'Aussie Normals': an a priori study to develop reference intervals in a healthy Australian population using the Beckman Coulter LH 750 Haematology Analyser as candidates for harmonised values.

Reference limits or intervals are important benchmarks or tools that help the clinician to distinguish between a result that is most likely to lie within a 'healthy' or diseased category. It has been suggested that a review of haematology reference intervals is long overdue. In this study we report on our findings for analytes routinely measured in a complete blood count (CBC) performed on the Beckman Coulter LH 750 analyser and an additional comparative study using the Beckman Coulter LH 750, the Sysmex XN and Abbott Sapphire. The results from the comparative study indicate that bias would not prevent harmonisation of reference intervals for these common haematology parameters. The results offered by the Aussie Normals study represent good candidates as the basis for harmonisation reference intervals.

'Aussie normals': an a priori study to develop clinical chemistry reference intervals in a healthy Australian population.

Development of reference intervals is difficult, time consuming, expensive and beyond the scope of most laboratories. The Aussie Normals study is a direct a priori study to determine reference intervals in healthy Australian adults. All volunteers completed a health and lifestyle questionnaire and exclusion was based on conditions such as pregnancy, diabetes, renal or cardiovascular disease. Up to 91 biochemical analyses were undertaken on a variety of analytical platforms using serum samples collected from 1856 volunteers. We report on our findings for 40 of these analytes and two calculated parameters performed on the Abbott ARCHITECTci8200/ci16200 analysers. Not all samples were analysed for all assays due to volume requirements or assay/instrument availability. Results with elevated interference indices and those deemed unsuitable after clinical evaluation were removed from the database. Reference intervals were partitioned based on the method of Harris and Boyd into three scenarios, combined gender, males and females and age and gender. We have performed a detailed reference interval study on a healthy Australian population considering the effects of sex, age and body mass. These reference intervals may be adapted to other manufacturer's analytical methods using method transference.

High-resolution SNP microarray investigation of copy number variations on chromosome 18 in a control cohort.

Copy number variations (CNVs) as described in the healthy population are purported to contribute significantly to genetic heterogeneity. Recent studies have described CNVs using lymphoblastoid cell lines or by application of specifically developed algorithms to interrogate previously described data. However, the full extent of CNVs remains unclear. Using high-density SNP array, we have undertaken a comprehensive investigation of chromosome 18 for CNV discovery and characterisation of distribution and association with chromosome architecture. We identified 399 CNVs, of which loss represents 98%, 58% are less than 2.5 kb in size and 71% are intergenic. Intronic deletions account for the majority of copy number changes with gene involvement. Furthermore, one-third of CNVs do not have putative breakpoints within repetitive sequences. We conclude that replicative processes, mediated either by repetitive elements or microhomology, account for the majority of CNVs in the healthy population. Genomic instability involving the formation of a non-B structure is demonstrated in one region.

NTproBNP concentrations in healthy children.

INTRODUCTION: There have been limited studies generating BNP and NT-proBNP reference intervals for paediatric populations. We prospectively assessed NT-proBNP levels in a cohort of 854 healthy school children from the Lifestyle of Our Kids (LOOK) prospective longitudinal study. MATERIALS AND METHODS: NT-proBNP analysis was performed on 172 girls and 212 boys with average age 8.1 years, 183 girls and 181 boys, average age 10.1 years and 183 girls and 180 boys with average age 11.9 years. Data were stratified according to age and gender with the median, range of results and 2.5th and 97.5th percentiles calculated RESULTS: There were no significant differences between males and females at any of the 3 study ages. Significant differences were seen between the 8 and 12 year-olds, 10 and 12 year-olds and the 8 and 12 year-old boys. DISCUSSION: Our study demonstrated that NT-proBNP concentrations in healthy children progressively decline between ages 8 and 12 years. Our selection of unambiguously healthy children produced similar median but lower 97.5th percentile NT-proBNP concentrations to previously published studies.

A randomised trial of peer review: the UK National Chronic Obstructive Pulmonary Disease Resources and Outcomes Project.

Peer review has been widely employed within the NHS to facilitate health quality improvement but has not been rigorously evaluated. This article reports the largest randomised trial of peer review ever conducted in the UK. The peer review intervention was a reciprocal supportive exercise that included clinicians, hospital management, commissioners and patients which focused on the quality of the provision of four specific evidence-based aspects of chronic obstructive pulmonary disease care. Follow up at 12 months demonstrated few quantitative differences in the number or quality of services offered in the two groups. Qualitative data in contrast suggested many benefits of peer review in most but not all intervention units and some control teams. Findings suggest peer review in this format is a positive experience for most participants but is ineffective in some situations. Its longer term benefits and cost effectiveness require further study. The generic findings of this study have potential implications for the application of peer review throughout the NHS.

Prognostic efficacy of cardiac biomarkers for mortality in dialysis patients.

BACKGROUND: The high prevalence of cardiovascular mortality in the end-stage renal disease population is well established. The aim of this current study was to document the relative prognostic significance of established cardiac biomarkers troponin T (TnT), troponin I (TnI), B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) in this population. METHODS: A prospective cohort study of dialysis patients undertaken in a single tertiary centre in Australia. Relevant clinical and biochemical information was collected at entry and all patients followed up prospectively without any loss to follow up. End-point of interest was all-cause mortality. Statistical analysis using Cox proportional hazards was used to study relationship between competing covariates and outcome. A total of 143 patients with a mean age of 59.67 +/- 15.49 years was followed up for a median duration of 30 months. Of these patients, 89.3% were white Australians of European ancestry. Twenty-seven per cent had an established diagnosis of diabetes mellitus. The mean concentrations (+/-SD) of TnT, TnI, BNP and N-terminal peptide pro-BNP (NT-pro-BNP) were 0.08 +/- 0.04 microg/L, 0.09 +/- 0.2 microg/L, 270 +/- 117 ng/L and 1434 +/- 591 ng/L respectively. RESULTS: Twenty-eight subjects died during the period of follow up. By univariate analysis, all cardiac markers (TnT, TnI, BNP, NT-pro-BNP and C-reactive protein) were significantly associated with an increase in mortality. On Cox proportionate hazards analysis, only albumin and NT-pro-BNP showed a significant association with mortality, with hazard ratios of 0.834, 95% confidence interval (CI) 0.779-0.893, P < 0.001, and 1.585, 95%CI 1.160-20165, P = 0.004 respectively. CONCLUSION: In patients with end-stage renal failure on dialysis NT-pro-BNP provides greater prognostic information compared with TnT and TnI.

Elevated serum cardiac troponin I in older patients with hip fracture: incidence and prognostic significance.

INTRODUCTION: Cardiovascular complications are the main causes of morbidity and mortality in patients with osteoporotic hip fracture (HF). The aim of this prospective study was to evaluate the incidence and prognostic significance of elevated cardiac troponin I (cTnI) in the early peri-operative period in older patients with HF. MATERIALS AND METHODS: A blind evaluation of myocardial injury as detected by cTnI elevation in 238 consecutive older patients with low-trauma HF (mean age 81.9 +/- 7.8 (SD) years; 72% females). Data on demographic and clinical characteristics, in-hospital mortality, hospital length of stay and discharge destination were collected prospectively. Serum cTnI level was analysed from blood collected routinely in the first 72 h of hospital admission. RESULTS: Sixty-nine (29%) patients had elevated cTnI (>0.06 microg/l) but myocardial injury was clinically recognised in only 23 (33%) and only 24 (34.8%) had a history of coronary artery disease (CAD). Patients with elevated cTnI were significantly older, more often had American Society of Anaesthesiologist status score >or=3, a history of CAD or stroke and more often were current smokers than the patients without cTnI elevation. In multivariate regression analysis only age was an independent predictor of cTnI elevation. Patients with cTnI release were twice as likely to have a length of stay >or=20 days (P = 0.047) and 2.7 times more likely to be discharged to a long-term residential care facility (RCF) (P = 0.013). cTnI level >or=1 microg/l was a strong independent predictor of all-cause mortality with 98.3% specificity and 89.1% negative predictive value. CONCLUSION: Peri-operative myocardial injury is common in older HF patients but is frequently unrecognised clinically. Elevated blood cTnI level is an independent predictor of prolonged length of hospital stay (>or=20 days), need for long-term RCF and mortality (if cTnI >or=1 microg/l).

Cushing's syndrome in a clinic population with diabetes.

BACKGROUND: A recent report has suggested that occult Cushing's syndrome (CS) may be present in a significant number of patients with type 2 diabetes mellitus. The aim of this study was to determine whether any patients in our clinic population with diabetes had this condition. METHODS: One hundred and seventy-one consecutive overweight attendees at the diabetic clinic were enrolled in a study to assess the presence of occult CS. The initial screen was with the 1 mg overnight dexamethasone suppression test and follow-up testing, where indicated was with a 24 h collection for urine-free cortisol. RESULTS: Thirty-one of 171 patients had a positive result from the overnight dexamethasone suppression test. Follow-up testing with 24 h urine-free cortisol reduced the number of patients with positive results to 3. Two of these were shown to have alcoholic pseudo-CS. The third patient has had several high urine-free cortisol results, in the presence of normal scans of pituitary and adrenals. He has no stigmata of CS and is being observed. CONCLUSION: Based on the results of our study, there would appear to be little value in screening type 2 diabetics for CS, in the absence of clinical suspicion.

Effects of hypoxia/reperfusion injury on drug disposition in the rat isolated perfused liver.

1. Ischaemia-reperfusion injury is known to be associated with a range of functional and structural alterations in the liver. However, the effect of this injury on drug disposition is not well understood. The present study was designed to examine the effects of hypoxia/reperfusion on the disposition of glutamate and propranolol in the rat isolated perfused liver. Both glutamate and propranolol are mainly metabolised in the pericentral region of the liver. 2. Hypoxia/reperfusion was established using the slow flow-reflow method of perfusion in both anterograde and retrograde perfusion. Glutamate metabolism was measured by the recovery of [(14)C]-glutamic acid and [(14)C]-labelled metabolites in a single pass in both anterograde and retrograde perfusion in the presence of a steady state concentration of unlabelled glutamic acid. Propranolol disposition, mean transit time and normalized variance were assessed from the outflow concentration-time profile of unchanged [(3)H]-propranolol determined after a bolus injection of [(3)H]-propranolol using HPLC and liquid scintillation counting. 3. Hypoxia/reperfusion of livers did not affect oxygen consumption, but caused significant changes in enzyme release, lignocaine hepatic availability and bile flow. 4. Hypoxia/reperfusion did not affect the hepatic metabolism of glutamate to carbon dioxide or the hepatic extraction of propranolol. Small but significant changes were evident in the distribution parameters of mean transit time and vascular disposition for the hypoxic-ischaemic liver. 5. It is concluded that reperfusion injury induced by slow flow-reflow perfusion did not influence the extraction of glutamate or propranolol, but may have affected pericentral morphology and solute distribution.

The comparative analytical performance of four troponin I assays at low concentration.

BACKGROUND: Low troponin concentrations have been shown to be informative in the prognosis of acute coronary syndrome. We have investigated the analytical performance of four commonly used cardiac troponin I methods at concentrations approaching their analytical limit of detection. METHOD: We assayed 167 patient samples within 24 h of collection using the Beckman Coulter AccuTnI, Dade Behring Dimension, Abbott AxSYM and Bayer Centaur methods and compared their relative analytical performance. RESULTS: Of the four assays compared, the AccuTnI was observed to have greater sensitivity at low concentrations. Using the limit of detection as the threshold, the Beckman assay showed superior performance at concentrations corresponding to a 20% coefficient of variation (CV), the Dade assay had a similar performance; and at concentrations corresponding to 10% CV most assays provide similar information. CONCLUSION: The newer or recently modified assays such as the Beckman Coulter AccuTnI and Dade Behring assays are best able to identify very low concentrations of troponin.

National clinical sentinel audit of evidence-based prescribing for older people.

OBJECTIVES: To audit the performance of hospitals in evidence-based prescribing. SETTING: All hospitals in England were invited to participate. The audit was completed in 62 hospitals. SUBJECTS: Prescribing and clinical data were collected on 100 consecutive medical inpatients aged >/= 65 years at each site, enabling evaluation of eight prescribing indicators before and after intervention. The data were collected using a specifically designed database. INTERVENTIONS: The results of the first audit were available immediately from the software and a national report with locally identifiable information was returned to hospitals. Hospitals were encouraged to design and deliver their own intervention strategy. A questionnaire was sent to all hospitals to document prioritization of indicators. RESULTS: Generic names were used for 36 061 (82.6%) in 1999 and 39 188 (86.4)% in 2000. In 1999, 50% (3074) of patients had documentation of allergy status. This increased to 60% (3684) in 2000. For 21.2% of patients prescribed paracetamol in 1999 and 18.1% in 2000, the prescription was written such that it was possible to exceed the maximum recommended dose of 4 g in 24 hours. Long-acting hypoglycaemic drugs were prescribed to 29 patients in 1999 and 20 patients in 2000. Anti-thrombotics were used appropriately for 54% (520/966) of patients in atrial fibrillation in the first audit and 57% (579/1019) in the second audit. The appropriate use of aspirin increased from 91% (595/651) to 94% (725/772) and the appropriate use of benzodiazepines dropped from 49% (537/1088) to 47% (460/966) between the audits. For three indicators, the allocating of a high priority translated into a bigger improvement between the audits. CONCLUSIONS: Local ownership of data and the quality improvement process, and provision of national benchmarking data did not result in a significant improvement in prescribing in the second audit.

Bone mineral density in Australian children, adolescents and adults with cystic fibrosis: a controlled cross sectional study.

BACKGROUND: Low bone mineral density (BMD) is recognised in individuals with cystic fibrosis (CF) although the pathogenesis remains unclear. The aims of this study were to compare BMD over a broad continuum of Australian individuals with CF with healthy controls and to examine the relationship between BMD and clinical parameters including physical activity, nutrition, and vitamin D levels. METHODS: BMD of the lumbar spine (LS), total body (TB), femoral neck (FN), cortical wrist (R33%), and distal wrist (RUD) was examined in 153 individuals with CF aged 5.3-55.8 years (84 males) and in 149 local controls aged 5.6-48.3 years (66 males) using dual energy x ray absorptiometry. Anthropometric variables, body cell mass, markers of disease severity, corticosteroid usage, measures of physical activity, dietary calcium and caloric intake and serum vitamin D were assessed and related to BMD. RESULTS: Compared with controls, mean BMD was not significantly different in children aged 5-10 years with CF. Adolescents (females 11-18 years, males 11-20 years) had reduced TB and R33% BMD when adjusted for age, sex, and height (difference in BMD (g/cm2) adjusted means between control and CF: TB=0.04 (95% CI 0.01 to 0.07); R33%=0.03 (95% CI 0.01 to 0.06)). BMD was reduced at all sites except R33% in adults (difference in BMD (g/cm2) adjusted means between control and CF: TB=0.05 (95% CI 0.02 to 0.09); LS=0.08 (95% CI 0.03 to 0.14); FN=0.09 (95% CI 0.03 to 0.15); RUD=0.03 (95% CI 0.01 to 0.05)). In children/adolescents BMD was weakly associated with nutritional status and disease severity. CONCLUSIONS: BMD was normal in a well nourished group of prepubertal children with CF. A BMD deficit appears to evolve during adolescence and becomes more marked in adults. Individuals with CF should optimise nutrition, partake in physical activity, and maximise lung health in order to optimise BMD. Further longitudinal studies are required to understand the evolution of reduced BMD in young people and adults with CF.

National sentinel clinical audit of evidence-based prescribing for older people: methodology and development.

RATIONALE, AIMS AND OBJECTIVES: This national clinical audit aimed to develop and implement a methodology to assess the appropriateness of prescribing for patients over the age of 65 in hospitals, general practice and nursing homes. METHODS: Organizations providing health care in the National Health Service in these three sectors were recruited into multi-disciplinary and inter-organizational local coalition teams. Prescription data and relevant clinical data were collected electronically on a customized database. The appropriateness of prescribing for specific conditions among the patients sampled was assessed by simple computerized algorithms, and users were provided with feedback to stimulate discussion and change. Use of the software tool was demonstrated to be feasible and its data reliable. Participants were re-audited, after a period of nationally guided and locally driven intervention, to evaluate levels of change. Local efforts to stimulate change and barriers to change were collected qualitatively. RESULTS AND CONCLUSIONS: The investigation revealed encouraging results and demonstrated the ability of audit to improve the quality of clinical services in given circumstances, although a multiplicity of questions relating to cost and methodology remain to be addressed.

Detrusor myotomy: a 5-year review in unstable and non-compliant bladders.

OBJECTIVE: To identify urodynamic factors that might determine the clinical outcome of detrusor myotomy in incontinent children. PATIENTS AND METHODS: Six girls and three boys (aged 5-14 years) underwent detrusor myotomy for severe urinary incontinence. Seven children had spina bifida, one had traumatic paraplegia and one had low bladder compliance. The patients were followed for a minimum of 5 years. RESULTS: Urodynamic studies before surgery showed that three patients had normal compliance with grossly unstable detrusor contractions, and six had low bladder compliance with few phasic detrusor contractions. Detrusor leak-point pressures were > 40 cmH2O in five patients and < 40 cmH2O in four. Only two patients, both with grossly unstable detrusor contractions and leak-point pressures of > 40 cmH2O, had a successful 5-year outcome. The other seven patients remained incontinent; six underwent further surgery and one died from unrelated causes. CONCLUSION: Detrusor myotomy appears to have the best outcome in those patients with marked phasic unstable detrusor contractions with a competent urethral sphincter. In this group it may have distinct advantages over more commonly used procedures.

Protein energy supplements in unwell elderly patients--a randomized controlled trial.

BACKGROUND: To determine whether oral protein energy supplements, prescribed during hospitalization to elderly medical admissions, affect nutritional status and if baseline nutritional state influences this status. We also considered the effects on mortality, length of hospital stay, functional recovery, and institutionalization. METHODS: A prospective randomized controlled trial with no placebo. Consenting patients were stratified in 3 nutritional categories, and patients from each stratum were randomized into treatment or control. Observers were blinded to randomization. The participants were emergency admissions from home to a Medicine for the Elderly Unit in a Scottish hospital. The inclusion criteria were as follows: no known malignancy, the ability to swallow, and nonobesity (BMI < 75th percentile). The intervention was a prescription of 120 mL sip feed, 3 times daily (540 kcal, 22.5 g protein per day) throughout hospitalization, using the medicine prescription chart. The trial was powered to detect change in mean percentage weight. The following outcomes were also considered: anthropometry; mortality, length of hospital stay, functional recovery, and rates of institutionalization. RESULTS: Included in the trial were 381 patients. Nutritional supplementation was associated with significantly better energy intake (p = .001) and weight gain (p = .003) pooled across all nutritional categories. In the most poorly nourished patients, the intervention was associated with reduced mortality (5/34 versus 14/40, p < .05) and more patients improved functionally (17/25 versus 11/28, p < .04). Overall mortality results were 21/186 versus 33/195, odds ratio (OR) 0.62, 95% confidence interval (CI) 0.35, 1.13. CONCLUSIONS: Prescribing sip feed supplements in the medicine prescription chart during hospital stay reduces weight loss. Our data also support other evidence for a reduction in mortality noted in elderly patients on nutritional supplementation. There were suggestions of other clinical benefits.

Oral supplements in the elderly.

Under-nutrition is common in elderly patients, especially for those in hospital. Hospital stay is often associated with further weight loss. Many authors have considered nutritional supplementation. A recent meta-analysis of the trials of nutritional supplementation in all age groups and pathologies found benefits from supplementation but suggested that further work was required. This review considers the work done since the meta-analysis until the end of 1999 and in particular considers the benefits evident to elderly patients using oral supplements.

Pharmacoeconomics of therapeutic drug monitoring in transplantation.

Immunosuppressive drugs have contributed significantly to the success of organ transplantation. Therapeutic drug monitoring is an integral part of transplant protocols. However, there is little information concerning its positive contribution to pharmacoeconomics. Before developing studies to demonstrate the potential benefits of TDM, consideration must be given to the type of TDM to be evaluated. It is argued that, given that the lymphocyte in the central compartment is the target for immunosuppressants, Area-Under-the-Curve monitoring may be a better reflection of control and toxicity than traditional trough monitoring.