Volume 184 Issue 9

A collaborative trial is needed At a time when there is a widely held perception that older people, and particularly nursing home residents, are occupying acute care hospital beds at the expense of others,1 the article by Finn et al2 in this issue of the Journal is very pertinent. It describes the presentation, over a 6-month period, of a cohort of 541 patients from aged care facilities (nursing homes and hostels) to the emergency department of a large tertiary hospital, and notes that the substantial majority (87%) of these presentations were considered to be appropriate. These patients were acutely unwell (most having been so for less than 2 days) and required the investigations and expertise available in the emergency department for diagnosis and management. Sixty per cent of these patients required hospital admission and most (90%) survived to be discharged back to their aged care facility. There are currently about 78 000 people in nursing homes across Australia and about 81 000 in hostel care.3 These numbers will continue to grow as the number of older people increases. Consequently, presentations to emergency departments and admissions to hospital are also likely to increase, placing further strain on already busy hospitals. Hospitals can be dangerous and unfriendly places for frail older people or people with dementia, who are most likely to be residents of aged care facilities. Polypharmacy, undernutrition, skin tears, pressure areas, fall-related injuries, nosocomial infections, and deconditioning are some of the hazards of hospitalisation.4 It is therefore now very appropriate to be looking at methods of reducing the need to hospitalise these patients by providing assessment and management of selected conditions within aged care facilities. Finn et al suggest some of the resources that would be required to prevent inappropriate hospital presentation (such as the ability to insert indwelling catheters and to replace percutaneous endoscopic gastrostomy tubes), but more than this will probably be necessary. Recently, a number of hospitals around Australia have identified the need to work more closely with aged care facilities and general practitioners to provide acute care to patients in nursing homes. For example, Gold Coast Hospital in Queensland has piloted a “Hospital in the Nursing Home” program that delivers acute care to nursing home residents using their own GP and nursing home staff, with medical and nursing input from Gold Coast Hospital staff.5 This service also provides education and information to nursing home staff in areas such as wound care, continence management and intravenous fluid administration, enabling staff to improve their skills in these areas. Clinical pathways are used for management of pneumonia, urinary sepsis, dehydration, palliative care and wounds. The service has treated 400 patients, resulting in hospital bed-day savings of more than 1500 days over 2 years and allowing residents to stay in familiar surroundings while receiving acute care (Ms Kerry Robinson, Project Officer, Aged Care Early Intervention and Management, Gold Coast Hospital, personal communication). This would appear to be a positive outcome for all parties, but a randomised controlled trial would be needed to confirm the effectiveness of the intervention. Finn and colleagues also raise a number of other issues that merit attention, and addressing these issues could potentially avoid some presentations and improve information sharing in others. Their study revealed that a GP had been consulted for only a quarter of patients presenting to the emergency department. Increased GP availability and involvement is clearly important, given that 126 out of the 136 presentations involving GP input were judged “appropriate”, whereas up to 45 of the 71 presentations considered “inappropriate” could have been avoided if GP review had occurred. With the increased use of Enhanced Primary Care Initiatives, in particular, comprehensive medical assessment for permanent residents of residential aged care facilities (Medicare Benefits Schedule item 712), and Aged Care GP Panels, it is hoped that there will be much greater direct involvement of GPs in the care of their patients in aged care facilities. Overseas experience indicates that increased availability of primary care (both medical and nursing) in nursing homes results in fewer hospital admissions.6 The lack of communication between aged care facilities and the emergency department in 61% of presentations is also of concern. Use of a common aged care facility transfer sheet may improve this, and as the use of technology increases (eg, electronic care plans for residents), the use of electronic referrals may assist the process of information transfer. Inadequate communication or documentation between aged care facilities and emergency departments has been shown to increase the likelihood of admission to hospital.7 The preparation and use of advance care directives was also suggested by Finn et al to guide response to acute events occurring in residential care. Advance care directives (also known as “health care directives” or “living wills”) allow residents to document their preferences for treatment and care. The directives may indicate a desire for hospital admission and full treatment or a preference for limited treatment in certain situations. Many aged care facilities already encourage their use and help residents and their families formulate such directives in the weeks following their admission. Advice in preparing these directives is available from a number of sources, such as NSW Health.8 Finn and colleagues have given us an understanding of current presentations of patients from residential care facilities to emergency departments that can assist us in developing different and better quality services for these people. Adequate training and resourcing of staff in aged care facilities, increasing involvement of GPs, and consultation with residents and their families are the first steps in developing these services.

Susan E Kurrle MB BS, DipGerMed, PhD

Evidence “beyond reasonable doubt” may never be achievable for low-volume drugs The recent publication of a randomised controlled trial (RCT) of inhaled cyclosporin in the New England Journal of Medicine represents another milestone in the evolution of lung transplantation (LTx) as a standard therapy in the management of severe lung and pulmonary vascular diseases.1,2 RCTs have been few and far between in lung transplantation, and this is the first in such a high-profile general journal. However, the big question is: how will we integrate the study results into the clinical practice in Australia? Lung transplantation is a relatively recent and very demanding form of solid organ transplantation. The first long-term survivor received a lung transplant in 1981,3 and, compared with kidney and liver transplantation, there have been proportionally fewer lung transplantation procedures performed annually in Australia (100 lung, 400 kidney and 170 liver cadaveric transplants in 20044). Nonetheless, the four Australian lung transplant programs have performed about 6% of all lung transplants worldwide.5 At present, 100 Australians are awaiting suitable donor lungs. The efficacy of the various lung transplantation procedures themselves is determined primarily by comparison with historical control data, and the results of small cases series. The clinical practice of lung transplantation has generally developed by inference from other types of solid organ transplantation, as well as clinical anecdote and deduction. Indeed, we can identify only a handful of RCTs performed in lung transplant recipients that directly guide therapeutic decision making. Typically, the conduct of RCTs requires substantial resources and patient numbers. In lung transplantation, unless the effect size is huge, this typically mandates multicentre, multinational trials.6,7 Australian lung transplantation centres have recognised the need for good quality trials, and have consistently taken lead or major roles in virtually every significant RCT of an immunosuppressant published over the last decade.6-8 Five-year survival after lung transplantation (50%) lags well behind that of other forms of solid organ transplantation (kidney, 85%; liver, 80%4), and we continue to strive to increase our evidence base with the ultimate objective of improving clinical outcomes. Therefore, it seems somewhat ironic that, despite core Australian involvement in clinical trials generating evidence of the utility of newer immunosuppressive agents (tacrolimus, sirolimus, mycophenolate mofetil, everolimus), this evidence has not been readily integrated into Australian clinical practice. The reimbursed immunosuppressive protocols employed by lung transplantation programs in this country (cyclosporin, azathioprine and prednisolone) reflect decade-old practices. By contrast, in the United States, United Kingdom and Europe, newer agents have been rapidly integrated into practice. In Australia, there appears to be a progressively widening gap between the point at which there are sufficient data to support the use of a drug in a clinical situation (clinical risk versus benefit), and the point at which funding can be achieved that will allow the drug to actually be administered to patients. We submit that central to the problem in Australia is the extremely complex system of health care funding. Gaining Therapeutic Goods Administration (TGA) registration of a drug allowing it to be prescribed for a series of indications is only the first (relatively small) step. After that, there is extreme complexity as to who (if anyone) will pay. Previously, public hospitals have provided drugs that were indicated on clinical grounds but not subsidised by the (federal) Pharmaceutical Benefits Scheme (PBS). With a shift to predominantly casemix funding, hospitals with cutting-edge clinical programs have been forced to limit access to non-PBS items to prevent institutional “fiscal meltdown” from these largely unsupported costs. Generally, equitable access to an expensive drug in Australia requires listing on the PBS on the advice of the Pharmaceutical Benefits Advisory Committee (PBAC). The process is rigorous, evidence-based, and includes detailed pharmacoeconomic evaluation with a benchmark of cost-effectiveness. Our concerns are that the same level of evidence is required for frequently used medications (such as statins) compared with low volume drugs (such as anti-rejection drugs for lung transplant recipients) and the cost-effectiveness benchmark is not stated specifically. It is quite appropriate for regulatory authorities, hospitals and individual transplant physicians to appreciate the financial implications of novel agents, and not just focus on the evidence of efficacy. It is also important for 21st century physicians to recognise the commercial reality of drug patent laws, generic alternatives and pharmaceutical company marketing strategies. However, these issues create particular difficulties in small clinical fields like that of lung transplantation, where there may be sufficient evidence to support the use of a therapy, despite the absence of the multiple randomised trials specific to lung transplantation. It becomes apparent that it may not be commercially viable for a pharmaceutical company to perform the necessary trials and successfully negotiate registration and reimbursement for such a small patient group as lung transplant recipients. These issues are again brought to our attention by the recent RCT in the New England Journal of Medicine.2,8 This small single-centre RCT in lung transplantation is welcomed with great interest, as it shows efficacy for a novel inhaled cyclosporin formulation in enhancing key outcomes, including chronic rejection-free and overall survival (Box).2 The study had an accompanying editorial noting several methodological issues and, consistent with conservative evidence-based medicine, the editorial suggests the lung transplantation community undertake multicentre trials to avoid being “doomed to recreate a series of anecdotal experiences”.8 We are concerned, however, that repeating the RCT will take years to complete. Indeed, given the particular complexities of this agent, where multiple entities hold patents and licensing rights to different components of the therapy, no trial may ever be undertaken. There is a push to market the treatment on the existing evidence, and a case could be made that not to facilitate access to this novel therapy for Australian lung transplant recipients may cause greater harm by preventing the use of what appears to be a safe agent that strikingly reduces the risk of chronic rejection and death. We face a dilemma as lung transplant physicians (which we believe will resonate with many other clinicians) that on the “balance of probabilities” (to use a legal analogy), the benefits to our patient are likely to be greater than the risks, so it would be better to use the drug than not. However, to have the drug funded (and thus, available to our patients in a practical sense) realistically requires evidence “beyond reasonable doubt”. For the many reasons alluded to, this standard may never be achievable for low-volume drugs. Australia has been very well served by a centralised drug reimbursement system like the PBS, but we also believe it disadvantages patients with uncommon diseases who need high-cost drugs. If health economics are to be the principle determinant of funding, we need a transparent, consistent benchmark of cost-effectiveness across the entire health system. In the meantime, we ask that the thresholds of support for pharmaceutical funding be based on clinical appropriateness from the best available evidence, otherwise evidence-based medicine is in danger of becoming an economic weapon rather than a key clinical tool. Key findings of the inhaled cyclosporin lung transplant study2 Design and primary outcome 58 patients were randomly allocated, early after transplant, to receive 300 mg inhaled cyclosporin or placebo for 2 years, in addition to standard therapy. The primary outcome was rate of histological acute rejection. Results Acute rejection rates were the same for the two groups (0.44 v 0.46 episodes per patient; P = 0.87) Nephrotoxicity and opportunistic infection rates were similar. Survival was improved in the inhaled cyclosporin group (relative risk of death, 0.2; P = 0.01) Chronic rejection-free survival was improved in the inhaled cyclosporin group (relative risk of chronic rejection, 0.38; P = 0.01)

Greg Snell MB BS · Tom Kotsimbos MD, FRACP · Trevor J Williams MB BS, FRACP

It all depends on compliance Earlier this year, public trust in research was dealt a severe blow when evidence emerged that a renowned Norwegian researcher, John Sudbo, had fabricated and falsified data in articles on oral cancer published in The Lancet and the New England Journal of Medicine.1 This news followed hot on the heels of the exposure of fraudulent research by the Korean stem-cell researcher, Woo Suk Hwang, published in Science and Nature.2 There is no doubt these events are but the tip of the iceberg, as research misconduct is endemic,3 and may well become more prominent as the competitiveness and commercialisation of research escalates.4,5 Currently there is strong public support for research, but this is linked to notions of honesty and altruism, and the ability of researchers to regulate themselves. The public expects that a framework is in place to prevent misconduct and to investigate and punish the perpetrators should misconduct occur. These expectations were aired when the Hall affair was played out at the University of New South Wales in 2001–2003.6 Allegations of research misconduct were levelled at Bruce Hall, a professor of medicine at the university, and a renowned immunologist. The investigation was painfully drawn out, with a legal challenge and at least three inquiries. As it progressed, the media had many field days, the reputation of the university was compromised, and the medical faculty and the university’s council were divided. My editorial published in this Journal soon after the controversial ending of the Hall affair proffered a set of principles for managing allegations of research misconduct (Box).6 It now appears that these principles have been incorporated into policy. The National Health and Medical Research Council, the Australian Research Council, and the Australian Vice Chancellors Committee have recently released for public consultation the second draft of the Australian code for the responsible conduct of research.7 The code outlines comprehensive directives for issues such as research data and record management, the supervision of researchers in training, publication of research, authorship, peer review, conflict of interest and matters related to collaborative research. It stresses the need for research institutions to “establish a climate of open exchange of ideas with peers, mutual cooperation, and respect for academic freedom of expression, in which responsible and ethical behaviour in research is expected.” Furthermore, it requires research institutions to have in place active and formal programs for induction of trainee researchers along with continuous professional development of all researchers in the culture and performance of research, including mentorship and effective research supervision. The more contentious aspects of the code are its details for managing research misconduct. Its definition of misconduct as “deviation from the Australian code for the responsible conduct of research” 7 casts a wide net, and raises the possibility that institu-tions as well as individuals can be guilty of research misconduct. Furthermore, the code’s criteria for misconduct, reflecting current patterns of researchers’ misbehaviour,8 extend well beyond fabrication, falsification and plagiarism. It lists 17 examples of research misconduct, including abusive supervision; failure to declare, avoid or manage serious conflict of interest; and inaccuracy and carelessness in record keeping or in the preparation of grant applications or publications. This new and expanded perspective of research misconduct is welcome, but needs to be debated. When does misbehaviour become misconduct, and is the distinction between the two warranted at all? The code proposes two key players in managing misconduct: an institutional advisor on research integrity, and a designated person. The former is a counsellor on research integrity and a confidant to whom the aggrieved and those with complaints can turn for advice. The latter is the institutional inquisitor empowered to conduct a preliminary investigation as to whether allegations have substance and advise whether to pursue a formal inquiry. And herein lies the rub. The principles previously espoused (Box) recommend this be an external and independent inquiry with statutory power. The draft code allows for this, but also allows an alternative option of an internal inquiry. Is an internal inquiry a good idea? Research institutions, including universities, live in fear of adverse publicity associated with misconduct,9,10 and have an inherent and glaring conflict of interest in pursuing an internal inquiry. The community expects that “justice must not only be done but should manifestly and undoubtedly be seen to be done”. The notion of an institution investigating itself will not go down well with a society afflicted by a mistrust of authority and institutions.11 The code is silent on two requirements which will have to be in place if it is to work at all: compliance and accreditation of research institutions, and the establishment of a national body to oversee and evaluate the handling of research misconduct. The research community has long resisted any interference with its privileged status, but the time for scrutiny of research institutions for compliance with the Australian code for the responsible conduct of research is long overdue. After all, research funding is public money, and the public has every right to expect that research institutions pursue “responsible and ethical behaviour in research”. One way to ensure this is through accreditation, with failure to be accredited placing institutions at risk of losing access to public funding. Currently, the United States and Denmark, Finland and Norway have overarching bodies to oversee and evaluate instances of research misconduct.12,13 In the US, the Office of Research Integrity (ORI) has a mandate that for institutions to receive federal funding for biomedical research, they must investigate all instances of alleged research misconduct. Although the US system is far from perfect, the ORI has been active in helping research institutions to conduct their own investigations. If the institutional investigation is deemed inadequate, the ORI can intervene and initiate its own investigation. The ORI’s substantial power lies in the threat to institutions of the potential loss of federal funding.10,14 This power may sit uneasily with Australia’s broad anti-authoritarian culture and with university autonomy, but the competitive and commercial nature of today’s research, and its limited funding, dictate that such a national body should be explored and debated in the Australian context. The creators of the Australian code for the responsible conduct of research7 are to be congratulated. The code represents the first milestone along the long and tortuous road towards maintaining the integrity of research. The six lessons from the Hall affair6 Allegations of serious scientific misconduct should be dealt with from the start by an external and independent inquiry. The inquiry should have statutory power to investigate and inquire. The inquiry should have sufficient scientific expertise to ensure credibility. To preserve public confidence, the inquiry should aim for the highest degree of transparency and accessibility of the final report. There is a need for uniform processes and procedures for dealing with and adjudicating on scientific research and fraud. There is a need to shift the emphasis from managing misconduct and fraud to preventing them.

Martin B Van Der Weyden MD, FRACP, FRCPA

Objective: To estimate the appropriateness of emergency department (ED) presentations by people aged ≥ 65 years living in residential care facilities.Design, setting and participants: Retrospective cohort study of older residents of residential care facilities who presented to the ED of the Royal Perth Hospital, Western Australia, between January and June 2002. Data were reviewed by an expert clinical panel.Main outcome measures: Appropriateness of ED presentation, presenting complaint, involvement of a general practitioner/locum doctor prior to transfer, proportion of patients admitted to hospital from the ED, survival to discharge.Results: 541 residents aged ≥ 65 years were transferred by ambulance to the ED, comprising 8.3% of all ED presentations of people in this age group. The mean age of the study cohort was 83.7 years (SD, 7.0 years), of which 68% were women. Of the 541 presentations, 326 (60%) resulted in hospital admission, and of these, 276 (85%) survived to hospital discharge. Musculoskeletal disorders accounted for 25% of all presentations, and 22% were falls-related; pneumonia (11% of presentations) was the single largest presenting complaint. ED attendance was deemed “inappropriate” for 71/541 cases (13.1%; 95% CI, 10.5%–16.2%); in only 25% of ED presentations was a GP/locum doctor involved prior to transfer.Conclusions: The majority of ED presentations by aged care residents were considered to be appropriate, but there was scope for improvement in coordinating care between the hospital ED and residential care institutions.

Judith C Finn PhD, RN, FRCNA · Leon Flicker MB BS, PhD, FRACP · Eileen Mackenzie RN, GDCritCare · Ian G Jacobs BAppSci, PhD, RN · Daniel M Fatovich MB BS, FACEM · Shelley Drummond RN · Michelle Harris RN · D'Arcy C D J Holman MB BS, MPH, PhD · Peter Sprivulis MB BS, FACEM, PhD

Objective: To survey prevocational doctors working in Australian hospitals on aspects of postgraduate learning.Participants and setting: 470 prevocational doctors in 36 health services in Australia, August 2003 to October 2004.Design: Cross-sectional cohort survey with a mix of ordinal multicategory questions and free text.Main outcome measures: Perceived preparedness for aspects of clinical practice; perceptions of the quantity and usefulness of current teaching and learning methods and desired future exposure to learning methods.Results: 64% (299/467) of responding doctors felt generally prepared for their job, 91% (425/469) felt prepared for dealing with patients, and 70% (325/467) for dealing with relatives. A minority felt prepared for medicolegal problems (23%, 106/468), clinical emergencies (31%, 146/469), choosing a career (40%, 188/468), or performing procedures (45%, 213/469). Adequate contact with registrars was reported by 90% (418/465) and adequate contact with consultants by 56% (257/466); 20% (94/467) reported exposure to clinical skills training and 11% (38/356) to high-fidelity simulation. Informal registrar contact was described as useful or very useful by 94% (433/463), and high-fidelity simulation by 83% (179/216). Most prevocational doctors would prefer more formal instruction from their registrars (84%, 383/456) and consultants (81%, 362/447); 84% (265/316) want increased exposure to high-fidelity simulation and 81% (283/350) to professional college tutorials.Conclusion: Our findings should assist planning and development of training programs for prevocational doctors in Australian hospitals.

Andrew W Dent FRCS, FACEM, MPH · Brendan Crotty MB BS, MD, FRACP · Helen L Cuddihy MD, CCFP, FRACGP · Glenn C Duns MDCM, CCFP-EM, FRACGP · Joan Benjamin MEd, BEd, GradDipUniversityTeachingLearning · Carol A Jordon BA, BEcon, MEd(MEPA) · Jacqueline F Satchell BSc(Hons) · Stephen Farish BSc(Hons), MEd · Tracey J Weiland BBSc(Hons), PhD · Brian C Jolly BSc(Hons), MA(Ed), PhD

Objective: To project the future size of the Australian medical workforce, from 2001 to 2012.Design and setting: Stochastic simulation modelling of the Australian medical workforce, taking into account recent increases in medical school capacity and trends in the intake of foreign graduates.Main outcome measures: Number of full-time equivalent (FTE) medical practitioners per 100 000 persons within various occupation groups from 2001 (baseline) to 2012.Results: The total medical workforce was projected to rise from 53 384 in 2001 to 67 659 by 2012 (95% CI, 63 924–71 036). On a per capita basis, the number of FTE clinicians was projected to rise from 331 per 100 000 persons in 2001 to 382 (95% CI, 359–403) per 100 000 persons in 2012. The general practice workforce was projected to fall from 133 FTE general practitioners per 100 000 persons in 2001, to 129 per 100 000 persons in 2003, and then remain at around this level through to 2012. The specialist workforce was projected to show steady growth, rising from 162 FTE specialists per 100 000 persons in 2001 to 206 (95% CI, 194–218) per 100 000 persons in 2012.Conclusions: The general practice workforce is likely to face continued chronic shortages, necessitating innovative policy responses to ensure that the community’s need for primary medical care is met. Retirement rates are a key determinant of workforce supply, suggesting a need to encourage general practitioners to remain active as long as they remain effective. Further refinement of stochastic models will help facilitate a more proactive approach to workforce planning.

Catherine M Joyce BA(Hons), MPsych, PhD · John J McNeil PhD, FRACP, FAFPHM · Johannes U Stoelwinder MD, FRACMA, FACHSE

Objective: To examine the conditions leading to sideswipe injury of the upper limb in motor vehicle accidents and to highlight the severity of these injuries.Design and setting: Prospective study of upper-limb sideswipe injuries in patients admitted to Royal Perth Hospital, Western Australia, between August 2003 and January 2005.Participants: Eleven patients sustaining sideswipe injuries to the upper limb.Main outcome measures: Accident pattern, type of injury, surgical management, complications, and functional and employment implications.Results: Ten patients required open reduction and internal fixation for open fractures of the humerus, ulna and radius, and nine underwent additional surgical procedures including nerve, artery and tendon repair, and free flaps and split-skin grafting. The injury severity scores ranged from 9 to 25. The severity of injuries led to extensive functional deficits in eight patients, affecting employment prospects in seven.Conclusion: Appropriate educational programs, legislation and improvements in traffic conditions, especially in rural areas, as well as changes in current car design, could contribute to preventing these devastating and complex injuries.

Vera Kinzel PhD, MD, AFRCS · Allan P Skirving MB BS, FRCS · Michael N Wren MB BS, FRACS · Rene Zellweger MD, PhD

Objectives: To identify expressions used by patients to describe worsening asthma; to examine the relevance of the word “exacerbation” to patients’ experience; and to investigate whether their language is influenced by the severity of the episode and/or the target audience such as family members, friends and work colleagues.Design and setting: Qualitative study carried out from 1 January to 30 December 2004 among community volunteers to a research institute. Semistructured face-to-face interviews were used to elicit descriptions of episodes of worsening asthma, and further questioning was used to examine language used with family, employer and doctor.Participants: 25 people with asthma, aged 22–75 years.Main outcome measure: Themes identified by open coding about patient language for worsening asthma.Results: 12 participants were not familiar with “exacerbation” and only three would use it themselves. “Attack” was the only specific term spontaneously volunteered (20 participants), but it was used for anything from mild to life-threatening episodes. Patients often downplayed the severity of worsening asthma to their families. Different language was used with employers, sometimes to justify sick leave and sometimes because of fear of perceived discrimination. When communicating with clinicians about worsening asthma, patients used symptom descriptors rather than specific terms.Conclusion: There are important differences in the language patients and clinicians use to describe worsening asthma, and the word “exacerbation” has poor utility for communication with patients.

Stephen D Vincent MB BS, FRACP · Brett G Toelle DipAppSc(Nursing), BA(Psychology), PhD · Rosalie A Aroni PhD · Christine R Jenkins MB BS, FRACP, MD · Helen K Reddel MB BS, FRACP, PhD

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in Australia and other Western countries. As there is no cure for AMD, and treatments to stop its progression have met with limited success, there is an interest in identifying modifiable risk factors to prevent or slow disease progression. To date, smoking is the only proven modifiable risk factor for AMD. Other factors under study include (i) cardiovascular risk factors such as hypertension, body mass index, and atherosclerosis; and (ii) dietary risk factors including fat and antioxidant intake, but so far these studies have produced conflicting results. Dietary fat in relation to AMD has recently attracted media attention. Despite very limited work supporting an association between vegetable fat and AMD, widespread publicity advocating margarine as a cause of AMD and encouraging use of butter instead has caused confusion and anxiety among sufferers of AMD and the general public, as well as concern among health professionals. The antioxidant carotenoids — lutein and zeaxanthin — found in dark green or yellow vegetables exist in high concentrations in the macula and are hypothesised to play a protective role. Of nine controlled trials of supplementation with carotenoids and other antioxidants, three suggested that various combinations of antioxidants and carotenoids were protective. While a low-fat diet rich in dark green and yellow vegetables is advocated in general, any specific recommendations regarding certain fats or antioxidant supplementation and AMD are not based on consistent findings at this stage.

Robyn H Guymer RANZCO, PhD, MB BS · Elaine Wei-Tinn Chong MB BS

Accurate diagnosis of bipolar disorder is essential for effective treatment. The diagnosis of bipolar disorder is particularly complex, resulting in lengthy delays between first presentation and initiation of appropriate therapy. Inappropriate therapy destabilises the course and outcome of the disease. Although the defining features of bipolar disorder are manic or hypomanic episodes, patients typically present for treatment of depression and commonly deny symptoms of mood elevation. A correct diagnosis can easily be masked by comorbidities, personality issues and complex phenomenology. A diagnosis of bipolar disorder can be assisted by: asking about symptoms of mania or hypomania in every patient presenting with symptoms of depression. recognising mixed states in which manic and depressive symptoms occur simultaneously. identifying the features of bipolar depression that distinguish it from unipolar depression. There is a risk of over-diagnosis of bipolar disorder among patients who are histrionic, show abnormal illness behaviour and/or have issues of secondary gain.

Michael Berk MB BCh, FRANZCP, PhD · Lesley Berk MA · Kirsteen Moss BSc(Hons) · Seetal Dodd PhD · Gin S Malhi MB ChB

As the Australian university sector awaits final decisions about the introduction and stipulations of a research quality framework (RQF), to assess the quality and impact of research, we have studied international commentary on the value of such exercises. This suggests there is little hard evidence to recommend the proposed RQF. The UK government led the field in 1986 with its research assessment exercise (RAE), which is widely believed to have compromised clinical academic medicine by failing to satisfactorily acknowledge the contribution of clinical academics, not only to research but also to teaching and clinical practice. After the 2008 RAE, the UK government will move to a simpler, metrics-based system for assessing research quality and allocating funding. The New Zealand Performance Based Review Fund (PBRF), introduced in 2003, is based on a combination of peer review and performance indicators. Several concerns have been raised; among them is the real cost–benefit ratio of participation, with reports that many universities have spent more on the exercise than they will gain in funding increases. The scoring system has received the most criticism and, after the partial round assessment scheduled for this year, the controversial unit of assessment will be reviewed. It might be more cost-effective for Australia to modify existing research assessment processes than to undertake a potentially costly and arduous exercise.

Louise G Shewan BA(Hons), PhD · Andrew J S Coats DM, DSc, FRACP

Clinical records Patient 1 A 41-year-old man presented with a 3-week history of watery diarrhoea (four to five bowel motions per day) and central abdominal pain. Two days prior, he had passed blood per rectum, for which his general practitioner had prescribed oral metronidazole without any effect. He had no nausea, vomiting, fevers or sweats. Abdominal examination was unremarkable, and he was afebrile. Blood tests showed 20% eosinophilia (1.6 × 109/L; normal range, 0–0.5 × 109/L), but were otherwise unremarkable. The result of two faecal examinations showed watery stool with occasional leukocytes, but no erythrocytes. Enzyme-linked immunosorbent assay (ELISA) for Clostridium difficile toxins A/B and immunoassay for Cryptosporidium and Giardia were negative. In accordance with local laboratory protocol, microscopy to determine faecal concentration of eggs, cysts and parasite was not performed, as there was no history of overseas travel. Colonoscopy revealed mild terminal ileitis. Biopsies of the affected area showed an eosinophilic infiltrate in the lamina propria and submucosa, but intact surface epithelium. Occasional adult worms measuring about 70 μm wide at the midbody were seen on the luminal surface (Box 1A and B), and were initially identified as Enterobius vermicularis. He was treated with two 100 mg doses of mebendazole 1 week apart. However, he re-presented 3 weeks later with no improvement in his symptoms and a persistent eosinophilia (1.4 × 109/L). On this occasion, faecal concentration was performed using formalin-ethyl acetate, and parasite eggs were detected on iodine wet mount (Box 1C). These were initially misidentified as hookworm eggs, but subsequent review confirmed that they were eggs of Trichostrongylus sp. The parasites seen on terminal ileal biopsy were also reviewed. Their morphology and dimensions (70 μm-wide body) were found to be consistent with adult Trichostrongylus.1 Further questioning revealed that the patient kept goats in a shed in his backyard in suburban Sydney. The goat manure was used as fertiliser on a nearby vegetable patch which supplied food for the household. The patient was treated with a single 13.5 mg dose of ivermectin, and his symptoms resolved. He remained symptom-free 3 months later. Patient 2 A 42-year-old vegetarian man presented with a 5-week history of severe cramping upper abdominal pain, nausea and diarrhoea. He had no fever, cough, wheeze, rash or weight loss. He had holidayed in Morocco and Spain 6 months previously. Examination showed epigastric tenderness. His blood tests showed eosinophilia of 11.0 × 109/L, peaking 11 days later at 27.7 × 109/L; his blood film was otherwise normal. There were no abnormalities on plain x-rays or computed tomography scans of the chest and abdomen. A bone marrow biopsy showed a marked eosinophilia (40%–60%), but was normocellular with a normal karyotype on cytogenetic analysis. Endoscopy showed small duodenal erosions. Biopsies of the duodenum, ileum and colon showed an inflammatory cell infiltrate, including plentiful eosinophils (Box 2). Repeated stool specimens yielded only Blastocystis hominis cysts, not considered relevant to the clinical setting. A terminal urine specimen revealed no schistosome eggs, and serological tests for Strongyloides, Fasciola and Schistosoma were negative. He was treated empirically with albendazole (400 mg orally for 3 days), with minor diminution in the frequency of abdominal cramps and diarrhoea, and later with metronidazole (400 mg orally three times daily for 1 week), without response. The patient revealed that 4 weeks before symptom onset, he had taken care of a pet goat at his house, and had used fresh goat manure as fertiliser for his lettuce and other vegetable seedlings. He ate the garden produce raw and unwashed. A sample of the goat faeces was obtained from the garden for examination (fresh samples were unavailable). Baerman isolation and iodine fixation of the goat stool showed larvae of various stages, including rhabditiform larvae (probably from soil contamination) and ensheathed larvae (presumed to have hatched from eggs which would have been present in a fresh specimen). A Trichostrongylus colubriformis larva is shown in Box 3. Since exhaustive investigation had failed to yield an alternative diagnosis, trichostrongylosis was diagnosed on the basis of this strong circumstantial evidence. The patient was subsequently treated with 15 mg of ivermectin as a single dose 24 days after his hospital admission. Within 2 days, his condition had improved dramatically, and his eosinophil count fell from 18 × 109/L to 3 × 109/L. He remained well thereafter. Trichostrongylus species are zoonotic nematode parasites, ubiquitous among herbivorous mammals worldwide. Human infection is most common in herders of sheep and goats, but may potentially be acquired from contact with faeces of other infected host animals such as cattle, camels and donkeys.2 Isolated cases or small series in humans have long been recognised in Australia: 60 cases were reported from Queensland by the Hookworm Campaign between 1923 and 1928, and more recently, five cases were detected out of 46 000 stool examinations at a Queensland laboratory between 1992 and 1995.3-7 Human prevalence data are difficult to acquire because misclassification is common, and symptoms may be mild or non-existent. Trichostrongylus eggs are most commonly mistaken for hookworm eggs, which have a similar shape, although the former are larger (73–94 × 40–53 μm), and slightly pointed at one or both ends (Box 3).2 Misidentification occurred twice in Patient 1; eggs were initially identified as those of hookworm, and adult worms seen on endoscopic biopsy as Enterobius vermicularis. Diagnostic difficulties also arise because of the long prepatent period. Even after the period of maturation from larval stage to egg-laying adults, passage of eggs may still be scanty or undetectable for some time (with reported delays of 4 months to 2 years between symptom onset and detection of eggs2,5). This probably explains the absence of detectable eggs in the stool specimens of Patient 2. When a documented travel history is not provided, stool immunoassays for Giardia and/or Cryptosporidium are now being used in many laboratories instead of the more labour-intensive traditional microscopic examination for parasites. This approach will miss a number of locally-acquired parasitic infections such as hookworm, Trichuris trichiura, Strongyloides stercoralis, Isospora belli, Fasciola hepatica and Brachylaima cribbi as well as Trichostrongylus sp. Practitioners should familiarise themselves with the methods used by their local laboratory for stool parasite examination, and request that faecal concentration and microscopy for parasites be performed, not only after travel, but also if there is a history of close contact with herbivores, or consumption of unwashed home-grown vegetables fertilised with herbivore droppings. Trichostrongylus infection can also be laboratory-acquired,3 in some cases through mouth-pipetting techniques (N C S, unpublished data). Lessons from practice Trichostrongylosis may be an under-recognised cause of eosinophilia and/or gastrointestinal symptoms in Australia. Stool microscopy for parasite eggs is the only means of diagnosing trichostrongylosis, but is no longer routinely performed by many laboratories. The eggs of Trichostrongylus sp. and hookworm are very similar and can easily be confused, even by experienced laboratory staff. People fertilising their vegetable gardens with manure from herbivores, especially goats, should be advised to thoroughly wash or cook their garden produce before consumption; efficient composting is also effective in killing larvae. The drug of choice is ivermectin, because of high rates of resistance to benzimidazoles. Adult Trichostrongylus parasites residing in the gut of an infected host produce eggs which hatch in faeces to produce larvae. Such larvae (Box 3) are difficult to distinguish from those of another parasitic genus infecting goats, Ostertagia (an organism which is non-pathogenic to humans), and may be difficult for anyone other than a trained parasitologist to distinguish from larval forms of hookworm or Strongyloides. Identification of these parasite species is usually based on features of the adult worm. The larvae pass through two free-living stages to become infective third-stage larvae. These larvae are motile and migrate to vegetation and are ingested when the vegetation is eaten. The third-stage larvae then exsheath and move to the duodenal mucosa, mature into adult worms over about 25 days, and live among the intestinal villi and mucus. Patients may be asymptomatic, with eosinophilia only noted incidentally. When symptoms are present, they are confined to the gastrointestinal tract, as there is no migratory phase. A high worm burden can lead to marked eosinophilia, desquamation of gut mucosa, and severe symptoms including epigastric pain and diarrhoea.2 The per rectum bleeding noted in Patient 1 is likely to have been a direct result of mucosal inflammation and trauma caused by adult worms attaching to intestinal epithelium. Our patients’ cases illustrate the value of a collaborative approach between medical and veterinary practitioners. Medical and veterinary parasitologists were able to facilitate diagnosis and recommend appropriate treatment (ivermectin 200 μg/kg given as a single dose), based on knowledge of resistance patterns of Trichostrongylus sp. in herbivores. Resistance to benzimidazoles is now common because of the widespread use of this anthelmintic class in grazing animals.8 The treatment failure with mebendazole in Patient 1, and initial partial response to albendazole in Patient 2, followed by complete response to ivermectin, is consistent with the efficacy of these anthelmintic agents against Trichostrongylus sp. in sheep and goat populations in Australia. Resistance to pyrantel would also be anticipated, and resistance to ivermectin is emerging.9 Human trichostrongylosis is a locally acquirable cause of eosinophilia, gastrointestinal symptoms, or both, which should be suspected and appropriately investigated in patients with a history of contact with herbivorous animals. 1 Samples from Patient 1 A: Biopsy of terminal ileum showing eosinophilic infiltrate in the lamina propria and submucosa, with a parasite on the luminal surface. B: Enlargement of parasite. C: Iodine wet mount of faecal specimen showing a Trichostrongylus egg. 2 Sample from Patient 2 Duodenal biopsy showing a profuse eosinophilic infiltrate. 3 Trichostrongylus colubriformis larva Trichostrongylus colubriformis third-stage larva obtained after culture of faeces from an artificially infected sheep.

Anna Ralph MB BS, FRACP · Matthew V N O'Sullivan MB BS, DTM · Nicholas C Sangster BSc(Vet), BVSc, PhD · John C Walker BSc, MSc, PhD

Charles Marshall died peacefully in his sleep at his home in Seattle on 12 November 2005, at the age of 93. He was born on 13 July 1912 in Cowell, South Australia, but his early years were spent with his parents in Scotland and England. In 1929, he returned to Australia and settled in Sydney, where he worked in a pharmacy for 2 years. This led to an interest in medicine, which he studied at the University of Sydney from 1934 to 1940. During World War II, from 1940 to 1946, he served with the Royal Australian Army Medical Corps in various locations in the Middle East and Australia. After 2 years at the Kanematsu Memorial Institute of Pathology, Charlie began his career as a pathologist at Sydney Hospital. Between 1950 and 1952, he did a postgraduate course in pathology at London University. He then returned to Sydney Hospital, where he spent several years working in bacteriology and anatomical pathology, and also worked as a Teaching Fellow at the University of Sydney from 1953 to 1955. Charlie was Associate Professor of Pathology at Dalhousie University in Halifax, Canada, from 1955 to 1957, then took up a position as Pathologist (the first ever appointed) at Group Health Cooperative of Puget Sound in Seattle, Washington, where he worked for the next 20 years. He also served as Assistant Professor of Pathology at the University of Washington during that time. He was a Fellow of the Royal College of Pathologists of Australasia and the College of American Pathologists, and a founding member and Fellow of the Royal College of Pathologists of England. Charlie’s published work included an essay on infectious hepatitis for which he was awarded a British Medical Association prize.1 Friends and colleagues will remember Charlie as an avid painter and musician, a kind and compassionate person, as well as a great friend to many whose lives he touched. He was a true gentleman at all times, with a wonderfully dry sense of humour. We will miss him greatly. Charlie was married to his wife Thelma from 1941 until her death in 1978. He is survived by his daughter Carol, granddaughter Diana and three great-grandsons, all of Orange County, California.

Carol MacDonald

To the Editor: On 1 November 2005, the Australian states and territories introduced quadrivalent, pentavalent or hexavalent vaccines for childhood immunisations. This simplifies vaccination for young children, but may impair the ability of health services to provide primary immunisation for refugees over the age of 8 years. The Australian refugee and humanitarian program targets refugees from many countries that have poor primary health infrastructure. In the 2004–05 financial year intake, at least 75% of the 12 096 entrants under the offshore resettlement program came from countries that had immunisation coverage rates below 50% in the 1990s.1,2 Adolescents and adults from these countries generally have patchy vaccination histories and no records. According to Australian guidelines, they warrant full catch-up vaccination, often involving a primary vaccination course.3 Primary vaccination against tetanus, diphtheria and pertussis requires three doses of vaccine. The dose of diphtheria toxoid in vaccines for children or adults over 8 years of age is significantly lower than in early childhood preparations because of potential adverse effects. In 2004, the conjugated pertussis–adult diphtheria–tetanus vaccine for adolescents (Boostrix, GlaxoSmithKline) was introduced to the immunisation schedule to provide boosters against pertussis, diphtheria and tetanus. However, Boostrix has no proven efficacy for primary vaccination against pertussis and is not recommended for adolescents and adults who have no primary cover against pertussis.3,4 As monovalent pertussis vaccine is not available, refugees over the age of 8 years cannot be provided with a primary vaccination course against pertussis. Adult diphtheria–tetanus vaccination (ADT) is the most-used primary vaccine for refugees over the age of 8 years. After the introduction of Boostrix, many state and territory health departments reduced their supply of ADT to immunisation providers. Some refugee health services have attempted to meet demand for ADT by collating individual doctors’ stocks provided under the Emergency Drug (Doctors Bag) supplies section of the federally-funded Pharmaceutical Benefits Scheme, which provides for up to 15 doses of ADT per month. But this is a cumbersome and unsustainable strategy. Some jurisdictions, such as the Australian Capital Territory, supply ADT directly to refugee health service providers. All the new polyvalent childhood vaccines include inactivated polio vaccine. Unless states and territories procure monovalent polio vaccine, primary vaccination against polio for people over 8 years will remain inadequate. People from refugee backgrounds warrant the same level of protection against vaccine-preventable diseases as other Australians. The level of protection may be reduced by failure to provide suitable vaccines. We encourage state and territory health departments to stock sufficient vaccines for adult and adolescent refugees, including ADT and monovalent inactivated polio vaccine. We also recommend that the Australian Technical Advisory Group on Immunisation provide detailed advice on the needs of refugees when crafting immunisation guidelines.

Christine B Phillips MPH, MA, FRACGP · Mahomed Patel FRACCP, FFAPHM

To the Editor: Leprosy rates in Australia are low (less than one case per million population)1 and predominantly occur in Indigenous Australians and immigrants from leprosy-endemic areas.2 A 21-year-old pregnant Burundian woman had migrated to Australia in 2005 from a refugee camp in Tanzania. In the year before her arrival, she had received intermittent courses of steroids for an undefined illness characterised by fever, nightsweats and painful symmetrical peripheral polyarthritis. Three months after arriving in Australia, the patient presented to a rural hospital with a recurrence of the previous symptoms. The symptoms improved on recommencement of prednisolone treatment. The patient was transferred to the Royal North Shore Hospital, where examination revealed bilateral peripheral sensory neuropathy (confirmed by nerve conduction studies); bilateral, enlarged, tender ulnar nerves; and tender hyperpigmented 2–3 cm nodules on the upper arms, but no other skin lesions or infiltrations. Skin biopsy revealed features consistent with erythema nodosum leprosum (ENL), but no acid-fast bacilli (AFB) were detected. Slit-skin smears were also negative for AFB. Leprosy was confirmed by histopathological examination of a sural nerve biopsy, which showed AFB and granulomatous changes of leprosy. The patient commenced multidrug therapy for multibacillary leprosy, with prednisolone for ENL. Leprosy is a chronic granulomatous infection of skin and peripheral nerves with Mycobacterium leprae. Host immune responses determine the spectrum of clinical presentations. Leprosy is classified into either multibacillary disease (≥ 6 skin lesions and/or skin smears positive for AFB) or paucibacillary disease (< 6 skin lesions, with no bacilli on skin smears).3 Type 1 (reversal) reactions are delayed-type hypersensitivity reactions and manifest as neuritis and increased inflammation of pre-existing skin lesions. Type 2 reactions (ENL) are a systemic response to immune complex deposition and manifest with multiple tender nodules, fevers, neuritis, arthritis and iritis.4,5 ENL occurs exclusively in multibacillary disease in 10%–20% of patients, and negative slit-skin smears (as in our patient) are unusual. Possible explanations include undisclosed diagnosis and treatment of leprosy in Tanzania or the combination of steroid therapy and immune changes that occur during pregnancy.6 Multidrug therapy is well established and regarded as safe for pregnant women. Diagnosis of infections that are uncommon in Western countries, especially leprosy, is often delayed.7 For refugees living in remote areas, access to expertise and support may be limited. Therefore, doctors, especially those involved in refugee health, should be aware of “exotic” infections and their varied presentations. Furthermore, effective referral networks should be encouraged, as this resulted in a swift positive outcome in our case.

Sebastiaan J van Hal MB ChB · Bernard J Hudson FRACP, FRCPA

To the Editor: Australia and the other member nations of the World Health Organization’s Western Pacific Region were declared free of circulating endemic poliovirus in 2000, although the last case of endemic polio in Australia occurred in the 1970s.1 Nevertheless, the low risk of vaccine-associated paralytic poliomyelitis (VAPP) persisted through the continued use of the Sabin live attenuated oral polio vaccine (OPV) until it was replaced by the Salk inactivated polio vaccine in the National Immunisation Program from 1 November 2005.2 Despite the eradication of indigenous wild poliovirus and the removal of the risk of VAPP, Australia cannot afford to be complacent with surveillance for cases of poliomyelitis. Polio is a highly infectious disease and is quickly spread through international travel. All countries risk importation of wild poliovirus from the four remaining endemic countries (Afghanistan, India, Nigeria and Pakistan) — as occurred in Indonesia and 11 other countries during 2005.3 Until the latest outbreak, involving over 300 cases, Indonesia had not reported a single case of poliomyelitis since 1995. Genetic sequencing of the wild polioviruses from Indonesia determined that they originated in Nigeria and were related to strains isolated in Sudan, Saudi Arabia and Yemen. Australia is also at risk from imported vaccine-related strains of poliovirus, as indicated by two reports from the United States in 2005. The first was a case of imported VAPP in an unimmunised adult, who had been in close contact with an infant recently immunised with OPV, while in Costa Rica.4 The second report described isolation of OPV poliovirus type 1 with a significant number of mutations (referred to as vaccine-derived poliovirus [VDPV]) from unvaccinated members of a religious community.5 Given that OPV has not been used in the USA since 2000, the source of the virus is unknown. VDPVs have been associated with paralytic polio worldwide. It is imperative that the Australian community maintains the current high rate of polio vaccination coverage, especially for travellers, which remains the best defence against all forms of imported polio. A surveillance scheme for investigation of children with acute flaccid paralysis, the major clinical presentation of poliomyelitis, was established in Australia in 1995. It is coordinated by the National Poliovirus Reference Laboratory and the Australian Paediatric Surveillance Unit (Box). While the scheme focuses on children, specimens from patients of all ages are tested. Notification of all cases with a clinical suspicion of poliomyelitis is essential for the detection of imported polio. Surveillance for acute flaccid paralysis (AFP) within Australia Paediatricians notify cases of AFP via a monthly report card to the Australian Paediatric Surveillance Unit and submit a clinical questionnaire to the National Poliovirus Reference Laboratory (NPRL). Stool specimens from AFP cases are tested at the NPRL for isolation of poliovirus. The Australian Polio Expert Committee reviews the clinical and laboratory data to determine whether the case is compatible with poliomyelitis. The Committee reports to the Australian Government Department of Health and Ageing and the World Health Organization. Protocol for investigation of suspected polio cases Clinicians should phone the NPRL to notify the case and arrange for two stool specimens to be collected 24 hours apart (due to intermittent virus shedding) and within 14 days of onset of symptoms, for testing at the NPRL. Polio antibody testing requires acute and convalescent serum, and is only performed when there is a clinical suspicion of poliomyelitis. Contacts National Poliovirus Reference Laboratory, Victorian Infectious Diseases Reference Laboratory Phone: (03) 9342 2607; fax: (03) 9342 2665; email: polioATmh.org.au; website: http://www.vidrl.org.au/labsandunits/polio/polio_activity.htm Australian Paediatric Surveillance Unit, Children’s Hospital at Westmead Phone: (02) 9845 3005/ 9845 2200; fax: (02) 9845 3082; email: apsuATchw.edu.au; website: http://www.apsu.org.au

Bruce Thorley PhD · Kerri Anne Brussen BAppSc · Elizabeth J Elliott MD, FRACP, FRCPCH · Heath A Kelly MB BS, MPH, FAFPHM

To the Editor: Rickettsia typhi is an endemic cause of atypical pyrexial illness worldwide.1 Its non-specific presentation can lead to misdiagnoses, with overseas reports of unwarranted laparotomies in affected patients.2,3 We describe a patient with R. typhi infection presenting as cholecystitis, in whom a cholecystectomy was avoided by vigilance for R. typhi. A 51-year-old businessman presented to a general practitioner with a 5-day history of fever, sore throat, headaches and myalgia. The illness had begun a week after his return to Sydney from a business trip to major cities in Asia, his last stop being Hong Kong. Investigations revealed mild lymphopenia and thrombocytopenia, negative results on screening for malaria, and normal results on chest x-ray. A non-specific viral illness was provisionally diagnosed. A week later, the patient presented again to a GP with fever, abdominal pain, cough, dehydration and confusion. Investigations revealed lymphopenia (0.7 × 109/L; reference range [RR], 1.5–4 × 109/L], thrombocytopenia (93 × 109/L; RR, 150–400 × 109/L), and raised serum levels of bilirubin (25 μmol/L; RR, 0–17 μmol/L) and hepatic enzymes (alanine aminotransferase, 307 U/L [RR, 5–40 U/L]; alkaline phosphatase, 381 U/L [RR, 30–115 U/L]; aspartate aminotransferase, 389 U/L [RR, 5–40 U/L]; and γ-glutamyl transferase, 364 U/L [RR, < 66 U/L]. Serological tests were negative for hepatitis viruses A, B and C, and dengue and Epstein–Barr viruses. The patient was referred to an emergency department. On presentation to the hospital, the patient was febrile, with severe right upper quadrant abdominal tenderness, and a slight truncal macular rash. Abdominal computed tomography and ultrasound examination indicated cholecystitis (Box). Acute cholecystitis was diagnosed, and treatment begun with intravenous fluids, ampicillin, gentamicin and metronidazole. Following clinical improvement, the patient was discharged on Day 8 with plans for an elective cholecystectomy. In view of the atypical symptom complex, serological testing for leptospirosis, syphilis, and rickettsial, amoebic and HIV infection had been requested during his admission. Results received after discharge indicated a R. typhi antibody titre of 1:1024 (RR, < 1:128). Results of the remaining serological tests were negative. The patient was contacted, and the cholecystectomy cancelled. He has remained well. Murine typhus is a zoonosis caused by R. typhi, and is acquired from rodent flea faeces, either by bite inoculation or inhalation. Hepatobiliary involvement occurs in up to 34% of cases. Histopathology specimens show neutrophilic sinusoidal infiltrates and cloudy swelling of hepatocytes,2 but hepatocyte injury and cholestasis are transient, resolving over 1–3 weeks. Diagnosis is by serological testing: a single indirect immunofluorescent antibody (IFA) titre against R. typhi of at least 1:400; or a fourfold rise in IFA titre from the acute to the convalescent phase (2 weeks apart). The treatment of choice is doxycycline. Although the clinical course is usually benign, the mortality rate can reach 4%.1 Rickettsial diseases remain an under-reported cause of febrile illness.4 As R. typhi has now been described throughout Australasia,1,5 it is important that murine typhus is excluded in patients with atypical pyrexial illnesses and abnormal liver function results. Computed tomography and ultrasound examination in a patient with murine typhus Computed tomography on admission showed pericholecystic inflammation, suggesting acute cholecystitis, and a possible gallstone at the lower pole (arrow), which was later noted to be a fibrous septum on ultrasound examination. Ultrasound examination also showed a thickened gall bladder wall and pericholecystic fluid.

Vidyut P Suttor MB BS, BSc(Med) · Robert B Feller MB BS, PhD, FRACP

To the Editor: Routine school vision screening has been discontinued in many regions.1 Since 2000, children around Newcastle and Lake Macquarie in New South Wales only have their vision checked at school if their parents request it. I am particularly concerned that this may disadvantage young children with diabetes, who may also have undetected amblyopia. These children are already at risk of diabetes-related vision impairment, and simple screening could prevent further disability related to amblyopia. Amblyopia, commonly known as “lazy eye”, is an asymptomatic, potentially treatable condition of poor vision in a “normal” eye. It is caused by the brain suppressing an unclear image from the affected eye. Amblyopia occurs in 2.5%–3.2% of the population.2 The condition needs to be detected early, and treatment needs to be instituted before the end of practical vision development at about 7–8 years of age, otherwise even intensive treatment is unlikely to restore normal vision.3 This is especially important because people with untreated amblyopia have an increased lifetime risk of loss or impairment of vision in their good eye,4 as well as the poor vision in their amblyopic eye. The current Australian screening guidelines for children with diabetes recommend screening for retinopathy after 5 years of diabetes in those who are prepubertal, and annually in adolescents after 2 years of diabetes.5 The International Society for Pediatric and Adolescent Diabetes recommends retinopathy screening in children with diabetes of prepubertal onset at 5 years after the onset of diabetes, or 11 years of age, or at puberty, whichever is earlier.6 Neither document specifies other visual screening (although the National Health and Medical Research Council guidelines do recommend a clinical examination of the eyes for cataract soon after diagnosis). Thus, a 6-year-old child with diabetes would not have his or her vision screened until 11 years of age. An eye with significant amblyopia detected at this age will not achieve normal vision, and the child would be reliant on only one eye for his or her lifetime. Even a 3-year-old child with diabetes would not have visual screening until 8 years of age, the end of practical vision development. The case has been made recently for biennial retinopathy screening for children with diabetes.7 I propose that diabetic children under 9 years of age have their vision fully assessed soon after the diagnosis of diabetes. Should amblyopia be detected then, treatment could commence before the end of active vision development.

Catherine Dunlop

To the Editor: I agree with Jones1 that the body surface area (BSA) formula printed in the position statement on reporting of estimated glomerular filtration rate (eGFR)2 is wrong, even though the authors say that he is mistaken.3 As stated by Jones, the correct formula4 for BSA in m2, for a body weight W kg and height H cm is: (i) BSA = W0.425 × H0.725 × 0.007184. However, the position statement2 gave the following formulas: (ii) BSA = W0.425 × H0.725 × 0.007184/1.73; and (iii) Uncorrected eGFR = GFR estimate (mL/min/1.73m2) × BSA. It appears that the denominator “1.73” has migrated from formula (iii) to formula (ii), so in fact both of these formulas are incorrect. This is potentially misleading for doctors and others who may want to calculate the eGFR for someone who is unusually big or small. Formula (iii) should in fact be: (iii) Uncorrected eGFR = GFR estimate (mL/min/1.73m2) × BSA/1.73. It is interesting that the same two errors in BSA calculations are present on the US National Kidney Disease Education Program website,5 which was presumably the source of the formulas used by the Australian Creatinine Consensus Working Group.

Alan McNeil PhD, FRACP, FRCPA

In reply: McNeil draws attention to the detail in the correction factor we published in an attempt to assist users to “uncorrect” the eGFR derived from the MDRD (Modification of Diet in Renal Disease) equation used in calculating GFR from a serum creatinine concentration. Recalculating the eGFR to remove the adjustment for body surface area (BSA) in an individual is unnecessary except at extremes of body size.1 Readers can be reassured that the formulas published in the position statement,2 if used as directed, will not lead to any error. However, it would have been clearer if we had labelled the “BSA” equation as “correction factor” instead of “BSA”. In the position statement2 it can be misinterpreted that the BSA formula has a denominator, whereas, when used primarily to calculate BSA, it of course does not. Both versions of the formulas (ours in the position statement and McNeil’s) therefore lead to identical answers. The reader can choose which one to use.

Timothy H Mathew MB BS, MRACP, FRACP · Graham Jones MB BS, DPhil, FRCPA · David Johnson MB BS, FRACP, PhD

To the Editor: This question was recently posed by Massie and colleagues in an editorial in the Journal.1 We have experience in providing cystic fibrosis (CF) carrier testing in pregnancy and in those planning pregnancy. In 1998, we ran a 12-month pilot program, the Double Testing Program, offering ΔF508 carrier testing to couples attending the John Hunter Hospital, Newcastle, NSW, for nuchal translucency screening. Of 491 participants, 84% chose CF carrier testing; 23 carrier–non-carrier couples were identified, and no carrier–carrier couples. A postnatal questionnaire compared knowledge of CF, anxiety levels and perceptions of the service between non-carrier couples and couples in which one partner was a carrier.2 Both groups were very satisfied with the service, with no increased levels of anxiety. The second initiative has been to offer CF carrier testing to clients attending the “drop-in” clinic at Hunter Genetics, Newcastle. This clinic has been available for 10 years and provides genetic counselling for clients referred by their general practitioners for pre-pregnancy or pregnancy counselling. Over the past 3 years, there have been 560 occasions of service with CF carrier testing in 499 individuals. Indications for testing include pregnancy screening or a family history of CF. With couples, both are tested for ΔF508, and, if one partner is identified as a carrier, the other partner is tested for 28 other mutations. The area health service, Hunter New England Health, meets the cost of the service and testing — $100 per couple for the ΔF508 test, and $250 for the full mutation screen. Of the 499 individuals, 65 (13%) were found to be CF carriers; after excluding those with a family history of CF, the carrier rate was 5.8%. Twenty carrier–non-carrier couples and one carrier–carrier couple with a family history of CF were identified. Benefits included enabling the carrier–carrier couple to know their 1 in 4 risk of having a child with CF. Most women who have a child with CF want to avoid having further affected children, and most who have a subsequent pregnancy choose prenatal diagnosis.3 Cascade testing can be offered to carrier families. Non-carrier couples can be reassured that they have a low risk. The uptake of CF couple screening is low, given that there are over 3500 births annually at the John Hunter Hospital. The main obstacles are lack of awareness and costs. CF tests are not covered by public health funding or by private health insurance, and this issue needs urgent attention. We believe that GPs are best placed to offer CF couple testing. Testing could be incorporated into routine first trimester pregnancy care. We can provide a distance CF learning package, pamphlets and informed consent material to those interested.

Louise M Christie · Elvira M Zilliacus · Angela J Ingrey · Gillian Turner

To the Editor: We were interested to note that the evolution of morning handover at Launceston General Hospital, as described by Fassett and Bollipo,1 closely parallels our own experience at the Canberra Hospital, and we endorse their points about running a successful meeting. Our hospital has a large Geriatric Unit and all subspecialties are covered, but we do not have a general medicine unit. In 2002, we began a formal morning handover meeting from 08:00 to 08:30 for junior medical officers (JMOs) in the Department of Medicine, with the initial intention of providing an opportunity for Royal Australasian College of Physicians (RACP) basic trainees to present cases they had seen overnight. Scrutiny of the individual’s clinical approach by consultants, in preparation for the RACP examination, was the main emphasis, and “interesting” cases were chosen. The meeting was also used for case presentations by specialty units. Attendance was variable, and many junior staff reported feeling somewhat threatened by having their patient management approach examined in a public forum. Handover of most newly admitted patients did not occur during this meeting. The format was incrementally modified over the following 3 years so that, by 2005, the meeting had become a formal handover of all patients admitted during the previous evening and overnight. Attendance is now compulsory (except for staff attending medical emergencies), and breakfast of brewed coffee and tea with fruit and muffins is provided (funded by the Canberra Hospital). We have over 40 daily attendees (comprising registrars, residents, interns, medical students and 5–10 consultants). We have minimised the number of specialty presentations: these now usually take the form of “red flag” sessions, in which a specialist unit highlights areas of common and/or life-threatening importance (eg, a patient with unstable angina needs admission, regardless of their troponin level; recurrent rigors in a middle-aged person usually signal a bacterial infection). A survey of 57 of the attendees this year revealed that over 90% thought the format and duration of meetings and attendance by consultants was appropriate; 54% and 39%, respectively, said they learned new information every day or every week. Over the past 4 years, the handover has become embedded in the clinical culture of the hospital. The long-term commitment of a small group of consultants has demonstrated that this is a safe and encouraging environment for clinical teaching, and the level of discomfort of the JMOs appears to have receded. The morning handover has been an important means of ensuring that young doctors are exposed to a broad perspective on patient care and that their after-hours patient care can be supervised.

Francis J Bowden MB BS, FRACP, MD · Christian Lueck FRCP, FRACP, PhD · Mark Hurwitz MB BCh, FCCO, FRACP · Karina Kennedy MB BS, FRACP

To the Editor: Healthy ageing is listed as a National Research Priority by the Australian Government. The higher prevalence of sensory, cognitive and mobility impairments in older people presents a major challenge in achieving this goal. The effects of single impairments are recognised,1,2 but the cumulative effects of multiple impairments have not been reported from population-based samples. We aimed to assess the impact of multiple impairments (vision, hearing, cognitive, mobility) on health-related quality of life (HRQOL), hospitalisation, and aged-care service use in an older Australian population. In the second cross-sectional Blue Mountains Eye Study,3 HRQOL was measured by means of the self-administered Short Form 36-item Health Survey (SF-36)4 (n = 3509; mean age, 66.7 years; 57% women). Visual impairment was defined as best-corrected visual acuity (after refraction) of less than 6/12 (better eye). Hearing impairment was defined as average hearing threshold (pure-tone air conduction, frequencies 500–4000 Hz) over 25 decibels (better ear). Possible cognitive impairment was defined as Mini Mental State Examination scores less than 24/30. Mobility impairment was recorded. General linear regression was used to calculate age-adjusted SF-36 mean scores,5 and logistic regression was used to estimate likelihood ratios for use of health and aged-care services. Models were age-adjusted to eliminate confounding. For 2873 participants who had completed the SF-36 (90.9%), the mean physical component score (PCS) was 44.9 (95% CI, 44.5–45.3) and the mean mental component score (MCS) was 51.9 (95% CI, 51.5–52.2). Age was significantly associated with the prevalence of these impairments (P < 0.001). After adjusting for age, people with any of the impairments had poorer mean PCS and MCS than those without the impairment (Box 1). Hospitalisation within the last year was reported by 743 participants (23.5%; 58.3% women), and 97 (3.1%; 65.0% women) reported regular use of community support services. Use of community support services was reported more frequently by people with any impairment, except possible cognitive impairment (Box 1). The presence of two or more impairments was associated with a cumulative, linear decline in HRQOL (Box 2). The successive addition of each impairment was associated with a decrease of 4.0 in mean PCS and 2.1 in mean MCS, and with greatly increased reporting of regular community support service use. The likelihood of participating in or completing the SF-36 decreased with increasing number of impairments. Hence, the prevalence of impairments and the extent of detrimental impacts on HRQOL may be underestimated. Nevertheless, our data highlight a linear increasing pattern of cumulative effects from multiple impairments on HRQOL, hospitalisation, and use of aged-care services. Preventing and reducing these impairments is crucial in maximising healthy ageing. 1 Prevalence, mean SF-36 physical and mental component scores, and use of services by impairment Impairments Prevalence (%) Age-adjusted mean SF-36 scores (95% CI) Use of services: %, age-adjusted and sex-adjusted odds ratio (95% CI) Physical component score Mental component score Hospitalisation in past 12 months Regular use of community services Visual impairment 2.7 42.8 (39.9–45.7) 47.6 (44.8–50.3)* 34.9%, 1.3 (0.8–2.2) 24.2%, 2.9 (1.4–6.0) Hearing impairment 33.4 43.8 (43.0–44.7)* 51.1 (50.3–51.9)* 27.5%, 1.1 (0.9–1.3) 7.4%, 2.7 (1.4–5.0) Cognitive impairment 2.2 42.2 (39.5–44.8)* 46.0 (43.4–48.5)* 28.2%, 1.0 (0.6–1.6) 14.1%, 1.7 (0.8–3.7) Mobility impairment 7.6 32.3 (30.8–33.7)* 48.1 (46.7–49.5)* 41.0%, 2.0 (1.5–2.7) 21.3%, 6.8 (4.2–11.0) All mean values adjusted to 66.7 years, the overall sample mean age. SF-36 = Short Form 36-item Health Survey.4 * Significantly lower than without disability. 2 Mean physical and mental component scores and use of services by increasing number of impairments No. of impairments* Age-adjusted mean SF-36 scores (95% CI) Use of services: %, age-adjusted and sex-adjusted odds ratio (95% CI) Physical component score Mental component score Hospitalisation in past 12 months Regular use of community services 0 (n = 1031) 46.6 (45.9–47.2) 52.8 (52.6–53.8) 22.0%, 1.0 0.4%, 1.0 1 (n = 616) 42.6 (41.8–43.3) 51.0 (50.3–51.7) 25.3%, 1.1 (0.8–1.3) 4.2%, 7.4 (2.7–19.8) 2 (n = 121) 38.6 (37.1–40.0) 48.8 (47.4–50.2) 35.5%, 1.5 (1.0–2.3) 19.0%, 24.9 (8.5–73.2) ≥ 3 (n = 31) 34.5 (32.2–36.8) 46.6 (44.5–48.8) 45.2%, 2.0 (0.9–4.1) 41.9%, 47.4 (13.1–171.4) SF-36 = Short Form 36-item Health Survey.4 * Includes vision, hearing, cognitive and mobility impairments.

Ee-Munn Chia · Jie Jin Wang · Elena Rochtchina · Paul Mitchell

To the Editor: Despite a new survey with some interesting results, the MJA’s Medicine and the Media special failed overall to advance the topic. Van der Weyden and Armstrong enthusiastically cite Schwartz and Woloshin: “don’t report preliminary findings”.1 (In fact, they wrote, “In general, don’t report preliminary findings”,2 but let’s allow this journalistic context tweak.) In their article, Schwartz and Woloshin contend that this is because “what is new may turn out to be wrong”. Many things reported in newspapers are subject to subsequent change. So, to be on the safe side, let’s exclude them all. No more Cabinet leaks: let’s wait till everything is resolved and perfect-bound by the government stationery office. An end to covering murder trials: what if the accused is found not guilty? Forget about half-time match scores, and definitely no celebrity weddings because they’ll be divorced within the year. A moratorium on discussing preliminary findings would put off-limits highly respected annual meetings such as those of the American Society of Clinical Oncology and the American Society for Reproductive Medicine, which set the treatment agenda annually for clinicians and patients in the fastest-paced medical specialties. It is nonsense to suggest the media should censor early results, a point that has been made previously.3 The world has moved on. News is no longer a series of monolithic reports, each entirely true and complete. Like life, news is a work in progress — a rolling tide of updates, each modifying the last. Everyone loves a winner, and it is gratifying to note the Sydney Morning Herald is currently top of the Media Doctor league table.4 This website is a useful focal point, and Smith and colleagues’ suggestion that researchers take some responsibility for how their results are presented to the public is helpful.5 But of the three solicited commentaries,6-8 not one was from a newsroom health reporter, or — better still — a daily news editor or producer who decides, amid the controlled chaos of breaking and evolving stories, which reports should run and how prominently. Was this because they were not approached? Imagine a five-article package on immunisation practice without a view from a general practitioner, or one on appendicectomy without the insight of a surgeon. It is a serious omission that undermines the credibility of the MJA’s package and calls its motivation into question. Genuine rapprochement might threaten the sport of media sniping that has become a lively sideline for some medical journals.

Julie Robotham BA (Oxon)

In reply: Would that we could convince newspaper editors not to publish inaccurate stories, cabinet leaks, sensational and one-sided details of trials in progress, hope-raising interim football scores or the details of celebrity weddings. However, our media package was not that ambitious! In the context of medical reporting, we stand by our advice against publishing interim results. The reason that clinical trials have protocols, power calculations and stopping rules is that (just as football is a game of two halves) the results are really not relevant or reliable until all the data have been collected and analysed. Our media package included contributions from two highly respected medical writers1,2 and a representative of Australian journalism’s peak body.3 Robotham is correct in surmising that we did not approach a newsroom health reporter or a news editor, but the immunisation analogy seems spurious. If we published a research paper that identified, for instance, deficiencies in general practitioners’ delivery of vaccinations, we would not necessarily accompany it with a commentary from a GP. Whatever their discipline, we would assign the task to someone who could point the way towards best practice. Nevertheless, we are grateful for Robotham’s interest and acknowledge the responsibilities shared by both journalists and medical journal editors, albeit with differing emphasis — the dissemination of accurate and timely information.

Ruth M Armstrong BMed · Martin B Van Der Weyden MD, FRACP, PhD

Basic clinical dialysis. David C Harris, Grahame Elder, Lukas K Kairaitis, Gopala K Rangan (eds). Sydney: McGraw Hill, 2005 (xxiv + 264 pp). ISBN 007471501 1. Many clinicians will have unpleasant memories of their first visit to their hospital’s haemodialysis unit. Unfortunately, this situation hasn’t improved much over the years, where the evening RMO is called to check Mr Jones’ “dry weight” pre-haemodialysis. This can be a difficult task for a nephrologist, so it was refreshing to review this handbook which states, after a series of helpful instructions, “In practice, initial determination of the dry weight of the patient is trial and error using the signs above and frequent assessment”. This is a handbook in every sense of the word, of use to its target population of students, RMOs, advanced trainees, nurses and paramedical staff. Information on haemodialysis and peritoneal dialysis as well as acute dialysis and plasmapheresis is backed up by protocols developed within the dialysis units of the Western Sydney Renal Service. While some protocols may be of little use in established units, they could easily be incorporated into the structure of any new department with benefit. Because many dialysis units have become the domain of the nursing profession over the past few decades, doctors’ dialysis knowledge and skills are often limited. Nevertheless, it is the RMO and rotating registrar that should benefit most from this book. Each section is well referenced with up to date reviews including Australian (CARI) and United States (K/DOQ1) guidelines. Basic clinical dialysis covers more than dialysis, with sections detailing normal renal function, chronic kidney disease stages, pre-dialysis management and transplantation. In my view, this additional coverage is the book’s main weakness. Excluding these ancillary areas may have allowed space to better cover emerging issues such as nocturnal dialysis. A more detailed guide to dosing of commonly prescribed drugs as found in The Oxford handbook of dialysis (Oxford University Press, 2001) would have been helpful. In handbooks such as this, it can be difficult to get the correct balance and cover all relevant areas without too much detail. This one gets it right most of the time and would complement the library of any dialysis unit. Shane L Carney Nephrologist John Hunter Hospital, New Lambton, NSW

Shane L Carney

Chance and commitment. Memoirs of a medical scientist. Basil S Hetzel. Adelaide: Wakefield Press, 2005 (xviii + 301 pp). ISBN 1 86254 686 7. The title Chance and commitment evokes Pasteur’s statement that chance favours the prepared mind. Basil Hetzel’s story combines good fortune and opportunity with a lifelong commitment to improving population health. Central to this narrative is the author’s 40-year commitment to elucidating iodine deficiency disorders (cretinism, neuromuscular disability and goitre), and pursuing worldwide remediation of this preventable scourge. The “chance” arose in the early 1960s when, as Reader in Medicine at Adelaide University, Hetzel reviewed a manuscript reporting goitre reduction by iodine supplementation of Papua New Guinea (PNG) adults. With his interest in hormones and stress physiology, Hetzel’s interest in iodine-dependent thyroid hormone duly heightened. His team undertook a trial in PNG that showed that pre-pregnancy iodine administration prevented cretinism. Hetzel subsequently made two unorthodox career moves (for a clinician) — first to the (Foundation) Chair of Social and Preventative Medicine at Monash University (1968–1976), and then to head the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Division of Human Nutrition. These moves, fortuitously, facilitated further epidemiological and animal experimental studies of iodine deficiency disorders (IDD), respectively. “Commitment” then became dominant. Hetzel helped establish the International Council for the Control of Iodine Deficiency Disorders (ICCIDD), and, in the late 1980s, as Executive Director of that body, persuaded the World Health Organization to support a program of IDD elimination via iodised salt. By century’s end widespread gains had been made. With detailed recollections of family, friends and colleagues, Hetzel recounts his school days, university studies, early clinical research, stress-hormone research in New York and London, his work at Adelaide University, Monash University and the CSIRO, and, in “retirement”, along with his ICCIDD activities, his Deputy Governship of South Australia and Chancellorship of the University of South Australia. There were highs and lows: the death of his first wife, Helen; his subsequent marriage to Anne (and their travels together); and, along the way, many honours and tributes. Basil Hetzel’s autobiography underscores how, with a little luck and risk-taking, much can be achieved via a mix of optimism, resilience, clarity of focus and commitment grounded in professional and religious conviction. Anthony J McMichaelDirector, National Centre for Epidemiology and Population Health Australian National University, ACT

Anthony J McMichael

Clinical intensive care and acute medicine. 2nd ed. Kenneth M Hillman, Gillian F Bishop. Cambridge: Cambridge University Press, 2004 (xvi + 685 pp). ISBN 0 521 78980 X. The practice of intensive care medicine is forever evolving to meet the demands of critically ill patients. Of particular importance has been the recent increasing advocacy for critical care outreach through improved surveillance outside intensive care units, and the provision of medical emergency teams. The authors of this book have been pioneers in this evolutionary process, and in this second edition the reader is presented with a very practical, commonsense approach to the care of the acutely unwell patient. The format is very easy to follow, and information about both generic and specific aspects of critical care medicine is easily accessed. The major emphasis of the book, however, is on general, practical topics rather than comprehensive reviews of diseases or specific organ failures (although these are very adequately covered). A junior hospital doctor wanting to refresh his or her knowledge of fluid and electrolyte therapy is as well served as a consultant in a peripheral centre who needs to urgently review planning priorities before transporting a sick patient. The text is concise and contains the right balance between practical and theoretical issues. There are troubleshooting sections at the end of selected chapters, and there is a further reading section at the end of every chapter. Clinical intensive care and acute medicine will be used widely by postgraduate medical trainees rotating through intensive care but will also be a very welcome companion for critical care vocational trainees and consultant intensive care physicians. Although there is a chapter on quality assurance and clinical audit, there is relatively little information about complications. This is partly due to the deliberate omission of descriptions of procedural techniques. Importantly, the authors have managed to provide an authoritative, practical guide to clinical decision making in this rapidly changing area of acute medicine. Larry P McNicol Director of Anaesthesia, Austin Hospital, VIC

Larry P McNicol

Smoke in your pancreas? Cigarette smoking — whether active or passive — may play a role in the development of glucose intolerance, suggest US researchers. They followed over 4500 young adults for 15 years as part of the Coronary Artery Risk Development In young Adults (CARDIA) study, looking at the relationship between smoking and glucose intolerance. A dose-response effect was found — increasing pack-years of smoking was linked with an increased risk of developing glucose intolerance. Further, those with passive tobacco smoke exposure were at greater risk than previous smokers. The researchers said passive smoke contains similar toxins to active smoke but is produced at different temperatures and different reducing conditions; thus, some toxic substances are even more concentrated in passive smoke. Smoking has previously been linked with chronic pancreatitis and pancreatic cancer, suggesting that tobacco smoke may be directly toxic to the pancreas. BMJ Online First, 7 April 2006 Stroke by mutant gene People with a mutation in a specific gene may be predisposed, especially after environmental stress, to haemorrhagic stroke, says a group of international researchers.1 The gene, COL4A1, affects the assembly of Type IV collagen, a component of the vascular basement membrane.2 Gould and colleagues found that newborn and adult mice with a mutation in the equivalent mouse gene were at risk of trauma-associated intracerebral haemorrhage. They also identified a human family with a COL4A1 mutation — members had experienced small-vessel brain disease, including retinal arteriolar tortuosity as well as intracerebral haemorrhage. The researchers suggested that the presence of the mutation compromises the vascular basement membrane and weakens the vessel. 1. N Engl J Med 2006; 354: 1489-14962. N Engl J Med 2006; 354: 1451-1453 Was Pauling right? Three decades ago, two-time Nobel Prize winner Linus Pauling co-authored papers which reported that high-dose vitamin C (ascorbic acid) therapy prolonged survival in patients with terminal cancer.1 However, the treatment strategy was discarded when subsequent randomised clinical trials based at the Mayo Clinic did not confirm the benefit. Now, North American authors are calling for Vitamin C’s role to be reassessed.2 Padayatty and colleagues reported three cases of usually progressive, advanced malignant disease (a renal cell carcinoma, a transitional cell bladder carcinoma and a diffuse large B cell lymphoma) that were effectively treated with high-dose intravenous vitamin C therapy. Although each case had a possible alternative explanation for good outcome, both the case report authors and commentators pointed out that there is a new known biological plausibility worthy of closer study — in vitro, high levels of vitamin C are selectively toxic to various cancer cell lines but not to normal cells, by a mechanism involving hydrogen peroxide.2,3 Such high doses are achievable only with intravenous administration, as used by Pauling and in these reported cases; the Mayo Clinic studies used only oral administration. 1. Proc Natl Acad Sci USA 1976; 73: 3685-36892. CMAJ 2006; 174: 937-9423. CMAJ 2006; 174: 956-957 Upping the anti The HPV Vaccine Study Group has reported a follow-up study to their randomised controlled trial of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18.1 The original trial results were published in the Lancet in 2004.2 At 4.5 years of follow-up, the story remains: “so far, so good”. The vaccine remains not only efficacious against HPV infection but also safe. Further, there is now evidence of cross-protection against infection with two other common HPV types associated with cervical cancers (HPV types 45 and 31). 1. Lancet online, 6 April 20062. Lancet 2004; 364: 1757-1765 A bit depressed? Which older patients with mild depression are most likely to benefit from close clinical monitoring? Analysis of data from the US PRevention Of Suicide in Primary care Elderly: Collaborative Trial (PROSPECT) has identified a trio of risk factors for a worse depressive outcome a year down the track — comorbidity, poor self-rated health and less social support.1,2 An editorialist said that, like diabetes, hypertension and many other chronic medical disorders, depression also fluctuates in severity and requires regular monitoring and therapeutic adjustments.2 The presence or absence of the three risk factors may help doctors target those most likely to benefit from a close eye. 1. Ann Intern Med 2006; 144: 496-5042. Ann Intern Med 2006; 144: 528-530 Dieting: the anti-ageing effect Australia-based researcher Leonie Heilbronn is first author of an original JAMA article which reports that 6 months of calorie restriction in 48 overweight but otherwise healthy adults led not only to reduced weight but also favourable changes in biomarkers of longevity, such as fasting insulin level and core body temperature. Further, there was reduced damage to DNA. JAMA 2006; 295: 1539-1548

Ann Gregory