Volume 180 Issue 9

Unravelling the uncertainties The antiphospholipid antibody syndrome is an autoimmune disease that commonly presents with either venous thromboembolism (VTE) (deep vein thrombosis, pulmonary embolism), arterial thrombosis (ischaemic stroke, coronary thrombosis, peripheral arterial occlusion) or unexplained fetal loss. A high index of suspicion for the diagnosis is raised in patients with unusual thrombosis, those without obvious risk factors, or those who experience recurrent events. The diagnosis is based on presentation with one of the above clinical criteria and detection in the laboratory of persistent antiphospholipid antibodies. Clinically relevant antiphospholipid antibodies are identified by either functional coagulation assays (lupus anticoagulant) or immunoassays (anticardiolipin antibody, β2-glycoprotein-1 antibody).1,2 When considering the diagnosis of the antiphospholipid antibody syndrome, it is important to perform both clotting and serological tests, as they are concurrently positive in 50% of unequivocal cases.3 The detection of a lupus anticoagulant and/or medium- to high-titre IgG antiphospholipid antibodies is associated with an approximately 10-fold increase in risk of VTE.4,5 Unlike the treatment for other autoimmune disorders, anticoagulation rather than immunosuppression is the mainstay of treatment.1-3 About 40 000 tests for thrombophilia are performed in Australia each year . . . Why are we performing these tests? Significantly elevated levels of antiphospholipid antibodies are detected in up to 20% of patients with VTE, compared with only 2% of healthy adults.6 This means that clinicians will be frequently asked to make decisions based on positive antibody test results. With about 40 000 tests for thrombophilia performed in Australia each year,7 the question arises as to the impact of testing for antiphospholipid antibodies in clinical practice. Why are we performing these tests? Up to now the reason has been twofold. Firstly, there is a perception that there is a high risk of recurrent thrombotic episodes, and even death, when anticoagulation treatment is stopped in people with antiphospholipid antibodies. Several retrospective studies have suggested that treatment with warfarin should be continued for at least 12 months, if not longer or lifelong, as up to 70% of patients will have recurrent events without ongoing treatment.8,9 For patients with arterial occlusion, particularly those without other atherosclerotic risk factors (eg, smoking, diabetes, hyperlipidaemia, hypertension), recurrence of thrombosis from significant levels of antiphospholipid antibodies would be catastrophic. For such patients, anticoagulation is usually continued. For patients with VTE and no obvious risk factors, testing of antibody levels may help to resolve the current uncertainty about the optimal duration of anticoagulation treatment and may even help to determine whether anticoagulation should be stopped at all. In a multicentre study, 412 patients were prospectively followed after a first episode of VTE: within 4 years after ceasing warfarin, 29% of patients with IgG anticardiolipin antibodies had experienced further events, compared with 14% without antibodies.6 However, maintaining people on long-term warfarin therapy carries the inevitable risk of serious haemorrhage (1.1 events/100 patient-years) and anticoagulant-related death (0.25 deaths/100 patient years).10 If we had further data on the optimal duration of anticoagulation treatment, we would be in a better position to discuss with patients the risk versus benefit of ongoing treatment. The second reason for determining the presence of antiphospholipid antibodies is that it assists in deciding the optimal intensity of anticoagulation treatment. There is evidence from retrospective case series that recurrence of thrombotic episodes can occur even with moderate-intensity warfarin therapy (target international normalised ratio [INR], 2.0–3.0) when compared with higher-intensity therapy (target INR, 3.0–4.5).8,9 However, this information comes from specialised expert clinics for high-risk patients, and to generalise the findings to a large number of VTE patients without better evidence is problematic. The cost of having a higher INR (3.0–4.4 rather than 2.0–2.9) is the doubling of the risk of any bleeding event.10 A recent prospective randomised controlled trial on the efficacy and safety of high-intensity warfarin treatment (target INR, 3.0–4.0) versus standard-intensity treatment (target INR, 2.0–3.0) in 114 patients with arterial thrombosis and VTE with antiphospholipid antibodies attempted to address this uncertainty.11 The results of the trial showed that there was no difference in the rates of recurrent thrombosis and bleeding between the two groups. Although the confidence intervals were wide because the number of events was small, the study does give some guidance regarding treatment decisions for the majority of patients with thrombosis and antiphospholipid antibodies. However, there are several caveats: Patients were included after already receiving warfarin for variable periods of time, and only a third of patients were allocated to one of the trial groups within 6 months of thromboembolism. This means that patients who were at highest risk of recurrence or bleeding while on warfarin were excluded; Patients who already had recurrent thrombosis while receiving warfarin with a target INR > 2.0 were specifically excluded; Control of INR range was supervised by expert clinic staff, who kept INRs within range 70% of the time for the standard-intensity arm and 40% of the time for the high-intensity arm. Most of the patients out of the INR target range in the high-intensity group were below the therapeutic range. Whether this degree of control for a given target INR is achieved in everyday practice is uncertain and needs further validation. It highlights the difficulty of maintaining a narrow therapeutic target INR range with warfarin despite the best intentions. Given the limitations of the published studies, the clinician is still faced with uncertainty in dealing with patients with thrombosis and antiphospholipid antibodies. For most people with thrombosis and antiphospholipid antibodies, long-term standard-intensity warfarin with a target range INR 2.0–3.0 may be appropriate. However, there will still be patients with extensive or unusual thrombosis for whom higher-intensity anticoagulation treatment could be considered. This situation applies particularly to people in whom recurrence may be threatening to life, limb or organ, particularly when no other recognised risk factor for either VTE or atherothrombosis can be removed or modified. To reliably answer the question of how to manage patients with thrombosis and a significant level of antiphospholipid antibodies would require an inception cohort study, with patients randomised at diagnosis to different intensities of anticoagulation treatment.

Ross I Baker MB BS, FRACP, FRCPA

Graded physical exercise is no panacea, but is beneficial Much remains unknown about the enigmatic clinical disorder chronic fatigue syndrome (CFS). Apart from clear evidence implicating certain infections as a trigger, and reproducible evidence of increased rates of comorbid depression, the aetiology remains obscure.1 Similarly, despite numerous tantalising hypotheses of pathogenesis, including immunological, neuroendocrine and metabolic disturbances, all remain unproven.1 On the positive side, the criteria for diagnosis are well accepted internationally,2 and have been the subject of recent refinements to improve reliability.3 The disorder is well recognised, and about 0.5% of patients attending general practice are identified as having CFS.4 What, then, of treatment for a disorder with so many unknowns? About 40 controlled trials of treatment interventions for patients with CFS have been published to date.1,5 The most striking features of these studies are, firstly, that no curative treatment has been found, and secondly, there has been a remarkable lack of benefit demonstrated from any of the broad array of antiviral, immunological, hormonal, antidepressant and other treatments evaluated. The sole exception lies in the relief of symptoms and improvement in functional capacity provided by programs incorporating graded physical exercise. Several studies have incorporated physical exercise as a component of cognitive–behavioural therapy (CBT). The CBT approach in treatment for patients with CFS is based upon the premise that cognitive attributions and behavioural patterns act as perpetuating factors for symptoms. In particular, given that the cardinal phenomenon of fatigue in CFS is characterised by a marked and prolonged exacerbation of symptoms following minor physical activity, patients may reach the conclusion that it is best to avoid exercise. Thus, patients may develop an understandable cognitive attribution that exercise is harmful in the short term (as symptoms are worsened) and detrimental in the longer term. This leads to altered behaviour in the form of reduced physical activity with consequent deconditioning. Similarly, as sleep typically takes on a characteristic unrefreshing quality, and fatigue is dominant in the symptom complex, patients may consider that increased sleep holds promise for symptom relief and for rapid recovery. This attribution commonly leads to a behavioural pattern of phase-shifted sleep (late night to late morning) and frequent daytime naps. Accordingly, the CBT approach generally seeks to alter these cognitive attributions and modify the associated behavioural patterns. Having established CBT as a beneficial treatment approach, subsequent studies have sought to identify the “active” components of the CBT package. In this regard, graded physical exercise therapy has been found in several studies to be significantly better than comparators such as relaxation therapy, notably in reducing symptom severity and gaining improved function.6-8 In particular, Fulcher and White6 reported that 16 of the 29 patients who completed exercise treatment rated themselves as “much” or “very much” better, compared with eight of the 30 patients in the “flexibility” control group. Similarly, Powell et al7 found that 84% of a selected patient group had significantly improved functional capacity and reduced fatigue 12 months after graded exercise therapy when compared with standard medical care. The report by Wallman et al (page 444) adds to this evidence with a systematic and well-controlled evaluation of graded exercise versus relaxation over 12 weeks.9 Importantly, these authors have incorporated the notion of “pacing” into the exercise program. This concept recognises that individual patients with CFS differ significantly from each other in the amount of physical activity they can achieve before symptoms become exacerbated. In addition, this “threshold” beyond which symptoms worsen may vary over time. Hence, the graded exercise program allowed patients who experienced worsened symptoms to temporarily reduce exercise duration and then to resume once symptoms subsided. Their findings are noteworthy in that multiple parameters of exercise performance, such as resting systolic blood pressure and work capacity, were improved in the active group, indicating that the reconditioning component of the program was indeed effective. In addition, measures of mood and cognitive performance also showed improvement. Interestingly, the proportion of patients who rated themselves as significantly better was not different in the two groups. Unfortunately, no commonly used measure of disability (such as the SF-36)10 was included as a primary outcome measure, as would be typical in studies of chronic medical illness. In addition, the durability of the effects was not examined after the completion of the intervention. Finally, although “pacing” was an important component of the exercise intervention, this approach was not formally evaluated against “unpaced” exercise. Nevertheless, one can safely conclude from these studies that graded physical exercise should become a cornerstone of the management approach for patients with CFS. When applied astutely, including via “pacing”, it may not be realistic to anticipate cure, but it is realistic to expect that patients will feel better and will improve their functional capacity. In combination with appropriate interventions to improve sleep hygiene and to treat any comorbid mood disturbance,11 patients with CFS managed in this way often achieve a substantially better quality of life while awaiting recovery.

Andrew R Lloyd MB BS, MD, FRACP

In diagnosis and prognosis, we should avoid intuitive “guesstimates” and seek a validated numerical aid One of the axioms of clinical practice is that, in medicine, there are few, if any, certainties. When assessing the likelihood of a specific disease in a particular patient, or the chance of a future adverse event in a patient with known disease, clinicians are estimating probabilities or risk. These estimates derive from a clinical gestalt — the process of interpreting findings from history, examination and simple investigations (diagnosis), or of disease-specific correlates of complications or death (prognosis). Clinicians use these estimates of probability or risk to decide whether they should intervene immediately, particularly if effective treatments are available. Alternatively, if the disease likelihood is low, or treatments toxic or only marginally effective, these estimates are used to decide whether to defer treatment and either observe expectantly or conduct more sophisticated tests whose results may substantially alter pre-test likelihood estimates. If the estimate is too high, patients may incur unnecessary treatments or confirmatory investigations, or, if the estimate is too low, they may suffer the consequences of delayed intervention. Thus, a fair bit is riding on how accurately we can judge the likelihood of current or future disease. Available research suggests that, for various reasons, we are not that good at it.2-4 Common pitfalls include: framing a clinical problem in a way that may exaggerate risk; overweighting or underweighting certain clinical features; erroneously extrapolating past, vividly recalled cases to current patients; or manipulating risk subliminally to better fit with a preferred course of action (or inaction). Overall, most of us, not surprisingly, are risk averse and will commit to action to avoid personal regret at witnessing an unfavourable but possibly preventable event, even if our perception of risk of such an occurrence seems low.5 In this issue of the Journal, Attia and colleagues (page 449) evaluate the extent to which clinicians’ estimates of probability or risk for commonly encountered case scenarios vary from the “correct” estimate, and which clinician-related factors may influence such variation.6 They distributed three hypothetical case scenarios to groups of general practitioners and physicians in Australia and the United Kingdom, and compared respondents’ estimated probabilities of angina (in a patient with chest pain), deep vein thrombosis (DVT) (in a patient with a swollen leg), and future stroke (in a patient with chronic atrial fibrillation) with the “correct” estimates derived from statistically validated clinical-decision rules. Two cautions come to mind: were the clinicians given sufficient information on which to base a reasoned judgement (keeping in mind that they could not examine the patients); and how accurate was the rule-based estimate as the reference standard? One could argue that, in the chest-pain scenario, few experienced clinicians would be comfortable estimating the likelihood of angina simply on being told of a 65-year-old man presenting with exertional chest pain, without more detail about the character of the pain, the existence of coronary risk factors, and any signs of vascular disease seen on physical examination. The decision rule applied to the same case is also suspect, as it includes, for example, rapid relief with nitrogylcerine as being positively predictive of angina, which recent evidence would challenge.7 In the other two scenarios, the clinical details provided were more complete, and the decision rules more robust. Another concern is that the “correct” estimate was stated as a single percentage, which clinicians were expected, perhaps unfairly, to closely approximate. This ignored the fact that, in developing the rule, the “correct” estimate is actually a mean within a range of observed frequencies, all of which would probably lead to the same clinical action. On the positive side, the strengths of the study were its large, representative samples of clinicians, use of three different scenarios, and use of logistic regression to identify clinician-specific predictors of accuracy. Setting aside methodological limitations, how did the respondents fare? Only slightly more than half of the whole group were within 20 percentage points of the “correct” probability estimate for the angina and stroke scenarios, and less than one in 10 achieved a similar result with the DVT scenario. In keeping with my earlier comments, most respondents overestimated rather than underestimated the risk, with estimates spread over a huge range, from 10% to 100% at least, for all cases. There was a notable lack of association between accuracy and experience as measured by age, years of practice, or field of specialty, with GPs performing as well as physicians. Unfortunately, the study by Attia et al did not have the power to determine whether graduating from a medical course that used problem-based learning — with emphasis on evidence appraisal — predisposed to better performance. The implications of this study and others are several. First, all clinicians, irrespective of experience, appear to have problems quantifying probability or risk of disease, and, while there may be exceptions, this difficulty is independent of the clinical circumstances. Consequently, we should avoid intuitive “guesstimates” and seek instead a validated decision-rule, scoring scheme or other numerical aid that gets us closer to the mark. Fortunately, an increasing number of such tools are becoming available8 and in a form compatible with hand-held computers. Second, if we are to choose the best rules and use them appropriately, we need to understand how such rules should be constructed and tested.9 Third, we may need to “unlearn” some of our cherished clinical “rules of thumb” if evidence arises that questions their validity.10 Finally, we should advocate for more research into decision aids that will help us to more accurately estimate and communicate likelihood of disease in individual patients. The results of such efforts should facilitate a more rational use of investigations and treatments and lead to better patient outcomes.

Ian A Scott FRACP, MHA, MEd

The modernisation agenda is a valiant attempt to move forwards, but is it real change and will it make a difference? As Australia reflects on healthcare directions after a quarter of a century of Medicare, what has the UK done to update its rather older National Health Service (NHS)? In 2000, the “NHS Plan” (www.nhs.uk/nationalplan/) set out an ambitious attempt at modernisation — “to give the people of Britain a health service fit for the 21st century”. It promised record investment and a number of defined dividends for that investment, such as extra hospital beds and more nurses and doctors. Modernisation became the catchword. A Modernisation Board was convened to oversee the process, a Modernisation Agency created to spread good practice, and a number of other organisations established. These include the National Institute for Clinical Excellence, which reviews drugs, new technology and procedures and then issues guidelines; and the Commission for Health Improvement (already re-engineered once), an independent inspection body that publishes reports, including performance ratings. . . . by the time this Postcard appears, it is likely that further reorganisation may have been put in place. The whole scope of the NHS reorganisation that has followed is not worth reporting in detail here, for, by the time this Postcard appears, it is likely that further reorganisation may have been put in place. But what does the government really mean by “modernisation”? Is it a fundamental shift or just words? Are there lessons for Australia and Medicare? The Modernisation Agency (www.modern.nhs.uk) has its sights on a number of areas: primary care, secondary (hospital) care, mental health services, leadership and workforce, clinical governance, innovation and improvement, and good practice. “3 Rs” have been coined — renewal, redesign, respect — and “5 simple rules” laid down: see things through the patient’s eyes; find a better way of doing things; look at the whole picture; give frontline staff the time and the tools to tackle the problems; and take small steps as well as big leaps. There is an obvious abundance of rhetoric, but is there any substance? One example in the primary care arena is coronary heart disease (CHD): 30 CHD Collaboratives have been established across England to improve cardiac services by bringing together professionals working in primary care and their hospital-based cardiological colleagues. Although these Collaboratives aim “to fundamentally redesign the systems for prevention, diagnosis, treatment and care of CHD”, what has actually been instituted (accompanied by fanatical fervour and exaggerated claims about its value) is a quality-improvement exercise that is difficult to generalise and impossible to evaluate. There is an expectation that modernisation initiatives should be evaluated, and the Modernisation Agency has espoused a commitment to “quick and clean” research to capture and share the learning gained through service improvement activities. Despite this commitment, the resources needed for adequate evaluation of modernisation projects are rarely set aside, and only occasionally are academics who are trained and experienced in evaluation of health services brought into the picture. Simultaneously, closure of the excellent NHS Research and Development Programme, established under a previous Conservative government, has seriously curtailed much of the investigator-initiated health services research. Instead, concerns about the slowness and “relevance” of academic enquiry have seen the ascendancy of change for the sake of being seen to be doing something within the NHS. In a world reminiscent of a kind of Maoist “continuous revolution”, an evaluation report, no matter what its quality, does become irrelevant if things have already changed again before the assessment of the earlier initiative is complete. Since the Modernisation Agency was established, Foundation Trusts have arrived on the scene. Those achieving Foundation status are allowed to set their own salary scales and to raise their own capital. The Bill to create them had a rough ride in the UK Parliament and only just survived. We don’t really know yet what Foundation Trusts will achieve, but, presumably, they are a further step towards encouraging private investment in the NHS. We have recently been told that “targets” (benchmarks of performance used as a management tool leading to the awarding of Michelin-like “star” ratings to individual Trusts) are out — they are not popular, nor usually evidence based. So, it’s change again — but is it real change and will it make a difference? Pieter Degeling and colleagues1 have attempted to cut through the rhetoric and suggested that the modernisation agenda requires healthcare workers and managers to accept loss of clinical autonomy. They need to share power through team-based approaches to dealing with the resource implications of clinical activity. These authors find that the top-down method of performance management is not appreciated — and that this displeasure is shared by clinicians not only in the UK but across continents. The change in work practices of clinicians is, of course, only part of the UK modernisation agenda, but it is fundamental to it. By contrast, “modernisation” in Australian healthcare has progressed through incremental change, which can be more sustainable. It needs to take into account Australia’s complex structures, fragmentation of providers and the idiosyncrasies of the State–Commonwealth divide. Yet, there is probably a stronger recognition of the need for incentives — to motivate clinicians, and to avoid heavy-handed, top-down approaches that can leave a workforce feeling demoralised and out of step. Despite its rather eccentric structure, the healthcare system in Australia manages to produce good outcomes. Surveys reveal reasonable levels of satisfaction with the healthcare sytem among workers and patients in Australia, and among the British public there are high levels of commitment to the NHS. However, the morale of the health workforce in the UK is extremely low. If the sceptics among the readers of this Postcard don’t believe there is a difference, come and work in the UK! The good news about the NHS modernisation agenda is that it exists, and is a valiant attempt to move forwards. It is, however, imposed from above, full of rhetoric, short on substance and poorly evaluated. It does not deal with the fundamental problems of the NHS — decades of infrastructure neglect, low staff-to-population ratios, chronic overload, and a focus on process rather than outcome.

Richard F Heller MD, FRCP, FRACP, FAFPHM · Konrad Jamrozik DPhil FAFPHM, MFPH · David P Weller MPH, PhD, FRACGP, FAFPHM

Objective: To investigate whether 12 weeks of graded exercise with pacing would improve specific physiological, psychological and cognitive functions in people with chronic fatigue syndrome (CFS).Design: Randomised controlled trial.Setting: Human performance laboratory at the University of Western Australia.Participants: 61 patients aged between 16 and 74 years diagnosed with CFS.Interventions: Either graded exercise with pacing (32 patients) or relaxation/flexibility therapy (29 patients) performed twice a day over 12 weeks.Main outcome measures: Changes in any of the physiological, psychological or cognitive variables assessed.Results: Following the graded exercise intervention, scores were improved for resting systolic blood pressure (P = 0.018), work capacity (W·kg-1) (P = 0.019), net blood lactate production (P = 0.036), depression (P = 0.027) and performance on a modified Stroop Colour Word test (P = 0.029). Rating of perceived exertion scores, associated with an exercise test, was lower after graded exercise (P = 0.013). No such changes were observed in the relaxation/flexibility condition, which served as an attention-placebo control.Conclusions: Graded exercise was associated with improvements in physical work capacity, as well as in specific psychological and cognitive variables. Improvements may be associated with the abandonment of avoidance behaviours.

Karen E Wallman BSc(Hons), BEd, PhD · Alan R Morton DipPE, MSc, EdD · Carmel Goodman MD, MB BCh · Robert Grove PhD · Andrew M Guilfoyle PhD

Objective: To assess the accuracy and variability of clinicians’ estimates of pre-test probability for three common clinical scenarios.Design: Postal questionnaire survey conducted between April and October 2001 eliciting pre-test probability estimates from scenarios for risk of ischaemic heart disease (IHD), deep vein thrombosis (DVT), and stroke.Participants and setting: Physicians and general practitioners randomly drawn from College membership lists for New South Wales and north-west England.Main outcome measures: Agreement with the “correct” estimate (being within 10, 20, 30, or > 30 percentage points of the “correct” estimate derived from validated clinical-decision rules); variability in estimates (median and interquartile ranges of estimates); and association of demographic, practice, or educational factors with accuracy (using linear regression analysis).Results: 819 doctors participated: 310 GPs and 288 physicians in Australia, and 106 GPs and 115 physicians in the UK. Accuracy varied from about 55% of respondents being within 20% of the “correct” risk estimate for the IHD and stroke scenarios to 6.7% for the DVT scenario. Although median estimates varied between the UK and Australian participants, both were similar in accuracy and showed a similarly wide spread of estimates. No demographic, practice, or educational variables substantially predicted accuracy.Conclusions: Experienced clinicians, in response to the same clinical scenarios, gave a wide range of estimates for pre-test probability. The development and dissemination of clinical decision rules is needed to support decision making by practising clinicians.

John R Attia MD, PhD, FRCPC · David W Sibbritt PhD · Ben D Ewald BMed, MMedSci · Balakrishnan R Nair FRCP, FRACP · Neil S Paget MA, DipEd · Rod F Wellard MEd, PhD · Lesley Patterson · Richard F Heller MD, FRCP

The impact of a computer-based infectious diseases electronic antibiotic advice and approval system (“IDEA3S”) was assessed as an alternative to a labour-intensive, phone-based approval system. IDEA3S-based approvals replaced 48% of all approvals for the most frequently requested antimicrobial agents (ceftriaxone/cefotaxime, vancomycin) and were associated with stable overall rates of antimicrobial use. Antibiotic prescribing for community-acquired pneumonia was 76% concordant with IDEA3S recommendations, and clinical acceptance of IDEA3S was excellent. Successful implementation required a coordinated, evidence-based approach between clinicians, pharmacists and hospital administration, together with ongoing staff education and feedback of results. IDEA3S is a useful new adjunct to routine clinician consultation to support appropriate antibiotic prescribing for a number of common indications in hospitals.

M Lindsay Grayson MD, FRACP, FAFPHM · Sharmila Melvani BPharm · Sue W Kirsa BPharm, GradDipHospPharm · Stephen Cheung BPharm, GradDipInfoSys · M Kent Garrett BPharm, GradDipHospPharm · Anthony M Korman MB BS, FRACP · William A Thomson BPharm, MSc, FSHPA

Objectives: To document diagnosis rates of type 2 diabetes mellitus in children and adolescents in Western Australia over the past 12 years, the clinical characteristics of these patients and any comorbidities.Design: Review of a prospectively recorded diabetes database.Setting: Tertiary paediatric referral centre (the only such centre in WA).Patients: All children and adolescents aged < 17 years diagnosed with type 2 diabetes between 1990 and 2002 and managed by Princess Margaret Hospital Diabetes Unit.Main outcome measures: Anthropometric and demographic data; glycohaemoglobin (HbA1c) level; blood pressure; lipid levels; presence of acanthosis nigricans.Results: 43 patients (15 males and 28 females) were diagnosed with type 2 diabetes. Age (SD) at diagnosis was 13.6 (1.8) years. The rate of diagnosis has been progressively increasing (average annual increase in the unadjusted overall rates of type 2 diabetes was 27%). Twenty-three patients (53%) were of Indigenous origin and 18 (42%) resided in rural areas. The mean (SD) HbA1c level at diagnosis was 10.0% (3.2%). Seventy-two per cent of patients had acanthosis nigricans, 59% had hypertension, and 24% had hyperlipidaemia.Conclusions: There has been an increase in the diagnosis rate of type 2 diabetes in children and adolescents in WA. Comorbidities are frequent.

Sarah K McMahon MB BS(Hons) · Aveni Haynes MB BChir · Nirubasini Ratnam BSc(Hons), RN · Maree T Grant RN · Christine L Carne PGRN(Paed) · Timothy W Jones FRACP · Elizabeth A Davis FRACP

No adverse pregnancy outcomes with metformin use have been reported, except in one unmatched study. Otherwise, the studies are small and non-randomised, with the exception of one prospective, randomised controlled trial, currently under way, comparing metformin with insulin in women with gestational diabetes mellitus (the MiG trial). No long-term follow-up data for offspring of mothers receiving metformin have been published. Any woman with diabetes should be as close to euglycaemia as possible before pregnancy. In some circumstances (eg, severe insulin resistance), metformin therapy during pregnancy may be warranted. When metformin treatment is being considered, the individual risks and benefits need to be discussed with the patient so that an appropriate decision can be reached.

David Simmons FRACP, MD · Barry N J Walters FRACP · Janet A Rowan FRACP · H David McIntyre FRACP

QuestionDoes high-impact exercise in the prepubertal period have an osteogenic effect in females? Trial details Design: Randomised, partially blinded clinical trial. Participants: 21 monozygotic twin pairs of prepubertal girls aged 7–10 years; 15 pairs recruited through a twin registry and 6 pairs recruited from local schools. Twin pairs were randomly allocated, one to the intervention group and one to the control group. Intervention: The twin in the intervention group engaged in 10 minutes of impact exercise on three occasions each week for 9 months, supervised by a teacher at school. The twin in the control group received no extra contact with teachers or researchers. Main outcome measures: Adipose tissue measured by skinfold measurements; body weight, lean tissue mass, relative fat mass (%fat) and bone mineral content (BMC) measured by dual-energy x-ray absorptiometry. Main results: At 9 months, girls in the impact exercise group had reduced adipose tissue compared with those in the control group (5.6% reduction v 0.6% increase in skinfold measurements [P < 0.05] and a 3.7% reduction v 1.5% reduction in %fat [P < 0.05]), but no difference in body weight or lean tissue mass. In a post-hoc analysis of 12 pairs of twins who were not undertaking impact activities outside the intervention program, there was a higher proximal femur BMC in the intervention v control group (11.9% v 9.4% increase [P < 0.001]). Conclusion: The authors conclude that a high-impact exercise intervention results in an additive osteogenic bone response in prepubertal girls not undertaking other impact activity, but has no effect on bone status in girls already involved in high-impact sports. CommentaryRationale for the trialTo prevent osteoporosis, it is important to maximise bone mineral accrual in early life and minimise bone loss in later life. It is thought that high-impact exercise in premenarchal years may influence the accrual component of this process, although the most effective exercise regimen remains unknown. Trial methodsMonozygotic twins were selected to assure inherent control of genetic confounders, such as prepubertal status, rate of maturation and body dimension and, to some extent, environmental confounders, such as diet. Twins were not selected on any basis of perceived need, such as low bone mass or low involvement in impact activities. The trial’s methods of randomising twin-pairs to intervention and control groups and group allocation concealment from the radiographer are not described, but would be needed for inclusion of this trial’s findings in a systematic review. Major outcome measurements were based on dual-energy x-ray absorptiometry, a non-invasive, objective test for measuring bone and body composition which was read by a radiographer blinded to group status. The primary outcome was bone mineral content (BMC), a mass measurement that can be estimated with more precision than bone mineral density (BMD). It is unclear whether those measuring physical characteristics or analysing the data were blinded. No measurement of dietary intake was reported, and physical activity was not monitored objectively before or during the study. One girl from each twin-pair was randomly assigned to an impact exercise program, while the other received no intervention. The effect of confounders, which has been problematic in many non-randomised studies of bone health in childhood, was minimised to some extent, but bias may have resulted from parents’, teachers’ and participants’ awareness of group status. Chances for contamination between groups were high, with twins cohabiting and attending the same school. The trial design could have been strengthened by the control group receiving a low-impact exercise program or a placebo intervention such as health education. The success of the intervention would have depended on sustainability of program goals and intensity and motivation provided by teachers, and any differences in teachers’ ability to provide these would influence the nature of the intervention. Effects often overlooked are that more efficient skill execution over time reduces workload and that well trained muscles can attenuate bone load. Load is difficult to measure, but would be an essential component of future trials of physical activity in children. A commentary on compliance from the participants’ perspective would also have been useful to inform future studies. The conclusion that the intervention was more effective in girls not undertaking impact activity outside the intervention is not reflected in the summary statistics. In the 21 girls in the high-impact exercise group, BMC increased by 11.96%, compared with 11.90% in the subgroup of 12 girls inactive outside the intervention. Without further information, it is difficult to understand the large difference in t values between the two analyses (t = 0.78 for the whole group v t = 2.97 for the otherwise inactive subgroup) and why a small effect size was significant in 12 twin-pairs. A mean-versus-differences plot would have shown if the effect was greater in girls with low BMC, and additional statistics, such as 95% confidence intervals and number needed to treat (say, to improve BMC by 5%), would help to clarify the clinical importance of the results. New informationResults of musculoskeletal gains should be interpreted cautiously, as groups improved their bone mass equally, and so the role of exercise in the acquisition and maintenance of peak bone mass remains unclear. Further studies are needed, because many public health recommendations are being made even though there is little evidence supporting them. Implications for clinical practiceIntervention activities were developmentally appropriate and the simplicity of the program, with only 10 minutes of exercise on three occasions each week, could be attractive for public health interventions and inclusion in planning and policy documents. However, it is important to ascertain if certain subgroups, such as inactive children or those with low bone mass, benefit most. Family-based activities to target such groups may be more efficient than wider school-based activities that involve many children who may not benefit. To reliably measure the effects of impact exercise on early bone health, larger studies with a more generalisable population will be needed, with stratified random allocation to groups for greater control of potential confounders, and with more attention paid to issues of quality program delivery. Although large trials are a challenge to conduct, they are essential for increasing confidence in their clinical implications. Risk versus benefit must also be considered. In programs for prepubertal children, it is essential that teachers and parents have the expertise to ensure safe landings from jumps and safe increases in workload.

Jennifer K Peat PhD · Geraldine A Naughton PhD

Clinical trials provide evidence of effectiveness of treatments as an average for a group of patients, yet, in clinical medicine, we usually wish to apply these results to individuals. Can we simply apply the overall trial result for each patient, or can the result be tailored to individual patients in some way? Consider a hypothetical example: a randomised trial comparing treatments A and B shows that treatment A is more effective than B among men (P < 0.001), but not among women (not signficant). Does this mean men should receive the new treatment, but women should not? Box 1 illustrates these results from three different studies. In Study 1, the estimated treatment effect in men and women is the same — a 25% reduction in mortality associated with treatment A — but the much smaller number of women in the study gives rise to wider confidence intervals for this subgroup. In this case, there is no basis to consider that the treatment is any less effective in women (no heterogeneity; ie, non-significant test for interaction). Treatment could be considered effective for any patient regardless of sex. In Study 2, the treatment effect in women is less than that in men (8% v 25% relative reduction, or 0.92 v 0.75 relative risk, respectively), but the effects in both are still consistent with the overall result of a 20% relative reduction, and there is no evidence of significant heterogeneity between groups (test for interaction, P = 0.20). Here, the different results between men and women could be simply due to chance, and it would still be appropriate to apply the overall estimate to both men and women (unless there was additional evidence).1 In Study 3, the observed effects for men and women are sufficiently different to suggest that this difference is unlikely to be due to chance (test for interaction, P = 0.01), and it is reasonable to conclude that the treatment effect differs between men and women. In this instance, the trial evidence should be considered separately for these subgroups. However, even here, a test of interaction can still give a low P value simply on the play of chance if many subgroups have been evaluated.2 A practical approachConsider applying the overall trial treatment effect to each subgroupHow should we decide in practice whether to consider the treatment effects for these subgroups separately? A practical approach is shown in Box 2. A controlled trial is usually designed with a sample size large enough to show an overall treatment effect, but not necessarily adequate to show significant effects in each subgroup separately. The overall treatment effect is considered the best estimate for each subgroup of patients in the trial (this is sometimes referred to as the effect domination principle1). Hence, the treatment-effect results should only be applied differently for different subgroups if there is evidence of heterogeneity (a significant difference between subgroups, sometimes called interaction or treatment-effect modification).3-7 In considering whether there is evidence of heterogeneity, it is also worth reviewing the other questions outlined in the checklist for subgroup analyses in the previous article in this series.1 If there is clear and reliable evidence of heterogeneity, using the treatment effects for each subgroup may be appropriate. However, as these may be unreliable (based on smaller numbers of patients) they may still be considered exploratory and motivate further trials rather than necessarily leading to different treatment guidelines. Further, evidence of heterogeneity may also lead to a search for underlying factors which may be linked to the particular subgroup and provide a more plausible biological explanation for such variation. For example, an apparent difference in treatment effect between men and women may truly relate to differences between these groups in age or smoking status (so-called confounding). Seek confirmatory evidenceIf there is still uncertainty whether differences between the subgroups in treatment effect are real, the following steps should be taken: seek confirmation from the results of an independent trial, a meta-analysis, or both; determine whether the effect is also present for a composite (expanded) endpoint, or surrogate endpoints; and establish whether independent evidence exists of a-priori biological plausibility of differences in the treatment effect. Without a good a-priori rationale for subgroup differences, the overall treatment effect provides a reasonable estimate for each subgroup, unless confirmatory evidence of treatment differences becomes available. Estimate treatment effect according to baseline riskIf the same (or similar) relative treatment effect applies to different subgroups of patients, then those with a greater baseline risk of an event will derive a larger treatment effect. The absolute risk reduction associated with treatment is simply the absolute baseline risk multiplied by the relative risk reduction (Box 2).8 For example, for a patient group with a 20% baseline risk, a treatment with a relative risk reduction of 25% would translate into a 20 × 0.25 = 5% reduction in absolute risk. For a patient group with a 10% baseline risk, this would translate into a 10 × 0.25 = 2.5% absolute risk reduction. The number of patients needed to treat (NNT) to avoid one event can be calculated as one divided by the absolute risk reduction (Box 2).8 This corresponds to 1 ÷ 0.05 = 20 NNT for a patient with a baseline risk of 20%, and 1 ÷ 0.025 = 40 NNT for a patient with a baseline risk of 10%. Smaller numbers needed to treat will result for patients at higher baseline risk. A practical exampleA 75-year-old woman who has had a previous myocardial infarction (MI) presents within 4 hours of symptom onset with suspected acute MI and ST elevation on electrocardiogram (ECG); she is being considered for aspirin and reperfusion therapy. Data from randomised trials of aspirin, thrombolytic therapy and immediate coronary angioplasty are considered. The patient has no known contraindications to these treatments. Based on evidence from the ISIS-2 trial,9 there is strong evidence that aspirin reduces the risk of short-term mortality, by about 23%, both overall and within most subgroups examined, including women and patients aged over 70 years. However, in this trial, among patients with a prior MI, no significant treatment benefit was observed. While the treatment effect in this subgroup apparently differed from patients without a prior MI, the interaction may have been a chance finding owing to the many subgroups examined. (For example, the chance of at least one significant result at the 5% level among 20 independent tests is over 50%.1) Consequently, the trial evidence still strongly supports the use of aspirin therapy in this patient. Randomised trials of thrombolytic therapy in the FTT overview10 have also demonstrated clear evidence of a reduction in mortality from such treatment for patients with acute ST elevation presenting within 12 hours of symptom onset. This overview also suggested diminished effectiveness of such treatment in the elderly (test for trend with older age, P = 0.01). However, in this case, much of the heterogeneity could be explained by the fact that older patients more often presented later (after 12 hours) and without the specific diagnosis of ST elevation on ECG. Lack of ST elevation and late presentation to hospital relate directly to the underlying biology and are linked to diminished effects of treatment. Once these confounding factors have been taken into account, there is much less rationale for considering different treatment or withholding thrombolytic therapy simply on the basis of the age of our patient.11 Next, the role of immediate coronary angioplasty in such a patient could be considered. Randomised trials, particularly in specialised centres, have suggested an additional treatment benefit for immediate coronary intervention compared with thrombolysis. An individual patient data overview of earlier randomised trials suggests a relative reduction in death or reinfarction of about 50%, with similar relative effects in each of the subgroups examined.12 However, the absolute benefits of treatment (absolute risk reductions) were estimated to be much greater in the patients at high baseline risk, particularly those aged over 70 years (see Box 3). Consequently, if treatment with immediate angioplasty is considered appropriate in the particular hospital setting, it would be likely to have greater absolute benefit for this older patient than the average patient. Finally, the role of long-term treatment in this patient could be considered. Should statin therapy be considered on the basis of the evidence from such trials as the LIPID and CARE studies?13,14 Both of these had insufficient evidence to show reductions in mortality with treatment for women separately. In the LIPID trial, older and younger patients had similar relative reductions in events (Box 3), but older patients at higher baseline risk had greater absolute benefit. Fewer women than men were studied in these trials, and yet the results for women were not inconsistent with those for men (Box 3). The effect of statin therapy for women with prior CHD is illustrated further by the results of the 4S, CARE and LIPID trials.14 The combined results of these three trials show an overall significant reduction in coronary events; the estimates from the separate trials vary but are still consistent with the overall result. Evidence of a similar relative treatment effect from statin therapy in both women and men has recently been confirmed by the results of the Heart Protection Study.15 Finally, for some of these decisions, different recommendations for treatment may still apply even when a similar relative treatment effect seems valid and patients are at the same baseline risk. Circumstances in which different recommendations will be appropriate include: Where the importance of different outcomes (of benefit and harm) varies for different patients Where patient preference varies for other reasons Where there are limitations in applying the trial results in a particular setting, related to such factors as the skill or experience of practitioners and access to technologies. Principles for applying subgroup analysis to decisions about individual patients are summarised in Box 4. Cautious interpretation of the results of subgroup analyses is generally advisable. 1: Treatment effects in subgroups of men and women in three hypothetical trials Overall relative risk: 0.75 for Study 1; 0.80 for Study 2; 0.87 for Study 3; represented by the vertical dashed line in each case. 2: Interpreting treatment effects in different subgroups within a controlled clinical trial* * The decision pathway assumes there was a reasonable basis to consider the subgroups to have the same underlying condition. 3: Absolute risk reduction (ARR) and numbers needed to treat (NNT) in age and sex subgroups In none of these cases is there evidence of treatment effect modification (all P values for interaction are non-significant). ARRs and NNTs are derived from the overall relative treatment effect. 4: Principles for using subgroup evidence for making decisions about individual patients Use the subgroup-specific result only when there is (unconfounded) evidence of interaction and, ideally, confirmatory evidence. Use the estimated overall treatment effect if there is no evidence of heterogeneity (no interaction or treatment-effect modification). Adjust the size of the treatment benefit (and harm) according to the patient’s baseline risk. Consider patient preferences regarding each outcome when there are significant trade-offs in benefit and harm.

R John Simes MD, SM, FRACP · Val J Gebski BA, MStat · Anthony C Keech MB BS MScEpid FRACP

Clinical record A 43-year-old man presented with myalgia and upper respiratory tract symptoms. He had noted weight gain of 7 kg, lethargy and cold intolerance over the previous 12 months. He had no chest pain, rash or fever. His past history included acute myocardial infarction (AMI) 12 years earlier. Subsequently, he had been taking low-dose aspirin. He commenced simvastatin 2 years after the AMI for hypercholesterolaemia (> 7 mmol/L). His sister and father have hypercholesterolaemia and his father had an AMI before 40 years of age, suggesting heterozygous familial hypercholesterolaemia. Two years before presentation, his hypolipidaemic therapy was switched from simvastatin to atorvastatin, although he denied experiencing any side effects of the former. He reported consuming 40–50 g/day of alcohol, and that he had recently quit smoking. Examination revealed that he was hypertensive (160/90 mmHg) and obese (body mass index, 32 kg/m2). He had marked corneal arcus, but no tendon xanthomas or xanthelasma, and no goitre. There was no muscle tenderness and power was normal. Reflexes were delayed. The results of some of the laboratory tests performed are shown below. In addition, normal findings were recorded for full blood count, erythrocyte sedimentation rate, and C-reactive protein, electrolyte, glucose, and calcium levels. Serological tests for hepatitis, and test results for protein electrophoresis, antinuclear factor, immunoglobulin and prostate-specific antigen levels, were all normal. There was no myoglobinuria, haematuria or proteinuria. Chest x-ray findings were normal, electrocardiography showed old Q waves, and an abdominal ultrasound showed hepatic steatosis. Apart from γ-glutamyltransferase, normal results were obtained for all other liver function tests. Statin-induced myositis was suspected and atorvastatin was stopped. Thyroid function tests instituted after endocrine review 5 days later revealed hypothyroidism (free T4, 1.9 pmol/L [normal range, 11.0–23.0 pmol/L] and thyroid-stimulating hormone, > 100 mU/L [normal range, 0.30–5.00 mU/L]). Tests for thyroid peroxidase and thyroglobulin antibodies both gave positive results, suggesting Hashimoto’s thyroiditis. The patient was prescribed thyroxine 50 μg daily, with subsequent slow-dose titration because of ischaemic heart disease. The Box (page 473) shows the gradual normalisation of the creatine kinase (CK) level over time. Lipid levels remained elevated despite thyroxine therapy. Simvastatin 10 mg/d was recommenced with careful monitoring. The dose was increased progressively up to 80 mg daily for persistent hyperlipidaemia. Despite full-dose statin therapy, there was no change in the findings of liver function tests and only mild asymptomatic elevation of CK levels. Investigation Result (normal range) Creatine kinase (CK) (IU/L) 4890 (< 240) CK-MB index (%) 2.0 (< 5.0) Total cholesterol (mmol/L) 9.0 (< 5.5) Triglycerides (mmol/L) 2.7 (< 2.0) High-density lipoprotein cholesterol (mmol/L) 1.2 (> 1.0) Urea (mmol/L) 6.7 (2.3–7.6) Creatinine (mmol/L) 0.197 (0.05–0.11) γ-Glutamyltransferase (U/L) 196 (10–55) Statin-related muscle complaints include myalgia, myositis and rhabdomyolysis.1 Hypothyroidism itself can cause musculoskeletal symptoms, including myalgia, Hoffmann’s syndrome (muscle stiffness, weakness and increased muscle mass, frequently with elevated creatine kinase [CK] level), Kocher–Debré–Sémélaigne syndrome (diffuse muscular hypertrophy and weakness in congenital hypothyroidism), a polymyositis-like syndrome (with proximal muscle weakness and markedly elevated CK level), and rhabdomyolysis.2 The coexistence of hypothyroidism and statin use may increase the risk of myopathy.3 Statin-induced myopathies tend to resolve within a few days to 1 month after ceasing statin use.4 Persistent elevation of CK level after stopping statin therapy has been reported, prompting further investigation and leading to the discovery of coexisting hypothyroidism.3,5 Thyroxine replacement therapy was reported as normalising CK and total cholesterol levels in these patients. However, to the best of our knowledge, ours is the first report of a patient with treated hypothyroidism in whom statin therapy was safely reintroduced after the resolution of myositis. While the exact aetiology of the myositis in our patient can not be proven, it seems most probable that it was precipitated by a combination of hypothyroidism and statin use. Full-dose statin therapy did not cause a recurrence of myositis once the hypothyoidism had been treated, implicating hypothyroidism as a contributing factor. However, it is uncertain whether the hypothyroidism would have resulted in myositis without coexisting statin therapy. The patient has mild asymptomatic elevation of CK level while taking simvastatin and with adequate thyroxine replacement. Such asymptomatic CK elevation is frequently seen in subjects during statin trials with both placebo and statin therapy, and continued treatment while asymptomatic and with CK levels up to 10 times the upper limit of normal has to date proven to be safe.6 As hypothyroidism can cause hyperlipidaemia, we suggest that thyroid function should be checked before commencing statin therapy, particularly if there are any clinical features to suggest its presence. We also suggest that patients who develop symptoms or signs suggestive of myopathy while taking statin therapy should be tested for hypothyroidism. As in our patient, it may be safe to cautiously reintroduce statin therapy in patients with a history of myopathy, once coexisting hypothyroidism has been treated. Lessons from practice Hypothyroidism should be considered as a secondary cause of hypercholesterolaemia in all patients. Patients developing myopathy when taking statin therapy should be tested for hypothyroidism. It may be safe to cautiously reintroduce statin therapy in patients with myopathy, once coexisting hypothyroidism has been treated. Biochemistry results and drug dosages over time Year 1 Year 2 Year 3 Year 4 Year 5 20 May 25 May 22 Jun 27 Jul 22 Aug 28 Sep 1 Nov 5 Jan 12 Apr 17Aug 18 Mar 17 Jan 23 Jan Thyroid-stimulating hormone (mU/L) (NR, 0.3–5.0) >100 90.9 53.9 23.9 8.13 4.35 1.23 1.02 0.85 0.64 0.58 Total cholesterol (mmol/L) 9 10.2 8.9 8.2 6.2 6.5 5.7 4.4 4.9 4.0 4.4 Creatine kinase (IU/L) (NR, < 240) 4890 1839 336 196 216 209 442 320 Creatinine (mmol/L) (NR, 0.05–0.11) 0.197 0.171 0.14 0.14 0.14 0.12 0.14 0.12 0.12 0.12 0.12 Statin (mg/d) Stopped atorvastatin Started simvastatin 10 10 20 40 80 80 80 80 Thyroxine (μg/d) Started thyroxine 50 75 100 125 150 150 175 175 175 175 175 175 NR = normal range.

Leo P Rando MB BS · Sarah AL Cording · Harvey H Newnham MB BS, FRACP, PhD

Improved understanding of the regulation of body weight and activity is leading to new treatment strategies

Joseph Proietto FRACP, PhD · Louise A Baur FRACP, PhD

Stephanie L Jones,* Eugene Athan,† Daniel O’Brien,† Stephen R Graves,‡ Chelsea Nguyen,§ John Stenos¶ * Infectious Diseases Registrar, † Infectious Diseases Physician, Geelong Hospital, Ryrie St, Geelong, VIC 3220; ‡ Medical Microbiologist, § Scientist, ¶ Senior Scientist, Australian Rickettsial Reference Laboratory, Barwon Health, Geelong, VIC. StephljonesATyahoo.com To the Editor: Murine typhus (caused by Rickettsia typhi) has not been previously described in the state of Victoria, although it is well known in Western Australia, Queensland and South Australia. In 2002, a 49-year-old man presented to Geelong Hospital, Victoria, with a 10-day history of fever, myalgia, rigors, headache, rash, sore throat, dry cough and pleuritic chest pain. On examination, he had a fever (temperature, 39.2°C), hypoxia (oxygen saturation, 91% in room air), tachycardia, a central maculopapular rash and conjunctivitis. Blood tests revealed hyponatraemia, thrombocytopenia, white cell count in the reference range, with left-shifted neutrophil change (toxic granulation and increased immature forms) and a C-reactive protein level of 377 mg/L (reference range, < 10 mg/L). The patient lived on a hobby farm close to Geelong. Two weeks before becoming unwell, he had cleaned out the contents of a shearing shed, including two rotten sheepskins in which rats had been nesting. He reported generating a lot of dust and debris in the air. He had not noticed any tick, flea or other insect bites. Serological testing was performed for rickettsia. Baseline serum, taken 10 days after symptom onset, showed antibodies to the typhus group of rickettsiae, R. typhi (murine typhus) and R. prowazekii (epidemic typhus), with a titre of 2000. The titre rose over the following 4 days to 64 000, a fivefold increase, diagnostic of typhus group infection. Antibody titre to the spotted fever group of rickettsiae was significantly lower (peak titre, 8000). The patient was treated with oral doxycycline and recovered completely. Murine typhus was first described in Adelaide in 19221 and is now considered endemic in parts of Western Australia and Queensland.2,3 A possible case reported from Melbourne4 was, in retrospect, probably Brill–Zinsser disease (relapsed epidemic typhus). Murine typhus has an incubation period of 8–16 days and is generally self-limiting, although fatalities have occurred.1 The disease typically presents with fevers, prominent myalgia, a central rash, nausea, conjunctivitis, and often significant pulmonary involvement. Unlike the tick-borne spotted fever group of rickettsiae, R. typhi is transmitted by rodent fleas. Transmission occurs either by aerosolisation and inhalation of infected flea faeces, often during demolition or cleaning of rat-infested environments, or, less commonly, by inoculation of faeces into a fleabite. Murine typhus is usually diagnosed retrospectively by serological testing using microimmunofluorescence. Antibodies are usually detectable 7 to 9 days after disease onset, and IgG may persist for years. Cross-reactivity is seen between R. typhi and R. prowazekii; it is not possible to identify the pathogen by serological testing alone.5 Specific diagnosis is based on known local epidemiology and, as epidemic typhus does not occur in Australia, we believe this was a case of murine typhus, the first described in Victoria.

Stephanie L Jones · Eugene Athan · Daniel O’Brien · Stephen R Graves · Chelsea Nguyen · John Stenos

Mark Little,* Peter L Pereira,† Richard Mulcahy,‡ Teresa Carrette,§ Jamie Seymour¶ * Emergency Physician, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009. † Director, ‡ Emergency Physician, Cairns Base Hospital, Cairns, QLD. § Research Officer, ¶ Senior Lecturer, Department of Tropical Biology, James Cook University, Cairns, QLD. Mark.littleAThealth.wa.gov.au To the Editor: We are concerned that a recent report announced that the Queensland Ambulance Service now treats patients with hypertension caused by Irukandji syndrome with sublingual glyceryl trinitrate, based on an uncontrolled, unrandomised, unblinded “trial” of three patients.1 We believe the authors have made the justification for such treatment on questionable assumptions. The authors claim that venom from Carukia barnesi is a sodium channel agonist that causes massive noradrenaline release. This claim is based on a letter which reported whole C. barnesi being crudely blended and injected into piglets.2 There is no mention in this letter of any proven sodium channel agonist action.2 We are unconvinced that it was solely the venom of the jellyfish that resulted in a rise in noradrenaline levels in the piglets, especially since there has been a recent report of toxicity from homogenised jellyfish with the nematocysts (ie, venom) removed.3 While we believe that magnesium may be a promising treatment for patients with Irukandji syndrome, there has only been one case reported,4 and we are aware of several anecdotal failures, including the first patient in the letter by Fenner and Lewin.1 This does not constitute the justification for “proven effective treatment”. Fenner and Lewin claim that patients were envenomed by Carukia barnesi and yet provide no evidence. Carukia barnesi has yet to be discovered or reported south of Townsville. Two of us have reported that more than one jellyfish is responsible for Irukandji syndrome, and a second jellyfish has recently been identified.5 Accurate identification of the envenoming animal is essential in toxinology. Patients who present with Irukandji syndrome are in severe pain, and pain is a well known cause of hypertension. In a series of 116 patients with Irukandji syndrome, the mean dose of morphine administered was 31 mg.6 In the three patients reported by Fenner and Lewin, all were in severe pain, but only received 10 mg of morphine. In light of subtherapeutic analgesia, attributing the persistent hypertension solely to an unmanageable disease process is therefore premature and possibly incorrect. As a further confounder, might the reduction of blood pressure in two patients have resulted from the delayed onset of action of intramuscular morphine and promethazine? Without the addition of control patients to this trial, no conclusions can be drawn on the causative factors associated with this treatment. Too often in the past, unsupported treatments have been adopted, only to be abandoned several years later when shown to be ineffectual, or even dangerous to patients. There are too many assumptions, unsupported claims and confounders in Fenner and Lewin’s letter. Toxinology research needs good science and not poor anecdotes.

Mark Little · Peter L Pereira · Richard Mulcahy · Teresa Carrette · Jamie Seymour

Geoffrey K Isbister Toxicologist, and Consultant Clinical Toxicologist, NSW Poisons Information Centre, Newcastle Mater Misericordiae Hospital, Locked Bag 7, Hunter Region Mail Centre, NSW 2310. gsbiteATferntree.com To the Editor: Fenner and Lewin describe three cases of Irukandji syndrome in which glyceryl trinitrate (GTN) was used to transiently lower blood pressure.1 However, they provide no evidence that this relieved the patients’ pain or improved their ultimate outcome (development of pulmonary oedema or myocardial injury); they therefore do not show sufficient evidence for instituting such therapy. It is worrying that, with little evidence, sublingual GTN is now recommended as a prehospital treatment in Irukandji syndrome. Although GTN has been used safely in other conditions, its use without adverse effects in three patients is not evidence that it can be used safely in treating jellyfish envenoming. It is of concern that the treatment of bites and stings remains based on anecdotal evidence, and that clinical toxinology has not moved with the rest of medicine to developing evidence-based approaches. Fenner and Lewin state, in their second paragraph, that intravenous magnesium has proven to be effective in treating symptoms of Irukandji syndrome. This is based on a single case report and no controlled trials. It simply provides a starting point so that properly designed studies can be done to determine if magnesium is effective and safe in Irukandji syndrome. It is not appropriate to suggest that magnesium is a proven therapy without further investigation. Are we not learning from previous problems in clinical toxinology and prehospital care? Both are areas of medicine where treatment protocols are rarely based on substantial evidence.2,3 The pressure immobilisation bandage was introduced for the first-aid treatment of Chironex fleckeri stings with no supporting evidence, and it has taken two well designed animal studies to show that this is dangerous.4,5 A recent well designed study in the United States showed that prehospital intubation by paramedics of patients with head injury resulted in transient desaturation in 57% of patients and significant bradycardia (< 50 bpm) in 19%.6 This occurred despite the paramedics describing the intubation as “easy” in 84% of the patients who desaturated. This shows that it is essential to properly evaluate the safety and efficacy of treatments before recommending them for prehospital use. Although the infrequency of many envenoming syndromes makes controlled studies difficult to do, it is essential that clinical investigators collaborate to institute such studies. This is now happening in Australia with the commencement of randomised controlled trials on redback spider antivenom, magnesium in Irukandji syndrome and hot-water first-aid in jellyfish stings. Hopefully we will move from anecdote to evidence in clinical toxinology with collaborative studies such as these.

Geoffrey K Isbister

Peter J Fenner National Medical Officer, Surf Life Saving Australia, Sydney, NSW, and Associate Professor, School of Medicine, James Cook University, Townsville, QLD; PO Box 3080, North Mackay, QLD 4740. pjfennerATozemail.com.au In reply: We did not provide evidence of any effect on pulmonary oedema, myocardial injury or any effect in stopping pain, as that was not our intention. Also, even intravenous nitrates that have been used for many years in hospital are ineffective in reducing the muscle-cramping pains of Irukandji envenomation, and, although they reduce hypertension and ischaemic myocardial pain, there is no correlation or evidence that they prevent pulmonary oedema or myocardial injury. The assumption that the Queensland Ambulance Service (QAS) introduced this treatment after our trial is incorrect. The QAS Medical Director will confirm that it was introduced independently of our trial and actually before we treated our first case. While pain causes hypertension, in our Patient 1 effective analgesia had been attained without any effect on his hypertension. Also, many patients with Irukandji syndrome have pain without hypertension, while others have severe hypertension even with effective pain control.1 Further evidence that the venom from Carukia barnesi is a sodium channel modulator has been submitted for publication (Ken Winkel, Director, Australian Venom Research Unit, Melbourne, personal communication). Carukia barnesi has now been caught in the Mackay region, 400 kilometres south of Townsville (identified by me, and confirmed by L A Gershwin, PhD student in cubozoan taxonomy, James Cook University, 2003, personal communication). A number of other species can cause the Irukandji syndrome, but the jellyfish causing the sting is rarely caught, so cause and effect are hard to establish at present. Our aim was to present early evidence that sublingual nitrates may be effective in reducing the hypertension that occurs in some cases of Irukandji syndrome; our suggestion was that they be further trialled.2 It seems worthwhile to do so, especially as sublingual nitrates have also been shown to be effective in dysreflexia from spinal injury,3 where hypertension also occurs from the massive release of similar catecholamines. At least two deaths have occurred after Irukandji envenomation, both as a result of cerebrovascular accidents from severe hypertension.4 When treating a patient with severe hypertension from Irukandji envenomation in a prehospital situation, it is reasonable to try to reduce the hypertension. Doing so might reduce the risk of a cerebrovascular accident and possible death, and so further trials of this prehospital treatment must take place. Other prehospital treatments must also be trialled, especially those for pain. Early promising leads need to be published early for all to evaluate. The Irukandji syndrome is a dreadful experience for the victim; all possible prehospital relief measures must be tried and evaluated.

Peter J Fenner

Richard J G Bonham Medical Director, Queensland Ambulance Service, PO Box 1425, Brisbane, QLD 4001. rbonhamATemergency.qld.gov.au Comment: I would like to clarify a few points. Firstly, all Queensland Ambulance Service (QAS) paramedics use glyceryl trinitrate (GTN) frequently to treat cardiac chest pain, and have done so for many years. They are very familiar with its effects and interactions. Secondly, a small number of intensive care paramedics (ICPs), the top tier of officer, with many years of training and experience and tertiary qualifications, have, for a number of years, been authorised to consult with the senior doctor at the receiving hospital for use of GTN to treat acute severe hypertension. In Queensland, GTN has been used for this indication in one or two patients per year, compared with its use in 25 000 patients with cardiac chest pain. Finally, QAS reviewed its protocol for managing marine envenomation after two people died from Irukandji syndrome two years ago. The current protocol for suspected Irukandji stings is now standard care, including oxygen, and vinegar if there is a visible sting, followed by aggressive pain management, including up to 30 mg of morphine intravenously. If the patient has significant hypertension (> 200/120 mmHg) after effective analgesia, ICP officers are able to consult with a senior doctor to administer GTN according to the above protocol. Obviously, the concern of the QAS Medical Advisory Council (comprising representatives of all medical specialty colleges and other medical groups) was to prevent avoidable cerebral haemorrhage or acute heart failure, as occurred in the two deaths from Irukandji syndrome, but, to date, such use of GTN has not been invoked.

Richard J G Bonham

Peter A Leggat,* Robin Griffiths† * Associate Professor, School of Public Health and Tropical Medicine, James Cook University, Townsville, QLD 4811; † Senior Lecturer in Occupational and Aviation Medicine, Wellington School of Medicine, University of Otago, Wellington, New Zealand. Peter. LeggatATjcu.edu.au To the Editor: Grace and Penny present some fascinating “travellers tales” concerning travel insurance and medical evacuation.1 Although I recognise that there may have been difficulties with individual cases, the article probably paints an unnecessarily bleak picture of travel insurance and medical assistance companies. About a fifth of travel insurance claims involve the successful use of the emergency assistance service, which mostly does not involve aeromedical evacuation.2 Evacuation by a dedicated air ambulance is uncommon among travellers.2 Almost all travellers in need of medical and dental treatment source treatment locally, for which they are generally reimbursed. Aeromedical evacuation, where needed, is more likely by scheduled airlines with or without an escort. The article may raise unrealistic expectations among travellers for aeromedical evacuation. Air ambulances do not operate and respond in the same way as ground ambulances. Time is required to assess and prioritise cases, select suitable aircraft, obtain flight plan clearance, check and equip aircraft, brief retrieval and receiving hospital personnel, and develop contingency plans. Aircraft may be required to refuel en route, as air ambulances tend to be based where they can be maintained and staffed adequately and safely — this may be far from the retrieval site. It is useful to raise travellers’ awareness of the possible difficulties in accessing adequate medical facilities in many developing countries, especially where tourism is promoted, and create a sense of travellers’ responsibility for their own health, safety and welfare. The International Society of Travel Medicine has articulated this in a recently released policy statement.3 Readers should be wary of generalising from a small number of case studies from a “popular tropical island holiday destination”.1 It would be useful to collect data on medical retrievals and emergency assistance provided from various sources and consult all interested parties before attempting to establish guidelines for medical evacuation. Grace and Penny do raise the important issue of the need for appropriate travel insurance for all travellers. This message needs to be conveyed by the travel industry and by travel health advisers. The article referred to a study of the travel health advice provided by general practitioners in New Zealand, but did not mention that only about half the GPs in that study routinely discussed travel insurance.4 A similar study in Australia indicated that less than 40% of GPs routinely give advice on travel insurance.5

Peter A Leggat · Robin Griffiths

Fred Gilligan,* Peter Sharley,† Andrew Berry‡ * Emeritus Director of Retrieval and Resuscitation, † Director, Retrieval Services, RAH Mediflight, Royal Adelaide Hospital, North Terrace, Adelaide SA 5000; ‡ Director, NSW Newborn & Paediatric Emergency Transport Services, Sydney NSW. To the Editor: As consultants in intensive care, experienced in transporting critically ill patients within Australia and internationally, we have also received complaints from clients about some travel insurance organisations.1 Poor service appears due partly to economic restrictions and partly to the paucity of experienced staff and specialised aircraft available. Assistance companies implement travel insurance policies for underwriters, quoting 24-hour emergency call centres. Some companies economise by subcontracting (eg, episodic diversion of calls to another organisation). This can result in coordinators lacking an understanding of regional geography, population and medical services and omission of the early, vital input of senior medical advisers. Information relayed between several people can be lost or distorted. Failure to ask key questions can result in inappropriate clinical planning. Furthermore, time zone differences can result in calls being received late at night, further reducing availability of immediate expert opinion. Only a well-organised (and thus expensive) control centre with a critical care focus can manage all these variables. Furthermore, it is difficult for a company to permanently employ current, high-grade healthcare staff in adequate numbers. Current critical care retrieval staff in Australia are confined to a few stand-alone aeromedical organisations or public hospitals which run aeromedical services for state governments and other organisations, using their regular anaesthesia, intensive care or emergency medicine staff. Reliable assistance companies tend to contract with these retrieval organisations or their off-duty staff. In Australia, ambulance aircraft able to travel offshore, with adequate oxygen systems, stretcher attachments, electrical power, and so on, are uncommon and expensive to equip. Portable equipment to care for a critically ill patient represents a capital investment of over $100 000, and some services try to achieve results with inadequate tools or by borrowing. ISAS (the International Society of Aeromedical Services, Australasian Chapter) promotes standards on staffing and equipment,2 including the Australian and New Zealand College of Anaesthetists/Australian College for Emergency Medicine standard for transporting the critically ill.3 Based on critical care practice, the standards are not legally binding, but one suspects they would be quoted in any litigation. It behoves all travellers to scrutinise their travel insurance policies closely — many think of them only in terms of lost or stolen baggage. Following serious injury or illness, the policy may dictate what kind of care is offered.

Fred Gilligan · Peter Sharley · Andrew Berry

Howard Roby Specialist in Anaesthesia and Intensive Care; and Medical Director, Customer Care Medical Assistance, Private Bag 913, North Sydney, NSW 2059. macrobyATozemail.com.au To the Editor: As the medical director of Customer Care Medical Assistance, which manages the travel insurance policies of most travelling Australians, I wish to reassure readers that none of the experiences chronicled by Grace and Penny1 related to our company. I have previously described the activities of Customer Care in the Journal.2 I would welcome any enquiries from colleagues about the way our company functions. I note that there was no declaration by Grace and Penny of their competing interests.

Howard Roby

Kirsty L Buising,* Karin A Thursky,† James F Black,‡ Graham V Brown§ * Clinical Research Fellow, † Infectious Diseases Physician, ‡ Head of Epidemiology, § Head, Victorian Infectious Diseases Service, Royal Melbourne Hospital, Grattan Street, Parkville, VIC 3050. Kirsty.buisingATmh.org.au To the Editor: The 2003 Australian guidelines on antibiotic therapy suggest that the Pneumonia Severity Index (PSI) may be used to triage site of care and antibiotic selection for patients with community-acquired pneumonia.1,2 The PSI was developed as a mortality prediction tool, using data from over 14 000 patients with community-acquired pneumonia.3 The antibiotic guidelines suggest specifically that PSI classes I and II represent patients suitable for outpatient therapy, and that class V can identify patients likely to require intensive care and broad-spectrum antibiotic therapy. We believe this is beyond the previously recommended applications of the PSI and advise caution about its use to identify patients with severe pneumonia. In the cohort used to validate the PSI, only 32% of patients with severe pneumonia (requiring intensive care) were in class V, indicating that the PSI has poor sensitivity for severe pneumonia.3 This finding has been reflected in other studies.4 The strength of the PSI lies in its ability to identify low-risk patients, as the title of the validating article suggests.3 The PSI is so heavily weighted by age and comorbidities that younger patients needing intensive care are unlikely to accumulate enough points to reach class V. This is important, as early identification of patients with severe pneumonia and initiation of broad-spectrum antibiotic therapy and intensive-care support improves outcomes. We are concerned that the PSI may be widely accepted for a purpose for which it was not intended and has not been validated. In underestimating the severity of illness in two-thirds of patients with “severe pneumonia”, the guidelines may provide false reassurance, while clinicians may lose confidence in the PSI if they find it “misses” most patients requiring intensive care. Current evidence does support use of the PSI to guide decisions about inpatient or outpatient therapy. However, the modified British Thoracic Society (BTS) Severity Score is a simpler, better-validated tool to identify patients with “severe pneumonia” who are likely to need intensive care assessment5 (Box). This tool is useful for junior staff to “flag” patients with potentially severe pneumonia and ensure that they are discussed with a senior clinician. As always, the final management and antibiotic selection should be guided by clinical judgement. We believe that the antibiotic guidelines are valuable to encourage appropriate antibiotic use; our aim is to promote discussion of their content relating to this particular condition. Suggested alternative approach to assessing patients with community-acquired pneumonia Step 1: Does the patient need admission to hospital? Assess with the Pneumonia Severity Index (PSI). Class I or II: consider outpatient management (but also need to consider comorbidities, social supports, likelihood of compliance). Class III-V: likely to need inpatient management. Step 2: Does the patient need admission to the intensive care unit? Assess with the modified British Thoracic Society (BTS) Severity Score. Class as severe if two or more of the following features are present on initial assessment or within 24 hours of presentation (and are not attributable to another cause): Confusion (acute onset) Serum urea level > 7 mmol/L Respiratory rate ≥ 30 breaths/minute Systolic blood pressure < 90 mmHg or diastolic blood pressure ≤ 60 mmHg If severe, discuss the case with a senior clinician and consider intensive-care review and aggressive broad-spectrum antibiotics.

Kirsty L Buising · Karin A Thursky · James F Black · Graham V Brown

Wenbiao Hu,* Anthony J McMichael,† Shilu Tong‡ * PhD candidate, Centre for Health Research, Queensland University of Technology; † Director, National Centre for Epidemiology and Population Health, Australian National University, Canberra; ‡ NHMRC Senior Research Fellow, School of Public Health, and Centre for Health Research, Queensland University of Technology, Kelvin Grove, QLD 4059. s.tongATqut.edu.au To the Editor: We examined the possible association between the Southern Oscillation Index (SOI) and the occurrence of hepatitis A in Australia using a Seasonal AutoRegressive Integrated Moving Average (SARIMA) regression model.1 Our results indicate that the SOI is statistically significantly associated with the transmission of hepatitis A. We obtained data on the monthly counts of hepatitis A cases in Australia and the monthly SOI between 1 January 1991 and 31 December 2000 from the Commonwealth Department of Health and Ageing and the Australian Bureau of Meteorology, respectively. Data on population sizes were obtained from the Australian Bureau of Statistics. Cross-correlations were used to compute a series of correlations between SOI and the incidence of hepatitis A over a range of time lags (defined as the time span between the SOI and the incidence of hepatitis A). A SARIMA model was used to estimate the independent contribution of SOI in our study. We adjusted for seasonality by “seasonally differencing” (ie, replacing each observation by the difference between it and the observation from the previous year). In the modelling process, attention was paid to observations well outside the main body of the data (outliers) and the only outlier was excluded in the final SARIMA model. We used the SARIMA [1,0,0] [1,1,0]12 model (ie, first-order autoregressive combined, first-order seasonal autoregressive, after adjustment for first-order seasonal integration) to assess the association between SOI and the incidence of hepatitis A. We found that a decrease in the SOI (ie, warmer and drier conditions) was statistically significantly associated, at a lag of 1 month, with an increase in the monthly incidence of hepatitis A (β = − 0.01; P = 0.001). Two El Niño events (1991–92 and 1997–98) were also clearly associated with an increased incidence of hepatitis A (Box). The results suggest that there was an increase of about 360 cases per year in Australia for an, on average, interquartile range decrease in the SOI. The residuals in the model fluctuated randomly around zero, and there was no apparent autocorrelation between residuals at different lag times (data are available from the corresponding author). These results indicate that the model fitted the data well, with no violation of assumptions. The significant association between SOI and the incidence of hepatitis A remained when the outlier was included in the model (β = − 0.013; P = 0.001). El Niño Southern Oscillation (ENSO) has been found to be related to various health outcomes, including waterborne disease, vectorborne disease, and natural disaster-related deaths (eg, floods, bushfires and cyclones).2-4 Our study adds further evidence of ENSO-related health effects. Infectious diseases are, in general, sensitive to climate variability, as climate can influence the development and transmissibility of pathogens, and can also affect people’s behaviour.3,5 If the relationship between ENSO and hepatitis A is confirmed by other studies, these findings may facilitate the development of early warning systems for controlling and preventing this widespread communicable disease. Incidence of hepatitis A in Australia and the Southern Oscillation Index between January 1991 and December 2000 Negative values of the SOI are associated with El Niño conditions (dry and warm in Australia), and positive values with La Niña conditions (wet and less warm in Australia).

Wenbiao Hu · Anthony J McMichael · Shilu Tong

A 28-year-old man presented with a cough of one month’s duration and intermittent fever. Physical examination showed reduced breath sounds and fine inspiratory crackles at both lung bases. A chest x-ray showed diffuse micronodules in both lung fields, and a computed tomography scan revealed tiny calculi (calco-spherites) in the alveolar air spaces (Box). Pulmonary alveolar microlithiasis is a rare disease of unknown aetiology; about 400 cases have been reported. Patients can present with any of a variety of chest symptoms (eg, a non-productive cough and dyspnoea on exertion). Most reported cases involve people in the 20 to 50 years age group. About 50% of cases are familial. There is no definitive treatment, but disodium etidronate has been tried. The prognosis is variable. It has been suggested that, in many patients, the microliths continue to form and increase in size as the disease progresses. When the disease does progress, it may do so very slowly — patients have been reported in whom respiratory failure and death ensued after a period as long as 40 years.

Bobby Bhalotra MB BS, MD · Atul Gogia MB BS · Pratibha Gupta MB BS · Neeraj Jain MB BS, MD

Re: “Medical management of osteoarthritis of the knee and hip joints”, a Clinical Update article by Grainger R and Cicuttini FM in the 1 March 2004 issue of the Journal (Med J Aust 2004: 180; 232-236). The authors have requested a correction because their statement “both diclofenac and celecoxib are more COX-2 selective than meloxicam” is incorrect, and should read “both meloxicam and celecoxib are more COX-2 selective than diclofenac.” The html and pdf versions of the article on the eMJA website were corrected on 28 April 2004. The COX-2 selectivity of meloxicam over diclofenac has been demonstrated in vitro using Human Whole Blood Assay and William Harvey Modified Human Whole Blood Assay (WHMA). In an in-vitro analysis assessing the degree of inhibition of COX-2 relative to COX-1 for over 40 non-steroidal anti-inflammatory drugs using the WHMA, both meloxicam and celecoxib demonstrated fivefold to 50-fold selectivity for COX-2 over COX-1, while less than fivefold selectivity for COX-2 over COX-1 was observed with diclofenac. Analysis of the percent inhibition of COX-1 seen when COX-2 is inhibited by 80% showed that the concentration of meloxicam sufficient to inhibit COX-2 isoenzymes by 80% produces only 25% inhibition of COX-1 isoenzymes. By contrast, the concentration of diclofenac necessary to produce 80% inhibition of COX-2 produced almost 70% inhibition of COX-1.1

Rebecca Grainger MB ChB (Distinction) · Flavia M Cicuttini FRACP, PhD

Robert Warnock, or “Doctor Bob” as he was known to his patients and friends, was an outstanding rural doctor for 3 decades in Far North Queensland. Bob was born in Belfast, Northern Ireland, on 5 March 1927, the youngest son of a rural family doctor. He excelled at school at Campbell College, Belfast, where he was school captain, captain of the first XV football team, and captain of the Northern Ireland schoolboys’ hockey team. He studied medicine at Cambridge University before doing his residency at St George’s Hospital, London. After a stint in the British Army, he migrated to Australia with his first wife, Valerie, and their three children in 1958. After a short period in general practice in rural Victoria, Bob drove 3000 km to Babinda, north Queensland, to take up the role of Medical Superintendent of Babinda Hospital in 1958. In Babinda, he developed a reputation as a compassionate, hardworking, supportive general practitioner. He was highly regarded in the disciplines of obstetrics and anaesthesia. Bob moved to Cardwell in 1974, where he established the town’s first general practice and continued working until his early retirement in 1987 due to ill health. Bob was a very active community member. In Babinda he was a Rotarian, President of the Kindergarten Committee and President of the Bowls Club. He was also involved in cricket, tennis and water sports. In Cardwell he was a member of the Cardwell Country Club, and his enduring commitment to lawn bowls was recognised with the award of the Royal Queensland Bowls Association’s Meritorious Medal in 1996 and a Commonwealth Medal in 2000. In his retirement, Bob enjoyed gardening, spending time with his family, and travelling to the United Kingdom to visit former colleagues. He was also a member of Legacy and Probus. Bob’s dedication to rural medicine was recently acknowledged with the announcement that the new Cardwell community health centre, soon to be officially opened, has been named “Cardwell’s Dr R F Warnock Community Health Centre”. Bob died in Townsville on 4 May 2003, of prostate cancer. He is survived by his second wife, Enora, and children Roberta, Julian, Tim, Rowland and Jason. Timothy Warnock

Timothy Warnock

On 15 January 2004, Jack Elliott died peacefully of cardiac failure after a long and productive life during which he made enormous contributions to the discipline of obstetrics and gynaecology — primarily in Newcastle and the Hunter Valley, but also at a national level. Jack was born in Nowra, NSW, on 12 February 1912. He did his Leaving Certificate in Nowra, but needed to attend Fort Street High School (in Sydney) for a year to matriculate to the University of Sydney. He graduated in pharmacy, science and finally medicine in 1940. He supported himself in those student years by working part-time or full-time, supplemented by playing professional rugby league. He also played district cricket and was awarded a university blue in rugby union. Jack was commissioned as a captain in the Royal Australian Army Medical Corps and served throughout most of World War II, including service in Papua New Guinea. After the war, he resumed his medical career at the Royal Newcastle Hospital, where he embarked on a lifetime involvement in obstetrics and gynaecology. He set up the first specialist unit in the Hunter Valley at the Royal, training generations of residents and registrars, and became the trusted consultant for general practitioners throughout the region, holding appointments at most of the region’s hospitals. Beginning in the 1950s, he implemented a remarkable series of new initiatives in obstetrics and gynaecology, including a dramatically increased role for midwives and rooming-in and demand-feeding for mothers. He embraced the principles of natural childbirth, encouraged fathers to attend antenatal classes — and eventually the labour ward (an idea considered very radical at the time!). He pioneered the use in Australia of magnesium sulfate to treat severe pre-eclampsia, advocated the increased use of caesarean section, and was one of the first to promote the use of vaginal hysterectomy rather than the older Manchester-type repair operation. In the 1960s, Jack was one of the first consultants to develop country hospital clinics and operating sessions. He obtained his membership of the Royal College of Obstetricians and Gynaecologists in 1953 and became heavily involved in the College, serving on the NSW committee and subsequently the Regional Council. He was a member of the inaugural Council of the Royal Australian College of Obstetricians and Gynaecologists in 1979. Jack was an extremely modest man and, sadly, recorded little of his knowledge and wisdom in the literature. But his enduring legacy is the gratitude of thousands of mothers and the babies he delivered and the adoption by his trainees and colleagues of many of the initiatives that he began 50 years ago. Alan D Hewson

Alan D Hewson

Obstetrics, gynaecology and women’s health. Vivienne O’Connor, Gabor T Kovacs (editors). Cambridge: Cambridge University Press, 2003 (xix + 681 pp). ISBN 0 521 81893 1. It is some time since there has been a new local textbook of obstetrics and gynaecology aimed at the undergraduate market. The editors of this book have considerable experience of undergraduate and postgraduate teaching, and have collected a formidable group of local experts to provide a modern, evidence-based text which should be extremely useful to all undergraduates and fill a significant gap in the market. What is unusual about this new work is that it goes beyond the traditional boundaries of an undergraduate curriculum and covers many important aspects of women’s health. It will also be useful for postgraduate students, especially those studying for general practice qualifications or in the early years of specialist training. The book is organised chronologically, by life stage, and takes a practical clinical approach by discussing typical presentations in a systematic way. Of note is the opening section that covers women’s health, which deals effectively with the interface between medicine and sociology. The chapter on the female child and adolescent contains a comprehensive coverage of clinical and legal issues for teenagers. Normal pregnancy, labour and birth and the postnatal period are all comprehensively dealt with. However, some aspects of the management of obstetric emergencies are not quite up to date with modern methods (eg, recommending diazepam for treating eclampsia). The book could also benefit from an expanded section on fetal monitoring in labour. The book is well illustrated and contains many useful tables, which summarise the information given in each chapter. There are two style matters which some may find a little irritating. Firstly, the font, tables and illustrations are quite small, giving an overall impression of overcrowding. Secondly, all of the references (most of which are very recent) are given at the end of the book rather than at the end of each chapter. However, these are minor criticisms of what is otherwise an excellent new textbook that is great value for money and should become very popular. David A EllwoodProfessor of Obstetrics & Gynaecology Canberra Hospital, ACT Order this book

David A Ellwood

Breast cancer and abortion Women who have had a pregnancy end in either a spontaneous or an induced abortion do not have an increased risk of developing breast cancer, according to an international study. The Collaborative Group on Hormonal Factors in Breast Cancer reanalysed 53 epidemiological studies which included data from 83 000 women with breast cancer in 16 countries, including Australia. Their finding differed from those of earlier case-control studies which they say may have been misleading because such studies had recorded induced abortion retrospectively (ie, after the breast cancer diagnosis had been made). Women with breast cancer may be more likely than other women to disclose previous induced abortions. Lancet 2004; 363: 1007-1016 Hypochondriasis: care v cure US researchers offer advice for doctors struggling to manage patients with hypochondriasis. Their randomised trial of 187 people with this disorder compared 6 sessions of scripted, individual cognitive behavioural therapy (CBT) administered by experts with usual care. At follow-up, six and 12 months down the track, CBT patients had fewer thoughts of disease, less health-related anxiety and improved health beliefs and attitudes. However, their somatic symptoms did not improve, indicating that CBT helps patients cope rather than cures them outright. Most study participants were women, middle-aged, with a mean 11-year history of hypochondriasis. JAMA 2004; 291: 1464-1470 Who’s looking out for you? Some hospital doctors end up neglecting their own basic needs while at work, according to a small prospective study of 11 critical care fellows (advanced trainees) at The Hospital for Sick Children in Toronto, Canada.1 The doctors were studied for a total of 35 shifts, with their post-shift urine specific gravity and ketone levels suggesting dehydration or altered metabolism. Of further concern, in a subset of six doctors studied with continuous Holter monitoring, not only did heart rate variability show general dominance of the sympathetic nervous system while working, but also a couple of arrhythmias. These doctors were working within the “new and improved” limits on hospital working hours in North America, which, as a linked commentary pointed out, are still outside the limits imposed by other hazardous industries.2 1. CMAJ 2004; 170: 965-970 2. CMAJ 2004; 170: 975-976 Big black spider bites Funnel-web spider bites are not easy to distinguish from bites by other “big black spiders”, say Australian researchers. In a prospective cohort study of definite spider bites with expert spider identification, Isbister and Gray collected 49 cases of these bites. The bites were inflicted by a range of spiders, including mouse spiders (13) and trapdoor spiders (20), as well as funnel-webs (16), but all occurred in similar circumstances — on distal parts of limbs and when gardening — and all resulted in similar early clinical effects: local severe pain, puncture marks and/or bleeding. Isbister and Gray say all such bites should be managed in the same way — with observation in hospital for 4 hours to exclude severe envenoming, unless the spider has been positively identified; two of the 16 funnel-web bites in this series led to severe envenoming requiring antivenom. Male Sydney brown trapdoor spider. Photo courtesy Mike Gray, Australian Museum. Toxicon 2004; 43: 133-140 Needling headaches Acupuncture leads to persisting, clinically relevant benefits in patients with chronic headache, in particular migraine, according to a randomised controlled trial in the UK.1 Compared with controls, the patients who received up to 12 acupuncture treatments over three months experienced 22 fewer days of headache per year, used less medication, made fewer visits to GPs and took fewer sick days. An accompanying cost-effectiveness analysis of the trial2 found that, although acupuncture increased the overall health care costs, gains in health-related quality of life made acupuncture for chronic headache relatively cost-effective. 1. BMJ 2004; 328: 744-747 2. BMJ 2004; 328: 747-749 It’s all in the timing The Carotid Endarterectomy Trialists Collaboration want the rule book re-written when it comes to the timing of surgery for carotid endoterectomy. They pooled data from 5893 patients in the European Carotid Surgery Trial and North American Symptomatic Carotid Endarterectomy Trial, with 33 000 patient-years of follow-up, and found that, for greatest benefit in appropriate patients, this procedure should be done within 2 weeks of the last symptoms. Lancet 2004; 363: 915-924 — Dr Ann Gregory