Letters

In reply: Marley makes an important point about the conclusions that can be drawn from our study on the effectiveness of medical school admissions tests. As acknowledged in our article, the size of the study and the restriction of range to which he refers do limit the strength of the findings. Nevertheless, it is precisely because admissions tests elicit such an emotional response from the general community, as well as being costly and stressful for both aspiring students and medical schools, that there is an urgent need for a large-scale multi-institutional evaluation of the process — a need that our results highlight. It is reassuring that the Australian Council for Educational Research, the developers of the Graduate Australian Medical School Admissions Test (GAMSAT), is currently conducting one such study in conjunction with several Australian graduate-entry medical schools. We hope that our study serves to stimulate still more discussion and analysis of medical student selection processes.

Michele A Groves

To the Editor: We welcome your recent focus on rural and remote health. Kamien and Cameron’s editorial addressed medical workforce supply issues,1 and the accompanying article ranged across not only workforce supply issues, but also broader systemic issues, including the roles of different levels of government.2 Coincidentally, the Australian Institute of Health and Welfare released its latest medical workforce report, which reported a rise in the number of doctors per head of population overall, particularly specialists, and particularly in urban areas, but decreased numbers of doctors in the bush, particularly in remote areas.3 Most of the media response ignored the contemporaneous nursing workforce report,4 which described a much more even geographical distribution of the nursing workforce — the largest health professional group. We agree that access to health care is more than a workforce supply issue.2 While we acknowledge the critical importance of general practice, perhaps part of the problem in improving access has been an almost exclusive policy focus on medical workforce supply issues, and not the broader consideration of a range of factors that will improve access to effective primary health care services for the 30% of Australians living in rural and remote areas. Our recent systematic review of models of rural and remote primary health care service delivery in Australia identified a number of essential requirements of successful primary health care models.5 These inter-related requirements are adequate workforce supply; appropriate workforce organisation; adequate funding and appropriate financing; leadership, good management and governance; adequate infrastructure; and strong linkages — both internal and external. Successful models also exhibited an appropriate level of community participation. There are a number of demonstrably successful rural and remote models, such as the Katherine West Health Board, an exemplary remote comprehensive primary health care service.5 To generalise these successful models and improve access, we need a rural and remote primary health care policy framework for Australia that coordinates national, state and territory resources to ensure that all of these essential requirements are systematically addressed. We agree with Kamien and Cameron1 that a solution will not be forthcoming until governments take a courageous stance in overcoming the implementation gap associated with translating research evidence into policies and programs. The time has never been riper for Commonwealth, state and territory governments to assume leadership and agree on an evidence-informed implementation strategy to assure rural and remote communities of accessible, high quality health care. Our systematic review5 provides a solid base to underpin such a response.

John Wakerman · John S Humphreys · Robert W Wells · Pim Kuipers · Philip Entwistle · Judith Jones

To the Editor: The report by See and colleagues on an accidental death from acute selenium poisoning1 draws attention to a misconception among some health-conscious consumers that, because selenium is obtainable without a prescription, it is safe to take in high doses. Selenium is available over the counter in tablets containing as much as 200 μg. The only advice printed on packs is not to exceed the recommended daily intake, which is not specified (the current Australian values are 70 μg and 60 μg per day for men and women, respectively). There is no mention of the upper limit of 400 μg, beyond which there is risk of toxicity. Selenium supplements are consumed by many people worldwide. Up to 9% of adults in the United States use these supplements.2 Consumption is much the same elsewhere in the Western world. They are used by many in the belief that their dietary intake of selenium is inadequate, and that the supplement will protect them against a variety of illnesses. Consumers get information from several sources, not least the general media and the Internet. These sources can seriously mislead, especially when they misinterpret the results of clinical trials and make exaggerated claims of health benefits. Those who rely on such popular, but simplistic, information can reach false and sometimes dangerous conclusions. Health advisors who become aware that patients are self-medicating with selenium need to point out the dangers. Unfortunately, after years of teaching students of medicine and other health-related fields about trace elements, I know that many graduates do not have enough knowledge in this area to provide accurate guidance. Even if they want to learn more by consulting current literature, the sheer volume of articles can deter them. It is for this reason that I wrote the book Selenium in food and health3 — to provide an up-to-date, scientifically based review of the nature and role of selenium in human health and metabolism. I hope that the book’s readable and user-friendly style will make it easy for overburdened professionals to learn enough about this element to help prevent the sort of tragedy described by See and colleagues.

Conor S Reilly

To the Editor: It is of great concern to me that the recent case report Accidental death from acute selenium poisoning by See and colleagues1 inappropriately cast doubts on the safety of complementary and alternative medicines (CAM). This incident should be placed in its correct context. The guidelines are clear for listed complementary medicines (ie, compounds or formulas registered and approved by the Australian Register of Therapeutic Goods for distribution in Australia).2 As a trace element, selenium is required in microgram amounts. The Therapeutic Goods Administration stringently regulates its use in nutritional supplements in Australia, with an allowed limit of 26 μg per daily dose (as selenomethionine) in unrestricted products, and 50 μg per daily dose (as selenite) in restricted, pharmacy-only supplements. This is considerably less than the “no observed adverse effects level” for selenium, which is as high as 400 μg per day,3 as noted by See and colleagues. Furthermore, even at these low doses, CAM products that contain selenium must carry substantial “red flag” label warnings. Bulk sodium selenite powder — the form which led to this fatality — is definitely not dispensed as a complementary medicine. Nevertheless, the authors of the case report conclude that “adverse outcomes of complementary and alternative medicines should be better publicised and more stringently reported to the Adverse Drug Reactions Advisory Committee (ADRAC)”. While this may be a commendable recommendation, it is inappropriate and incongruous with the findings presented in this case report. Furthermore, the sodium selenite used by nutritional doctors is administered as a liquid at a dose of 50 μg per drop, and is a restricted S4 prescription-only product. To achieve a dose of 10 g of sodium selenite, as taken by the reported patient, would require ingestion of 115 bottles of the registered S4 supplement or, even less plausibly, 400 000 doses of a listed CAM supplement. Neither of these preparations was implicated in the reported case. So why then are the authors of this case report asking for increased vigilance for complementary medicines? It is surely the interchange between the pharmacist and the customer that lies at the heart of this matter. Had a listed selenium product been dispensed, this poisoning would not have occurred.

Ian Brighthope

To the Editor: I wish to address a statement made in a recent case report in the Journal entitled Accidental death from acute selenium poisoning.1 The authors claim that the death of a 75-year-old man after ingesting 10 g of sodium selenite “exposes the myth that natural therapies are inherently safe”. The patient actually purchased sodium selenite powder and tablets. This is a restricted substance and an industrial chemical which would certainly have been labelled a poison. It should be noted that the maximum recommended daily dose of selenium in complementary medicines in Australia is 52 μg.2 The authors of the case report do point out that the patient took more than 10 000 times the recommended dose of selenium which would be available from a medicine. (My calculations put this closer to 20 000 times.) An individual drinking more than 10 000 times even the daily recommended amount of water would probably not end up in much better shape. Is this evidence of an underlying agenda to discredit natural products? The Complementary Healthcare Council of Australia recommends that consumers take steps to thoroughly inform themselves about products, preferably by asking their health care practitioner. We also urge them to inform their health care practitioner of which medicines, complementary or otherwise, they are taking. The incident involving the sodium selenite is regrettable, but for the authors to link the product and this case of fatal ingestion to exposing the myth that natural therapies are safe is, at best, ridiculous, with no foundation. They also state that adverse reactions to complementary and alternative medicines should be better publicised and more stringently reported to the Adverse Drug Reactions Advisory Committee. Adverse reactions are routinely reported and publicised for all medicines, and have been for some time, as any check of the website of the Therapeutic Goods Administration will show.3,4 I agree with the authors that the case highlights the dangers of consumers’ reliance on the Internet. Local Internet sites that advertise therapeutic goods must conform to the requirements of the Therapeutic Goods Advertising Code, as well as the Therapeutic Goods Act 1989 (Cwlth) and Regulations. However, overseas sites are not necessarily regulated or policed, and may provide inappropriate and misleading information. While our industry’s products are low risk, they should be taken, like other medicines, with due care.

Tony Lewis

In reply: The myth we referred to is the commonly held misperception by a significant percentage of the population that natural therapies are inherently safe. As Lewis and Brighthope very correctly point out, the dose ingested by our patient was hugely in excess of any recommended maximum. We believe this is evidence of the misperception, as most patients would not dream of taking 10 or 20 thousand times the maximum dose of “non-natural” remedies, because they recognise that all such remedies have side effects. Our patient’s confidence that he could safely take such a huge dose was, we consider, at least partly a consequence of his belief in the myth that natural therapies are safe. The fact that the dosage of selenium in nutritional supplements is strictly regulated does not prevent problems such as this — where patients obtain information of variable quality on the Internet, make their own arrangements to obtain the product, and then ingest a toxic amount. Our article was in no way part of “an underlying agenda to discredit natural products”; it merely highlighted the risks inherent in self-medication based on information of variable quality obtained from the Internet, coupled with the impression that natural therapies are inherently safe. We hope that our call for adverse outcomes of complementary and alternative medicines to be better publicised will go some way to preventing such a tragic error occurring again.

Peter S Lavercombe

To the Editor: We read with great interest the article by Bambrick et al relating to the potential impact of the Australia–United States Free Trade Agreement (AUSFTA) on supply of blood products in Australia.1 Our recent experience with Octagam (Octapharma Australia, Sydney, NSW), an intravenous immunoglobulin (IVIg) product produced overseas, highlights some of the quality concerns raised in their article. Routine practice in our bone marrow transplant unit is to administer IVIg weekly for 100 days after allogeneic stem cell transplantation. Until December 2004, locally produced IVIg, Intragam-P (CSL, Melbourne, Vic), was used exclusively as the IVIg product for these patients. From October 2005, because of limitations in the supply of Intragam-P, the Australian Red Cross Blood Service (ARCBS) also provided Octagam for IVIg replacement therapy in transplant recipients. It has also been routine practice within our transplant unit to repeat serological tests for a variety of transfusion-transmitted viral infections, including human T-lymphotropic virus type I and type II (HTLV-I and HTLV-II), in all transplant patients 100 days after transplantation. Until 2006, none of our patients had ever tested positive for HTLV-I or HTLV-II antibodies. After the introduction of Octagam, the first two transplant patients who received this product for IVIg replacement tested positive for HTLV-I/HTLV-II antibodies at 100 days after transplant (signal to cut-off [S/CO] ratios, 4.36 and 6.33, respectively). Subsequent investigation revealed that these results were probably secondary to passive transfer of HTLV antibodies from the IVIg product used. Both patients received Octagam from the same batch, and subsequent testing of this batch was positive for the presence of HTLV-I/HTLV-II antibodies. Of note, both patients tested negative for HTLV-I/HTLV-II antibodies before transplantation (S/CO ratio < 1.00). Their stem cell donors were also negative for HTLV on testing immediately before stem cell donation, and the only other blood product shared between the two patients (platelets from a common donor) also tested negative for HTLV. Follow-up testing for HTLV-I/HTLV-II antibodies at about 12 months after transplantation gave a negative result in both patients (S/CO ratio < 1.00). Given that Octagam is a plasma (acellular) product processed with appropriate viral inactivation steps,2 we believed it to be extremely unlikely that direct transfer of HTLV virus had occurred. The most likely explanation was the passive transfer of HTLV antibodies. It followed that Octagam must have been sourced from HTLV-positive plasma donors — a practice that is in direct conflict with current ARCBS policy, which specifies that all blood and plasma donors must be screened for HTLV-I and HTLV-II, and that any donors testing positive should be excluded from blood or plasma donation.3 The HTLV-I/HTLV-II serostatus of donors used to source plasma for Octagam are not reported on the product information sheet.2 Testing of one patient sample at the National Serology Reference Laboratory (Melbourne, Vic) suggested the positive serological results in our patients were due to the presence of HTLV-II antibodies. In collaboration with Octapharma, it was subsequently determined that plasma for Octagam was sourced from paid donors from the southern United States, an area where HTLV-I and HTLV-II seropositivity is known to be prevalent among blood donors.4 The clinical implications of our findings are unclear. Our results were reported rapidly to the ARCBS and subsequently to the Therapeutic Goods Administration. Our main concerns are that Octagam plasma is sourced from donors who would normally be excluded from plasma donation within Australia,3 and that there appears to be no current mechanism for addressing this issue. Some of the quality concerns raised by Bambrick et al appear to be not so theoretical after all.

Glen A Kennedy · Judy Cummings · Simon T Durrant

In reply: I would like to respond to the letter by Kennedy et al regarding the passive transfer of human T-lymphotropic virus (HTLV) antibodies following Octagam (intravenous immunoglobulin [IVIg]) administration. Octapharma does not routinely test Octagam for HTLV antibodies — this is in line with Australian regulatory requirements.1 Furthermore, in accordance with global regulatory requirements (including those defined by the Australian Therapeutic Goods Administration), plasma from sources in Europe and the United States is also not routinely tested for HTLV antibodies.2,3 It is important to note that the patients described by Kennedy et al tested positive for HTLV antibodies rather than the HTLV virus, and that the presence of antibodies in the finished product does not pose an infection risk. As noted by the authors, the manufacturing process for Octagam includes viral inactivation. There are two dedicated viral inactivation and removal steps: Solvent/detergent treatment, which is a highly effective step for inactivating lipid-enveloped viruses; Incubation at pH 4 and 37°C for 24 hours. The combination of these two processes ensures that lipid-enveloped and several non-lipid-enveloped viruses are inactivated. Since the initial launch of Octagam in Europe in 1993, more than 33 million grams of the product have been infused, corresponding to more than 2.5 million infusions. During this time, there have been no documented cases of viral transmission resulting from the use of Octagam. Since the launch of Octagam in Australia in 2005, Octapharma has supplied over 600 kg of IVIg, representing about 40 000 infusions to Australian patients. Therefore, taking into account the steps used to remove and/or inactivate lipid- and non-lipid-enveloped viruses, the fact that there have been no documented cases of transmission of any virus since the launch of Octagam, and that plasma sources and testing meet both Australian and global regulatory requirements, the positive HTLV antibody results reported by Kennedy et al have no bearing on either the quality or safety of Octagam.

Wolfgang Frenzel

To the Editor: Bambrick et al1 suggest that the importation of overseas plasma products or the processing of Australian plasma overseas may pose a threat to the safety and security of Australia’s supply of plasma products. The National Blood Authority (NBA) and the Therapeutic Goods Administration (TGA) would like to respond to these issues to ensure that clinicians have confidence in the safety of products currently available in Australia and a better understanding of current blood processing and supply arrangements. Australia is largely self-sufficient in plasma products, a position supported by all Australian governments.2 The governments also agree to the supply arrangements for imported plasma products when demand exceeds domestic supply (as in the case of intravenous immunoglobulin [IVIg]), and for products not supplied by Australian manufacturers (eg, fibrin sealant and other coagulation products). All these products are purchased by the NBA on behalf of Australian governments. Standards applied in Australia ensure that all products on the Australian market are derived from sources — in Europe, the United States and Australia — approved by the relevant authorities. The TGA regulates all plasma products to ensure that they meet international standards of safety, quality and efficacy, irrespective of their source.3 No centres sourcing blood from countries in the developing world, as cited by Bambrick et al, are used. National health systems around the world strive to attain degrees of self-sufficiency that suit their particular economic and policy objectives. However, as the US supplies 60%–70% of global plasma (while consuming only 40% of products sourced from this plasma4), many patients outside the US are dependent on the system of both compensated and uncompensated donors operating in the US. It is worth noting that definitions of “remuneration” vary across countries. The Commission of the European Communities reported in 2006 that “the principle of voluntary and unpaid donations does not exclude compensation for donors, if it is limited to making good the expenses and inconveniences related to the donation”.5 Examples of compensation that this article cites include tax relief of up to €70 per annum in the Czech Republic, an expense allowance of up to €25 for a whole blood donation in Germany, and up to €50 for an apheresis donation in Austria. Thus, the boundary between compensated and non-compensated donors is not distinct globally. Bambrick and colleagues’ contention that products manufactured from paid donors may be less safe is not supported by evidence. The history of blood safety clearly demonstrates that there were major safety issues with both fresh blood and blood products in the 1980s. These problems were more a result of pathogen epidemiology and governments’ blood safety policies than whether donors were paid or unpaid. For example, the Canadian and French blood systems relied entirely on volunteer donors, but the delayed implementation of safety measures and good governance measures led to pathogen risks that exceeded those of the US.6,7 In Australia, the incidence of HIV/AIDS in people with haemophilia exposed to only one type of product in the 1980s approached that of the same patient group in the US, despite the product being sourced entirely from domestic voluntary donors.8 Currently, robust plasma product safety measures in the US have proved to be effective in minimising contamination from both known and emerging pathogens, such as West Nile virus. This virus did not infect the recipients of plasma products from compensated donors, but did infect the recipients of (uncompensated) fresh blood transfusions.9 The equivalence in safety between plasma products sourced from compensated and uncompensated donors has been confirmed by the European Medicines Agency.10 Ensuring the security of supply is central to Australia’s plasma fractionation arrangements. The NBA’s contracts include provisions to ensure product supply security and product safety, including compliance with TGA requirements. Under Australia’s emergency response plans, plasma could be supplied from fresh stock, while the inventory of product in the system and the national reserve of products (funded by the NBA to cover contingencies) could provide fractionated products. A range of other supply security measures is implemented by the NBA on behalf of Australian governments, including secondary suppliers for critical products. These measures take into account the fact that Australian plasma used to manufacture fractionated products is not produced in sufficient quantities to permit storage of excess. Thus, Bambrick and colleagues’ concern that geographical factors may restrict access to Australian plasma has limited relevance in an emergency situation. In summary, Australia has a comprehensive system that draws on international best practice and national jurisdictional arrangements to ensure the supply of high-quality, safe, efficacious plasma products, irrespective of their source.

Alison Turner · Albert Farrugia

In reply: Turner and Farrugia highlight important issues about the safety and supply of Australia’s blood and plasma that constituted key findings of the recent Australian Government review of Australia’s plasma fractionation arrangements.1 These included the desirability of self-sufficiency and the need for a viable contingency plan in the event of local supply failing to meet demand, in the context of probable increased uncertainty in relevant security and supply circumstances. The authors note the importance of a rapid regulatory response to new risks, and rightly emphasise the important role of our National Blood Authority and the Therapeutic Goods Administration in relevant safety assurance processes. However, a crucial issue highlighted in the review that they fail to address is the difficulty of relying on the application and enforcement of regulatory standards if the bulk of Australia’s fractionation occurs offshore.1 After an exhaustive study of arrangements in Europe and the United States, the review concluded that overseas fractionation of Australian plasma would involve significant costs in moving away from the current local arrangements ($75 million) and, because of yield considerations, there would be the potential for an ongoing shortfall in the supply of intravenous immunoglobulin (IVIg) and other plasma-derived products. The review also found that overseas fractionation was potentially associated with major risks to the supply chain, with increased distance and handling providing more opportunities for loss and error, while a doubling or tripling of the turnaround period would have implications for continuity of supply. The review recommended that the federal government maintain the reservation exempting plasma fractionation services from the government procurement provisions of Chapter 15 of the Australia–United States Free Trade Agreement.1 The review confirmed that volunteering for blood donation should be institutionally reinforced as an important exemplar and means of sustaining Australia’s national culture, and that donor payment endorsed a very different set of values and was unlikely to assure sustainability of supply.2 It did, however, suggest initiatives such as tax relief or other institutional ways to encourage donation.1 We fully endorse the summary assessment of the review that: [T]he current structural arrangements, whereby domestically collected plasma is fractionated by CSL Bioplasma, are, subject to careful monitoring of prices, in Australia’s best interests. The present system is well entrenched in the “hearts and minds” of the Australian population and of the Australian medical community and, particularly, in the strategy, thinking and reliance of all end user groups.1

Hilary J Bambrick · Thomas A Faunce

To the Editor: Gleason et al describe the continued tendency of hospitals to allow prevocational, newly graduated doctors to flounder as they provide the cannon fodder to keep those hospitals running.1 For about 5 years, I coordinated an education program for junior medical staff. It is a model that other areas could consider. The Northern Sydney Area Health Service — as it was then — had two primary allocation centres for junior staff, and three local secondment hospitals. During their time in Sydney, all interns at those five hospitals were required to attend a 3-hour program of education provided for them, off site, each fortnight. In the first week, half of the interns attended; the program was repeated the following week to allow the other half to attend. A separate program was developed for Postgraduate Year 2 doctors that provided day-long programs centred on a particular topic (eg, renal disease or paediatrics). Each hospital put half of their Postgraduate Medical Council of New South Wales (now NSW Institute of Medical Education and Training) funding towards the cost. The teaching was provided by clinical staff within the area health service. The size of the area health service meant that there was an enormous pool of expertise to call on. The very size of that pool meant that we did not over-use the same keen teachers. The quality of the teaching was regularly rated as high by the doctors who attended. The off-site venue meant that time was truly quarantined. The provision of breakfast and morning tea meant an opportunity for junior medical staff to spend time with their cohort, compare experiences, complain, commiserate, and congratulate, in an informal atmosphere. Of course senior staff — administrative and medical — would complain. However, they gradually grew used to the format, and learned to time rounds, to make allowances and to value their happier, better educated staff. Of course there were problems of all sorts, and the system was not perfect, but it signalled to junior staff that they were valuable and valued. As Gleason et al noted: Hospitals must meet their training responsibilities and should not continue to place service demands above the training needs of doctors. Teaching time needs to be a regular, protected, paid part of every junior doctor’s day. In 2007, it is completely unacceptable to continue to see junior medical staff as “workforce”. It shames us all as senior clinicians that we have not ensured that all hospitals meet their educational and training responsibilities to these valuable members of our profession.

Lilon G Bandler

To the Editor: Medical education faces a number of significant challenges in the coming years. The most concerning problem is that there are insufficient medical educators. To compound this problem further, clinicians with an interest in teaching lack academic recognition, funding, time for medical education, and institutional support.1 While this is already creating problems for training of medical students and junior doctors, the situation will only become worse as the number of graduates increases to meet workforce shortages. A greater number of medical students and graduates will put further pressure on an already over-stretched health system to deliver adequate medical education. Therefore, we need to consider new ways of creating effective clinical teachers and learning materials that are educationally sound and supported by research. One way to address some of these deficits is to create specific training positions for doctors interested in pursuing a career in medical education, perhaps called “medical education registrars”. These positions could be jointly funded by hospital networks, universities and other interested groups, such as the postgraduate medical councils, and could be aimed at doctors with a strong interest in medical education, especially those at an early stage in their career, such as postgraduate year (PGY) 3 and PGY4. This joint funding would support hospitals and universities working collaboratively, and taking responsibility for making medical education “a priority, rather than an add-on”.2 The hospital appointment would maintain the registrars’ clinical knowledge, and the university appointment would allow opportunities for further study in medical education theory and research methods. Both environments would allow for academic mentoring. These registrars would then be ideally placed to assist in the development, implementation and evaluation of education materials using the newly released Australian Curriculum Framework for Junior Doctors as a guide. While agreeing that the Framework provides a “unique opportunity to improve the quality of medical training in Australia”, Gleason et al expressed concerns about how the Framework would be implemented.3 Medical education registrars could play a pivotal role in this process, and would be strong advocates for junior doctors. Medical education registrar positions are a simple, cost-effective way to encourage clinicians, especially those early in their careers, to pursue medical education as a serious and satisfying career path. Urgent action is required now to avert certain disaster in a few years, when hospitals are full of medical students and junior doctors, and there is no one to supervise and train them.

Andrew M Foote

In reply: A teaching registrar position is a great idea. It could foster development of knowledge and skills in interested clinicians, and perhaps higher degrees in learning and teaching, as well as serving as the start of a career pathway.1 The United Kingdom allows specialist trainees to take a year out to develop skills in education or research. Here, however, it is doomed to fail, unless there is a receptive environment for these registrars to work in or a career path that is attractive. What kind of educational environment is needed? We need leaders with vision, knowledge, new ideas and resources to lead the development of programs and assessment. We need teachers whose main focus is to teach and implement programs. And we need to support all clinicians to continue to supervise and teach. Not all these roles need to be performed by a medical practitioner.2 Without all of this, someone who is “interested in teaching” may be burdened with an unsustainable level of teaching and administration. Better integration at a local level across undergraduate and prevocational training3 (not to mention linking with other professional groups) and a culture of teaching are needed. Importantly, we need coherent and visionary leadership at national and state levels to underpin these endeavours.3,4

Fiona R Lake

To the Editor: Cryopreservation has been an integral tool in the development of modern assisted reproductive technologies, beginning with sperm cryopreservation in 1953 and extending to embryo cryopreservation in 1983, with the evolution of in-vitro fertilisation (IVF) and embryo transfer as a major tool in the treatment of infertility.1 Until recent times, however, there has been a lack of reliable cryopreservation methods for human oocytes. The world’s first recorded pregnancy arising from frozen oocytes occurred in Australia in 1984,2 and although occasional live births following oocyte cryopreservation were subsequently announced,3 it was another 11 years before more reliable protocols were developed4 — hundreds of live births have since been reported.5 The most common protocol follows that of embryo cryopreservation, using slow freezing with propanediol as the cryoprotectant, although rapid vitrification methods are also being developed. Reliable oocyte cryopreservation protocols are important for patients for whom embryo cryopreservation is unacceptable under some national laws or religions, and in whom there may be sperm collection problems or unexplained azoospermia during IVF procedures. We report four live births, one ongoing pregnancy, and an ectopic pregnancy following oocyte cryopreservation. Three of these cases involved religious opposition to embryo freezing. In each case, only two oocytes were fertilised fresh and the remainder frozen. No pregnancies resulted from the fresh embryo transfers, and the frozen oocytes were subsequently thawed, fertilised, and transferred, to produce the pregnancies. Two cases involved idiopathic azoospermia on the day of IVF, while in another, no sperm could be obtained from testicular aspiration on the day. Oocytes from these men’s partners were frozen until the sperm supply problems were resolved. As these cases demonstrate, oocyte cryopreservation can serve as a valuable adjunct to assisted reproduction programs, by providing a solution to the occasional logistical problems caused by unavailable spermatozoa. It also provides another option for patients with ethical or religious objections to the cryopreservation of embryos, and for fertility preservation in women with cancer facing chemotherapy or for women who may wish to insure against age-related fertility decline. The six pregnancies described here arose from embryo transfers in 13 women who had oocytes cryopreserved. The results, combined with others achieved worldwide, suggest that oocyte cryopreservation may at last be coming of age.

Keith L Harrison · Michelle T Lane · Jeremy C Osborn · Christine A Kirby · Regan Jeffrey · John H Esler · David Molloy

To the Editor: We write in response to recently published consensus recommendations for the off-label use of pharmaceuticals, which provide a common-sense, evidence-based approach to a commonly encountered clinical problem.1 The recommendations indicate that, other than for exceptional or research indications, off-label use of a medicine is generally not recommended unless there is high-quality evidence supporting such use. However, for some older pharmaceuticals, there is little incentive to perform additional trials to generate good evidence to support off-label use. An example is rifampicin, which is commonly used in combination with fusidic acid to treat methicillin-resistant Staphylococcus aureus (MRSA) infection, but is not licensed or subsidised by the Pharmaceutical Benefits Scheme (PBS) for this indication. Rifampicin has a well defined toxicity profile, with a long history of use in treating tuberculosis and preventing meningococcal disease. Rifampicin-based combinations for staphylococcal infection are recommended by Australian and international guidelines,2,3 and supported by small clinical trials.4 For rifampicin, a generic drug, there is no financial incentive for the manufacturers to apply for an additional indication for treating MRSA infection. Since 1998, an orphan drugs policy has encouraged sponsors of patented pharmaceuticals to apply for indications that may only involve small numbers of patients and has waived Therapeutic Goods Administration (TGA) fees for such marketing applications. A “rule of rescue” has also operated, lowering the regulatory bar for serious diseases that are otherwise untreatable. Despite these initiatives, no application to add the treatment of MRSA infection as an indication for rifampicin (in combination with another active agent) has been received by the TGA.5 A solution would be for the National Health and Medical Research Council (NHMRC) to commission clinical trials where further evidence is required. This proposal could see an expanded role for the National Institute of Clinical Studies (NICS), which will soon be incorporated into the NHMRC. The NICS/NHMRC could also make applications to the TGA for the approval of pharmaceuticals for particular indications, particularly for orphan diseases and generic drugs. Reviews of evidence could be generated from within the NHMRC or from external bodies such as professional Colleges and societies, or groups of experts such as those appointed by the Board of Therapeutic Guidelines Limited. Clinical trials could be performed in conjunction with overseas research agencies and draw from within the existing budget of the NHMRC. This initiative would improve prescribing through the generation of appropriate evidence and may also redefine the utility of some established off-label indications. It could reduce out-of-pocket expenses for patients by facilitating PBS listing. As this initiative would focus on relatively low-cost generic drugs and/or uncommon orphan indications, it would be unlikely to have a significant impact on the cost of the PBS. It would also help focus the clinical research agenda on clinical practice and encourage the use of appropriate generic pharmaceuticals.

Allen C Cheng · Priscilla M Robinson · Ken Harvey

To the Editor: The human costs of the war in Iraq are mounting. The war has already claimed the lives of about 3000 Coalition service men and women1 and well over half a million Iraqi men, women and children.2 Reports by the United Nations Assistance Mission for Iraq indicate that hundreds of thousands of civilians have been displaced, and that military operations in the country are limiting civilian access to health and education services, food, electricity and water supplies.3 Furthermore, the reports describe a generalised breakdown of law and order in the country, continued growth of militias and organised gangs, and abhorrent human rights violations such as torture in the form of electrical and chemical burns, injury inflicted to eyes and genitals, and wounds from power drills and nails.3 Currently, the Iraqi health system is unable to cope with the health care needs of its population. Iraqi health infrastructure has not escaped the damage or destruction of war. Hospitals lack basic medical supplies such as intravenous fluids, antibiotics, oxygen, disinfectants and bed sheets.4 The precarious security situation in the country has also contributed to a severe shortage of medical personnel. About 25% of Iraq’s physicians have left since the beginning of the war, while those remaining are the targets of violence, intimidation and kidnappings.4 Such an exodus of health personnel has required many of the remaining medical staff to undertake procedures for which they are not qualified.4 Recognising the need for action in Iraq, a workshop was arranged by the International Committee of the Faculty of Public Health, Royal Colleges of Physicians of the United Kingdom, in 2003. The workshop, which included representation from the World Health Organization and the Iraqi Ministry of Health, called for health organisations to be active advocates for improving the health of Iraqis and to provide technical support and assistance to their Iraqi health colleagues.5 Training and professional development opportunities for health staff and the provision of up-to-date health information were identified as specific areas of need in the Iraqi health sector to which health organisations could make a meaningful contribution. In Australia, there has been a small move in this direction, with the federal government providing in-principle support for an initiative to train three Iraqi physicians in emergency surgery. Australian health associations, agencies and professionals need to do more to respond to the humanitarian crisis in Iraq. Carefully coordinated training programs, particularly in the areas of medicine and public health, and the provision of medical aid, resources and information by Australian health organisations, would enhance the capacity of the Iraqi health system to alleviate the effects of war on its citizens. Furthermore, health organisations and professionals need to advocate on behalf of Iraqis, raise awareness of the inadequacies of Coalition government aid, and demand a more effective humanitarian relief effort for victims of the 2003 invasion.

Luke Wolfenden · John Wiggers

To the Editor: I was surprised by Wong’s letter on the role of history-taking and examination in the diagnostic process.1 I would suggest that Wong, as a surgical registrar, receives the majority of his abdominal pain referrals from the medical staff of the emergency department. Although he advocates the liberal use of abdominal computed tomography (CT) scanning, I believe he ignores the fact that another medical practitioner has already taken a history and performed an examination that has suggested a surgical cause of pain for which a surgical opinion is then requested. Wong would thus remain unaware of other cases in which patients present with abdominal pain but the case is ruled non-surgical on the basis of history, examination and limited investigation not involving abdominal CT scanning. History, examination and even appropriately targeted investigations remain imperfect diagnostic tools, but I agree with Schattner2 that history-taking and examination are very important adjuncts in the diagnostic process.

Andrew P Wright

To the Editor: Like Schattner, I am appalled by the attitude to diagnosis displayed by Wong regarding the use of computed tomography (CT) scanning in preference to initial history-taking and physical examination in abdominal pain.1 Unfortunately, this approach is becoming increasingly more prevalent among junior staff (and even among some senior staff). Wong poses the question, “[W]hy do some clinicians continue to routinely promulgate the sacred and arcane ritual of taking a history and doing an examination, which, as diagnostic tools, are clearly second-rate?” There are several reasons why I continue to promulgate the classical paradigm. Firstly, I would remind him of Bayes’ theorem: post-test probability equals pre-test probability multiplied by the likelihood ratio of the test. Put simply, this means that, for a test that is not 100% accurate (ie, effectively, all imaging tests), you cannot interpret the meaning of the result without having some idea of the pre-test probability of a diagnosis. And how can you satisfactorily arrive at a pre-test probability without having clinically assessed the patient? In addition, the radiologist is able to interpret the images more accurately when there are clinical details provided.2 Secondly, is Wong seriously suggesting that all patients with abdominal pain, including young adults and children, undergo CT scanning without any kind of clinical filtering or assessment? This is wrong and potentially negligent. The radiation dose received by the patient from an abdominal CT scan is a serious consideration. Assuming a total effective body dose of 10 mSv, there is an excess risk of a radiation-induced fatal cancer of about 1 in 2000.3 Apart from the risk to the individual, the number of iatrogenic cancers potentially induced in the community by indiscriminate use of CT would be a major concern.4 Thirdly, the implication of Wong’s letter is that clinical assessment and imaging are somehow in competition with each other, whereas nothing could be further from the truth. Of course, modern imaging has contributed to making diagnosis far more accurate than in the time of Hippocrates, but a complementary approach is far more rewarding for patients and doctors. Lastly, in patients with abdominal pain, there are many occasions when no imaging is required and others when ultrasonography is more appropriate than CT, because it avoids ionising radiation in young patients and is more accurate for diagnosing gynaecological causes of pain.5

Richard M Mendelson

To the Editor: It is clear Dr Wong1 has a practice rather different from mine. He is not used to the truly undifferentiated patients that present in their thousands to emergency departments and general practices every day. There, the art of history and examination is truly alive. No one questions the value of complex imaging. It has its place after a detailed history has been taken and focused examination and relevant investigations have been carried out, leading to a risk assessment and management plan. One does not order computed tomography (CT) scans willy-nilly. For example, the Canadian CT Head Rule2 for patients with minor head injury sets out which patients should have a head CT scan, based on a simple set of historical and examination findings. Moreover, CT scans are wasted on conditions for which CT imaging is inappropriate — it is rare that I order a CT scan for a child with abdominal pain. When I ask surgical registrars for their opinion, I am actually asking for their consultant’s opinion. Nothing guides like an experienced hand, whether it be feeling a belly or writing a CT request form. On many occasions, I have concluded that all the imaging performed on a patient with abdominal pain did not contribute to the diagnosis and the patient simply needed a laparotomy. At my insistence, the consultant is called, appropriate treatment commences, and the patient boards the experience express on the track to recovery. As Shem quips, in his satirical book on medical training and hospital life — nothing heals like cold steel.3 CT is not the be-all and end-all of medicine. Hopefully, by the end of his training, Wong will have developed the hand of experience and be able to continue the art of medicine through the ages. In the words of William Osler: The practice of medicine is an art, not a trade; a calling, not a business; a calling in which your heart will be exercised equally with your head. Often the best part of your work will have nothing to do with potions and powders, but with the exercise of an influence of the strong upon the weak, of the righteous upon the wicked, of the wise upon the foolish.4

James L Mallows

To the Editor: Apropos the letter by Wong entitled “Clinical paradigms revisited” in the Christmas issue,1 declaring fossilisation of the very pillars on which medicine stands, we would like to express a contrary opinion. To be adept physicians, clinicians must hone their skills at taking a lucid and informative history and conducting a thorough physical examination. It would be a crying shame if young doctors, having slaved for 5 or more years to obtain a medical degree, had to rely solely on expensive investigations when they have the God-given tools of the five senses. To confirm a clinical diagnosis and assess the extent of disease, doctors should order specific and appropriate investigations, rather than ordering tests that may be irrelevant and financially bleeding the patient. The issues of cost, radiation hazard, availability of trained personnel, and need for expensive equipment have been trivialised. In a country like India, where the majority of the population cannot afford even minimal hospital fees, to even contemplate using a computed tomography scan as a first-line diagnostic tool for something as basic as abdominal pain is absurd. Moreover, the use of advanced technology does not guarantee a correct diagnosis. A recent case of aortic dissection was misdiagnosed as acute coronary syndrome on the basis of electrocardiography.2 If due emphasis had been given to pulse and blood pressures in both limbs, this mistake could have been avoided. In another case, involving recurrent loss of consciousness, investigations were non-contributory, but a history of substance misuse at home pointed to the correct diagnosis.3 In another study, clinical judgement regarding the severity of pneumonia was found to be a more reliable predictor than a standardised scoring system based on clinical signs and laboratory findings.4 Doctors ought to be able to make a clinical judgement in the first instance, rather than resorting blindly to expensive investigatory tools. We do not deny the usefulness of modern technological devices for confirming or ruling out clinical possibilities, but they must be used judiciously. Such investigations cannot take precedence over physicians’ reliance on their clinical skills, lest we become helpless without technology.

Sandeep Chauhan · Ruth D’Cruz · Sanjay D’Cruz · Ram Singh · Atul Sachdev

To the Editor: Schattner1,2 and Wong3 raise issues that examine what has been the core of medical practice since antiquity. Grasping antiquity for its own sake is problematic, at best, and possibly heralds the extinction of long held practices, at worst. As technology improves, we are witnesses to improved imaging modalities that provide higher diagnostic yields, with improved sensitivity and specificity, at increasingly reduced costs. Refusal to even acknowledge the possibility that the history and examination may be terminal is not prudent. Instead, we need to examine carefully our mantra(s) with respect for the temporal nature of medicine. History and examination evolved in their current form because previous generations could not see inside the body, or examine physiological and pathological processes in real time. Our predecessors amassed a series of verbal cues and physical rules that generally conformed to the presentation of a particular disease. The future of medicine heralds dramatic departure from the world view that preceded computed tomography and magnetic resonance imaging. Wong raises an important issue with regard to diagnosing emergency abdominal conditions in busy hospital practice. He does not discount a role for the history or physical examination. He does, however, challenge their pre-eminence in “conditions that require emergency surgical treatment”. Is it really in the best interests of patients and the health care system for the emergency department intern/resident, then the registrar/consultant, then the surgical fellow, to all take the history and perform a physical examination? In essence, doesn’t Wong’s “scan first approach” reflect a prudent reliance on, and respect for, the information already gathered? Schattner4 states that “all imaging studies combined (computed tomography, magnetic resonance imaging, ultrasound, and echocardiography) were decisive in only 10.5% of cases” whereas “the patient’s history and the evolution of the condition proved to be the decisive diagnostic method in 23% of cases”. Doesn’t this show that Wong’s approach provides a heuristic that increases the diagnostic yield, reduces delays and guesswork, and streamlines the processing of patients presenting with acute abdominal pain — or is it acceptable to miss the significant percentage of diagnoses that are decided by imaging alone?!

Stuart Kostalas

To the Editor: In his message From the Editor’s Desk,1 Van Der Weyden laments what he perceives to be “the absence of many voices in protest” against the current Council of Australian Governments’ (COAG) proposals2 for national systems of registration and accreditation of the Australian health workforce. The absence of an “overwhelming public response” to the proposals can surely be attributed to the general public’s lack of awareness of the proposals. It cannot be said, however, that the medical profession has been idle. By the time this letter is published, the situation in regard to the proposals is likely to be much clearer. To date, all elements of the medical profession have been very active in seeking to achieve the best possible outcomes from the COAG proposals for our patients and for the profession. These efforts were impeded initially by the lack of specificity available from the COAG Health Working Group. Clear evidence of the effectiveness of the efforts of the Australian Medical Council, the Australian Medical Association, and the Committee of Presidents of Medical Colleges (CPMC) and its individual member Colleges was the abandonment of the second consultation paper after the profession’s analysis and evaluation of the proposals presented. As I write, government officials are meeting to develop a new model which recognises the profession’s criticisms and views. The profession’s message clearly has reached the federal Minister for Health, who asserted recently that it appeared that “the best way forward is to have separate national registration boards for medicine and for each of the other health professions”.3 This is a significant departure from the original COAG proposal. The CPMC and its member Colleges are well aware of the undesirable developments in other countries where governments are attempting to take control of regulation of the medical profession, as mentioned by Van Der Weyden.1 At their meeting on 15 February, the College presidents endorsed a two-page statement of key issues in regard to the COAG proposals. This statement has been sent to the premiers, chief ministers and health ministers in each state and territory, as well as to the relevant federal government agencies. At the same time, it is appropriate for the Colleges to cooperate responsibly with government initiatives, provided those initiatives do not diminish in any way the safety and quality of health services provided in Australia or threaten the sovereignty of the Colleges in the determination and maintenance of standards for their respective disciplines.

Michael J Cousins

To the Editor: Your statement that the present “grab for control [of Australian medicine] by governments” is unprecedented is not correct.1 Between 1946 and 1949, the federal government came close to nationalising the medical profession.2 The lines were drawn earlier. In 1941, the Federal Council of the British Medical Association (BMA) in Australia (now the Australian Medical Association) made recommendations about the provision of medical services. Two years later, in response to a report by the National Health and Medical Research Council, Outline of a possible scheme for a salaried medical service, the BMA laid down a more detailed policy, with retention of the existing (largely private) general practitioner and specialist services. The government responded by proposing a scheme under which patients would pay nothing directly for medical care, with costs to be met from general revenue.3 Asking the doctors to cooperate, the government indicated that it would if necessary seek other means to achieve its object.4 The referendum of 1946, one of the few to be passed, gave the federal government power to provide a range of social services, including pharmaceutical and hospital benefits and medical and dental services. There were, however, a few words of critical importance in the question put to the people — “but not so as to authorise any form of civil conscription”. It was the Leader of the Opposition, Mr (later Sir) Robert Menzies (acting on a request from Sir Henry Newland, President of the BMA Federal Council and a surgeon of great distinction), who moved the amendment, which the government accepted. The referendum enabled the government in 1948 to pass the National Health Service Act 1948–49 (Cwlth). Resistance by the BMA to what it regarded as objectionable features led to an attempt to coerce the profession by enforcing the Pharmaceutical Benefits Act 1947 (Cwlth), which required compulsory use of a Formulary issued to all doctors. (In the event, only 2% of doctors ever used it.) The BMA took the issue to the High Court of Australia, which decided in August 1949 that a section of the Act amounted to civil conscription and was invalid. Later in the year, the heavy defeat of the government, the result of its attempt to nationalise the banks, sealed the doctors’ victory.5 Over the next few years, the coalition led by Menzies introduced a health service based on the principle of voluntary insurance for hospital and medical benefits, which is still in force. There are clear lessons to be learned from this history.

Derek H Meyers

To the Editor: Safe sports participation has become a key national issue, especially in view of the potential for concerns about safety to inhibit sports participation,1 in a nation where obesity rates are rising2 and more exercise is recommended. Australians participate in many sports, but the safety of the football codes is especially criticised by the media and the community because of the intense focus on injuries to players at the elite level. This is particularly the case for Australian Football (AF) and its elite game, the Australian Football League (AFL). National reports released in 2006 have identified AF as the sport most associated with injury admissions to hospital3 and with private health insurance claims.4 These have sparked media commentary about the safety of AF. Response to these injury reports prompted an unprecedented media release5 from the country’s peak sports medicine body, Sports Medicine Australia, detailing issues with the report figures, urging caution in their interpretation and supporting the efforts of the football codes in improving participant safety. The modified version of the game (Auskick), which is played by children, has been shown to be safer,6 but there is a progression to adult rules by the under-15 age group, and the umbrella of safety provided by modified rules is eventually gone, raising the question of how safe the non-modified version is. Recently released AFL figures suggest that injury rates at the elite level are at a historical low,7 but the report provided insufficient information to assess whether this represents a significant decline since 1997, and the data are already one season behind. Equivalent information for the more than 450 000 adult, non-elite participants is not available. Published literature related to injury prevention highlights a dearth of knowledge relating to the causes of injuries in non-elite participants and a very small evidence base for ways to prevent injuries in AF. With AF played almost exclusively in Australia, the onus to provide evidence for improving the safety of participation clearly falls on the stakeholders of the sport here. Gains in reducing both the public health impact of football injuries and the fear of injury associated with participation will only come from substantial investment in large-scale trials at the non-elite level, and a multidisciplinary approach to safety and injury issues across all levels of play. This will require active and committed collaboration of key stakeholders such as clinicians, allied health practitioners, researchers, clubs, sports administrators, coaches and the participants themselves.

Belinda J Gabbe · Caroline F Finch · Peter A Cameron

To the Editor: The recent viewpoint by Kamien1 and letter by Gunasekera2 rightly highlight the benefits of folate fortification and the unlikely occurrence of masking pernicious anaemia. Food Standards Australia New Zealand recently submitted a proposal supporting the mandatory fortification of bread-making flour to increase folate intakes in women of child-bearing age, with the aim of reducing the risk of children being born with neural tube defects.3 This proposal has had extensive public comment and will be considered by the Australia and New Zealand Food Regulation Ministerial Council. Several public groups and individuals continue to raise concerns that higher dietary folate levels could increase B12 deficiency. Our data, collected from a population-based sample of 2596 older people in the Blue Mountains region, from 1997 to 2000, do not suggest that this is a likely outcome. We recently reported the prevalence of low serum vitamin B12 levels in the Blue Mountains Eye Study cohort of people aged 50 years and older. We found that 22.9% had low serum B12 levels (< 185 pmol/L).4 New data from this study show that higher intakes of folate (from diet and supplements) did not increase the likelihood of low serum B12 levels; in fact, people whose diets included folate in the highest quintile of intake had significantly higher serum B12 levels than those consuming lower dietary folate (Box), after accounting for age and sex (P < 0.001). After also adjusting for vitamin B12 from diet and supplements, there was no significant difference in mean serum B12 levels for the various quintiles of folate intake. We also investigated older people who reported consuming high amounts of folate (> 500 μg dietary folate equivalents [DFE] [n = 645] and > 1000 μg DFE [n = 123]) and found higher mean serum B12 levels in these groups than in people who consumed < 500 μg DFE, after adjusting for age and sex (P for trend < 0.001). After further adjustment for vitamin B12 intake, there were no significant differences in mean serum B12 levels for these high dietary folate intakes (Box). We also examined the frequency of macrocytic anaemia in our cohort (n = 6; 0.2%); two of these had low serum B12 levels (0.3% of subjects with low serum B12 levels). In the United States, where mandatory folate fortification began a decade ago, a study of the presence of anaemia in people with B12 deficiency found no significant change in the proportion with anaemia before and after the introduction of mandatory fortification.5 Although many older Australians have low serum levels of vitamin B12, our data show that higher intakes of folate do not increase the likelihood of low serum B12 levels. Given the relatively high prevalence of low serum B12 levels among older people, it would seem reasonable for this to be monitored more frequently in this age group. We suggest that this is not a valid concern that should prevent moves to proceed with mandatory folate fortification of key foods in Australia. Mean serum vitamin B12 levels in a population of older Australians, for various folate intakes (from diet and supplements) (n = 2596) Folate intake Mean serum B12 (95% CI) adjusted for age and sex Mean serum B12 (95% CI) adjusted for age, sex and B12 intake (diet and supplements) Folate (μg DFE) Quintile 1–4 (< 571.8) (n = 2077) 273 (263–289) 278 (267–289) Quintile 5 (> 571.8) (n = 519) 316 (295–337) 297 (275–319) P < 0.001 0.132 Folate cut-points < 500 μg DFE (n = 1828) 273 (261–284) 278 (267–290) 500–1000 μg DFE (n = 645) 294 (276–314) 289 (270–308) > 1000 μg DFE (n = 123) 346 (303–389) 300 (253–348) P for trend < 0.001 0.239 DFE = dietary folate equivalents.

Victoria Flood · Paul Mitchell