Volume 176 Issue 6

Screening by high-quality programs successfully detects cancers at an earlier stage In 2002, the 10th anniversary of Australia's national program of mammographic screening for breast cancer, it is perhaps timely to reflect and review. The need for reassessment is highlighted by the recent furore in the breast-screening world1-4 precipitated by a Cochrane review by Olsen and Gøtzsche.1 In this issue of the Journal, the article by Barratt et al5 (page 266) also encourages us to review breast-screening policies — in this case for women 70 years and over who are no longer in the target group for free mammographic screening (50–69 years). Barratt et al5 estimated the benefit of screening women 70–79 years to be about one-third to three-quarters that achieved in women aged 50–69 years. As women age, the benefit of screening — reduced risk of death from breast cancer — is increasingly offset by the other causes of death. Furthermore, while the benefit is delayed, the hazards of screening — tests for false-positive films, discomfort and anxiety — are immediate. Thus, with increasing age, the data show a further decline in benefit, which is exaggerated when adjustment is made for qualit-of-life factors.5 Barrett et al also provide a rough estimate of the cost-effectiveness of screening older women. The wide range of cost estimates (per quality-adjusted life-year saved) underlines their imprecise nature, but suggests that mammographic screening of women aged 70–79 years is as cost-effective as screening the other outlier group — women 40–49 years. However, Barratt et al remind us that the estimation of benefits, harms and costs would be improved with data from randomised trials in the appropriate age group — which unfortunately are still lacking. In 1999, 63.7% of women in the target age group for mammographic screening in Victoria (50–69 years) were screened.6 In view of Barratt and colleagues' estimates of benefits and costs per quality-adjusted life-year saved, it could be argued that money for screening older — or younger — women could be better spent on recruiting more women in the target group to achieve the desired 70% participation. Trials of mammographic screening commenced in the 1960s and seven have been completed and reported. On the basis of these trials, which showed a reduction in mortality from breast cancer in screened women, mammographic screening recommendations have been drawn up (eg, in the United States), and in several countries political decisions were made to institute national programs (eg, in the United Kingdom, Australia and New Zealand). In 2000, Gøtzsche and Olsen, publishing a "Cochrane review" of the seven trials in the Lancet,7 reported that they found no reliable evidence that screening for breast cancer reduced mortality. However, this report did not fulfil the Cochrane Group protocol for such a review. Since then Gøtzsche and Olsen have worked with the Cochrane Breast Cancer Editorial Group, and in October 2001 part of their review was accepted and included in the Cochrane Library.1 Almost simultaneously, the Lancet published Gøtzsche and Olsen's review in full on its website, and a research letter in its printed journal2 with an editorial commentary3 criticising the Cochrane Breast Cancer Editorial Group for interference. The whole episode has drawn a flurry of criticism and countercriticism.4. After all this, what should women believe, especially as the systematic review of Barratt et al5 suggests that screening for women over 70 years may be of some benefit (and as cost-effective as it is for those under 50 years), on the basis that screening is beneficial in women aged 50–69 years? Although clinical-trial methodology has improved in four decades, population-health intervention studies remain notoriously difficult to perform because of problems associated with large cohort numbers, the randomisation process and guaranteeing reliable stratification. It is not surprising that the seven, now old, trials can be criticised. However, not all would suggest ditching them and their conclusions on these grounds. The Cochrane Breast Cancer Editorial Group has not accepted the other conclusion of Olsen and Gøtzsche — that screening leads to more aggressive treatments8 — and has not included that section of their review in the Cochrane Library. Others4 reject Olsen and Gøtzsche's conclusions because they are based on all-cause mortality, which may be inappropriate in population studies. Do we have other surrogate measures to guide us? Cancer registry data from Victoria9 suggest a "slight downward trend since 1994" in breast cancer mortality, but it cannot be assumed that any of this trend is due to screening. However, from 1982 to 1996, there was no change in breast cancer mortality in Australia.10 The impact of breast screening may be seen more readily in the stages at which breast cancer is detected. In 1997, when the national program was six years old and well established, 30% of new breast cancers were detected through screening. Data suggest that screen-detected invasive cancers were smaller, less likely to involve nodes, and, if node positive, more likely to involve fewer nodes (Box).11 Tumour size, nodal involvement and number of nodes involved — the basis of the tumour–node–metastases (TNM) staging system — are all known to be of prognostic significance. Hence, it is likely that the cohort of women with screen-detected invasive cancer will have a better prognosis and live longer, provided lead-time bias does not negate the prognostic effect of lower staging by detecting cancer earlier while not influencing the natural history of the disease. The prognostic significance of non-invasive cancer (ductal carcinoma in situ), its treatment and the appropriateness of various local and systemic treatments for any breast cancer can be debated and argued. However, the histopathological prognostic (TNM) data would suggest that mammographic screening by high-quality programs successfully detects cancers at an earlier stage, giving a better prognosis and probably improved survival. Women should be made aware of these facts, along with any doubts raised by reviewers of somewhat out-of-date trials. Impact of breast screening on stage at which cancer is detected11 Tumour size/node involvement Screen detected All cancers < 15 mm 60.3% 42.7% Node positive 22.5% 30.0% 1–3 nodes positive 18.7% 23.4% > 3 nodes positive 8.4% 14.2%

Alan Rodger

A study design that was simple, relevant and that avoided particular sensitivities in the study population might have helped, as might considerably more guidance from the national funding body The combination of hazardous consumption of alcohol, Aboriginal people, primary care and a randomised controlled trial (RCT) of interventions sets a daunting challenge as a research project. In this issue of the Journal, Sibthorpe et al (page 273) describe, with disarming candour, how they took on this challenge and failed.1 After two false starts, and having recruited only one participant per fortnight (when they had originally aimed to enrol two per working day), the research team felt they had no option but to abandon the project and return the funds to the National Health and Medical Research Council (NHMRC). There is little that is new for clinical practice here, but there are important lessons about the design, execution and funding of research studies. The project was motivated by concerns about the limited external validity of existing evidence about the impact of simple interventions on hazardous drinking in an Indigenous primary care setting. The attempt to conduct a new RCT in such a setting was laudable, but the NHMRC process of reviewing grant applications apparently did not detect that failure was predictable. The inability of the team to conduct the study as conceived should not compound any negative perceptions about Aboriginal Medical Services and Aboriginal patients. Rather, the NHMRC might have served them better by advising the researchers about simplifying recruitment, need for consent and statistical power, as well as taking a more critical view of the underlying rationale for the project. It is not clear whether the original application to the NHMRC was supported by a feasibility study, but, given the challenge faced by the investigators, funding should not have been granted without one. As the project was initially designed, the complexity of the screening and recruitment processes flew in the face of well established principles.2 Simple requirements for enrolment make participation in RCTs easy for both patients and providers of healthcare services. By contrast, the combination of a detailed interview about a taboo subject, extensive paperwork and the need for blood all act as disincentives to participation by members of a community whose standard of education and reading ability are often poor, that sees paperwork as the hallmark of an officialdom that too often has been oppressive, and that attaches special significance to body fluids. All of these should have been identified by the NHMRC's assessors as likely to be prejudicial to success. A requirement to seek informed consent to participation runs contrary to the stated aim of the study to assess "effectiveness" (as opposed to "efficacy"3) of brief advice about drinking in a primary care setting. Alerting potential participants to the existence of a trial of this kind is likely to have a Hawthorne effect, thereby eroding statistical power. It is not clear from the account whether gaining consent was originally proposed by the investigators or imposed by an ethics committee — both would be conscious of the special nature of the target population — but it is another neat example of ethics getting in the way of good science.4 Trials of effectiveness do need ethical oversight, but clear thinking about ethical requirements is required when the control group is to receive "usual care". The counterargument that consent was needed because the study required additional blood tests that did not form part of routine care would not have any bearing when screening and recruitment were simplified. The investigators may have wanted to use γ-glutamyltransferase as an endpoint, but this is "medicalising" a social problem long before it becomes a biochemical one, and, in any case, represents a further departure from a study of "effectiveness". Part of the challenge of working in primary care and Aboriginal health is to devise and apply measures of impact and outcome that are relevant and robust, but also simple and credible. The trial as conceived was almost certainly underpowered statistically through overestimating the likely net effect of a brief intervention. In the study on general practitioner intervention in excessive alcohol consumption by Wallace et al,5 the initial prevalence of imprudent drinking was 35%, and the trial was designed on the assumption that 30% of men drinking excessively would respond to the intervention compared with 20% in the control group, the corresponding figures for women being 40% and 20%. Sibthorpe et al were aiming for an absolute difference in response between intervention and control groups of 20%, a bigger average change. They calculated correctly that 200 participants per group would be required to have a 90% chance of detecting such a difference and declaring it significant at P < 0.01. However, it is easy to overestimate the likely impacts of treatments, and changing personal and social behaviour can be even more difficult. Rather than anticipating that anywhere between 5% and 50% of members of the control group might stop drinking hazardously during the course of the study, a pilot study would have been particularly useful for clarifying the likely absolute prevalences and between-group difference in heavy drinking at follow-up. Finally, the whole concept of this study again throws into sharp focus the tension between high-risk and population-wide approaches to prevention, intervention and control of common health problems so eloquently described by Geoffrey Rose.6 Notwithstanding the fact that the prevalence of drinking alcohol is actually lower in the Aboriginal than in the mainstream population, the damage done by hazardous drinking affects a very great proportion of many Aboriginal communities and social factors play a significant role in the behaviour. Rose has clearly identified the futility of trying to get individuals to change their own health-threatening behaviour in such unsupportive circumstances. In Sibthorpe's project, the principles enunciated by Rose would have dictated that, from the outset, one should simply have attempted to ascertain which of the patients drank alcohol at all; given all of these a simple and unambiguous message about the NHMRC's recommendations about patterns of drinking consistent with best health; told them all about the Aboriginal Sobriety Group; and offered to provide extra help, probably at a separate consultation, to those who then felt that they needed it to achieve change. Eventually, Sibthorpe and colleagues began to stumble down something like this path, but the lesson is a salutary one. Too often, clinicians identify the screening/high-risk/selective medical intervention sequence as a first response to problems that are actually present on a mass scale. There is also an important lesson about both investigators and the NHMRC having available good epidemiological, biostatistical and public health advice at all phases of development and assessment of applications for research funding.

Konrad Jamrozik MB BS, DPhil

Comprehensive management of pregnancy loss is enhanced by psychological support and follow-up counselling It is generally accepted that 12%–15% of confirmed pregnancies do not progress to term, with the risk of pregnancy loss increasing with maternal age. In particular, early pregnancy loss (< 20 weeks' gestation) is experienced by one in four women. In about half these women, a medical explanation can be found,1 although, in clinical practice, investigations to identify the cause are rarely pursued. Most women go on to have successful subsequent pregnancies, although there is a slightly increased risk of a second miscarriage that increases incrementally with each subsequent loss.1 Although early-pregnancy loss is relatively straightforward medically, the psychological outcome is more problematic and the grieving process is complicated.2 First, there is no tangible life or memory to grieve. Instead, the woman has to come to terms with grieving for a potential life with all its hopes and aspirations. Second, the grieving is often complicated by feelings of self-blame, particularly when there is no medical explanation for the loss or the woman has engaged in potentially hazardous behaviour (eg, alcohol consumption or smoking). Her partner may also harbour feelings of responsibility for the loss. Other factors which may influence the grieving process and the emotional outcome include miscarrying later in gestation (especially if the woman has felt the fetus move and formed an emotional attachment to it);2,3 the importance and meaning of the pregnancy (eg, a first, wanted pregnancy lost near the end of the reproductive lifespan); and the difficulty experienced in conceiving the pregnancy (eg, an assisted conception). Finally, psychosocial factors, such as a woman's support network (especially her intimate relationship) and her personality style and culture, will affect how she appraises her loss and her level of distress. The psychological sequelae after a late pregnancy loss and stillbirth are well described;3 those after an early pregnancy loss are similar but may not be as severe. There can be high levels of psychological distress characterised by anxiety, depression and somatisation, which can persist for at least six months4 and are only partly accounted for by grieving for the loss of a potential child. There is an increased risk of developing a depressive or anxiety disorder in the six months after a pregnancy loss, and any pre-existing psychotic disorders can be precipitated. The risk of developing depression is high, with studies reporting rates between 10%5 and 48%,6 depending on the study methods.7 One of the more rigorous controlled studies5 reported that 10.9% of women developed major depression after a miscarriage, compared with 4.3% of women (controls) from the same community who had not been pregnant in the previous year. Depression is more likely in women with a history of depression or past psychopathology, and in women who have had a previous pregnancy loss or have no other children. Other factors precipitating depression, such as poor social support or having a vulnerable personality style, are well recognised. The rates of anxiety disorder are lower than those for depression. Recently, exacerbation of obsessive–compulsive disorder after miscarriage has been reported.8 Finally, if the pregnancy loss has been traumatic (eg, an ectopic pregnancy or the woman's life was at risk), post-traumatic stress disorder can arise.9 The comprehensive management of pregnancy loss will be enhanced by psychological support and follow-up counselling.7,10 This can be provided by the woman's obstetrician, general practitioner or another health professional involved in her care, who can address medical as well as psychological issues.11 The purpose is to allow open discussion about the loss, monitor progress and counsel the woman about future pregnancies. In the initial stages, she will benefit from the opportunity to talk about her loss and have her grieving acknowledged. Providing information about the normal grief process may help a woman who is masking her grief or does not believe it is legitimate. The grief process will be facilitated by the opportunity to talk about feelings of guilt and self-blame, particularly when there is no medical explanation.12,13 In our opinion, there should also be an opportunity to discuss dissatisfaction with medical care, as the woman may feel angry and blame her medical practitioner for the loss. An open discussion about this will help her, and may reduce the possibility of litigation. Medical practitioners, particularly when the issue is pregnancy loss or stillbirth, are often reluctant to use the phrase "I'm sorry" because of fears that this equates with an acknowledgement of guilt and may have legal implications. Bereaved parents are often highly aware of this omission, angered by it, and may actually retaliate through litigation. Both obstetricians and insurance companies need to seriously look at the distinction between empathic expression of "sorrow" for the distress experienced as opposed to an apology for negligent action. Regular follow-up is recommended for the first six months. Distinguishing between feelings of grief (which may require grief counselling) and the onset of a depressive illness (which may require specific treatment) can be difficult. Depression is suggested by persistence of depressed mood, lack of enjoyment in pleasurable activities, low self-esteem or excessive guilt, and sleep or appetite disturbance or fatigue.14,15 A pathological grief reaction, characterised by excessive distress, guilt feelings or a preoccupation with the loss, may require more specific counselling. Sometimes a woman may have her depressed feelings dismissed as "grieving" and miss out on appropriate and effective treatment for a depressive disorder. Other family members may also need psychological support. The woman's partner may experience similar feelings of loss.16 In such situations, the father is often neglected ("men aren't expected to talk about their feelings"). He will also benefit from an opportunity to talk about his feelings of loss, as will other children in the family, especially as they may feel responsible if they had feelings of jealousy about the new sibling. The sense of loss may dissipate when the woman becomes pregnant again, and some studies suggest that the shorter the time between a pregnancy loss and a subsequent pregnancy the better the outcome for the woman.13 Such women usually feel anxious during the stage of pregnancy at which the previous loss occurred. Finally, women may benefit from the opportunity to talk to other women who have experienced a pregnancy loss through support groups such as SANDS <http://www.sands.org.au/>.

Philip M Boyce MD, FRANZCP · John T Condon MD, FRANZCP · David A Ellwood DPhil(Oxon), FRANZCOG

How real is the threat, and how prepared are we? The world changed on September 11, 2001, and again on October 4, when the first case of inhalational anthrax in the United States raised worldwide fears of bioterrorism. Although the threat of bioterrorism in Australia has been assessed as low,1 defence and civil authorities had upgraded preparations before the 2000 Olympics.2 Those plans, coordinated by Emergency Management Australia, provided a basis for responses by state emergency services, health services and postal services to the numerous false alarms, "white powder" incidents and hoaxes that followed the US events. No anthrax spores or human anthrax cases associated with these incidents have been detected in Australia, but understandably they have caused considerable public anxiety. In retrospect, it now appears that the anthrax-containing letters in the US were probably of domestic origin, with no targets outside that country.3 After the US incidents, health departments were swamped with calls from the public asking what had been done to protect them. They wanted to know how to protect themselves, and whether they needed antibiotics, vaccines for anthrax or smallpox, or gas masks. Health authorities emphasised communication to reassure those who were worried, as well as to provide authoritative information and planning advice about anthrax and other conceivable threats. Should a biological incident ever occur in Australia, communication would be even more important, not only in managing the emergency, but also in minimising community alarm, which could cause more damage than the biological agent itself. In any incident, healthcare agencies would play a key role in recognising resulting illnesses and managing the health consequences. The anthrax threat has highlighted the importance of multidisciplinary approaches to biological emergencies. Security intelligence must be wedded to health intelligence, and the lessons learned from past disaster management appropriately applied. As an editorial in the Lancet recently said, "Appropriate reaction to such deliberate attacks, but also to any other emerging epidemic, by a well-organised and well-functioning public health system requires preparedness at all times on all levels".4 Australia's federal system requires close collaboration between the Commonwealth, States and Territories. Emergency service responses are coordinated by Emergency Management Australia. Public health agencies work with emergency services in the States and collaborate through the Communicable Diseases Network Australia and the Public Health Laboratory Network to coordinate national reporting, surveillance, laboratory diagnosis and public health responses for communicable disease outbreaks. Biosecurity planning in Australia has built on these existing disease and disaster surveillance systems.2 Recently, these networks have collaborated to revise training schedules and case definitions to support the earliest possible recognition of any event resulting from deliberate release of a biological agent. Health authorities, through the Communicable Diseases and Public Health Laboratory networks and the network of Chief Health Officers of the States, have also strengthened their linkages with Emergency Management Australia, the federal department of Defence and other government agencies. Anthrax: The review of Australia's policies has adapted advice from the US Centers for Disease Control and Prevention (CDC), World Health Organization (WHO) and United Kingdom Public Health Laboratory Service for local needs. Guidelines for anthrax treatment and post-exposure prophylaxis have been developed by public health physicians, microbiologists and infectious disease specialists, and endorsed by Australia's Chief Health Officers and directors of public health services. It has been agreed that primary care providers should not prescribe chemoprophylaxis in the event of suspected anthrax. Instead, they should immediately contact their local public health unit for advice about referral for diagnosis and further management (contact details for State and Territory health authorities are available on Fact sheet — anthrax <http://www.health.gov.au/pubhlth/strateg/communic/factsheets/anthrax_fact.htm>). To minimise inappropriate antibiotic use, general practitioners should not provide individuals with a contingency supply of antibiotics for prophylaxis. State and Territory health authorities are ensuring that there are adequate supplies of appropriate antibiotics in case of an emergency, and the Commonwealth Government is working with pharmaceutical companies to ensure continuity of supply. Anthrax vaccine is not currently registered for use in Australia and is not recommended as a first-line response to an anthrax incident. Smallpox: The US government's intention to procure 250–300 million doses of smallpox vaccine for mass vaccination appears to have been modified after expert advice. Existing vaccine is effective but has significant adverse effects. The calf-lymph-derived live smallpox vaccine used in the WHO smallpox eradication program is associated with a post-vaccinal encephalitis rate of 3–4 per million primary vaccine doses.5 Forty per cent of encephalitis cases are fatal, and some survivors have permanent neurological deficits. Progressive vaccinia occurs among those who are immunocompromised. WHO guidance is that, given the substantial risk of adverse events after vaccination, mass vaccination of populations is not recommended when there is little or no real risk of exposure. Despite the stated intention of the US to develop a new vaccine supply against a possible bioterrorism incident, no country is planning to give smallpox vaccine routinely to its citizens. Smallpox is not transmissible until the onset of rash, when the individual becomes ill and is likely to be confined to bed. This provides the rationale for measures to contain any outbreak: after the first cases are identified and isolated, contacts are vaccinated; vaccination prevents or ameliorates disease, even when it is undertaken after exposure to the virus.5 Thus, both WHO and CDC recommend an approach which involves early case detection and post-exposure vaccination with a view to "ring fencing" any outbreak.5-7 Australia has no smallpox vaccine available at present. As a precautionary measure, the Commonwealth Government has arranged with international agencies to secure access to vaccine in the unlikely event of a smallpox incident; arrangements have also been made to secure supplies of vaccine to be held in Australia. If smallpox were introduced into Australia, we would then be in a position to implement a strategy of surveillance, quarantine and vaccination. WHO has pledged support to any country in which an incident occurs, as this would constitute an international emergency. WHO will help countries pool resources to contain any outbreak as rapidly as possible. Conclusions: Although the risk to Australia is regarded as low, we need to be prepared for a bioterrorism incident. Australia's strong public health infrastructure forms the basis for an effective response to any such incident. While much of the initial planning has focused on anthrax and smallpox, progress has been made on public health and clinical protocols for other potential bioterrorism agents. No public health or security system can guarantee complete safety from bioterrorism attack, but Australia's public health expertise will ensure that harm to the community is minimised. For the assistance of doctors, a comprehensive guide for dealing with patient inquiries is available on the website of the Commonwealth Department of Health and Ageing (<http://www.health.gov.au/pubhlth/strateg/bio/index.htm>). This also contains a list of contacts for public health authorities around Australia. Relevant information can also be accessed through the WHO and CDC sites (<http://www.who.int/emc/deliberate_epi.html> and <http://www.cdc.gov>, respectively).

Richard A Smallwood · Angela Merianos · John D Mathews

Current practices should be re-examined in light of current evidence Antenatal care includes screening asymptomatic pregnant women, with the aim of detecting, and thereby preventing, both maternal and neonatal adverse events. The introduction of antenatal care in 1913 has been widely attributed to the efforts of Ballantyne at the University of Edinburgh. He suggested that the high maternal and perinatal mortality rates observed at the beginning of the 20th century reflected inadequate maternity care during pregnancy and lack of supervision of the progress of labour. Ballantyne's flow diagram, an antecedent of guidelines, defined interactions of many disciplines in antenatal care. During the 1930s, there was increased emphasis on educating healthcare professionals who provided maternity care. Women were encouraged to present during pregnancy, and were advised to give birth in hospital. The subsequent fall in perinatal mortality rates was attributed to antenatal care, without consideration of the contribution from social and other medical improvements.1 The falling mortality rates corresponded with a gradual increase in the number of antenatal visits recommended. By the 1950s, a schedule of monthly visits to 28 weeks, fortnightly visits to 36 weeks, and then weekly visits until birth had become standard.1 Although programs with fewer visits have been proposed, this schedule is widely accepted in clinical practice. This has remained largely unchallenged, as noted by Archie Cochrane, who stated "by some curious chance, antenatal care has escaped the critical assessment to which most screening procedures have been subjected".2 Traditional antenatal care was critically appraised in a retrospective review of 1907 pregnant women who gave birth at the Aberdeen Maternity Hospital in 1975.1 Antenatal and birth records were reviewed to determine the rates at which complications were diagnosed, misdiagnosed and overdiagnosed, in addition to the rate at which complications occurred despite routine antenatal care. Breech presentation and pre-eclampsia were the only complications reliably detected in the antenatal period, and the benefit in the detection of pre-eclampsia was confined to primigravid women beyond 34 weeks' gestation. Most antenatal admissions, apart from admissions for labour and birth, were for conditions that had arisen despite routine antenatal care — conditions that had not been prevented or detected by it. More recently, randomised controlled trials have assessed the optimal frequency of antenatal visits in preventing maternal and fetal complications. The main hypothesis tested in these trials is that models of care with fewer antenatal visits are as effective as the traditional model in terms of clinical outcomes and maternal satisfaction.3 A systematic review of seven randomised controlled trials involving 57 418 women found no differences in the detection of pre-eclampsia (odds ratio [OR], 0.91; 95% CI, 0.66–1.26), urinary tract infection (OR, 0.93; 95% CI, 0.79–1.10), low birthweight (OR, 1.04; 95% CI, 0.93–1.17) or maternal mortality (OR, 0.91; 95% CI, 0.55–1.51) when a schedule of reduced antenatal visits was compared with more traditional regimens of antenatal visits.4 However, women were more dissatisfied with fewer visits. Whether increased maternal satisfaction is of measurable benefit in terms of pregnancy and birth outcomes remains less certain. Clinical practice guidelines should define best practice, limit variations in the provision of care, recommend care that is cost-effective, and provide care in a way that meets the needs of all patients. In this issue of the Journal (page 255), Hunt and Lumley have reviewed guidelines used in Australian maternity units.5 They found that recommendations for the content of antenatal visits and screening procedures vary considerably across Australia. The value of certain tests or interventions can be readily appreciated in terms of a low cost treatment capable of disease modification (eg, provision of anti-D to rhesus-negative women); however, evidence of benefit is lacking in other circumstances (eg, routine screening for carbohydrate intolerance), although current clinical trials will address some of these issues. Routine antenatal screening for syphilis, although low cost and with effective therapy available for patients testing positive, could be questioned given the low prevalence of the disease among pregnant white Australians. However, selective testing and treatment has not been supported.6 Hunt and Lumley also demonstrate the other end of the clinical spectrum, where good-quality evidence exists to support a treatment or policy but institutions have no relevant guidelines. Good-quality evidence exists to support the cessation of smoking during pregnancy,7 and yet remarkably few institutions had a guideline providing practical information for caregivers to support women in smoking cessation. This also highlights the difficulty of implementing changes in policy, despite evidence of an important clinical effect, and reflects the wider challenges of translating research findings into clinical practice. The article by Hunt and Lumley describes the broad range of accepted antenatal care in Australia. Where to from here? The purpose of antenatal care needs to be redefined. The aims may differ for consumers and caregivers, and both should be incorporated into the "ideal" model of care. In addition, current practices (including timing and frequency of visits, and "routine" screening investigations) should be questioned in light of predetermined outcome measures and best available evidence. The principles of antenatal care were adopted over half a century ago; their maintenance can only be supported when rigorously tested against the best currently available evidence, which can then be incorporated into national guidelines for best practice.

Jodie M Dodd · Caroline A Crowther · Jeffrey S Robinson

Objective: To describe the variability and evidence base of recommendations in Australian protocols and national policies about six aspects of routine antenatal care.Design: Comparison of recommendations from local protocols, national guidelines and research about number of visits, screening for gestational diabetes (GDM), syphilis, hepatitis C (HCV), and HIV, and advice on smoking cessation.Setting: Australian public hospitals with more than 200 births/year, some smaller hospitals in each State and Territory, and all Divisions of General Practice were contacted in 1999 and 2000. We reviewed 107 protocols, which included 80% of those requested from hospitals and 92% of those requested from Divisions.Main outcome measures: Frequency and consistency of recommendations.Results: Recommendations about syphilis testing were notable in demonstrating consistency between local protocols, national policies and research evidence. Most protocols recommended screening for GDM, despite lack of good evidence of its effectiveness in improving outcomes. Specific approaches to screening for GDM varied widely. Coverage and specific recommendations about testing for HIV and HCV were also highly variable. Smoking-cessation information and advice was rarely included, despite good evidence of the effectiveness of interventions in improving outcomes. No national policies about the number of routine visits and smoking cessation could be identified. There were inconsistent national policies for both HIV and GDM screening.Conclusions: Antenatal care recommended in protocols used in Australia varies, and is not always consistent with national policies or research evidence. Producing and disseminating systematic reviews of research evidence and national guidelines might reduce this variability and improve the quality of Australian antenatal care.

Jennifer M Hunt MPH, FAFPHM · Judith Lumley PhD, FFPHM(UK)

Objectives: To study the incidence of and factors associated with single-vehicle rollover (SVRO) accidents in the "Top End" of the Northern Territory (NT); to identify factors associated with major injury and death from SVRO accidents.Design: Retrospective analysis of records from the NT Department of Transport and Works' police database, Royal Darwin Hospital's trauma database, coroner's records, and case notes from public hospitals in the Top End.Study population: All patients involved in SVRO accidents in the Top End between 1 January 1996 and 31 December 1997 whose accident was documented by the police, who attended a public hospital, or who died.Main outcome measures: Types and incidence of all accidents; details of the accident scene, vehicle features, and population groups associated with SVRO accidents; factors associated with major injury and death.Results: SVROs accounted for 30% of all accidents and 29% of all injuries and deaths (441 people) in the whole of the NT over the study period. Some of the factors associated significantly more frequently with SVRO accidents were (i) occurrence of the accident on a straight, dry, unsealed road; (ii) presence of a vehicle defect; (iii) travelling at excessive speed; and (iv) the person being male, aged 41–50 years, of Aboriginal descent. Among the 147 people who were admitted to hospital or died from SVRO accidents in the Top End, major injury occurred significantly more frequently if the person was under the influence of alcohol, was not wearing a seatbelt and was ejected; if the accident occurred in a rural area; and if the vehicle was speeding. Major injuries occurred in 21% (31/147), and death was more likely in those with head, chest and neck injuries.Conclusion: SVRO accidents are a major cause of morbidity and mortality in the Top End of the NT. Effective methods of limiting speeding, drink-driving and driver fatigue should be sought. Populations most at risk should be targeted.

P John Treacy MD, FRACS · Kerrie Jones BMBS, FACEM · Carole Mansfield RN

Neuromuscular paralysis and death up to four days after removal of ticks is well documented and apparently unique to Australian tick envenomation.1-5 Generally, obvious symptoms and signs are present at the time of tick removal. In contrast, onset of local neurotoxicity many hours after tick removal has not, to my knowledge, been reported previously in the medical literature. Clinical recordA 48-year-old man with tick infestation was referred to our hospital emergency department by his general practitioner. The patient complained of lumps on his scalp (present over the previous few weeks), lethargy, myalgia, unsteadiness on his feet and numb lips. He stated that he spent a lot of time walking in bushland around his home. His friend's dog had recently died from tick paralysis. Multiple engorged ticks were evident on the man's face, scalp, neck, back and limbs. An engorged tick was removed from his left cheek, but there were no intra-aural or peri-aural ticks. He had multiple associated urticarial lesions and generalised lymphadenopathy. His pulse was 114 beats/minute, blood pressure 148/100 mmHg and he had a temperature of 37.5°C. Neurological examination revealed no cranial-nerve deficits. In particular, there were no motor or sensory deficits of the face. The numbness of the lips, which the patient had earlier described, had now resolved. His gait, muscle power, tone and reflexes were normal. Light touch and pinprick sensations in his limbs were also normal. Forty-four ticks (41 females [32 engorged] and 3 males) were removed with forceps (see Box), carefully avoiding pressure on the ticks' abdomen, which is thought to trigger expression of venom.1,3,5 The species was later formally identified as Ixodes holocyclus (Mr Bruce Dixon, Senior Microscopist, Olympus Imaging Unit, Parasite Identification and Diagnostics Program, Adelaide University, personal communication). In view of the magnitude of the infestation, the patient was asked to return the following morning for reassessment. A review 20 hours after tick removal revealed left facial-nerve palsy. In addition to the lower motor neurone motor deficit, the patient complained of altered sensation over his left cheek and upper lip, and subjective loss of light touch and pinprick sensation from the left cheek to the upper lip were demonstrated. As tick venom has not been shown to affect sensory-nerve conduction, the most likely explanation is that this apparent dysaesthesia is akin to that seen with idiopathic Bell's palsy, in which patients commonly complain of altered sensation in what is purely a disorder of the motor neurone. The phenomenon appears to relate to altered proprioception. No other neurological abnormality could be detected and there were no residual ticks found after a thorough search. The facial paralysis took seven days to completely resolve. After two weeks the patient felt well and had resumed his previous activities. He was advised to ask a friend or relative to check him thoroughly for ticks after spending any time in the bush. DiscussionOf the 19 identified species of Australian tick in the Ixodes genus,6 only three have been shown to secrete paralytic toxins.7 With the exception of one case of I. cornuatus envenomation,8 all human cases of paralysis in which the tick was identified were due to I. holocyclus. The structure of the protein neurotoxin, also known as holocyclotoxin, has not been elucidated. It is secreted from the massive salivary glands of engorged female ticks late in the feeding cycle. Like botulinum toxin, holocyclotoxin is thought to act presynaptically at the neuromuscular junction to inhibit acetylcholine release.9 In Australia there have been 20 reported deaths from tick envenomation, all before 1945. Ticks have caused more deaths than any other Australian arachnid, including the funnelweb spider (Atrax robustus) (13 attributable deaths) and the redback spider (Latrodectus hasselti) (14 deaths).10 Tick paralysis has been frequently misdiagnosed, and this envenomation syndrome must be included in the differential diagnoses of any patient presenting with an ascending symmetrical paralysis. Generalised paralysis most commonly affects children under three years, but there are three documented fatalities in Australian adults due to tick envenomation.10 Late discovery of ticks hidden on the scalp or in bodily creases and orifices is a recurring, and often lethal, theme.1,11 The diagnosis may not be immediately apparent, and any child with ataxia or progressive weakness should be carefully examined for ticks. Cases of isolated local paralysis, usually facial, are less commonly reported.1,4,12-14 Usually, the palsy is present at the time of tick discovery, and, in the case of facial-nerve palsy, the tick is found most often behind the ear or within the external auditory meatus. Cases of isolated facial palsy have lasted three days to three weeks.4,12,13 I am aware of one other case of delayed-onset facial-nerve paralysis in a child secondary to tick envenomation. This resolved spontaneously within a few days (Dr Bill Whyndham, Registrar, Emergency Department, Gosford Hospital, personal communication). A case of median-nerve palsy caused by local (axillary) I. holocyclus envenomation has also been described (Dr Bill Whyndham, personal communication, from a presentation to the Australasian College for Emergency Medicine Winter Symposium, Lorne, VIC, July 1999). Local paralysis is a well documented, albeit unusual, complication of tick envenomation. The case described here emphasises the potential for late onset of paralysis, even many hours to days after removal of the tick(s), and the need to closely follow up any patients with symptoms suggesting tick envenomation. Admission for several days' observation of children with any signs of neurotoxicity should be considered. Ticks removed from the patient.

Mark K Miller BMed, FACEM

Objective: To assess the (i) benefits, (ii) harms and (iii) costs of continuing mammographic screening for women 70 years and over.Data sources and synthesis: (i) We conducted a MEDLINE search (1966 – July 2000) for decision-analytic models estimating life-expectancy gains from screening in older women. The five studies meeting the inclusion criteria were critically appraised using standard criteria. We estimated relative benefit from each model's estimate of effectiveness of screening in older women relative to that in women aged 50–69 years using the same model. (ii) With data from BreastScreen Queensland, we constructed balance sheets of the consequences of screening for women in 10-year age groups (40–49 to 80–89 years), and (iii) we used a validated model to estimate the marginal cost-effectiveness of extending screening to women 70 years and over. Results: For women aged 70–79 years, the relative benefit was estimated as 40%–72%, and 18%–62% with adjustment for the impact of screening on quality of life. For women over 80 years the relative benefit was about a third, and with quality-of-life adjustment only 14%, that in women aged 50–69 years. (ii) Of 10 000 Australian women participating in ongoing screening, about 400 are recalled for further testing, and, depending on age, about 70–112 undergo biopsy and about 19–80 cancers are detected. (iii) Cost-effectiveness estimates for extending the upper age limit for mammographic screening from 69 to 79 years range from $8119 to $27 751 per quality-adjusted life-year saved, which compares favourably with extending screening to women aged 40–49 years (estimated at between $24 000 and $65 000 per life-year saved).Conclusions: Women 70 years and over, in consultation with their healthcare providers, may want to decide for themselves whether to continue mammographic screening. Decision-support materials are needed for women in this age group.

Alexandra L Barratt MB BS, PhD · Les M Irwig MB BCh, PhD · Glenn P Salkeld B Business, PhD · Paul P Glasziou MB BS, PhD · Nehmat Houssami MB BS, MPH

To fill a gap in knowledge about the effectiveness of brief intervention for hazardous alcohol use among Indigenous Australians, we attempted to implement a randomised controlled trial in an urban Aboriginal Medical Service (AMS) as a joint AMS–university partnership. Because of low numbers of potential participants being screened, the RCT was abandoned in favour of a two-part "demonstration project". Only 16 clients were recruited for ...

Beverly M Sibthorpe BA(Hons), PhD · Ross S Bailie MD, FAFPHM · Maggie A Brady MA, PhD · Sandra A Ball BCom, GradDip Public Administration · Polly Sumner-Dodd DipManagement · Wayne D Hall BSc, PhD

Malpractice litigation is now a substantial cost in the provision of healthcare. Despite new attitudes of Australian courts towards medical evidence, expert reports remain the cornerstone of most medical negligence cases. There is evidence that hindsight bias, which may cause the expert to simplify, trivialise and criticise retrospectively the decisions of the treating doctor, is inevitable when the expert knows there has been an adverse outcome. If possible, outcome information should be withheld from experts providing reports. If outcome information is not withheld, courts should be made aware of the probability of hindsight bias.

Thomas B Hugh FRCS, FRACS · G Douglas Tracy AO, FRCS, FRACS, FACS

Australian law embodies a "communitarian" conception of the doctor's responsibility to respect the confidentiality of the doctor–patient relationship. This implies that respect for confidentiality sits alongside two other responsibilities: proper care for the patient's general wellbeing and proper attention to the safety of the community. Most jurisdictions now require drivers to advise their local driver-licensing authority of any permanent or long-term injury or illness that affects their ability to drive safely. Some jurisdictions require doctors to inform the driver-licensing authority about patients whose medical condition may impair their driving to the extent that they are likely to endanger the public. If you can not persuade a patient to inform the driver- licensing authority of the need for an assessment of his or her ability to drive safely, then you should inform the relevant authorities yourself.

Bernadette M Tobin MA, PhD · Stephen R Leeder PhD, FRACP, FFPHM · Ernest R Somerville MB BS, FRACP, FRCP

The CONSORT statement is a checklist and flow diagram developed by an international group of clinical triallists, statisticians, epidemiologists and biomedical editors for reporting randomised controlled trials.1 Item 4 in the checklist relates to interventions (Box 1). The interventions used in a randomised clinical trial should be clearly defined in the protocol and reported in enough detail to be replicated. The control or placebo treatment arms should be described with the same degree of detail as the treatment arms. If the control group receives standard care rather than an intervention, this care must be described in detail, as it may differ between institutions or countries. The characteristics of any placebo (eg, tablet or capsule form, taste) and the way it is administered should be documented. If the study interventions are delivered in a blinded (masked) fashion, details of how the blinding was achieved should be described, including any procedures for unblinding subjects during the study. The use of blinding is desirable to reduce reporting and measurement bias.1 A study is classified as single-blind when only the study subject is unaware of which treatment has been assigned, and double-blind when the responsible clinician is also unaware of the assigned treatment. Double-blind studies, in which data are presented to the data-monitoring committee in a blinded fashion (ie, as treatments A and B), are sometimes referred to as triple blind.2 If blinded interventions are not feasible or ethical, blinded assessment of outcomes should be attempted. For example, in a study comparing psychological outcomes after coronary surgery or percutaneous angioplasty for coronary heart disease, the assessor can still be blinded to treatment if patients are carefully gowned to obscure the presence or absence of a surgical scar and trained not to disclose the type of treatment received (assessments can even be videotaped to check that the blinding is preserved). Pharmaceutical interventionsGenerally, the dose of a drug intervention used in a comparative trial would be the maximum effective tolerated dose determined from earlier-phase trials. The dose may be the same for all patients or modified according to criteria such as body weight or surface area. Alternatively, dose escalation or reduction may be appropriate to achieve a particular degree of response (eg, lowering of cholesterol or raising of haemoglobin levels) or where known side-effects have been reported. In addition to the usual monitoring of patients' details, any special safety investigations required as part of the trial should be reported. For instance, if a medication has been known to cause liver toxicity in some patients, the schedule used for monitoring liver enzymes should be included in the protocol and study report. The description of pharmaceutical interventions should include the generic name, proprietary name (where brand substitution is not allowed), dosage formulation, route of administration, frequency of dosage, duration of therapy and any criteria for dosage modifications or cessation of the intervention during the course of the trial.3 Any special handling procedures and storage conditions should be noted. Non-pharmaceutical interventionsInterventions that do not use drugs, such as surgical procedures and behavioural therapies, are more likely to vary in the way they are administered. It is therefore important to document the aspects of such interventions that were controlled closely by the protocol to enable readers to best ascertain how the intervention differed from their own practice. Similarly, multimodality treatments may follow specific schedules of delivery, and should be detailed in reports.4 How was the intervention received?Some indication of the proportion of patients receiving the interventions and how well these were tolerated should be reported. Poor compliance generally results in an underestimation of the actual benefits of treatment and may even produce a false negative result. Pilot studies can be useful in identifying problems with the delivery of treatments before a major study is initiated. Ancillary careDetails relating to ancillary care and the criteria for providing it should be reported. Some studies stipulate that, except for the intervention under investigation, all other patient care is left to the discretion of the attending clinician. As ancillary care varies depending on the study centre, clinician preferences and patient comorbidities, key details should be documented. Ancillary care may also be specified in the protocol. For example, antiemetics may be used routinely in an oncology trial to allow for a planned fixed dose of a chemotherapy regimen for all patients. Many interventions are used with specified "rescue or salvage options" in the event of treatment failure. Other aspectsStudy sponsors and suppliers of any intervention should be acknowledged and any potential conflicts of interest declared. Documentation that appropriate ethical and regulatory approval has been obtained to conduct the trial is essential. All drugs and devices not listed on the Australian Register of Therapeutic Goods require Therapeutics Goods Administration (TGA) approval for use in a trial under the Clinical Trial Notification (CTN) or Clinical Trial Exemption (CTX) schemes. This also applies to trials evaluating new doses of drugs or indications for approved products. In conclusion, a checklist for specifying interventions is shown in Box 2. 1: CONSORT checklist of items to include when reporting a trial1 Section and topic Item no. Descriptor Methods Interventions 4 Precise details of the interventions intended for each group and how and when they were actually administered 2: Checklist for specifying interventions in a clinical trial Is enough detail provided so that the intervention could be replicated by others? Is the control group intervention described in enough detail? If blinding was used, has this been described and was it maintained? Is background and evidence for choice of dose included? Have criteria for dose modification or cessation of therapy been included? Were additional investigations or non-standard monitoring schedules required to ensure patient safety? Is any evaluation of compliance or tolerance included? Was ancillary care described or specified?

Jackie K Brighton BAppSc, MPH · Val J Gebski BA, MStat · Anthony C Keech FRACP, MSc(Epi)

Trial: PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033-1041. QuestionIn patients with a history of stroke or transient ischaemic attack, can further stroke be prevented by lowering blood pressure, even when it is not elevated? Trial details Design: Multicentre, randomised, double-blind, placebo-controlled trial with a mean 3.9-year follow-up. Setting: 172 centres in 10 countries including Asia, Australasia and Europe. Patients: 6105 patients, mean age 64 years, in stable condition after a stroke or transient ischaemic attack within the previous five years and with no definite indication or contraindication to an angiotensin-converting-enzyme (ACE) inhibitor. Intervention: In 3051 patients, a flexible blood-pressure-lowering regimen based on the ACE inhibitor perindopril (4 mg daily), with the addition (in 58% of actively treated patients) of the diuretic indapamide (2.5 mg daily, or 2 mg daily in Japan), at the discretion of the treating physicians. Matching placebo in 3054 patients. Main outcome measures: All strokes (fatal or non-fatal); secondary measures included fatal or disabling stroke, total major vascular events (non-fatal stroke, non-fatal myocardial infarction, vascular death), total and cause-specific deaths, hospital admissions, and (not reported yet) dementia and cognitive function. Main results: Active treatment reduced blood pressure by a mean of 9/4 mmHg. Against a background of standard treatment, over four years active therapy reduced strokes from 14% in those assigned placebo to 10% (relative risk reduction, 28%; 95% CI, 17%–38%, P < 0.0001). Risk reduction was similar in those who were normotensive or with baseline systolic and diastolic blood pressures ≥ 160 or ≥ 90 mmHg, respectively, irrespective of any treatment. Active therapy also reduced the risk of total major vascular events by 26% (95% CI, 16%–34%; P <0.0001) and major coronary events by 26% (95% CI, 6%–42%). After initial screening for tolerance during a four-week run-in, only 1% more patients stopped active therapy than those stopping placebo because of hypotension. In a subgroup analysis, combination therapy, but not monotherapy, had a significant benefit. In absolute terms, one in every 11 patients given combination therapy avoided death, myocardial infarction or stroke over five years of treatment. Conclusion: Blood pressure lowering was beneficial; in the trial context, perindopril plus indapamide (but not perindopril alone) prevented stroke and major vascular events in patients whose condition was stable after a previous stroke or transient ischaemic attack. CommentaryRationale for the trialAbout one in five stroke survivors suffer another stroke in the five years after the initial incident.1 Blood pressure is related in a continuous manner to the risk of an initial stroke, but many strokes occur in individuals with normal blood pressure. However, there are fewer data on the relationship between blood pressure and recurrent stroke. Systematic reviews of randomised trials of blood-pressure-lowering drugs in patients with hypertension who do not have clinical evidence of cerebrovascular disease show that sustained lowering of blood pressure reduces risk for stroke by about a third.2 Fewer data are available on the effect of lowering blood pressure in individuals with a history of cerebrovascular disease. Trial methodsImportantly, the trial tested the effect of treatment in patients with a wide range of entry blood pressures, including those who were normotensive, defined as systolic blood pressure less than 160 mmHg and diastolic blood pressure less than 90 mmHg. Because of this, the results of the trial are more generalisable than if it only included patients with hypertension. The design also allowed for clinician choice for single or combination therapy. The predefined outcomes were adjudicated by an expert committee and were deemed to be clinically relevant. Randomisation was appropriate with stratification for known prognostic factors. The sample-size estimates were robust and based on worthwhile and plausible differences in stroke rates. Analysis was on an intention-to-treat basis and subgroup analyses were prespecified. Both absolute benefits as well as relative-risk reductions were reported. New informationThe study establishes the value of blood pressure lowering to prevent recurrent stroke (both ischaemic and haemorrhagic). In particular, it demonstrates the role of blood pressure lowering for secondary prevention of stroke in normotensive patients. PROGRESS is the first study to show benefit for Asian as well as white populations. The trial also showed that blood pressure lowering can prevent coronary events in patients with previous stroke, and that blood pressure lowering was safe at least two weeks after a stroke or transient ischaemic attack. Implications for clinical practiceIn patients who have just had a stroke (irrespective of their age, whether they are hypertensive or normotensive and whether they have sustained ischaemic or haemorrhagic stroke), after two weeks, or when their condition is judged to be clinically stable, blood-pressure-lowering intervention should be considered. In those who have had a stroke at some time in the past, treatment should similarly be considered. In some patients, such as those with bilateral carotid occlusive disease, there may be some risks, and the trial does not provide information relating to these. However, in most patients, ACE inhibitor therapy could be started initially at the time of discharge or at postdischarge follow-up. However, to maximise the blood-pressure-lowering effect, most patients should receive combination therapy. The trial provides data to support use of a combination of perindopril and indapamide. PROGRESS does not provide data to show that other ACE inhibitors, other diuretics or other classes of antihypertensives would have the same demonstrable quantitative effects, nor was it designed to provide information on specific target blood pressure levels.

Andrew M Tonkin MB BS, MD, FRACP

Clinical questionAfter mastectomy, chemotherapy and radiotherapy for high-grade ductal carcinoma with nodal involvement and lymphatic infiltration, a 48-year-old woman had premature menopause, with symptoms of loss of libido. Her general practitioner wanted to know how safe and effective hormone replacement therapy (HRT) would be for this patient. Search questionThe revised question was: "Does HRT increase the likelihood of recurrence in a patient previously diagnosed with breast cancer?". The ideal study to answer this question would be a randomised controlled trial of HRT versus placebo comparing outcomes of mortality and recurrence in women previously treated for breast cancer or high-grade ductal carcinoma of the breast. SearchWe searched two online databases: PubMed Clinical Queries <http://www.ncbi.nlm.nih.gov/entrez/query/static/clinical.html> and the Cochrane Library, using the search terms "hormone replacement therapy", "breast cancer", "breast neoplasm", "mastectomy" and "libido". Summary of findingsNo ideal studies have been published. However, five observational studies (three cohort and two case–control) were identified that reported the occurrence of adverse events after administration of HRT in women previously treated for breast cancer. Two of the cohort studies were prospective studies of 24 and 25 women who had received HRT after treatment for breast cancer.1,2 No recurrences were reported in the 24 women observed over a period of 24–44 months;1 and three recurrences occurred in the 25 women after a mean follow-up of 30.4 months (survival rate, 96%).2 In the retrospective cohort study, seven recurrences occurred in 77 women;3 the average interval from diagnosis to relapse was 45.3 months. A case–control study was conducted in a subset of the 77 patients in the cohort study mentioned above. Forty-one patients who received HRT were matched with 82 controls not receiving HRT. There were no significant differences in disease-free times and survival times between the two groups.4 The second case–control study of women after primary surgical treatment, in which 21 women received HRT and 42 matched controls did not, reported relapse in four patients in the treatment group (19%) and five in the control group (11%). The authors estimated the risk of relapse of breast cancer among women who had received HRT for a mean of 28 months compared with the control group (odds ratio [OR], 1.74; 95% CI, 0.34–8.88), and among those who had received HRT for less than 24 months (OR, 0.65; 95% CI, 0.02–7.85).5 CommentIn the studies identified in this search, there was little evidence of increased recurrence of breast cancer with the use of HRT in patients previously diagnosed with breast cancer. However, these studies involved small numbers of patients, the duration of follow-up was not long, and there was potential for bias. Caution should prevail until appropriate clinical trials are conducted. OutcomeAfter weighing up the evidence against the benefits of menopause symptom control, the general practitioner continued to prescribe HRT for this patient.

Christopher B Del Mar · Paul P Glasziou · Anneliese B Spinks · Sharon L Sanders · Deborah J Hilton

About 6% of patients acquire an infection in hospital, and the incidence of hospital-acquired infections may be increasing. Common hospital-acquired infections are respiratory and urinary tract infections, surgical wound infections and infections associated with intravascular cannulas. The common hospital pathogens are methicillin-resistant Staphylococcus aureus, antibiotic-resistant gram-negative bacilli and, more recently, vancomycin-resistant enterococci. Surveillance is the cornerstone of effective infection control and prevention of hospital-acquired infections. Strategies to prevent both development of antibiotic resistance and spread of resistant organisms are necessary. Preventive strategies include prudent antimicrobial use, timely handwashing, aseptic technique, short hospital stays, minimal use and early removal of invasive devices, adequate staffing and an active infection control program. Sound infection control practice and prudent antibiotic use will reduce antimicrobial-resistant organisms and hospital-acquired infections

Series Editors:

To the Editor: The report by Mangion et al1 draws attention to a serious risk in the environment. The general public has been increasingly protected against the risk of harm from domestic products by a combination of legal liability actions and government regulation. Thus, the continuing availability to the general public of hydrofluoric acid (HF) in concentrations that are hazardous is something of an anachronism. While we applaud Mangion and colleagues for raising the issue of HF burns, we feel that their article is deficient in failing to mention a number of important points. Topical calcium gluconate has been shown to be more effective in treating HF burns if the preparation contains dimethyl sulfoxide (DMSO).2 There is a great risk of blindness with ocular exposure to HF. Slow local injection with 10% calcium gluconate using fine needles, titrating its effect against the patient's pain, is a well described technique. This is another treatment option that could have been tried. Nail removal, described by Mangion et al as an "extreme measure", is, unfortunately, often required. It is less likely to be required with the application of DMSO/calcium gluconate solution and retrograde ischaemic intravenous injection of calcium. Local excision of contaminated tissue may be required after exposure to concentrated solutions. Management should be a team effort from the first moment, involving an intensivist/toxicologist and surgeon, as burns surgeons are trained in the care of HF exposure, and surgery is often needed. The availability, packaging, and labelling of preparations containing HF have recently been changed. Since 1 December 2001 it has no longer been possible for the general public to purchase any HF preparation stronger than 1%. All preparations now carry prominent labelling drawing attention to the risk of blindness if even dilute solutions of HF get into the eyes. Containers are now less easy to open by children. These changes have been introduced by the National Drugs and Poisoning Committee of the Therapeutic Goods Administration as a result of an independent review and lobbying by the Australian and New Zealand Burn Association (ANZBA). The ANZBA guidelines for referral to a specialised burns unit include chemical burns. The peculiar challenge posed by HF burns emphasises the need for the guidelines to be more widely disseminated. Currently, the New South Wales Department of Health has adopted the guidelines, so this policy is official throughout New South Wales.

Hugh C O Martin · Michael J Muller

To the Editor: A recent editorial in the Journal attempted to define a role for angiotensin II receptor (AIIR) antagonists in patients with type 2 diabetes.1 This was in the light of recent trial evidence that these agents reduce progression to renal failure in patients with type 2 diabetes and diabetic renal disease. Unfortunately, the guidelines provided were somewhat confusing and fragmented. I believe that a simpler treatment guide can be constructed, particularly when it is emphasised that the aim in diabetes is to use agents that prevent not only renal failure but also cardiovascular events. Substantial evidence already supports a role for the angiotensin-converting enzyme (ACE) inhibitor ramipril in treatment of diabetes. The HOPE study included 3577 people with diabetes and another risk factor for cardiovascular disease who were randomised to either placebo or ramipril (10 mg) for 4.5 years.2 This group had a mean baseline blood pressure of 142/80 mmHg and no clinical proteinuria. Ramipril lowered the risk of the combined primary outcome of myocardial infarction, stroke and cardiovascular death by 25% (P ≤ 0.001), and this effect was independent of blood-pressure lowering. Furthermore, ramipril reduced progression to overt nephropathy by 22%, with a reduction evident in patients with or without proteinuria.2 This protective effect of ramipril on renal function is consistent with previous evidence that ACE inhibitors slow progression of chronic renal failure in diabetes,3,4 and that ramipril slows progression of chronic renal failure in non-diabetic nephropathy.5 Whether other ACE inhibitors have the same effect as ramipril on cardiovascular events, and what doses obtain such an effect, remains speculative. Similarly, while there is now evidence that AIIR antagonists also have renal-protective effects, there is no definitive evidence that they protect against cardiovascular events. In view of this, and in the absence of comparative trials, ramipril (and not other ACE inhibitors or AIIR antagonists) is currently the first choice for treatment for diabetic patients with hypertension, with normotension and microalbuminuria, or with hypertension and micro- or macroalbuminuria. As most patients with diabetes and hypertension require multiple agents to achieve a target blood pressure less than 130/80 mmHg, additional therapy with a β-blocker, diuretic or calcium-channel blocker is often necessary. The significance of the newly available trial data is that AIIR antagonists provide an alternative to ramipril for reducing progression to chronic renal failure in patients with diabetic nephropathy who cannot tolerate ACE inhibitors because of the side effect of cough.

Roger E Peverill PhD, FRACP

In reply: Peverill raises the question of how to integrate the new data on renal protection by angiotensin II receptor (AIIR) antagonists with existing data on cardiovascular protection by angiotensin-converting enzyme (ACE) inhibitors in patients with type 2 diabetes. An AIIR antagonist would be favoured for renal protection for a diabetic patient with hypertension and evidence of early or overt nephropathy. With regard to patients with microalbuminuria, the HOPE and MICRO-HOPE studies showed that therapy with the ACE inhibitor ramipril (10 mg/day) was associated with a 24% relative risk reduction for the development of overt nephropathy over 4.5 years.1 In contrast, treatment of similar patients with the AIIR antagonist irbesartan (300 mg/day) for 2.6 years resulted in a 70% risk reduction for the development of overt nephropathy.2 Use of an AIIR antagonist in patients with overt nephropathy has also been shown to slow progression to end-stage renal failure.3,4 As the HOPE and MICRO-HOPE studies specifically excluded such patients, evidence supporting use of an ACE inhibitor in this context is lacking. An ACE inhibitor could be used if a diabetic patient has microalbuminuria and a history of coronary heart disease or additional risk factors for cardiovascular disease, especially if normotensive. However, almost all patients with microalbuminuria require antihypertensive therapy as well as therapy to protect target organs. The relative importance of blood-pressure-lowering versus non-lowering effects of antihypertensive therapy on reducing risk of cardiovascular disease remains uncertain.5 Furthermore, a recent meta-analysis of cardiovascular protection in 62 605 patients with hypertension (including the HOPE and United Kingdom Prospective Diabetes studies) did not find that ACE inhibitors affected cardiovascular prognosis beyond their antihypertensive effects.6 Finally, it is important to note that neither ACE inhibitors nor AIIR antagonists provide total protection from cardiovascular and renal events, and that further improvements are needed for both microvascular and macrovascular protection in patients with type 2 diabetes.

George Jerums · Mark E Cooper · Richard E Gilbert · Robert C Atkins

To the Editor: The review by Brodaty and colleagues1 on drug treatment of Alzheimer's disease provides a good, concise and balanced overview. However, Pfizer takes issue with some of the referenced safety data. In Box 3 of that article (Profiles of cholinesterase inhibitors), in reference to adverse effects of donepezil (Aricept, Pfizer), it is stated that "At 10 mg/day, nausea (17% of patients), diarrhoea (17%) and vomiting (10%) may occur.49" Reference 49 at this point appears to be an incorrect citation. The figures of 17%, 17% and 10% for nausea, diarrhoea and vomiting, respectively, appear to have been taken from an article by Rogers and Friedhoff.2 It is important to note that this was a non-comparative, open-label extension study, and these incidences of gastrointestinal adverse events are inconsistent with data presented in the Australian Product Information for donepezil,3 which quote rates of nausea, diarrhoea and vomiting of 11%, 10% and 5%, respectively. These incidences are derived from a patient cohort of 1102 patents who participated in appropriately designed comparative (active and placebo) pre-registration studies of donepezil. These data have recently been confirmed in a one-year, randomised, placebo-controlled study of donepezil in patients with mild to moderate Alzheimer's disease.4 Incidences of 11.3%, 7.0% and less than 5% for nausea, diarrhoea and vomiting, respectively, are quoted in that study. We contend that, while the citation referenced by Brodaty et al was incorrect, the figures quoted for the gastrointestinal safety incidences for donepezil are also inconsistent with the Product Information and current published data.

William Lam MB ChB, PhD

In reply: We thank Lam for pointing out an error in the referencing in Box 3 of our article1 regarding the figures for adverse events for donepezil. The correct reference was number 48 in our list, not 49, and was to Rogers, Farlow, Doody et al,2 not to Rogers and Friedhoff,3 as suggested by Lam. The other references in Box 3 were given as 20, 21, 23 and 48, but should have been listed as 19, 20, 21 and 47, respectively. Secondly, issue is taken with the rates of 17%, 17% and 10% for nausea, diarrhoea and vomiting, respectively, in people taking donepezil. We agree with the overall tenor of this letter that rates of side effects are generally lower in everyday practice. The figures we quoted for adverse events are higher than the 11%, 10% and 5% cited in the Australian Product Information for donepezil,4 as the article by Rogers and colleagues2 refers to rates of adverse events experienced by those on the 10 mg dose, after a forced titration after only one week on 5 mg. We presented data for adverse events at the 10 mg dose, as this was the dose recommended for donepezil given the findings of greater benefit on the higher dose. The Australian Product Information does not indicate whether the rates of adverse events refer to the 5 mg or 10 mg dose. Usual clinical practice, which is to start with 5 mg daily and increase to 10 mg after 4–6 weeks, results in fewer adverse events. The figures of 11.3% for nausea, 7% for diarrhoea and less than 5% for vomiting presented in the Nordic study,5 in which over 80% of patients were taking 10 mg of donepezil daily, with a more flexible titration schedule, appear to be more realistic.

Henry Brodaty AO, MB BS(SYD), MD(NSW), FRACP, FRANZCP · Jane R Hecker MB BS(Hons), FRACP · John A Snowdon MPhil, MD, FRCPsych, FRACP, FRANZCP · David J Ames BA, MD, FRCPsych, FRANZCP

To the Editor: I read with interest the recent article by Olynyk's group at Fremantle on the prevalence of coeliac disease in rural Western Australia.1 It is now increasingly realised that coeliac disease is underdiagnosed in adults because it may be clinically silent — but not necessarily asymptomatic. The symptoms, however, may be non-specific and not those traditionally associated with coeliac disease. In a recently reported small study from suburban Melbourne,2 I demonstrated that about 5% of patients (5/97) undergoing gastroscopy had coeliac disease based on small-bowel biopsy results. In only one of the patients was the disease suspected clinically. I have used these figures to argue the case for routine duodenal biopsy at the time of gastroscopy, regardless of the indication. It is important to note that in my study none of the patients presenting with diarrhoea, and only one of six with anaemia, had coeliac disease — so that restricting biopsy to this group would have missed most patients with coeliac disease. Timely diagnosis is important, as symptoms may be alleviated, presymptomatic nutritional deficiencies corrected, and the risk of cancer reduced by instituting a gluten-free diet. People presenting for gastroscopy represent a high-yield group for histological screening for coeliac disease in Australia.

Jeremy Ryan FRACP

In reply: We agree with Ryan that coeliac disease is common in the Australian community, with a prevalence of 1 in 250.1 Furthermore, all individuals positive for antiendomysial antibody who undergo small-bowel biopsy have typical features of coeliac disease.1 Clearly, there is a need to increase awareness relating to coeliac disease and determine appropriate screening strategies for our population. Ryan suggests that patients presenting for upper gastrointestinal endoscopy represent a group in whom a high diagnostic yield of coeliac disease is expected. However, clinical expression of the disease is variable.1 In this setting, we believe that it is important to determine the cost-effectiveness of the various screening strategies before introducing broad-based screening.3 There is no doubt that treatment of symptomatic patients who present with coeliac disease is appropriate, but there are limited data on outcomes for asymptomatic patients who are discovered in population-based screening programs. As we stated in our article, we recommend screening by serology and small-bowel biopsy if the clinical suspicion is high or the patient is in a high-risk group.

John K Olynyk BMedSc, MD, FRACP · Digby J E Cullen MB BS, FRACP · Guy Vautier BM, MRCP · Judith A Collett MB ChB, FRACP · Dominic F Mallon MB BS, FRACP · Chris J Hovell MRCP, DM

To the Editor: We are writing in response to the editorial of Ben-Tovim et al.1 Although we agree that more research into treatment efficacy in eating disorders is needed, we believe that the study to which reference is made2 is seriously flawed. The study should not be presumed to provide evidence about the effect of treatment on outcome, particularly as the majority of patients studied received no treatment. The high death rate (3/95 [3.2%] among patients with anorexia nervosa and 2/37 [5.4%] among patients with "eating disorders not otherwise specified") in such mildly ill patients (few of whom would have warranted hospitalisation on the basis of their weight) approximates that of seriously emaciated patients in longer-term studies of treatment outcome3,4 and could more properly be said to illustrate the results of having no treatment or inadequate treatment. Exactly what constituted specialised treatment is never actually described in the original article,2 in which "extended inpatient treatment" is defined as treatment lasting more than two weeks and "extended outpatient treatment" as three or more visits. Thus, the so-called "resource intensive treatment" the authors refer to would not necessarily represent even adequate management of these conditions. In our own 6–10-year outcome study5,6 cited by the authors, 61 emaciated patients with anorexia nervosa received, on average, 11 weeks of inpatient treatment consisting of nutritional rehabilitation and psychotherapy. Only one patient died (of suicide) and, of the patients fully assessed, 41/50 (82%) had a good or intermediate outcome. The degree of weight restoration achieved by the end of treatment correlated with the degree of osteoporosis 10 years later.7 In other studies, duration of illness and early intervention have been shown to significantly influence outcome.4 This contrasts with the findings of Ben-Tovim et al,2 which may have been skewed by an unusual level of chronicity in the study group. A recent study of 69 patients with eating disorders treated in our own multidisciplinary program showed that, on 12–18-month follow-up, 48/69 (70%) had improved and 34/69 (49%) no longer had an eating disorder diagnosis. Mean levels of all but one of the major behavioural and psychological features rated by the EEE-C (Eating and Exercise Examination by Computer) instrument8 were significantly reduced. The advice given by Ben-Tovim and colleagues to the parents of the hypothetical 15-year-old girl with anorexia nervosa is regrettably nihilistic and, if based on their Lancet study,2 not founded on sound or generalisable evidence. Parents should be referred to a program for which good outcomes have been demonstrated, treatment accords with published guidelines, the clinicians are suitably experienced, and in which early intervention is the aim.4

Janice D Russell MD FRACP FRANZCP · Suzanne F Abraham PhD

In reply: The commitment of Russell and Abraham to their own program has distracted them from accurate reporting and sound epidemiological principles. They say that the majority of patients that we studied received no treatment. Not so. We clearly stated that only 34 of the 220 patients studied received no treatment.1 They then draw a range of inferences from the fact that "3/95 (3.2%)" patients with anorexia nervosa died. In fact, only 2 of 95 patients with anorexia nervosa died as a consequence of that disorder during the five years of our study. At 2.1%, this is similar to the crude death rate of 1/61 (1.6%) that they describe in their own study. However, it is only acceptable to use a rare outcome as a measure of the efficacy of a treatment program if the clinical characteristics that put patients at risk for such an outcome are known and accounted for. We do not know the specific factors that put people at particular risk of dying from anorexia nervosa. Without such knowledge, small differences in crude death rates can not of themselves inform us whether treatment programs diminish or accentuate such risks. Unfortunately, there are no other studies against which to compare the outcomes of the patients with "eating disorders not otherwise specified" in our study. We have dealt with issues such as the representative nature of our study elsewhere.2 I stand by our work and the conclusions we draw from it.

David I Ben-Tovim PhD FRANZCP

Ben Haneman's army of friends were greatly shocked to learn that Ben had collapsed in the State Library of New South Wales, was admitted to St Vincent's Hospital, and died the following day, 18 December 2001, without regaining consciousness. His life of service has enriched us all. Ben was born into a Jewish family in Florence, Italy, on 13 February 1923. They migrated to Australia in 1927, where Ben thrived. He attended Canterbury Boys' High School, then entered the University of Sydney's Faculty of Medicine at the age of 15. After graduating in 1944 and completing residencies in Perth, he settled into general practice in Carlton, NSW, in 1947. He became a Member (1960) and Fellow (1971) of the Royal Australasian College of Physicians. Officially, Ben served St George Hospital (as Honorary Medical Officer and then Visiting Medical Officer) from 1947 until 1990, particularly in the field of gastroenterology. His effective service was much longer. He loved teaching, and would take students to Lidcombe Hospital on Sunday mornings to see rare and interesting neurological cases. Naturally, he became St George's first Warden of Students. For many years he contributed a monthly essay to the St George Hospital Post Graduate Medical Bulletin. He was also a regular contributor to RACP News, Australian Doctor and the Jewish press. He became a physician of extraordinary energy, enthusiasm, erudition, generosity, compassion and good humour. Ben gave continuing support to the University of Sydney and University of NSW medical schools. For many years he was Warden of Warrane College (a student residential college) at the University of NSW. Recently, he presented a fascinating discourse on the history of Sydney University's Faculty of Medicine to a large and appreciative audience of fellow graduates. At the time of his death, he was Vice President of the NSW Society of the History of Medicine and President of its national body. Ben had an enormous range of interests. He was a committed Jew and was chairman of the Social Justice Committee of the Jewish Board of Deputies. He had a valuable personal library containing many thousands of volumes, and a highlight of a visit to his home was to share his enjoyment of some recent "find". For over 30 years he was a greatly respected member of the Library Committee of the Royal Australasian College of Physicians. He also had a passion for Spain and its culture. Having learnt Spanish in his youth, he became enamoured of the country and its people. He was an honorary professor for many years at the University of Navarre, and in 1984 the Spanish government appointed him a Knight of the Order of Civil Merit. In 1997, he generously donated to the State Library of NSW 1100 editions of Don Quixote in various languages and a further 1000 books on Cervantes. He became the first Life Member of its Library Society, the Friends' Group, in November 2001. A passionate soul, Ben was truly quixotic himself ("one who strives with lofty enthusiasm for visionary ideals" — Oxford English Dictionary). Generations of students and patients are indebted to him. In 1988, Ben was appointed a Member of the Order of Australia for services to medicine and the Spanish community. He is survived by his sons David and Peter.

George C Wilson AM MB BS FRACP

Avoiding ulcers In Hong Kong, a randomised controlled trial found that treatment for H. pylori significantly reduced the risk of ulcers, for patients starting long term NSAID treatment. The study recruited patients without prior NSAID treatment, who had a positive urea breath test for H. pylori, and moderate dyspepsia or a history of confirmed peptic ulcer. Fifty-one patients received amoxycillin 1 g and clarithromycin 500 mg twice daily for a week, while 49 controls had identical placebos. All patients also received omeprazole 20 mg twice daily for a week and diclofenac sustained release 100 mg daily for six months, followed by endoscopy. Confirmed ulcers were present in 5 of 51 patients in the eradication group and 15 of 49 patients in the control group (6-month probability of ulcers, 12.1% [95% CI, 3.1–21.1] v 34.4% [95% CI 21.1–47.7]). Lancet 2002; 359: 9-13 Food for court A large international study has found that passive smoking in the workplace increases the likelihood of respiratory symptoms, and that it is still a big problem in many countries. The cross-sectional survey, conducted in 36 centres in 16 countries between 1990 and 1994, considered a random sample of 7882 people who had never smoked. Each person was interviewed and respiratory function tests were completed on a subsample. Rates of exposure to passive smoking in the workplace correlated with the overall smoking rates in each country. One centre in Spain recorded the highest rate (54%), with the lowest from Sweden (2.5%). Passive smoking in the workplace was significantly associated with wheeze (OR, 1.59; 95% CI, 1.23–2.07) and current asthma (OR, 2.73; 95% CI, 1.58–4.74), as well as increased bronchial responsiveness (effect, –0.06; 95% CI, –0.23 to 0.10). Lancet 2001; 358: 2103-2109 Genes and smoking Some maternal genes, combined with smoking during pregnancy, may place the infant at particularly high risk of low birthweight. A case–control study, done in inner-city Boston, included 207 preterm or low-birthweight infants and 534 full-term infants of normal weight. Most mothers (567) had not smoked during the pregnancy; 50 had quit and 124 had smoked continuously. Two highly polymorphic genes determine the metabolism of the chemicals in cigarette smoke to toxic intermediates (CPY1A1), and the detoxification of these metabolites (GSTT1). Comparing mothers who had smoked continuously with those who had not smoked, mean reductions in birthweight were as follows: for the CPY1A1 AA genotype, 252g v Aa/aa genotype, 520g; for the GSTT1 present genotype, 285g v absent genotype, 642g. The greatest reduction in mean birthweight (1285 g) occurred in the group with CYP1A1 Aa/aa and GSTT1 absent genotypes. Among non-smoking mothers, genotype alone did not make a significant difference to birthweight. JAMA 2002; 287: 195-202 Sequelae of war All modern wars have been associated with a syndrome characterised by unexplained medical symptoms, say a team of British and American researchers. British war pension files were randomly sampled for six conflicts since 1854, excluding prisoners of war. The researchers identified 94 possible symptoms (later reduced to 25) in 1856 individuals. The detailed medical notes, regular pension reviews, specialist reports and longitudinal perspective permitted exclusion of cases with organic disorder or major mental illness. Using sophisticated clustering techniques, three varieties of post-combat disorder were identified: a debility syndrome associated with the 19th and early 20th centuries; a somatic syndrome, related primarily to the First World War; and a neuropsychiatric syndrome, associated with the Second World War and the Gulf conflict. The authors conclude that approaches to management may be more effective if each new post-combat syndrome is recognised as part of a pattern of normal responses to the physical and psychological stress of war, rather than a novel illness. BMJ 2002; 324: 1-7 Unnatural causes It is well recognised that people with schizophrenia have high rates of death from suicide. A recent study found that men with schizophrenia were also seven times more likely to die from homicide. Researchers identified all persons aged >15 years who were admitted to hospital with a psychiatric disorder between 1973 and 1993 from the Danish Psychiatric Case Register, and linked this with the Danish National Register of Causes of Death, using each person’s unique identifier. Standardised mortality ratios (SMRs) were confirmed, with rate ratios standardised to a common age distribution. For men with schizophrenia SMRs were for, homicide, 734 (95% CI, 350–1539); for accidental death, 213 (95% CI, 168–269); and, for suicide, 1073 (95% CI, 973–1183). Lancet 2001; 358: 2110-2112