Volume 191 Issue 1

Evidence-based therapies offer hope of prolonged survival for selected patients with this disease There is now a substantial body of published evidence of the survival benefits conferred by cytoreductive surgery (peritonectomy) and perioperative intraperitoneal chemotherapy comprising hyperthermic intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis. The technique of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is described in the Box. Here, we, the clinicians at the St George Hospital Peritoneal Surface Malignancy Program, who have had more than 12 years of experience in this treatment, provide a review of this topic. Peritoneal carcinomatosis refers to the dissemination of tumour onto the surfaces of the peritoneum. If left untreated, it is considered a terminal disease with a mean survival time for affected patients of 6 months.1 Over the past decade, the clinical view of peritoneal carcinomatosis has evolved from it being regarded as a terminal and untreatable condition that is palliated with systemic chemotherapy and bypass surgery, to a locoregional disease that is potentially curable in a defined group of patients after aggressive cytoreductive surgery and perioperative intraperitoneal chemotherapy. Unlike liver resection for colorectal liver metastases, for which there is no randomised clinical trial to justify its use, the current literature provides level I evidence to suggest the routine use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in suitable patients with colorectal cancer peritoneal carcinomatosis. Two randomised controlled trials and a multi-institutional study of 506 patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have been conducted. The body of these current results, and results from other non-randomised clinical series, as previously summarised,2 have shown a median survival time ranging from 13 to 29 months, and a 5-year survival rate ranging from 11% to 19%. To date, we have treated 60 patients with colorectal peritoneal carcinomatosis at our unit with a median survival time of 33 months and a 3-year survival rate of 38%.3 Pseudomyxoma peritonei or “jelly-belly” is a clinical syndrome characterised by the production and accumulation of mucinous ascites within the peritoneal cavity after the rupture of a mucinous tumour in the appendix. For patients treated in our unit who had favourable findings on histological examination of the tumour (disseminated peritoneal adenomucinosis), the median survival time for 73 patients was 97 months, with a 5-year survival rate of 70%. In patients with unfavourable histological findings (peritoneal mucinous carcinomatosis), the median survival time for 11 patients was 33 months, with a 3-year survival rate of 30%.4 These outcomes are similar to those published for 863 patients, who had median survival times ranging from 51 to 156 months, and a 5-year survival rate ranging from 52% to 96%.5 Long-term survival results, with a 10-year survival rate of 21%, have also been reported in a series of patients treated with debulking surgery.6 However, this treatment is associated with high rates of recurrence. The incidence of malignant mesothelioma is rising in Australia as a consequence of widespread exposure to asbestos in the 1970s. A third of malignant mesothelioma arises from the peritoneum. A recent systematic review of cytoreductive surgery and perioperative intraperitoneal chemotherapy for malignant peritoneal mesothelioma from seven observational studies reported a median survival time ranging from 34 to 92 months, with a 1-year survival rate of 60%–80% and a 3-year survival rate of 43%–65%.7 In a recent report of 20 consecutive patients from our institution, the overall median survival time was 30 months, with a 3-year survival rate of 46%. In patients who had favourable prognostic features (complete cytoreduction and epithelioid tumour), the median survival time was 87 months, with a 1-year survival rate of 90%.8 The 5-year survival rate of patients with advanced ovarian cancer is less than 25%.9 Intraperitoneal chemotherapy is the standard of care following a Gynecologic Oncology Group (GOG) Phase III trial that compared intravenous chemotherapy with intravenous plus intraperitoneal chemotherapy in Stage III ovarian cancer.10 However, the adoption of this therapy into standard practice has been slow, perhaps because of its poor tolerability.11 A systematic review of 15 studies of 512 patients with primary advanced ovarian cancer and recurrent ovarian cancer reported an overall median survival time of 29–64 months. In patients with an optimal cytoreduction, survival time ranged from 29 to 66 months, with a 3-year survival rate of 35%–63% and a 5-year survival rate of 12%–66%.12 In our unit, we have only treated patients with recurrent ovarian cancer who are not responsive to conventional treatment options. In 12 patients with recurrent ovarian cancer and peritoneal carcinomatosis whom we have treated with cytoreductive surgery and early postoperative intraperitoneal chemotherapy, the median survival was 36 months, with a 3-year survival rate of 39%. St George Hospital in Sydney is the only high-volume specialist institution offering cytoreductive surgery and hyperthermic intraperitoneal chemotherapy treatment in Australia. Despite the limited number of randomised trials of these therapies, there is strong evidence from Phase II studies of the survival benefits. The unit’s mortality rate has been 3% in the last 210 patients and we have demonstrated a learning curve effect.13 Our treatments are in accordance with the consensus statements from the Peritoneal Surface Oncology Group International.14-16 We emphasise that, in carefully selected patients, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is able to offer the hope of prolonged survival for cancer patients who are diagnosed with what many still regard as a terminal disease. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) Cytoreductive surgery and HIPEC combines surgery and intraoperative chemotherapy. This combined therapy is an aggressive approach to treating patients with diffuse and widespread intra-abdominal cancers localised to the peritoneal cavity, and is performed with the aims of cure and life prolongation. The surgery involves stripping the diseased peritoneum and performing multiple visceral organ resections to achieve maximal cytoreduction, leaving a minimal residual tumour volume within the abdomen. Following surgery, but intraoperatively, a heated chemotherapy perfusate is administered into the abdomen to cover all raw peritoneal surfaces. Intraperitoneal chemotherapy allows a high local concentration of a cytotoxic drug to be achieved for microscopic cytoreduction to target any microscopic residual tumour volume with minimal adverse systemic effects. Hyperthermia has been shown to act synergistically with the chemotherapy, and can thus enhance the cytotoxicity of the drug.

Terence C Chua BScMed(Hons) · Winston Liauw FRACP · David L Morris MD, PhD, FRACS

Could a technique using fetal DNA from the maternal circulation mean the end of invasive prenatal testing? Since the first application of ultrasound to it 50 years ago, the “black box” that is the pregnant uterus has gradually yielded to efforts to gain increasingly precise information about the condition of the fetus. Technological advances in ultrasound and, more recently, magnetic resonance imaging have seen the production of high-resolution displays of fetal anatomy and physiology. Specific information about the fetal genome, however, has until now only been available through the application of invasive techniques. Amniocentesis and chorionic villus sampling have been used to diagnose fetal aneuploidy (such as Down syndrome) and an ever-increasing range of genetic conditions. But these invasive procedures come at a cost — an associated 1% risk of pregnancy loss1 limits their application and causes significant stress for women thinking of undertaking such testing. Screening tests such as ultrasound and maternal serum screening to assess aneuploidy risk have been developed to allow more judicious application of invasive procedures, but of themselves cannot accurately diagnose the fetal condition, and false negatives and positives both occur. Now, the era of non-invasive prenatal diagnosis beckons — offering the ability to obtain specific and accurate genetic information from the fetus without the need for an invasive procedure and its associated risks. The article by Hyland and colleagues in this issue of the Journal reports on the first potential clinical application of non-invasive prenatal diagnosis in an Australian population — the determination of fetal RHD status in Rhesus (Rh) D-negative women.2 About 17% of Australian women are RhD-negative.3 These women are at risk of isoimmunisation, caused by the passage of RhD-positive fetal red blood cells across the placenta during pregnancy and childbirth. The resultant antibodies produced by the mother can cross the placenta and cause fetal anaemia due to haemolysis of fetal red blood cells. Women who are isoimmunised require intensive fetal surveillance, and are at risk for fetal death and neonatal brain injury if timely intervention is not performed. The incidence of isoimmunisation has been dramatically reduced since the introduction of preventive strategies, but these rely on administration of plasma-derived RhD immunoglobulin to all RhD-negative women. The technique employed by Hyland et al involves detecting cell-free fetal DNA (ffDNA) in maternal plasma by real-time polymerase chain reaction (PCR).2 ffDNA constitutes about 4%–6% of all cell-free DNA in the maternal circulation and can be reliably detected as early as 7 weeks after conception.4 The use of ffDNA to detect the RHD gene in RhD-negative pregnant women was first described by Lo and colleagues in 1998.5 Others have since applied the technique, and a recent meta-analysis demonstrated 96.1% sensitivity and 96.5% specificity for correctly determining fetal RHD status.6 To minimise false-negative results, internal controls are used to confirm the presence of fetal DNA. The SRY gene was initially used for this purpose, but as this only detects male fetuses, Hyland and colleagues have also utilised the RASSF1A gene to confirm the presence of fetal DNA from female fetuses.2 Where they were able to determine the fetal RHD status, their predictions showed 100% accuracy when compared with the infants’ serotype determined from cord blood after delivery. In a small number of cases, determination of fetal status could not be achieved. This technique requires further evaluation in larger studies to clarify the true performance characteristics of the test, and to allow algorithms to be developed for dealing with indeterminate results and the RHD gene variants seen in some ethnic groups. However, if these issues can be satisfactorily addressed, the potential applications are significant. In the small group of women with isoimmunised pregnancies, it will allow the determination of fetal RHD status without resorting to invasive tests. In addition to the risk of pregnancy loss, invasive procedures also have the potential to cause further sensitisation and worsen the natural history of the condition. More broadly, this testing has the potential to reduce unnecessary exposure of pregnant women to RhD immunoglobulin. Currently, RhD immunoglobulin is administered for antenatal prophylaxis, potential sensitising events, and postnatally for RhD-positive infants. This regime has been very effective, reducing the incidence of sensitisation during pregnancy by more than 90%.7 However, up to 40% of RhD-negative women receive treatment unnecessarily, as they will be carrying an RhD-negative fetus from a heterozygous partner.8 Routine introduction of non-invasive fetal DNA testing would therefore be likely to have cost implications for delivery of this preventive treatment. Non-invasive detection of fetal RHD status is already being incorporated into clinical practice in Europe, and the feasibility of using this approach to make decisions about prophylaxis has been demonstrated.9 The use of ffDNA can also be applied more broadly than determination of fetal RHD status. Already, reports exist of the non-invasive prenatal diagnosis of Huntington disease,10 cystic fibrosis11 and other conditions. Detection of the SRY gene allows determination of fetal sex in women at risk of carrying a fetus with an X-linked condition.12 The non-invasive diagnosis of Down syndrome and other aneuploidies remains challenging, but newer techniques such as methylation-dependent PCR and digital PCR hold promise.13 As with many technological advances involving reproductive choices, there are ethical concerns associated with this test. Sex determination for social rather than health reasons, for example, could result from unregulated use of such technologies. There is a pressing need for vigorous discussion of these issues. Non-invasive diagnosis of specific fetal gene status using fetal DNA from the maternal circulation without any risk to the pregnancy may be the “holy grail” of prenatal diagnosis. The determination of fetal RHD status is nearing availability as a clinical tool, and is likely to be the first of many applications of non-invasive prenatal testing over the coming decade. Is a future without amniocentesis and chorionic villus sampling dawning? Not quite yet, but at least there is some light on the horizon.

Stephen A Cole MB BS, FRANZCOG, CMFM · Helen F Savoia MB BS, FRCPA

The Australian Commission on Safety and Quality in Health Care is providing doctors with an opportunity to say what they think about safety and quality Early in 2009, the Australian Commission on Safety and Quality in Health Care (ACSQHC) developed a draft national safety and quality framework that sets out a vision for a health system that delivers safe and high-quality care (Box). At the ACSQHC, we now want to talk to Australians about how the safety and quality of the nation’s health care system can be improved. We are keen to hear from patients, consumers, clinicians, health service managers, policymakers and researchers about what aspects of safety and quality are important to them, the barriers they perceive to providing optimal care and suggestions for improving safety and quality. We have produced a detailed discussion paper as a starting point,1 and we need to know what you, the people on the ground, think about the ideas it contains. Opportunities for providing input include completing a short survey available on our website,1 providing written submissions and participating in meetings and focus groups. The result of these conversations will be a report, to be released mid 2010, that will include strategies for achieving sustainable, safe and high-quality patient care in all settings. The Journal has recently published articles by leading commentators and academics advocating health care reforms,3-7 and we have taken note of their views. A common theme was the need for a sustained focus on implementation — turning words into action — not just creating new policy. We know that safe and high-quality care requires the vigilance and cooperation of a wide range of health care staff, and that the success of initiatives to improve safety and quality requires the participation of doctors.8-11 Thus we believe it is crucial that frontline medical staff be involved in developing health policy in this area. Your participation in the conversations about safety and quality is essential to ensure that our final report is both practical and powerful. We know that it can be difficult for doctors to find time to participate in activities such as this one. However, we need to know about what you are doing to keep your patients safe, what gets in the way of this, and what changes you think are needed. We look forward to talking with you over the coming months and working with you to build a future of safe and high-quality patient care in Australia. Drop in to our website1 to read the discussion paper or fill in the survey to give us your views. Draft national framework for a health system that delivers safe and high-quality care1 Characteristics of safe, high-quality health care What it means for me as a patient or consumer Strategies for action by administrators, policymakers and providers 1. Patient-focused This means providing care that is respectful of and responsive to individual preferences, needs and values. It means a partnership between consumers, family, carers and their health care providers. Processes of care are designed to optimise the patient experience. I can access high-quality care when I need it. Develop service models which improve access to health care for patients. I can obtain and understand health information so that I can make decisions about my own care and participate in ensuring my safety. Increase health literacy. Involve patients so that they can make decisions about their care and plan their lives. Provide care that is culturally safe.* My health care is coordinated because people and systems work in partnership with me. Enhance continuity of care. Minimise risks at handover. Provide case management for complex care. Facilitate patient-centred service models. I know my health care rights.2 Promote health care rights. If I am harmed during health care, it is dealt with fairly. I will get an apology and a full explanation of what happened. Inform and support patients who are harmed during health care. 2. Driven by information This means enhancing knowledge and evidence about safety and quality. Safety and quality data are collected, analysed and fed back for improvement. Action is taken to reduce unjustified variation in standards of care and to improve patients’ experiences and clinical outcomes. My care is based on the best knowledge and evidence. Reduce unjustified variation in standards of care. Collect and use data to improve safety and quality. My clinical outcomes and experiences are used to build the evidence base for care and for strategies designed to improve care. Learn from patients’ and carers’ experiences. Encourage and apply research that will improve safety and quality. Continually monitor the effects of health care interventions. 3. Organised for safety This means that safety is a high priority in the design of health care. Organisational structures, work processes and funding models recognise and reward those who take responsibility for safety. I know that governments, health care managers and health care staff take responsibility for my safety. Clinicians, managers and governments recognise their responsibilities for safety. Our money funds a safe and efficient health system. Restructure funding models to support safe, appropriate care. Support and implement e-health. Design facilities, equipment and work processes for safety. I know that, when something goes wrong, actions are taken to prevent it happening to someone else. Take action to prevent or minimise harm resulting from health care errors. * Clinicians provide care that is culturally safe by recognising and respecting the cultural differences of the patient or consumer. Cultural safety goes beyond cultural appropriateness by creating better partnerships with people of different backgrounds.

Christopher J Baggoley FACEM, BM BS · Imogen E Curtis BComm(Hons) · Nicola J Dunbar BSc(Hons), PhD, MPS · Christine M Jorm MB, PhD, FANZCA

Acute medical units can help fast-track medical patient assessment and admission to hospital Hospitals in Australia are experiencing increasing numbers of medical presentations (ie, patients requiring admission under the care of a physician rather than a surgeon) in a context of ongoing restriction of inpatient beds. The resulting pressure on emergency departments (EDs) causes frustration for health care workers and administrators alike, as they struggle to meet key performance indicators that are designed to minimise the time that patients spend on trolleys in the corridors of EDs. Many hospitals have responded to this challenge by developing acute medical units (AMUs) that are equipped to fast-track patients with medical problems to the care of inpatient physicians (ie, staff physicians and visiting medical officers) and multidisciplinary teams who can best plan the management, care and disposition (destination after leaving the AMU) of these patients. On 24 April 2009, a seminar titled “Acute medical assessment units: improving care and flow for medical patients” was held at the Royal Children’s Hospital, Melbourne. The meeting was called by The Alfred Hospital, Melbourne, to assess the current state of evolution and performance of AMUs in Australia and New Zealand, and was supported by the Victorian Government Department of Human Services (DHS), Monash University National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Patient Safety (CRE-PS) and the Internal Medicine Society of Australia and New Zealand (IMSANZ). Speakers from Australia and NZ addressed 210 attendees, including 78 doctors, 45 nurses, 17 DHS staff, 14 business analysts, 18 allied health professionals and pharmacists, 20 research educators and 10 representatives of relevant medical colleges. Here, we present the major themes presented for discussion and debate; speaker slides are available at http://www.crepatientsafety.org.au/seminars/. In the keynote presentation, Associate Professor John Henley (Visiting Professor, The Alfred Hospital) drew on years of experience running the AMU at Auckland City Hospital, NZ, and consulting on AMUs throughout Australasia. He emphasised the value of AMU staff working closely with ED staff, collocating the AMU and ED, and sharing administration across both units. At Auckland City Hospital, the AMU provides infrastructure, administration, and nursing and allied health support, but patients are seen by inpatient physician teams, with no default service provided in the AMU. This arrangement places the onus on the inpatient physician teams to attend to their patients promptly, and encourages continuity of care. This continuity is more difficult to achieve in AMUs that have their own medical staff, as distinct from inpatient physician teams. Henley also emphasised the importance of monitored beds, imaging equipment that is in close proximity to the AMU, and consulting rooms that permit urgent review of patients who are likely to require admission at the request of local general practitioners (thus bypassing the need for their assessment in the ED). In 2006, Henley co-authored a position statement on AMUs on behalf of IMSANZ.1 An international and historical perspective on AMUs was provided by one of us (P F J), drawing on extensive involvement in the establishment of AMUs in the United Kingdom. When the UK National Health Service applied severe penalties for hospitals that failed to move most patients from the ED within 4 hours, AMUs were developed throughout the country, supported by a new subspecialty — acute medicine. Introduction of a 4-hour rule is now pending in Western Australia, further focusing attention on AMUs. The importance of designing units according to the functionality required by individual hospitals was also emphasised — some units are designed to manage only patients with acute medical emergencies; some are designed to manage all medical admissions other than intensive care and critical care unit admissions; and some are primarily aimed at managing hospital bed issues, without a particular medical focus. Some units also accept surgical patients. This point was later reinforced by Associate Professor David Russell (Director, General Medicine, Royal Melbourne Hospital), who noted that the AMU should be regarded as a “philosophy of care”, not simply as a geographical entity. The value of effective change-management strategies in successful introduction of the AMU, particularly from the nursing perspective, was illustrated by one of us (L T O). Ms Glynis Jenkins (Project Coordinator, Acute Assessment Unit, Royal Perth Hospital, Perth) highlighted the importance of effective engagement with allied health staff, who play a crucial role in the AMU in both the UK and WA. Access block that results from delayed discharge and poor “back-door” availability of subacute and community care (paucity of options for discharging current inpatients who no longer require acute care but are not well enough to go directly home) is a major barrier to patient care, patient flow and ED key performance indicators. Dr Pieter De Villiers Smit (Acting Director, Emergency Department, The Alfred Hospital) described examples of how access block can impede patient management and safety. Professor Peter Cameron (Physician, Emergency Department, The Alfred Hospital, and Director, NHMRC CRE-PS), who chaired the session on identifying and addressing barriers, recently expanded on this topic in this Journal.2 Access block increases patient length of stay and incidence of adverse events, and decreases quality of care. In Australia, the excess mortality in hospitals attributable to access block matches that of the national road toll. Access block is a hospital-wide responsibility, rather than a problem within and for the ED itself, but is rarely acknowledged as such. Lugubrious specialty referral processes (whereby a patient can be referred, in turn, to several different subspecialties before being accepted for management) and significant delays in allocation of hospital beds contribute to access block. Associate Professor Ian Scott (General Physician and Director, Department of Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital, Brisbane) reviewed the limited evidence base for efficacy of AMUs. In uncontrolled and often poor-quality studies, AMUs reduced estimated bed costs, and probably contributed to decreases in mortality, patient length of stay in hospital, ED admission waiting times and numbers of outlier patients (ie, patients whose allocated hospital bed is in a ward other than the ward that is usually managed by their admitting team). AMUs can also increase the allocation of patients to appropriate subspecialties, increase staff and patient satisfaction, and facilitate the direct discharge of patients from hospital without an increase in the readmission rate. Professor Don Campbell (Head, General Medicine Department, Clayton Campus, Monash Medical Centre, Melbourne) illustrated how simulation modelling and clinical audit data can be used to optimise the use of resources in AMUs. In the UK, acute medicine is practised as an independent subspecialty that has its own Society of Acute Medicine, whereas in Australia and NZ it is part of the training of a general physician. An ageing general physician workforce with a paucity of young trainees and consultants threatens the development of AMUs in Australia. One of us (H H N) presented alarming data from the 11th annual report of the Medical Training and Review Panel (MTRP),3 the Medical Labour Force Survey4 and the Specialist Advisory Committee in General Medicine of the Royal Australasian College of Physicians (RACP) (Surinder Ahluwalia, Education Officer, Education Deanery, RACP, personal communication). In 2006, general medicine was the third most populated physician specialty in Australia, after cardiology and gastroenterology, but had the highest proportion of ageing physicians and the smallest number of new graduates — only four general physicians received their RACP Fellowship in 2006, in contrast with 42 cardiologists and 19 gastroenterologists. At least 200 additional general physicians are required in Australia, although a structured workforce analysis in this area has not been undertaken recently. The numbers of trainees entering cardiology and gastroenterology exceeded the MTRP recommendations, but no recommendation is provided for general medicine. There appears to be little regulation of trainee numbers in each subspecialty by the RACP or health departments, and a relative oversupply of cardiology and gastroenterology trainees. Numbers of general medicine trainees in 2009 are higher than for 2007, but fewer than 40% of those who do some advanced training in general medicine actually practise in this specialty. A major workforce strategy to replenish the ranks of general physicians is required. Cross-training of subspecialty trainees (who are encouraged to maintain their general medicine skills) could provide an interim solution until numbers of dedicated general medicine trainees and dual specialty trainees increase. Additional appointments of full-time general physicians and affirmative action in remuneration could also help — this has been successful in the training of geriatricians. The meeting concluded with Professor Paddy Phillips (Chief Medical Officer, South Australia) summarising what administrators want from those designing and running their AMUs. He focused on four themes: clarity, reliability, accountability and working together, a useful checklist for any initiative. This was a timely presentation, as it was part of the session on implementation that was chaired by Ms Margaret Grigg, Assistant Director of the Access and Metropolitan Performance Branch within the Victorian Government DHS. This department will no doubt receive requests for additional funding of Victoria’s AMUs from the inspired attendees of the seminar.

Harvey H Newnham MB BS, FRACP, PhD · Campbell H Thompson DPhil, FRACP, MD · Paul F Jenkins MB BChir, FRCP, FRACP · Lauri T O’Brien RN, RM, BN

Objective: To examine the response of the Victorian State Trauma System to the February 2009 bushfires.Design and setting: A retrospective review of the strategic response required to treat patients with bushfire-related injury in the first 72 hours of the Victorian bushfires that began on 7 February 2009. Emergency department (ED) presentations and initial management of patients presenting to the state’s adult burns centre (The Alfred Hospital [The Alfred]) were analysed, as well as injuries and deaths associated with the fires.Results: There were 414 patients who presented to hospital EDs as a result of the bushfires. Patients were triaged at the emergency scene, at treatment centres and in hospital. National and statewide burns disaster plans were activated. Twenty-two patients with burns presented to the state’s burns referral centres, of whom 18 were adults. Adult burns patients at The Alfred spent 48.7 hours in theatre in the first 72 hours. There were a further 390 bushfire-related ED presentations across the state in the first 72 hours. Most patients with serious burns were triaged to and managed at burns referral centres. Throughout the disaster, burns referral centres continued to have substantial surge capacity.Conclusions: Most bushfire victims either died, or survived with minor injuries. As a result of good prehospital triage and planning, the small number of patients with serious burns did not overload the acute health care system.

Peter A Cameron MB BS, MD, FACEM · Biswadev Mitra MB BS, MHSM, FACEM · Mark Fitzgerald MB BS, FACEM · Carlos D Scheinkestel FRACP, FJFICM, DipDHM · Andrew Stripp BBSc(Hons), MSc · Chris Batey CCRN · Louise Niggemeyer RN, ICCert, MEd · Melinda Truesdale MB BS, FACEM, GradDipHSM · Paul Holman ASM, GradDipHealthAdmin, MACAP · Rishi Mehra MB BS, PGDipEcho, FANZCA · Jason Wasiak MPH, BN, GradDipCritCareNurs · Heather Cleland MB BS, FRACS

Objective: To understand the current organisation of services for people with transient ischaemic attack (TIA) and the processes of assessment and management across Australian hospitals.Design and setting: Cross-sectional survey in 2008 of 134 Australian hospitals, mostly urban centres that treat large numbers of stroke patients.Main outcome measures: Survey questions covered assessment, early management and follow-up practices, as well as organisation of services for TIA.Results: Seventy-four hospitals (55%) responded: 47 (64%) reported access to a stroke unit, and 19 (26%) to a specialist clinic for TIA. Initial assessment included blood tests, electrocardiogram and brain computed tomography at most sites (92%–94%), and carotid imaging at more than half (65%), but magnetic resonance imaging at only 3% of sites. A tool to stratify the risk of subsequent stroke was used at 38 sites (51%), more commonly in hospitals with a stroke unit than in those without such a unit (64% v 30%; P = 0.005). Treatment was initiated at the initial assessment at 42 sites (58%), more commonly at stroke unit than non-stroke unit sites (68% v 37%; P = 0.007). Formalised policies for management of TIA patients were used at 38 sites (54%), with clear differences between sites with a stroke unit and those without (70% v 25%; P < 0.001).Conclusion: Access to rapid assessment and management services for TIA varies considerably between Australian hospitals. The presence of organised stroke care at a hospital leads to improved processes of care for patients presenting with TIA.

Christopher J Price BSc, BSW · David J Blacker MB BS, FRACP · Rohan S Grimley MB BS, BScMed, FRACP · Helen M Dewey PhD, FRACP, FAFRM(RACP) · Richard P Gerraty MD, FRACP · Simon A Koblar BM BS, FRACP, PhD · Sonia M Denisenko BPhys, MPH · Catherine E Storey MB BS, MSc, FRACP · Christopher F Bladin MB BS, MD, FRACP · Kelvin M Hill BApplSci(Physiotherapy), GradDipBusComm

Objective: To evaluate a non-invasive molecular test using free circulating fetal DNA in maternal plasma to predict the fetal RHD type.Design: A prospective cohort study.Participants and setting: Venous blood samples were collected from 140 Rhesus (Rh) D-negative women booked for antenatal care in two tertiary maternity hospitals in Sydney and Brisbane between November 2006 and April 2008. Cell-free DNA, including free maternal and fetal DNA, was extracted from maternal plasma in the tertiary Australian Red Cross Blood Service laboratory, and three exon regions of the RHD gene were amplified.Main outcome measures: Comparison of the predicted fetal RHD status and the infant’s RhD serotype. Secondary analysis involved using SRY and RASSF1A assays as internal controls to confirm the presence of fetal DNA in RHD-negative samples.Results: Of 140 samples tested, results for RHD status were assigned for 135, and all 135 predictions were correct. A result was not assigned in five cases: three did not meet strict threshold criteria for classification, and two were due to RHD variants. Fetal SRY status was correctly predicted in 137 of 140 cases. In 16 samples typed both RHD- and SRY-negative, a positive RASSF1A result verified the presence of fetal DNA.Conclusions: Non-invasive testing of multiple exons provides a robust method of assessing fetal RHD status, and provides a safer alternative to amniocentesis for the management of RhD-negative pregnant women who are isoimmunised.

Catherine A Hyland PhD, MSc · Glenn J Gardener MB BS, DipRACOG, FRANZCOG · Helen Davies BSc, GDPH · Minna Ahvenainen BSc · Robert L Flower PhD, MSc · Darryl Irwin PhD, MIndProp, BAppSc · Jonathan M Morris MB ChB, FRANZCOG, PhD · Christopher M Ward MB ChB, PhD, FRACP · Jonathan A Hyett MB BS, MRCOG, FRANZCOG

The future of academic medicine in Australia has been identified as a significant issue, but received little mention in the interim report of the National Health and Hospitals Reform Commission. Australia is at particular risk of failing to capitalise on what is happening globally with academic medicine. New “partnerships” between health services, universities and health research institutes should be encouraged for stimulating research and learning across the health sector. Such partnerships can drive translational research, provide full costing of research, and establish national and international networks of researchers and research funding. There are many interactions between Australian state and federal jurisdictions and their hospitals and primary care organisations, but these are often loosely coordinated and with little understanding of how universities and research institutes can help to deliver better and more efficient health care. Academic health science centres, as recently designated by the National Health Service in the United Kingdom, provide a useful model for consideration in Australia.

Peter M Brooks MD, FRACP, FAFRM

The uncritical adoption of production-line manufacturing practices (such as “lean thinking”) into work design processes in hospitals creates a fundamental tension between the production of health care and protection of the patient. There is scant evidence that re-engineering health care services in line with industrial models increases their efficiency. Indeed, reducing the richness of health care practice to impoverished snippets of work may add to the problems of hospital misadventure and inefficiency rather than solve them.

Sarah Winch BA(Hons), PhD · Amanda J Henderson BSc, MScSoc, PhD

The current escalation in costs of Australia’s health care system does not appear to be sustainable. Sustainable financing requires direct engagement of consumers — instead of the current political process driven by special interest groups, targeted at gaining a larger share of the federal and state governments’ budgets. Reforms in the Netherlands, directed at achieving universal insurance with consumer choice of health fund, provide valuable lessons for Australia on how to design sustainable financing.

Johannes U Stoelwinder MD, FRACMA, FACHSE · Francesco Paolucci BEcon, MSc, PhD

Medical education research is a relatively new but growing discipline. There is an overall perception of lack of confidence in the quality of the research, which is not entirely justified. The scientific quality of any research is defined by the appropriate application of method to a particular problem. There is a need for programmatic research focused on developing medical education policy. University medical education units need to be research-focused. Medical Deans Australia and New Zealand and the Australian and New Zealand Association of Medical Education (ANZAME: the Association for Health Professional Education) can provide leadership. Funding bodies need to develop their relationship with medical education research.

Chris Roberts MB ChB, MRCGP, PhD · Jennifer J Conn BSc(Hons), MClinEd, FRACP

Contemporary medical education must train skilled and compassionate health care professionals who are rigorous in their approach to patient care and their pursuit of knowledge and solutions. Problem-based learning has been widely introduced, but there is no evidence that it leads to better outcomes than more traditional programs, and fundamental gaps in conceptual knowledge may result. Recently, emphasis has been placed on a solid grounding in underlying concepts combined with a systems-based approach, and ability to transfer information and solve problems. Integrating traditional scientific and clinical disciplines with progressive and continuous assessment, may be a better means of achieving the combined aims of clinically relevant curriculum design, vertical integration of medical knowledge, and facilitation of the continuum of training. Being adaptable and flexible, cognisant of costs, and driven by evidence are key features of delivering medical education and contemporary medical practice. Educational research should lead to continuous improvement, but innovation without evaluation and attention to costs may create as many, or more, problems as are solved.

Gary A Wittert MD, FRACP, FRCP · Adam J Nelson

With the recent outbreak of swine influenza, the world may be facing this century’s first influenza pandemic. In Mexico, around 2000 patients have been hospitalised with respiratory illness and almost 150 people have died. Several other countries have reported smaller numbers of suspected and confirmed cases of swine influenza. This 2009 influenza A virus is a strain of the H1N1 subtype, and appears to be a human–avian reassortment swine virus influenza. It is likely that sustained human-to-human transmission of swine influenza has occurred, at least in Mexico. Despite there being so many hospitalised patients in Mexico, cases outside Mexico have demonstrated a mild influenza-like illness, with only one fatality to date. In contrast to the 1918 influenza pandemic, we now have a more robust public health system, with widespread global networks; vaccines can be developed rapidly; and there are antiviral medications to which the swine influenza A(H1N1) virus is sensitive. Many resources have been invested in pandemic preparedness programs in the health care and public health systems in Australia over the past few years.

Sanjaya N Senanayake MB BS, MAppEpid, FRACP

A 6-week old infant who had been conceived through in-vitro fertilisation (IVF) presented with a skin lesion and enlarged lymph nodes, and developed severe respiratory distress. Mycobacterium tuberculosis was identified; his mother was the only potential source identified. To our knowledge, this is the first case of congenital tuberculosis after IVF reported in Australia and the second worldwide. It highlights the importance of adequate screening during investigation of infertility and the difficulties in diagnosing congenital tuberculosis. Clinical recordsA 29-year-old Bosnian woman, who had migrated to Australia 8 years earlier, conceived through in-vitro fertilisation (IVF). Her baby, a boy, was born at 28 weeks’ gestation by emergency caesarean section for fetal distress in labour. His mother made an uneventful recovery after the delivery. The baby’s birthweight was 1154 g (50th percentile), and neonatal assessment was consistent with gestational age. He developed mild respiratory distress syndrome and required a short period of endotracheal intubation and artificial ventilation, from which he was successfully weaned. He had several significant problems during the early neonatal period, including prolonged neonatal jaundice (which required repeated episodes of phototherapy), hypothyroidism (serum thyroid-stimulating hormone, 9.2 mU/L; reference range, 0.30–5.00 mU/L) and right-sided Erb palsy. At 6 weeks of age, while still in hospital, the infant developed a 1 cm brown–pink macular lesion on the left side of the neck, and was noted to have an enlarged (1.5 cm) left axillary lymph node. Empirical antistaphylococcal therapy was introduced without any apparent effect. Biopsy of the lymph node was planned, but before this could be performed, the lymph node became acutely more enlarged, and the infant’s condition deteriorated rapidly. He developed severe respiratory distress and required re-intubation. A large mediastinal lymph node mass was noted on chest x-ray and magnetic resonance imaging (Box 1), and bronchoscopy showed extrinsic compression of the trachea and bronchi at the level of the carina. Excision biopsy of the axillary lymph node showed necrotising granulomatous inflammation, and acid-fast bacilli were identified on Ziehl–Neelsen and auramine–rhodamine staining. Mycobacterium tuberculosis was identified in lymph node tissue and endotracheal aspirates by polymerase chain reaction (PCR) and culture. M. tuberculosis was not identified in cerebrospinal fluid, blood or gastric aspirate by PCR or culture. Empirical treatment with isoniazid, rifampicin, ethambutol and pyrazinamide was commenced, along with prednisolone, and the infant’s condition stabilised, then improved. Abdominal ultrasound examination did not show features of a primary complex in the liver. The M. tuberculosis isolate was sensitive to all first- and second-line agents. The baby developed moderate neutropenia after 4 weeks of therapy, which resolved after discontinuation of ethambutol; pyrazinamide was ceased after 12 weeks of therapy. After 4 months of therapy, further left axillary and cervical adenopathy was noted. The largest node was about 1 cm in diameter and fluctuant. The nodes settled spontaneously without excision or treatment change. The infant experienced two episodes of wheezing associated with clinical features of viral upper respiratory tract infection (at 8 and 10 months into the course of antituberculous therapy, respectively). Chest x-rays on each occasion did not show evidence of mediastinal node enlargement. His recovery was otherwise uncomplicated, and he completed a planned 12 months of therapy. The child’s mother had no significant medical history apart from infertility. Infertility investigations had included ultrasound, hysteroscopy and diagnostic laparoscopy. A uterine curettage (as part of the work-up for infertility) 5 years before the pregnancy had shown “granulomas” in the endometrium (Box 2), but stains for acid-fast bacilli were negative. Culture for M. tuberculosis had not been performed at the time. Following the diagnosis of tuberculosis (TB) in her child, an interferon-gamma release assay (IGRA [QuantiFERON-TB Gold, Cellestis, Melbourne, Vic]) was performed, and gave a positive result. Chest x-ray revealed old fibrotic changes in the right upper lung, but no evidence of active tuberculous disease. She was prescribed antituberculous medication. Extensive contact tracing was performed. The father and all close contacts of the baby during his stay in the neonatal unit (including 118 health care workers, 20 neonates and 32 relatives) were screened with an IGRA or tuberculin skin test, and positive results were followed up with chest x-ray. No other cases of active TB were found, suggesting that the index patient did not acquire TB postnatally, but had congenital tuberculosis. DiscussionThis is the first case of congenital TB after IVF reported in Australia, and to our knowledge only the second case reported in the literature.1 This case suggests two valuable lessons: the importance of considering congenital TB in babies who develop a suggestive clinical illness in the first weeks of life, and the need for accurate assessment for and exclusion of TB in women proceeding to IVF. Congenital TB is a rare condition, with around 350 cases reported in the literature.2-10 The fetus can be infected by direct spread through the umbilical cord, by aspiration or swallowing of infected amniotic fluid, or by direct contact with maternal genital lesions during delivery.11 TB can be difficult to recognise in infants as symptoms may be non-specific and easily mistaken for more common neonatal illnesses, such as bacterial sepsis or congenital viral infections.12 Symptoms usually present 2–3 weeks after birth, and the disease can quickly progress to dissemination and death if not promptly treated. In 1994, criteria for diagnosis of congenital TB were revised.3 They comprise documentation of tuberculous lesions in the infant and one or more of the following: lesions in the first weeks of life; a primary hepatic complex or caseating granuloma; documented tuberculous infection of the endometrium or placenta; or exclusion of the possibility of postnatal transmission by investigation of close contacts. Our patient met the criteria for congenital TB: he had tuberculous lesions in early life; his mother had documented granulomas of the endometrium; and extensive contact tracing found no evidence of transmission to the child from other close contacts. Confirmation of endometrial TB in the mother, by repeat endometrial biopsy with PCR and culture for TB, would have been ideal, but would not have altered management in either the mother or the neonate. Thus, it was elected to treat the mother on the basis of the neonate’s culture results, rather than subject her to another procedure. Globally, there has been a slow decline in the incidence of TB; but this is more than offset by population growth, with the number of new cases worldwide increasing between 2005 and 2006 from 9.1 to 9.2 million (an increase of 0.6%). Increases occurred in the African, Eastern Mediterranean, European and South-East Asian regions.13 In Australia, the total number of TB cases reported in 2006 was 1201 (5.8 cases per 100 000 population). The incidence varies dramatically between populations in Australia, with 0.9 cases per 100 000 population in the non-Indigenous population, climbing to 20.1 per 100 000 population in those born overseas.14 Within the group born overseas, incidence ranges from 2.0 per 100 000 population for those born in the United Kingdom to 405 per 100 000 population for those born in Somalia.14 Genital TB is a major cause of infertility in women belonging to high-risk groups, causing up to 17% of cases of infertility.15 Its incidence is increasing in Western continents. Twenty-nine cases of genitourinary TB were reported in Australia in 2006 (2.5% of all reported cases of TB).14 In Australia, it is estimated that one in every 60 babies is conceived through IVF .16 As IVF is a useful treatment for infertility caused by TB, it can be expected that in the future more women with TB as a cause of their infertility will present for IVF. It is therefore imperative that women from high-risk groups undergo evaluation for and exclusion of TB. Investigations should include an IGRA or tuberculin skin test. If either gives a positive result, expert opinion should be sought to determine the need for more invasive investigations, such as endometrial biopsy. If an endometrial biopsy reveals granuloma, it is imperative that the specimen be sent for PCR and culture for TB, even in the absence of acid-fast bacilli. Consultation with an infectious diseases physician or clinical microbiologist is then warranted. In summary, this case highlights the fact that TB should be considered and excluded in high-risk women undergoing IVF, and that TB should be considered in ill neonates who have a poor response to conventional antibiotic therapy. 1 Magnetic resonance imaging scan of a 6-week old infant A scan showing multiple enlarged lymph nodes in the mediastinum measuring up to 13 mm (right paratracheal, subcarinal and right hilum) and in the axillae (largest on the left) and cervical area. 2 Section of endometrium from the infant’s mother A section of endometrium sampled 5 years before the infant’s birth showing a granuloma. (Image courtesy of Dr John Rees, Southern Health Pathology Department, Melbourne, Vic.)

Rhonda L Stuart MB BS, FRACP, PhD · Anthony Lewis MB BCh, MMed(Microbiology), FRACP · C Andrew Ramsden FRCP, FRCPCH, FRACP · Richard R Doherty MB BS, FRACP

To the Editor: We both are ear, nose and throat (ENT) specialists at a tertiary university hospital and cover 1–2 nights of emergency calls each month. Over 8 months in 2008, we witnessed four emergency patients (aged 25–39 years; three men, one woman) who had sore throat, mild fever and pain on swallowing, without any respiratory distress symptoms. One patient presented with “hot potato voice”. All had had a palatine tonsillectomy in childhood. On examination, the oral pharynx appeared normal to mildly hyperaemic, without any suppuration. To exclude potentially fatal epiglottitis, all patients underwent transnasal flexible laryngoscopy, which revealed swollen lingual tonsils covered with fibrinous exudate typical of streptococcal infection. Distal structures, including the epiglottis and endolarynx, were normal. Acute lingual tonsillitis was diagnosed, and the patients quickly responded to penicillin therapy. Some degree of infection of the lingual tonsils probably occurs when the pharynx is otherwise infected, but is usually left undiagnosed because it is not easily visible without laryngoscopy.1 Although none of our patients had any life-threatening symptoms, this condition could potentially cause upper airway compromise, and the course would certainly be more arduous without antibiotics. The flexibility of our health care system in Croatia allows for some emergency patients’ to refer themselves to the relevant specialty services. If these patients had presented to general practice rather than to our department, where we performed transnasal laryngoscopy, this diagnosis would have probably gone unnoticed, and antibiotic therapy would not have been prescribed. Thus, is acute lingual tonsillitis a neglected cause of severe sore throat? A search of the current literature and ENT textbooks did not reveal many reports of this disease.2,3 Even if our observations referred to rare cases, considering our hospital catchment population for ENT emergencies of more than 300 000, they still outnumbered all cases of epiglottitis treated at our emergency service during the same period. Therefore, it is our opinion that acute lingual tonsillitis should be at least kept in mind as a condition that can cause severe sore throat that is oropharyngoscopically silent or mimics simple viral infection, but is effectively and readily treated with antibiotics.4 Because the base of the tongue cannot be visualised by routine intraoral examination, confirmation of the diagnosis must be made by an ENT specialist who will perform laryngoscopy.

Sasa Janjanin · Drago Prgomet

To the Editor: We read with interest the work presented by Markovic and Natoli, highlighting the importance of recognising the nutrient density of foods in managing overweight and obese patients.1 We present data to support their observation that it should not be assumed that a patient who is overweight or obese has a nutritionally adequate diet. Our data were obtained as part of the Geelong Osteoporosis Study from an age-stratified sample of men randomly selected from electoral rolls for the Barwon Statistical Division in Victoria. Dietary intake was estimated using a food frequency questionnaire developed by the Cancer Council Victoria.2 Basal metabolic rate (BMR) was estimated from the Schofield equations, based on age and weight. Data were excluded if the ratio of energy intake (EI) (from food and alcohol combined) to BMR was < 0.9. The sample comprised 1175 men aged 20–93 years (median age, 56 years [interquartile range, 39–73 years]; mean weight, 81 kg [SD, 14 kg]; mean height, 1.75 m [SD, 0.07 m]). Participants were grouped by body mass index (BMI) into three categories: normal weight (BMI < 25 kg/m2), overweight (BMI 25.0–29.9 kg/m2) and obese (BMI ≥ 30 kg/m2). Estimates of physical activity were derived from self-report. Written, informed consent was obtained from participants, and the study was approved by the Barwon Health Human Research Ethics Committee. We investigated the breakdown of macronutrients, vitamins and minerals listed in the “virtual” case report presented by Markovic and Natoli1 and expressed intakes as a percentage of recommended dietary intake (RDI).3,4 Despite adequate EI, the diets of men in all BMI categories were low in zinc, calcium, folate and fibre (Box). We acknowledge that there are limitations posed by self-reported dietary intakes and physical activity levels. The EI–BMR ratio decreased with increasing BMI (median [interquartile range], 1.4 (1.2–1.7), 1.3 (1.1–1.6) and 1.2 (1.0–1.5) for normal weight, overweight and obese subjects, respectively), suggesting that under-reporting may have been more common with increasing BMI. We also acknowledge that RDIs are not thresholds for dietary deficiencies. Within these constraints, however, these data suggest that where there are nutritional shortcomings in diets, they are not limited to men of normal weight-for-height, but are also apparent among those who are overweight and obese. These shortcomings suggest that nutrient-dense foods, such as whole grains and vegetables (particularly leafy green vegetables) are underconsumed, while processed foods with high saturated fat and salt content are consumed excessively. These observations underscore the importance of recognising the nutrient density of foods so that nutrition is not compromised when EI is restricted. Nutritional intake expressed as a percentage of recommended dietary intake (RDI) in a cohort of 1175 men,* by weight category† Nutrient RDI3 Normal weight (n = 471)‡ Overweight (n = 530)‡ Obese (n = 174)‡ Energy (kJ) § 92% (78%–111%) 97% (83%–119%) 105% (88%–124%) Protein (g) 64 (20–70 y); 81 (> 70 y) 139% (109%–181%) 143% (115%–185%) 157% (124%–195%) Total fat (g) 70* 124% (97%–158%) 123% (97%–153%) 127% (102%–173%) Saturated fat (g) 24* 146% (112%–190%) 145% (109%–188%) 154% (115%–206%) Carbohydrate (g) 310* 77% (64%–94%) 78% (65%–92%) 77% (65%–90%) Sugar (g) 90* 117% (90%–142%) 115% (88%–148%) 106% (84%–131%) Fibre (g) 30¶ 78% (60%–100%) 80% (61%–99%) 80% (64%–98%) Iron (mg) 8 173% (136%–225%) 180% (148%–223%) 185% (151%–229%) Zinc (mg) 14 88% (69%–110%) 92% (74%–113%) 93% (79%–120%) Calcium (mg) 1000 (20–70 y); 1300 (> 70 y) 87% (66%–117%) 89% (70%–116%) 90% (68%–109%) Folate (μg) 400 78% (62%–99%) 81% (64%–99%) 82% (67%–102%) Vitamin C (mg) 45 279% (194%–402%) 283% (204%–409%) 294% (213%–434%) Vitamin A (μg) 900 100% (80%–131%) 104% (82%–126%) 104% (82%–127%) Sodium (mg) 460–920¶ 306% (247%–399%) to 611% (494%–799%) 314% (259%–382%) to 628% (518%–764%) 345% (258%–412%) to 690% (515%–824%) BMI = body mass index. y = years. * As no National Health and Medical Research Council (NHMRC) RDIs exist for total fat, saturated fat, carbohydrate and sugar, we used Food Standards Australia New Zealand RDI values for these nutrients.4 † Normal weight, BMI < 25 kg/m2; overweight, BMI 25.0–29.9 kg/m2; obese, BMI ≥ 30 kg/m2. ‡ Data are presented as median (interquartile range). § RDI for energy was based on age and height and a physical activity factor derived from self-report. ¶ Adequate intake.

Julie A Pasco · Margaret J Henry · Mark A Kotowicz · Geoffrey C Nicholson

To the Editor: Markovic and Natoli draw attention to the frequent presence of nutritional deficiencies in obesity.1 While the authors detail various nutrient deficiencies that may arise from a nutrient-poor diet, they do not discuss the possibility of vitamin D deficiency. Normally the main source of vitamin D is that synthesised in skin exposed to ultraviolet B radiation. A nutrient-rich or nutrient-poor diet alone is unlikely to provide adequate vitamin D unless foods are supplemented with vitamin D. Vitamin D deficiency in obese people is prevalent, and Holick has described an inverse relationship between body mass index and 25-hydroxyvitamin D levels, with sequestration of vitamin D in body fat reducing its availability.2 Vitamin D deficiency is associated with various conditions for which obesity is a risk factor, including cancer, depression, altered glucose metabolism and cardiovascular disease.2 A prospective study would be required to determine whether vitamin D supplementation is able to modify some of these associations. Increasing vitamin D levels are associated with improved muscle strength,2 and thus vitamin D supplements may be of benefit in obese patients with reduced vitamin D levels. Furthermore, combined vitamin D and calcium supplementation may have a small beneficial role in preventing type 2 diabetes.3 Pending more evidence, it would be prudent to consider measuring 25-hydroxyvitamin D levels in obese people and correcting any deficiency. In view of the large amount of adipose tissue in obese people, it is likely that they would require higher than normal doses to achieve repletion of their vitamin D stores.

Barbara Depczynski

To the Editor: We concur wholeheartedly with Gill and colleagues1 in support of recognising obesity as a public health issue, and we dispute claims that the current problem of obesity is being exaggerated. Gill and colleagues point out that obesity trends have climbed over decades, and state that 6%–8% of Australian school children are affected.1 While this is a substantial burden of over a quarter of a million children, we also consider that restricting definitions of obese to arbitrary cutoff points may underestimate the problem, given that the entire distribution of childhood weight is increasing, not just the extreme group classified as obese. Adiposity is related to cardiovascular outcomes such as myocardial infarction and stroke in a (curvi)linear fashion. Defining obesity by arbitrary cutoff points is vulnerable to differences between sexes, ethnicity and age, and limits our understanding of obesity-related diseases. It is well known that cardiovascular risk factors cluster, particularly the adiposity-driven components of the so-called metabolic syndrome. In the Western Australian Pregnancy Cohort (Raine) Study, we have used cluster analysis to identify a group of children at risk of future cardiovascular disease with features of the metabolic syndrome.2 The differences in characteristics are shown in the Box. The “high risk” and “low risk” cluster groups differ widely in terms of not only body mass index, the most widely used measure of obesity, but also waist circumference (a measure of central adiposity), insulin resistance, blood pressure, and levels of triglycerides, high-density lipoprotein cholesterol, total cholesterol (data not shown) and low-density lipoprotein cholesterol (data not shown). Not only the conventionally used 95% confidence intervals, but also the 99% confidence intervals do not overlap for any of these intermediate cardiovascular risk factors. We found that 29% of children were in the high-risk cluster at the age of 14 years2 and a similar analysis suggested that even at age 8 years, 25% of children were at increased risk of future obesity, cardiovascular disease and diabetes.3 C-reactive protein (CRP) level is known to be associated with future cardiovascular diseases in adults,4 and with an adverse metabolic profile in children.5 The “high risk” children had significantly higher CRP levels at the age of 14 years than their low-risk counterparts. Certainly, the magnitude of this problem, affecting up to a third of our youth, needs to be addressed by government and health-planning bodies. We suggest our approach of cluster analysis will help identify earlier those children at substantially increased risk of cardiovascular and other adiposity-related disorders in Australia. Features of the cluster groups with respect to components of the metabolic syndrome, showing 99% CIs* BMI = body mass index. HOMA = homeostatic model assessment (for quantifying insulin resistance). SBP = systolic blood pressure. HDL = high-density lipoprotein cholesterol. * From Huang et al.2 Reprinted with permission from the American Diabetes Association.

Rae-Chi Huang · Fiona J Stanley · Lawrence J Beilin

To the Editor: There is a substantial volume of evidence from a range of national and state-based surveys illustrating increases in the rates of obesity and overweight among Australian children over the past two decades,1 concurring with trends observed in most developed countries.2 The recent article by Gill and colleagues highlighted questions that have been raised publicly regarding the extent and impact of levels of obesity and overweight among Australian children, including whether trends have been exaggerated.1 To examine these issues using the latest data available, we present data from the three most recent national surveys in which weight and height of Australian children were measured: the Australian Health and Fitness Survey (1985),3 the National Nutrition Survey (1995),4 and the Australian National Children’s Nutrition and Physical Activity Survey (2007).5 We examined overweight and obesity levels among young Australians from comparable age groups at three time points over more than 20 years, using the same internationally accepted definitions of childhood overweight and obesity. For 1985 and 1995 data, we used the figures reported by Magarey et al in 2001,6 which compared results from the 1985 and 1995 surveys using new standard international definitions to classify overweight and obesity among Australian children and adolescents.7 We calculated body mass index for the 2007 Australian National Children’s Nutrition and Physical Activity Survey using the raw data file obtained through the Australian Social Science Data Archive,8 categorising children as overweight or obese based on the same international definitions used by Magarey et al.6 We based our calculations on the age group common to each of the three surveys: 7–15-year-olds. As shown in the Box, the prevalence of overweight and obesity in boys aged 7–15 years has risen from 11.0% (95% CI, 10.99%–11.01%) in 1985 to 20.0% (95% CI, 19.97%–20.03%) in 1995 and 23.7% (95% CI, 23.68%–23.72%) in 2007. In 7–15-year-old girls, the prevalence of overweight and obesity has increased from 12.2% (95% CI, 12.19%–12.21%) in 1985 to 21.5% (95% CI, 21.47%–21.53%) in 1995 and 25.8% (95% CI, 25.78%–25.82%) in 2007. While data from additional time points are required to map national trends more comprehensively, our analysis clearly indicates an upward trend in overweight and obesity levels in both boys and girls aged 7–15 years between 1985, 1995 and 2007. This trend is cause for alarm, given the widely recognised body of evidence on the significant short-term and long-term consequences of childhood obesity.9 Prevalence of overweight and obesity in Australian children aged 7–15 years, 1985–2007 * Data weighted for age, sex and region with the weighting variable in the raw data file obtained from the Australian Social Science Data Archive.8

Lyn M Roberts · Tessa R Letcher · Alexandra A Gason · Tim Lobstein

To the Editor: Davis and colleagues stated that the Framingham and United Kingdom Prospective Diabetes Study (UKPDS) cardiovascular risk equations are not suitable for predicting risk in an Australian population with type 2 diabetes.1 If confirmed, this would be extremely disappointing. However, before accepting this conclusion the following important considerations should be noted. Davis noted that the Fremantle Diabetes Study (FDS) patient group differed significantly from the UKPDS baseline group (eg, 38% of the FDS patients were aged outside the validated age range of the risk engine [25–65 years] and were assessed by non-validated extrapolation). Similarly, it cannot be assumed that the FDS group is representative of patients in general practice and hospital diabetes clinics around Australia. Moreover, it would be interesting to know how well the engine performs in FDS patients in the age group in which it was validated (ie, patients diagnosed with diabetes at age 25–65 years). It is likely that the low rate of cardiovascular events in the FDS (4.8% with at least one myocardial infarction, and 2.9% with at least one stroke)1 affects the accuracy of the results obtained with the UKPDS risk engine. The Framingham risk score has already been found to vary considerably in accuracy between populations, with predicted-to-observed ratios ranging from underprediction of 0.43 to overprediction of 2.87.2 Further, the UKPDS risk engine recently overestimated the risk of cardiovascular disease events in a UK general practice population.3 In purely pragmatic terms, most patients with type 2 diabetes aged over 50 years are at “high risk” for cardiovascular events (cardiovascular risk of more than 20% over 10 years),4 and the UKPDS risk engine is unlikely to influence prescribing practice significantly. However, we have found the engine to be a useful educational tool for explaining risk to patients. Even if the UKPDS risk engine is not optimally calibrated, the FDS analysis revealed that the coronary heart disease risk equation had modest discrimination (area under the receiver operating characteristic curve [AUC], 0.68), and the stroke risk equation had good discrimination (AUC ≥ 0.86),1 identifying those at highest risk. We believe that, rather than being irrelevant in Australians, the UKPDS risk engine continues to identify those at highest risk for cardiovascular events, operates well within its validated age group, and provides a motivational tool for encouraging changes in patient behaviour. Until a large dataset is pooled from various Australian studies, we believe the UKPDS risk engine should not be discarded.

Roland W McCallum · John R Burgess · Timothy M Greenaway

In reply: We thank McCallum and colleagues for their comments. In relation to their specific points: The Fremantle Diabetes Study (FDS) cohort is representative and drawn from a typical Australian urban centre.1 The 488 cardiovascular disease-free FDS participants with type 2 diabetes who were aged 25–65 years at both diagnosis and study entry had 22 coronary heart disease (CHD) events compared with 72 predicted, with a similar area under the receiver operating characteristic curve (AUC) to that for all 791 patients who were included in the analysis2 (0.66 v 0.68). Calibration indicated significant discrepancies between predicted and actual outcomes (P ≤ 0.02), and positive predictive values were low (≤ 3.5%). Therefore, restricting our patient sample to a “UKPDS” cohort did not alter our conclusions. We agree that the low observed CHD event rate in the FDS compared with that predicted by the UKPDS risk engine undermines its validity in Australians with type 2 diabetes. There was a similarly low CHD event rate in the FIELD study, which included many Australasians.3 Contemporary diabetes care clearly differs from that during the Framingham Study and UKPDS. Although the study cited by McCallum and colleagues, in a UK general practice population, is not strictly comparable to our study, it also found that the UKPDS cardiovascular disease risk engine performed only moderately (AUC, 0.72).4 Accurate risk prediction should be a basis for cost-effective care. We have developed an FDS risk calculator which should improve clinical management for Australians with diabetes.5

Wendy A Davis · Stephen Colagiuri · Timothy M E Davis

A woman with metastatic breast cancer developed diarrhoea, vomiting, and hand and foot discomfort within about 10 days of ceasing therapy with capecitabine and starting docetaxel therapy. The palms of both hands and feet were inflamed and tender, with confluent blanching erythematous areas (Figure). Extensive desquamation occurred from Day 12 to Day 19 after admission, with return to normal skin by Day 30. Hand–foot syndrome has been reported after therapy with various antineoplastic agents, most commonly cytarabine, liposomal doxorubicin, capecitabine, 5-fluorouracil, sorafenib and sunitinib. Increased metabolism of capecitabine in the palms may contribute to the local reaction;1 as may the concentration of docetaxel in eccrine glands in the palms and soles.2 Management involves stopping therapy with the implicated drug, analgesia, and preventing superinfection. Palmar surfaces of the hands showing confluent and erythematous lesions, and the plantar surface of one foot showing a blanching erythematous rash.

Chitra Sivaramamoorthy · Eddy S Thientosapol · Martin H Tattersall

Ablating Barrett’s Intestinal metaplasia of the oesophagus (Barrett’s oesophagus) is associated with an increased risk of oesophageal adenocarcinoma through the development of epithelial dysplasia. In a randomised controlled trial involving 127 patients, researchers in the United States have found that radiofrequency ablation of dysplastic Barrett’s oesophagus was successful in achieving a high rate of eradication of the abnormality, along with a reduced risk of disease progression. The authors caution that the results must be interpreted in relation to the grade of severity of oesophageal dysplasia, which has varying risk of progression to cancer. They also comment on potential side effects, including oesophageal stricture, and suggest the need for cost–benefit analyses. N Engl J Med 2009; 360: 2277-2288 Depression and chronic pain Primary care providers are well aware that depression and chronic pain are common causes for presentation to a GP, and that these two problems commonly coexist. A combined pharmacological and behavioural approach appears to improve both depression and pain in patients with musculoskeletal pain and comorbid depression, according to the results of a recent randomised controlled trial. The intervention group was placed on optimised (supervised) antidepressant therapy for 12 weeks, followed by a 12-week pain self-management program, and a further 6 months of assessment and assistance. Significant improvements in both depression severity and level of pain were reported in the treatment group compared with the controls. The authors comment that, although the non-specific effect of care-manager contact is difficult to determine, the results have important clinical and economic implications. JAMA 2009; 301: 2099-2110 Sleep apnoea damages brain function The damaging effects of obstructive sleep apnoea (OSA) on brain function may be more serious than previously thought, according to Australian researchers. Using 31P magnetic resonance spectroscopy, a non-invasive tool for measuring the relative intracellular concentrations of several phosphorus metabolites, scientists studied the brains of 13 men with severe OSA during apnoeic episodes occurring during sleep. Oxygen saturation was measured via pulse oximetry throughout scanning. The spectra revealed that moderate oxygen desaturation during sleep resulted in significant effects on brain bioenergetic status. In particular, compensatory protective mechanisms appear to be inactive in the transient hypoxia experienced during sleep apnoea. The authors comment that the effects of new therapeutic agents aimed at protecting brain function in OSA may be measured using this method. J Cereb Blood Flow Metab 2009; 13 May [Epub ahead of print] An aspirin a day? The relative benefits and risks of prophylactic aspirin therapy were the subject of a recent large collaborative meta-analysis. In an advance on previous studies, individual patient data from several randomised controlled trials were included, using data from 95 000 individuals from six randomised controlled trials. This allowed researchers to estimate the magnitude of risk factors such as age, male sex, diabetes and high blood pressure for different outcomes including stroke, myocardial infarction, and vascular death. The risk of major bleeding with aspirin therapy was also assessed in the primary and secondary prevention of these vascular diseases. The investigators concluded that, in primary prevention without previous disease, the use of aspirin is of uncertain net benefit when the risks of occlusive events and major bleeds are weighed up against each other. Lancet 2009; 373: 1849-1860 Genes for autism The search for genetic markers of autism spectrum disorders (ASDs) is narrowing, say US scientists who have performed a whole-genome study aimed at identifying genetic variations that confer susceptibility to ASDs. Along with some previously reported ASD candidate genes, several new susceptibility genes were revealed. These genes were found to encode neuronal cell-adhesion molecules which are critical in the development of the nervous system. A second association was identified with genes from the ubiquitin pathway, which is involved in the turnover of synaptic components, and has been linked to other human neurological syndromes, including juvenile Parkinson’s disease and intellectual disability. The authors suggest functional studies need to be carried out to assess the biological effects of abnormalities in these candidate genes. Nature 2009; 459: 569-573

Tanya Grassi