Volume 188 Issue 11

Ethical issues are constantly changing as clinical research and practice push out the boundaries of what we know and do The beginnings of ethical and regulatory oversight of the human research enterprise are customarily traced to the Nuremberg Code, a set of principles and standards for medical experiments outlined by the Nuremberg war crimes tribunal in 1947 following revelations of the infamous Nazi experiments conducted during World War II.1 Ironically, Germany was the first Western country to officially require informed consent for non-therapeutic research. In 1900, the Prussian minister for religious, educational and medical affairs issued a directive after it came to light that Albert Neisser had injected syphilitic serum into prostitutes without their knowledge or consent;2 and in 1931, the Reich Minister of the Interior introduced Guidelines on innovative therapy and scientific experimentation following an inquiry into the Lübeck disaster, in which 75 infants died and 168 others developed tuberculosis after receiving a contaminated batch of oral BCG vaccine.3,4 In 1964, after more than a decade of drafting, the World Medical Association (WMA) issued the Declaration of Helsinki, elaborating on the basic principles in the Nuremberg Code.5 This was ratified in Australia the following year, and in 1966 the National Health and Medical Research Council (NHMRC) issued its first Statement on human experimentation.6 The requirement for ethical approval of NHMRC grant applications in 1973 and the addition of Supplementary Note 1 in 1976, defining the role and functioning of human research ethics committees (HRECs),6 marked the beginning of the current ethics oversight system in Australia. The devolution of responsibility for evaluation and approval of clinical trials from the Therapeutic Goods Administration (TGA) to local HRECs and the rapid growth of multicentre trials during the 1990s highlighted a number of weaknesses in the system, particularly the requirement for each HREC to give separate consideration to projects involving research in more than one institution.7 Recognising these issues, as well as the importance of applying ethical principles to all types of human research, the NHMRC released a significantly revised National statement on ethical conduct in research involving humans in 1999.8 Subsequently, concern that HRECs have become overburdened with management and regulatory functions that are primarily the responsibility of research institutions has generated discussion of the notion of “research governance”, defined as an organisational framework through which institutions are held accountable for maintaining standards of quality, safety, privacy, risk management and financial management of research, in addition to ensuring its ethical acceptability.9,10 Despite concerns about the risk of creating a massive new bureaucracy,11 the concept has been enthusiastically embraced12 and the 2007 revision of the NHMRC national statement has an entire section devoted to governance.13 The publication in this issue of the Journal of a survey of current knowledge of research governance by Babl and Sharwood14 is thus particularly timely (→ Research governance: current knowledge among clinical researchers). Researchers, students and clinicians were asked about their familiarity with “the essential national and international documents guiding GCRP” (good clinical research practice), namely the Declaration of Helsinki,5 the NHMRC national statement13 and Australian code for the responsible conduct of research.15 The results appear to show a worrying lack of familiarity with the content of some of these “key” documents, and Babl and Sharwood conclude that institutions are failing in their responsibility to provide adequate training for those engaged in research. Few would disagree that more resources should be devoted to training; however, the study probably overestimates the depth of ignorance. Babl and Sharwood seem unaware that formal guidelines for GCRP were originally published by the TGA in 1991 and superseded in 200016 by the Note for guidance on good clinical practice, a quality standard agreed to by the International Conference on Harmonization for the design, conduct, recording and reporting of clinical trials.17,18 While it is essential that principal investigators running clinical trials are familiar with its contents, it is of little relevance to students, researchers and clinicians not directly engaged in drug trials. As for the Declaration of Helsinki,5 this is no longer considered a key document. The sixth edition released in 2000 created a worldwide furore centred on two paragraphs, one concerning use of placebos in clinical trials, and the other asserting participants’ right of access to the best-proven treatment identified by the trial. Influential American and European regulatory bodies refused to accept the revisions, forcing the WMA to water down the offending paragraphs.19 As a consequence, the Declaration of Helsinki has declined in moral force and influence. Whereas in 1999, the NHMRC national statement listed it as a relevant publication,8 in the 2007 revision, it is relegated to a historical reference in the preamble.13 Also in this issue of the Journal, Ballantyne and Rogers report their survey of chairs of Australian HRECs on the fair inclusion of men and women in clinical research (→ Fair inclusion of men and women in Australian clinical research: views from ethics committee chairs ).20 They correctly point out that, historically, women have been excluded from clinical trials, resulting in inadequate data on safety and efficacy of marketed drugs, and their findings suggest a lack of awareness, concern and action on the part of HREC chairs. Following the thalidomide tragedy in the 1960s, there was major strengthening of the drug regulatory agencies in the United States, United Kingdom, Europe and Australia. At that time, in the absence of widespread use of effective means of contraception, there were justifiable ethical concerns about enrolling women of childbearing potential in clinical trials. Exclusion was commonplace until the late 1980s, when the increasingly powerful HIV/AIDS lobby pressured the US Food and Drug Administration into reviewing its drug approval policies.21 By 1990, the US National Institutes of Health (NIH) had introduced guidelines covering the inclusion of women in clinical trials, strengthened by legislation in 1993, and the most recent policy update in 2000 stated: “NIH experience has indicated that inclusion has been accomplished”.22 In Australia, a Women and Clinical Trials Working Party was established in 1995 to advise on changes to NHMRC guidelines,23 and its recommendations were incorporated into the 1999 National Statement,8 albeit in rather general terms. Ballantyne and Rogers are critical of this, believing that “HRECs require further instruction from the NHMRC about how to interpret and apply the generic principle of fair inclusion.” However, detailed instructions were, in fact, provided in the Human research ethics handbook, issued by the NHMRC in 2002.24 The fact that chairs of HRECs may not be aware of them probably indicates that unfair sex discrimination in clinical trials is no longer a significant issue. So, where to next in the field of human research ethics? Times have changed. With the increase in off-label prescribing in paediatric practice, our challenge now lies in ensuring that children are adequately represented in clinical trials — with responsibility shared by researchers, sponsors, HRECs and regulators. Human research ethics is a work in progress, and will remain so for the foreseeable future.

Robert H Loblay PhD, FRACP

Patients’ simple vital signs are a highly reliable predictor of life-threatening clinical events At a time when hospital staff are becoming increasingly dependent on new technologies, the review by Cretikos et al1 entitled “Respiratory rate: the neglected vital sign” is refreshing. It is a timely reminder that understanding, documenting and acting on changes in patients’ simple vital signs are of fundamental importance to clinical outcomes. An abnormal respiratory rate (high or low) is known to be a highly reliable predictor of life-threatening clinical events. However, daily documentation of this simple number in many hospitals is remarkably poor. More controversial is the question of how best to develop systems that use changes in vital signs to trigger clinicians to respond rapidly and effectively. In recent years, many Australian hospitals have embraced medical emergency teams (METs) as the answer.2 METs enable rapid, skilled medical responses to changes in patients’ vital signs, aiming to intervene and reverse patients’ downhill slides towards intensive care unit (ICU) admission, cardiac arrest, or death. Call criteria for the MET (changes in respiratory rate, pulse rate, blood pressure, and coma score) have been carefully researched and are highly predictive of adverse events. METs are resource-intensive and are usually comprised of an intensive care registrar, a medical registrar and skilled nursing staff. They provide resuscitation skills at short notice in busy hospitals, where the primary medical teams may be busy, inexperienced, under-resourced or slow to respond. Australian studies based on single centres with historical controls,3,4 and on a single-centre before-and-after study,5 have reported that the introduction of METs was associated with reductions in key adverse events. Although before-and-after studies cannot separate the effect of an intervention from other factors that may have changed over time, studies like these were used to justify the enthusiasm and funding needed for the Medical Early Response Intervention and Therapy (MERIT) study investigators, with the Australian and New Zealand Intensive Care Society’s Clinical Trials Group, to conduct the world’s first large multicentre randomised controlled trial of MET introduction versus usual care.6 In clinical trial terms, the results of the MERIT study were clearly negative. There was no difference between intervention and control hospitals for either a composite endpoint (incorporating cardiac arrest, unexpected death or unexpected ICU admission) or for the same key study outcomes analysed separately. Adverse events decreased in both the intervention and control hospitals during the study period (as they had also done in the previous single-centre studies3-5), suggesting that factors other than the introduction of METs were improving key endpoints in both intervention and control hospitals during the study period. The MERIT study also found that introducing METs markedly increased the number of calls to hospital emergency teams and increased the early designation of suitable patients with “do not resuscitate” (DNR) orders. Total hospital deaths (unexpected plus expected [DNR] deaths) were marginally higher in MET hospitals than in non-MET hospitals during the study period. The MERIT study was remarkable in that it involved 23 Australian hospitals and over 36 000 patients, used a vigorous education process, and changed established systems in 12 hospitals.6 In order to account for its negative findings, the study has been criticised for inadequate power, for inadequate calling of the MET in the MET centres, and for a Hawthorn effect likely in the unblinded study design. It has also been said that changes after MET introduction may take longer to mature than was allowed for in the study design. These criticisms have validity, but it is also highly likely that the results of the unique MERIT trial were essentially correct. METs do not provide a single solution to the complex problem of clinician management of clinical instability in hospital patients. However, they do enhance appropriate designation of patients with resuscitation status, and they do encourage education, documentation and attention to patients’ key vital signs. Supporting this view is the recent experience of a hospital in Victoria that has focused, for the past 10 years, on using the MET system to improve management of clinically unstable ward patients.7 Cardiac arrest rates fell before and after the introduction of a formal and informal education process and a MET in this hospital, but then continued to decrease annually for each of the following 5 years (to extremely low rates). This was despite the fact that the MET was unchanged over the 10-year period. It appeared that the most important parts of a MET system are not the MET at all, but rather the audit, educational programs and DNR designations associated with it. The article by Cretikos et al and the MERIT trial results inform us that understanding, education, documentation, rapid clinical response to abnormal vital signs, and early designation of patients with an appropriate resuscitation status really do matter. To improve our hospitals we need mechanisms for simple, real-time communication of abnormal vital signs to hospital clinicians, so that timely management can occur across all acute hospital beds. Communication systems that do this, and also report, audit, and provide staff education and training, exist now, and may enable improved clinical management of unstable in-hospital patients. METs are a simplistic “bandaid” response to a complex problem in our hospitals. They are not the best response. Instead we need better education, focused on those critical vital signs. We need earlier appropriate DNR designation, and we need to test real-time emergency information systems. The evidence is that patient outcomes can be improved.

D James Cooper MD, FRACP, FJFICM · Michael D Buist MD, FRACP, FJFICM

What will it take to break the funding drought in Australia? Donations to health and medical research have recently made headlines, with mining magnate Clive Palmer pledging $100 million to medical research and Indigenous needs.1 While this amount is an Australian record, it is somewhat eclipsed by “gigaphilanthropists” Bill and Melinda Gates’s multibillion dollar inputs to research and health delivery. The prefix “gigas” is Latin for “giant” and it is worth asking: Where are the giants of Australian giving? As Daniel Petre (an Australian philanthropist and former Microsoft vice-president) recently slammed the lack of generosity of richer Aussies,2 it is timely to consider where health and medical donation stands in Australia. How do we compare with other nations and what is the forecast for the future? Australia is blessed with superb philanthropists — just not enough of them. To borrow from poet Dorothea Mackellar,3 the comparison is in the order of “droughts and flooding rains”, particularly when pitted against the philanthropy-rich landscape in the United States. US philanthropy is a veritable flood. Since the mid 1990s, 2% of the US gross domestic product has been given to charities;4 the percentage in Australia is less than half of this — a relative drought.5 More recently, the prescribed private fund — a new style of private foundation akin to the US family foundation — has burgeoned in Australia, with some 610 formed since this tax-effective structure was instigated in 2001. Many of these were established by people far from the wealth apex. Still, when it comes to health and medical research, as prominent medical research leader and former Chief Medical Officer Professor Judith Whitworth points out, “Australian philanthropic funding — both corporate and private — lags way behind”.6 Australian health and medical research non-profit organisations (eg, the Royal Children’s Hospital Foundation, the Leukaemia Foundation) attract one in seven of all individual donation dollars.5 So the area is popular, ranking second to religious institutions. However, it is not even a close second, as it is a case of many donors but small dollars.5 While three in five donating Australians support health and medical research, the average gift is comparatively low: just $77 per annum (pa) compared with $529 pa to religion, $234 pa to international aid, and $220 pa to arts and culture.5 By contrast, in the US, the average gift to health causes by the most modest households is US$173, ranging to US$92 289 in households with incomes over a million dollars.7 Philanthropy worldwide has been the crucible of fine medical research institutes and the trusts that fund them: consider our Walter and Eliza Hall Institute, the US Howard Hughes Medical Institute and the Wellcome Trust in the United Kingdom. Indeed, through the Wellcome’s input, UK charitable funding matches that of its nation’s Medical Research Council. Where is Australia’s Wellcome equivalent? The possibilities for a luminary local funder to alter the landscape are profound. With mean affluent household income growing by 36% in the decade to 2005, it is concerning that charitable giving by this income band has not kept apace. The most common affluent band of Australians (taxable incomes from $100 000 to $500 000) give less than 0.5% of their income to charitable causes.8 Longitudinal corporate research provides an international benchmark, with an average of 3%–11% of portfolios allocated to giving in some other countries.9 Despite comparable wealth levels, Australian givers trail the US, the UK and Canada. Yet Australia is said to have one of the world’s fastest growing rates of millionaires. Ironically, US philanthropist Chuck Feeney, a founder of the conglomerate Duty Free Shoppers, is thought to be Australia’s most generous philanthropist. His approach of leveraging funding sources through his foundation, Atlantic Philanthropies, has catalysed potent funding partnerships. Atlantic Philanthropies offers a significant amount, providing the recipient organisation can convince governments and others to match the pledge. Consider, for example, the $900 million research program at the University of Queensland generated by leveraging state, federal and other monies from Feeney’s $150 million input.10 People commonly believe medical research is the government’s responsibility. However, as a Nature editorial asserted last year, “In scientific funding, as in agriculture, monoculture is risky”.11 The lithe and flexible philanthropic dollar can trek where more risk-averse government or corporate dollars cannot. Untrammelled by politics, elections, profit, shareholders, disease numbers, or directives not to fund infrastructure, the philanthropic dollar can more readily finance risky ideas, chart cumulative progress over decades, consider orphan diseases, and trial venturesome backing that generates social profit. The future for the US, and most likely Australia, looks set to see more of this “venture philanthropy” model. A growing number of organisations (Box) are using their philanthropic agility to fund promising science through its pre-proof of principle, “Valley of Death” phase — the critical translational funding gap between basic research and later stage drug development. The concept of successful people “investing” donations to move innovative research to the point where venture capital may kick in is an enticing model that is working. For instance, the Alzheimer’s Drug Discovery Foundation reports seeding 22 biotechnology companies and supporting 148 academic international researchers who have created new classes of drugs for Alzheimer’s disease, screened millions of compounds, and are now entering clinical trials of several new drugs. Still, more debate is needed. Is it appropriate that philanthropy influences the research agenda? How valid is “personal whim” funding over majority need? Discovering better treatments sometimes means more expensive medicines, and is this progress for all? Change in the Australian health and medical research philanthropic landscape is needed, and the climate is right. Research Australia Philanthropy now exists to foster contribution to research (http://thankyouday.org/ra/philanthropy.aspx). The National Health and Medical Research Council added philanthropy to its strategic plan in 2006 and is working on fruitful partnerships with health and medical research charities (eg, co-funding with the Junior Diabetes Research Foundation Australia of the Diabetes Vaccine Development Centre). The national peak body, Philanthropy Australia (http://www.philanthropy.org.au/), provides forums for interested existing and potential funders to collaborate and exchange. The challenge is one of communication and culture change: convince philanthropic trusts, companies, individuals and households that funding medical research is not just a job for government, but a task for all Australians to shoulder. With governments increasingly unlikely to meet the spiralling costs of complex medicine for an ever-ageing population, the funding drought needs to be broken. Everyone can — and maybe should — play rainmaker. Organisations exploring “venture philanthropy” for medical research Goldman Philanthropic Partnerships was set up by a former merchant banker and his wife to accelerate the way cures are discovered through a business model of research funding partnerships (http://www.goldmanpartnerships.org) The Alzheimer’s Drug Discovery Foundation was set up by the Lauder family, of cosmetics renown (http://alzdiscovery.org/) The Washington, DC-based think tank, FasterCures (http://www.fastercures.org) The Epilepsy Therapy Development Project acts as a catalyst and a clearing house for innovative research and early commercialisation of new epilepsy therapies (http://www.epilepsy.com/epilepsy_therapy_project) CFF Therapeutics, a non-profit drug discovery and development affiliate of the Cystic Fibrosis Foundation (http://www.cff.org/research/CFFT/) Accelerate Brain Cancer Cure supports researchers and creates collaborations between medical, academic, industry and government partners (http://www.abc2.org)

Myles McGregor-Lowndes BA/LLB, MAdmin, PhD · Wendy Scaife BBusComm, MBusMgnt, PhD

Objective: To assess the efficacy of a multimodal, centrally coordinated, multisite hand hygiene culture-change program (HHCCP) for reducing rates of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia and disease in Victorian hospitals.Design, participants and setting: A pilot HHCCP was conducted over a 24-month period (October 2004 to September 2006) in six Victorian health care institutions (4 urban, 2 rural; total beds, 2379). Subsequently, we assessed the efficacy of an identical program implemented throughout Victorian public hospitals over a 12-month period (beginning between March 2006 and July 2006).Main outcome measures: Rates of hand hygiene (HH) compliance; rates of MRSA disease (patients with bacteraemia and number of clinical isolates per 100 patient discharges [PD]).Results: Mean HH compliance improved significantly at all pilot program sites, from 21% (95% CI, 20%–22%) at baseline to 48% (95% CI, 47%–49%) at 12 months and 47% (95% CI, 46%–48%; range, 31%–75%) at 24 months. Mean baseline rates for the number of patients with MRSA bacteraemia and the number of clinical MRSA isolates were 0.05/100 PD per month (range, 0.00–0.13) and 1.39/100 PD per month (range, 0.16–2.39), respectively. These were significantly reduced after 24 months to 0.02/100 PD per month for bacteraemia (P = 0.035 for trend; 65 fewer patients with bacteraemia) and 0.73/100 PD per month for MRSA isolates (P = 0.003; 716 fewer isolates). Similar findings were noted 12 months after the statewide roll-out, with an increase in mean HH compliance (from 20% to 53%; P < 0.001) and reductions in the rates of MRSA isolates (P = 0.043) and bacteraemias (P = 0.09).Conclusions: Pilot and subsequent statewide implementation of a multimodal HHCCP was effective in significantly improving HH compliance and reducing rates of MRSA infection.

M Lindsay Grayson MD, FRACP FAFPHM · Lisa J Jarvie RN · Rhea Martin RN, MPH · Paul D R Johnson PhD, FRACP · Meryanda E Jodoin RN · Celene McMullan RN · Roger H C Gregory RN · Kaye Bellis RN · Katie Cunnington RN · Fiona L Wilson RN · Diana Quin RN, BA, MPH · Anne-Maree Kelly MB BS, FACEM

Objective: To determine if the recent rapid fall in use of hormone replacement therapy (HRT) in Australia has been followed by a reduction in breast cancer incidence among women aged 50 years or older, but not among younger women.Design and setting: Analysis of trends in annual prescribing of HRT, using Pharmaceutical Benefits Scheme data, and in annual age-standardised breast cancer incidence rates in Australian women for the period 1996–2003.Results: In Australia, prescribing of HRT increased from 1996 to 2001, but dropped by 40% from 2001 to 2003. Age-standardised breast cancer incidence rates in women aged ≥ 50 years also increased to 2001 but declined thereafter. The incidence rates in this age group were lower by 6.7% (95% CI, 3.9%–9.3%; P < 0.001) in 2003 compared with 2001, equivalent to 600 (95% CI, 350–830) fewer breast cancers (out of about 9000 incident breast cancers annually for women this age). There was no significant change in breast cancer incidence for women aged < 50 years.Conclusions: While other factors may have contributed to a recent reduction in breast cancer incidence among Australian women aged ≥ 50 years, the available evidence suggests that much of the decrease is due to the recent fall in use of HRT. This is consistent with other evidence that the HRT-associated increase in risk of breast cancer is reversible after ceasing use of HRT.

Karen Canfell DPhil · Emily Banks MB BS(Hons), PhD, FAFPHM · Aye M Moa MPH · Valerie Beral FRS

Objective: To describe the pattern of stillbirths by cause and gestation period in New South Wales since the introduction of the Perinatal Society of Australia and New Zealand perinatal death classification (PSANZ-PDC); and to assess the agreement between classifications on cause of death between local hospital committees and the Perinatal Outcomes Working Party (POWP — a subgroup of the NSW Department of Health Ministerial Maternal and Perinatal Committee).Design, participants and setting: Population-based retrospective cohort study of all 258 045 births in NSW and all 1264 stillbirths classified by the POWP in 2002–2004, based on linked data on perinatal deaths from the NSW Midwives Data Collection and the NSW Ministerial Maternal and Perinatal Committee.Main outcome measures: Pattern of stillbirths by cause and gestation period; and interobserver agreement on classification of cause of death (according to the PSANZ-PDC) between local hospital review committees and the POWP.Results: The most common classification was unexplained antepartum death, comprising 41.5% of the cohort and 60% of stillbirths of ≥ 37 weeks’ gestation. These unexplained stillbirths were more likely to have had an autopsy performed than the explained stillbirths (45% v 36%; χ2 = 10.1; df = 1; P = 0.001). Agreement on cause of death differed by cause of death classification, with an overall κ statistic of 0.638.Conclusion: Unexplained antepartum death is the most common classification of stillbirths near term, and these stillbirths are more likely to have had an autopsy. Although reported interobserver agreement is high for PSANZ-PDC, in practice it is relatively low between hospital mortality review committees and the POWP.

Adrienne Gordon FRACP, MPH(Hons) · Heather E Jeffery FRACP, MPH, PhD

Objective: To characterise the understanding of good clinical research practice (GCRP) among clinical researchers.Design, participants and setting: Survey of all staff within the largest clinical research group (Critical Care and Neurosciences) of a non-government research institute affiliated with a major children’s hospital, between 1 April and 31 May 2007.Main outcome measures: Staff’s role and research activity; knowledge of relevant guidelines and translation into practice; GCRP training; and experience of research audits.Results: 122 of 154 research staff (79%) responded and were divided into three categories: clinicians (45%); research students/junior researchers (32%); and researchers (23%). While 60% of researchers reported they had read (at least in part) the two key Australian documents (the National statement on ethical conduct in human research and the Australian code for the responsible conduct of research), only 36% of clinicians and 30% of students/junior researchers stated they had done so. GCRP, such as obtaining consent and document storage, was only partially understood. 13% of all respondents had experienced a research project audit and 10% had undertaken formal GCRP training. Reasons given for the lack of GCRP training included insufficient resources, no training provided, and no time. 79% of staff felt that research auditing was important and 74% would like more education in GCRP.Conclusions: Many clinical researchers are unaware of all the responsibilities involved in GCRP. A formal mandatory training program and GCRP auditing would be likely to improve practice.

Franz E Babl MD, MPH, FRACP · Lisa N Sharwood RN, BN, MPH

Objective: To explore the role played by human research ethics committees (HRECs) with regard to the fair inclusion of men and women in Australian clinical research.Design and participants: Semi-structured face-to-face and telephone interviews with 25 chairs (or their nominees) of Australian HRECs between 9 June 2006 and 24 January 2007.Main outcome measures: Chairs’ views about the role of HRECs in identifying sex discrimination, monitoring the inclusion of men and women in clinical research, and interpreting and applying National Health and Medical Research Council (NHMRC) guidelines relating to fair inclusion in research.Results: In general, HRECs do not take an active role in monitoring the sex of research participants. They do not ask for or often receive information about the sex of participants. Most HREC chairs did not believe that sex discrimination in research is currently a significant or widespread problem, and were confident that their committees would be able to identify arbitrary exclusion of either men or women from research. However, many chairs expressed a lack of familiarity with debates about sex equity in research. Most chairs were unaware that anti-sex-discrimination legislation could apply to research. “Fair inclusion” was interpreted in a number of ways by chairs, but most frequently that the sex balance among research participants should reflect the sex distribution in the community of the condition under investigation. Chairs said their committees would be reluctant to reject a research protocol on the grounds that the sex balance among participants was perceived to be unfair.Conclusion: Views about, and expertise on, sex equity in research vary among chairs of HRECs. Many HRECs require further guidance about the appropriate standards for fair inclusion of men and women in Australian clinical research.

on behalf of the Australian Gender Equity in Health Research Group

The level of documentation of vital signs in many hospitals is extremely poor, and respiratory rate, in particular, is often not recorded. There is substantial evidence that an abnormal respiratory rate is a predictor of potentially serious clinical events. Nurses and doctors need to be more aware of the importance of an abnormal respiratory rate as a marker of serious illness. Hospital systems that encourage appropriate responses to an elevated respiratory rate and other abnormal vital signs can be rapidly implemented. Such systems help to raise and sustain awareness of the importance of vital signs.

Michelle A Cretikos MB BS, MPH, PhD · Rinaldo Bellomo MD, FJFICM · Ken Hillman MB BS, FRCA, FJFICM · Jack Chen MB BS, MBA · Simon Finfer MB BS, MRCP, FRCA · Arthas Flabouris MB BS, FANZCA, FJFICM

Premature ejaculation (PE) is ejaculation occurring without control, on or shortly after vaginal penetration and before the subject wishes it, causing marked distress or interpersonal difficulties. PE is the most common male sexual complaint. Primary (lifelong) PE has a physiological basis. Therapy should involve the man and his partner. The primary aims of therapy are for the man to regain a sense of control over his ejaculation time and for him and his partner to feel satisfaction with sexual intercourse. The most effective therapies for primary PE are certain selective serotonin reuptake inhibitors, given on a daily basis or “on demand” before sexual activity. Topical anaesthetics have also been shown to be effective. The most common cause of secondary PE is declining erectile function. The approach to treating secondary PE is to treat the underlying condition.

Neil R Palmer MB BS DObstRCOG · Bronwyn G A Stuckey BA, MB BS, FRACP

The critical shortage of the rural medical workforce in Australia continues. There is pressure on medical schools to produce not only more doctors, but to supply them in geographical areas of need. The latest policy to tackle these problems will increase medical student numbers while the supply of clinical teachers and patients for teaching remains static. This challenges the traditional apprenticeship model for learning medicine. Coupled with this is the requirement of medical schools to provide compulsory rural clinical placements for all students. The success of rural clinical schools and University Departments of Rural Health (UDRH) is increasingly apparent, but they must find new strategies to maintain a quality clinical experience and exposure to rural lifestyle for all medical students. The dilemma is providing this quality rural experience to all medical students in the immediate future. We suggest approaches to meet this challenge at a policy, organisational, student and teaching level.

Diann S Eley MSc, PhD · Louise Young MPsychEd, PhD · David Wilkinson MD, FRACGP, FACRRM · Alan B Chater MB BS, FACRRM, FRACGP · Peter G Baker ChB, MD, FRACGP

A 79-year-old man presented with painless dysphagia. Results of an oesophagogastroduodenoscopy were unremarkable. A dynamic videofluoroscopic examination was diagnostic, revealing hypertrophic cervical osteophytes indenting the hypopharynx and oesophagus. The osteophytes were also seen on a lateral cervical spine radiograph (Box). The dysphagia responded to dietary modification. Although cervical osteophytes are seen in 20%–30% of the geriatric population, they are an unusual (and treatable) cause of dysphagia. Dysphagia occurs because of mechanical blockage as well as inflammation of the peripharyngeal and peri-oesophageal tissue. As enlarged cervical osteophytes may be an incidental finding, it is important to exclude other potential causes, such as neoplasm.1,2 Lateral radiograph of the cervical spine showing multiple enlarged anterior and bridging cervical osteophytes, with the most prominent bridging osteophyte between the C4 and C5 vertebrae (arrow).

Shoaib Faruqi · Muthu Thirumaran · Parry Blaxill

CorrectionRe: “Are Australian children iodine deficient? Results of the Australian National Iodine Nutrition Study”, by Mu Li, Creswell J Eastman, Kay V Waite, Gary Ma, Margaret R Zacharin, Duncan J Topliss, Philip E Harding, John P Walsh, Lynley C Ward, Robin H Mortimer, Emily J Mackenzie, Karen Byth and Zelda Doyle, in the 20 February 2006 issue of the Journal (Med J Aust 2006; 184: 165-169). The article as originally published did not include unbiased estimates across all mainland states for the statistics presented in Box 1 and Box 4. This omission is corrected in the tables presented here. All data in these tables are the same as in the original article, but an extra row showing estimates for mainland states has been added. The “Total” row refers to the study sample only. The unbiased estimate of the national median urinary iodine excretion (UIE) in the results section of the abstract should read 96 μg/L, not 104 μg/L, showing that children in mainland Australia are mildly iodine deficient according to World Health Organization criteria (mild iodine deficiency, UIE 50–99 μg/L). 1 Summary data on participating schoolchildren by state together with weighted estimates across all mainland states State Students participated/ students targeted M:F ratio Mean (SD) age (years) Mean (SD) weight (kg) Mean (SD) height (cm) Mean (SD) body surface area (m2) Median urinary iodine excretion (μg/L) (interquartile range) NSW 427/400 (106%) 1:1 9.3 ± 0.6 34.9 ± 8.5 138.5 ± 6.7 1.16 ± 0.15 89.0 (65.0–123.5) VIC 348/400 (87%) 1:0.8 9.7 ± 0.5 38.2 ± 8.9 141.0 ± 6.8 1.22 ± 0.15 73.5 (53.0–104.3) SA 317/400 (79%) 1:0.9 9.0 ± 0.5 35.3 ± 7.9 137.3 ± 7.3 1.16 ± 0.15 101.0 (74.0–130.0) WA 323/400 (80%) 1:0.8 8.9 ± 0.6 32.8 ± 7.6 136.9 ± 6.4 1.11 ± 0.14 142.5 (103.5–214.0) QLD 294/400 (73%) 1:1.3 9.1 ± 0.4 32.9 ± 7.2 137.3 ± 6.3 1.12 ± 0.13 136.5 (104.3–183.8) Total for sample 1709/2000 (85%) 1:0.9 9.2 ± 0.6 34.9 ± 8.3 138.3 ± 6.9 1.20 ± 0.10 104.0 (71.0–147.0) Estimates for mainland states* 1:1 9.3 ± 0.6 35.2 ± 8.5 138.7 ± 6.8 1.16 ± 0.15 96.0 (66.0–135.0) M:F = male to female. * Formed by weighting the sample data from each state according to the distribution of all Year-4 schoolchildren by mainland states. 4 Percentage of children with a thyroid volume (mL) greater than the new international standard 50th and 97th percentile values (P50 and P97) Based on body surface area (% [95%CI]) Based on age (% [95%CI]) State Boys Girls Total Boys Girls Total Percentage > international standard P50 NSW 58.1 (51.3–64.9) 57.6 (50.9–64.3) 57.9 (53.1–62.7) 61.3 (54.6–68.0) 63.8 (57.3–70.3) 62.6 (57.9–67.3) VIC 18.0 (12.6–23.4) 18.3 (12.2–24.4) 18.2 (14.1–22.3) 24.9 (18.8–31.0) 26.1 (19.1–33.1) 25.4 (20.8–30.0) SA 41.0 (33.5–48.5) 46.3 (38.3–54.4) 43.5 (38.0–49.0) 50.9 (43.3–58.5) 54.4 (46.4–62.4) 52.5 (47.0–58.0) WA 70.0 (63.1–76.9) 71.6 (64.3–78.9) 70.8 (65.8–75.8) 75.3 (68.8–81.8) 81.1 (74.8–87.4) 78.0 (73.4–82.6) QLD 55.0 (46.4–63.6) 50.0 (42.3–57.7) 52.2 (46.4–58.0) 61.5 (53.1–69.9) 60.6 (53.0–68.2) 61.0 (55.4–66.6) Estimates for mainland states* 47.1 (43.3–50.9) 46.2 (42.5–49.9) 46.6 (44.0–49.2) 52.5 (48.8–56.3) 54.1 (50.4–57.8) 53.3 (50.7–55.9) Percentage > international standard P97 NSW 3.9 (1.2–6.6) 7.1 (3.6–10.6) 5.6 (3.4–7.8) 6.4 (3.0–9.8) 10.0 (5.9–14.1) 8.2 (5.6- 10.8) VIC 0 0 0 0 0.7 (0–2.0) 0.3 (0–0.9) SA 4.8 (1.5–8.1) 10.1 (5.3–14.9) 7.3 (4.4–10.2) 6.6 (2.8–10.4) 10.7 (5.7–15.7) 8.5 (5.4–11.6) WA 11.2 (6.5–15.9) 14.9 (9.2–20.6) 12.9 (9.2–16.6) 11.8 (7.0–16.6) 19.6 (13.2–26.0) 15.4 (11.4–19.4) QLD 2.3 (0–4.9) 3.1 (0.4–5.8) 2.8 (0.9–4.7) 3.1 (0.1–6.1) 5.6 (2.0- 9.2) 4.5 (2.1–6.9) Estimates for mainland states* 2.9 (1.7–4.2) 5.0 (3.3–6.6) 4.0 (3.0–5.0) 4.3 (2.7–5.9) 7.2 (5.2–9.1) 5.7 (4.5–7.0) * Formed by weighting the sample data from each state according to the distribution of all Year-4 schoolchildren by mainland states.

Mu Li · Creswell J Eastman · Kay V Waite · Gary Ma · Margaret R Zacharin · Duncan J Topliss · Philip E Harding · John P Walsh · Lynley C Ward · Robin H Mortimer · Emily J Mackenzie · Karen Byth · Zelda Doyle

Marshall and Ruedy’s On call: principles and protocols. Mike Cadogan, Anthony F T Brown, Antonio Celenza. Sydney: Saunders Elsevier, 2007 (xvi + 576 pp). ISBN 978 0 7295 3803 9. Being on call can be a daunting experience. You are called to a patient you don’t know who has become unwell. They might have developed a severe headache, be short of breath or have chest pain. What are you going to do? When should you call for more experienced help? On call principles and protocols attempts to systematically answer such questions. Based on the book of the same name by Canadian authors Shane Marshall and John Ruedy, it differs in its arrangement, separating interpretation of common investigations and procedures, with a brief formulary to separate sections. For the common problems encountered, the authors detail what questions to ask over the phone and what initial instructions to give. Conditions under which the patient should be given immediate priority are listed. Assessment and management of life-threatening problems are dealt with first, followed by a more complete discussion, including when to call for more experienced help. Interestingly, the authors are all emergency physicians who have probably not been on call for ward patients for many years, but all have experience in medical education and the principles of assessing the emergency patient are not dissimilar. Some hospitals have their own handbooks dealing with hospital emergencies but the approach taken in this text is more systematic and comprehensive. One omission is a discussion of common surgical problems, such as management of diabetes peri-operatively and postoperative analgesia. Guidelines given for managing patients on aniticoagulation therapy, a common on-call problem, are restricted to over-anticoagulation and do not provide detail on heparin and warfarin prescribing. These omissions aside, the style and content of On call principles and protocols is well laid out and the book fills a niche for doctors practising hospital medicine. With a recommended retail price of $60 the book represents value for money.

Robert P Dowsett

To the Editor: The review of issues faced when training international medical graduates (IMGs) by Pilotto and colleagues is indeed timely.1 Their systematic presentation of these issues resonates loudly with many of the daily challenges of hospital practice. While their review referred to the shortfall of doctors, it failed to emphasise how critical this shortfall already is in some areas of hospital practice. As workloads escalate, IMGs increasingly underpin the provision of critical care clinical services. Among trainees in my department, the rise in the proportion of IMGs whose first language is not English has been dramatic, increasing from 22% of trainees in 2000 to 83% in 2007 (Box). In my experience, these doctors arrive with high expectations of the system that will train them to be critical care specialists, and place enormous pressure on themselves to achieve this. IMGs with English as a second language require greater early supervision to orient them to differences in hospital systems and language. Later, they require more assistance in preparing for the Fellowship examinations than IMGs whose first language is English. Between 2000 and 2007, an increasing clinical workload has left less time and resources for their training, and currently the needs of these IMGs are often not being met. These doctors are crucial to the provision of clinical services in our hospital, and their needs should not be ignored. Anecdotally, we are already seeing IMGs previously desperate for any training position now “cherry picking” hospitals with better resourced training programs. On average, compared with Australian medical graduates, IMGs with English as a second language spend longer in Fellowship training programs and are more likely to reattempt examinations; and the registration, training and examination fees for IMGs are considerable. The specialist medical colleges should already be in a position to fund initiatives for IMGs whose first language is not English. However, regrettably, as far as I am aware, they receive no specific help in undertaking the language-rich examination process for a Fellowship in critical care medicine. When I reflect on my specialty training, the thought of having to pursue this in an unfamiliar language is overwhelming. Not surprisingly, IMGs constantly perform under the pressure of “not measuring up”. Their appreciation of the help and training they receive is immense. However, I think one of my more important tasks as Supervisor of Training, particularly early in their training, is to remind IMGs of the great clinical work they perform day in, day out. The debt we owe them is also immense — who needs whom the most? Number of critical care trainees at Flinders Medical Centre, Adelaide, South Australia, 2000–2007, by origin and English-speaking status IMG = international medical graduate.

Andrew W Holt

To the Editor: In Victoria from 2000 to 2006, infectious syphilis notifications (primary, secondary and early latent infections) increased about 25-fold from 0.2 cases per 100 000 population in 2000 to 4.7 cases per 100 000 population in 2006.1 The number of new diagnoses of HIV has also increased since 2004.1 After observing a few patients presenting with both syphilis and a concurrent new HIV diagnosis, we investigated the association of the two diseases using retrospective laboratory data. As the Victorian Infectious Diseases Reference Laboratory (VIDRL) incorporates the state HIV reference laboratory and also acts as the reference laboratory for syphilis serological testing, it was possible to identify the HIV status and/or time of HIV diagnosis of 85% of patients identified with infectious syphilis, based on syphilis serological findings and polymerase chain reaction testing as previously described.2 Three hundred and forty-seven male patients fulfilled the criteria for infectious syphilis in the period 1 January 2000 to 30 December 2006. This represents 68% of all patients with infectious syphilis notified to the Victorian Department of Human Services over the period. Within the group of 347 patients, there were 310 with a single episode of Treponema pallidum infection, of whom 44.5% were HIV-positive. Thirty-seven patients were reinfected with syphilis, including 21 with their first episode recorded since 2000, and 11 with a serological pattern consistent with old treated syphilis recorded before reinfection during the study period. Of the 37 patients, 33 (of whom 23 were HIV-positive) had a second recorded episode and four (of whom three were HIV-positive) had a third recorded episode within the study period. Overall, 70.3% of patients with multiple episodes of syphilis were infected with HIV. Twenty patients presented with a concurrent diagnosis of infectious syphilis and previously un-diagnosed HIV infection. The trend over time is shown in the Box. Several international studies have highlighted the disproportionate incidence of syphilis in patients infected with HIV in recent years. There is now good evidence that syphilis and HIV act synergistically with regard to both transmission and progression of both diseases.3-5 The above data clearly demonstrate the strong association between HIV infection and infectious syphilis in Victoria, and this trend continued in the first half of 2007. Given the more frequent syphilis reinfections observed in the HIV-infected group, it indicates persons with HIV form a potential reservoir for syphilis infection in this state. We would strongly recommend that any patient presenting with possible syphilis or HIV infection in Victoria or elsewhere in Australia should be tested for both diseases. Episodes of infectious syphilis in Victoria by year of infection and HIV status * Patients with evidence of prior syphilis infection at an unknown time.

David E Leslie · Nasra Higgins · Christopher K Fairley

To the Editor: A 37-year-old male Sudanese refugee presented with lethargy, nausea, abdominal discomfort and bloating. He had chronic hepatitis B and a 2-year history of hazardous levels of alcohol consumption (90 g/day). On examination, there were no features of chronic liver disease. His liver enzyme levels were elevated (alkaline phosphatase, 189 U/L [reference range (RR), 40–110 U/L], γ-glutamyltransferase, 456 U/L [RR, < 50 U/L], alanine aminotransferase, 51 U/L [RR, < 45 U/L], and aspartate aminotransferase, 53 U/L [RR, < 40 U/L]), but synthetic function was preserved and serum bilirubin level was normal. Hepatitis B virus DNA was 1.3 × 103 IU/mL, consistent with a low-level viraemia, while HBeAg and anti-HBeAb were both non-reactive. His platelet count was reduced (115 × 109/L [RR, 140–400 × 109/L]), suggesting portal hypertension. The remainder of his chronic liver disease screen was unremarkable. Endoscopy revealed four grade 1 oesophageal varices, mild portal hypertensive gastritis, and patchy erosive duodenitis. The irregular liver and periportal fibrosis seen on ultrasound (Box 1) raised the possibility of cirrhosis. Subsequently, a biopsy of the liver showed preserved liver architecture, with periportal fibrosis and active schistosomiasis (Box 2). A diagnosis of Schistosoma mansoni infection was made, based on the histological appearance of the ova. S. mansoni is the leading cause of chronic liver disease and portal hypertension in sub-Saharan Africa.1,2 Adult worms reside in mesenteric vessels, but their migrating eggs lodge in hepatic presinusoidal radicals, resulting in inflammation and granuloma formation. The inflammatory reaction eventually leads to occlusion of portal veins and secondary portal hypertension.3 Hepatocellular function usually remains normal.1 Although the “gold standard” for diagnosis of S. mansoni infection is microscopic examination of faeces, this test may be negative (as it was in this case). Serological screening is recommended, but these assays cross-react with other helminthic infections and are unable to distinguish active infections from previous exposure.1 Praziquantel should be offered to previously untreated patients with positive serology results; after a single dose, 70%–100% of patients cease to excrete eggs.1 In patients who have left S. mansoni-endemic areas, an oral dose of 60 mg/kg split in two and given several hours apart should ensure cure.1 Our patient was treated with praziquantel, with ongoing follow-up for hepatitis B and portal hypertension. In retrospect, the patient’s history and the sonographic appearances were consistent with schistosomiasis. This clinical scenario is of increasing relevance, with a growing number of people from Africa now living in Australia. 1 Liver ultrasound Ultrasound shows an irregular liver with marked periportal fibrosis. There is no intra- or extrahepatic biliary tree dilatation. The portal vein flow is antegrade. No focal hepatic lesion is seen. 2 Liver biopsy specimen Preserved round to oval parasites with ova, some with a refractile exoskeleton and small lateral spine, can be seen. The viable forms suggest active infection. The surrounding inflammation contains numerous eosinophils, with fibrous expansion of the portal tracts. The adjacent liver revealed a preserved architecture with a normal METAVIR score of A0F0 (haematoxylin–eosin stain; low-power [A] and high-power [B] magnification).

James Daveson · Graeme Macdonald

To the Editor: Australians are fatter than they have ever been before. The prevalence of overweight and obesity (body mass index ≥ 25.0 kg/m2, or waist circumference > 80 cm for women or > 94 cm for men) in Australian adults is approaching 60% for both sexes and has more than doubled in the past 25 years.1 A prudent public health policy to fight the growing obesity epidemic would undoubtedly be to target strategies that avert this condition in the first place. So we were perplexed by the Australian Medical Association’s recent proposal to the Victorian Government to fund five public hospitals to provide 3000 obesity-related operations (ie, bariatric surgery) over the next 3 years.2 It appears the blueprint for the new millennium is to invest taxpayers’ money in modern technologies in an attempt to arrest overt clinical disease states. To attack the growing burden of obesity by investing in strategies that target secondary and tertiary treatment is an admission that we may win battles on a few fronts, but lose the war. We propose placing greater emphasis on implementing and enforcing primary prevention strategies to fight obesity. Primary defence mechanisms can decrease obesity prevalence by preventing the condition in the first place! Indeed, the health care industry is paradoxical in that its principal goal is to end health problems and human suffering, and by so doing put itself out of business.3 We need to attack the environmental roots of obesity, namely our sedentary lifestyles and caloric excess. Emphasis on secondary and tertiary prevention is too little, too late and will not reverse the growth of obesity — the funds to treat obese individuals are finite, while the number of Australians with the potential to become overweight or obese is not! In a letter to President Roosevelt voicing concerns about the Manhattan Project (the project to develop the atomic bomb during World War II),4 Niels Bohr wrote: A weapon of an unparalleled power is being created which will completely change all future conditions of warfare. Unless some agreement about the control of the use of the new active materials can be obtained in due time, any temporary advantage, however great, may be outweighed by a perpetual menace to human security. Obesity-related disorders impact on daily living. While bariatric surgery may provide a “magic bullet” for a few individuals, the time has come to legislate for minimum health standards, and to provide support for people to effect lifestyle changes to meet these requirements. Otherwise, obesity will remain a permanent threat to Australian society.

John A Hawley · David W Dunstan

Comment: Obesity is a complex public policy issue. There are no easy solutions, and the medical profession needs to work with communities, governments, researchers, teachers, parents, industry and others to help all Australians achieve and maintain a healthy weight. The Australian Medical Association (AMA) Victoria has six priority action areas to promote healthy weight: Ban food advertising to children; Simplify food labels; Promote physical activity every day; Improve clinical tools; Improve treatment options; and Evaluate and educate. Bariatric surgery is one of the treatment options that needs to be further explored. Among many other items, AMA Victoria’s state budget submission for the 2008–09 financial year1 calls for a trial of 3000 bariatric surgical procedures to be performed in public hospitals, as part of a comprehensive approach to weight loss. The evidence before AMA Victoria indicates that bariatric surgery is a safe and cost-effective treatment for a proportion of morbidly obese Victorians.2-5 However, bariatric surgery is an extreme response that should only be explored in extreme circumstances. There are many morbidly obese people who find themselves in these extreme circumstances and may benefit from the surgery if other approaches have failed. Further, bariatric surgery is cost-effective, as the costs are lower than the ongoing costs of treating chronic conditions associated with obesity. Bariatric surgery is not the only policy approach to obesity being pursued by AMA Victoria. We see it as a small part of the solution, although it has been a larger part of recent media attention on the issue. I am pleased that the AMA has been able to highlight obesity as an important public policy issue, and I look forward to working with a range of partners to explore possible solutions.

Douglas G Travis

To the Editor: The article by Haug and colleagues on household food stockpiling is a useful contribution to a neglected aspect of disaster planning.1 However, rather than providing a guide to what foods should be stockpiled, it may be more valuable to encourage families to increase the amount and rotation of the non-perishables they currently purchase. The authors seek to promote a balanced nutritional diet, but encouraging a family to continue their usual purchasing patterns when stockpiling for a pandemic or other disaster is a simpler, more sustainable, and possibly more effective way to promote household food stockpiling. We must assume that the family currently survives, for better or worse, on their current food purchase pattern. While the article states that supermarket stocks will become depleted within 2–4 weeks, it is likely that stocks would become significantly depleted at an individual store level within 2–3 days of the last truck delivery, particularly if panic stockpiling occurs. How long interruptions to the food supply chain last will depend on the nature of the disaster, but the Australian Government Department of Health and Ageing recommends that people have “enough fluids and food on hand to last you and your family a week.”2 It does not provide guidance on how much water is required per day. This is an important issue, as mains water could be unavailable within hours to days of electricity supply outages, because electricity is required to pump water into elevated water reservoirs to maintain water pressure. People may be unaware of their daily fluid requirements and may run out of water and other potable fluids before they run out of food. The US Health and Human Services recommends a 2-week food and water stockpile (“one gallon of water per person per day”), which is roughly equivalent to four litres per person per day.3 A random household survey in the Hunter Region of New South Wales after a storm-related disaster in June 2007 revealed that over 80% of households had enough non-perishable food for 3 days, but less than 40% had enough stored drinking water for 3 days (Hunter New England Health, unpublished data). Community continuity planning should be based on an understanding of baseline household food and water reserves, and household capacity and willingness to stockpile across all social strata. Governments should actively promote household stockpiling and identify strategies to bridge the shortfall in households unable to stockpile.

Craig B Dalton · Michelle A Cretikos · David N Durrheim

In reply: Dalton et al have raised several important points for discussion. They suggest that an adequate food “lifeboat” can be procured by simply encouraging a family to continue their usual purchasing patterns. Unfortunately, accumulating non-perishable items in this way would be a fast route to certain nutritional deficiency. It is the perishable items — fruit and vegetables, bread, meat and dairy products — that supply the bulk of micronutrients in modern food supplies. Within a few short months, an individual relying on usual pantry supplies could be suffering from acute deficiencies of vitamin C, and folate and other B vitamins. Babies conceived during this period would be at risk of neurological defects. We agree that an important issue is the possibility of failure of the mains water. Indeed, many of the foods in our list require water for cooking (rice, pasta etc). Rainwater tanks and the ability to sterilise water by gas heating or chemical means may be lifesavers. We agree that governments should be actively promoting appropriate stockpiling in homes, places of employment and in areas of essential infrastructure.

Jennie C Brand-Miller · Jennifer McArthur · Anna Haug

* It should be noted that the question mark in the title was added at the Editor's discretion. To the Editor: Why are those who market officially sanctioned information about pharmaceutical products not constrained by the advertising standards imposed on those who sell these products? Medicines Australia, which formulates a code of conduct for the pharmaceutical industry, imposes penalties, both financial and withdrawal of offending material, against misleading advertising of pharmaceutical products1,2 Why are similar standards not applied to advertising of information about these products? There are well documented flaws in Australian drug information sources,2,3 such as MIMS (the Monthly Index of Medical Specialties), that are based on product information (PI) authorised by the Therapeutic Goods Administration (TGA). Some PI is decades out of date;2 bottlenecks in updating TGA-approved PI are apparent.4 In this light, advertising of PI-based information in the bimonthly MIMS summaries seems anomalous. The April–May 2008 bimonthly print edition of MIMS claims to present “100% pure knowledge”, and states that “you can count on MIMS being up-to-the-minute”, and that “MIMS is essential knowledge that Australian health professionals can trust”. Previous bimonthly MIMS summaries make similar assertions. Until PI can be brought to an acceptable professional standard — a task that may be slow4 — it would seem appropriate to rein in misleading claims about PI widely used by health workers. Medicines Australia, or the National Prescribing Service, a government-funded body committed to “quality use of medicines”, could lead this initiative.

Jim R Stockigt

In reply: MIMS is held — and has long been held — in high regard in the Australian health care market. The vast majority of MIMS subscribers recognise that the quality information provided by MIMS is essential in their daily encounters with their patients. However, the product information (PI) produced in MIMS publications is only part of the information provided to health care professionals through various MIMS publications. Furthermore, it must be stated clearly that MIMS is not responsible for producing the PI-based drug information. This responsibility remains with the manufacturer, and the PI is subsequently approved by the Therapeutic Goods Administration (TGA). MIMS collates information from various sources, both locally and overseas, and publishes it in an easy-to-use, well structured and familiar format for its customers. MIMS has long been committed to providing such “essential knowledge that Australian health professionals can trust” since the introduction of the first MIMS publication 45 years ago. However, MIMS does acknowledge that there is an issue with some PI not being reviewed more regularly, and is committed to working closely with any appropriate organisation to address deficiencies in the current process. Nevertheless, it would seem inappropriate to say that PI for all drugs is not a quality information source. PI for the vast majority of drugs published in MIMS is as current as possible, given the constraints of publishing, the updating process by pharmaceutical companies and the delays in approvals through the TGA. The study reported and referenced by Stockigt focused on old, generic-based medicines.1 While there is an issue with manufacturers keeping these current, this is clearly a responsibility of the TGA and the manufacturer, not MIMS. PI for newer products is an important quality information source for the prescribers of medicines; if it were not, then the TGA would not permit manufacturers to make PI available in the first place. With respect to Stockigt’s concerns about the accuracy of MIMS advertising, we stand by our assertion that it is MIMS policy to provide the most up-to-date medicines information available, capably delivered by the MIMS professional editorial team.

Elizabeth A Donohoo

Placebo pleases The placebo debate continues to rear its head and provoke heated discussion following the publication of a randomised controlled trial in the United Kingdom involving patients with irritable bowel syndrome.1 Researchers set out to determine if placebo effects can be separated into the responses by patients to three components of a placebo medical encounter. A total of 262 adults (76% women) with irritable bowel syndrome were randomly assigned to three groups: waiting list (observation); placebo acupuncture alone (limited); or placebo acupuncture in which the patient-practitioner relationship was accompanied by warmth and attention (augmented). After 3 weeks, participants completed a global improvement scale and symptom severity assessment. Researchers hypothesised that the factors contributing to the placebo effect can be progressively combined in a way resembling a graded dose escalation. The outcome measures showed a trend: a significant increase in the reported improvement of symptoms as the three components of the placebo effect were progressively added. Enhancing the patient-practitioner relationship component appears to be the most significant factor in the observed improvement. The authors acknowledge the limitations of their study, including the subjective nature of the outcome measures, and call for further research into the components of the placebo effect. Spirited debate among the medical community has ensued, raising interesting questions about the nature of the therapeutic relationship.2 1 BMJ 2008; 336: 999-1003 2 BMJ 2008; 336: 967-968 B vitamins and the heart Supplementation with a combination of B vitamins does not appear to reduce the risk of cardiovascular events among high-risk women, despite reducing homocysteine levels, according to the results of a US randomised controlled trial. The trial involved 5442 female health professionals with a history of cardiovascular disease (CVD) or three or more cardiovascular risk factors. Participants, who were aged 42 years or older, were allocated at random to two groups receiving either a combination pill containing folic acid, vitamin B6 and vitamin B12, or a placebo. Treatment continued for 7.3 years, and outcome measures were a composite of myocardial infarction, stroke, coronary revascularisation, or CVD mortality. The treatment group showed a significant reduction in plasma homocysteine levels, as expected with vitamin B supplementation. As the authors point out, high homocysteine levels have been associated with increased cardiovascular risk in some observational studies. Despite this effect, vitamin B supplementation did not appear to reduce the incidence of total cardiovascular events among the population of high-risk women included in the trial. JAMA 2008; 299: 2027-2036 Hypertension — to treat or not to treat? The benefit of treating patients with hypertension who are over 80 years of age has been unclear, with conflicting results from various studies confounding the issue. In an international randomised controlled trial involving almost 4000 people with hypertension and a mean age of 83.6 years, participants were randomly assigned to groups receiving either a diuretic or a placebo. An angiotensin-converting enzyme (ACE) inhibitor (or matching placebo) was added if necessary to achieve a target blood pressure of 150/80 mmHg. Active treatment with the diuretic, with or without the ACE inhibitor, appeared to result in a significant (30%) reduction in the rate of stroke and significant reductions in the rate of heart failure, rate of death from stroke and death from any cause. The authors discuss the differences between their findings and those from other trials and meta-analyses, concluding that there is good evidence that treatment in this subgroup with the prescribed medications is beneficial. N Engl J Med 2008; 358: 1887-1898 Bone density in the genes An international research group investigating the heritability of osteoporosis has identified evidence for an association between bone mineral density and certain genetic loci. In a genome-wide association study with over 8500 participants, researchers measured bone mineral density at the lumbar spine and femoral neck and identified people with osteoporosis and osteoporotic fractures. Two single nucleotide polymorphisms were identified on chromosomes 8 and 11, which showed evidence for an association with bone mineral density and osteoporotic fracture. The authors comment that the combined risk of the presence of both of these alleles was similar to or greater than that of several other osteoporotic risk factors, including low body mass index, glucocorticoid exposure, and smoking. They propose that a panel of genetic markers may eventually become available as a screening tool to identify individuals at risk for osteoporotic fractures. Lancet 2008; 371: 1505-1512

Tanya Grassi