Volume 194 Issue 11

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

Amy P Abernethy MD, FRACP, FAAHPM

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

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

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

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

Objectives: To describe hospital and emergency department use in the last year of life by people for whom death from cancer or one of another nine conditions was an expected outcome.Design, participants and setting: Retrospective cross-sectional study based on death registrations and morbidity data for 1071 Western Australians who died between 1 August 2005 and 30 June 2006. Decedents had an informal primary carer, did not live in residential aged care and died of a condition amenable to palliative care.Main outcome measures: Total number of hospital admissions; emergency presentations (with and without hospital admission); days spent in hospital by age group at death, sex, metropolitan or rural place of residence and cancer versus non-cancer diagnosis; proportion in hospital on any day in the last 365 days of life; time points of change in the last 365 days of life at which there was an increasing proportion of hospital admissions for those with cancer and non-cancer conditions.Results: All but 4% of the decedents spent time in hospital with a marked increase in hospitalisations in the last 108 days of life for people who died of cancer and the last 83 days of life for people who died of non-cancer conditions. Those with cancer spent less time in hospital than those with other diagnoses. Seventy per cent of the cohort had at least one emergency presentation. On the last day of life, 61.5% of people were in hospital and 4.0% had been seen in emergency departments.Conclusions: Western Australian hospitals currently provide extensive and progressively greater care at the end of life. Identifying patterns of emergency and inpatient use for various disease trajectories will assist in the planning of appropriate services for people where death is an expected outcome.

Lorna K Rosenwax BAppSc(OT), MSc, PhD · Beverley A McNamara BA(Hons), Dip(Teach), PhD · Kevin Murray BSc(Hons), MSc · Rebecca J McCabe BBus, GradCertBus, MCom(Bus Admin) · Samar M Aoun BSc(Hons), PhD, MPH · David C Currow BMed, FRACP, MPH

Objective: To measure the growth in emergency ambulance use across metropolitan Melbourne since 1995, to measure the impact of population growth and ageing on these services, and to forecast demand for these services in 2015.Design and setting: A population-based retrospective analysis of Ambulance Victoria’s metropolitan emergency ambulance transportation data for the period from financial year 1994–95 to 2007–08, and modelling of demand in the financial year 2014–15.Main outcome measures: Numbers and rates of emergency ambulance transportations.Results: The crude annual rate of emergency transportations across all age groups increased from 32 per 1000 people in 1994–95 to 58 per 1000 people in 2007–08. The rate of transportation for all ages increased by 75% (95% CI, 62%–89%) over the 14-year study period, representing an average annual growth rate of 4.8% (95% CI, 4.3%–5.3%) beyond that explained by demographic changes. Patients aged ≥ 85 years were eight times (incident rate ratio, 7.9 [95% CI, 7.6–8.3]) as likely to be transported than those aged 45–69 years over this period. Forecast models suggest that the number of transportations will increase by 46%–69% between 2007–08 and 2014–15, disproportionately driven by increasing usage by patients aged ≥ 85 years.Conclusions: These findings confirm a dramatic rise in emergency transportations over the study period, beyond that expected from demographic changes. Rates increased across all age groups, but more so in older patients. In the future, such acceleration is likely to have major effects on ambulance services and acute hospital capacity. This calls for further investigation of underlying causes and alternative models of care.

Judy A Lowthian MPH, BAppSc(SpPath), LMusA · Damien J Jolley MSc(Epidemiology), MSc, AStat · Andrea J Curtis BSc(Hons), PhD · Alexander Currell BE, BA, MEngSc · Peter A Cameron MB BS, MD, FACEM · Johannes U Stoelwinder MD, FRACMA, FACHSE · John J McNeil MB BS, PhD, FRACP

Objectives: To assess the prevalence of latent tuberculosis infection (LTBI) in recently arrived refugees in the Northern Territory and to obtain comprehensive data for rates of treatment acceptance and completion for this condition.Design, setting and participants: Prospective data collection and follow-up of all 471 newly arrived refugees seen at the Centre for Disease Control, NT refugee health clinic from February 2006 to January 2009.Main outcome measures: Rates of LTBI determined by tuberculin skin testing; subsequent assessment and treatment compared with local protocols.Results: 458 of 465 eligible refugees were adequately assessed for LTBI, of whom 146 (31.9%) were diagnosed with LTBI. Older age, male sex and World Health Organization Eastern Mediterranean region of birth were associated with increased prevalences of LTBI. Of the refugees diagnosed with LTBI, 10 failed to attend for follow-up and 15 were not offered treatment. Isoniazid therapy was accepted by 93 of 121 refugees (76.9%), and 41 of these (44.1%) completed treatment. The most common reasons for discontinuation of therapy were medication-related side effects (most often gastrointestinal) and loss to follow-up. Increasing age was associated with failure to complete treatment.Conclusion: Outcomes of assessment and treatment for LTBI in newly arrived refugees in the NT are comparable to those for other target groups screened in developed countries. Loss to follow-up caused significant attrition in numbers, but complete data were obtained for a large proportion of eligible refugees. Most refugees who are offered treatment for LTBI accept, but less than half complete treatment.

James M Trauer MB BS · Vicki L Krause FAFPHM

Objective: To reduce the rate of central line-associated bacteraemia (CLAB).Design: A collaborative quality improvement project in intensive care units (ICUs) to promote aseptic insertion of central venous lines (CVLs). A checklist was used to record compliance with all aspects of aseptic CVL insertion, with maximal sterile barrier precautions for clinicians (“clinician bundle”) and patients (“patient bundle”). CLAB was identified and reported using a standard surveillance definition.Participants and setting: Patients and clinicians in 37 ICUs in New South Wales, July 2007 – December 2008.Main outcome measures: Compliance with aseptic CVL insertion; rates of CLAB.Results: 10 890 CVL checklists were reviewed for compliance with the clinician and patient bundles: compliance with aseptic CVL insertion improved significantly (P < 0.001). The CLAB rate dropped from 3.0 to 1.2 per 1000 line-days (P < 0.001). Regardless of CVL type, the relative risk (RR) of CLAB in patients with CVLs inserted by clinicians not compliant with the clinician bundle was 1.62 times greater (95% CI, 1.1–2.4; P = 0.018) than the RR with CVLs inserted by clinicians compliant with both bundles. Compliance with both the bundles was associated with a 50% reduction in risk of CLAB (RR, 0.5; 95% CI, 0.4–0.8; P = 0.004).Conclusions: Compliance with all aspects of aseptic CVL insertion significantly reduces the risk of CLAB. A difficulty we experienced was that most ICUs lacked the organisation and staff to support quality improvement and audit.

Anthony R Burrell MB BS, FANZCA, FCICM · Mary-Louise McLaws DipTropPH, MPH, PhD · Margherita Murgo BN, MN(Critical Care) · Eda Calabria LLB, BBus · Annette C Pantle MB BS, MPH, FRACMA · Robert Herkes MB BS, FRACP, FCICM

Objectives: To describe the characteristics of patients with burn injury admitted to a major trauma hospital in Melbourne following the Black Saturday bushfires of 7 February 2009, and to provide a detailed analysis of the hospital’s response to the crisis.Design, setting and participants: A retrospective chart review of ambulance and hospital records of patients admitted to the Victorian Adult Burns Service (VABS) at The Alfred Hospital (The Alfred) following the bushfires.Main outcome measures: Patient characteristics and outcomes: age, sex, total and full thickness body surface area burnt, type and site of burn, hospital and intensive care unit length of stay (LOS) and receipt of standard burn care practices. Estimated glomerular filtration rate, theatre time and LOS data for the bushfire cohort compared with corresponding data for historical cohorts from VABS and from a similar institution in New Zealand.Results: Nineteen patients were admitted to VABS over the first 48 hours after the bushfires. Of these, nine patients were subsequently admitted to The Alfred’s intensive care unit. Most patients (74%) were men with a mean age of 52.7 years (SD, 12.4 years). Seventeen patients (89%) underwent at least one surgical procedure, which resulted in 4355 minutes of theatre time for the bushfire cohort in the first week. Hospital LOS was similar for the bushfire and New Zealand cohorts. Compared with the VABS historical cohort, there was a higher incidence of abnormal renal function among the bushfire cohort patients.Conclusions: Although relatively few patients with severe burns were admitted to VABS, significant increases in resource allocation were required to manage them in terms of additional theatre time, consumables and staffing. The experience of VABS may aid planning for future mass burns casualty events.

Heather J Cleland MB BS, FRACS · David Proud MB BS · Anneliese Spinks PhD · Jason Wasiak MPH

Mental health researchers Jane Pirkis and Meredith Harris say the government got it right YES The federal Budget provides $2.2 billion for mental health care over the next 5 years. From our point of view, this budgetary provision is doubly positive because we feared the Australian Government’s Better Access to Mental Health Care initiative would be axed or irrevocably altered to fund other necessary mental health services. Better Access enables consumers to receive a specified number of Medicare-reimbursable sessions of mental health care from an allied health professional (on referral from a general practitioner who completes a Mental Health Care Treatment Plan), or from a GP directly. The Budget has modified the Better Access rules to achieve savings that are not insignificant ($580 million over 5 years), but its integrity has largely been retained. We conducted an evaluation of Better Access which drew on 20 different data sources, including Medicare data and a study of outcomes for nearly 900 consumers who received care from psychologists and GPs, funded under the Better Access initiative.1 Our evaluation highlighted a number of positives. Better Access delivered over 11 million services to over two million people between 2007 and 2009. Typically, these services involved evidence-based treatments like cognitive behavioural therapy. Half of all Better Access users had not received mental health care before, and over 90% had diagnoses of depression and/or anxiety. The vast majority of those who used Better Access services had positive outcomes, with most shifting from high or very high levels of psychological distress before treatment to much more moderate levels after treatment. Although Better Access has cost the Australian Government more than originally anticipated ($1.45 billion from its introduction in November 2006 to June 2010, which is about 2.5 times more than originally anticipated), it appears to provide good value for money. The above positive outcomes were achieved at an average cost of about $750 per episode; this compares favourably with previous estimates of about $1100 for the optimal treatment for anxiety and depression.2 The first of two Budget-related changes to Better Access is a reduction in the permissible number of sessions with allied health professionals. Previously, consumers were entitled to an initial six sessions of care, with the option of an additional six after review by the referring medical practitioner (and a further six in exceptional circumstances). Under the new rules, the number of additional sessions will be capped at four, bringing the total to 10 and saving an estimated $174.6 million. The evidence from our evaluation suggests that this will not affect large numbers of consumers; we found that 75% of consumers received 1–6 sessions, 20% received 7–12, and 5% received 13–18.1 The new arrangements therefore seem reasonable, but ongoing evaluation will be needed to ensure that consumers with complex conditions are not disadvantaged. The second Budget-related change to Better Access is the creation of a two-tier rebate for GP Mental Health Care Plans ($126.43 or $99.55 for a session of 40 minutes or longer, depending on whether GPs have completed a basic 6-hour training course; $85.92 or $67.65 for a session of 20–40 minutes). The existing rebate for the Mental Health Care Plan, irrespective of the duration of the session, is $163.35 for GPs who have completed training and $128.20 for GPs who haven’t; the anticipated saving from this change is $405.6 million. The rationale for this change comes not from our evaluation but from analysis of the Bettering the Evaluation and Care of Health (BEACH) data,3 which indicated that over 80% of Mental Health Care Plans were being completed in under 40 minutes. In our evaluation, GPs and allied health professionals had mixed views about the value of Mental Health Care Plans. Some allied health professionals felt that they were a useful means of improving collaborative care, as did some GPs. Other allied health professionals and GPs were less sanguine, but for different reasons. Some allied health professionals claimed that the information they received from GPs was often insufficient and others expressed resentment that the GP’s rebate for the Mental Health Care Plan was frequently more than what allied health professionals received for providing an individual session of care (between $50.95 and $140.15, depending on the type of provider and the length of the session). Some GPs were critical of the training requirements to receive the higher rebate; they felt that their referral went into a “black hole” and that ongoing communication with the allied health professional was limited. It seems reasonable to provide a time-dependent rebate which is commensurate with the time spent in preparing the Mental Health Care Plan, although it will be necessary to monitor the effect this change has on the likelihood that GPs will prepare Mental Health Care Plans. Better Access is part of a suite of mental health care reforms that received attention in the Budget. Many of the others complement Better Access by reaching groups that may not be best served by a fee-for-service approach. We believe the Budget reforms have struck an appropriate balance between retaining the core features of a program that appears to be working well while at the same time providing additional resources for important existing and new initiatives.

Jane E Pirkis MPsych, MAppEpid, PhD · Meredith G Harris MPASR, MPH

Mental health policy expert Sebastian Rosenberg and psychiatrist Ian Hickie want more change NO The Australian Government had little option but to reform the Better Access to Mental Health Care initiative in the federal Budget. The surprise is their timidity. The changes reduce some of the bureaucracy and waste while promoting more targeted services for those in greatest need. Better Access was the largest single component of the Council of Australian Governments’ 2006 National Action Plan on Mental Health, and has been likened to a runaway giant,1 already costing more than three times its initial 4-year estimate of $538 million, or more than $10 million each week. The focus of the federal government’s changes are GP Mental Health Care Plans. Under pressure from doctors, Better Access removed the requirement for the collaborative, interdisciplinary approach embodied in the earlier Better Outcomes in Mental Health program, despite repeated positive evaluations.2 The professions championed shifting their role in primary mental health care to fee-for-service, a model of payment shown to be ineffective in generating collaborative care. The Better Access program suggests that, after several sessions of psychological therapy, patients return to their general practitioners for review of their mental health care plans. Latest data indicates that this is happening for only one in every three plans written. Consumers are not receiving a full episode of care. The number of GP Mental Health Care Plans prepared by GPs (Medicare Item 2710) has also declined significantly over the past 12 months. Twenty per cent of all Better Access clients are now having their mental health managed through their GP using Medicare Item 2713 — the GP Mental Health Care Consultation — alone.3 GPs have allowed their role in Better Access to dwindle to that of glorified referrers. No wonder the government is now backing better value services. The Budget’s support for the Access to Allied Psychological Services (ATAPS) program is an admission that better ways to engage GPs productively as key players in the delivery and management of primary mental health care do exist. The government did not choose to make significant changes to psychological services, which continue their unbridled growth. The Budget trims subsidised sessions of cognitive behaviour therapy (CBT) from 12 to 10 per year. On average, people are receiving five sessions, though ironically, the government’s most recent evaluation of the Better Access program indicated that health outcomes were optimised after six.4 Better Access has generated controversy within the psychology profession, with clinical psychologists arguing it devalues their specialised skills. Consumers lack the information to differentiate clinical from other psychologists. Better Access service users have frequently reported receiving psychoeducation and non-specific counselling rather than the evidence-based CBT programs. This type of inadequate treatment was one of the main reasons that the Better Outcomes and Better Access initiatives were supported by most health professionals.5 The minimalist Budget changes leave key issues unaddressed. The significance of out-of-pocket expenses (around $30 for each session of CBT) associated with the Better Access program has been noted.3 There is considerable evidence to indicate that the program is failing to reach people aged less than 15 years, men, and people living in areas of high socioeconomic disadvantage and non-urban areas.3 Analysis of Medicare data shows that Queenslanders receive clinical psychological services at half the rate of Tasmanians. There are as many clinical psychology services provided in the Australian Capital Territory as in the whole of New South Wales! In 2008, 68% of people using the Better Access program were using it for the first time. In 2009 this figure had dropped to 57%. An initiative originally designed to offer short, focused regimens of CBT may be becoming a program of continuing care instead. Although the 2011 Budget makes only minor changes to the most obvious deficits in the current Better Access to Mental Health Care program, it does clearly indicate that it is now a major problem that will be monitored closely for value, efficiency and equity, particularly in comparison with more attractive and collaborative alternatives. There is a clear role for GPs in coordinating genuine primary mental health care. At present, that role is largely vacant. The timing is right for the professions to abandon self-interest and argue for a planned, evidence-based overhaul of the Better Access program.

Sebastian Rosenberg MPAdmin, BA · Ian B Hickie MD, FRANZCP

Medical Assessment Units (MAUs) provide an opportunity for multidisciplinary staff to manage recently admitted acutely unwell patients with complex medical illnesses. We propose concerted development of robust mechanisms for identifying and managing patients whose condition is unstable as they move through hospital departments. Track, trigger and response (TTR) systems (eg, medical emergency team calls and early warning scores) have been introduced to hospital practice, but evidence for their effectiveness is, so far, incomplete. The current variation in TTR systems within and between hospitals impairs intersite comparisons. A range of outcome measures, including risk of physiological deterioration, mortality and projected hospital length of stay, could be usefully investigated by future intersite collaborative research. More deliberate, systematic, evidence-based design of “response” in TTR systems may help in identifying patients who need early attention from skilled medical staff. We need more uniform TTR systems, more research on TTR systems and more multisite research; MAUs are ideally situated to address this important area.

Paul F Jenkins MB BChir, FRCPE, FRACP · Campbell H Thompson MD, DPhil, FRACP · Lorna L Barton MB BS, MRCP

The Australian Government is planning to pilot a model of prepaid funding for coordinated care of patients with diabetes in general practice. Patients will register with a practice that undertakes to coordinate their care, and practices will manage pre-allocated funds to provide services instead of billing Medicare. Systems to manage prepaid funds in Australian general practice have not yet been developed. In the model that has been proposed, practices with a small register of patients will be at risk of overspending, which may threaten practice viability and patient services. If the initiative is to have integrity, all patient services should be paid from the prepaid funds and patients should only attend the practice with which they have registered. Risks should be delineated and contingency plans made explicit before practices and patients commit to the initiative.

Douglas A Pritchard MB BS, FRACGP, PhD

In 2010, an immigrant from Burma was the first person to be diagnosed in New Zealand with extensively drug-resistant tuberculosis (XDR-TB). The strain of Mycobacterium tuberculosis is the most resistant reported to date in Australasia. Key difficulties of managing this disease in a low-prevalence country were delays from drug-susceptibility testing and in acquiring appropriate medicines, and a lack of evidence-based guidelines. Solutions are needed for New Zealand and the wider region as more cases of XDR-TB are likely to be encountered in the future. (MJA 2011; 194: 602-604) Clinical recordA 29-year-old man presented to his general practitioner in Otago, New Zealand, in March 2010 with discharge from an enlarged left anterior cervical lymph node (Box 1). He reported two episodes of night sweats but no weight loss, fever or chills. He was not coughing or producing sputum, and had no haemoptysis or chest pain. He was born in Burma (Myanmar) but had emigrated to New Zealand in 2006. At that time, chest x-ray screening did not detect tuberculosis (TB). He had no personal history of TB and no known contacts with TB. Fine needle aspirate that was collected in late March from the affected lymph node grew Mycobacterium tuberculosis after 30 days’ incubation. The isolate was sent to a reference laboratory for drug-susceptibility testing (DST). Eight days later, the isolate was reported to be “presumptively” resistant to isoniazid, rifampicin and ethambutol based on the results of broth-based DST methods. Resistance to pyrazinamide was also reported on the basis of a negative Wayne test. Additional DST was performed against the second-line drugs capreomycin, ethionamide, ofloxacin and amikacin. A further 10 days later, the isolate was reported to be resistant to all four of these second-line drugs and a report of “presumptive” extensively drug-resistant TB (XDR-TB) was issued. Because of the isolate’s unusually resistant profile on conventional phenotypic testing, molecular tests were used to cross-check these results by identifying gene mutations associated with resistance (Box 2). Fourteen days after the preliminary report of XDR-TB was made, and a total of 66 days after the sample was initially collected, a final laboratory report confirming XDR-TB was issued. Further DST performed by an international reference laboratory revealed susceptibility to cycloserine and para-aminosalicylic acid. DST was not performed against imipenem and clofazimine owing to a lack of standardised methods. After the isolation of M. tuberculosis, the patient was initially treated in the community with standard first-line drugs. On receipt of the preliminary DST results, his urgent admission to hospital was arranged, with provision for isolation to prevent airborne disease transmission. A chest x-ray at this time showed fibrosis in the left upper zone, and a computed tomography (CT) scan showed an enlarged lymph node in the left anterior cervical chain (Box 3). The patient’s HIV serology results were negative, and an induced sputum sample set for TB was negative for acid-fast bacilli. Treatment was instituted with cycloserine 250 mg orally twice daily, para-aminosalicylic acid 4 g orally twice daily, linezolid 600 mg orally once daily, moxifloxacin 800 mg orally once daily, imipenem 1 g intravenously twice daily, clofazimine 200 mg orally once daily and isoniazid 600 mg orally once daily. The hospital pharmacy had difficulty in obtaining cycloserine, clofazimine and para-aminosalicylic acid. A 2-week supply of these agents was obtained from Auckland, New Zealand, but the remainder had to be imported from the United States. After 5 weeks of treatment, the patient’s enlarged lymph node had reduced in size and the discharge had stopped. Treatment with imipenem was stopped and treatment with amoxycillin–clavulanate 625 mg orally three times daily was begun. Three further sets of induced sputum samples were negative for TB. The patient was discharged back to the community, as the risk of him passing on the infection was now low. He attended weekly follow-up by a respiratory specialist and was monitored for treatment adherence by public health staff. A follow-up CT scan of the neck 2 months after discharge showed further significant improvement. Initially, surgical removal of the lymph node had been planned. However, with resolution of the lymph node after 5 months of medical therapy, surgery was not required. Apart from transient nausea, the patient is tolerating the treatment well and it is planned to continue treatment for a minimum of 18 months. Public health contact tracing of people who had resided with the patient showed they did not have TB. DiscussionMultidrug-resistant TB (MDR-TB) is defined as M. tuberculosis infection that is at least resistant to both isoniazid and rifampicin. XDR-TB is defined as resistance to not only isoniazid and rifampicin but also any fluoroquinolone and one of the second-line injectable drugs (such as capreomycin, amikacin or kanamycin).1 This report describes the first case of XDR-TB in New Zealand; it also describes the most resistant strain of M. tuberculosis reported to date in Australasia. By 2009, 58 countries had reported at least one case of XDR-TB. Despite this, there has been no new drug licensed to combat TB for 40 years.2 Given the increasing frequency of travel and immigration from high-risk areas, New Zealand and other countries in the region are likely to encounter more cases of XDR-TB in the future. The current cost of our patient’s medication to the government is about NZ$10 000 per month. Burma is one of 22 countries with a high health burden due to TB; in 2004, 4% of new TB cases and 15.5% of those previously treated were of MDR-TB.3 No cases of XDR-TB have been reported in Burma, but this is likely to be due to underreporting secondary to resource and laboratory constraints.1 In New Zealand, the incidence of TB is about seven per 100 000 people annually, and the rate of drug resistance for TB has been very low;4 from 2000 to 2009 there were 22 cases of MDR-TB.4 Since 2009 there have been a further nine cases reported to date (unpublished data obtained by J T F). From a regional perspective with regard to XDR-TB, Australia reported one case in the period 2002–2005 and the Pacific Islands did not report any.5 A second case was reported in Australia in 2010.6 Our patient showed primary resistance, in contrast to secondary resistance which develops from inadequate or inappropriate therapy: he arrived in New Zealand with latent infection, having been infected with XDR-TB in Burma. DST provides key information for the management of XDR-TB. This case highlights the integral role of diagnostic laboratories in rapidly and accurately reporting results to guide appropriate treatment. In this case, commercially available molecular-based methods enabled highly unusual DST results to be cross-checked and confirmed once the results of conventional, broth-based phenotypic DST had become available. However, in principle, such assays could have been used before obtaining the results of conventional DST. This could potentially have resulted in a report of MDR-TB being issued 12 days earlier, and in second-line DST results and the XDR nature of the isolate being reported about 20 days earlier. Notably, this patient came from a geographical area known to have a high prevalence of MDR-TB. It may be that, in future, risk-based laboratory DST algorithms can be devised so that molecular DST can be selectively applied as the initial method of testing for patients at high risk of MDR-TB. However, the cost-effectiveness of such risk-based testing algorithms in low-prevalence settings would need to be established. Hypothetically, if the patient had active pulmonary TB, molecular DST could have been performed directly on a respiratory specimen rather than waiting for the culture to grow.7 Use of such a test in this scenario could have potentially reduced the turnaround time by over 60 days. There are limited data available to definitively guide the management of XDR-TB, but current regimens recommend the use of four or more effective medications, based on DST.8 This includes any first-line agent that is effective, a fluoroquinolone, a second-line injectable agent and any third-line agent to make up four to six medications. Pyrazinamide and ethambutol should be included if possible, as this improves survival.8 Kanamycin can be used in streptomycin-resistant cases, and amikacin if there is resistance to both kanamycin and streptomycin. Capreomycin and viomycin can also be considered. The fluoroquinolones have variable potency — moxifloxacin and gatifloxacin are more potent then ofloxacin and levofloxacin. Ciprofloxacin is not recommended as an antituberculous agent.9 Other second-line agents like ethionamide, para-aminosalicylic acid and cycloserine can also be used. Linezolid, meropenem and amoxycillin–clavulanate are not licensed for this use but can be added if no alternatives are available. Monitoring for adverse drug reactions is important.8-10 For pulmonary XDR-TB, treatment for at least 18 months is recommended after conversion to negative sputum cultures.9 Directly observed therapy should be instituted, and treatment success may be up to 60% in patients without HIV infection.10 Surgical resection in conjunction with medical management is useful in selected patients with XDR-TB.11 However, most surgical studies are focused on pulmonary XDR-TB. There is a lack of research on surgical outcomes for head and neck XDR-TB. Early recognition of cases, with isolation in negative pressure rooms and high efficiency particulate air filtration, is necessary to prevent spread, but standard chemoprophylaxis with isoniazid, rifampicin, or rifampicin and pyrazinamide for contacts is unlikely to be effective in XDR-TB.12 Although our experience indicates that there is potential for treatment success, definitive treatment guidelines are needed and more data are required to inform treatment and help contain spread. Further, it illustrates the importance of maintaining an adequate supply of second-line drugs in New Zealand. Confirming XDR-TB in a young man from Burma who had no history of previous TB treatment suggests that XDR-TB may be more common in Burma than has been widely believed, reinforcing the need for strengthening laboratory support networks and TB surveillance systems in South-East Asia. 1 External appearance of the patient’s left anterior cervical lymph node on presentation 2 Gene mutations identified in the Mycobacterium tuberculosis isolate, and associated known antibiotic resistance Gene Mutation Associated antibiotic resistance katG S315T Isoniazid rpoB S315L Rifampicin gyrA D94A Moxifloxacin rrs A1401G Amikacin and capreomycin embB M306I Ethambutol 3 Computed tomography scan of the patient’s neck on presentation, showing an enlarged left anterior lymph node

Tze Liang Goh MBChB · Cindy R Towns PhD, MBChB, BSc(HighHons) · Katharine L Jones BMedSci, BM BS, MRCP · Joshua T Freeman MBChB, FRCPA, PGDipID · Colin S Wong DM, FRACP

Jim Gardiner was born in Ballarat on 5 May 1922. He studied medicine at the University of Melbourne, where he met his future wife Jenny, and received his Doctor of Medicine degree in 1948. From 1945 to 1947, Jim was a Resident Medical Officer at Royal Melbourne Hospital, after which he took up the position of Assistant Pathologist at The Alfred Hospital in Melbourne. In 1949, he moved to London, where he was a Registrar at the Brompton Hospital for Consumption and Diseases of the Chest. In 1952, Jim returned to Melbourne as Kimpton Research Scholar at the Baker Medical Research Institute, where he was involved in developing new methods in cardiac diagnosis. At the Baker Institute, he pioneered cardiac catherisation with Dr Tom Lowe and established the Cardiovascular Diagnostic Service in 1953. When the diagnostic service moved from the Baker Institute to The Alfred in 1954, Jim became its first director, a position he held until 1959. The diagnostic service played an instrumental role in the development of cardiopulmonary bypass surgery and the first successful open-heart surgery operation in Australia in 1957. From 1957 until his retirement in 1982, Jim was an Honorary Physician and then Visiting Physician at The Alfred, where he also served as Dean of the Clinical School from 1975 to 1978. Throughout his career, Jim made important contributions to advancing the treatment of hypertension. He was also highly regarded as a teacher and a mentor. Jim occupied several important positions in professional bodies. He was a member of the Board of Censors of the Royal Australasian College of Physicians (1966–1976), and secretary/treasurer (1956–1959) and president (1972–1974) of the Cardiac Society of Australia and New Zealand. Jim was known for his warmth, willingness to support others and broad humanitarian outlook. Outside of his professional commitments, his great interests were astronomy, classical music and golf. Jim died from cancer on 19 February 2011. He is survived by his children Jamie, Gillian and Christopher.

Baker IDI Heart and Diabetes Institute

Objective: To determine the prevalence of patient-initiated aggression toward general practitioners in Australia.Design, setting and participants: A cross-sectional national survey, conducted during February – May 2010, of 3090 GPs in 19 Divisions of General Practice, purposively sampled to represent urban, rural and remote areas.Main outcome measure: Proportion of GPs experiencing patient-initiated aggression.Results: Eight-hundred and four GPs returned completed surveys (response rate, 26.3%). In the previous 12 months, 58% of GPs had experienced verbal abuse and 18% had experienced property damage or theft. Very few GPs had experienced physical abuse (6%), stalking (4%), sexual harassment (6%) or sexual assault (0.1%). After controlling for other demographic variables, GPs with fewer years of experience (P = 0.003), or who worked full-time or in larger practices (both P = 0.03) experienced significantly more verbal abuse than their counterparts, and GPs who worked full-time (P = 0.004) or in metropolitan areas (P = 0.01) experienced significantly more property damage or theft. Female GPs experienced significantly more sexual harassment than male GPs (P < 0.001).Conclusions: This is the first national evidence of the prevalence of patient aggression toward GPs in Australia, which could inform the development of policies and guidelines that aim to reduce the prevalence of patient aggression toward GPs.

Laura E Forrest BSc, GradDipGenCouns, PhD · Pushpani M Herath MB BS, MSc · Ian S McRae BSc(Hons), MSc, PhD · Rhian M Parker PhD

Clinical record A 22-year-old woman of European ancestry who had a 4-year history of treatment-resistant bipolar disorder presented with symptoms of mania. On admission to hospital, a full blood examination and biochemistry results were normal. Her current doses of lithium (1500 mg daily) and risperidone (2 mg daily) were maintained while treatment with carbamazepine was commenced at 100 mg daily and then increased by 100 mg every 3 days. The patient was discharged from hospital on a regimen of 400 mg carbamazepine daily. Her plasma carbamazepine level at this time was 19 μmol/L (reference range [RR], 16–50 μmol/L). She was in good physical health, and a full blood examination and biochemistry results were normal. Three weeks after starting to take carbamazepine, the patient developed a mild, barely visible, erythematous maculopapular rash on her arms and chest that disappeared after a few days. She had no other symptoms, and full blood examination and biochemistry results remained normal. After a further 3 weeks, the patient developed marked lethargy, exercise intolerance, muscle aches, night sweats, rigors and a rash. There had been no changes to her medication and she had been complying with her treatment regimen. She lived with her family, and her parents contacted her family general practitioner as well as me (her psychiatrist). She was advised to stop taking carbamazepine, increase the dose of risperidone and seek urgent medical attention. The carbamazepine was stopped over 2 days — 45 days after it was first administered. The family consulted an emergency service on four occasions over 6 days, and the patient was variously diagnosed with contact dermatitis, non-specific allergic reaction, cytomegalovirus and rubella. She was finally admitted to hospital and was found to be febrile (temperature, 38–40º C) and tachycardic (heart rate, 108 beats per minute), with an intensely pruritic maculopapular rash that had spread over most of her body. Her face was swollen, showing periorbital oedema. There was no mucosal involvement or epidermolysis. She had occipital, supraclavicular and inguinal lymphadenopathy, and hepatosplenomegaly. Liver function test results were markedly abnormal (alanine aminotransferase [ALT], 1203 IU/L [RR, < 41 IU/L]; alkaline phosphatase, 156 IU/L [RR, 30–120 IU/L]) and her serum albumin level was low (29 g/L [RR, 35–50 g/L]. She had lymphocytosis (lymphocyte count, 5.9 × 109/L [RR, 1.0–4.0 × 109/L), but her C-reactive protein level was not raised. A diagnosis of anticonvulsant hypersensitivity syndrome was made. The patient was transferred to the intensive care unit, where she remained for 48 hours, and treatment with prednisolone 40 mg daily was commenced. Her physical state improved rapidly. After 7 days her ALT level had dropped to < 500 IU/L and she was deemed well enough to be discharged. The prednisolone was gradually tapered by 5 mg per week. Topical betamethasone helped to soothe her pruritus and inflammation, and some mild exfoliation occurred. The patient continued to improve over the next 6 weeks. Her rash disappeared, as did her hepatosplenomegaly, and liver function test results normalised. She recovered fully and has remained on lithium and risperidone. Anticonvulsants are being used increasingly for mood disorders and chronic pain. Anticonvulsant hypersensitivity syndrome (ACHS) has been reported to occur with use of phenytoin, carbamazepine, phenobarbitone and lamotrigine, but not valproate. It is a rare and potentially fatal complication. ACHS is indicated by the presence of a triad of characteristic clinical features — fever, rash and internal organ involvement. It is estimated to occur in about 1 in 1000 to 1 in 10 000 patients who are exposed to these anticonvulsants.1 A similar reaction has also been described with exposure to sulfonamides, sulfones, allopurinol and non-steroidal anti-inflammatory drugs (piroxicam in particular).2 This reaction has also been referred to as drug-related rash with eosinophilia and systemic symptoms (DRESS) syndrome, and drug-induced hypersensitivity syndrome (DIHS).3 This patient showed a pattern of symptoms quite typical of ACHS, which usually appears after a brief delay of 2–4 weeks after anticonvulsant exposure, but may appear up to 12 weeks later.1 Her symptoms began to emerge about 6 weeks after she commenced taking carbamazepine, although a mild rash appeared after 3 weeks. Transient rashes are quite common following initiation of carbamazepine therapy and are not an indication for stopping the drug. Clinicians often fail to consider a diagnosis of ACHS.4 Although the seriousness of the illness was initially not obvious, it was fortunate that administration of carbamazepine had been stopped as soon as significant symptoms began to emerge. It is noteworthy that the patient’s physical state continued to deteriorate following withdrawal of carbamazepine, and only improved 1 week later, after hospital admission and treatment with prednisolone. Her mental state did not worsen during her acute illness, and she showed great resilience. Prednisolone has potent mood-altering properties and presents a significant risk for inducing either depression or mood elevation. Close monitoring of mental state and psychiatric involvement is recommended. Carbamazepine has been linked with a variety of hypersensitivity reactions, ranging from mild and benign urticaria and erythematous maculopapular eruptions to Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). ACHS is usually not as serious as SJS or TEN but can be life-threatening, and deaths from it have been reported.5 The skin condition can be extensive in ACHS, but is not as severe as the detachment of body surface area seen with SJS or TEN, which often involves gastrointestinal or tracheobronchial epidermal surfaces. Lessons from practice Anticonvulsant hypersensitivity syndrome (ACHS) is a rare and potentially fatal complication of treatment with the anticonvulsants phenytoin, carbamazepine, phenobarbitone and lamotrigine. Diagnosis is clinical and based on a triad of features: fever, rash and internal organ involvement. Early suspicion of diagnosis is essential, as the critical component of treatment is cessation of the implicated drug. Pharmacogenetic testing for the human leukocyte antigen allele B*1502 should be considered before commencing carbamazepine in patients of Asian ancestry. Genetic factors predispose individuals towards the development of these reactions, and recent data have linked human leukocyte antigen allele B*1502 as a marker in Asian populations, except among people of Korean and Japanese ancestry. Genotyping is recommended for at-risk groups;6 the prevalence of the allele is negligible in other ethnic groups.6 ACHS is associated with complex immunological changes that include chemotoxic and T-cell-mediated inflammatory injuries to tissues containing cytochrome oxidases.2 Viral infection may increase an individual’s vulnerability.7 The most critical component of management of ACHS is discontinuation of the implicated drug.1 All clinicians who prescribe anticonvulsant drugs therefore need to be aware of ACHS and the requirement for early suspicion of the diagnosis. General supportive measures and systemic corticosteroids are usually given, which in most instances results in full recovery. There is cross-sensitivity among aromatic anticonvulsant drugs (phenytoin, carbamazepine, phenobarbitone and lamotrigine), which means that patients who have had ACHS should avoid all of these drugs.4 In addition, a familial association with ACHS exists, and family members of these patients need to be informed that they may be at increased risk of developing this syndrome. Anticonvulsant drugs that are generally considered safe are valproate and benzodiazepines.4

Isaac Schweitzer MD, DPM, FRANZCP

To the Editor: A recent study of adult bodyweights recorded in 199 countries showed an increase in mean body mass index (BMI) of 0.4 kg/m2 per decade between 1980 and 2008.1 The increase in Australia was even greater: 0.9 kg/m2 for men and 1.2 kg/m2 for women.1 This increase in BMI, sometimes referred to as an “obesity epidemic”, has also been reported in coronial cases in South Australia, with the percentage of morbidly obese individuals (BMI > 40 kg/m2) undergoing autopsy rising from 1.3% to 4.8% between 1986 and 2006.2 While attention is often focused on complications of obesity such as diabetes mellitus, hypertension and cardiac disease, there is also a link to pulmonary thromboembolism (PTE). A recent prospective forensic autopsy series found that 24 of 32 cases of fatal PTE were in individuals who were overweight or obese.3 To examine this association further, we performed two analyses. First, we recorded the numbers of sudden deaths subject to coronial autopsies in SA from 2000 to 2009 (inclusive) where the cause of death was PTE. These were divided into two periods (2000–2004 and 2005–2009) and expressed as the percentage of the total number of coronial autopsies. Second, we analysed all deaths due to PTE that were the subject of coronial autopsies in SA in 2008 (the most recent year for which complete autopsy data were available at the time that the study was initiated). Age, sex and BMI were recorded, and the group was compared with an age- and sex-matched control group taken from other coronial autopsy cases. Despite considerable yearly fluctuations, the death rate due to PTE showed a small increase over time (Box). The rate of deaths due to PTE per total number of autopsies increased from 3.59% (198/5521) in 2000–2004 to 3.71% (239/6442) in 2005–2009. In 2008, there were 44 individuals (21 men, 23 women) with PTE as cause of death. The age range of this group and the 44 matching controls was 27–93 years (mean, 67 years). The mean BMI for individuals dying of PTE (29.6 kg/m2; range, 19.0–51.8 kg/m2) was significantly higher than for the controls (25.9 kg/m2; range, 17.7–44.6 kg/m2) (Student t test, P < 0.05). If PTE is conclusively found to be associated with BMI, there may be significant effects on hospital diagnostic services, coronial forensic investigation units and public expenditure in the future. Coronial cases in South Australia where death was due to pulmonary thromboembolism, 2000–2009

Roger W Byard · Hannah Rosenfeld

To the Editor: Colchicine is an alternative to anti-inflammatory agents for the treatment of acute gout.1 It is potentially toxic and can cause multiorgan dysfunction, including hepatotoxicity, neutropenia, acute kidney injury, rhabdomyolysis and hypotension. We report three cases of toxicity from supratherapeutic dosing that occurred within 2 weeks of each other. In each case, no alternative diagnoses (in particular, sepsis) were considered likely. An 87-year-old man presented with vomiting after 3 days of profuse diarrhoea, nausea and generalised myalgia without other infective symptoms. He had been prescribed 0.5 mg colchicine daily, but he was taking 1.0 mg four times daily. Clinical features included generalised abdominal tenderness, pancytopenia, rhabdomyolysis and hepatic dysfunction. These resolved over 5 days with supportive treatment. A 67-year-old woman presented with lethargy, diaphoresis, fever, nausea, vomiting and diarrhoea. She had been prescribed 1.0 mg colchicine initially, then 0.5 mg every 6 hours “until diarrhoea develops”. She was taking colchicine every hour despite diarrhoea. Initial clinical features included tachycardia, hypotension, tachypnoea and fever. Multiorgan dysfunction developed rapidly and despite aggressive resuscitation, including an intra-aortic balloon pump and broad-spectrum antibiotics, she died within 24 hours. A 77-year-old woman presented with nausea, vomiting and profuse diarrhoea. She had been prescribed 1.0 mg colchicine three times daily “until diarrhoea develops”. On presentation, she was dehydrated but haemodynamically stable, with mild renal and hepatic dysfunction and creatine kinase level elevation. These resolved over 4 days with supportive treatment. A recent randomised controlled trial demonstrated that low-dose colchicine (1.8 mg over 1 hour) was as effective as a higher dose (4.8 mg over 6 hours). Further, the adverse effects of the lower dose were similar to placebo and significantly less than those of the higher dose.2 Adapting to the Australian formulation, 1.0 mg initially and 0.5 mg 1 hour later is now recommended.3 In contrast, repeat doses of 0.5 mg until clinical improvement or side effects (in particular, diarrhoea) was previously recommended. In the cases above, the apparent dosing regimen differed significantly from current recommendations. Ineffective patient education may have also contributed to the conditions of patients 1 and 2, who up-titrated their dose. Patients 2 and 3 persisted with dosing despite gastrointestinal symptoms. Health professionals should be aware of the new dosing recommendations. These are highlighted by the National Prescribing Service4 and the Australian medicines handbook.3 Patients with renal or hepatic impairment, or concomitant use of cytochrome P450 3A4 or P-glycoprotein inhibitors (eg, clindamycin), are at increased risk.5

Myles W H Smith · Darren M Roberts · Siobhann M Ritson · Richard O Day

To the Editor: Warfarin is an orally administered vitamin K antagonist and has many well described interactions with commonly prescribed medications.1 However, only a handful of case reports worldwide have shown that flucloxacillin, a widely used antibiotic, may affect warfarin therapy by reducing its anticoagulant effect — in one instance contributing to the development of ischaemic stroke.2,3 There are several reports describing potential mech-anisms of interaction for flucloxacillin with warfarin.4,5 We describe the case of a 64-year-old man who was diagnosed with infective endocarditis on the basis of mitral valve vegetations and blood cultures that were positive for methicillin-sensitive Staphylococcus aureus. The patient underwent mitral valve replacement with a prosthetic valve and received prolonged antibiotic therapy with intravenous flucloxacillin for 8 weeks. Initially, for nearly 4 weeks, therapeutic anticoagulation with warfarin was difficult to achieve with warfarin doses ranging between 5 and 10 mg per day (target international normalised ratio [INR], 2.5–3.5). During this time, the patient was receiving intravenous flucloxacillin at a total daily dose of 8 g (2 g every 6 h). Flucloxacillin was increased to 12 g per day (2 g every 4 h) and there was a subsequent fall in the patient’s INR, which was sustained despite increasing the dose of warfarin to 25 mg per day (Box). Completion of flucloxacillin therapy was associated with a rise in the patient’s INR and a reduction in his warfarin dose requirement. No other relevant medications were commenced during this period of observation. This case highlights the potential for a dose-related effect of intravenous high-dose flucloxacillin (up to 12 g per day) on warfarin metabolism and the need for vigilance when prescribing antibiotics in conjunction with oral vitamin K antagonists. Other penicillins such as amoxicillin can, conversely, enhance the anticoagulant effects of warfarin, so the warfarin–flucloxacillin interaction may not be intuitive for many clinicians. Doses* for oral warfarin and intravenous flucloxacillin administered to a 64-year-old man with infective endocarditis, and corresponding INR INR = international normalised ratio. * Graph shows abbreviated, not daily, data. Intervals are weekly up to Week 9, then vary according to when INR was measured.

Philip Y-I Choi · Katherine L Phillips · Ian Rae

To the Editor: We read with interest the article by Ng and colleagues on life-threatening hypokalaemia associated with ibuprofen-induced renal tubular acidosis,1 and wish to present our own experience of four patients presenting to our hospital over a year (Box). The patients all presented with biochemical signs of renal tubular acidosis with severe hypokalaemia and a normal anion gap metabolic acidosis from long-standing misuse of ibuprofen taken in combination with codeine from over-the-counter (OTC) medications. Patients 1 and 2 presented acutely with deliberate misuse that included an ibuprofen–codeine combination product. Both patients subsequently admitted to long-standing misuse of ibuprofen and codeine taken in combination. Patients 3 and 4 presented with constitutional symptoms and generalised weakness with a history of taking large amounts of an ibuprofen–codeine combination product. Both these patients required intensive care unit admission for central venous access and potassium replacement. As in the case series by Ng and colleagues, there was no history to suggest gastrointestinal loss of potassium, and medication histories were negative for drugs known to cause intracellular potassium movement or potassium wasting (eg, diuretics). Ibuprofen cessation, potassium replacement and supportive care resulted in biochemical recovery in all four patients. Opioid addiction appears to be the common thread reported by Ng et al and in our case series. Other case reports support this.2,3 Paracetamol taken in supratherapeutic doses is known to cause hepatotoxicity, and it appears that patients with opioid addiction may now be turning to ibuprofen–codeine combination products. More evidence of the danger of these products comes from a case series reporting 27 patients with ibuprofen–codeine misuse that resulted in significant morbidity, including presentations for opioid dependence, gastrointestinal haemorrhage, hypokalaemia, anaemia and/or renal failure.4 In Australia, ibuprofen–codeine combination products are available OTC, albeit in restricted amounts due to problems related to codeine misuse.1 Further restrictions may need to be considered in light of the significant morbidity related to the ibuprofen component. Baseline laboratory investigations and other characteristics of four patients with ibuprofen-induced renal tubular acidosis* RR Patient 1 Patient 2 Patient 3 Patient 4 Sex, age in years Female, 35 Male, 55 Male, 41 Female, 39 Ibuprofen dose† Unclear, years’ duration 9.0–18.0 g/day 5.0 g/day 8.0 g/day Other medications Amitriptyline 50 mg at night Esomeprazole 40 mg daily Multiple medications Nil Serum pH 7.35–7.45 7.29 7.13 7.26 7.32 Pco2, mmHg 35–45 45 42 30 28 HCO3-, mmol/L 22–32 21 13 13 14 Anion gap, mmol/L 7–17 3 9 12 11 Na+, mmol/L 136–146 137 139 142 135 Cl-, mmol/L 98–106 116 120 120 111 Urea, mmol/L 3.0–8.0 4.7 4.4 3.0 6.9 Creatinine, μmol/L 60–120 70 123 125 99 K+ on presentation, mmol/L 3.5–5.0 2.8 2.9 2.5 1.4 K+ on discharge, mmol/L 3.5–5.0 3.5 3.8 3.7 4.5 RR = reference range. Pco2 = partial pressure of carbon dioxide. HCO3- = bicarbonate ion. Na+ = sodium ion. Cl- = chloride ion. K+ = potassium ion. * Same format as used in Ng et al case series1 to allow direct comparison. † Maximum recommended: 3.2 g/day.

Colin B Page · Paul A Wilson · Aidan Foy · Michael A Downes · Ian M Whyte · Geoffrey K Isbister

To the Editor: We have previously argued that the recent rapid increase in the popularity of low-carbohydrate (“low-carb”) beers, in Australia and other countries, is more a community health risk than a healthy alternative to traditional beers.1 This contention has since been supported by a survey conducted by the Victorian Health Promotion Foundation (VicHealth), which found that “low carbohydrate beer drinkers mistakenly believe these beverages are a healthier choice than other varieties”.2 Seventy-one per cent of respondents believed that low-carbohydrate beer is healthier than full-carbohydrate beer, despite having the same alcohol content. Alarmingly, 15% of respondents indicated that they consume more beer when drinking low-carbohydrate beer because they believe it is healthier than full-carbohydrate beer. The potentially insidious marketing of health benefits for alcohol products has recently been followed by the release of lower-alcohol, lower-calorie wines such as the McWilliam’s Balance range, Cockatoo Ridge’s Low Calorie Brut Cuvée, Beringer Blass’s White Lie, and the JMB Beverages Brightlite range. These are represented as containing a “lower” rather than “low” alcohol content because, at between 6.5% and 9.5% alcohol by volume, these wines clearly contain a far higher alcohol content than the ≤ 1.15% alcohol by volume that is required by Australian food standards to be represented as a low-alcohol product.4 The health-based marketing of these wines is similar to that of low-carb beer — it implies that consuming these products is healthier than consuming traditional versions. This implied health benefit message is reinforced by endorsement of McWilliam’s Balance wines by Weight Watchers and inclusion of these wines in the Weight Watchers diet program, which is followed by over 1.8 million Australians annually.4 According to its manufacturers, “McWilliam’s Balance is destined for incredible consumer demand”.4 McWilliam’s Balance wines contain about one-third less alcohol and one-third fewer kilojoules than regular wines.4 If these wines are being consumed to replace regular wine consumption in the same quantity, they could offer a community health benefit. If they are consumed instead of soft drinks or water in the belief that they are healthier than regular wines, or consumed in larger quantities than regular wine in the belief that they are healthier, they could represent a community health threat. Presently, the Australian Government is considering making alcohol companies display nutritional information and ingredients on all beer, wine and spirits labels as a result of a submission by the Alcohol and other Drugs Council of Australia.5 Governments need to modify food regulations to help make the message more explicit: lower-alcohol, lower-calorie wines are not a licence to drink to your own health.

Stephen P McKenzie · Evie R Leslie · Peter G Miller

To the Editor: I refer to the article by Cameron and Cooke,1 and the letter from Forero and colleagues.2 Cameron and Cooke correctly identified key problems associated with using a time-based process standard as a solution to poor patient outcome linked to overcrowding in emergency departments (EDs). They highlighted the need for monitoring to ensure “patient safety and quality of care are not compromised at any stage of the emergency pathway”. Forero et al challenged their assertion that the United Kingdom has replaced the 4-hour rule, and suggested there are three new time-based measures used as indicators of performance. Unfortunately, Forero et al have not noted the critical difference in new UK policies, in which no specific time cut-off is used as the benchmark for good performance.3 While acknowledging the importance of timeliness of care, “clinical outcomes and the experience of the patient” will be the focus of emergency care in the UK under the new Department of Health initiative effective April 2011.4 Surely Andrew Lansley’s (UK Secretary of State for Health) statement that “the four hour standard should be abolished”5 must mean nothing else but complete abandonment of this standard!. Concerns regarding a time-based performance indicator (and funding) were previously illustrated by Nocera in this Journal, who showed that numerical key performance has been a primary motivation for data fraud in Victoria and New South Wales, relating to ED waiting time.5 Furthermore, there is a possibility of admitting an unprepared patient to a ward at 4 hours,6 without acceptance of care by specialist team. A patient not properly worked up and sent to ward will not have the same automatic privileged access to critical care staff ratios or fast-tracked requests for pathology or radiology investigation provided in the ED. This can contribute to the excessive length of stay and, indirectly, hospital bed block. I caution against overly enthusiastic support for the 4-hour rule being instituted in Australian hospitals as a panacea to access block in the ED, and stress the need for better discharge planning, experienced patient flow and bed management, and improved hospital staff rostering for after hours. The latter include rethinking of ED doctors’ 24-hour staffing, with ED specialists attending to patients primarily,7 and junior doctors as assistants (if a 4-hour standard is to be attained), especially when facing an imminent glut of junior doctors, who will require close supervision, rotating through the ED.8

Shyan L Goh

To the Editor: We read with interest the recent cover article by Bhonagiri and colleagues detailing increased standardised mortality rates for patients admitted to Australian intensive care units (ICUs) out of hours.1 Have the authors considered a secondary analysis controlling for night-time staffing ratios? Aside from staffing levels, human factors such as the effects of fatigue and sleepiness due to circadian rhythm misalignment and sleep deprivation should be considered and further investigated. Studies have consistently shown that human cognitive and motor performance is substantially worse at night than during the day,2 due to the influence of the endogenous circadian clock. A recent study of emergency medicine registrars at an Australian tertiary hospital showed a 21% decrease in performance at night, in clinical scenarios of fellowship examination standard.3 Sleep during the day is of poorer quality and shorter duration than sleep during the night,4 resulting in chronic sleep restriction that exacerbates the impairment occurring in night work.5 Consecutive night shifts are associated with an increasing risk of accidents and injuries.6 In doctors, including consultants, inadequate sleep (fewer than 6 hours) is associated with harmful effects on patient outcomes.7 Despite our cultural beliefs, doctors are likely to suffer from the same biological effects of sleep loss and circadian rhythm disturbance as suffered by other humans. ICUs may provide one of the best hospital environments in which to study medical error, because of defined and limited personnel compared with non-ICU ward areas. ICUs also usually have better record-keeping and error-recognition systems, because of higher staff:patient ratios. Possible risk mitigation strategies include increasing the number of night staff, implementing oversight mechanisms for specified procedures and decisions, and ensuring that rosters and shift lengths are designed according to evidence linking sleep disturbance with poor patient outcomes. Such evidence should form the basis of any regulatory frameworks.

Dev A S Kevat · Andrew R Davies · Peter A Cameron · Shantha M W Rajaratnam

Reducing costs of surgical vampires As governments worldwide struggle to balance their health care budgets, a US study has found that a simple and almost free intervention can significantly reduce spending on routine blood tests. Researchers calculated the weekly costs of complete blood cell counts and chemistry panel tests for all non-intensive care unit patients at Rhode Island Hospital for 11 consecutive weeks. Each week an announcement was made to surgical staff and attending physicians of the total dollar value of these tests, as well as the charges per patient per day. The paper, called “Surgical vampires and rising health care expenditure”, reports that the baseline phlebotomy charges were $147.73 per patient per day. During the intervention, the costs dropped as low as $108.11 per patient per day, with almost $55,000 saved over 11 weeks. In an editorial on the research, Dr A Benedict Cosimi (Department of Surgery, Massachusetts General Hospital) writes that the study is “convincing evidence that cost consciousness can provide a potent weapon for reducing some of the wasteful medical spending”. Arch Surg 2011; 146: 524-527 Antioxidants up in smoke Doctors trying to encourage parents to quit smoking can point to new evidence which shows that second-hand smoke is bad news for children. Using data from a national health survey, American researchers analysed the serum cotinine levels of 2218 American children, aged 6–18 years, to determine their level of exposure to second-hand smoke. The children’s micronutrient levels, including vitamins C, E, A, B6, B12, betacarotene and folate, were also analysed. The study found that higher cotinine levels were strongly associated with lower levels of antioxidant micronutrients and folate, even after controlling for dietary intake and supplementation. Non-antioxidant micronutrients such as vitamins B6, B12 and D were not affected. Researchers commented that parents should be counselled on these specific risks from second-hand smoke exposure. Nicotine Tob Res 9 May 2011 (Advance Access) Sweet solution to chronic infections Chronic and recurrent bacterial infections are often caused by bacterial persisters: bacteria that survive an antibiotic onslaught by going into metabolic hibernation. While the patient initially appears to be cured, the infection recurs when the persisters “wake up”. Now a team of American biological engineers have developed a sweet and simple solution to boost the efficacy of antibiotics by targeting these persisters. The team found that adding glucose, mannitol, fructose or pyruvate to gentamicin, an antibiotic, reduced Escherichia coli persister viability by three orders of magnitude. Treating Staphylococcus aureus with fructose plus gentamicin also rapidly killed persisters. The mechanism of action appears to be that the sugar acts as a stimulant, generating proton-motive force, to increase the uptake of the antibiotic. It’s just like Mary Poppins (almost) said: a spoonful of sugar makes the medicine work. Nature 2011; 473: 216-220 Stenting v surgery: which is safer for women? Women with carotid stenosis may face more risks from stenting than from surgery, according to a study of 2502 patients from 117 centres in the US and Canada. Women who underwent carotid artery stenting had twice the rates of adverse events (stroke, heart attack and death) than women who had carotid endarterectomy (6.8% vs 3.8%); however, for men, the two procedures posed similar risks. The main contributor to the high rate of adverse events for women after stenting was the prevalence of strokes. However, researchers in the Carotid Revacularization Endarterectomy versus Stenting Trial said that more data are needed to determine whether the differential risk should affect clinical management of carotid stenosis for women. Lancet Neurology 9 May 2011 (Online) Fewer mastectomies with aromatase inhibitors A new US study has confirmed that using aromatase inhibitors pre-surgery can reduce the need for mastectomy for patients with stage 2 or 3 oestrogen-receptor (ER) positive breast cancer. Patients with these larger tumours sometimes undergo chemotherapy to reduce tumour size before surgery. Aromatase inhibitors are a low toxicity alternative that reduce the amount of oestrogen in the body, to stop or slow the growth of ER-positive tumours. The study found that of 159 post-menopausal women who were candidates for mastectomy at baseline, 81 were able to undergo breast-conserving surgery after 16 weeks’ treatment with aromatase inhibitors. The research compared three different aromatase inhibitors (exemestane, letrozole and anastrozole). J Clin Oncol 9 May 2011 (online)

Sophie McNamara

Med J Aust 2011; 194 (11 Suppl).