Volume 194 Issue 8

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

Objective: To quantify and describe current cancer clinical trial activity in Australia and help guide future trials research using trial registries.Design and setting: Data from cancer trials recruiting in Australia at 31 March 2009 were extracted from the Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov. A regression model was used to identify factors associated with industry sponsorship.Main outcome measures: The proportion of cancer trials compared with estimated burden of disease for each cancer.Results: There were 368 interventional cancer trials open to recruitment. The most-researched cancer was breast cancer, accounting for 17% of trials. Only 7% of trials were in lung cancer, yet lung cancer is responsible for the greatest burden of disease. Industry was the primary sponsor in 43% of trials. Drug treatments were tested in most trials (69%). Trials were more likely to be industry sponsored if they tested systemic rather than local treatments (OR, 16.71; 95% CI, 4.70–59.43), included patients with advanced rather than early disease (OR, 3.76; 95% CI, 1.78–7.94) and used random rather than non-random allocation (OR, 1.78; 95% CI, 1.06–3.00).Conclusion: There is variation in the number of trials according to cancer site, with some cancers being underrepresented relative to their burden of disease. Industry sponsorship is more likely for trials that investigate systemic therapy, recruit patients with advanced disease and are randomised.

Rachel F Dear MB BS, FRACP · Alexandra L Barratt MB BS, MPH, PhD · Kevin McGeechan BSc, MBiostatistics · Lisa Askie PhD, MPH · John Simes MD, FRACP · Martin H N Tattersall MD, MSc, FRACP

Objective: To audit general paediatric outpatient practice in Australia, including consultation characteristics and management patterns, diagnoses, factors associated with diagnoses, and billing practices.Design, setting and participants: In October – November 2008, members of the Australian Paediatric Research Network (APRN; a national network of paediatricians established to facilitate multisite secondary care research) were invited to prospectively complete brief standardised data collection forms for 100 consecutive patients or all patients during a 2-week period, whichever came first.Main outcome measures: Length of consultation and type of diagnoses made; proportions recorded as having medications, investigations or referral; odds ratios for factors associated with diagnoses; and proportions of Medicare items billed.Results: Of 300 APRN members, 199 (66%) completed data forms for 8345 consultations in which 15 375 diagnoses were made (mean, 1.8 diagnoses per consultation); 46.0%, 30.9% and 22.8% of consultations involved 1, 2 and ≥ 3 diagnoses, respectively. New and review consultations lasted a mean of 41 (SD, 20) and 26 (SD, 15) minutes, respectively. The most common diagnoses were attention deficit hyperactivity disorder (18.3%), baby checks (9.1%), and learning difficulties (7.5%). Patients seen in 47.5% of consultations had medications (eg, prescriptions, vaccinations) recorded, and patients in 27.2% of consultations were referred elsewhere, usually to a subspecialist or psychologist (31.6% and 26.6% of referrals, respectively). Male sex of the child and owning a Health Care Card were associated with most developmental–behavioural diagnoses. Paediatricians tended to bill for single disease/non-complex consultations, even when seeing a child with multiple problems.Conclusions: Australian paediatricians see children with a range of diagnoses that are often multiple and complex. Our findings provide directions for future secondary care research, and may inform workforce planning and paediatricians’ training requirements.

Harriet Hiscock MB BS, FRACP, MD · Gehan Roberts MB BS, FRACP, PhD · Daryl Efron MB BS, FRACP, MD · Jillian R Sewell MB BS, FRACP · Hannah E Bryson BA(Hons) · Anna M H Price BA(Hons) · Frank Oberklaid MD, FRACP, DCH · Michael South FRACP, MD, FCIM · Melissa A Wake MB ChB, FRACP, MD

Objective: To determine uptake of treatment for hepatitis C virus (HCV) infection and predictors of deferral of treatment for HCV by using prospectively collected data from the Australian Chronic Hepatitis C Observational Study (ACHOS).Design, patients and setting: Cohort study involving interview and medical record review at enrolment and routine follow-up clinic visits of patients with chronic HCV and compensated liver disease attending a national network of 24 HCV clinics between April 2008 and December 2009. Eligible patients were those who had not been previously treated, were enrolled within 6 months of their first clinic visit, were eligible for treatment and had been enrolled for at least 6 months.Main outcome measure: Predictors of patients undergoing HCV treatment within the first 6 months of assessment.Results: 1239 patients were enrolled in ACHOS, of whom 406 met the criteria for inclusion in the subcohort for this study. Among this subcohort, 171 (42%) received treatment within 6 months of their first clinic visit. Current injecting drug use (odds ratio [OR], 0.26; 95% CI, 0.08–0.77), past and current treatment for drug dependency (OR, 0.34; 95% CI, 0.18–0.67, and OR, 0.42; 95% CI, 0.22–0.81, respectively) and alcohol use above 20 g/day (OR, 0.20; 95% CI, 0.08–0.46) were independent predictors of deferral of treatment. At least one of these factors applied to 41% of the subcohort. Clinical factors, including HCV genotype, HCV RNA level, and stage of liver disease were not associated with deferral of treatment for HCV.Conclusion: Factors related to drug and alcohol use, rather than clinical factors, influenced uptake of treatment for HCV. Further support for patients with drug and alcohol dependency is required to optimise treatment uptake.

on behalf of the ACHOS investigator team

Legislative changes made without public discussion allow disclosure without patient consent Of all the ethical principles underlying medical practice, confidentiality is so fundamental that its breach is an illegal, high-order betrayal of responsibility. Disclosing personal medical information without consent profoundly violates the autonomy, beneficence and privacy that patients have always rightly expected.1 Although disclosure without consent has only rarely been necessitated by an urgent threat to life or health, two recent legal erosions of doctor–patient confidentiality illustrate how privacy-invading legislation can so easily and silently harm individuals who do not form sufficiently clamorous rights-demanding groups. In one, a state government directs that private medical records be lodged in an Orwellian sounding “Central Register” without regard for the individual’s knowledge, and risking privacy breaches by seeking consent for disclosure to third parties. The other permits disclosures of a patient’s medical information against their wishes even without any urgent threat to the life or health of another person. Both represent unreasonable intrusions on privacy and erosion of personal liberty. Recently, the New South Wales Government made a legislative amendment, without parliamentary debate or public discussion, in the last days of their current term. This amendment to the Assisted Reproductive Technology Act 2007 (NSW)2 forces doctors to provide the identity of anonymous sperm donors to a central register when their genetic offspring submit a request for information to the Director-General of NSW Health. This transfer of identifying information can occur regardless of the sperm donor’s consent, and overrides any prior condition of strict confidentiality guaranteed at the time of sperm donation. Although it is argued that identifying information cannot be released without the donor’s consent, the Director-General’s possession of donor contact details creates a situation where a stranger to the donor might try to contact him to seek consent for disclosure. The donor, however, did not ever consent to such an approach from a government instrumentality which, in itself, is virtually certain to breach the donor’s strict confidentiality. Inevitably, once the Director-General possesses identifying information and this contact and consent process proves unworkable, the logical next step is eliminating the troublesome consent requirement. This retroactive legislation is starkly at variance with the recent Australian Senate’s report of its inquiry into donor conception in Australia,3 which recognised that all states’ legislation on donor conception respected the time-honoured principle of rejecting legislative retrospectivity. Sperm donors have often long forgotten their altruistic act, two decades previously, motivated by a wish to help infertile couples and thought of as akin to blood donation; certainly they would not have provided sperm without the guarantee of enduring and strict confidentiality. Now, merely expecting undisturbed privacy, they do not constitute any sort of group to oppose the persistent, vocal donor-conception lobby groups demanding involuntary disclosure that overrides donors’ legal and moral rights. Sperm donors’ lives over the decades since donation could have changed in every imaginable way so that forced disclosure may be unwelcome, and damaging to some. It denies natural justice to disregard the usual requirement for their consent. We hope that a new NSW Government will show regard for consent and amend the retrospectivity of this assault on the privacy and personal liberty of well intentioned individuals. The other legal assault on privacy is highlighted in a recent update of the National Health and Medical Research Council (NHMRC) guidelines on medical genetic testing.4 These guidelines endorse a recent amendment to Commonwealth privacy legislation that widens the legal exemption allowing disclosure of patients’ genetic information to others, even against a patient’s wishes. Rarely, the situation arises where a patient is unwilling to inform relatives of a genetic test result that, in a doctor’s opinion, should be disclosed. Such disclosure was previously only permitted to resolve an imminent danger to another person’s health. After the previous exemption for imminent medical danger created a precedent, a recent amendment has removed the requirement altogether. In effect, this now creates genetic testing without consent by proxy — a situation where the relative may be informed, against the patient’s wishes, of the patient’s genetic status without the relative soliciting the information and possibly without wishing to know. The arbitrary nature of this new standard is illustrated by its vague boundaries — only a “serious threat to life, health or safety” extending to “third-degree relatives” is required to override the patient’s denial of consent. The NHMRC guidelines even encourage not disclosing that the original genetic testing occurred, piling dishonesty upon breach of faith. The widened loophole creates an elastic legal excuse for the well meaning (but impatient) to breach individuals’ privacy. This disavowal of patient confidentiality at a doctor’s sole discretion has the net effect of allowing one individual’s subjective, value-laden judgement, triggered by any remote threat to health or welfare, to override a patient’s refusal of consent. Inevitably, unintended perverse outcomes should be expected — bringing to mind the legal maxim “hard cases make bad law”. In practice, this loophole will encourage the taking of the lazy path of legal coercion rather than gradual persuasion and ultimate acceptance of a patient’s decision. If forced disclosure is really required, such a momentous breach of a patient’s expressed wishes in the absence of genuine life-threatening circumstances should require approval from an independent legal tribunal, a standard well established for surgery on children whose parents refuse consent, or for sterilisation operations or other major elective procedures for those unable to consent. Both these legislative assaults on privacy reflect the fashionable belief in genetic determinism prevailing over any ethical, moral and legal constraints of everyday life. But ditching the trusted confidentiality of medical information for doctors’ convenience or to satisfy lobby groups permits arbitrary and damaging intrusion on personal liberty — the price of which remains eternal vigilance.

David J Handelsman MB BS, FRACP, PhD · Leo A Turner RN, MSc Med · Ann J Conway MB BS, FRACP

Chronic heart failure (CHF) is a complex and lethal clinical syndrome accounting for an increasing number of Australian hospital separations and more than 2700 Australian deaths in 2008. In 2006, the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand published Guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006. Results from recently published clinical trials provide additional information to be considered in the prevention, detection and management of CHF. In some cases, this new evidence strengthens recommendations previously made in the 2006 guidelines; in others, it provides new approaches to current recommended practice. Areas in which there have been significant new developments include: Use of B-type natriuretic peptide (BNP) or N-terminal proBNP plasma level measurement in guiding treatment of CHF New pharmacological approaches to the treatment of systolic heart failure Drugs to avoid or use with caution in CHF Treatment of cardiac arrhythmias in patients with CHF Multidisciplinary care and post-discharge management programs. While patient circumstances and clinical judgement should guide the interpretation of these findings in the clinical context, this update, together with the 2006 guidelines, provides current clinical guidance on CHF.

Henry Krum PhD, FRACP, FCSANZ · Michael V Jelinek MD, FRACP, FCSANZ · Simon Stewart PhD, FAHA, FCSANZ · Andrew Sindone MD, FRACP, FCSANZ · John J Atherton PhD, FRACP, FCSANZ

From public health pariah to pin-up bunny? Chocolate manufacturers around the world know that the Easter bunny (EB) is highly effective at enticing us to eat chocolate. Up to 28% of one manufacturer’s yearly chocolate sales occur in the lead up to Easter.1 Another company produces about 500 million of one particular Easter egg variety — the United Kingdom’s most sold Easter confectionery.2 The EB has been popularised and exploited by chocolate manufacturers and other companies selling this energy-dense, nutrient-poor (EDNP) food. Since when did bunnies lay eggs made of chocolate? Is this a conspiracy to sell lucrative chocolate eggs? I have argued that Santa Claus is a public health pariah who advertises unhealthy products to children and normalises obesity,3 but what about the EB — is this bunny an innocent fairytale character4 or another unhealthy childhood role model? Eggs, rabbits, Easter and chocolateFor millennia, eggs were gifts to celebrate the coming of spring, while rabbits and hares represented fertility and new life after winter.5 With the commercialisation of Easter in the 20th century, chocolate Easter eggs grew in popularity and, through some excellent marketing, chocolate manufacturers bred a chocolate-egg-bearing rabbit. Then, in a move that would have made Willy Wonka proud, they made Easter bunnies of chocolate (Box 1) and sold both the bunny and the eggs!5 EDNP foods, obesity and chronic diseaseAlthough the EB’s delivery practices may provide a better role model than Santa’s, with its vigorous round-the-world hopping sustained only by carrots, the EB may have a more direct impact on obesity by promoting and distributing EDNP food. Excess chocolate has been linked to dental caries and obesity, and obesity has been linked to a significantly higher risk of type 2 diabetes,6,7 hypertension,8 gall bladder disease,9 liver disease,10 and heart disease and stroke,11 and to a small increased risk of cancer (breast, colorectal and endometrial cancers).12,13 Chocoholics and EDNP food companies quote studies showing that cocoa polyphenols protect against cardiovascular disease (CVD).14 However, such studies do not adequately account for confounders, such as comorbidities, or the effect on those with existing CVD who are advised to avoid EDNP food. Also ignored is the fact that most Easter eggs have only a small proportion of cocoa solids and high levels of hydrogenated vegetable oil (trans fats). The negative health effects of chocolate are minimal when it is consumed sensibly, but at Easter this seems to be rare.1,2 Marketing, exploitation, children and advertisingIn the same way that Santa was a feature of Coca-Cola advertising,15 the EB’s role is to sell chocolate eggs to children. This is not the first time that iconic childhood figures have been used successfully to market products to children and create associations between a product and happy times.16,17 Fictional characters such as Ronald McDonald have become more familiar to children in the United States than the American President or the Pope.17 International reviews have found that heavy marketing of EDNP food, high in salt, sugar and fat, is likely to have deleterious effects on children’s diet.18 According to the World Health Organization, such advertising contributes to children being overweight and obese and is an important area for preventive action.19 Given that the EB’s marketing may influence hundreds of millions of children, chocolate intake only needs to increase in one in 10 000 children to have a deleterious effect on the health of millions of children. In Australia, the National Preventative Health Taskforce recommends phasing out “premium offers, toys, competitions and the use of promotional characters, including celebrities and cartoon characters, used to market EDNP food and beverages to children”.13 Similar regulation is occurring in the UK, the US, Canada, Norway and Sweden.20-22 In Sweden and Norway and the Canadian province of Quebec, there are extensive legislative prohibitions on advertising to children. These commercial advertising laws might mean the end of the EB in advertising; after all, wherever the EB hops, it is advertising to children. As a “promotional character”, will the EB be phased out in Australia? Adults, childhood memories and learned behaviourSome ground-breaking research has shown that belief in the EB decreases with age,4 but the public health implications do not — much of the chocolate consumed at Easter is in fact consumed by adults.23 Having been conditioned as children to associate the EB and chocolate with happy memories of Easter, adults (over)consume chocolate at Easter as they relive these happy feelings and memories. Conceivably, the positive psychological effects of low doses of Easter chocolate consumption might outweigh the negative ill health effects, but at higher doses of sugar and fat, the marginal benefit decreases and is eventually negated. The EB promotes high-dose chocolate overindulgence by children at Easter, a habit which then becomes normalised behaviour for many adults. Easter egg hunts, violence, injury and chokingAt Easter, egg hunts are common, as children search for eggs hidden by the EB. Conceivably, these might encourage healthy physical activity: children can run very fast when chocolate Easter eggs are awaiting discovery. Simple modelling, however, debunks this theory (Box 2). Assuming the average child finds, and then consumes, fourteen 10 g eggs and one 125 g egg (5819.9 kJ), a basic energy expenditure formula suggests that a 338-minute (5.6-hour) Easter egg hunt is required to burn off the kilojoules gained from the eggs consumed.25 Not only do Easter egg hunts promote an unhealthy energy balance, they may also contribute to the burden of injury in children (with injury being the most significant cause of mortality in 1–18-year-olds).26 Given that sharing chocolate eggs is not instinctive for young children, Easter egg hunts have the potential to cause emotional distress and interpersonal violence. We have probably all witnessed, or been involved in, a fight over the EB’s treats. Furthermore, the stimulant effect of the caffeine and theobromine compounds in chocolate may accentuate this risk. Admittedly, children taking part in Easter egg hunts do not normally sustain serious injury, but, as eminent epidemiologist Geoffrey Rose detailed in his seminal work The strategy of preventive medicine, when a rare risk is widespread, the impact can be large.27 For example, suppose that the Easter egg hunt injury rate is one in 10 000 participating children (ie, a very low risk); if, on Easter Sunday in the US, 30 million children participate in hunts, then more than 3000 children would be injured! Another danger is choking. One could scarcely design a more perfect choking hazard: small, colourful, foil-wrapped chocolates marketed specifically to our most vulnerable consumers (Box 3). Given the EB’s potential to promote this kind of injurious behaviour, I consulted surveillance sources for injuries related to “Easter bunny” or “Easter eggs”. The codes in the Victorian Emergency Minimum Dataset related to choking are: “Foreign object obstructing airway” (W44) and “Inhalation and ingestion of food causing obstruction of respiratory tract” (W79),28 but there is no category permitting analysis of choking related to Easter eggs. Perhaps W79 should be further differentiated into “Inhalation and ingestion of Easter egg causing obstruction of respiratory tract”. Easter, chocolate and international public healthThe EB, like Santa, has an international profile as an export item to the developing world. The potential for the EB to be misused may be even greater in countries where advertising is less regulated. For example, Easter is celebrated in countries such as India, where Good Friday and Easter Monday are national holidays.29 Just as Coca-Cola and Santa have colonised the developing world, the EB is sure to follow. How can we make the EB the pin-up bunny of public health?Although bordering on the ridiculous, my article highlights the fact that, due to its popular acclaim, the EB, like Santa, can be used to promote unhealthy behaviour. Giant multinational food and beverage companies realised long ago that celebrities, like the EB, sell commodities, including unhealthy ones, and children are a particular target. We could change this by: Minimising the harmful effectsEducating parents to protect their children from the deleterious effects of belief in the EB. Ferreting out the EB is not the “nanny state” imposing health behaviour on our community; it is protecting children from “nanny parents” imposing an unhealthy EB belief on their children.4 Children are generally very happy with themselves for having worked out that their parents are deluded in this belief. They always knew Easter was all about chocolate and not the EB anyway. Instituting better surveillance so we can measure the EB’s impact on public health (eg, include “EB-related deaths” in the WHO’s standardised documentation).30 Restraining EDNP companies from employing the EB as their chief marketing consultant to sell unhealthy food to children, perhaps through employment conditions such as a levy on the EB’s advertising activities (consistent with the recently recommended levy on advertising of EDNP food and alcohol31). Changing the EB’s imageGiven the EB’s potential for good, it could become a public health pin-up bunny, supporting campaigns that encourage children to eat the recommended daily five servings of vegetables and two servings of fruit. Chocolate egg hunts could become brussels sprout hunts! After all, the EB itself would advocate for this change, given that bunnies do not digest chocolate particularly well. 1 Would you trust this bunny? 2 Easter egg hunts — hunting time needed to burn off chocolate eggs consumed No. of 10 g Easter eggs Chocolate (g) Energy (kJ) consumed Running time required (min) 5 50 1098.3 63 10* 100 2196.6 127 15 150 3294.9 190 20 200 4393.2 255 25 250 5491.5 318 30 300 6589.8 381 * The average Australian consumes 10 Easter eggs.24 3 A perfect choking hazard

Nathan J Grills DPhil(Oxon), MPH, MB BS

Multidose vials (MDVs) for injectable therapeutic agents, including vaccines, pose a risk of infection to injected patients as a result of contamination of the vials. The Australian Government Department of Health and Ageing (DoHA) distributed the vaccine against pandemic (H1N1) 2009 influenza in MDVs. The distribution was accompanied by consent forms. The consent forms provided an inadequate basis for a discussion with patients about the risks associated with the use of MDVs. The High Court of Australia has previously held that medical practitioners who fail to explain the material risks of medical procedures to their patients might be held liable in negligence for any adverse sequelae of the procedures, even if the risks are very low. Medical practitioners, nurses, medical indemnity insurers and the DoHA should prepare now for the probable future use of MDVs by developing a consent form that would provide a solid foundation for a discussion of material risks with patients seeking vaccination.

Mark R Diamond PhD · Angela O’Brien-Malone PhD

War wounds: medicine and the trauma of conflict. Ashley Ekins and Elizabeth Stewart, editors. Wollombi: Exisle Publishing, 2011 (240 pp, $49.99). ISBN 9781921497872. ORIGINALLY presented at an international conference by the Australian War Memorial (AWM) and the Department of Veterans’ Affairs in September 2009, this book is edited by two military historians at the AWM. It is well illustrated and contains 14 chapters covering both World Wars and the Korea and Vietnam conflicts, written predominantly by Australian historians and military medical and nursing personnel. There are four chapters on World War I. American historian Jay Winter expounds on shell shock syndrome. Ashley Ekins, head of the Military History Section at the AWM, discusses self-inflicted wounds. Kerry Neale, from the Australian Defence Force Academy (ADFA), provides an excellent narrative on the facially disfigured soldier. Melbourne historian Marina Larsson takes a sensitive look at the psychiatrically impaired veteran. There are similar contributions on World War II. Paul Weindling, a professor in the history of medicine at Oxford Brookes University in the United Kingdom, describes the “medical” experiments at Ravensbrück concentration camp. Debbie Lackerstein, a lecturer in history at ADFA, writes of the overwhelmed Allied forces’ medical response to survivors of concentration camps. Professor Simon Gandevia, deputy director of the Prince of Wales Medical Research Institute in Sydney, gives an account of his father’s service in Korea and his contribution to medical history. The essays on the Vietnam War cover a regimental medical officer’s experience in managing sexually transmitted infections, the work of the Australian civilian surgical teams, and Agent Orange. The book concludes with three personal accounts: Tony White on the nightmare of treating injured soldiers in a minefield; nurse Sharon Cooper on medical recovery after a helicopter crash in Timor-Leste; and Graham Edwards on how, after sustaining double lower limb amputations, he overcame severe disability to enter federal Parliament. I recommend this book to those working in military medicine, to military medical historians, to present and past serving members and their families, and to the enquiring general reader.

Bruce H Short

Breast cancer: taking control. John Boyages. Sydney: Boycare Publishing, 2010. (367 pp, $39.99). ISBN 978098063111. RIGHT FROM when you first pick up this book, it captures your attention — starting with a cover that pictures a delightful old tree supporting a woman gazing into the distance. The author, Professor John Boyages, an oncologist with nearly 30 years’ experience treating the disease, uses a gardening analogy to introduce a very tough subject. His aim is to enable patients and their families to understand the experience of having a diagnosis of breast cancer and to take control of its management. Key information is explained in a direct and easy manner that addresses the anxiety and shock experienced in this situation. Boyages takes the reader through the different parts of “the garden” and the decisions that need to be made for gaining the best outcomes. He continues to use the gardening metaphor to describe medical pathology and techniques, thus simplifying information that could otherwise be overwhelming. The book has a practical design. Its 20 “control points”, or important steps or decisions, are divided into three parts according to the phases of treatment, and I felt like I was referring to a trusty roadmap or GPS (global positioning system) that would help me to reach my destination safely. Colour coding the key control points as “red for stop”, “amber for caution” and “green for proceed with care” makes it easier for readers to understand the treatment options and decision-making process. The use of real-life stories enables the reader to relate to these experiences. All the explanations are evidence-based and well referenced, to help patients make informed choices. Although this book is primarily for women and men diagnosed with breast cancer, and their families and friends, it is also a valuable resource for health professionals. It is well illustrated and includes over 75 web links, 20 flowcharts and 96 figures, which make it an easy read. I would recommend it to anyone involved with breast cancer or interested in learning more about it.

Elaine Arnold

With the expansion of the Second World War into the Pacific in 1941, and due to the deleterious impact of malarial infection on fighting capacity, the Australian Army devoted significant resources to new research into the prevention and treatment of malaria between 1943 and 1945 by forming the Land Headquarters Medical Research Unit in Cairns, Queensland. The documentation of this research became a significant subject for leading Australian artist Nora Heysen, when she was commissioned as the first female war artist by the Australian War Memorial in 1943.

Cherie L Prosser BSc, MA(Art History) · Ian A Clark BVSc, PhD, DSc

Visual field defects typically caused by lesions in the optic nerve or optic chiasm may be caused indirectly by subdural haematomas. A 61-year-old man survived transtentorial herniation caused by subdural haematomas that resulted from shaking his head in an attempt to remove a cockroach impacted in his external auditory canal. Bilateral incomplete posterior cerebral artery infarction of both inferior tips of the occipital lobe resulted in bilateral superior quadrantanopia. There are no previous reports of tentorial herniation causing this permanent outcome. (MJA 2011; 194: 420-422) Clinical recordA 61-year-old man presented to the emergency department with a 3-day history of worsening headache and drowsiness. He had a past medical history of renal calculi and gout and was not taking any regular medication. He had a history of consuming 5–6 standard units of alcohol per day, but no antecedent falls or head injury were reported. On physical examination, his Glasgow Coma Scale (GCS) score was 15/15 and his vital signs were normal, apart from mild hypertension (154/80 mmHg). His right pupil measured 4 mm, and his left pupil, 3 mm. His reflexes were documented as brisk in the upper limbs. Results of liver and coagulation studies were normal. A cerebral computed tomography (CT) scan showed large bilateral frontoparietal subdural haematomas (Box 1, A). The right-sided haematoma had mixed hyperdense and isodense areas suggestive of acute on subacute bleeding, while the left frontal haematoma was isodense. The CT scan also showed marked mass effect (Box 1, B) and early tentorial herniation of the uncus (Box 1, C) without tonsillar descent. There was a delay of 8 hours, including transfer of the patient to a neurosurgery centre, before surgery. The patient’s medical notes showed that before undergoing surgery he had developed bilateral extensor Babinski responses and had a GCS score of 14/15. One hour before the operation, the nursing records indicated “GCS 13/15, patient too drowsy and disoriented to consent [to surgery]”. No further imaging was undertaken and no further notes were made before surgery. The patient made an uneventful recovery after bilateral craniotomy and drainage. A CT scan of the brain on discharge about a week later confirmed evacuation of the haematomas and normalisation of brain position. During routine follow-up 10 weeks later, the patient reported persistent difficulty with reading since the operation and that he was experiencing problems differentiating colours. His visual acuity was found to be 6/5 in the right eye and 6/18 in the left, with symptoms of defective colour vision (3/14 Ishihara plates correctly identified with the right eye, and 4/14 with the left). A minor cataract was found in his left eye, but there was no other intraocular abnormality in either eye. His optic discs appeared healthy without pallor in both eyes (and remained so on further follow-up several years later). Computerised visual field perimetry testing conducted at 10 weeks showed bilateral superior altitudinal defects (Box 2). Routine visual evoked potentials showed normal latencies. However, multifocal visual evoked potentials showed normal latencies with decreased amplitude in superior fields bilaterally. Magnetic resonance imaging (MRI) of the brain and orbits conducted 6 months after the surgery showed chronic infarction involving the inferior tip of both occipital lobes medially, more marked on the right side (Box 1, D and E). There was evidence of residual blood products from the evacuated bilateral subdural haematomas, with no evidence of new bleeding. There was no abnormality of the optic nerves or optic chiasm, and venous drainage on magnetic resonance venography was normal. Upon further questioning at this time, a reason for the apparent spontaneous subdural haematomas became evident. The patient described an incident 7 weeks before admission when he awoke with an insect inside his ear. Despite, in his words, “shaking my head from side to side and banging on the side of my head with my fist”, the patient was not able to get the insect out. He was seen at the emergency department, where his ear was syringed and, eventually, a German cockroach (Blatella germanica) was removed with further shaking of the head (which was documented in the hospital records). He recalled a marked headache for the next 2 weeks, which gradually subsided. Recurrence of the headache 5 weeks later prompted him to present to the emergency department again, and the subdural haematomas were detected. DiscussionThis is an unusual and to the best of our knowledge a novel case of bilateral visual field defects related to earlier impaction of a cockroach in the external auditory canal. Subdural haematoma is an uncommon cause of bilateral homonymous hemianopia.1 It can occur as the result of direct local injury to the occipital lobes, or alternatively, mass effect from subdural haematoma can result in tentorial herniation, potentially compromising the blood supply of the posterior cerebral artery (PCA) and placing the regions it supplies at risk. Visual field defects as a consequence of this indirect effect of subdural haematoma have been reported in some surviving patients, but posterior cerebral infarction is more commonly recognised in postmortem examinations of the brain.2-4 Altitudinal visual field defects are typically due to optic nerve lesions and are usually unilateral. Theoretically, the minimal lesion required to produce a bilateral superior quadrantanopia is one located in the inferior optic chiasm; however, this occurs rarely. Typically, injury causes splaying of the chiasm, which is more commonly associated with bitemporal hemianopia. Transtentorial herniation is a well recognised cause of uncal and brainstem displacement and third cranial nerve palsy, but it can also cause stretching and compression of the PCA — thereby compromising the blood supply and leading to infarction.4,5 Survival from tentorial herniation with residual bilateral homonymous hemianopia has been occasionally reported in the literature.6-9 To date, there is no documentation of it causing bilateral superior quadrantanopia. The regions of the brain at risk secondary to PCA ischaemia or infarction are the inferior and medial temporal and occipital cortices. The actual area of involvement depends on which tributaries (and distributions) are affected. The calcarine branch of the medial occipital artery, which supplies the medial occipital lobe, is most commonly involved.10,11 In our patient, there was evidence of mass effect and tentorial herniation secondary to the enlarging subdural haematoma. This would have placed the PCA blood supply at risk. The MRI findings of bilateral infarction of the inferior tip of the medial occipital lobe, together with field test findings of bilateral superior altitudinal defects, confirm the involvement of the visual cortex, which is topographically organised with the cortical representation of the superior field localised inferiorly.5,12 The affected region corresponds to the striate cortex and most posterior part of the prestriate cortex. Both areas are involved in aspects of colour visual processing, suggesting an explanation for the patient’s defective colour vision despite a normal optic chiasm and optic nerves, although a congenital cause cannot be excluded.13 The patient’s history of daily alcohol consumption may have predisposed him to bleeding tendencies and subdural haematomas, although results of his liver and coagulation studies were normal. A diagnosis of acute on subacute subdural haematoma fits well with the timing of the patient’s violent attempts to remove a foreign body from his ear about 7 weeks previously, and with subsequent delayed re-bleeding and increasing supratentorial pressure resulting in uncal herniation and infarction of the part of the primary visual cortex known to correlate with the superior visual fields. A preferred method of removing a cockroach from the ear canal is to drown it with non-toxic vegetable or mineral oil so it can then be easily extracted with forceps. Cautious suction can also be used, taking care not to cause barotrauma by occluding the canal. Lignocaine 2% also rapidly kills the insect or results in it leaving the canal, but entry of lignocaine through any perforation into the middle ear can produce severe sustained vertigo with nystagmus for some hours.14-17 1 Initial computed tomography scan of the brain (A–C), and magnetic resonance images 6 months later (D, E) A: Isodense subdural haematomas (arrows) extending over the convexities longitudinally with effacement of sulci. B: Right hyperdense frontal acute component of a subdural haematoma (arrows) consistent with delayed re-bleeding. C: Uncal herniation, particularly on the left (arrow). D, E: Sagittal fluid-attenuated inversion-recovery magnetic resonance image 6 months later, left and right of midline, respectively (arrows), showing inferior occipital pole infarction. 2 Computerised visual field perimetry of the right eye (A) and left eye (B) The left superior and right superior visual fields are abnormal for both eyes (black areas). The left superior quadrant is slightly worse for both eyes, suggesting this is homonymous and that the lesion is posterior to the chiasm. We describe this as a bilateral superior quadrantanopia rather than a hemianopia to distinguish this circumstance from the normally lateral hemianopias, and because the lesion required to cause this finding is bilateral.

Wan Yi Ng BBus, MB BS · Brian E Chua MB BS, BSc, MPH · Todd A Hardy MB BS, PhD · David Wechsler MB BS · Stephen W Reddel MB BS, PhD

Clinical record A 33-year-old woman was admitted to our service for investigation and management of acute hepatitis. She reported symptoms of nausea, fatigue, pruritus and right upper abdominal discomfort. The symptoms had first occurred 3 weeks earlier, resolving over 5 days, then recurred 2–3 days before presentation. The symptoms were temporally related to varicose vein sclerosing procedures, of which she had had three in total. The first procedure occurred 4 weeks before admission, with no subsequent side effects. It was after the second procedure, 1 week later, that symptoms first developed. The final procedure occurred a week before admission. During each procedure, the patient was given methoxyflurane as an inhaled analgesic administered from a 3 mL disposable cartridge. Other medications administered during the procedures were the sclerosing agent sodium tetradecyl sulfate and fexofenadine. There was no history of exposure to alcohol or to other prescription or over-the-counter medications. The patient had no risk factors for viral hepatitis, and there was no history of hepatitis or liver disease in her family. Clinical examination revealed jaundice and mild tender hepatomegaly only. Initial investigations showed hepatic enzymosis, with an elevated alanine transaminase level (2710 U/L [reference range, < 34 U/L]) and hyperbilirubinaemia (bilirubin 92 μmol/L [reference range, < 20 μmol/L]). Markers of liver synthetic function (albumin and prothrombin time) were within normal limits, as were full blood counts, electrolyte levels and renal function. Abdominal ultrasound demonstrated a normal-sized spleen and mild hepatomegaly, with an increased liver echotexture. Doppler sonography of the portal vein was normal. Serological tests for hepatitis A, B and C, Epstein–Barr virus, cytomegalovirus and HIV were negative. Iron and copper studies and levels of α-1-antitrypsin, antinuclear antibodies, antimitochondrial antibodies, anti-liver/kidney microsomal antibodies, anti-smooth-muscle antibodies and antinuclear cytoplasmic antibodies were all normal. Paracetamol was undetectable. Bilirubin levels continued to rise over the following 8 days (peaking at 202 μmol/L), although liver synthetic function remained normal throughout this time. A liver biopsy revealed evidence of resolving acute hepatitis with confluent perivenular hepatocyte dropout and bridging necrosis. There was no evidence of cholestasis or underlying fibrosis. The pathological diagnosis was of an idiosyncratic drug reaction, with the implicated drug being methoxyflurane. The patient’s condition continued to improve, with resolution of symptoms over 4 weeks and associated normalisation of liver enzyme and bilirubin levels. She has since remained well, and has been advised to avoid future exposure to methoxyflurane. Methoxyflurane, a short-chain halogenated ether, is a volatile anaesthetic agent. It was used for inhalational anaesthesia in the 1960s, but was withdrawn from use for this purpose when newer anaesthetic agents with more acceptable side effects became available.1,2 Methoxyflurane also has significant analgesic properties at subanaesthetic concentrations,3 and is thought to have minimal side effects in analgesic doses.4 These properties led to its adoption for use as an analgesic in a variety of settings for over 40 years.4 It is widely used by paramedic services in Australia,5 and has recently been studied for use in procedural analgesia in children and adults.4-6 It is provided in single-dose, pre-filled delivery devices (Penthrox, Medical Developments International, Melbourne, Vic), allowing accurate dosing and convenient delivery. In 2010, Penthrox was added to the Australian Schedule of Pharmaceutical Benefits as an item available free of charge for doctors’ bags. Although subanaesthetic doses of methoxyflurane (in the form of Penthrox) are used widely in Australia by ambulance services for prehospital analgesia, there is a paucity of data on its efficacy and safety. A recent observational case series and a review article found no significant side effects associated with its use for this purpose.4,5 Over three million inhalers have been dispensed in Australia since 1970,4 with the majority of doses administered for single-episode analgesia. Lessons from practice Taking a history of all medication exposures is important in assessing acute hepatitis. Repeated exposure to methoxyflurane may increase the risk of acute hepatitis. Reporting of suspected adverse drug reactions, such as this case, are important to raise awareness of possible rare side effects of commonly used medications. Hepatotoxicity resulting from the use of methoxyflurane as an inhalation agent in general anaesthesia is well described.1-3 However, hepatotoxicity associated with low doses of methoxyflurane for analgesic purposes appears to be rare. Three cases of hepatitis complicating methoxyflurane use (at subanaesthetic doses) during labour have been reported.7,8 In another case report, repeated exposure in the form of misuse of methoxyflurane was found to be associated with hepatotoxicity.9 The mechanisms of methoxyflurane-induced hepatotoxicity are unclear and may be multiple. Adverse effects of halogenated ethers are thought to be related to immune-mediated, direct toxic effects of metabolites and/or host idiosyncrasy.1 Reactive intermediates formed during metabolism of methoxyflurane can lead to tissue acetylation, with proteins modified by acetylation forming neoantigens that may trigger an immune response.1 Drug re-exposure has also been implicated as a factor contributing to methoxyflurane-induced hepatitis.2 Although unproven, it is possible that our patient’s repeated exposure to the drug may have contributed to the development of hepatitis through dose-dependent toxicity. In the prehospital setting, where methoxyflurane is being widely used, the side effect profile is minimal.5 It seems the exposure to methoxyflurane in our patient was the likely cause of acute hepatitis, and it may be that repeated exposure was a contributing factor. This observation has implications for the way methoxyflurane is prescribed, including its use for procedural analgesia in cases in which several procedures (and hence, repeated dosing) are required.

Kacey M O’Rourke BAppSc, MB BS · Stuart McMaster MB ChB, FRACGP · Karin M C Lust MB BS, FRACP

A 55-year-old woman, who had undergone a total hysterectomy decades previously, presented with lower abdominal fullness and urinary frequency. An abdominal–pelvic contrast-enhanced computed tomography scan (Box) showed a large cystic lesion measuring 20 × 17 × 15 cm, with a smaller “daughter” cyst, a compressed urinary bladder and bilateral hydronephrosis. The patient subsequently had an ovarian cystic tumour weighing 1822 g removed, and had an uneventful postoperative course. The tumour contained serous fluid, which established the diagnosis of serous borderline ovarian tumour (SBOT). An SBOT manifesting as such a large cyst that mimics neurogenic bladder is rare.1 In general, conservative, fertility-sparing surgery is recommended for its promising outcomes.2 Computed tomography scan showing an ovarian cyst (white arrows) with a daughter cyst (white arrowhead) and a compressed urinary bladder (yellow arrowhead)

Chih-Chung Shiao · Pi-Jen Hong · Shu-Chinh Chao · Jsun-Liang Kao

Robert Desmond Marshall was born in Nhill, Victoria, on 3 May 1926, one of five siblings who all became involved in medicine (Betty, a general practitioner, Gwen, a physiotherapist, and surgeons Vernon and Donald). After a brilliant student career at the University of Melbourne, he graduated in 1948 and trained at Royal Melbourne Hospital. Bob lectured in anatomy at the University of Melbourne from 1951 until 1953, when he returned to Royal Melbourne Hospital. In 1955, he gained Fellowship of the Royal Australasian College of Surgeons (RACS) and received his Master of Surgery from the University of Melbourne. After working in London at Hammersmith Hospital in 1955 and 1956, Bob returned to Australia to assist Sir Edward “Weary” Dunlop at Royal Melbourne Hospital. From 1963 to 1991, he was a consultant surgeon at Prince Henry’s Hospital. He then continued his private practice until the last year of his life. Bob also served on the Victorian Branch Council of the Australian Medical Association, the Victorian Regional Committee of the RACS, and as Chairman of the Combined Chairmen of Senior Medical Staff Associations. Bob cowrote Principles of pathology in surgery (Oxford: Blackwell Scientific, 1980), and his consummate knowledge of anatomy culminated in the publication of his seminal book Living anatomy: structure as the mirror of function (Melbourne: Melbourne University Press, 2001). This led to him being awarded Doctor of Medicine from the University of Melbourne in 2006, the oldest graduate to earn this qualification. To honour the contributions to surgery of Bob and his brothers Vernon and Donald, Monash University established the Marshall Prize in Surgical Training in 2001. Bob was an excellent, hardworking surgeon, astute clinician and a generous teacher, mentor and friend. But he also found time for his great passions — skiing and trekking in the mountains. In 2009, he wrote K2: lies and treachery, an account of the controversy surrounding the 1954 ascent of K2 by Italian mountaineer Walter Bonatti. Bob presented Bonatti’s case in fluent Italian to the Italian Alpine Club to officially restore the climber’s reputation in 2007. It was a measure of Bob’s search for truth and honesty. Bob Marshall died on 29 January 2011. He is survived by his wife Phyllis and five children Diane, David, Robert, Andrew and Lisa. Our world will be less interesting without him.

Kenneth A Myers

Ronald Nicolson O’Reilly was born on 18 January 1921 in Winton, Queensland. Raised in Winton and Barcaldine, he went to Brisbane Boys’ College, and then studied medicine at the University of Queensland, graduating in 1945. Ron completed his residency at Brisbane General Hospital and established a general practice in suburban Chermside. He soon realised that his vocation was with children, and undertook training in paediatrics at the Royal Children’s Hospital in Melbourne. He was very highly regarded in Melbourne as a clinician and researcher, but in 1957, Ron returned to Brisbane, where he worked as a physician and then Deputy Medical Superintendent at the Royal Children’s Hospital. In 1961, he received his doctorate from the University of Melbourne for his thesis on bronchiectasis. In 1962, Ron was appointed Senior Visiting Paediatrician at the Royal Children’s Hospital, where he remained until mandatory retirement at age 60 in 1981. He also entered private practice on Wickham Terrace, which he continued until he was in his seventies. In 1975, Ron became a Member of the Royal Australasian College of Physicians and, in 1978, a Fellow. Ron was an outstanding teacher and clinician, and he cared for many doctors’ children — an expression of the respect held for him. He served on the boards of the Asthma Foundation of Queensland, Montrose Home for Crippled Children, Xavier Home, Tufnell Home, and St Helen’s Hospital as it evolved into the Wesley Hospital. Ron retired from practice in 1994 to live on Bribie Island, where he became very active in the Bribie Island Environmental Protection Association. His wife Elva, who had been a great support in his work, predeceased him by 22 years. Ron died on 13 September 2010, soon after suffering a massive stroke. He is survived by his son Graham, daughter Annise, and several grandchildren who appreciated his wise and gentle counsel. For those of us who came under his influence, memories of an excellent clinician and stimulating teacher will endure. He did not seek honours or awards but deserved many.

D Barry Appleton

To the Editor: A middle-aged male night-shift driver experienced dizziness, vomiting, sudden onset of limb weakness, and then collapsed and became delirious. He had no past history of renal impairment or hypertension. At presentation in an emergency department, he was hypertensive (blood pressure, 220/140 mmHg) and hyperglycaemic. An upper motor neurone pattern of persistent dysarthria and left hemiparesis was evident. An electrocardiograph and transthoracic echocardiogram confirmed sinus rhythm and left ventricular hypertrophy. Magnetic resonance angiography of the brain showed subacute basal ganglia haemorrhage (Box) and an anterior communicating artery aneurysm. Renin levels were elevated at 124.7 mU/L (reference range, 4.5–46.0 mU/L) but renal artery stenosis was absent on ultrasound. Evaluation of an elevated initial normetadrenaline level of 1610 pmol/L (reference range, < 900 pmol/L) with a diagnostic algorithm1 suggested that phaeochromocytoma was unlikely. Hypertension, proteinuria, suboptimal renal function, inactive urine sediment and normal fasting blood glucose suggested hypertensive nephropathy. Antihypertensives were initiated to mitigate the risk of further stroke, nephropathy and cardiomyopathy. Results of an electroencephalogram were normal. Further history revealed that the patient had nicotine dependence with occasional amphetamine and cannabis exposure. Before admission, he had an estimated intake of 1–2.5 bottles of cough mixture episodically (600–1500 mg of pseudoephedrine). A pattern of ingesting excessive amounts of various brands of over-the-counter combination pseudoephedrine and codeine cough mixture developed over 20 years, and he suffered cravings when abstaining. He visited various pharmacies, provided identification, was repeatedly cautioned, but rarely consulted doctors. A Naranjo score2 of 7 indicated a probable adverse drug reaction to pseudoephedrine, resulting in a disabling hypertensive haemorrhagic stroke. During 2.5 months of inpatient rehabilitation, he regained full independence in self-care and mobility. His unstable employment was interdependent with pseudoephedrine misuse. He accepted counselling regarding constructive, non-pharmacological coping strategies for social stressors. Financial, legal and housing difficulties complicated his discharge plan. He planned to return to work as a driver. Pseudoephedrine is associated with a modest elevation in blood pressure3 and hypertensive crises.4 Intracerebral haemorrhage associated with pseudoephedrine usage is anecdotally reported.5 Dependence and chronic psychoses have been reported6,7 but their prevalence is unknown. Night-shift workers, students, recreational or self-medicating users, and athletes are potentially vulnerable to misuse. Project STOP is an initiative of the Pharmacy Guild of Australia (http://www.projectstop.com.au/index.html) to curb diversion of pseudoephedrine-containing medications from retail pharmacies into illegal amphetamines. However, it is not mandatory and the National Drugs and Poisons Schedule Committee has rejected the Pharmacy Guild’s proposal to enhance Project STOP’s capabilities using an electronic messaging tool for pharmacists (NotifyRx, RelayHealth, Atlanta, Ga, USA) to regulate codeine sales (excluding cough mixtures). In contrast, New Zealand authorities now restrict the supply of pseudoephedrine to prescription only. A concerted effort from all relevant parties, including tighter regulation or legislation, is essential for harm minimisation. We urge regulatory bodies to review the effectiveness of current practice. Magnetic resonance angiogram of the patient’s brain showing likely hypertensive right basal ganglia haemorrhage

Ajay Bharatula · Peter W New

To the Editor: Laparoscopic adjustable gastric banding (LAGB) is the most common bariatric surgery performed in Australia, and diabetic patients represent an important target population.1 In one of few trials in type 2 diabetes, 73% of 30 LAGB-treated obese patients reverted to normal glucose tolerance by 2 years, compared with 13% of 30 obese patients randomly assigned to treatment with changes to their lifestyle.2 These Australian data precipitated publicity implying that many people with type 2 diabetes were cured by LAGB.3,4 However, only recently diagnosed patients were recruited. The benefits of LAGB in those with diabetes of long duration (and usually with a substantial loss of pancreatic beta-cell function5) may not be as dramatic. We reviewed the records of eight patients with insulin-treated type 2 diabetes (aged 40–65 years, with a diabetes duration of 4–39 years) referred for LAGB by one of us (T D) to two established bariatric surgical units over 4 years. All eight patients had a diabetes-specific review within 2 months of surgery and at 3 and 6 months postoperatively, and six patients had a further review at 12 months. Perioperative diabetes management was coordinated by the anaesthetist and ward staff, but patients were encouraged to contact their doctor or regional diabetes education unit for advice at any time if necessary. Patients attended the bariatric unit for saline insertion into the band once or twice before their diabetes-specific review at 3 months. No patients developed postoperative complications. The median weight loss was 14% at 6 months and 20% at 12 months (Box). By 3 months, insulin doses had been reduced in all patients and two had stopped using insulin. However, most had increased their insulin doses at 6 months (and the two who had discontinued insulin started using it again) because of unsatisfactory glycaemic control. During the 12 months’ follow-up, only one patient stopped using insulin and remained without its use without an unacceptable glycated haemoglobin (HbA1c) increase. Although our eight patients achieved the same median percentage weight loss at 1 year as trial patients with diabetes of relatively short duration achieved over 2 years,2 insulin use was still required in most cases. When asked, the patients suggested that inappropriate initial insulin reductions were not because they experienced hypoglycaemia, but rather because they expected substantial LAGB-associated metabolic improvement. Perhaps this was encouraged by media coverage3,4 and/or concerns of bariatric unit staff that continuing their insulin therapy might retard their LAGB-associated weight loss. In some cases, problems with insulin adjustment and glycaemia overshadowed the psychological benefits of progressive weight loss. These preliminary observations suggest a need for more data on diabetes management after LAGB, to inform acute treatment modification and to provide a realistic idea of the effects of LAGB on longer term disease outcomes. Changes in body weight, insulin dose and HbA1c after LAGB in eight patients with insulin-treated type 2 diabetes HbA1c = glycated haemoglobin. LAGB = laparoscopic adjustable gastric banding. Open-circle line = patients who discontinued insulin during the first 3 months of follow-up.

Timothy M E Davis · Catherine Coleman

To the Editor: Two key paradigm shifts are occurring with regard to diagnostic imaging services in Australia that may have far-reaching medicolegal and professional consequences for all doctors, have an impact on patient care and, ironically, increase costs to the health budget. First, the federal government announced a 3-year cost-saving trial in the 2009–10 Budget. Since 1 November 2010, the trial allows doctors to request certain “image-only” radiological investigations without an accompanying radiologist report.1 The investigations attract a lower rebate to cover only the technical component of image acquisition. The changes should not alter the cost to patients as most imaging studies, which currently include radiologist reports, are bulk billed. The trial currently involves chest x-rays and certain facial examinations. The government’s presumption is that for these investigations a radiologist’s assessment is not required and referring practitioners will assume full responsibility for the correct identification and interpretation of all primary, secondary and incidental findings. In doing so, referring doctors will also accept all liability for errors. While the incentive for referrers to request these new item numbers is unclear, the increased risk and responsibility borne by them is obvious. Second, in a measure to mimic the National Health System in the United Kingdom, there is advocacy from some levels of health administration to implement role extension for allied health professionals within diagnostic imaging. This would involve the provision of descriptive reports from non-radiologists with no conclusive interpretation, leaving referring doctors to draw their own clinical conclusions. Error rates for these types of reports are not insignificant when compared with a radiologist’s report.2,3 Disposing of a specialist’s evaluation may delay referral or management, and will again transfer responsibility for errors to the referring doctor.4 The false inference underpinning this model is that general medical and specialist training can be fast-tracked or circumvented without any detriment. The most concerning ramifications from these proposed changes are those for standards of patient care. Reduced radiologist input will result in higher error rates and inaccurate diagnoses;5 will remove the option of clinical discussion regarding difficult cases; and may compromise elements of patient care. Ironically, such medical errors often increase downstream burdens for health systems, negating any short-term cost savings. From a medicolegal perspective, undertaking independent interpretation of images and acting on descriptive reports is a high-risk activity and insurance premiums for doctors may ultimately reflect this.

Nicholas I Brown · Lawrence B Josey

To the Editor: The levels of ferritin and folate in the blood are regarded as the “gold standards” for measuring deficiencies in iron and folate, but they are complex and expensive tests. The red cell distribution width (RDW-CV%) measures variability in red blood cell (RBC) size, helps in early detection of deficiencies and is available in all automated analyses of RBCs. It is seldom listed on haematology reports, though it can be printed out at no extra cost. A raised RDW-CV% should prompt the treating doctor to consider underlying latent deficiencies and to order specific tests. Pasricha and colleagues outlined the most efficient ways of diagnosing and managing iron deficiency anaemia.1 However, they did not mention RDW-CV%. Haemoanalysers measure the haemoglobin (Hb) content and size of individual RBCs. The average RBC size is the mean cell volume (MCV), and the variation in sizes is calculated as a standard deviation (SD). The haemoanalyser converts the MCV and SD to a coefficient of variation (CV) using the formula: Normal RBCs vary slightly in size, so the normal value of the RDW-CV% is 10%–15%. Greater variability gives a higher RDW-CV%. When a person becomes iron deficient, he or she forms small RBCs. The circulation will then contain a mixture of older normal RBCs and increasing numbers of newer small cells, until all the normal cells reach the end of their 120-day lifespan. It therefore takes several weeks for the Hb level and MCV to drop low enough to diagnostic levels for iron deficiency. However, the mixture of normal and small RBCs rapidly increases the variability in the size of circulating RBCs, so the RDW-CV% reaches pathological levels before other RBC measurements do.2 A raised RDW-CV% is the first haematological sign of iron deficiency. My computer model demonstrating the mechanism and timing of changes in Hb level and RDW-CV% showed a large and early rise in the initial stages of iron deficiency before anaemia (Box).3 In the anaemia of thalassaemia, the RDW-CV% is usually normal. In combination with other parameters, the RDW-CV% helps to classify anaemias. The sensitivity and specificity for diagnoses is about 80%,4 so the RDW-CV% result should be used as a screening tool to alert the clinician to a possible disorder that can be investigated using standard tests. I recommend the RDW-CV% be included in all routine blood reports. Computer model of changes in haemoglobin (Hb) levels and red cell distribution width (RDW-CV%) in developing iron deficiency anaemia. Iron deficient red blood cells were formed from Day 0

Alan E Dugdale

To the Editor: Van Der Weyden states that “obesity” has negative connotations and the capacity to stigmatise.1 “Intending to give minimal offence and shifting the focus from the person to the condition”, people substitute politically correct terms.1 Medical practice should be scientifically, rather than politically, correct. Language aside, obesity is a blind spot in clinical practice because of the lack of any useful and accurate measure to categorise the condition. Body mass index (BMI) is the universal standard, but it is a very flawed measure. The results of epidemiological studies that support its use depend on huge population numbers, ethnic homogeneity and the exclusion of confounders including smoking and coexisting chronic disease. There is an absence of any epidemiological data showing that reducing overweight or obesity improves outcomes, despite them being frequently cited as risk factors. However, bariatric surgery has been shown to reduce cardiovascular disease, diabetes and cancer incidence.2 Central obesity is a much more powerful predictor of total mortality and cardiovascular disease mortality than BMI.3 In particular, the waist-to-hip ratio (WHR) is useful in population studies, showing precision and a lack of bias over a wide range of ethnic groups.4 Waist circumference is a better predictor than BMI but, like BMI, requires ethnic-specific criteria and is difficult to implement in today’s multiracial societies. WHR performs better as a predictor of cardiovascular disease than all lipid fractions, including total cholesterol and low-density lipoprotein cholesterol.3,5 Lowering lipid levels by drug therapy in the clinical trial setting reduces cardiovascular end points by 20% to 25%. In this context it is pertinent to note that the cost of subsidising prescriptions for lipid-lowering drugs in the financial year 2009–10 was almost $1.5 billion.6 In contrast, there is no simple prescription available to reduce levels of obesity. Healthy eating will always be important. And to make an impact on obesity, 60–90 minutes of moderate physical activity daily is required,7 but the importance of exercise is constantly overlooked and underprescribed. Studies in the United States show that physical activity, recorded daily, reduces cardiovascular disease mortality by about 37%–53%.8 Japan has undertaken an ambitious campaign to identify and counsel employees with excessive waistlines.9 This initiative will be followed with interest. A public health focus on early identification and prevention of central obesity is therefore at least as important in reducing cardiovascular disease mortality as is the measurement and treatment of lipids and hypertension. People with central or abdominal obesity have a serious health hazard and should be informed. “Political correctness” describes a practice that avoids giving offence to minorities. In view of the current epidemic of obesity, the language that we use should be explicit.

Timothy A Welborn · Satvinder S Dhaliwal

To the Editor: We read with interest the recent editorial by Nordin,1 which makes several imprecise observations on our recent position statement in the Journal.2 Here, we analyse some of his statements, as we believe that they are misleading to your readers and hazardous to institutionalised older persons. The Consensus Conference on Treatment of Osteoporosis in Residential Aged Care Facilities (RACFs) was organised as a unique type of meeting in which Australian experts in osteoporosis and geriatric medicine, including representatives from the Australian and New Zealand Bone and Mineral Society (ANZBMS) and Osteoporosis Australia, participated in multiple interactive sessions with 50 geriatricians and general practitioners who practise in RACFs. The goals were to appraise current evidence in the field of falls and fracture prevention in RACFs and to define practical, evidence-based recommendations. A similar meeting took place in 2004 in Canada,3 where conclusions played a pivotal role in optimising osteoporosis care in RACFs. Conclusions of the Australian meeting and recommendations subsequently published in the Journal are products of both the general consensus of the participants in the final plenary session and contributions of all the coauthors.2 Our article states, “In adults with a baseline calcium intake of 500–900 mg/day, increasing or supplementing this intake by a further 500–1000 mg/day has a beneficial effect on BMD [bone mineral density]”.2 In light of the evidence that we cited4 and more recent evidence,5,6 it is Nordin’s responsibility to highlight the potential risks of excessive calcium intake, from dietary sources plus supplements, in a population that is at high risk of cardiovascular disease.7 Moreover, we are not alone in raising this concern — a recent statement from the American Society for Bone and Mineral Research has expressed similar concern.8 In addition, Nordin cites the seminal work of Chapuy and colleagues; although this study was carried out in nursing homes and apartments for older people, it only looked at independent, ambulatory older people.9 Furthermore, the statement regarding calcium compliance is again supported by a study performed in ambulatory populations, in which compliance is likely to differ from that in our population of interest. Finally, Nordin asserts that our article promotes the use of bisphosphonates, particularly the intravenous variety, and makes the unfounded suggestion that the recommendation of bisphosphonates was due to the relationship between the sponsor and some of the coauthors. This is inaccurate. The University of Sydney, funded by a medical education grant, organised the Consensus Conference. Also, both the ANZBMS and Osteoporosis Australia endorsed the meeting and the integrity of the funding process. Indeed, maintaining independence from the sponsor was a major goal of the Consensus Conference, which was attested to by the feedback from participants. In conclusion, a basic knowledge of geriatric pharmacology and a good understanding of the current literature on geriatric medicine are enough to value the recommendations presented in our article.

on behalf of Jacqueline J Close, Julien P de Jager, Peter R Ebeling, Charles Inderjeeth, Stephen Lord, Andrew J McLachlan, Ian R Reid, Bruce R Troen and Philip N Sambrook

To the Editor: The report by Leyden and colleagues highlights the value of examining the total experience of stroke thrombolysis in one population.1 The results are devastating: protocol violations in more than a third of cases (consistent with other reports of up to 50%2), and a 10% symptomatic intracranial haemorrhage (ICH) rate (representing a number needed to harm [NNH] of 10). As a clinician, I would be “gutted” if my treatment harmed every 10th patient. The 22% mortality at 3 months is consistent with real-world evidence that stroke thrombolysis increases mortality.3 Although the authors state that the rate of symptomatic ICH was not statistically significantly different to that in the National Institute of Neurological Disorders and Stroke (NINDS) study, an absolute increase of 3.6% (10% versus 6.4%) is clinically important to patients and their families. Presumably, this is largely related to the age protocol violations: 10 of 53 resulted in symptomatic haemorrhage (19%; NNH = 5), including seven cases of intracerebral haemorrhage and five deaths. In all, there were 39 cases of any ICH (25%; NNH = 4). The article highlights that 54% of thrombolysis cases were not on the Safe Implementation of Thrombolysis in Stroke (SITS) registry. This result adds to the concerns of a selection bias in the SITS registry. As the authors point out, the sample size is small — too small, in my opinion, to draw any rigorous conclusions. This highlights that registry results should, at best, be hypothesis generating. However, it has also been highlighted that patients in the SITS International Stroke Thrombolysis Register do worse than those in the placebo group of the European Cooperative Acute Stroke Study III (ECASS III).4 The authors also refer to the ECASS III results, which contend that the time window for stroke thrombolysis should be extended to 4.5 hours. However, methodological and analytical flaws in this study, as well as the NINDS study, cast doubt on this statement.5 A recently published independent review of evidence on stroke thrombolysis concluded, “There is no consistent or proven benefit to thrombolytics”; it included all 11 clinical trials, of which nine had no benefit (with four of these causing harm).6 There are multiple examples in medicine where small studies suggest a benefit, but larger more definitive studies confirm otherwise. Hence, it is very important to look at the totality of the evidence.7 While I agree with the authors that poor access to acute stroke units is deplorable, the real challenge is to define the role, if any, for thrombolysis in acute stroke. Pronouncements that we need to be thrombolysing more are a disservice to those who seek the truth.

Daniel M Fatovich

In reply: To a carpenter, everything looks like a nail, and to a stroke thrombolysis sceptic, every study seems to confirm their opinion. A result cannot be “clinically important” yet statistically not so. We found no difference in symptomatic intracranial haemorrhage rates between our study and others using the same definition. The most widely accepted estimates of the true number needed to harm (for functional outcome at 3 months, following treatment within 3 hours) is about 30, as opposed to a number needed to benefit of around three.1 Our study does not suggest that thrombolysis increases mortality. Mortality cannot be compared between different populations, with different aetiology and severity. We have demonstrated a large number of relative “protocol violations” according to 2007 guidelines, the most common of which was that the patient was older than 80 years, but there is robust evidence that thrombolysis is safe and effective in this cohort.2 The benefit of a therapy cannot be assessed by a tally of “positive” and “negative” trials. A recent meta-analysis of all tissue plasminogen activator trials (seven trials, 2199 patients),3 and the relevant Cochrane review,4 confirm benefit in appropriate patients treated with tissue plasminogen activator within 4.5 hours. Stroke thrombolysis is effective. We must overcome the barriers to administering it frequently, safely and rapidly.

Tim Kleinig · James M Leyden · Andrew Lee · Jim Jannes

Rethinking skull surgery After traumatic brain injuries, decompressive craniectomy is an increasingly common procedure used to reduce intracranial pressure, but there have been few randomised studies of this invasive technique. Australian and Saudi researchers randomly assigned 155 adults with severe traumatic brain injuries and intracranial hypertension that had not responded to first-tier therapy, to either standard care or decompressive craniectomy. The latter did reduce intracranial pressure and length of intensive care unit stay, but increased the likelihood of a poor outcome 6 months after the injury. The proportion of people who died within 6 months of their injury was similar in both groups. Researchers were surprised that craniectomy was linked to fewer favourable outcomes. “Our findings differ from those of most non-randomized studies of decompressive craniectomy and are contrary to our hypothesis”, wrote Dr James Cooper of Alfred Hospital, Melbourne, and colleagues. N Engl J Med 25 March 2011 (Online first) Hep C treatment hope There’s new hope for people with the most hard-to-treat strain of hepatitis C virus (HCV), known as genotype 1. Less than half of patients with this genotype do not respond to the standard two-drug treatment regimen, of peginterferon and ribavirin. But new international research shows that adding the protease inhibitor boceprevir to the mix significantly increases the proportion of people who clear the virus. The HVC RESPOND-2 Investigators led by Dr Bruce Bacon from the Saint Louis University School of Medicine, Missouri, randomly assigned 403 patients with previously treated HCV to one of three groups: the usual treatment regimen plus placebo for 44 weeks, the usual treatment plus boceprevir for 32 weeks, or the usual treatment plus boceprevir for 44 weeks. The rate of sustained virological response was significantly higher in the boceprevir groups compared with the control group.1 A related paper reports similar results for patients with HCV genotype 1 who had not previously received any treatment.2 1 N Engl J Med 2011; 364: 1207-1217 2 N Engl J Med 2011; 364: 1195-1206 Airport scanners radiation risk The radiation risk from full-body airport scanners is extremely small, an American study has concluded. The analysis estimated that the amount of radiation emitted from the controversial backscatter scanners is equivalent to less than 1% of the radiation a passenger is exposed to on a 6-hour flight. Compared with medical procedures, a passenger would have to undergo 1000 airport scans to equal the exposure of a chest radiograph, or 4000 airport scans to equal the exposure of a mammogram. The research also estimated cancer risks from the scanners. It found that for the 100 million passengers taking 750 million flights each year, six cancers could result from the backscatter scanner radiation over these passengers’ lifetimes, compared with the background lifetime incidence of 40 million cancers that would be expected to develop in these individuals. Backscatter scanners are the most commonly used airport scanner in the United States, and the Australian Government is considering their use in Australian airports. Arch Intern Med 28 March 2011 (Online first) Will I get another cancer? Only a small proportion of second cancers are related to radiotherapy treatment for a first cancer, according to an American analysis of almost 650 000 5-year cancer survivors. The researchers compared the relative risk of a second solid cancer in adult patients who had received radiotherapy with those who did not receive radiotherapy, during an average 12-year follow-up period. The study concluded that only about 8% of second solid cancers were related to radiotherapy treatment, suggesting that the remainder are due to factors such as lifestyle or genetics. The proportion of second cancers related to radiotherapy was lowest for patients initially treated for cancers of the eye and orbit (4%), and highest for those treated for testicular seminoma (24%). Researchers say the results should reassure patients that the risk of radiation-related cancer is small compared with the treatment’s benefits. Lancet Oncol 30 March 2011 (Online first) Guess who binges? People who get a buzz from alcohol are more likely to become problem drinkers than those who simply feel sleepy after drinking, new research shows. Almost 200 drinkers aged 21-35 years attended three laboratory sessions where they were randomly assigned to receive either placebo, low-dose alcohol, or high-dose alcohol. Those who experienced more rewarding and stimulating effects from the stronger drink were more likely to increase their frequency of binge drinking during a 2-year follow-up than those who were more sedated by the strong drink. The research is at odds with the prevailing theory that people who experience a weaker alcohol response are more likely to misuse the booze. Arch Gen Psychiatry 2011; 68: 389-399

Sophie McNamara