to improve the benefit–risk ratio. A final issue relates to who should perform liver biopsy. Clearly, appropriately trained clinicians should do so.5 If out-of-hospital biopsy becomes routine, there will be less opportunity to provide supervised training for registrars in this procedure. Current Gastroenterological Society of Australia guidelines for advanced training recommend that around 50 successful, supervised biopsies be performed to ensure adequate training. So, who should be trained to perform liver biopsy and how do we accredit such individuals? Liver biopsy provides invaluable information and a histological diagnosis remains the gold standard in many liver disorders. However, the benefits for diagnosis and management need to be clearly defined before subjecting patients to an invasive procedure, albeit one with low risk. While the study by Pokorny and Waterland9 tempts us to move to an out-of-hospital, short-stay approach to liver biopsy, the issues of safety and diagnostic adequacy of relatively small core biopsies need to be well proven before this approach can be more widely adopted.

Adrian Griffiths MB BS, MRCP · Charlie H Viiala MB BS · John K Olynyk MD, FRACP

Over the past 50 years, advances in biological and physical science have fuelled an unprecedented expansion of medical knowledge and change in medical practice.1,2 We now have effective treatments for many conditions, including infectious diseases, cardiovascular disease, mental illness, peptic ulceration and diabetes. Advances in surgery and anaesthesia have made these disciplines not only safer, but also bolder. Imaging technology now exposes the most secret recesses of the human body and, with other diagnostic disciplines, threatens to make the art of clinical diagnosis redundant. Technology has revolutionised human reproduction and erased many of its uncertainties. The organisation of the profession has also changed. The Commonwealth Jubilee issue of The Medical Journal of Australia in 1951 chronicled the advances in Australian medical disciplines in the first half of the 20th century. At that time, these disciplines numbered 16 — anaesthesia, child health, clinical pathology, dermatology, general practice, internal medicine, obstetrics and gynaecology, ophthalmology, orthopaedic surgery, otorhinolaryngology, physical medicine, psychiatry, public health, radiology, surgery and urology.3 The kaleidoscope of disciplines in modern medicine now exceeds 50 and this expansion shows no signs of remaining static, as new knowledge and technology further subdivide specialties. Sadly, this mitosis of medical specialties has not led to interconnecting, communicating cells. Instead, specialist and subspecialist "silos" have evolved which serve to contain and isolate. Each specialty has its own body of workers, is sustained by its own agenda, and drives its own research programs, the outcomes of which are discussed at specialist meetings and published in specialist journals. How much does one such silo know about the latest repository in another? To redress the poor external communication of specialist silos, this issue of the Journal features Updates on advances in more than 40 of medicine's current disciplines. We asked Australian doctors to share with us the more significant advances and changes in their disciplines, with three qualifiers: individual contributions were limited to one Journal page to enforce a focus on pertinent issues; contributors were to identify developments which were most likely to remain viable; and advances were to be explored from the perspectives of prevention, diagnosis and intervention. What emerges is a collage of Updates in which the unifying themes are more distinct than the differences. These are: disease prevention is in the ascendancy; clinical medicine is increasingly embracing advances in molecular biology and the attendant implications for prevention and diagnosis; the tools of health informatics are revolutionising clinical decision making — with their capacity to store and analyse vast amounts of information, we can now process anything from nucleotide sequences to clinical evidence; and no discipline is an island, and input from several disciplines made many of these advances possible. What is apparent too is that the doomsday predictions that medicine is on the wane may well be premature. In his epic analysis The rise and fall of modern medicine, James Le Fanu argues that the "golden age" of medicine ended in the 1980s, "when the main pillars of the post-war medical achievements — clinical science, medical chemistry and . . . technological innovation — were in trouble".2 However, the depth and richness of developments outlined in this issue of the Journal support the view that human ingenuity repeatedly confounds predictions that medicine has reached its limits.4 The Updates also highlight problems yet to be solved. The ethical and social implications arising from some uses of new technologies are challenges that face us. The divide between developed and developing countries is alluded to. Resource allocation that is driven by economic and political imperatives places boundaries on what can be achieved. There are pressures to allocate resources that sustain the use of complex technologies and new drugs rather than priorities such as disease prevention programs and population health. That medicine is increasingly isolated into specialist silos is clearly visible in these Updates. Yet, it is equally clear that innovation is not dead unless these silos become even more airtight. On a broader landscape, we live in a world irrevocably changed by the dramatic events of September 11, 2001. The notion that collective values do matter, despite (or perhaps because of) the fact that we live in an unequal, insecure world, has been reiterated by many. We in the medical profession would do well to be driven by a similarly collective and collaborative vision for health. As John Martin, a British Heart Foundation professor of cardiovascular science, recently observed, "a multidisciplinary team is more likely to give rise to non-linear fantasy [or innovation] than a monovalent team".5

Mabel Chew FRACGP, FAChPM · Martin Van Der Weyden

Editoral Environment, sustainability and health: the learning curve steepens Recent international strife is showing that a divided, unequal and insecure world is inimical to peace, wellbeing and health. We should be seeking a sustainably ordered world, and not a political New World Order. MJA 2001; 175: 569-570 The dramatic events of September 11, 2001, have compelled a refocusing of minds on wider state-of-the-world issues. Indeed, this refocusing may yet emerge as the silver lining to the cloud of tragedy, trepidation and tension that followed that shocking terrorist episode. Many people, on deeper reflection, are now confronting the question "Why?" — of what underlying malaise is such violence and resentment a symptom? The interdependence, reciprocity and increasing connectedness of the world's nations are now more evident than ever before. We are "globalising". This, in turn, entails an increased flow of information that reveals economic disparities, inequalities of trading regimens, persistence of poverty in many poor populations, and the magnitude and ubiquity of serious environmental deterioration.1 The economic, social and political systems that prevail today have thus heightened the risk of non-sustainability — both by overloading the earth's environmental "carrying capacity" (of humans) and by straining the fabric of social and political cohesion.2 . . . even in the modern, affluent, urbanising world, humankind is dependent on intact life-support systems and is subject to the constraints of environmental carrying capacity. Here, though, there is another tension. Despite the incipient evidence of global-scale environmental damage such as climate change and biodiversity losses,2 and the marked widening of the rich-poor gap over recent decades,1 humankind has undoubtedly done well on various environmental indicators.3 We have manifestly become more efficient at generating material wealth — at creating technology-enriched and comfortable lives — and we have achieved a doubling of average life expectancy over the past century.4 In most countries, fertility rates and infant mortality rates have continued to fall. True, various countries of the ex-Soviet Bloc and of HIV-afflicted Sub-Saharan Africa have experienced recent losses in life expectancy. But, overall, the prospects for the world's health seem good. However, this is where we in the health sector need to get serious about highlighting the significance, and the fundamental determinants, of population health. The world's policy-makers and international agencies are preparing for a major international conference on Sustainable Development, to be held in Johannesburg next September. This will be "Ten Years After Rio" (the United Nations Conference on Environment and Development, held in Rio de Janeiro). Yet, we still have not managed to formulate a clear view of population health as a central criterion of "sustainable development".5 That view would recognise that the prospects for population health are, at least in the long run, largely determined by the conditions and assets of the natural and social environments. Lacking that essentially ecological understanding, we will continue to encounter other limiting, indeed sometimes misguided, views about the significance of population health in the overall schema. The World Health Organization will continue to argue (at least for political reasons) that the population's health is an important input — a resource that enhances economic performance6 (which, in turn, benefits population health7). Others will emphasise that poverty is bad for health, that transnational market forces constrain healthcare for the poor, and that uncontrolled industrialisation poses toxic hazards to local communities. In other settings, however, a more profound argument is now being forged. Through three cycles of scientific assessment, the Intergovernmental Panel on Climate Change (IPCC) has paid steadily more attention to the risks posed to future population health by the continuing change in world climatic conditions.8 Likewise, effects on human health are now a central consideration in the several ongoing international scientific reviews of the human consequences of biodiversity loss, stratospheric ozone depletion, the widespread disruption of ecological systems, and the deregulation of international trade. We have begun to understand that, even in the modern, affluent, urbanising world, humankind is dependent on intact life-support systems and is subject to the constraints of environmental carrying capacity.2 We may achieve some technological alleviation, through developments such as genetic engineering and nanotechnology, but there is no guarantee — and we are rather short of time. The recent international strife has begun to underscore the uncomfortable realisation, for the United States and its Western allies, that a divided, unequal and insecure world is inimical to peace, wellbeing and health. This awareness may, one hopes, prompt serious collective action to avert the various global environmental changes that endanger health and life. Such policy changes will require a broad visionary effort. After all, America's recent rejection of the Kyoto Protocol for reducing greenhouse gas emissions is merely the most notorious of several acts of international policy delinquency. Various myopic governments have preferred immediate national economic growth over the longer-term need for prudent, shared international action in a more equitable world. The US exemplifies this self-serving short-termism, and, in recent years, Australia has sometimes followed suit. However, we are learning that the mere maintenance of economic growth is not what "sustainability" is about.9,10 Our economies should be means to social ends, not material ends in themselves. Further — and this is most important — the human-made economy is embedded within, and is ultimately beholden to, nature's "economy", the biosphere.2 The terrorist attack on New York has shown us that there can be no safe havens in a world riven by environmental stresses, social and political instability, and improvised weapons of mass terror and destruction. The rapid increase in numbers of environmental and political refugees, the outbreaks of slaughter in overpopulated regions (such as Rwanda in 1994), the early, tentative evidence of the impact on health of climate change11-14 — these and other signs tell us that we should now be seeking a sustainably ordered world, not a political New World Order. Our task in this evolving discourse, as health professionals, is to make clear that population health is a central criterion in the sustainability transition.5 Population health should be neither an instrumental policy sweetener nor a sideshow. The long-term good health of human populations is dependent on, and an essential measure of, our stewardship of the natural and social environments.2 Anthony J McMichael Professor National Centre for Epidemiology and Population Health Australian National University, Canberra Butler CD. Inequality, global change and the sustainability of civilisation. Glob Change Human Health 1: 156-172. McMichael AJ. Human frontiers, environments and disease: past patterns, uncertain futures. Cambridge: Cambridge University Press, 2001. Lomborg J. The sceptical environmentalist. Cambridge: Cambridge University Press, 2001. Feachem RG. Globalisation is good for your health, mostly. BMJ 2001; 323: 504-506. McMichael AJ, Smith KR, Corvalan CF. The sustainability transition: a new challenge. Bull World Health Organ 2000; 78: 1067. Bloom DE, Canning D, Sevilla J. Health, human capital and economic growth. Working Group I, Paper 8. WHO Commission on Macroeconomics and Health. Geneva: World Health Organization, 2001 (see www.comhealth.org/docs/wg1_paper8.pdf). Dollar D. Is globalization good for your health? Bull World Health Organ 2001; 79: 827-833. Intergovernmental Panel on Climate Change. Climate change 2000. Impacts and adaptations. Cambridge: Cambridge University Press, 2001. Kates RW, Clark WC, Corell R, et al. Environment development: sustainability science. Science 2001; 292: 641-642. Costanza R, Daly H, Folke C, et al. Managing our environmental portfolio. BioScience 2000; 50: 149-155. Lindgren E, Gustafson R. Tick-borne encephalitis in Sweden and climate change. Lancet 2001; 358: 16-18. Kovats RS, Campbell-Lendrum D, McMichael AJ, et al. Early effects of climate change: do they include changes in vector-borne disease? Philos Trans R Soc Lond B Biol Sci 2001; 356: 1-12. Tulu AN. Determinants of malaria transmission in the highlands of Ethiopia: the impacts of global warming on morbidity and mortality ascribed to malaria [PhD thesis]. London: University of London, 1996. Epstein PR, Diaz HF, Elias SA, et al. Biological and physical signs of climate change: focus on mosquito-borne diseases. Bull Am Meteorol Soc 1997; 78: 409-417. Make a comment

Anthony J McMichael

Editorial Bridging the divide: global inequities in access to HIV/AIDS therapy Australia should take a greater role in reducing the global burden of HIV/AIDS MJA 2001; 175: 570-572 Our recent visit to HIV/AIDS hospital units in Phnom Penh, Cambodia, sharply delineated the contrasting capacity to respond to HIV/AIDS in First World countries, such as Australia, and resource-poor countries. Common to both settings is the relatively young age of those affected, the close attention of loved ones and the dedication of healthcare workers. The contrasts lie in the enormous gaps in quality of healthcare facilities and access to effective HIV treatments. HIV/AIDS may be only one of several major public health issues for these countries, but, probably more than any other issue, it highlights global resource inequities. Over the past decade, Australia has been at the forefront of advances in HIV treatment,1-4 which have provided optimism for many people living with HIV/AIDS. Combination antiretroviral therapy is one of the most cost-effective therapies for a chronic disease in the developed world,5 and most First World countries provide ready access to combination antiretroviral therapy through publicly funded programs. However, 90% of the estimated 36 million people living with HIV/AIDS are in resource-poor countries,6 where access to new HIV treatments is extremely limited: an estimated 0.5% of the global market for antiretroviral therapy is sold in the poorest third of the world.7 Indeed, most people with HIV in resource-poor countries experience inexorable decline in immune function leading to death, just as people in First World countries did before the mid-1990s. If the challenge of the past decade was to develop therapeutic agents to control HIV infection, then the even greater challenge of the current decade is to provide access to effective HIV treatments for people in resource-poor countries. The political commitment to achieve this is growing. Earlier this year, a Declaration of Commitment was signed at the United Nations General Assembly Special Session (UNGASS) on HIV/AIDS in New York. This Declaration recognised that "access to medication in the context of pandemics such as HIV/AIDS is one of the fundamental elements to achieve progressively the full realisation of the right of everyone to the enjoyment of the highest attainable standard of physical and mental health".8 The Declaration also set a resource target of US$7-$10 billion per year for HIV/AIDS prevention, care and support initiatives, to be reached by 2005.8 However, expanding access to effective HIV treatments also depends on other factors. Affordability of antiretroviral therapy: Recent endeavours to reduce the price of antiretroviral therapy for resource-poor countries need to be continued. Affordability can be improved through tiered pricing systems (maintaining current pricing levels in industrialised countries to subsidise lower pricing in resource-poor countries), further development of generic production, and use of compulsory licences and other health safeguards of the Agreement on Trade-Related Aspects of Intellectual Property Rights from the World Trade Organization.7 Within these measures, pharmaceutical industry profitability needs to be maintained at reasonable levels to enable continued research and development. Current pricing of some triple combination regimens should make potent antiretroviral therapy cost-effective for many middle-income countries. For example, stavudine-lamivudine-nevirapine, as produced by Cipla, an Indian-based generic producer, sells for A$700 per year, or about 5% of standard pharmaceutical industry pricing. In Brazil, a generic drug program established by the government was followed by 80% price reductions for several component agents of antiretroviral therapy,9 enabling universal access to antiretroviral therapy. Although encouraging, these price reductions are not enough for most resource-poor countries, where annual health budgets are often less than $20 per capita.7 Further, while implementation of antiretroviral therapy is being scaled up, it is realistic to expect that only a minority of people living with HIV/AIDS can be treated. This will necessitate difficult decisions about selecting patients for antiretroviral therapy, which might take into account social criteria (eg, family support and employment status) in addition to biological criteria (eg, symptomatic patients only to be treated). Therapy delivery and monitoring: Simply making antiretroviral therapy "available" is not the whole solution and may be counterproductive.10 Inappropriate antiretroviral therapy use may lead to viral resistance and considerable drug toxicity. Healthcare systems must therefore be developed to deliver and monitor HIV treatments effectively. However, implementation of antiretroviral therapy programs cannot wait for the optimal conditions that exist in industrialised countries. Therapy programs and infrastructure should be scaled up concurrently. Education and training of healthcare workers in antiretroviral therapy and more broadly in clinical management of HIV/AIDS will also be required. Antiretroviral therapy needs to be provided within an integrated system of HIV/AIDS treatment, care and support services. This may be helped by closer collaboration between HIV/AIDS and tuberculosis programs, which have been proposed as a platform for antiretroviral therapy implementation.11 Tuberculosis programs are the clinical entry point for many people with HIV/AIDS, as tuberculosis is the most common AIDS-related illness in resource-poor countries,12 and also have experience in delivering combination pharmacotherapy in resource-poor settings. Establishing referral networks between hospital-based and home- and community-based HIV/AIDS care programs will also improve delivery of a comprehensive package of treatment, care and support. Earlier diagnosis: In resource-poor countries, people with HIV/AIDS generally present with very advanced AIDS-related illness or die before presentation. Although antiretroviral therapy is still effective when commenced late in HIV disease, earlier HIV diagnosis would allow HIV preventive education and other HIV treatments, such as prophylaxis against common opportunistic infections, to be delivered. To achieve earlier diagnosis, rapid scale-up of voluntary HIV counselling and testing services is needed, including routine offering of HIV testing in antenatal clinics in settings with relatively high HIV prevalence. The latter would provide the foundations for preventing mother-to-child transmission and introducing treatment and care strategies, including antiretroviral therapy, earlier to many women with HIV/AIDS. Research on implementing antiretroviral therapy: Priorities should include evaluating pilot antiretroviral therapy programs in resource-poor settings, searching for more cost-effective means of monitoring therapy, and developing simpler therapeutic regimens (preferably, once-daily dosing) to enhance adherence. An example of Australia's contribution to the regional HIV/AIDS response is the HIV Netherlands-Australia-Thailand Collaboration, which has conducted HIV therapeutic research in Thailand since 1996.12 Australia now has the opportunity to contribute to HIV/AIDS research and care in countries such as Cambodia, where the burden of HIV/AIDS is increasingly being felt (Box). HIV prevention: Finally, if the UNGASS commitment to reverse the spread of HIV/AIDS by 20157 is to succeed, a heightened response is required to HIV/AIDS prevention as well as care. Both arms need increased priority and allocation of resources. They also need close interlinking in a broadly based response at national and community levels. However, implementing antiretroviral therapy may enhance HIV prevention through increased incentive for HIV testing accompanied by HIV preventive education. If the HIV/AIDS treatment divide between industrialised and resource-poor countries is to be bridged, we urgently need Australian research, medical, and educational institutions to become more involved, and public and private sector funding to be enhanced. Gregory J Dore Senior Lecturer, National Centre in HIV Epidemiology and Clinical Research University of New South Wales; and Infectious Diseases Physician HIV/Immunology/Infectious Diseases Clinical Services Unit St Vincent's Hospital, Sydney, NSW gdoreATnchecr.unsw.edu.au David A Cooper Professor, National Centre in HIV Epidemiology and Clinical Research University of New South Wales; and Director HIV/Immunology/Infectious Diseases Clinical Services Unit St Vincent's Hospital, Sydney, NSW Acknowledgements We would like to thank Professor John Kaldor and Dr Sean Emery (National Centre in HIV Epidemiology and Clinical Research, University of New South Wales) for their helpful comments on an earlier draft of this article. References Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283-291. CAESAR Coordinating Committee. Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 1997; 349: 1413-1421. Montaner JS, Reiss P, Cooper D, et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada, and Australia Study. JAMA 1998; 279: 930-937. Danner SA, Carr A, Leonard JM, et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group. N Engl J Med 1995; 333: 1528-1533. Bozzette SA, Joyce G, McCaffrey DF, et al. Expenditures for the care of HIV-infected patients in the era of highly active antiretroviral therapy. N Engl J Med 2001; 334: 817-823. Joint United Nations Programme on HIV/AIDS. AIDS epidemic update: December 2000. Geneva: Joint United Nations Programme on HIV/AIDS, 2000. Attaran A, Gillespie-White L. Do patents for antiretroviral drugs constrain access to AIDS treatment in Africa? JAMA 2001; 286: 1886-1892. Declaration of Commitment on HIV/AIDS: "Global crisis - global action. <www.un.org/ga/aids/coverage/FinalDeclarationHIVAIDS.html> Accessed, Sep 2001. Gottlieb S. US concedes on cheaper drug production in Brazil. BMJ 2001; 323: 12. Horton R. African AIDS beyond Mbeki: tripping into anarchy. Lancet 2000; 356: 1541-1542. Harries AD, Nyangulu DS, Hargreaves NJ, et al. Preventing antiretroviral anarchy in sub-Saharan Africa. Lancet 2001; 358: 410-414. Grant AD, Djomand G, De Cock KM. Natural history and spectrum of disease in adults with HIV/AIDS in Africa. AIDS 1997; 11 Suppl B: S43-S54. Kroon ED, Ungsedhapand C, Ruxrungtham, et al. A randomized, double-blind trial of half versus standard dose of zidovudine plus zalcitabine in Thai HIV-1-infected patients (study HIV-NAT 001). HIV Netherlands Australia Thailand Research Collaboration. AIDS 2000; 14: 1349-1356. National Centre in HIV Epidemiology and Clinical Research. HIV/AIDS, viral hepatitis and sexually transmissible infections in Australia. Annual surveillance report 2001. Sydney: National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, 2001. World Health Organization, Western Pacific Region. STD/HIV/AIDS surveillance report, no. 10. Manila: WHO, October 1997. Make a comment Australia14 (based on AIDS notifications; total population, 18 million). Cambodia15 (based on an estimated and projected AIDS incidence; total population, 11 million). Back to text

Gregory J Dore · David A Cooper

Editorial Are the new Lipid Management Guidelines good for Australia's health? Recommendations, possibly resulting in the long-term treatment of one million Australians, require a serious cost-benefit analysis MJA 2001; 175: 452-453 The new Australian Lipid Management Guidelines 2001, published as a supplement with this issue of the Journal, provide an excellent overview of the current evidence on the cardiovascular disease (CVD) benefits of cholesterol lowering. They also signal the acceptance by Australian experts that treatment decisions should be driven primarily by a patient's estimated "absolute CVD risk" — the probability of developing CVD over a specified time period — rather than primarily by his or her blood lipid level. The Guidelines comprehensively summarise the extensive evidence showing the benefits of cholesterol-lowering interventions in people with low-density lipoprotein (LDL) levels above about 2.5-3.0 mmol/L (equivalent to a total cholesterol level above about 4.5-5.0 mmol/L). But they don't tell us that over 90% of Australians aged 45-75 years have a total cholesterol level above 4.5 mmol/L (Dr Danny Liew, Department of Epidemiology and Preventive Medicine, Monash University, VIC, unpublished analysis). The Guidelines correctly emphasise the need to base treatment decisions primarily on absolute CVD risk rather than on lipid levels, as the benefits of cholesterol lowering are determined far more by individual absolute risk than by pre-treatment level of LDL cholesterol. But the advice provided on how to identify patients at high absolute risk, particularly those without previous symptomatic disease, is rather loose, as discussed below. Moreover, the potential size of the target group for drug-based primary prevention is not mentioned. ...it is estimated that this year statins will account for almost a fifth of the total Australian Pharmaceutical Benefits Scheme budget. Lipid-lowering drugs are appropriately recommended for secondary prevention when the total cholesterol level is above 4 mmol/L, given the high absolute risk and large potential benefit of treatment. This patient group includes about 5% of Australians aged 30-79 years (Professor Andrew Tonkin, National Heart Foundation Australia, personal communication). Aboriginal people and Torres Strait Islanders are appropriately identified as high-risk groups, as are people with diabetes (types 1 and 2), although the recommended treatment threshold for Indigenous people and people with diabetes is unclear. If the cholesterol threshold for treatment is also 4 mmol/L in these groups, I estimate this will add at least another 5% of the middle-aged and older Australian population to the numbers eligible for treatment. The authors of the Guidelines endorse the CVD risk charts used in New Zealand for estimating absolute CVD risk.1 This brings Australian lipid management recommendations more in line with those of the international community. Similar charts or risk calculators, all based on data from the Framingham Heart Study, are now included in most major national and international CVD management guidelines.2-6 The Guidelines state that people with an estimated five-year absolute CVD risk of 10%-15% or above (identified using risk charts) are the "at-risk" group who should be targeted for treatment. Alternatively, for doctors who don't use risk charts, the at-risk group includes everyone over 45 years of age with at least one of seven listed risk factors, some of which are ill-defined in the Guidelines (ie, "hypertension" and "overweight"), yet are very prevalent using some common definitions. For people less than 45 years of age, having two listed risk factors also places them in the at-risk group. This "count the risk factors" definition of at-risk is an unnecessarily crude approach and will identify some people with only a 5% five-year CVD risk and exclude others with a five-year risk above 15%. It is also difficult to find a clear statement in the Guidelines about when to initiate drug treatment in this "at-risk" group, and no mention is made of the potential size of the group. I estimate it will include at least another 20% of Australians aged 45-75 years if the cut-off for drug treatment is an LDL cholesterol level of 4 mmol/L or a total cholesterol level of 6 mmol/L (Professor Michael Hobbs, Department of Public Health, University of Western Australia, personal communication). The authors of the Australian guidelines are to be congratulated for their high quality review of the evidence of effectiveness of both population- and individual-level interventions, and for explicitly linking the level of evidence with their recommendations. However, they are remiss in not considering the implications of implementing the recommendations. For example, it is estimated that this year statins will account for almost a fifth of the total Australian Pharmaceutical Benefits Scheme budget.7 While this may or may not be good value for money, it is increasingly accepted that clinical leaders, as well as taking responsibility for individual patients, must also consider the wider resource implications of their recommendations. The practical implications and potential alternative uses of the substantial dollar and people resources required to implement these recommendations should have been considered. For example, it may (or may not) be better value to fund more coronary angioplasties, or to develop more comprehensive rehabilitation programs for patients who have had a myocardial infarction, than to give statins to hundreds of thousands of Australians with a modestly raised risk of CVD. It would also be illuminating to estimate the implications of these recommendations for health professionals, particularly general practitioners and dietitians. It may be that the implementation costs of the new Lipid Management Guidelines 2001 are justified by the magnitude of the benefits. But recommendations that could result in the long-term treatment of perhaps one million Australians, require a substantial amount of general practitioner and dietitian time and consume a significant proportion of the national pharmaceutical budget will require a serious cost-benefit analysis if they are to be endorsed by healthcare funders. Healthcare costs will be cut by insiders with a scalpel or by outsiders with a meat axe.7 In their current form, these Guidelines unfortunately present an exposed neck to a large axe. Rodney T Jackson Professor; and Head, Division of Community Health and Effective Practice Institute, Faculty of Medical and Health Sciences, University of Auckland, NZ Jackson R. Updated New Zealand cardiovascular disease risk-benefit prediction guide. BMJ 2000; 320: 709-710. Dyslipidaemia Advisory Group. 1996 National Heart Foundation clinical guidelines for the assessment and management of dyslipidaemia. N Z Med J 1996; 109: 224-232. Wood D, Durrington P, Poulter N, et al. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998; 80 (Suppl 2):S1-S29. Wood D, De Backer G, Faergeman O, et al. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Atherosclerosis 1998; 140: 199-270. Guidelines Subcommittee. 1999 World Health Organization - International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999; 17: 151-183. Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. JAMA 2001; 285: 2486-2497. Health Insurance Commission. Annual Report 1999-2000. <www.hic.gov.au/statistics/dyn_pbs/forms/pbs_tab1.shtml> Eddy D. What do we do about costs? JAMA 1990; 264: 1161-1170. Make a comment

Rodney T Jackson

Editorial Chronic pain in children Despite the effects on children and their families, children's pain is often under-recognised MJA 2001; 175: 453-454 The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage".1 Implicit in this definition is that pain is a subjective experience and is modulated not only by biological factors, but also by previously painful experiences, the meaning and context of the pain, fear, anxiety, depression, and a range of other factors. Chronic pain is defined as continuous or recurrent pain that persists past the normal time of healing, most commonly about three months' duration.1 If chronic pain refers simply to any pain with this predetermined duration, then all persistent pain of childhood, such as that related to chronic disease (eg, cancer, arthritis, sickle-cell disease), neuropathic pain (eg, complex regional pain syndrome, phantom limb pain) and recurrent pain syndromes (eg, migraine, recurrent abdominal pain), could be classified as causes of chronic pain in children. Little is known about the epidemiology of chronic pain in children. A recent random survey of more than 6000 children in the Netherlands aged 0-18 years indicated an overall prevalence of 25%.2 The prevalence of chronic pain increased with age, and was significantly higher for girls, particularly girls 12-14 years old. The most common types of pain were limb, abdominal pain or headache. Half of the respondents who had experienced chronic pain reported multiple sites of pain, and a third experienced pain as frequent and severe.2 Multiple sites of pain and severe pain were reported more often by girls. The combination of headache and abdominal pain was reported most frequently. These findings indicate that chronic pain is common in children and adolescents. In this issue of the Journal, Chalkiadis presents the first report on chronic pain in children in Australia.3 It is a prospective, descriptive study of the demographic and clinical characteristics of 207 children presenting to the Chronic Pain Clinic at the Royal Children's Hospital, Melbourne, over a two-year period. The study reveals that chronic pain had disturbing consequences for many children. The incidence of school absenteeism, sleep disruption and inability to play sport was high. Implied in these data is a significant psychological burden for the children and the families caring for them. Despite a relatively high prevalence of chronic pain in paediatrics and its significant physical, psychological, social and economic impact on children and their families, it is often under-recognised by clinicians. The reasons for this are multiple and include children's dependency on caregivers to be their advocate. Children with chronic pain can often be met with a dismissive attitude from their caregivers, especially if no organic cause of their pain is found. Furthermore, the advancement in our understanding of the pharmacology of analgesics in children is a relatively recent development.4 The extent to which children may suffer from inadequately managed chronic pain is not known. Recently, in the United States, a major study of children in the terminal phase of cancer painted a chilling picture of suffering, including a high incidence of problems associated with the treatment of pain.5 According to the parents surveyed, 89% of the children suffered "a lot" or "a great deal" from at least one symptom in their last month of life, most commonly pain, fatigue, or dyspnoea. Of the children who were treated for specific symptoms, treatment was successful in 27% of those with pain and 16% of those with dyspnoea.5 Given the many physical and psychological variables in children experiencing chronic pain and the different modalities of treatment now available, the assessment of a child with chronic pain needs to be comprehensive. The team approach involves: an assessment of the physical, psychological and environmental parameters; developing pain management strategies, including pharmacological and non-pharmacological approaches; and individual and family therapy as required. The long term outcomes of these strategies are not known, although Chalkiadis's report reveals at least short term benefit. There has been a long-standing recognition of the need for a comprehensive assessment of chronic pain in adults. In Australia, this has led to multidisciplinary pain centres in many of the major teaching hospitals. In addition, five medical specialist bodies recently came together to form a single physician training program and examination process for the Faculty of Pain Medicine of the Australian and New Zealand College of Anaesthetists. In contrast, it is only in recent years that a team approach to chronic pain in children has evolved in Australia and other countries. It is disturbing to read in Chalkiadis's report that only three paediatric centres in Australia and New Zealand have chronic pain management services which meet the minimum requirements for multidisciplinary staffing. Given the prevalence of chronic pain in children and the potentially serious physical and psychological consequences, a review of these services for children is required. On the basis of US data,5 strategies for the incorporation of pain management and palliative care principles into the care of children with life-threatening and life-limiting illness are a high priority. John J Collins Head, Pain and Palliative Care Service Lynette J Lane Coordinator, Chronic Pain Clinic, Pain and Palliative Care Service Susan Thompson Child and Adolescent Psychiatrist, Chronic Pain Clinic The Children's Hospital at Westmead, Sydney, NSW Merskey H, Bogduk N, editors. Classification of chronic pain: description of chronic pain syndromes and definitions of pain terms. Seattle: IASP Press, 1994. Perquin CW, Hazebroek-Kampschreur AAJM, Hunfeld JAM, et al. Pain in children and adolescents: a common experience. Pain 2000; 87: 51-58. Chalkiadis GA. Management of chronic pain in children. Med J Aust 2001; 175: 476-479. McGrath PJ, Unruh AM, Branson SM. Chronic nonmalignant pain with disability. In: Tyler DC, Krane EJ, editors. Advances in Pain Research and Therapy. Volume 15. New York: Raven Press, 1988. Wolfe J, Grier HE, Klar N, et al. Symptoms and suffering at the end of life in children with cancer. N Engl J Med 2000; 342: 326-333. Make a comment

John J Collins · Lynette J Lane · Susan Thompson

Editorial Breaking the back of back pain Public policy initiatives directed towards managing the disability of back pain can be highly successful MJA 2001; 175: 456-457 Disability from low back pain is a growing public health problem in Australia and developed countries worldwide, and one of the major issues targeted in the Bone and Joint Decade (2000-2010).1 Most population-based surveys of back pain report a point prevalence of 15%-30%, a one-year prevalence of 50%, and a lifetime prevalence of 60%-80%.2 Although episodes of acute low back pain are mostly short-lived, back complaints still constitute the second most common symptom (after upper respiratory complaints) prompting general practice encounters.3 Furthermore, disability from back pain places a significant socioeconomic burden on the individual and the community. In Australia, back problems are the leading specific musculoskeletal cause of health system expenditure, with an estimated total cost of $700 million in 1993-1994.4 Moreover, these costs are rising: in Victoria alone, claims lodged for back injury with the workers' compensation scheme cost the community $510 million in the 1999-2000 financial year.5 Attempts to reduce the burden of disability associated with back pain have often been directed towards prevention of pain per se, particularly in an occupational setting. Although direct involvement of workplace management in primary prevention strategies has had positive effects, interventions such as education, training and exercise programs for the back, ergonomic interventions and screening potential employees for risk factors for the development of back pain or injury have had limited success.6 Paradoxically, interventions aimed at preventing chronicity, such as early exercise, physiotherapy, rehabilitation and education programs, when implemented early (ie, within the first few weeks of back pain), are largely ineffective for improving longer-term outcomes.7 Attitudes and beliefs, particularly fear-avoidance beliefs, pain-coping strategies and illness behaviours, are important issues to consider when treating patients with back pain.8 While psychosocial approaches that seek to remedy unfounded fears and poor coping methods have met with limited success in treating patients with established chronic back disability, these approaches may be effective when implemented early in the course of back pain and could even be of value when directed towards those who have yet to develop back complaints. Provision of positive messages, such as those designed to improve attitudes to back pain and diminish fear, reduce self-reported disability in patients presenting with low back pain in general practice.9 These interventions also reduce extended work absence in industrial settings.10,11 The Victorian WorkCover Authority's statewide media campaign "Back pain — don't take it lying down", which commenced in 1997 (Box 1), aimed to provide a new approach through prime-time television advertisements featuring health professionals, and sports and local television celebrities. The messages, all endorsed by the relevant professional healthcare organisations, were simple: back pain is not a serious medical problem; disability can be reduced and even prevented by positive attitudes; and treatment should consist of continuing to perform usual activities, not resting for prolonged periods, exercising and remaining at work. The campaign counselled individuals with low back pain, their doctors and employers to avoid excessive medicalisation of the problem, and unnecessary diagnostic testing and treatment. A three-part evaluation of this campaign (evaluating general population attitudes, general practitioners, and the WorkCover Authority claims database) suggests that there has been widespread adoption of these messages (Box 2).13,14 The campaign successfully managed to: "de-medicalise" a public health problem; ease the burden on general practitioners and specialists; empower workers to solve their own health challenges; and save workers' compensation payments. The success of the campaign has been attributed to many factors, including the simple, direct language used to convey the messages, and the evidence-based content, both pioneered by the authors of The back book.12 In addition, virtually every professional body with a stake in back pain in Australia supported the campaign. Before this campaign, there was limited empirical evidence that primary preventive interventions reduce the overall burden of illness associated with low back pain. Now, evaluation of the campaign has shown that a public policy initiative directed towards managing the disability of back pain can be highly successful. There are compelling arguments for this approach. These include, firstly, the impression that informative interventions may be of more value when initiated early, even before the onset of symptoms; and, secondly, predictive models of low back pain are not presently able to identify those at risk of disability. By targeting the entire population, this public health approach reaches those hard-to-identify high-risk groups. There is evidence that a population strategy of universal change has greater overall effect than targeted high-risk strategies. Finally, the population approach may be an effective way of modifying doctors' behaviour, both through direct influences as well as through a change in the attitudes of their patients. Media campaigns are an established strategy for delivering preventive health messages. They have been particularly successful in Australia in altering health-related behaviours, such as sunlight exposure through the Slip! Slop! Slap program and smoking through the Quit program. With good evidence that negative attitudes and beliefs are important predictors of disability related to back pain, altering societal views of back pain would seem a highly appropriate policy to adopt. The long-term impact of this campaign is not clear. Recent publicity by the Victorian WorkCover Authority has focused on ergonomic interventions in the workplace — strategies that the United States has controversially rejected. Clinical effectiveness is not the only influence on policy:15 policymakers' own interests and ideologies are often significant. We may have to look to other interested industrialised societies, such as Sweden, the Netherlands or Canada, for evidence of this novel campaign's long-term effectiveness. Competing interests We received funding from the Victorian WorkCover Authority to conduct an independent evaluation of the media campaign. Rachelle Buchbinder Director, Department of Clinical Epidemiology, Cabrini Hospital; and Associate Professor, Monash University Department of Epidemiology and Preventive Medicine, Melbourne, VIC Damien Jolley Associate Professor, School of Health Sciences Deakin University, Melbourne, VIC Mary Wyatt Occupational Physician, Melbourne, VIC Brooks PM, Hart JAL. The Bone and Joint Decade: 2000-2010. Med J Aust 2000; 172: 307-308. Nachemson A, Waddell G, Norlund A. Epidemiology of neck and back pain. In: Nachemson A, Jonsson E, editors. Neck and back pain: The scientific evidence of causes, diagnosis, and treatment. Philadelphia: Lippincott Williams & Wilkins, 2000: 165-188. Bridges-Webb C, Britt H, Miles DA, et al. Morbidity and treatment in general practice in Australia 1990-1991. Med J Aust 1992; 157(Suppl Oct 19): S1-S56. Mathers C, Penn R. Health system costs of injury, poisoning and musculo-skeletal disorders in Australia 1993-94. Canberra: Australian Institute of Health and Welfare, 1999. AIHW Catalogue No. HWE 12 (Health and Welfare Expenditure Series No. 6). Annual Report Victorian WorkCover Authority 1999/2000. Melbourne (VIC): Victorian WorkCover Authority, 2001. Frank JW, Kerr MS, Brooker A-S, et al. Disability resulting from occupational low back pain. Part I: What do we know about primary prevention? A review of the scientific evidence on prevention before disability begins. Spine 1996; 21: 2908-2917. Frank JW, Brooker A-S, DeMaio SE, et al. Disability resulting from occupational low back pain. Part II: What do we know about secondary prevention? A review of the scientific evidence on prevention after disability begins. Spine 1996; 21: 2918-2929. Waddell G, Newton M, Henderson I, Somerville D, Main CJ. A Fear-Avoidance Beliefs Questionnaire (FABQ) and the role of fear-avoidance beliefs in chronic low back pain and disability. Pain 1993; 52: 157-168. Burton A, Waddell G, Tillotson KM, Summerton N. Information and advice to patients with back pain can have a positive effect. A randomised controlled trial of a novel educational booklet in primary care. Spine 1999; 24: 1-8. Symonds TL, Burton AK, Tillotson KM, Main CJ. Absence resulting from low back trouble can be reduced by psychosocial intervention at the work place. Spine 1995; 20: 2738-2745. Indahl A, Velund L, Reikeraas O. Good prognosis for low back pain when left untampered. A randomized clinical trial. Spine 1995; 20: 473-477. Roland M, Waddell G, Moffat J, et al. The back book. London: The Stationery Office; 1996. Buchbinder R, Jolley D, Wyatt M. Population based intervention to change back pain beliefs and disability: three part evaluation. BMJ 2001; 322: 1516-1520. Buchbinder R, Jolley D, Wyatt M. Effects of a media campaign on back pain beliefs and its potential influence on management of low back pain in general practice. Spine 2001. In press. Black N. Evidence based policy: proceed with care. BMJ 2001; 323: 275-278. Make a comment 1: Victorian WorkCover Authority back pain campaign (1997-2000): "Back pain — don't take it lying down" The campaign was based on the messages outlined in The back book, an evidence-based patient educational booklet.12 Messages Positive advice to stay active and exercise, not to rest for prolonged periods, and to remain at work; Encouragement for patients to take responsibility for getting better and coping; Advice that physical activity and work won't cause harm, that investigations may not be helpful, and surgery may not be the answer. Campaign Concentrated campaign for 3 months initially, followed by a low-key maintenance campaign, with a top-up 3-month concentrated campaign 2 years later; Television commercials, aired in prime-time slots; radio and printed advertisements; outdoor billboards, posters, seminars; workplace visits and publicity articles; Promotion by recognised international and national medical experts, Australian sporting and television personalities, and endorsement by the relevant national professional bodies; The back book, translated into 16 languages, made widely available; and Management guidelines for compensable back pain provided to all Victorian doctors. Target audience The general community, health professionals, and employers. Back to text 2: Evaluation of the Victorian WorkCover Authority back pain campaign Study design Quasi-experimental, non-randomised, non-equivalent, before-after telephone surveys of the general population in Victoria, with New South Wales as the control group; Similar before-after postal surveys of general practitioners in both States; and Descriptive analysis of Victorian WorkCover Authority claims database Results Attitudes of the general population to back pain and its treatment in Victoria changed by more than 10%, while in NSW they remained essentially static. Doctors in Victoria, in contrast to those in NSW, reported much lower probabilities of instigating medical interventions for patients presenting with low back pain. There was an immediate and significant impact of the campaign on the patterns of workers' compensation back claims in Victoria. The rate of medical payments for back claims fell by more than 25% during the period October 1997 - October 2000, and the rate of compensated days for back claims dropped from 75 days per 1000 claim-days to 55 days per 1000 claim-days during the same period. Back to text

Rachelle Buchbinder · Damien Jolly · Mary Wyatt

Glucosamine is not invariably effective for osteoarthritis, and its use should be approached with a degree of realism MJA 2001; 175: 399-400 Osteoarthritis is the most common chronic joint disease worldwide.1 It generates a considerable healthcare burden, and has been identified by the World Health Organization as one of several musculoskeletal disorders for special study during the Bone and Joint Decade, initiated in January 2000.2 In recent years, osteoarthritis has attracted increasing attention, with the development of classification criteria,3 radiographic standards,4 clinical trial guidelines,5 core set measures (ie, a minimum set of required outcome measures),6 responder criteria (ie, quantitative changes which differentiate treatment successes from treatment failures),7 and the conduct of clinical trials to evaluate the efficacy of treatments for symptom-modifying or structure (disease)-modifying effects. Enthusiasm for the use of complementary medicines is not new, but recent years have seen formal evaluation of compounds that historically were not subject to the rigorous assessment standards required of commercial pharmaceuticals. Glucosamine sulfate is one such example. In the community of arthritis sufferers, products such as glucosamine sulfate are often viewed as having the potential for benefit with little or no risk of adverse events. Extensive marketing of these types of products exists within the popular literature and on the Internet and may drive consumer interest, particularly given the relatively low cost and emphasised "benefits" of these products. However, expectation and other forms of bias can distort an accurate appreciation of both the benefit and risk, distortions which can only be resolved by properly executed, double-blind, randomised controlled clinical trials. A small number of such trials have been conducted with glucosamine, and, over the short term, the general conclusions are that evidence exists for some degree of efficacy (measured by pain reduction and improved functional outcome) of glucosamine products. A recent meta-analysis of glucosamine and chondroitin8 noted that quality issues affect many available trials, and publication bias is likely to exist. Current glucosamine trials may suffer from one or more of the following limitations: patient selection not based on standard classification criteria;9 small sample sizes;10 short duration of follow-up;10 poor or absent description of radiographic grade of damage at point of entry;10 heterogeneous patients,5 and non-use of standardised primary clinical outcome measures, such as the WOMAC or Lequesne indices (both used as primary outcome measures for lower-limb osteoarthritis studies).5 It is not surprising, therefore, that the most recent American College of Rheumatology management guidelines for knee osteoarthritis11 state that: While a number of studies support the efficacy of both glucosamine and chondroitin sulfate for palliation of joint pain in patients with knee OA, the subcommittee [on osteoarthritis guidelines] believes that it is premature to make specific recommendations about their use at this time because of methodologic considerations, including lack of standardized case definitions and standardized outcome assessments, as well as insufficient information about study design in a number of these published reports. A recent Cochrane systematic review concurs with the College's position. The authors state, "Further research is necessary to confirm the long term effectiveness and toxicity of glucosamine therapy in OA".12 Reginster and colleagues13 recently reported a methodologically rigorous three-year study of glucosamine versus placebo in 212 patients with knee osteoarthritis, which demonstrated statistically significant, symptom-modifying and structure-modifying effects favouring the glucosamine group. The symptom-modifying effects appear to be clinically important in the short-term. However, the authors acknowledge that the long-term clinical efficacy remains to be established, and consensus has not yet been reached on the clinical importance of structural conservation effects. There is thus a growing body of evidence for the efficacy of glucosamine in symptom modification, and, given the low level of adverse side effects noted from these products and the relatively low cost, it may be reasonable for some patients with knee osteoarthritis to try taking glucosamine. It should be noted, however, that a very recent review co-authored by a senior and highly respected academic rheumatologist in the United Kingdom concluded "there is more confusion and hype than magic about glucosamine". The authors cautioned against its wholesale use and recommended the need for "further large clinical trials without company interference".14 From a practical standpoint, glucosamine is not invariably effective for osteoarthritis, and its use should be approached with a degree of realism. It is well recognised that there is considerable interindividual variability in the response to treatments for osteoarthritis based on non-steroidal anti-inflammatory drugs (NSAIDs),15 and glucosamine is not likely to differ in this regard. It is likely that glucosamine may meet the symptom-modifying needs of some, but not all, patients. Furthermore, the patient profile and determinants of a glucosamine "responder" are yet to be discovered. Given the severity and multiplicity of joint involvement, it is likely that glucosamine will be taken as a monotherapy in some patients, but as a co-therapy in others. Furthermore, given the long time course of osteoarthritis, it is likely that glucosamine, even in respondents, may be suitable at some points in time, but not others, and discontinuations due to inefficacy can be anticipated. To date, there does not appear to be a substantial basis for major concerns about safety, although this issue continues to attract occasional attention (concerning the effect of glucosamine in glucose metabolism).16 It is likely that, together with non-pharmacological therapies, analgesics, NSAIDs, selective and specific COX-2 inhibitors, viscosupplements, and intra-articular steroids, glucosamine will be useful in the management of patients with knee osteoarthritis, as all of these therapies have been shown to be superior to placebo in symptom-modifying studies. Whether glucosamine is efficacious in advanced disease, in particular patient subgroups, or, indeed, whether it is superior to any of the aforementioned interventions, remains to be evaluated. The study of Reginster and colleagues raises the question of whether glucosamine may have structure-modifying potential, but this issue requires considerable further study before any general recommendation can be made for the use of glucosamine in this context. The best current advice for the use of glucosamine in osteoarthritis is for practitioners to be aware of, and follow, the general spirit of the American College of Rheumatology guidelines for the management of knee osteoarthritis, which include not only the use of pharmacological agents and devices, but also the role of non-pharmacological interventions such as patient education, self-management programs, weight reduction, aerobic exercise, muscle strengthening, and physical therapy.11 For more information on the Bone and Joint Decade, see <www.bonejointdecade.org> Nicholas Bellamy Professor and Director Sean G Lybrand Musculoskeletal Research Associate Centre of National Research on Disability and Rehabilitation Medicine The University of Queensland, Brisbane, QLD nbellamyATmedicine.uq.edu.au Felson DT. Epidemiology of osteoarthritis. In: Brandt KD, Doherty M, Lohmander LS, editors. Osteoarthritis. New York: Oxford University Press, 1998. Brooks PM, Hart JAL. The Bone and Joint Decade 2000-2010. Med J Aust 2000; 172: 307-308. Altman RD. Criteria for classification of clinical osteoarthritis. J Rheum 1991; 18: 10-11. Altman RD, Hochberg M, Murphy WA Jr, et al. Atlas of individual radiographic features in osteoarthritis. Osteoarthritis Cartilage 1995; 3(Suppl A): 3-70. Osteoarthritis Research Society (OARS). Task Force Report: Design and Conduct of Clinical Trials of Patients with Osteoarthritis: Recommendations from a Task Force of the Osteoarthritis Research Society. Osteoarthritis Cartilage 1996; 4: 217-243. Bellamy N, Kirwan J, Boers M, et al. Recommendations for a core set of outcome measures for future phase III clinical trials in knee, hip and hand osteoarthritis. Consensus development in OMERACT III. J Rheumatol 1997; 24: 799-802. Dougados M, LeClaire P, van der Heijde D, et al. Response criteria for clinical trials on osteoarthritis of the knee and hip: a report of the Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative. Osteoarthritis Cartilage 2000; 8: 395-403. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000, 283: 1469-1475. Hochberg M, Altman R, Brandt K, et al. Recommendations for the medical management of osteoarthritis of the hip and knee. 2000 update. Arthritis Rheum 2000; 43: 1905-1915. Qiu GX, Gao SN, Giacovelli G, et al. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung 1998; 48: 469-474. Towheed TE, Anastassiades TP. Glucosamine and chondroitin for treating symptoms of osteoarthritis: evidence is widely touted but incomplete. JAMA 2000; 283: 1483-1484. Towheed TE, Anastassiades TP, Shea B, et al. Glucosamine therapy for treating osteoarthritis (Cochrane Review) [abstract]. In: The Cochrane Library, 2, 2001. Oxford: Update Software. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001; 357: 251-256. Chard J, Dieppe P. Glucosamine for osteoarthritis: magic, hype, or confusion? Lancet; 2001, 322: 1439-1440. March L, Irwig L, Schwarz J, et al. N of 1 trials comparing a non-steroidal anti-inflammatory drug with paracetamol in osteoarthritis. BMJ 1994; 309: 1041-1045. Rovati LC, Annefeld M, Giacovelli G, et al. Glucosamine in osteoarthritis [letter]. Lancet 1999; 354: 1640. Make a comment

Nicholas Bellamy · Sean G Lybrand

Editorial Confronting conflict of interest in research organisations: time for national action There is a pressing need for an open inquiry and the formulation of national guidelines MJA 2001; 175: 396-397 Public trust in universities and research institutes is embedded in notions of intellectual integrity and independence. Crucial to this trust is the belief that these virtues are protected by an environment that values intellectual freedom, an unfettered exchange of information and ideas, and the pursuit of research for the public good. Of late, however, this trust is threatened by the increasing involvement of industry in research funding and a blurring of research ideals and corporate interests.1,2 At the present time, this situation is more acute in the United States, but, as our governments, universities and research institutes increasingly pursue policies which blend research creativity and corporate capital,3-5 there is no reason to believe that Australia will escape placing research integrity and public trust at risk. Developments in the United States that have prompted a focus on the propriety of biomedical and clinical research include: A shift in the source of research funding from predominantly government and private foundations to industry. A substantial proportion of the US$55-$60 billion of industry research and development capital is now directed to basic biomedical research and clinical trials.6 Indeed, in 1999, the top 10 pharmaceutical companies spent US$22.7 billion primarily on clinical research, compared with the US$17.8 billion provided mostly for basic research by the US National Institutes of Health.2 A shift away from academic centres to non-academic research organisations for the performance of clinical trials. In the United States, contract research organisations now receive up to 60% of the research funding available from the pharmaceutical industry for clinical trials.7 This shift has seen untoward effects on the control of trial design, the access to and analysis of data, and the publication of results.8 There is growing evidence that researchers with industry ties are more likely to report results favourable to corporate sponsors,9-12 to conduct research of lower quality,13,14 and to either delay publication15 or not to publish at all.16,17 A shift in the free flow of information. Researchers receiving funding from industry are more likely to restrict communications with their colleagues.18 A shift to an entrepreneurial ethos in universities and research institutes. The securing of the all-important patent plays an increasing role in research and often represents the first move of researchers and institutions towards entrepreneurship. In the United States, university-generated patents have increased from about 250 per year before 1980 to nearly 5000 in 1998.19 At the centre of the disquiet attending these developments are concerns about conflict of interest — a conflict which may affect ethical behaviour, the quality of research undertaken, or the dissemination of its outcomes. Most guidelines for conflict of interest pertain to individual researchers or faculty members, but conflicts of interest may also apply to institutions such as universities or research institutes. Can these entities effectively oversee their investigators when both the institutions and the investigators share parallel aspirations in acquiring industry funding, equity or royalties? In Australia, extensive examination of and public debate on conflict of interest involving institutions is of low priority; indeed, some of our leaders in academia, research and bureaucracy have dismissed this issue as irrelevant to the business of research.20,21 Not so in the United States, where exploring the extent of and solutions to conflict of interest is firmly on the national agenda.22,23 Indeed, Moses and Martin have recently advanced some general principles that may guide the exploration of appropriate frameworks.6 These include: The veracity of results of basic research and clinical trials research should not be compromised. Research integrity is best protected by isolating research from economic pressures. Oversight of the industry-research relationship should be by a disinterested party. Independent individuals without a financial stake should examine the relationship from its inception and at appropriate junctures. Proprietary rights, control of intellectual property and the right to publish should be established at the onset, with minimal caveats on non-disclosure and confidentiality and provisions to ensure future flexibility of research directions. Financial and non-financial incentives should be designed to fulfil the needs of both the researchers and the institution. Potential solutions advanced by Moses and Martin to accommodate the fusion of industry, academia and research include: The creation by universities of separate entities to isolate commercially sponsored research from other research, yet still allow movement of researchers back and forth within defined limitations. The creation of entities independent of universities or research institutes to hold and control equity, thus solving the problem of the holding of equity by individuals. Individual components of equity could be managed as a portfolio of investments, with individuals assigned units of equity.6 All the above considerations are propelled by concerns about conflict of interest. But, as Korn recently noted: Conflicts of interest are ubiquitous and inevitable in academic life; indeed, in all professional life. The challenge for academic medicine is not to eradicate them, which is fanciful and would be inimical to public policy goals, but to recognize and manage them sensibly and effectively.24 In 2000, the US Department of Health and Human Services sponsored a conference to explore new ways to deal with financial conflict of interest and to ensure the integrity of research and the protection of human subjects in research.22 Such a public discourse is long overdue in Australia. We are at the beginning of industry involvement in research and this involvement should be vigorously promoted and pursued. But, instead of some time in the future, inheriting the US concerns about the propriety of biomedical research and clinical trials, should we not now confront institutional conflict of interest by open inquiry and the formulation of national guidelines? This will require a more visible leadership by the national overarching bodies in academia, science and medical research. Failure to do so will only lead to the impression that research is yet another commercial commodity and invite the inevitable erosion of public trust. Without public trust medical research is doomed. Martin B Van Der Weyden Editor, Medical Journal of Australia Angell M. Is academic medicine for sale [editorial]. N Engl J Med 2000; 342: 1516-1518. DeAngelis CD. Conflict of interest and the public trust, [editorial]. JAMA 2001; 284: 2237-2238. Wills PJ (Chair). The Health and Medical Research Strategic Review. The virtuous cycle — working together for health and medical research. Canberra: Commonwealth Department of Health and Aged Care, 1999. Innovation. Unlocking the future. Final report of the Innovation Summit Implementation Group. Canberra: Commonwealth Department of Industry, Science and Resources, 2000. Backing Australia's ability: an innovation plan for the future. Canberra: Commonwealth Department of Industry, Science and Resources, 2001. Moses H III, Martin JB. Academic relationship with industry. A new model for biomedical research. JAMA 2001; 285: 933-935. Henderson L. More AMCs finding growth from reform. Centerwatch 2000; 7(6) 1: 10-13. Bodenheimer T. Uneasy alliance. Clinical investigators and the pharmaceutical industry. N Engl J Med 2000; 342: 1539-1543. Bero LA, Galbraith A, Rennie D. The publication of sponsored symposiums in medical journals. N Engl J Med 1992; 327: 1135-1140. Rochon PA, Gurwitz JH, Simms RW, et al. A study of manufacturer-supported trials of nonsteroidal anti-inflammatory drugs in the treatment of arthritis. Arch Intern Med 1994; 154: 157-163. Cho MK, Bero LA. The quality of drug studies published in symposium proceedings. Ann Intern Med 1996; 124: 485-489. Stelfox HT, Chua G, O'Rourke K, Detsky AS. Conflict of interest in the debate about calcium channel antagonists. N Engl J Med 1998; 338: 101-106. Rochon P. Evaluating the quality of articles published in journal supplements compared with the quality of those published in the parent journal. JAMA 1994; 272: 108-113. Bero LA, Rennie D. Influences on the quality of published drug studies. Int J Technol Assess Health Care 1996; 12: 209-237. Rennie D. Thyroid storm. JAMA 1997; 227: 1238-1243. Friedberg M, Saffran B, Stinson TJ, et al. Evaluation of conflict of interest in economic analysis of new drugs used in oncology. JAMA 1999; 282: 1453-1457. Blumenthal D, Campbell EG, Anderson MS, et al. Withholding research results in academic life science. Evidence from a national survey of faculty. JAMA 1997; 277: 1224-1228. Blumenthal D, Campbell EG, Causino N, Louis KS. Participation of life-science faculty in research relationships with industry. N Engl J Med 1996; 335: 1734-1739. The United States Association of University Technology Managers (AUTM). The AUTM Licensing Survey. FY 98. http://www.autm.net/ and http://www.autm. net/pubs/survey/1998/execsumm.html (accessed September 2001). Quiddington PT. When science, knowledge, truth and sex collide. Science debate turns up the heat. Campus Review August 29-Sept 4 2001; 1. Moynihan R. The devil's dollar: the commercial pressure on science and medicine. The Australian Financial Review, 2001; Sept 8-9: 22-23. Agnew B. HHS Conference on conflict of interest in clinical research will raise a new question: should research universities worry about their own conflicts of interest? Washington Fax July 20 2000 <http:// www.washingtonfax.com/p1/ 2000/20000720.html> (accessed September 2001). Stolberg SG. Biomedicine is receiving new scrutiny as scientists become entrepreneurs. The New York Times 2000; February 20. <http:// www.nytimes.com> (accessed September 2001). Korn D. Conflicts of interest in biomedical research. JAMA 2000; 284: 2234-2237. Make a comment

Editorial Holistic care in hospital patients Patients who require long-term, frequent specialty care may have their primary healthcare needs ignored MJA 2001; 175: 292-293 In this issue of the Journal, Jang and colleagues highlight an apparent neglect of women's health issues in a cohort of women undergoing regular haemodialysis in Victoria.1Their cross-sectional survey of 48 women undergoing haemodialysis in hospitals or satellite dialysis centres contributes to the scarce literature on reproductive health issues in women with end-stage renal disease (ESRD). It also clearly illustrates the potential for holistic care to be neglected when patients are managed in a highly specialised environment. The most startling finding of the study is the poor adherence to accepted guidelines for cervical cancer screening and mammography: 55% of patients had not had cervical screening within the previous two years, while 38% of those aged 50 years or over had not had mammography within the same period. These findings are echoed in a recent report on women undergoing haemodialysis in the United States.2 The figures compare with contemporary Australian screening adherence rates of 64% for cervical screening (women aged 20-69 years)3 and 54% for mammography (women aged 50-69 years).4 Thus, despite intense contact of dialysis patients with the healthcare system, adherence to screening is lower than in the general population. Results from the survey also indicate the need to improve sexual counselling, contraceptive advice, menopausal management and fracture prevention among these women. . . . why are nephrologists, or indeed other hospital-based specialists, not currently dealing with patients' global health issues? . . . Consideration of hormone replacement therapy (HRT) and osteoporosis treatment is difficult in women with ESRD. As the authors outline, HRT carries a potential risk of vascular access thrombosis, and there are currently no evidence-based data on the risk-benefit ratio in this group.5 Treating or preventing bone disease in ESRD is complex, and currently limited by lack of efficacy and side effects of the common therapeutic agents and lack of data on agents such as bisphosphonates. Nevertheless, it is surprising that few of the 11 postmenopausal patients with fractures could recall HRT being discussed with them, and only one was taking this therapy. An important question raised by this survey is "Who should be responsible for general healthcare issues in these patients?". The report does not say how many respondents claimed to have a general practitioner (GP) and, if so, maintained regular contact with this GP. However, a reason usually given by dialysis patients for not attending a GP is that they already spend many hours at the hospital or dialysis centre (usually about four hours, three times a week) and, not unreasonably, expect all their health issues to be dealt with during that contact. Jang and colleagues conclude from their survey that hospital-based dialysis services should include a service that deals with women's health issues to ensure that this aspect of their routine health management is not neglected. So, why are nephrologists, or indeed other hospital-based specialists, not currently dealing with patients' global health issues? Clearly, specialists are generally aware of guidelines for women's health screening. However, it is not a major daily focus of the already complicated care of their patients and is more likely to be overlooked by a physician focusing on time-consuming, dialysis-related problems. The burgeoning number of dialysis patients combines with limited funding to compound this problem. In view of these real-life pressures, I suggest an alternative approach that involves patients' GPs, whose daily practice already encompasses women's health screening. Since 1995, the Renal Unit at the Princess Alexandra Hospital, Brisbane, has implemented a "Renal Care and Support Program" to consolidate links between GPs and dialysis and transplant centres. Interaction is via a booklet which contains a summary of the patient's active and past problems, status of their health screening checks (such as those raised by Jang and colleagues), list of medications, information pages and key guidelines for care of the ESRD patient. Advances in information technology continue to enhance these lines of communication. Many studies have shown that integrated management involving GPs achieves outcomes similar to, and in some instances better than, hospital care.6 Our program aims to address the global health issues of patients.7In comparison, the model proposed by Jang seems limited. It would underutilise the skills of primary care physicians in healthcare screening, duplicate services available in general practice, and move these aspects of patient care to a system and staff not resourced to deal with them. However, if GPs are to be significantly involved in the care of patients with ESRD, we must consider the suitability of applying general principles of care to these patients. This, I believe, can be achieved by providing guidelines in specific areas where approaches differ. For example, it is reasonable to exercise caution in administering HRT to a patient with recurrent vascular-access thrombosis, and some women with ESRD have such a poor prognosis that applying general population guidelines is not appropriate. This issue has not been addressed by Jang and colleagues. The findings of Jang's study illuminate an increasing problem in our contemporary healthcare system: patients who have frequent contact with subspecialty care may have primary healthcare issues ignored. One way of addressing this issue is a hospital-based service to deal with women's health issues, as proposed by Jang and colleagues, while an alternative is shared care between the specialist service and GPs. Clearly, further consideration and research is required. The issues raised are also likely to translate to subspecialty services other than nephrology. Carmel M Hawley Director of Nephrology Princess Alexandra Hospital, Brisbane, QLD carmel_hawleyAThealth.qld.gov.au Jang C, Bell RJ, White VS, et al. Women's health issues in haemodialysis patients. Med J Aust 2001; 175: 298-301. Rush H, Neugarten J, Coco M. Women's health issues in a dialysis population. Clin Nephrol 2000; 54: 455-462. Cervical screening in Australia 1997-1998. Canberra: Australian Institute of Health and Welfare, 2000. (AIHW Cat. No. CAN 9.) BreastScreen Australia achievement report 1997 and 1998. Canberra: Australian Institute of Health and Welfare, 2000. (AIHW Cat. No. CAN 8.) Weisinger JR. Role of hormone replacement in the management of osteoporosis in haemodialysis women: perspectives for the future. Nephrol Dial Transplant 2000; 15 Suppl 5: 36-37. Hampson J, Roberts R, Morgan D. Shared care: a review of the literature. Fam Pract 1996; 13: 264-279. Smith R, de Looze F, Kelly B, Rigby R. "Shared care". An integrated model of service delivery for renal and renal transplant patients [abstract]. Abstracts of the 35th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology; 3-5 Mar, 1999; Brisbane (QLD). Make a comment

Carmel M Hawley

Editorial Tumour banks: providing human tissue for cancer research Providing there are safeguards to protect the rights of patients, the supply of human tissue for research can benefit the community as a whole MJA 2001; 175: 293-294 Unprecedented insights into the biology of cancer cells are coming from research using recently developed methods such as global gene expression analysis.1 In clinical oncology, the benefits of these advances are likely to be significant in the diagnostic classification of tumours and informed design of novel anticancer agents. However, for this potential to be realised, the molecular analysis of large numbers of tumours is required, which in turn is dependent on the availability of collections of well-preserved and well-characterised tumour tissue for research. Coincident with increased need for human tissue specimens in cancer research is the increased complexity of the attending ethical issues. Ironically, it is the power of modern genetic analysis that creates the most difficult ethical dilemmas. The potential for discovering inherited genetic lesions that confer an increased risk of developing cancer (eg, a mutation in the breast cancer susceptibility gene BRCA1) has led to concern that "genetic research" may uncover information that is unwanted by the patient, has implications for family members and could potentially lead to discrimination.2 Serious ethical questions are also raised by the involvement of commercial interests in human-tissue-based research, in particular relating to potential conflicts of interest and the distribution of financial benefits.2,3 Moreover, these ethical issues must be negotiated in the current climate of public concern following recent media reporting on the retention of human organs following autopsy.4,5 Cancer remains a leading cause of morbidity and mortality in our community and the continued need for research into its nature and treatment is undisputed. It is also clear that society's view on involvement of individuals in all aspects of their healthcare has changed, resulting in the expectation of a more stringent regulatory environment for the conduct of research. This is reflected in a number of initiatives relevant to the collection and use of human tissue. In 1999, the National Health and Medical Research Council (NHMRC) issued updated guidelines for the conduct of ethical research involving humans.6 The guidelines incorporate the internationally accepted principles of integrity, respect for persons, beneficence and justice in the conduct of research, and reaffirm the crucial role of independent human research ethics committees (HRECs) to review and regulate research in specific institutions. Recently, the necessity for legislation on these issues has been considered, with a proposed review of the Human Tissue Act 1983 (NSW)7 and a joint inquiry into protection of human genetic information by the Australian Law Reform Commission and the Australian Health Ethics Committee of the NHMRC.8 The supply of human tissue for cancer research requires an integrated system of safeguards to protect the rights of patients, allow research that may benefit the wider community to continue, and offer a workable framework for hospitals, and, in particular, pathology departments, to support the process. Increasingly, tumour banks are emerging as an appropriate response to the concerns of involved parties. A tumour bank is an independent facility that collects samples of surgical specimens removed in the course of usual treatment from cancer patients who have given informed consent for their removal and use in research. The tissue taken is in excess of requirements for histopathological assessment and may include both cancer and normal tissue. The tumour bank also includes a database of relevant demographic, clinical and follow-up information.9 Researchers may apply to the tumour bank for samples to use in projects that have appropriate HREC approval. The decision to supply samples is generally made by a committee, comprised of clinicians and scientists, on the basis of scientific merit, available resources and the extent of collaboration with groups involved in collection of tumour bank specimens. The key safeguard in the conduct of ethical research is the involvement of an HREC, and the most important issues for the HREC to oversee in relation to a tumour bank pertain to donor consent and privacy protection.6 The informed consent process relating to tumour banks does not involve supply of the specific details of research projects, as these may not be known at the time of sample collection. The non-specific nature of this consent needs to be taken into account by the HREC when researchers proposing to use tumour bank specimens submit projects for review.6 The extent to which research participants are identifiable is an important factor. Tumour banks maintain links between donor identity and tissue samples, but supply samples to researchers without identifying information.9 The benefits of this system are that the privacy of donors is protected while maintaining the capacity to collect valuable follow-up information and to recontact donors if necessary. In the event that research studies uncovered information that might be relevant to the wellbeing of a donor, the HREC would play a pivotal role in consideration of the issues. Establishment and management of a tumour bank is a long-term commitment requiring substantial resources and secure funding. However, these costs must be met to ensure that progress in cancer research continues, ethical challenges posed by new investigative technology are met and public confidence in the conduct of research is maintained. Rosemary L Balleine Staff Specialist Karen E Humphrey Senior Tumour Bank Officer Christine L Clarke NHMRC Senior Research Fellow, and Department Head Department of Translational Oncology, Westmead and Nepean Hospitals Westmead, NSW rosemary_balleineATwmi.usyd.edu.au Marx J. DNA arrays reveal cancer in its many forms. Science 2000; 289: 1670-1672. Reilly PR, Boshar MF, Holtzman SH. Ethical issues in genetic research: disclosure and informed consent. Nat Genet 1997; 15: 16-20. Magnusson RS. The use of human tissue samples in medical research: legal issues for human research ethics committees. J Law Med 2000; 7: 390-403. Jacobsen G. Morgue chief removed over "sickening" tests. Sydney Morning Herald 2001; 19 March; 3. Retention of organs after necropsy. Lancet 2001; 357: 157. National Health and Medical Research Council. National statement on ethical conduct in research involving humans. Commonwealth of Australia, 1999. Available at: <http://www.nhmrc.gov.au/publications/pdf/e35.pdf>. Accessed 14 August 2001. Review of the Human Tissue Act 1983 (NSW). Discussion paper. Organ and tissue donation and use and post mortem examination. October 1999. Available at <http://www.health.nsw.gov.au/csd/llsb/organ/issuespaper.pdf>. Accessed 7 August 2001. Protection of human genetic information. A joint inquiry of the Australian Law Reform Commission and Australian Health Ethics Committee of the National Health and Medical Research Council. Commonwealth of Australia, February 2001. Available at: <http//:www.alrc.gov.au/current/genetic/overview.htm>. Accessed 14 August 2001. Grizzle WE, Aamodt R, Clausen K, et al. Providing human tissues for research: how to establish a program. Arch Pathol Lab Med 1998; 122: 1065-1076. Make a comment

Rosemary L Balleine · Karen E Humphrey · Christine L Clarke

MJA 2001; 175: 294-296 As editors of general medical journals, we recognise that the publication of clinical-research findings in respected peer-reviewed journals is the ultimate basis for most treatment decisions. Public discourse about this published evidence of efficacy and safety rests on the assumption that clinical-trials data have been gathered and are presented in an objective and dispassionate manner. This discourse is vital to the scientific practice of medicine because it shapes treatment decisions made by physicians, and drives public and private healthcare policy. We are concerned that the current intellectual environment in which some clinical research is conceived, study subjects are recruited, and the data analysed and reported (or not reported) may threaten this precious objectivity. Clinical trials are powerful tools; like all powerful tools, they must be used with care. They allow investigators to test biological hypotheses in living patients, and they have the potential to change the standards of care. The secondary economic impact of such changes can be substantial. Well-done trials, published in high-profile journals, may be used to market drugs and medical devices, potentially resulting in substantial financial gain for the sponsor. But powerful tools must be used carefully. Patients participate in clinical trials largely for altruistic reasons — that is, to advance the standard of care. In the light of that truth, the use of clinical trials primarily for marketing, in our view, makes a mockery of clinical investigation and is a misuse of a powerful tool. Until recently, academic, independent clinical investigators were key players in design, patient recruitment, and data interpretation in clinical trials. The intellectual and working home of these investigators, the academic medical centre, has been at the hub of this enterprise, and many institutions have developed complex infrastructures devoted to the design and conduct of clinical trials.1,2 The academic enterprise has been a critical part of the process that led to the introduction of many new treatments into medical practice and contributed to the quality, intellectual rigour, and impact of such clinical trials. But, as economic pressures mount, this may be a thing of the past. Many clinical trials are performed to facilitate regulatory approval of a device or drug rather than to test a specific novel scientific hypothesis. As trials have become more sophisticated and the margin of untreated disease harder to reach, there has been a great increase in the size of the trials and consequently in the costs of developing new drugs. It is estimated that the average cost of bringing a new drug to market in the United States is about $500 million.3 The pharmaceutical industry has recognised the need to control costs and has discovered that private non-academic research groups — that is, contract research organisations (CROs) — can do the job for less money and with fewer hassles than academic investigators. Over the past few years CROs have received the lion's share of clinical-trial revenues. For example, in 2000 in the United States, CROs received 60% of the research grants from pharmaceutical companies, as compared with only 40% for academic triallists.1 As CROs and academic medical centres compete head to head for the opportunity to enrol patients in clinical trials, corporate sponsors have been able to dictate the terms of participation in the trial, terms that are not always in the best interests of academic investigators, the study participants, or the advancement of science generally.4 Investigators may have little or no input into trial design, no access to the raw data, and limited participation in data interpretation. These terms are draconian for self-respecting scientists, but many have accepted them because they know that, if they do not, the sponsor will find someone else who will. And, unfortunately, even when an investigator has had substantial input into trial design and data interpretation, the results of the finished trial may be buried rather than published if they are unfavourable to the sponsor's product. Such issues are not theoretical. There have been a number of recent public examples of such problems, and we suspect that many more go unreported.5,6 As editors, we strongly oppose contractual agreements that deny investigators the right to examine the data independently or to submit a manuscript for publication without first obtaining the consent of the sponsor. Such arrangements not only erode the fabric of intellectual enquiry that has fostered so much high-quality clinical research, but also make medical journals party to potential misrepresentation, since the published manuscript may not reveal the extent to which the authors were powerless to control the conduct of a study that bears their names. Because of our concern, we have recently revised and strengthened the section on publication ethics in the Uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication, a document developed by the International Committee of Medical Journal Editors (ICMJE) and widely used by individual journals as the basis for editorial policy. The revised section is in the Box. (The entire uniform requirements document is currently undergoing revision; the revised version should be available at the beginning of 2002.) As part of the reporting requirements, we will routinely require authors to disclose details of their own and the sponsor's role in the study. Many of us will ask the responsible author to sign a statement indicating that he or she accepts full responsibility for the conduct of the trial, had access to the data, and controlled the decision to publish. We believe that a sponsor should have the right to review a manuscript for a defined period (eg, 30-60 days) before publication to allow for the filing of additional patent protection, if required. When the sponsor employs some of the authors, these authors' contributions and perspective should be reflected in the final paper, as are those of the other authors, but the sponsor must impose no impediment, direct or indirect, on the publication of the study's full results, including data perceived to be detrimental to the product. Although we most commonly associate this behaviour with pharmaceutical sponsors, research sponsored by governmental or other agencies may also fall victim to this form of censorship, especially if the results of such studies appear to contradict current policy. Authorship means both accountability and independence. A submitted manuscript is the intellectual property of its authors, not the study sponsor. We will not review or publish articles based on studies that are conducted under conditions that allow the sponsor to have sole control of the data or to withhold publication. We encourage investigators to use the revised ICMJE requirements on publication ethics to guide the negotiation of research contracts. Those contracts should give the researchers a substantial say in trial design, access to the raw data, responsibility for data analysis and interpretation, and the right to publish — the hallmarks of scholarly independence, and ultimately academic freedom. By enforcing adherence to these revised requirements, we can, as editors, assure our readers that the authors of an article have had a meaningful and truly independent role in the study that bears their names. The authors can then stand behind the published results, and so can we. International Committee of Medical Journal Editors (signatories to the revised statement) Frank Davidoff, MD, Editor Emeritus, Annals of Internal Medicine. Catherine D DeAngelis, MD, MPH, Editor, The Journal of the American Medical Association. Jeffrey M Drazen, MD, Editor-in-Chief, The New England Journal of Medicine. M Gary Nicholls, MD, Editor, The New Zealand Medical Journal. John Hoey, MD, Editor, Canadian Medical Association Journal. Liselotte HØjgaard, MD, DMSc, Editor-in-Chief, Ugeskrift for Læge (Journal of the Danish Medical Association). Richard Horton, FRCP, Editor, The Lancet. Sheldon Kotzin, Executive Editor, MEDLINE/Index Medicus. Magne Nylenna, MD, Editor-in-Chief, Tidsskrift for Den norske Lægeforening (Journal of the Norwegian Medical Association). A John P M Overbeke, MD, PhD, Executive Editor, Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine). Harold C Sox, MD, Editor, Annals of Internal Medicine. Martin B Van Der Weyden, FRACP, Editor, The Medical Journal of Australia. Michael S Wilkes, MD, PhD, Editor, wjm Western Journal of Medicine. Henderson L. More AMCs finding growth from reform. Centerwatch 2000; 7(6): 1, 10-13. Kowalczyk L. Harvard, other medical schools aim to give drug firms faster pace for trials. Boston Globe 2000; Jul 28, C4. Mathieu MP. Parexel's pharmaceutical R&D statistical sourcebook, 1998 edition. Waltham, Mass: Parexel International Corporation, 1999. Rennie D. Thyroid storm. JAMA 1997; 277: 1238-1243. Kahn JO, Cherng DW, Mayer K, et al, for the 806 Investigator Team. Evaluation of HIV-1 immunogen, an immunologic modifier, administered to patients infected with HIV having 300 to 549 x 106/L CD4 cell counts. A randomized controlled trial. JAMA 2000; 284: 2193-2202. Blumenthal D, Campbell EG, Anderson MS, et al. Withholding research results in academic life science: evidence from a national survey of faculty. JAMA 1997; 277: 1224-1228. Make a comment Publication ethics From the Uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication (the full revised Uniform requirements will be published later) Conflict of interest Public trust in the peer review process and the credibility of published articles depend in part on how well conflict of interest is handled during writing, peer review, and editorial decision making. Conflict of interest exists when an author (or the author's institution), reviewer, or editor has financial or personal relationships with other persons or organisations that inappropriately influence (bias) his or her actions. The potential of such relationships to create bias varies from negligible to extremely great; the existence of such relationships does not necessarily represent true conflict of interest, therefore. (Relationships that do not bias judgement are sometimes known as dual commitments, competing interests, or competing loyalties.) The potential for conflict of interest can exist whether or not an individual believes that the relationship affects his or her scientific judgement. Financial relationships (such as employment, consultancies, stock ownership, honoraria, paid expert testimony) are the most easily identifiable conflicts of interest and the most likely to undermine the credibility of the journal, the authors, and of science itself. Conflicts can occur for other reasons, however, such as personal and family relationships, academic competition, and intellectual passion. All participants in the peer review and publication process must disclose all relationships that could be viewed as presenting a potential conflict of interest. Disclosure of these relationships is particularly important in connection with editorials and review articles, because bias can be more difficult to detect in those publications than in reports of original research. Editors may use information disclosed in conflict of interest and financial interest statements as a basis for editorial decisions. Editors should publish this information if they believe it will be important to readers in judging the manuscript. Potential conflicts of interest related to individual authors' commitments When authors submit a manuscript, whether an article or a letter, they are responsible for disclosing all financial and personal relationships between themselves and others that might bias their work. To prevent ambiguity, authors must state explicitly whether potential conflicts do or do not exist. Authors should do so in the manuscript on a conflict of interest notification page that follows the title page, providing additional detail, if necessary, in the accompanying cover letter. Investigators should disclose potential conflicts to study participants, and should state in the manuscript whether they have done so. Editors also need to decide when to publish information disclosed by authors about potential conflicts. If doubt exists, it is best to err on the side of publication. Potential conflicts of interest related to project support Increasingly, biomedical studies receive funding from commercial firms, private foundations, and government. The conditions of this funding have the potential to bias and otherwise discredit the research. Scientists have an ethical obligation to submit creditable research results for publication. As the persons directly responsible for their work, researchers therefore should not enter into agreements that interfere with their access to the data or their ability to analyse the data independently, to prepare manuscripts, and to publish them. Authors should describe the role of the study sponsor(s), if any, in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the report for publication. If the supporting source had no such involvement, the authors should so state. Biases potentially introduced when sponsors are directly involved in research are analogous to methodological biases of other sorts; some journals therefore choose to include information about the sponsor's involvement in the methods section of the published paper. If a study is funded by an agency with a proprietary or financial interest in the outcome, editors may ask authors to sign a statement such as, "I had full access to all of the data in this study and I take complete responsibility for the integrity of the data and the accuracy of the data analysis". Editors should be encouraged to review copies of the protocol and/or contracts associated with project-specific studies before accepting such studies for publication. Editors may choose not to consider an article if a sponsor has asserted control over the authors' right to publish. Conflicts of interest related to commitments of editors, journal staff, or reviewers Editors should avoid selecting external peer reviewers with obvious potential conflicts of interest — for example, those who work in the same department or institution as any of the authors. Authors often provide editors with the names of persons they feel should not be asked to review a manuscript because of potential conflicts of interest, usually professional. When possible, authors should be asked to explain or justify their concerns; that information is important to editors in deciding whether to honour such requests. Reviewers must disclose to editors any conflicts of interest that could bias their opinions of the manuscript, and they should disqualify themselves from reviewing specific manuscripts if they believe such disqualification would be appropriate. As in the case of authors, silence on the part of reviewers concerning potential conflicts may mean either that such conflicts exist that they have failed to disclose or that conflicts do not exist. Reviewers must therefore also be asked to state explicitly whether conflicts do or do not exist. Reviewers must not use knowledge of the work, before its publication, to further their own interests. Editors who make final decisions about manuscripts must have no personal, professional, or financial involvement in any of the issues they might judge. Other members of the editorial staff, if they participate in editorial decisions, must provide editors with a current description of their financial interests (as they might relate to editorial judgements) and disqualify themselves from any decisions where they have a conflict of interest. Editorial staff must not use the information gained through working with manuscripts for private gain. Editors should avoid submitting to their own journal reports of original research to which they have contributed as authors. If they do so, they should recuse themselves from the editorial process and delegate editorial decisions on those manuscripts to other members of the editorial staff. Editors should publish regular disclosure statements about potential conflicts of interests related to the commitments of journal staff. Back to text

Revision of statement on publication ethics by the International

Editorial Vitamin D deficiency and multicultural Australia Oral vitamin D supplementation may be needed in women with dark skin pigmentation or dress codes which prevent adequate sunlight exposure MJA 2001; 175: 236-237 Although the first written descriptions of rickets date from the mid-1600s, it was not until the 1920s that the problem was linked to a deficiency of vitamin D. With the widespread use of vitamin D supplementation, rickets became a rare syndrome. However, in the 1970s, immigrants from the Indian subcontinent living in the United Kingdom began presenting with florid symptoms of osteomalacia — bone pain, myopathy and pseudofractures.1 Vitamin D occurs in two forms, cholecalciferol, or vitamin D3, and the plant-derived ergocalciferol, or vitamin D2. These two forms are biologically equivalent in human beings. For most ambulatory people, the majority of the vitamin D in the body is derived from the action of ultraviolet B light on 7-dehydrocholesterol in the skin, converting it to previtamin D3, which, at body temperature, thermally isomerises into vitamin D3.2 A smaller proportion of vitamin D comes from dietary sources, particularly oily fish, eggs, butter and margarine.3 In contrast to the United States, few foods in Australia are fortified with vitamin D. Vitamin D made in the skin or ingested in the diet is biologically inert and must undergo conversion to 25-hydroxyvitamin D3 in the liver and then in the kidney to 1,25-dihydroxyvitamin D3 (calcitriol). The amount of high energy ultraviolet B light reaching the skin depends on factors such as latitude, season, smog (which reduces penetration of ultraviolet light through the atmosphere), and the actual amount of direct sun exposure, which is further modified by clothing and the use of sun protection agents.2,4 Vitamin D deficiency was therefore thought to be a rare disorder in populations living at latitudes where sunlight abounds for most of the year, and for this reason no recommended daily allowance for vitamin D has been established for Australia. Vitamin D deficiency, however, is now known to affect a substantial proportion of older people in this country, including those in institutions, patients with dementia and older men with hip fracture.5-8 In older people, the factors leading to this problem are reduced mobility; limited sunlight exposure; the assiduous use of sun-protection agents; and, in particular, a reduced ability of aged skin to produce vitamin D from a given dose of ultraviolet B light. In this issue of the Journal, two independent reports by Grover and Morley9 and Nozza and Rodda 10 draw attention to a new high-risk group for vitamin D deficiency in multicultural Australia. Grover and Morley report that 80% of dark-skinned or veiled women attending an antenatal clinic at the Royal Women's Hospital in Melbourne who took part in the study had biochemical evidence of vitamin D deficiency, with values of 25-hydroxyvitamin D3, the major blood metabolite, below the reference range.9 Nozza and Rodda examined paediatric records to identify children with vitamin D deficiency.10 In just over four and a half years, 55 children had presented with clinical features of rickets, including delayed walking, leg bowing, seizures and failure to thrive. Of those tested for parathyroid hormone levels, over 80% had secondary hyperparathyroidism. At the time of each child's presentation, none of the mothers had volunteered symptoms of vitamin D deficiency in themselves, but over half had 25-hydroxyvitamin D3 concentrations measured, and 81% of these had values below the reference range (< 25 nmol/L). All except one of the mothers of the children presenting with rickets were from Africa, the Indian subcontinent, the Middle East or southern Europe. The one mother of northern European descent was agoraphobic and depressed. As well as identifying a new high-risk group for vitamin D deficiency, these two reports highlight an important message for medical practitioners -- not only patients presenting for medical attention, but also other members of the family, may have vitamin D deficiency. As most of the vitamin D in neonates is acquired from maternal transfer,11 vitamin D deficiency in mothers is likely to have adverse consequences for their infants. In adults, vitamin D depletion causes a reduction in intestinal calcium absorption, resulting initially in a negative calcium balance, leading to secondary hyperparathyoidism with high bone turnover, bone loss, low bone density and an increased risk of vertebral and hip fractures. This may occur with serum 25-hydroxyvitamin D3 concentrations of less than 40 nmol/L, a value within most reference ranges.12,13 After a prolonged period, osteomalacia may become evident, manifested by an accumulation of demineralised bone, radiological pseudofractures or progressive bone pains with myopathy and a waddling gait. These clinical findings usually occur with frankly low serum 25-hydroxyvitamin D3 concentrations of less than 20 nmol/L. Women who are veiled or have dark skin pigmentation are susceptible to vitamin D deficiency because most clothing effectively absorbs ultraviolet B irradiation and increased melanin pigmentation reduces the cutaneous production of vitamin D.2,4 The absolute ultraviolet dose required to stimulate skin synthesis of vitamin D3 is about six times higher in African-Americans than in people of European descent.14 It has been estimated that, for lightly pigmented skin, exposure of hands, face and arms to a suberythemal dose of summer sunlight for about 15 minutes about three times per week is likely to be adequate for normal vitamin D requirements, even in the north-east of the United States.4 The presence of darker pigmentation and/or veiling may significantly impair adequate sun-derived vitamin D production, even in sunny regions like Australia. It remains unclear whether dietary factors, such as low calcium intakes, contribute to the problem. During the epidemic of rickets among Asian immigrants to the United Kingdom in the 1970s, it was speculated that diets low in calcium and containing certain types of cereal contributed to the development of vitamin D deficiency.15 Furthermore, there is evidence for accelerated metabolic inactivation and removal of vitamin D in primary or secondary hyperparathyroidism.16,17 Two recent reports also noted the significant clinical morbidity associated with vitamin D deficiency in the high-risk groups identified by Grover and Morley9 and Nozza and Rodda.10 In the first, Muslim women presenting with bone densitometric evidence of osteoporosis, most of whom were veiled, were found to be 2.5 times more likely to have biochemical evidence of severe vitamin D deficiency than women of European descent.18 In the second, a group of Arab women with vitamin D deficiency living in Denmark experienced decreased muscle function and muscle pain and weakness, which improved after three months of vitamin D treatment.19 How much vitamin D is required to prevent vitamin D deficiency in multicultural Australia? In regions where sunlight abounds, educational programs should encourage cutaneous production of vitamin D, with due deference to the problems of overexposure. When dark skin and/or veiling prevent adequate exposure, supplementation with oral vitamin D is likely to be required. The active hormone, calcitriol, which requires careful monitoring of serum and urinary calcium levels, is not the agent of choice in these circumstances. As there is a large therapeutic window, the risk of hypercalcaemia with plain vitamin D, such as ergocalciferol, is low.20 Susceptible groups, including pregnant women, should have their serum 25-hydroxyvitamin D3 concentrations measured. As there are no high-dose oral or intramuscular vitamin D preparations available in Australia, supplementation with oral vitamin D (eg, ergocalciferol 1000 units daily) is indicated if serum 25-hydroxyvitamin D3 concentrations are below 20-40 nmol/L. Rebecca S Mason Associate Professor Department of Physiology, and Institute for Biomedical Research University of Sydney, NSW rebeccamATphysiol.usyd.edu.au Terrence H Diamond Senior Endocrinologist St George Hospital; and Conjoint Associate Professor Faculty of Medicine, University of New South Wales, NSW Reprints: Associate Professor T H Diamond Department of Endocrinology, St George Hospital, Private Medical Complex, Kogarah, NSW 2217 Preece MA, McIntosh WB, Tomlinson S, et al. Vitamin D deficiency among Asian immigrants to Britain. Lancet 1973; 1: 907-910. Holick MF. McCollum Award lecture, 1994: Vitamin D — new horizons for the 21st century. Am J Clin Nutr 1994; 60: 619-630. Truswell AS, Dreosti IE, English RM, et al, editors Recommended nutrient intakes, Australian papers. Sydney: Australian Professional Publications, 1990. Holick MF. Sunlight"D"lemma: risk of skin cancer or bone disease and muscle weakness. Lancet 2001; 357: 4-6. Morris HA, Morrison GW, Burr M, et al. Vitamin D deficiency and femoral neck fractures in elderly South Australian women. Med J Aust 1984; 140: 519-521. Kipen E, Helme RS, Wark JD, Flicker L. Bone density, vitamin D nutrition, and parathyroid hormone levels in women with dementia. J Am Geriatr Soc 1995; 43: 1088-1091. Stein MS, Scherer SC, Walton SL, et al. Risk factors for secondary hyperparathyroidism in a nursing home population. Clin Endocrinol 1996; 44: 375-383. Diamond T, Smerdly P, Kormas N, et al. Hip fracture in elderly men: the importance of subclinical vitamin D deficiency and hypogonadism. Med J Aust 1998; 169: 138-141. Grover SR, Morley R. Vitamin D deficiency in veiled or dark-skinned pregnant women. Med J Aust 2001; 175: 251-252. Nozza JM, Rodda CP. Vitamin D deficiency in mothers of infants with rickets. Med J Aust 2001; 175: 253-255. Clements MR, Fraser DR. Vitamin D supply to the rat fetus and neonate. J Clin Invest 1988; 81: 1768-1773. Chapuy MC, Schott AM, Garnero P, et al. Healthy elderly French women living at home have secondary hyperparathyroidism and high bone turnover during winter. EPIDOS study group. J Clin Endocrinol Metab 1996; 81: 1129-1133. Gallagher JC, Kinyamu HK, Fowler SE, et al. Calciotropic hormones and bone markers in the elderly. J Bone Miner Res 1998; 13: 475-482. Clemens TL, Henderson SL, Adams JS, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 1982; I: 74-76. Ford JA, McIntosh WB, Dunnigan MG. A possible relationship between high-extraction cereal and rickets and osteomalacia. Adv Exp Med Biol 1977; 81: 353-362. Clements MR, Davies M, Fraser DR, et al. Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism. Clin Sci 1987; 73: 659-664. Clements MR, Johnson L, Fraser DR. A new mechanism for induced vitamin D deficiency in calcium deprivation. Nature 1987; 325: 62-65. Diamond T, Levy S, Smith A, Day P. Vitamin D deficiency is common in Muslim women presenting with bone pains and osteoporosis. Proceedings of the 9th Annual Scientific Meeting of the Australia and New Zealand Bone and Mineral Society, Cairns, June 1999; p 32, abstract 3B. Glerup H, Mikkelsen K, Poulsen L, et al. Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int 2000; 66: 419-424. Mason RS, Posen S. The relevance of 25-hydroxycalciferol measurements in the treatment of hypoparathyroidism. Clin Endocrinol 1979; 10: 265-269. Make a comment

Rebecca S Mason · Terrence H Diamond

Editorial Adult living donor liver transplantation: another Pandora's box? Important issues of safety and consent must be addressed MJA 2001; 175: 179-180 In 1990, the world's first successful living donor liver transplantation, from a mother to her child, was performed in Brisbane.1 Over the past three years, living donor liver transplantation has taken off in both the United States and Europe.2 In this issue of the Journal, House and colleagues from Western Australia report the first adult-to-adult living donor liver transplantation in Australia.3 This report is worthy of comment because it raises questions as to whether this procedure should be widely adopted in Australia, whether donor safety issues have been adequately addressed, and whether adult-to-adult living donor liver transplantation should be monitored and regulated in Australia. The upsurge of adult-to-adult living donor liver transplantation in the US and Europe reflects pressures from a mismatch between the demand for liver transplantation and the availability of cadaveric donor organs. In the US, there is a waiting list for liver transplantation of more than 14 000 patients, and a transplantation rate between 4000 and 5000 per year.4 The situation in the US is aggravated by an organ allocation system which gives priority to time on the waiting list for non-urgent cases: a patient entering the waiting list "late" is likely to receive a transplant only when there is deterioration to a more urgent category. In this system, deaths of patients while waiting for a transplant have dramatically increased over the past few years (in the US, about 1800 in 1999).4 The availability of living donor liver transplantation in an elective setting would presumably reduce or minimise these tragedies by increasing supply to match demand. This situation is not likely to apply in Australia because, although deaths on the waiting list have risen in the past few years, cases can be prioritised without the need to take time on the waiting list into consideration. Furthermore, in Australia, as in the US, patients with acute liver failure have a national priority listing that potentially minimises death while waiting for a suitable cadaveric donor. Nevertheless, the case report by House et al indicates that some of our liver transplantation units wish to introduce this procedure as an option. Hence, there is a need to address some important issues. What are the indications for adult-to-adult living donor liver transplantation? In Australia and New Zealand, it has been agreed to offer adult-to-adult living donor liver transplantation only to patients who have already fulfilled the criteria for a cadaveric donation. In the US and Europe, there is also general agreement on this, although some individual units feel that this is too restrictive and perform adult-to-adult living donor liver transplantation on patients who do not fulfil current criteria for liver transplantation, such as patients with large hepatocellular cancers or with acute alcoholic hepatitis. We believe that this is inappropriate; it is nonsensical to argue for the introduction of adult-to-adult living donor liver transplantation to address the supply-demand imbalance and simultaneously expand recipient criteria to increase demand. How are donors selected? Donor selection clearly requires an agreed formal informed consent process.5,6 The potential donor should be prepared by a team independent of the team advising and caring for the liver transplant recipient. Input from liaison psychiatrists is crucial. Any hint of coercion should lead to automatic exclusion, with the donor team having the final veto for progressing with adult-to-adult living donor liver transplantation. Potential donors should be selected using criteria that include psychological stability, appropriate vascular and biliary anatomy, age, and absence of underlying systemic or liver disease (eg, donation is contraindicated in an obese subject who is a smoker). A donor should be required to have a major emotional link to the recipient and should not be under any financial indebtedness to the recipient. A donor will usually, but not necessarily, be a close family member. A "cooling off" period after donor consent is also recommended. Size-matching of donor and recipient is crucial, since "shortchanging" of functioning hepatic mass in either may be fatal. In Australia, this would generally mean that the donation of an adult right hemiliver is required, although in Japan the left liver volume is often sufficient.7-9 What is the donor morbidity and mortality with adult-to-adult living donor liver transplantation? More than 1000 living donor liver transplantations have been performed worldwide with at least four deaths, although a report of only one has been published.4 Significant biliary complications have occurred in up to 5% of donors, and 2%-3% have required more than one surgical procedure. The donor is usually unable to work for 2-3 months, and 70% have persisting symptoms at six-month follow-up.10 Most living donor liver transplantations have been performed between adults and children, and those between adults include a large number of left liver grafts. This means that the true incidence of morbidity and mortality for right liver grafts remains unresolved. One would expect it to be higher for technical and other reasons related to hepatic mass. What are the outcomes for the recipient? The survival outcomes for recipients of adult-to-adult living donor liver transplantation are the same as with cadaveric donation, although biliary and vascular complications are increased.4 In the case reported by House et al, the patient met the listing criteria for liver transplantation and was on the urgent Australian and New Zealand list for the first available suitable cadaveric donation. The donor was prepared by an independent team in a process that took five days. The outcomes were favourable for both recipient and donor, although the follow-up of the donor is short and the recipient has already had significant biliary complications. However, the use of adult-to-adult living donor liver transplantation for fulminant hepatic failure requires comment. There is an Australasian priority listing for such patients. In the US, such a priority listing has usually obviated the need for adult-to-adult living donor liver transplantation.11 In Australia and New Zealand, waiting list deaths for fulminant hepatic failure are high, in the order of 30%. In Western Australia, the rate is 60%; the reason for this is unclear. Furthermore, in many patients with fulminant hepatic failure, for whom transplantation may be required within 24-72 hours of presentation, a donor consent "cooling off" period may not be possible. In the reported case, five days passed without a cadaveric donor, allowing such fears to be allayed. In many cases, this may not be so. In the US, it has been estimated that 600 transplantations per year may be possible with the widespread introduction of adult-to-adult living donor liver transplantation.4 If this figure is extrapolated to Australia and New Zealand, then between 20 and 30 cases can be expected each year. This amounts to only 1-15 cases in each Australian unit. Is this enough to justify widespread adoption of this procedure? Probably not. A recent commentary suggests that adult-to-adult living donor liver transplantation be restricted to "high case load" institutions,12 and states: The rapid proliferation of programmes that perform (liver) transplantation in adults with the use of grafts from living donors (most of those in the United States have performed fewer than 10 procedures each) is alarming for an innovative, nonstandardised operation that places two people, one of whom is healthy, at risk. It is clear there is a significant learning curve, with higher morbidity in donors and increased complications in recipients at units that have performed fewer than 50 adult-to-adult living donor liver transplantation procedures.4 Perhaps a single Australian centre should be established to do these procedures in the elective setting, although this may be logistically difficult to achieve. What is certainly achievable, however, is an agreed Australian and New Zealand protocol for donor and recipient selection, together with a central registry of transplantations performed. The Transplant Society of Australia and New Zealand is currently undertaking this process with the support of all liver transplantation units. The resulting protocol will be placed in the public arena for comment. Similarly, the Australian Safety and Efficacy Registry of New Interventional Procedures (Royal Australasian College of Surgeons) is undertaking a review of the need for adult-to-adult living donor liver transplantation in Australia. House and colleagues are to be recognised for their courage and ethical and technical skill in performing this procedure in a life-or-death situation. However, only time will tell whether this Pandora's box, containing within it all the issues of adult-to-adult living donor liver transplantation, should have stayed shut.13 Geoffrey W McCaughan A W Morrow Professor of Medicine, and Director Australian National Liver Transplantation Unit Royal Prince Alfred Hospital, Sydney, NSW Stephen V Lynch Associate Professor of Surgery, and Director, Queensland Liver Transplantation Unit Princess Alexandra Hospital, Brisbane, QLD Strong RW, Lynch SV, Ong TN, et al. Successful liver transplantation from a living donor to her son. N Engl J Med 1990; 322: 1505-1507. Renz JF, Busuttil RW. Adult-to-adult living-donor liver transplantation: a critical analysis. Sem Liver Dis 2000; 20: 411-424. House AK, Jeffrey GP, Edyvane KA, et al. Adult-to-adult living donor liver transplantation for fulminant hepatic failure. Med J Aust 2001; 175: 202-204. Proceedings of the 2nd international symposium dedicated to expand the donor pool. Rome. 26 August 2000. Tokyo: CD Toppon Medical Science, 2000. Abecassis M, Adams M, Adams P, et al. Consensus statement on the live organ donor. JAMA 2000; 284: 2919-2926. American Society of Transplant Surgeons' position paper on adult-to-adult living donor liver transplantation. Liver Transpl 2000; 6: 815-817. Yamaoka Y, Morimoto T, Inamoto T, et al. Safety of the donor in living-related liver transplantation — an analysis of 100 parental donors. Transplantation 1995; 59: 224-226. Marcos A. Right lobe living donor transplantation: a review. Liver Transpl 2000; 6: 3-20. Fan S, Lo C, Liu C, et al. Safety of donors in live donor liver transplantation using right lobe grafts. Arch Surg 2000; 135: 336-340. Trotter J, Talamantes M, McClure M, et al. Right hepatic lobe donation for living donor liver transplantation: impact on donor quality of life. Liver Transpl 2001; 7: 485-493. Hymar A, Durand B, Knaak M, et al. Sharing of livers for status I recipients in Region 7 — A good thing. Am J Transpl 2001; 1 Suppl I: 283 (A587). Cronin DC, Millis JM, Siegler M. Transplantation of liver grafts from living donors into adults — too much, too soon. N Engl J Med 2001; 344: 1633-1637. Strong RW. Whither living donor liver transplantation? Liver Transpl Surg 1999; 5: 536-538. Make a comment Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company.

MJA 2001; 175: 183-184 In this issue of the Journal, Braunack-Mayer and colleagues present a manifesto for an ethics core curriculum for Australasian medical students.1 It is a position paper by teachers of ethics from most of the medical schools in Australasia. The authors wisely "offer" this curriculum framework and ask that it be a "living document, open to challenges . . .". Some will debate its contents, while others will debate whether an ethics curriculum should be delivered separately from other key areas of the curriculum needed to train new doctors. Both these debates will be more productive if the ethics curriculum is considered from other perspectives, which include context, continuity and challenges. Firstly, the context. There has been a quiet revolution taking place in medical education in Australia over the past 10 years, with origins traceable to the Doherty Report on medical education and the workforce,2 and encouraged and fostered by the medical schools accreditation system of the Australian Medical Council.3 Australia now has four medical schools with graduate-entry programs, and virtually all Australian and New Zealand schools have made significant changes to their curricula as they seek to train doctors to meet the needs of our society.4 Foremost among the changes has been the vertical integration of the theme of "professional and personal development", a domain that covers elements such as communication skills, professional attitudes, ethics, health law and issues of health and fitness to practise. The core ethics curriculum outlined by Braunack-Mayer et al should form part of this domain, and, if delivered effectively, may not be readily visible. Similarly, assessment of the acquisition of the skills, knowledge and attitudes of the ethics component of this domain should be fully integrated into the broader assessment of professional skills. Secondly, achievement of continuity between undergraduate and postgraduate curricula needs to be considered. Some attention has been paid to ethics and health law as part of the professional development programs offered to interns,5 but our specialist training and continuing education programs have lagged behind. The most common response when a problem relating to doctors' professionalism arises is to add the topic to the undergraduate or primary medical curriculum! Few of the medical colleges responsible for postgraduate training address or examine important aspects of professionalism such as communication skills, professional attitudes and ethical and medicolegal issues. A notable exception is the Australasian College of Dermatologists, which, every two years, gathers its trainees for a four-day course that includes a day of interaction between trainees and dermatologists on ethical and medicolegal topics. Other colleges need to take up the challenge and devise their own ethics programs. It is to be hoped that the proposed process of external accreditation of providers of postgraduate education currently being piloted by the Australian Medical Council (in concert with the colleges) will give impetus to this.6 Thirdly, there is no lack of ethical and professional challenges for today's doctors. The changes to the medical curricula reflect responses to community concerns about communication skills, attitudes and common ethical and medicolegal problems, as identified by consumer groups, healthcare complaints commissions and medical boards.7 More recent challenges include the possible adverse consequences for patient care of corporatisation of medical practices, the risks of unfettered advertising, and dilemmas for doctors who are expected to act as patient advocates as well as "gatekeepers" of the public purse. Most currently practising doctors were not required to consider these issues as part of their medical training. It is unwise for the medical profession to put its efforts solely into training tomorrow's doctors and overlook the need to engage today's doctors in the challenge of meeting changing community expectations. If we can successfully implement postgraduate training programs in ethics, some of the difficulties that our ethics teachers have identified (eg, faculty awareness and role-modelling) might be more rapidly overcome. No one today should argue against the need for medical ethics to be a central element of medical education, but we do need to debate how this can best be done. Braunack-Mayer and colleagues seem to suggest, by their request for resources and recognition, that they are not truly committed to an integrated curriculum. I argue that, if ethics teaching is not fully integrated, medical ethics risks being perceived by students as irrelevant to medical practice. The new curricula introduced throughout Australia and New Zealand have been designed with this integration in mind. The Association of Teachers of Ethics and Law in Australian and New Zealand Medical Schools is well positioned to examine whether our current approach is working. My own belief is that medical students are now very aware of ethical issues, but that there is a failure to build on this in the early postgraduate years. Kerry J Breen Immediate Past President, Australian Medical Council, Canberra Association of Teachers of Ethics and Law in Australian and New Zealand medical Schools (ATEAM). An ethics core curriculum for Australasian medical schools. Med J Aust 2001; 175: 205-210. Doherty RL (chairman). Committee of Inquiry into Medical Education and Medical Workforce. Australian medical education and workforce into the 21st century. Canberra: AGPS, 1988. Australian Medical Council. Guidelines for the assessment and accreditation of medical schools. Canberra: AMC, 1998. Lawson KA, Armstrong RM, Van Der Weyden MB. A sea change in Australian medical education. Med J Aust 1998;169: 653-658. Australian Medical Council. National guidelines for intern training. Canberra: AMC, 1996. Australian Medical Council. Specialist recognition and accreditation. AMC, 2001. Available at <http://www.amc.org.au/nsqac.asp>. Accessed 10 July 2001. Daniel AE, Burn RJ, Horarik S. Patients' complaints about medical practice. Med J Aust 1999; 170: 598-602. Make a comment

Kerry J Breen

The establishment of NICS is an ambitious attempt to promote quality improvement at both practice and organisational levels. MJA 2001; 175: 124-125 Nearly 10 years since its inception, evidence-based healthcare (EBH) remains focused on encouraging informed decision-making by integrating clinical expertise with the explicit and judicious consideration of the best available "scientific" evidence. The language and concepts of EBH are being institutionalised in almost every facet of the healthcare system, from medical education, policy development and resource allocation to research funding and consumer advocacy. But has EBH delivered on its promises? Despite the explosion in the number of controlled trials, systematic reviews and clinical practice guidelines, there remain large gaps between what should be done and what is actually done. Clearly, we can't hold EBH responsible for the outcomes of the entire healthcare system, but we should be asking why the gap between the best available evidence and current practice persists. We now have in place many of the "upstream" strategies to support EBH. For example, clinical research is being strengthened and more strategically aligned to target the areas where evidence is required.1 Systems are in place through organisations like the Cochrane Collaboration to provide up-to-date summaries of rigorous research in an accessible format.2 Organisations such as the clinical colleges and societies have embraced the concepts of EBH through initiatives such as evidence appraisal of new technologies and procedures and development of clinical guidelines, as well as refocusing much of the content and methods used in their continuing education and quality assurance programs. But what about the "downstream" strategies? What happens to the endless sets of evidence reports, guidelines and audits? What strategies are in place to ensure effective uptake and implementation of the evidence? How can clinicians' behaviour be changed where necessary? What systems are in place to collect the necessary data to monitor the effect of applying evidence in daily practice? The further downstream we look, the greater the challenges. Generating and synthesising the evidence is the easy part; effectively implementing it is not. Our understanding of the effective methods of implementing evidence is limited. Research into behavioural and organisational change in healthcare has been poorly funded, so, while we may have access to some of the best treatments and technologies in the world, our understanding of the strategies needed to promote their effective use is rudimentary. Enter the new National Institute of Clinical Studies Ltd (NICS). Established in December 2000 as a Commonwealth-owned company (with the Federal Minister for Health and Aged Care as the sole shareholder), NICS aims to provide a national, integrated focus for work being undertaken to continuously improve the quality of clinical practice and its delivery to patients. Its terms of reference are broad ranging Box. Unlike international bodies with similar names (such as the National Institute of Clinical Excellence in the United Kingdom), NICS is not a disguise for a new form of rationing or a new national guideline development agency. Rather, NICS, by fostering a scientific approach to the implementation of evidence, will help to turn evidence into action by working in partnership with consumers, healthcare professionals, researchers and organisations to close the gap between evidence and practice. NICS enters an arena in which there is already much activity to do with quality improvement and best practice. Clearly, NICS will need to develop a close relationship with groups such as the National Health and Medical Research Council, the Australian Council for Safety and Quality in Health Care, the Medicare Services Advisory Committee, the Pharmaceutical Benefits Advisory Committee and the National Health Priorities Action Council. Each of these has a different focus from NICS, whose purpose will be complementary to such groups. NICS will engage clinicians from all disciplines and practice settings to identify and prioritise the gaps between evidence and practice, and then develop strategies to close or minimise the gaps, using a scientific approach to quality improvement. These strategies, together with the findings of related initiatives in Australia and internationally, will help to develop practical resources to support clinicians in providing best clinical practice. Finally, NICS will work with other public and private organisations to create an environment in which these resources can be used to maximum effect. NICS is in its early days and is still very much engaged in dialogue and planning. Its challenge will be to use its modest funding to stimulate innovative approaches to promoting the use of best clinical practice. If NICS can't deliver, it runs the risk of becoming just another forgettable acronym! Chris A Silagy Professor, and Director, Monash Institute of Health Services Research, and Chair, Board of National Institute of Clinical Studies Ltd Monash Medical Centre, Melbourne, VIC chris.silagyATmed.monash.edu.au Wills P, Chairman. The virtuous cycle. Working together for health and medical research. Health and Medical Research Strategic Review. Canberra, 1999. Bero L, Rennie D. The Cochrane Collaboration. Preparing, maintaining, and disseminating systematic reviews of the effects of health care. JAMA 1995; 274(24): 1935-1938. Make a comment Terms of reference and composition of the National Institute of Clinical Studies (NICS) Terms of reference Map current activity around improving quality and clinical care, and provide a focus for the consolidation and dissemination of that work; Support research to assess and evaluate aspects of the system within which care is provided — including the processes, interactions and relationships — to identify mechanisms to improve care delivery and the most effective means to influence their implementation; Identify the best mechanisms to influence and improve clinical practice, in concert with the profession; Establish working groups and advisory structures to report and advise on a wide range of matters relating to clinical improvement in the Australian healthcare system; Champion best practice within the healthcare system through education and training; Build links between professionals, consumers and other stakeholders to improve exchange of information and experience about the operation of the healthcare system and minimise duplication of effort; In collaboration with the relevant agencies and bodies, promote the collection and analysis of data and the development of effective data systems; Build links both nationally and internationally with organisations with similar objectives, and identify and assess relevant overseas approaches to clinical practice improvement. Composition of NICS A nine-member Board has been appointed by the Minister for Health to oversee NICS, of whom eight are medical practitioners (three general practitioners, a surgeon, a cardiologist, a paediatrician, a medical administrator and an emergency medicine physician). A Chief Executive Officer is to be appointed to take responsibility for NICS's day-to-day operations. NICS will operate with a small core staff managing a series of outsourced projects and working groups, collaborating as much as possible with other relevant professional and government organisations. By virtue of its company structure, NICS will maintain some distance from direct government involvement, although it remains publicly accountable for the expenditure of its funds (initially $3.5 million per year, provided by the Federal Government for a three-year period). The performance of NICS will be reviewed after the first two years. Back to text

Chris A Silagy

Editorial Systemic lupus erythematosus: current management Use the available agents innovatively, and aggressively treat the risk factors for premature vascular disease MJA 2000; 173: 125-126 Systemic lupus erythematosus is an autoimmune disease that may affect many organs, especially the skin, musculoskeletal, vascular and renal systems. It occurs predominantly in women of childbearing age, but also affects people in their sixth decade or older. In these patients, female predominance is less marked and renal disease less common. The natural history of the disease has changed over the past 20-30 years; survival rates have increased from 50% at five years in the 1950s to 80%-90% at 10 years in the 1990s. The explanations for this improvement include earlier diagnosis, recognition of milder disease, advances in medical therapy, and better supportive care, including renal replacement therapy. Despite these advances, the standardised mortality ratio for lupus remains at 3. Morbidity and mortality rates are bimodal, with early events related to disease activity or infection and later events often due to premature vascular disease such as stroke and myocardial ischaemia. Currently, minor manifestations of systemic lupus erythematosus (cutaneous, musculoskeletal, fatigue) are managed with non-steroidal anti-inflammatory drugs (NSAIDs), antimalarial drugs (particularly hydroxychloroquine) and low-dose corticosteroids. The selective COX-2 inhibitors, celecoxib (a sulfonamide) and rofecoxib, are now available in Australia. With their lower gastrointestinal toxicity, they represent a significant advance. Patients with lupus, however, have a high prevalence of sulfonamide allergy (20% in some studies) and 30%-50% have antiphospholipid antibodies, which are associated with arteriovenous thrombosis and miscarriages (the antiphospholipid syndrome). Case reports of thrombotic events in patients with antiphospholipid antibodies taking COX-2 inhibitors necessitate judicious use of these drugs until further data are available.1 Hydroxychloroquine should no longer be restricted to those with minor disease. Data from the Canadian Hydroxychloroquine Study Group suggest that taking hydroxychloroquine causes a reduction in flares and a lower risk of organ-threatening dissemination.2 An ability to lower blood glucose and cholesterol levels, combined with an antiplatelet effect, makes this drug an attractive therapeutic option for all patients with lupus. The risk of retinal toxicity with hydroxychloroquine may have been overstated in the past, and the Royal College of Ophthalmologists, London, recommends routine ophthalmic screening in adults only if the dosage of hydroxychloroquine is greater than 6.5 mg/kg lean body weight per day, if there is impaired renal or hepatic function, if visual symptoms develop, or if the duration of therapy extends beyond five years.3 Patients refractory to hydroxychloroquine may show improvement with chloroquine, although with chloroquine the risk of retinal toxicity is greater. Treatment-resistant cutaneous lupus has been treated with thalidomide, with improvement in up to 84% of patients.4 However, its use will remain limited because of the risk of fetal abnormalities and the high rate of neuropathy. There is increasing concern about the long term use of steroids, including low-dose therapy, in patients with lupus. With time, musculoskeletal damage, including avascular necrosis and osteoporosis, heads the organ damage list. Petri has shown that avascular necrosis is strongly associated with the highest prednisolone dose used and osteoporosis with the cumulative dose. She has also shown that an increase in prednisolone dose is associated with an aggravation of cardiovascular risk factors. If the prednisolone dose is increased by 10 mg, the average weight gain is 2 kg, and increases in serum cholesterol level and mean arterial blood pressure occur.5 The management of major organ involvement (eg, renal, neuropsychiatric) necessitates combining steroids and immunosuppressants such as cyclophosphamide and azathioprine, and, more recently, cyclosporin A and mycophenolate mofetil. Intermittent monthly pulses of intravenous cyclophosphamide is the standard treatment for diffuse proliferative nephritis and results in a significant improvement in outcome compared with steroid use alone. The appropriate treatment for other classes of lupus nephritis has not been subject to the same level of scrutiny, and uncertainty exists as to what is the optimum management of membranous nephropathy. Although successful in the management of lupus nephritis, high-dose pulse cyclophosphamide (0.75-1.0 g/m 2 monthly) and steroids have been associated with significant toxicity, including premature ovarian failure in 55% and infection in 29% of patients.6 Understandably, fertile women are reticent to accept such therapy and alternatives need to be considered. In retrospective studies, a short, low-dose cyclophosphamide regimen followed by azathioprine has been found to be a successful combination, with reduced incidence of ovarian failure and infection.7 A European prospective study comparing high- and low-dose cyclophosphamide for treating lupus nephritis has now completed recruitment; initial short-term remission rates are comparable in both groups.8 In small series, mycophenolate mofetil has been found to be effective, including in some patients who have shown resistance to cyclophosphamide. Chan et al found mycophenolate to be equal in efficacy to oral cyclophosphamide in patients with diffuse proliferative lupus nephritis.9 Long term data (at least five years' follow-up) will be necessary to determine the incidence of relapse and complications. Cyclosporin has been shown to reduce proteinuria in patients with membranous and diffuse proliferative nephropathy. However, concern continues about nephrotoxicity and relapse on ceasing to take the drug. Cyclophosphamide combined with plasmapheresis has not been shown to provide additional benefit compared with cyclophosphamide alone, and its use is now limited to patients who develop a thrombotic thrombocytopenic purpura-like illness or who have very treatment-resistant disease.10 There is growing interest in the use of immunoablation and stem-cell transplantation in a variety of autoimmune disorders. Autologous stem-cell grafting is feasible in systemic lupus erythematosus and anecdotal reports of success exist. The appropriate timing of stem-cell transplantation, however, remains difficult. Ideally, transplantation should occur in patients who have shown resistance to standard therapy, but before they develop significant irreversible damage. At this stage, the prognostic markers are not sufficiently refined to allow early identification of patients likely to fail immunosuppressive therapy.11 Increased understanding of the pathogenesis of systemic lupus erythematosus has led to the development of numerous novel therapeutic agents. Several of these are in phase II and phase III studies and show promise. However, manipulating the immune system is not without risk, and the expense, particularly of biological agents, will initially limit availability to those with severe disease. While we eagerly await the arrival of such agents, the care of lupus patients in the early years of the 21st century involves innovative approaches with available agents, as well as recognising and aggressively treating the risk factors for premature vascular disease. Timothy R Godfrey Rheumatologist, Rheumatology Unit The Alfred and St Vincent's Hospitals, Melbourne, VIC Peter F J Ryan Clinical Associate Professor of Medicine; and Head Rheumatology Unit, Alfred Health Care Group, Melbourne, VIC Gupta S, McCune WJ, Kaplan M, et al. Thrombosis and ischaemia in patients with systemic lupus erythematosus treated with celecoxib: a series of two cases. Arthritis Rheum 1999, 9(Suppl): S149. Tsakonas E, Joseph L, Esdaile JM, et al. A long term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus 1998; 7: 80-85. Royal College of Ophthalmologists. Ocular toxicity and hydroxychloroquine: guidelines for screening. London: RCO, 1998. Ordi-Ros J, Cortes F, Cucurull, Mauri M, et al. Thalidomide in the treatment of cutaneous lupus refractory to conventional therapy. J Rheumatol 2000; 27: 1429-1433. Petri M. Hopkins Lupus Cohort 1999 Update. Rheum Dis Clinics 2000; 26: 199-213. Gourley MF, Austin III HA, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. Ann Intern Med 1996; 125: 549-557. Martin-Suarez I, D'Cruz D, Mansoor M, et al. Immunosuppressive treatment in severe connective tissue diseases: effects of low dose intravenous cyclophosphamide. Ann Rheum Dis 1997; 56: 481-487. Houssiau F, Vasconcelos C, Abramovicz D, et al. The Euro-Lupus Nephritis Trial: comparison between a low dose and a high dose cyclophosphamide regimen. Ann Rheum Dis 1999 (EULAR abstracts): 116. Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000; 343: 1156-1162. Schroeder J, Schwab U, Zeuner R, et al. Plasmapheresis and subsequent pulse cyclophosphamide in severe SLE: preliminary results of the LPSG Trial. Arthritis Rheum 1997, 40(Suppl): S325. Formiga F, Moga I, Pac M, et al. High disease activity at baseline does not prevent a remission in patients with systemic lupus erythematosus. Rheumatology 1999; 38: 724-727. Make a comment

In 1993, a group of researchers led by Andrew Wakefield at the Royal Free Hospital, London, suggested an association between both wild and vaccine measles viruses and inflammatory bowel disease (IBD), based on a small case series of children with Crohn's disease.1 In 1998, the same researchers reported another series of 12 children, and described an apparently new syndrome of an unusual type of IBD associated with developmental disorders such as (but not limited to) autism.2 They suggested that measles-mumps-rubella (MMR) vaccine may cause IBD, resulting in decreased intestinal absorption of essential vitamins and nutrients and possibly leading to developmental disorders such as autism. Wakefield has also expressed the opinion (without any scientific evidence) that such perturbations are less likely if the components of MMR are given separately, spaced several months apart. Measles remains one of the most severe infectious childhood diseases (Box), and the current vaccine is 95% effective. Yet parents worry about sensational media reports of possible links between vaccines and a variety of medical conditions. Autism and IBD (Box) and their alleged relationship to MMR vaccine have recently been highlighted in the media. Epidemiological evidence Expert groups around the world have expressed the opinion that the suggested associations between the MMR vaccine, IBD and autism are weak and the studies flawed. The studies at the Royal Free Hospital1,2 were conducted on highly selected patients referred for gastrointestinal ailments. The studies had no controls, were unblinded and were not designed to test aetiology or harm. There were multiple potential sources of bias. For example, the association between vaccination and autism was based primarily on parental recall — parents are likely to link changes in behaviour with memorable events such as vaccination, thereby introducing "recall" bias. Such a case-series analysis is unable to determine causal links. Moreover, the onset of autism and MMR vaccination may appear to be associated in time because the average age at which parents report concerns about child development is 18-19 months and most children receive MMR vaccine before their second birthday. In contrast to Wakefield and colleagues' two small, poorly designed studies,1,2 large, well designed epidemiological studies have shown no association between MMR vaccine and autism. These include a UK population-based study of the vaccination status of 498 children with autism,6 a study of the rates of IBD and autism among 6100 French schoolchildren,7 and an examination of trends in the incidence of autism and MMR vaccine coverage over time in California3 and in UK general practices.4 Similarly, a Finnish study of 1.8 million children over 14 years that looked at adverse events after MMR vaccination did not document a single case of autism or IBD as a consequence of MMR vaccination.8 Virological evidence In their 1993 study, Wakefield and colleagues reported identification of measles virus in bowel tissue of patients with Crohn's disease.1 Other laboratory studies using similar methodology have not found measles virus in patients with IBD. In fact, one group suggested that the reported "measles virus" represented a cross-reaction with another protein structurally similar to certain measles antigens.9 More sensitive testing methods have not revealed any evidence of measles virus in the gut of patients with Crohn's disease or ulcerative colitis.10Recently, Wakefield and O'Leary presented data to the Immunisation Safety Committee of the US Institute of Medicine suggesting that measles virus has been detected by very sensitive polymerase chain reaction (PCR) methods in the gut of selected autistic children.11 These data have not been published in the peer-reviewed scientific literature. Kawashima and colleagues in Japan have published a study reporting the detection of measles virus by PCR in peripheral mononuclear cells of individuals with autism and bowel disease. However, these findings have not been replicated by other laboratories, and most studies have found no evidence for the presence of measles virus in the gut in inflammatory disease.11 Interestingly, there was no mention of detection of vaccine viruses in the bowel or brain tissues of any patients in the 1998 study of Wakefield and colleagues,2 in contrast with their 1993 report.1 Level of evidence Wakefield's studies provide very weak (National Health and Medical Research Council Level IV) evidence for harm or causation relating to the MMR vaccine.12 The "Bradford Hill" criteria for causation13 are poorly fulfilled by Wakefield's studies.1,2 Specifically, there is no estimate of the strength of association, no evidence of a dose-response relationship or temporal sequence, no consistent findings from other investigators, no coherence with established facts, and poor specificity of association.14In addition to there being no evidence to support a causal relationship between MMR and autism, Wakefield's proposal that the vaccine components of MMR be given separately is unsupported by any evidence. Indeed, giving these vaccines separately has many disadvantages. First, children will receive some components later than recommended, risking exposure and infection in the intervening time. Second, there are additional injections and some may be omitted, or viral interference may reduce vaccine effectiveness if components are given separately but too close together. Except for monovalent rubella, these vaccines are not currently available separately in Australia, and requests to give them separately should be strenuously resisted. Consensus about the safety of MMR by expert groups The World Health Organization rejects an association between MMR and autism, and "strongly endorses the use of MMR . . . vaccine on the grounds of its convincing record of safety and efficacy".15 In 1998, a meeting of the British Medical Research Council and a group of national and international experts concluded that there was "no evidence to indicate any link between MMR vaccination and bowel disease or autism".16 In April 2001, the Institute of Medicine released its report Immunization safety review: measles-mumps-rubella vaccine and autism,11which concluded that the available evidence rejects a causal association between MMR and autism, although recommending that further research into the issue be conducted because of public concern. In view of considerable epidemiological evidence on the safety of MMR vaccine, we believe that Wakefield's small, unsubstantiated case series should be seen in correct perspective, and that parents and healthcare professionals should be reassured that there is no evidence that the MMR vaccine is associated with autism or IBD. C Raina MacIntyre Senior Lecturer Peter B McIntyre Deputy Director National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, Children's Hospital, Westmead, NSW. rainamAToptusnet.com.au Wakefield AJ, Pittilo RM, Sim R, et al. Evidence of persistent measles virus infection in Crohn's disease. J Med Virol 1993; 39: 345-353. Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998; 351: 637-641. Dales L, Hammer SJ, Smith NJ. Time trends in autism and in MMR immunization coverage in California. JAMA 2001; 285: 1183-1185. Kaye JA, del Mar Melero-Montes M, Jick H. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ 2001; 322: 460-463. Fombonne E. The epidemiology of autism: a review. Psychol Med 1999; 29: 769-786. Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999; 353: 2026-2029. Fombonne E, Du Mazaubrun C, Cans C, Grandjean H. Autism and associated medical disorders in a French epidemiological survey. J Am Acad Child Adolesc Psychiatry 1997; 36: 1561-1569. Patja A, Davidkin I, Kurki T, et al. Serious adverse events after measles-mumps-rubella vaccination during a fourteen-year prospective follow-up. Pediatr Infect Dis J 2000; 19: 1127-1134. Iizuka M, Chiba M, Yukawa M, et al. Immunohistochemical analysis of the distribution of measles related antigen in the intestinal mucosa in inflammatory bowel disease. Gut 2000; 46: 163-169. Afzal MA, Armitage E, Ghosh S, et al. Further evidence of the absence of measles virus genome sequence in full thickness intestinal specimens from patients with Crohn's disease. J Med Virol 2000; 62: 377-382. Institute of Medicine. Immunization safety review: measles-mumps-rubella vaccine and autism. Washington, DC: National Academy Press, 2001. Available at: <http://books.nap.edu/html/mmr> (Accessed 4 July 2001). Levine M, Walter S, Lee H, et al. Users' guides to the medical literature. IV. How to use an article about harm. Evidence-Based Medicine Working Group. JAMA 1994; 271: 1615-1619. Wilkinson L. Sir Austin Bradford Hill: medical statistics and the quantitative approach to prevention of disease. Addiction 1997; 92: 657-666. Halsey NA, Hyman SL. Measles-mumps-rubella vaccine and autistic spectrum disorder: report from the New Challenges in Childhood Immunizations Conference convened in Oak Brook, Illinois, June 12-13, 2000. Pediatrics 2001; 107(5): 1-23. World Health Organization. Statement on the use of MMR vaccine. Available at: <http://www.who.int/vaccines-diseases/safety/hottop/mmrstatement.htm> Accessed 4 July 2001. Medical Research Council. Report from the Working Party on MMR. London: MRC, 1998. Make a comment Measles, inflammatory bowel disease and autism Measles Measles is virtually universal among unimmunised children in all countries: 99.9% of unimmunised people will contract measles, 90% before the age of 20. One in every 5000-10000 cases results in death from the acute effects of the disease. Worldwide, there were 888000 deaths due to measles in 1998, more than the number due to breast or skin cancer, homicide or violence. Inflammatory bowel disease (IBD) IBD is a group of chronic inflammatory disorders of the small and large bowel, the commonest being ulcerative colitis and Crohn's disease. The cause of IBD is not understood, but both an immune mechanism and a genetic predisposition are probably involved. IBD is relatively rare, with an incidence of 6-8 cases per 100000 population for ulcerative colitis and 2 cases per 100000 for Crohn's disease. It usually occurs in people aged between 15 and 30 years, but can occur in children. Autism Autism is a developmental disorder that is usually identified between the ages of 18 months and three years. Four times more common in boys than girls, autism occurs in all racial and social groups. Autistic children and adults typically have difficulties in verbal and non-verbal communication, social interactions and leisure or play activities. A single cause of autism has not been identified, but current research implicates neurodevelopmental, genetic and environmental factors. The sex differential suggests a strong genetic component. Many children have some features of autism but do not fulfil all the diagnostic criteria. There has been an apparent increase in the incidence of autism in recent decades. In the United States the rate increased from 44/100000 births in 1980 to 208/100000 births in 1994,3 while in the United Kingdom the rate increased from 3/100000 births in 1988 to 21/100000 births in 1999.4 This has been attributed largely to changing case definitions and classifications (which now include less severe forms of the disease) and improved recognition.5 The discrepancy between the US and UK rates may be evidence of inconsistent case definitions. It is uncertain how much, if any, of the increased incidence is independent of diagnostic practice. Back to text

Editorial Australian general practice at a fork in the road: which way forward? An opportunity to respond to the challenges and choose renaissance MJA 2001; 175: 62-63 Worldwide, there is a new phenomenon — dispirited doctors.1 They are afflicted with a debilitating disease characterised by disinterest, disillusion and despair. The roots of this disease are embedded in the havoc wrought by constant change and uncertainty, and the inevitable clash between doctors' professional and personal ideals and the changing circumstances of their practices. Australia has not escaped this disease. That it is endemic in Australian general practice is evidenced by reports of GPs' discontent and despondency.2,3 They see themselves as overworked, undervalued, unsupported and over-regulated. They are no longer in control.1-3 This issue of the Journal, celebrating Family Doctor Week, explores some of the crucial challenges facing Australian general practice as it arrives at a defining fork in the road. How GPs and their leaders respond to these challenges will determine whether Australian GPs continue down the road of despondency, or choose a road of renaissance and rid themselves of this malaise. First, there is the accelerating trend to corporatisation of Australian general practice, and for this issue of the Journal we sought out an eclectic array of views on this development. Catchlove explores the triggers for and potential outcomes of corporatisation;4Sprogis suggests alternative corporate models;5Fitzgerald examines ethical dilemmas;6 and Mott provides a pragmatic consumer perspective.7 The corporate sector's aggressive invasion into general practice comes as no surprise. It is symptomatic of a global movement in which governments, chanting the mantra of cost containment and consumer choice, have abrogated their public roles and responsibilities to the private sector.8 Moreover, as doctors seek "the right balance in life: enough money and enough time off",9 medicine is increasingly regarded less as a vocation and more as a job. Any job that promises professional satisfaction in the provision of high quality care, with the added bonus of more time for partners, family and friends, is undeniably attractive. These are the human appeals of corporate practice, which unquestionably has other benefits both for the profession and the community. But clouding these benefits is the uncertainty of the long term effects on professional autonomy and discretionary practice. Crucial questions need to be answered, such as the content of and compliance with corporate codes of conduct, and the precise nature and impact of corporate-doctor agreements. Then there is the uncharted impact on healthcare delivery and funding of vertical integration of general practices with diagnostic and specialist services, hospitals, pharmaceutical suppliers and health insurance organisations. Ultimately, what will be the attractiveness of such seamless healthcare coverage to governments? These are all questions for the future, but the consequences of unbridled corporatism for our profession are unlikely to be entirely benign. As Milton Friedman, a Nobel Prize laureate in economics, once observed ". . . there is one and only one social responsibility of business — to use its resources and engage in activities designed to increase its profits . . . ".10 Second, there is the challenge of general practice research and education, which has received little attention in the corporatisation debate. One of the defining characteristics of a viable medical discipline is its capacity to enrich itself through research, and this is sorely deficient in Australian general practice, and contributing in part to the malaise. The reasons for this impoverishment include: GPs are patient- and service-oriented and have to ensure practice profitability. Any activity such as research that is not fiscally rewarded is understandably of low priority. GPs attract a low level of research funding. Between 1996 and 2000, general practice received only 35 (1.6%) of the 2116 newly funded National Health and Medical Research Council (NHMRC) research projects, and a mere $3.7 million (0.5%) of the $795 million allocated to NHMRC-sponsored research activities (Dr Greg Ash, Director, Research Policy, NHMRC, personal communication). According to Kamien, Australian academic general practice departments are the "poor relations" in the medical faculty family, with their inadequate infrastructure and low research output,11 as instanced by their publication performance.12 Indeed, Askew and colleagues show that this performance lags considerably behind that of other Australian health specialties, namely medicine, surgery and public health.13 In short, poor resourcing, a deficient research capacity and little recognition of general practice in our universities have all combined to stifle what should be a rich and flourishing research culture. More than a year ago, Michael Wooldridge, the Federal Minister for Health, announced the Primary Health Care Research and Development Strategy to address these shortcomings. Its aim is to build a research capacity in general practice through multiple strategies (Box). However, the success of this strategy is not assured — the devil is always in the detail. Success depends on the strategy's ability to engage GPs in research performed in and relevant to general practice. Success also entails changes in our medical faculties — in attitudes, structures and resource allocation — acknowledging the pivotal role of general practice in disease prevention, in coordinating community care of patients with chronic disorders, and in caring for our ageing population. All these initiatives provide an opportunity for corporatised general practice to be involved in the renaissance. If, however, our experience of corporatism mirrors that in the United States, with adverse effects on research14 and educational outcomes,15 Australian general practice will be the loser and its renaissance will be stymied. I hope that these fears are ungrounded and Australian corporatism affirms education and research as integral to the social contract between medicine and society. As our dispirited colleagues stand at the fork in the road, unsure which direction to take and uncertain of what lies ahead, the words of Robert Frost seem apt: I shall be telling this with a sigh Somewhere ages and ages hence: Two roads diverged in a wood, and I — I took the one less traveled by, and that has made all the difference. (The road not taken — 1916) Martin B Van Der Weyden Editor, The Medical Journal of Australia BMJ survey: why are doctors so unhappy? <http://www.bmj.com/cgi/content/full/322/7294/DC4#league>(accessed May 18 2001). Schatter PL, Coman GJ. The stress of metropolitan general practice. Med J Aust 1998; 169: 133-137. McGlone SJ, Chenoweth IG. Job demands and control as predictors of occupational satisfaction in general practice. Med J Aust 2001; 175: 88-91. Catchlove BR. GP corporatisation. The why and the wherefore. Med J Aust 2001; 175: 68-70. Sprogis A. GP corporatisation. The divisional alternative. Med J Aust 2001; 175: 70-72. Fitzgerald PD. GP corporatisation. The ethics of doctors and big business. Med J Aust 2001; 175: 73-75. Mott K. GP corporatisation. The consumer perspective. Med J Aust 2001; 175: 75-76. Funnell W. Government by fiat. The retreat from responsibility. Sydney: University of New South Wales Press, 2001. Dworkin RW. Why doctors are down. Commentary (New York) 2001; 111 (May): 43-47. Friedman M. Capitalism and freedom. Chicago: University of Chicago Press, 1962: 133. Kamien M. Has Australian academic general practice really come of age? Med J Aust 2001; 175: 81-83. Ward AM, Lopez DG, Kamien M. General practice research in Australia. Med J Aust 2000; 173: 608-611. Askew DA, Glasziou PP, Del Mar CB. Research output of Australian general practice: a comparison with medicine, surgery and public health. Med J Aust 2001; 175: 77-80. Moy E, Mazzaschi AJ, Levin RJ, et al. Relationship between National Institutes of Health research awards to US medical schools and managed care market penetration. JAMA 1997; 278: 217-221. Ludmerer KM. Time to heal. American education from the turn of the century to the era of managed care. Chapter 17: Medical education in an era of containment and managed care. New York: Oxford University Press, 1999: 349-369. Make a comment The Primary Health Care Research Evaluation and Development Strategy* Priority setting A comprehensive program of consultation with stakeholders — to establish research priority areas (commenced in 2000). Development and research capacity building Funding over five years for Departments of General Practice and Rural Health — to develop or augment research infrastructure. Grants program Contestable Primary Health Care Research Grants — to be added to the NHMRC research funding pool (commencing in 2001). GP Fellowships (postdoctoral) and Primary Health Care Scholarships (for higher degrees) — to be offered annually by the NHMRC (commenced in 2000). Capacity development grants — to build research experience. Research secondments — to enable researchers to undertake six-month placement in relevant primary care organisations. The Institute for Primary Care Research To provide leadership and support in primary care research. *Ms M MacDonald, Director, Research and Quality Section, General Practice Branch, Commonwealth Department of Health and Aged Care, personal communication. Back to text