Volume 184 Issue 7

To tackle this problem we need a systems approach involving multiple strategies An article in this issue of the Journal by Miller and colleagues1 provides further evidence of the magnitude and seriousness of the problem of adverse drug events (ADEs) in general practice. Their study highlights our ongoing failure to address the problem of ADEs — medication-related incidents that cause patient harm. “Consumer Medicine Information needs to be routinely used in medical encounters, so that patients can recognise ADEs and know what to report to their GP . . .” Each year in Australia, about 17.5 million people make 95 million visits to their general practitioner.2 Based on Miller et al’s estimate — that 10.4% of patients attending general practice experience an ADE — almost 2 million people have an ADE annually. Moreover, their findings show that these ADEs are not trivial, with about 1 million being moderate or severe and 138 000 requiring hospitalisation, a finding consistent with previous estimates.3 Many of these ADEs are preventable, although the exact proportion of preventable events can be debated. There have now been more than 30 Australian studies estimating the number of ADEs in different settings.3 It is clear that counting is not enough — it is time for action, but what can be done? Every developed country is trying to cope with the problem of ADEs. Australia has many structures and initiatives in place to reduce the occurrence of ADEs, and preventing ADEs necessarily involves them all.3 Regulatory agencies, the medicines industry, quality use of medicines organisations and information providers, safety and quality organisations, professional bodies, health professionals and consumers can all assist. Prevention of ADEs cannot occur without better knowledge. It is noteworthy that the Therapeutic Goods Administration has adopted the European Medicines Agency guideline on pharmacovigilance planning. Increased pharmacovigilance, including observational studies, will require a substantial increase in resources. In Canada, less than 10% of the budget for drug regulation is allocated to issues concerning marketed products, including safety. Yet, in 50% of new drugs, serious adverse drug reactions are detected after market approval.4 We need systems that can deal with the reality that only limited numbers of highly selected patients are studied before a drug is marketed. Regulators may have to consider restricting prescribing of new medications if they have limited safety information, particularly when equally efficacious therapy is available. New systems for detecting early signals of potential adverse drug reactions in expanded populations could complement the current reporting system for adverse drug reactions. An example is the Drug Safety Research Unit in the United Kingdom, which captures information on the first 10 000 patients using a newly marketed drug.5 We need to capitalise on and expand the importance and significance of consumer reporting. Instead of relying on pharmaceutical representatives (as a considerable proportion do), health professionals require easily accessible, balanced information sources that can be used in a timely manner for their clinical decisions.6 Pharmaceutical representatives frequently fail to supply safety information,7 and their promotional techniques may lead to more widespread use of new medications. In Canada, there were almost 50 000 visits by pharmaceutical representatives to doctors for rofecoxib, and over 1 million samples were handed out in its first year on the market. This helped increase rofecoxib prescriptions by 125% in the following year and, in Ontario, led to increased hospital admissions for gastrointestinal bleeds.8 By the time rofecoxib was withdrawn for safety reasons, it accounted for 40% of Australian expenditure on non-steroidal anti-inflammatory agents,9 possibly exposing excessive numbers of people to unnecessary risk. The activities of pharmaceutical representatives are regulated by Medicines Australia’s code of conduct governing pharmaceutical promotion.7 Medicines Australia must find ways to improve the provision of information to health professionals by the medicines industry through active monitoring of the code. If this is not possible, other methods of regulating promotion may need to be considered. Leadership from professional bodies and quality use of medicines agencies is required. Promoting balanced information sources, as a key element of professional standards, may assist in preventing ADEs. Activities sponsored by the National Prescribing Service also should have just as much of a role in preventing ADEs as they do in promoting appropriate management options. Developing a culture of safety in community practice will require leadership from the newly established Australian Commission on Safety and Quality in Health Care. We need a no-blame culture, supporting safer systems in practice, as well as incident monitoring, with timely feedback to practitioners and consumers. Medication safety improvement toolkits, similar to those developed for hospital practice,10 may be suitable for community practice, but their effectiveness in this setting must first be assessed. A study monitoring all incidents of potential or actual harm to general practice patients, including ADEs, found that the most common contributing factor was poor communication between practitioners and patients.11 Professional bodies and medical schools might help by providing educational programs to improve GPs’ communication skills about ADEs. Failure to recognise the signs and symptoms was another contributing factor to incidents.11 Consumer Medicine Information needs to be routinely used in medical encounters, so that patients can recognise ADEs and know what to report to their GP, even if he or she fails to ask. Case-conferencing and reviewing patients’ medication at home have the potential to reduce ADEs.3 These services are funded, but still underutilised. Poor communication between health professionals was another common cause of incidents,11 highlighting the need for better information systems in community practice. It is health professionals, in consultation with patients, who must identify ADEs in practice. Therefore, computerised systems should alert GPs when patients receive new prescriptions and identify all medications they are receiving from any provider.12 This knowledge can trigger GPs to ask about ADEs when patients first return after a new medication has been prescribed, as this is the interval in which most ADEs occur. Knowledge of what their patients are taking can help GPs flag which of their patients are at high risk; ADEs in this group are more likely to be fatal.13 If we do not develop a culture of safety, we will continue to have an extra 140 000 hospitalisations per year caused by ADEs. Although ADEs commonly occur in general practice, preventing them is not solely the responsibility of GPs. We need a systems approach involving multiple strategies to tackle this problem. Otherwise, patients will continue to suffer needlessly from ADEs.

Elizabeth E Roughead BPharm, MAppSci, PhD · Joel Lexchin MSc, MD

This European approach to insulin management is now being introduced in Australia Since the publication of the Diabetes Control and Complications Trial (DCCT) in 1993,1 improved glycaemic control in type 1 diabetes has been acknowledged as a desirable goal in theory, but frustratingly difficult to achieve in practice. Although bodies such as the American Diabetes Association recommend a glycated haemoglobin (HbA1c) target of < 7%,2 only around 20% of adults with type 1 diabetes under specialist supervision in Australian centres achieve this goal (data from the Australian National Diabetes Information Audit and Benchmarking Survey; Associate Professor Jeff Flack, Director, Diabetes Centre, Bankstown–Lidcombe Hospital, NSW, personal communication). Intensive insulin treatment in the North American-based DCCT involved an initial inpatient stay of 2–4 days. Patients received formalised dietary and insulin prescriptions, emphasising consistent distribution of carbohydrate across the day and intensive glucose monitoring. The program was medically directed and labour intensive, with patients maintaining weekly telephone contact and attending monthly clinic visits. No Australian diabetes centre has been able to routinely offer this level of support to patients. The reduction in microvascular complications seen with intensive treatment in the DCCT was accompanied by a threefold increase in severe hypoglycaemia and a 33% increase in the risk of becoming overweight.1 Overall quality of life did not improve.1 These adverse effects have been seen by many as inevitable consequences of tight glycaemic control and may have discouraged many clinicians and patients from pursuing a “DCCT-style” approach to intensive insulin treatment. As in other endeavours, the Europeans took a different approach from that used in North America. The Dose Adjustment for Normal Eating (DAFNE) program3 is a UK-based adaptation of the German Diabetes Training and Treatment Programme (DTTP).4 DTTP has been progressively developed in Germany since the late 1970s, under the leadership of the late Michael Berger (former President of the European Association for the Study of Diabetes). It is a 5-day structured inpatient education program facilitated by diabetes educators and dietitians. It aims to encourage and equip people who have type 1 diabetes to manage their insulin regimens actively and independently. DTTP has also been adopted in Romania,5 Austria6 and Russia,7 with positive results reported by all groups. In DTTP, patients follow a normal diet and receive intensive training in precise, but not restrictive, estimation of dietary carbohydrate in terms of 10 g carbohydrate portions. Prandial short-acting insulin doses are calculated as a ratio to intake of carbohydrate portions at each meal and major snack (eg, 1 unit per carbohydrate portion). Basal insulin generally comprises twice daily isophane (NPH) insulin or once or twice daily long-acting insulin analogues. Insulin ratios and basal insulin doses are adjusted to meet defined preprandial and bedtime glycaemic targets, with corrective insulin or carbohydrate given as required. General care of diabetes, adaptations of insulin for exercise and alcohol intake, and management of “sick days” are also addressed in the 35-hour program. The 5-day inpatient DTTP course has become part of standard care for type 1 diabetes in Germany. Active clinical audits involving a network of 96 diabetes clinics across Germany continue to demonstrate clinically meaningful improvements in HbA1c (especially for those with poor baseline control) and reduced hypoglycaemic episodes (especially for those with good baseline control) after DTTP training.8,9 Reduced rates of ketoacidosis and hospital admissions have also been noted.9 In Austria and the UK, DTTP has been adapted to a 5-day outpatient program with eight patients per group. Content remains very similar to the German program. The UK DTTP (DAFNE) approach was evaluated in a formal randomised controlled trial.3 Reported benefits in a cohort of 169 patients with poorly controlled type 1 diabetes included a fall of 1% in HbA1c without increased hypoglycaemia or mean weight gain. Quality of life was also improved.3 However, DAFNE is a complex intervention, and it remains unclear which element of the program is most important in improving diabetes control. Aside from the efficacy of the insulin algorithms per se, the effect may be in part due to increased contact with health care professionals and peer group support. Further, there are some weaknesses in the DTTP–DAFNE approach. Only two randomised controlled trials have been conducted,3,5 and, by current standards, the first3 would not be considered of high quality. Also, DAFNE is more expensive than current “routine” diabetes education. To benefit from DAFNE, patients need to perform regular glucose testing and self-adjustment of insulin doses, so it is unlikely to benefit those who struggle with the day-to-day demands of basic diabetes self-care. DAFNE insulin adjustment requires reasonable English literacy and numeracy, which may exclude some patients. Developed in the 1980s, DAFNE was designed around soluble and isophane insulin, rather than more recent insulin analogues. It does not include glycaemic index concepts. The standard glucose targets used in DAFNE (eg, fasting glucose 5.5–7.7 mmol/L) are higher than those recommended for pregnancy10 and will require revision in patients planning to become pregnant. Participation in a DAFNE course is clearly not the only possible pathway to improved glycaemic control in type 1 diabetes. Some people with this condition have been able to achieve excellent glycaemic control over many years without such a program, generally using either multiple-dose insulin regimens or continuous subcutaneous insulin infusion (or insulin pump) therapy. A recent randomised controlled crossover trial reported HbA1c values 0.25 percentage points lower with subcutaneous insulin infusion than with multiple dose insulin therapy,11 but this must be weighed against the increased cost. DAFNE has been costed in the UK at $A1300 per patient,12 and a published health cost modelling analysis suggested mean savings of $A5500 per patient over 10 years, arising primarily from a reduction in microvascular complications.12 Even the most conservative analyses have suggested that DAFNE is cost-saving rather than simply cost-effective.12 The use of DAFNE as one means of improving care for people with type 1 diabetes has been supported by reviews conducted by the UK National Institute for Clinical Excellence13 and the UK Department of Health.14 In January 2006, provision of structured patient education for people with type 1 diabetes became a requirement of the National Service Framework for diabetes in the UK, with DAFNE recognised as the one program which currently meets all the Framework’s requirements for type 1 diabetes.15 DAFNE courses are now provided in 39 centres across the UK, with 3537 DAFNE “graduate” patients reported in January 2006.16 In November 2004, clinicians from four centres in Australia completed DAFNE course observation and post-course training in the UK. The UK DAFNE course materials were then adapted to the Australian health care context. These four centres have now conducted around 12 DAFNE courses in Australia, with positive patient feedback. All centres have committed to the collection of baseline and follow-up data. An “OzDAFNE” collaborative, with strong links to the UK, has been established to ensure consistent standards of course resources and delivery across Australia, and to facilitate training and accreditation of further DAFNE centres within Australia. The processes of accreditation, peer review and quality assurance are seen as essential by all groups involved in the DTTP–DAFNE collaboratives and represent a great strength of the program. The capacity of current OzDAFNE centres to make DAFNE available to people with type 1 diabetes is limited. We hope that other diabetes services will undertake DAFNE training and join the OzDAFNE collaborative. This requires a doctor, diabetes educator and dietitian to observe a 5-day DAFNE course, attend further training and participate in peer review and quality assurance. Two further centres in Queensland have recently completed training and plan to provide courses, while further training is planned in Victoria in the near future. The study reported by Davis and colleagues in this issue of the Journal clearly demonstrates that poor glycaemic control affects people with type 2 as well as type 1 diabetes in Australia.17 The authors also note distinct therapeutic procrastination in proceeding from diet to oral agents to insulin in patients with type 2 diabetes. Previous studies have described “provider frustration” in dealing with diabetes care,18 and this may represent a further barrier to effective implementation of published guidelines. DAFNE was designed with type 1 diabetes in mind, but type 2 patients with marked insulin deficiency, requiring intensive insulin treatment, might also benefit. However, the DAFNE insulin algorithms have not been formally evaluated in patients with type 2 diabetes. The “dietary freedom” of DAFNE may be less appropriate in type 2 diabetes, in which obesity is a common comorbidity. DESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed) is a 1-day structured education program for type 2 diabetes developed in the UK, primarily targeted at the earlier stages of this condition.14 Currently, most people with type 1 and type 2 diabetes in Australia have suboptimal glycaemic control and remain at risk of the devastating long-term complications of diabetes. Active strategies to improve glycaemic control and meet other therapeutic targets, including the expansion of DAFNE programs for patients with type 1 diabetes, should be developed across Australia.

H David McIntyre FRACP

It is time for less talk and more action In Australia each year, close to 1600 medical graduates set off on the long and lonely road of prevocational and vocational education and training. To a casual observer, this journey might seem a simple matter, but two articles in this issue of the Journal1,2 refute this. Systemic shortcomings that these authors and others3 raise include a lack of coordination in the provision of education and training to junior doctors and a lack of integration of undergraduate prevocational and vocational training programs. For possible solutions, both McGrath et al1 and Paltridge2 look overseas to Canada and the United Kingdom. In Canada, the university medical schools are responsible for training medical specialists. There are strong links between medical schools and training hospitals, and a major commitment by hospitals to education and training. As well, senior clinical staff are committed and appropriately well paid to teach. Furthermore, medical students in Canada must decide before or at graduation which specialty they wish to enter — there is no internship. The different but comprehensive UK program is of two years’ duration, and “shifts medical education away from the apprentice-style of training to working and learning in teams.”4 Postgraduate deans, attached to each National Health Service Trust, fund and manage postgraduate programs across all specialties, and a new statutory body, the Postgraduate Medical Education and Training Board, will oversee all programs. Neither of these programs would sit comfortably in Australia. Our medical school graduates lack the skills and experience to enter directly into specialist training; medical schools lack the resources to oversee all postgraduate programs; and the current thrust in Australian medical education is to attempt to shorten the overall training period. Currently, accreditation and registration focus on process rather than outcomes, and a more flexible approach to linking progress to competencies rather than time spent in training is being considered.5 What both the Canadian and UK systems have that we do not is appropriate funding of undergraduate teaching. We also lack adequate numbers of medical students, recognition that good clinical teaching is as important as research or clinical practice, delineation of our overall medical workforce needs, medical student intakes that reflect projected workforce needs and the training to meet these needs and, finally, an appropriately coordinated and integrated system of undergraduate and prevocational and vocational medical education and training. Let us examine these issues in greater detail, beginning with the issue of appropriate funding of undergraduate teaching. Reduced federal government funding in recent years for undergraduate teaching supported by the Higher Education Contribution Scheme (HECS) has meant an increased intake of full-fee-paying overseas and also local students. The February 2006 meeting of the Council of Australian Governments (COAG) announced an increase in Australian full-fee-paying students from 10% to 25%, and a further increase of HECS places through to 2008.6 The fees generated by these full-fee-paying students will assist medical schools, but the tensions with clinical teachers who are required to teach overseas students, and who gain no recompense for this training, will remain even though pragmatic changes to the immigration act are allowing overseas students to remain in Australia. It should be noted that university administrations retain some 40% of medical student fees for “general revenue”. Medical schools should not be fundraisers for the whole university. Secondly, clinical teaching requires appropriate recognition. Most medical practitioners are willing to teach junior colleagues, but are hindered by time and money. Time needs to be set aside within teaching hospitals for teaching postgraduate students; a prerequisite for appointment to the staff of teaching hospitals should be a willing commitment to teach; and teaching time should be appropriately funded. Further, all hospital administrators and health bureaucrats must recognise the dual role of teaching and clinical service within teaching hospitals. The days of pro-bono teaching are long gone, and there must be budgeting for clinical training.5,7 Thirdly, overall workforce needs need to be delineated. Workforce planning is not a precise science and has many inherent difficulties, as shown in the Productivity Commission’s 2005 health workforce report.8 This report recommends establishing a single workforce secretariat to replace both the Australian Health Workforce Advisory Committee and the Australian Medical Workforce Advisory Committee, which would report directly to the Australian Health Ministers’ Advisory Committee. In making this recommendation, the Productivity Commission accepted the advice of many submissions, and stated that workforce projections undertaken by the secretariat should be directed at advising government that meeting different levels of health service demands requires equal consideration of the need for training and education of health care workers. Simply put, service demands require similar demands in education and training. Fourthly, both intakes and training of medical students need to meet projected workforce needs. The major problem in planning medical student numbers is the 8–10-year lag between entering medical school and unsupervised medical practice. The reduction in medical school intakes in the early 1900s led to a shortage of medical practitioners and the need to recruit overseas-trained doctors. This recruitment has not been without difficulties.1 The pendulum is now swinging in the opposite direction, with a recent increase in HECS places, the decision to allow overseas students to remain in Australia and enter specialist training, the creation of new medical schools, and the very recent COAG decision to increase the number of local fee-paying students and increase the number of HECS places through to 2008. These decisions will increase student numbers, but it is not clear how, where, and by whom they and future postgraduate trainees will be trained. This important issue is well recognised. Olson and colleagues, writing in this Journal, point out that medical students cannot acquire appropriate clinical experience because of the unavailability of patients in teaching hospitals.9 They state, “. . . it is clear we must find alternatives to teaching hospitals for acquiring clinical skills.”9 Crotty takes the matter further, pointing out the multiple factors that reduce the value of the so-called teaching hospitals for student training, and the lack of consultation in developing new medical schools.10 He advocates teaching in private hospitals and private clinics, simulation-based clinical teaching, and increasing teaching in general practice and the community. This would require adequate funding, and agreements forged between universities, public and private hospitals and federal, state and territory governments. Finally, we come to the issue of needing a coordinated, integrated, and accredited system of undergraduate, prevocational and vocational medical education and training. McGrath et al1 and, to a lesser extent, Paltridge,2 lament our current lack of coordination and planning. While there is some ad-hoc integration of education, by and large, the various “units” involved in education act separately. There are at least 10 different agencies involved in postgraduate training. This modern Tower of Babel includes: the Australian Government Department of Education, Science and Training and Department of Health and Ageing; state and territory governments and health departments; teaching hospitals and training units; specialist colleges; Committee of Presidents of Medical Colleges; Confederation of Postgraduate Medical Education Councils; university medical schools; Australian Medical Council (AMC); state prevocational medical councils; and the Medical Training Review Panel. Overlying each of these are the special requirements for assessing standards for overseas-trained doctors. In an article on this subject, Dowton et al concluded by saying, “It is time to comprehensively review the oversight and governance of postgraduate medical education and training.”3 There have been numerous national workshops, national conferences, and review articles suggesting the way forward, but little has been achieved. A recent conference hosted by the Committee of Deans of Australian Medical Schools and the AMC recommended that registration, accreditation and clinical progress be linked to competencies rather than time spent in training.5 The conference also recommended the establishment of a National Healthcare Education Council, which should be independent, funded by and reporting to the Australian Health Ministers’ Conference (AHMC), and should include all stakeholders. The Productivity Commission also recommends a body along these lines — the Advisory Health Workforce Education and Training Council — to provide the AHMC with independent and transparent assessments of health care workforce and education and training needs, and of the implications of courses, curricula and accreditation. The importance of combining assessments of workforce (ie, service delivery) needs with education and training cannot be overestimated, and cooperation between the federal health department and DEST is essential. The overall solution also requires changes at state and territory levels. New South Wales has long been a leader in postgraduate medical education, with the formation of the Postgraduate Medical Council of NSW (PMCNSW) in 1988. The recent establishment of the Institute of Medical Education and Training,11 combining the roles of PMCNSW and the Medical Training and Education Council, is a major step forward. The new Institute has a broad brief to: provide high quality and appropriate medical education and training for trainees, supporting quality and safe care and services to patients; provide support to area health services and other public health organisations that control public hospitals in relation to postgraduate medical education and training; develop systems and processes to enable the distribution of medical training positions within area health services and other public health organisations that control public hospitals in a manner aligned with their service and training and education; and develop postgraduate medical training networks and other training support infrastructures for area health services and other public health organisations that control public hospitals. The Institute has broad professional representation and reports through its advisory board directly to the NSW Minister for Health. Each state and territory needs to establish such an independent body reporting directly to the Minister for Health, and so create order and coordination in the medical workforce and in education and training. This will require political will and less talk and more action. It is time.

Geoffrey W Dahlenburg OAM, MD, FRACP, FRCPCH

Objective: To investigate the frequency, cause, and severity of adverse drug events (ADEs) among general practice patients.Design: Between May 2003 and February 2004, a subsample of 282 general practitioners in the BEACH (Bettering the Evaluation And Care of Health) data collection program recorded patient responses to questions about ADEs.Main outcome measures: Frequency, cause, and severity of ADEs; and frequency of hospitalisation and proportion of events that were preventable.Results: From 8215 encounters, GPs reported that 852 patients (10.4%) had experienced an ADE in the previous 6 months. Patients aged over 45 years (versus under 45 years), children aged 1–4 years (versus older children), and female patients (versus male patients) were significantly more likely to have experienced an ADE. Most patients (83.5%) had experienced only one ADE, with 10.7% and 5.8% experiencing two and three or more events, respectively. For 71.9% of patients, one reason for the most recent event was a recognised side effect, followed by drug sensitivity (12.4%) and allergy (11.0%). Over half of patients were rated as having a “mild” event, with 35.8% rated as “moderate”, and 10.0% as “severe”. GPs classified 23.2% of events as preventable, and 7.6% of events resulted in hospitalisation.Conclusion: Our study reveals the high frequency of ADEs in patients attending general practice. This level of morbidity makes ADEs one of the most significant causes of morbidity in the Australian community.

Graeme C Miller MB BS, PhD, FRACGP · Helena C Britt BA, PhD · Lisa Valenti BEc

Objective: To assess the effectiveness of the management of type 2 diabetes in an urban Australian setting.Design and setting: The Fremantle Diabetes Study (FDS), a community-based longitudinal observational study.Patients: 531 FDS participants with type 2 diabetes, with mean age, 62.4 years (95% CI, 40.9–79.3 years), 54% male, median diabetes duration 3.0 years (interquartile range [IQR], 0.7–7.0 years), with valid data from the baseline FDS assessment and five subsequent annual reviews between 1993 and 2001.Main outcome measures: Glycated haemoglobin (HbA1c) levels at annual review visits before and after change in blood glucose-lowering therapy.Results: Over 2893 patient-years of follow-up, 97 patients (18%) progressed from dietary management to therapy with oral hypoglycaemic agents (OHA), and 45 (9%) progressed from OHA to insulin therapy, after a median duration of diabetes of 4.0 years (IQR, 2.9–5.5 years) and 8.1 years (IQR, 5.5–13.0 years), respectively. Median HbA1c concentrations (IQR) at the review before OHA or insulin were started were 7.7% (6.9%–8.8%) and 9.4% (8.0%–10.7%), respectively. At the next annual review, HbA1c levels in the two groups had fallen to 7.4% (6.5%–8.1%) and 7.9% (7.2%–9.5%), respectively (P ≤ 0.001). Intensification of therapy was associated with beneficial changes in serum lipid profiles, but not with an increase in frequency of hypoglycaemia.Conclusions: Most Australian patients with type 2 diabetes may be spending most of the duration of their disease with suboptimal glycaemic control (HbA1c > 7.0%), despite the availability of a range of effective therapies, including insulin.

Timothy M E Davis BMedSc, MRCP, DPhil, FRACP · Wendy A Davis BA(Hons), MSc, MPH, PhD · David G Bruce MD, FRACP

Objective: To investigate the effectiveness of hot water immersion for the treatment of Physalia sp. (bluebottle or Portuguese Man-of-War) stings.Design: Open-label, randomised comparison trial. Primary analysis was by intention to treat, with secondary analysis of nematocyst-confirmed stings. One halfway interim analysis was planned.Setting: Surf lifesaving first aid facilities at two beaches in eastern Australia from 30 December 2003 to 5 March 2005.Participants: 96 subjects presenting after swimming in the ocean for treatment of an apparent sting by a bluebottle.Interventions: Hot water immersion (45°C) of the affected part versus ice pack application.Main outcome measures: The primary outcome was a clinically important reduction in pain as measured by the visual analogue scale (VAS). Secondary outcomes were the development of regional or radiating pain, frequency of systemic symptoms, and proportion with pruritus or rash on follow-up.Results: 49 patients received hot water immersion and 47 received ice packs. The two groups had similar baseline features, except patients treated with hot water had more severe initial pain (VAS [mean ± SD]: 54 ± 22 mm versus 42 ± 22 mm). After 10 minutes, 53% of the hot water group reported less pain versus 32% treated with ice (21%; 95% CI, 1%–39%; P = 0.039). After 20 minutes, 87% of the hot water group reported less pain versus 33% treated with ice (54%; 95% CI, 35%–69%; P = 0.002). The trial was stopped after the halfway interim analysis because hot water immersion was shown to be effective (P = 0.002). Hot water was more effective at 20 minutes in nematocyst-confirmed stings (95% versus 29%; P = 0.002). Radiating pain occurred less with hot water (10% versus 30%; P = 0.039). Systemic effects were uncommon in both groups.Conclusions: Immersion in water at 45°C for 20 minutes is an effective and practical treatment for pain from bluebottle stings.

Conrad Loten MB ChB · Barrie Stokes BSc, MMath · David Worsley BMed · Jamie E Seymour BSc, PhD · Simon Jiang · Geoffrey K Isbister BSc, MB BS, FACEM, MD

Objective: To investigate the change in pattern of discharge of patients from an intensive care unit (ICU) to hospital wards and to determine the impact of discharge time on subsequent hospital mortality.Design and participants: A retrospective cohort study of 10 903 patients discharged alive from a single ICU between 1 January 1992 and 31 December 2002.Main outcome measure: In-hospital mortality.Results: Of the 10 903 patients discharged alive from the ICU, 486 (4.5%) died in hospital wards. When discharge times were categorised according to nursing shift (morning, 07:00–14:59; afternoon, 15:00–21:59; and night, 22:00–06:59), patients were more likely to be discharged on an afternoon shift (odds ratio, 3.63; 95% CI, 3.05–4.30) or night shift (4.52; 95% CI, 3.15–6.64) in 2000–2002 compared with 1992–1994. In a multiple logistic model, hospital mortality after discharge from the ICU was increased by higher APACHE II score (1.14; 95% CI, 1.12–1.16); admission to ICU from the operating room (1.47; 95% CI, 1.11–1.95) and from the general ward (1.75; 95% CI, 1.37–2.23); and discharge during the afternoon (1.36; 95% CI, 1.08–1.70) and night shifts (1.63; 95% CI, 1.03–2.57).Conclusion: Over an 11-year period, more patients are being discharged from the ICU in the afternoon and night suggesting increasing pressure on ICU beds. Patients discharged on these shifts have an increased risk of death.

Antony E Tobin MB BS, FRACP, FJFICM · John D Santamaria MD BS, FRACP, FJFICM

Objective: To examine the influence of geographical and seasonal factors on duration of solar ultraviolet (UV) radiation exposure of skin to produce recommended vitamin D levels without producing erythema.Design and setting: An ecological study using daily Ultraviolet Index (UVI) data collected in major population centres across Australia for 1 year (1 January – 31 December 2001) to calculate sun exposure times for recommended vitamin D production and erythema.Main outcome measures: Sun exposure times to produce either serum vitamin D concentrations equivalent to an oral intake of 200–600 IU/day or erythema for people aged 19–50 years with fair skin (Fitzpatrick type II skin) exposing 15% of the body.Results: In January, across Australia, 2–14 minutes of sun three to four times per week at 12:00 is sufficient to ensure recommended vitamin D production in fair-skinned people with 15% of the body exposed. However, erythema can occur in as little as 8 minutes. By contrast, at 10:00 and 15:00, there is a greater difference between exposure time to produce erythema and that to produce recommended vitamin D levels, thereby reducing the risk of sunburn from overexposure. From October to March, around 10–15 minutes of sun exposure at around 10:00 or 15:00 three to four times per week should be enough for fair-skinned people across Australia to produce recommended vitamin D levels. Longer exposure times are needed from April to September, particularly in southern regions of Australia.Conclusion: Our study reinforces the importance of existing sun protection messages for the summer months throughout Australia. However, fair-skinned people should be able to obtain sufficient vitamin D from short periods of unprotected sun exposure of the face, arms and hands outside of the peak UV period (10:00–15:00) throughout Australia for most of the year. The greater variability in sun exposure times during winter, means that optimal sun exposure advice should be tailored to each location.

Amanda J Samanek BPhysEd, GDipHlthProm · Emma J Croager PhD · Peter Gies PhD · Elizabeth Milne MPH, PhD · Richard Prince MD, FRACP · Anthony J McMichael PhD · Robyn M Lucas MB ChB, PhD, FAFPHM · Terry Slevin BA(Hons), MPH

Long-acting β2 agonists are an effective and convenient treatment for chronic obstructive pulmonary disease (COPD), but do not significantly improve lung function. The long-acting anticholinergic tiotropium, which can be taken once daily, decreases exertional dyspnoea and increases endurance by reducing hyperinflation. The role in COPD of the combination of a long-acting β2 agonist and a glucocorticoid in a single inhaler remains unclear. The minimum duration of an effective pulmonary rehabilitation program that includes exercise training is 6 weeks. Long-term treatment with inhaled glucocorticoids may reduce the rate of decline in lung function, but the effect is small. Aminophylline should no longer be routinely used in acute exacerbations of COPD. Non-invasive positive pressure ventilation (NPPV) reduces mortality and hospital stay in patients with acute hypercapnic ventilatory failure; it is also an effective weaning strategy for patients who require intubation. Further studies are required to clarify the role of NPPV in the long-term management of stable COPD.

Michael J Abramson PhD, FRACP, FAFPHM · Alan J Crockett PSM, PhD, FANZSRS · Peter A Frith MD, FRACP · Christine F McDonald PhD, FRACP

The lack of cohesion across health and education sections and national and state jurisdictions is counterproductive to effective national policies in medical education and training. Existing systems in Australia for medical education and training lack coordination, and are under-resourced and under pressure. There is a need for a coordinated national approach to assessment of international medical graduates, and for meeting their education and training needs. The links between prevocational and vocational training must be improved. Tensions between workforce planning, education and training can only be resolved if workforce and training agencies work collaboratively. All prevocational positions should be designed and structured to ensure that service, training, teaching and research are appropriately balanced. There is a need for more health education research in Australia.

Barry P McGrath MB BS, MD, FRACP · Ian S Graham MB BS, MHP, FRACMA · Brendan J Crotty MB BS, MD, FRACP · Brian C Jolly PhD

The workplace remains the most important learning environment for junior doctors in their postgraduate years. There is no national curriculum to guide the education of prevocational doctors. The apprenticeship model is under threat, and is not sustainable in the future without significant changes to the system. Supervision is crucial for junior doctors’ learning and for safe, quality patient care.

Deborah Paltridge BApplSci(Phyt), MHSc(Ed)

Although clinical trials of the antipsychotic amisulpride revealed no cardiac adverse effects, four patients with severe cardiac toxicity after overdose were reported to Australian poisons information centres in 2004–2005. All four had QT prolongation over 500 ms, two had rate-dependent bundle branch block, two developed torsades de pointes, and one died after cardiac arrest. Pending further studies, we recommend electrocardiogram assessment until at least 16 h after amisulpride overdose and, if QT interval is prolonged, cardiac monitoring until the patient is clinically well and conduction intervals are normal. Clinical recordsPatient 1A 39-year-old woman presented to a rural hospital 2 hours after ingesting 24 g of amisulpride (therapeutic dose, 50–1200 mg/day), and unknown quantities of nitrazepam and diazepam. On examination, she was drowsy with a Glasgow Coma Score (GCS) of 14, heart rate of 100 beats per min (bpm), and systolic blood pressure of 70 mmHg. Activated charcoal (50 g) and intravenous normal saline (2 L) were administered, and the hypotension resolved. She was transferred to a tertiary emergency department. On arrival, 7 h after the overdose, her condition remained unchanged. An electrocardiogram (ECG) showed sinus rhythm, heart rate of 67 bpm, QRS interval of 128 ms, prolonged QT interval of 560 ms and bifid T waves (Box 1). Twelve hours after ingestion, her level of consciousness decreased (GCS, 4), and broad complex tachycardia was observed on the electrocardiography monitor and subsequent ECG. No hypotension was recorded. She was intubated, hyperventilated, given NaHCO3, magnesium and calcium gluconate, and transferred to the intensive care unit. The QRS interval narrowed to 112 ms within 4 h, but the QT interval remained prolonged for another 12 h. Patient 2A 40-year-old man presented to a hospital emergency department after ingesting amisulpride (32 g), mirtazapine (300mg), valproate (7 g), amitriptyline (1.25 g) and omeprazole (unknown quantity). On arrival, he had a GCS of 14, heart rate of 90 bpm, and blood pressure of 120/70mmHg. An ECG at presentation showed sinus rhythm with a heart rate of 90 bpm, QT interval of 460ms and bifid T waves. He was admitted to the intensive care unit. About 12.5 h after ingestion, he developed a broad complex tachycardia with rate 120 bpm (left bundle branch pattern), but remained haemodynamically stable. The QRS complex did not significantly narrow when the patient was treated with a bolus of NaHCO3. An NaHCO3 infusion was started, and he was intubated and ventilated. Eighteen hours after ingestion, the QT interval was 560ms, with heart rate of 79 bpm and a normal QRS interval (Box 2A). About 29 h after ingestion, the patient developed pulseless torsades de pointes, but sinus rhythm with a QT interval of 560ms was restored after a single direct current cardioversion shock (Box 2B). He had a second episode of torsades de pointes 32.5 h after ingestion, and an episode of ventricular tachycardia 34 h after ingestion. By 5 days after the overdose, the QT interval had shortened to 360ms (Box 2C). Serum amisulpride level was measured by high performance liquid chromatography using a modified method of Bohbot et al,1 and was 23.2 mg/L at 12.5 h after ingestion. Patient 3A 39-year-old woman presented to hospital about 12 hours after ingesting amisulpride (16–24 g). At presentation, she was drowsy, with a heart rate of 59 bpm and blood pressure of 81/44 mmHg. She was given 1 L of intravenous fluid. An ECG demonstrated sinus rhythm with heart rate of 62 bpm, and QT interval of 600 ms. Two hours after presentation, her condition deteriorated rapidly, with a GCS of 7, heart rate of 99 bpm, and blood pressure of 109/42 mmHg. Multiple intubation attempts were made, and the oxygen saturation fell, but recovered between intubation attempts (91% after 25 minutes). She was successfully intubated 28 minutes after her condition deteriorated. She then developed bradycardia, pulse became undetectable, and cardiac pulmonary resuscitation was begun 30 minutes after the deterioration. Despite resuscitation, she died 17 minutes later. No ECG or telemetry traces were recorded during the resuscitation. Postmortem toxicology analysis performed by the Division of Analytical Laboratories, Sydney, was made available by the coroner: amisulpride (140 mg/L) and fluoxetine (0.2 mg/L) were found in serum, but no tricyclic antidepressants or drugs of abuse. Patient 4A 22-year-old man presented to hospital 2 h 20 min after ingesting amisulpride (4.6 g). There was no family history of sudden death or cardiac arrhythmias. On arrival, he was alert and oriented, had a heart rate of 69 bpm, and blood pressure of 136/61 mmHg. The ECG showed sinus rhythm, heart rate of 63 bpm, and QT interval of 600 ms (Box 3A). Repeat ECGs showed QT intervals between 580 ms and 640 ms. Seven hours after ingestion, he had an episode of pulseless torsades de pointes (Box 3B). Cardioversion was achieved with a 200 J direct current shock. As the QT interval remained prolonged (600 ms), therapy with isoprenaline (60 μg/h) was begun. After an hour, the dose was decreased to 30 μg/h and continued for 20 h. The patient had a second episode of torsades de pointes almost 24 h after ingestion. This was asymptomatic and resolved spontaneously within 30 seconds. He had bradycardia (heart rate, 40 bpm) for 24 h after isoprenaline was ceased. The QT interval gradually decreased to 460 ms at 62 hours after ingestion and was 360 ms 3 weeks later (Box 3C). Box 3D illustrates the time course of serum amisulpride concentration and absolute QT interval over the first 60 h after ingestion. DiscussionAmisulpride is an antipsychotic that has been available on the Pharmaceutical Benefits Scheme in Australia since 2003. A benzamide derivative, it is well tolerated, with relatively few side effects and minimal behavioural toxicity in doses with antipsychotic effect.2 Amisulpride overdoses were first reported to Australian poisons information centres in early 2004, and about 60 telephone calls about amisulpride overdose were made from hospitals to the New South Wales and Western Australian Poisons Information Centres between July 2004 and June 2005, including the four cases reported here. A review of clinical trials of amisulpride reported that it had no effect on the ECG in therapeutic doses and did not produce arrhythmias.3 There are no published data on animal toxicity. It was therefore surprising that such severe effects were seen in overdose. There were a few published reports of overdose in the literature before its introduction in Australia,4,5 and a reference to QT prolongation and torsades de pointes in the manufacturer’s product information, but little indication that overdose could have effects as severe as those reported here, including the first cases of torsades de pointes. During the past decade, there have been sporadic reports of amisulpride poisoning, including two deaths.4-9 Significant QT prolongation was reported in a recent series of eight cases with limited clinical details9 and in another two cases, where it was suggested to be related to hypocalcaemia.7 A patient who suffered multiple cardiac arrests has also been reported. Although torsades de pointes was suspected, it was not confirmed on ECG.6 These cases demonstrate that amisulpride overdose may be associated with clinically significant QT prolongation. The absolute QT interval was over 500ms in all four of our cases and close to 600ms in three. Amisulpride overdose was associated with ECG-confirmed torsades de pointes in two cases and a cardiac arrest resulting in death in another. Unfortunately, no ECG was available to determine if torsades de pointes had occurred in that patient. The magnitude of the effect on the QT interval and the number of cases of torsades de pointes from about 60 cases of overdose reported to the Poisons Information Centres suggests that amisulpride overdose is associated with significant cardiac toxicity. Amisulpride also caused a ratedependent bundle branch block in two cases. Although this coincided with a decreased level of consciousness, it was unlikely to have caused it. Drowsiness occurred in three of the four patients and profound sedation in two, suggesting that amisulpride also causes central nervous system depression. Amisulpride was detected in high concentrations in three of our patients — three to four orders of magnitude above that reported in therapeutic studies.2 In these studies, the peak concentration after a dose of 50mg of amisulpride was 55.7 µg/L (SD, 3.7). Citalopram is another drug that appeared to cause minor or no cardiac effects in clinical trials of therapeutic doses,10 but in overdose has been associated with moderate QT prolongation,11,12 rate-dependent bundle branch block and, rarely, torsades de pointes.13,14 A pharmacokinetic and pharmacodynamic model of citalopram intoxication clearly demonstrated a dose-dependent relationship between drug concentration and QT interval.12 Fortunately, citalopram-associated torsades de pointes appears very rare, with only two published reports. This case series underlies the importance of overdose surveillance by poisons information centres after the introduction of new drugs, or the introduction of new formulations. Clinicians should be aware that amisulpride overdose can cause severe cardiac toxicity, including QT prolongation, bundle branch block and torsades de pointes. Until the risk assessment can be further refined, we recommend assessing the ECG until at least 16 hours after ingestion of an amisulpride overdose. If there is QT prolongation, we recommend cardiac monitoring in a critical care area until the patient is clinically well, and conduction intervals are normal. 1 Electrocardiogram changes in Patient 1 Electrocardiogram 7 hours after ingestion of amisulpride showed sinus rhythm with a prolonged QT interval of 560 ms. 2 Electrocardiogram changes in Patient 2 A: Eighteen hours after ingestion, the electrocardiogram (ECG) showed prolonged QT interval of 560 ms. B: About 29 hours after ingestion, the ECG showed segment of torsades de pointes, before direct current cardioversion and recovery of sinus rhythm. C: Five days after the overdose, ECG showed shortening of QT to 360 ms. 3 Electrocardiogram changes and amisulpride levels in Patient 4 A: Prolonged QT interval on admission (2.3 hours after ingestion). B: Torsades de pointes 7 hours after ingestion. C: A normal QT interval D: Plasma amisulpride concentration (logarithmic scale) and absolute QT interval over the first 60 hours after ingestion.

Geoffrey K Isbister FACEM, MD · Lindsay Murray MB BS, FACEM · Sally John MB BS · L Peter Hackett MRSC · Tedo Haider MB BS · Phebe O'Mullane MB BS · Sophie Gosselin MD · Frank Daly MB BS, FACEM

GPs can play an important role in helping women to realise their plans for a family You don’t think of a first-time, breastfeeding mum experiencing hot flushes, but that’s how my story begins. I was 40 years old when I conceived my daughter — and very easily, I might add. When Abby was about a year and a half old, my husband and I began trying to conceive a second child. Deceived by our luck the first time, we assumed we’d have no problem. Misguided by the prevailing advice, we persevered for 12 months before seeking professional help. When we finally did, my general practitioner advised that I discontinue breastfeeding even once a day, and, a month later, sent me to have my serum follicle-stimulating hormone (FSH) level tested. We might have reversed those steps because the results showed, at 98 IU/L, that I wasn’t conceiving, not because I had been breastfeeding, but because I was menopausal. The penny dropped — the sweatiness I’d been experiencing while still breastfeeding had been hot flushes. My doctor was as surprised as we were that menopause would follow so closely upon the heels of immediate conception and birth, but the results were confirmed. A fertility centre informed us that the only real option for conception was with donated eggs. And, fortunate as we were to have a friend to donate hers (Box 1), after three failed in-vitro fertilisation (IVF) cycles we have resigned ourselves to the reality that Abby will be our one and only child. That resignation is not without some resentment, however, that my GP, knowing that I was already 41 and trying to conceive, didn’t intervene with a fertility assessment well before a crucial year was lost. Given my age and very sporadic cycles (which naively I had attributed to my still once-daily breastfeeding), my chances of becoming pregnant were slim to remote1 and conception at that point called for a more aggressive strategy. At the age of 40, or even 35, a basic infertility evaluation has been recommended after 6 (rather than the usual 12) months of trying unsuccessfully to conceive,2 as has early referral to a fertility specialist.3 In fact, given my age, rather than prescribing birth control pills postpartum, as you might with a younger woman, a candid discussion about whether I intended to try for a second child, while perhaps awkward in those early days, could have been key to conserving my chances. Why wait?But isn’t it a woman’s own responsibility, and not her doctor’s, to begin a family while she’s still fertile? Perhaps, but what if she lacks accurate information about how long to expect to remain fertile? The current trend to delay childbearing is the result of many factors.4 Maybe I did take my mother’s admonition not to marry early a bit too far — but not by choice. I was eager to start a family and would have done so well before turning 40 if I had I found a suitable partner. And I was in very good company. A full 50% of women surveyed at Monash IVF reported that they had delayed childbearing because they lacked a partner.5 Another study found that many women delay childbearing in favour of establishing careers, relationships and financial security (often believing fertility treatments will be available as a “backup” if needed).2 And if we take into consideration the tendency of women to overestimate their window of fertility,6 or to be unaware of the relationship between age and fertility,5 we can only expect my experience to be repeated many times over. I am writing this article to give a wake-up call to GPs and family planning professionals and to urge them to proactively address a suite of problems related to the rapidly ageing population of women seeking to become mothers for the first time. I hope that, in this way, my experience may help to prevent similar “missed conceptions”. “Positive” family planningThe feminist movement that helped to shape me and my choices was itself shaped by women escaping the confines of the traditional roles of wife and mother. Largely because of this, an emphasis has been placed on “negative” family planning — helping women to prevent unwanted pregnancy or to control the number and timing of children. Contraception and the availability of affordable, legal abortion have meant that women have been free to develop other important dimensions of their lives, such as robust careers and relationships, before having children. But times have changed — again. Years down the track, major advances in women’s ability to break through professional “glass ceilings” and the perception that we can extend indefinitely our ability to become parents have contributed to a growing number of women reaching “biological ceilings” that are even more difficult to break through. It is therefore now time that “positive” family planning be promoted as well. Health practitioners, particularly GPs, now need to provide guidance about the waxing and waning of fertility, preconception care and protective fertility — conception as well as contraception.7 A partnership between government, GPs and their representative organisations, as well as the family planning community, could help to educate women to have a more realistic understanding of their reproductive lifespan, enabling them to make more informed choices. Because although there may be many women who would not be surprised to find themselves infertile at 42, there are others, some as publicly prominent as ABC Television’s Virginia Haussegger, who have been as surprised as I was.8 The “misconception” seems to prevail, consciously or unconsciously, that we can expect to be able to naturally conceive throughout our forties, or if we can’t, that we can expect IVF treatment to “fix it” for us.6 And the truth is, not only does fertility take a nose-dive at about 30 years of age, but the success of IVF, as astounding as its results can be, dives as well (Box 2).7,10 Knowing betterThe media are teeming with fertility information. Books with names like What, no baby?,11 Inconceivable12 and Hot flashes, warm bottles13 have been published in recent years describing women’s experiences of meeting the challenges of subfertility, of being older first-time mothers, and of dealing with the social problem of infertility. While one news article might bust the “you can have everything” myth and report on the challenges of age-related infertility, another may announce a “miraculous” birth at 60, perpetuating the evergreen fertility myth still further. In the absence of individualised guidance by GPs, patients (as in many areas of medicine) arm themselves with information obtained on the Internet.14 Fertility consumers seek advice from sites such as the “Over 40 high FSH” discussion group (www.network54.com/Forum/53068) and “Mothers via egg donation” (www.surrogacy.com/online_support/mved). Such sites are replete with research, anecdotes and coaching about endocrinology, variations in protocols and success rates, and offer moral support to women wanting to take on the expertise of their reproductive endocrinologists, together with advice on how to discern valid treatments from quackery. Such sites also bring to the surface a widespread fervour relating to the desire to conceive, with some women willing to try almost anything to have a child. As in other areas, less scrupulous operators prey on this desperation and confusion. In another, parallel universe, new fertility innovations and studies are continually being reported in scientific and medical research. And while we medical consumers may be able to sift through to the best information on our own, how much more likely are we to find what we are looking for if we have the help of a GP who knows us? What’s a doctor to do?Because of their ongoing interactions with so many women, their knowledge and the resources available to them, GPs are uniquely well suited to convey from the medical world the current and reliable information a woman will need to realise her plans for a family — whether or not to have one, its timing and its size. GPs can play a central and vital role in educating women patients about our fertility’s natural expected lifespan while there is still time to act on it.5 Perhaps this is more important than ever, given the federal government’s recent attempts to restrict Medicare-funded access to assisted reproductive technology — especially for older women.15 The first step involves a doctor’s willingness to broach the subject. And if most Australian doctors are not inviting patients to discuss their family plans, they would not be alone. In one German study, many of the GPs surveyed viewed infertility as a private matter.16 In a related study of GPs and their infertile patients, most GPs did not ask childless patients about their plans to have children, even though 25% of infertile women and 50% of infertile men said they would prefer their doctor to raise the issue.17 Beyond that, I offer some suggestions for what GPs and others can do (Box 3). ConclusionThe growing tendency of women to delay parenthood either by choice or circumstance has implications as we have discussed for the likelihood of successful conception, for the wellbeing of the mother compressing her fertility, and for the children.21 It has repercussions not only for the individuals involved, but on the overall fertility rate.22 Sadly, there is cause for concern that patients may now be bypassing GPs and going directly to fertility specialists.23 This would be an unfortunate trend likely to lead to more heartbreak, more unnecessary individual and public expense and less holistic and continuous care for the woman or couple involved. All of these factors provide compelling reasons for GPs to engage in “positive” family planning by helping younger women to grasp the biological imperative to start their families earlier and helping older women to salvage their residual fertility. Of course, “positive” family planning will not solve all fertility problems. It will not be a treatment for endometriosis, chlamydia or polycystic ovaries. It will not necessarily help women to choose suitable partners during their more fertile years (although it may sharpen their focus). And it will not, in itself, effect the industrial and societal changes required to relieve mothers of the burden of having to compromise their professional lives so much more than fathers do. What it will do, however, is give women the information and tools they need to plan and create families responsibly. 1 Donor’s superovulation ultrasound image 2 Live births per transfer for ART cycles using fresh embryos from own and donor eggs, by ART patient’s age, 2002* ART = assisted reproductive technology. * Reproduced with permission from the US Centers for Disease Control and Prevention.9 3 “Positive” family planning* What an individual general practitioner could do When a childless woman comes for a health check-up or for contraceptive advice or prescription, take the opportunity to refresh her understanding of her reproductive lifespan, discuss her plans for children and make contraceptive recommendations commensurate with those plans.18 Advise women over 35 of the technological advances available for helping to salvage residual fertility. For example: Ovarian reserve screening by transvaginal sonography to establish when a woman’s fertility window is likely to close19 and whether she is a candidate for in-vitro fertilisation (IVF);20 Ovulation tracking by blood testing; Cryopreservation of embryos (or eggs, when the technology to achieve that becomes readily available). What organisations could do Family Planning Australia and its local affiliates could draw from relevant courses they currently offer to doctors, nurses and others to address “positive” family planning, the growing problem of the postponement of parenthood and age-related infertility. With government support, the divisions of general practice could incorporate fertility into their women’s health priorities and assist with informational posters, brochures and other strategies. The Royal Australian College of General Practitioners’ Women’s Health Committee could incorporate fertility into their agenda and urge fertility updates in continuing education programs. In light of Australia’s declining fertility,4 rather than simply cutting off access to IVF at a given age, the government should launch an educational campaign that would help to prevent the need to spend such large sums on IVF. * Planning for conception rather than contraception.

Amy Bachrach BA

Delayed childbearing is not an issue to “keep mum” about For fertility specialists, there is no more difficult and depressing news to break to a woman seeking a baby than “Sadly, it’s too late. You’re menopausal.” In our experience, this situation is encountered with ever-increasing frequency as the age of first attempting to conceive increases. With 1% of the female population menopausal by 40 years and 5% by 43 years,1 and with many more perimenopausal, the rising number of disappointed older women is not surprising. Breaking the bad news requires compassion but realism. Pregnancies are extremely rare in “menopausal” women. Even for those still menstruating, a high follicle-stimulating hormone level in the early follicular phase sounds alarm bells. Pregnancy rates in such women are much less than 2% per cycle, even with “high-tech” approaches such as in-vitro fertilisation (IVF).2 How big is the problem of delayed childbearing?The average age of women bearing their first child in Australia has risen from less than 26 years in 1991 to nearly 30 years in 2003.3 First births in women over 35 years now account for 12% of all births, compared with 6% a decade ago — and those women are the lucky ones. The average age of women undergoing IVF treatment has risen from 31 years in 1993 to just over 35 years in 2003.3,4 The proportion of women commencing such treatment in their 40s has risen from 13% to almost 25% over the same period — that is, one in four women undergoing IVF treatment is at least 40 years of age. Why is childbearing delayed?Bachrach, in her Personal Perspective,5 raises the critical issues that lead to delayed childbearing — career goals, the perceived need for financial security, and/or delay in finding a long-term partner (either through distraction by the pursuit of personal development, or because of lack of interest from a man in forming such a relationship). While 20th century feminism carries significant responsibility for encouraging women to be more self-centred and independent, a changing male attitude to early childbearing also must be acknowledged.6,7 Life can be too much fun to be tied down by wife and children. What are the limits to what we can achieve?Belief in the ability of assisted reproductive technology (ART) to overcome the “biological clock” and achieve a pregnancy in most women and at almost any age is ill-founded. Despite great advances in ART (a woman at 40 years in 2006 now has the same chance of becoming pregnant with an IVF cycle as a 30-year-old woman in 1995),4 over 80% of women having ART treatment will not conceive in their first cycle. Even when a pregnancy occurs, older women have a substantially higher risk of miscarriage and fetal abnormality.4 One in six pregnancies miscarries in a 30-year-old, but by 40 years the risk is one in four. Down syndrome occurs in 1 : 1000 pregancies at 30 years of age but 1 : 100 pregancies at 40 years. The success of technology will always be limited and probably never be able to reverse the relentless deterioration in egg quality and number in the late reproductive years. What can the medical profession do?The general community certainly does not seem to sufficiently appreciate how age affects fertility. Our personal experience with referring general practitioners suggests that the concept of age affecting fertility is widely acknowledged but that the specific, current facts are not known, and there is some evidence to support this.8 Some GPs carry the message they learnt at medical school, that only after a year of trying is it appropriate to refer for help. This is fine for women younger than 35 years, but for older women, earlier referral should be the norm — even if only to confirm that there are no potential barriers to conception. As in Bachrach’s experience, blind reassurance for 12 months may be seen, in time, to have been a terrible mistake. We suggest that any GP, or appropriate other doctor, consulted by a woman over 30 years of age should initiate queries about any plans for parenthood. Doctors can educate women and their partners about the loss of fertility with increasing age and encourage early conception. Similarly, when a doctor sees a new couple over 35 years of age, the doctor should initiate a positive push to consider childbearing — if that is part of their life-plan — as a matter of some urgency.9 We need to reverse any view that raising this matter would be paternalistic or “not politically correct”.10 What can be done in the community at large?Increased public awareness of the risks of delaying childbearing is vital. Government concerns about the rising costs of ART could best be addressed by reversing the trend towards increasing age of first conception. We believe that a little money spent on education would be more than repaid by a reduction in the age-related demand for ART. In 2004, the Fertility Society of Australia initiated the concept of a national education campaign focusing on fertility preservation. As part of their presentation to the Abbott Committee on ART in October 2005, the Fertility Society of Australia and the IVF Directors’ Group urged the Committee to recommend the provision of federal government funding for the campaign. While it would cover many health issues that affect fertility (eg, smoking, obesity and sexually transmitted diseases), a major plank of the campaign could also be to encourage earlier childbearing. This would focus not only on women but also on men, who are often the procrastinating party.7 Barriers to the decision to seek pregnancy earlier need to be examined. For example, workplace reforms should encourage rather than discourage childbearing. Flexible hours and on-site, affordable childcare would bring women back into their jobs earlier and so assist in their desire to be successful on all fronts. But, ultimately, we need to spread the message that there are significant risks of long-term failure and disappointment if women delay attempts to conceive until they reach the age of 35 years or more. Early referral could potentially prevent the disappointment expressed in Bachrach’s Personal Perspective.5

Michael G Chapman FRANZCOG, MD, CREI · Geoffrey L Driscoll FRANZCOG, FRCOG, CREI · Bryony Jones MB BS, MRCOG

Raymond David Rothfield (commonly called “David”) was born in London on 22 June 1920. The family emigrated to Australia in 1924 and David grew up in Sydney. He attended Sydney Grammar School and went on to study medicine at the University of Sydney. After graduating in 1943, David did his residency at Royal Prince Alfred Hospital (RPAH), then worked for a short time with Keith Inglis, who aroused his interest in pathology. In 1944, he enlisted in the Australian Defence Force, serving as a Medical Officer in Morotai and then with the occupation forces in Japan. From 1945 to 1950, while a Postdoctoral Fellow at RPAH, he joined the Citizen Military Forces. He joined the pathology department at St Vincent’s Hospital (SVH), Sydney, in 1950 and obtained a Diploma of Clinical Pathology in the same year. In 1957, David became one of the early members of the College of Pathologists of Australia (later to become the Royal College of Pathologists of Australasia [RCPA]). He was appointed Director of Biochemistry at SVH in 1964, a position he held till his retirement in 1986. In 1968, he became a Fellow of the Australian Association of Clinical Biochemists. David had a passion for excellence and quality in the laboratory. In the early 1980s, he persuaded (I could say “hassled”) the Executive Committee of the RCPA to join with the National Association of Testing Laboratories (NATA) to establish a laboratory accreditation scheme. The resultant NATA/RCPA scheme stands as a lasting tribute to his dedication to quality laboratory practice. On his retirement, he became NATA’s staff pathologist, a position he held part time until his death in 2005. He was also an enthusiastic teacher whose contribution to training young pathologists was valued highly. As acknowledgement of his contribution to pathology, David was awarded both an Order of Australia Medal and an RCPA Meritorious Service Award. Alongside his career, David maintained an involvement with the military. In 1970, he served as a pathologist in Vietnam. In 1982, he was promoted to the rank of Colonel and in 1984 was appointed Consultant Pathologist and supervisor of the multidisciplinary laboratory for the Australian Defence Force at Holsworthy. David also had an abiding interest in boxing, became a qualified instructor and helped many socially disadvantaged youngsters. David was deeply religious, and liturgical music was yet another of his varied interests. He was a kind, gentle and considerate person with an impish sense of humour that made him a delightful companion. David died of metastatic prostate cancer on 21 September 2005. He is survived by his wife Diana, brother Neville and sons Andrew and James.

Eva Raik AM, MB BS, FRCPA, FRACP

To the Editor: Q fever is a serious disease caused by Coxiella burnetii, and usually occurs in people exposed to livestock. In Australia, acute Q fever generally manifests as nonspecific febrile illness. We report a case of spontaneous splenic rupture as a complication of acute Q fever acquired in Australia. A 29-year-old, previously well man presented in March 2005, with 5 days of fever, rigors and severe headache. On examination he had a temperature of 40°C, was tachycardic at 100 beats per minute, but normotensive. There were no focal examination findings. Investigations revealed thrombocytopenia at 123 × 109/L, a normal white cell count, and clear chest x-ray. The patient worked at a factory that processed animal placentas and fetal products. A provisional diagnosis of Q fever was made based on the illness and this exposure. The man was admitted and treated with empiric doxycycline, penicillin, and ceftriaxone. On Day 1 of the admission, he developed sudden, severe, left upper quadrant abdominal pain with shoulder tip radiation, diaphoresis and hypotension. An urgent computed tomography scan of the abdomen revealed splenomegaly with a diameter of 14 cm, and a crescentic, subcapsular splenic haematoma with rupture into the peritoneal space (Box). There was no history of trauma. He was admitted to the high dependency unit for monitoring. His haemoglobin level dropped from 151 g/L to 102 g/L, but he was managed conservatively and discharged from the high dependency unit 24 hours later. Acute Q fever was confirmed by polymerase chain reaction on Day 2, and antibiotic therapy was simplified to doxycycline 100 mg twice daily for 14 days. He was discharged from hospital on Day 5, and recovered fully. Seroconversion to Q fever was subsequently confirmed. His workplace now practices Q fever prevention policies, including pre-employment vaccination. Common presentations of Q fever include nonspecific febrile illness, pneumonia and hepatitis. There are five reported cases of Q fever associated with spontaneous splenic rupture, but this is the first Australian case.1-5 The other patients presented with flu-like symptoms and abdominal pain of 2–14 days’ duration, and required splenectomy between Day 1 and 4 of admission. Clinicians should be aware of splenic rupture as a potential complication of Q fever in Australia. Abdominal computed tomography scan A crescentic, subcapsular splenic haematoma is visible (arrow).

Amanda J Wade MB BS · Tim Walker MB BS · Eugene Athan MB BS, FRACP · Andrew J Hughes MB BS, FRACP

To the Editor: Current Australian guidelines for urgent warfarin reversal recommend withholding warfarin, and giving vitamin K as well as factor replacement (Prothrombinex HT; PTX) with or without fresh frozen plasma (FFP).1 PTX administration without FFP is recommended only when FFP is unavailable, as PTX factor VII levels are low and unquantified.2 Transfusion of 25–50 IU/kg PTX and 150–300 mL of FFP is advised. We examined the effectiveness of warfarin reversal using PTX alone or combined with FFP. One hundred and fifty-five patients given PTX were identified from the transfusion medicine unit’s computer records. Fifty patients were excluded — no warfarin (19), non-hospital patients (11), no record of PTX administration (14), no monitoring (5), normal international normalised ratio (INR) (1). One hundred and five patients who had received warfarin were reviewed. The reasons for anticoagulation were atrial fibrillation (45 patients), venous thromboembolism (22 patients), cardiac valve replacement (21 patients), myocardial infarction (9 patients), and other (8 patients). PTX was administered for bleeding in 51 patients (32 had major bleeds), suspected bleeding in eight patients, high INR in 11 patients, and before a procedure in 35 patients. Bleeding severity was graded using published criteria.3 Post-treatment INR and patient details were used to determine clinically significant INR lowering and haemostasis. The patients were divided into two groups — patients administered PTX without FFP (n = 74) and patients administered PTX and FFP (n = 31) (Box 1). Seventy-four patients (71% receiving PTX; 67.7% PTX + FFP) were given vitamin K (71 intravenously) to ensure ongoing correction of coagulopathy. This was administered within 2 hours of PTX (77%), with doses 1–2.5 mg (44 patients), 3–6 mg (13 patients), and 10 mg (17 patients). The mean PTX dose used was 862 IU or 12.9 IU/kg. Slightly higher PTX doses were administered to patients in the PTX group (913 IU or 13.1 IU/kg) than to patients receiving PTX and FFP (742 IU or 12.3 IU/kg) (Box 1). Seven of 89 patients (7.9%) received the published recommended PTX dose.1 The remaining patients received < 25 IU/kg. Neither the degree of warfarin coagulopathy nor FFP transfusion appeared to influence PTX doses administered. One patient in the PTX group with end-stage renal impairment failed to show any reduction in INR, but did achieve haemostasis. All patients with bleeding achieved haemostasis after PTX. The degree of INR correction after PTX varied considerably, with the percentage reduction in INR after PTX ranging from 0 to > 90% per vial of PTX transfused (Box 2). Achievement of haemostasis did not require normalisation of INR (Box 2). The INR is designed for monitoring therapeutic warfarin levels and its accuracy declines with excessively prolonged clotting times. As PTX is more likely to produce correction of coagulopathy through increased thrombin rather than through factor VII replacement, INR may not be the best test for monitoring haemostatic changes after PTX. Our data suggest that FFP may be unnecessary when PTX is used to reverse warfarin coagulopathy. We have also shown that doses of PTX under 25 IU/kg are effective. Administration of low-dose PTX will produce cost savings and may reduce PTX-associated adverse events (including infusional reactions, thrombocytopenia [secondary to heparin], and thrombosis). The risks associated with FFP transfusion (including allergic reaction, transfusion-related acute lung injury, fluid overload, and infection transmission) would be eliminated. A prospective study is necessary to confirm our findings and assess the efficacy of lower PTX doses, so that, if our results are confirmed, warfarin reversal guidelines can be reviewed. 1 International normalised ratio (INR) before transfusion of Prothrombinex HT (PTX) and dose of PTX in patients in the two groups (PTX and PTX + fresh frozen plasma [FFP]) at increasing levels of anticoagulation INR before PTX PTX group (n = 74) PTX + FFP group (n = 31) No. of patients PTX dose IU (range) PTX IU/kg* (range) No. of patients PTX dose IU (range) PTX IU/kg† (range) FFP units (range) < 2.0 8 556 7.69 1 500 9.09 2 (500–1000) (5.32–11.1) — — — 2.0–3.9 22 929 12.81 16 562 8.48 2.2 (500–2000) (4.85–31.25) (500–1000) (5.1–17.54) (1–10) 4.0–5.9 12 1083 16.2 7 1000 15.51 4 (500–3000) (6.67–34.8) (500–2000) (7.14–44.4) (2–6) 6.0 + 32 1187 14.17 7 929 12.65 4.7 (500–2000) (4.17–27.03) (500–1000) (7.69–19.23) (2–10) * PTX doses calculated for the 89% of patients in the PTX group whose weight was recorded in notes. † Doses calculated for the 77% of patients in the PTX + FFP group whose weight was recorded in notes. 2 Absolute and percentage reduction in international normalised ratio (INR) per vial of Prothrombinex HT (PTX) transfused for the 74 patients in the PTX group (treated with PTX without fresh frozen plasma) INR after PTX INR before PTX < 1.5 1.5–1.9 2.0–2.9 3.0–3.9 4.0–5.9 6.0 + < 2.0 No. of patients (no. with bleeding) 5 (0) 3 (1) — — — — Mean percentage reduction in INR (range) 18.6% (7.1%–31.3%) 9.3% (0–16.7%) — — — — 2.0–3.9 No. of patients (no. with bleeding) 7 (4) 9 (2) 6 (1) — — — Mean percentage reduction in INR (range) 35.9% (21.4%–53.6%) 23.5% (9.1%–44.4%) 30.5% (9.6%–40.0%) — — — 4.0–5.9 No. of patients (no. with bleeding) 1 (1) 7 (5) 3 (3) 1 (1) — — Mean percentage reduction in INR (range) 33.8% 34.4% (9.9%–65.5%) 31.7% (25.5%–39.5%) 21.8% — — 6.0 + No. of patients (no. with bleeding) 8 (4) 4 (1) 8 (5) 8 (2) 2 (1) 2 (0) Mean percentage reduction in INR (range) 52.8% (19.4%–86.4%) 66.9% (44.5%–90.1%) 55.7% (33.6%–82.5%) 37.8% (19.9%–40.2%) 39.6% (35.7%–43.5%) 26.7% (19.0%–34.4%)

Julie H Crawford MB BS · Bradley M Augustson FRACP, FRCPA

To the Editor: Obesity-related glomerulopathy (ORG) is a condition that is partially reversible by weight loss. A 48-year-old morbidly obese man presented with massive proteinuria (8.4 g/day; reference range[RR], < 0.03 g/day). His medical history included hypertension of 4 years, morbid obesity, gout and impaired fasting glycaemia. His hypertension had been relatively well controlled, with no known end-organ complication until the current review. His urinary protein excretion rate measured 6 months earlier had been 0.13 g/day. Longstanding medications included aspirin, lisinopril and allopurinol. The patient weighed 125 kg and was 1.77 m in height (body mass index, 40 kg/m2 [class III obesity]). His blood pressure was 130/70 mmHg, with no postural hypotension. The fundi were normal, with no evidence of hypertensive retinopathy. There was no peripheral pitting oedema and there were no tendon xanthomata. A repeat urinary protein measurement showed an excretion rate of 7.9 g/day, confirming the earlier result. Renal and liver function tests were normal. Other laboratory tests produced the following results: fasting cholesterol, 5.5 mmol/L (RR, < 4.0 mmol/L); triglycerides, 2.4 mmol/L (RR, < 1.8 mmol/L); serum creatinine, 92 μmol/L (RR, 60–110 μmol/L); albumin, 38 g/L (RR, 35–45 g/L); fasting glucose, 6.8 mmol/L (RR, < 5.5 mmol/L); serum insulin, 66 mU/L (RR, 5–25 mU/L); and C-peptide, 6.8 nmol/L (RR, 0.2–0.6 nmol/L). All relevant tests for glomerulonephritis, including serum antinuclear antibodies, antinuclear cytoplasmic antibodies, C3 and C4 levels, protein electrophoretic studies, and hepatitis B and C serology were negative, making a diagnosis of glomerulonephritis unlikely. While awaiting the renal biopsy, the patient decided to attempt rapid weight loss. He began consuming mostly one meal a day of about 5000 kJ (which included about 2000 kJ of protein). Six weeks later, his weight had fallen to 118 kg and his blood pressure was 130/80, with no oedema. His urinary protein excretion rate was 7.6 g/day. After 18 weeks, the patient weighed 110 kg and his urinary protein excretion rate had fallen to 2.1 g/day. At 6 months, his weight loss had plateaued at 102 kg and urinary protein excretion was 0.85 g/day. The renal biopsy showed features consistent with ORG1 (Box). No other abnormality was detected. A concomitant minimal change lesion with spontaneous remission would be a possible explanation, but such a lesion is exceedingly rare and difficult to exclude in the absence of electron microscopy. It is also unlikely given the patient’s age and abnormal light microscopy finding. It is apparent that class III obesity, through unknown mechanisms,2 is a major contributing factor in causing ORG and massive proteinuria — conditions that can be readily improved by weight loss. It remains to be seen in this case whether further weight reduction will further reduce the proteinuria, which, on the other hand, may also be confounded by the hypertension. Impaired fasting glycaemia is not a cause of proteinuria.3 This clinical vignette reinforces the need to check vigilantly for proteinuria and rigorously advise obese patients to attempt weight reduction, especially now that obesity has been confirmed to be an independent risk factor for end-stage renal disease.4 Histopathology of a representative glomerulus There is prominent vascular pole/perihilar sclerosis (broken circular line) and mild fibrosis of the Bowman capsule (arrow) (haematoxylin–eosin stain; original magnification, 3 40). No evidence of hypertensive diabetic nephropathy or tubular disease was detected. Other histological findings (not shown here) included glomerulomegaly, peripheral hyalinosis and mild basement membrane thickening.1 Morphologically, obesity-related glomerulopathy can be difficult to separate from idiopathic focal and segmental glomerulosclerosis.1

Huy A Tran FRACP, FRCPA

To the Editor: Motor neurone disease (MND) is a relentlessly progressive neurodegenerative disease with a median survival of 1–3 years. It results in the death of nearly 400 Australians per year.1 The management of MND remains problematic, tending to be offered in a heterogeneous and ad-hoc fashion across Australia. This heterogeneity arises in part from a lack of understanding of the aetiology of the disease and its progression in different patients,2 the absence of established guidelines for standard care,3 and a lack of concentrated experience among medical practitioners, nursing and allied health care workers in treating patients with MND. With new diagnostic techniques, treatments and interventions for MND undergoing trials, there is a clear need for more baseline information on MND management and outcomes and a method for monitoring any changes on a population basis.4 To facilitate this, the Australian Motor Neurone Disease Registry (AMNDR) has been developed. The Registry is governed by a steering committee comprising specialist physicians from each state and territory around Australia, neuroscientists, an epidemiologist and patient representatives. AMNDR was launched in Sydney in June 2004 to coincide with Motor Neurone Disease Global Awareness Day and, to November 2005, had enrolled 351 patients from 67 study locations, with 88% of registrations coming from 10 major sites. As of September 2005, 90 patients had undergone at least one further follow-up assessment. A copy of the registration, assessment and completion case report forms can be viewed on the AMNDR website (http://ww.amndr.org.au). From the patient information collected in the registration data, three distinct clinical phenotypes have emerged (Box). Patients with the “global” MND phenotype (combined upper and lower motor neurone signs in at least two regions) tended to have the shortest survival time. AMNDR was designed to obtain information that will increase the understanding of MND and its progression in different patients. Through the process of registry establishment, those involved in care, management and scientific research related to MND have been galvanised into a more effective and cooperative working unit. Ownership of the database has been retained by all who have contributed to data collection, and the information has been increasingly used to promote research into the causes and treatment of MND, locally and internationally.5 Through participation, it is expected that treating doctors will be able to evaluate their current management and associated patient outcomes relative to other centres around Australia. Demographic data for 351 patients with motor neurone disease enrolled in the Australian Motor Neurone Disease Registry to November 2005, by phenotype Phenotype, site of symptom onset Percentage of all registrations* Mean age at onset in years (SD) Sex ratio (F : M) Mean survival time in months (SD; range)† Deaths (%) Global† Bulbar 27% 64 (13) 1.5 : 1 27 (10; 20–48) 24% Cervical 25% 55 (19) 0.4 : 1 20 (10; 7–33) 13% Lumbar 19% 61 (10) 1.1 : 1 36 (16; 14–63) 24% Flail limb§ Arm 10% 63 (13) 0.07 : 1 95 (85; 30–238) 27% Leg 10% 58 (10) 2 : 1 59 (28; 33–100) 7% Primary lateral sclerosis¶ All regions 11% 54 (9) 0.9 : 1 103 (55; 24–259) 0 * Sum > 100% because of rounding. † Censored at November 2005. ‡ Global phenotype = combined upper and lower motor neurone signs in at least two spinal regions. § Flail limb variants = predominantly lower motor involvement of arms or legs, with prolonged disease duration. ¶ Primary lateral sclerosis = characterised by pure upper motor neurone involvement.

Matthew C Kiernan PhD, FRACP · Paul Talman FRACP · Robert D Henderson FRACP · Rodney Harris BA, GradDipBusStud, MAICD · on behalf of the Australian Motor Neurone Disease Registry Steering Committee

Medical statistics from A to Z. A guide for clinicians and medical students. B S Everitt. Cambridge: Cambridge University Press, 2003 (vi + 230 pp). ISBN 0 521 53204 3. Medical research articles are increasingly populated by statistical terminology. Many non-statistical readers of the literature would therefore value a resource providing a quick sense of the broad meaning of statistical terms. This book is such a resource, written by a respected world expert on medical statistics. Don’t expect a textbook. Despite its title, this book will not teach you medical statistics from A to Z. It is written in dictionary style, with bite-sized, non-technical references to an extensive range of topics relevant to the application of statistics in medicine and public health. Each entry provides a few lines of information, sufficient for a quick exposure to the term’s meaning. This will leave some readers wanting more, so references to further reading are provided for many of the terms. This is one of the best features of the book, greatly expanding its usefulness. The book can be effectively used as a first point of reference, and as a pointer to a wider and more in-depth body of literature. More than 1500 terms are covered in just over 200 pages. At one end of the spectrum are items such as “relative risk”, for which the terms, but not necessarily the meanings, may already be known to the reader. At the other end are terms of a more esoteric statistical nature, to which many readers will have had little exposure. This feature, combined with the alphabetical ordering, means that readers will find themselves wandering from their chosen term to other previously unfamiliar concepts. For example, referencing the advantages and disadvantages of a “multicentre study” will lead to an overview of “multicollinearity”, while those wanting to brush up on “age standardisation” will soon find themselves exposed to “agglomerative hierarchical clustering methods”. The back cover proclaims that Medical statistics from A to Z will be a lifesaver for doctors and students alike. Whether or not this is true, the book is a genuine timesaver — a quick reference for a plethora of medical statistics terms and an efficient pointer to more in-depth literature. Ian C MarschnerDirector, Asia Biometrics Centre, Pfizer Australia Sydney, NSW

Ian C Marschner

Stemming stroke effects A small pilot trial conducted in Taiwan has suggested that stem cell therapy may have a place in the future treatment of ischaemic stroke.1 Shyu and colleagues allocated at random 10 patients who presented within 7 days of acute cerebral infarction localised within the middle cerebral artery territory to receive either 5 days of subcutaneous injections of granulocyte colony-stimulating factor (G-CSF) or usual care. Six months later, the seven patients who received G-CSF showed a greater improvement in neurological functioning. Four patients who started treatment within 1 day after onset of cerebral ischaemia showed the greatest improvement. G-CSF is known to mobilise endogenous stem cells from the bone marrow into the peripheral blood, from where they can “home in” on the brain and have a protective or even restorative effect;2 in animal studies, G-CSF has also been shown to have anti-inflammatory and neuroprotective properties. 1. CMAJ 2006; 174: 927-9332. CMAJ 2006; 174: 954-955 Atomic thyroid Survivors of the atomic bombings in Hiroshima and Nagasaki are still experiencing the effects of radiation, say Japanese researchers.1 From 2000 to 2003 — at least 55 years after these events — Imaizumi and colleagues surveyed over 4000 survivors for thyroid diseases, finding that 44.8% had such a disorder. Further, a linear dose-response relationship existed between thyroid radiation dose, based on distance from the hypocentre of a bombing, and the prevalence of thyroid nodules, both malignant and benign. The dose effects were significantly higher in those survivors exposed when young; a commentator suggested that this finding probably related to proliferative activity of the thyroid gland during growth subsequent to the radiation exposure.2 1. JAMA 2006; 295: 1011-10222. JAMA 2006; 295: 1060-1062 Texting teenagers Australian researchers say that mobile phone text messaging — that is, short message service (SMS) use — is little exploited in clinical research. They found it both a feasible and an acceptable way of gathering primary care research data from adolescents and young adults. In their general practice-based study, 87 of 96 (91%) young participants (aged 16-24 years) had a mobile phone; further, all but two agreed to provide their phone number for research purposes. Nearly three in four participants (73%) who were sent a text message as part of the study actually replied. Aust Fam Physician 2006; 35: 175-176 Is your time up? US researchers have developed an index which can predict whether a community-dwelling person over 50 years of age is likely to survive for another 4 years. Lee and colleagues developed and validated their index using data from nearly 20 000 people, nearly 2500 of whom had died within a 4-year period. The researchers considered 41 predictor variables in all, with the final model only needing 12 simple predictors, which all rely on patient report rather than medical record review or laboratory testing. As the total point score rises, so does the chance of dying. JAMA 2006; 295: 801-808 Clotting in the air Women using oral contraception and people with a factor V Leiden mutation who are about to take a flight should be offered deep venous thrombosis (DVT) prophylaxis with compressive stockings or single-dose low-molecular-weight heparin.1 So advises Stricker, a Swiss expert, commenting on a Dutch study which compared coagulation activation in 71 healthy volunteers before, during and after three different situations: a specially chartered 8-hour flight, an 8-hour movie marathon and 8 hours of normal daily activities.2 Coagulation activation was markedly raised only after the flight, particularly (but not only) in women using oral contraception and those with a factor V Leiden mutation. The researchers suggested that hypobaric hypoxia rather than immobilisation could account for coagulation activation during air travel. 1. Lancet 2006; 367: 792-7942. Lancet 2006; 367: 832-838 Are we missing the point? When it comes to intramuscular injections, standard blue and green needles may no longer be long enough to reach the gluteal muscles in some patients, according to a UK researcher. In 100 consecutive adult patients referred for computed tomography (CT) scan of the pelvis, Nisbet used automated CT callipers to measure the minimum distance between the skin surface and the nearest edge of muscle at gluteal intramuscular injection sites. The posterior gluteal site fared worst, with the smaller blue needle failing to reach muscle in 72% of patients; the anterior gluteal site did better, but even so, the larger green needle did not reach muscle in 12% of patients. In general, the intramuscular site was likely to be deeper in women. Presumably, we have increasing obesity to thank for this observation. Nisbet suggested that the gluteal route be avoided for the intramuscular injection of most drugs. If alternative routes are not possible, a longer needle should be considered. BMJ Online First, 8 March 2006

Ann Gregory