Volume 182 Issue 9

The 2004 meeting of the American College of Obstetricians and Gynecologists featured a session, prompted by the dwindling numbers of male obstetricians, called “Find the man”. A month later, a kerfuffle erupted in Britain when The Independent ran the story, “The Medical time bomb: too many women doctors”, based on an interview with Professor Carol Black, President of the Royal College of Physicians. She raised concerns about risks to the medical profession’s power and influence because “too many female doctors were scaling its ranks . . . and action was needed to correct [a future] imbalance of the sexes”. Black also aired problems flowing from the skewed distribution of women in subspecialties and their reduced status and involvement in professional bodies, and stated that women find it impossible “to do all the things we expect a doctor to do to be at the top of the profession”. Not unexpectedly, feathers were ruffled. The Lancet repudiated Black’s call to correct the sex imbalance of doctors, labelling it “highly inappropriate”. In response, it suggested increasing the numbers of graduates, both men and women, and rectifying the reasons for women’s lesser professional status and involvement. What are we to make of all this? The downstream effects of feminisation of the medical workforce are only one aspect of the medical time bomb. Ticking away are the tensions between professional and personal lives, the attitudes of modern graduates to medicine, the widening workforce gaps with inadequate doctor numbers and shorter working hours, and the failure to meet the differing needs of the sexes to ensure satisfying clinical careers. To defuse the medical time bomb, we sorely need more leaders like Carol Black to give voice to tomorrow’s problems, today.

Martin B Van Der Weyden

Not so sneezy If your patients are baffling you with queries about "anti-allergy" probiotics and goat’s milk formulas see a summary of the Australasian Society of Clinical Immunology and Allergy Position Statement on allergy prevention in children. Pregnant pause A timely editorial for International Midwives Day (5 May) discusses how turf wars between midwives and obstetricians might become a thing of the past. Quite apart from the need for mutual respect, Weaver and colleagues point out that workforce shortages and benefits to mothers and babies make collaboration imperative (→ Obstetricians and midwives modus vivendi for current times). On another sensitive obstetric issue, statistics on induced abortion in Australia have always been difficult to ascertain. Chan and Sage attempt to fill this gap by examining Medicare claims and hospital morbidity statistics (→ Estimating Australia’s abortion rates 1985-2003). The full picture? In the constant dialogue about the wellbeing of Australian children, there is an astounding diversity. There are many unanswered questions about the impact of social, cultural and economic changes on our society’s youngest members. Despite everyone’s best efforts, in the Australian Institute of Health and Welfare’s recent report A picture of Australia’s children, some of the questions remain unanswered. Patton leads the report’s authors in explaining what we do and don’t know (→ A picture of Australia’s children). Less than benign Some conditions can still catch us out, say Skowronski and Fitzgerald in their Notable Case. A well child with cystic fibrosis develops acute respiratory failure and is found to have a condition that’s seldom considered life-threatening (→ Life-threatening allergic bronchopulmonary aspergillosis in a well child with cystic fibrosis). Last-ditch gene therapy When you're born into a family where other males have died in infancy and you've just been diagnosed with the X-linked form of severe combined immunodeficiency, the options are not plentiful. A child in exactly this situation became the first in Australia to undergo gene therapy, as reported by Ginn et al (→ Treatment of an infant with X-linked servere combined immunodeficiency (SCID-X1) by gene therapy in Australia) However, being a pioneer is not easy. The treatment failed in this child, while three others overseas have since developed a lymphoproliferative disorder. So what stance should we now take on gene therapy? Thrasher’s editorial discusses its efficacy, safety and regulation in France, the US and the UK (→ Gene therapy: great expectations?). From Australia, Trent’s commentary discusses our regulatory checks and balances (→ Oversight and monitoring of clinical research with gene therapy in Australia). Sleepers, wake! We hope anyone found nodding off at last year’s Sleep Loss Symposium got lots of sympathy and good advice. Sleep deprivation is a price we pay to live in a 24/7 world, but its effects can range from illness and burnout to major accidents, such as the 1989 Exxon Valdez grounding. Rogers and Grunstein give us the highlights from the Symposium, including the medical, behavioural, technological and legal measures against sleep loss (→ 24/7 Health. Second annual Sleep Loss Symposium: working and sleeping around the clock). Drawing blood How can we reasonably exclude DVTs in patients? And if a patient does have a DVT, for how long should anticoagulation be continued to prevent recurrence? Ho et al answer these and other common questions on venous thromboembolism in their Clinical Update (→ Venous thromboembolism: diagnosis and management of deep venous thrombosis). And for a snapshot of how anaemia is treated in patients with cancer, turn to the results of the Australian Cancer Anaemia Survey (→ The Australian Cancer Anaemia Survey: a snapshot of anaemia in adult patients with cancer) by Seshadri et al. Take it to the limit Are you thinking of employing Super-nanny to solve your patients' parenting problems? Or could it be that you're raising your own little insomniac? Rather than lose any more sleep over these vexing issues, take the advice of Heussler in this issue’s MJA Practice Essentials —Paediatrics article and set some limits! (→ 9. Common causes of sleep disruption and daytime sleepiness: childhood sleep disorders II) Attacking ataxia Friedreich ataxia is the commonest inherited ataxia. On average, it affects people at 10 years of age and leads to death within 40 years of onset. These are all good reasons to look hard for a cure and, although we're not there yet, Delatycki et al describe the genetic and molecular findings that are spawning new therapies (→ Friedreich ataxia: from genes to therapies?). Cancer talk We all know the aphorism "men are more likely to die with prostate cancer than from it". However, this may be misleading, say Baade and colleagues, particularly for men diagnosed in their 50s or 60s. The authors make their case for what to tell patients about their risk of prostate cancer in "Communicating prostate cancer risk: what should we be telling our patients?". Another time ... another place That we are not much sicker and much madder than we are is due exclusively to that most blessed and blessing of all natural graces, sleep. Aldous Huxley, 1894-1963

Obstetric services need to be women-centred and based on mutual respect and collaboration Obstetricians and midwives have complementary roles in the care of pregnant women, and each group would find survival without the other difficult. Nor would women necessarily receive the best care if access to one or other of these professions were restricted. Having complementary roles, though, has not prevented hostility or “turf” wars between the two groups, with midwives claiming that maternity services are over-medicalised,1 and obstetricians counter-claiming that there is no demand for midwife-led care.2 So what is the current modus vivendi for obstetricians and midwives, and to where feasibly could it evolve by 2020? By 2020, it can only be hoped that an Australian National Maternity Policy will be in place. Maternity services in Australia in 2005 provide much choice for women, including private or public care by obstetricians, general practitioners and midwives. These services can take place in traditional hospital obstetric units, birthing centres and, now less frequently, at home. Australia has not followed the New Zealand model of care in allowing women to choose a midwife as a “lead maternity carer” as a mainstream option in the public health system. However, in some Australian states, this may soon change.3 If this were to eventuate, Australia would do well to look at the lessons learned from the experience in New Zealand. Across the Tasman many positive changes have resulted from maternity services reform, such as significant improvement for many women in continuity of maternity caregiver, and greater availability of non-medically based models of care for those women wanting them. But negative changes have also occurred, such as the effective loss of the option for women to have a GP involved in their maternity care, and an initial exodus of experienced midwives out of the public hospital system. In particular, the sheer pain of major change, for both women and care providers, could have been minimised by thorough and consultative planning. Given all this choice, why should there be hostility between obstetricians and midwives? The main criticisms from midwives stem from a perception that obstetric care in Australia is too medicalised and that obstetric intervention rates are too high.4 Because better continuity of care from a known midwife may lead to fewer obstetric interventions5 and greater certainty for women, there has been a strong push by midwives and consumer groups, such as the Maternity Coalition, for funded midwife-led care.6 On the other hand, obstetricians point to an established system of care, with low rates of maternal and perinatal morbidity as well as generally high levels of community satisfaction.2 Provision of maternity services in Australia has also been made more difficult by workforce issues. The average age of obstetricians in Australia is 51 years7 and of midwives 41 years.8 The workforce survey carried out by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) in 2003 revealed that a quarter of Australian Fellows were now aged 60 or more.7 The same workforce survey also highlighted the possibility of a major shortage of obstetricians in the next 10 years, due to retirements, new RANZCOG Fellows not wishing to practise obstetrics, increased feminisation of the obstetric workforce, and problems associated with safe working hours.7 There has also been a major decrease in GPs practising obstetrics, especially in rural areas, for lifestyle reasons and because of the cost of medical indemnity.9 The shortage of midwives is also a problem. The Australian Health Workforce Advisory Committee estimates a current national shortage of 1850 midwives, and this is expected to increase over the remainder of the decade.8 Problems with recruiting and retaining midwives seem to be related to midwives’ perceptions of a lack of professional recognition, stress and workload issues, as well as limited opportunities for midwives to practise as primary carers and provide continuity of care to women.10 To facilitate discussion between maternity care providers, the RANZCOG re-established the Joint Committee for Maternity Services in 2002. This has representatives from the RANZCOG, the Australian College of Midwives, the Royal Australian College of General Practitioners, and the Australian College of Remote and Rural Medicine, as well as consumer representation. Each representative feeds back to his or her governing body, with the committee proving useful in airing problems and encouraging a collaborative approach to maternity care provision. The committee has made some progress in reviewing international clinical guidelines for possible use in Australia, but has been hampered by lack of funding, obstetricians suspicious of change, and midwives frustrated by lack of change. Difficulties have arisen in reconciling differences between obstetricians, GPs and midwives in how to provide safe evidence-based care that will not diminish current levels of safety. By 2020, it can only be hoped that an Australian National Maternity Policy will be in place. At present, there is none. If this is to occur, obstetricians, GPs and midwives must work to develop collaborative policies that are women-centred, not provider-centred, and which will ensure individualised care to meet the particular needs of each pregnant woman. The development of adequate continuing professional development programs (CPD) for all maternity care providers should be mandatory, and the development of some joint CPD programs crossing profession groups would be useful. There should be development of systems of care that allow for continuity of care for women during pregnancy, labour and postnatally, but which protect against burnout of care providers. There are already good examples of effective services in various places across Australia, ranging from large metropolitan units, such as the Adelaide Women’s and Children’s Hospital Community Midwifery Program, to rural services, such as those provided at Wangaratta Hospital in Victoria, that are women-centred and based on mutual respect and collaboration between obstetricians and midwives. The challenge is to make this the norm for the benefit of mothers and babies as well as their care providers.

Edward W Weaver MB BS, FRACOG · Kenneth F Clark MB ChB, FRANZCOG · Barbara A Vernon BA(Hons), PhD

Do we have a clear enough picture to guide rational health and social policy responses? Australia’s economic prosperity has long brought incremental health gains through better living conditions, sanitation, education, medical care and vaccination.1 The effects on child health and mortality have been striking. The latest report from the Australian Institute of Health and Welfare (AIHW), A picture of Australia’s children, documents this continuing trend. Infant and child mortality rates halved again in the past 20 years.2 The fall in deaths from sudden infant death syndrome (SIDS) to a third of 1991 rates is a tribute to outstanding Australian child health research, as well as the work of child and family health nurses and the SIDS Council of Australia.3 A steady decline in deaths from injury in later childhood has also contributed to lower childhood mortality. Judged by these indices, the present generation of Australian children is the healthiest ever. Key findings of A picture of Australia’s children The infant mortality rate in Australia halved over the past two decades, from 9.6 per 1000 livebirths in 1983 to 4.8 in 2003. The Indigenous infant mortality rate also declined by 3.3% per year, but was still 2.5 times that of other Australian infants. Rates of non-communicable health problems, such as obesity and mental disorders, appear to be rising, but lack of up-to-date national data makes it difficult to accurately assess the current rates. Rates of vaccination among children aged 1 and 2 years have increased over time, with the coverage in 2004 being over 90%. Between 1990 and 2000, children’s dental health improved, with a decrease in the mean number of decayed teeth in 6 year olds (from 2.1 to 1.7), and 12 year olds (from 1.4 to < 1). However, since 2000, tooth decay in Australian children seems to be on the increase again. The number of children on care and protection orders has risen almost 50% in the past 6 years, with the rates sixfold higher in Indigenous children. The proportion of children placed in out-of-home care also rose from 3 per 1000 children in 1997 to 5 per 1000 in 2004. Economic progress has also altered the lives of children through changing the social context of development. The transformation of Australian families has been striking. Fewer children, smaller households, older parents, working mothers, and parental separation and divorce, all affect the way in which families provide a nurturing and secure base.4 There are concerns that a greater investment in fewer children, tied with heightened parental anxieties, has produced a “bubble-wrap generation”. The effects of limiting independent exploration, risk taking and physical activity on children’s physical, cognitive and emotional development may be profound.5 Socioeconomic changes have also affected child health in other ways, such as altering material consumption and lifestyle. Industries, ranging from fashion to food and entertainment, now market to children, regarding them not only as the consumers of tomorrow but as major agents of influence on family spending.6 In this changing social context, the AIHW report attempted to capture a broad picture of the health and development of our children (Box). In preparing the report, emerging morbidities, such as childhood obesity, were to be an important focus. Obesity not only poses risks for later cardiovascular disease and diabetes, but also profoundly affects children’s quality of life and self-concept.7 However, the best available national data are 10 years old, from a time when around one in five children were overweight or obese. Moreover, national data are not available on patterns of physical activity or nutrition. Because of longer-term effects on adult health and prosperity, the socioeconomic circumstances of childhood are central in social policy considerations.8 Nowhere are these continuities between childhood circumstances and adult health clearer than in Aboriginal and Torres Strait Islanders. For this reason the report attempted to capture broader data on family functioning, local neighbourhoods, educational attainment, and the welfare of children in contact with health and social services. Some of the trends revealed by the study provide food for thought. The number of children on care and protection orders has increased almost 50% in 6 years, and rates in Indigenous children are over sixfold higher. The proportion of children in out-of-home care (ie, having to live away from their parents) has risen over 60% in the same period. Around one in ten families with children currently report that their neighbourhoods feel unsafe at least some of the time. This experience is three times commoner in poorer families. What effects these trends may be having on the mental health and emotional development of children is uncertain. Again our picture is incomplete, with the best available national data on child mental health now 7 years old.9 Data from this 7-year-old study suggested that, at any point in time, one in eight children had a diagnosable mental or behavioural disorder. These rates were twice as high in sole parent and blended families (ie, families formed by second marriages between parents with children). Thus, in attempting to paint a bigger picture of child health, development and wellbeing, the AIHW report has exposed huge gaps in the information needed for rational health and social policy responses. Perhaps the clearest gaps concern the emerging non-communicable illnesses of childhood. A need for up-to-date national data on the social and geographic distribution of childhood obesity and mental disorders stands out as a priority. What data we have suggest that these problems vary greatly according to geographic location and socioeconomic status and are worsening. If current social changes persist, the worsening trends in obesity and mental disorders seem likely to continue, and the children most affected will be those in disadvantaged and disrupted families. The federally funded Longitudinal Study of Australian Children will address some of the gaps by providing a better understanding of how current social and family contexts affect children.10 However, the study is of two cohorts separated by 4 years and will not be able to adequately capture the continuing and ongoing changes in the social context of childhood that we may expect to see in the coming years. Other gaps relate to our service systems for children and families. The aggregation of service system data to create ongoing national minimum datasets for areas such as juvenile justice, child protection and children’s services is an important first step in understanding how these systems are working. But much more is needed. The development of brief measures of development and social context in early and later childhood11,12 heralds the possibility of efficiently capturing ongoing shifts in the lifestyles, social development and health of our children. The new health problems of childhood are complex in their origins and likely to be complex in their solutions. A clearer picture of our children is needed to guide our responses — whether these be through priority research, informed government policy, better functioning of our service systems or, most importantly, the efforts of Australia’s parents, schools and local communities.

George C Patton MD, FRANZCP · Sharon R Goldfeld FRACP · Indrani Pieris-Caldwell PhD · Meredith Bryant MA · Graham V Vimpani FRACP

Most cases are caused by a single mutation, paving the way for therapeutic advances for this fatal disease Friedreich ataxia (FRDA), an autosomal recessive disease, is the commonest of the inherited ataxias’, affecting around 1 in 30 000 people.1 With an average age of onset of 10 years, those affected by this condition become wheelchair-bound on average 10 years after onset. The symptom that heralds onset in the vast majority of cases is increasing incoordination. Onset after 30 years of age is rare. Death ensues, on average, 36 years after disease onset and is largely due to hypertrophic cardiomyopathy.2 Other sources of morbidity in FRDA include an increased incidence of diabetes mellitus, dysarthria, swallowing difficulties, scoliosis, optic atrophy, hearing loss and foot deformity.1 FRDA is caused by mutations in the FRDA gene which encodes the protein frataxin. The pathogenic mutation is an expanded GAA triplet repeat in intron one of the FRDA gene in 98% of mutant alleles.1 The other 2% are point mutations. The fact that one mutation accounts for the vast majority of FRDA means that there is a relatively simple diagnostic test available for this disease. The genetic basis of FRDA was elucidated in 1996, and much has since been learnt about its pathogenesis. The first evidence of the role of frataxin came serendipitously, when the yeast equivalent of the FRDA gene (yfh1) was removed and increased levels of mitochondrial iron were detected.3 Human studies have confirmed that FRDA is indeed a disease of mitochondria. The accumulated evidence suggests that the marked reduction in frataxin results in decreased production of iron–sulfur cluster-containing proteins, which leads to deficiencies of some of the mitochondrial respiratory chain complexes and to secondary iron accumulation.2 Oxidative damage has been strongly implicated, although recent evidence brings this into question.4 These genetic and molecular findings have led to a number of therapies being proposed for FRDA. Interventions to maximise quality of life are of paramount importance, while the quest to find disease-modifying therapies continues. Hopes for the obvious prospect of iron chelation therapy have been tempered because none of the current iron chelators approved for clinical use preferentially reduce the levels of iron in mitochondria without also reducing cytosolic iron levels.5 Antioxidant therapy has shown the most promise. High-dose coenzyme Q10 and vitamin E has been shown to reverse the surrogate marker of reduced energy production in muscle magnetic resonance spectroscopy.6 Idebenone, an analogue of coenzyme Q10, reduces cardiac hypertrophy, although it has not been shown to relieve the neurological aspects of FRDA.7 A multicentre placebo controlled trial of idebenone is to start soon in the United States. An antioxidant targeted at mitochondria, mitoquinone, has been developed in New Zealand.8 Because mitochondria have a very strong membrane potential of about 150 mV (positive outside, negative inside), the drug is concentrated in mitochondria about 500-fold compared with antioxidants without a mitochondrial-targeting moiety. Clinical trials of this agent are planned to commence this year. Another approach that has promise is identifying agents that increase frataxin expression.9 The rationale for this approach is that all patients with FRDA produce low levels of normal frataxin, and, in experimental animal models, production of 25% of normal levels is enough to prevent development of disease. Therefore, a 5–10 fold increase in frataxin production may be therapeutic for most patients, while lower levels of induction may still produce significant amelioration of the disease.2 A small number of pharmacological agents have been screened thus far, causing up to a 2.5-fold induction in frataxin expression. It is hoped that high throughput screening of approved drugs and chemical libraries will lead to the identification of more effective and safe inducers. A major challenge facing FRDA clinical investigation is the development of appropriate outcome measures for clinical trials.10 FRDA is rare, and its rate of progression is not predictable, but occurs in a step-wise fashion. Therefore, a multicentre approach is vital to enable development of scales to measure the effects of therapies so that pharmacological discoveries can be quickly translated to patient benefit. The discovery of the underlying genetic mechanism for FRDA has led rapidly to better understanding of its pathogenesis. It is likely that this expanding knowledge will lead to therapies that slow the progression of, and ultimately cure, this fatal disease.

Martin B Delatycki MB BS, FRACP, PhD · Panos A Ioannou PhD · Andrew J Churchyard MB BS, FRACP, PhD

Unrealistic expectations may overshadow genuine advances and focus attention more on failures For many years, scientists and clinicians have sought to harness the power of genes for treating disease. The potential for gene therapy to cure otherwise untreatable conditions, and to offer a completely new strategy where conventional medicine has limited efficacy, has attracted huge interest and investment of time and money from both academic and commercial biotechnology sectors. The field of gene therapy has therefore grown rapidly. However, unrealistic expectation has overshadowed genuine advances and focused attention more on clinical failures and unnecessary mistakes. Only recently, federal law enforcement officials announced a substantial settlement with the University of Pennsylvania after the death of a patient in a gene therapy trial in 1999. Consequently, gene therapy has been viewed with suspicion, and the tight regulatory control on the conduct of clinical studies has to some extent restricted progress. But is the frequently cited accusation that gene therapy has failed to deliver in the clinical arena justified, or is it another manifestation of unrealistic expectation? At the start of the 1990s, the first clinical trials of gene therapy were attempted for an inherited severe combined immunodeficiency (SCID) caused by deficiency of the intracellular enzyme adenosine deaminase (ADA).1-4 In the absence of definitive treatment, SCID of any molecular type is usually fatal within the first year of life, although patients with ADA deficiency can be supported by administration of exogenous bovine enzyme. Even so, this is often only partially effective, and is extremely expensive. The rationale for the development of gene therapy for SCID therefore derives from the severity of the illness, the inadequacy of conventional therapy, and the considerable morbidity and mortality associated with stem-cell transplantation, particularly from a mismatched donor. Efficacy in these early studies was limited, but a decade further on, gene transfer technology and cell handling protocols had been refined sufficiently to produce real clinical benefit. Four recent studies have demonstrated highly effective gene therapy for the X-linked form of SCID (SCID-X1) and ADA deficiency, using retroviruses to deliver the therapeutic genes into haemopoietic stem cells ex vivo5-8 (also Gaspar and Thrasher, unpublished data). Bearing in mind the outcome and adverse effects of conventional therapy, these are remarkable results and the first clear indication that gene therapy can offer a cure for some human diseases. In a few patients, including one reported in this issue of the Journal (page 458),9 the treatment has failed, indicating that there is more to learn about the effective dose of corrected cells and the potential for host factors to influence immune cell development.10 Many different types of vector have been tested in laboratory experiments to deliver therapeutic genes, and their effectiveness is largely determined by the host and tissue type. For stable gene transfer to dividing cells, such as haemopoietic cells, the new genetic material has to be retained through cell division and passed on to daughter cells. Although retroviruses are highly effective for this, their dependence on chromosomal integration brings with it the risk of inadvertent gene activation or inactivation. Having initially achieved successful immunological reconstitution, three patients with SCID-X1 (out of a total of 18 SCID-X1 and seven ADA-deficient patients treated to date) developed T cell lymphoproliferative disease about 3 years after the gene therapy pro-cedure. 11 In two of these patients, the enhancer sequences in the retroviral vector, which are responsible for effective transgene expression, had activated the LMO-2 proto-oncogene. There are likely to be other factors that contributed to cell transformation, but they have not yet been defined. It is therefore unclear whether all patients are at significant risk, or whether this is restricted to a few with SCID-X1. All this makes decision-making by regulatory authorities very difficult, as it would be unfortunate to withdraw potentially life-saving therapy from patients who have few rational alternatives. It is also difficult for families faced with deciding whether to participate in a new therapy with proven curative potential but an element of uncertainty in the longer term. In light of the third adverse event reported earlier this year, regulatory authorities in both France and the United States have put ongoing SCID-X1 studies on hold, although the US Food and Drug Administration have preserved the potential to treat patients in whom allogeneic transplantation has failed. Having considered all options, UK authorities have allowed trials to continue as before, with case-by-case review. This response seems to offer the most flexibility, as patients in whom conventional therapy is judged to be of very high risk can continue to benefit from gene therapy. Importantly, it also empowers families to participate, with informed consent, in the decision-making process. The Australian position is outlined in this issue of the journal (page 441).12 Fortunately, it is likely that much can be done to improve efficiency and safety of current protocols, and these developments are expected to enter clinical trial quite soon. The design of vectors used for gene delivery is clearly important, and modifications are possible that limit the risks of mutagenesis, such as incorporation of DNA and RNA insulator sequences in integrating vectors; use of self-inactivating vectors in which the powerful viral enhancer sequences are deleted; or targeting of safe regions in the genome. Ultimately, the development of homologous recombination or gene repair to accurately correct genetic mutations, or the construction of mitotically stable extrachromosomal vectors, would obviate many of these problems, but current technologies are inefficient. The potential for gene therapy to treat human disease is clear, and the clinical evidence is beginning to emerge. The time between concept and delivery of therapeutic success is really no different from that of other significant medical advances, and the continuing occurrence of side effects associated with established approaches, such as organ and bone-marrow transplantation, should not be forgotten. Undoubtedly, similar strategies will be applied to other severe conditions, but also to a larger number of non-lethal conditions associated with significant disability. In this latter case, the risks of therapy have to be more clearly defined in biologically relevant model systems. The expectation that this exciting new therapeutic modality will produce major immediate effects in the absence of either predictable or unexpected adverse events is unrealistic. More than ever, human clinical trials are necessary to establish the efficacy of gene therapy and to inform future technological development.

Adrian J Thrasher

The NHMRC has set up the Gene and related Therapies Research Advisory Panel (GTRAP) to oversee gene therapy research The cornerstone of clinical research involving humans in Australia is the HREC (Human Research Ethics Committee). All studies must be approved by an HREC at the investigators’ institute(s). The demands on these committees are considerable, particularly when cutting-edge technology is involved. This was the situation in 1994 when the National Health and Medical Research Council (NHMRC) formed GTRAP (Gene and related Therapies Research Advisory Panel). The function of GTRAP was to provide the NHMRC, researchers, clinicians and HRECs with advice on medical, scientific and technical issues related to gene therapy,1 a novel form of treatment that had just been introduced in the United States. Its use in Australia — to treat severe combined immunodeficiency (SCID) — is described in this issue of the Journal (page 458).2 The NHMRC, through its Australian Health Ethics Committee, required that HRECs not give final approval for a gene therapy trial unless that trial had also been reviewed and approved by GTRAP. In Australia, gene therapy requires both local HREC and national GTRAP oversight. The reason for this was the novelty of the treatment, which does not involve traditional drugs or chemicals, but cells that have been genetically modified. Risks such as insertional mutagenesis, now tragically seen after gene therapy of SCID-X1, were known in the early 1990s to be possible. 3 Another concern was the unintentional involvement of germ cells, although the original targets for gene transfer were somatic cells. Genetic errors in somatic cells would harm the patient, but those in germ cells could be passed on to future generations. GTRAP works closely with the Therapeutic Goods Administration (Australia’s equivalent of the US Food and Drug Administration [FDA]), the Office of the Gene Technology Regulator and the Australian Health Ethics Committee through members in common. The “and related” component of GTRAP’s title reflects the growing use that will be made of cellular therapies in clinical practice. The NHMRC has recently expanded the GTRAP terms of reference to include cell therapies in the broader sense, given the future possibility that genetically engineered stem cells (or xenotransplants) will be trialled in clinical research. This move parallels the Therapeutic Goods Administration’s proposed new regulatory framework for tissues and emerging biological therapies.4 Because of the inherent uncertainty surrounding these novel therapies, GTRAP requires that all treated patients (or their families) be contactable should problems develop in the longer term. All studies require the sponsors or investigators to provide annual reports, notifications of adverse events, and a final report on completion of the study. GTRAP’s current position on trials of gene therapy for X-linked SCID or other therapy involving potential risk combinations (retroviral vectors and stem cell targets) is similar to that followed by the FDA, outlined in this issue of the Journal.5 For SCID-X1, this means that gene therapy can still be considered as an option if there are no alternative treatments, such as a suitable allogeneic bone marrow transplantation, or if such transplantation has failed. In the case of the potential risk combinations outlined above, gene therapy could continue after review of the risk–benefit analysis, ongoing monitoring which now would need to include 6-monthly integration-site analysis (analysis of the patient’s cells to detect any potential oncogenic events early), and inclusion in the patient information sheet and consent form the information that acute leukaemia has occurred in children as a complication of gene therapy. In Australia, the clinical investigator and sponsor of two ongoing gene therapy studies involving SCID-X12 and HIV, respectively, placed their studies on voluntary clinical hold when two cases of leukaemia were reported in children who had received gene therapy for SCID-X1. Since then, the SCID-X1 clinical study has remained on voluntary hold. The HIV study, which uses a retroviral vector targeted to haemopoietic stem cells, came off voluntary hold when reassessed by GTRAP. This reassessment included a review of the risk–benefit analysis, implementation of the additional monitoring requirement, and rewording of the consent documents, as described above. Following the report of a third leukaemia complication, the HIV study, which is also being conducted in the United States, has continued pending further advice from the FDA as well as GTRAP. At present, there are no additional scientific data available to GTRAP that would require a clinical hold on the HIV study, although the patient information sheet and consent forms must again be changed to reflect three, rather than two, leukaemia cases. More information on GTRAP (including a list of all gene therapy studies undertaken in Australia) can be found on the NHMRC website (www.nhmrc.gov.au/research/gtrap.htm).

Ronald JA Trent PhD, FRACP, FRCPA

Accidents, such as the Exxon Valdez grounding, show how long work hours and fatigue can affect health and performance — pharmacological, behavioural, technological and legal countermeasures are available Thanks to Edison and other 19th century inventors, we now live in a 24/7 society. Electric lighting keeps factories, supermarkets and airports operating around the clock. Planes fly across multiple time zones. Trucks are driven all night. Health care delivery is a 24-hour business. The price we pay is that lack of sleep and circadian disruption are contributing to work, parenting, social and family pressures, sleep and other medical disorders, and voluntary sleep curtailment. The second annual Sleep Loss Symposium, held in Sydney on 17 November 2004, was organised by the Woolcock Institute of Medical Research, University of Sydney. The symposium focused on the risks associated with working and sleeping around the clock, with presentations from internationally recognised experts from the United States, Sweden and Australia. Health effectsTorbjörn Åkerstedt (Professor of Behavioral Physiology, Karolinska Institute, Stockholm) reviewed evidence in shiftworkers of the increased risk of cardiovascular disease (50% higher incidence of coronary heart disease and increased risk of myocardial infarction), gastrointestinal complaints (50% greater risk of developing peptic ulcers) and breast cancer.1,2 He highlighted recent studies showing that shortened sleep leads to reduced insulin responses to high glucose levels, decreased leptin and increased ghrelin levels, increased triglyceride levels, higher cortisol levels, reduced thyroid axis activity and altered timing of melatonin secretion. The term “shift work sleep disorder” is used to describe insomnia or excessive sleepiness in relation to work schedules that occur during the habitual sleep phase. Shiftworkers have higher risk of peptic ulcer, fatigue-related accidents and depression than those without the disorder. Åkerstedt’s work has recently focused on an increasingly common result of sleep disturbance and chronic exposure to stress —“burnout” — a major burden on the Swedish social security system and common in health care workers. The clinical symptoms of burnout include overpowering fatigue with a lack of restitution from sleep, impairment of memory function, depressive symptoms, poor work performance and lack of empathy; it is distinct from chronic fatigue syndrome. Åkerstedt highlighted the impact of disturbed sleep in more severe cases of burnout, and described positive responses to individual sessions of cognitive behaviour therapy during about a 12-month period. Neurobehavioural effectsNaomi Rogers (Senior Research Fellow, Woolcock Institute, Sydney) presented data illustrating the effects of chronic sleep loss with and without circadian disruption. People with sleep restricted to 3–7 hours in each 24 hours for up to 2 weeks had performance decrements comparable to those of people kept awake continuously for 3 days and nights. Importantly, individuals fail to recognise their level of impairment, highlighting the ineffectiveness of self-monitoring sleepiness and accident risk. Many speakers highlighted the importance of individual differences in susceptibility to sleep loss, with some individuals being particularly sensitive to sleep loss, while others remain relatively resistant.3 Evidence for individual differences in tolerance to shift work, ability to sleep and subsequent sleepiness were also described by Åkerstedt. David Dinges (Professor of Psychology in Psychiatry, University of Pennsylvania) gave examples of real-world effects of sleep loss, including the grounding of the Exxon Valdez on Bligh Reef in Alaska and air crashes (eg, American Airlines crash in Little Rock, Arkanas in 1999). The Exxon Valdez grounding on Bligh Reef just after midnight on 24 March 1989 was found to be directly contributed to by fatigue due to sleep loss. The captain, first mate and second mate had all been awake and working excessive hours loading the vessel and had gone below deck to sleep. The third mate was also sleep-deprived and in violation of the federal statute governing hours of duty in ship mates, but was left to guide the vessel out of Prince William Sound. On leaving the Sound, the third mate failed to correctly manoeuvre the vessel, and it ran aground. As a result of this accident, eight cargo tanks were ruptured and about 250 000 barrels of crude oil emptied into the ocean, causing a serious environmental catastrophe. The Exxon company was ordered to pay $US5.25 billion in damages — a decision it is still appealing. In June 1999, an American Airlines flight (AA1420) from Dallas to Little Rock, Arkansas, overran the end of the runway and crashed into lighting towers, killing 11 (including the captain). At the time of the crash, the captain had been working for at least 16 consecutive hours, and was attempting to land the plane at a time that was 2 hours after his normal bedtime. As well, in the United States, the National Transportation Safety Board (NTSB) estimates that at least 100 000 crashes, 71 000 injuries and 1500 deaths in motor vehicle accidents are a result of the driver falling asleep. Serious accidents resulting from fatigue and sleep loss are not restricted to the transportation area. Dinges also presented recently published data about serious medical errors in hospitals. In one report, it was found that when nurses worked more than 12.5 hours in one shift (which was the case in nearly 40% of their shifts) the chance of a near error was nearly double, and there was a threefold greater incidence of there being one or more serious errors during that shift.4 A recent study of sleep and errors among first-year and second-year medical residents reported that 66% of residents slept for an average of 6 hours or less per night, and 22% of residents slept for an average of 5 hours or less per night. In those averaging 5 hours or less of sleep, there was an increased likelihood of serious accidents or injury, conflicts with other professional staff members, use of medications to maintain wakefulness, working in an impaired condition, significant medical errors, and being named in a malpractice suit.5 Reducing the work hours of intensive care unit residents from an average 85 hours to 65 hours per week resulted in increased sleep duration and a reduction in errors and performance failures.6,7 On 85-hour work weeks, residents had 50% more attentional lapses during the day and more than twice the attentional lapses at night compared with the 65-hour work week schedule. In addition, during the 85-hour work week, residents made 35.9% more serious medical errors, including 56.6% more non-intercepted serious medical errors, 20.8% more serious medication errors and 5.6 times more serious diagnostic errors. CountermeasuresDinges described the use of various countermeasures including pharmacological, behavioural and technological. He spoke about the need to reduce the use of illegal and dangerous pharmacological wake-promoting substances (such as amphetamines), and discussed safer alternatives (such as caffeine and modafinil), and behavioural countermeasures such as naps. Technological countermeasures, such as fitness-for-duty devices and automated fatigue-detection devices (eg, those that monitor the rate and number of eye closures), were reviewed. However, to date there is no validated and accurate device for predicting when someone is likely to fall asleep. Dinges also provided a critique on one of the controversial areas in sleep and circadian research, as industries try to manage their fatigue-related problems — biomathematical models to predict fatigue and performance. He discussed the currently available models (widely used in Australian rail and other transport industries) that were recently objectively tested using a variety of sleep loss and circadian disruption scenarios, with the results published in a special edition of the journal Aviation, Space and Environmental Medicine.8 While all models were able to accurately predict fatigue during total sleep deprivation, none could accurately predict fatigue and performance during different chronic sleep restriction or circadian disruption scenarios. This presentation highlighted the need to validate these models before they are ready to be used in the real world, despite the fact that some models have been adopted into industry settings already. MedicolegalRon Grunstein (Clinical Associate Professor, Woolcock Institute, Sydney) provided an overview of the current medicolegal situation when an accident or injury is related to fatigue induced by sleep loss and long work hours. Examples included the Selby train crash in the United Kingdom, in which the driver of a motor vehicle caused two trains to crash, killing 10 people and injuring more than 70 others. The driver had not slept the previous night and was sentenced to 5 years in prison. In a recent case in Australia, it was deemed that a commercial truck may be considered a part of the work place, and an employer was held liable for the death of the driver, who had not slept for 2 days before the crash because of work demands. In another case, a medical officer at a Queensland hospital made a diagnostic error resulting in the death of a young patient; fatigue due to extended work hours and lack of sleep was deemed to be the underlying cause of his misdiagnosis. The doctor’s work hours were restricted by the Medical Board, and professional bodies called on Queensland Health to change its work practices. Grunstein highlighted how occupational health laws and work hours may potentially affect hospital administrators and supervising consultants, who may be liable for fatigue-related errors by junior doctors working extended hours under their supervision. Panel discussionThe symposium concluded with a wide-ranging, interactive panel discussion with all the speakers. Many delegates expressed frustration at the lack of action in some industries, where work hours and excessive shiftwork place not only individuals, but large sections of the community, in danger. Some panelists identified specific areas for attention by occupational health practitioners, including screening for sleep disorders and ensuring that work hours were a health, and not just an industrial, issue. The conclusion was that 24/7 operations were here to stay — health researchers will need to develop ways to maximise the health and safety of workers, patients and the community at large.

Naomi L Rogers BSc, PhD · Ronald R Grunstein MD, PhD, FRACP

Aim: To estimate national rates of induced abortion in Australia from 1985 to 2003, using Medicare claim statistics for private patients and hospital morbidity statistics for public patients.Design and setting: Estimates were based on Australian and South Australian data collections relating to abortions. SA hospital morbidity statistics were compared with SA statutory notifications of abortions to estimate the accuracy of these collections. Medicare statistics on abortion procedures performed on private patients in South Australia were then compared with hospital morbidity statistics for private patients. National statistics on abortion derived from Medicare and hospital morbidity statistics were adjusted for inaccuracies found in these sources.Main outcome measures: Numbers of induced abortions in Australia for each year from 1985 to 2003; abortion rates per 1000 women aged 15–44 years.Results: Abortion numbers based on Medicare claims by private patients overestimated by 18.7% the number of abortions derived from statutory notifications in South Australia during the period 1988–89 to 1999–00. Hospital morbidity data using principal diagnosis codes relating to medical abortion overestimated statutory notifications by 2.3% (mainly because of readmissions). National statistics were adjusted for these overestimations and for the estimated 14.1% of private patients who would not have submitted Medicare claims (based on surveys of private-clinic patients in New South Wales and Victoria). The estimated Australian abortion rate increased from 17.9 per 1000 women aged 15–44 in 1985 to a peak of 21.9/1000 in 1995, then declined to 19.7/1000 in 2003 (estimated number of abortions, 84 460).Conclusion: There are no data currently available for deriving accurate numbers of induced abortions in Australia. Suggestions are made for collection of national statistics.

Annabelle Chan MB BS, FAFPHM · Leonie C Sage RN, RM

Objective: To evaluate the frequency and management of anaemia in Australian adults with solid and haematological malignancies.Design: 6-month observational, prospective, multicentre study.Participants: 694 patients recruited from outpatient oncology clinics in 24 hospitals in five Australian states between 9 April 2001 and 31 July 2001.Main outcome measures: Frequency of anaemia (haemoglobin [Hb] level < 120 g/L) at enrolment and over ensuing 6 months, by tumour type, disease status and cancer treatment; anaemia treatment and “trigger” Hb level for this treatment.Results: Participants had median age 60 years, and 61% were women. Prevalence of anaemia at enrolment was 35% (199/562), with 78% of these 199 having mild anaemia (Hb, 100–119 g/L). Frequency of anaemia (either present at enrolment or developing during the study) was 57% overall (323/566), and varied with tumour type, from 49% (lymphoma/myeloma) to 85% (urogenital cancer). Patients who received radiotherapy either in combination or concomitant with chemotherapy were more likely to have anaemia (73%) than those receiving chemotherapy alone (58%) (P = 0.004). Of all chemotherapy patients not anaemic at enrolment, 23% developed anaemia by the second monthly follow-up. Independent predictors for anaemia in chemotherapy patients were low baseline Hb level (odds ratio [OR], 5.4; 95% CI, 2.7–10.9) and use of platinum chemotherapeutic agents (OR, 4.8; 95% CI, 2.1–11.4) (P < 0.001). Anaemia was treated in 41% of patients with anaemia at enrolment — by transfusion (36%), iron (5%) and erythropoietic agents (2%). Frequency of anaemia treatment varied between tumour types, from 19% (breast cancer) to 60% (leukaemia). The mean “trigger Hb” for initiating transfusion was 95 g/L.Conclusions: Anaemia is prevalent among Australian patients with cancer managed in hospital oncology units. Its management varies between tumour types. Many patients do not receive treatment for their anaemia.

Tara Seshadri MB BS · H Miles Prince FRACP, MD · David R Bell FRACP · Paul B Coughlin FRACP, PhD · Philip P B James DM, FRACP · Gary E Richardson FRACP · Boris Chern FRACP, FAChPM · Peter Briggs FRACP · John Norman FRACP · Ian N Olver MD, PhD, FRACP · Chris Karapetis FRACP, MMedSc · John Stewart FRACP

Objective: To report the outcome of gene therapy in an infant with X-linked severe combined immunodeficiency (SCID-X1), which typically causes a lack of T and natural killer (NK) cells.Design and setting: Ex-vivo culture and gene transfer procedures were performed at The Children’s Hospital at Westmead, Sydney, NSW, in March 2002. Follow-up to March 2005 (36 months) is available.Patient: A 9-month-old male infant with confirmed SCID-X1 (including complete absence of T cells) with an NK+ phenotype (a less common variant of SCID-X1), and no HLA-identical sibling donor available for conventional bone marrow transplantation.Procedure: CD34+ haemopoietic progenitor cells were isolated from harvested bone marrow and cultured with cytokines to stimulate cellular replication. Cells were then genetically modified by exposure to a retrovirus vector encoding human γc (the common γ chain of several interleukin receptors; mutations affecting the γc gene cause SCID-X1). Gene-modified cells (equivalent to 1.3 × 106 CD34+/γc+ cells/kg) were returned to the infant via a central line.Results: T cells were observed in peripheral blood 75 days after treatment, and levels increased rapidly to 0.46 × 109 CD3+ cells/L at 5 months. Within 2 weeks of the appearance of T cells, there was a distinct clinical improvement, with early weight gain and clearance of rotavirus from the gut. However, T-cell levels did not reach the reference range, and immune reconstitution remained incomplete. The infant failed to thrive and developed weakness, hypertonia and hyperreflexia in the legs, possibly the result of immune dysregulation. He went on to receive a bone marrow transplant from a matched unrelated donor 26 months after gene therapy.Conclusions: This is the first occasion that gene therapy has been used to treat a genetic disease in Australia. Only partial immunological reconstitution was achieved, most likely because of the relatively low dose of gene-corrected CD34+ cells re-infused, although viral infection during the early phase of T-cell reconstitution and the infant’s NK+ phenotype may also have exerted an effect.

Samantha L Ginn BSc(Hons), PhD · Julie A Curtin PhD, FRACP · Christine M Smyth MSc, PhD · Margot Latham BSc · Sharon C Cunningham BSc(Hons), PhD · Maolin Zheng BSc(Hons), MSc · Linda Hobson BPharm(Hons) · Peter B Rowe MD, FRACP · Ian E Alexander PhD, FRACP · Belinda Kramer BSc(Hons), MSc · Melanie Wong PhD, FRACP · Alyson Kakakios FRACP · Geoffrey B McCowage FRACP · Debbie Watson BSc(Hons) · Stephen I Alexander FRACP · Alain Fischer MD, PhD · Marina Cavazzana-Calvo PhD · Salima Hacein-Bey-Abina PhD

A family history of allergy and asthma identifies children at high risk of allergic disease. Dietary restrictions in pregnancy are not recommended. Avoiding inhalant allergens during pregnancy has not been shown to reduce allergic disease, and is not recommended. Breastfeeding should be recommended because of other beneficial effects, but if breast feeding is not possible, a hydrolysed formula is recommended (rather than conventional cow’s milk formulas) in high-risk infants only. Maternal dietary restrictions during breastfeeding are not recommended. Soy formulas and other formulas (eg, goat’s milk) are not recommended for reducing food allergy risk. Complementary foods (including normal cow’s milk formulas) should be delayed until a child is aged at least 4–6 months, but a preventive effect from this measure has only been demonstrated in high-risk infants. There is no evidence that an elimination diet after age 4–6 months has a protective effect, although this needs additional investigation. Further research is needed to determine the relationship between house dust mite exposure at an early age and the development of sensitisation and disease; no recommendation can yet be made about avoidance measures for preventing allergic disease. No recommendations can be made about exposure to pets in early life and the development of allergic disease. If a family already has pets it is not necessary to remove them, unless the child develops evidence of pet allergy (as assessed by an allergy specialist). Women should be advised not to smoke while pregnant, and parents should be advised not to smoke. No recommendations can be made on the use of probiotic supplements (or other microbial agents) for preventing allergic disease at this time. Immunotherapy may be considered as a treatment option for children with allergic rhinitis, and may prevent the subsequent development of asthma.

Susan L Prescott BMedSci, PhD, FRACP · Mimi LK Tang PhD, FRACP FRCPA

Australia has so far been spared serious mishaps in health research, but rising pressures on researchers, deemed to have contributed to two deaths of research participants in the United States, clearly also exist in Australia. Health research investment in our institutions is large and represents an often overlooked area of risk by boards of management. Research governance (the framework through which institutions are ultimately accountable for the scientific quality, ethical acceptability and safety of research conducted in the institutions) has not received sufficient attention. An adequate governance framework requires institutions to have policies and procedures in place to meet national ethical, legal and research practice standards. We suggest that many institutions presently do not have such frameworks in place and inappropriately rely too heavily on human research ethics committees. To ensure ongoing adequate protection of research participants, we recommend some simple improvements for research governance and suggest ways by which institutions can demonstrate adherence to agreed national standards.

Michael K Walsh MB BS, MPA, FRACMA · John J McNeil MB BS, PhD, FRACP · Kerry J Breen MB BS, MD, FRACP

Until definitive evidence of the effectiveness of prostate cancer screening is available, most guidelines advocate that men make their own decisions about testing, after being fully informed. A man’s perception of his personal risk is a key element in the decision-making process. In this decision-making, the current routine use of population risk estimates may be misleading. Risk estimates need to be relevant to the man making the choice. In particular, they should be age-specific and, where possible, include adjustments for known risk factors such as family history. As an example, although the population risk of lung cancer mortality is twice that of prostate cancer, for a non-smoking man with a family history of prostate cancer the direction of this comparison would be reversed. A man aged 50 diagnosed with prostate cancer has a greater likelihood (60%) of dying prematurely (before 80 years) from prostate cancer than a man diagnosed when aged 70 (38%). This can be attributed to the longer time available for the prostate cancer to progress, and the increased effect of competing causes of death among older men. This suggests that the oft-used statement “men are more likely to die with prostate cancer than from prostate cancer” is misleading, particularly for men diagnosed in their 50s or 60s. Decisions need to be made by men based on the best possible understanding of their personal vulnerability, and the individualisation of risk provides a more realistic appraisal of potential threat posed by the disease.

Peter D Baade PhD · Suzanne K Steginga PhD · Joanne F Aitken PhD · Carole B Pinnock PhD

Venous thromboembolism (VTE) affects 1–2 per 1000 people in the general population each year. Clinical diagnosis of deep venous thrombosis (DVT) is unreliable, and must be confirmed by compression ultrasonography or venography. A low clinical pretest probability of DVT and negative D-dimer result reliably exclude the diagnosis, with no need for diagnostic imaging. Initial treatment of DVT is with low-molecular-weight heparin or unfractionated heparin for at least 5 days, followed by warfarin (target INR, 2.0–3.0) for at least 3 months. A vena cava filter is indicated in patients who are ineligible for anticoagulant therapy or who experience embolism despite therapeutic anticoagulation. Thrombolysis or surgical embolectomy may be used as a limb-saving measure in patients with extensive proximal DVT and circulatory compromise that threatens the viability of the leg. Decisions regarding the optimal duration of anticoagulation to prevent recurrent VTE should be individualised and balance the risk of recurrence if warfarin is stopped against the risk of major bleeding and inconvenience of continuing treatment. The risk of recurrence is highest in people with recurrent unprovoked DVT or chronic predisposing factors (eg, cancer) who require indefinite anticoagulant treatment.

Wai Khoon Ho MB ChB, FRACP, FRCPA · Graeme J Hankey MD, FRACP, FRCP · Cindy H Lee MB BS · John W Eikelboom MB BS, FRACP, FRCPA

Allergic bronchopulmonary aspergillosis (ABPA) is an uncommon condition which may complicate asthma and cystic fibrosis; it is seldom considered life-threatening. We report a well 8-year-old boy with cystic fibrosis and normal lung function who progressed to respiratory failure over several days, attributable to ABPA. He recovered with non-invasive ventilation and oral corticosteroid and antifungal medications, regaining normal lung function within 2 months. To our knowledge, such an acute severe presentation of ABPA in a previously well child has not been reported before. Clinical record An 8-year-old boy with pancreatic insufficient, homozygous ΔF508 cystic fibrosis (CF) was transferred from a district hospital with a 7-day history of progressive cough, wheeze and tachypnoea, despite 4 days of broad-spectrum antibacterial therapy (intravenous flucloxacillin and cefotaxime with oral roxithromycin), frequent nebulised salbutamol, oral prednisone (2 mg/kg/day) and chest physiotherapy. There were no other systemic symptoms such as rash, myalgia, arthralgia, diarrhoea or headaches. Initial sputum cultures isolated only normal respiratory flora. The provisional diagnosis was an atypical lower respiratory tract infection, attributed to a viral infection or Mycoplasma pneumoniae. Cystic fibrosis had been diagnosed at newborn screening. His height and weight had tracked along the 10th percentile. Lung function had been normal. Previous sputum cultures had grown Staphylococcus aureus but never Pseudomonas aeruginosa or Burkholderia cepacia. He had not previously wheezed. On arrival, he was mildly dyspnoeic on supplemental mask oxygen at 6 L/minute with a blood oxygen saturation (Spo2) of 94%. He was tachypnoeic (44 breaths per minute), tachycardic (112 beats per minute), afebrile and normotensive. He had bilateral expiratory wheeze with basal crackles. Within 24 hours of transfer, our patient’s condition deteriorated, and he required more frequent nebulised salbutamol and developed signs of respiratory fatigue. At this point an arterial blood gas analysis in 12 L of mask oxygen showed: pH, 7.3; partial pressure of oxygen (Po2), 58 mmHg; partial pressure of carbon dioxide (Pco2), 62.7 mmHg; bicarbonate (Hco3) level, 30 mmol/L; and base excess, 2.7. He was transferred to the paediatric intensive care unit (PICU) for respiratory support with mask continuous positive airway pressure (CPAP). Subcutaneous emphysema developed over the chest wall and neck during the first 48 hours of his PICU admission. A full blood count showed leukocytosis (19.6 × 109/L), and his initial mycoplasma complement fixation test titre was low (< 4). The mycoplasma IgM test result was subsequently negative. Immunofluorescence and culture of nasopharyngeal secretions to isolate a viral pathogen were negative. Total serum IgE titre was 1664 IU (normal range, 0–180 IU) and the skin prick test was positive for Aspergillus fumigatus. The provisional diagnosis was changed to allergic bronchopulmonary aspergillosis (ABPA). Prednisone therapy was continued, and antifungal treatment with oral itraconazole (100 mg twice daily) was added to his therapy. His respiratory status gradually improved and he was weaned off the nasal mask CPAP after 5 days, avoiding endotracheal intubation. He had clinically apparent subcutaneous emphysema, a small pneumomediastinum, but no pneumothoraces during his PICU stay. The chest radiograph before discharge from PICU (Box 1) showed increased perihilar opacities and left lower lobe infiltrates with resolution of the pneumomediastinum and subcutaneous emphysema. His improving spirometry measurements with treatment are shown in Box 2. He was discharged on Day 13 of admission with marked improvement in symptoms and an FEV1 (forced expiratory volume in 1 second) 66% of predicted. A provisional diagnosis of ABPA was confirmed by the significantly elevated serum IgE titre, positive skinprick tests for aspergillus, positive IgG aspergillus precipitins (× 4) and clinical findings consistent with the diagnostic criteria outlined in Box 3.1-5 He received decreasing doses of oral corticosteroids over 3.5 months, as well as oral itraconazole. Within 2 months, his spirometry results had returned to normal. Predictably, he became transiently cushingoid, developed mild untreated hypertension (maximum recorded blood pressure, 116/84 mmHg), and gained 4 kg in weight, but had no glycosuria. He was weaned from corticosteroids and itraconazole, and the side effects resolved within 3 months of discontinuing corticosteroids. Ten months later, he remains well, with normal lung function. DiscussionAlllergic bronchopulmonary aspergillosis (ABPA) is an uncommon condition that can complicate asthma and cystic fibrosis (CF),6,7 and is seldom considered life-threatening.7 The rapid deterioration in the condition of our previously well patient highlights the spectrum of disease severity that can occur in ABPA, and is a reminder that not all deteriorations in respiratory function in patients with CF are attributable to Pseudomonas aeruginosa or Burkholderia cepacia.7,8 Furthermore, this patient’s prompt clinical response to systemic corticosteroids with a return to normal lung function within 2 months suggests that his prognosis will not be adversely affected.9 The presence of Aspergillus species in the sputum cultures of patients with CF has been reported in up to 57% of patients,9 yet the prevalence of ABPA is reported to be between 2% and 14%.1,6 The diagnostic criteria are listed in Box 3. ABPA is a hypersensitivity reaction to the inhalation of aspergillus spores manifesting as chronic wheeze, pulmonary infiltrates and systemic immune activation.5 This results in elevated IgE, IgG and IgA titres.9 Interestingly, although aspergillus grows in the bronchial mucus, this is not an invasive disease.3-5,9 The exact mechanism by which bronchial wall damage evolves and how this gives rise to bronchiectasis and fibrosis is poorly understood.10 Aspergillus fumigatus infection often occurs months before a clinical diagnosis of ABPA is considered. Moreover, as about 40%–50% of school-aged patients with CF have aspergillus in their sputum, comparatively few develop ABPA.3 The reasons for this are not clear, but presumably relate to genetic predisposition, host defences and environmental exposure to aspergillus. Most children with CF who develop ABPA have relatively mild symptoms, respond to treatment over weeks and can often avoid hospital admission altogether.7 Patients with ABPA complicating CF more commonly follow a course of gradually worsening lung function (because of progression of their CF related bronchiectasis) with recurring relapses of ABPA, particularly in summer and autumn, when spore levels in the environment are at their highest.9,10 Treatment of ABPA has centred on the use of systemic corticosteroids for periods of 2–6 months, reducing from doses of 1.0 mg/kg/day of prednisone.4 The adjunctive use of oral antifungals has been advocated for the treatment of ABPA complicating CF11,12 and asthma.6 The response can be dramatic, as in our patient (Box 2). Itraconazole in combination with inhaled corticosteroids was recently shown to be useful for reducing eosinophilic airway inflammation, reducing systemic immune activation and reducing severe exacerbations over a period of 16 weeks in adults with ABPA complicating asthma.13 The use of itraconazole in children is less well studied. However, a recent case series of patients aged 9 to 33 years with CF and ABPA, treated with inhaled budesonide (800–1600 μg/day) and itraconazole (400–600 mg/day), showed a high prevalence of biochemical adrenal insufficiency on adrenocorticotropin testing. This was attributed to an increased systemic budesonide concentration through a reduced or inhibited metabolism (potentially caused by itraconazole), leading to inhibited steroidogenesis.14 This reminds us to use caution when treating patients who take inhaled steroids with courses of itraconazole for exacerbations of ABPA. In conclusion, we are unable to find another case report in which a previously well child with ABPA presented with severe acute respiratory failure. This case highlights the importance of considering a diagnosis of ABPA in highly unusual presentations which may complicate cystic fibrosis. 1 Chest x-ray 3 days after admission to intensive care Shows hyperinflated lung fields, perihilar inflammatory changes, emergence of an interstitial infiltrate in the left lower lobe and a small right-sided pleural effusion. 2 Relationship between IgE levels and FEV1 (forced expiratory volume in one second) before, during and after admission Inverse relationship between IgE levels and FEV1 over time (non-linear scale), showing the drop in lung function at the peak of the disease. 3 Classic case criteria for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis1-5 Clinical deterioration (increased cough, wheezing, exercise intolerance, increased sputum, decrease in pulmonary function) Immediate cutaneous reactivity to aspergillus or presence of serum IgE from A. fumigatus Total serum IgE concentration >1000 IU/L Precipitating antibodies to A. fumigatus or serum IgG from A. fumigatus Abnormal chest x-ray (infiltrates, mucus plugging, or a change from earlier films) Adapted from the ABPA Consensus Conference of the Cystic Fibrosis Foundation4

Emma Skowronski BMedSci · Dominic A Fitzgerald PhD, FRACP

There are strong associations between childhood sleep disorders and behavioural, concentration and mood problems. Sleep disorders caused and maintained by behavioural factors (eg, sleep-onset association disorder) are common in young children, and have a significant impact on families. Evaluation should include a medical history, a physical, neurological and developmental examination, a description of any nocturnal events or daytime effects of the child’s disturbed sleep, and a good understanding of the family situation and parental management of the child. Management involves recognising the developmental age of the child and the family dynamics, and educating and supporting families in applying behavioural techniques to establish good sleep hygiene. Children with parasomnias (eg, night terrors) also benefit from good sleep hygiene, while those with respiratory or neurological causes of sleep disturbance should be referred for specialist treatment.

Helen S Heussler MB BS, FRACP

Laurelle J Burrell,* Elizabeth A Grabsch,† Alexander A Padiglione,‡ M Lindsay Grayson§ * Infectious Diseases Research Nurse, † Infection Control Scientist, § Director of Infectious Diseases, Austin Hospital, Studley Road, Heidelberg, VIC 3084; ‡ Infectious Diseases Physician, Department of Epidemiology and Preventive Medicine, Monash University (Alfred Hospital), Melbourne, VIC. Lindsay. GraysonATaustin.org.au To the Editor: Patients with end-stage renal failure are a key risk group for colonisation and infection with vancomycin-resistant enterococcus (VRE). Consequently, many renal units in Australia screen these patients regularly for VRE colonisation, to assist with infection control and treatment.1-3 Screening protocols are usually applied equally to inpatients and outpatients, even though the risk of VRE colonisation among outpatients (and therefore the cost–benefit of such screening) has not been clearly defined. To assess the prevalence of faecal VRE colonisation among haemodialysis outpatients, we conducted a cross-sectional survey of outpatients attending 12 Victorian in-centre haemodialysis units — Austin Health (four units), Southern Health (three units) and five regional haemodialysis units (Bendigo, West Gippsland, La Trobe Valley, Central Gippsland and Bairnsdale). Patients attending these units represent about a third of the state’s in-centre haemodialysis population. The study was approved by the ethics committee at each hospital, and written informed consent was obtained from all participants. All patients who attended the units between 1 October 2001 and 3 April 2002 were invited to participate. VRE faecal carriage was assessed by three rectal swabs and one faecal specimen taken on at least three separate occasions. Specimens were inoculated onto Enterococcosel agar (BBL, Sparks, USA) containing 6 μg/mL vancomycin. All cultures were processed by standard methods for VRE identification, as described previously.2,3 Of 345 available haemodialysis patients, 269 (78%) consented to participate in the study (205 [76%] metropolitan, and 64 [86%] regional; participation rate per centre, 70%–91%). The 269 patients represented approximately 30% of Victorian in-centre haemodialysis patients. Overall, 74% of participants had assessment of all three rectal swabs and a faecal specimen. VRE faecal colonisation was found in three of the 269 participants (1.1%) — two were from separate metropolitan hospitals, and one from a regional centre. All isolates were Enterococcus faecium vanB (the most common type of VRE in Australia).3 None of these three patients were known to be previously colonised. This 1.1% prevalence was substantially lower than the 3.0%–4.6% prevalence previously described in renal inpatients in Melbourne,2,3 and the 10% rate reported in the United States (where 33% of dialysis centres have one or more VRE-positive patients).1,4 Statistical comparisons of this study with our previous two Australian studies2,3 should be undertaken cautiously, as screening methods differed in specimen frequency, type and number. Bearing in mind this caveat, the rate of faecal VRE carriage was significantly lower among the haemodialysis outpatients in our current study compared with renal inpatients in a 1997 study by Grayson et al2 (3/269 v 9/194; P = 0.02 by χ2 test), but less definitely so when compared with renal inpatients in the 1998–1999 study of Padiglione et al3 (3/269 v 22/739; P = 0.09, by χ2 test). Since the outpatient study, screening surveys at our hospital have shown intermittent high rates of colonisation in renal inpatients and environmental contamination (unpublished data). Given our findings in outpatients, we believe future VRE screening protocols in Australian hospitals should focus primarily on inpatients, rather than faecally continent outpatients, who have both a low rate of colonisation and low potential risk for VRE transmission or acquisition. Good compliance with practical infection control guidelines remains important to avoid widespread dissemination of VRE in our haemodialysis centres.5

Laurelle J Burrell · Elizabeth A Grabsch · Alexander A Padiglione · M Lindsay Grayson

Adam P Morton,* H David McIntyre† * Endocrinologist, † Director, Endocrinology and Obstetric Medicine, Mater Hospital, Raymond Terrace, Sth Brisbane, QLD 4101. AmortonATmater.org.au To the Editor: We read with interest the article by Hussein and colleagues on their experience with thiazolidinediones (TZDs).1 These agents are only approved by the Pharmaceutical Benefits Scheme as part of dual therapy. We wish to present our experience of adding TZDs to metformin and sulfonylureas — hence, triple therapy — in patients with suboptimally controlled type 2 diabetes mellitus. The records of 28 patients (15 men, 13 women) with type 2 diabetes, for whom pioglitazone was added to maximal doses of metformin and sulfonylurea because of suboptimal control, were reviewed. Baseline patient characteristics are shown in . Mean follow-up was 9.6 months (range, 3–24 months); the average pioglitazone dose was 31.3 mg. The mean fall in the level of glycohaemoglobin (HbA1c) was 1.26% — 10 patients achieving an HbA1c level of less than 7% at last review. Four patients did not respond to therapy; none withdrew because of side effects. Eight patients whose HbA1c fell less than 0.5% after 3 months continued taking pioglitazone, achieving an average fall in HbA1c of 1.25% after a mean of 12 months follow-up. Mean weight gain was 3.35 kg (– 3.2 kg to 11.6 kg). Mean changes in HbA1c level and weight compared with baseline over 24 months are shown in . There was no correlation between these outcomes, and no baseline characteristic predicted glycaemic response. Six studies have reported the efficacy of TZDs in triple therapy (), and show a consistent fall in HbA1c level at the expense of weight gain, with a low rate of withdrawals because of adverse effects. Our findings were similar to those of these previous reports in terms of glycaemic response and low rate of side effects. The much higher rate of side effects reported by Hussein et al1 is likely to be the result of the coprescription of TZDs with insulin in 64% of patients in their study. While fluid retention has been reported in up to 5% of patients taking TZDs as monotherapy or in combination with oral hypoglycaemics, 15% of patients using TZDs with insulin may develop significant oedema. Most reports describing precipitation of cardiac failure with TZDs have been in patients using combination therapy with insulin. It would be interesting to know what proportion of the patients who developed peripheral and pulmonary oedema in the study by Hussein et al1 were also receiving insulin. One prospective randomised trial comparing the addition of pioglitazone and bedtime insulin to maximal metformin and sulfonylurea found similar efficacy in improving glucose control, but less hypoglycaemia and improved high density lipoprotein cholesterol levels with pioglitazone.3 A study of the long-term efficacy of triple therapy found 26 of 35 patients (74%) had good control after a mean follow-up of 37 months, their HbA1c level having fallen from 8.7% to 6.9%.8 In conclusion, the experience of our unit and the published literature is that TZDs are efficacious in improving suboptimal diabetic control in patients on maximal doses of metformin and sulfonylurea. Eight individuals in our group had a significant improvement in control subsequent to minimal response after the initial 3 months of treatment, suggesting a longer trial of TZDs should be employed before classifying patients as non-responders. It is to be hoped that the regulatory authorities will allow the use of TZDs in triple therapy. 1 Characteristics of our 28 patients at baseline Variable Mean (range) Age (years) 57.4 (31–74) Weight (kg) 96.3 (56–137) Body mass index (kg/m2) 34.6 (24–50.3) Duration of diabetes (years) 11 years (1–48) Glycohaemoglobin (HbA1c) level (%) 9.0 (7.1–10.4) 2 Changes in glycohaemoglobin (HbA1c) level and weight compared with baseline values 3 Studies of thiazolidinediones added to maximal dose metformin and sulfonylurea Variable Roy et al2 Aljabri et al3 Dailey et al4 Kiayias et al5 Kiayias et al5 Byrne et al6 Yale et al7 Thiazolidinedione Rosiglitazone Pioglitazone Rosiglitazone Rosiglitazone* Rosiglitazone† Rosiglitazone Troglitazone Duration (weeks) 16 16 24 20 20 nr 24 No. of patients 48 30 181 19 19 24 101 Baseline body mass index (kg/m2) nr 26 32 31 31 nr 30.1 Baseline HbA1c level (%) 9.3 9.7 8.1 8.9 9 9.6 9.6 Fall in HbA1c level (%) 1.8 1.9 0.9 1.1 1.4 1.2 1.3 Weight gain (kg) nr 2.6 3 4.2 4.6 0.7 0.9 % Patients withdrawn 4.2 0 5.5 0 0 0 2 % Patients with satisfactory control (HbA1c level) 65 (< 7.5) 23 (< 7) 42 (< 7) nr nr nr 43 (< 8) HbA1c = glycohaemoglobin. nr = not reported. * 4 mg/day; † 8 mg/day.

Adam P Morton · H David McIntyre

Nirusha Arnold,* Mark McLean,† David R Chipps,† N Wah Cheung† * Advanced Endocrinology Trainee, † Endocrinologist, Centre for Diabetes and Endocrinology Research, Westmead Hospital, Hawkesbury Road, Westmead, NSW 2145. nirusha_arnoldATozemail.com.au To the Editor: It was with interest that we read the recent article on real-life experience with thiazolidinediones by Hussein et al.1 The authors noted the absence of severe liver toxicity with the newer agents, rosiglitazone and pioglitazone, in contrast to troglitazone, which was withdrawn because of cases of hepatic failure.2 However, the sample was too small to conclude that these thiazolidinediones (TZDs) carry no hepatic risk, and they endorsed the current Pharmaceutical Benefits Scheme recommendations that liver function tests (LFTs) be monitored every 2 months. We have collected similar clinic data showing that the development of significant abnormalities in results of LFTs with TZD therapy is uncommon, and in fact, there are often improvements in LFT findings. We reviewed the files of 166 patients with type 2 diabetes treated with TZDs between 1 August 2000 and 30 November 2002, with the aim of assessing their long-term effect on LFT results. Therapy was discontinued within 3 months in 26 patients. The reasons were non-compliance (7), therapy ineffective (8), weight gain (5), dyspnoea (1), peripheral oedema (1), malaise (1), dizziness (1), angio-oedema (1), and pre-existing LFT abnormality (1). We analysed data on the remaining 140 patients (see Box) treated for a mean of 188 ± 4 days with either pioglitazone (109 patients) or rosiglitazone (31 patients). All LFT results improved significantly (Box). At baseline, 90 patients had abnormal findings on LFTs. These findings normalised in 43 of these patients (including one with steatohepatitis proven on biopsy); improved in 29 patients; and were unchanged in nine patients. LFT findings deteriorated in nine patients, leading to cessation of therapy in two. Most patients with normal LFT results at baseline experienced improvements of these parameters within the normal range. Three patients developed new abnormalities in their LFT findings, and therapy was stopped in one patient, leading to resolution of LFT abnormalitites. Changes in glycohaemoglobin (HbA1c) levels correlated positively with changes in activity of alkaline phosphatase (correlation coefficient [r], 0.33; P < 0.01), aspartate aminotransferase (r, 0.27; P < 0.01) and alanine aminotransferase (r, 0.29; P < 0.01). Our findings support those of Hussein et al, that TZD therapy is usually stopped for reasons other than hepatic dysfunction. In contradistinction to early concerns about their hepatic safety, the improvements in LFT findings seen in our patients suggest that TZDs may even benefit hepatic function. In patients with diabetes, abnormal findings on LFTs are often attributed to fatty liver, which predisposes to steatohepatitis. TZDs may well alleviate or prevent steatohepatitis,3 thereby providing benefits beyond that of improved glycaemic control, and mild abnormalities in LFTs should not discourage their use in patients with diabetes. Changes in liver function and glycohaemoglobin (HbA1c) level Variable Baseline 6-month follow-up Change P* Weight (kg) 93 ± 2 96 ± 2 3 ± 0.4 < 0.001 HbA1c (%) 8.9 ± 0.1 7.9 ± 0.1 – 1.0 ± 0.1 < 0.001 Albumin (g/L) 41 ± 0.2 41 ± 0.2 – 0.5 ± 0.2 < 0.02 Bilirubin (μmol/L) 9.4 ± 0.4 8.5 ± 0.3 – 0.9 ± 0.3 < 0.003 ALP (U/L) 92 ± 2 79 ± 2 – 13 ± 2 < 0.001 GGT (U/L) 44 ± 3 31 ± 2 – 13 ± 2 < 0.001 AST (U/L) 26 ± 1 22 ± 1 – 3 ± 1 < 0.001 ALT (U/L) 33 ± 2 25 ± 1 – 8 ± 2 < 0.001 ALP = alkaline phosphatase. GGT = γ-glutamyl transferase. AST = aspartate aminotransferase. ALT = alanine aminotransferase. * Paired t test.

Nirusha Arnold · Mark McLean · David R Chipps · N Wah Cheung

Huong V Nguyen,* Katherine B Ingram,† Jonathan Beilin‡ * Endocrinology Registrar, ‡ Endocrinologist, Royal Perth Hospital, Box X2213 GPO, Perth, WA 6847; † Geriatrician, Swan District Hospital, Middle Swan, WA Huong. NguyenAThealth.wa.gov.au To the Editor: Zoledronic acid is a new bisphosphonate treatment for hypercalcaemia of malignancy, multiple myeloma and documented bone metastases from solid tumours, in conjunction with standard chemotherapy.1 Transient hypocalcaemia, a side effect of bisphosphonate therapy, can occur with zoledronic acid.2 We describe a patient with transient severe hypocalcaemia after zoledronic acid treatment. An 88-year-old white woman with multiple myeloma presented with left hip pain. Imaging revealed multiple lytic lesions in the spine, pelvis and upper femurs. She was commenced on zoledronic acid 4 mg and a 5-day course of melphalan 10 mg/day and prednisolone 100 mg/day. At this stage, her serum calcium concentration was 2.38 mmol/L (normal, 2.15–2.55 mmol/L) and serum phosphate concentration was 0.8 mmol/L (normal, 0.8–1.5 mmol/L). She had renal impairment with reduced creatinine clearance of 35 mL/min. Nine days later, she underwent surgical repair of a duodenal ulcer. Post-operatively, she was found to be hypocalcaemic, with serum calcium concentration of 1.34 mmol/L and ionised calcium concentration of 0.78 mmol/L (normal, 1.14–1.29 mmol/L). Serum phosphate concentration was 0.4 mmol/L and magnesium concentration was 0.87 mmol/L (normal, 0.70–0.90 mmol/L). Her serum 25-hydroxyvitamin D concentration was 14 nmol/L (normal > 50 nmol/L) and her parathyroid hormone level was 44 pmol/L (normal, 1.5–8.0 pmol/L). The patient displayed no symptoms of hypocalcaemia and had negative Chvostek and Trousseau signs. Her QTc interval was normal. Her hypocalcaemia was managed with oral calcium carbonate 4.5 g/day and calcitriol 0.5 g/day. Ten days later, her total serum calcium concentration rose to 2.31 mmol/L and her phosphate concentration was 0.9 mmol/L. Bisphosphonates inhibit osteoclast-mediated bone resorption, thereby reducing serum calcium concentration. Compensatory secondary hyperparathyroidism prevents significant hypocalcaemia by enhancing renal calcium conservation, 1,25-hydroxyvitamin D production, and osteoclastic bone resorption.1,2 In our patient, the 1,25-hydroxyvitamin D concentration was not measured. However, in view of the low 25-hydroxyvitamin D and impaired renal function, this level may have been low, further exacerbating the hypocalcaemia. Transiently low phosphate concentration in this patient may be due to fasting and co-administration of 5% dextrose, as our patient was fasted for 3 days peri-operatively and given a combination of intravenous 5% dextrose and normal saline. Vitamin D insufficiency afflicts a large proportion of the elderly population,3 and its existence needs to be recognised before commencement of bisphosphonate therapy, so that adequate calcium and vitamin D supplementation can be given to reduce the occurrence of hypocalcaemia.

Huong V Nguyen · Katherine B Ingram · Jonathan Beilin

Peter A Frith Head of Southern Respiratory Services, Respiratory Unit, Flinders Medical Centre, Bedford Drive, Bedford Park, SA 5042. Peter.frithATrgh.sa.gov.au To the Editor: The informative study by Simons and colleagues1 has highlighted a major concern. Chronic obstructive pulmonary disease (COPD) is one of Australia’s top four causes of death and burden of illness,2 yet the authors have made no mention of COPD. Failure to recognise the importance of this disease is an endemic attitude in Australia and globally3-5 that results in under-representation of COPD in epidemiological surveys and in inadequate funding for effective treatments and research. The study found that peak expiratory flow (PEF) provides the highest hazard ratios for predicting time to death in women (and the second highest in men). There is even a “dose–response” effect. Using the term “impaired PEF” is a bit like saying “impaired ECG” without attributing a diagnosis. PEF is a measure of airway calibre, and impairment of PEF indicates airway disease — largely COPD in this population. Smoking accounts for about 85% of the risk of COPD, and about 50% of smokers develop airflow limitation,4-6 so it is not surprising that the interaction between PEF and smoking was the most important predictor of reduced survival in this large cohort. It’s time to stop hiding our heads in the ashtray! Smoking combined with low PEF is COPD. We must demand that our medical and epidemiological professions uncover people with undiagnosed COPD. Early diagnosis is simple.5 It’s not normal to be unable to keep up with friends at work or during recreation because of breathlessness, and a daily cough is really an airway disease. If symptoms are acknowledged, spirometry will confirm the diagnosis. We should help our patients to enunciate these hidden symptoms so their condition can be diagnosed accurately, and effective management begun, as highlighted in the “COPDX management guidelines”.5 Primary and secondary prevention must focus on reducing smoking among young people. Smoking cessation, the use of effective drugs, and pulmonary rehabilitation are the cornerstones of COPD therapy that lead to better quality survival. COPD is common and under-diagnosed. Simons et al have partly exposed this deadly condition. Their data, added to other Australian data,7 should trigger actions that facilitate earlier diagnosis throughout Australia and support delivery of effective treatment to the thousands “dying a slow death” from COPD. Australia’s illness burden from COPD is high. Its prevalence and burden in Australia are rising, especially in women. Globally, the World Health Organization expects COPD to rise from 12th to 5th as a cause of illness burden by 2020. We must acknowledge that PEF impairment is not simply a mysterious risk factor for early “all-cause mortality”, but is indicative of COPD being a major contributor to death in this population.

Peter A Frith

Leon A Simons,* Judith Simons† * Director, Dubbo Study of the elderly, † Data Manager, Lipid Department, St Vincent’s Hospital, Darlinghurst, NSW 2010. L. SimonsATnotes.med.unsw.edu.au In reply: The prospective Dubbo Study of the elderly has produced a series of publications in which reduced peak expiratory flow (PEF) has been shown to be associated with increased risk of death,1,2 as well as increased risk of heart attack,3 ischaemic stroke4 and admission to a nursing home. 5 We have employed a purely statistical definition of impaired PEF, namely the lowest third of our sex-specific population distribution. We agree that many subjects so defined with impaired PEF, and who are smokers, will have underlying and potentially undiagnosed chronic obstructive pulmonary disease (COPD). Epidemiological studies have highlighted the importance of impaired PEF. It is now time for health professionals to implement the COPDX management guidelines referred to by Frith6 in a still more effective manner and to devise better prevention programs.

Leon A Simons · Judith Simons

Bernard M Bourke Vascular Surgeon, Gosford Hospital, 4/213 Albany Street North, Gosford, NSW 2250. Dr. BourkeATgvs.com.au To the Editor: Up and coming surgical registrar, Ken Wong, presents a revolutionary plan to allow him to look after surgical patients in the operating theatre.1 The use of the telephone for communication has merit, but he won’t feel so smug when he gets to the chapter entitled “The management of surgical patients in NSW public hospitals in winter”. There will be nowhere for Dr Wong to “hide” when he realises our operating theatres are, in fact, solar powered and that, when the sun goes down in winter, the theatres conk out. Surely now, with the statewide mergers of health services, there will be enough excess “committee people” to form a collaboration with the western NSW farmers so that the mice plague can be harnessed and trained to run on the cogs and at least provide lighting during power shortages. I’m sure my daughter could lend a few cats to chase the mice. In the absence of the provision of more hospital beds, the substitution of cat-and-mouse power for solar power is the best “winter strategy” I’ve heard in the last 10 years. This concept will feature in our next chapter, “How to train surgeons without patients or operating time”.

Bernard M Bourke

Bruce Gutteridge, a distinguished Queensland pathologist, died in the company of his wife and family at his beach house in Noosa, Queensland, on 12 January 2005, from metastatic colonic cancer. Over 1000 people attended his funeral. His father Noel was one of the three founders of pathology services in Queensland. Bruce and his brother Donald were the fourth generation of medical graduates in the family. Bruce was born in Toowoomba on 10 September 1928. After graduating in medicine in 1951, he spent several years at Brisbane Hospital, first as a Resident Medical Officer then as a Pathology Registrar. In 1956, he topped the Diploma in Clinical Pathology course at the Postgraduate Medical School (PGMS) in London. He then successively held three prestigious teaching registrar posts at the PGMS — in Chemical Pathology, Haematology and Histopathology. On returning to Brisbane in 1959, he joined his father in the Gutteridge Laboratories, which had eight staff and branches in Gympie, Nambour and Southport. While Noel expanded into country areas, Bruce directed technical improvements, initially establishing departments of radioisotopes, nuclear medicine and cytology. From 1967, the name “Queensland Medical Laboratory” (QML) was adopted. After his father’s departure in 1974, Bruce was Senior Partner until his retirement in 1994, when QML had over 1500 staff. Bruce was Visiting Specialist in Histopathology and Haematology at the Royal Brisbane Hospital from 1959 to 1988. He also provided 52 years of continuous service to the Royal Australian Army Medical Corps (RAAMC) (1952–2004). He was Supervisor in Pathology at 2 Military Hospital Yeronga (later 2 Health Service Battalion, Enoggera), Brisbane (1959–2004). In 1969, he spent 4 volunteer months in Vietnam as a Lt. Colonel–Senior Pathologist and resuscitationist, 1 Australian Field Hospital, Vung Tau. He published a number of papers on his work in the United Kingdom, Vietnam and Australia. Bruce’s hobbies were golf, snow skiing, contract bridge and fishing. For 20 years (1972–1992), as President of the Ski Division, Queensland Branch of the Australian Sports Medicine Federation, he led an annual medical educational and skiing pilgrimage to Smiggin Holes. His favourite saying was, “Life is like an empty bucket — you get out of it what you put into it”. His son Andrew commented that Bruce’s bucket ran at overflow level — his energy and enthusiasm for life, exercise, family, friends and humorous tales was boundless; his generosity legendary. Attacks on his health (including 22 operations in his last 10 years) did not dim his joie de vivre. He was a giant of a man in stature, energy and outlook, and has left his mark — on Australian pathology, on the RAAMC and on society — as a dedicated doctor, patron of the arts, and proud and generous family man and friend.

Donald H Gutteridge

Re: MJA Practice Essentials – Paediatrics “Investigation and treatment of upper-airway obstruction: childhood sleep disorders I”, by Kennedy JD and Waters KA (Med J Aust 2005; 182: 419-423). In printed version of this article, the last two paragraphs were missing from the Case study on page 422. The complete Case study is given below. The html version of this article was correct on publication and the pdf version was corrected on 27 April 2005. Case study — a 5-year-old boy with obstructive sleep apnoea syndrome (OSAS) A mother brings her 5-year-old son to you, as she is concerned about his loud snoring. He has been snoring for 2 years, but it is gradually becoming louder. Although she is unaware of whether or not her son has obstructive apnoeas, she is anxious about his breathing during sleep. She often sits up to watch him breathe before retiring herself. The mother reports that the boy’s teacher at school says that her son has a poor concentration span and is easily distracted in class. Both the father and grandfather snore loudly but neither has sought medical advice or investigation. Management On examination, you find that the boy has relatively small tonsils and you initially reassure his mother. However, as his symptoms persist, you refer him to a paediatric respiratory physician. An overnight home oximetry study shows only mild desaturations that appear to be associated with movement. A lateral x-ray of the neck confirms adenoidal hypertrophy but a patent postnasal space. A polysomnogram shows an obstructive respiratory disturbance index of nine per hour. Based on the data from the polysomnogram, the boy undergoes adenotonsillectomy. After the operation, the boy’s snoring resolves, his behaviour and concentration improve, and his mother describes him as a “different boy”. At the 1-year follow-up, the boy’s mother reports that his snoring has returned. You resume frequent clinical monitoring, and subsequently refer him for repeat polysomnography, as his history once again suggests the presence of OSAS. If polysomnography confirms that OSAS has returned, and a lateral neck x-ray shows that his adenoids have not regrown, the use of night-time continuous positive airway pressure (CPAP) support will be considered.

J Declan Kennedy MD, FRCP, FRACP · Karen A Waters MB BS, FRACP, PhD

Women's health in general practice. Danielle Mazza. Edinburgh: Butterworth Heinemann, 2004 (viii + 317pp). ISBN 0 7506 8773 8. According to the most recent Bettering the Evaluation and Care of Health (BEACH) study data, nearly 58% of general practice consultations in Australia are with women; for women GPs, this proportion is most likely even higher. Practising GPs will find Danielle Mazza’s new textbook Women's health in general practice a gem. This Melbourne author’s research and teaching experience, and time spent as a family planning director, shine through in the book. But more importantly, her experience as a general practitioner has clearly influenced all aspects of the book’s development, from the choice of topics to the specific content and layout. Mazza adheres to a narrow definition of women’s health. All the expected topics are covered, taking a life cycle approach, concluding with a chapter on violence against women, which has been a research interest of the author’s and has also been recently identified as the major source of morbidity for younger women. Although traditional in the topics covered, Mazza explores these issues with sensitivity, makes excellent use of existing evidence and does not shy away from controversy. The chapter on menstrual problems includes some qualitative research on how women view their menstrual cycle. The “Screening women” chapter covers extensively and intelligently the current debate about the value of mammographic screening programs, placing the discussion in an international framework. The layout is practical and engaging. Each chapter includes its explicit learning objectives, short clinical cases to illustrate major themes, useful definitions and highlighted tips and conclusions. The evidence is invoked for what works and what doesn’t, and sometimes briefly covers common complementary therapies, for example, lactobacillus for vaginitis and cranberry for urinary tract infections. The text is not exhaustive — for example, menstrual migraine is barely mentioned — but rather is an accessible useful reference for many common health issues that affect women. I imagine it will become compulsory reading for those studying for the fellowship exams and a valuable reference for busy GPs. Marie V Pirotta Senior Lecturer in General Practice University of Melbourne, VIC Order this book

Marie V Pirotta

About obesity therapy Anti-obesity drugs, in general, lead to only a modest weight loss of about 5 kg or less at 1 year, according to a meta-analysis of data from more than 75 clinical trials. The US researchers who reported the meta-analysis results examined not only agents specifically approved for use in obesity, such as orlistat and sibutramine, but also other medications being used for weight loss, including sertraline, fluoxetine and bupropion. Despite the somewhat disappointing overall finding, the researchers said this modest amount of weight loss may still be clinically significant. They said the choice of medication for weight loss probably depended on the patient’s tolerance to the side effect profile of each agent. Ann Intern Med 2005; 142: 532-546 Biomarker on the horizon A protein found in urine and serum holds promise as an early, highly predictive biomarker for acute renal injury.1 US researchers assayed levels of neutrophil gelatinase-associated lipocalin (NGAL) at baseline and at 2-hourly intervals in 71 children undergoing cardiopulmonary bypass for surgical correction of congenital heart disease. In the 20 children who developed acute renal injury, urine and serum NGAL levels peaked at 2 hours after the bypass followed by a lesser but sustained increase over the 5 days of the study. By comparison, diagnosis of acute renal injury with serum creatinine was only possible 1-3 days after bypass. Earlier detection of acute renal failure would allow for the timely institution of potentially effective treatments and, in an interesting twist, NGAL may also be a mediator of repair mechanisms.2 1. Lancet 2005; 365: 1231-1238 2. Lancet 2005; 365: 1205-1206 Balanced teenagers Balance training with a wobble board can reduce sport-related injuries in healthy adolescents, say Canadian researchers. In a cluster randomised controlled trial, they found that high school students assigned to a daily 6-week, followed by a weekly 6-month, home-based balance-training program using a wobbleboard improved their balance on testing. These students were also less likely to report a sporting injury over the 6-month follow-up period than students who were also tested but not trained. Most of the injuries reported in the study were to the lower extremity and occurred while playing sports that involve a high degree of pivoting or change of direction as well as rapid acceleration and deceleration, such as soccer, basketball, volleyball and hockey. CMAJ 2005; 172: 749-754 Aspirin and the gentler sex Low-dose aspirin for primary prevention of cardiovascular disease appears to have different effects in women compared with men. Whereas in men, low-dose aspirin prevents myocardial infarction but not stroke, evidence from the US Women’s Health Study suggests the converse for women. The study randomly assigned nearly 40 000 healthy women, aged 45 years or older, to receive either 100 mg of aspirin or placebo on alternate days. After 10 years of follow-up, there was a reduced risk of stroke but not myocardial infarction in the aspirin group. N Engl J Med 2005; 352: 1293-1304 Where’s the lung cancer? The shift to lower-tar cigarette smoking may have led to a shift in the location of smoking-related cancer, say US researchers. They reviewed the chest x-rays and CT scans of 330 smokers diagnosed with lung cancer between 1993 and 1999 at either of two urban academic medical centres in New York. Compared with smokers of higher-tar cigarettes (> 21 mg), smokers of lower-tar cigarettes (< 21 mg) were more likely to have peripheral rather than central lung tumours. This finding supported the hypothesis that lower-tar cigarette smokers compensate for the lower yield of nicotine with deeper inhalation, enhancing the delivery of carcinogenic compounds to peripheral lung regions. Cancer Epidemiol Biomarkers Prev 2005; 14: 576-581 Avoid compound tragedy Bioethics commentators have missed an important moral question posed by the case of Terri Schiavo, according to a Canadian expert. The case involved a patient in a long-term persistent vegetative state, familial disagreement about her likely prognosis and consequently disagreement about appropriate care, resulting in much prolonged legal action. Professor Charles Weijer says that the overwhelming message from most bioethicists — that the widespread use of living wills would prevent future Schiavo-like situations from happening — did not address the question of how we should deal with disagreement among family members when a patient is incapable of directing his or her own care. Weijer suggested that health care teams allow all family members to participate in the decision-making process, affirming the legitimate role of all relatives in seeking what is best for their loved one and, among other things, allow them the time to seek and reach consensus. CMAJ 2005; 172(8): Online Dr Ann Gregory, MJA

Ann Gregory

Med J Aust 2005; 182 (9 Suppl).