Volume 190 Issue 11

One of the dilemmas in delaying sex-assignment surgery is the increased risk of gonadal malignancy Few areas of medicine are as controversial as the management of disorders of sex development (DSD). The use of the term DSD to describe patients born with ambiguous genitalia has undergone major change from older terms with negative connotations, such as “intersex”, “testicular feminisation” and “hermaphroditism”.1 Meanwhile, international debate continues about the ethics of performing genital surgery on affected infants and children. In fact, the debate has been raging for more than a decade between the medical profession and patient advocacy groups in Western countries, and has been documented by anthropologist Katrina Karkazis in a recent book.2 A long-term outcome study of 50 patients aged 18–32 years who had been treated in Melbourne when they were children showed that mental and physical health outcomes were as good for most of the DSD patients as for those in two control groups; however, there was a small minority of patients whose gender identity as adults was a source of such profound discomfort that they felt compelled to undergo treatment to change it.3 Clearly, this is unsatisfactory, and management practices have been reviewed internationally by clinicians looking for ways of minimising the risk of making such mistakes about gender assignment. The main problem relates to feminising genitoplasty (Box), which involves the removal of phallic erectile tissues and skin that cannot be replaced. This type of operation is considered appropriate for 46,XX girls with congenital adrenal hyperplasia (Box), who rarely identify as male when they are adults if they are treated with appropriate hormones to maintain androgen suppression from soon after birth and throughout childhood.4 However, feminising genitoplasty is much more of a problem in patients with a Y chromosome. For example, in one study of 14 adult patients with genetically confirmed partial androgen insensitivity who were treated at Johns Hopkins University in the United States as children, 25% experienced gender dysphoria (Box) as adults, and a small number wanted to undergo sex change surgery.5 Although policy changes are still being discussed, it seems likely that fewer and fewer XY patients with frankly ambiguous genitalia due to DSD will have feminising genitoplasty and be raised female. The option to assign a gender but postpone surgery until the child is able to give consent has been strongly advocated in some quarters,6 but has not gained much traction because of concerns that children might suffer psychological harm if left with ambiguous genitalia. In 2008, clinicians from Melbourne’s Royal Children’s Hospital, recognised for their expertise in the management of DSD, were required to meet representatives of the Victorian state Justice Department. They were asked to respond to a proposal — advanced by an advisory committee representing the interests of the gay, lesbian, bisexual, transsexual and intersex communities — that doctors wanting to perform surgery to treat ambiguous genitalia in children too young to consent on their own behalf should have to seek approval from the Family Court of Australia on a case-by-case basis. Also in 2008, the Australian Human Rights Commission decided to initiate a public inquiry into the same question, and circulated a draft discussion paper called Genital surgery for babies born intersex to health professionals for comment. Thus, in Australia as elsewhere, the arm wrestle between medical professionals and patient advocacy groups continues. What has largely been missing from the debate is recognition of the fact that surgery forms a necessary part of the risk management strategy for preventing gonadal malignancy. In any DSD associated with a Y chromosome, there is an increased risk of germ cell cancer,7 especially when the testes are intra-abdominal (the risk of seminoma in partial androgen insensitivity is 50% for an intra-abdominal testis) or when there is gonadal dysgenesis. In this issue of the Journal, a salutary case report by Parker and colleagues8 reminds us of the need to be mindful of this risk, and also to take a long-term view of risk. If the intra-abdominal gonad in the patient described had been removed at the initial surgery, he would never have needed to fear this tumour. It had not been removed because, by today’s standards, he had been inadequately investigated in the past, and therefore the intersex condition was not recognised. The trend for surgeons to recommend male-sex rearing for greater numbers of children with DSD could also mean greater reluctance to remove testes that pose a significant risk of cancer on the grounds that physiologically useful hormone secretion might be retained. It is therefore imperative that a risk management strategy be prepared for each patient. This would mandate: educating parents and patients about risk; removing all intra-abdominal gonads that cannot be brought down into the scrotum; regular clinical and ultrasound surveillance of scrotal gonads with removal of any that contain suspicious lumps; biopsy of testes after the onset of puberty, looking for early signs of malignant change; and effective communication between paediatric and adult care-providers at the time of transition. It is also important for all children identified as having DSD to be referred to a centre of excellence where they will be seen by paediatric endocrinologists, surgeons and other health care professionals with expertise in the field and who recognise the importance of a multidisciplinary team approach.9 Case conferences about patients diagnosed as having a DSD in adult life would be enhanced if paediatric specialists in DSD were asked to comment. Of equally great importance is the need for an accurate aetiological diagnosis wherever possible. At the moment, about 40% of patients with 46,XY forms of DSD are left without a precise diagnosis.10 The application of microarray (gene chip) technology,11 which is available in Australia, is an exciting and promising step forward in identifying genetic mutations. In this technique, samples of very large numbers of genes are arranged in a regular pattern on a solid surface or membrane, which is then incubated with DNA from a patient. Alterations in known (and even unknown) genes are rapidly detected by studying patterns of matches and mismatches. The current challenge for researchers is to develop new tools, such as microarray technology, that will lead to gene discovery and to better methods of screening patients for mutations in all the known genes. Glossary of terms relating to disorders of sex development DSD: Disorders of sex development, previously known as intersex. Congenital conditions in which development of the chromosomal, gonadal or anatomical sex is atypical. Feminising genitoplasty: Surgery carried out to give genitalia that were originally ambiguous a more female appearance. Usually involves clitoral reduction (removal of erectile tissue) and surgery to create a vaginal opening separate from the urethra. Congenital adrenal hyperplasia: A genetic disorder caused by a deficiency of the enzyme 21-hydroxylase in the adrenal cortex, and the commonest adrenal disorder of childhood. Cause of virilisation in an affected female fetus. Partial androgen insensitivity: An X-linked genetic disorder causing ambiguous genitalia in 46,XY individuals. Caused by a lack of androgen receptors in androgen target tissues, such as genital skin. Gender dysphoria: Mental distress caused by unhappiness with one’s own sex and the desire to be identified as the opposite sex.

Garry L Warne MB BS, FRACP · Jacqueline K Hewitt MB BS

Robust evidence remains to be gathered Whenever possible, clinical decision making should be evidence-based. In reality, the evidence may be incomplete and the practitioner must use personal clinical judgement. This should be based on recommendations or guidelines provided by authoritative groups. An example of clinical practice reliant on guidelines with an incomplete evidence base is the use of low-dose aspirin for primary prevention of cardiovascular disease (CVD) events in people with diabetes mellitus. Diabetes Australia, the Royal Australian College of General Practitioners, and the National Health and Medical Research Council (NHMRC), as well as numerous associations in the United States and United Kingdom, have all recommended low-dose aspirin for men and women with diabetes (Box). Until very recently, there were no randomised controlled trials of aspirin use for people with diabetes to provide the evidence for these guidelines. Rather, the recommendations are based on the rationale that low-dose aspirin should benefit people with diabetes because aspirin has proven benefit for secondary prevention of CVD events, and people with diabetes have a risk of CVD events equivalent to the risk found in secondary prevention populations. However, people with diabetes represent a heterogeneous population, and an individual patient’s risk of CVD events varies according to factors such as age at diagnosis and duration of diabetes.8 Therefore, the guidelines for aspirin use in people with diabetes, based on extrapolation from secondary to primary prevention, may be flawed. Two substudies of the Bettering the Evaluation And Care of Health (BEACH) program, one undertaken in 20069 and the other in 2007,10 generated data about patients with diagnosed type 2 diabetes and allowed us to determine the compliance of Australian general practitioners with the relevant guidelines. Using the BEACH substudy data, we analysed aspirin usage by patients with and without diagnosed CVD comorbidity. The results indicated that 39% of people with type 2 diabetes were taking aspirin for primary prevention. In late 2008, two randomised controlled trials of low-dose aspirin in people with diabetes were reported.11,12 They showed no significant effect of aspirin on the primary endpoint (CVD events). These studies attracted a good deal of attention, not only in the medical press but the lay press as well (eg, Norman Swan’s The health report on Radio National13). They also left medical practitioners with a conundrum — whether or not to prescribe low-dose aspirin to their patients with diabetes but no overt CVD. In this editorial, we highlight the deficiencies in these trials; suggest that the evidence for the use of aspirin in this context is still lacking; and inform clinicians of ongoing trials that should provide adequate power to address this issue reliably. The two 2008 trials of low-dose aspirin therapy for people with diabetes were substantially underpowered to address the question of aspirin effectiveness for reducing CVD events.14,15 The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) study of low-dose aspirin (100 mg daily)11 followed 1276 participants with diabetes and asymptomatic peripheral arterial disease but no CVD events for a median of 6.7 years. The annual CVD event rate was less than 3% in those assigned placebo (lower than the expected rate of 8% per annum). There were 116 primary CVD events in subjects receiving aspirin, compared with 117 in those not receiving aspirin (hazard ratio, 0.98). In the open-label Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) study,12 2539 patients with type 2 diabetes and no history of CVD were treated either with aspirin (81 mg or 100 mg daily) or with no aspirin. The median follow-up period was 4.37 years. In both groups, actual event rates were about three times lower than anticipated rates. A 20% reduction in the primary endpoint of composite CVD events for the group assigned aspirin was not statistically significant because of wide confidence intervals. Nevertheless, the secondary endpoint of CVD mortality was significantly reduced, and, in a sub-analysis of subjects aged 65 years and over at baseline, aspirin significantly reduced CVD events. For both the POPADAD and JPAD trials, there was no significant difference in the occurrence of adverse events among subjects receiving or not receiving aspirin. As a result of the lower than expected event rates (possibly related to effects of more optimal background therapies) and the relatively low numbers of people included in the trials, results of POPADAD and JPAD have not ruled out important benefits or risks of aspirin. Larger trials are needed. A major study (A Study of Cardiovascular Events in Diabetes [ASCEND])16 is underway in Britain to determine whether low-dose aspirin has a benefit for primary prevention of CVD in people with diabetes. About half of its estimated sample size of 10 000 men and women has been recruited. In Australia, our own trial of aspirin therapy for primary prevention in 19 000 people aged 70 years and over, the Aspirin in Reducing Events in the Elderly (ASPREE) study17 (clinical trial registration number ISRCTN83772183), will also be including participants with diabetes on the basis that equipoise prevails between the benefits and risks of aspirin therapy. In the ASPREE study, a GP co-investigator will help decide whether the patient is a suitable candidate for the placebo-controlled trial. A recent editorial in the Journal of the American Medical Association concluded that [T]he decision to prescribe aspirin should be made on an individual patient basis after careful evaluation of the balance between the expected benefits and the risk of major bleeding. The issue of aspirin therapy for patients with diabetes is an example of how, in the presence of a long-lasting uncertainty, scientific organizations or governmental bodies should provide the foundation for answering this question by promoting pragmatic, large-scale clinical trials.14 We concur that an enhanced evidence base can inform a more rational approach to therapy. Guidelines for the use of aspirin for primary prevention in people with diabetes Source Recommendation Diabetes Australia and Royal Australian College of General Practitioners (guidelines updated annually)1 Prophylactic aspirin (75–325 mg/day) for people with diabetes unless contraindicated National Health and Medical Research Council2 Prophylactic aspirin (75–325 mg/day) should be considered for people with type 2 diabetes unless contraindicated United States Preventive Services Task Force3 Aspirin (75 mg/day) should be used for primary prevention in people with diabetes who have a 5-year risk ≥ 3% of a CHD event American Diabetes Association and American Heart Association4 Aspirin (75–162 mg/day) strongly recommended for people aged > 40 years with diabetes or with an additional risk factor for vascular disease British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society and British Diabetic Association5,6 Cardioprotective use of aspirin (75 mg/day) in people with diabetes or other risk factors aged > 50 years with an absolute CHD risk ≥ 15% over 10 years International Diabetes Federation7 Low-dose aspirin (75–100 mg/day) prophylaxis recommended for people with diabetes CHD = coronary heart disease.

Robyn L Woods BSc(Hons), PhD · Andrew M Tonkin MB BS, MRACP, FRACP · Mark R Nelson MB BS, MFM, PhD · Helena C Britt BA, PhD · Christopher M Reid BA, MSc, PhD

The challenge of providing a multidisciplinary response to complex health problems A developmental disability is a neurological abnormality having its onset in childhood that is associated with long-term neurological and developmental deficits (for example, spastic quadriplegic cerebral palsy). Although the degree of physical and intellectual disability varies greatly, people with a severe developmental disability often have very limited mobility, are dependent on caregivers for their daily needs, and usually have several concomitant medical problems. Because of their complex health needs, consensus is growing that multidisciplinary clinics provide the optimal setting for assessment and management of patients with a developmental disability. Life expectancy is significantly reduced in people with developmental disabilities compared with the general population.1-3 Review of the causes of death of people with a disability living in state-funded supported accommodation in New South Wales shows that respiratory disease accounts for about 40% of deaths (Kelly Savage, NSW Ombudsman, personal communication). Similar findings have been reported from Victoria and the United Kingdom.2,3 Multiple factors contribute to the increased mortality in this group. Gastro-oesophageal reflux disease is common in people with severe developmental disability,4,5 with or without intellectual disability, and is an important comorbidity in individuals with incoordinate swallowing. Respiratory disease, often secondary to recurrent aspiration, is also common and under-recognised. Malnutrition caused by reduced food intake (related to swallowing difficulties) frequently accompanies neurological impairment. Previous studies from our group6 identified profound levels of protein energy malnutrition, severe disturbance of body composition, and almost universal osteoporosis in subjects with spastic quadriplegic cerebral palsy. Seizure activity can also compromise food intake. Orthopaedic problems such as joint contractures, hip dislocation and kyphoscoliosis further contribute to limited mobility and may exacerbate lung disease. Kyphoscoliosis also poses technical challenges for surgical procedures, such as gastrostomy device insertion and fundoplication. The interrelationships of these conditions clearly require the coordinated input of several disciplines. However, there have been no clinical trials attesting to the efficacy of multidisciplinary clinics in improving patient outcomes in this group of patients. We recently reported our experience with 452 adults and children with severe developmental disability, most of whom had cerebral palsy.7 These patients were seen at tertiary referral dysphagia–nutrition multidisciplinary clinics at Westmead Hospital and the Children’s Hospital at Westmead in NSW between 2001 and 2006. The treating teams included a developmental paediatrician–physician, paediatric gastroenterologist, clinical nurse coordinator, speech pathologist, dietitian, and paediatric physiotherapist. Patients ranged in age from 7 months to 53 years; 90% were wheelchair-dependent and 60% had epilepsy. Among other things, we found that: 90% of patients had dysphagia; three-quarters of the children and half of the adults were malnourished due to inadequate food intake; 60% of the total clinic population reported respiratory symptoms; and half of the patients undergoing upper endoscopy had reflux oesophagitis, and 66% of patients undergoing computed tomography scans of the chest had chronic suppurative lung disease. In our series, simple interventions such as dietary advice, change of food consistencies, appropriate positioning during feeding and sleeping, use of proton-pump inhibitors, and implementation of a chest management plan were effective for many patients. However, a significant number of patients required gastrostomy with or without fundoplication for nutritional rehabilitation and to control gastro-oesophageal reflux and pulmonary aspiration. Improving the quality of life of the person with a developmental disability is the primary goal of management. Quality of life of the patient’s family and carers is also an important consideration when formulating management plans. Studies of children with a severe level of disability suggest that gastrostomy tube insertion has a positive impact on quality of life for both the children and their caregivers.8 However, the news is not all positive. Studies of caregivers’ attitudes to health professionals indicate that the way the health system dealt with their child with a disability was seen as a significant negative factor in the carer’s quality of life.9 Caregivers describe problems such as a lack of information, communication difficulties with health professionals, and lack of experience and expertise in managing the complex health needs of patients with a disability. Many of the medical problems described here are relatively easy to diagnose, and most respond to simple interventions, but they are often overlooked or undertreated in the general medical system. Interventions include treatment of nutrient deficiencies, management of reflux oesophagitis, saliva management, strategies to reduce episodes of aspiration pneumonia, and active management of chronic suppurative lung disease. Seizure control can also be problematic and may require regular specialist review. Coordination and provision of satisfactory health care to this population is a challenge to the health system, especially as these patients often present acutely to already overcrowded emergency departments.10 There are few specialist multidisciplinary clinical services in Australia for people with a developmental disability and complex health needs. Training opportunities in disability medicine are few outside of paediatrics, where developmental paediatrics is an essential component of paediatric training. Specific expertise and support services are often not available, and care may be significantly compromised in the adult health system. Communication barriers, lack of up-to-date medical records, difficulty doing a simple examination or routine investigations, and confusion about consent for even simple interventions all conspire to challenge the system to provide optimal care. These problems can be compounded by preconceived ideas about the quality of life of a person with a disability. Many of the problems confronting people with a developmental disability and complex health needs, and their carers attempting to access health services, need to be addressed. Increased awareness of their needs, improved education and training of health professionals, and the development of multidisciplinary clinics and support services are basic requirements to improve their health status.

Edward V O’Loughlin MD, FRACP · Helen M Somerville MB BS, MPaed · Ernest R Somerville MB BS, FRCP, FRACP

Objective: To determine whether there is an association between compensation factors and health care utilisation following major trauma.Design and setting: Retrospective cohort study within a major metropolitan trauma centre in New South Wales.Participants: Major trauma patients aged ≥ 18 years, admitted between May 1999 and April 2004. Patients were included if they had an accidental injury and an Injury Severity Score > 15. In total, 355 of 582 potentially contactable patients returned completed questionnaires (response rate, 61%).Main outcome measure: Health care utilisation, defined as the number of times patients visited specified health care professionals (general practitioners, medical specialists, psychiatrists, physiotherapists, chiropractors and massage therapists) in the previous 3 months. For statistical analysis, health care utilisation was dichotomised into low and high (0–3 or ≥ 4 health care visits over the previous 3 months).Results: Health care utilisation was significantly higher for patients engaging the services of a lawyer (odds ratio, 3.3; 95% CI, 2.0–5.5; P < 0.001) after allowing for time since injury, chronic illness, presence of a head injury and employment status. Having a head injury and increased time since injury were significantly associated with lower health care utilisation, whereas being unemployed and having a chronic illness were associated with higher health care utilisation.Conclusion: Compensation-related factors are significant predictors of health care utilisation in a major trauma population.

Ian A Harris MB BS, MMed(ClinEpid), PhD · Darnel F Murgatroyd MScHSci(ManipPhysio), DipPhysio · Ian D Cameron MB BS, PhD, FAFRM · Jane M Young MB BS, MPH, PhD · Michael J Solomon MB ChB, MSc, FRACS

Objective: To compare the clinical effectiveness of point-of-care testing (PoCT) and that of pathology laboratory testing, as measured by therapeutic control in chronic conditions.Design: Multicentre, cluster randomised controlled trial using non-inferiority analysis.Setting: 53 Australian general practices in urban, rural and remote areas across three Australian states, September 2005 to February 2007.Participants: 4968 patients with established type 1 or type 2 diabetes, established hyperlipidaemia, or taking anticoagulant therapy.Intervention: The intervention group (3010 patients in 30 practices) had blood and urine samples tested by PoCT devices in their general practices, and the control group (1958 patients in 23 practices) had samples tested by their usual pathology laboratories. Main outcome measures: The proportion of patients and of tests with results in the target range, and change in test results from baseline.Results: For the proportion of patients with results in the target range, PoCT was found to be non-inferior to pathology laboratory testing for measuring glycated haemoglobin (HbA1c), urine albumin, albumin–creatinine ratio (ACR), total cholesterol and triglyceride levels but not for high-density lipoprotein (HDL) cholesterol level and international normalised ratio (INR). For the proportion of tests with results in the target range, PoCT was found to be non-inferior to pathology laboratory testing for measuring all variables except HDL cholesterol. For the proportion of patients showing an improvement in their test result from baseline, PoCT was non-inferior to pathology laboratory testing for HbA1c, total cholesterol and triglyceride levels, but not for HDL cholesterol level.Conclusions: This study provides important evidence for those considering the introduction of PoCT into general practice. For all tests except INR and HDL cholesterol, the PoCT approach demonstrated the same or better clinical effectiveness than pathology laboratory testing.Trial registration: Australian Clinical Trials Registry ACTRN12612607000628448.

Tanya K Bubner GradDipHlthServMg, BSocSc(HumServ) · Caroline O Laurence PhD, MHlthServMg · Angela Gialamas BHSc · Lisa N Yelland BMa, CompSc(Hons) · Philip Ryan MB BS · Kristyn J Willson BSc(Hons) · Philip Tideman FRACP · Paul Worley MB BS, PhD · Justin J Beilby MD

Integration of research and education into health care delivery leads to improved outcomes and facilitates rapid translation of results into policy and practice. Australia is at great risk of losing the important contribution of clinical research conducted in our public hospital system. This risk is increasing as research and educational training are targeted for expenditure reduction in the current business models of health service delivery, which focus only on short-term outcomes. The Centres of Clinical Research Excellence Scheme — initiated by the National Health and Medical Research Council (NHMRC) — is an excellent step towards redressing this problem, but it cannot succeed in isolation. We must improve and optimise care through promotion of attractive sustainable career pathways to provide strong clinical and translational research capabilities in hospital settings that address current health priorities and new disciplines. Targeted investment in talented people is the greatest long-term contribution that governments can make to guarantee quality in national systems of health.

Graham V Brown PhD, FRACP, MPH · Tania C Sorrell MD BS, FRACP

The absolute benefit of a treatment varies between individuals depending on their prognosis before treatment and whether their response to the treatment varies from the overall relative risk reduction measured in clinical trials. Based on these principles, biomarkers that can provide information about an individual’s prognosis or predict his or her treatment response can be used to tailor treatment decisions to individual patients. Many novel molecular biomarkers are currently available. Although there is evidence to show that some of these can improve patient outcomes through improved biomarker-guided treatment strategies, others are yet to be adequately evaluated. Randomised controlled trials (RCTs) can distinguish whether a biomarker provides prognostic or predictive information and assess whether using a biomarker to guide treatment improves patient outcomes. Targeted RCTs can be used to demonstrate the efficacy of treatment in a restricted biomarker-defined population, and non-targeted RCTs can compare biomarker-guided versus conventional test-guided treatment strategies in broader populations.

Chee K Lee MB BS, MMedSci, FRACP · Sarah J Lord MB BS, MS(Epi) · Alan S Coates AM, MD, FRACP · R John Simes MB BS, FRACP, SM

Objective: To determine the frequency of smoking on The Simpsons television show, and the relationship with the sex and age groups of characters shown smoking, and with positive, negative and neutral connotations associated with instances of smoking.Design and setting: Content analysis (performed from January to October 2008) of instances of smoking that appeared in the first 18 seasons of The Simpsons television show, which aired from 1989 to 2007.Main outcome measures: Frequency, impact (positive, negative, neutral) of instances of smoking; and frequency associated with age (child or adolescent versus adult characters), sex and types of characters on the show.Results: There were 795 instances of smoking in the 400 episodes observed. Most (498; 63%) involved male characters. Only 8% of instances of smoking (63) involved child or adolescent characters. Just over a third of instances of smoking (275; 35%) reflected smoking in a negative way, compared with the majority, which reflected smoking in a neutral way (504; 63%) and the minority, which reflected smoking in a positive way (16; 2%). Child and adolescent characters were much more likely to be involved in instances of smoking reflected in a negative way compared with adult characters (odds ratio, 44.93; 95% CI, 16.15–172.18).Conclusions: There are a large number of instances of smoking in The Simpsons television show. Child and adolescent characters are much more likely to be portrayed in instances of smoking reflected in a negative way than adult characters. Viewing The Simpsons characters smoking may prompt children to consider smoking at an early age.

Guy D Eslick PhD, MMedSc(ClinEpi), MMedStat · Marielle G Eslick

Individuals vary in their response to a medication with regard to efficacy and adverse effects. The human leukocyte antigen (HLA) region of DNA offers the key to predicting drug hypersensitivity reactions. Single nucleotide polymorphisms for hypersensitivity reactions with carbamazepine, abacavir and allopurinol have been identified. A randomised controlled trial demonstrated the effectiveness of prospective screening for the predisposing genetic marker in preventing all cases of the hypersensitivity reaction with abacavir. Further pharmacogenetic investigation of hypersensitivity reactions could be conducted in Australia by establishing a network of sentinel hospitals.

Kathlyn J Ronaldson BSc, MSc, DPhil · John J McNeil PhD, FRACP, FAFPHM

Disorders of sex development (DSD), previously termed intersex, are uncommon, and are usually, but not always, diagnosed at birth. Issues of gender assignment, psychosexual development and the potential for malignant change in a dysgenetic gonad need to be considered. Here, we report a rare presentation of advanced malignancy in an abdominal gonad associated with the formation of a uterus in an adult male with a previously undiagnosed DSD. Clinical recordA 59-year-old man presented with haematuria and gynaecomastia, and was subsequently found to have a large pelvic mass. Examination of his left breast identified a 3–4 cm mobile mass. Ultrasonography of the breast confirmed a mass, but could not distinguish between glandular tissue and a breast tumour. Computed tomography (CT) of the abdomen and pelvis showed a 10 cm complex pelvic mass that was thought to extend to the seminal vesicles. A core biopsy showed mixed cytological and immunohistochemical features of a possible granulosa cell tumour, but the precise diagnosis was limited by the small amount of material present for examination. A provisional diagnosis of gonadal malignancy in a dysgenetic gonad was considered. A bone scan was negative and a thoracic CT scan showed three 5–7 mm lesions in the lung fields, suggestive of possible metastases. His prostate-specific antigen (PSA) level was very low (0.01 ng/mL), and tests for testicular tumour markers were negative (alpha-fetoprotein, 3 ng/mL; human chorionic gonadotropin, < 5 U/L). Other biochemical tests showed the following levels: serum oestradiol, 372 pmol/L (male reference range [RR], < 160 pmol/L); testosterone, 1.1 nmol/L (RR, 8–38 nmol/L); follicle-stimulating hormone, < 0.1 U/L (male RR, 1.0–9.2 U/L); luteinising hormone, 2.1 U/L (male RR, 2–8 U/L); prolactin, 385 mU/L (RR, 0–500 mU/L). The patient had a history of penoscrotal hypospadias, cryptorchidism and right inguinal hernia that were surgically repaired in infancy. The hypospadias was corrected at 20 months of age. He had a right inguinal hernia repair at 3 years of age and, at that time, was found to have an undescended right testis that was treated by orchidopexy. The patient’s parents were told that the left testis was removed during this procedure. He was married with no children, and we do not know whether the issue of fertility had ever been questioned. He was noted to have minor obstructive urinary symptoms at 47 years of age that were thought to be caused by a urethral stricture secondary to his previous hypospadias repair. He re-presented 8 years later with a bloody urethral discharge that settled after treatment with antibiotics. On rectal examination at age 55, he had a small prostate and his PSA level was low (0.02 ng/mL). At that time, an intravenous pyelogram showed normal kidneys, ureters and bladder. At cystoscopy, he was found to have a mid-urethral stricture from his previous hypospadias repair, with a number of hairs present in the skin at the stricture site. The hairs were thought to be from graft skin used to repair his hypospadias, and this was felt to be the cause of his bleeding. He re-presented with intermittent urethral blood loss 2 years later, at 57 years of age, and repeat cystoscopy again showed a mid-urethral stricture that was treated by dilatation. At 59 years of age, a laparotomy was performed and the patient was found to have a large left adnexal mass (Box 1, A) and a normally formed uterus. The mass was removed and a subtotal hysterectomy performed as there was no distinct lower margin of the cervix (Box 1, B). The patient was informed of the operative findings and the diagnosis of intersex. Peripheral blood karyotyping showed a 46,XY genotype. The histopathology of the gonadal tumour showed a sex cord-stromal tumour of indeterminate differentiation (Box 2). The histopathology of the uterus showed simple endometrial hyperplasia. The patient was treated with postoperative chemotherapy, but died 18 months later. DiscussionDisorders of sex development (DSD) are rare in the general population, and comprise a wide variety of clinical, anatomical and genetic problems. Most patients with DSD are diagnosed at birth, but diagnosis may not be made until childhood, adolescence or, more rarely, in adulthood, as in our case. This case shows how incomplete initial assessment and treatment of a neonate with abnormal genital development, and failure to recognise this rare disorder in adulthood can have tragic, adverse health consequences. An international consensus statement on intersex disorders and their management proposed the term “disorders of sex development” to describe congenital conditions with atypical development of chromosomal, gonadal and anatomical sex.1 It was considered that previous terminology, such as hermaphroditism, was controversial, pejorative to patients and confusing. DSD are a heterogeneous group of conditions, all of which interfere with normal sex differentiation in the embryo and fetus. The incidence of DSD in the population is estimated to be one in 5500.2 Patients with DSD can present at birth with ambiguous genitalia, apparent female or apparent male genitalia. Patients with apparent female genitalia can have an enlarged clitoris, posterior labial fusion or an inguinal / labial mass. Patients with apparent male genitalia can have non-palpable testes, micropenis, isolated perineal hypospadias or hypospadias with undescended testes. Congenital adrenal hyperplasia is the most common cause of ambiguous genitalia in the newborn period.2 The birth of an infant with ambiguous genitalia requires a strategy of clinical, hormonal, genetic, molecular and radiographic investigations to determine the aetiology and to plan a therapeutic approach.3 Clinical and diagnostic evaluation protocols are available.2 Although most DSD are diagnosed in the neonatal period, a wide variety of clinical presentations have been reported in childhood, adolescence and adulthood. Later presentations include previously unrecognised genital ambiguity, inguinal hernia in a girl, delayed or incomplete puberty, primary amenorrhoea, virilisation in a girl, breast development in a boy and gross haematuria in an adolescent male.1,2 A wide variety of clinical presentations have been reported in adults with undiagnosed DSD. These include psychiatric disturbances,4 short stature, infertility,4,5 lower abdominal pain6 or haematuria. Our patient presented with intermittent haematuria that was initially investigated with cystoscopy and an intravenous pyelogram. A computed tomography urogram with intravenous contrast has now replaced intravenous pyelography as the standard investigation of the urinary tract in patients with haematuria. If this investigation had been performed at the time of his earlier presentations, a pelvic mass may have been identified and further investigated. Recent advances in molecular genetics have increased our understanding of both normal and abnormal sex development. The bipotential gonad develops at the urogenital ridge between 5 and 6 weeks’ gestation and a number of genes involved in testis determination are expressed at this stage.7 The first histological evidence of testis formation occurs at 7 weeks’ gestation. Leydig cell synthesis of testosterone mediates the development of the vas deferens, epididymis and seminal vesicles, and conversion of testosterone to its more potent form, dihydrotestosterone, masculinises the external genitalia to form a penis and scrotum. Sertoli cell synthesis of anti-Müllerian hormone prevents the Müllerian ducts from developing into a uterus and fallopian tubes.7,8 The development of internal reproductive organs is controlled by the ipsilateral gonad, and prenatal male sex development is finally completed at term by descent of the testes into the scrotum.7 Our patient appears to have produced enough testosterone from the small right testis to promote penile development, albeit with hypospadias. The left gonadal dysgenesis appears to have resulted in inadequate anti-Müllerian hormone production, allowing a uterus to develop. The risk of malignancy in dysgenetic gonads is significantly increased in some patients with DSD.8 The presence of the SPY gene on the GBY region of the Y chromosome is a prerequisite for malignant transformation.9 Tumours can arise in any of the gonadal cells or their precursors.8 Precursor lesions for the development of cancers occur as carcinoma-in-situ in testicular tissue and gonadoblastoma in undifferentiated gonadal tissue. A number of malignant tumour types may occur in dysgenetic gonads.8,10 These include germ cell tumours and sex cord-stromal tumours. Patients presenting with abdominal tumours in dysgenetic gonads in adulthood provide histopathologists with complex diagnostic dilemmas. Histopathological examination of the tumour in our case showed mixed elements, with cells resembling ovarian follicles, testicular tunica, granulosa cells, Sertoli cells and Leydig cells. No germ cell components were identified. The final consensus was a diagnosis of malignant sex cord-stromal tumour of indeterminate differentiation. It is likely that the oestrogen-secreting gonadal tumour had been present for some years in our patient, resulting in endometrial hyperplasia. The uterus is likely to have been connected to the urethra, with endometrial bleeding causing the apparent haematuria. Persisting elevated levels of oestrogen would also have caused gynaecomastia, which resolved after surgical removal of the tumour. Serum follicle-stimulating hormone was likely to have been suppressed by the elevated level of oestradiol, and a normal level of serum luteinising hormone and low level of testosterone are consistent with the history of incomplete external genital development and infertility. Clinicians managing neonates with cryptorchidism and proximal hypospadias should have a high index of suspicion of an underlying DSD.11 Once a DSD is identified, a series of investigations should be initiated with the aim of making a specific diagnosis.7,12 Physical examination and imaging studies should be performed to attempt to locate inguinal or abdominal gonads so that surgical removal can be considered in patients thought to be at high risk of subsequent malignancy.2,10 The sequence of events in our case highlights the diagnostic difficulties that can occur in patients who present in adulthood with unsuspected gonadal dysgenesis. 1 Macroscopic photographs of the left adnexal mass A: Macroscopic photograph of malignant sex cord-stromal tumourdisplaying widespread necrosis and haemorrhage. B: Macroscopic photograph of bisected uterus with a thickened endometrium. 2 Histopathology of the gonadal tumour Microscopic photograph of gonadal tumour. The better differentiated areas of the tumour showed nests of cells with peripheral palisadingand small Call–Exner body-like structures (arrows), suggesting granulosa cell differentiation. Microscopic photograph of gonadal tumour. Also present were areas showing primitive sex cord-like structures (white arrow), lumened tubules lined by eosinophilic epithelial cells and adjacent clustered Leydig cells (black arrow).

Jim L Parker BMed, DRACOG, FRANZCOG · Deborah L Ekman BAppSc · Lawrence J Hayden FRCS

To the Editor: A 71-year-old man presented with a firm erythematous painful swelling over the sternoclavicular region. He had undergone coronary artery bypass grafting (CABG) 18 months earlier. A chest x-ray showed the presence of sternal wires and mediastinal clips from the surgery, and pleural thickening in the right costophrenic angle. There were no focal abnormalities seen on the x-ray when compared with pre-CABG radiographs. A computed tomography scan of the chest showed a destructive lesion of the manubrium, with an associated soft tissue mass extending into the pectoralis muscle and anterior mediastinum. A sternal suture was noted within the lesion, and a separate surgical clip was identified in the suprasternal notch region (Box, A). Surgical exploration of the sternotomy wound revealed tumour in the muscle around the proximal sternum, with bone destruction. Histopathological examination of the tumour confirmed the presence of an osteosarcoma (Box, B). (A section of normal trabecular bone [Box, C] is shown for comparison.) There have been few reported cases of primary sternal tumours. To our knowledge, primary osteosarcoma arising contiguous to a surgical suture has never been reported. It is unknown why the osteosarcoma originated in the part of the sternum that contained the sternal suture rather than originating de novo in another part of the bony skeleton. Chronic localised sternal inflammation or mechanical irritation of the proximal sternum by the suture may have been contributory factors in triggering carcinogenesis in this uncharacteristic site.1 However, the effect of trauma and mechanical stimulation on development of primary cancers and their metastases has never been proven. Patients who present with bony tumours frequently have a history of previous trauma to the area where the tumour develops. While there have been numerous reports suggesting some relationship between trauma/chronic inflammation and oncogenesis,1-5 there is no evidence that a single incident of trauma can cause cancer. The combination of trauma, in-situ metal and malignancy after CABG is rare, and there are currently no grounds for suspecting a direct relationship between them. A: Computed tomography scan of the chest showing a destructive lesion in the cortex of the manubrium. A sternal suture, surgical clip and soft tissue mass are visible within the tumour (A = anterior, R = right). B: Histopathological section of osteosarcoma of the sternum. Pleomorphic and hyperchromatic cells are present in a disorganised immature bone matrix (osteoid) (haematoxylin and eosin stain; original magnification, × 20). C: Histopathological section showing normal trabecular bone of the sternum (haematoxylin and eosin stain; original magnification, × 2.5).

Laurence Weinberg · Joseph Mathew

To the Editor: We report a case of reactive arthritis with an unusual cause in a previously well 47-year-old male landscape gardener. The patient presented with acute onset of left ankle arthritis. He had a 10-day history of a productive cough associated with mild fever, back pain and arthralgias. His temperature was 37.7°C and occasional crackles were audible at the lung bases. His left ankle was tender, with decreased range of movement. The provisional diagnosis was atypical pneumonia with reactive arthritis. A chest x-ray was normal. Laboratory tests showed an elevated white cell count of 11.93 × 109/L (reference range [RR], 4–11 × 109/L), with a C-reactive protein level of 326 mg/L (RR, < 3 mg/L). Arthrocentesis showed increased white cells but was negative for crystals and bacteria. Serological tests were positive for Chlamydia psittaci (IgM, IgA and IgG were all elevated and increased during illness), and the patient was also positive for human leukocyte antigen (HLA)-B27. He was initially treated with meloxicam for the arthritis. Oral prednisone was added when his joint symptoms became more disabling. Weaning of prednisone was attempted, but symptoms recurred. Sulfasalazine was subsequently added. Symptoms took about 8 weeks to resolve. Sufferers of psittacosis are infected by inhaling the obligatory intracellular bacterium, Chlamydia psittaci, from the faeces of infected birds in soil or grass. As a landscape gardener, our patient was at risk. Clinical presentations of psittacosis vary considerably, but patients usually present with flu-like and respiratory symptoms.1 Reactive arthritis is unusual, being more commonly associated with pathogens such as Salmonella, Shigella, Campylobacter and Yersinia spp.2 Although reactive arthritis usually involves asymmetrical large joint oligoarthropathies, patients with Chlamydia psittaci infection usually have a polyarticular pattern.3 HLA-B27 has a high association with spondyloarthropathies, including reactive arthritis. Contact with infected birds is often not obvious, making the diagnosis challenging. Microimmunofluorescence (showing a fourfold increase in antibodies or IgG titre greater than 16) has become available for diagnosis. Differential diagnosis of reactive arthritis includes other causes of arthritis such as sepsis and crystal deposition. Management of Chlamydia psittaci reactive arthritis includes early use of the antibiotics doxycycline or erythromycin, or possibly ceftriaxone.4 Anti-inflammatory drugs are the mainstay for symptomatic treatment of all reactive arthropathies. Intra-articular steroid injections may be helpful. There is conflicting evidence regarding the benefit of systemic corticosteroids. Sulfasalazine may be a helpful adjunct.5 For gardeners, preventive measures include the use of masks, gloves and lawnmower catchers.

Peter N Gonski · Bobby Chan

To the Editor: The management of pregnant women with pre-existing diabetes is often challenging for clinicians. A 38-year-old woman presented with an unplanned pregnancy at 8 weeks’ gestation. She had a 4-year history of type 2 diabetes treated with metformin, which she stopped taking on confirmation of her pregnancy. Her glycated haemoglobin (HbA1c) level was 9.0% at her first antenatal visit, and therapy with pre-meal insulin aspart and twice daily isophane was commenced. Her insulin requirement rapidly escalated, rising to 400 units per day by the end of the first trimester. Metformin therapy was reintroduced in the second trimester. Despite strategies including splitting her insulin doses and trialling different insulin regimens, control of her diabetes remained poor. At 30 weeks’ gestation, U-500 insulin became available, and that allowed rapid titration of insulin doses (Box). Her HbA1c level improved to 6.4% in the third trimester. At 35 weeks, her daily insulin requirement had reached 1455 units and her membranes ruptured prematurely. During labour, an intravenous insulin infusion rate of 90 units per hour was needed to achieve normoglycaemia. At birth, the neonate weighed 2005 g (11th percentile) with no evidence of congenital abnormalities, but she suffered transient hypoglycaemia on Day 1. Postpartum, the mother’s daily insulin requirement decreased to 28 units per day. In pregnant women with pre-existing type 2 diabetes, the insulin requirement increases substantially in the second half of pregnancy.1 In the past 12 months, among 25 pregnant women with type 2 diabetes who attended our antenatal clinic, the median insulin dose at the end of their pregnancies was 123 units per day, with 6 women requiring doses exceeding 200 units per day. At daily doses above 200 units, the therapeutic response to further increments in the insulin dose is attenuated.2 Current insulin preparations in Australia (100 units/mL) can be problematic for these patients as it is difficult to administer large volumes of insulin subcutaneously. U-500 is a preparation of regular insulin at a concentration of 500 units/mL. It is invaluable for patients with extreme insulin resistance, as a smaller volume is needed for injections. Its application during pregnancy has been previously reported.3-5 U-500 insulin is not readily available in Australia, and the preparation has to be administered by syringe. Hence, the volume of insulin must be drawn up accurately, as insulin syringes in Australia are designed for conventional lower-concentration insulin preparations (100 units/mL). This case highlights one of the many difficulties in managing pregnant women with pre-existing diabetes. The use of U-500 may be considered for women on extremely large doses of insulin and whose diabetes is still suboptimally controlled. The safety aspects of U-500 during pregnancy will need further examination. Insulin requirements during pregnancy of a 38-year-old woman with diabetes

Vincent W Wong · Alexia V Pape

To the Editor: In November 2008, a residential balcony collapse in Brisbane, Queensland, resulted in one person killed and 25 injured.1 Moments after the accident, tertiary hospitals across the city were placed on alert. Valuable hospital resources, including intensive care beds and staff, were allocated to the care of potential casualties; surgical theatres were kept on standby; and elective operating lists were cancelled. In 2008, injuries in more than 40 people across Australia and New Zealand were caused by residential balcony collapses.1-3 About 8000 Australian timber balconies are considered at risk of collapsing and potentially causing human fatality.4 Timber balconies constructed between 1970 and 1990 are at most risk of collapse.4 Many were constructed with inappropriate timber, without building approvals, and by unqualified tradespeople. When properly constructed, a well maintained timber balcony generally lasts for about 20 years.4 Collapse is not limited to timber balconies. In February 2002, a concrete cantilever balcony on a Sydney apartment fell under its own weight, shearing off the balcony under it.5 According to the Australian Concrete Repair Association (ACRA), many concrete balconies appear “safe” but have never been loaded to their maximum capacity, giving residents a false sense of security.5 As balcony parties and outdoor living become more popular, the ACRA believes that it is only a matter of time before more balconies collapse.5 A well maintained concrete balcony can be expected to last for about 40 years.4 In April 1995, the Cave Creek disaster in Pararoa National Park, NZ, resulted in the deaths of 14 people when an unstable wooden viewing platform, unable to support the weight of the 18 park visitors who had crammed onto it, collapsed into a gully.6 Following the accident, the NZ Department of Conservation made it mandatory that warning signs, indicating the maximum number of people permitted, be installed at every public viewing platform in the country.6 Why do suspended structures and public transport vehicles (such as viewing platforms, elevators and buses) have clearly displayed maximum capacity warning signs, but not balconies? Warning signs showing maximum capacity and recommended inspection dates would remind people to maintain and use their balconies safely. A prospective buyer of a home with a balcony should find out when the balcony was built and check local government records for building approvals. If no record exists, a balcony should be professionally inspected. We believe regular safety inspections and clearly displayed maximum capacity warning signs should be mandatory for all balconies. We also believe a review of building codes and standards is needed to protect residents of older homes and apartments — perhaps with an initial amnesty on unapproved balcony constructions — to encourage owners to seek professional inspections and have structural deficits corrected so that future tragedies need not occur.

Shinichiro Sakata · Craig A McBride · James W Nixon · Roy M Kimble

To the Editor: Population health and clinical researchers have long endured time-consuming submission of applications for a single study to multiple human research ethics committees (HRECs), which each have their own application forms and processes. Each HREC form collects similar information, with slight variation but much repetition. They invariably differ in emphasis and space provided, precluding a simple cut-and-paste among forms. The resource burden of completing this step in the research process has been highlighted previously.1,2 Rarely does completion of multiple applications add value. Responding to researchers’ protestations, the Australian Health Ethics Committee developed a National Ethics Application Form (NEAF). An improved version (NEAF2) was released in August 2008, with recommendations it be adopted by ethics committees Australia-wide.3 While some state health departments have embraced the new form and reform processes,4 rationalisation has not occurred in all jurisdictions. As investigators on a 3-year (2008–2010) study of cardiovascular disease that is funded by the National Health and Medical Research Council (NHMRC) and requires access to hospital records throughout Western Australia, our first ethics application was submitted in November 2007. Sequential preparation and submission to other HRECs led to the requisite approval from all 12 HRECs taking a further 12 months to achieve after the first approval. Few of these committees accepted an application using NEAF at the time. Adopting the current version of NEAF5 — adding supplementary questions pertinent to each institution (if necessary) — and rationalisation of processes to access public hospital medical records would be enormously more efficient for researchers. Centralised processes could also reduce the impost on HRECs. Our experience with contrasting requirements of the various HRECs has included different reporting timelines (6–12 months), different reminders to report, different periods of study approval (1–4 years), use of institutional letterhead, requirements for at least one chief investigator to be a staff member of the institution auspicing the HREC, requirements that investigators personally attend the HREC meeting, and differences in whether faxed and digital signatures are accepted. Such differences in requirements and processes are documented,2,6 and inevitably delay substantive research. This ongoing waste of resources and energy — in processes that distract from quality research but do not enhance ethical integrity — increases the burden on both researchers and members of HRECs. Rationalising and streamlining ethics processes could free resources, allowing greater attention to research monitoring by HRECs and research translation by researchers. We urge expedited implementation of NEAF2 and further reform. State health departments and affiliated organisations should collaborate to rationalise processes and expedite centralised or reciprocal approvals where appropriate. The bold proposal for a national system to streamline the ethics review process within and across Australian jurisdictions7 will invigorate discussion of overdue reform.

Sandra C Thompson · Frank M Sanfilippo · Tom G Briffa · Michael S T Hobbs

To the Editor: We read with interest Talley’s excellent and informative editorial about the risks associated with proton-pump inhibitors (PPIs).1 Other possible serious side effects of PPIs that need to be taken into account are potential drug interactions with aspirin and clopidogrel. Aspirin is a weak acid that crosses the mucosa in its lipid state. The suppression of acid production reduces the lipophilic nature of this drug and, theoretically, might reduce its absorption and bioavailability.2 On the other hand, clopidogrel is a prodrug that is converted in the liver to an active metabolite. This bioactivation is mediated by hepatic cytochrome P450 isoenzymes,3 with cytochrome P450 2C19 (CYP2C19) playing a particularly important role. There is evidence suggesting that some PPIs (omeprazole, lansoprazole and rabeprazole) can inhibit CYP2C19, which would alter the effectiveness of clopidogrel and potentially lead to an increased risk of adverse cardiovascular outcomes. In a recent Canadian case–control study among patients prescribed clopidogrel after acute myocardial infarction, current use of PPIs was associated with an increased risk of reinfarction (adjusted odds ratio, 1.27; 95% CI, 1.03–1.57).4 The risk was limited to patients currently taking a PPI (the authors did not find any association with more distant exposure to PPIs), and did not extend to pantoprazole, a drug that does not interfere with the conversion of clopidogrel to its active form.

Francisco J Fernández-Fernández · Gonzalo Pía · Pascual Sesma

To the Editor: In his recent editorial, Talley discusses a range of risks of proton-pump inhibitors (PPIs).1 Another rare but serious side effect of PPIs of which every doctor should be aware is hyponatraemia. Eleven cases of hyponatraemia caused by PPIs have been published.2,3 Consistent features were the rapid onset of hyponatraemia within days of commencement of the PPI therapy, the severity of hyponatraemia often being associated with confusion or delirium, and rapid recovery after cessation of the PPI medication. Test results in each case were consistent with inappropriate release of antidiuretic hormone. One case occurred 5 days after a patient changed from lansoprazole to esomeprazole.4 Hyoponatraemia needs to be considered whenever there is clinical deterioration, even after brief exposure to a PPI.

Adam P Morton

In reply: Proton-pump inhibitors (PPIs) are often coprescribed for patients taking aspirin and clopidogrel to reduce gastrointestinal bleeding. There are emerging data that omeprazole diminishes the therapeutic effect of clopidogrel because the active enzyme in the liver, cytochrome P450 2C19 (CYP2C19), metabolises omeprazole and activates clopidogrel.1,2 In a large cohort study of 8205 patients with acute coronary syndrome and taking clopidogrel, 64% were also taking a PPI (60% omeprazole); 21% of those who were taking clopidogrel but no PPI died or were rehospitalised for acute coronary syndrome, versus 30% of those taking clopidogrel as well as a PPI.3 Notably, not all the PPIs have the same metabolic pathway. For example, omeprazole and esomeprazole are principally metabolised by CYP2C19 in contrast to lansoprazole, which is metabolised by cytochrome P450 3A4 (CYP3A4), and pantoprazole, which is metabolised by CYP2C19 O-demethylation then rapid sulfate conjugation. Thus, the negative interaction with clopidogrel may not apply to all PPIs (and pantoprazole may be the drug of choice if a PPI is required, as cytochrome P450 interactions are least likely).1 However, until more data are accumulated, all PPIs should probably be avoided where possible in patients who have been prescribed clopidogrel, unless there is no alternative. It is correct that hyponatraemia has, rarely, been reported in patients taking PPIs. However, this knowledge is based solely on case report data, and therefore the level of evidence for cause and effect is relatively weak.

Nicholas J Talley · Aneta Dimoska · Kevin Gan

To the Editor: I read with interest the article by Medi and colleagues,1 but note that the authors do not mention the effect of supraventricular tachycardia on atrial natriuretic peptide — a hormone that causes vasodilation and renal excretion of sodium and water. Plasma levels of atrial natriuretic peptide increase markedly during supraventricular tachycardia.2 Pacing studies reveal that release of atrial natriuretic peptide occurs when the heart rate is greater than 120 beats/min.3 The resultant diuresis would lead to an urge to urinate and, in a prolonged episode of tachycardia, to polyuria.4,5

Weekitt Kittisupamongkol

To the Editor: We read with interest the article by Alexander and colleagues on child protection issues in severe childhood obesity.1 With one quarter of Australian youth either overweight or obese, individual families (or the health care system) will not benefit from widespread involvement of child protection services in obesity. The authors are clear on this, and describe their case as “sufficiently extreme”. The difficulty lies in defining what is “extreme” and, as health professionals, we have a duty to the community to emphasise that these kinds of cases rarely occur. The illustrative case in the article by Alexander and colleagues required an amalgamation of details from several patients (for confidentiality purposes), and we believe it would be very unusual for a 40 kg 4-year-old girl to exhibit the degree of obesity-related comorbidity described.2,3 Such a degree of “medical urgency” is usually absent when managing young obese children and, in our experience, is thankfully very extreme and markedly different from the more usual scenario of discussions around potential long-term health problems. Also, there are currently no fail-safe mechanisms in place to be 100% certain that there is not an underlying genetic, hormonal or metabolic reason for continuing weight gain in a young child. With the childhood obesity pandemic, it is impossible to routinely investigate all obese youth and, even if it were, research teams are continually finding new causes for why some children continue to gain weight irrespective of lifestyle change. Indeed, the more severe the obesity, the more likely for there to be an organic cause.4 It is not in anyone’s interests for child protection services to be automatically involved because of standard recommendations when, at a later date, an underlying medical cause is discovered. Alexander and colleagues should be congratulated on re-igniting a public discussion on this highly emotive and difficult area of health care. We agree that parenting styles may influence weight regulation in young children5 but, for the above reasons, we would urge extreme caution when considering that parents may be “neglectful”. Within our obesogenic environment, perhaps (deliberate or intentional) non-compliance is an indication that society is neglecting parents, rather than that parents are medically neglecting their children? We are concerned that the development of child protection guidelines will alienate parents and families, leading to a decline in the uptake of programs aimed at preventing and/or treating overweight and obesity. We would recommend that each case be taken on its individual merit and that primum non nocere is as important as Aristotle’s phrase of “practical wisdom”.

Matthew A Sabin · Zoe McCallum · Kay Gibbons · George A Werther · Joseph Proietto

In reply: Primum non nocere means both “first, do no harm” and “above all, do no harm”. We acknowledge there may be both potential harms (the most significant being removal of the child from the family) as well as hoped-for benefits in involving child protection services in cases of severe childhood obesity. Though we strenuously oppose notification of child protection authorities as a general policy, we raised the idea that, in exceptional circumstances, health care professionals may nonetheless have a professional and legal obligation at least to consider notifying such authorities. We did so cautiously because we fear an exception becoming a rule, particularly in services such as ours where we frequently care for children very like the “child” we describe. We agree that the development of obesity usually has multifactorial causes which will include a genetic element. We also agree on the need for public health approaches to the prevention of childhood (and adult) obesity. But whatever the underlying cause of severe obesity in a particular case, and especially in circumstances where parents seem unable to attend to the physical needs of their child, health professionals have an obligation to consider all reasonable means to limiting excess weight gain.

Shirley M Alexander · Louise A Baur · Roger Magnusson · Bernadette Tobin

To the Editor: We report a case of proximal myopathy attributed to varenicline therapy to assist with smoking cessation. A previously fit and well 27-year-old man presented to the emergency department with a 1-week history of lethargy, myalgia and limb weakness. The pain and progressive weakness incapacitated the patient to the extent of him requiring assistance to move from bed to chair. The patient’s only medication on admission was varenicline (Champix [Pfizer]), which he had started taking about 6 weeks previously to assist with smoking cessation. He denied drinking excessive alcohol or using illicit drugs. There were no symptoms of recent infection. On examination, a proximal myopathy with weakness of grade 2/5 for both upper and lower limbs was noted. The patient’s muscles were mildly tender, reflexes were preserved, and both cranial nerves and sensory examinations were normal. Respiratory function was not impaired and there was no evidence of fatigability. The clinical impression was of proximal myopathy of uncertain cause. An adverse drug reaction to varenicline was considered and the medication ceased. Appropriate blood investigations and clinical neurophysiological studies were requested. A full blood count, thyroid function tests and autoimmune screen were all normal, as were levels of electrolytes, calcium, phosphate and magnesium. The erythrocyte sedimentation rate was 15 mm/h (reference range [RR], 1–15 mm/h), the C-reactive protein level was 20 mg/L (RR, < 5 mg/L), and the creatine kinase level was 1100 U/L (RR, 30–190 U/L). Cushing disease was excluded. Two days after cessation of varenicline, the muscle weakness had improved and the creatine kinase level had normalised. The patient declined neurophysiological studies and was discharged home. On review 1 week later, he had made a full recovery. Varenicline is a recently marketed smoking cessation drug treatment that has been shown to be more effective than placebo and bupropion treatment.1 Varenicline acts as a partial agonist at nicotinic acetylcholine receptors in the brain.2 The agonist activity at these receptor sites reduces the symptoms of nicotine withdrawal and craving, while the antagonist activity blocks the reinforcing and rewarding properties of nicotine binding. Recognised adverse effects include nausea, headache, insomnia and abnormal dreams. Musculoskeletal effects are uncommon and limited to joint stiffness and muscle spasms.2 Potential mechanisms for myopathy include muscle cell degeneration induced by excess acetylcholine activity at the neuromuscular junction3 or possibly by varenicline’s affinity for the serotonin receptor.4 Enquiries to the Australian Adverse Drug Reactions Advisory Committee (ADRAC) and searches of the Canadian adverse drug reaction database and PubMed database failed to identify any reports of myopathy associated with varenicline. Thus we believe this to be the first reported case of proximal myopathy due to varenicline, and have reported the case to ADRAC accordingly.

Shelley E Wood · P Gerry Fegan

To the Editor: We are pleased that Simpson and colleagues brought the important matter of drug-dose calculation skills among Australian hospital doctors to the attention of the wider medical community.1 Data similar to theirs, suggesting inadequate calculation skills, have been reported from the United Kingdom and Germany.2-4 As teachers in the MB BS course of the University of Adelaide, we have been concerned with deficiencies in the clinical numeracy skills of our students for some time. Such deficiencies among medical students have been reported from North Carolina,5 but to our knowledge no information has been available about Australian medical students. In 2008, we included three questions on drug-dose calculations in the 90-item multiple choice question (MCQ) section of the final examination for Years 1, 2 and 3 of our course. For each question (Box), students were required to select one correct answer from five options. Although Question 1 required the knowledge that one standard drink contains 10 g of ethanol, as well as calculation skills, Questions 2 and 3 solely examined numeracy skills. The exam was completed by 177 students in Year 1, 155 in Year 2, and 119 in Year 3. The distribution of their responses is shown in the Box (with correct responses in bold). The percentage of correct responses to these questions was significantly lower than the overall score for the MCQ paper, with the exception of Question 3, which may have been too easy (as it did not discriminate between students). We believe these data support our hitherto anecdotal concerns that many students in the MB BS program have inadequate calculation skills. Although tertiary students’ numeracy problems have been attributed, at least in part, to the level of mathematics teaching in secondary schools,6 we consider they must be addressed at university level. We plan to make available an online calculation learning tool that begins with real-life non-medical examples. We are currently developing this tool with the University of Adelaide’s Mathematics Learning Centre and plan to publish our experience, including evaluation, with a view to making the tool widely available. Distribution of medical student responses to examination questions requiring numeracy skills* Question 1 (Year 1 and Year 3) A 21-year-old woman recalls drinking 5 glasses of champagne at her birthday party. Her glass holds 200 mL and the champagne has an alcohol content of 12.5%. How many standard drinks did she consume during her party? % of respondents Options Year 1 (n = 177) Year 3 (n = 119) A. 12.5 standard drinks* 50% 49% B. 5 standard drinks 6% 7% C. 18 standard drinks 1% 2% D. 6.25 standard drinks 20% 15% E. 10 standard drinks 23% 27% Question 2 (Year 2 and Year 3) You are treating a 60 kg patient for a laceration, which you will need to suture under local anaesthetic. Given that the maximum safe dose of lignocaine is 3 mg/kg, what is the maximum volume of a lignocaine 1% weight per volume (w/v) solution that can be administered safely? Options % of respondents Year 2 (n = 155) A. 1.8 mL 46% B. 6 mL 2% C. 18 mL* 35% D. 20 mL 14% E. 60 mL 1% Year 3 (n = 119) A. 60 mL 1% B. 6 mL 0 C. 180 mL 41% D. 18 mL* 38% E. 180 μL 19% Question 3 (Year 3) A 10 kg infant has viral meningitis and a high temperature. You want to treat her fever symptomatically with oral paracetamol. The preparation is paracetamol 50 mg/mL and the recommended dose is 15 mg/kg. How many mL of paracetamol syrup is the equivalent of one dose? Options % of respondents (n = 119) A. 1.5 mL 0 B. 3 mL* 96% C. 6 mL 1% D. 12 mL 2% E. 15 mL 1% * The correct options are shown in bold.

Kingsley J Whittenbury · Hubertus P Jersmann · Anne L Tonkin

Clinical cases in infectious diseases: a public health approach. Sanjaya Senanayake. Sydney: McGraw-Hill, 2007 (x + 398 pp). ISBN 978 0 07 471662 5. In the preface to this text, Sanjaya Senanayake quotes the introductory voiceover to the television series “Law and Order” about the connecting roles of the police and district attorneys in criminal law. This analogy is particularly apt for the practice of infectious diseases, and this book, by an infectious diseases physician with experience in public health, attempts to bridge the divide between clinicians and public health practitioners. Clinical cases in infectious diseases provides a useful insight into 22 examples of infectious diseases that encompass a diverse range of epidemiological and clinical features. They are set out almost as a TV script, interspersed with referenced facts about each disease. At first I found this style a little irritating, particularly as the doctors in the scenarios seem to inhabit a parallel universe where they diagnose botulism and Bairnsdale ulcer within the first page. However, with the more realistic and common scenarios, the style works well to enliven what might otherwise be a dry subject. Some of the diseases included are rare in Australia, whereas others, such as influenza and tuberculosis, are common. A strength of the author’s approach is his focus on answering the practical questions — specific tests and treatments, the period of infectivity, isolation measures and responses. As such, this easily read book succeeds as an introductory text for medical students and junior doctors, public health staff and laboratory microbiologists. It is necessarily difficult for a book of this nature to be complete, and it does not pretend to be a textbook of infectious diseases. However, notable omissions are sexually transmitted infections, particularly HIV. Other more controversial issues could also be considered, such as the ethical implications of quarantine of infectious patients or dealing with reckless conduct. Yet this should not detract from what is an entertaining and informative read for junior staff interested in the interface between clinical practice and public health practice.

Allen C Cheng

Textbook of disaster psychiatry. Robert J Ursano, Carol S Fullerton, Lars Weisaeth, Beverley Raphael, editors. Cambridge: Cambridge University Press, 2007 (xii + 346 pp). ISBN 978 0 521 85235 7. Disasters, by their nature, are unexpected and often occur when services are least able to respond, such as the tsunami on Boxing Day in 2004. Therefore, the ready availability of resource material is particularly important in disaster management. Due to recognition of the importance of well coordinated and planned recovery programs, there is also growing interest in providing structured academic courses in the disaster field. For these activities, the Textbook of disaster psychiatry is a high-quality, welcomed edition to an already competitive stable. The editors are doyens of the field and bring together a richness of experience, knowledge, and anecdote that combine to provide a text of unusual depth. They focus not only on the challenges facing clinicians, but also on the obstacles the broader systems confront in the face of disasters. A text providing an integrative methodology for a broader public health approach is a valuable tool to ensure optimal long-term outcomes. This is not simply a disguised textbook on post-traumatic stress disorder; it has relevance beyond mental health practitioners. Despite the fact that individuals’ adaptive behaviour determines the success or otherwise of physical disaster relief programs, mental health programs are often seen as a low priority in disaster management. As a consequence, this text will be valuable to coordinators of medical services and those involved in community and social reconstruction. While the editors are truly an international group, the authors of the text are all, bar one, from the United States. Nevertheless, this does not detract from the international applicability of the content and approaches that it espouses. This is a book to have on the shelf for the day when the sky falls in.

Alexander C McFarlane

John Murtagh’s practice tips. 5th ed. John Murtagh. Sydney: McGraw-Hill, 2008 (xix + 244 pp). ISBN 978 007015898 6. Medical education is based on a master-and-apprentice model, assuming an eager, interested apprentice, and an experienced, intelligent and thoughtful master. Enter Professor John Murtagh, doyen of Australian general practice. First published in 1991, this is the fifth edition of Practice tips; he’s been master of many apprentices. Reading his guide to palpation of the cervical spinous processes, I think I can hear him teaching the person who taught the person who taught me. Beginning a term in obstetrics, I found many postnatal patients had salad in their bras! Midwives reassured me that grated carrot and cabbage leaves were effective. When Professor Murtagh writes “Cabbage leaves have been used in some cultures for hundreds of years in the treatment of . . . some breast problems”, I must confess to wishing for some evidence.1 I’d also like to know the evidence for excising axillary sweat glands,2 and the place of frenotomy in modern management3 before I snipped. My general practice work is urban, in Sydney. We tend towards cautious, defensive medicine amid patients keen to see our specialist colleagues. We don’t routinely repair eyelid lacerations, or remove meibomian cysts. However in rural, remote or very remote practice, I’d be particularly grateful for Murtagh’s information about intercostal nerve blocks, clear diagrams of pulley sutures, and good advice about psoriasis. “Lithium batteries . . . create an emergency . . . the electric current they generate destroys mucous membranes . . .” There’s almost too much here! I might long for a speedy electronic search function when I wanted to manage a dislocated patella. Generations of general practitioners owe Professor Murtagh a debt. No doubt when someone takes up my offer to work as a rural locum, I’ll be glad of John Murtagh’s practice tips by my side. I couldn’t ask for a better or a more willingly generous tutor.

Lilon G Bandler

Screening at any age Screening for cervical cancer should continue in older women despite previous negative smear results, say Dutch researchers. In the study, over 200 000 women aged 45–54 years and over 400 000 women aged 30–44 years were followed for 10 years after their third consecutive negative smear result. Both groups had a similar rate of screening after the last negative result. Unlike previous studies, the researchers used invasive cervical cancer as an endpoint. The cumulative incidence of cervical cancer was similar in both groups after 10 years. The authors conclude that age is not a good discriminator for early cessation of cervical cancer screening. BMJ 2009; 338: b1354 The proof is molecular Potentially serious patient identification errors in pathology samples may be resolved using molecular confirmation, according to the results of an Australian study. Researchers investigated 14 cases of suspected pathology sample misidentifications and mix-ups arising in public and private laboratories. Most of the 23 individual samples from these cases were prostate tissue, with some other tissue biopsies and a haematological sample. The identification tests were performed with the forensic ABI Identifiler kit on DNA from paraffin-embedded tissues or blood specimens. Six of the 23 specimens were found to be discordant, indicating that an identification error had occurred. The authors comment that the high sensitivity of forensic identity multiplex systems, which use either single nucleotide polymorphisms or microsatellites, makes these tests ideal for resolving problems with identification of pathological specimens. Pathology 2009; 41: 280-283 HDL, glucose, and diabetes The evidence is clear that high-density lipoprotein (HDL) is associated with a decreased risk of harmful cardiovascular outcomes, and that low plasma levels of HDL are seen in type 2 diabetes and the metabolic syndrome. A group of Australian and Danish researchers have set out to find the key to the mechanism behind this observation. They hypothesised that HDL has a role in modulating glucose metabolism by elevating plasma insulin and activating the metabolic regulatory enzyme, AMP-activated protein kinase, in skeletal muscle. In a double-blind crossover study, participants with type 2 diabetes were given intravenous HDL and a placebo on separate days, and plasma glucose and insulin were measured. Activation of skeletal muscle AMP-activated protein kinase was assessed by biopsy. HDL infusion was associated with a significant fall in plasma glucose, increased plasma insulin, and increased muscle cell enzyme activity. Associated in-vitro studies of pancreatic and skeletal muscle cell lines confirmed the effects of HDL. The authors comment that the effect of therapies aimed at raising HDL should be examined in large trials measuring metabolic parameters such as glucose and insulin. Circulation 2009; 119: 2103-2111 Burnt out and on benefits It seems stress at work can not only make you sick, it can result in a life of dependence as well. Occupational burnout appears to be a predictor of eventual permanent work disability and dependence on a disability pension, say Finnish researchers. Burnout was defined in the study as a combination of exhaustion, doubts about the value of one’s work (cynicism) and competence (diminished professional efficacy). After adjusting for baseline health and sociological factors, workers with burnout were significantly more likely to be on a disability pension in the future. The pension was most likely to be granted on the basis of mental and behavioural disorders and musculoskeletal diseases. The authors conclude that working conditions and burnout need to be assessed regularly in the work environment to prevent early losses from the workforce. Occup Environ Med 2009; 66: 284-290 Sugar Tax A tax on sugar-sweetened beverages would have a huge impact on consumption and thus result in major benefits to public health, say the authors of a recent US perspective that is sure to generate debate. Citing the success of taxes on tobacco products, they quote cost analyses which suggest that for every 10% increase in price, consumption of sweetened carbonated drinks decreases by 7.8%. In a detailed discussion of the ethics and benefits of, and opposition to, such taxes on sugared beverages, the bottom line appears to be that, although it might be unpopular, the magnitude of the result would far outweigh that achieved through education campaigns alone. Finally, they comment that the revenue thus generated could be directed to efforts to improve public health. N Engl J Med 2009; 360: 1805-1808

Tanya Grassi

Med J Aust 2009; 190 (11 Suppl).