Volume 176 Issue 5

Few areas of medicine have undergone greater change during the past 50 years than infectious diseases. The optimism and clinical confidence associated with the development of antimicrobial agents from the 1940s onwards has been tempered by the emergence of new diseases, such as AIDS and infections associated with transplantation and cancer therapy, and by the widespread development of antibiotic resistance. Despite many advances, infectious diseases continue to account for about a quarter of all deaths worldwide1 (Box 1). Furthermore, a security dimension has emerged. A recent report on The global infectious disease threat and its implications for the United States from the US Central Intelligence Agency (CIA) analysed this "non-traditional threat": The dramatic increase in drug-resistant microbes, combined with the lag in development of new antibiotics, the rise of megacities with severe health care deficiencies, environmental degradation, and the growing ease and frequency of cross-border movements of people and produce have greatly facilitated the spread of infectious diseases.2 Clinicians today require more knowledge of infectious diseases than ever before. In this issue of the Journal (page 229), we begin MJA Practice Essentials — Infectious Diseases. This series cannot hope to cover all new aspects of infectious disease. Instead, we aim to discuss clinically important areas where recent advances have occurred in diagnosis or treatment, new diseases have been identified, or healthcare changes have necessitated new clinical approaches to "old" diseases (eg, endocarditis and cellulitis) (Box 2). Some important topics, such as HIV infection and bioterrorism, are beyond the scope of this series. Wherever possible, recommendations are evidence-based, with the evidence graded according to the system of the National Health and Medical Research Council3 (Box 3). As with much of medicine, management of infectious diseases is affected by the competing needs for prompt empirical treatment and for a definite diagnosis to allow focused therapy. Advances in diagnostic technology have enhanced the possibilities for rapid, accurate diagnosis of conditions such as sexually transmitted diseases, deep-seated infections such as endocarditis and osteomyelitis, and common viral infections.4 However, identification of bacterial pathogens and their antibiotic susceptibilities still requires careful specimen collection and slow, generally labour-intensive, microbiological culture methods. Furthermore, many rapid diagnostic tests are sufficiently expensive that initial empirical "shot-gun" therapy without investigation can seem attractive. As effective antiviral agents become ever more readily available, many of the issues faced with antibiotics, such as rapid diagnosis, susceptibility testing and dosage monitoring, must also be considered. Current administrative pressure for shorter hospital stays and fewer outpatient or general practitioner consultations appears to encourage use of broad-spectrum empirical antibiotic and antiviral therapy, rather than careful investigation, review and directed therapy. Combined with the community's apparent ready acceptance or expectation of antibiotic therapy, this may explain Australia's ranking as the world's second-largest per-capita consumer of antibiotics (after France).5-7 Similarly, in the US and Canada, it is estimated that about 50% of all outpatient prescriptions for antibiotics are unnecessary.7,8 Antibiotic resistance is now emerging as a key challenge to many healthcare programs. Indeed, developments such as multidrug-resistant tuberculosis and resistance among common pathogens in developing countries (eg, Salmonella and Shigella spp. and malaria) threaten to totally undermine many current healthcare gains.7 It is therefore essential that all Australian clinicians accept the responsibility that goes with the privilege of prescribing antimicrobial agents. In both developed and developing regions, hospital-acquired infections are increasingly recognised as a major contributor to healthcare morbidity and costs.7 For this reason, good hospital infection control practices are no longer simply a concern for microbiologists and infection control committees, but must be understood by all staff, including hospital administrators — even if the latter consider them merely as "risk management". Few health issues attract more media attention than nosocomial infection. Current training about infectious diseases appears relatively limited among some medical personnel. A recent review of the general training curricula of the 12 Australian medical colleges found that five (Anaesthetists, Ophthalmologists, Medical Administrators, Radiologists and Psychiatrists) did not mention antibiotics at all.6 Similarly, among the 19 subspecialty groups in the Royal Australasian College of Physicians, only two specify the need for training in antibiotics (Thoracic Medicine and Infectious Diseases).6 The challenge for Australian clinicians in the current era of "information overload" is to improve the appropriateness of investigations and treatment of infectious diseases to avoid unnecessary antimicrobial therapy.6,7,9,10 Thus, MJA Practice Essentials — Infectious Diseases focuses on practical clinical problems that are either common or are sufficiently acute or severe that early recognition is important to limit morbidity or restrict disease spread. Whenever possible, recommendations are evidence-based. 1: Causes of death worldwide in 1998 (% of all deaths)* * Adapted from World Health Organization leading causes of death for 1998 (total of 53.9 million deaths from all causes worldwide).1 † Cancers, cardiovascular, respiratory and digestive deaths can also be caused by infections, further raising the percentage of deaths caused by infectious diseases. 2: Infectious diseases series contents Infections in pregnancy Hospital-acquired infections Community-acquired pneumonia Acute community-acquired meningitis and encephalitis Hospital-in-the-home Emerging viral infections in Australia Sexually transmitted infections Soft tissue, bone and joint infections Infections in the returned traveller Herpes simplex and varicella Antibiotic resistance 3: Levels of evidence Throughout the series, evidence is graded using the system of the National Health and Medical Research Council:3 E1 Level I: Evidence obtained from a systematic review of all relevant randomised controlled trials. E2 Level II: Evidence obtained from at least one properly designed randomised controlled trial. E31 Level III-1: Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). E32 Level III-2: Evidence obtained from comparative studies (including systematic reviews of such studies), with concurrent controls and allocation not randomised, cohort studies, case–control studies, or interrupted time series with a control group. E33 Level III-3: Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4 Level IV: Evidence obtained from case series, either post-test or pre-test/post-test.

M Lindsay Grayson MD, FRACP, FAFPHM · Steven Wesselingh PhD, FRACP

In a rejoinder to Benjamin Franklin's observation that nothing is certain in life bar death and taxes, people's fondest wishes seem to be to live forever and pay no tax. The timely and provocative study of Weston et al in this issue of the Journal (page 208),1 reporting high acceptability of a hormonal male contraceptive among new fathers, prompts a reflection on wishful thinking, as such a new contraceptive remains unavailable. In some respects, contraception is closer to a consumer lifestyle choice than a conventional medical treatment, as illustrated by the impact of media-inspired contraceptive "scares" that have led to panic-driven abandonment of contraception and subsequent unwanted pregnancies.2 Creating a need for novel products is the raison d'être of advertising, and in the world of public relations presentation is the whole game. Responses to unfamiliar products or services are sensitive to how they are described, and almost any outcome may arise depending on how the access, convenience, safety and efficacy of hypothetical or existing contraceptive methods are described. At face value, however, the observations of Weston et al are consistent with recent findings from other cultures3,4 and earlier World Health Organization (WHO) studies,5,6 all of which similarly rely on forcing choices between hypothetical options. Even if the responses accurately reflect attitude, there is a vast gulf between human attitude and behaviour. This is the starting point for much of behavioural medicine, as illustrated by the failure of even low expectations of interventions that rely upon behavioural change (eg, interventions to deal with anger, smoking, drug addiction, obesity). Nevertheless, the strikingly positive attitudes reported by Weston et al herald major progress and the imminent availability of practical hormonal male contraceptives. Arguably, the epitome of successful applied science in the 20th century was the development of reliable and reversible contraception. The universal availability of numerous highly effective female contraceptives fostered unprecedented social change extending well beyond medicine and science. At the start of the 21st century, it is a sad reflection that the previous century passed without the addition of a single new contraceptive method that men could use to share more equitably the burden of reliable family planning.7 Historically, all deliberate family planning methods (apart from abortion) were shared responsibilities requiring active male involvement. The phenomenal success of female-oriented contraceptive development in recent decades has shifted the burden of responsibility for family planning disproportionately onto women. Worldwide, however, male involvement in family planning remains remarkably high, considering the inadequate means available.8 The central dilemma for men in stable relationships seeking to share more responsibility for family planning is that the reversible methods are not reliable and the reliable method (vasectomy) is not reversible. What is needed is a reversible male method as reliable as modern female methods. The biologically unique processes of sperm development offer ever-increasing numbers of new ways for clever biotechnology to interrupt male fertility temporarily, notably by modification of sperm and male reproductive tract ion channels. However, these require full development as new drugs, whereas hormonal methods are close to practical realisation. Although hormonal contraceptive methods were always equally feasible for men and women, during the decades when female contraceptive development flourished the development of analogous male methods languished, as it depended solely upon the limited resources available to academic researchers without pharmaceutical company product development. A decade ago, proof-of-concept for a hormonal male contraceptive was achieved jointly by the US Contraceptive Research and Development Agency and WHO's Male Task Force, which conducted the first efficacy studies for any chemical male contraceptive.9,10 These studies showed high reliability of a reversible prototype hormonal regimen, a crucial empirical finding about which the biggest surprise is that this finding lagged three decades behind the wide availability of analogous female hormonal methods. Continued impressive progress towards a practical product has been achieved. There is consensus that a combination progestin-plus-androgen approach is optimal, with several combinations approaching the ideal of universal azoospermia.7 Finally, some large pharmaceutical companies have recently upgraded their involvement from being spectators to participating in some active development of the well-advanced research produced by the academic community within the public sector. New hormonal male contraceptives are needed for couples in stable relationships rather than for those with changing partners, among whom condom use prevents sexually transmitted disease as well as pregnancy. The survey of Weston et al highlights a likely niche for the use of a hormonal male contraceptive — the postpartum period. This period is ideal, because it focuses on a stable couple with a predictable timing of contraceptive need and a situation in which reliable female contraceptives are not well suited, particularly during lactation. Other niche purposes for a hormonal male contraceptive include delaying vasectomy, offering an alternative to conventional female methods when they are not well tolerated, and replacing less reliable male methods. The finding that a hormonal male contraceptive is acceptable to an appropriate Australian target population is consistent with Australasian men having the highest rate of vasectomy in the world.11,12 These observations highlight the substantial need and market for a hormonal male contraceptive. Hopefully, this decade will see the long-overdue development of an eminently feasible and widely desirable product. The desultory response from multinational pharmaceutical companies, even after completion of much early-phase clinical research by the public sector, suggests implementation may be driven by populous countries such as China, Indonesia and India, whose family planning priorities value such developments more highly. In Western countries, development may require a more enterprising start-up company to capitalise on this opportunity, which eludes the imagination, or lurks beneath the commercial horizon, of the pharmaceutical industry behemoths.

David J Handelsman MB BS, PhD, FRACP

The Australian Council for Safety and Quality in Health Care (ACSQHC) plans to publish data about the performance of the Australian healthcare system. It is probably inevitable that this kind of information, which is actively disseminated and reported in such a way as to encourage readers to draw comparisons, will be used in the near future by the media, the public and politicians to make public judgements about the relative performance of individual hospitals or even individual doctors or groups of doctors. Initiatives such as these will therefore be perceived as a threat by some health professionals and some organisations. Would this negative response be justified? What might be gained from public disclosure and how can the policy be implemented successfully? We believe that a negative response to public disclosure in Australia would be counterproductive. Greater openness in healthcare is inevitable. Information is freely available about most areas of modern life and many believe that healthcare is one of the last bastions of protectionism. When millions of dollars are spent on healthcare, those who pay have a right to know that the money is being spent effectively, and the publication of comparative data sends a strong message about the willingness of health professionals and organisations to be accountable. In addition, public disclosure appears to be an effective way of improving quality.1 There is a growing body of evidence that the current level of quality of care is unacceptable2,3 and that quality-improvement initiatives using confidential data have been largely ineffective at changing the behaviour of health professionals.4 When comparative data are released to the public, it appears to remind providers of the issues and refocuses them towards taking action.5 Arguments in support of the status quo — that the data are inadequate, the public won't understand them and the media will misuse them — are not sustainable if public disclosure is introduced properly. There are lessons that can be learnt from other countries to guide the process of disclosure in Australia. The United States has nearly 15 years' experience of publishing data in the form of "report cards", or "provider profiles". The initiative was launched by the federal government and the momentum has been maintained by a variety of public, private, commercial and not-for-profit organisations. Consumers and purchasers of healthcare were expected to play a key role by selecting high-performing providers, but recent evidence suggests that the providers themselves make greater use of the data than the service users.6 There are some notable examples of improvements in both the processes and outcomes of care associated with the publication of performance data.1 Public reporting in Europe is less well established than in the United States, but hospital "league tables" have been published in the Netherlands for several years, and the UK government plans to introduce incentives linked to a range of publicly reported performance criteria.7 What can we learn from the initiatives that have already been introduced? First, a backlash from some doctors, professional groups and institutions (particularly those seen to be performing badly) is predictable. Some criticisms were justified in the early days of report cards but lessons are being learnt. For example, we know that forcing new initiatives on reluctant professionals is not the most effective way of changing attitudes, and the introduction of report cards is more likely to be successful if doctors are encouraged to take a lead, particularly in selecting the performance measures. Bringing the media on board at an early stage to ensure fair and balanced coverage also helps. In addition, delaying publication for a short period to allow providers time to look at and act upon the data is a useful strategy. Second, it is important that those who publish the data show a commitment to investing in the process and progressively improving the quality of the data and the validity of comparisons arising from the data. However, it makes little sense to "wait for better data" — data will always be imperfect and, as one commentator stated, it is important not to let "perfect be the enemy of good".8 Experience suggests that the process of publication can in itself act as a catalyst for data improvement. Third, the utility of comparative data comes less from making absolute judgements about performance than from the discussion arising from using the data to benchmark performance. There is therefore a strong educational component to the effective use of comparative data, and resources are required to facilitate this process.6 Finally, it is important to be cognisant of the risks of publishing comparative data.9 The danger of institutions refusing to treat certain disadvantaged groups in order to improve their apparent performance is well recognised, although probably overstated,10 and can be reduced by careful adjustment of risk and casemix. A tendency to focus on what is being measured at the expense of other areas of practice can be minimised by publishing a wide range of quality indicators. The risk of "short-termism" — an inappropriate focus on annual reporting cycles — can be reduced by ensuring a balance between short-term targets and long-term strategic aims. A greater degree of public reporting of information about healthcare quality is an inevitable and desirable way forward. Practitioners and policymakers in Australia have an opportunity to ensure that the policy is implemented in a manner that is most likely to produce positive change.

Martin N Marshall MSc, MD, FRCGP · Robert H Brook MD, ScD

Aim: To survey the attitudes of a population of Australian men to potential use of male hormonal contraception (MHC). Design: Survey of male partners of women who had recently given birth. Men were approached while visiting their female partners on the ward. Participants: 118 out of 148 Australian-born English-speaking men who were approached. Setting: Postnatal ward of Monash Medical Centre (a public teaching hospital in Melbourne), between October 2000 and April 2001. Main outcome measure: Attitudes towards potential use of MHC, rated on a five-point scale. Results: 89/118 men surveyed (75.4%; 95% CI, 67.7%–83.2%) indicated that they would consider trying MHC if it were available. The three most popular choices for method of administration of MHC were (in descending order) an oral pill, a three-monthly injection, or a two-yearly injection. A statistically significant association was found between acceptability of vasectomy and acceptability of MHC (70.5% of men who indicated they would try MHC [MHC "triers"] found vasectomy acceptable versus 44.5% of MHC "non-triers"; P = 0.011). Triers reported a higher rate of approval of MHC by their female partners than non-triers (79.8% v 13.8%, respectively; P < 0.0001). Conclusions: MHC appears to be acceptable to a majority of Australian men when surveyed in a postpartum context. Attitudes of men towards existing male contraception, as well as the attitudes of their partners, appear to exert a strong influence on acceptability of MHC.

Gareth C Weston MB BS · Michelle L Schlipalius MB BS · Meabh Ni Bhuinneain MRCOG, MRCPI · Beverley J Vollenhoven PhD, FRANZCOG

Objectives: To determine the proportion of patients with established coronary heart disease (CHD) in two Australian studies (VIC-I in 1996–1998, and VIC-II in 1999–2000) who achieved their risk-factor targets as recommended by the National Heart Foundation of Australia, and to compare this proportion with those in studies from the United Kingdom (ASPIRE), Europe (EUROASPIRE I and II) and the United States (L-TAP).Design and setting: Prospective cohort study with VIC-I set in a single Melbourne university teaching hospital and VIC-II set in six university teaching hospitals in Melbourne, Victoria.Participants: 460 patients (112 in VIC-I, 348 in VIC-II) who completed follow-up in the control groups of two randomised controlled trials of a coaching intervention in patients with established CHD.Main outcome measures: The treatment gap (100%, minus the percentage of patients achieving the target level for a particular modifiable risk factor) at six months after hospitalisation.Results: The treatment gap declined from 96.4% (95% CI, 91%–99%) to 74.1% (95% CI, 69%–79%) for total cholesterol concentration (TC) < 4.0 mmol/L (P = 0.0001) and from 90.2% (95% CI, 83%–95%) to 54.0% (95% CI, 49%–59%) for TC < 4.5 mmol/L (P = 0.0001). This reduction in the treatment gap between VIC-I and VIC-II appears to be entirely explained by an increase in the number of patients prescribed lipid-lowering drugs. The treatment gaps in the UK and two European studies were substantially greater. The treatment gap for blood pressure (systolic ≥ 140 mmHg and/or diastolic ≥ 90 mmHg) in VIC-II was 39.5%, again less than corresponding European data. There were 8.1% of patients who had unrecognised diabetes in VIC-II (fasting glucose level ≥ 7 mmol/L), making a total of 25.6% of VIC-II patients with diabetes, self-reported or unrecognised. The proportion of patients in VIC-II who were obese (body mass index ≥ 30 kg/m2) was similar to the overseas studies, while fewer patients in VIC-II smoked compared with those in the UK and European studies.Conclusions: A substantial treatment gap exists in Victorian patients with established CHD. The treatment gap compares well with international surveys and, at least in the lipid area, is diminishing.

on behalf of the COACH study group

Objective: To assess the incidence and nature of postoperative serious adverse events (SAEs) among inpatients having surgery in a tertiary hospital, and to determine which subgroups of patients might be at greatest risk.Design: Prospective observational study from 1 December 1998 – 31 March 1999.Setting: Tertiary teaching hospital in Melbourne, Victoria.Subjects: 1125 subjects having inpatient surgery during the study period.Main outcome measures: Inhospital mortality, length of hospital stay, and SAEs (myocardial infarction, pulmonary embolism, acute pulmonary oedema, unscheduled tracheostomy, respiratory failure, cardiac arrest, stroke, severe sepsis, acute renal failure, and emergency admission to intensive care unit [ICU]).Results: There were 414 SAEs in 190 of the 1125 patients (16.9%); 80 patients died (7.1%). The most common adverse events were emergency admission to ICU (95), respiratory failure (52) and readmission to ICU (37). In patients without SAEs, mean duration of hospital stay was 18.4 days (95% CI, 15.4–21.4), while in those with SAEs it was 38.5 days (95% CI, 35.3–41.7) (P < 0.0001). SAEs, including deaths, were more common after unscheduled surgery and in patients over 75 years of age. The combination of these two factors carried a 20% mortality. There were no differences in the incidence of SAEs among the major surgical specialties.Conclusions: SAEs are common and result in high mortality, especially in older surgical inpatients and those having unscheduled surgery. These findings raise important issues of optimal perioperative management in tertiary hospitals.

Rinaldo Bellomo MD, FRACP · Donna Goldsmith RN · Sarah Russell RN, PhD · Shigehiko Uchino MD

Objectives: To review Australian adverse drug reaction reports describing hyponatraemia and hypokalaemia attributed to indapamide and compare the characteristics of the patients with those in Australian reports implicating two other diuretic products (hydrochlorothiazide and amiloride hydrochloride; chlorothiazide).Design: Descriptive analysis using reports from the database of the Adverse Drug Reactions Advisory Committee (ADRAC).Main outcome measures: Numbers of reports of hyponatraemia and hypokalaemia; proportion of such reports in total reports of adverse reactions to each drug; severity of electrolyte disturbances.Results: Between August 1984 and September 2000, 84 Australian reports of hyponatraemia and 87 reports of hypokalaemia, in which indapamide was the sole suspected drug, were submitted to ADRAC. Most reports involved an indapamide dose of 2.5 mg daily. There was a significantly greater proportion of reports of hyponatraemia with indapamide and with the hydrochlorothiazide and amiloride combination than with chlorothiazide; hypokalaemia was significantly more common for indapamide than for the other two drugs. Of the 87 reports of hypokalaemia with indapamide, 35 patients also had hyponatraemia. For all three drugs, at least 80% of reports of hyponatraemia were in people aged 65 or over, and electrolyte disturbance was most commonly reported in elderly women.Conclusions: Hyponatraemia and hypokalaemia have been described in 20.9% and 21.7%, respectively, of reports to ADRAC in which indapamide was the sole suspected drug. The electrolyte disturbances can be severe.

Michael D Chapman · Ross Hanrahan · John McEwen MB BS, MSc, MPS · John E Marley MD, MB ChB

Mistakes in medicine, particularly when patients have suffered harm as a result, are of ethical concern as breaching a fundamental injunction in medicine: "first do not harm". To minimise the chances of a recurrence, an effective response to harm must take into account both the concerns of patients who have been harmed and the concerns of doctors who may fear extreme outcomes if a mistake is admitted. There is an apparent conflict between a need to respond to errors non-punitively, on the one hand, and ethical and legal requirements for accountability and compensation for anyone harmed, on the other. There is also confusion between arguments for a "blame-free" culture in the healthcare system and the need to attribute responsibility in some cases. Important elements in an ethical response to mistakes include disclosure to the patient and family; taking appropriate clinical steps to mitigate any harm that may result from a mistake; identifying the process leading to harm; and responding in an appropriate and humane manner to minimise the likelihood of any recurrence.

Paul M McNeill MA, LLB, PhD · Merrilyn Walton BA, MSW

Rapid and radical change in almost every facet of society has brought in its wake community anxiety, suspicion and hostility. Current examples in Australia include the impact of globalisation, the introduction of the goods and services tax, and the actions of the banks in phasing out local branches. Even the health industry faces increased levels of public scrutiny and criticism. A recent example has been the aged-care institutions, charged with providing suboptimal facilities and services.1 Hospitals, too, both in the private and public sector, have received embarrassing media attention — the organ-harvesting scandal in the United Kingdom being but one example.2 Surprisingly, while such public pressure has resulted in many large companies formulating corporate codes of ethics, few hospitals, with the exception of some with religious affiliations, have adopted such codes. This may be due in part to many hospital staff having their own professional codes of ethical behaviour. However, a hospital is more than the sum of its professional staff, and decision-making at a corporate level raises ethical issues. For example, ethical issues need to be taken into account in the allocation of scarce financial resources and the sometimes fierce interdepartmental battles for funding. The size of many hospital budgets brings them into the ambit of "big business" and, as such, boards must be sensitive to the bottom line of financial accountability. Currently, there is increasing pressure on all businesses, large and small, to establish their activities on a sustainable basis, incorporating "triple-bottom-line" accountability — decision-making must take into account not only financial outcomes but also human rights and the impact on the environment.3 Only when all these issues are addressed, it is argued, can legitimate and responsible decisions be made. The question might be asked, why bother with a code of ethics when hospitals are governed by highly prescriptive laws and regulations covering just about every aspect of their activities — from occupational health and safety to environmental protection to paternity leave — and where the threat of litigation hangs heavily over the system? The simple answer is that, to maintain and develop a reputation with customers and the community and create credibility and trust in a "brand" or image, any organisation must these days go beyond pure legal compliance with regulations and avoidance of litigation. This requires a willingness to communicate the values under which the organisation will operate, and to be judged against those values. This is particularly important for community service organisations such as hospitals and even medical practices. In a code of ethics, a hospital is stating the values to which it is committed and which, in seeking to achieve its objectives, it will never violate. In short, the end never justifies the means. Codes of conduct have been in use in the Australian medical world for many years (eg, the Central Sydney Area Health Service has had a code of conduct in operation since the early 1990s),4 and A statement of ethical principles for those who shape and give health care has been developed by the Tavistock Group (a group comprised mostly of UK and US healthcare professionals and ethicists).5 However, a recent initiative by the Austin and Repatriation Medical Centre (ARMC), a major metropolitan teaching hospital in Melbourne, is believed to be the first code of ethics adopted by a major non-religious public hospital in Australia. Codes of ethics and codes of conduct are often assumed to be synonymous, whereas they perform quite different, but complementary, roles. To quote Lagan: 6,7 A code of ethics sits alongside a code of conduct and together they provide the ground rules for day-to-day behaviour as well as guiding how decisions might be made in unanticipated situations. Typically a code of ethics spells out an organisation's values and principles; it both reflects and shapes the organisation's culture. It makes transparent the values framework by which management will manage the business and its employees and the core values that will underpin company policies. [On the other hand] a code of conduct is about what types of behaviour are acceptable in the workplace. It outlines the rules and measurements by which employees will be held accountable in observing the stated corporate values and principles. Like all tertiary teaching hospitals engaged in research, ARMC conforms with the ethical requirements of the National Health and Medical Research Council. It also has a Patient Care Ethics Committee that deals with such issues as patient autonomy, and limitation-of-treatment policies. In 1995, a decision was made by the then Liberal State Government that the ARMC would be privatised. This naturally caused considerable concern. A major factor in this concern was whether the new "owners" of the hospital would adhere to the hospital's perceived high level of ethical concern and care for its patients. These ethical standards were nowhere codified. Therefore, a committee that included professional staff from the hospital — doctors, nurses and allied health professionals — together with community representatives set about developing a corporate code of ethics, to which some 200 staff members subsequently contributed. The plan was to present the code to the prospective purchasers of the hospital and seek their acceptance of it. In the event, the decision to privatise the ARMC was reversed, but the code had aroused so much interest that the ARMC Board decided to adopt it. While staff contributions to the development of the ARMC Code of Ethics were substantial, its continued relevance depends on effective promulgation or it risks going the way of many similar well-meant projects. Firstly, the code must be displayed within the hospital in such a way that staff, patients and visitors are constantly reminded of its ethical standards. One American hospital, which has a code of ethics, has achieved this by placing framed copies of the code in critical positions, such as reception, outpatients, emergency and other departments. Secondly, staff intake programs must include a session on the importance of the code. Finally, publicity in the community is vital. Above all, a code of ethics must be a living document, and genuinely form the basis for the value system on which every person in the hospital operates, and is seen to operate — from the boardroom to the bedside to the boiler room. The challenge to every incorporated body in the medical field, big or small, is to formulate a code of ethics that demonstrates its adherence to fundamental human values in the face of rapidly changing circumstances. Reconciling the ethics of responsible financial accountability and best-practice medical care has, in recent times, caused difficulties for hospital boards. Hence, the need for a code of ethics which covers both business and medical practice, and whose standards are higher than the minimum required by law. It is not an easy task and will become even more difficult in the future, but, in the long run, it will save hospitals and the practice of medicine many potential difficulties and enhance their status in the community. It is particularly important that such a code be regularly updated to reflect, among other things, emerging ethical issues in patient care and treatment in end-of-life situations and in the rapidly developing fields of life science, such as gene technology. Corporate code of ethics The Austin & Repatriation Medical Centre (ARMC) has adopted this Corporate Code of Ethics as an expression of its commitment to the community that it will apply the highest ethical standards to all its activities Values The Austin & Repatriation Medical Centre upholds the following values as being self evident and having both intrinsic worth and universal application: The inherent dignity of each and every human being The autonomy of the individual The exercise of care and compassion The practice of justice, fairness, honesty and integrity The proper stewardship of resources The advancement of knowledge and learning The striving for excellence Principles These values will be guided by the following principles: 1. All individuals of whatever culture, class or belief will be treated with respect, including and especially those who are intellectually or physically impaired or disabled, incompetent or deceased. 2. All individuals, especially patients, have the right to make or be involved in decisions which affect their lives, and where applicable this right extends to include consultation with those who are close to the patients concerned. 3. The primary concern of the hospital will be the provision of compassionate care and treatment to its patients with every effort made to relieve suffering. 4. The principle of justice will be observed in the avoidance of all discriminatory practices and the provision of equal opportunity. 5. Organisational activity, including administration, will be conducted in a fair, open and collaborative manner. 6. Responsibility and accountability will be exercised in all decisions and actions at every level to ensure that the best use of resources is achieved. 7. The importance of research and teaching in every clinical discipline will be recognised and every effort made to ensure that all research is conducted at the highest scientific and ethical standards. 8. The hospital acknowledges that it shares both a natural and a cultural environment with a wider community and affirms its commitment to respect and nurture those environments. 9. The pursuit of excellence will be encouraged not only in clinical practice but in every field of activity with the aim of improving standards of service to the community. Practices In accordance with "best practice" policy of the hospital, the principles enunciated in this Corporate Code of Ethics will be implemented as follows. Principle 1. Respect The conduct of all staff will reflect a respect for the uniqueness of every individual regardless of disability, impairment or incompetence. Such respect will be accorded to patients not only when they are living but also when they are deceased. "End of life" decisions will be made with due regard to the patient's known wishes, the responses of the next of kin and the relevant hospital policies. Principle 2. Autonomy Patient participation in decisions relevant to their condition will be regarded as both important and valued. They will be provided with information relevant to their condition openly and honestly, encouraged to ask questions and, where clinically viable, given time to reflect and consult before responding. Whenever possible, information will be made available both orally and in written form and in the patient's customary language. Clinicians will explain clearly to patients the difference between procedures which are accepted practices and those which are related to research. In the latter case, ARMC research ethics policies will be strictly observed. Principle 3. Compassion Every effort will be made to relieve patients of unnecessary suffering as speedily and effectively as possible. Special efforts will be made to identify and respond to unarticulated fears and anxieties. Where possible the needs of next of kin and others closely related to the patient will be addressed with care and concern. Principle 4. Justice The hospital recognises that this principle applies to dealings with staff and "stakeholders" as well as with patients. All patients will be afforded best possible treatment and care appropriate to their medical condition. There will be no discrimination based on race, culture, religion, sex or position in society. Treatment will be determined according to need, likely benefit, and the responsible use of resources. Legislation related to discrimination, harassment and equal opportunity will be observed both in the spirit and the letter of the law. Grievance issues will be addressed speedily and fairly. Principle 5. Collaboration Mutuality of respect will be encouraged between those engaged in clinical treatment and patient care. The sharing of information and decision making will be practised in the best interest of the patients. Unnecessary duplication of examinations, investigations and patient interviews will be avoided. External agencies and individuals including ministers of religion who contribute to the patient's welfare will be afforded respect and assistance. Before any innovative or experimental procedures are undertaken they will be discussed with other health professionals engaged in the patient's care. Principle 6. Accountability Clear guidelines of responsibility for the care of patients will be established. Health care professionals will be encouraged to express concerns without fear of recrimination. The allocation of human, financial and technical resources will be in accord with the hospital's policies and the responsible spending of public monies. There will be a continuing review of resource allocation in the light of subsequent outcomes. Principle 7. Research and teaching All professions represented at the hospital will be encouraged to engage in high quality research both in clinical practice and academic study. All research conducted within or under the auspices of the hospital will be subjected to scrutiny as to its scientific value and validity and according to the high ethical standards which the hospital holds. As a teaching hospital it will endeavour to provide students of relevant disciplines with opportunities for clinical study at the highest standard. The hospital will encourage and support the conduct of forums, seminars and other methods of education designed to assist staff and the wider community to a better understanding and practice of health related issues. Principle 8. Environment The hospital acknowledges that it shares a common natural environment with the surrounding community and will ensure that any potential threat to this environment emanating from the hospital will be speedily and effectively identified and addressed. The hospital will support community initiatives for the preservation and enhancement of the natural environment. Recognising the multicultural character of the social environment in which it operates, the hospital will encourage community involvement in its activities. Principle 9. Excellence The hospital will promote the pursuit of excellence at every level of its activities. Continuous quality improvement programs will be regarded as fundamental to this process. The hospital will recognise and appropriately reward outstanding achievements on the part of individuals and departments. The hospital will strive for world leadership in its clinical, research, teaching and administrative practices.

Max M J Griffiths MBE, BA, BCom, BD · Ian T Dunlop MA(Cantab), FAICD, FAIMM

Some infections are more serious in pregnant than non-pregnant women because of the potential for vertical transmission to the fetus or infant (eg, varicella, rubella, cytomegalovirus infection, toxoplasmosis and listeriosis). Pre-pregnancy or routine antenatal screening for presence of, or susceptibility to, some of these infections and appropriate management can prevent adverse fetal or perinatal outcomes; screening should include rubella IgG, hepatitis B surface antigen, serological tests for syphilis and HIV antibody. If certain other vertically transmissible infections are suspected because of a positive antenatal test result, confirmatory tests for maternal and, if indicated, fetal infection are essential before intervention is considered (eg, cytomegalovirus infection). For some vertically transmissible infections that are not readily preventable, appropriate management of maternal infection can reduce fetal damage (eg, toxoplasmosis).

Series Editors:

Clinical question "What is the risk of taking oral contraceptives in patients with a history of migraine with transient neurological signs?" A woman with a history of migraine associated with hemiparaesthesia, and possibly dysphasia, attended her general practitioner suffering from irregular and frequent menstrual cycles. The doctor considered treatment with oral contraceptives to control her cycles and possibly relieve her migraine attacks. He asked about the risk of treatment with oral contraceptives, compared with no treatment, in a patient with transient neurological signs associated with migraine. Search question The interventions of interest were oral contraceptives. Ideally, we sought evidence from prospective follow-up studies of women taking oral contraceptives (OCs), in which groups were compared according to relevant outcomes. Case–control studies are a good research design to investigate the association between common exposures and rare outcomes, as in the current question. Unfortunately, this design is also subject to a range of possible biases that can distort the findings — recall bias, observation bias and various biases involving subject and control selection. Search PubMed and the Cochrane Library were searched for relevant articles with English abstracts published since 1989. Search terms included "migraine" combined with terms for oral contraceptives ("contraceptive agents"; "contraceptive agents, female"; "contraceptives, oral"; "contraceptives, oral, combined"; "contraceptives, oral, hormonal"; "contraceptives, oral, synthetic", "contraceptives, oral, sequential"; "progestational hormones, synthetic"), and "stroke" or "cerebrovascular disorders." Summary of findings This evidence search demonstrated the difficulties involved in, firstly, assessing the incidence of adverse effects of treatments and, secondly, in conveying these data to patients. We found no prospective studies comparing stroke risk in women taking OCs who did and did not have a history of migraine. Similarly, we found no prospective studies comparing stroke risk in women taking OCs who experienced migraine with neurological signs and those taking OCs who experienced uncomplicated migraine. Nevertheless, other kinds of evidence suggested that women taking OCs who had a history of migraine have a markedly increased relative risk of ischaemic stroke, although the difference in absolute numbers of women affected may not be as marked. A case–control study of women aged 20–44 years1 found that the relative risk of ischaemic stroke in women with migraine and taking OCs was 16.9 times (95% CI, 2.72–106) that of women without migraine and not taking OCs. Women with migraine who used low dose OCs (< 50 µg oestrogen) had 6.59 times (95% CI, 0.79–54.8) the risk of ischaemic stroke than women without migraine who did not take OCs, but this estimate came from a small number of cases and did not reach statistical significance. The relative risk of ischaemic stroke in women with migraine who took OCs and smoked cigarettes was 34.4 times higher (95% CI, 3.27–361) than in women with none of these risk factors. Similar results were found in a case–control study of women younger than 45 years.2 Ischaemic stroke was 13.9 times more likely (95% CI, 5.5–35.1) in women with migraine and taking OCs than in women without migraine and not taking OCs. A pooled analysis of two US population-based case–control studies3 found that women currently taking OCs who had a history of migraine were only twice as likely (95% CI, 1.19–3.65) to have any kind of stroke than women not taking OCs who did not have migraines. While this supports the general finding, it quantifies a much lower increased risk. The evidence from the identified research for an increased risk of stroke in these circumstances is convincing, but the size of the effect remains in dispute. Interpretation of the evidence in this case was complicated because the studies did not allow calculation of absolute-risk differences between groups. In giving advice to patients, the known increased relative risks for individuals must be balanced against the absolute effects at a population level. The identified studies show not only an increased relative risk of ischaemic stroke in women with migraine who take OCs, but also a greater than multiplicative increased risk introduced by coexistent smoking. On the other hand, since the overall risk of stroke for women in this age group is small (5.5 per 100 000 woman-years according to the World Health Organization Collaborative Study4), and is smaller still in younger age ranges, the observed risk estimates suggest ischaemic stroke will be a comparatively rare outcome in any of the identified risk groups. Clinical advice should incorporate these data as well. The ultimate decision remains with the patient. Outcome The patient was treated with OCs pending the outcome of the evidence search and gained relief of her gynaecological symptoms. However, she decided to discontinue taking OCs when the evidence became available.

Vivienne F Bernath · Ornella Clavisi · Jeremy N Anderson

To the Editor: A 27-year-old hospital medical officer received a penetrating needlestick injury to her left hand, drawing blood, after using a 22-gauge needle to deroof a vesicle for diagnosis in a two-year-old patient with orolabial herpes simplex virus type 1 (HSV-1). The medical officer had no significant medical history, took no regular medication, and had no previous history of oral or genital herpes. On Day 4, a vesicle appeared at the site of inoculation, with surrounding erythema. The medical officer first presented on Day 6, by which time the vesicle was crusting over, with several satellite lesions (see Figure). She described mild pain in her left axilla, but no fevers or sweats. A 10-day course of oral famciclovir (250 mg, three times daily) was prescribed and she was restricted from work until the lesions had completely healed (Day 16). During 12 months of follow-up there has been no clinical recurrence. Specimens from the two-year-old child were positive for HSV-1 by direct immunofluorescence, and HSV-1 DNA was detected by polymerase chain reaction (PCR). Specimens from the medical officer on Day 6 were negative for HSV-1 by direct immunofluorescence, but positive by PCR. There was no evidence of HSV-2 or varicella zoster virus in either specimen. To our knowledge this is the first reported transmission of HSV-1 after needlestick injury. Herpetic whitlow (HSV of the hands), a well-recognised occupational hazard for dentists and anaesthetists, is frequently misdiagnosed, resulting in unnecessary surgical procedures and delayed healing. In healthcare workers, pain and also work restrictions to limit cross-infection reduce productivity. Horizontal transmission can occur in the absence of clinical lesions, but latex gloves are an effective barrier.1 There are few guidelines available for postexposure prophylaxis for HSV-1, and no controlled clinical trials in humans. The short incubation period and early establishment of latency in HSV infection remain obstacles for effective delivery of postexposure prophylaxis. HSV can establish latent infection of neurones in the absence of peripheral replication.2 In an animal model, postexposure treatment with famciclovir or valaciclovir inhibited peripheral replication of HSV, reducing latent infection but not preventing it altogether.2 In one case report, a patient who started taking famciclovir within one hour of a needlestick injury did not develop whitlow and remained seronegative for HSV.4 Famciclovir and valaciclovir have high oral bioavailability, minimal toxicity and proven efficacy in treating HSV. Available data suggest that treatment with these drugs after documented exposure to HSV reduces the severity of acute disease, limits the number of neurones infected and may reduce the frequency of subsequent recurrences. If started early enough, postexposure prophylaxis may prevent latent infection altogether.

Mark W Douglas FRACP, BScMed(Hons) · Jane L Walters MB BS(Hons), MSc, DTM · Bart J Currie FRACP

To the Editor: We report two episodes of serotonin toxicity (or serotonin syndrome) caused by drug interaction in one individual chronically treated with dexamphetamine. The interacting drugs were venlafaxine, then later citalopram. We are not aware of any previous reports of serotonin toxicity caused by dexamphetamine in combination with either venlafaxine or any selective serotonin reuptake inhibitor (SSRI). A 32-year-old man presented after two days of marked agitation, anxiety, shivering and tremor. He was being treated with dexamphetamine, 5 mg three times daily, for adult attention deficit hyperactivity disorder. He had started venlafaxine (75 mg daily) two weeks previously, and this had been increased to 150 mg daily after a week. On examination, he was alert and oriented, but diaphoretic, shivering and had fine motor tremor. His heart rate was 140 bpm, blood pressure was 142/93 mmHg and temperature 37.3°C. Pupils were 3 mm diameter and reactive, with no nystagmus or ocular clonus. There was generalised hypertonia, hyperreflexia, 1–2 beats of inducible ankle clonus, frequent myoclonic jerking and tonic spasm of the right side of his orbicularis oris muscle. His abdomen was tense, but non-tender, with normal bowel sounds. An electrocardiogram showed sinus tachycardia with a baseline tremor, but no other abnormality. Therapy with dexamphetamine and venlafaxine was ceased, and cyproheptadine (8 mg doses up to a total of 32 mg over three hours) was given. The patient had a stepwise reduction in heart rate, with complete resolution of his symptoms, and was discharged the next morning. Dexamphetamine therapy was restarted three days later and citalopram therapy was commenced one week after discharge. Two weeks after discharge, he reported similar symptoms, and ceased citalopram. Three days later he was still agitated, with nausea, diarrhoea and teeth clenching. There was no rigidity, tremor or diaphoresis, and his heart rate was 76 bpm. He was given two 8 mg doses of cyproheptadine and was asymptomatic two days later. Some of this patient's symptoms could be attributed to noradrenaline excess. However, the combination of neuromuscular and autonomic features is more consistent with serotonin toxicity. The fact the symptoms resolved after administration of cyproheptadine (a 5-HT2-receptor antagonist) supports this hypothesis. There is no theoretical reason why the interaction of citalopram (a pure SSRI) and dexamphetamine should cause catecholamine excess, and again the more likely explanation is serotonin toxicity. Dexamphetamine causes psychostimulation and increased peripheral sympathomimetic activity. Centrally it causes presynaptic release of serotonin,1 and dopamine and catecholamine release.2 Venlafaxine and its metabolite, O-desmethylvenlafaxine, inhibit both neuronal 5-HT reuptake and noradrenaline reuptake,3 whereas citalopram, an SSRI, has little effect on noradrenaline reuptake.4 The combination of serotonin reuptake blockade and either presynaptic release of serotonin or monoamine oxidase inhibition by dexamphetamine will cause increased serotonin levels in the central nervous system, and is the likely mechanism of toxicity in this patient. This is consistent with the mechanism for other reports of serotonin toxicity.5 Increased awareness and cautious monitoring is advised when using a combination of dexamphetamine and either venlafaxine or an SSRI. This is particularly important in people using amphetamines recreationally and in children taking dexamphetamine for attention deficit hyperactivity disorder.

Felicity H Prior BPharm, GradDipEpi · Geoffrey K Isbister BSc, MB BS · Andrew H Dawson MB BS, FRCP, FRACP · Ian M Whyte MB BS, FRACP FRCP

To the Editor: We report a case of bilateral acute angle closure glaucoma associated with venlafaxine. A 45-year-old woman with a history of bipolar affective disorder and borderline personality traits was admitted with increasing depression and suicidal ideation. She was taking sodium valproate (1500 mg/day) and slow-release lithium (450 mg/day). She had also taken dothiepin (50 mg nightly) for seven days, but this therapy was ceased on admission. Her only previous ophthalmological history was hypermetropia, and she had been taking low-potency neuroleptic medications and selective serotonin reuptake inhibitors in the past with no significant adverse effects. She was treated with chlorpromazine (up to 150 mg daily), and venlafaxine therapy (extended release, 75 mg/day) was commenced. After three days of taking venlafaxine, she developed left retro-orbital pain associated with nausea and vomiting, with subsequent swelling and drooping of the left upper lid and a dilated and fixed pupil. The eye was congested and visual acuity was reduced to counting fingers. She was diagnosed with acute angle closure glaucoma, treated with timolol, and transferred to a tertiary referral hospital. During this period, she sustained an injury to her right eye following an assault by a third party. A computed tomography scan revealed a right blow-out fracture with inferior rectus muscle entrapment. On admission, intraocular pressures were 16 mmHg in the right and 50 mmHg in the left eye, and gonioscopy revealed closed angles (grade 1–2). Ninety minutes after being given intravenous mannitol, topical apraclonidine hydrochloride, latanoprost and pilocarpine eye drops, the intraocular pressure dropped to 35 mmHg in the left eye. Initial laser iridotomy was unsuccessful because of a hazy cornea. Laser iridotomy was repeated several times after topical steroid therapy until it was successful. The right orbital floor fracture was repaired with a Medpor implant (Porex Surgical Products Group, Atlanta, Georgia). Eight days after starting venlafaxine therapy, she developed similar symptoms in her right eye, despite prophylactic treatment with pilocarpine eye drops four times a day. Venlafaxine was discontinued, and three days later a successful right laser iridotomy was performed. Her visual acuity was 6/5 in her right and 6/18 in her left eye. After eight weeks she was receiving no ophthalmic treatment and her intraocular pressures were well controlled. In a MEDLINE search, we found no published reports of venlafaxine associated with acute angle closure glaucoma. The manufacturers report it as a rare adverse event (fewer than 1/1000; data on file; Wyeth-Ayerst Laboratories). There has been one previous report of increased intraocular pressures in two patients with known narrow-angle glaucoma who began taking venlafaxine.2 Glaucoma has also been reported with paroxetine.3-4 Our patient had no associated family history of glaucoma, but her eyes were predisposed to angle closure glaucoma owing to hypermetropia. Patients with acute angle closure glaucoma usually have a structural defect that produces a narrow drainage angle, and thus moderate dilation of the pupil may precipitate an attack. Drugs like tricyclic antidepressants cause mydriasis and may cause the narrow angles to close as a result of anticholinergic effects. Venlafaxine, however, is a serotonin and noradrenaline reuptake inhibitor without anticholinergic activity. This fact and the time course suggest that a combination drug interaction may have occurred in this patient, perhaps by the hepatic inhibition of chlorpromazine metabolism by venlafaxine, increasing anticholinergic activity, or by a direct effect of venlafaxine on the eye unrelated to mydriasis.

Bradley Ng MB ChB · G Mark C Sanbrook MB BS, FRANZCP · Anthony J Malouf · Smita A Agarwal

To the Editor: Akathisia is a clinical syndrome that manifests as the subjective sense of unease or restlessness, or observable motor manifestations such as shuffling or tramping movements of the legs and feet, or both.1 The marked distress associated with akathisia can lead to impulsive suicide attempts.2 It is commonly associated with antipsychotic medications, as well as various antidepressants, including tricyclics and selective serotonin reuptake inhibitors (SSRIs). Mirtazapine is a novel antidepressant. It acts centrally to increase both noradrenergic and serotonergic neurotransmission. Common side effects include sedation, weight gain and increased appetite. Tremor is listed as an adverse reaction, but this does not represent akathisia. A MEDLINE database search (up to September 2001), using the words "akathisia" and "mirtazapine", did not reveal any reports of an association. However, as of mid-November 2001, the Adverse Drug Reactions Advisory Committee (ADRAC) had received five reports of "hyperkinesia (probably equivalent to akathisia)" associated with mirtazapine. We would like to report two cases of acute akathisia associated with mirtazapine. A 52-year-old man was referred by his psychiatrist for inpatient management of his depressive illness. He had previously tried multiple antidepressants, including various tricyclics and SSRIs. However, because of the sexual side effect anorgasmia, adherence to antidepressant treatment was poor. He was prescribed mirtazapine (30 mg at night). Within an hour of taking the first dose, he complained of feeling restless and unable to keep his legs still. He was given 1 mg of clonazepam, which settled his symptoms after 30 minutes. He was also observed to jiggle his legs and feet while at rest. His symptoms recurred the next day, necessitating further successful treatment with clonazepam. Mirtazapine therapy was continued, and the patient's depression improved significantly over the next few days, and the akathisia gradually resolved with regular use of clonazepam. A 73-year-old woman with chronic depression was admitted after an overdose. Her medications on admission were omeprazole, amiodarone, bendrofluazide and fluvoxamine (50 mg). The fluvoxamine was changed to mirtazapine (15 mg/day initially, increased to 30 mg/day after three days). After the first 30 mg dose, she described intense restlessness in her legs lasting up to two hours. The distress necessitated reintroducing the fluvoxamine in place of the mirtazapine. Within three weeks the patient was readmitted with depressed mood and suicidal ideation. Mirtazapine (30 mg at night) was re-introduced, with consequent acute return of restless legs. The patient's akathisia settled when the mirtazapine was reduced to 15 mg at night. No additional treatment was required. The neurobiological basis for akathisia remains unclear. Involvement of central serotonergic and adrenergic neurotransmitter systems has been postulated. One of mirtazapine's main actions is blockade of α2-adrenoreceptors. Clonidine, an α2-agonist, is effective in treating akathisia.3 We suggest that mirtazapine's adrenoceptor action might be the basis for the occurrence of akathisia in these patients.

Boregowda G Girishchandra MB BS, DPM, DipNB · Liana Johnson BPharm, MPS · Rebecca M Cresp MB BS · Kenneth G D Orr MB BS, FRANZCP

To the Editor: In a recent editorial, Mason and Diamond state that ergocalciferol (vitamin D2) is bioequivalent to cholecalciferol (vitamin D3) and that 1000 IU/day of ergocalciferol is sufficient for the treatment of vitamin D deficiency.1 Both statements are contentious. Although ergocalciferol (vitamin D2) is the only single prohormonal form of vitamin D available on prescription in Australia, there are three reasons to be cautious about the use and dose equivalence of ergocalciferol (vitamin D2) compared with cholecalciferol (vitamin D3). Cholecalciferol (and not ergocalciferol) has been shown in two randomised trials to reduce fracture rates when administered concomitantly with calcium to elderly patients.2,3 Furthermore, all recently studied agents for treating postmenopausal osteoporosis (alendronate, risedronate, raloxifene and parathyroid hormone 1-34 [the first 34 amino acids of the hormone]) were shown to lower fracture rates, but study participants were routinely given supplementary calcium and vitamin D when deficiency was established. At least two studies specified the use of cholecalciferol. Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are probably not bioequivalent.4,5 Ergocalciferol administration to vitamin-D-replete premenopausal women reduced the amount of circulating 25-hydroxyvitamin D3 (25OHD3) while only modestly increasing 25OHD2 levels, with a resultant marginal effect on the total 25OHD level.4 In contrast, the equivalent dose of cholecalciferol increased the circulating level of 25OHD3 significantly.4 Lastly, while radioimmunoassays (RIAs), such as the INCSTAR/DioSorin assay (Stillwater, Minnesota, USA), used in both studies of vitamin D levels published recently in the MJA6,7 are able to measure 25OHD levels, they are incapable of differentiating between 25OHD2 and 25OHD3. Furthermore, neither of the commercially available RIAs (the other one is made by IDS Ltd, Tyne and Wear, UK) is able to measure both vitamin D metabolites with equivalent accuracy. In a study comparing RIAs for the measurement of 25OHD against high performance liquid chromatography (the gold standard method) both assays did not recognise 25OHD2 as well as 25OHD3, with r2 of 0.74 and 0.58, respectively, for 25OHD2.8 Until further research is available, using more patients and a greater number with vitamin D deficiency, caution must be exercised in the interpretation of 25OHD levels measured with RIAs. This applies especially to individuals taking ergocalciferol (vitamin D2) for the treatment of vitamin D deficiency. Thus, it would appear that cholecalciferol (vitamin D3 ) has a role to play in the reduction of osteoporotic fractures, but only when administered with calcium. If administering ergocalciferol (vitamin D2), a far greater dose than 1000 IU/day may be needed, and the use of commercial RIAs to determine the therapeutic response may be misleading.

Paul Glendenning PhD, FRACP · Rebecca S Mason · Terrence H Diamond

In reply: Glendenning raises a number of interesting points, which require some clarification. Are ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) biologically equivalent? The statement that ergocalciferol and cholecalciferol are bioequivalent in humans is made by most authoritative textbooks, based mainly on evidence from early studies of the antirachitic efficacy of ergocalciferol and cholecalciferol compounds, and contrasts with reduced efficacy of ergocalciferol in birds and monkeys.1 Recent studies using more precise measurements have raised some doubts as to the absolute equivalency of ergo- and cholecalciferol, but the differences are marginal2 and not universally found.3 There are few recent data on relevant biological endpoints. Serum concentrations of the active hormone, 1,25-dihydroxyvitamin D, were not different after administration of ergo- or cholecalciferol,2 and increases in bone mineral density were greater after ergocalciferol therapy than after cholecalciferol in patients taking anticonvulsants.1 In short, on current evidence, differences in biological activity between ergocalciferol and cholecalciferol are likely to be relatively minor. Are there problems monitoring therapy? 25-Hydroxyvitamin D values may be used for monitoring treatment. The possibilities of impaired detection of the 25-hydroxy metabolite of ergocalciferol by some assays,2 and perhaps a smaller rise in total 25-hydroxyvitamin D concentrations after low doses of ergocalciferol, should be borne in mind when monitoring therapy. What is the current recommendation for vitamin D supplementation? While the availability of larger dose sizes and/or cholecalciferol preparations would be helpful, 800 IU of ergocalciferol and 1 g of calcium for six months was shown to reduce secondary hyperparathyroidism in older patients,1 and 600 IU/day (same for ergo- and cholecalciferol) is the new recommended adequate intake for older patients with limited sun exposure.1

Paul Glendenning

To the Editor: A recent editorial in the Journal focused on the "blurring of research ideals and corporate interests".1 But there are other funding and commissioning bodies, including government, whose wants or needs also have the potential to blur research ideals and exert control over what can be published. In recent times, those who pay the piper increasingly want to call the tune. Understandably, this is also an issue for research into Aboriginal ill health.2,3 Van Der Weyden's plea for the development of national guidelines on institutional conflict of interest should therefore be broadened to include all funding bodies. One suggestion for inclusion in these guidelines, to enhance public interest in research, is an obligation for authors to state not only their sources of funding, but "the origin of the research question they are attempting to answer"4 and the person or group who initiated the funding of the project.

Max Kamien

To the Editor: We report the appearance of erythromycin and inducible clindamycin resistance in the south-west Pacific strain of non-multiresistant methicillin-resistant Staphylococcus aureus, which has recently appeared in eastern Australia. Infections occur predominantly in Polynesian people and are usually community-acquired. Most strains belong to Western Samoan phage patterns (WSPP1 or WSPP2) and pulsotype A when typed by pulsed-field gel electrophoresis.1,2 These strains are resistant to all β-lactams, but are usually susceptible to erythromycin, clindamycin, gentamicin, tetracycline, trimethoprim–sulfamethoxazole and ciprofloxacin. Although most of these antibiotics would not be recommended for therapy,3 clindamycin has been recommended for non-parenteral treatment of soft-tissue and bone infections, as it is efficacious in treating similar infections caused by methicillin-susceptible S. aureus.4 Twenty isolates of community-acquired, non-multiresistant pulsotype A MRSA were collected from patients from southern Brisbane and Logan in 1997 and 1998.2 A further 16 isolates were obtained from Ipswich patients between December 1998 and February 2001. We found that all 36 isolates were susceptible in vitro to gentamicin, tetracycline, trimethoprim–sulfamethoxazole, ciprofloxacin, rifampicin, fusidic acid and vancomycin. However, two of the Ipswich isolates had erythromycin and inducible clindamycin resistance. When susceptibility testing was performed using standard disc methods, both isolates appeared resistant to erythromycin but susceptible to clindamycin. However, on testing for inducible macrolide resistance (MLSB phenotype) using a disc-approximation method, both showed inducible clindamycin resistance.5 These isolates were from superficial abscesses in Polynesian people with community-acquired infection. They were indistinguishable by pulsed-field gel electrophoresis, but there were no epidemiological links. As yet, we have found no community-acquired pulsotype A strains of MRSA with erythromycin resistance and constitutive (ie, non-inducible) clindamycin resistance. Two other recent Australian studies found erythromycin resistance in 13 of 153 and three of 29 isolates of non-multiresistant MRSA, respectively.3,6 These studies did not report clindamycin susceptibilities, and it was not clear what proportion of the isolates belonged to phage patterns WSPP1 or WSPP2, or were community-acquired. As clindamycin has been recommended as a therapeutic option for soft-tissue and bone infections caused by non-multiresistant MRSA, this finding of inducible clindamycin resistance has important implications. Microbiology laboratories should screen for inducible clindamycin resistance in erythromycin-resistant strains, and, if found, an alternative antibiotic should be used for treatment.7 Alternatively, rather than assessing inducible clindamycin resistance with a disc-approximation test, some laboratories may prefer to report all erythromycin-resistant strains as clindamycin-resistant. Also, given the increasing incidence of community-acquired MRSA infection in Australia, all suspected staphylococcal infections that are not responding to empiric therapy with β-lactam antibiotics should be swabbed for culture.

Wendy J Munckhof MB BS, FRACP FRCPA, PhD · Jacqueline Harper BSci (Hons), PhD · Jacqueline Schooneveldt BAppSci, MAppSci, GCM · Graeme R Nimmo MB BS, MSc MPH, FRCPA

To the Editor: We strongly support the proposal1 that it is time to create a special grant category for curiosity-based research proposals. Having been in biomedical research for over 50 years, we have experienced a period when most research was curiosity based. We can thus compare with the present situation — research aiming for a rapid, practical and commercial outcome has become almost a necessity for survival because of the increasingly severe reduction in government funding for universities and research institutes. We would like to illustrate the value of curiosity-based research with a few Australian examples from our own fields. In 1946, one of us (F F) was working on the experimental epidemiology of the causative agent of infectious ectromelia of mice (related to vaccinia virus). A chance observation — that the mice which survived the infection developed a skin rash — led to further study of the virus as a model for smallpox, measles and chickenpox infections. Thus, unexpected discoveries were made about the way the virus spreads through the body during the incubation period of these diseases.2 In 1951, myxomatosis spread in rabbits in the Murray–Darling basin of south-eastern Australia. The virus was initially extremely virulent (99% fatal), but the rabbits slowly developed genetic resistance. One of us (F F) studied the virus for 15 years, and this work was acknowledged as the best example of the co-evolution of viral virulence and host resistance.3 In 1957, Macfarlane Burnet proposed the clonal selection theory of antibody formation — that individual B lymphocytes made antibody of a single specificity.4 This was one of the most original concepts ever proposed in biology and it took 10 years to be widely accepted. It has since led to the production of monoclonal antibodies, which are used as basic reagents in research and diagnostic laboratories, and are now being used in immunotherapy. In the 1970s, Peter Doherty and Rolf Zinkernagel studied the role of the newly discovered cytotoxic T cells (which could lyse virus-infected cells) to find out how T cells recognised the infected cells. They showed that killing was restricted by the major histocompatibility complex (MHC) and that its role was to signal "altered self" to the T cell.5 These studies led to the award of the Nobel Prize in 1996. Cytotoxic T cell activity has since been shown to be the main immune mechanism for controlling and clearing many intracellular infections. Induction of a strong cytotoxic T cell response is the mechanism of candidate vaccines currently being trialled against HIV-1. In the late 1960s, one of us (G A), together with Chris Parish, showed that a bacterial protein, flagellin, induced antibody tolerance over a wide dose range. Parish was the first to show the inverse relationship between antibody and cell-mediated immune responses, which led others to describe two classes of helper T lymphocytes.6 These have been shown to be important in the development of allergy in infants, and offer the opportunity for immunotherapy to reduce the later incidence of allergy. None of these research programs was initiated with a commercial goal in mind. Benjamin Franklin, when asked about the importance of some research, replied "Of what use is a baby?".

Gordon L Ada AO, DSc, FAA · Frank Fenner MB BS, MD

To the Editor: There is much conflicting evidence that increased intake of vitamin C enhances the natural protective mechanisms of the body and decreases both the incidence and severity of the common cold.1 It is regrettable that the study by Audera and colleagues failed to show a significant therapeutic effect of megadose vitamin C in treatment of the common cold.2 The groups compared had, on average, similar composition after randomisation. However, the viral infections that cause the common cold and its progression to ill health, as evidenced by multiple symptoms, are affected by many factors, while symptom severity is well known to vary greatly. Therefore, the study's reliance on respondents' self-diagnosis of symptom severity and onset is a significant weakness in design. Randomisation of participants to the treatment groups may have been insufficient to override this design deficit, thereby significantly biasing the outcome. A better design might have combined patient self-report of symptom severity with physical examination, thus allowing independent and professional assessment of severity. Also, proper assessment of previous history of severity of cold symptoms is crucial for proper randomisation to treatment groups. If Audera and colleagues' study failed to control for this history, then randomisation may have also failed to balance its effect equally between treatment groups, significantly compromising the study's validity to detect any therapeutic benefit of vitamin C. Cold symptoms also vary diurnally, while severity varies with alcohol use and smoking status,3,4 which also affect vitamin C absorption.5,6 No information was provided on study participants' alcohol consumption and smoking status. Finally, the study did not assess stress, which may constitute a further, important uncontrolled bias. A recent cohort study of stress and the common cold concluded that all four dimensions of stress investigated — stressful life events, negative affects, positive affects and perceived stress — were significantly related to occurrence of the common cold.7 Stress may also have significantly affected symptom severity and participants' perception of their symptoms. Certainly, the trend observed in the placebo group of shorter duration of some symptoms and lower mean severity could have been due to less severe symptom history, compounded by a lower degree of overall stress.

Luis Vitetta · Avni Sali · Bill Paspaliaris · Nicola J Reavley

In reply: Precisely because of the temporal variation in symptom severity described by Vitetta and colleagues, we judged that medical professionals are not as well able, in a variably timed interview, to quantify patients' cold symptoms as the patients themselves can do on a continuing basis. Therefore, we consider that our study1 would have been no more valid if the detailed symptom severity cards had been supplemented by one or more physical examinations. In that respect, we are in good company with others who have studied the common cold over many years.2 We agree that double-blind randomisation does not necessarily distribute all relevant variables equally. That is why, in Box 2 of our study report, we presented four variables — age, sex, mean number of colds in the previous year, and mean number of days unwell with colds in the previous year.1 The likelihood that stress, smoking and alcohol status would have been sufficiently maldistributed in this large group to mask a significantly beneficial effect in even one of the three groups which received high-dose vitamin C seems vanishingly small. Nevertheless, we acknowledge that the study would have been stronger if we could have reported the distribution of these three potential confounders. We contest the view of Vitetta and colleagues that the evidence from randomised controlled trials of vitamin C in treating the common cold conflicts significantly (see Box 1 of our article1). The overview finding — that mega-doses of vitamin C for prophylaxis produce a relatively trivial reduction in cold severity but no reduction in incidence3 — was the stimulus for our own study. No community studies of this issue have been flawless, but the mounting collective evidence suggests that we should look elsewhere for a cold panacea.

Carmen Audera · Roger V Patulny · Beate H Sander · Robert M Douglas

Medicine and literature: The doctor's companion to the classics. John Salinsky. Abingdon, UK: Radcliffe Medical Press, 2002 (vi + 236 pp, $53.50). ISBN 1 85775 535 9. It is not easy, in a busy medical life, to find time to read literature. Spare time is devoted to reading medical journals and newspapers to try and keep abreast of medical developments and world events. Occasionally, we see a movie or read something frivolous, but serious books often remain unfinished on the bedside table. John Salinsky is a general practitioner from Middlesex, UK, who uses classical literature in teaching his registrars. He is responsible for the "Medicine and literature" column in the journal Education for primary care, and the present work includes 17 contributions from this column. Most pieces are by Salinsky himself, and he writes clearly and entertainingly, making it a joy to read. Salinksy's argument is that the classics are classics not just because of the quality of the writing, but because they describe human relationships in a manner that is both engaging and timeless. From these works of literature we can learn much about human behaviour, its strengths and frailties, and become better at the "art" of medicine. Some of the writers he talks about are doctors, like Mikhail Bulgakov, or were the sons of doctors, like Dostoyevsky or Flaubert. Others tell stories in which doctors play central roles, like Kafka, whose A country doctor contains the wonderful line, "To write prescriptions is easy, but to come to an understanding with people is hard". Salinsky's purpose is not to introduce us to stories by or about doctors, but rather to stories that contain characters that we will recognise in our practices. Our familiarity with and love of these personalities will increase our understanding of those of our patients who are excessively garrulous, who seem unable to take control of their lives or whose characters seem inherently flawed. If you already love good literature, this book will delight and inform you. If you have forgotten how much pleasure can be obtained from a great story, it may motivate you to return to a world that provides a wealth of entertainment and stimulation. Almost everybody will be introduced to something unfamiliar, but at just over $53 it is probably best borrowed from the library rather than added to one's own.

John Ward

Steve Hocking was a respected anaesthetist in Perth who died at the age of just 39. He was born on 18 April 1962 and attended primary school at Jolimont in Perth and secondary school at Mentone Grammar School in Melbourne. He graduated in medicine from the University of Western Australia in 1986 and spent his internship and residency at Royal Perth Hospital. On secondment from Royal Perth Hospital, Steve worked in Kalgoorlie as a Resident Medical Officer. While there he took up parachuting, until his fellow RMO broke his ankle participating in the same activity, forcing Steve to do the work of both of them. In 1995 he spent three months in Port Hedland working as Anaesthetic Registrar, and, after obtaining his Fellowship of the Australian and New Zealand College of Anaesthetists in 1996, he spent a year in Pittsburgh, Pennsylvania, as Associate Professor of Anaesthesiology. He returned to Western Australia in 1997, where he worked as a sessional anaesthetist at Royal Perth Hospital before moving solely to private practice. As a doctor and anaesthetist, Steve's focus was always his patient. Woe betide any clipboard-carrying nurse who tried to get in the way of his postoperative analgesia orders. His fierce advocacy and compassion for his patients was perhaps partly a result of having been a surgical patient himself and having experienced a chronic illness. This was always something that he bore privately and without complaint. His attitude to his own illness was to accept it and just get on with life. In the operating theatre he was always calm and precise; the sort of anaesthetist that other doctors would want to be anaesthetised by. He was also funny, but his humour was delivered in a characteristically dry sort of way that people would miss if they didn't know him well. Steve developed metastatic cholangiocarcinoma in October 2000 as a complication of ulcerative colitis, which had been diagnosed when he was only seven years old. He pursued active treatment for as long as this gave him the opportunity to return home to spend more time with his wife Jane and children Oscar and Rupert. He died on 6 October 2001. Steve told his wife that the only regret of his life was his death. He will remain forever young. The measure of Steve's life should not be in its length but in its worth and in the legacy that he leaves. He was a good man.

Robert J Davies MB BS FRACS

A case for prevention Pterygium occurs in 1.1% of Australians. However, it is more prevalent with higher exposure to ultraviolet radiation and in older men, occurring in 12% of men aged over 60 years. A recent narrative review estimated the direct treatment costs for pterygium in Australia as $8.3 million for one year, 1997-98. This included the cost of 8661 pterygium removals and 3292 conjunctival autografts. No data were available on the proportion of surgical interventions done because of visual impairment. Recurrence rates are believed to remain high (20%–40%) and recurrences may grow aggressively. Although mitomycin C (an antibiotic–antineoplastic agent) has been shown to reduce recurrence rates if used perioperatively, use remains limited because of potentially serious vision-threatening complications. Clin Exp Ophthalmol 2001 29: 370–375 Getting up to scratch Researchers have suggested a way in which individual surgeons can engage in a continuous quality improvement process. A group of 16 surgeons in the United States completed a two-day accredited course in sentinel lymph node (SLN) mapping, then recorded outcome data in a secure database each time they attempted to map an axillary sentinel lymph node. The data were used to plot learning curves as serial failure rate versus the serial number of procedures performed. Of 2255 consenting patients, 1880 were from a subgroup of six surgeons. These surgeons needed an average of 22 cases to achieve at least a 90% success rate, and 63 cases for a 95% success rate. For the whole group, surgeons performing fewer than three SLN biopsies per month had an average success rate of 86.23% ± 8.30%, while those doing more than six SLN biopsies per month had a success rate of 97.81% ± 0.44%. J Am Coll Surg 2001; 193: 593-600 Bad Press New evidence from a large prospective study in Taiwan further implicates the Epstein–Barr virus (EBV) in the causation of nasopharyngeal carcinoma. Most residents of Taiwan are infected with EBV in childhood and have persisting IgG antibodies against EBV capsid antigen. However, the presence of IgA antibodies against capsid antigen reflects frequent reactivation of latent EBV in B cells, repeated viral infection, or both. These IgA antibodies and the neutralising antibodies against EBV Dnase are highly specific markers for nasopharyngeal carcinoma. Of 9699 Taiwanese men aged > 30 years, 1176 tested positive for one or both of these serological markers of EBV. During 16 years of follow-up, there were 22 new cases of nasopharyngeal carcinoma. After adjustment for age and family history, the relative risk of nasopharyngeal carcinoma was 32.8 for subjects with both markers (95% CI, 7.3–147.2) and 4.0 for subjects with one marker (95% CI, 1.6–10.2), as compared with subjects with neither marker. Measurement of these antibodies may be useful for early detection of nasopharyngeal carcinoma in high- risk populations. N Engl J Med 2001; 345: 1877-1882 Ready to go The second reported prospective study of near-death experiences (NDE) is of 344 consecutive patients from 10 Dutch hospitals who were successfully resuscitated following cardiac arrest. The patients ranged in age from 26 to 92 years (mean, 62 years) and 73% were men. At interview within five days of resuscitation, 248 patients were asked what (if anything) they recalled from the period of unconsciousness. Experiences such as awareness of being dead, positive emotions, observations of a celestial landscape and out-of-body experiences were later coded and scored. A total of 62 patients reported some recollection of the time of death, classified as superficial (21), core (18), and deep or very deep (23). Those aged < 60 years had NDEs more often than older people (P = 0.012) and women had more frequent deep experiences than men (P = 0.011). Mortality during and shortly after hospitalisation was significantly greater in those who reported an NDE than those who did not (13 of 62 [21%] v 24 of 282 [9%]; P = 0.008). The difference was even more marked in those who had reported a deep experience (10 of 23 [43%] v 24 of 282 [9%]; P < 0.0001). Lancet 2001; 358: 2039-2045 It’s in the stars Canadian researchers used the birth dates of 171 Nobel laureates in medicine and physiology and a control group of 375 scientists to test the hypothesis that zodiac sign is associated with the odds of winning the Nobel Prize (see Table). A help-line is available for devastated Leo readers. Lancet 2001; 358: 2039-2045