Editorials

The current whole-cell vaccine and protocol for Q fever prophylaxis are effective At the end of 2006, the Australian Ministers for Health and Agriculture announced funding for an upgraded facility to allow CSL Limited to recommence production of the Q fever vaccine (Q-Vax) and comply with changed biocontainment regulations.1 Production of the vaccine had ceased at the end of 2005 because of inability to meet these new regulations and other production pressures. Federal government support is a welcome step forward in the control of a major infective disease in Australia, and comes as a substantial relief to the rural community and meat processors. In addition, it keeps faith with the considerable efforts by state health department immunisation teams and medical practitioners to extend the use of the vaccine from abattoirs to the at-risk rural community during the government-subsidised National Q Fever Management Program, 2001–2003/2004 (http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/q-fever-man). Attempts to control Q fever by vaccination have a long history.2 After the discovery of clinical Q fever and isolation of the causative organism by Edward Derrick in Queensland in the 1930s, and the subsequent identification of the isolates (an obligate intracellular bacterium) by Macfarlane Burnet, the disease emerged as an important “campaign” infection (Balkan grippe) for armies in the Mediterranean arena during World War II. At the time, various vaccine formulations were prepared from the coxiella grown abundantly in chick embryo yolk sacs, as devised by H R Cox at the National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratory, Montana, USA. Suspensions of infected yolk sac were inactivated with formalin and ether (eg, by Smadel and colleagues).2 These were protective in animals and in human volunteer and challenge trials. But use in humans produced unpredictable, severe local reactions. Derrick expressed a common view of these early Q fever vaccines in his 1964 Elkington Oration: “What of the future; there is an effective vaccine but it produces unacceptable reactions”.3 His assessment is still repeated uncritically in the medical literature. The experience in Australia from 1980 to 2005 with the present generation of whole-cell vaccines (eg, Q-Vax [CSL Limited]) and a different vaccination protocol has been quite the reverse. The contemporary whole-cell, formalin-inactivated Q fever vaccine has also sometimes been dismissed as “old-fashioned”— ignoring a protective efficacy of over 95%. In fact, the formulation is appropriate for the complex immunopathology of acute Q fever. Insight into the critical components for an improved whole-cell vaccine started in Cambridge in the 1950s with Stoker and Fiset’s4 discovery of the antigenic phase variation of Coxiella burnetii. Concurrent studies, also in Cambridge, by Abinanti and Marmion5 showed that antibody to the Phase I antigen (ie, the lipopolysaccharide of coxiella cells with a complete set of sugar residues in its O-chains) was protective in a mouse spleen model of Q fever infection. On the other hand, protection was not conferred by antibody to Phase II antigens (ie, from coxiella with a full complement of proteins, but with genetically driven or other variations in the level of synthesis of complete lipopolysaccharide O-chains — recent research reports6,7 give a more detailed explanation of the chemistry of phase variation). Subsequently, Ormsbee et al8 at Rocky Mountain Laboratory extended these observations to show that a formalin-inactivated vaccine made from coxiella predominantly in the Phase I antigenic state was significantly more protective in a guinea pig model of Q fever on a weight-for-weight basis than one made from cells predominantly in Phase II. The latter preparation, and indeed the earlier vaccines developed by Smadel, probably owed their partial protective properties to residual Phase I cells in a population of Phase II variants. The importance of Phase 1 lipopolysaccharide as a protective immunogen is supported by the finding that a Phase I Q fever vaccine loses its protective efficacy in mice when treated with potassium periodate to ablate the sugar residues in the lipopolysaccharide (unpublished data). The major host cells for C. burnetii in animals and humans are in the monocyte–macrophage lineage. The interactions of coxiella with this key regulatory cell series for the cellular immune system underlie both the immunopathogenesis of Q fever and the prophylaxis afforded by the vaccine. The coxiella proteins (as peptides) stimulate T-lymphocyte immunity and memory, with the generation of interferon-γ and other cytokines that control intracellular replication of coxiella.2 On the other hand, interactions of coxiella and monocyte–macrophage cells produce mediators that down-regulate the cellular immune system and the formation of interferon-γ by T lymphocytes.9,10 A possible explanation for the central requirement of the Phase I determinant in a vaccine is that antibody to it blocks interaction of coxiella and the monocyte–macrophage cells. Consequently, down-regulation of the cellular immune system does not occur and coxiella growth is restricted. A contributory component for vaccine efficacy may be the slow biodegradability of the small-cell variant of coxiella. This displays both Phase I lipopolysaccharide and protein antigens, thus providing continuing antigenic stimulation and protection. An important step in the development of the current protocol for vaccination was the finding by Lackman and colleagues2 at Rocky Mountain Laboratory that adverse reactions to whole-cell vaccine could be minimised by intradermal skin testing of potential vaccinees with a dilute vaccine to detect prior cellular immune sensitisation. In the early 1980s, 50 years after Derrick’s discovery — and probably after some 40 000 overt cases of Q fever — Dick Ormsbee and I asked CSL Limited to make Ormsbee’s highly purified version2 of Q fever vaccine with its negligible residual yolk protein. At the time we knew that Hornick, Fiset and colleagues,2 under the auspices of the Commission on Rickettsial Diseases (US Armed Forces), had vaccinated volunteers with whole-cell vaccine and challenged them with aerosols of living C. burnetii. Even small doses (1–10 μg) of vaccine were protective. Open clinical trials of the Ormsbee-type vaccine (Q-Vax) (produced by CSL) at a dose of 30 μg as a subcutaneous injection were performed in workers at four abattoirs in South Australia in the 1980s.2 These established the vaccine’s safety in an industrial environment in which prior clinical or subclinical infection and immune sensitisation were common. As in the US volunteer trials, the vaccine was protective. A formal “blind” comparison of Q-Vax and influenza virus vaccine performed at three Queensland abattoirs also showed complete protection.2 Box 1 shows the practical value of vaccine prophylaxis in a large abattoir group in Queensland, 1992–2005. Occupationally acquired, laboratory-proven Q fever is compensable. Compensation claims — a significant expense for the industry — declined steadily after the vaccination program started. Box 2 shows the number of Q fever cases notified to the National Notifiable Diseases Surveillance System across Australia, 1991–2006. The yearly totals include Q fever cases both in and outside abattoirs. Abattoirs across the country gradually took up vaccination from 1993–1994, greatly aided by CSL’s vaccine consultants. During the period 1994–2000, although the number of Q fever notifications stabilised at around 500–600 per year, probably reflecting fewer cases in abattoirs, an unambiguous downward trend in Q fever notifications for the country as a whole did not occur. This is not surprising, as it has been apparent since the 1930s that only a variable proportion of Q fever cases occurs in abattoirs (eg, 68% of Derrick’s series of 273 cases11). During the National Q Fever Management Program, state immunisation teams worked intensely to vaccinate abattoir workers, and rural and other at-risk groups in the population. Evaluation continues, but Box 2 shows an encouraging and significant decline in case numbers from 2003 to 2006. What of the future? Further refinement of existing vaccine protocols is needed as problems surface from wider use. Efforts to produce less reactogenic vaccines for use without pretesting are summarised in Box 3.2 Balanced against the continuing and substantial Q fever problem in Australia, the current whole-cell vaccine and protocol are effective, they have been tested in over 150 000 subjects, and prophylaxis for this disease is available now. 1 Control of abattoir-associated Q fever in a major Queensland abattoir complex Claims per annum for compensation for clinically and laboratory-proven, occupationally acquired Q fever. (Data supplied by and reproduced with permission of Australian Meat Holdings, Queensland.) 2 Vaccination and changing trends in the numbers of notified cases of Q fever across Australia, 1991–2006 Means (SEs) for 1991–2002 and 2003–2006; P = 0.01 for comparison of means. (Yearly totals for Q fever notifications and the basic curve are from the National Notifiable Diseases Surveillance System.) 3 Efforts to produce less reactogenic, alternative vaccines without the need for pretesting Extracts of coxiella containing lipopolysaccharides and protein (eg, chemovaccine)2 or delipidated coxiella cell residues2 are protective in animals. Chemovaccine has been used in Eastern Europe in laboratory workers and some industrial groups. It is protective, but about as reactogenic as whole-cell vaccine. To establish efficacy, duration of protection and reactogenicity (severe adverse incidents are rare and idiosyncratic), comparative trials are needed of these vaccines versus whole-cell vaccine in larger numbers of subjects. There is also active research into simpler vaccines of coxiella proteins prepared by recombinant DNA methods.12 So far, coxiella proteins alone appear not to be protective,13 although a recombinant fusion protein given with Freund’s complete adjuvant (a potent macrophage activator) protected in a mouse model.14 The quest for a simpler vaccine should continue; whether successful or not, it is yielding valuable insights into the immunobiology of Q fever. But the three-component nature of the existing vaccine and the roles in protection of lipopolysaccharides, macrophages and antibody need to be taken into account.

Barrie Marmion AO, MD, FRCPA, DSc

Testing for Helicobacter pylori, and acid-suppression therapy are nearly always better strategies Most patients with upper gastrointestinal symptoms can be effectively managed without investigation. Recent long-term follow-up of patients with upper gastrointestinal symptoms shows that most have a benign course.1,2 A recent follow-up of 300 patients 9 years after investigations showed that 40% were asymptomatic; 70% of these without medication.2 Such a good outcome is the result of the decline of Helicobacter pylori3 (making peptic ulcer uncommon and gastric cancer rare in the absence of genetic or ethnic predisposition) and the easy availability of effective acid-suppression therapy (making gastro-oesophageal reflux disease easily treatable). For the vast majority of patients, upper gastrointestinal symptoms are now a dis-ease, not a disease. These changes in epidemiology and treatment simplify the management approach to upper gastrointestinal symptoms (Box). Gastroscopy now has a low diagnostic yield. A review of 22 studies investigating dyspepsia found that, overall, findings in 50% of gastroscopies were normal, 12% revealed reflux oesophagitis, 33% gastroduodenal ulceration, and 1.2% malignancy.5 International management guidelines recommend two alternatives to gastroscopy: empiric acid-suppression therapy; or H. pylori testing and treatment.4 Acid-suppression therapy is effective treatment for gastro-oesophageal reflux disease (GORD), and the “omeprazole test” (a simple trial of omeprazole [40 mg twice daily for a week]) diagnoses GORD more accurately than endoscopy, and with a sensitivity of around 80%.6 For population groups with a high prevalence of H. pylori infection, such as the elderly and some ethnic groups, H. pylori testing and treatment has advantages. For younger patients, H. pylori infection is unlikely, as childhood domestic hygiene has improved. If a test for H. pylori is positive, treatment provides: definitive treatment of peptic ulcer disease; no adverse outcome for non-ulcer disease; risk reduction for ulcer disease associated with non-steroidal anti-inflammatory drug (NSAID) treatment; and possible risk reduction for future H. pylori-associated gastric cancer. For those who test negative for H. pylori, the test provides reassurance. Population studies have shown that people who do and those who don’t consult general practitioners for their upper gastrointestinal symptoms have similar symptom severity, suggesting that reasons for consultation may include anxiety about the significance of symptoms.7 Patients should be asked why they present. For those who want information, data show that lifestyle contributes to GORD and adenocarcinoma development, in particular, obesity, smoking, poor fruit and vegetable intake and a sedentary lifestyle.8,9 This information is a useful tool in encouraging patients with GORD to modify their risk and improve their overall health. Overly rapid prescription of acid-suppression therapy may waste opportunities for lifestyle modification. H. pylori testing should be offered to those likely to be infected because of advanced age, ethnic background, or a past or family history of ulcer disease, and to those who take NSAIDs. After advice, and serological or urea breath testing and treatment of patients with a positive result, symptomatic patients can be offered empiric therapy. Whether this should be a step-up approach with initial antacids followed by H2-receptor antagonists, or a step-down approach with proton-pump inhibitors followed by H2-receptor antagonists remains controversial, as does on-demand versus ongoing treatment. Population data show that, after initial consultation, a substantial proportion of patients cease therapy or continue on an intermittent basis.2 There are no data to indicate that for most patients this is harmful. Non-responders often have non-ulcer or functional dyspepsia and treatment is unrewarding. Prescribed and complementary medications, a frequent cause, should be reviewed. Delayed gastric emptying affects up to 40% of non-ulcer dyspepsia patients and is particularly frequent in patients with long-standing diabetes. Previous gastroenteritis is a recently identified cause of non-ulcer dyspepsia. Prokinetic therapy (with drugs that increase the contactility of the smooth muscle of the upper gut, such as motilium) may benefit both groups. Endoscopy should be reserved for those with a familial or ethnic risk of upper gastrointestinal cancer, older patients with alarm symptoms such as dysphagia, haematemesis or weight loss10 and cancer-phobic patients, as its role in patient reassurance is small and not cost-effective compared with other strategies.11 Concern about missing a cancer diagnosis should be tempered by awareness of its low incidence and the limited value of “alarm symptoms”.5,10 In 2001, there were 10 gastric cancers and fewer than six oesophageal cancers per 100 000 population reported in Australia.12 A recent meta-analysis found alarm symptoms had sensitivity of 0–83% and specificity of 40%–98%, and a study of patients with newly diagnosed gastric cancer found poor correlation between symptoms and resectability with: 41% having symptoms; 81% of these having alarm symptoms; 12% of patients with early gastric cancer having prior symptoms; and no correlation between symptom duration and disease stage.10,13 In clinical practice, a third of people with upper gastrointestinal symptoms consult their GP within 6 months of symptom onset.2,6 As oesophageal adenocarcinoma is associated with severe, long-standing upper-gastrointestinal symptoms, “one-off” endoscopy is unlikely to improve early diagnosis.10,13 Today, most patients, particularly those aged under 55 years, can be reassured that: their symptoms are benign; organic disease, if present, is likely to be responsive to H. pylori eradication or acid-suppression therapy; and their lifetime risk of upper gastrointestinal cancer is exceedingly small and may best be reduced by primary prevention with lifestyle modification. If the temptation to refer a patient for endoscopy persists, then the question is, is this to meet an unmet need or is an un-need being met? Algorithm for the management of uninvestigated dyspepsia* * Adapted from Talley.4 OGD = Oesophago-gastro-duodenoscopy. PPI = Proton-pump inhibitor.

Anne E Duggan MHP, FRACP, PhD

Vaccination response has been impressive, but the hypermutable meningococcus is likely to continue to challenge us In the past 100 years there have many dramatic fluctuations in the incidence of meningococcal disease in Australia, as Patel describes in this issue of the Journal.1 Rising socioeconomic status with reduced household crowding has probably been the major factor in curbing the overall incidence of the disease in recent decades,1 but the introduction in early 2003 of a routine vaccination against serogroup C for all infants (and a catch-up campaign for those aged under 20 years) has also had an undeniably impressive impact. Worldwide, surges in the incidence of meningococcal disease due to serogroups A, B, C, W135 and Y have each been associated with the advent of a new strain to which the community largely lacks immunity. Furthermore, new strains are often associated with a higher case-fatality rate and a shift to the right in age incidence, with the disease especially affecting older teenagers. More commonly, these young people do not have the disease but are colonised by the organism and may become “superspreaders” of infection.2,3 The epidemiological signal of rising serogroup C meningococcal disease incidence was detected in the United Kingdom in 1994. A triumvirate of government, industry and academia combined to produce a “win, win, win” situation — an effective and safe vaccine being researched, developed, mass produced and introduced within a mere 5 years.4 As a consequence of vaccination, serogroup C disease is now controlled in a number of developed countries. However, the incidence of serogroup C meningococcal disease in teenagers had already peaked in half the regions of the UK and was declining before the vaccine was introduced in 1999. Similarly, in New South Wales, disease incidence was falling before the vaccine was introduced (perhaps due to naturally acquired herd immunity5), whereas, in Victoria, vaccination led to a rapid fall in incidence. Western Australia and South Australia had not seen the same surge of serogroup C disease as in the eastern states.6,7 However, it should be emphasised that, in the 3 years after the vaccine was introduced, there was a decrease in notification rates in all states and territories except WA, where notification rates remained low. As in the UK, a catch-up campaign was undertaken in Australia for those younger than 20 years of age. Unlike the UK, where routine vaccination was given as a three-dose course in the first 6 months of life, Australia was able to follow a simpler, more cost-effective approach and offer a single dose at 12 months of age. This was because almost all serogroup C disease was seen in older children, teenagers and young adults, and also because the vaccine is more immunogenic in older infants and children. Australia’s approach has proved successful. A similar outcome has been achieved in the Netherlands, where a single dose is administered routinely at 14 months of age.8 In 2005, only 50 laboratory-confirmed serogroup C cases were notified in Australia. This is a greater than 75% reduction from the 213 cases in 2002. There is also evidence that, in the absence of vaccination, disease incidence may fall as naturally acquired immunity rises5 but the impact is not as rapid; herd immunity may also be induced by vaccination but its longevity is uncertain.9 Given the extraordinary velocity of the vaccine’s development in the UK, inevitably some issues received attention later than desirable. One was cost-effectiveness — data on this were published well after vaccine introduction.10 There was interest in both the UK and Australia in the possible use of the cheaper polysaccharide vaccine, as it is effective in the age ranges mostly affected by serogroup C disease and may also be more cost-effective.11 This approach was tried in Spain, but waning immunity after several years led to a follow-up conjugate C vaccine campaign. Given that this disease can progress with frightening rapidity and has a high case-fatality rate, it receives, arguably, inordinate media attention. The political pressure and impetus to implement a vaccination program that this publicity generates is often lacking for diseases with a lesser public profile. When meningococcal C vaccine was introduced in Australia, there was debate about its merits in relation to, for example, the pneumococcal conjugate vaccine, which is now also part of the routine schedule. Australia was arguably the first country in the world to fund universal immunisation against Haemophilus influenzae type b, meningococcus C, and pneumococcus in early childhood. Long-term follow-up will be required to assess the ultimate success of the meningococcal C vaccine program and determine whether booster doses of vaccine might be required or whether serogroup replacement develops. The problem of serogroup B disease remains. New Zealand has recently completed a large and expensive public health intervention to vaccinate its young people against a particular serogroup B strain that, beginning 15 years ago, caused a major upsurge in incidence. This vaccine would cover only a small proportion of serogroup B cases in Australia,6,7 so a different product will be required here, and studies are underway in several Australian centres to assess candidate serogroup B vaccines. Without a vaccine, it is questionable whether behaviour modification would mitigate risk. Patel claims that “the societal determinants of the current hypersporadic disease pattern are unknown”.1 This is at odds with Australian and overseas data clearly showing that crowded environments, including university colleges and nightclubs, and risk-taking behaviour (eg, smoking and multiple deep-kissing contacts) are important risk factors12 and may be modifiable. Despite the recent unravelling of sequence data for the entire genomes of representative strains of meningococcal serogroups A, B and C, the hypermutable meningococcus will likely continue as an “accidental tourist” causing havoc in a small proportion of vulnerable hosts1 and go on challenging public health control measures throughout the 21st century.

Robert Booy MD, FRACP, FRCPCH · Jane Jelfs PhD · Haitham El Bashir FRCPCH, MRCP · Michael D Nissen FRACP, FRCPA

Medical education needs recognition and strengthening through research Modern medical practice relies heavily on research evidence to guide us towards predictable, safe outcomes of investigations and procedures that aim to improve the quantity and quality of life. As there are still substantial gaps in knowledge, researchers are supported to add to the evidence base. New technologies are proven to be (or not to be) safer or more effective. This continual reflection on practice and drive to expand options and reduce error margins is lauded as scientific progress. On the other hand, modern practice in medical education relies mostly on experience, opinion and rumour as it strives to produce graduates to meet the increasingly high standards of the community, partly in reaction to well publicised medical errors.1,2 Until recently, medical graduates received biomedical science training and apprenticeship-style clinical teaching without defined national exit standards. The current trend is towards broader (and possibly shallower) curricula guided by contemporary definitions of medical practitioner roles, such as CanMEDS from Canada, Good Medical Practice from the United Kingdom and local adaptations.3-5 National licensing examinations are either in place or under consideration, and international curriculum frameworks and accreditation are being developed.6 We are amidst an expansion in medical education driven by a workforce shortage. However, do we know how to achieve this expansion and maintain quality? There is a relatively small evidence base to support changes in medical education practice. The science of medical education has evolved much more slowly than the science of biomedicine. Lectures have been around for centuries, human dissection for about 500 years, and laboratory sessions for over 100 years. The only two real jolts to the conventions of medical education during the 20th century were the Flexner report, which standardised pre-clinical and clinical training phases because of concerns about a proliferation of small, lower quality medical schools in the United States,7 and problem-based learning, which was based on an attractive theory that case-based, integrated learning was more likely to be remembered when similar clinical presentations were encountered later. Neither change was based on strong evidence, and many years later there is still little education research evidence that any curriculum approach is better.8,9 A fundamental problem is that the academic basis of medical education receives little recognition amidst complex agendas. From a health care management perspective, the main role of the health care system is the provision within budget of quality clinical care, and it is difficult to direct funding towards academic development. From a university perspective, medical schools are sources of resources and prestige, but mostly through research achievement. As a result, medical schools are becoming “two-team” institutions. First, there are the researchers, who charge ahead, based on well planned and supported ventures, aiming to “score” grants and publications, win competitions and attract attention, usually based on advances in biomedical and clinical sciences. Then there are the teachers, who stay in the background and guide the students. This is the team that earns the core, stable funding of the school and is responsible for seeing that graduates meet the broader curriculum objectives, but it receives little attention except during medical school accreditation processes. The focus on research means that the real rewards of medical academic life generally go to members of the research team. Consider these questions: Why do some basic scientists who participate in education research decline to list that on their curricula vitae? Why are there apparently clear measures of research success, but not of teaching success? How hard is it for exemplary teachers to gain senior promotion without research success? How many national honours go to people who teach rather than research? How many prizes are available to reward great teachers? Why are there “league tables” for medical schools according to research success, reputation and difficulty of entry (based on very high academic performance), rather than for teaching quality? Just as clinical practice and research inform each other, so too do educational practice and research, and yet there are concerns about the variable quality and focus of recent research in medical education.10,11 There is a need to go beyond short term evaluation projects and to address current gaps in medical education research evidence, some of which are listed in Box 1. Most medical schools now have medical education units, but these are often seen as organisers of the teaching team, rather than contributors to a recognised academic agenda. These are missed opportunities, as medical schools manage large amounts of data about teaching and learning implementation, and could convert much of their teaching and learning activity to research without substantial cost. Medical education funding often underpins priority-driven research, and could more overtly support medical education research. The external funding environment could make medical education research more attractive to the research community. More medical academics could be trained in the methodology of education research, which differs from that of clinical and laboratory research, to increase research capacity. In summary, it is time for medical education research to enter mainstream research agendas and become a research priority for universities. Unless we strengthen academic medical education, teaching and learning will continue on a relatively uninformed basis, and our aim to produce safer, more efficient doctors will be under threat. This strengthening requires high level intervention to promote a culture change in medical schools, facilitated by strategies such as those listed in Box 2. Even if all these strategies were implemented, the impact on support for biomedical research would be small, yet the potential reward would be high. We would know much more about what we are doing in medical education, and medical schools could gain academic credibility not just through traditional indicators of success, but for doing what they were founded to do — to teach medical students well. After all, medical schools depend increasingly on their students’ fees. 1 Some current gaps in evidence in medical education Current basic medical education programs, including prior degree requirements for graduate entry, are 5, 6 or 7 years long. Which is better? Can selection procedures reduce the proportion of unhappy or unsuitable medical graduates? How much anatomy, chemistry, pharmacology, psychology and other basic and biomedical sciences do medical graduates really need to know? How can we measure the quality of teaching? What is the impact on learner performance of poor versus good teaching? Is it true that academic clinical groups provide better care? What is in the “black box” of small group learning that makes its cost worthwhile? What is good role modelling, and how can we facilitate it? To what extent can e-learning replace other modes of delivery? To what extent can skills laboratories replace real patient contact? How often should experienced doctors be reassessed for registration? Can poorly performing doctors be predicted or remediated? 2 Strategies to achieve better support for medical education Medical schools should be required to base curriculum development on medical education research wherever possible. Medical schools should be required to spend a certain proportion of their teaching income on education research that supports their program. Medical education units should be acknowledged as having research as well as service delivery roles. National research priorities should include issues beyond the scope of individual medical schools, such as identified gaps in evidence on medical education. Research funding bodies should establish panels for medical education research and allocate quarantined funds for proposals that address priority issues. Medical education research should be awarded its fair share of research fellowships at PhD and postdoctoral levels. Medical career structures should reward excellence in teaching and education research as much as other scholarly endeavours.

Richard B Hays PhD, MD, FRACGP, FACRRM

Does drug product information need a use-by date? Do not rely on the Australian approved product information for up-to-date advice about drug therapy. This seems to be the main message of Stockigt’s review of entries for thyroid disease in prescribing references, which are based on the product information supplied for each drug. In some cases the information was so out of date, its recommendations were potentially harmful.1 While these findings will not surprise everyone,2 many health professionals will be disturbed to know that they cannot completely trust the product information approved by the Therapeutic Goods Administration (TGA). It is often the source that people turn to when seeking detailed drug information. As the product information also underpins consumer medicines information and sets the boundaries for advertising, flaws could have far-reaching consequences. The Therapeutic Goods Act 1989 (Cwlth) has little to say about product information other than it relates to “the safe and effective use of the goods, including information regarding the usefulness and limitations of the goods”. Details about what should be in the document are contained in the Australian regulatory guidelines for prescription medicines.3 These guidelines do not state that the product information should be kept up to date. When a sponsor company applies to have a new drug registered in Australia, it supplies a draft of the product information. This is scrutinised by the TGA and the Australian Drug Evaluation Committee to check that the information reflects the evidence supporting the drug’s safety and efficacy. Although the sponsor can make safety-related notifications, the product information cannot be changed after registration without the TGA’s approval. At the time of registration, the accuracy of the product information is at its zenith; however, it may soon be outdated. With the pressure to approve drugs quickly, new information is likely to emerge after the product is marketed. Some drugs seem to be approved mainly on the results of phase II trials. Their product information will therefore need updating when the results of phase III trials become available. Adverse effects may only emerge after marketing. A review in the United States of 548 new drugs found that more than 10% later acquired a “black-box” warning about serious adverse effects or were withdrawn.4 While major safety concerns are likely to trigger an update of the product information, less prominent problems may be overlooked. In Australia, the sponsor is responsible for keeping the information up to date. How seriously this responsibility is taken is unclear. Updating product information, particularly about old and possibly less profitable products, and disseminating the changes may not be a top corporate priority. The TGA also has to set priorities. It has limited resources but many areas of regulatory responsibility, including complementary medicines. While the TGA was once government-funded, it now has to recover all its costs in fees and charges. Having the regulator funded by fees from the industry it regulates may have disadvantages. Industry probably prefers to pay the TGA to register new drugs, than to dust off the product information of old drugs. To manage within its resources the TGA has adopted a “risk management approach” to regulation.5 Activities with a low risk of adverse outcomes receive less scrutiny. This is why complementary medicines are not evaluated before they are listed in the Australian Register of Therapeutic Goods. Similarly, the TGA’s risk analysis may not identify the product information of old drugs as a high risk. Many old drugs only have brief product information. This may not have been updated for years and it can be difficult to know its currency. The date of approval at the end of the document reflects the most recent change. However, this change may have been a minor variation rather than a rigorous review. Perhaps there is a need for a “use-by date”. Drugs have an expiry date, so why not extend the concept to product information? This would require a date to be set for a comprehensive check of the product information. Such reviews would be more frequent early in the product’s life to ensure emerging data were included. For older products the reviews could be less frequent, but at least there would be a mechanism for checking that the information was not obsolete. This could be an opportunity for specialist societies to assist the TGA with updating. Regularly reviewing product information would require greater resources for the TGA. As the TGA can charge for changes to the product information, the mechanism exists to recover the additional costs. (Changes to the product information involving the evaluation of data currently cost about $4000.) Although an agreement between the TGA and industry to keep product information up to date seems sensible, there are likely to be commercial objections. The TGA’s philosophy is to regulate while “freeing industry from any unnecessary regulatory burden”. Most corporations aim to cut costs, so it is possible that a company may withdraw an old drug rather than be forced to review the product information and then pay to have it approved. In 2005, the TGA circulated a discussion paper on improving access to information about prescription medicines.6 This contained several suggestions for greater use of electronic methods to make up-to-date product information easily available. The outcome of this discussion is currently unknown. Would a recommendation to update the product information regularly be accepted in a business environment focused on new products, cost containment and reduced regulation?

John S Dowden MRCGP, MICGP, FRACGP

Expert guidance is needed to balance the benefits and risks of sun exposure Vitamin D (defined in this article as serum 25-hydroxy-vitamin D) is largely obtained through the effect of sunlight on the skin. Vitamin D plays an undeniably important role in maintenance of bone health, preventing the development of rickets and osteomalacia. However, there has been increasing recent media attention given to research findings that suggest other possible benefits of vitamin D, such as prevention of certain cancers or multiple sclerosis.1,2 In the first 6 months of 2006, seven of 124 daily updates on “cancer-related news” (6%) monitored by The Cancer Council Australia featured at least one item on the importance of sun exposure for obtaining sufficient vitamin D to prevent chronic diseases. Given that the primary source of health information for most Australians is the media,3 such reports have the potential to change attitudes and behaviours to sun exposure. Some commentators have compared doctors with sherpas who need to guide their patients through an increasingly complex medical world.4 The “vitamin D story”, in which sun exposure appears to both cause cancer and prevent cancer, is one example where health consumers will need the guidance of health professionals in making an informed decision. Since the 1980s, the “Slip! Slop! Slap!” and then the “SunSmart” campaigns have sought to reduce population exposure to sunlight with the ultimate aim of reducing the burden of skin cancer in Australia.5 The challenge, given current levels of evidence, is to provide a public health message that ensures skin cancer risk is minimised while taking a precautionary approach to the possible harms of insufficient circulating levels of vitamin D. Several agencies have initiated conferences and meetings within the past 2 years, resulting in articles recommending changes to current sun-protection messages,6-8 and this year, the first issue of the journal Progress in Biophysics and Molecular Biology was wholly devoted to ultraviolet (UV) radiation exposure guidance. In Australia, a position statement on the risks and benefits of sun exposure was approved in 2005 by the Australian and New Zealand Bone and Mineral Society, Osteoporosis Australia, the Australasian College of Dermatologists and The Cancer Council Australia. The statement’s intention is to guide health professionals in giving information to the public on sun-protection behaviour. Four recommendations were made, and are summarised in the Box.9 Given the uncertainty about whether the subgroups within the population with the highest prevalence of vitamin D deficiency (the frail and elderly, people who cover themselves with clothing for cultural or religious reasons, those with dark skin pigmentation, those with mental illnesses) would benefit from a relaxation of sun-protection messages, each recommendation should be a starting point for further research. For example, considering the first recommendation (Box), the few studies available to date mostly indicate that, while most people are aware of the UV index, very few adjust their sun-protection behaviour accordingly.10-13 We need to determine ways to ensure that the UV index is routinely reported in weather forecasts in both summer and winter, and to increase public understanding of the implications of the UV index for sun-exposure behaviour. Additionally, it is likely that the association between the UV index and vitamin D production is not linear, and this needs to be explored in greater detail.14 Will the second recommendation (Box) lead to a more relaxed attitude towards sun protection in summer in southern states? Basal cell carcinomas and squamous cell carcinomas most commonly occur on the habitually sun-exposed skin sites.15 While these skin cancers are rarely fatal, their treatment can require surgical or destructive intervention and cause considerable morbidity.16 An unintended consequence of the second recommendation might be to increase incidental sun exposure of the arms and face and hence the incidence of skin cancer. Thus, the way this recommendation should be translated into a public health message needs careful consideration. For the third recommendation (Box), previous research has shown that people find it difficult to correctly assess their personal risk for skin cancer,17,18 and clinicians may need to help patients identify their risk. With regard to the fourth recommendation (Box), even though there is mandatory fortification of margarine in Australia, this is unlikely to achieve sufficient oral intake of vitamin D, especially among those most in need, and further supplementation may be necessary.19 The acceptability and effect of fortification and supplementation among at-risk groups still requires testing, and other food sources suitable for fortification need to be identified. At present, these complex recommendations are not being widely promoted to the general public, and further evidence on how to best communicate them is required, particularly in light of the media interest. Anecdotal evidence from the Queensland Cancer Fund suggests that the number of callers to their Helpline seeking advice about correct sun-protection behaviour is increasing. Further, unpublished data from a population-based survey conducted by the Queensland Cancer Fund in 2004 indicates that 837 of 5611 participants (15%) agreed with the statement, “If I regularly protect myself from the sun, I am in danger of not getting enough vitamin D”.20 These people were more likely to deliberately sunbathe than those who did not agree with this statement (odds ratio, 1.65; 95% CI, 1.30–2.09).20 Assuming that the association between various chronic diseases and vitamin D can be unequivocally established, and that the appropriate vitamin D level and the UV radiation dose required to obtain it can be quantified — which is by no means certain — it still may not be possible to provide a single message about “healthy” sun exposure appropriate for the whole of Australia, a continent that spans more than 35 degrees of latitude. It has been estimated that only 6–12 minutes of winter sun exposure three to four times a week may be sufficient to produce “healthy” levels of vitamin D in Brisbane, compared with 51 minutes in Melbourne.21 Many factors in addition to latitude (age, skin type, sun-exposure habits, other skin cancer risk factors, photoprotection, body mass index, food choices, amount of physical exercise, liver and renal health, environmental conditions such as smog, season, ozone) contribute to either people’s risk of skin cancer or their ability to synthesise vitamin D, or both. More research is needed to better understand the photobiology of vitamin D formation in the skin, and the precise effect of UV radiation on vitamin D synthesis within various subgroups of the population. We don’t yet know the minimum amount of sunlight needed to maintain healthy bones (let alone prevent internal cancers or chronic diseases, if indeed these benefits can be realised), nor whether these effects may not be better obtained through supplements. It is unlikely that the daily requirement for vitamin D could be obtained from foods fortified with vitamin D alone.22 A meta-analysis of randomised trials of vitamin D supplementation found that daily doses of 700–800 IU (17.5–20.0 μg) reduced the incidence of fractures, but lower doses did not.23 Even after the answers to these fundamental research questions are known, translating these complex messages to the Australian public effectively will remain a challenge. In the interim, the effect of current campaigns and media reports about vitamin D on sun-protective behaviours and sunburn rates should be monitored carefully, sun-safe practices should be encouraged and supplements used where necessary until we increase our basic understanding of the relationships between chronic disease, vitamin D and sunlight. Sun exposure is the primary cause of skin cancer. If sun exposure and sunburn were to increase as a result of concern about the requirement for vitamin D, several decades of effective public health promotion to reduce the incidence of the most common cancer in Australia would be jeopardised. Summary of the risks and benefit of sun exposure position statement* Sun protection is usually required if the ultraviolet (UV) index is 3 and above (and people are advised to check the forecast UV index in their local area); Most people achieve adequate vitamin D levels through incidental sun exposure, but people living in the southern Australian states in winter may need 2–3 hours of sun exposure on the hands, arms and face each week; Some people are at high risk of developing skin cancer and need more rigorous sun protection than the general population; Some subgroups of the population, such as the frail and elderly, and people who cover most of their body with clothing for cultural reasons may need to consult their doctor to have their Vitamin D status investigated and supplemented if necessary. * Modified from the full statement.9

Monika Janda MPhil, PhD · Michael G Kimlin MAppSc, PhD · David C Whiteman FAFPHM, PhD · Joanne F Aitken MSc, PhD · Rachel E Neale BVSc, PhD

A program of this size is bound to experience challenges The National Health Service (NHS) in the United Kingdom is undertaking the world’s largest civil information technology (IT) project,1 committing £12.4 billion over 10 years to improve services and quality of patient care through the strategic use of IT.1 The size of this commitment makes the NHS National Programme for IT (NPfIT), delivered by the NHS Connecting for Health (CfH) agency, of major international importance. NPfIT covers 330 acute hospitals and mental health trusts, and primary and community care organisations across England (Scotland, Wales and Northern Ireland have opted not to participate). At the core of the program is the “Spine”, a central link to a patient register, electronic prescription service, messaging service, and a summary care record. A web-based booking system, Choose and Book, which allows patients to select or change appointment times, is currently used for 12% of bookings. Radiology picture archiving, electronic prescription transfer, email, and an NHS-wide directory have been implemented, but electronic patient records, a common user interface and secondary use of data are significantly delayed. The NHS chose to procure systems centrally and implement them locally. Procurements included NHS-wide systems (email and Choose and Book), enterprise-wide agreements (eg, with Microsoft), and five local service providers to implement the regional solutions. Local service providers are free to choose and change subcontractors. Local systems must conform to national standards, as in Australia where all jurisdictions have agreed to use standards promulgated by the National E-Health Transition Authority. Clear differences are our federal structure that allows each state its own procurement process, financial and regulatory framework, and controls, thus hindering the unified “big bang” approach possible for England. Once all costs of implementation and training are accounted for, the final budget for NPfIT could blow out to as much as £30 billion.2 In June 2006, the UK’s National Audit Office reported on CfH.3 Despite the cost overruns, delays,4 and growing clinical unrest, the report was less damning than expected. The muted response may reflect that some things have gone well, that a program of this size is bound to experience challenges, and the political cost should the program be perceived as a failure. Other nations grappling with health service reform can already learn many lessons from NPfIT. Get the procurement model right. Procuring contracts centrally resulted in vigorous supplier competition and saved about £4.5 billion. However, the speed of procurement meant that the NHS had not prepared key policy areas (eg, information governance), standards (eg, for messaging and clinical coding), and information system architecture (neither enterprise architecture nor detailed technical architecture was ready). Further, the contracts bound suppliers to a vague specification that has cost the NHS around £30 million in legal fees to sort out. Payment to suppliers is contingent on delivery of “working” systems (although up-front payments have occasionally been made). Consequently, the significant delays in systems roll-out have not as yet resulted in a national scandal because the public purse appears protected. Under-performing companies have not been paid, and some have suffered large, late-delivery penalties. For example, iSOFT is reported to be struggling because of its failure to deliver on time and the resulting penalties. It posted a £344 million annual loss, has taken a hammering in its share price, and is being investigated by regulators.5 It is not clear what risk- management process can handle the worst-case scenario of one or more providers going bankrupt, leaving complex “legacy software” that cannot be maintained by other organisations. Safety comes first. IT can be a powerful enabler, but if poorly implemented or used, it can result in patient harm.6 Yet system safety was not written into the initial procurement specifications.7 Somewhat late in the day, CfH developed a safety accreditation process and appointed a National Clinical Safety Officer. Failure to account for safety also brings commercial risks. A program failure, such as failing to correctly populate patient data into the allergy field of the shared records on the Spine, could easily generate widespread clinical misadventure, triggering massive legal claims and a stock market hammering. The delayed common user interface should have additional safety benefits. Once trained on one system, clinical staff can change their employment and, regardless of the next system used, still have some consistency of user interface and information presentation, hopefully resulting in reduced training time, increased clinician effectiveness and safer practices. Skills shortages will impede progress. CfH has been hampered by a workforce that lacks experience in large-scale IT implementation and familiarity with health services.8 Compounding this, the severe procurement contracts paradoxically may send some health IT companies to the wall, reducing the number of organisations able to implement systems in the UK, or elsewhere. Perhaps a staged approach, with systems roll-out designed to also increase the skills base and capacity of the workforce, might have been more sustainable. For the lifetime of CfH, there will always be questions about the capacity of CfH suppliers to deploy their best and brightest to other parts of the world. This is in part because suppliers may see success with CfH as a “loss leader” into the global market, and failure or delay there will also generate significant penalty. “Fast follower” nations hoping to capitalise on the investment of an “early adopter” nation like England may end up paying a premium on UK prices, rather than the cheaper prices some expect, as companies seek to recoup any losses incurred in the UK. Clinical engagement comes first, not last. A significant criticism in the National Audit Office report was that procurement occurred before clinical engagement, perhaps because extensive consultation was thought to slow the process. This has resulted in significant disquiet among some clinicians and the priorities of the program not fully matching those of the clinical community.9 How significant a failure this decision was will become clearer in time. Picking the wrong patient consent model may be a deal breaker. Patients must give consent for their information to be stored electronically and made available to others.10 CfH has chosen an “opt out” model in which patients by default are included within the system, and make an informed choice to leave it. For this to be fair, patients would need to be reached by an educational campaign before system implementation. Strident critics, such as the British Medical Association, counter that an informed choice to “opt in” would be a fairer model, as there is no room for doubt about a patient’s intentions. Given that the shared record is not yet widely available, there is significant room for increasing disquiet in years to come, not just among clinicians, but also the public. “Opting out”, while technically simpler, may end up being the Achilles heel of the new system should significant examples of breach of confidentiality hit the media. “Opting in” might eventually prove to be the cheaper model when all costs are considered, not just the technical ones. Clinical knowledge services are an early clinical winner. Almost ignored in the CfH program hype has been the NHS National Knowledge Service which provides, among other things, the electronic National Library for Health — a vast array of evidence sources for working clinicians. With no apparent significant delays in its delivery, no dependence on other components of CfH, and a relatively small budget by the program’s standards, it is likely that the IT system most clinicians see first and gain immediate benefit from will be Internet access to clinical evidence. Political leadership is key. CfH exists because of strong political support within the government and Cabinet, and direct leadership from the Prime Minister. Without such political leadership, it seems unlikely that modernisation on this scale would ever be attempted, nor steered over the inevitable road humps encountered on the way. Evaluation is not an afterthought. Too often, token effort is expended on measuring clinical improvements long after major decisions have been made and systems delivered. CfH has therefore established and funded an evaluation board. However, evaluation also has a major formative role — early versions of systems are iteratively trialled to make sure they fit into clinical workflows, are acceptable to clinicians, and don’t have negative side effects. The CfH decision to consult late with clinicians has meant that there were limited opportunities for formative evaluation to shape specifications, and we may now be seeing the opportunity cost of that decision. Perhaps history will record that the NHS was not sufficiently prepared to take on such a fast-paced, radical and extensive modernisation program, that it was compromised by workforce shortages in health informatics, and fell into the trap of leading with technology rather than clinical need. Perhaps countries like Australia will draw another, somewhat heretical, conclusion from the exercise — that IT is not like water, which can be delivered equally to all. With scarce resources, Australia should begin its IT modernisation program with just a few national clinical centres of excellence, where IT skills and efforts can be concentrated. With time, successful technologies, processes and work practices, as well as the personnel trained in them, can then migrate to the rest of the health system.

Enrico W Coiera MB BS, PhD

Getting the message right will help the public reduce their risk of mental illness In the 2006–07 budget, the Australian Government announced expenditure of $21.6 million over 4 years to improve community awareness of the link between using illicit drugs and the development of mental disorders. Community awareness programs to reduce the prevalence of unhealthy behaviours are nothing new; they have been around for decades for cancer, heart disease and infectious diseases. While campaigns focusing on the negative effects of drug misuse have already been delivered, this initiative breaks new ground. It will be the first large-scale campaign in Australia to tell the public what actions they can take to reduce their risk of developing mental disorders. Australia is not alone in this area, with both France and the United States launching campaigns in 2005 to alert the public to the potential link.1,2 However, it is too early to know whether these campaigns have had any effect. Probably the main reason that there have not been earlier campaigns on how to reduce the risk of mental disorders is a lack of evidence for causal links. How good then is the evidence that illicit drugs cause mental disorders? First, there is substantial agreement that an association exists between early onset of cannabis use and later psychotic symptoms or disorder,3 but there is ongoing disagreement regarding the causal basis of this association.4 Clearly, cannabis use is “neither a sufficient nor necessary cause for psychosis”,3 but it may “unmask” psychotic disorders in individuals who are vulnerable. The timing of drug exposure may be particularly critical here, especially given recent evidence that a specific polymorphism of the COMT (catechol-O-methyltransferase) gene conveyed increased risk of later psychosis only if cannabis was consumed during adolescence.5 Second, a number of studies have reported a modest association between early onset of regular cannabis use and later depression, although further research is required to determine whether this relates to a direct causal role or common psychosocial factors.6 The evidence implicating other illicit drugs is more limited. Methamphetamine, which is rapidly growing in popularity in Australia, has been consistently associated with a transient psychotic state that is more common in people dependent on this drug.7 A growing body of literature suggests that a significant minority of those regularly using methamphetamine are also at risk of more entrenched patterns of psychosis.8 While there is currently limited evidence of a direct causal relationship between illicit drug use and mental disorders, the issue becomes whether we can afford to wait and see if increasing early use of illicit drugs actually does lead to a rise in the incidence of mental disorders. If a community awareness campaign is to be effective, it needs to be appropriately targeted. Initiation of illicit drug use typically starts in adolescence, and the evidence points to those with the earliest onset of drug use as being at greatest risk of subsequent mental disorders. A campaign targeting an early adolescent audience requires clear, coherent and credible evidence-based messages that are balanced and free from political dogma. The messages must also be delivered in a format that is appealing and meaningful to adolescents and informed by current trends in media and information technology. This might include web-based campaigns and the development of related Internet sites. Whether the campaign also focuses on providing information for parents will need to be determined, as this would require a complementary set of relevant information and materials. Mass media campaigns in other areas of health have typically had very little effect, including when drug misuse prevention has been the goal.9 In many cases, the weak effect has been due to campaigns being insufficient in intensity. Nevertheless, there are lessons that can be learned from earlier campaigns and these need to be applied (see Box). Given that the campaign discussed here will be the first to address risk of mental disorders, it needs to be well evaluated, either through a staggered roll-out in which some regions serve as controls, or through a time-series analysis in which there are repeated measurements over time — before, during, and after the campaign. As the first of its kind in Australia, it is important that this campaign is done well. A bad start could set back a field with considerable potential. Reducing the prevalence of risky behaviours, like illicit drug use, is not the only approach. It is also possible to promote positive actions that all individuals can take to reduce their risk of mental disorders.12 Campaigns that focus on educating the public about other effective preventive strategies (eg, exercise) should also be a clear priority, similar to other areas of health policy. Indeed, we have good evidence regarding psychosocial factors that increase risk for both substance misuse and mental disorders, and we need to communicate this information to the wider community. We envisage a future in which the public will know as much about how to reduce their risk of mental disorders as they currently do about how to reduce their risk of cancer and heart disease. Principles of effective mass media campaigns9 and possible applications to a campaign promoting awareness of illicit drugs as a risk factor for mental disorders Carry out preliminary research with the target audience Carry out qualitative research with young people to help design the campaign and to get feedback about the effectiveness of messages. Use a theory to give the campaign a conceptual foundation There are several relevant theories of behaviour change, including the transtheoretical model (which specifies how to communicate with people who are at various stages of readiness to change)10 and the theory of planned behaviour (which looks at how behaviour is influenced by a person’s attitudes and those of the people closest to them, and whether the person believes that the behaviour is under volitional control).11 Segment the audience into subgroups of people whose message preferences are similar to one another Potential audience subgroups might include: young people currently using illicit drugs, adolescents not using drugs, people with a personal or family history of mental disorders, and parents. Design messages that are targeted to the audience subgroups Messages need to appeal to each group. For example, messages for young people might need to avoid preaching, use suitable role models, and include features such as humour, novelty and a fast pace. Place messages through appropriate media that are widely used by the audience The appropriate media may be quite different for each group (eg, the Internet or youth radio might be more appropriate for young people than for parents). Conduct a process evaluation to see that the messages reach the audience Surveys should be conducted to ensure that the messages have reached the target audiences with a high frequency of exposure. The approach should be changed if an audience is not being reached. Evaluate outcomes to find out whether the campaign caused any changes in target audience behaviour Measure changes in attitudes towards the link between drug use and mental disorders, as well as changes in drug use. Evaluate the effects using a staggered roll-out, with some regions used as controls, or a time-series design, which involves multiple measures before, during, and after the campaign.

Anthony F Jorm MPsychol, PhD, DSc · Dan I Lubman PhD, FRANZCP, FAChAM

The more things change, the more they stay the same Nearly 100 years ago, George Bernard Shaw, in the preface to his play The doctor’s dilemma, savagely attacked the medical profession for its direct personal and pecuniary interest in the treatment of patients and argued that doctors could not be trusted to act in their patients’ best interests.1 He observed that medicine was not driven by science but rather by patient demand and service. Nor was Shaw particularly impressed with medical science, noting that “medical science is as yet very imperfectly differentiated from common curemongering witchcraft”. In short, he argued that the medical practice of his time was mostly ineffectual and that doctors should advise patients that wellness is not attained through a bottle of medicine but through decent housing, clothes, food and clean air. The doctor’s dilemma was that providing this advice would jeopardise his already meagre income. Despite Shaw’s vitriolic criticism, doctors of that era enjoyed the respect of society because of their care and compassion — attributes poignantly captured by Sir Luke Fildes’ famous painting “The doctor” (1891), which portrays a pensive doctor sitting by lamplight at the bedside of a sick child, with her anxious father hovering in the dark background. It is tempting to speculate what Shaw would make of the medical profession in Australia if he were sitting in judgement today. He would note that health care has become an economic giant, consuming large chunks of our gross domestic product (GDP) each year. In the financial year 2004–05, this amounted to 9.8% of GDP, or $4319 for each Australian.2 And this will only increase with the ageing of our population, the increase in chronic disorders, and the public demand for new drugs, biotechnology, medical devices and sophisticated surgery. As a prominent Fabian, Shaw would enthusiastically endorse Australia’s Medicare scheme, with its ideals of universal and unfettered access to medical care and provisions for meeting its costs. But public health insurance comes with a price — the overwhelming bureaucratisation of medical care with regulations, red tape and incessant reviews of activities.3 It also means the dominance of politicians and public servants in health decisions, with the medical profession relegated to myriad special interest and lobby groups. Considering Shaw’s scepticism about medical science, he would welcome evidence-based medicine and marvel at medical research and the role it has played in reducing infectious diseases, in widening the scope of surgery and in providing sophisticated tools for diagnosis. And with stem cell technology and medical genomics on the horizon, the sky’s the limit. He would note that medical research has become entangled with industry. In 2003, biomedical research funding in the United States reached the astronomical figure of US$94.3 billion. Industry accounted for 57% of the funding, the three major contributors being pharmaceutical, biotechnology and medical device firms.4 With this level of involvement, the purpose of biomedical research has passed from being purely for the public good to being for the good of researchers, institutions and corporations.5 Critical to this process is the promotion of products to doctors through incentives such as “taking meals, gifts, trips and . . . joining company advisory boards and speaker bureaus . . .”.6 Shaw might also be taken aback by the complexity of the organisation of medicine. From a simple structure of general practitioners supported by physician and surgeon consultants, it has evolved into numerous silos of medical subspecialties, each with their own technical territory and professional and political purposes. Doctors now work as members of health care teams, and the doctor–patient relationship has shifted from paternalism to partnerships in which doctors are health and social advisors. The ready availability of information via the Internet has given patients more knowledge and control of their own health. Patients’ expectations have also changed. The success of medical research and medicine’s capacity to cure many illnesses have led to unrealistic expectations of what doctors can achieve. Furthermore, Shaw would be amazed at how health concerns have mesmerised modern society, fuelled mainly by hyped reports of cancer “breakthroughs”7 and the shroud-waving of epidemiologists about yet another lifestyle danger to health.8 Finally, Shaw would congratulate the medical profession for being consistently endorsed by the public as an ethical and honest profession9 and be comforted by doctors’ prosperity.10 In his day, doctors were “hideously poor” and were “offered disgraceful prices for advice and medicines”.1 However, Shaw would also detect undercurrents of discontent, and debate and dilemmas for doctors in several domains: Medical practice. The burden of bureaucracy has had an insidious impact on medical practice and the independence of doctors. Conforming to evidence-based and protocol-driven practice continually erodes the capacity for discretionary practice and dampens its intellectual challenge. These sources of discontent, along with pressure from patients and the need to keep up with rapid changes in knowledge, have eroded professional satisfaction.11 The dilemma for some doctors is whether to continue in clinical medicine, to retire prematurely, or to pursue other career options. The profession. Subspecialisation of medical practice has hastened the decline of the generalist and led to compartmentalisation and segmentation of the profession, with extra burdens imposed by accreditation, registration and calls for recertification. But more daunting is an emerging identity crisis: firstly, what is a doctor?, and secondly, what does a doctor do? The first question has spawned a spate of definitions of what constitutes a doctor12,13 and what modern professionalism means.14,15 The second question has prompted calls for devolving medical practice through task transfer,16 which Shaw, with uncanny prescience, foreshadowed: “There are cases that present no difficulties and can be dealt with by a nurse or student, at one end of the scale, and cases that require watching and handling by the very highest existing skill, at the other.” The dilemma for the profession is to decide whether to continue down the subspecialisation route or to encourage a return of the generalist. The profession also needs to decide how task transfer will evolve. Trust in doctors. Trust underpins the doctor–patient relationship and is critical to society’s acceptance of medicine as a profession. In the words of Jerome Kassirer, former Editor of the New England Journal of Medicine, “Patients must be able to trust that their doctors’ motives are not subverted by financial gain, that their doctors are recommending treatments that benefit them, and that their doctors are involving them in research projects for the right reasons. Their doctors must not only be at their sides, but on their sides.”6 The entry of industry into medicine has raised questions about its role in continuous medical education, scientific and professional meetings, and support for travel and research. In these relationships, perfunctory declarations of conflict of interest by doctors are seen as the panacea for any concerns about honesty and transparency, but mostly they amount to little more than window-dressing. The dilemma for the profession is whether to confront conflict of interest head-on or persist with its comfortable approach of tolerating many “shoulds” but not many “musts”.6 Leadership. The Royal College of Physicians’ (London) recent report on professionalism stressed the need for a common forum that speaks with a “unified voice”.15 Nowhere is this more applicable than in Australia, if the conflict between professional bodies of general practice is anything to go by.16 Indeed, there are questions about whether the professional organisation of Australian medicine and its regulatory and representative bodies are appropriate to meet our current challenges, which include inexorable subspecialisation, the ability to absorb the projected increased output of our medical schools, and the development of a functional e-health system.17 The dilemma for doctors is whether they will continue to allow multiple leaders of multiple organisations to pursue multiple interests, or whether they will insist on an effective common forum that is proactive and speaks with a unified voice. Shaw’s report card on the medical profession of his time was a harsh and bruising affair. One can only surmise what he would make of medical practice and doctors in Australia today. But, in many ways, the fundamentals haven’t changed. The doctor’s dilemma remains that of how to deal with personal and professional conflicts of interest in order to maintain a position of trust and independence.

Martin B Van Der Weyden MD, FRACP, FRCPA

Moving beyond the uncertainties of risk, and limited, often difficult, preservation options, will require consensus and collaborative research The remarkable cure rates achieved in childhood cancer mean that large numbers of survivors are currently among the young adult population. However, the treatment that has achieved this success may have adverse effects in many organ systems, including the reproductive organs. These adverse effects may result from the impact of cytotoxic chemotherapy (alkylating drugs such as cyclophosphamide, iphosphamide, procarbazine and busulfan, in particular) on gametogenesis, from radiation damage to the gonads, or from radiation delivered to the hypothalamic–pituitary axis. To preserve fertility, it is necessary to determine the risk of fertility impairment before instituting cancer therapy. Predicting the impact of treatment on reproductive function in individual children based on expected exposures is notoriously unreliable. Current tools, both biochemical and biophysical, are unsuitable for assessing actual reproductive impacts in prepubertal and peripubertal children. Even when pubertal onset and progression is apparently normal, the integrity of gametes may have been compromised. A case–control study of 33 male survivors of childhood cancer showed that only a third had normal semen quality, and even in those who were not azoospermic, there were significant differences from normal controls. Seven of 11 azoospermic young adults were prepubertal at treatment, implying that the prepubertal state does not afford protection.1 Similarly, a study of young adult female survivors treated in childhood, all of whom had regular menses or had a history of normal menses if they were using combined oral contraception, revealed partial reduction in ovarian reserve as shown by elevated follicle-stimulating hormone (FSH) levels, lower anti-Mullerian hormone levels and smaller ovary size on ultrasound in those with spontaneous menstruation, and failure to elevate inhibin B levels in response to FSH stimulation in those using combined oral contraception.2 On the other hand, pregnancies have been noted in individuals predicted to be sterilised by their exposures to cancer therapies. The treatment protocols applicable to a child’s particular diagnosis may suggest higher risk. Those exposed to dose-intensive regimes of cyclophosphamide3 and other alkylators, particularly those with Hodgkin’s lymphoma treated with MOPP (mustine hydrochloride [nitrogen mustard], Oncovin [vincristine], procarbazine and prednisone) and other alkylator-intense regimens, including those with metastatic sarcomas, or bone marrow transplantation, are at increased risk. Others at higher risk are those who need pelvic or testicular irradiation, or total body irradiation before marrow transplantation. At the other end of the spectrum, children about to commence therapy on low-intensity protocols, such as those used for low-stage Wilms’ tumour or acute lymphoblastic leukaemia, are at minimal risk of infertility. However, a substantial proportion of children beginning treatment fall into an intermediate risk category for which prediction is fraught with inaccuracy. The cut-off of 7.5 g/m2 of cyclophosphamide recommended by the Children’s Oncology Group as the exposure level to trigger screening for fertility is a reasonable approximation of elevated risk, but not a reliable predictor of outcome at the beginning of therapy. Given the uncertainty of predicting fertility outcomes, what options exist for preserving fertility in children facing cancer therapy, and how should parents and patients be counselled? Cryopreservation of semen and subsequent in-vitro fertilisation is the only standard option for postpubertal males, and spermarche is the watershed around which options for boys are defined. Spermarche typically is an early to mid-pubertal event and occurs before the ability to achieve ejaculation.4 In the mature adolescent, semen is usually obtained by masturbation, with electrostimulation or vibratory stimulation as alternatives (the latter two may be applicable in peripubertal boys). However, the rate at which viable samples are obtained is highly variable. These adolescents are often sick as well as embarrassed and uncomfortable. One study of 62 attempts by adolescents to bank sperm before therapy resulted in totally normal semen in only four.5 Adolescents may be more successful if unaccompanied by parents.6 The advent of intracytoplasmic sperm injection (ICSI) enables in-vitro fertilisation of ova with even single sperm and so, despite the low yield rate, semen cryopreservation should be encouraged — as appears to be the case in the survey of practice in Australia and New Zealand by Heath and Stern in this issue of the Journal.7 Whether ICSI will increase the incidence of abnormalities in the offspring of cancer survivors remains to be seen — the incidence of abnormalities in offspring of cancer survivors conceived by natural means is not elevated.8,9 However, ICSI may bypass the normal protective mechanisms which terminate abnormal embryos. In adult men unable to produce semen for cryopreservation, harvesting of testicular sperm has been undertaken, either from testicular biopsy or percutaneous aspiration. However, in the presence of circulating cancer cells, breaching the blood–testicular barrier may pose the risk of testicular cancer recurrence analogous to the increased rate of central nervous system leukaemia after traumatic lumbar puncture. Of interest, even when sperm is banked, studies in adults suggest that a small proportion of men (10%–30%) retrieve and use the banked specimen.10 For prepubertal males, no current routine option exists. Approaches that may develop include testicular tissue cryo-preservation, and germ cell cryopreservation and autografting. Both are entirely experimental at this time.11 For female patients, the options are more limited. For mature women, oocytes can be harvested and fertilised, and resulting embryos preserved. However, this requires at least 2 weeks of hormonal preparation (daily injections of FSH), and an existing sperm source. Similarly, oocytes can be preserved and subsequently fertilised when a sperm donor is available, although success rates are lower.12 Neither technique is applicable to children or adolescents. As ovarian tissue contains significant numbers of primordial follicles in younger females, the harvesting and storage of ovarian tissue (preferably removed as ovarian cortical strips by laparoscopic techniques) before starting cancer therapy, with subsequent autotransplantation, is an experimental option. There is some evidence of successful restoration of hormone production and two reports of successful pregnancy.13,14 Which patients should be subjected to such invasive techniques needs clarification and consensus, and this procedure should only be undertaken under strict clinical trial conditions in centres with the necessary expertise. The risk of reintroducing cancer cells has not been accurately assessed, but is a real possibility.11 In the face of uncertainty and limited options, many of which are invasive, the paediatric oncology community has been slow to embrace routine and consistent counselling of families about fertility preservation options. Heath and Stern have demonstrated this hesitation among Australian and New Zealand oncologists,7 and similar results have been obtained in North America.15 To be able to provide effective counselling and improve pre-emptive interventions to preserve fertility, paediatric oncologists must inform themselves of the options for their patients, forge links with paediatric endocrinologists and reproductive medicine specialists, define at-risk patients by consensus, and commit to participating in research in this area — as they have already done so well in the context of defining best cancer treatments.

Mark L Greenberg MB ChB, FRCPC · Stacey L Urbach MD, MPH, FRCPC

There is now an inexpensive first-line approach for diagnosing pigmented skin lesions Over the past decade, the number of published reports on new technologies for diagnosing primary melanoma and other pigmented lesions of the skin has grown exponentially. However, there is still confusion about the relative merits of the various technologies and in which patient setting they are best used. The technologies discussed here are dermoscopy (also known as surface microscopy, epiluminescence microscopy, or dermatoscopy) and its digital modifications. In dermoscopy, hand-held magnification devices (usually × 10 magnification), together with either application of liquid at the skin–microscope interface or the use of cross-polarising filters that require no liquid, allow the visualisation of morphological features not seen with the naked eye. This increases the accuracy of diagnosis for virtually all pigmented skin lesions, including melanoma.1,2 In a meta-analysis of 13 studies comparing dermoscopy with the naked-eye examination, the mean sensitivity for the diagnosis of melanoma (percentage of melanomas correctly diagnosed) increased by 19%, and the mean specificity (percentage of non-melanomas correctly diagnosed) increased by 6.2%.3 While this analysis suggested that dermoscopy did not markedly increase specificity, other studies have shown it to have a dramatic effect on reducing biopsy rates. In a clinical trial of dermatologists randomly allocated to either naked-eye examination or naked-eye examination plus dermoscopy, there was a 42% reduction in the number of patients referred for biopsy in the dermoscopy arm of the trial.4 This trial followed the observation that, for dermatologists trained in the use of dermoscopy, there was a significant reduction in the benign to malignant ratio of excised melanocytic lesions — from 18 : 1 (pre-dermoscopy era) to 4 : 1 (post-dermoscopy era).5 The impact of dermoscopy has also been assessed in general practice. In a study of the diagnosis of melanoma using dermoscopy by Australian general practitioners, my colleagues and I reported a 39% improvement in sensitivity. No improvement was noted in specificity.6 Our finding has been reproduced in a recent clinical trial of primary care providers in Europe.7 The major endpoint of the trial was the result of re-evaluation by two participating specialists of lesions identified as suspicious. The percentage of suspicious lesions correctly detected (sensitivity) increased by 46% in the dermoscopy group. Again, the specificity remained unchanged. Furthermore, there was a significant improvement in the identification of malignant lesions by the dermoscopy group (although the trial lacked adequate power to detect differences in melanoma diagnosis). Since 2000, there has been an increasing interest in digital dermoscopy sequential imaging.1,2 Digital (computerised) dermoscopy monitoring devices take digital dermoscopy images and allow tiling on the computer screen for comparing change in melanocytic lesions over time. Such devices are used in two clinical settings. First, short-term digital monitoring over a 3-month period is used to monitor suspicious melanocytic lesions lacking features of melanoma on dermoscopy. Patients may present with changing common or mildly atypical naevi, or atypical naevi without an accompanying history of no change in their appearance. In contrast, patients with multiple atypical naevi are monitored for periods of 6–12 months (long-term monitoring). Both these monitoring techniques have been shown to detect dermoscopically featureless melanoma.2 In a large series of 91 melanomas detected by sequential digital monitoring in Australia and Europe, more than half of the lesions were in situ and all were less than 1 mm thick, indicating the safety of monitoring lesions over time.8 Recently, the impact of digital dermoscopy was demonstrated in a cohort of patients at high risk of primary melanoma; 34% of melanomas detected lacked dermoscopic features of melanoma and were exclusively detected by sequential digital dermoscopy monitoring.9 With the realisation that melanoma is a relatively uncommon presentation in general practice and may be suboptimally diagnosed even in a specialist setting, automated diagnostic instruments have been developed that require no diagnostic input by the operator. While many are commercially available, such devices are at various stages of development, so that attempting to compare their impact on diagnosis with that of any other technology in the field is difficult.2 Nevertheless, comparisons can be made of the various instruments by contrasting ideal requirements, as outlined elsewhere.10 While it is difficult to draw robust conclusions about the impact of such instruments in the absence of supporting clinical studies, such studies are being performed and their results are eagerly awaited. In summary, dermoscopy has been shown to improve both the sensitivity and specificity of the diagnosis of melanoma by specialists and to improve the sensitivity of melanoma diagnosis by GPs. As it is an inexpensive technique, it should be recommended to all clinicians as a first-line approach for diagnosing pigmented skin lesions. Sequential digital dermoscopy monitoring devices are readily available and are restricted to diagnosing melanocytic lesions (naevi and melanoma). They have been shown to allow the detection of dermoscopically featureless melanoma in any patient presentation, but, to date, studies have only been performed in a specialist setting. Such devices are more expensive and may currently be beyond the reach of general practice. Nevertheless, a clinical trial on the impact of dermoscopy and sequential digital dermoscopy monitoring on excision rates or patient referrals for biopsy by Australian GPs is due to be completed at the end of this year.

Scott W Menzies MB BS, PhD

New guidelines extend opportunities for GPs to respond In July 2006, new international consensus clinical guidelines — Management of the whole family when intimate partner violence is present: guidelines for primary care physicians — were launched simultaneously in Melbourne by the Victorian Community Council on Crime and Violence and at the General Practice and Primary Health Care Research Conference in Perth (Box).1 Partner violence is prevalent globally, exacerbated by poverty, war and gender inequality.2 In Australia, while 3% of women in the community report partner violence in the previous 12 months, the proportion among primary care patients is 8%.3 Men can also be victimised, but the evidence suggests that women suffer most of the significant harm, especially in the early child-rearing years, affecting the health of the whole family. Partner violence is no less prevalent among gay and lesbian families, and Indigenous families are particularly at risk of harm from partner or family violence, including murder of female partners.4 Abused women are more likely than non-abused women to experience physical and psychological symptoms and seek health care for stress-related and chronic ailments.5 There is also evidence of the damaging effect partner violence can have on children’s emotional, behavioural and cognitive development, as well as on their physical and mental health.6 Perpetrators can exhibit significant comorbidities, especially drug and alcohol misuse, and there is growing concern about early childhood development in this context. Increasing rates of depression and mental illness focus attention on the contribution partner violence makes to adverse social and economic circumstances.7 With a pattern of poor health and increased health care attendances by victims, perpetrators and their children, there are potential opportunities for health care providers to intervene. However, barriers to identification and management include lack of training, time and effective interventions.8 Advice for general practitioners in the medical literature focuses mainly on victims; there is a little on abusive male partners, but children or the wider dilemmas of whole-family management are rarely included.9 As recent systematic reviews concluded that there was inadequate evidence to guide clinical care,10 a Melbourne group of primary care researchers brought together, in a rigorous consensus process, an international collaborative team of clinical experts in partner violence. A systematic review of existing guidelines identified those of best quality, when assessed according to the Appraisal of Guidelines Research and Evaluation (AGREE).11 AGREE helps readers assess, firstly, whether the potential biases of guidelines development are adequately addressed; secondly, whether the recommendations are externally and internally valid; and finally, whether they are feasible for practice. Recommendations endorsed by more than three guidelines were supplemented by those addressing key gaps. These gaps included advice about investigating harm to children and adolescents, and parenting issues (addressing any parenting difficulties that the victim faces as a consequence of the abuse). Further gap recommendations deal with clinic management, including training of all staff in safety protocols when doctors are seeing different members of the family. With each recommendation, further narrative offers clarification and practical advice to strengthen the recommendation’s applicability. The controversial issue of screening had experts in Europe, the United Kingdom, Canada and Australia arguing that the guidelines should recommend case finding only. This was based on the need to obtain evidence that intervention does not harm women and children in the longer term, and the available evidence that practitioners are largely untrained and unsupported. In contrast, participants from the United States believed that, in view of the prevalence of the problem, screening was still vital, and that not screening was bordering on unethical. The majority recommendation resolved that physicians should routinely ask all pregnant women and girls about partner violence, because of their particular vulnerability and the association between partner violence and adverse pregnancy outcomes; they should undertake case finding with all other women and with men. While primary care intervention trials are only just underway, these guidelines offer the best current advice. Clinicians need to be mindful of the range of issues within the family that they may face. Many doctors continue to feel that asking about partner violence is “opening Pandora’s box”.8 There is increasing evidence that partner abuse is an underlying issue in many serious, recurrent symptoms in primary care, and that the damage to the family’s health creates continuing harm. Consequently, federal and state governments should ensure that doctors are provided with sustainable and effective training, support and resources to play their part in society’s efforts to prevent ongoing generations of damaged families. The partner violence whole-family guidelines are endorsed by the Royal Australian College of General Practitioners and available on the College’s website.1 Key selected recommendations from the guidelines on managing partner violence (as numbered in the document)1 Screening 1. Family practitioners should routinely ask all pregnant adult and adolescent women about partner violence 2. In other situations, doctors should ask patients with symptoms of partner violence and those with symptoms of abusive behaviour (case finding only) Men 5. Encourage a patient who has disclosed their abuse of a partner to take responsibility for their behaviour and change Children 14. Discuss any parenting concerns in the partner abuse context 15. Assess the risk to and adult perception of the impact on children 16. Consider the risk to and children's perception of the impact on their lives 17. Consider children's access to significant supportive others Clinic 27. Seek own and staff family violence training for management of all family members experiencing violence 29. Use a clinic protocol for monitoring danger to patient and other family members by any clinician seeing patient

Angela J Taft PhD · Kelsey L Hegarty MB BS, PhD · Gene S Feder MD, FRCGP

Major changes to the screening environment dictate a review of this successful program Internationally, cervical cancer prevention programs based on cytological surveillance have been among the most successful public health achievements in modern history. Almost all developed health jurisdictions have tackled the world’s second commonest cancer among women, and implemented successful screening programs. The achievements within each country have been variable, and Australia now has the lowest mortality and second lowest incidence in the developed world1,2 (see Box). However, Australia’s achievements did not come without considerable effort across the community. In the 1980s, many observers noted that ad-hoc screening in Australia was not achieving its potential in cancer prevention. This concern led the Australian Health Ministers’ Advisory Council (AHMAC) to establish a consultative committee, which in turn issued a critical, insightful and comprehensive review of cervical screening and made substantial recommendations to improve the program.1 The report was accepted by AHMAC, and a long process of substantial change began. The AHMAC recommendations involved the historic adoption of a national screening policy in 1991, active recruitment of women for screening, the development and implementation of quality measures across the screening pathway, the establishment of cervical cytology registers in all states and territories, and the endorsement of clinical practice guidelines for the management of screen-detected abnormalities. The success of these changes relied on broad consensus, collaboration and cooperation across the public and private sectors and state, territory and national jurisdictions, and also on the commitment of a broad range of stakeholders. In this issue of the Journal, Canfell and colleagues show that these achievements have been mirrored in the United Kingdom, where similar proportional reductions in incidence and mortality have been noted.3 Nevertheless, absolute incidence and mortality rates in the UK remain substantially higher than those in Australia (Box).1 Since the progressive implementation of the Organised Approach to Preventing Cancer of the Cervix (as the program was titled) began in 1992, both the incidence and mortality of cervical cancer in Australia have been halved.4 Although calculations show that this translates to 1200 women each year whose squamous cancers are being prevented,5 success has come at a cost. Each year, two million women are screened, about 100 000 receive a report of an abnormal smear, and about 15 000 (mostly young) women undergo treatment for a high-grade lesion. Since the 1980s, much about cervical cancer prevention has changed. The appreciation that human papillomavirus (HPV) is the necessary cause of cervical cancer, and increased understanding of the epidemiology of genital HPV infection, the role of acute HPV infection as the cause of most low-grade cervical abnormalities, and the natural history of cervical cancer precursors have all demanded a change in our approach to this disease. Most significantly, a vaccine that successfully prevents the most significant HPV infections, most cervical abnormalities and most cervical cancers is now available through private prescription. An application for public funding of this vaccine is currently before the Australian Government. Despite the dramatic achievements described above, the recent history of introducing change has not been one of consensus and collaboration. An attempt to incorporate HPV natural history into clinical management algorithms through review of the National Health and Medical Research Council (NHMRC) guidelines6 led to widespread controversy in the clinical community.7 A universal mass vaccination program with the HPV vaccine is a cost-effective primary prevention strategy. Markov modelling shows that this will further reduce cervical cancer incidence and mortality, with accompanying substantial reductions in the morbidity associated with our current approach.8 Failure to implement a mass vaccination program will further exacerbate the inequities of access that have been historically associated with cervical cancer prevention in most jurisdictions, such as the lower participation rate for Indigenous women in the Northern Territory that is documented by Binns and Condon in this issue of the Journal.9 Notwithstanding this opportunity, substantial questions remain regarding implementation of the vaccine program. For example, how will the substantial cost of this vaccine be met, even if it is cost-effective? Should the existing cervical screening program be obliged to find savings to cover its cost? Can the current intensive screening program still be justified in a population of young vaccinated women, when the rate of abnormalities will be significantly lower, and the risks of screening will almost certainly exceed the benefits? How will Australia monitor the effectiveness of its vaccination investment? How will the state-based cytology registers incorporate vaccination status into their management recommendations? There are no current plans to establish or incorporate HPV vaccination into any existing register system. Unfortunately, little capacity is evident within current health infrastructure to address any of these issues. The current cervical screening program also has many issues to resolve. There are major questions about the capacity of the cytology workforce to continue servicing a cytology-based program.10 HPV testing offers potential for an efficient reorganisation of the current approach. The registers could contribute to a more organised approach by switching to a recall system where women would be individually recalled for their test when it was due rather than their current reminder system which acts as a safety net for women who are overdue in having the test. However, these changes require substantial cross-sector consultation and consensus. The Australian Screening Advisory Committee was disbanded in May 2006 following an AHMAC review of population health advisory structures. This leaves no national structures available to consider, promote or implement any change within the screening program. Canfell and colleagues seem to be suggesting that the national screening policy in Australia should be modified.3 When the environment of screening is so altered, broader changes are needed than a simple variation to policy on screening interval. Clinicians and consumers do not appear willing to accept any potential increase in cancer rates; they will quickly mobilise to resist such a change. Cervical screening survives on a complex interaction of emotional, professional and commercial interests which are intertwined and sometimes in conflict. Australia needs to undertake a comprehensive review of cervical screening and to carefully consider potential modifications to this outstandingly successful program. Perhaps it’s time in Australia for a “Reorganised Approach to Preventing Cancer of the Cervix”. International variation in incidence and mortality from cervical cancer for selected countries, 2002 Country Incidence per 100 000 women (ASR) Mortality per 100 000 women (ASR) New Zealand 10.0 3.2 United Kingdom 8.3 3.1 Sweden 8.2 3.1 United States 7.7 2.3 Canada 7.7 2.5 Australia 6.9 1.7 Finland 4.3 1.8 ASR = age-standardised rate (World Standard Population). Source: GLOBOCAN.2

Gerard V Wain FRANZCOG, CGO

On balance, new guidelines for parents and practitioners are helpful and workable Which infants at the margins of viability should receive neonatal intensive care and how should such decisions be made? These challenging questions are posed in this issue of the Journal by Lui and colleagues.1 Their answers, arrived at by means of a multidisciplinary conference, are presented as a consensus statement that makes several recommendations for practice. Although similar multidisciplinary conferences have been held in Australia over the past 20 years, there are no contemporary publications on the subject and this statement is timely. As has been apparent from other commentaries both here and overseas,2 these guidelines for New South Wales and the Australian Capital Territory confirm that the area of most debate concerns infants of 23–25 weeks’ gestation. However, several important questions can be asked about the consensus statement itself, including: How appropriate was the process undertaken to arrive at the statement? Was consensus reached? And, are the recommendations helpful and “workable”? As to the appropriateness of the process, there are several options for dealing with these difficult ethical and management decisions. I recall that, at two earlier conferences held at Westmead, Sydney, in 1985–1986, four approaches were identified: a “look to the courts” approach (this approach is not readily available, is expensive and generally produces conservative rulings); a “right to life” approach or, “if it can be done, it should be done”, whatever the burden this imposes on the patient, their family and society; a “muddle through” approach or, “doing what seems best at the time”; and an “institutional” approach. The “muddle through” approach has been a pragmatic solution in the past, leading to a great deal of sensible practice, and it is increasingly subject to controls, including audits and peer review. However, the “institutional” approach — particularly in the guise of a multidisciplinary conference — was, at that time, put forward as the most logical and coherent way of informing community debate and public policy. This approach has worked well in other areas (eg, providing guidelines for human organ transplantation). It would also seem very appropriate for this current debate. A prerequisite for this process would be that good data are available on the consequences of choosing resuscitation over comfort care. In this instance, the process worked well, because the workshop was presented with comprehensive population-based data from NSW and ACT on survival after live birth and neurodevelopmental status at 2–3 years of age. Although the numbers of infants at each gestational age were relatively small, the data are similar to those obtained from other Australian population-based studies.3 A longer-term follow-up would have been preferable, but such data are subject to the problem that elements of neonatal intensive care change over time. On the question of whether consensus was reached, the statement revealed that not all recommendations were agreed to by all participants; not surprisingly, there was considerable divergence of views in some areas. Delegates were asked to vote anonymously (using a five-point scale) on a range of scenarios and related statements. “Consensus” was defined as more than 90% “agree” or “strongly agree” or, for some statements “of lesser gravity”, as 75% “agree” or “strongly agree”. The process was rigorous and likely to have honestly reflected the group’s views. However, only 72% of participants agreed with a statement about not initiating resuscitation at a gestational age of between 25 weeks and 25 weeks 6 days (250–6) if requested by parents in an otherwise uncomplicated pregnancy. Although this was clearly a majority view, it did not, strictly speaking, reach the stated definition of “consensus”, but was incorporated in the consensus statements. The composition of the multidisciplinary group would also seem crucial to the process. Here, perhaps, there were some shortcomings. The group of 112 delegates convened by Lui and colleagues were mainly health professionals, although eight were non-clinical health administrators and seven were parents or community advocates. Including others, such as educationalists, ethicists, lawyers and religious leaders, would have made the delegates more broadly representative of society, and possibly different views would have emerged. However, various professional and consumer groups as well as the NSW Health Clinical Ethics Advisory Panel have subsequently reviewed the agreed guidelines. Are the guidelines helpful and “workable”? Certainly, it is helpful to have widely agreed and ethically approved written guidelines in this area of neonatal practice. In a commentary published in 2004, Jerold Lucey, the long-serving Editor-in-Chief of the leading United States journal Pediatrics, made it clear that in his view any treatment of these infants is experimental.4 In some sense, all medical treatment is an experiment, although commonly the outcome is more predictable than in the case of extreme prematurity. At these gestational ages, there are too few data relating to treatments found to be effective in more mature infants (eg, exogenous surfactant) to pretend that their use is evidence- based. Thus, as a key consensus recommendation says, within this gestational age range (23 weeks to 25 weeks 6 days) when gestation is known with reasonable certainty, “parents’ involvement in the decision-making process during prebirth counselling or subsequent management is mandatory”. The issue of non-directive counselling was discussed at the workshop. Not all parents demand total autonomy in decision making;5 indeed, some may be impossibly overburdened by the prospect.6 The important issue, as emphasised in these and earlier guidelines on preterm care,7 is that good communication is at the very core of the partnership between the medical team (the current caregivers) and parents (the future caregivers) that unfolds as perinatal and neonatal intensive care progresses. Information provided to parents by different members of the team should be consistent. Having appropriate written material, which will be available as a result of this consensus workshop, will facilitate this process. Perhaps the most important consensus recommendation states that, at gestational ages between 23 weeks and 25 weeks 6 days, treatment is discretionary. Lui and colleagues use the term “grey zone” to emphasise that, at these gestations, there is a complexity of maternal, obstetric and clinical factors known to influence outcome that need to be considered in making individualised decisions. Sex of the infant was not included in the discussions because it was stated that it was not usually known before birth. However, there is now extensive evidence that, at these short gestations, female infants do have a better survival rate, to some extent a better long-term outcome, and essentially are the equivalent of a week more mature than their male counterparts.8 Increasingly, the sex of the neonate is known before birth, and otherwise is immediately apparent at birth. It could be argued that there should be different grey zones for female and male infants. Certainly, not to consider the infant’s sex may be to discriminate against female infants.9 Many factors, including the sex of the neonate, should influence decisions not only within the zone but at its margins. Data from the Australian and New Zealand Neonatal Network show that survival rate at these short gestations increases by about 3% with each day of increased maturity.10 This, added to the fact that gestational age is often an estimate, means that the margins of any grey zone are somewhat indistinct. The consensus statement’s abstract states that “poor condition at birth” has an important influence on the decision not to initiate intensive care in this zone. However, there are few data to support the predictive value of condition at birth for survival and certainly not for neurodevelopment.11 A prediction that an infant of a certain gestational age will do poorly, coupled with non-aggressive resuscitation, is likely to be a self-fulfilling prophecy. However, a poor response to adequate resuscitative measures must clearly be a factor in decisions about ongoing intensive care. In their statement, Lui and colleagues have provided valuable guidelines for parents and practitioners dealing with impending extremely preterm delivery; they should be congratulated on the rigour of their process. It is now up to others to use these guidelines wisely. In the abstract (which may be the only part some people will read), the description of the grey zone seems a little too black and white, with clear margins. The main text of the statement — which should be read in its entirety — makes it clear that this zone is not uniform grey and that its limits are indistinct.

Brian A Darlow MD, FRACP

Inequity in rural cancer survival in Australia is not an insurmountable problem: it is a test of our health systems Australia has lower cancer mortality rates than comparable nations like the United States, United Kingdom, Canada and New Zealand. However, there is increasing evidence that this success may be bypassing the 2.8 million Australians who live in rural and remote Australia.1-3 Indeed, the further from a metropolitan centre patients with cancer live, and adjusting for stage of presentation, the more likely they are to die within 5 years of diagnosis.2-4 Geographical isolation, a relative shortage of health care providers, and a higher proportion of disadvantaged groups such as Indigenous people are acknowledged to be contributing factors.3 How access to specific treatment and support services may explain the differences in cancer survival was a central question of the first national mapping of rural and regional oncology services, commissioned by the Clinical Oncological Society of Australia. The study showed that the availability of oncology services diminished as geographical isolation increased, and that quality and availability of services by location directly influenced survival rates. For all survey criteria assessed, service provision was measurably and significantly poorer in rural and remote centres than in benchmark metropolitan and large regional centres (see Box). Established rural and visiting oncologists, nurses and other cancer care professionals provide a vital service, but they are evidently stretched well beyond capacity. While much of the study’s findings are alarming, the data support our rationale for what we believe are achievable reforms to reduce the geographical inequity in cancer services. Access may not be the only explanation — some remote patients may, for example, choose not to have treatment — but there are ways in which access to quality care can be improved. The centrepiece of our recommendations is the establishment of Regional Cancer Centres of Excellence (RCCEs) in regions with a suitable population. These centres would provide multidisciplinary care, improve support and educational services and, by being mentored by major metropolitan centres, could provide a link to smaller, more remote services. They would also boost access to clinical trials and may provide a critical mass for technological platforms like positron emission tomography scanning. We have pragmatic evidence that RCCEs do work, through the success of a centre in Albury–Wodonga, a former outreach facility that now has five resident oncologists, a clinical trials unit and a two-machine radiotherapy service. Reported benefits include an increase in the number of new patients treated locally from 150 to 750 a year, an eightfold increase in chemotherapy day treatments, establishment of multidisciplinary clinics and more than 10% of new patients participating in a clinical trial.4 The Border Cancer Care Coordination Project, a pilot study funded by the Australian Government, with contributions from the Victorian and New South Wales governments, showed that a modest investment in expanding the Albury–Wodonga service has significantly improved the coordination of care and quality of experience for patients, carers and health professionals. The pilot study employed cancer care coordinators, an oncology social worker, clinical psychologists, a multidisciplinary meeting co-ordinator and a researcher. Information gathered through this project and reported to key stakeholders showed that patients across the wider catchment area were better able to access multidisciplinary care, regardless of their postcode, insurance status or whether they were treated in an acute or community setting. The best way to gradually roll out a network of similar centres is to build them where a radiotherapy unit is in place. Radiation oncology is essential to multidisciplinary cancer care. And, while it is costly in capital outlays and maintenance, and generally immobile, it is the most cost-effective in terms of operational cost versus efficacy.6 A number of non-metropolitan centres have radiotherapy units (Wagga Wagga, Wollongong, Albury–Wodonga, and units are soon to be operational in Coffs Harbour and Port Macquarie in NSW; Ballarat, Bendigo, Geelong and Latrobe Valley in Victoria; and Townsville, Tugun and Nambour in Queensland). There are plans for new units in Darwin, Toowoomba and the NSW far north coast. The combined population of these centres is more than 1.5 million, and an additional 700 000 people are estimated to live within a 150 km radius. Attracting two medical oncologists and a range of allied health service providers to each of these centres would provide a platform for a multidisciplinary team approach to patient care, and enhanced remote supervision by engaged clinicians. It would also be consistent with the Australian Medical Workforce Advisory Committee’s recommendations on practitioner-to-patient numbers. Moreover, a recent unpublished survey by the Medical Oncology Group of Australia showed a high proportion of medical oncology trainees would consider regional practice provided there was adequate support. While awaiting this longer-term solution, we also advocate structural reforms such as a national quality assurance framework (eg, service accreditation, and the use of clinical practice guidelines). Investment and improved innovation in delivering psychosocial support services and the coordination of government-funded travel and accommodation schemes are also required in the interim. Telemedicine is another flexible model that should be supported, as it has proven beneficial in reducing the impact of extreme distance.7,8 Distance education and mentoring are also proving effective.9 RCCEs would provide many of these improvements within their region. Inequity in rural cancer survival is not an insurmountable problem, but it is a real test of our health systems. Investment needs to be made now to deliver long-term benefits. The first step is recognising the extent of the problem and identifying practicable solutions. The second step will require a whole-of-government response. Mapping rural and regional oncology services5 — key findings Nationally, 21% of all 157 rural hospitals administering chemotherapy (RHACs) had a resident medical oncology service; 41% had access to a visiting service, with times of availability ranging from weekly to once in 6 months; 38% had neither a resident nor visiting medical oncology service, and this was more likely to occur as remoteness increased. Chemotherapy-trained nurses administered chemotherapy in 61% of RHACs Australia-wide. Chemotherapy was increasingly administered by people other than a chemotherapy-trained nurse, such as other nurses and general practitioners, as the remoteness of RHACs increased. Medical oncologists write most chemotherapy orders in 100% of benchmark metropolitan centres, but only 58% of RHACs reported that most orders are written by a medical oncologist. The degree of supervision and involvement by medical oncologists or haematologists is not always clear. 22% of RHACs had a dedicated palliative care doctor and 59% had dedicated palliative care nurses. 7% of non-metropolitan hospitals that reported administering chemotherapy had access to a radiation unit — a total of 11 radiation units for all 157 RHACs. Of the 26 available radiotherapy machines in regional centres, fewer than half (46%) were reported as fully staffed. Most RHACs provided access to allied health care services, but many reported long waiting times, out-of-pocket expenses or services restricted to inpatients. Multidisciplinary clinics were held in 43% of RHACs. Dedicated oncology counselling services were available at 39% of RHACs. 61% of all RHACs requested urgent access to psychological services and support; 65% indicated travel support was a problem for rural patients. Patient transport refunds were criticised in many returned surveys. Results from the two metropolitan centres and one large regional centre surveyed were used as a benchmark for comparison of service provision in RHACs.

Craig R Underhill MB BS, FRACP · David Goldstein MB BS, MRCP, FRACP · Paul B Grogan

Tackling the problems of men’s health requires a comprehensive national policy Health care service delivery takes into account many patient factors, such as age, ethnicity, socioeconomic status — and sex. While the place of “women’s health” is now well established in health care, many contributors to this special men’s health issue of the Journal believe that “men’s health” has not received sufficient, specific attention. Are they right? Enter “men’s health” into PubMed and you will retrieve about 400 citations; do the same for “women’s health” and you will get about 18 000. Perhaps “men’s health” is a relatively new concept in the coding world. Or perhaps there is uncertainty about what the term encompasses, and thus a tendency to prefer other, better defined, keywords. Should men’s health be largely concerned with the functioning and diseases of uniquely male organs, such as the prostate, penis and testis, and related sexual health concerns? Or, should it be a response to the lower life expectancy and higher rates of many health problems and risk factors for men in our society? In this issue, various perspectives of the developing discipline of men’s health are acknowledged. In Australia, it is well known that men do not live as long as women, and that Indigenous men live nowhere near as long as non-Indigenous men. Less well known is that the mortality rate ratio in Australia in 1998–2000 for men aged 25–64 years in the most socially advantaged group of the population was higher than that for women in the same age range in the most socially disadvantaged group — 218.8 v 206.7 per 100 000 people, respectively1 (see Malcher, "What is it with men's health?" Men, their health and the system: a personal perspective). So, it seems that Australian men in all circumstances are at a disadvantage when it comes to health. Common health problems well known to be more prevalent in men include ischaemic heart disease in men aged 40–74 years2 (see Harris and McKenzie, Men's health: what's a GP to do?) and the metabolic syndrome when two of three commonly used definitions are applied (see Chew et al, Revisiting the metabolic syndrome). Lung cancer in men causes nearly one in four of all cancer deaths in Australia.3 Suicide is higher among males than females in the 15–24-years and the over-65-years age groups.4 Further, one in three men over the age of 40 years reports erectile dysfunction, prostate disease and/or lower urinary tract symptoms (see de Kretser et al, The Men in Australia Telephone Survey (MATeS) — lessons for all). While there can be no dispute that men suffer significant health problems, there is ongoing debate about the contributions of biological, psychological, social and environmental influences on men’s health, including their fertility (see Aitken et al, Male reproductive health and the environment; Cram et al, Y chromosome microdeletions: implications for assisted conception). What also seems to be at issue is whether a male sex-based approach to health care service delivery would (or even could) make a significant difference to health outcomes. Here, the different approaches to men’s health do seem to have several key features in common; in particular, emerging evidence that common stereotypical presumptions about men and their health may not be true. Contrary to commonly held notions, contributors to this issue believe that men do seek to be physically and emotionally healthy and some men do see doctors (see Macdonald et al, Men’s health: Indigenous and non-Indigenous men getting together; Holden et al, Men in Australia Telephone Survey (MATeS): predictors of men’s help-seeking behaviour for reproductive health disorders; Woodhouse, Woody's story: fighting prostate cancer). These contributors also share a conviction that men may be more willing to engage with health care services if such services better met (or, at least, acknowledged) specific needs — for example, the needs of “men who have sex with men” (see Pitts et al, Men who have sex with men (MSM): how much to assume and what to ask?), veterans (see Cooper et al, Mental health initiatives for veterans and serving personnel) or men at particular stages of their life cycle (see Fletcher et al, Addressing depression and anxiety among new fathers; White et al, Is there a case for differential treatment of young men and women?; Handelsman, Testosterone: use, misuse and abuse). Lastly, contributors to this issue of the Journal share a belief that, while there is much that organisations and individual medical practitioners can achieve, our men, our relationships, our families and our society will better benefit if we direct our efforts through coordinated, sustained activity. Such activity might be spearheaded by an Australian national men’s health policy. Such a policy might incorporate and build on as many perspectives as possible, including the social determinants of men’s health (see Macdonald, Shifting paradigms: a social-determinants approach to solving problems in men’s health policy and practice) and existing position statements. Such statements would include the Australian Medical Association’s position statement on men’s health5 and the Royal Australian College of General Practitioners’ position statement.6 Having identified and taken up the baton of men’s health, it’s time for us to keep running with it.

Ann T Gregory MB BS, GradDipPopHealth · Michael P Lowy MB BS, MPM, FAChSHM · Nicholas A Zwar MPH, PhD, FRACGP

Dispelling the belief that men are not interested in their health Despite the well known shorter life span of men compared with women,1 strategies to raise awareness of the burden of disease in men — such as social population health approaches2 — have only recently emerged. While men’s increased risk of disorders such as atherosclerotic vascular disease is well known, there has been little focus on male reproductive health — the emerging specialty of andrology. In particular, the prevalence of disorders such as prostate disease, lower urinary tract symptoms (LUTS), erectile dysfunction, androgen deficiency and male infertility have been poorly defined. The Men in Australia Telephone Survey (MATeS) conducted in 2003 is the first whole-of-nation, population-based study focusing on the reproductive health and other problems of middle-aged and older Australian men3 (Box). As the first accurate picture of reproductive health in Australian men over the age of 40 years, it provides prevalence data not previously available, stratified by age and state. The depth of questioning provides a unique snapshot, not only of reproductive health, but also of issues relating to general health, lifestyle and sexual behaviour.3,4 Ongoing data-mining of this comprehensive dataset may help identify risk factors and potential areas of preventive health. For example, in this issue of the Journal, Holden and colleagues explore the sociodemographic factors that affect help-seeking behaviour of men aged over 40 years with reproductive health disorders.5 But, beyond biomedical outcomes, the MATeS study uniquely challenges several general misconceptions about men’s health. MATeS differs from most other reported population studies in that it covers a broader demographic group; previous studies have been confined to geographic areas, such as Massachusetts in the United States,6 and South Australia,7 or to particular population groups, such as men recruited from general practice.8 The results of MATeS are thus better able to be extrapolated to the entire Australian population of men. In addition, studies on male reproductive health tend to be restricted to single components (eg, erectile dysfunction, LUTS or prostate disease), while MATeS provides prevalence rates for a range of conditions and allows interactions to be explored. Similarly, while the large Australian Study of Health and Relationships (Sex in Australia)9 has provided the cornerstone of research and understanding in Australia on sexual health, behaviour and relationships in a younger population (aged 16 to 59 years),10 its findings cannot be directly extrapolated to an older population. MATeS is thus unique in allowing us to challenge existing men’s health constructs for this older age group. Firstly, MATeS demonstrates that significant numbers of men are affected by reproductive health disorders, with one in three men over the age of 40 years reporting erectile dysfunction, prostate disease and/or LUTS. Prevalence rates in the over-40-years age group are: erectile dysfunction, 21%; LUTS, 16%; prostate disease, 14%; and infertility, 8%. The rates of the first three conditions increase sharply with age. While these conditions are not considered life-threatening, the significant numbers of men affected and the potential link with other chronic diseases, such as cardiovascular disease, hypertension, diabetes and depression,6,11 highlight the need to educate both the community and health professions to ensure reproductive health disorders are not overlooked or dismissed. They may be early warning signs of more serious disease. Secondly, the study challenges the belief that men are not interested in or concerned about their health.1 Almost 90% of men aged over 40 years had visited a doctor in the 12 months before interview, and men expressed high levels of concern about developing reproductive health problems as they age: 80% were concerned about developing erectile dysfunction, and 57% about developing prostate cancer.3 However, the study suggests that men are selective about the issues they will discuss openly, and the social, cultural and environmental influences that modulate such health behaviours need to be better understood. In a clinical setting, these barriers need to be overcome by allowing men, particularly older men, opportunities to disclose reproductive health concerns that may otherwise remain unspoken. Health promotion strategies that address men’s health concerns may assist in overcoming barriers to help-seeking behaviour.5 Examples include targeted health education sessions and promotional displays as part of other social events, such as community men’s health nights,12 and workplace or local community events.13 Thirdly, MATeS achieved a high response rate of 78%. Not only does this response rate ensure the validity of the dataset, but it also demonstrates the acceptance of this research by the target group, which is commonly considered to be more difficult to recruit and is often excluded from studies on sexual health.14 Finally, MATeS also challenges the widely accepted notion that older couples are sexually inactive (37% of men aged over 70 years were sexually active4), thereby implicitly dismissing their sexual health needs in many settings. The inclusion of older couples in sexual health studies needs to be considered as part of the healthy ageing research agenda, as relationships and sexual expression are a key component of ongoing good health across the life span. In addition, medical practitioners and allied health professionals need to consider that sexual relationships remain important for many couples as they age, and should not be overlooked or dismissed on the basis of patient age. A progressive decline in male reproductive health with advancing age is well recognised.3,6 However, the physiological causes of this decline may be multifaceted and influenced by lifestyle, social, cultural and environmental issues. Population-based studies of the incidence and progression of disease and related health issues are necessary components of public health and health outcomes research to allow the development of strategies for promotion, prevention and intervention. This was recognised in 1995 when the Commonwealth Department of Health and Aged Care commissioned the Australian Longitudinal Study of Women’s Health to assess a wide range of women’s health and health-related issues.15 Although longitudinal studies of men’s health issues have been conducted overseas,6 there is no similar study in Australia. With Australia’s increasingly ageing population, MATeS provides the impetus for a formal longitudinal study to help us understand the impact of social and biomedical determinants on the health of middle-aged and older Australian men. This would help us to lessen the burden of disease and ensure that quality of life and wellbeing are maintained as far as possible in later life. Outcomes from such a longitudinal study would potentially help the development of better clinical management options for men as they approach their middle years. An effective men’s health research agenda should be implemented in Australia to coordinate the research effort, involve the many and varied stakeholders, address the prevailing assumptions in men’s health, and develop a sound evidence base for future policy and practice. However, any development of men’s health research should not be used to argue for a diminution of the existing emphasis on women’s health. Instead, it should be recognised that biological and sociocultural factors can profoundly affect the behavioural responses of both sexes to disease, the environment and the stresses of life.1,16 Overview of MATeS (Men in Australia Telephone Survey)3-5 Design A representative sample of men aged 40 years and over was contacted from 7636 households which had been randomly selected from the Electronic White Pages. Unbiased sampling stratified by age (40–49, 50–59, 60–69 and 70 + years) and across all states and territories. All men participated in a 20-minute computer-assisted telephone interview exploring general and reproductive health, including related knowledge and beliefs, and sociodemographic and lifestyle factors. Participants 5990 men participated from 7636 randomly selected households, with an individual response rate of 78%. Outcomes High rates of reproductive health disorders and related concerns. A low level of specific enquiry and treatment for reproductive health disorders. This suggests that opportunities to talk to general practitioners about reproductive health problems are being missed. A strong link between reproductive health disorders and age. This suggests that more men will seek help in the future.

David M de Kretser MB BS, PhD · Megan Cock PhD · Carol Holden PhD

Are xenobiotics in the environment affecting fertility in Australian men? Australia is one of a long list of nations experiencing a recent and dramatic decline in fertility rate.1 The reasons behind this trend are complex, recent, and generally appear to be independent of the socioeconomic status of the country. Deferred childbearing and improved contraceptive use are undoubtedly major factors. However, it is also intriguing that population growth is below replacement rate in several countries such as Sri Lanka, Denmark and Spain, where there have been no obvious increases in abortion rates or contraceptive use. This loss of fertility has affected countries such as Denmark to the point that about 7% of all newborn babies are now being generated by assisted conception.2 In Australia and New Zealand, the number of babies born as a result of assisted conception procedures has increased threefold over the past 10 years and, despite recent increases, our birth rate is still well below that needed to maintain the population at its present level. Although it has long been acknowledged that both male and female partners contribute to human infertility, the past 20 years have witnessed a growing awareness of the importance of the male factor in the aetiology of this condition. Indeed, the late Mike Hull and colleagues asserted that defective sperm function is the largest single, defined cause of human infertility.3 Current estimates suggest that one in 20 Australian men suffer some degree of infertility.4 Human semen quality is notoriously poor compared with other mammalian species, and in some major capital cities, such as Paris and Copenhagen, there is evidence that it is getting poorer over time.2 Whatever factors are responsible for this deterioration in semen quality, they do not appear to be universal, because in other areas, such as Finland5 or the United States,6,7 similar changes have not been found. Nevertheless, at present, 30% of young Danish men seem to have sperm counts that are in the subnormal range according to World Health Organization guidelines and, in 10% of this population, the semen parameters are indicative of substantially reduced fertility prospects.2 The particularly low sperm counts recorded in Denmark are linked with other male reproductive pathologies, including one of the highest rates of testicular cancer in the world and an increasing occurrence of other male genital tract abnormalities such as cryptorchidism and hypospadias.2,8,9 The increasing incidence, severity and interdependent nature of these pathologies has led to the suggestion that some cases of male infertility should be grouped together with other reproductive problems under one heading — the testicular dysgenesis syndrome (TDS).2,10 Further, it has been proposed that environmental factors are involved in the aetiology of TDS and that these factors have their effect during early fetal life, when the male genital tract is attempting to differentiate away from the default female condition.2 Whether the outcome of TDS is impaired spermatogenesis or testicular cancer may depend on the timing and nature of the xenobiotic attack and the genetic background on which these factors are acting. In this context, a key factor will be the patient’s polymorphism profile for proteins involved in detoxification, such as the cytochrome P450s and glutathione-S-transferases. An important and intriguing feature of the pathologies comprising TDS is the way in which their incidence varies in different regions of the world. In northern Europe, for example, Denmark has high rates of testicular cancer and low sperm counts, but Finland has the opposite — high sperm counts and low rates of testicular cancer.2 Such geographical variability, coupled with the rapidity with which male reproductive pathologies are increasing in affected countries, suggests an important contribution from environmental factors, including modern Western lifestyle.11 This conclusion is supported by analysis of the incidence of testicular cancer in the offspring of Nordic parents who have migrated to Sweden, which adjusts to the rate typical of the host country.12 If environmental factors are truly responsible for impaired semen quality or testicular cancer, what kind of agents could be involved? Industrial growth since the end of World War II has introduced many complex chemicals into the environment that are novel to biological detoxification systems. Some of these molecules are reproductive toxicants, capable of impairing fertility and inducing developmental abnormalities in the embryo, including errors in normal sexual differentiation. To some extent, the inadvertent introduction of such toxicants reflects the complexity of the safety evaluation process, given the large numbers of xenobiotics used in modern industrialised societies. It may also reflect the inadequacy of the animal models used for screening purposes and a certain lack of commitment on the part of the regulatory agencies to undertake detailed analyses of reproductive toxicity. In societies dependent upon the chemicals industry, there is clearly a trade-off between economic and social advantage on the one hand and the aspiration to eliminate all risk on the other. A well celebrated example of such an effect is the ability of environmental endocrine disruptors (including certain insecticides and detergent-derived products) to impair male sexual development in aquatic species, including oysters, alligators and fish.13 Another example, closer to home, is the ability of vinclozolin, a fungicide used in the wine industry, to disrupt the fertility of male rats.14 Alarmingly, just one exposure of a pregnant female rat to this fungicide was found to disrupt spermatogenesis in more than 90% of the male offspring for at least four generations via an effect that was exclusively transmitted through the male germ line. The power of reproductive toxicants that target the germ line lies in their capacity to generate damage that can be passed down the generations via genetic or epigenetic means. Both vinclozolin and the pesticide methoxychor induce epigenetic changes in male germ cells, giving the resultant spermatogenic defect a high level of penetrance into subsequent generations. Genetic changes in the germ line may be less efficient in generating transgenerational pathological phenotypes, but they are nonetheless important. Paternal smoking provides one example of such a genetic change. Men who smoke heavily generate spermatozoa that suffer from high levels of DNA damage, largely as a result of oxidative stress. One of the consequences of this DNA damage is that the children of such men exhibit an increased incidence of childhood cancer.15 While we have traditionally focused on the ability of cigarette smoke to induce lung cancer, a far more sinister effect of this activity is its ability to induce DNA damage in the germ line and thereby influence the health and wellbeing of future generations. We are probably all carrying around in our genes the genetic legacy of our great-grandfather’s pipe-smoking habit. In light of such data, the search for reproductive toxicants is now being joined in earnest. Groups of toxicants that might be involved in the aetiology of male infertility and possibly TDS include phenols (including oestrogen-like compounds) and phthalate esters, both of which are heavily represented in the environments (including food) of industrialised countries. Such compounds may exert their genetic or epigenetic effects on the germ line via several potential routes of exposure. Firstly, women may be exposed to xenobiotics during pregnancy, thereby disrupting the normal differentiation of the germ line in the fetus; vinclozolin is a good example of such a reagent. Secondly, women exposed to toxicants may transmit xenobiotics to their offspring via breast milk. A third possibility involves paternally mediated toxicity through effects on DNA integrity in the male germ line. Once male germ cells have completed meiosis, they lose their capacity for DNA repair, discard their cytoplasm (containing the defensive enzymes that protect most cell types from oxidative stress) and eventually become separated from the Sertoli cells that have nursed and protected them throughout their differentiation into spermatozoa. In this isolated state, spermatozoa must spend a week or so journeying through the male reproductive tract and, uniquely in our species, a further period (up to 3 or 4 days) in the female tract waiting for an egg. During this period of isolation, sperm DNA is vulnerable to damage by both xenobiotics and electromagnetic radiation. Such DNA damage is associated with male infertility, and its aberrant repair in the fertilised egg may result in mutations in the embryo with the potential to either induce abortion or impair the health and fertility of the offspring.11,16 Toxicological studies in animal models reporting infertility, abortion and birth defects as a result of male exposure to xenobiotics demonstrate that such associations are possible.16 Epidemiological studies suggest that they are clinically significant.2,8 In conclusion, male infertility is a common condition that affects one in 20 Australian men. Although there are no data to suggest that semen quality in Australia is deteriorating with time, testicular cancer rates are rising in every state, and this may suggest an environmental effect on germ cell development. That exposure to environmental chemicals can impair semen quality is clearly plausible and, in some heavily polluted environments of Europe, such effects are clearly evident.2,17 However, it should be emphasised that most of the human data are correlative and involve mechanisms that await resolution. In light of the extensive efforts that are being made in Europe and the US to monitor the effects of toxicants on reproductive processes, there is clearly pressure on the equivalent Australian authorities to establish whether environmental factors are to blame for the significant rates of testicular cancer and infertility seen in Australian males.11

R John Aitken PhD, ScD, FRSE · Niels E Skakkebaek MD · Shaun D Roman PhD

Australians look forward to dividends from increased funding Despite our relatively small population, Australia has made an impressive global impact in health and medical research (HMR). Our research output is twice the Organisation for Economic Co-operation and Development (OECD) average on a per capita basis,1 with high international visibility by citation,2-4 and Australia boasts five Nobel Prizes in Physiology or Medicine. HMR is a “golden egg”. Its consequences — disease prevention, improved longevity and quality of life — reduce hospital admissions and stays, and contribute to both workforce productivity and wealth creation. Examples of outstanding success in Australian translational HMR include Frazer’s cervical cancer vaccine, Cade’s use of lithium for treating bipolar disorder, Clark’s bionic ear technology, and Marshall and Warren’s unravelling of the role of Helicobacter pylori in peptic ulcer. The Access Economics report commissioned by the Australian Society for Medical Research in 2003 put figures on the value of the golden egg: every dollar invested in health research and development (R&D) yields an average annual return of $5.5 Despite these successes, and the Australian Government’s visionary legislation for a 6-year phased-in doubling of the National Health and Medical Research Council (NHMRC) budget enacted in 1999, Australia has slipped down the OECD ladder in terms of government spending on health R&D (this was 0.12% of gross domestic product [GDP] just a few years ago, compared with the OECD average of 0.2%).1 Many of Australia’s best and brightest health and medical researchers, judged by their peers to be in the top 10% internationally, have been missing out on NHMRC Fellowship support (almost 35% of applicants scoring in the “excellent” category were not funded in 2005). Moreover, without further increased HMR spending, projections indicate that success rates for Fellowships would fall by a further 50% by 2011, with project grant success rates dropping from 21% in 2006 to 8%–9% in 2011. This 5-year scenario, however, was averted in the May federal budget when the government allocated an additional $905 million for HMR. This injection was universally applauded and includes $670 million to be administered by the NHMRC, made up of $500 million over 4 years for research grants, and $170 million for Australian HMR Fellowships which will run over the next 9 years supporting 50–65 outstanding researchers over 5-year terms. The $500 million for grants will be incorporated into NHMRC’s base allocation for research, increasing this from $420 million in 2006 to over $700 million by 2010. The NHMRC will continue to serve as the main administrator of these funds, as it should, for transparency and equitable distribution based on peer review. The remaining $235 million earmarked in the federal budget for HMR will support adult stem-cell research ($22 million) and infrastructure and capital works programs shared among 17 research facilities nationally ($213 million). This is on top of the $200 million in infrastructure provided to institutes last year, builds on Wills’ Strategic review,2 and is the government’s response to the 2004 Grant Investment review.1 The NHMRC has now become a statutory agency. This development strengthens its independence and facilitates clear lines of responsibility for governance and financial accountability. Increased funding coupled with this restructure provides a key opportunity for the NHMRC to improve HMR outcomes through new strategic initiatives, wide-ranging stakeholder consultation, organisational resource-building, and articulating its vision and plan early in its triennium. A recent editorial in the Journal suggested that much of the NHMRC’s success under the new governance structure would be dependent on effective leadership by the new Chief Executive Officer (CEO), who now reports directly to the Health Minister.6 The NHMRC’s new CEO is Warwick Anderson, past Head of the School of Biomedical Sciences at Monash University, and its Chair is Michael Good, Director of the Queensland Institute of Medical Research. In April last year, Anderson described 10 challenges for Australian HMR, which included the capacity to respond rapidly to national and international health needs, improving collaborative links, enhancing our strong record of discovery-based research, and developing a more “wide and deep” workforce.7 Effective change will require a fresh look at policy by the NHMRC and all levels of government, for example, by (i) encouraging increased private sector investment from sources “outside the square” (eg, health and superannuation funds, life insurance companies), possibly through tax incentives; (ii) expanding established schemes (ie, development grants) for increased leverage of non-government monies; (iii) greater recognition of high-performing “David” (rather than “Goliath”) research organisations, that may be embedded in universities and hospitals, with adequate infrastructure support; (iv) restoring faith in career structure for the nation’s best health and medical researchers (eg, narrowing the growing gulf between Career Development Awards and Fellowships; providing local allowances for Fellows just as allowances are provided to C J Martin overseas postdoctoral Fellows depending on location; and encouraging more clinician–scientist researchers into the sector); (v) increased state government support of HMR, building on local strengths in technology and innovation (eg, “Smart State” and “Health Futures” initiatives); (vi) ensuring Australia’s record of groundbreaking fundamental research is not compromised by the “translational (applied research) wave”; and (vii) ensuring health services and population health research continue to develop in capacity and quality, as these will be increasingly relied on as the population ages and socioeconomic differentials widen. The longer term needs to be in our sights, and we should be mindful of sustainability in the post-2010 era, particularly if issues arising from the now complete doubling of the United States National Institutes of Health budget are any guide.8 This is true of the Australian HMR Fellowship scheme, which will attract top scientists (including the most senior NHMRC Fellows, presumably drawing more junior Fellows into the existing scheme), yet the program’s fate is unclear after individual terms. Moreover, even with increased HMR investment, which starts with a modest (around 5%) increase in 2007, the NHMRC has received close to 30% more applications for project grants this year compared with 2005, which may negatively impact on success rates, and mean missed opportunities for knowledge, health and wealth creation unless additional funds can be sourced for 2007. This becomes more of a concern in the current evaluation round, despite commendable intentions of improving efficiency and reducing “reviewer fatigue”, given the absence of external peer review or the opportunity for applicant rebuttal. Mechanisms of perpetually increasing funding for HMR should therefore be explored and debated. This could include indexing the HMR budget to the health budget or the OECD average for government HMR funding. Investment in HMR is vital and should be an ongoing priority for any government in the developed world. Greater funding will help Australian researchers build on previous gains, and turn both curiosity-driven and priority-driven knowledge into new medicines and treatments, with flow-on health, social and economic returns nationally and abroad. We are opening an exciting new chapter in Australian HMR and I can’t wait to turn the pages.

Levon M Khachigian PhD, DSc

Napping at night may benefit both health professionals and their patients Delivering medical care is a 24-hour business that inevitably involves working the night shift. However, night shift requires the health professional to work when the body’s clock (circadian system) demands sleep. Added to this is the problem of “sleep debt”, arising from both prolonged prior wakefulness on the first night shift and cumulative sleep debt after several nights’ work and repeated unsatisfactory daytime sleeps. A further aggravation, particularly for trainee medical staff in teaching hospitals, has been the demand for excessive work hours across the working week. As has been dramatically shown in recent well controlled studies, the net result of this assault on the sleep of health professionals can be impaired patient safety,1 and the health and safety of health professionals themselves.2 The good news is that health organisations and regulators are beginning to treat the matter seriously. In Australia, the United States and Europe, work hours of medical staff have recently been shortened by government regulation, and bodies such as the Australian Medical Association and professional colleges are advising their members on strategies to improve their sleep health and thus work safety. A recent publication prepared by the Royal College of Physicians (London) (RCP), Working the night shift: preparation, survival and recovery. A guide for junior doctors, is an excellent example.3 One proposed countermeasure for excessive sleepiness is the use of strategically placed naps both before and during the night shift. But does napping either before or during the night shift reduce sleepiness and improve performance, and, if so, how practical is it? There are two important, independent mechanisms of sleep and sleepiness that hold the key to these questions.4 Probably the more potent mechanism impairing night-shift alertness is the circadian system. For most individuals, even those working permanent night shift, the circadian system is in sleep mode during the night. This causes slowed reactions, increased feelings of fatigue, impaired concentration, and increased sleep propensity. The second important mechanism affecting night-time alertness is homeostatic sleep drive. This increases in intensity the longer we are awake and, like appetite which is sated by eating, homeostatic sleep drive is reduced by sleeping. If the first night shift starts at midnight following a normal wake time at about 8 am, about 16 hours of wake sleep debt has already been accrued and the rest of the night shift will be performed under intense homeostatic, in addition to circadian, sleep drive. Performance decrements during this night period can be similar to those measured in the daytime with a blood alcohol concentration of 0.05%–0.10%.5 Day sleep in the home environment is likely to be shorter and less effective than night sleep so, even though second and subsequent night shifts may follow fewer wakeful hours (8–10 hours), homeostatic sleep drive is likely to remain elevated during night shifts because of incomplete repayment of the previous sleep debt. To a limited extent, it is possible to “bank” sleep (or pay off residual sleep debt) before the first night shift, potentially reducing subsequent night-time homeostatic sleep drive and improving alertness and work safety. A long (1–2 hours) nap in the afternoon, as recommended in the RCP report, is best. Afternoon sleep is more efficient than early evening sleep as it uses the natural afternoon “dip” in circadian physiology6 and avoids the risk of post-sleep grogginess or sleep inertia impinging on the start of night duty. Between subsequent night shifts, the aim should be to maximise daytime sleep length (at least 7 hours) and efficiency by including the afternoon sleepy period (1–4 pm). What about napping during a night shift to improve alertness and reduce errors and accidents? Brief afternoon naps of 10–30 minutes (so-called power naps) improve alertness and performance. We compared afternoon naps of 5, 10, 20, and 30 minutes of total sleep.7 The 10 minute sleep (about a 15 minute nap opportunity) produced improvements over the 3 hour post-nap period in all eight alertness and performance measures, without any of the post-nap impairment of sleep inertia that followed the 20 and 30 minute naps. Whether these results would be replicated at, say, 3 am in a night-shift environment, with considerably greater homeostatic and circadian sleep drive, is now being tested. Only a few studies have measured the effects of night-shift napping. Long naps of about 2 hours appear as effective at about 3 am as at 3 pm.8 However, 1–2 hour naps were followed by sleep inertia, during which alertness was impaired for up to an hour.9 Longer naps, although beneficial once sleep inertia has been dissipated, may be used reluctantly by medical staff wishing to maintain continuity of patient care.10 Briefer naps (18–26 minutes) have also improved performance in night-shift environments.11 Therefore, the picture emerging from night-shift napping studies is similar to that from the afternoon studies. Very brief naps (10–15 minutes of sleep) may improve alertness immediately without the negative effects of sleep inertia. How long this improvement lasts and what is the optimal nap length on the night shift remains to be determined. In the meantime, as recommended in the recent RCP guide, health professionals who work night shift should, for the sake of their own health and safety and that of their patients, consider the benefits of night-shift napping. Optimal benefit and a higher take-up rate are likely for sleep lengths of 10–15 minutes.

R Doug McEvoy MD, FRACP, BMedSc · Leon L Lack BA, PhD

Medicare funding could jeopardise the research needed to establish the benefits and risks of this procedure Recent publications and regulatory decisions about the therapeutic use of vertebroplasty, or injection of bone cement into diseased vertebrae such as osteoporotic fractures, call for a closer look at the evidence. New drug treatments are not considered to have proven efficacy until, at the very least, they have been evaluated in randomised controlled trials. Even then, their safety is not guaranteed, particularly for uncommon adverse effects, or those for which there is a long delay between exposure and clinical manifestation. Adverse effects that have a high prevalence may also be difficult to detect, as exemplified by the much-delayed recognition of the association between myocardial infarction and strokes and rofecoxib.1 In Australia, drugs must also be shown to be cost-effective compared with existing subsidised treatments before they are accepted into the Pharmaceutical Benefits Scheme. The Medical Services Advisory Committee (MSAC) recently recommended vertebroplasty for interim public funding for restricted indications, including painful osteoporotic vertebral compression fractures confirmed by diagnostic imaging and not controlled by conservative medical therapy.2 While technology appraisals of vertebroplasty by health policymakers in a variety of settings, including Australia, have recognised that there is inadequate high-quality evidence on which to base a reimbursement decision, many have subsequently recommended public funding.3 Making these reimbursement decisions in the face of limited evidence raises some concerns. Firstly, while uncontrolled studies have suggested that vertebroplasty may be an efficacious treatment for painful osteoporotic spinal fractures not responsive to conservative management, uncontrolled studies tend to overestimate treatment benefit for a variety of reasons.4 They fail to take into account the natural history of the condition, which is that it improves over time; they make no allowance for the statistical artefact of “regression to the mean”; and they do not adjust for the placebo response, which is likely to be accentuated with an invasive procedure.5 At present, the best available evidence for efficacy of vertebroplasty are data from two controlled before–after studies that compared volunteers who were offered the treatment with those who refused it.6,7 This constitutes level III-2 evidence in the National Health and Medical Research Council (NHMRC) hierarchy of levels of evidence, which ranges from I for the highest level to IV for the lowest level.8 While these studies showed an early benefit of vertebroplasty over conservative treatment, it is likely that they too have overestimated the treatment effect,9 particularly as volunteers who agree to have a new therapy are known to have a better outcome than those who refuse it. Patient self-selection bias in one study meant that, in comparison to those who refused treatment, those who agreed were considerably more disabled at baseline and so had more potential to improve.6 Participants in the other study were treated relatively early after presentation with an acute vertebral fracture, and most of them were admitted as inpatients, so the results may not be relevant to patients who have had pain for longer than a few weeks.7 Of more concern than questionable efficacy is the potential for harm. The risk of subsequent vertebral fracture once a spinal fracture has occurred in patients not exposed to vertebroplasty is very high — the risk within a year of a single vertebral fracture has been estimated to be about 20% in those with untreated osteoporosis and about 10% in those treated with bisphosphonates.10 Several uncontrolled studies have now suggested an increased incidence of vertebral fractures after vertebroplasty, particularly in vertebrae adjacent to treated levels or if cement has leaked into the adjacent disc,11,12 while the two controlled before–after studies have yielded conflicting results in this regard.6,7 Yet, like heart attacks and strokes with rofecoxib, in the absence of rigorous controlled trials that are powered to detect an increased incidence of an already prevalent condition, this may take time to become evident. Furthermore, while the risk of immediate complications (such as cement leakage into the spinal canal, adjacent disc and venous circulation) from the procedure when it is performed by experienced operators, is estimated from published case series to be low, it is likely that the incidence of immediate complications will be higher in routine use, where there is likely to be a learning curve, and there are no restrictions on who can perform the procedure.13 Now that proponents of vertebroplasty have the imprimatur of MSAC approval, promotion of this procedure to the medical community and the public has intensified. For example, a recent “advertorial” in Australian Family Physician claimed that vertebroplasty is a safe, effective, and cost-effective procedure when performed in an appropriate technical environment by adequately trained interventional radiologists.14 Yet, as outlined above, the available evidence is weak and does not justify these strong claims. The way forward is to gather the necessary evidence. To this end, a multicentre, randomised, double-blind, placebo-controlled trial of vertebroplasty for painful osteoporotic spinal fractures has been funded by the NHMRC and is currently underway in Australia. In addition to gathering evidence on short-term efficacy, all trial participants are being followed up for 2 years so that the question of long-term safety and, in particular, risk of future fractures can be assessed. However, public funding of vertebroplasty through Medicare has the potential to seriously undermine the success of this and other trials by not only providing easy access to an unproven treatment, but also by lending implicit support to its use. This may result in a situation where the true effects of this treatment may never be established. At present, the trial has recruited almost a quarter of the required sample and, at the current rate of recruitment, is expected to be complete within 4 years. A second randomised, double-blind, placebo-controlled trial of vertebroplasty for osteoporotic spinal fractures is in progress in the United States. These trials will provide pivotal evidence on the value of vertebroplasty. At present, vertebroplasty, while promising, is of unproven safety, effectiveness and cost-effectiveness. Thus, the promotion and routine use of this procedure outside of the research setting remains unjustified and premature, and the onus remains on the proponents of vertebroplasty to prove their claims. Primum non nocere, or first, do no harm.

Rachelle Buchbinder MB BS(Hons), MSc, FRACP · Richard H Osborne PhD

Rotavirus vaccines are finally available, and introducing them into the routine vaccination schedule will have a significant impact on the health of children After a dramatic false start, oral rotavirus vaccines are now available to prevent severe, dehydrating diarrhoea in small children. Rotavirus infection in children can be as severe as cholera in adults, but affects a group who cannot complain. Since its discovery in Australia in 1973, rotavirus has become accepted as the single most common cause of severe diarrhoea in children worldwide. It still kills over 500 000 young children each year. In Australia, it is estimated that 10 000 children require hospitalisation annually1,2 (more than 4000 actually coded for proven rotavirus3), and as Schultz reports in this issue of the Journal, the impact on Indigenous children is especially severe.4 Oral rehydration has greatly reduced mortality, but the World Health Organization recognises the potential of rotavirus vaccines to further reduce under-5-year mortality rates, Goal 4 of the Millenium Development Goals.5 It is exciting to have two efficacious oral rotavirus vaccines, RotaRix (GlaxoSmithKline [GSK], Boronia, VIC) and RotaTeq (Merck/CSL, Parkville, VIC) licensed this year in Australia. Each has been extensively tested in placebo-controlled trials of more than 60 000 participants. Both vaccines prevented severe disease, and reduced the need for hospitalisation by 85%–94%. There was a reassuring lack of intussusception, a rare (one in 10 000–32 000) event associated with RotaShield, the first licensed rotavirus vaccine, which led to its withdrawal from the United States market in 1999, just 12 months after its introduction.6 Re-analysis of the data suggested that the intussusception risk emerged in infants receiving the first vaccine dose after 3 months of age.7 Thus both GSK and Merck/CSL state that the first dose should be administered before that time. Several issues remain to be resolved with these two new vaccines. Efficacy has not been established in developing countries. Availability will depend on distribution (including the need for a cold chain), the ability to piggyback rotavirus vaccines with other routine vaccinations, and manufacturing capacity. The greatest uncertainty is the cost of the vaccine. Current prices exceed $200 per course in the private market. While tier pricing and subsidisation by international agencies for poorer countries is being considered, it is not clear whether these mechanisms will sustain programs in most parts of the world. Hence, other candidate vaccines linked to developing country manufacture are under early development in China, India, Indonesia and elsewhere. Who should get rotavirus vaccine in Australia? Ideally all children under 3 months of age, as all will eventually be exposed to rotavirus, and one in 25 will be admitted to hospital for rotavirus gastroenteritis during the first 5 years of life. Morbidity across our country is high. Apart from the 10 000 annual hospital admissions, there are 22 000 visits to emergency departments and 115 000 visits to general practitioners.2 Nosocomial infection rates are as high as 14% in children’s hospital wards and may be higher in childcare centres.8,9 Schultz’s report indicates that Indigenous children have 2–4 times the disease burden of non-Indigenous children.4 Gastroenteritis in Indigenous children comes with comorbidities and a significantly increased average length of hospital stay. Add to that the large costs of air transport of patients for hospital admission in northern and western Australia and the disruption to remote families, and the case for rotavirus vaccination of Indigenous infants becomes compelling. The Northern Territory Health Department recognised the importance of rotavirus infection by making it a notifiable disease, and Queensland recently followed suit. Breaking news is that from October 2006, the NT Government will include rotavirus vaccine in the routine vaccination schedule for NT children.10 The only real issue is cost. A 1999 cost–benefit analysis suggested that break-even vaccine cost was $78 per course,11 somewhat less than current prices. However, the community should be prepared to pay something to prevent this wretched disease. For maximum benefit, the first dose should be given before 3 months of age. Infants under 6 months of age accounted for 24% and 9% of rotavirus gastroenteritis cases in studies in the NT and Melbourne, respectively.4,12 In Africa, many infants are infected in the first 2 weeks of life.13 There is enthusiasm for giving the first dose of vaccine within the first month of life, but neither licensed vaccine has been tested at this age. Roll-out of a universal program in Australia has a few caveats. The inevitable concern about intussusception, in spite of the reassuring clinical trial results, probably means that catch-up campaigns, where the first dose is given after 3 months of age, will not happen. Evidence of the spectrum of protection afforded by both vaccines against the full range of human rotavirus serotypes is still lacking. There is a need to continue national strain surveillance to ensure that the current vaccines are appropriately protective against the range of serotypes in Australia, and to monitor the effect of vaccine pressure on the evolution of strains. After three decades, there is real excitement at suddenly having such an effective tool to prevent a common, miserable disease affecting infants and children. Rotavirus vaccination is not only justified on the basis of disease burden, but will be welcomed by all who care for sick children. It will not be hard to measure real improvement for Indigenous children in the NT, given the baseline data presented elsewhere in this issue of the Journal.4 While other candidate vaccines are in development, there is no excuse for waiting any longer for a national program. The improvement in child health will be obvious.

Graeme L Barnes MD, FRACP · Ruth F Bishop AO, DSc, PhD

It is in doctors’ and the drug industry’s best interests that their interactions be openly declared There is no such thing as a free lunch. Pharmaceutical companies lavish meals, five-star travel, cash and gifts on doctors for one reason: to encourage them to prescribe their drugs. The standard retort from the medical profession is that doctors have sufficient clinical objectivity — and personal integrity — not to be so crudely swayed. Perhaps so.1 The interaction between doctors and the pharmaceutical industry was recently catapulted into the public domain by a piece of investigative journalism published in The Australian, detailing the wining and dining of doctors by the pharmaceutical giant, Roche, at an educational meeting in Sydney.2 What surprised many observers was not the revelations regarding the extent of hospitality provided by pharmaceutical companies to doctors, but the response of the Australian Medical Association (AMA). The AMA’s public stance was that pharmaceutical industry sponsorship of accommodation and restaurant meals is perfectly acceptable, that drug company sponsorship serves to “oil the wheels” of medical education, and that industry-sponsored events provide valuable opportunities for doctors “to critically question the companies’ products” and that “no patient harm comes from this practice”.2 A review of the literature, however, suggests that this is not true.3,4 The Australian Competition and Consumer Commission (ACCC) had a differing view. Following the recent release of the ACCC’s revised guidelines for disclosure of industry support, the Chairman of the ACCC noted that “Consumers should be able to have confidence that decisions made by their doctors are made solely having regard to their best interest without any potential for influence by benefits or perks”.5 Stated in these terms, the issue is not so much the pharmaceutical industry itself, but the prevention, assessment and management of conflict of interest and, more fundamentally, the importance of public trust in doctors. The moral core of medicine and the therapeutic relationship has always been expressed in terms of the possession and expression of values such as honesty, integrity, benevolence, respect, compassion, courage and trustworthiness. Trust, which in relation to health care may denote faith, commitment, respect, belief and confidence, has been the focus of extensive academic exploration by a broad range of writers.6-10 All have pointed to the centrality of trust in therapeutic relationships, the “non-legal” expression of trust, the specific and contextual nature of trust and the manner in which trust can be threatened, diminished or destroyed by actions or behaviour including professional incompetence, abuses of power, boundary violations, experience of harm or the lack of care or respect, deception and manifest conflicts of interest.11 Of those things that may damage trust in doctors, much of the attention in recent years has been on recognising and managing conflict of interest. What then constitutes a conflict of interest and how may we avoid it occurring? Although medical codes of ethics and statements of medical professionalism often give the impression that doctors have a single higher duty to care for the sick, in reality, the relationships that doctors have with their patients are determined by multiple interests, many of which may influence care or decision making. Doctors may hold patient care as their highest professional ideal, but they may also be concerned with community welfare, participation in research, career advancement, student teaching, continued employment, public or professional recognition, and the obligations they have to their care for themselves and their families. While it is inevitable that doctors will have multiple interests, true conflicts of interest (a set of conditions in which professional judgement concerning a primary interest, such as a patient’s welfare, is unduly influenced by a secondary interest, such as financial gain) are neither inevitable nor common.12 But distinguishing where there are no conflicts between these interests from where there is a genuine conflict of interest is sometimes difficult, as any assessment of behaviour must take into account the ethical standards of the profession, the nature of the relationship in question, and the values of the community within which it occurs. What makes this assessment even more difficult is that standards of doctors’ behaviour may change as a consequence of deeper sociocultural changes, and according to changes in professional interests, and changes in public or patient needs and expectations. This means that the only way to establish that a conflict of interest exists is to have all the relevant facts available for scrutiny by the participants in the relationship, and by the community or an independent third party. This is only possible if there is a genuine commitment to disclosure and transparency in all areas of medical practice. Unfortunately, a review of the history of medicine suggests that the medical profession has, until recently, generally been reluctant to be exposed to public scrutiny, either out of fear of legal or social repercussions that may result from such disclosure, or on the grounds that that there is no need for it or no public desire for it. Although such concerns may be understandable, for the most part they are unfounded. Transparency and honest disclosure may actually reduce loss of trust, formal and informal complaints and litigation, and it is the culture of secrecy and sense of moral superiority that sometimes runs through the health professions, rather than “unnecessary” exposure to a disinterested public, that threatens public trust and undermines the doctor–patient or researcher–patient relationship. In this regard, it is of note that a recent randomised trial in the United States of disclosing doctors’ financial incentives to patients found that patients’ trust in their doctors was unharmed, and their loyalty to their doctor’s practice was strengthened.13 Therefore, it is hard to disagree with the ACCC that there is merit in increasing the degree to which the relationships between doctors and the pharmaceutical industry are transparent. It may, as has been claimed, ultimately prove to be the case that these relationships do not give rise to conflicts of interest and that the ACCC’s new reporting requirements are excessive or unreasonable, but at this stage we do not know that this is true, and we have ample evidence that interaction with industry can create complex and dependent relationships and influence decision making, prescribing, formulary requests, attitudes and knowledge regarding pharmaceuticals and therapeutics, and the design and interpretation of research.14 In light of this, it is in doctors’ and the industry’s best interests that their interactions be openly declared in the relevant context. This will enable informed public and professional consideration of the legitimacy of each group’s interest and determination of whether a conflict of interest exists and what measures should be taken to deal with it. There are many means for encouraging transparency, responsibility and accountability in health care, including the incorporation of ethics in medical education; support for inquiries into professionalism and trust; introduction of templates for disclosure of secondary interests in the research and clinical setting;15 development and compliance with codes of ethics by the major medical colleges and industry groups; incorporation of patients’ representatives and conflict of interest committees into hospitals; and establishment of health care complaints commissions by government. All are deserving of support, even though currently there are insufficient data to evaluate the effect of most such interventions. Given what we know about the fragility of trust in medicine and the interaction between doctors and the pharmaceutical industry, the profession should support moves to increase disclosure. Even though disclosure may not, in itself, reduce the frequency of unethical behaviour or relationships, and may have no effect on public awareness, it is impossible to adequately identify, manage or prevent conflicts of interest if doctors, the peak bodies that represent them, and the industry groups with which they deal are not completely open about their interactions. Claims that the medical profession is not subject to influence, that the possibility of conflicts of interest arising in relationships between doctors and the pharmaceutical industry does not exist, and that disclosure requirements will lead to the collapse of continuing medical education are naïve, unfounded, inappropriate, and counterproductive. Doctors occupy a unique position of trust in society. They should act solely in the best interests of the patient — as many do. But drug companies spend billions of dollars on promotions because they work. The medical profession cannot have it both ways. If doctors want to be seen to be beyond influence, the remedy is simple. Be willing to say thanks, but no.1

Martin H N Tattersall FRCP, FRACP, MB BChir · Ian H Kerridge FRACP, FRCPA, MPhil

Strategies to close the gap between development and implementation of guidelines In the past decade, evidence-based clinical guidelines have become a major feature of health care. Researchers and clinicians in many countries have established programs to summarise the evidence for managing specific health problems and to disseminate practice guidelines. However, clinical use of guideline recommendations does not necessarily follow. Numerous studies show that recommendations are frequently not applied in practice and that many patients do not profit from evidence-based insights.1 Large variations in performance between clinicians, practices and institutions are commonly observed. Two reports in this issue of the Journal (Bryant et al and Irving et al) illustrate this well.2,3 In the first, an audit in a hospital outpatient clinic showed that large numbers of patients with diabetes do not achieve recommended treatment targets for control of glycaemia, blood pressure and lipid levels, despite evidence that control of these risk factors produces better outcomes.2 The second, a study of six Australian dialysis units, showed that, despite high levels of awareness of iron guideline recommendations in participating units, there is considerable variation in achievement of targets and widely differing practices in unit processes for iron management.3 Guidelines are expensive — the cost of producing a single guideline may range from US$50 to US$500 000, not to mention the substantial donated time from many contributors.4 Given the lack of practical impact of many clinical guidelines, a critical observer might well ask, “Why spend so much money and effort on something that is so poorly adhered to in practice?” However, the question should really be, “What can we do to increase the use of best evidence guideline recommendations?” Guideline developers, research funders, health care managers and policymakers may need to consider a few key strategies: the need for greater focus on producing guidelines in formats that promote their use; the requirement for planned (and funded) implementation programs that take into account the complexity of change in health care; and the need to improve our knowledge about cost-effective methods of achieving sustained practice changes. Worldwide, many guideline developers give little consideration to the use of their products in the real world. The reality is that guidelines are too often “lost in translation”.5 Many current programs for guideline development seem to be “science-driven”, rather than scientifically based but “customer-driven”. Guideline developers would do a far better job if they focused on the needs of the end user and provided clear statements, decision aids, patient education materials and practical tools to manage difficult problems in practice. More guidelines need to identify specific evidence-based indicators and criteria for clinical performance (as the guidelines discussed in this issue of the Journal do). These provide the capacity to monitor performance and give feedback to clinicians. Public reporting of significant aspects of care quality would help meet the urgent need in society for more transparency about important aspects of health care provision, and would provide a clear imperative to improve implementation and ensure guideline recommendations are feasible and do not become outdated. There is also a need to seek a better balance between the resources devoted to summarising evidence and developing guidelines and those spent on finding the most effective ways to improve patient care. Evidence-based guideline development reflects just one specific approach to improving care — it assumes that professionals are rational decisionmakers who will act on convincing information about the pros and cons of specific routines. Most of the time, effective change in health care demands other models, ranging from those that emphasise patient involvement in decision making to those that focus on organisational development.6 Sadly, good evidence for the cost-effectiveness of many of these strategies aiming to change practice is lacking.6-8 Greater investment by research funders in studies that would improve this knowledge base would help direct implementation resources and effort to where they could be of most use. Policymakers who seek to change health care practices need to understand that some current expectations about the impact of clinical guidelines are unrealistic. A belief that developing and disseminating systematic reviews and guidelines will improve patient care ignores the complexity of change in health care. Guidelines do not implement themselves — most need well developed, well executed and sustained implementation programs,7 and even such programs usually have only a moderate effect on performance in terms of care improvement (around 8%–10%).8 Many factors play crucial roles in blocking or stimulating relevant changes in performance. These are not only related to professional decision making, but also to patient behaviour, interaction with colleagues, team functioning, organisational conditions for change, resources, and economic or legal conditions.7,9,10 This aspect was clearly demonstrated in the renal impairment study.3 For most complex changes in health care, we need to build bridges between the different approaches to better care — guidelines, performance indicators and feedback; patient empowerment; quality management; organisational change; improving culture, teamwork and leadership in the workplace; and creating the necessary financial incentives.6 So, with a change of focus in current guideline development and more realistic expectations of the role of guidelines in improving patient care, with better knowledge about costs and effects of change strategies, and with clinical guidelines embedded in comprehensive programs for change, evidence-based guidelines for clinical practice may become more relevant in the future.

Richard Grol PhD · Heather Buchan MB ChB, MSc, FAFPHM

There is a desperate need for effective mental health services for prisoners and ex-prisoners Deinstitutionalisation in Australia has seen the number of public and private psychiatric hospital beds fall from 30 000 in the early 1960s to 8000 today. The population of Australia doubled during this time. There is no doubt that many people with serious mental illness are not being managed well in the community.1 Some mental health researchers,2-4 as well as the popular press, argue that there has been a recent related transmigration of people from psychiatric beds to remand centres (which house prisoners who have been charged with an offence but not yet convicted) and prisons. Australian remand centres often contain more seriously mentally ill people than general hospital mental health inpatient units. However, it is unclear whether the apparent rise in prevalence of mental illness among prisoners reflects a genuine increase or an improvement in detection rates. Statistical modelling of the effect of deinstitutionalisation on the number of prisoners with mental health problems is fraught with methodological challenges and the absence of longitudinal data.5 This debate has tended to overshadow other major areas of concern about mental illness among prisoners.6 As Herrman et al pointed out 15 years ago, whatever the cause, services for people with mental illness in Australian prisons are inadequate and in need of urgent reform.6 On 30 June 2005, there were 25 353 people in prisons in Australia. This represents an overall imprisonment rate of 163 per 100 000 adults, although there was considerable variation between states. The average age was 34.5 years (with 20.2% aged under 25 years); 6.8% were women; 22.2% were Indigenous people (the Indigenous imprisonment rate was 2021 per 100 000); and 60.4% had been in prison previously. In Queensland, the Department of Corrective Services estimates that the custodial population will increase by 90% over the next 10 years. Australian and New Zealand studies have shown that many people involved in the criminal justice system have had psychiatric contact before entering the system. Prevalence rates for all psychiatric morbidities in the prison population are markedly higher than rates in community samples.6-14 This is particularly evident for substance misuse, with up to 80% of remandees and prisoners dependent on alcohol, cannabis or amphetamines before entering prison.6,7,12,14 However, few published studies allow direct comparison with rates of psychiatric morbidity in community populations. Butler et al9 compared the 12-month prevalence rate for prisoners in their survey to the results of the National Survey of Mental Health and Well-Being, a community-based survey. Prevalences of psychiatric disorders in prisoners were more than double those among people living in the community (Box). Studies in remandees have found prevalences of psychotic illness, such as schizophrenia, ranging from 5.1% to 9.6%.10,13 By comparison, in the general community, the 1-month prevalence is 0.5% for psychosis and 0.3% for schizophrenia.15 Other Australian and New Zealand studies of prisoners have found prevalence rates of between 25% and 50% for non-psychotic disorders such as major depression, anxiety disorders and post-traumatic stress disorder.6,8-10,12 Ex-prisoners also have an increased relative risk of mortality. Death from all causes in some groups was found to be 17 times higher than in the general population in the 2 weeks following release.16 The main causes of excess death are associated with drug and alcohol misuse. These deaths have been cited as an indicator of the poor mental health of prisoners. The experience of release may present an additional challenge to prisoners’ mental health and wellbeing, particularly in the absence of ongoing support. Despite these high morbidity and mortality rates, treatment services for prisoners and ex-prisoners are very limited and often ineffectual. This makes little sense, even from a criminal justice perspective, as comprehensive services can delay or prevent recidivism in mentally ill offenders.17 In February 2006, the Council of Australian Governments (COAG) announced a major reform of mental health services in Australia.18 In April 2006, the Prime Minister announced the Australian Government would commit $1.8 billion over 5 years to this reform. In July 2006, COAG released a National Action Plan on Mental Health, to be supported by a total federal, state and territory government commitment of almost $4 billion over 5 years.19 While only some of the funding announced at COAG by the states and territories is new funding, there is a clear commitment by governments to improve the state of mental health services in Australia. As COAG reforms bind all government agencies, they bring with them the opportunity to improve services in all the relevant government departments in order to provide the range of health, housing and community services needed by people with mental illness. This must include improved and expanded prison mental health services, court diversion programs, and well resourced inpatient and community forensic services that link mental health, judicial and correctional services and provide specialist pre-release assessment, consultation and liaison for clinical managers. Diversion from the criminal justice system of mentally ill people who have committed minor offences is one of the few opportunities for community-based prevention. Access to stable housing and to appropriate vocational rehabilitation services is essential for functional recovery. All of these programs will need specially trained and supported mental health and custodial personnel, including psychologists, psychiatrists and specialist case managers. Adequate training of other personnel involved, such as court and police staff, is also necessary. Thus, crucial to the success of the COAG package will be necessary workforce reforms. Forensic and prison mental health services are target areas for the COAG National Action Plan. However, drafting and funding an action plan is one thing; turning good intentions and money into better services is another, much harder task. To know whether services are improving, we will need public reporting of specific performance indicators, which are currently being developed. In time, the data may be able to tell us whether the historical deficiencies in care for people disadvantaged by both mental illness and involvement in the criminal justice system are at last being addressed. Comparative prevalence of psychiatric disorders in prisoners and in people living in the community9 Prevalence Disorder In prisoners In community Any psychiatric disorder 80% 31% Psychosis 7% 0.7% Affective disorder 23% 9% Anxiety disorder 38% 11% Substance abuse disorder 66% 18% Personality disorder 43% 9%

Paul White MB BS, FRANZCP · Harvey Whiteford MB BS, MPH, FRANZCP