Volume 179 Issue 4

Two recent RCTs have clarified the benefits In Australia, about 12% of the population, and 34% of people over 50 years of age, suffer from osteoarthritis.1 The most commonly affected joint is the knee.2 For patients with knee osteoarthritis and symptoms that are refractory to drugs, arthroscopic surgery is often performed. Arthroscopy may be diagnostic or therapeutic, and potentially may delay more extensive surgery such as replacement arthroplasty.3 It allows for resection of meniscal tears and debridement of the articular surface, as well as joint lavage to remove debris and inflammatory factors (eg, interferon gamma), which are believed to be a major but remediable source of the pain of osteoarthritis. The procedure has a low incidence of morbidity and can be repeated.4 Although the number of arthroscopic procedures undertaken for knee osteoarthritis in Australia is not available, a considerable proportion of the 56 000 knee arthroscopies performed each year would be for knee osteoarthritis.2 The role of arthroscopy for osteoarthritis of the knee [is] now challenged. Evidence for the effectiveness of lavage and debridement for knee osteoarthritis comes largely from case series and cohort studies. These have shown that about 50% of patients report pain relief after the procedure.5 Predictors of poor outcomes from arthroscopy include marked malalignment, restricted range of motion, marked radiographic evidence of osteoarthritis, and prior surgery.6,7 Better outcomes are predicted by preoperative mechanical symptoms, such as those resulting from loose bodies or meniscal tears, or radiographic evidence of only mild articular degeneration.8-10 However, other studies have not been able to identify any predictive factors for outcome.11 Two recently reported randomised controlled trials have attempted to clarify the benefits of these forms of treatment. In one, 180 patients with knee osteoarthritis were randomly allocated to tidal needle irrigation or sham irrigation (in which the knee capsule was not punctured by the needle).12 After 12 months, the study found that patients in both groups had a 17% improvement in pain and physical function scores, with no statistically significant difference between the two groups. It was suggested that most, if not all, of the benefit of irrigation was a placebo effect. In a more recent randomised controlled trial, 180 patients were randomly allocated to three treatment groups — arthroscopic lavage and debridement, arthroscopic lavage alone, or sham surgery.5 Follow-up at 12 months found little improvement in patients in each of the three groups (as assessed by outcome measures such as the Knee Specific Pain Scale, the Arthritis Impact Measurement Scales and the SF-36 Health Survey), and no statistically significant difference between the groups. The inclusion of sham procedure groups and the adequate power of these randomised controlled trials allowed them to better address questions about comparative benefits and placebo effects raised in previous smaller randomised trials. However, although selection criteria for both studies were clearly stated, specific clinical indications for arthroscopy were not clearly defined. Such indications can vary considerably between practitioners. A recent study found that agreement between two groups of surgeons (research fellows and attending staff), independently predicting which patients undergoing arthroscopic debridement for knee osteoarthritis would improve, was only slightly better than chance, with neither group predicting the correct outcome more than 59% of the time.13 One indication for which arthroscopic treatment of knee osteoarthritis has been widely regarded as successful is the presence of meniscal tears. Unfortunately, neither of the recent randomised trials analysed patients with meniscal tears separately. Such an analysis would have been especially valuable in the light of a report that meniscal tears in patients with osteoarthritis were not associated with any increase in pain or impairment.14 Few studies specify treatment failure with alternative or less invasive therapies as a prerequisite to enrolment, although this may have a substantial impact on their overall success. An earlier randomised controlled trial found that, of 200 patients screened during the enrolment period, more than half improved sufficiently with conservative medical management (exercise and medication) such that no further medical or surgical treatment was warranted at the follow-up visit.8 The authors noted that “none of the studies of arthroscopy for this population in the orthopaedic surgery literature specified previous rehabilitation treatment . . . and many patients included in previous studies would have benefited from medical and rehabilitation therapy alone”. With the role of arthroscopy for osteoarthritis of the knee now challenged, but concerns about the enrolment criteria of recent studies persisting, there remains a need for further investigation. Randomised controlled trials of surgical interventions are notoriously difficult,15 but, compared with other surgery, there are features about arthroscopic surgery for knee osteoarthritis that would facilitate undertaking such trials. Equipoise over the benefits of the procedure is now well established in the medical literature, and the high prevalence of knee osteoarthritis means that, even if only a small percentage of patients are willing to be enrolled in trials, it is likely that sufficient power could still be achieved to test most clinical hypotheses. In addition to randomised controlled trials, population-based studies are needed. A Canadian evaluation of 14 391 arthroscopic knee debridement procedures for osteoarthritis found that almost 10% of patients required total knee replacement within 1 year after debridement. Rates of arthroplasty were particularly high in those aged 70 or older, and it was suggested that debridement may currently be overutilised in elderly patients.16 Given the increasing prevalence of knee osteoarthritis with an ageing population, it is important for clinicians to recommend options such as arthroscopy with good reason. At present, both the benefits of therapeutic arthroscopy and its role among alternative treatments for knee osteoarthritis remain unclear.

Adam B Chapman BA/BSc(Hons), MPH · Julian A Feller MB BS FRACS

Necrotising arachnidism should be a diagnosis of last resort The article by Isbister and Gray (page 199),1 documenting 130 confirmed cases of bites by white-tail spiders, will, we hope, become one of the last acts in a prolonged and sad medical fable in Australia, regrettably now exported beyond our shores.2 In 1982, a paper on possible spider bite necrosis in Australia was presented at the International Society on Toxinology World Congress in Brisbane,3 and followed by an editorial in the MJA in 1983.4 In 1987, Spring reported a case of severe skin damage following a presumed spider bite;5 the article and the associated editorial6 mentioned the white-tail spider. Speculation about the causative spider continued, with two “likely” candidates charged with the crime by the non-medical media,7 supported by a few in the medical community. These spiders were the wolf spider and the white-tail spider. The former was suspected partly because of evidence from Brazil, subsequently debunked, implicating these spiders in causing skin necrosis. The actual cause in Brazil has since been shown to be recluse spiders (loxoscelism).8 However, it was the white-tail spider, Lampona cylindrata, that was the principal focus of attention. Within a short time, at least a few doctors were diagnosing necrotising arachnidism caused by these spiders, and within about five years the popular association of these spiders with skin necrosis was well established. The lack of strong evidence to support this association seemed to be a triviality to be ignored. Research projects were proposed and funded to examine white-tail spider venom to understand its necrotic potential. Calls were made for governments to fund development of an antivenom. General practitioners regularly and confidently diagnosed skin lesions as “white-tail spider bite”. A few voices called “foul”. Where was the evidence to support the veracity of this new venomous scourge of urban Australia? Some confirmed bites by white-tail spiders were published, with no evidence of skin damage.9 Early research on the venom found no necrotic activity.10 The spider is native to Australia, yet most people ignored questions about the absence of cases of necrotising arachnidism in the 200 years before Spring’s article. Arachnologists questioning the validity of white-tail spider bite necrosis were also dismissed. In both the general and the medical community, the era of “white-tail spider bite necrosis” had arrived. But the evidence cast ever stronger doubt about the veracity of white-tail spider bite necrosis, despite occasional published “cases”. What was needed was a large number of cases of confirmed white-tail spider bite to clearly show the true range of its effects. Isbister and Gray’s article defines a clear and consistent pattern of clinical effects, based on a large series, with no evidence of necrosis. As the authors point out, the inappropriate diagnosis of spider bite in cases of skin damage is not isolated to Australia or the white-tail spider, but our episode is particularly disturbing, because there was never any strong evidence to link this spider with necrosis. Publication of Isbister and Gray’s article should herald the demise of the spurious diagnosis of white-tail spider bite necrosis. This will, we hope, bring an end to conditions such as basal cell carcinoma being misdiagnosed as spider bite, and to cases of feigned white-tail spider bite necrosis (where the patient inflicts skin damage with chemicals, then claims a spider bite). This does not mean spider bite never causes necrosis. Recluse spiders have clearly been shown to cause necrosis in some parts of the world, including two cases in Australia,11 where the spiders have been introduced. However, there is no evidence recluse spiders are widespread in Australia, and it would be erroneous to now label skin damage of uncertain origin as “loxoscelism” instead of “white-tail spider bite”. When presented with skin damage of initially uncertain origin, medical practitioners must look for all the many and varied non-spider-bite causes for such damage, leaving necrotising arachnidism as a diagnosis of last resort and uncertain validity after all other possibilities are excluded. Any future research into necrotising arachnidism in Australia should focus on accurately determining the cause.

Julian White MB BS, MD, FACTM

Balancing commercial patent rights and public interest is a complex matter In this issue of the Journal, Walpole and his colleagues (page 203) squarely raise the difficult issue of balancing public access to genetic health services with enforcement of gene patents.1 They explore this issue using the case study of the hereditary breast cancer gene patents (the BRCA patents).1 This timely and important article coincides with the work of the Australian Law Reform Commission (ALRC). On 5 June 2003, the ALRC released the final report of its joint inquiry with the Australian Health Ethics Committee on the protection of human genetic information.2 The report proposes that access to genetic testing for healthcare should be better regulated, and emphasises the need for ongoing development of ethical standards, particularly in relation to consent and counselling (Recommendations 11-1 to 11-4). The ALRC has now turned its attention to the separate, but related, issue of gene patenting and human health.3 The ALRC will soon be releasing its Issues Paper and calling for submissions. It is likely that limitations on the use of disease gene patents will feature prominently in the submissions and in the ALRC’s responses. The ALRC is required to report its findings by 30 June 2004. The issues associated with gene patents and genetic services are complex and warrant detailed consideration. The role of patents is to encourage innovation, but this needs to be balanced against other values, including equitable access to healthcare. The ALRC may decide that the balance needs to be adjusted. However, a simple prohibition on gene patents is unlikely, of itself, to achieve this end. More comprehensive reform options may need to be considered, including changes to the requirements for obtaining a patent and restrictions on how patents are used. One option might be to include a requirement that the usefulness of the invention be fully examined. At present, the applicant only needs to show that the invention has some commercial value. It may be appropriate to follow the United States’ lead of requiring the applicant to prove “specific, substantial and credible utility”, and restricting the scope of the patent to proven uses.4 Even if patent law is reformed, it will not necessarily assist in dealing with gene patents that are already in existence. As patents have a 20-year life, the effect of the BRCA patents and others could be felt for many years, unless their validity is challenged in the Federal Court. In Europe, L’Institut Curie started proceedings in October 2001, challenging the validity of the BRCA patents.5 Since then, other individuals and organisations across Europe have joined in, including research institutes, hospitals, ministries of health, and human genetics societies. They raise a number of grounds for invalidity, including that the invention is neither new nor inventive. Genetic service providers in Australia could challenge the equivalent Australian patents. However, the costs and risks of such litigation are such that this course of action should not be embarked upon lightly. It is equally important to consider limitations to the ways in which patents may be used. The Patents Act 1990 (Cwlth) grants patent holders the exclusive right to make, hire and sell the invention for the life of the patent. There are few controls on how this right may be used, but the controls that do exist warrant consideration. Sections 133 and 135 of the legislation allow applications to be made for compulsory licences when “the reasonable requirements of the public” have not been met. Although subject to certain limitations, a compulsory licence protects a person from infringement action for using a patented invention without the patent holder’s permission. Perhaps surprisingly, there have been few compulsory licensing applications to date. The Act also provides protection from infringement for “Crown use”: use of the patented invention “for the services of the Commonwealth or State” where “necessary for the proper provision of those services” (section 163). Examples of the applicability of this provision include use of an invention by a state rail authority for construction of rail carriages,6 and use by a local government authority of a meter for measuring water supply.7 It is debatable whether Crown use extends to the provision of public genetic services. In addition to these provisions, the Patents Act 1990 prohibits arrangements that tie use of the invention to use of other products or processes. The role of this provision and of the competition law provisions in the Trade Practices Act 1974 (Cwlth) both need further examination. Although a “research exemption” is often relied on for non-commercial research use of a patented invention, there is no specific law in Australia to support it. The ALRC may recommend that patent legislation should be amended to incorporate this exemption, perhaps together with an exemption for non-commercial clinical use, or it may recommend changes to the other limitations on use discussed above. It may be preferable to adopt the suggestion of Walpole et al and empower an expert body to require broad licensing of patented tests. In making its recommendations, the ALRC has to be mindful of Australia’s international obligations. Australia is a signatory to the World Trade Organization Agreements, one of which is the Agreement on Trade-related Aspects of Intellectual Property Rights (TRIPS).8 TRIPS lays down fairly stringent requirements for the patent laws in member countries. One stumbling block may be the requirement that there should be no discrimination in the applicability of patent rights between technologies (Article 27). Clearly, there are no simple answers to questions about what patents should be granted and what restrictions should be imposed on the ways in which granted patents are used. The ALRC faces a challenging year.

Dianne Nicol PhD, LLM

Some women with pre-eclampsia develop hypertension and cardiovascular disease in later life Pre-eclampsia Awareness Week (August 17–23) is an opportune time to reflect on what we know about this malady. Why does it develop? Can it be predicted or, more importantly, prevented? What will happen to affected women and their babies with further pregnancy? And, finally, does pre-eclampsia have long-term health effects? About one in 10 pregnancies is complicated by hypertension: about 3%–4% have pre-eclampsia, a similar proportion have gestational hypertension and 1%–2% have pre-existing chronic hypertension. The latter is apparent when hypertension is present in the first half of pregnancy, whereas pre-eclampsia and gestational hypertension usually occur later. Despite pre-eclampsia being a placental disease, the mother rather than the fetus may bear the brunt, with, commonly, increased blood pressure, abnormal kidney (proteinuria or renal insufficiency) or liver function (elevated transaminases or severe right upper quadrant or epigastric pain), neurological disturbances including convulsions (eclampsia), and thrombocytopenia or disseminated intravascular coagulation. The fetus may be affected by growth restriction (about one in four cases), and about 20 per 1000 cases die either in utero or as a result of prematurity. Why does pre-eclampsia occur?There appears to be an ill-defined genetic predisposition to pre-eclampsia, with some studies suggesting an autosomal recessive inheritance. However, discordance for pre-eclampsia among monozygotic twins questions some of the genetic postulates. Paternal influence on fetomaternal genetic mismatch is important, and being born of a pre-eclamptic pregnancy increases the likelihood for males of fathering an infant whose gestation will also be complicated by pre-eclampsia. Immune theories abound, largely arising from epidemiological observations that pre-eclampsia is more common in a first pregnancy, and that changing partners for a subsequent pregnancy increases the risk of pre-eclampsia in women with a previous normal pregnancy and decreases the risk in women with previous pre-eclampsia.1 Prolonged sexual cohabitation before pregnancy appears to protect against pre-eclampsia, the implication being that this allows development of greater maternal “tolerance” to paternal antigens present in sperm or seminal fluid.2 Shallow trophoblast invasion of the placental spiral arteries is common in pre-eclampsia, leaving blood vessels that cannot deliver the same placental blood supply as in normal pregnancies. Although this is a common finding, it also occurs in idiopathic fetal growth restriction in which there are no maternal abnormalities. Thus, the factor (or factors) linking placental underperfusion or relative hypoxia to the multisystem effects of pre-eclampsia is yet to be established. Maynard et al3 have recently reported increased placental production of the soluble fms-like tyrosine kinase 1 (sFlt1) receptor, which mops up circulating vascular endothelium growth factor (VEGF) and placental growth factor. sFlt1 given to pregnant rats caused proteinuria, hypertension and glomerular endotheliosis, all features of human pre-eclampsia.3 Whether this factor proves to be significant in humans remains to be seen. Whatever the factor(s) causing pre-eclampsia, it is best understood as a vasoconstrictive process associated with capillary leak and subsequent reduction in perfusion of maternal kidneys, liver, and brain, as well as the placenta. Can pre-eclampsia be predicted?It follows that without a precise understanding of the aetiology of pre-eclampsia there is little we can do to prevent its occurrence. Nonetheless, it now appears that endothelial dysfunction predates the clinical appearance of pre-eclampsia,4 and we know a range of situations in which pre-eclampsia is more likely. These include primipaternity, essential hypertension, renal disease, multiple pregnancies, donor sperm or donor oocyte pregnancy, history of previous pre-eclampsia or maternal or paternal family history of pre-eclampsia, obesity, diabetes and (probably) thrombophilias, such as Factor V Leiden or prothrombin gene mutations. This allows us to screen such women more often during pregnancy for the emergence of hypertension or fetal growth restriction, although this is not a fail-safe method of detecting all such cases. Taking aspirin 60–150 mg/day from about 14 weeks’ gestation until late pregnancy offers a 15% reduction in the likelihood of developing pre-eclampsia, but about 90 women need to be treated to prevent one such case, and it is difficult to select these women.5 Management of pre-eclampsiaThe development of day assessment units has changed our approach to management of hypertension in pregnancy in Australia. Women with hypertension in the second half of pregnancy previously spent weeks in hospital having their blood pressure controlled. This is now almost always done on an outpatient basis; this applies to women with gestational hypertension (about 25% of whom will develop pre-eclampsia at a later stage) and to a selected number of women with mild pre-eclampsia who have initially been observed in hospital. The Magpie trial6 has shown the benefits of magnesium sulfate for convulsion prophylaxis, but most units in Australia have such low rates of eclampsia (convulsions) that use of magnesium sulfate in all women with pre-eclampsia hardly seems justified. Antihypertensive drugs have been shown to reduce the likelihood of episodes of severe maternal hypertension and fetal respiratory distress syndrome, and several antihypertensive drugs, including oxprenolol, methyldopa, clonidine, hydralazine, and nifedipine, are widely used for this purpose. The most important aspect of managing women with pre-eclampsia is timing of the delivery. This means determining when the woman’s condition is deteriorating or when the fetus is at high risk of intrauterine death. Clearly, such management should be undertaken by highly specialised groups, with a team approach of obstetrician, physician, perinatologist and midwife. What happens after pre-eclampsia?The most common question asked by women who have had pre-eclampsia is whether it will occur in subsequent pregnancies. Estimates of recurrence vary enormously — anywhere from 5%–8% in late onset cases to 25% in early onset cases — but there is a gap in our knowledge about recurrence rates in Australian women. To help prevent pre-eclampsia, the Australasian Society for the Study of Hypertension in Pregnancy recommends low-dose aspirin. Women should take aspirin from early in their pregnancy, if, in the previous (pre-eclamptic) pregnancy, delivery was necessary before 32 weeks’ gestation or fetal death occurred.7 Perhaps the more important question is what effect pre-eclampsia has on long-term health. The traditional view was that having pre-eclampsia imposed no greater long-term cardiovascular risk than a normal pregnancy. However, a recent large study from Norway has shown that developing pre-eclampsia before 37 weeks’ gestation imposes an eightfold increased risk of cardiovascular death over a median follow-up of 13 years.8 Given the young age of women with pre-eclampsia, this is quite a significant finding. Further, a study from Scotland has found that both pre-eclampsia and gestational hypertension increase the risk of hypertension in later life, with women who have had pre-eclampsia having an increased risk of death from stroke.9 Based on these findings, it is reasonable to recommend that all women who have had pre-eclampsia should have their cardiovascular risks assessed regularly (ie, annual blood pressure measurement, assessment of fasting lipids and blood sugar every few years) and should be encouraged to maintain a healthy lifestyle to reduce these long-term risks. ConclusionIn Pre-eclampsia Awareness Week, we know that, for most women with pre-eclampsia in Australia, the outcome is a healthy mother and baby. However, pre-eclampsia should now be thought of as a lifelong disorder, with some women destined in later life to develop hypertension, and cardiovascular and cerebrovascular disease. Indeed, it is this recognition of the long-term health consequences for women with pre-eclampsia that is the more recent important achievement in this field.

Mark A Brown FRACP, MD

Objectives: To compare the effectiveness of ototopical ciprofloxacin (0.3%; CIP) with framycetin (0.5%), gramicidin, dexamethasone (FGD) eardrops (5 drops twice daily for 9 days) together with povidone-iodine (0.5%) ear cleaning as treatments for chronic suppurative otitis media (CSOM) in Aboriginal children.Design and participants: Aboriginal community-controlled, community-based, multicentre, double-blind, randomised controlled trial in eight Aboriginal Community Controlled Health Services across northern Australia, involving 147 Aboriginal children with CSOM.Main outcome measures: Resolution of otorrhoea (clinical cure), proportion of children with healed perforated tympanic membrane (TM) and improved hearing, 10–21 days after starting treatment.Results: 111 children aged 1–14 years (CIP, 55; FGD, 56) completed treatment. CSOM cures occurred in 64% (CIP, 76.4%; FGD, 51.8%), with a significantly higher rate in the ciprofloxacin group (P = 0.009, absolute difference of 24.6% [95% CI, 15.8%–33.4%]). TM perforation size and the level of hearing impairment did not change. Pseudomonas aeruginosa was the most common bacterial pathogen (in 47.6%), while respiratory pathogens were rare (in 5.7%).Conclusions: Twice-daily ear cleaning and topical ciprofloxacin is effective at community-level in achieving cure for CSOM. Healthcare providers to Aboriginal children with CSOM should be given special access to provide ototopical ciprofloxacin as first-line treatment.

Sophie Couzos FRACGP, FACRRM, FAFPHM · Traven Lea MAEIH, DipPHTM · Margaret Culbong · Reinhold Mueller MSc, PhD · Richard Murray FRACGP, MPH

Objective: To assess the reported rate of local reactions after administration of acellular pertussis vaccine (DTPa) according to dose number and type of pertussis vaccine (whole-cell or acellular) used for the primary course, and to document the severity and outcome of fourth-dose local reactions.Design and setting: Retrospective review. Reports of adverse events after vaccination in South Australia between 1 January 1997 and 31 December 2000 were reviewed, and a questionnaire administered to all parents who reported a local reaction after the fourth dose of DTPa.Main outcome measures: The number, and rate per 100 000 administered doses, of local reactions following the primary and booster doses of DTPa, and of local reactions after the fourth-dose in cohorts of children whose primary vaccinations were with either DTPw or DTPa. Redness and/or swelling at the injection site as reported by parents.Results: Of 581 reported adverse events after vaccination, 138 were local reactions after a pertussis-containing vaccine. Primary vaccinations with DTPa was a significant risk factor for a fourth-dose local reaction (relative risk, 6.7; 95% CI, 2.4–18.5). Parental questionnaires were completed for 45 of the 71 children (63%) with reported local reactions after the fourth dose of DTPa; extensive limb swelling was reported in 8 children (18%) and all except one child had recovered by the time of review.Conclusions: Parents should be informed that children receiving booster doses of DTPa vaccine, after primary doses with DTPa, are at increased risk of local reactions (which tend to resolve spontaneously) but not of systemic effects. Studies should be initiated to investigate the pathogenesis and the risk of recurrence of local reactions to further improve vaccination schedules.

Michael S Gold MD, FRACP · Sara Noonan RN · Maggi Osbourn RN · Stella Precepa RN · Ann E Kempe RN, MPH, BSc

Objectives: To review the approved product information (PI) of prescription medicines to determine the extent and nature of information available on paediatric dosing and the availability of paediatric dosage formulations in Australia.Methods: The PIs for all prescription medicines listed in the Australian Monthly Index of Medical Specialties (MIMS) were reviewed. Dosing information for each PI was categorised according to age groupings. PIs claiming suitability for use in paediatric patients were reviewed for information on the availability of paediatric dosage forms.Main outcome measures: Proportion of PIs providing paediatric dosing information; availability of dosage forms suitable for children.Results: A total of 1497 PIs were reviewed. The proportions, for each age group, of PIs with inadequate paediatric dosing information were: < 1 month (80.5%), 1–3 months (79.1%), 3 months–2 years (77.5%), 2–6 years (73.2%), and 6–12 years (71.6%). The proportions, for each age group, of PIs that gave specific paediatric dosing information but did not provide a paediatric dosage form were: < 1 month (26.5%), 1–3 months (25.1%), 3 months–2 years (23.3%), 2–6 years (21.9%), and 6–12 years (24.0%).Conclusions: The PIs for many prescription products listed in MIMS do not adequately detail paediatric doses. Many medicines for which specific paediatric dosing information is given are not available in dosage forms appropriate for children.

Elaine Tan BPharm, BPharmSc(Hons) · Craig R Rayner BPharm, BPharmSc(Hons), PharmD · Colin B Chapman BPharm, PhD, FPS · Noel E Cranswick MB BS, FRACP

Objective: To investigate the circumstances and clinical effects of bites by white-tail spiders, including the two species Lampona cylindrata and L. murina commonly encountered by humans, and the incidence of necrotic lesions.Design: Prospective cohort study of definite white-tail spider bites. Cases were only included if there was a clear history of bite, the spider was caught and was identified by an expert.Setting: Calls to Australian poisons information centres and emergency departments.Patients: 130 patients with a definite bite by a white-tail spider from February 1999 to April 2002.Results: There were 79 bites by L. cylindrata and 51 by L. murina. Bites occurred in warmer months, 95% indoors and 75% between 16: 00 and 08: 00. The activity at the time of the bite was characteristic and the spider was encountered between bedclothes, towels or clothing. 25% of bites occurred on distal limbs. Pain/discomfort occurred in all cases, and was severe in 27%. Other effects included puncture marks (17%), redness/red mark (83%) and itchiness (44%). Systemic effects occurred in 9%. There were no cases of necrotic ulcers (97.5% CI, 0–2.8%) or confirmed infections. Median duration of effects was 24 hours (interquartile range, 1–168 hours). There were three distinct clinical patterns: pain only (21%), pain and red mark for < 24 hours (35%), and a persistent painful or irritating red lesion (44%).Conclusions: Bites by Lampona spp. cause minor effects in most cases, or a persistent painful red lesion in almost half the cases. White-tail spider bites are very unlikely to cause necrotic ulcers, and other diagnoses must be sought.

Geoffrey K Isbister BSc, MB BS, FACEM · Michael R Gray MSc, PhD

The patent system has been seen as a critical factor driving innovation in clinical medicine, particularly in medical devices and diagnostic assays. The licence terms and business model proposed by Myriad Genetics Inc. for testing the hereditary breast cancer susceptibility genes BRCA1 and BRCA2 could stifle innovation (particularly if other companies adopt similar business models), and are likely to limit the ability to provide high quality public genetic testing services in Australia. Under the Myriad model, testing for the BRCA1 gene would be undertaken by an organisation removed from the integrated public healthcare system. Based on overseas experience, Australia can expect a 2–3-fold increase in the cost of this testing, which will provide only partial information on the hereditary breast cancer status of the patient. Commercial exploitation of gene patents needs to be regulated to balance the patent holders’ right to profit from their inventions (necessary to drive further innovation) and the public policy objective of high quality, equitable healthcare.

Ian R Walpole FRACP · Hugh J S Dawkins PhD, Senior Project Officer · Peter C O’Leary PhD · Peter D Sinden LLM

The Australian medical workforce, like those of most developed countries, is increasingly “feminised” and exposed to the global market for doctors. Demand for healthcare services is increasing in the Australian community. Concern in relation to doctor shortages is increasing, particularly in rural areas. There should be greater flexibility for entry of highly-trained overseas doctors. There is an urgent need to increase medical school student intake. Issues of workforce practice, including “task” substitution, should be explored.

Peter M Brooks MD, FRACP · Helen M Lapsley MEc, FCHSE · David B Butt MBA, AFCHSE

Clinical records Patient 1 An 88-year-old man gave a 12-month history of seeing insects attacking his legs and crawling along the floor of his house. He described these insects as 4 cm long, black and white bugs with beaks, which pecked at his legs, causing wounds. He often felt a sharp stinging sensation heralding their presence. He also had burning pain in both legs below the knees. He had had his house fumigated twice in the previous year and put various chemicals across his doorways and bed to ward off the bugs. He described no other hallucinations or delusions. He was not using any regular medications and had never been a consumer of alcohol. He lived alone and managed all activities of daily living independently. His home was clean, and he had no pets. Score on Folstein Mini Mental State Examination was 28/30. Neurological examination revealed signs of peripheral neuropathy of the lower limbs. His visual acuity was poor. During the examination, he pointed to several “bugs” on his legs, which were actually pieces of skin peeling from superficial ulcers. Nerve conduction studies confirmed peripheral neuropathy. Computed tomography and magnetic resonance imaging of the brain showed ischaemic changes. Magnetic resonance angiography showed severe stenosis of the left internal carotid artery. Septic screen and serological tests for syphilis gave negative results. The patient’s symptoms were thought to be due to neuropathic pain. He was prescribed carbamazepine (100 mg twice daily) to alleviate the sensory stimuli, and risperidone (0.5 mg in the morning, 1 mg at night). After 2 weeks, the pain and delusions had decreased substantially. Diagnosis: Delusional parasitosis associated with medical conditions — neuropathy and poor visual acuity. Patient 2 A 72-year-old woman had a 20-year history of the delusion of worms crawling throughout her body, especially around a scar on her hip. She was convinced that the scar should be surgically explored. Past medical history included type 2 diabetes mellitus, normal pressure hydrocephalus with shunt insertion, ischaemic heart disease and fractured right neck of femur. She lived in a hostel. Her cognition was normal, and clinical examination found no abnormalities. She was treated briefly with thioridazine (40 mg daily), which provided some benefit but caused drowsiness. She was then treated with pimozide (2 mg twice daily), which was changed to olanzapine (2.5 mg in the morning, 5 mg at night) because of continuing agitation, paranoid ideation about her neighbours and “intruders”, and aggression to neighbours and hostel staff. Her symptoms decreased but did not resolve, and compliance was poor. Diagnosis: Paranoid schizophrenia with major psychotic symptom related to infestation. Patient 3 An 81-year-old woman was referred with a persistent belief that she had scabies and lice infestation of her eyes, nose, arms and anus. This resulted in her persistently washing her clothes and herself and reporting the retirement village where she lived to the Health Department. She had received anti-scabies treatment empirically. She had a long history of severe depression after the death of her husband, for which she took doxepin. She had paranoid ideation about her neighbours and saw things crawling down the walls, and had moved residences several times to avoid these problems. Other medical problems included treated hyperthyroidism, oesophageal stricture and partial pneumonectomy. She did not drink alcohol. Score on Folstein Mini Mental State Examination was 28/30. She was prescribed haloperidol (0.5 mg twice daily) and continued taking doxepin. The delusions of scabies subsided. Four years later, she developed new thoughts that dirt was being deposited in her unit by builders working nearby. She had stopped taking haloperidol in the interim. She became agitated, covering her furniture and closing all gaps around doors and windows. She was prescribed olanzapine (2.5 mg at night). Diagnosis: Delusional parasitosis in conjunction with depressive illness. Patient 4 A 74-year-old woman was referred for assessment of tactile hallucinations. She had a 2-month history of presumed worm infestation and persistent complaints of anal and vaginal pruritus despite multiple courses of an anthelminthic. She had complained previously of feeling head and body lice. Her past medical history included chronic airways limitation, trigeminal neuralgia, which was treated with sodium valproate, and temporal arteritis, which had responded previously to corticosteroid therapy. She lived alone and was previously active, but had became depressed and isolated because of these delusions. No abnormalities were found on physical examination. Examination of a skin specimen, which the patient thought contained worms, showed cotton threads. Full blood count was normal, with no eosinophilia and normal erythrocyte sedimentation rate. Sigmoidoscopy found no abnormalities, while computed tomography of the head showed a previous left parietal infarct. She was prescribed pimozide (2 mg daily), with complete resolution of the worm sensation. Diagnosis: Isolated delusional parasitosis. An older person requesting treatment for an infestation may not seem unusual. However, when the complaint persists despite repeated treatments for lice, scabies and other parasites, and examination shows no evidence of an infestation, the differential diagnosis includes delusional parasitosis. Management of this condition is challenging but rewarding, as it may cause severe emotional, social and physical disability in both the afflicted individuals and those around them. We describe four patients with delusional parasitosis who were managed in our department of geriatric medicine (see Clinical records). Delusional parasitosis, named in 1946,1 is a chronic psychiatric disorder in which patients have a false and fixed belief that they are infested by parasites. It is not a phobia.2 The core of the disease is the delusion of infestation and, although it is a psychiatric disorder, patients usually seek help from dermatologists. Its onset is insidious, and the delusion is typically preceded by a primary tactile experience, such as pruritus or paraesthesia, or tactile hallucination, which precipitates the secondary delusion of infestation. The condition may occur as an isolated thought disorder in a person whose psyche is otherwise intact, as illustrated by Patient 4. This has also been termed monosymptomatic hypochondriacal psychosis3 and “primary” delusional parasitosis.4 When associated with a psychiatric condition, such as schizophrenia (Patient 2) or depression (Patient 3), delusional parasitosis has been termed “secondary functional”, and, when caused by a medical illness (eg, diabetes, malignancy or nutritional deficiency), medication or substance misuse, it has been termed “secondary organic”5 (Patient 1). In the classification system of the Diagnostic and statistical manual of mental disorders (DSM-IV), primary delusional parasitosis corresponds to “delusional disorder, somatic type”, while the secondary organic type corresponds to “psychotic disorder due to general medical condition”.6 The prevalence of delusional parasitosis is unknown, but our literature review identified several hundred cases reported by dermatologists and entomologists.2,3,5,7,8 It can occur at any age, the average being in the fifth decade. In the older age group, women are more often affected than men.2,7 Mean duration of symptoms before attending tertiary care was 1.3 years in one study.8 Patients with no precipitating medical problems or psychiatric illness often have a personality disorder and isolate themselves, but function well in other aspects of their day-to-day living.3 Patients provide incredibly detailed descriptions of the “bugs” and explanations about why they are not visible on examination. They often bring in “specimens” in a small container, which are actually pieces of skin, lint or hair (“the matchbox sign”), or may identify “bugs” during examination by probing into skin until they are able to pick up a small piece of tissue. This may produce traumatic ulcers of varying size, typically on areas the patient can reach, in an asymmetrical distribution corresponding to the dominant hand. Secondary dermatitis may develop as a result of repeated washing and application of chemical preparations.2 Management involves first excluding a real infestation and any underlying condition, including psychiatric disorders, medical conditions with altered sensation, use of drugs (prescribed and illicit) or withdrawal from alcohol or cocaine. Mental state, including cognition, needs to be assessed. Other investigations may include examination of skin scrapings and skin biopsies. In therapy, the most important step is to establish a trusting doctor–patient relationship. An empathic approach is required, acknowledging the reality of patients’ symptoms without challenging or confirming their views about the cause. Samples of any alleged parasites presented must be examined. Ideally, patients should be referred to a psychiatrist, but many resist this. Consequently, medication with an antipsychotic should be initiated by the doctor who makes the diagnosis. Treatments include pimozide2,3,5,7 and the newer atypical antipsychotics, such as risperidone.9 Medication compliance can be a problem. There have been some reports that tricyclic antidepressants and anxiolytic agents alleviate the reactive component of the condition without much effect on the delusions.2,7 Doxepin has strong antihistamine and anxiolytic effects, in addition to its antidepressant effect, and, based on its effectiveness in chronic neurotic excoriation,10 may be useful in patients who frequently experience intense pruritus, anxiety and agitation as well as depressive symptoms. Corticosteroid creams and lotions may be helpful adjuncts to alleviate skin symptoms. Lessons from practice Delusions of parasitosis may occur alone or in association with medical or psychiatric illness. Antipsychotic agents are the mainstay of medical management. Empathy and a good doctor–patient relationship are required to optimise outcome.

Linda Le BM BS, DCH · Peter N Gonski BMedSc, FRACP

The draft human genome sequence (about 3 billion base pairs) was completed in 2001. Humans have fewer protein-coding genes than expected, and most of these are highly conserved among animals. Humans and other complex organisms produce massive amounts of non-coding RNAs, which may form another level of genetic output that controls differentiation and development. Aside from classical monogenic diseases and other differences caused by mutations and polymorphisms in protein-coding genes, much of the variation between individuals, including that which may affect our predispositions to common diseases, is probably due to differences in the non-coding regions of the genome (ie, the control architecture of the system). Within 10 years we can expect to see: increased penetration of DNA diagnostic tests to assess risk of disease, to diagnose pathogens, to determine the best treatment regimens, and for individual identification; a range of new pharmaceuticals as well as new gene and cell therapies to repair damage, to optimise health and to minimise future disease risk; and medicine become increasingly personalised, with the knowledge of individual genetic make-up and lifestyle influences.

John S Mattick AO, PhD, FRCPA

Christopher M Doran,* Julia E Fawcett,† Anthony P Shakeshaft,‡ Marian D Shanahan,§ Richard P Mattick¶ * Health Economist, † Research Officer, ‡ NHMRC Fellow and Senior Investigator, § Health Economist, ¶ Director, National Drug and Alcohol Research Centre, University of New South Wales, NSW 2052. C. DoranATunsw.edu.au To the Editor: An estimated 512 935 Australian adults satisfy criteria for alcohol dependence (3.5% of the population aged 18 years and over).1 Pharmacotherapy for this condition typically comprises a benzodiazepine, such as diazepam, for withdrawal and disulfiram for relapse prevention.2 Acamprosate and naltrexone have also recently become available for treating alcohol dependence in Australia, but little is known about their uptake or cost. One indicator of uptake is the proportion of alcohol-dependent individuals who have a script filled. Based on the number of scripts for these drugs filled in Australia in 2001, and assuming 50% compliance with the recommended treatment periods, we estimated that 4602 people took acamprosate and 8899 naltrexone in that year (Box). This is equivalent to a maximum of about 3% of alcohol-dependent individuals taking either drug (13 501 individuals using either drug/512 935 alcohol-dependent individuals). We also estimated the cost of visits to medical practitioners for scripts for these drugs, assuming that most were written by general practitioners, and the costs of the drugs themselves to the Australian government and to individual patients (Box). Total treatment and medication cost of the two drugs in 2001 was $7 420 741. These estimates are based on assumptions about the relevant population sub-group (age >18 years), rate of compliance with the recommended regimen (50%), source of scripts (GPs), and GP fees (first visit, $25.05; subsequent visits, $11.14). Varying these assumptions makes little difference to the likely uptake of either acamprosate or naltrexone; applying more conservative assumptions suggests that either medication is unlikely to have been used by more than 5% of alcohol-dependent individuals in Australia. Although use of these medications is not necessarily appropriate for all dependent individuals, their low uptake raises serious concerns about why they are being under-utilised: it may be because they are poorly marketed, or it may be that they are of limited effectiveness in Australia outside the context of clinical trials. The latter possibility is exacerbated by the nebulous nature of the comprehensive treatment programs recommended for their use.5 Without methodologically rigorous Australian data, it is difficult to confidently allay such concerns. However, these results indicate a considerable amount of resources are being devoted to acamprosate and naltrexone as treatments for alcohol dependence, with little Australian evidence as to whether this investment represents value for money. Use and cost of new medications for alcohol dependence in Australia in 2001 Acamprosate Naltrexone Number of scripts filled3 27 613 13 349 Estimated number of users* 4602 8899 General practitioner visits Estimated number† 13 807 8899 Estimated cost§ $251 129 $240 794 Medication cost3,5 Cost to government $4 442 204 $2 115 315 Estimated cost to patients¶ $252 407 $118 892 Total cost $4 945 740 $2 475 001 * Number of scripts filled/number of scripts needed for recommended treatment period (12 months for acamprosate and 3 months for naltrexone,4 with each script providing one month’s supply5)/compliance (assumed to be 50%). † Based on 6 visits per year for acamprosate prescription (12 scripts; 1 repeat per script), and 2 visits per year for naltrexone prescription (3 scripts; 1 repeat per script), but assuming 50% compliance with recommended treatment period. § Based on 2001 Medicare rates (85% of MBS code 23 [$25.05] for first visit, and 85% of MBS code 3 [$11.14] for subsequent visits) plus mean patient cost per GP/vocationally registered GP visit for 2001 of $2.62.6 ¶ Taking into account variation in patient Medicare classification (general, concessional or safety net), which varied over the year.3,5

Christopher M Doran · Julia E Fawcett · Anthony P Shakeshaft · Marian D Shanahan · Richard P Mattick

Robert G Moses,* Alison J Webb,† Christine D Comber‡ * Clinical Director, † Nurse, Diabetes Service; ‡ Nurse, Department of Obstetrics and Gynaecology, Illawarra Area Health Service, PO Box W58, Wollongong West, NSW, 2500. mosesrATiahs.nsw.gov.au To the Editor: Gestational diabetes mellitus (GDM) is glucose intolerance of variable severity with onset or first recognition during the current pregnancy.1 GDM is one of the conditions requiring an entry on the New South Wales Midwives Data Form. Effective healthcare planning is dependent on accurate data collection. To our knowledge, the verity of the midwives data with respect to GDM, or indeed other entities, has not been checked for many years. A previous article has demonstrated that the accuracy of GDM data collection is poor, with the incidence of GDM being under-reported.2 Recently, an article from Victoria also showed a recorded rate of GDM about half that of the acknowledged incidence.3 We have recently completed a review of compliance with GDM testing in our area and, knowing the true incidence of GDM, this has allowed us to revisit the accuracy of the data being recorded on the Midwives Data Collection Form. In the city of Wollongong, NSW, with a population of around 280 000 and about 3000 births each year, all deliveries take place at two public hospitals (Wollongong and Shellharbour) and a private hospital (Illawarra Private Hospital). It is the policy of both the Obstetric Department and the Division of General Practice that all pregnant women should be tested for GDM in accord with the ADIPS guidelines.4 All women who delivered at the three hospitals over the 6-month period from January 2002 to June 2002 were identified from the Labour Ward records. A hospital-based delivery is used by 99.3% of women in the area.5 The results of testing for GDM were determined for all of these women. There were 1655 deliveries at the three hospitals over the 6-month period. Seven women with known type 1 or type 2 diabetes were excluded, leaving 1648 women whose data could be examined. Women were considered to have been tested for GDM (n = 1518) if they had had either a glucose tolerance test (n = 1502) or a glucose challenge test (n = 16). There were 101 women diagnosed with GDM, giving an overall incidence rate of 6.6% (prenatal clinic, 7.1%; shared-care, 6.6%; private patients, 6.3%). The most recent midwives data indicate an incidence of 5.7% at the public hospitals and 3.1% at the private hospital. It is thus apparent that the official statistics still underestimate the incidence of GDM. A similar degree of error may also be found for other entries, and hence data should be extrapolated with caution. A redesign of the collection form may help remove some of the errors and omissions. For the question regarding GDM, we feel accuracy could be enhanced if there were separate “Yes” and “No” boxes, rather than a single check box. This might encourage further consideration of the problem. Accuracy could be further enhanced by allowing space for the glucose tolerance test results at 0 and 2 hours — these would also be useful data in their own right.

Robert G Moses · Alison J Webb · Christine D Comber

Lee K Taylor Manager, Surveillance Methods, Centre for Epidemiology and Research, NSW Department of Health, Locked Bag 961, North Sydney, NSW 2059. ltaylATdoh.health.nsw.gov.au In reply: Moses et al are correct in noting that gestational diabetes mellitus (GDM) is under-reported to the New South Wales Midwives Data Collection (MDC). The most recent validation study of the MDC was carried out in 1998. We reviewed a random sample of 1680 medical records from NSW public and private hospitals, representing 1.9% of births reported in 1998. The sensitivity and specificity of reporting of GDM to the MDC were 86.7% and 99.6%, respectively.1 In this sample, the incidence rate of GDM was 3.5% according to the MDC, and 4.0% according to the medical record review. These population rates are lower than the rates reported by Moses et al among women attending hospitals in Wollongong. In addition to incomplete recording of diagnosed GDM on the MDC, the low rate of recording of GDM in medical records in our sample suggests that GDM was also under-ascertained at a population level. This is probably due to variations in the implementation of pregnancy screening for GDM between clinicians and across NSW hospitals. In February 2003, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists endorsed the Australian Diabetes in Pregnancy Society GDM Management Guidelines.2 The guidelines recommend universal screening for GDM, noting that selective screening may be appropriate because of limited resources or known low GDM incidence. The suggestions for trying to improve reporting of GDM by redesigning the MDC form are welcome, and we will certainly consider them at the next review. We are also considering using the hospital Inpatient Statistics Collection (ISC), in which discharge diagnoses are classified according to the International Classification of Diseases, as an alternative source of information on maternal morbidity. We are currently reviewing a random sample of 500 medical records of mothers who gave birth in hospitals throughout NSW. The information obtained will be compared with matched ISC records provided to the NSW Department of Health to determine whether the ISC is a more reliable source of information on maternal morbidity than the MDC. In the longer term, I anticipate that the integration of the MDC with computerised medical records in hospitals will also contribute to improved reporting. Under-reporting of maternal morbidity, including GDM, is an issue for all state and territory perinatal data collections in Australia. The information is used for planning and evaluation of healthcare services, so it is important that we get it right. I would like to thank Moses et al for raising this issue.

Lee K Taylor

David Simmons,* Amanda Fieldhouse,† Leslie E Bolitho,‡ Grant J Phelps,§ Rob Ziffer,¶ Gary J Disher** * Professorial Fellow, Department of Rural Health, University of Melbourne, Shepparton; and Professor of Medicine, University of Auckland Waikato Clinical School, Waikato Hospital, Hamilton, New Zealand; † Health Care Consultant, South Yarra, VIC; ‡ Physician, Wangaratta, VIC; § Physician, St John of God Hospital, Ballarat, VIC; ¶ Physician, Sale, VIC; ** Deputy Director – Health Policy, Royal Australasian College of Physicians, Sydney, NSW. simmonsdATwaikatodhb.govt.nz To the Editor: Rural Australia has a substantial shortage of specialist physicians. In 1999, Victoria had 52 specialist physicians for 1.3 million people (a physician to population ratio of 1:25 000).1 The Australian Medical Workforce Advisory Committee recommendation is 1:10 000.2 Although much has been written about the shortage of rural general practitioners, there is little about rural specialist physicians. However, evidence from Western Australia showed that advanced trainee physicians interested in rural practice were diverted to city-based practice during their training.3 Here, we outline a state-wide approach to encourage advanced trainee physicians to complete their training in rural Victoria. The University of Melbourne Department of Rural Health in Shepparton provided support for rural Victorian physicians to develop a state-wide network, the Victorian Rural Physicians Network, under the Victorian State Committee of the Royal Australasian College of Physicians (RACP). A pilot survey in the 14 major rural Victorian centres demonstrated capacity for at least nine Advanced Physician Trainee positions across rural Victoria. The RACP accredited five positions initially, with others to be reviewed for accreditation if required. These positions were funded largely by the joint Federal–State Government Advanced Specialist Training Program in Rural Australia. Four trainees completed 12 months of rural training in 1999–2000, and three are now working as rural physicians. These trainees were recruited through advertisements in the RACP newsletter and personal contacts. The trainees provided substantial benefits, both in service delivery, as their presence reduced the load on other doctors in the same hospital, and in medical education, as they provided more education and supervision for junior doctors and doctors from overseas. In 2001, a similar approach to recruitment identified eight potential applicants, but none came to interview. In 2002, three new strategies were therefore introduced: Flexible, joint rural–metropolitan positions were created; A rural physicians’ conference was organised;4,5 and A management consultant was employed to contact personally all 99 Victorian basic physician trainees expected to enter advanced training. The response to the new approach is shown in the Box. A third of contactable trainees indicated an interest in rural practice at the end of their basic training. Ten applications were received for the rural training positions, and seven trainees were appointed (three withdrew). We believe that our new strategies have merit, and that the personal touch has created goodwill which may improve the response for 2004. Recruiting for the 2003 Advanced Physician Training Programme for Rural Victoria

David Simmons · Amanda Fieldhouse · Leslie E Bolitho · Grant J Phelps · Rob Ziffer · Gary J Disher

Nicholas A Tonti-Filippini Consultant Ethicist, 15 Alburnum Crescent, Lower Templestowe, VIC 3107. ntfATcyberspace.net.au. To the Editor: Jansen’s study1 of the effect of maternal age on IVF outcome yields information that has not been available. However, the presentation of the data raises two questions. Firstly, are the births reported all attributable to IVF intervention? A couple is considered infertile if they are unable to achieve conception after a year of unprotected intercourse, or the mother is unable to carry a pregnancy to a live birth.2 In reports of infertility, there is a natural conception rate of about 25%–30% per annum,3-6 and Jansen’s study, in effect, covers a 3-year period (or 4 years if you include the period for assessing the outcome of the pregnancies). We need to know whether natural conception has contributed; whether the couples continued to have unprotected intercourse during the course of the study; and what means was used to identify a pregnancy as an IVF pregnancy (as distinct from a natural conception, if that distinction was made). Jansen notes that there was a group of women who dropped out after treatments were initiated and before egg retrieval, and a further group for whom eggs could not be retrieved. It is unclear whether the former included those who had a natural conception. In terms of evaluating the success of IVF, more information on these groups would be valuable. The second question relates to comparative embryo survival rates. Jansen gives the number of live births per egg retrieval procedure, and fresh and frozen embryo transfer is combined in the live-birth result. Separating live embryo transfer from frozen embryo transfer, which is done in the Victorian Infertility Treatment Authority annual reports 1998–2001, would indicate that the transfer of a fresh embryo has about a 9.5% chance of resulting in a live birth, and the transfer of a frozen embryo has about a 3.1% chance of resulting in a live birth. In the current discussion of embryos being available for research, this information about embryo survival rates would be informative.

Nicholas A Tonti-Filippini

Robert P S Jansen Medical Director, Sydney IVF, 4 O’Connell Street, Sydney, NSW 2000. robert.jansenATsivf.com.au In reply: The pregnancies and live births I reported are all attributable to IVF intervention. The physiological and pharmacological reasons for this certainty follow. Firstly, neither an egg-retrieval treatment nor an embryo-transfer treatment (both of which require hormone administration from the start of menstruation) can be embarked on if a woman is pregnant. This is established not just by the fact of menstrual bleeding, but by showing low levels of oestradiol and progesterone. Thus, no treatment cancellations or retrieval failures were for reasons of pregnancy. In an egg-retrieval treatment cycle, preovulatory eggs are removed from mature follicles with high efficiency, and so are not available to be ovulated, which virtually precludes natural conception in the retrieval cycle. As described in my article, transfer of cryostored embryos occurs during a month in which the ovaries are suppressed by the cyclical regimen of ethinyl oestradiol and a progestin (used to develop the endometrium predictably). The effect is that of the sequential oral contraceptive regimens of the 1960s,1 and ovulation is reliably inhibited. Tonti-Filippini’s estimate of a 25%–30% annual natural pregnancy likelihood with just 12 months’ infertility would be more or less correct for couples in their 20s, but does not pertain to our population (median age, 36 years; median duration of infertility, 3.5 years). The arithmetic that predicts an expected, approximately 5% annual natural conception for such a population is given in Jansen.2 The time during which natural pregnancy could have occurred began with the month after the egg-retrieval cycle and ended, as reported, with the month before either (a) an embryo transfer resulted in a live birth, or (b) the last stored embryo from that retrieval was transferred. There were no natural conceptions that we know of, but, even if there were, such pregnancies would not and could not have been attributed to IVF treatment. Thus, the published figures are reliable. I reported the implantation rate per embryo for women under the age of 35 as 24.7%. Subtracting the reported 10.5% miscarriage risk yields a live-birth rate of 24.7% minus (24.7% × 0.105), or about 22% per embryo transferred, which is indistinguishable from the expected 20% natural monthly fertility rates among normal couples of this age group.3 Similar calculations yield 11% live births per embryo for those 35–39 years, and 4% live births for those over 40 years. With present practices at Sydney IVF (Day 5 blastocyst transfers, generally single embryos), the chance of a baby per embryo transferred is 41% (< 35 years), 24% (35–39 years) and 12% (> 40 years). The embryo implantation and live birth data Tonti-Filippini reveals for live births per embryo in Victoria are therefore very low compared with the IVF results I report.

Robert P S Jansen

Corrine R Balit,* Geoffrey K Isbister,† Andrew H Dawson,‡ Frank F Daly,§ Ian M Whyte‡ * Research Pharmacist, NSW Poisons Information Centre, The Children's Hospital, Locked Bag 4001, Westmead, NSW 2145; † Lecturer and Clinical Toxicologist, ‡ Associate Professor, Newcastle Mater Misericordiae Hospital and the University of Newcastle, Newcastle, NSW; § Clinical Toxicologist, Royal Perth Hospital and University of Western Australia, Perth, WA. corrinebalitATaol.com To the Editor: Paracetamol availability is an important public health issue. Kisely et al have further investigated the impact of two paracetamol recall periods on analgesic poisoning using a dataset derived from hospital admissions.1 We are concerned about the robustness of data that uses ICD codes, because of significant coding problems that occur with poisoning admissions. The aim of their study was as a follow-up to our own,2 to look at the impact of removing paracetamol tablets from the shelf during a recall period. Availability is reported to be the most common reason for patients choosing to take paracetamol in overdose3 and, as such, has the potential to affect acute deliberate self-poisoning. However, Kisely et al recognised that it was difficult for them to distinguish between intentional and unintentional ingestions because of the limitations of their dataset1 and hence they considered both of these together. This is inappropriate if the aim is to assess the effect of availability on paracetamol deliberate self-poisoning. For example, there is no evidence that presentations with therapeutic errors in dosing are related to availability and these should be excluded. This is not possible by using ICD codes and was therefore not done by Kisely et al.1 In addition, it is only relevant to include accidental ingestions of tablet formulations of paracetamol, because only these were affected by the recall. There are significant numbers of presentations of children, who accidentally ingest liquid formulations of paracetamol (hence not related to the recall period), that are coded as paracetamol admissions. This introduces a further significant potential bias in the Kisely study. A more concerning problem is the reliability of ICD coding in separating out different analgesics. Poisoning with prescription products such as paracetamol-codeine combination analgesics, which were not affected by the recall period, are also likely to be included in the study being coded as T39.1 (paracetamol overdoses).1 There are significant limitations in using ICD codes, resulting in the dataset analysed not being a true reflection of the impact of the recall of paracetamol tablets. Our study took into account only tablet formulations of the paracetamol alone compounds.2 Paracetamol ingestions following therapeutic error were excluded and accidental ingestions of only tablet formulations were included. While the numbers in the study were small for the hospital presentations, the data set for the NSW Poisons Information Centre was much larger and showed significant increases in intentional and accidental ingestions of ibuprofen, the next most available analgesic.2 In an environment where paracetamol restriction is a hotly debated topic, particularly in light of recent coroners’ cases, it is vital to consider the impact of paracetamol restriction on all types of deliberate self-poisoning by using an appropriate dataset that reflects the measures taken to reduce availability. The challenge for state and federal health departments is to fund appropriate postmarketing toxicovigilance for accidental and intentional self-poisoning in order to clarify these important public health issues.

Corrine R Balit · Geoffrey K Isbister · Andrew H Dawson · Frank F Daly · Ian M Whyte

Elizabeth A Hender,* Jeremy Raftos† * Scientific Officer, Hazardous Substances Section, Department of Human Services, PO Box 6, Rundle Mall, Adelaide, SA 5000; † Director, Paediatric Emergency Department, Women’s and Children’s Hospital, Adelaide, SA. Elizabeth. HenderATdhs.sa.gov.au To the Editor: We read with interest the study of Kisely et al,1 which showed a decrease in admissions for poisoning with paracetamol, but no coincident increase in use of other agents, as a result of the paracetamol recalls. We had noticed there was an unusually high number of presentations (18) to the Paediatric Emergency Department at the Women’s and Children’s Hospital, Adelaide (WCH), for poisoning with aspirin in 2000, compared with one presentation in 2001 and one in 2002. We wondered if the presentations in 2000 were temporally associated with the paracetamol recalls. We extracted all WCH presentations with a primary diagnosis of paracetamol poisoning (ICD-9 code 965.4), aspirin poisoning (965.1), nonsteroidal anti-inflammatory drugs (965.6) and poisoning with all other drugs (960–979.9) for the two recall periods (16 March 2000 to 21 May 2000; 6 June 2000 to 23 August 2000)2 and the same periods in 2001 and 2002. It could not be determined whether an over-the-counter preparation of a nonsteroidal anti-inflammatory drug had been taken. The results are shown in the Box. Presentations (P) and admissions (A) for poisoning with paracetamol, aspirin, NSAIDs and other drugs at the Women’s and Children’s Hospital, Adelaide 2000 restricted 2001 available 2002 available P A P A P A Aspirin 15 13 1 0 0 0 Paracetamol 23 6 34 13 34 14 NSAID 3 1 0 0 1 0 Other drugs 86 43 89 35 60 23 NSAID = non-steroidal anti-inflammatory drug. These data show that the number of paracetamol poisoning presentations and admissions was lower during the recalls than in the same period in subsequent years, but there was a higher number of presentations and admissions for poisoning with aspirin. All the aspirin poisoning presentations and admissions during the period when paracetamol was recalled were during the second recall (affecting SmithKline Beecham products). The other three aspirin poisoning presentations in 2000 occurred within 10 days of the end of the second recall. All but one of the 18 patients with aspirin poisoning who presented during 2000 were adolescents (17 females). Most of these exposures were likely to be due to intentional self-poisoning. Although it is not possible to reach any definite conclusion from these observations, we share the concerns of Balit et al2 that limiting the availability of paracetamol could result in an increase in poisonings with potentially more acutely dangerous agents such as aspirin, particularly for adolescents. There needs to be further consideration of the motivation of patients in choosing paracetamol and the source of the drug when taken for intentional self-poisoning before measures are taken to restrict access to paracetamol.

Elizabeth A Hender · Jeremy Raftos

Stephen R Kisely,* David Lawrence,† Neil J Preston‡ * Professor of Health Outcomes, Department of Psychiatry, Dalhousie University, Canada; † Post-doctoral Fellow, Institute for Child Health Research, Perth, WA; ‡ Research Psychologist, Fremantle Hospital and Health Service, Fremantle, WA. stephen.kiselyATcdha.nshealth.ca In reply: Balit et al raise the problem of distinguishing between intentional and unintentional ingestions. As stated in our article, we did look at deliberate and accidental poisonings separately, but space restrictions, not limitations of our dataset, prevented us from presenting the results.1 Of 2266 paracetamol poisonings, 1731 (76%) were coded as deliberate, 433 (19%) were accidental and in 103 (4.5%) the intention could not be determined. Restricting the analysis to the deliberate cases yields almost identical results. Our dataset may have contained poisonings with liquid or combination formulations of paracetamol that were not recalled. This factor would have operated before, during and after the recall and would only serve to reduce the magnitude of any effect, rather than accentuating it. We considered 2663 admissions for over-the-counter analgesic poisoning,1 as opposed to 143 in the NSW study.2 We did not look at telephone calls, as reliance on data from calls to a poisons information centre raises far more concerns about data quality than hospital statistics do. How reliable was the informant? How serious was the poisoning? Do telephone data contain less serious cases that do not require admission? Hender et al report the findings of an observational study restricted to a single paediatric emergency department attached to the Women’s and Children’s Hospital, Adelaide. Unfortunately, data for only three years are presented, with no information for the years before the recall. Neither do we know how many were intentional or unintentional. By definition, their data exclude adults. As they state themselves, it is not possible to reach any definite conclusions from their observations. We should not prematurely dismiss the possible benefits of restrictions on the availability of paracetamol. If there are concerns that restricting the availability of paracetamol might increase the use of other over-the-counter analgesics in poisonings, we should be investigating the effectiveness of restrictions on the availability of these as well. Who precisely benefits from continued sales of over-the-counter analgesics in catering pack sizes?

Stephen R Kisely · David Lawrence · Neil J Preston

Barbara M Miflin,* Kevin L Forbes† * Lecturer in Teaching and Learning Development, † Deputy Head, Years 3 and 4 MB BS Program, School of Medicine, University of Queensland, Herston Road, Herston, QLD 4006. barbara.miflinATuq.edu.au To the Editor: All established disciplines that have contributed to medical curricula in the past should play, as Weedon1 argued recently for pathology, a pivotal role in contemporary medical curricula. Indeed, students should be able to acquire better knowledge of a discipline through a problem-based learning (PBL) approach than through traditional teaching methods. The crux of the PBL approach is that knowledge, skills and the other professional attributes are learnt in a way that puts them into context and thus makes them meaningful and better remembered by medical students. The trouble is, as Weedon pointed out, the number of academics in the discipline of pathology is dwindling. The scarcity of academic pathologists, combined with the increased workloads of private pathologists, means that their input into designing and developing curricula and into pathology teaching may be increasingly inadequate. Pathology is not the only discipline to be underserved in today’s medical schools. In response to concerns about the medical curriculum, the Royal College of Pathologists of Australasia and other Colleges and interest groups have developed core syllabuses for use in medical programs. These developments are most welcome in view of the diminishing resources available for teaching in universities. In a PBL-oriented curriculum, teaching staff work in a multidisciplinary team in which the aspirations and limitations of each group are acknowledged, respected and acted upon in the context of realistic expectations of what is possible and what is necessary for medical graduates in the 21st century. Currently, in Queensland, a series of pathology modules for students to use during their clinical rotations would be well received. The use and interpretation of pathology tests are already built into PBL case studies, and could be extended into a module set as prerequisite learning for an attachment to a public or private pathology laboratory. Pathologists may also be able to use the syllabus to guide their teaching in mentorships for the elective components of medical programs. The needs of disciplines such as pathology will be best achieved through genuine understanding of the aims of medical schools to ensure appropriate, realistically achievable learning for students. When students are motivated to acquire knowledge of a discipline because they can see its relevance to solving patients’ problems, their enthusiasm for the discipline will be enhanced and they will learn well.

Barbara M Miflin · Kevin L Forbes

Donald D Beard Surgeon, 134 Beulah Road, Norwood, SA 5067. To the Editor: The issues raised in the editorial by Weedon1 are a sad reflection on current medical education. Weedon voiced the serious concern of the Royal College of Pathologists of Australasia regarding the downgrading and marginalising of the teaching of pathology because of the ascendancy of problem-based learning, to the detriment of the basic sciences pathology, physiology and anatomy. Weedon reminded us of Virchow’s pronouncement that applying the doctrines of pathology “helps to deepen biological knowledge, and to light up still further that region of the unknown which still envelops the intimate structure of living matter”. That statement also applies to anatomy and physiology. It could not have been said better. Some years ago, while I was on the Curriculum Committee of the University of Adelaide, the Committee agreed to recommend that the basic sciences continue to be taught throughout the medical course. Unfortunately, the recommendation was not accepted, and now the position is even worse. I find it very difficult to understand the priorities of the current medical curricula and who is making the recommendations. I feel the excitement of the study of medicine is disappearing, and hope it is not too late to reverse the current trend.

Donald D Beard

H Reginald Magee Vascular Surgeon (retired), “Alexandra”, 201 Wickham Terrace, Brisbane, QLD 4000. reginaldmATbigpond.com To the Editor: I was most interested in Weedon’s editorial on the teaching of pathology in the present medical curriculum.1 I have lamented the demise of anatomy teaching in undergraduate courses and regret that pathology is going the same way. In my view, anatomy, physiology and pathology are fundamental to understanding the disease process. They enable physical symptoms and signs to be interpreted in a logical manner so that a provisional diagnosis can be made. Once this has been done, it is reasonable to progress to ancillary aids to confirm or refute the original diagnosis. When doing operative surgery I used to ask my assistants questions, usually on anatomical features that were being exposed. Many, including some who possessed the primary surgical fellowship, could not identify simple structures such as the sartorius muscle when the popliteal artery was being exposed. Questions on structures in the neck were even less well answered. The present medical curriculum is directed towards problem-solving methods and the patient’s condition in relation to the environment and other conditions. But how much thought goes into the mechanism of disease and understanding physical findings? I consider medicine and surgery to be applied pathology, and therefore knowledge of the basic facts is essential. Future doctors may be proficient in the general and social aspects of medicine, but it would seem that their knowledge of the basic facts of anatomy, physiology and pathology and their understanding of the mechanism of disease may be no better than that of a “medicine man”.

H Reginald Magee

Geoffrey Henry Moore was born on 26 August 1913 at Waverley, in Sydney. He grew up in humble circumstances in Riverstone, near Windsor, and attended Parramatta High School. He went on to become a highly regarded surgeon, well known and well respected for his clinical judgement. After graduating in medicine from the University of Sydney in 1935, Geoff did his residency at Royal Prince Alfred Hospital and Prince Henry Hospital. It was here that he met Gladys Duncan, whom he later married. He obtained a Fellowship of the Royal College of Surgeons (Edinburgh) in 1939, then spent two years at Harrow Road County Hospital in London during the Blitz. Geoff was destined to make a number of “lucky escapes” in life. When he decided to return to Australia, his development of chickenpox — thought at the time to be smallpox — prevented his embarkation on a ship that was subsequently sunk in the Atlantic. When, in 1941, he finally arrived in Australia on another ship, he attempted to enlist for service in Singapore, but was “manpowered” to Townsville instead. His replacement was interned in Changi prison for the duration of World War II. Geoff was directed to Townsville General Hospital (the largest state hospital outside Brisbane) as superintendent. He was faced with the enormous task of reorganising and re-establishing medical services, which were in disarray and decline. Apart from the decrepit facilities, discipline had broken down in a background of US occupation, imminent Japanese invasion and plans for evacuation of personnel west to Charters Towers. Geoff took on a horrendous workload, managing hospital inpatient and outpatient services, reorganising and re-establishing hospital administration, and improving medical and nursing training standards. He remained at Townsville General Hospital until 1949, when he resigned to enter private surgical practice. However, he continued as a visiting gynaecologist and representative of the Queensland Radium Institute to the hospital until forced retirement in 1976. Thereafter, he continued as honorary consultant gynaecologist until 1986 and as surgical assistant to younger surgeons until 1994. He obtained Fellowships of the Royal Australasian College of Surgeons (1969) and the Royal Australian College of Obstetricians and Gynaecologists (1979), and was awarded a Medal of the Order of Australia in 1986 for services to medicine. In his younger years Geoff was a keen tennis player and horseman. A quiet man, he was an avid reader with a large library of books, particularly history books. He enjoyed gardening, and had a special interest in native plants of North Queensland. He died on 14 December 2002 from a secondary malignancy. He is survived by his wife Gladys, two sons (both doctors) and a daughter (ex-nurse). Graeme G D Moore

Graeme G D Moore

A 44-year-old woman was brought to hospital by police. Over a period of years she had isolated herself and her daughter from society, arousing the concern of neighbours. A scant history of “schizophrenia”, personality disorder and intellectual disability was obtained from distant relatives. Examination revealed classic clinical features of profound hypothyroidism. In addition, a lump was found on the patient’s ring finger (Box 1, A). Her mental state necessitated admission, after a psychiatric consultation, as an involuntary patient. Investigations confirmed the diagnosis of hypothyroidism and indicated anaemia due to iron deficiency (Box 2). An x-ray of the lump (Box 1, B) revealed a wedding ring totally encased in the soft tissue. The patient was started on thyroxine and antipsychotic medication and transferred to a psychiatric institution, with marginal improvement in her mental state. Her daughter was removed to the care of child welfare authorities. The wedding ring was surgically removed. Histopathological examination of the lump revealed a foreign body granuloma with chronic low-grade Staphylococcus aureus infection. Photographs and x-ray of lump on patient’s ring finger 2: Results of biochemical and haematological tests Test Result Reference range TSH (thyrotropin) 404 mIU/L 0.1–4.0 mIU/L T4 (thyroxine) 3 pmol/L 9–26 pmol/L Antithyroglobulin antibody >2000 IU/mL < 100 IU/mL Antithyroid peroxidase antibody >3000 IU/mL <100 IU/mL Total cholesterol 9.0 mmol/L 2.0–5.5 mmol/L Triglycerides 2.4 mmol/L < 1.7 mmol/L Haemoglobin 67 g/L 115–155 g/L White cell count 4.1 x 109/L 4.0–11.0 x 109/L MCV 72 fL 80–96 fL MCHC 315 g/L 300–350 g/L Platelets 329 x 109/L 150–400 x 109/L Vitamin B12 619 pmol/L 150–600 pmol/L Serum folate 17 nmol/L 7–39 nmol/L Red cell folate 965 nmol/L 390–1600 nmol/L Iron 8 μmol/L 7–35 μmol/L Transferrin 3.5 g/L 1.9–3.2 g/L Transferrin saturation 9% 20%–60% Ferritin 7 μg/L 20–120 μg/L MCV = mean cell volume. MCHC = mean cell haemoglobin concentration. TSH = thyroid-stimulating hormone.

Andrei Catanchin MB BS · Peter R Ebeling MD

Med J Aust 2003; 179(4): 217 Driving change As Australians eagerly await the release of our new Medical Standards for Drivers later this year, the experience of the US State of Arizona may be of interest. In 1994, Arizona reduced the seizure-free interval for driving in people with epilepsy from 12 to 3 months. Motor vehicle accident (MVA) data for 3 years before and 3 years after 1994 revealed no statistically significant change in the incidence of seizure-related MVAs in the second period. While seizures accounted for about a third of all medically related MVAs, they caused only 0.04% of the total. Mayo Clin Proc 2003; 78: 819-825 An unsuitable girl The WHO has reported that sex disparities in health and education are higher in South Asia, including India, than anywhere else in the world. Even banning sex-determination tests (since 1994) has failed to improve the lot of India's female infants. Researchers in Delhi hypothesised that death rates from easily treatable diseases, such as diarrhoea, would be higher in girl babies (indicating neglect) whereas the rates of less preventable or less treatable conditions, such as birth asphyxia, septicaemia and congenital anomalies, would be the same in both sexes. They were right. They also found that 75% of unexplained (suspicious) infant deaths were in girls. Confirming the gloomy outlook for girls was a birth ratio of only 869 females:1000 males, and a 1.3 times higher mean infant mortality rate. BMJ 2003; 327: 126-128 Menopause mayhem The bottom seems to have fallen out of the menopause treatment market. Hormone therapy remains under a cloud, and now an American study of an Australian company's popular phytoestrogen preparations shows only a modest placebo effect. Promensil (a dietary supplement of isoflavones extracted from red clover) did reduce the average number of hot flushes per day from about eight to about five, but so did the placebo. Promensil reduced the frequency of the hot flushes faster than both the placebo and another product containing different proportions and a lower dose of isoflavones, so there still may be a biological effect. But where to now? JAMA 2003; 290: 207-214 Turning down the heat The MJA has published several case reports of deaths from hyperthermia among users of ecstasy (MDMA) and related drugs. Animal research conducted by an Australian group suggests a role for the atypical antipsychotic drugs in reversing MDMA-induced hyperthermia (which is partly caused by sympathetically induced cutaneous vasoconstriction). In a controlled trial, rabbits and rats given clozapine or olanzapine, as well as MDMA, developed less cutaneous vasoconstriction than those given MDMA alone, and did not become hyperthermic. The exact mechanism of this effect is uncertain, as is the efficacy of clozapine and olanzapine in humans with MDMA toxicity J Neurosci 2003; 23: 6385-6391 Joint statement While recent research has highlighted the psychological effects of recreational cannabis use, a position paper from The Thoracic Society of Australia and New Zealand reminds us that respiratory health should not be overlooked in the cannabis debate. The evidence is not as strong as that for tobacco smoking — as there are fewer cannabis smokers, there have been fewer studies of sufficient duration and the effects of cannabis and tobacco are often confounded (up to 69% of users also smoke tobacco). However, both substances contain a similar range of harmful chemicals, they have similar histopathological effects on respiratory tissue, and most studies indicate that their respiratory effects are additive and independent. The authors concluded that the adverse respiratory effects of smoking cannabis are similar to those of smoking tobacco. Contrary to common belief, the effects are not mitigated by using a water pipe (bong). Intern Med J 2003; 33: 310-313 Life in the too hard basket To those GPs who have done the hard yards with patients whose illnesses defy diagnosis, the results of a Scottish study of people with unexplained neurological symptoms will not be surprising. Having found that about a third of new patients seen at a neurology clinic fell into this category, researchers followed them up 8 months later. Over half of the 66 patients felt the same or worse than before, and no patient had received an organic diagnosis for their symptoms. Not surprisingly, the patients who considered themselves improved showed improvements in various domains including physical function, degree of pain, social function and mental state. The others continued to suffer, prompting the researchers to call for further research into the management of this neglected group of patients. J Neurol Neurosurg Psychiatry 2003; 74: 897-900