Editorials

Avoidance of allergenic foods in the first year of life is no longer recommended Since the 1980s, the world has experienced an epidemic of allergic disease. The prevalence of asthma rose rapidly during the 1990s, followed by increases in the prevalence of eczema and allergic rhinitis, both of which continue to rise. Of great concern is new evidence that yet another allergic condition — food allergy — is also on the rise, particularly in infants and young children. An estimated 10%–15% of the population report symptoms of food allergy,1 although the prevalence of IgE-mediated food allergies (ie, symptoms such as urticaria, angioedema, vomiting or anaphylaxis within minutes of food ingestion, in the context of a positive skin prick test result or food-specific serum IgE level) has not, until recently, been adequately studied at the population level. Results of population studies examining food allergy prevalence have been hampered by small sample sizes, selection bias related to sampling methodology and response rates, and use of parental or self-report of allergy or a skin prick test result as a proxy for food allergy diagnosis. Even studies that have used the diagnostic gold standard of oral food challenge, where the allergen of interest is fed to the child, have been limited by a lack of predetermined objective criteria to define the outcome. However, there have now been reports that hospitalisations for food allergy-related anaphylaxis — the most serious and life-threatening manifestation — have increased markedly since 1990 in the United Kingdom, the United States and Australia,2 most dramatically, with a fivefold increase, in 0–4-year-olds. The HealthNuts study was recently mounted to describe the prevalence of food allergy in 1-year-old infants in Melbourne, using a sampling frame designed to recruit a representative population sample and predetermined criteria to assess food allergy outcomes at oral food challenge.3 Recruitment occurred at childhood vaccination sessions. Participants’ parents completed a questionnaire, and the infants received skin prick testing for commonly allergenic foods. Among 2848 participants (73% participation rate), those with any sensitisation to one of three foods (egg, peanut and sesame) were invited to attend an allergy research clinic for formal oral food challenge. Using this method, the study found population-based prevalences of 2.9% (95% CI, 2.3%–3.6%) for peanut allergy, 8.9% (95% CI, 7.8%–10.0%) for egg allergy, and 0.8% (95% CI, 0.5%–1.1%) for sesame allergy in 1-year-old infants.4 Certainly, these rates are the highest yet reported in the Western world, with up to 10% of 1-year-old infants in this study population exhibiting signs of IgE-mediated food allergy in a challenge setting. Although it is anticipated that many of those with egg or cows milk allergy will develop tolerance to these foods in the first 3–4 years of life, the high prevalence of peanut allergy remains concerning, as only 20% of children are expected to achieve resolution of this allergy by 5 years of age.5 Furthermore, there is now evolving evidence that food allergy, including cows milk and egg allergy, may represent the first step on the allergic pathway referred to as the “atopic march”.6 As such, the question remains as to whether this reported high prevalence of food allergy may reflect a second and evolving epidemic of allergic disease, with an early onset in the form of food allergy that will translate into increased rates of asthma and other chronic allergic disease later in life. The reasons behind this apparent increase in serious food allergy are unknown and there is little evidence to guide effective prevention. One of the most topical theories for the rise in allergic disease in general — the hygiene hypothesis — states that very early exposure to microbial antigens promotes healthy immune development and reduces the risk of developing allergies. However, this hypothesis has not been examined specifically with regard to risk of food allergy. Another theory relates to vitamin D insufficiency, with recent reports in both the northern and southern hemispheres showing increasing rates of food allergy with increasing distance of children’s residence from the equator.7 A further factor that has been thought to be important in the development of food allergy is food allergen exposure. Until very recently, expert guidelines for infants with a family history of allergy typically recommended delaying introduction of allergenic foods (including avoiding eggs until 2 years and nuts until 3 years of age in the US), as well as delaying solid foods until after 6 months of age, and breastfeeding for at least 12 months, to reduce the risk of food allergy. Until the publication of the HealthNuts study,4 no population study had directly examined the relationship between infant feeding in the first year of life and risk of challenge-confirmed infant food allergy. Data from the HealthNuts study were used to assess the impact of timing of introduction of allergenic foods. Compared with introduction at 4–6 months, introducing egg into the diet later was associated with higher rates of egg allergy (adjusted odds ratio for introduction after 12 months, 3.4 [95% CI, 1.8–6.5]).8 Most interestingly, introducing cooked egg (such as scrambled, boiled or fried) was more protective than simply introducing egg in baked goods (such as cakes and biscuits). Those introduced to cooked egg at 4–6 months of age were five times less likely to develop egg allergy than those waiting until the normally recommended age of 10–12 months, even after adjusting for confounding factors. There was no protective effect among infants who first had egg in baked goods introduced into their diet between 4 and 6 months of age, presumably because exposure to a lower dose does not provide protection. A further possibility is that early introduction of egg might increase the dose of vitamin D in the diet, and therefore the effect might indeed be mediated through a unifying concept of vitamin D sufficiency. These results are the first evidence-based findings to inform recently revised feeding guidelines, in Australia9 as well as in Europe and the US, that avoidance of any allergenic food in the first year of an infant’s life is no longer recommended. The findings also represent the first report of a modifiable lifestyle factor found to be associated with food allergy and, if these results are replicated in randomised controlled trials, it will have important public health implications for infant feeding worldwide. The emergence of this new epidemic of allergic disease poses significant questions relevant to ensuring a healthy start to life for future generations of children, including whether some aspects of the modern lifestyle, which includes unquestionable improvements in public health, have had an unexpectedly adverse effect at the population level. We also need to understand whether this new wave of food allergy in early childhood is likely to persist into later childhood, and further assess whether early-onset food allergy plays a role in the development of other chronic allergic diseases such as asthma.

Katrina J Allen MB BS, FRACP, PhD

HbA1c may be a practical alternative to blood glucose for the diagnosis of diabetes For more than 15 years, glycated haemoglobin (HbA1c) has been recommended as the key tool for assessing glycaemic control in people with diabetes. Only in 2009 did the first advice to use HbA1c levels for diabetes diagnosis appear, using a cut-point of ≥ 6.5%.1 To date, no clear argument has been articulated to explain why HbA1c levels have been deemed superior to laboratory-determined blood glucose levels for determining the need for insulin therapy, but not for diagnosing diabetes; however, it is likely that implications of the former are greater than those of the latter, for both individuals and society. Blood glucose values are considered the gold standard for diabetes diagnosis, but they have significant limitations. Day-to-day variability in glucose levels is considerable, and the glucose concentration in a plasma sample falls within a short period, even if the blood has been collected in a fluoride tube. In addition, when stable samples are tested in two different laboratories, the results will differ by at least 14% in more than a third of cases.2 Furthermore, even when using a single laboratory, only 70% of people with a blood glucose value that indicates a diagnosis of diabetes have the diagnosis confirmed by repeat testing 2 weeks later, compared with 83% for HbA1c.2 So, is HbA1c the answer to the challenges of diabetes diagnosis? Until recently, the problem with HbA1c has been the concern that results vary considerably between laboratories. In the 1990s, laboratory differences of more than two percentage points were not uncommon, but the United States National Glycohemoglobin Standardization Program (NGSP) has progressively driven improvements in assay standards. The latest results from the largest global survey of quality of HbA1c measurement show that, for reference samples with HbA1c levels of 4.0%–6.0%, 91% of more than 3000 laboratories could obtain an HbA1cvalue that was within 6.0% of the target.3 In a recent Australian study, whole blood samples were sent to more than 200 laboratories and more than 90% obtained HbA1c values that were within 6% of the median.4 Thus, for a sample with a median value of 5.3%, over 90% of laboratories obtained values within the range 5.0%–5.6%, and for a median value of 7.4%, over 90% obtained values within the range 7.0%–7.8%. In addition, combined data from eight studies conducted between 1988 and 2004 (using assays in eight different laboratories, none of which may have performed as well as those available now) showed that HbA1c levels were at least as strongly correlated with diabetic retinopathy as were blood glucose levels.5 HbA1c is not without limitations. First, an HbA1c test is more expensive than a fasting glucose test, but costs about the same as an oral glucose tolerance test. The extra cost of using HbA1c instead of fasting glucose as the initial blood test needs to be weighed up against the potential for the HbA1c test (which does not require the patient to fast) to be used more widely, to identify more undiagnosed cases of diabetes, and to save money by preventing complications of diabetes. To our knowledge, no cost–benefit analyses comparing the HbA1c test with the fasting glucose test have been published — this should be a high priority. Second, HbA1c can be unreliable in the presence of haemoglobin variants or alterations in red blood cell turnover. Most HbA1c assays are now able to adjust for the most common haemoglobin variants, but where there is uncertainty relating to the reliability of HbA1c, blood glucose will remain the preferred test. If the potential exists to use HbA1c for the diagnosis of diabetes, how can a practitioner know whether a particular laboratory can be relied on? A joint working party of the Australian Diabetes Society, the Royal College of Pathologists of Australasia, and the Australasian Association of Clinical Biochemists is developing a formal laboratory and clinical framework within which the diagnosis of diabetes by HbA1c testing can be undertaken. In the meantime, it would be reasonable to think that a laboratory can be relied on, in the context of using HbA1c as a diagnostic tool, if the routine coefficient of variation is ≤ 3.0% (the 2010 accreditation target used by the NGSP) and the external quality assurance results are consistently within the Royal College of Pathologists of Australasia Quality Assurance Programs method-specific performance targets (allowable limits of performance). This information should be available from laboratories on request. Practical aspects of using HbA1c for the diagnosis of diabetes remain to be finalised. One option may be to request a fasting glucose test and HbA1c test at the same time, with the HbA1c to be performed only if the fasting glucose level is ≥ 5.5 mmol/L. This strategy would limit the additional costs of HbA1c testing while decreasing the number of patients who are lost to follow-up for an oral glucose tolerance test. The cost of an HbA1c test that is used for diagnosis is not currently reimbursed by Medicare. However, when used appropriately, the HbA1c test appears to be at least as useful for diagnosing diabetes as a blood glucose test. Australia may soon be ready to join countries such as the United States and Japan in using HbA1c, a measure of chronic glycaemia, for the diagnosis of diabetes, a disease of chronic glycaemia.

On behalf of the Joint HbA1c Working Party of the Australian Diabetes Society, the Royal College of Pathologists of Australasia, and the Australasian Association of Clinical Biochemists

Promising outcomes from the Australian register include a fall in fetal malformation rates associated with changes in antiepileptic drug prescribing The burden of epilepsy for those with the disorder is significant. For women of childbearing age, the uncertainty surrounding their ability to bear children who are free of the disorder, without birth defects, and cognitively and psychologically normal adds to this burden. Although factors other than medication exposure influence these questions, there is no doubt that antiepileptic drugs (AEDs) used to prevent seizures, such as valproate, have a significant, and possibly preventable, role in teratogenicity.1 Pregnancy registers are now showing promising results in elucidating this role and influencing changes in practice for the benefit of women with epilepsy and their children. Some detailed information on the relative risks associated with AEDs has emerged over the past three decades,2 but it has largely been based on small-scale retrospective studies, with various and incomplete methods of recording data, no set protocols, and other shortcomings. It was clear that better information regarding teratogenicity, preferably from prospective studies, was needed. It was also clear that the expectant mother, as well as the infant, should be a primary consideration. The process of studying pregnancies in women with epilepsy should start well before conception and requires extensive consultation with the expectant mother about the planned management of her pregnancy and medication administration.3 In the late 1990s, these issues provided the rationale for setting up registers of pregnant women with epilepsy who were taking AEDs. There are now several international collaborative, independent and pharmaceutical company-initiated registers. The latter are concerned with single drugs and are not prospective. The collaborative and independent registers generally aim to collect prospective observational data from participating women according to an extensive protocol, with the data computerised for subsequent analysis. None of the registers dictate treatment and all have ethics approval, as well as informed consent from the participating women.4 The major registers are the International Registry of Antiepileptic Drugs and Pregnancy (EURAP),4 which includes data from 46 countries in Europe and elsewhere, and registers in North America, Denmark and the United Kingdom that publish reports independently. The Australian Pregnancy Register of Antiepileptic Drugs for Women in Pregnancy with Epilepsy and Allied Conditions (the Australian Pregnancy Register), established in 1999, is affiliated with EURAP, but also publishes its findings independently. It collects data from women who have volunteered to participate through a series of five interviews held at various times during pregnancy and after the infant’s birth.5 Over the past decade, all these registers have contributed considerable knowledge, improved prescribing practices and, although they were initially intended to focus on teratogenicity, have been extended to examine maternal wellbeing and seizure control, and cognition of the offspring. In terms of teratogenicity, the data collected in the registers can be used to assess the contributing roles of heredity, social factors, substance misuse, alcohol consumption, social status, intake of other medications, and accurately defined type and activity of epilepsy. The registers represent prospective studies on treatment efficacy and compliance, seizure freedom before pregnancy, interactions between AEDs and hormones, the role of folate supplementation, and many other factors involved in producing normal pregnancies and outcomes. The international registers have not used untreated control groups until recently — the North American register has used historical controls but is now enrolling a control group of pregnant untreated women, while EURAP compares the effects of different drugs. The Australian Pregnancy Register has from the outset collected data from a control group of untreated women with epilepsy, comprising about 10 per cent of the total, as well as (less successfully) women receiving AEDs for non-epileptic indications such as pain or bipolar disorder. Although there is no ideal control group, collecting data from untreated women with epilepsy provides an important comparison baseline.6 Recent analyses of data from the Australian Pregnancy Register have examined the role of AEDs in teratogenicity. For several decades, the use of AED polytherapy has been enshrined in the international literature as being harmful to the fetus, but our recent analysis of register data casts doubt on this, suggesting that it is the specific composition of polytherapy that is critical, not intake of multiple drugs per se.7 Most recently, analysis of register data has focused on dose issues that are associated with most of the AEDs, and examined the question of whether lower doses of drugs such as valproate may be effective in achieving seizure control without posing a higher risk of teratogenicity than other, less effective drugs.8 The role of AEDs in teratogenicity has become even more complicated as a series of new second-generation drugs have become available, because it takes a long time with many participants to define their role compared with the traditional drugs.9 Findings from the Australian Pregnancy Register have shown that seizure freedom before conception is demonstrably important in predicting the course of future pregnancies; the longer a woman is seizure-free, the better the outlook. The question of repeated pregnancies in women who have had a malformed baby while taking an AED, and advice to women contemplating extending their family, has also been studied. Findings such as these are of immediate importance to women and their babies, contribute to medical knowledge and have demonstrably altered prescribing practices in Australia and internationally. Recent data indicate that, while prescribing of valproate has risen in the general Australian population, possibly as a result of increasing use for patients with psychiatric illness, especially bipolar disorder, there has been a fall in the number of prescriptions and doses of valproate for women of childbearing age.10 This change in prescribing, which was influenced by register data, has been associated with a fall in fetal malformation rates.11 Increasing the number of women enrolled in the Australian Pregnancy Register is highly desirable to continue study of these important and complex topics. Pregnancy is an important health issue, and we must all collaborate to make it safer for women and their children.

Frank J E Vajda MD, FRCP, FRACP · Terence J O’Brien MB BS, MD, FRACP · Cecilie M Lander MB BS, FRCP, FRACP · Mervyn J Eadie MD, PhD, FRACP

Hard lessons for device manufacturers, regulators and surgeons in the wake of a market recall Hip replacement is one of the most cost-effective surgical procedures undertaken today. It relieves pain and restores mobility and independence for almost 35 000 individuals each year in Australia. However, recent publicity in Australia and overseas about the recall of hip prostheses from the market has created uncertainty and anxiety in patients who have undergone or are about to undergo hip replacement or other types of joint replacement surgery. Medical practitioners need to have a clear understanding of the issues and their implications so they can assist and advise patients appropriately. In December 2009, the ASR (articular surface replacement) hip system, manufactured by DePuy Orthopaedics (Warsaw, Ind, USA), a division of Johnson and Johnson, was withdrawn from the Australian market. The ASR system consisted of resurfacing (ASR Hip Resurfacing System) and conventional total hip replacement (ASR XL Acetabular Hip System) prostheses. The resurfacing prosthesis was introduced in Australia in 2003 and the conventional prosthesis in 2004. Both prostheses used a chromium–cobalt metal-on-metal articulation. The Australian Orthopaedic Association National Joint Replacement Registry (AOA NJRR) first published concerns about the outcome of the ASR resurfacing prosthesis in its 2006 annual report.1 In its 2007 report, it identified the ASR resurfacing prosthesis as an outlier,2 meaning that its revision rate was greater than twice the rate for all other resurfacing prostheses combined and that this difference was statistically significant. In 2008 and 2009, the Registry identified both the ASR resurfacing and conventional prostheses as outliers.3,4 DePuy voluntarily recalled both prostheses from the Australian market at the end of 2009. At that time, more than 5500 patients in Australia had received these devices (4410 conventional ASR and 1167 resurfacing ASR). After receiving further information from the National Joint Registry of England and Wales, DePuy undertook a worldwide recall of both prostheses in August 2010. It is estimated that 93 000 patients globally had received these devices.5 The most recent (unpublished) data from the AOA NJRR show that, at 6 years, the ASR conventional prosthesis has a 13.6% cumulative percentage revision rate (after 1.5 years: hazard ratio, 4.92 [95% CI, 4.25–5.70], P < 0.001) and the ASR resurfacing prosthesis has an 11.1% cumulative percentage revision rate (hazard ratio, 2.24 [95% CI, 1.81–2.77], P < 0.001). It is not currently possible to know how many patients with an ASR prosthesis will eventually require revision, but this number could potentially be high. It remains unclear why the ASR system has a high revision rate. It is known that these prostheses can wear at an accelerated rate, but the mechanisms causing this have yet to be established. Such wearing results in high local concentrations of both metal particles and metal ions, which cause an inflammatory response that can be quite marked and associated with significant bone and soft tissue damage.6 Revision surgery is usually required, but the outcome is often less than satisfactory. Very high serum levels of chromium and cobalt have also been detected in some patients,7 raising concerns about the potential for serious systemic toxic effects. In this issue of the Journal, Mao and colleagues report the first Australian patients with ASR prostheses to show a potential association between high serum metal ion levels and systemic toxicity.8 Their report also highlights the difficulties in understanding the relevance and significance of these high metal ion levels. To date, there have only been anecdotal case reports of potential toxicity,7 and this is another such publication. The authors have been clear in stating that it is not possible to draw conclusions because there is not enough evidence to determine if the problems these patients have experienced are coincidental rather than causal. What this and other reports have done, however, is highlight the urgent need to undertake comprehensive research to examine the relationship between high serum metal ion levels after total hip replacement and the risk of toxicity. It is critical to determine at what concentration elevated cobalt and chromium serum levels may cause toxicity, and how the extent and severity of toxicity varies with the level. This is important because surgeons currently have no information on whether a hip should be revised based simply on the patient’s serum metal ion levels. Revision surgery has significant morbidity and mortality risks and should not be undertaken without good indications to do so. The high revision rate of the ASR system raises the question of whether this is a prosthesis-specific problem or a wider issue with all metal-on-metal prostheses. The ASR system certainly has a higher rate of revision than other metal-on-metal prostheses, but there is increasing evidence that some metal-on-metal hip prostheses are not performing as well as those that use other articulations, particularly where larger femoral head sizes are used.4,9 The AOA has recently advised its members to use metal-on-metal prostheses with caution. There has been discussion within the orthopaedic and wider community regarding the role of surgeons in the design, development and subsequent use of new prostheses. Surgeon involvement can be a very good thing as it may ensure that not only the design, but also the approach to implanting the device, is optimised. However, it is clear that transparency and accountability are needed around any relationship a surgeon may have with a device manufacturer. In 2010, the AOA developed a code of conduct for its members, which incorporates a position statement on interaction with the medical industry.10 This clearly defines surgeons’ responsibilities when dealing with companies. The global experience with the ASR system, and potentially all metal-on-metal devices, has important ramifications for arthroplasty device regulation. How is it that the ASR was approved for use? Could this situation occur again? Currently, it is not mandatory in Australia for a new hip or knee prosthesis to have clinical evidence specific to the device that indicates it is either safe or effective. The regulatory requirements for medical devices are stratified according to perceived risk. This situation is not unique to Australia. Some years ago, the AOA recommended to the Therapeutic Goods Administration (TGA) that clinical evidence requirements for joint replacement prostheses should be increased. In particular, it requested that these devices be reclassified from Class 2B to Class 3. Class 3 requires greater scrutiny of clinical evidence before a device is approved. The TGA is currently considering the reclassification of these devices and it is hoped that the experience with the ASR system will ensure it happens soon, as this would significantly reduce the likelihood of another similar occurrence. The good news story out of all this is that Australia clearly has a very effective post-market surveillance system for joint replacement prostheses. The early identification by the AOA NJRR that the ASR system had a higher than anticipated rate of revision significantly reduced the local use of these prostheses and eventually resulted in Australia being the first country to have the ASR system recalled. The AOA NJRR has been supported by the Australian Government since its inception, and Commonwealth legislation passed in 2009 has ensured the ongoing funding of the Registry. The most recent data from the Registry indicate that 95% of people undergoing hip replacement still have a functioning joint 10 years after surgery. Despite the experience with the ASR system, the risk of revision is declining. These results will be further enhanced if device manufacturers, regulators and surgeons take heed of the lessons learned from the ASR system recall.

Stephen E Graves MB BS, DPhil, FAOrthA

Research fraud is an unacceptable breach of trust Few issues in medicine provoke the wrath of the profession more than research fraud. In an era when evidence-based medicine has become the cornerstone of information about the safest and most effective way to practise medicine, fraudulent or unethical medical research represents an unacceptable breach of trust for clinicians, health policymakers and the general public. Research fraud takes many forms, including plagiarism, duplicate publication and fabrication by falsifying or omitting data to create “positive” results. When the latter occurs, the damage to the reputation of investigators, institutions, specialties and the broader profession is often permanent. An article published in Anesthesia and Analgesia in December 2009 by Joachim Boldt compared the effects of two colloid cardiopulmonary bypass pump-priming solutions — albumin and hydroxyethyl starch (HES) — on physiological variables in 50 patients undergoing cardiac surgery.1 It was retracted in October 2010.2 Following concerns about the validity of some of the results, raised in letters from readers, an enquiry to the institution where the study was conducted confirmed that no institutional review board approval had been obtained. A formal inquiry by the state medical authority of Rheinland-Pfalz, Germany, confirmed that the study had been entirely fabricated on the basis that there were no original patient or laboratory data to support the findings. Furthermore, Boldt had confessed to forging the signatures of the coauthors, who denied participating in the fabrication.3 Boldt had been a prolific author and the retraction of this report immediately cast doubt on the scientific and ethical validity of his previous and subsequent publications. This suspicion was confirmed in two open letters published by the editors-in-chief of 18 journals that retracted a further 87 reports. While these publications concern a range of topics in anaesthesia and perioperative care, 11 were reports on the safety and efficacy of a relatively new HES preparation used for fluid resuscitation, 6% HES 130/0.4. These reports constitute a substantive body of literature that has been used in manufacturers’ product information sheets and submissions to regulatory authorities, including the Therapeutic Goods Administration (TGA). Although HES preparations have been used as resuscitation fluid for over 40 years, particularly in Europe, 6% HES 130/0.4 was the first HES approved by the TGA (in November 2006). Since 2008, the use of 6% HES 130/0.4 in Australia has increased, which is consistent with reports that show that it is the most commonly used resuscitation fluid on a global basis, although there is marked variability in selection and use of resuscitation fluids from country to country.4 Before confirmation of the first retraction, two updated Cochrane systematic reviews on resuscitation fluids — comparing colloids with crystalloids5 and comparing different colloid solutions6 — included a sensitivity analysis excluding studies published by Boldt. Both reviews concluded that excluding these reports did not change the conclusions that there was no evidence from randomised controlled trials that (a) resuscitation with colloids reduced the risk of death compared with crystalloids or (b) any one colloid was more effective or safer than any other. The reviews highlighted the urgent need to conduct large-scale high-quality trials of fluid therapy. The Crystalloid Versus Hydroxyethyl Starch Trials, being conducted by the Australian and New Zealand Intensive Care Society Clinical Trials Group and the George Institute for Global Health, are underway. These trials will compare the effects of 6% HES 130/0.4 and saline for resuscitation in intensive care units, using patient-centred outcomes — specifically, mortality and the incidence of acute renal injury. The magnitude of the Boldt case is unprecedented in intensive care medicine. It ranks with the fraudulent research conducted by Wakefield (measles–mumps–rubella vaccine),7 Sudbo (non-steroidal anti-inflammatory drugs and the risk of oral cancer)8 and Hwang (embryonic stem cell cloning).9 That these cases of major research fraud have occurred within the past decade, despite increases in ethics governance and regulatory processes within the jurisdictions involved, highlights the determination of fraudulent researchers to publish their reports. The reasons driving this are complex and include career pressure, financial incentives, the ease of fabricating data, and the proliferation of electronic media.10 Researchers and institutional human research ethics committees are expected to act in accordance with the Australian Code for the Responsible Conduct of Research. This code was established by the National Health and Medical Research Council and the Australian Research Council to bolster responsibilities of research organisations.11 Equally, journals have a key role in verifying that appropriate ethics review processes have been completed and ensuring that only studies of the highest levels of internal and external scientific validity are published. While the protection of patients who participate in clinical trials is the ultimate consideration of ethics governance processes, it is imperative that high-quality research conducted with the highest levels of ethical integrity and scientific validity continues to provide the best information for clinicians.

John A Myburgh MB BCh, PhD, FCICM

We need to balance the technical challenges of hospital standardised mortality ratios with the need to improve care processes That “sunshine is the best disinfectant” is attributed to the distinguished American jurist Louis Brandeis, who spent much of his career supporting individual rights in the context of corporate and monopoly power.1 State and federal governments, in conjunction with bodies such as the Australian Commission on Safety and Quality in Health Care and the Australian Institute of Health and Welfare, are developing indicators for the safety and quality of Australian hospital care, presumably with the intention of using them to illuminate some of the inner workings of our hospital system for the benefit of both health care providers and the community at large. The challenges posed by such a program are illustrated in this issue of the Journal by Scott and colleagues2 and Gallagher and Krumholz.3 Health care professionals face a basic dilemma. The vast majority of us are hard working, conscientious and altruistic. Yet the hospitals in which we work collectively expose patients to substantial risks over and above those posed by their clinical conditions, and improving hospital safety and quality is work that ultimately can only be done by hospital staff. The United Kingdom Department of Health recently summed up the task of a safety and quality indicator such as the hospital standardised mortality ratio (HSMR): A high HSMR is a trigger to ask hard questions. Good hospitals monitor their HSMRs actively and seek to understand where performance may be falling short and action should not stop until the clinical leaders and the Board at the hospital are satisfied that the issues have been effectively dealt with.4 The challenge is that exposure to a safety and quality indicator will trigger hard questions about the technical qualities of the indicator rather than underlying care processes, and opportunities for improvement will be lost. The technical issues canvassed2,3 include the value of coded administrative data as a source for risk adjustment; analysis and interpretation of data from small hospitals; and problems related to classifying and coding hospital palliative care provision. All require detailed work, such as is in progress for HSMRs.5 Furthermore, the Australian Commission on Safety and Quality in Health Care is going through a rigorous development process for at least 16 measures.6 A dilemma in indicator development is whether to accept the merely good or await the perfect. Discussion about technical matters should not divert attention from the basic questions about what available indicators such as relative hospital mortality actually measure, and how they, and other indicators, should be used and distributed. Mortality indicators compare observed mortality against a risk-adjusted expected mortality derived from a broader reference source. Differences are silent as to cause. They are simply a prompt for hard questioning. Process measures of adherence to evidence-based care pathways are well established quality indicators that provide immediate feedback on areas for improvement. Mortality measures do not correlate well with process measures.2 Does this undermine the validity of mortality as a safety and quality indicator? Only if process measures are taken as the gold standard of hospital safety and quality. But what if a measure of getting evidence-based steps right (a process measure) is not directly related to a measure of what happens when things go wrong? What if hospital mortality measures are at a tangent to process measures, rather than directly consequential?7 Then the hard questions provoked by an elevated mortality rate of any kind might do well to begin with examining the capacity to rescue patients when things go wrong,8 as they will in even the best-organised departments. Scott and colleagues2 provide excellent practical advice on how institutions might use indicators of various kinds to provoke hard questions. They are wary, however, of providing hospital staff, or the public at large, with comparative information on hospital outcomes. The efficacy of comparative and public reporting as a prompt to improving hospital safety and quality cannot be settled by rigorous scientific means. It is just not possible to carry out randomised double-blind trials of accurate versus inaccurate dummy comparative reporting. The extent of public reporting is a public policy issue in which the risks to institutional reputation and morale have to be balanced against a need for accountability and the opportunity for informed choice by current and future users of health care institutions.9 Gallagher and Krumholz note that Australia has lagged behind other countries in publicly reporting hospital outcomes.3 As Brandeis might have argued, one of the most important virtues of public reporting is that it makes it harder for vested interests, whether they are in government or institutions, to suppress unwelcome information. No doubt the debate has just begun.

David I Ben-Tovim PhD, MB BS, FRANZCP

A patient-focused learning health system, using integrated data sources, will facilitate optimal care of individuals and result in better care of our populations and society In this issue of the Journal, two articles report strikingly high use of health services in Australia.1,2 Lowthian and colleagues document a 75% increase in emergency ambulance transportations, and forecast another 46%–69% increase by 2015.1 Rosenwax and colleagues demonstrate that 96% of Western Australians dying of life-limiting illnesses were admitted to hospital in their last year of life.2 These authors raise three points: use of health care is expanding; solutions are needed to care for people with chronic complex illness; and we can improve understanding and solutions through analysis of growing datasets. Both studies use linked, large database analyses to understand care patterns. Remarkably, neither proposes algorithms to repeat the analyses at prespecified intervals to monitor change, link findings to other work through data integration, and test interventions. Rising health care use is obviously unsustainable, and the strain will magnify with more elderly people suffering coexisting chronic illnesses. Individual patient needs are also evolving, and here lies a critical tension. The scaling back of use of health care services seems straightforward; equally straightforward is the decision to admit this woman with refractory cancer pain to hospital, or to call an ambulance for this man with presyncope and facial numbness. Few contemporary patients have simple illnesses; it isn’t “just cancer”, but is a woman with multiple treatments for breast cancer, metastases, osteoporosis, heart disease and emphysema, any of which can stimulate hospitalisation; thus, health care use balloons. How do we reduce health care use — or at least stabilise it? Health promotion and better prevention is the obvious answer but the processes leading to potentially preventable illnesses among our ageing population are already well underway and unlikely to be substantially modified. A solution is needed, and we must find the right blend of interventions for patients and populations. Data-driven prognostication should guide understanding of an illness trajectory and facilitate decision making. Treatments should be personalised and interventions matched to the patients most likely to benefit. Continuous monitoring of outcomes and adverse effects should be used to ensure promotion of helpful interventions and discontinuation of ineffective or burdensome interventions. In other words, it’s time to make the transition from isolated findings and single research reports to “learning health care”.3 The care of individuals should be improved by the use of information about all preceding people with similar clinical scenarios, and information about care of a patient reinvested into the growing body of linked data to guide care in the future. In this paradigm, use of available data and evidence will ensure quality of treatments. The learning health care system forms around three fundamental purposes, which are to: generate and apply the best evidence relevant to each patient; propel scientific discovery as a “natural outgrowth of patient care”; and support quality assessment and improvement, spark innovation, enhance patient safety and maximise health care value.3 According to the United States Institute of Medicine: A ... comparative effectiveness research enterprise will require a supporting infrastructure [and] large-scale clinical and administrative data networks that enable observational studies of patient care ... New methods for linking patient-level data ... will promote inclusion of populations frequently omitted from clinical trials.4 Driving the learning health care system is a powerful, integrated, linked data network. Data sources include clinical care, health resource and administrative data, basic science information, clinical research datasets, and patient-reported outcomes.5,6 Patient-level data are used to inform individual care and summarised to improve general health care. Advances in information and data analysis technology will help clinicians temper professional judgement with clinically relevant evidence. Rapidly increasing health care costs within the context of the need to take care of individual people presents an important contemporary conundrum. A simple solution is not possible. We need a patient-focused learning health system to facilitate best care of individuals and target the right treatment at the right time, while reducing waste and harm. Better care of individuals wraps up to better care of populations and society.

Amy P Abernethy MD, FRACP, FAAHPM

As tuberculosis resistance increases linearly, the cost and complexity of managing these cases increases exponentially New Zealand’s first case of extensively drug-resistant tuberculosis (XDR-TB) is reported in this issue of the Journal.1 Even though the patient did not have transmissible pulmonary TB, the case highlights the complexity of managing such patients and draws attention to the long delay between suspecting TB and confirming XDR-TB. Two cases of XDR-TB have been reported in Australia, one in 20042 and one in 2010,3 but there have been many more cases overseas.4 Still, only three cases in our two countries — should we care? A quick revision of history can help us to understand why multidrug-resistant TB (MDR-TB), and now XDR-TB, are so important. Tens of thousands of Australians and New Zealanders died of TB during the 19th and early 20th centuries.5 For generations, TB engendered the same dark fear that we now associate with cancer. One face in the crowd provides a poignant example. Archie Jackson, who in 1929 became the youngest cricketer to have scored a test century against England, was also one of the youngest to die — he was just 23 when he died from pulmonary tuberculosis in 1933.6 The advent of safe and effective antibiotic therapy after World War II meant the end of the great fear, and TB seemed defeated. In fact, rates of TB were already falling before the age of antibiotics, partly due to improvements in nutrition and living conditions.7 However, it would be folly to assume “game over, TB”. TB notifications have stopped falling in Australia and New Zealand, although they remain very low by international standards (about seven new cases per 100 000 population per year).8 In contrast, drug-resistant TB is out of control in several regions of the world. In Burma (Myanmar), the country of origin of the patient described in the case report from New Zealand, there were an estimated 4250 cases of MDR-TB in 2006 alone.4 The reasons for the worldwide emergence of resistance include poverty, breakdown in public health systems following the fall of the Soviet Union,4 the interaction of TB with AIDS in Africa, and a laissez-faire attitude to antibiotic control in some increasingly wealthy emerging nations.9 Because of the biphasic biology of TB, whereby frequent asymptomatic infection is followed unpredictably by active transmissible disease, there is no practical way of isolating Australia and New Zealand from TB drug resistance. Infection with Mycobacterium tuberculosis is initially acquired by breathing but the risk depends heavily on the local prevalence of active TB. If a person lives for many years in a high-risk country, infection is likely, but usually remains silent and can only be detected by performing a Mantoux test or interferon-gamma release assay. Neither test detects bacterial cells directly, so will not reveal the resistance profile of the infecting strain. The silent stowaways then travel with refugees, overseas students and migrants who come seeking sanctuary or opportunity. Screening by chest x-ray allows early detection in some, but it is not always appreciated that people with normal chest x-rays may also carry latent M. tuberculosis. For example, as described in this issue of the Journal by Trauer and Krause, of 146 refugees arriving in the Northern Territory who were found to have latent TB infection (LTBI), only 6% had chest x-rays showing abnormalities.10 Those with LTBI were offered isoniazid preventive therapy in accordance with current guidelines, but this is unlikely to reduce future reactivation of antibiotic-resistant TB. Fortunately, most people with LTBI remain well, but a small group will develop active disease, often relatively soon after arrival. In Victoria, the median time between arrival in Australia and notification of TB was 2 years in a 10-year review of MDR-TB.11 About half of new cases of TB in Australia and NZ have transmissible pulmonary disease, mostly caused by the same strain of TB that they breathed in years earlier, antibiotic susceptible or otherwise.11 In this way, good public health practice at home can be undone by poor public health practice abroad. Why does resistance matter? First, there is the cost. The World Health Organization has estimated that the cost of treating a patient with MDR-TB is about 100 times the cost of treating fully susceptible disease.12 For the patient, there is a long and difficult 18–24-month treatment course. And then, there is the return of the age-old fear — although patients with XDR-TB can be treated too, resistance to the most effective second-line antibiotics increases the risk of treatment failure and death.13,14 Definitions of tuberculosis-related terms TB Tuberculosis — a clinically apparent disease caused by Mycobacterium tuberculosis that typically presents with one or more systemic symptoms (eg, night sweats, fever, loss of weight) and a local symptom indicating the site of active infection (eg, cough, headache, back pain, neck gland swelling). MDR-TB Multidrug-resistant tuberculosis — TB caused by M. tuberculosis that is resistant to at least rifampicin and isoniazid, the most active first-line antibiotics. XDR-TB Extensively drug-resistant tuberculosis — MDR-TB that is also resistant to any fluoroquinolone, and to at least one of three injectable second-line anti-TB drugs (capreomycin, kanamicin, or amikacin). LTBI Latent TB infection — an individual is infected but has no symptoms or signs of active disease. TB reactivation A person with LTBI develops active TB. The lifelong risk is thought to be about 5%, but is much higher in patients with HIV or who are medically immunosuppressed. Primary resistance Resistance in M. tuberculosis obtained from a patient with no history of treatment. Secondary resistance The development of resistance during treatment of drug-susceptible TB due to incorrect prescribing and/or poor patient compliance. Secondary case [of TB] A person who is infected by someone with active pulmonary TB before this initial diagnosis is made and the patient is isolated. So what is a rational response to this threat in low-risk countries such as Australia and New Zealand? Predicting where new cases of resistant TB will appear is very difficult. In Australia, there were only 153 cases of MDR-TB and one case of XDR-TB in the period 1995–2007.2 There have been about 2700 more cases of TB diagnosed since then,15 with an expected MDR-TB rate of about 2.5%.2 If you are a manager thinking that maybe you could put your TB funds to work elsewhere, think again. Resistant TB in a low-prevalence country is an example of a low-probability, high-impact event — a “black swan”, to borrow a concept recently popularised by the economist Nassim Taleb.16 A black swan is something too improbable to worry about, but then it happens and everything changes. For Europeans, swans had been axiomatically white for millennia. In 1697, a black swan was observed during the exploration of what is now Western Australia, and an axiom collapsed because of a single exception. Moreover, according to Taleb, such events are immediately rationalised and considered to have been obvious in retrospect.16 Consider the impact of a delayed diagnosis of pulmonary XDR-TB if the patient were an overseas-trained nurse or doctor working in a paediatric hospital. There is no proven postexposure prophylaxis; there is a risk of treatment failure and drug toxicity that would further distress already anxious parents; and the cost of successfully treating even one secondary case of XDR-TB has been estimated at US$600 000 in a Californian case series.17 Something like this will happen — we just don’t know when. Here are some suggestions for how we can try to out-swim the black swan. First, we must sustain and extend our existing overseas programs that support our neighbours in their struggle to control TB. This is not philanthropy, it is just common sense. One example involves clinics that have been providing treatment for MDR-TB to Papua New Guinea nationals who cross the Torres Strait to receive it. A recent decision taken on cost grounds by the Queensland and Commonwealth governments to close these clinics is unlikely to save Australia any money in the long run.18 Our next line of defence is the primary care clinician. Rapid diagnosis of pulmonary TB minimises secondary transmission, whatever the resistance pattern of the isolate. Then we need to strengthen our local TB public health services and recognise that as TB resistance increases linearly, the cost and complexity of managing these cases increases exponentially. Finally, we need to keep up to date with new technology. The latest molecular methods are now able to directly detect the presence of M. tuberculosis and rifampicin resistance simultaneously in primary specimens, including in some that are smear-negative (ie, acid-fast bacilli present but too few to be seen by microscopy).19 This is an important advance because rifampicin resistance is a marker for MDR and XDR-TB and the result could be available within just a few hours. Molecular diagnostics are not yet perfect — we will need to retain culture-based methods for a while yet — but they are now becoming widely available and progressively cheaper. We should embrace these new technologies and make molecular screening of primary specimens standard practice, even though the upfront costs will seem high initially. We need to be organised and up to date if we want to stay ahead of TB.

Paul D R Johnson MB BS, PhD, FRACP(Infectious Diseases)

The cost differential between these two drugs is no longer defensible Federal Health Minister Nicola Roxon recently met with an alliance of consumer, industry and other stakeholders to justify the government’s plan to indefinitely delay the listing of seven new medicines on the Pharmaceutical Benefits Scheme (PBS). She argued that, after considering the advice of the Pharmaceutical Benefits Advisory Committee (PBAC), it was the government’s responsibility to decide whether or not to list a new drug, taking into account other priorities across the health portfolio and current fiscal circumstances.1 Clearly, the cost of the PBS must be sustainable. However, there are other ways of reducing its cost apart from delaying the listing of drugs recommended by PBAC as cost-effective. The treatment of macular degeneration provides an illustrative example. Age-related macular degeneration (AMD) is responsible for almost half of all cases of blindness in Australia.2 In neovascular (or “wet”) macular degeneration, vision loss results from the abnormal growth and leakage of blood vessels in the macula. Ranibizumab (Lucentis), developed by Genentech and marketed by Novartis in Australia, is currently the only drug approved by the Therapeutic Goods Administration (TGA) and available on the PBS to treat wet AMD. It is administered as an intravitreal injection, usually 4–8-weekly, for 12 to 18 months or longer. The PBS-listed price of each injection is $1967. Ranibizumab is the antigen-binding fragment of a recombinant, humanised, monoclonal antibody that binds to vascular endothelial growth factor A (VEGF-A), the cytokine primarily responsible for blood vessel growth. The inhibition of VEGF-A reduces the permeability and growth of the neovascular vessels. Blindness is prevented in most patients, and the majority of treated patients go on to have some improvement in vision.3-5 Bevacizumab (Avastin) is an anti-VEGF-A humanised, monoclonal antibody (also developed by Genentech, and marketed in Australia by Roche; Genentech is a wholly owned subsidiary of Roche) that has been approved by the TGA for the systemic treatment of certain cancers. It was successfully used “off-label” for the treatment of wet AMD before ranibizumab became available, but has also been used to some degree since the availability of ranibizumab, especially in the United States, where patients bear more of the costs of drugs.5-7 It is prepared for ophthalmic use in a sterile pharmacy by taking a dose used in chemotherapy and splitting it for use in treating wet AMD for up to 25 patients. The cost of its off-label use has been significantly less than that of ranibizumab (around a 40th of the cost, at $50 per dose). Ranibizumab received PBS listing for use in treating wet AMD in 2007 and has since largely replaced bevacizumab for the treatment of AMD in Australia. Although therapy with ranibizumab has been successful, its PBS listing has come at great expense, costing taxpayers $237 million in 2010 (second only to atorvastatin and rosuvastatin). It is consistent with many of the principles of quality use of medicines (QUM), outlined in the National Medicines Policy,8,9 for ophthalmologists to select a PBS-listed therapy that has been demonstrated to be safe and effective. But advocates of QUM also emphasise the importance of choosing medicines that are cost-effective for individuals and the community. A recent study by the US National Eye Institute10 has raised the question of whether use of ranibizumab can be justified economically. The study compared bevacizumab and ranibizumab for the treatment of wet AMD, administered either monthly or as needed, in 1208 randomly assigned patients. At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity, when administered according to the same schedule. Ranibizumab given as needed, with monthly evaluation, had effects on vision that were equivalent to those of ranibizumab administered monthly. The comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. Differences in rates of serious adverse events were higher with bevacizumab but did not reach statistical significance, and require further study. Results from the second year of this study and from other comparative trials and experiential databases will provide additional information. Despite this new information having come to light, in Australia there is little motivation for clinicians, the pharmaceutical companies involved, or government bodies to pursue a broader economic agenda. There is no incentive for Australian ophthalmologists or patients to use bevacizumab off-label because the price to the patient for the PBS-listed ranibizumab is only that of the copayment, and the costs for the ophthalmologist visits are the same. There is little incentive for the sponsor of bevacizumab (Roche) to seek a new indication (wet AMD) for this drug — first from the TGA and then from PBAC — because of the substantial costs involved and the doubtful rewards. Also, the relationships between the companies involved appear to militate against moves that might change the present situation. Applications to both the TGA and PBAC are now fully cost-recovered by charges levied on the sponsor of the drug — a unique situation among equivalent developed countries. This provides a considerable disincentive for applications that are primarily in the public interest. While charges can be reduced or eliminated for so-called orphan drugs, this provision would not apply in this case because ranibizumab is currently available and patent-protected.11 And although it has been suggested that a third party, such as a Royal College, might sponsor an application to the TGA and PBAC in the public interest, this concept has foundered because the sponsor is also responsible for product liability. This leaves us with the question: what policy options might circumvent the difficulties outlined here and save taxpayers substantial amounts of money when treating neovascular AMD with anti-VEGF-A drugs? First, the drug committees and administrations of public hospitals with significant eye services could recommend off-label use of bevacizumab for AMD, in the light of the National Eye Institute study. Currently, in New South Wales public hospitals, there is no PBS access to ranibizumab. This would also accommodate public patients unable to pay for private ophthalmologist visits. Given the issues with bevacizumab of dose preparation, sterility and shelf life, combining services for efficiency and geographical coverage would make sense, as would amalgamating public clinics that already use bevacizumab off-label for other related indications (eg, diabetic retinopathy). Second, the government could consider ways in which it could withdraw the PBS listing for ranibizumab for the treatment of wet AMD, on the grounds that treatment with bevacizumab in public eye hospitals is likely to be more cost-effective. This is likely to be problematic for several reasons: the limited capacity of the public sector to provide this treatment; opposition by ophthalmologists operating privately and those who deliver public services; and opposition from the sponsor. Third, the government could negotiate with Novartis to reduce the cost of ranibizumab, or with Roche to apply to have bevacizumab approved and listed for use in treating AMD. It should be noted that the effort needed to register, list and distribute medicines internationally and in Australia should be considered in these negotiations, but the cost differential now extant in the light of the National Eye Institute study results is no longer defensible. Finally, the government could accept that it is the only body with the responsibility and capability of acting in the public interest in these matters. The Minister for Health and Ageing could ask the TGA and PBAC to consider listing bevacizumab for neovascular AMD in the public interest, perhaps with a temporary or provisional licence pending accumulation of more data, with the government accepting any liability that may accrue. Although the challenges of achieving an equitable solution to this problem are considerable, the significance to the PBS budget and subsequently for analogous situations is now a strong incentive for action.

Ken J Harvey MB BS, FRCPA · Richard O Day MD, FRACP · William G Campbell MB BS, FRANZCO · Wendy Lipworth MB BS, MSc, PhD

Our health and medical research sector is under threat and needs the support of the clinical community Until quite recently, it was believed that peptic ulcers were caused by stress and lifestyle and that the most effective treatment was a bland diet and rest. However, in 1982, two Australian medical researchers (Barry J Marshall and J Robin Warren) discovered the bacterium Helicobacter pylori and demonstrated its role in gastritis and peptic ulcer disease.1 Thanks to this discovery, millions of people worldwide are now cured of peptic ulcer with a short regimen of antibiotics and acid secretion inhibitors. This is just one of hundreds of examples of effective translation of Australian health and medical research into clinical practice and, importantly, better outcomes for patients. Over the past 50 years, health and medical research has saved the Australian health care system trillions of dollars and delivered better quality of life for all Australians. It is estimated that between 1960 and 1999, medical research was responsible for a longevity gain of 8 years worth $2.9 trillion and gains in quality of life worth $2.5 trillion in avoided health expenses.2 Regrettably, these hard-won advances now stand to be undermined by potential cuts to National Health and Medical Research Council (NHMRC) funding in the May federal Budget. Over the past decade, the nation’s research community has achieved a level of critical mass, thanks to the vision and leadership of successive governments. But the sector was coming off a very low base and, compared with overseas competitors, Australian Government funding for research as a proportion of gross domestic product still remains low, at only 0.11%–0.12%.3 Over the same period, demand for medical research and the knowledge to cope with emerging disease patterns has grown with the inexorable rise in chronic disease, an ageing population and the impact of globalisation on health epidemics. In order to manage these new health challenges with the financial resources available, we will inevitably see more and more health care delivery taking place in the community and away from acute settings. In preparation for this seismic change, we need research breakthroughs and long-term, evidence-based solutions. A cut to the annual $775 million NHMRC budget will not just affect Australians today but will compromise the health outcomes of our children, grandchildren and great-grandchildren. Health and medical research is an essential component of the current health reform agenda and plays a vital role in providing better outcomes for a self-improving health system. A large proportion of Australian health and medical research is now focused on translational outcomes, such as disease prevention, improved clinical care, and new diagnostics, therapies and vaccines, which have a demonstrated capacity to reduce the nation’s health budget and deliver better patient care. Indeed, without such research, the impact of health reform on patient-relevant outcomes such as death and disability will remain substantially uncertain. Another illustrative example of Australia’s contribution to global health gains is the development by Professor Ian Frazer and colleagues, in collaboration with CSL Biotherapies, of the quadrivalent human papillomavirus vaccine (Gardasil; Merck Sharp & Dohme) for cervical cancer prevention. According to an Access Economics report, the vaccine is expected to prevent around 70% of cervical cancers and result in significant economic returns in averted health care costs in Australia.4 As well as making significant contributions to global health, it is crucial that we maintain a strong Australian health and medical research sector in order to identify solutions for unique local health problems. Last year, researchers at The George Institute launched a major international trial of a very low-cost, once-a-day “polypill” for the prevention of cardiovascular disease. This treatment is particularly promising for Australia’s Indigenous communities, for whom cardiovascular disease is the leading cause of death and disability. Compared with other Australians, Indigenous Australians suffer heart attacks at three times the rate, at an average of 10–15 years younger, and have 3–4 times higher rates of diabetes.5 We are unlikely to “close the gap” in Indigenous health by reading reports of research conducted in the United States or Europe. Moreover, cuts to research funding will seriously impair Australia’s ability to respond effectively to health crises, through delays in access to the latest and most effective vaccines and treatments. This applies equally to mobilising a rapid and successful response to acute emergencies such as severe acute respiratory syndrome, pandemic (H1N1) 2009 influenza or, in the context of the recent floods, outbreaks of Ross River fever. For all these reasons, a cut to the NHMRC budget will increase health care costs in the long term and harm the Australian economy, through the failure to use the capacity of existing and new state-of-the-art facilities, a downturn in productivity and lost intellectual property as we are forced to “buy back” health innovations from international pharmaceutical and device companies. There is also the very likely spectre of our brightest scientists and clinicians leaving Australia for rapidly growing biomedical research hubs in Asia and beyond, as well as a loss of future capacity through the failure to train an adequate research workforce. Interestingly, in the United Kingdom, medical research has been protected, despite wide and deep cuts in other public sectors, and in the US, biomedical research has been identified as a priority for government support by President Obama. India, China and Singapore are also making unprecedented investments in medical research and associated intellectual and capital infrastructure. Proposed funding cuts will place emerging Australian medical researchers in a particularly vulnerable position, given that their training extends over a 10–15-year period. The effects of reducing training places, even in the short term, through a reduction in any of the funding programs will be felt for more than a decade. It would only take a small cut to the NHMRC budget to have a serious impact on medical research outputs, denying Australians access to the best available preventive therapies, diagnostics and treatments, today and in the future. For this reason, the medical research sector has been forced to take its fight public in a bid to safeguard leading research programs that are a lifeline for children and adults suffering from heart disease, cancer, genetic diseases and many other forms of serious illness. The support of Australia’s clinical community will be crucial to ensuring that our research sector continues to deliver translational benefits to Australians. There are a number of ways clinicians can provide this support. Writing letters to and raising the issue with members of parliament and the Prime Minister is critical to maintaining the profile of this issue. Research Australia has developed an online petition to the federal government (http://researchaustralia.org/personal-stories/petition-to-federal-government.html), and concerned clinicians can vote for community advocacy organisation GetUp! to take on the campaign (http://suggest.getup.org.au/forums/60819-campaign-ideas/topics/61385-i-suggest-a-campaign-about-/filter/top). More information is available at the Discoveries Need Dollars website (http://www.discoveriesneeddollars.org).

Garry L R Jennings MD, FRACP · Stephen MacMahon DSc, PhD · Geoffrey A Donnan MD, FRACP

New results from an Australian collaborative randomised trial will change practice Every year in Australia, 1000 people are admitted to intensive care units with severe traumatic brain injury, mostly as a result of motor vehicle accidents.1 Despite high standards of prehospital and medical care, 50% of these people either die or survive with severe lifelong disability.2 Most of the survivors with severe disability are young men aged in their mid 20s;2 they cannot return to work and will never be able to live independently. The cost of severe traumatic brain injury in human terms is huge, and in economic terms has been recently independently calculated to be $4.8 billion every year in Australia.1 In the United States, the annual economic burden of traumatic brain injury is $60 billion.3 Half of patients with severe traumatic brain injury have haematomas that may require neurosurgical evacuation; management of these patients before and after surgery is not controversial. However, about 10% of patients have diffuse brain injury,4 and also have persistent brain swelling that cannot be effectively controlled in intensive care units by airway management, mechanical ventilation, intracranial pressure monitoring, heavy anaesthesia, resuscitation fluids, osmotherapy, and drainage of cerebrospinal fluid from ventricular catheters. Over the past decade, management of these patients has been shifting in many centres from barbiturate therapy, and sometimes hypothermia, to decompressive craniectomy5 — a well established neurosurgical procedure in which a large piece of skull bone is removed (stored for 1–2 months, and then replaced) to enable better control of intracranial pressure and a more rapid decrease of sedation, with the ultimate goal of improving patients’ long-term functional outcomes. About 20 case series of adult patients from many countries have reported mainly favourable results from this procedure.6 However, all suffer from a lack of prospective randomised control groups and of objective blinded outcome assessment at defined time points. To objectively assess decompressive craniectomy for the first time and to establish its true efficacy in adult patients with traumatic brain injury, intensivists and neurosurgeons in Australia, New Zealand and Saudi Arabia collaborated between 2003 and 2010 to conduct the Decompressive Craniectomy (DECRA) randomised trial. The results of the DECRA trial have recently been published.7 This was the first randomised trial of any neurosurgical technique to be completed in complex adult neurotrauma patients. Patients were randomly assigned to receive decompressive craniectomy plus standard care (maximised intensive care therapies, which could include barbiturate anaesthesia) or standard care alone. The study found that early decompressive craniectomy clearly and dramatically achieved its short-term goals: it decreased intracranial pressure, markedly decreased medical therapies required for intracranial pressure, shortened mechanical ventilation time, and shortened stay in the intensive care unit by 5 days compared with the standard care group. The dramatic short-term effects meant that the study was difficult to complete because neurosurgeons and intensivists were aware of group allocation, could see the early benefits, and increasingly preferred to conduct early surgery rather than recruit patients to the trial. However, despite these positive short-term effects, the findings in relation to patients’ eventual functional outcome, measured carefully at 6 months, were startling and the reverse of what had been expected. There were 19% more patients with poor functional outcomes (odds ratio, 2.21; 95% CI, 1.14–4.26; P = 0.02) and 23% more survivors with severe disability in the decompressive craniectomy group compared with patients who received standard care alone. The cause of these poor outcomes is speculative. They may have related to the surgery itself or to surgical complications (including hydrocephalus), but surgical complications seem an unlikely explanation given that the rates overall were less than those reported in published case series. A more likely explanation is that “axonal stretch” that occurred during swelling of the brain outside the skull through the craniectomy defect8 exacerbated brain injury in a way that has not previously been described in humans and was not anticipated. Multimodal magnetic resonance imaging may enable confirmation of this. We might now coin the term “brain volutrauma”, analogous to the “lung volutrauma” observed in mechanically ventilated patients with acute lung injury. A second ongoing randomised trial — the Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) — is addressing similar questions in the United Kingdom and Europe. The RESCUEicp trial also includes patients with brain haematomas and intervenes at a slightly higher intracranial pressure threshold,9 so the results will be complementary to the DECRA trial and are likely to be equally important. What is unequivocal is that functional outcomes of future patients with severe diffuse traumatic brain injury in Australia and New Zealand can be substantially improved by choosing best intensive care medical and surgical therapies, based on established guidelines,10 without early decompressive craniectomy, despite increases in intracranial pressure that may be concerning to clinicians. The role of decompressive craniectomy as a rescue therapy in the context of very high intracranial pressure has not been resolved by this study, but is now clearly uncertain. It is also unequivocal that the Australian health care system will save many tens of millions of dollars annually when the less invasive treatment regimen is chosen. Although careful cost–benefit analyses are urgently required (and can be done using existing databases), it is already clear from independent costing analyses, which confirmed that most of the traumatic brain injury cost burden relates to rehabilitation costs of survivors with severe disability,1 that the savings to Australia of choosing intensive medical therapies instead of craniectomy in appropriate patients will be greater than $100 million annually. Savings in the US and Europe are likely to be proportionately greater. Finally, the DECRA trial illustrates with new clarity that carefully designed randomised controlled trials are the only way to correctly advance clinical practice, even in complex, critically ill patients, and despite the clear inherent difficulties of such trials.11 Recent calls for “comparative effectiveness research” in neurosurgery,12 based on aggregations of non-randomised databases, do not represent a valid substitute. In the DECRA trial, a collaborative network of clinician-investigators (the Australian and New Zealand Intensive Care Society Clinical Trials Group), which was supported by the National Health and Medical Research Council (NHMRC) and co-funders, unfettered by industry, and motivated by a strong desire to improve the quality of outcomes in critically ill patients, enabled the trial to be supported to completion and to influence clinical practice for the better. These are the essential ingredients needed to make meaningful improvements in health care.

D James Cooper MD, FRACP, FCICM · Jeffrey V Rosenfeld MD, MS, FRACS

Australian and US collaborators provide evidence on outcomes of mammographic screening in previously affected women Women with a personal history of breast cancer (PHBC) represent an increasing group of cancer survivors, and have a lifelong increased risk of developing a new or recurrent cancer in the conserved (ipsilateral) breast, or a contralateral cancer. The risk of a “second” breast cancer in women with PHBC has been estimated at 5.4 to 6.6/1000 woman-years.1 Evidence of screening benefit in PHBC women comes from observational studies2-4 and extrapolation of benefit from randomised mammographic screening trials; consensus-based recommendations include annual mammography in routine surveillance of PHBC women.5-7 Early detection may also minimise the physical and psychosocial burden and consequences of a second breast cancer. Evidence reviews have consistently acknowledged the lack of quality data on mammographic screening in PHBC women,4,8 and research into screening high-risk women has mostly focused on those with breast and ovarian cancer susceptibility genes; evaluation of screening in women with PHBC has received relatively little attention.4,8 Together with other collaborators from Australia and the United States, we recently reported the most comprehensive study to date of mammographic screening in women with a history of early-stage breast cancer.9 Based on data from mammography facilities affiliated with the US National Cancer Institute-funded Breast Cancer Surveillance Consortium for the years 1996–2007, we examined the accuracy and outcomes of screening in 58 870 mammograms from 19 078 women with PHBC. These were matched to 58 870 screening mammograms from 55 315 women without PHBC, to ensure that characteristics that affect mammography accuracy (such as age group and breast density) were similar in both cohorts.9 Key findings from the study are summarised in the Box. Although the cancer detection rate of screening was substantially higher in PHBC women relative to women without PHBC (6.8 v 4.4/1000 screens), screening detected a smaller proportion of the cancers occurring in PHBC women at 1-year follow-up (65.4% v 76.5%). Due to this lower sensitivity of mammographic screening, as well as the higher underlying breast cancer risk in PHBC women, the interval cancer rate in women with PHBC was more than twice the rate in women without PHBC (3.6 v 1.4/1000 screens). The lower sensitivity and higher interval cancer rate occurred despite more imaging work-up in PHBC women relative to women without PHBC (18.1% v 8.3%) and more recommendations for biopsy or surgical consultation (2.3% v 1.4%). Unique aspects of this study were characterisation of screening outcomes and underlying cancer risk according to characteristics of the women and their first cancer treatment, and ascertainment of ipsilateral and contralateral second cancers.9 The latter has not previously been possible because notification of recurrent cancer is not obligatory in most countries, but was achieved through the data-linkage processes of the Breast Cancer Surveillance Consortium. Hence, the twofold higher rate of breast cancer in women with PHBC relative to those without (Box) represents a reliable risk estimate. We found heterogeneity of both breast cancer risk and screening accuracy across subgroups of women and by the treatment received for the first cancer. The highest rates of second cancers (> 12 cancers/1000 screens) were in women younger than 50 years, women with extremely dense breasts, women who received breast-conserving surgery without radiation therapy or who did not receive any systemic therapy, and women with previous ductal carcinoma-in-situ (the latter probably reflects the infrequent use of adjuvant therapy in the treatment of ductal carcinoma-in-situ). Should these findings change our practice or recommendations for women with PHBC? Superficially, these results9 could be interpreted as casting doubt on the efficacy of mammographic screening in women with PHBC. However, careful consideration of the data shows that although mammographic screening was relatively less sensitive in PHBC women, it detected their second cancers at an early stage, with similar stage distributions to women without PHBC.9 The evidence from this study therefore supports consensus recommendations that advise mammographic screening in women with PHBC, and which also include clinical breast examination as part of annual surveillance.5-7 Many of the interval cancers were also early-stage, suggesting that cancers not detected at time of mammographic screening were detected through clinical examination or investigations prompted by symptoms, or possibly through ad-hoc adjunct screening (using breast ultrasound or magnetic resonance imaging). Currently, adjunct screening is not routinely recommended for women with PHBC (unless they are known to have breast cancer gene mutations), and our study did not evaluate adjunct imaging. Our data may, however, guide future evaluations of adjunct screening in subgroups of PHBC women who had high interval cancer rates; specifically, women younger than 50 years and/or with extremely dense breasts, and those who had breast conservation without radiation therapy for their first cancer. It is essential that evaluations of strategies integrating adjunct screening for PHBC women consider the impact this may have on false positives and overdetection, as well as whether enhanced screening sensitivity through adjunct imaging translates into a reduction in interval cancers. Recommendations from the BreastScreen Australia evaluation10 included the potential provision of annual screening through BreastScreen for women with PHBC, from 5 years after their first cancer diagnosis. Our study shows that screening sensitivity improves after 5 years from the first cancer diagnosis and supports the idea of allowing PHBC women access to screening in BreastScreen-accredited facilities, which undergo rigorous quality assurance, to ensure that they receive high-quality mammographic screening. BreastScreen may also be ideally placed to implement screening evaluations for PHBC women to provide insight into screening outcomes in these women in the Australian setting. Mammographic screening in women with a personal history of early-stage breast cancer (PHBC)9* Screening outcomes were significantly different (P < 0.001) for comparison of screening mammograms in women with PHBC relative to women without PHBC: Cancer rate: 10.5 (9.7–11.3) v 5.8 (5.2–6.4)/1000 screens Cancer detection rate: 6.8 (6.2–7.5) v 4.4 (3.9–5.0)/1000 screens Interval cancer rate: 3.6 (3.2–4.1) v 1.4 (1.1–1.7)/1000 screens Screening sensitivity: 65.4% (61.5%–69.0%) v 76.5% (71.7%–80.7%) Sensitivity for detection of invasive cancers: 61.1% (56.6%–65.4%) v 75.7% (70.4%–80.3%) Screening specificity: 98.3% (98.2%–98.4%) v 99.0% (98.9%–99.1%) Abnormal mammogram results (based on final imaging assessment): 2.3% (2.2%–2.5%) v 1.4% (1.3%–1.5%); this also reflects the percentages recommended for biopsy or surgical consultation. Screen-detected breast cancers in women with and without PHBC were predominantly early-stage cancers (ductal carcinoma-in-situ [DCIS] or stage I–II invasive cancer in > 90%, for both groups). In women with PHBC, screening sensitivity was similar for detection of ipsilateral cancer (66.3% [60.3%–71.8%])† and contralateral cancer (66.1% [60.9%–70.9%]); however, sensitivity differed significantly (P < 0.05) for the following: Higher for detection of DCIS (78.7% [71.4%–84.5%]) than invasive cancer (61.1% [56.6%–65.4%]) Higher in women with non-dense breasts (BI-RADS category 1–2: 69.6% [63.3%–75.3%]) than in women with dense breasts (BI-RADS category 3–4: 60.2% [54.0%–66.2%])‡ Higher after 5 years from first cancer (70.8% [65.4%–75.6%]) than within the initial 5 years (60.2% [54.7%–65.5%]) Lower in women who received any systemic therapy§ (54.1% [47.5%–60.6%]) than in those who had not received any systemic therapy (71.0% [66.0%–75.5%]) for first cancer. Low screening sensitivity (about 55% or lower) was observed in women younger than 50 years, women with extremely dense breasts, and women who received chemotherapy§ for first cancer. BI-RADS = Breast Imaging Reporting and Data System. * 95% confidence intervals are shown in parentheses. † Excludes ipsilateral relapse in women who had mastectomy. ‡ BI-RADS tissue density categories: 1 = almost entirely fatty; 2 = scattered fibroglandular tissue; 3 = heterogeneously dense; 4 = extremely dense. § After adjusting for age, breast density, stage and treatment of first cancer, only women who received chemotherapy were significantly less likely to have their second breast cancer detected by mammographic screening than women who had not received any systemic therapy.

Nehmat Houssami MB BS, FAFPHM, PhD · Diana L Miglioretti PhD

Upcoming large studies may shed light on why this technique was not rapidly widely adopted like certain other laparoscopically assisted procedures Laparoscopic “keyhole” surgery has been the gold standard for gall bladder surgery for a few decades. It has also been widely used for appendicectomies, a multitude of gynaecological procedures and, to various extents, for other procedures such as hernia repair, splenectomy and nephrectomy. However, the uptake of laparoscopically assisted resection in elective surgery for colorectal cancer (CRC) has been slow, both in Australia and overseas. This is the subject of the article by Thompson and colleagues in this issue of the Journal (→ National trends in the uptake of laparoscopic resection for colorectal cancer, 2000–2008).1 The authors searched the National Hospital Morbidity Database (NHMD), which uses codes based on Medicare Benefits Schedule item numbers, for elective laparoscopic resections for CRC. Their search was somewhat restricted and the internal validity was not tested, but Thompson and colleagues reported that, in about a quarter of elective CRC resections performed in Australia in the financial year 2007–08, an item number for a laparoscopy was included. Reliance on databases may overestimate or underestimate outcomes. Three studies from the United States reported percentages of laparoscopic resections for cancers of the colon ranging from 3.3% to 5.2%2-4 in the period July 2003 to June 2004, based on the National Cancer Data Base and Nationwide Inpatient Sample. However, a fourth US study that used the Perspective Rx Comparative Database (Premier Inc, Charlotte, NC), which relies on procedure codes, reported a percentage of 33.7% for the period July 2004 to June 2006.5 Such an increase is far greater than what would be expected to be the result of the publication of the Clinical Outcomes of Surgical Therapy trial.6 The adoption of laparoscopic surgery for CRC has been slow despite the proven short-term benefits of laparoscopic compared with open resection, which include a shorter hospital stay.7,8 In line with other published articles, the Australasian Laparoscopic Colon Cancer Study (ALCCaS) — the largest Australasian study to date of laparoscopic resection for CRC — showed that the laparoscopic method was associated with a smaller number of patients with complications and a shorter length of stay than open resection.9 However, the ALCCaS group also reported that reviews show that the short-term advantages for laparoscopic resection for CRC are arguably relatively minor and often subjective, and that patients who benefit most from improved outcomes are patients who are aged 70 years or older whose procedures were completed laparoscopically.10 The median length of stay for patients younger than 70 years of age undergoing laparoscopic resection in the ALCCaS trial was 7 days (range, 1–30 days) compared with 8 days (range, 4–49 days) for open resections in the same age group — a difference of only 1 day.10 The average hospital stay for conventional open resection has been reported to be about 10 days (range, 7–12 days).7,11-13 It seems likely that authors of large series, trials and reviews report more conservative (and perhaps more realistic) results than earlier series reporting a new surgical procedure or innovation. The first published series of laparoscopic colorectal surgery in 1991 reported achieving the aim of a 5-day hospital stay in 14 out of 20 patients undergoing sigmoid resections (70%).14 Most subsequent larger studies, reviews and meta-analyses report lengths of stay of around 8 days for laparoscopic resection.7-9,11,12 Thompson and colleagues (→ National trends in the uptake of laparoscopic resection for colorectal cancer, 2000–2008) recommend exploring whether the short-term benefits of laparoscopic resection are experienced outside of the clinical trial environment.1 If we accept the limitation of using secondary data, such as those from the NHMD, in exploring the uptake of laparoscopic surgery for CRC, then a quarter of elective resections for CRC performed in Australia in 2007–08 were laparoscopic. That represents an increase from zero to 25% in more than 17 years. There are no comparable studies that used similar methods to assess the uptake of laparoscopic cholecystectomy in the late 1980s. However, many of us experienced first-hand the rapid uptake of laparoscopic gall bladder surgery. The first laparoscopic cholecystectomy was probably performed in France by Phillippe Mouriat of Lyons in 1987.15 There are published data that show that laparoscopic surgery was well and truly the gold standard for gall bladder surgery in 1992.16 That represents an increase from zero to close to 100% in less than 5 years. The contrast is stark. In 1999, Kehlet and Mogensen introduced the concept of fast-track surgery to colorectal resections;17 this concept is now known as Enhanced Recovery After Surgery (ERAS). It involves a multimodal rehabilitation program that commences before surgery to optimise all aspects of care using evidence-based protocols that hasten recovery. Kehlet and Mogensen reported a median hospital stay of 2 days (range, 2–6 days) after 16 consecutive elective open sigmoid colectomies. Fifteen of the 16 patients resumed bowel function before discharge.17 The results of a systematic review of five studies comparing laparoscopic with open colorectal surgery using an ERAS rehabilitation program were inconclusive.18 Further, the authors of a meta-analysis of 11 studies (1021 patients) reported a 2.5-day shorter length of stay for patients on an ERAS rehabilitation program who had resections compared with those not on an ERAS program.19 These authors assumed an added benefit to the laparoscopic approach, but an advantage was not clearly demonstrated. They concluded that ERAS programs should become a mainstay of elective colorectal surgery.19 These later and larger series, trials and reviews have shown that an average length of stay of 5 days seems to be quite achievable within an ERAS protocol, regardless of whether the surgical approach is open or laparoscopic. Many of the aspects of the ERAS program are now included in “standard” care regardless of whether a structured protocol is in place or not. It seems that, on the whole, laparoscopic surgery for CRC has probably not been successful in delivering the outstanding benefits suggested by early reports. This may be partly responsible for its slow uptake. Attention to a multimodal approach such as an ERAS program may, in fact, produce more clinical benefits for patients and cost benefits for hospitals. Whether the laparoscopic approach “adds” to these benefits or not has not been established.20 The Australasian Laparoscopic Cancer of the Rectum Trial (A La CaRT), with a target sample size of 470 patients, is expected to shed more light on the safety and efficacy of laparoscopic compared with conventional open resection for rectal cancer.21 The Dutch Laparoscopy and/or Fast Track Multimodal Management (LAFA) trial, with a target sample size of 400 patients, will examine laparoscopic versus open CRC surgery with or without an ERAS rehabilitation program.22

Ned S Abraham MMed, FRACS, PhD

Using registry data to identify gaps in research and enhance our clinical trial activity The data collected by clinical trial registries have many applications. Clinicians and patients can search for trial options for specific conditions when standard treatments have been exhausted, or where no effective treatment exists. Comparisons between trials registered and those subsequently reported can suggest publication bias. Researchers planning new trials can avoid duplication by identifying gaps in the targeting of cancer types in current trials. In this issue of the Journal (→ Landscape of cancer clinical trials in Australia: using trial registries to guide future research), Dear and colleagues have analysed data from the Australian New Zealand Clinical Trials Registry and an international registry based in the United States, ClinicalTrials.gov, to describe the landscape and funding sources of cancer trials in Australia, to aid the planning of future cancer trials.1 They found that the Australian situation reflects the international situation, where investment in trials for specific cancer types does not correlate with the disease burden caused by those cancers. For example, breast cancer accounted for 17% of trials, with high levels of patient recruitment, while lung cancer represented only 7% of trials despite its higher disease burden. The authors concede that this observation from the registry data may be inaccurate because registration of trials is not mandatory in Australia, and there is no way of recording the nature of unregistered trials. Also, the registries more comprehensively list Phase III trials than early phase trials, so overrepresentation of some tumour types could partly reflect more success in identifying potentially effective new drugs to treat them, which then progress to Phase III trials. If such disparities in research do exist, one remedy is targeted funding to attract research on different tumour types. Similarly, some types of tumour receive more popular exposure in the media than is warranted by their burden of disease, which allows speculation about the impact of consumers on the research agenda.2 This was postulated from the high number of non-drug intervention, non-industry-sponsored trials for breast cancer compared with other tumour types.1 It is also clear from the trial registries that non-drug trials, such as psychosocial trials, are generally underrepresented. These will rarely be funded by industry and require investment from government and community research funds. The importance of pharmaceutical industry sponsorship to the cancer clinical trial effort in Australia is underpinned by the finding that 64% of drug trials are funded by industry. It is not unexpected that industry was found to predominantly sponsor drug trials involving metastatic disease, where therapeutic gains can be more promptly translated into commercial success. Adjuvant trials are often multinational and, because survival is often the endpoint, take many years to achieve a result, unless an earlier surrogate endpoint can be identified. It is surprising that tumour type was not found to correlate with pharmaceutical industry sponsorship, as more trials involving higher-incidence tumours would have been anticipated. But the finding that systemic therapies attracted more industry sponsorship than local therapies was expected, as most sponsored studies would have new drug development as their goal. With the increasing development of targeted therapies, the histological type of cancer will become less important, but it remains a potential concern that financial incentives favour drug development for high-incidence tumours and that progress in treating rarer cancers is delayed. The registry data can provide a guide as to where future trial funding should be directed. An additional issue of great concern that may be reflected by clinical trial registries is a decrease in clinical drug trials being conducted in Australia.3,4 Clinical trials are essential to developing the evidence base for improving cancer treatments, and traditionally Australia has had a high trial recruitment rate relative to its population.4 A robust clinical trial program fosters and retains local expertise in scientific and medical research and clinical care. It also ensures the opportunity of early access to new treatments and improved quality of care and monitoring for patients participating in clinical trials, which enables translation into improved routine care and outcomes.5,6 There are also economic benefits of clinical trials: the average dollar invested in health research and development returns $2.17 in health benefits, and sponsored trials of new drugs serve to reduce a hospital’s drug expenditure.5 What is required to enhance clinical trial activity in Australia is to both support independent cooperative trial groups and encourage increased pharmaceutical industry investment. Infrastructure funding for trial groups, such as that provided by Cancer Australia, is vital, but hospitals must also see support of clinical research as a core part of their business rather than a source of additional revenue through facilities fees, which increasingly make trials more expensive to perform. E-health platforms will also enhance trial capabilities by centralising data for easier access and sharing, and making verification of source data easier.7 Clinical trial registries that are more consumer-friendly should play a role in enhancing patient recruitment by making it easier for them to find suitable trials. Centralising ethical review of multicentre trials, as is encouraged by the Australian Government’s Harmonisation of Multi-centre Ethical Review (HoMER) initiative, will streamline the ethics approval process, particularly for Phase III trials, without compromising the rigour of the review.8 Similarly, as part of the HoMER intiative, setting standards for the quality and timeliness of governance review of trials, which still must be done by individual health units, will also help facilitate the approval process. Data from clinical trial registries should be used to monitor the progress of such efforts to ensure Australia has a robust clinical trial capability.

Ian N Olver MD, PhD, FRACP

The Thoracic Society of Australia and New Zealand has updated its guidelines on corticosteroid use in childhood asthma The understanding of childhood asthma has increased substantially since the publication of the Thoracic Society of Australia and New Zealand (TSANZ) position statement The role of corticosteroids in the management of childhood asthma in 2002.1 In particular, recognition of the need for separate asthma management guidelines for children aged 5 years or younger has increased,2 and considerably more clinical research evidence on the role of asthma medications in children has become available. The 2010 revision of the TSANZ position statement provides updated recommendations on the roles of inhaled corticosteroids, oral corticosteroids, leukotriene receptor antagonists and combination medications (inhaled corticosteroids plus long-acting β-agonists) in childhood asthma management based on recently published evidence.3 The role of leukotriene receptor antagonists in the management of childhood asthma has also been addressed in detail in a recent National Asthma Council Australia information paper.4 The National Asthma Council Australia provides a comprehensive overview of the role of preventive treatment in childhood asthma in its Asthma management handbook 2006.5 It advocates a stepwise approach to drug therapy that is based on asthma severity. If control is not achieved using initial preventer therapy, it is important to review the diagnosis of asthma — particularly in children aged 5 years or younger — as many children with recurrent cough are mislabelled as having asthma6 and different wheezing phenotypes require different treatment approaches.2 Before escalating the level of preventer therapy, it is also essential to check the child’s inhaler technique and adherence to treatment. Step-down treatment (“back titration”) is advocated once control has been achieved and sustained for at least 3 months. Two placebo-controlled studies of montelukast have established the efficacy and safety of this medication and form the basis of its current Pharmaceutical Benefits Scheme listing for children with frequent intermittent or mild persistent asthma.3,4 Compared with placebo, regular montelukast therapy produces a modest reduction in exacerbation risk in children with viral-induced wheezing.3,4 An additional benefit of montelukast therapy is its proven efficacy for protecting against exercise-induced bronchoconstriction,3,4 being more effective than long-acting β-agonists without development of the tolerance seen with long-acting β-agonists.3 This information led to the current Pharmaceutical Benefits Scheme listing of montelukast for children aged 6–14 years who have ongoing activity-related asthma despite inhaled corticosteroid treatment. The effectiveness of prophylactic inhaled corticosteroids in persistent childhood asthma is well established.3 In contrast, regular inhaled corticosteroid treatment for intermittent, viral-induced wheezing does not reduce rates of hospitalisation, use of oral corticosteroids, or frequency and duration of acute episodes.3 Systemic effects of inhaled corticosteroids in children are well documented; they include impaired linear growth, adrenal suppression, and effects on bone mineralisation.3 Although the clinical significance of these adverse effects is uncertain, factors such as individual susceptibility, severity of asthma, age, pubertal status, total dose, and dose delivery may affect risk of systemic toxicity. Although it is common to add a long-acting β-agonist to inhaled corticosteroids (as a single combination inhaler) there are few paediatric studies examining this practice, and these suggest that, while the combination improves lung function, it does not reduce exacerbation risk — in fact, it may increase it.3 These recent studies support the current National Asthma Council recommendations of reserving the addition of long-acting β-agonists for children with asthma that is not adequately controlled by 200–250 μg/day fluticasone propionate or equivalent doses of other inhaled corticosteroids,3 and highlight the potential role of montelukast as an alternative add-on therapy. The use of long-acting β-agonists is not, however, recommended for children aged 5 years or younger.2,3 Our recommendations for preventer treatment in childhood asthma are summarised in the Box. Children with infrequent intermittent asthma require no preventer therapy. Current evidence suggests that non-steroidal preventers should be trialled first in children with frequent intermittent or mild persistent asthma, while inhaled corticosteroids are indicated as first-line preventer treatment in children with moderate–severe persistent asthma. Long-acting β-agonists or montelukast are add-on options in children with persistent symptoms despite adequate inhaled corticosteroid treatment. In terms of acute asthma management, oral corticosteroids improve outcomes in children presenting to hospital with acute asthma, but the efficacy of oral corticosteroids for children aged 5 years or younger with acute, mild–moderate, viral-induced wheezing has been questioned.3 Based on current evidence, we recommend oral corticosteroids be reserved for children with moderate–severe acute asthma exacerbation and children with an incomplete response to β-agonists. However, in children aged 5 years or younger (particularly those with intermittent, viral-induced wheezing) the use of oral corticosteroids should be limited to those with severe wheeze who require hospital admission; an initial dose of 2 mg/kg prednisolone (maximum 60 mg) is recommended, followed by daily doses of 1 mg/kg if required. Although a 3-day course is generally sufficient, a more prolonged course may be indicated in severe cases. There is some evidence for the benefit of intermittent inhaled corticosteroids and leukotriene receptor antagonists in acute asthma, but oral corticosteroids remain the treatment of choice — particularly for more severe episodes, because of ease of administration, low cost and greater proven efficacy in severe acute asthma. The need for recurrent systemic corticosteroid therapy requires reassessment of the child’s interval therapy, particularly in cases of persistent asthma, and specialist referral. Preventer therapy for children who have frequent intermittent or persistent asthma symptoms* FP = fluticasone propionate. BDP–HFA = beclomethasone dipropionate – hydrofluoroalkane. BUD = budesonide. CIC = ciclesonide. * Modified from the Asthma management handbook 2006 with permission from the National Asthma Council Australia.5 † Long-acting β-agonists not recommended for children aged 5 years or younger.

Peter P Van Asperen MB BS, MD, FRACP · Craig M Mellis MPH, MD, FRACP · Peter D Sly MD, DSc, FRACP · Colin F Robertson MSc, MD, FRACP

Guidelines for private sector practitioners implementing the new provisions in the Privacy Act Every health care practitioner must respect confidentiality. Patients reasonably expect that private information offered or identified during an episode of care will not be divulged without their consent. The fundamental importance of confidentiality finds formal expression in the National Privacy Principles. Practitioners in the private sector must comply with the National Privacy Principles, which are embodied in the Privacy Act 1988 (Cwlth).1 Public sector employees are obliged to comply with the relevant legislation in each jurisdiction. Knowledge of a history of disease in relatives can be crucial for making a diagnosis in a patient. Similarly, medical care of relatives may be affected by the patient’s diagnosis. For example, a family history of colorectal cancer may assist in identifying the cause of a patient’s abdominal pain, and the diagnosis of colorectal cancer in the patient would then place his or her close relatives at increased risk of the same condition. In general, a practitioner is not obliged to inform relatives about the diagnosis of a familial disorder. There are some situations in which a practitioner may be required to advise a third party about a patient’s non-genetic diagnosis because of an immediate threat to the safety of others, as is the case with certain infections such as hepatitis A.2 These legally sanctioned breaches of confidentiality do not apply to the risk of a relative developing a familial disorder at some unspecified time in the future. Nonetheless, a practitioner cannot ignore the medical implications of a familial diagnosis for the patient’s relatives, and must inform the patient (or the patient’s authorised representative) of these implications and recommend that they seek medical advice in their own right.3 It is unusual for a patient to refuse to share such information with relatives,4 but such situations do arise and present the practitioner with a challenging dilemma.5 On the one hand, the patient has a right to make an autonomous decision about the use of personal information. On the other hand, this information has a direct bearing on the future health of relatives who may welcome the opportunity to make strategic decisions regarding their health. Whose rights should prevail? Before 2006, the privacy legislation in Australia was unequivocal: in the absence of an immediate threat to the health or wellbeing of a third party, the patient’s right to privacy prevailed and relatives could not be informed without the patient’s consent. This situation has since changed. In response to a recommendation from the Australian Law Reform Commission,6 the federal government amended the Privacy Act in 2006 to make specific provision for this situation.7 The Privacy Legislation Amendment Act 2006 (Cwlth) allows for the disclosure and use of information without consent, provided that such disclosure is necessary to lessen or prevent a serious threat to the life, health or safety (whether or not the threat is imminent) of an individual who is a genetic relative of the individual to whom the genetic information relates ... The significant provision is that the threat need not be imminent and may occur at an unspecified time in the future. There are some important features of this amendment that must be borne in mind. First, the amendment applies only in the setting of managing a familial disorder in a health care setting. A medical practitioner must authorise disclosure, and there must be consultation with appropriate colleagues. Second, the amendment does not require the practitioner to notify relatives about a familial disorder. The amendment provides a potential legal mechanism for doing so but does not create an obligation. Third, the amendment only applies to the disclosure and use of genetic information that is necessary to lessen the risk of a familial disorder for a genetic relative. There is no provision to release other information about the patient (including the patient’s identity), or to release information to a non-genetic relative (other than the authorised representative of a genetic relative). Finally, the Privacy Act currently applies only to practitioners in the private sector. The amendment does not apply to health care practitioners in the public sector. It is anticipated that similar provisions and processes will be developed in the local legislation of the states and territories, which would apply to practitioners in the public sector. The potential to disclose a patient’s confidential information to a relative against the patient’s wishes represents a major departure from longstanding views on confidentiality in health care. It is appropriate that such an action be taken rarely and with great circumspection. Furthermore, the process for disclosure must recognise that many relatives do not use the genetic information provided to them.8 The National Health and Medical Research Council (NHMRC) has developed guidelines for practitioners who might use this amendment;1 the principles that form the heart of the document are summarised in the Box. Readers should refer to the full guidelines for details, and to a more general NHMRC discussion paper on genetic testing in health care.9 It is important to note that the guidelines1 are not simply recommendations regarding best practice — they are the formal mechanism for implementation of this federal legislation, and practitioners who wish to use the provisions of the Privacy Legislation Amendment Act must comply with the guidelines and requirements of the Privacy Commissioner.10 There is another important sense in which the guidelines do not reflect “best practice”. With careful and considerate communication, especially before embarking on genetic tests that might diagnose a familial disorder, it is usually possible to resolve issues of concern that a patient may have about sharing this personal, confronting, and potentially useful information with relatives. Best practice is represented by striving to avoid the need to use the provisions of this amendment. With a combination of professionalism and patience, most apparent conflicts can be resolved without recourse to disclosing private information without consent. NHMRC guidelines for the use or disclosure of genetic information to a patient’s genetic relatives1 The guidelines developed by the NHMRC* for implementing the new provisions of the Privacy Act 1988 (Cwlth) are as follows: 1. Use or disclosure of genetic information without consent may proceed only when the authorising medical practitioner has a reasonable belief that this is necessary to lessen or prevent a serious threat to the life, health or safety of a genetic relative. 2. Specific ethical considerations must be taken into account when making a decision about whether or not to use or disclose genetic information without consent. 3. Reasonable steps must be taken to obtain the consent of the patient or his or her authorised representative to use or disclose genetic information. 4. The authorising medical practitioner should have a significant role in the care of the patient and sufficient knowledge of the patient’s condition and its genetic basis to take responsibility for decision making about use or disclosure. 5. Prior to any decision concerning use or disclosure, the authorising medical practitioner must discuss the case with other health practitioners with appropriate expertise to fully assess the specific situation. 6. Where practicable, the identity of the patient should not be apparent or readily ascertainable in the course of interprofessional communication. 7. Disclosure to genetic relatives should be limited to genetic information that is necessary for communicating the increased risk and should avoid identifying the patient or conveying that there was no consent for the disclosure. 8. Disclosure of genetic information without consent should generally be limited to relatives no further removed than third-degree relatives. 9. All stages of the process must be fully documented, including how the decision to use or disclose without consent was made. NHMRC = National Health and Medical Research Council. * NHMRC’s Working Committee (Dr Sandra Hacker, Ms Sharon Caris, Dr Elizabeth McCusker, Dr Graeme Suthers and Dr Samantha Wake) developed the guidelines in collaboration with the NHMRC’s Australian Health Ethics Committee and Human Genetics Advisory Committee.

Graeme K Suthers PhD, FRACP, FRCPA · Elizabeth A McCusker MB BS, FRACP · Samantha A Wake BSc(Hons), PhD, FHGSA

What can we do to prevent this from becoming the most common health care-associated infection in Australia? Clostridium difficile, a gram-positive, anaerobic, spore-forming, toxigenic bacterium, is the most common infectious cause of nosocomial diarrhoea. The severity of infection varies from mild diarrhoea to pseudomembranous colitis, toxic megacolon and death.1 In the United States, C. difficile now rivals methicillin-resistant Staphylococcus aureus (MRSA) as the most common health care-associated infection, accounting for US$3.2 billion in excess costs annually.1,2 Since 2000, there has been an increase in the rates of C. difficile infection (CDI) in some health care facilities in the US, Canada and Europe, associated with an epidemic strain of C. difficile. This strain (B1/NAP1/027, toxinotype III or PCR ribotype 027) is characterised by its increased resistance to fluoroquinolones, increased toxin production (toxins A, B and binary toxin), increased sporulation, and increased morbidity and mortality.1,3 Risk factors for CDI include exposure to antimicrobial drugs, gastric acid-suppressive therapy, advanced age, prolonged hospitalisation, cancer chemotherapy, comorbidity and immunosuppression.3 Although most cases have been in hospital inpatients, increasing numbers of community-associated cases are now being reported in the US and Europe.4,5 Australia is now also in the grip of this new strain of C. difficile. The first infected patient was reported in 2009 in Western Australia, but the infection was thought to have been acquired in North America.6 In this issue of the Journal, Richards and colleagues report the first case of C. difficile ribotype 027 thought to have been acquired in Australia (→ Severe infection with Clostridium difficile PCR ribotype 027 acquired in Melbourne, Australia).7 The strain was identified after clinicians alerted the laboratory to the severity of the infection and the possibility of a hypervirulent strain. Since this case was first reported, there have been further clusters of C. difficile ribotype 027 infection centred around residential aged care facilities. Currently, surveillance for C. difficile is not consistent across Australia, so rates of CDI across the continent are unknown. However, some states have commenced surveillance and show overall rates varying between 1.27 and 2.3 CDIs per 10 000 bed-days.8 This contrasts with a reported overall rate in Canada of around 3.8–9.5 CDIs per 10 000 bed-days based on surveys conducted in 1997 and 2005.9 Clinicians need to be aware of the clinical picture, diagnostic methods and new therapeutic approaches to this disease. The Australasian Society for Infectious Diseases has published guidelines in this issue of the Journal that clearly outline clinical assessment, diagnostic issues and treatment guidelines (→ Australasian Society for Infectious Diseases guidelines for the diagnosis and treatment of Clostridium difficile infection).10 Identification of hospitalised patients with CDI is the key to preventing transmission. Hospitals need to have an optimal surveillance program in place to expedite patient testing and identification. As a minimum standard, all patients with hospital onset of diarrhoea (> 48 hours after admission) should be screened for CDI. The case definition for CDI should include: (i) symptoms (usually diarrhoea); and (ii) a stool test positive for toxigenic C. difficile or its toxins, or colonoscopic or histological findings of pseudomembranous colitis.9 Similarly, clinicians working in residential aged care facilities need to be alert to the possibility of CDI in residents, to undertake testing in the presence of symptoms and to focus on decreasing transmission of the infection within the facility. In the hospital setting, infection control precautions around cases of CDI need to be enforced. Infection control guidelines for CDI from the Australasian Society for Infectious Diseases and the Australian Infection Control Association have recently been released.11 The main management principles for control of CDI include: all health care organisations, including residential aged care facilities, giving CDI prevention and control the highest priority, even if the prevailing incidence of CDI is low; surveillance being integrated into quality improvement programs to optimise prevention and control of CDI and clinical care of infected patients; antimicrobial stewardship programs being in place that are aimed at minimising the frequency and duration of antibiotic use and promoting a narrow-spectrum antibiotic policy; emphasis on compliance with hand disinfection and glove use for care of patients with CDI to minimise spore contamination; contact precautions being employed for symptomatic patients with CDI, including the donning of gowns or aprons and gloves on entry to patient rooms; use of sporocidal environmental cleaning and disinfection in high-risk areas such as toilets, bathrooms and rooms of patients with CDI, and elimination of other potential fomites by either using disposable equipment or ensuring that equipment is adequately cleaned and disinfected before reuse; and education of all health care staff, patients and visitors about CDI, its prevention and management. It is sobering to contemplate that what has occurred in the US, Canada and Europe is potentially and imminently on our doorstep. We must learn from the experience of experts in these countries so that Australia can avoid a similar experience — we already have the benefit of their hindsight to guide us. Our challenge is implementing the necessary interventions — enhanced surveillance and diagnosis, antimicrobial stewardship, environmental cleaning and stringent infection control. Although this solution re-echoes the usual infection control mantra, it is essential that we act pre-emptively to prevent CDI from occurring, especially to the most vulnerable of our patients.

Rhonda L Stuart MBBS, FRACP, PhD · Caroline Marshall FRACP, PhD, GradDipClinEpi

Screening plus equitable provision of vitamin D supplements could mitigate many adverse outcomes For nothing worthy proving can be proven, Nor yet disproven: wherefore thou be wise, Cleave ever to the sunnier side of doubt. Alfred, Lord Tennyson, The ancient sage Tennyson may not have been alluding to the need for high-level evidence from randomised controlled trials (RCTs) to alter clinical practice, but he would have been aware of children with rickets. Evidence has accumulated linking vitamin D deficiency to adverse outcomes in pregnancy, such as pre-eclampsia, hypertension, higher rates of caesarean section and preterm delivery. Lau and colleagues (→ Serum 25-hydroxyvitamin D and glycated haemoglobin levels in women with gestational diabetes mellitus) contribute to this evidence by demonstrating that, in women with gestational diabetes mellitus (GDM), a lower serum 25-hydroxyvitamin D (25[OH]D) concentration was independently associated with poorer glycaemic control.1 Of 147 women who were studied late in pregnancy (at a mean of 35 weeks’ gestation), about 40% had vitamin D insufficiency or deficiency (serum 25[OH]D concentrations ≤ 50 nmol/L). Most of the women in this study were not white, and ethnicity, occupational status and season, not surprisingly, all influenced 25(OH)D concentrations, while body mass index did not. Perhaps more surprisingly, however, 25(OH)D concentrations were inversely associated with fasting and 2-hour glucose levels measured during an oral glucose tolerance test and with the marker of glycaemic control, glycated haemoglobin. Most importantly, serum 25(OH)D was an independent predictor of glycaemic control. In adults, a number of large cross-sectional studies have shown a consistent, independent and positive relationship between serum 25(OH)D and insulin sensitivity, and an inverse relationship with risk of diabetes.2-5 Serum 25(OH)D levels have been shown to account for 42% of the variation in insulin sensitivity assessed by hyperglycaemic clamp.3 Consistent with Lau et al’s findings, fasting and 2-hour levels of glucose and insulin have been shown to be independently and inversely associated with serum 25(OH)D levels.3-5 In a United States study, the odds ratio for diabetes was 0.25 (95% CI, 0.11–0.60) for non-Hispanic white participants in the highest versus the lowest serum 25(OH)D quartile.2 The highest-level evidence to date comes from a large prospective study with a 17-year follow-up that showed people in the highest quartile of serum 25(OH)D had a 40% decreased risk of type 2 diabetes compared with those in the lowest quartile.6 Based on these data, RCTs of vitamin D supplementation in adults to improve insulin sensitivity and reduce diabetes risk are underway. GDM is becoming increasingly more common, affecting up to 10% of pregnancies. The presence of GDM is not trivial and has long-term implications for the health of mothers and their children. The former have an increased risk of developing type 2 diabetes, while their offspring have an increased risk of obesity and diabetes later in life. Vitamin D deficiency is also very common in pregnancy. The prevalence of inadequate levels of vitamin D in Lau et al’s study is comparable with rates of vitamin D insufficiency of 47.1% and 83.5% in white and black pregnant women, respectively, in the northern US (defined as 25[OH]D < 80 nmol/L)7 and 65.3% in pregnant women in rural Victoria (defined as 25[OH]D < 75 nmol/L).8 RCTs of vitamin D supplementation, initiated early in pregnancy, are now required to demonstrate whether vitamin D supplementation might reduce the incidence or severity of GDM. International debate is currently focused on the optimal level of serum 25(OH)D. Based on meta-analyses using musculoskeletal end points in older individuals, cut points of 60 nmol/L and 75 nmol/L seem appropriate to prevent falls and fractures, respectively.9 However, a recent Institute of Medicine report recommended at least 50 nmol/L,10 which appears overly conservative and does not take season into account. The public health implications of vitamin D deficiency in pregnancy are far broader than glycaemic control. In Australia, there has been a resurgence of rickets — partly owing to an increased refugee population comprising dark-skinned and veiled women with vitamin D deficiency, and also because of decreased exposure of babies to sunlight, lack of supplementation of infant feeds with vitamin D and weaning of infants onto non-milk liquids. Milder forms of bone disease may also occur with vitamin D deficiency. Recently, a study that used three-dimensional ultrasonography in pregnant women showed that vitamin D deficiency was associated with increased femur metaphyseal cross-sectional area and increased femur splaying (the ratio of femoral metaphyseal cross-sectional area to femoral length) at as early as 19 weeks’ gestation.11 In addition, it was previously shown that children born to mothers with vitamin D deficiency (< 50 nmol/L) during pregnancy exhibit deficits in total body bone mineral content as great as 11% at 9 years of age.12 This could lead to an increased risk of osteoporotic fracture later in adult life, but this is unlikely to be evaluated in long-term studies. In addition, maternal or early life vitamin D deficiency has been linked to an increased risk of several other disorders, including neonatal craniotabes, prematurity, type 1 diabetes mellitus, schizophrenia, and childhood respiratory infections and wheeze.13,14 Current evidence strongly supports routine screening for vitamin D deficiency early in pregnancy. Furthermore, vitamin D supplementation to correct deficiency should be initiated early in pregnancy as it might reduce the incidence or severity of GDM and because changes in skeletal morphology of the fetus associated with deficiency are seen as early as 19 weeks’ gestation. The most common recommended daily doses of cholecalciferol are 1000 IU–2000 IU, however, daily doses of up to 4000 IU have recently been shown to be safe in pregnancy (Bruce W Hollis, Professor, Department of Paediatrics, Medical University of South Carolina, USA, personal communication). What is problematic is the equitable provision of vitamin D supplements to pregnant Australian women with deficiency. Pregnant and breastfeeding women who are most at risk of vitamin D deficiency are often the least likely to be able to afford supplements. In the United Kingdom, vitamin D supplements are provided free of charge to such women through the Healthy Start program.15 There is evidence to support more widespread use of vitamin D supplements during pregnancy in Australia, although more research is required. One way to increase access might be to alter the scheduling of higher-dose, lower-cost vitamin D supplements.

Peter R Ebeling MB BS, MD, FRACP

An estimated four out of five Australians with coeliac disease are undiagnosed — we need greater awareness and increased testing According to criteria published in 1990, which remain the most widely accepted, the diagnosis of coeliac disease is based on typical histological features of the small intestine of an individual on a gluten-containing diet: villous atrophy, crypt hyperplasia and intra-epithelial lymphocytosis.1 Serological tests for coeliac disease, such as for endomysial IgA or transglutaminase IgA, are predictive, but alone are not sufficient for diagnosis. The diagnosis of coeliac disease is confirmed by clinical, serological or histological improvement on a gluten-free diet.1 To become a member of a state coeliac society in Australia, a person requires a doctor’s letter indicating a medical need for a gluten-free diet. As a result, over 80% of members have biopsy confirmation of coeliac disease; this is also the case in the United Kingdom. Over the past 10 years, there has been a steady compound annual growth of a little less than 10% in new memberships for coeliac societies in the UK and Australia (Norma McGough, Head of Diet and Health, Coeliac UK; Graham Price, President, Coeliac Society of New South Wales; and Jane Davies, Executive Officer, Coeliac Society of Victoria, personal communication). Both countries have now developed active education programs for doctors in family medicine. It appears that these programs have been successful in increasing serological testing and reducing the “backlog” of symptomatic patients with coeliac disease who were previously unrecognised.2 Today, coeliac disease is very much a diagnosis made in adulthood; children under the age of 10 years make up only 11% of new members joining coeliac societies in the UK and Australia, while the median age of new members is 40 years. However, best estimates, based on there being about 1% prevalence of coeliac disease in Western populations, suggest that no more than one in five Australians with coeliac disease are now diagnosed.3,4 Finland, where about 0.5% of the total population have now been formally diagnosed with coeliac disease,5 is accepted as having the most coeliac-aware health system. Australia still has a long way to go to achieve the level of awareness present in Finland, where gluten-free Big Macs have been available for more than 20 years and restaurant menus routinely indicate whether food is gluten free. Although awareness of coeliac disease has generally been low in the United States, a recent report by Mayo Clinic suggested that in Olmsted County, the home of Mayo Clinic, as many as 0.35% of the local community have been formally diagnosed with coeliac disease, suggesting a 35% ascertainment rate.6 It was also reported that no additional mortality was observed in the residual group of individuals with unrecognised coeliac disease in Olmsted County, suggesting that aware physicians and prompt, appropriate diagnosis of symptomatic coeliac disease are effective in minimising serious complications.7 Conversely, very low clinical awareness of coeliac disease, observed by researchers of historical cohorts in Germany and the US, is associated with substantially increased mortality, usually caused by malignancies and infection.8,9 Experience in Finland also supports the principle that high levels of clinical awareness and diagnosis minimise morbidity and mortality among individuals with unrecognised coeliac disease.10 Three reports, including one published in July 2010, suggest that, because of the rise in the disease’s prevalence, progress in clearing the backlog of undiagnosed coeliac disease may be slower than we thought.5,8,9 In Finland, the prevalence of coeliac disease doubled from 1% to 2% between 1979 and 2000, while diagnosed coeliac disease increased from 0.03% to 0.52% of the population.5 In the US, Mayo Clinic researchers showed that the seroprevalence of coeliac disease rose almost five times, from 0.2% to 1%, between 1950 and 2000.8 Now researchers have shown that, in a cohort of mostly adult volunteers in Maryland, US, who were enrolled in 1974 and followed up in 1989, the seroprevalence of coeliac disease more than doubled from 0.2% to 0.5% in 15 years.10 Those who showed seroconversion between 1974 and 1989 were all adults, indicating that coeliac disease does not necessarily begin in childhood. Data from Finland also show that the prevalence of coeliac disease in older people is double that in children.11-13 Although confirmation of coeliac disease by biopsy is ideal, these new epidemiological insights are reshaping our understanding of coeliac disease and should better inform clinical practice. No longer can we assume that a single serological test for coeliac disease is adequate to exclude coeliac disease for life. The only test that seems capable of excluding coeliac disease for life is HLA-DQ genetic testing.14,15 Absence of genes encoding the susceptibility antigens HLA-DQ2 or HLA-DQ8 effectively excludes coeliac disease; however, over a third of European populations possess these genes, while only 1% to 2% of the population has coeliac disease.16 Increased testing for coeliac disease using transglutaminase IgA and the new generation “deamidated gliadin peptide” IgA and IgG, and more systematic collection of small bowel biopsy samples by endoscopists, will steadily define those patients with coeliac disease who have a clear medical need for a strict gluten-free diet.17,18 The popularity of the “fad” gluten-free diet might be peaking,19 but the medical need for gluten-free diets continues to rise.

Robert P Anderson MB ChB, PhD, FRACP

How one man’s vision to fund health research grew to become the country’s largest non-government funder of research into mental illness This year marks the 30th anniversary of the founding of Australian Rotary Health (ARH), a uniquely Australian organisation operating under the auspices of Rotary International (a worldwide organisation of humanitarian service clubs) that allows Rotary clubs to support health research. From small beginnings, ARH has evolved to become a key non-government funder of research relevant to preventing and treating mental illness. ARH had its birth in 1981, when Ian Scott, a bank manager from Mornington in Victoria, heard a radio interview about the tragedy of sudden infant death syndrome (SIDS) and the lack of funding available for research into the problem. He resolved to do something about it. As a member of Rotary, Ian approached his club with an ambitious proposal to set up a research foundation, with a principal of $2 million to provide funds for health research, and the initial grants to be allocated to research into SIDS.1 Scott’s aims were achieved within a few years. By 1983, the Australian Rotary Health Research Fund had been established, and in 1985 the first grants were given for research into SIDS. By 1987, the initial goal of raising $2 million had been reached through appeals to Rotary clubs and Rotarians to donate some of their fundraising money to ARH. The organisation had spectacular success with its initial grant funding, when a study investigating the incidence of SIDS in Tasmania identified prone sleeping position of infants as a key risk factor.2 Within 5 years of this finding, promotion to parents of the importance of infant sleeping position led to a dramatic decline in the incidence of SIDS.3 Subsequently, ARH gradually grew and supported research in a range of other areas including environmental health problems of the aged, adolescent health, family health, Ross River virus, and first aid and emergency care. A major change in direction occurred in 2000, when it was decided that ARH would fund mental illness research. This decision was in response to the Global Burden of Disease Study, which found that mental illness was a major source of disease burden and the biggest source of disability globally,4 and findings from the 1997 National Survey of Mental Health and Wellbeing, which showed that around one in five adults in Australia were affected with mental disorders in a 12-month period.5 The move into mental illness research was strongly supported by senior policymakers in the then Commonwealth Department of Health and Aged Care.1 Support for mental illness research has continued for over a decade, and ARH is now the largest non-government funder of research in this area. During this time, ARH has also offered PhD scholarships and postdoctoral fellowships, and supported research symposia. Support from ARH has complemented research funding provided by the National Health and Medical Research Council (NHMRC) by focusing on more applied projects, particularly intervention research, that offer more immediate benefits to the community. ARH has also supported work in its earliest stages, when research questions and ideas are still evolving and data are needed to guide planning for larger-scale proposals. It has been a major source of support for emerging areas such as prevention of mental illness in children and adolescents, and innovative approaches to treatment such as e-therapy. A strong partnership has developed between ARH and the Australian Government Department of Health and Ageing, which has encouraged ARH to broaden its focus beyond supporting research. This reflected the recognition by policymakers that Rotary clubs had the potential to play an important role in destigmatising mental illness, because their membership encompasses influential members of local communities who could lead the way for greater understanding and acceptance of people affected by mental illness. To facilitate this work, the Department funded ARH to run community forums on mental illness across Australia. This involved Rotary clubs organising meetings in their local community where mental health professionals, people with mental health problems and carers presented information and personal experiences, and local mental health services promoted what they had to offer. More recently, the Department has engaged ARH to increase community understanding of mental illness by supporting Rotary clubs to deliver Mental Health First Aid courses in their local communities.6 Despite the significant support that ARH provides to Australian health research, the demand for funding continues to greatly exceed the available funds. In 2010, ARH was only able to fund 10% of applications it received for mental illness research projects. To overcome this problem, ARH is broadening its base of support beyond Rotary clubs, which have to date been the major sources of donations. In 2011, ARH will launch a national appeal to the Australian public for funding to support mental illness research. Over 30 years, ARH has grown from one man’s vision to fund health research to become an organisation that plays a key role in supporting research relevant to mental illness, funding research training, and advocating for the needs of those with mental disorders. This reflects the recognition by ARH of the benefits of involving Rotary clubs as agents for health promotion and stigma reduction, rather than simply as a source of research funds. No other country has involved Rotary clubs in this way, but we believe it is a model that deserves to be emulated.

Anthony F Jorm PhD, DSc, FASSA · Michael G Sawyer MB BS, PhD, FRANZCP · Joy Gillett OAM

The MJA bids a fond farewell to its Editor of 16 years When Martin B Van Der Weyden, 11th Editor of the Medical Journal of Australia, retired a few weeks ago, it was the end of a remarkable chapter in the Journal’s history. Sixteen years earlier, in his first message as Editor to the Journal’s readership,1 Martin had promised to oversee the MJA’s return to relevance for the medical profession and the abolition of its sometime reputation as the “Blue Comic”. He achieved this, and more, taking the Journal to a new level, not just for readers but among its international peers. Martin rose from humble beginnings, as the third of seven children of postwar Dutch immigrants, to become a prodigious researcher and a leader in his specialty of haematology, before taking on the editorship of the Journal, one of the most influential positions in Australian medicine. As Editor, Martin raised the profile of the MJA locally and internationally to make it one of the key drivers of change in Australian medical practice. He significantly improved the academic calibre of the MJA’s content; broadened its reach, relevance and readership; and presided over the biggest change in the Journal’s 97-year history with the embrace of electronic publishing. Martin’s intelligence and diligence took him from a migrant camp at Bathurst when he was 8 years old and a “good Catholic school” in Wollongong, where his family settled (near the steelworks, the employment mecca for migrant workers), to win a bursary at age 12 to attend Holy Cross College in Ryde as a boarder, and then a Commonwealth scholarship to study medicine at the University of Sydney. He graduated MB BS in 1966 and spent his early postgraduate years at Sydney Hospital, supported as a medical registrar by a Penfold family scholarship. Martin trained in clinical medicine and pathology, obtaining Membership of the Royal Australasian College of Physicians (RACP) in 1969 (and Fellowship of the RACP in 1974), and moved to the Alfred Hospital and Monash University in Melbourne to take up a position as Research Fellow in Clinical Haematology with the late Professor Barry Firkin (a position made possible by a scholarship from the Alfred Hospital Research Fund). In 1972, Martin was awarded a Merck Sharp & Dohme International Fellowship in Clinical Pharmacology to work with Professor Bill Kelley in the Division of Rheumatic and Genetic Diseases at the Duke University Medical Center in Durham, North Carolina. While at Duke, a further scholarship from the United States National Science Foundation allowed him to contribute to major work in the delineation of the effect of adenosine deaminase deficiency in patients with severe combined immunodeficiency. He quickly gained a reputation at Duke for his prodigious output and quirkiness. Many remember him as the “mad” Aussie who wandered into a ward one snowy morning, totally oblivious to the fact that he was on fire! Lost in thought, he had plunged his briar pipe into his overcoat pocket while it was still smouldering. Despite offers of positions at the US National Institutes of Health and at US medical schools, Martin returned to Australia in 1975 on yet another scholarship, as a National Health and Medical Research Fellow at the Alfred Hospital and Monash University. Having been supported by scholarships for most of his life, Martin finally got his first full-time paid job in 1977, when he became a Senior Lecturer in Medicine at Monash University. He graduated MD from Monash in 1978, and became a Fellow of the Royal College of Pathologists of Australasia in 1980. His clinical and research interests encompassed aspects of haematology, immunology, marrow transplantation, and haematological oncology. In 1981, Martin was awarded the RACP’s prestigious Eric Susman Prize for research into purine and pyrimidine enzyme activities in haematological malignancies. He was appointed Professor of Haematology at Monash University in 1985 and Director of the Department of Haematology at the Alfred Hospital. From 1985 to 1987, Martin served as President of the Haematology Society of Australia and New Zealand, presiding over the International Convention of Haematologists held at the Sydney Opera House. In 1989, he became Chairman of the Division of Investigative Medicine, and then Chief of Investigative Medicine Services to the Alfred group of hospitals in 1993. During this time he squeezed in a voluntary position as Haematology Subeditor for the Australian and New Zealand Journal of Medicine and a short, intensive stint at Harvard Business School in 1994. Working as an administrator during the time of the frenetic dismantling of the Victorian hospital system, Martin’s priorities were always the preservation of first-rate patient care and the provision of quality academic and clinical medical education. In time, the strictures of economic rationalism on medical services were to prove demoralising for the profession as a whole. When the frustrations of seemingly soulless restructuring became overbearing, Martin looked for a new challenge, and found it in the Journal. Though sad to leave Melbourne, his children were overjoyed that he no longer paced the front garden in the dead of night, shrouded in a smoky haze from his much loved Dutch cigarillos. Thus, in 1995, Martin, his wife Merle, and their three children moved back to Sydney. Martin’s medical, scientific, research and administration experience, and his familiarity with the research communities in Melbourne and Sydney, placed him well for taking on the mantle of Editor of Australia’s leading peer-reviewed general medical journal. He quickly stamped his mark on the Journal and earned the respect of the medical community, by following the principles of good communication: clarity, brevity, simplicity and humanity. Martin boosted the quality of the Journal’s articles by increasing the number of editorials and encouraging authors to confront controversial topics; introducing a higher academic standard for research articles in particular (and thus significantly increasing the manuscript rejection rate); and expanding the reach of the Journal to cover health policy and reform, workforce issues, medical politics and medical education. Because many Australian researchers choose to submit their best work to higher profile US or British journals, the MJA suffers from “small country syndrome” in terms of international rankings, but Martin made significant inroads to address this. In 1993, before Martin took over, the MJA languished at 30th (out of about 100) in the ranking of general medical journals; in 2008, it reached an all-time high of 18th, with an impact factor of 3.32. Martin is a clear thinker: decisive, with strong opinions and astute judgement. He is a diligent observer of all things medical, is politically savvy, and is a forthright speaker and writer who abhors “bullshit” and has never toadied to political correctness. At times he would play the classic Editor, making a frenzied string of phone calls to his impressive collection of friends and experts to get to the bottom of a story or current event. But he has never published anything that did not meet his own rigorous academic standards, understanding the value of the MJA’s reputation as an unbiased, accurate source of information. He has a wicked sense of humour and an enduring enthusiasm to challenge people to think outside the square. The same qualities that made Martin an excellent Editor also make him a sought-after speaker and a highly valued guest at meetings and conferences, where he can be relied on to stir up debate, ask the difficult questions and offer insightful and constructive criticism. A year into the job as Editor, Martin also took on the demanding role of Chief Executive Officer (CEO) of AMPCo (the Australasian Medical Publishing Company, which publishes the Journal and the Medical Directory of Australia and manages Australia’s largest commercial medical database). He continued in the dual positions of Editor and CEO for 14 years. He is also a member of the International Committee of Medical Journal Editors, which sets the standards for biomedical publishing, and has recently served as a Director of the Executive Board of the World Association of Medical Editors. Under Martin’s leadership, the Journal was an early adopter of electronic publishing, including an innovative trial of interactive, electronic peer review. By 2001, all Journal content was freely available on the web, remaining free until 2009 when, against his better judgement, some articles became accessible to subscribers only. Technical capacity was always a limiting factor but, last year, the Journal finally launched MJA InSight, an online newsletter for doctors. His own background and self-confessed political left-leaning tendencies made Martin open to some of the more marginalised elements of Australian society, providing those working in prison and refugee health, drugs and alcohol, sexual health, mental health and Indigenous health with a much needed mainstream outlet for their research and commentary (but only if they met the Journal’s high academic standards). Two annual theme issues, one on Indigenous health and another on general practice, were established, and remain of great importance to the target contributors and readers. As Martin matured into the job, he became the heart, soul and, indeed, the face of the Journal. His fortnightly column, “From the Editor’s desk”, was frequently on the MJA’s top 10 website hits list from its inception in 2004 — a tribute to his reputation as an astute observer with a long-range view of Australian health care. Dr Martin Van Der Weyden with portrait by (Dr) Ann Theresa Gregory. Those of us who worked with Martin understand how he was able to achieve so much. Even in his spare time, his mind was never far from the Journal. He would often turn up on a Monday morning, brandishing a book he had just read on medical history or health policy, or an editorial he had written over the weekend. He had a knack for appearing erratic, distracted or even perverse, and then coming up with the exact solution required for the problem at hand. On an initial meeting, he liked to shock with a blunt statement or seeming non sequitur, before revealing his incisive intellect and, ultimately, a humane and surprisingly soft inner core. When congratulated for his work at the Journal, he maintained that his genius had been in assembling a competent team: there was method in his madness — to get the best out of people. In his rare spare time, Martin listens to Bach, Beethoven and Haydn, and is a voracious reader of crime fiction and books of medical miscellany with a philosophical bias. His wife Merle remains a huge source of inspiration and moderation, as does his Catholic faith and his involvement in his local parish. When asked how he would like his tenure at the Journal to be remembered, Martin is typically offbeat. His success may be measured in many ways: the rise of the Journal’s impact factor and standing in the international ranking of journals; an increase in high-quality submissions; a robust presence in the media and in health policy machinations; the respect of medicopolitical, Indigenous and other leaders; and the unswerving loyalty of those who worked for him. Yet, 16 years after he penned that first editorial, he was most proud of one outstanding achievement. Nobody, anywhere, was referring to the MJA as the Blue Comic.

Bronwyn Gaut MB BS, DCH, DA · Ruth M Armstrong BMed · Ann T Gregory MB BS, GradDipPopHealth · Peter C Arnold BSc, MB BCh, BA

In the absence of conclusive evidence, the winner is the mask that has the confidence of clinicians Australian infection control strategies for pandemic influenza are influenced by world authorities — the Centers for Disease Control and Prevention (CDC) and the World Health Organization. WHO guidelines1 take into account the lack of health resources in many communities, and focus on affordability as well as reductions in infection risk. CDC guidelines2 presuppose a well resourced health sector and are aimed at achieving zero risk. The different approaches of the two organisations are manifest in their conflicting recommendations for the type of face mask to use in routine care of patients with influenza: CDC recommends the N95 respirator (equivalent to the P2 mask used in Australia), while WHO recommends the cheaper surgical mask. By giving the world free access to their guidelines, the organisations have saved countries the cost of guideline development. Yet, the gain in risk reduction with the adoption of the CDC’s recommendation is unknown and may not be cost-effective. Conversely, those who opt for the WHO guideline might not appreciate that health care workers (HCWs) in well resourced settings are unlikely to accept a strategy if they perceive it to be significantly riskier than the more costly alternative. The important question is whether either guideline is based on the best evidence and relates the potential risk reduction to the cost involved. A potted history of CDC’s change in preference from surgical to P2 masks may help those seeking well informed policies about the use of masks for routine patient care. The history of the use of masks by HCWs has been classified into three eras: development and testing (1905–1920); “awareness of the importance of masks” (1920–1940); and the “unimportance of masks secondary to antibiotics” (1940 and beyond).3 We nominate a fourth era, “over-importance of masks” (1990s to the present), which was set in motion by changes to CDC guidelines.4 The CDC’s decision to recommend P2 masks instead of surgical masks for routine care of patients with tuberculosis (TB) was prompted by an unusual outbreak of multidrug-resistant TB in HCWs.5 The CDC made the change despite acknowledging that (1) P2 masks were manufactured to filter industrial, non-pathogenic aerosols and tested to filter out 95% of 0.3 μm sodium chloride particles, not airborne or droplet-sized bioaerosols; (2) some surgical masks were also capable of filtering out 95% of 0.3 μm sodium chloride particles; and (3) the protective efficiency of P2 masks against specific pathogens was unknown. The revised recommendation instigated a widespread non-evidential assumption of a link between wearing masks and preventing aerosolised transmission of pathogens based on particle size: that is, it was assumed that P2 masks prevent disease transmission by airborne particles (≤ 5 μm in size), and surgical masks prevent transmission by droplet particles (> 5 μm in size).4 With neither laboratory nor in vivo efficiency data to compare mask types, why were P2 masks advocated to protect HCWs against TB? The answer lies in the principles of evidence-based medicine. Despite its deceptive moniker, evidence-based medicine values not only research evidence, but costs and the “needs and values” of stakeholders, including clinicians. CDC leaders moved from surgical masks to P2 masks to solve the “problem of merging scientific and theoretical data into a sound infection control approach for the protection of HCWs against tuberculosis”.6 The problem was not resolved on evidential grounds because the evidence was simply not there. Rather, the solution prioritised the needs and values of clinicians concerned that the surgical mask permits transmission of multidrug-resistant TB because it allows a gap between the face and mask. As a consequence, this revision bred a legacy that associates mask type with particle size rather than with HCWs’ needs and values.6 Confronted with a similar debate about influenza transmission, the Australian Department of Health and Ageing commissioned us to review the protectiveness of masks,7 antiviral prophylaxis and vaccination, and to develop evidence-based infection control algorithms8 for the protection of HCWs during a pandemic. Development of the algorithms was informed by the following considerations. Proper use of a mask is more protective than not using a mask, but research findings show that neither the P2 nor surgical mask type is statistically superior. This concurs with findings from a review9 as well as results of a randomised control trial showing non-inferiority of surgical masks.10 The effectiveness of antiviral prophylaxis against future strains cannot be tested. However, antiviral prophylaxis is effective against seasonal influenza when administered in the first 48 hours of illness and if the drug-resistance of the virus is low.11 Given the efficacy of seasonal vaccines, a novel pandemic vaccine may provide a similar level of protection. Implementing the recommendation that HCWs wear P2 masks for routine patient care in a pandemic has several difficulties, including cost and fit-testing. The need for fit-testing was added to both CDC and WHO infection control guidelines1,2 after occupational-acquisition of the severe acute respiratory syndrome (SARS) by HCWs. However, there is no evidence that fit-testing affords higher levels of protection than a comfortably fitting mask. During our study of stakeholders’ needs and values, local clinicians unanimously disputed the recommendation for the use of surgical masks for routine care despite the recommendation being only one part of our multi-tool infection control strategy, which included antiviral prophylaxis, vaccination and a face shield for eye protection.8 The clinicians told us that they were taught, when training in the management of SARS, that P2 masks give superior protection. Nearly a century ago, the recommendation for use of the gauze mask came with a warning that it should not provide the wearer with an “unwarranted feeling of security”, but should be considered as one part of an infection control process.12 Research evidence7 suggests that a surgical mask plus face shield, rather than a P2 mask, is sufficient protection against pandemic influenza, but will this measure serve as sufficient protection for a health care system that needs healthy HCWs to manage a pandemic-sized caseload? Conventional evidence-based principles give equal importance to research evidence, economic cost, and needs and values of stakeholders. When research is inconclusive, principles should be prioritised. WHO guidelines1 prioritise research evidence within the limitations of resources of different socioeconomic settings; CDC guidelines2 prioritise the needs and values of clinicians within the limitations of research evidence. The new infection control algorithms8 compensate for weak research evidence — they remove the “over-importance” given to masks by prioritising needs and values of HCWs, while presenting masks as just one component of an infection control strategy. Without seminal research evidence of influenza being transmitted exclusively by airborne transmission, and in the absence of studies testing for superior protection of P2 masks, it would be prudent for health care executives to view providing P2 masks to HCWs, not as an additional cost, but as an additional investment in the continuity of health service provision — and in the full knowledge that, on today’s evidence, P2 masks provide a level of protection equivalent to that of surgical masks.

Mary-Louise McLaws DipTropPubHlth, MPH, PhD · Jan Gralton BSc(Hons)

New ablative techniques can eradicate dysplastic Barrett oesophagus more effectively, but require longer-term follow-up to strengthen their evidence base Barrett oesophagus is a precursor lesion that can progress to oesophageal adenocarcinoma. Barrett oesophagus affects about 1% of the population and is believed to be due to chronic gastro-oesophageal reflux disease.1 Patients with Barrett oesophagus have a 30–40-fold relative risk of developing oesophageal adenocarcinoma, which usually occurs via progression through low-grade dysplasia (LGD) to high-grade dysplasia (HGD).2 Management of patients with non-dysplastic Barrett oesophagus comprises surveillance endoscopy and biopsies every 2–3 years, along with acid suppression. The traditional approach for treating LGD has been intensified endoscopic surveillance. A new trend has evolved in the management of patients with HGD and intramucosal cancer. Oesophagectomy has been standard treatment for these patients because of studies showing that cancer is discovered in about 40% of oesophagectomy specimens after a preoperative diagnosis of HGD.3 Oesophagectomy in high-volume centres now carries a mortality rate of around 1%; however, morbidity rates can be up to 30%.4 Recently, improved capacity to identify early cancers with modern endoscopes and advances in endoscopic resection and ablation techniques have resulted in excellent outcomes for individuals with HGD and intramucosal cancer treated with endoscopy alone. Staging dysplastic Barrett oesophagus requires meticulous endoscopic assessment, using the newest generation of high-definition endoscopes to identify nodules and subtle mucosal abnormalities that can harbour cancer. Biopsy samples are taken from visible abnormalities, and four-quadrant biopsy samples are taken from every 1 cm of Barrett oesophagus. New endoscopic technologies, such as narrow band imaging and confocal endomicroscopy, appear to aid identification of dysplastic areas and may reduce the need for random biopsies. Endoscopic mucosal resection is a technique to remove 10–15 mm areas of mucosa, to the depth of the submucosa. Larger areas, or the entire Barrett oesophagus up to 3–5 cm in length, can be completely removed by this method with several contiguous resections. Endoscopic mucosal resection of focal mucosal abnormalities is essential to identify and remove early cancers and to determine the depth of invasion. If dysplasia or cancer is confined to the mucosal layer, the chance of spread to perioesophageal lymph nodes is less than 5%. On the other hand, if cancer extends into the submucosal layer, the chance of lymph node involvement is about 30% and oesophagectomy is therefore indicated.5,6 In expert hands, focal endoscopic mucosal resection achieved complete removal of HGD and intramucosal cancer in 96% of 231 patients.7 However, metachronous lesions occurred in 22% of patients at mean follow-up of 61 months; incomplete removal of the residual Barrett oesophagus was the main risk factor for recurrence. This highlights the importance of removal of the entire Barrett segment.7 To address this issue, a few European centres have advocated stepwise complete resection of short segments of Barrett oesophagus. In a recent multicentre study, complete eradication of all neoplasia was achieved in 98% of patients (165/169) after median follow-up of 32 months.8 Endoscopic mucosal resection has a 1% risk of serious complications, such as major bleeding or perforation. Symptomatic stenosis requiring dilatation develops in up to 50% of patients following stepwise complete resection.9 Endoscopic ablation therapies rely on the fact that squamous mucosa will replace the ablated Barrett oesophagus in a non-acid environment. Older endoscopic therapies include argon plasma coagulation, photodynamic therapy and multipolar electrocoagulation. These techniques are limited by variable mucosal ablation and “buried Barrett” under squamous mucosa. The HALO radiofrequency ablation system (Barrx Medical, Sunnyvale, Calif, USA) consists of two devices for delivering radiofrequency energy to the Barrett oesophagus. The HALO360 device is a balloon that is inflated in the oesophagus to deliver a 3 cm circumferential burn, which can be repeated to treat long segments. The HALO90 is a flat device attached to the tip of the endoscope to ablate smaller areas of Barrett oesophagus. Energy delivery is automated, leading to a more predictable and uniform ablation, enhancing safety and efficacy compared with other ablative therapies. A randomised controlled trial of HALO radiofrequency ablation compared with a sham procedure has shown much higher rates of complete remission after 12 months in individuals with HGD (81%) and LGD (91%) compared with the control groups.10 The 2–3-year follow-up of patients who remained in the study has confirmed durability of response, with 95% of patients who achieved complete remission of Barrett oesophagus at 12 months remaining so at 2 years. Furthermore, 85% of those who failed to eradicate Barrett oesophagus at 12 months achieved complete eradication at 2 years with a mean of 1.2 further focal ablation sessions. Longer-term follow-up beyond 5 years is required to address maintenance of remission and reduction in cancer progression.10 The principle of combination therapy is to remove visible mucosal abnormalities that may harbour invasive cancer with endoscopic mucosal resection, then to ablate the remaining Barrett oesophagus with HALO radiofrequency ablation. Using this approach, 22 of 23 patients with early cancer or HGD achieved complete remission of Barrett oesophagus, with no neoplasia recurrence after 22 months.11 Endoscopic therapy with HALO radiofrequency ablation and/or endoscopic mucosal resection has now emerged as a credible alternative to surgical oesophagectomy and should be considered as a valid alternative to surgery for patients with HGD and intramucosal cancer. Our institution favours the combination endoscopic approach. The optimal management of patients with dysplastic Barrett oesophagus requires meticulous assessment and an individualised approach. Patients who undergo endoscopic therapy will need to be informed, motivated and compliant, as careful endoscopic surveillance after eradication is required to ensure that any recurrence is detected and treated early. Therefore, endoscopic therapy is best performed at tertiary centres with expertise in this evolving area.

Chatura S Jayasekera MB BS(Hons), FRACP · Finlay A Macrae MD, FRACP, FRCP · Paul V Desmond MB BS, FRACP · Andrew C F Taylor MB BS, FRACP, MD

The Journal has a new Editor and big plans for the future With this issue, Dr Martin Van Der Weyden retires after 16 years as Editor of the Journal. A tribute to Martin and his many achievements will appear in the next issue. Martin has been a generous and wise teacher, and his columns have set the benchmark in editorial writing. Under his guidance, the Medical Journal of Australia has become the leading publisher of general medical research in Australia. It makes a vital contribution to the debate on local and global medical issues including Indigenous health, patient safety, the honesty and integrity of scientific publishing and peer review, and Australian health policy. The Journal he bequeaths is robust and central to medical communication in this country. As the Journal of the Australian Medical Association, the MJA has a freedom that is unavailable to most other general medical publications in the country: to publish and report free of commercial interests. You can be confident that studies published in the MJA are subject to strict rules requiring disclosure of conflicts of interest, and that they have been expertly peer reviewed. The MJA is uniquely placed to inform and facilitate discussion and education across our profession, and to anchor it within the context of the broader Australian health system. To keep abreast of changes in clinical medicine and professional issues, and to meet the challenge of maintaining the Journal’s relevance for all doctors in the face of these changes, there are plans for the continued evolution of our print publication and an enhanced presence on the web. The MJA will continue to publish major Australian research studies and remain the natural place for publication of data that are important to all Australian clinicians. I want to foster this role for the Journal. My dilemma, however, is that of the editor of any general medical journal: it is difficult to produce an article that meets the needs of both researchers who are interested in the minutiae of their topic and readers who may prefer a brief overview.1 While many Australian studies are appropriately published in specialty and international journals, general medical journals such as the MJA have a crucial role in building and disseminating a strong, usable base of medical knowledge. All doctors have specialised educational requirements and have to be selective in their reading — 75 trials and 11 systematic reviews are published daily2 — thus there is a greater need than ever for relevant interpretation and commentary. I will be inviting the authors of these “specialty” or “international” papers to write editorials for the MJA, which interpret their data. This will feed into an increased emphasis on articles, written by leaders in their field, that synthesise new information for our readership. I want to develop the MJA ’ s natural role as a forum for the presentation of news relevant to doctors and for debate that develops around these issues. Currently, too many medical issues play out in the public media before the profession has a chance to consider or respond. A prime example has been the coverage of prescribing rights for non-doctors.3 Other important issues include the delivery of effective and efficient health care, the planning for, and training of, our medical workforce, and the improvement of Indigenous health outcomes. Our engagement in this process will determine the degree to which we remain an independent and vital profession and will also help to improve health outcomes for the community. One crucial issue is health funding. Currently, Australia spends over 9% of its gross domestic product on health,4 increasing at up to 0.5% per annum.5 The population is ageing and demands on the health system are increasing, necessitating hard choices with respect to the way a limited health budget is spent. As doctors, we need to understand the opportunity costs of ordering a test or admitting an elderly patient to intensive care. In this way, we can participate in decisions involving the allocation of funds within the health budget. The MJA is the appropriate forum for this informed conversation. Discussion about the practice of medicine needs to continue. Good medical practice: a code of conduct for doctors in Australia, adopted by the new Medical Board of Australia, was developed with little discussion within the profession.6 How this code is implemented is yet to be defined, and we should take this opportunity to explore and, perhaps, refine the way we practise. This debate should include doctors’ contributions to the public health care system, the organisation of medical practices, billing practices and time spent with patients, and the complexities of patient education and obtaining informed consent. Our future doctors also need to be included. I plan to engage more with our readers via electronic media. Inevitably our website, planned to be relaunched, will become increasingly important in the life of the Journal. It will embrace new technologies and media, allow for the publication of more research and medical content and facilitate timely discussion around issues. Soon, I hope you will enjoy easy access to the Journal from mobile electronic devices and that you will use this resource to have your say in these conversations. The MJA is your forum. Already, our recently launched email newsletter, MJA InSight, boasts the highest audited email circulation of any medical newsletter in the country.7 My background is as a general practitioner and medical editor, and I will be seeking to both broaden and strengthen the MJA community so that many voices (not just the loudest or best-positioned) are heard. I will be expanding our base of peer reviewers and plan to introduce a rotating position of “Guest Medical Editor”. This person will commission work in his or her field of expertise and refresh and inform our editorial team about advances in his or her area of interest. Already, I have been overwhelmed by the passion and generosity of the MJA community, who, without favour, payment or (much) recognition, contribute to this publication. Peer reviewers are indeed our “unsung heroes”.1 Thank you to all who already contribute to the MJA and to those who will help in the future. I envisage that an enhanced MJA will play an even more important role in the discussion of issues that affect medicine in Australia. With an expanded range of content and new technologies, we have the potential to engage the entire profession. As the new Editor of the MJA, I look forward to guiding its evolution and to working with you.

Annette G Katelaris MB BS, MPH, FRACGP

Is it time to relax or tighten the legislation on human embryo research? Over the past decade, human embryo research has generated both enormous scientific interest and extensive public debate. In response to this, Australia passed two Acts in 2002: the Research Involving Human Embryos Act 2002 (Cwlth) and the Prohibition of Human Cloning Act 2002 (Cwlth). Together, these Acts, and mirror legislation passed by all states and territories, enabled Australian scientists to undertake specific research involving human embryos, provided that they obtained a licence from the Embryo Research Licensing Committee of the National Health and Medical Research Council (NHMRC), reported regularly to this committee, and had their research approved and monitored by the appropriate institutional ethics committee. At the same time, these Acts prohibited a series of practices — including human cloning, creation of animal–human cybrids, maturation of research embryos beyond 14 days, and the buying and selling of human oocytes — and provided substantial penalties for breaches of the provisions. Consistent with the provisions of the Acts, the legislation was reviewed in 2005–2006 by the Lockhart Committee (the Legislation Review Committee chaired by the late John Lockhart). After extensive community consultation, the Committee made 54 recommendations for amending the existing legislation. Following further public and parliamentary debate (which culminated in a conscience vote in both federal chambers), almost all of these recommendations were accepted and implemented, by the amending legislation in 2006 or administrative changes made by the NHMRC and other relevant regulatory bodies. (The current federal legislation is the Research Involving Human Embryos Act and the Prohibition of Human Cloning for Reproduction Act 2002 [Cwlth].) As a consequence, while the major prohibitions present in the 2002 Acts remained, Australian scientists were able to create an embryo by somatic cell nuclear transfer (SCNT) for research purposes and conduct research on human embryos deemed unsuitable for implantation and on eggs in the process of fertilisation up to syngamy. The legislation is again up for review and, as in 2005–2006, the review must consider: developments in assisted reproductive technology and embryonic stem cell (ESC) research, international developments and legislation relating to the use of human embryos in research, the effectiveness of existing legislation (including whether it has acted as a barrier to important research or clinical practice), and community standards. Since 2006, research involving autologous and allogeneic transplantation of adult somatic stem cells has continued to advance (although the best evidence continues to be for treatment of malignant and immunological diseases) and early studies have confirmed that autotransplantation of haematopoietic and mesenchymal stem cells may have regenerative capacity in treating hepatic, pulmonary, cardiac, neurological and arthritic diseases. Over this period, human ESC research has also provided important insights into normal and pathological cellular biology, reproduction and embryogenesis, and the creation of disease models and systems for screening drugs and predicting toxicity.1 Animal studies of ESCs have also shown promising results in the treatment of spinal injury, neurodegenerative and demyelinating disorders and retinal disease, and the first Phase 1 clinical studies involving adults with spinal injury and stroke and children with macular dystrophy have begun.2-4 At the same time, a series of developments in related fields have also created enormous excitement. In 2006 and 2007, teams of scientists in Japan and the United States reported that they were able to derive induced pluripotent stem (iPS) cells by inducing forced expression of specific genes in adult somatic cells.5 These iPS cells, which resemble ESCs in terms of morphology, mitotic activity, telomerase activity and expression of stem cell genes and proteins, appeared to be an important breakthrough as they allowed generation of stem cells without the use of human embryos, did not require the use of donor oocytes, and avoided the problems of immune rejection and graft-versus-host disease because they were autologously generated.6 While proof-of-concept and animal studies of iPS cells in a range of degenerative disorders show great promise, recent research suggests that iPS cells may have a slightly different gene expression profile to human ESCs, have limited differentiation capacity and undergo premature ageing. Also, significant hurdles remain with regard to the efficiency and safety of iPS cells before human trials can begin.7-9 Recent research has also demonstrated that nuclei from “terminally differentiated” adult somatic cells can be induced (“reprogrammed”) to express genes that are typical of ESCs or of other lineages, and differentiated to form other cell types, thereby enabling autotransplantation of normal tissue to areas of disease, or the generation of new organs or tissues using tissue-engineering technologies.10-12 Despite the fact that this research is in its infancy, the promising results of research involving iPS cells and reprogrammed adult somatic stem cells has (predictably) led some to proclaim the demise of ESC research and to call for the repeal of legislative amendments enabling human ESC research and SCNT. This would be a mistake. Although developments in iPS cell research show promise and human ESC research has not yet been translated into medical therapies, this does not provide a reason for prohibiting ESC research. It remains unclear whether human ESCs, reprogrammed adult somatic stem cells and iPS cells will prove to be bioequivalent or to offer alternative or complementary cellular therapies.7 In addition, as the history of medical research demonstrates, the realisation of clinical benefits from basic research can take decades. Furthermore, the stem cells derived from SCNT may also yield benefits other than medical therapies, including cell lines for drug screening and for research into early embryonic development, normal organogenesis and certain disease states. And, perhaps most importantly, the idea that advances in one field of research should mean researchers are prevented, by law, from exploring another related field of research is, in many ways, antithetical to the principles and processes of science in a liberal democratic society. Australia’s existing regulatory framework provides the most effective means for ensuring that research is important, rigorous and ethically sound in its design and conduct. Should research yield important benefits consistent with the needs and goals of the community, it will prosper. Should it prove redundant, useless or totally at odds with the values of the community, it will not. For all these reasons, and because human embryo and stem cell research enjoy high levels of public support, we should not again seek to prohibit research involving human embryos or the derivation of stem cell lines by SCNT. Whether the current legislation needs to be liberalised further to enable research into mitochondrial diseases, the creation of cybrid embryos or the payment of egg donors, is a matter for debate.

Ian H Kerridge MPhil, FRACP, FRCPA · Aric Bendorf BA, MBioethics