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Background: Knowledge of individual changes in insulin resistance (IR) and longitudinal relationships of IR with lifestyle-associated factors are of important practical significance, but little longitudinal data exist in asymptomatic children. We aimed to determine (a) changes in the homeostatic model of insulin resistance (HOMA-IR) over a 2-yr period and (b) comparisons of longitudinal and cross-sectional relationships between HOMA-IR and lifestyle-related risk factors. Methods: Our subjects, 241 boys and 257 girls, were assessed at age 8.1 yr (SD 0.35) and again 2 yr later for fasting blood glucose and insulin, dual X-ray absorptiometry-assessed percentage of body fat (%BF), pedometer-assessed physical activity (PA), and cardio-respiratory fitness (CRF) by multistage running test. Results: HOMA-IR was initially 9% greater in girls than boys and 27% greater 2 yr later. There was no evidence of longitudinal relationships between HOMA-IR and %BF in boys or girls, despite significant cross-sectional relationships (p < 0.001). In boys, there was evidence of a longitudinal relationship between HOMA-IR and both PA (p < 0.001) and CRF (p = 0.05). In girls, we found a cross-sectional relationship between HOMA-IR and CRF (p < 0.001). Conclusions: HOMA-IR increases between 8 and 10 yr of age and to a greater extent in girls. Longitudinal, unlike cross-sectional, relationships do not support the premise that body fat has any impact on HOMA-IR during this period or that PA or CRF changes affect HOMA-IR in girls. These data draw attention to difficulties in interpreting observational studies in young children. [ABSTRACT FROM AUTHOR]

BACKGROUND: Potassium is usually the most important analyte affected by in vitro haemolysis and the result obtained may falsely indicate or disguise a life-threatening abnormality and so give rise to inappropriate treatment. The purpose of the study was to provide a solution to the problem of reporting potassium on haemolysed samples, taking into account both clinical needs and analytical concerns (inter-individual and inter-sample variability). METHODS: Using a new procedure that mimics the collection process in an actual clinical setting, haemolysed samples were prepared from 41 volunteers with a range of inter-individual factors - haemoglobin 80-173 g/L, red blood cells 2.42-6.77 x 10(12)/L, leucocytes 3.0-306 x 10(9) /L and platelets 31-710 x 10(9)/L - in order to develop a more accurate correction equation using a haemolytic index (HI) corresponding to g Hb/L in plasma. RESULTS: The mean (range) potassium increase was 0.0036 mmol/L (0.0029-0.0053 mmol/L) per unit HI. The following equation was developed to estimate potassium increase per HI, in order to compensate approximately for potassium leakage in haemolysed samples: Corrected K+ = Measured K+ -(HI x 0.004). CONCLUSION: The balanced solution is this: instead of reporting the post-haemolysis corrected potassium result a qualitative comment is given, indicating the likely range of the potassium concentration. If the potassium result is in a critically low or high range, it is communicated promptly to the requesting clinician. [ABSTRACT FROM AUTHOR]

To improve birth outcomes, all pregnant women without known diabetes are recommended for an oral glucose tolerance test (OGTT) to screen for hyperglycaemia in pregnancy (diabetes in pregnancy or gestational diabetes mellitus (GDM)). This narrative review presents contemporary approaches to minimise preanalytical glycolysis in OGTT samples with a focus on GDM diagnosis using criteria derived from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. The challenges of implementing each approach across a diverse Australian healthcare setting were explored. Many Australian sites currently collect and transport OGTT samples at ambient temperature in sodium fluoride (NaF) tubes which is likely to lead to missed diagnosis of GDM in a significant proportion of cases. Alternative preanalytical solutions should be pragmatic and tailored to individual settings and as close as possible to the preanalytical conditions of the HAPO study for correct interpretation of OGTT results. Rapid centrifugation of barrier tubes to separate plasma could be suitable in urban settings provided time to centrifugation is strictly controlled. Tubes containing NaF and citrate could be useful for remote or resource poor settings with long delays to analysis but the impact on the interpretation of OGTT results should be carefully considered. Testing venous blood glucose at the point-of-care bypasses the need for glycolytic inhibition but requires careful selection of devices with robust analytical performance. Studies to evaluate the potential error of each solution compared to the HAPO protocol are required to assess the magnitude of misdiagnosis and inform clinicians regarding the potential impact on patient safety and healthcare costs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Knowing the intra-individual variation (CVi), also termed within subject biological variation, of an analyte is essential to properly interpret apparent changes in concentration. While there have been many studies assessing the CVi of cardiac troponin (cTnI), they have been limited in looking at CVi in different settings, and there is no data available on whether CVi might change in different settings., Methods: We used our large cTnI data bank to look at the CVi of cTnI in Emergency Department (ED) patients who had an acute myocardial infarction event excluded. We looked at the effects of gender, age, climatic season, and time between samples to assess whether CVi changed. To assess the effect of age, after exclusion, we collected two samples from each subject for each study which were used to calculate the CVi between those identified groups. There were 139 males and 98 females aged <65 years and 109 males and 98 females aged ≥65 years. For gender and season, there were 122 males and 94 females in the summer period and 126 males and 102 females in the winter period. To assess long term variation there were 195 males and 153 females who had further admissions after more than 12 months., Results: For the four variables listed, there were no significant differences in within individual variation (CVi), but there was a significant difference in between individual variation (CVg) for men and women with regard to age. The Index of Individuality (II) was <0.20 for all conditions studied. We noted that >90% of subjects had an reference change value (RCV) <9 ng/L., Conclusions: Because troponin concentration in patients without an identified cardiac condition change so little, delta changes are potentially of great value in assessing patients in the ED. Significant delta changes in troponin can occur without the 99th percentile being exceeded., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Troponins are proteins that are integral components of the contractile mechanism of muscle, including cardiac muscle. Cardiac troponins Iand T can be detected in the blood of most people after puberty, at concentrations reflecting cardiac mass, sex and age. Current laboratory assays are approximately 1000 times more sensitive than those used previously. They also have higher sensitivity than point-of-care assays. The measurement of cardiac troponins is used primarily to assist in the diagnosis or exclusion of myocardial injury. Serial tests in acute coronary syndrome are guided by the Universal Definition of Myocardial Infarction., Competing Interests: Conflicts of interest: none declared, ((c) NPS MedicineWise.)

Background: Reference intervals are an important aid in medical practice as they provide clinicians a guide as to whether a patient is healthy or diseased.Outlier results in population studies are removed by any of a variety of statistical measures. We have compared several methods of outlier removal and applied them to a large body of analytes from a large population of healthy persons., Methods: We used the outlier exclusion criteria of Reed-Dixon and Tukey and calculated reference intervals using nonparametric and Harrell-Davis statistical methods and applied them to a total of 36 different analytes., Results: Nine of 36 analytes had a greater than 20% difference in the upper reference limit, and for some the difference was 100% or more., Conclusions: For some analytes, great importance is attached to the reference interval. We have shown that different statistical methods for outlier removal can cause large changes to reported reference intervals. So that population studies can be readily compared, common statistical methods should be used for outlier removal., (© American Association for Clinical Chemistry 2020.)

Objective: Preanalytical processing of blood samples can affect plasma glucose measurement because ongoing glycolysis by cells prior to centrifugation can lower its concentration. In June 2017, ACT Pathology changed the processing of oral glucose tolerance test (OGTT) blood samples for pregnant women from a delayed to an early centrifugation protocol. The effect of this change on the rate of gestational diabetes mellitus (GDM) diagnosis was determined., Research Design and Methods: All pregnant women in the Australian Capital Territory (ACT) are recommended for GDM testing with a 75-g OGTT using the World Health Organization diagnostic criteria. From January 2015 to May 2017, OGTT samples were collected into sodium fluoride (NaF) tubes and kept at room temperature until completion of the test (delayed centrifugation). From June 2017 to October 2018, OGTT samples in NaF tubes were centrifuged within 10 min (early centrifugation)., Results: A total of 7,509 women were tested with the delayed centrifugation protocol and 4,808 with the early centrifugation protocol. The mean glucose concentrations for the fasting, 1-h, and 2-h OGTT samples were, respectively, 0.24 mmol/L (5.4%), 0.34 mmol/L (4.9%), and 0.16 mmol/L (2.3%) higher using the early centrifugation protocol ( P < 0.0001 for all), increasing the GDM diagnosis rate from 11.6% ( n = 869/7,509) to 20.6% ( n = 1,007/4,887)., Conclusions: The findings of this study highlight the critical importance of the preanalytical processing protocol of OGTT blood samples used for diagnosing GDM. Delay in centrifuging of blood collected into NaF tubes will result in substantially lower rates of diagnosis than if blood is centrifuged early., (© 2020 by the American Diabetes Association.)

Background: Gestational diabetes mellitus (GDM) is glucose intolerance first diagnosed during pregnancy not due to overt diabetes. Recent changes to the diagnostic guidelines have been shown to increase the apparent occurrence of GDM., Aim: The aim of this study was to compare retrospectively the neonatal outcomes between groups defined using the new and old criteria to assess the impact of guideline changes on pregnancy outcomes., Methods: The study was of singleton babies delivered of 641 women, who had oral glucose tolerance testing and pregnancy care at a single tertiary centre between 2011 and 2015., Results: Compared to the population of women not now considered to have GDM by International Association of Diabetes and Pregnancy Study Groups criteria (two-hour glucose concentration ≤8.4 mmol/L), neonates born to women with the new lower fasting criterion (5.1-5.4 mmol/L) and/or the new 60-min group (glucose ≥10 mmol/L) combined were significantly more likely to have birthweight ≥90th percentile (22% vs 5%, P < 0.0001). In contradistinction, there was a significant excess number of small-for-dates babies (birthweight ≤10th percentile) in all subgroups previously diagnosed and treated for GDM by the Australian Diabetes in Pregnancy Society criteria (17% vs 7%, P = 0.001). Rates for lower uterine segment caesarean section, admission to the neonatal intensive care unit / special care nursery and Apgar scores at one and five minutes were not statistically different across all groups., Conclusions: Outcomes support the lowering of the fasting criterion to extend management of GDM to limit growth of large birthweight neonates. An unexpected outcome was that in women previously treated for GDM, there were increased numbers of low-birthweight neonates., (© 2019 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: Because the 99th percentile is of such importance in defining myocardial injury and myocardial infarction, it is important to know whether there are real age-related differences in troponin 99th percentiles., Methods: We went to our database from the Canberra Heart Study where 1062 apparently healthy subjects were extensively screened for occult cardiac disease, and looking at persons aged <65 years and >65 years, for men and women separately, we compared a variety of cutpoints from the 99th percentile down to the 50th percentile., Results: With our rigorous criteria for defining cardiac health, we excluded 67.2% of males aged >65 years and 53.8% of women aged 65 years and older. Even with these rigorous exclusions we found that at every cutpoint examined between the 99th percentile and the 50th percentile, persons aged <65 years had lower troponin I concentrations that persons aged 65 years and older. Similarly, at every cutpoint examined, women had lower troponin I concentrations than did men. For the 4 separate groups examined (men and women, age < 65 years and 65 years and older) after the exclusions of persons with subclinical cardiac disease, the distributions were not significantly different to a Gaussian distribution., Conclusions: With the rigorous exclusions of persons with subclinical cardiac disease, and the fact that our populations have a Gaussian distribution, our data suggests that age-related hs-cTnI concentrations are real. This has important implications particularly when assessing older persons in the Emergency Department., (Copyright © 2019 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: With the advent of the new high-sensitivity troponin assays, it is becoming critical to measure troponin accurately to low concentrations. To ensure assay performance is acceptable, appropriate QC must be run., Methods: In addition to the routine use of commercial QC material, we prepared pools of human QC material with low troponin concentrations close to the limit of quantitation, and ran these regularly on our laboratory analysers., Results: Over 3 years we found no drift or shift in our hs-cTnI assay. We found that only the very low concentration human QC material gave warning of precision problems with the hs-cTnI assay. At the time of the documented poor assay precision, the higher concentration QC material indicated satisfactory performance., Conclusions: Choice of QC material with an appropriate concentration is important for any assay. For hs-cTn assays, it is of particular importance to use control material with a concentration near to the limit of quantitation., (Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Immunoassay procedures have a wide application in clinical medicine and as such are used throughout clinical biochemistry laboratories both for urgent and routine testing. Clinicians and laboratory personnel are often presented with immunoassay results which are inconsistent with clinical findings. Without a high index of suspicion interferences will often not be suspected. Artifactual results can be due to a range of interferences in immunoassays which can include cross reacting substances, heterophile antibodies, autoantibodies and the high dose hook effect. Further, pre-analytical aspects and certain disease states can influence the potential for interference in immunoassays. Practical solutions for investigation of artifactual results in the setting of the routine clinical laboratory are provided., (Copyright © 2017 The Canadian Society of Clinical Chemists. All rights reserved.)

Objectives: While persons with overt renal failure have a well-described rise in troponin and NT-proBNP, it is less well described what the relationship is between cardiac markers and persons with impaired renal function, not requiring dialysis., Design & Methods: We have collected ALL samples referred to our pathology practice over a 24h period and measured hs-cTnI, hs-cTnT, NT-proBNP, calculated the eGFR, and related our measurements to clinical outcomes., Results: For both men and women, for all of hs-cTnI, hs-cTnT and NT-proBNP, there was a graded response, as renal function worsened, the concentration of the cardiac marker increased., Conclusions: There is a graded inverse relationship between eGFR and the concentrations of hs-cTnI, hs-cTnT and NT-proBNP. For women only there appeared to be an increase in mortality at lowest eGFR., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 Royal College of Pathologists of Australasia. All rights reserved.)

The troponin 99th percentile is used as the laboratory decision point in the diagnosis of acute myocardial infarction. A recent publication has shown that the statistical treatment for outlier removal may dramatically change the calculated troponin 99th percentile. We have used our large database from the previously reported Canberra Heart Study to independently assess the effect of various methods for removing outliers on the calculated 99th percentile. We have performed the same exercise using the troponin 97.5th percentile as an exercise to assess how outlier removal may affect calculated upper reference intervals for any analyte which uses this boundary. For healthy males aged <75years the hs-cTnI troponin 99th percentile varied by a factor>3× depending upon the outlier removal method chosen and for the 97.5th percentile the variation was >50%. For women the variation in the hs-cTnI 99th percentile varied by a factor of nearly 2×. Qualitatively similar results were obtained forhs-cTnT. This is not simply a problem for troponin reference intervals. All analyte reference intervals have the potential to be significantly affected by the method chosen for outlier removal. To ensure that studies can be meaningfully compared, guidance on procedures for removing outliers needs to be standardized as a matter of urgency., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objectives: Cardiac troponins are specific for the heart, but not for the acute coronary syndrome. We wanted to assess how common elevated cardiac troponin concentrations were, in a population with significant non-cardiac disease., Design & Methods: We measured both hs-cTnT and hs-cTnI on all samples submitted to the laboratory during one 24h period, and assessed the magnitude of the cTn concentration with the location and severity of disease of the patient., Results: Community patients and patients from the maternity ward had the lowest cTn concentrations with results above the 99th percentile being only 0-2% of the total. As expected, the highest proportion of results >99th percentile came from Coronary Care and Intensive Care. However, substantial numbers of persons on Medical and Surgical wards, without a primary diagnosis of cardiac disease, also had cTn >99th percentile. Particularly for cTnT, there was a highly significant odds ratio predicting mortality when results above and below the 99th percentile were compared., Conclusions: Significant illnesses apart from the acute coronary syndrome are important causes of a rise in cTn to above the 99th percentile, and appear to reflect the total body burden of disease. Even when the high hs-cTn concentration is not due to the acute coronary syndrome, there is a significant association with all-cause mortality., (Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objective: Thyroid disease can be subtle in its presentation, and TSH reference intervals may be artefactually increased by including persons with subclinical thyroid disease. We have therefore used a thyroid disease-free population to determine TSH and fT4 reference intervals., Design: Apparently healthy subjects were assessed by health questionnaire, drug history, clinical assessment and measurement of thyroid antibodies., Patients: Healthy subjects in a community setting., Measurements: TSH, free T4, antithyroglobulin and anti-TPO were measured on the Abbott Architect analyser. Subjects with clinical abnormalities, consumption of thyroid-active medications or with thyroid antibodies above the manufacturer-quoted reference intervals were excluded. TSH and fT4 data were log-transformed, and the central 95% was used to calculate reference intervals. We assessed whether these data were normally distributed. We compared samples spanning the reference intervals for both TSH and fT4 between different assays looking at biases., Results: From a population of 1,606 subjects, 140 males (18%) and 284 females (34%) were excluded. The central population 95% for TSH was 0·43-3·28 mU/l and for fT4 10·8-16·8 pmol/l. There were no age- or sex-related differences. For both analytes, the distribution was not significantly different to a Gaussian distribution (P > 0·05). For 5 commonly used assays for TSH, the maximum difference in the upper limit of the TSH reference interval was 0·48 mU/l and for fT4 the maximum difference for the upper reference limit was 4·1 pmol/l., Conclusions: A substantial proportion of apparently healthy persons have subclinical thyroid disease. These subjects must be excluded for any thyroid hormone reference interval studies., (© 2016 John Wiley & Sons Ltd.)

For more than a decade there has been a global effort to harmonise all phases of the testing process, with particular emphasis on the most frequently utilised measurands. In addition, it is recognised that calculated parameters derived from these measurands should also be a target for harmonisation. Using data from the Aussie Normals study we report reference intervals for three calculated parameters: serum osmolality, serum anion gap and albumin-adjusted serum calcium. The Aussie Normals study was an a priori study that analysed samples from 1856 healthy volunteers. The nine analytes used for the calculations in this study were measured on Abbott Architect analysers. The data demonstrated normal (Gaussian) distributions for the albumin-adjusted serum calcium, the anion gap (using potassium in the calculation) and the calculated serum osmolality (using both the Bhagat et al. and Smithline and Gardner formulae). To assess the suitability of these reference intervals for use as harmonised reference intervals, we reviewed data from the Royal College of Pathologists of Australasia/Australasian Association of Clinical Biochemists (RCPA/AACB) bias survey. We conclude that the reference intervals for the calculated serum osmolality (using the Smithline and Gardner formulae) may be suitable for use as a common reference interval. Although a common reference interval for albumin-adjusted serum calcium may be possible, further investigations (including a greater range of albumin concentrations) are needed. This is due to the bias between the Bromocresol Green (BCG) and Bromocresol Purple (BCP) methods at lower serum albumin concentrations. Problems with the measurement of Total CO 2 in the bias survey meant that we could not use the data for assessing the suitability of a common reference interval for the anion gap. Further study is required.

There is a high cardiac mortality in patients on long-term renal dialysis. No studies have reported long-term outcomes relating to both high-sensitivity cardiac troponin T (hs-cTnT) and high-sensitivity cardiac troponin I (hs-cTnI) in these patients. Patients who underwent long-term dialysis at the Canberra Hospital had blood samples collected for both cardiac and other biomarkers. Samples were stored at -80°C until analysis. Mortality data were collected at 5 years, and univariate and multivariate analyses were performed to identify which biomarkers were predictive of mortality at 5 years. After multivariate analysis, albumin, C-reactive protein (CRP), and hs-cTnT remained independently predictive of all-cause mortality, with hs-cTnT having the highest hazard ratio. If hs-cTnT was excluded from the analysis, then hs-cTnI was independently predictive of mortality. For hs-cTnT, for both genders, the ninety-ninth percentile, derived from a population with subjects with subclinical disease excluded, served as an excellent partition between survivors and nonsurvivors. Receiver-operating characteristic curve analysis for hs-cTnT had area under the curve of 0.798 and for hs-cTnI of 0.774. Kaplan-Meier curves for the aggregation of albumin, CRP, and hs-cTnT showed a stronger predictive power with receiver-operating characteristic area under the curve of 0.805. The addition of echocardiographic data in an analysis of all patients who had an echocardiogram for clinical reasons (n = 105) did not alter the final observations in this subgroup. In conclusion, hs-cTnT retains a superior predictive power in a dialysis-dependent population for identifying those at risk for death and when aggregated with albumin and CRP also has substantial additive value for identifying mortality risk in a renal-dialysis population., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: This study aims to determine whether blood lipids in healthy preadolescent children are sensitive to normally occurring changes in percent body fat, physical activity (PA), cardiorespiratory fitness (CRF), and macronutrient intake., Methods: Repeated measurements of fasting serum LDL cholesterol, HDL cholesterol, and triglycerides (TG); percent body fat (dual-energy x-ray absorptiometry); PA (pedometers); CRF (multistage run); and carbohydrate, sugar, and fat intake (dietary recall and record) were carried out in 469 children (51% girls) age 8, 10, and 12 yr., Results: Longitudinal relationships in boys showed that, for every one-unit increase in percent body fat, there was a 1.3% (95% CI, 0.9-1.8; P < 0.001) increase in LDL cholesterol; among girls, the increase was 0.8% (95% CI, 0.3-1.2; P = 0.003). In addition, we found a positive longitudinal relationship between TG and percent body fat (P < 0.001) in girls, and a negative longitudinal relationship between HDL cholesterol and percent body fat (P = 0.03) in boys. There were also longitudinal relationships between TG and CRF in both sexes (P < 0.05), but these were not sustained upon adjustment for percent body fat. Although cross-sectional relationships occurred in girls for both HDL cholesterol and TG with PA (P < 0.05), we found no evidence of any relationships between lipids and fat or sugar intake. By age 12 yr, LDL cholesterol was elevated (>3.36 mmol·L) in 16% and 20% of girls and boys, respectively., Conclusions: Blood lipids in preadolescent children appear sensitive to normal changes occurring in their percent body fat and, thus, fitness. Our data support early attention to body composition in community strategies designed to prevent cardiovascular disease in later life.

Objective: Reperfusion injury (RI) is associated with high generation of reactive oxygen species (ROS), but the extent of involvement of these agents in the injury remains controversial. The present study aimed to examine the effectiveness of ROS scavengers against hepatic reperfusion injury in the rat., Methods: The RI was induced in the liver using an isolated slow-flow, reflow perfused rat liver in both anterograde and retrograde perfusion. The effects of gentisic acid, N-acetyl cysteine, and trolox C on the superoxide production, liver function, and morphological changes were examined using different biochemical and histological assays., Results: The hepatic RI caused a significant (p < 0.05) increase in superoxide production and enzyme releases and a decrease in bile flow in both directions. Histological changes induced by RI include apoptosis, necrosis, pale cytoplasm, cell vacuolation, and attenuation of cell cords. Although the production of superoxide in retrograde direction was significantly less than the anterograde, the extent of the injury in the retrograde was greater than the anterograde direction. Pretreatment of the livers with each of the test compounds significantly reduced the release of lactate dehydrogenase and aspartate aminotransferase and improved bile flow in the liver exposed to hypoxia/reperfusion. However, they failed to protect the liver against the structural alterations induced by RI., Conclusion: ROS scavengers can reduce superoxide-induced damage and improve the liver function, but they are not able to prevent the structural changes. It shows that ROS are not the sole causative mechanism of hepatic RI and other mechanisms and mediators may be involved.

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.

Cardiac troponin is the preferred biomarker for defining the acute coronary syndrome and acute myocardial infarction. Currently, the only decision limit formally endorsed with regard to the cardiac troponins is the 99th percentile. This is a "rule-in" criterion, intended to ensure that only persons with the acute coronary syndrome are reviewed. The 99th percentile is an arbitrary cut point and there are many problems associated with its application, including defining a truly healthy population, the difficulty of standardisation of cardiac troponin assays, especially but not only cardiac troponin I, and the effects of age and sex on this parameter. The Emergency Department (ED) screens many more persons for possible acute coronary syndromes than actually have the condition and their needs are best met by a "rule-out" test that enables them to clear their busy departments of the many persons who do not actually have the condition. The needs of the ED are not optimally met using the 99th percentile. The index of individuality for the cardiac troponins is small and significant changes consistent with an acute coronary syndrome can occur without the 99th percentile being exceeded. It appears that the ED may be better served by use of delta troponin changes rather than the 99th percentile, but there are problems with this approach, particularly in persons who present late when troponin release has plateaued. In addition, there are many non-acute coronary syndrome causes for cardiac troponin release. The needs of the cardiologist and the ED physician are so different that it may be inappropriate for both groups to use the same diagnostic criteria for cardiac troponin, and it is of great importance that cardiac troponin measurement be used as only one part of the assessment of the person presenting with possible acute coronary syndrome.

Harmonisation of reference intervals for routine general chemistry analytes has been a goal for many years. Analytical bias may prevent this harmonisation. To determine if analytical bias is present when comparing methods, the use of commutable samples, or samples that have the same properties as the clinical samples routinely analysed, should be used as reference samples to eliminate the possibility of matrix effect. The use of commutable samples has improved the identification of unacceptable analytical performance in the Netherlands and Spain. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) has undertaken a pilot study using commutable samples in an attempt to determine not only country specific reference intervals but to make them comparable between countries. Australia and New Zealand, through the Australasian Association of Clinical Biochemists (AACB), have also undertaken an assessment of analytical bias using commutable samples and determined that of the 27 general chemistry analytes studied, 19 showed sufficiently small between method biases as to not prevent harmonisation of reference intervals. Application of evidence based approaches including the determination of analytical bias using commutable material is necessary when seeking to harmonise reference intervals.

Background: Many patients presenting to the emergency department (ED) for assessment of possible acute coronary syndrome (ACS) have low cardiac troponin concentrations that change very little on repeat blood draw. It is unclear if a lack of change in cardiac troponin concentration can be used to identify acutely presenting patients at low risk of ACS., Methods: We used the hs-cTnI assay from Abbott Diagnostics, which can detect cTnI in the blood of nearly all people. We identified a population of ED patients being assessed for ACS with repeat cTnI measurement who ultimately were proven to have no acute cardiac disease at the time of presentation. We used data from the repeat sampling to calculate total within-person CV (CV(T)) and, knowing the assay analytical CV (CV(A)), we could calculate within-person biological variation (CV(i)), reference change values (RCVs), and absolute RCV delta cTnI concentrations., Results: We had data sets on 283 patients. Men and women had similar CV(i) values of approximately 14%, which was similar at all concentrations <40 ng/L. The biological variation was not dependent on the time interval between sample collections (t = 1.5-17 h). The absolute delta critical reference change value was similar no matter what the initial cTnI concentration was. More than 90% of subjects had a critical reference change value <5 ng/L, and 97% had values of <10 ng/L., Conclusions: With this hs-cTnI assay, delta cTnI seems to be a useful tool for rapidly identifying ED patients at low risk for possible ACS., (© 2014 The American Association for Clinical Chemistry.)

Objective: Using objective laboratory and clinical criteria to more accurately determine the 99th percentile values for cardiac troponin I and T., Design and Methods: We measured cardiac troponin T and cardiac troponin I with high-sensitivity assays in a large cohort of apparently healthy community subjects and calculated 99th percentiles for different sexes and ages. Subjects with possible subclinical disease were eliminated based on objective laboratory criteria, eGFR and NT-proBNP, and clinical criteria, history and examination and echocardiogram., Results: For men and women of all ages, separately, more than 50% of subjects were excluded using these criteria, with a lesser proportion of younger subjects being excluded. In men aged <75 years, the 99th percentile for cTnI decreased by more than 50% from 22.9 ng/L to 10.3 ng/L. In other age groups and for cTnT the decrease was smaller (%) but still considerable., Conclusions: For establishing cardiac troponin 99th percentiles, simply using self-reporting of health is insufficient. Objective laboratory measures and clinical and echocardiographic assessments are essential to define a healthy population, especially in older persons., (© 2013. Published by Elsevier Inc. on behalf of The Canadian Society of Clinical Chemists. All rights reserved.)

Introduction: A number of hepatic ischemia/hypoxia-reperfusion models have been described. This study characterised the functional and structural changes induced by the most commonly used in vivo and in situ models for hypoxia/ischemia-reperfusion in the rat liver., Methods: A range of no-flow, slow-flow and lobar ischemia and reperfusion models were established in the rat liver. Changes following reperfusion were monitored using physiological, biochemical, histological and pharmacological assessments, including bile production, oxygen consumption, lignocaine extraction, enzyme release, and disposition of exogenous markers., Results: Short periods of hepatic ischemia/hypoxia-reperfusion led to minimal changes in liver function whereas long periods of ischemia-reperfusion led to substantial liver injury. The most severe injury was found with the slow flow, reflow model. The formation of cell vacuoles, blebs and focal hepatitis were the most important liver morphological changes observed as a consequence of ischemia/hypoxia. The major liver histological findings after reperfusion were dispersed apoptosis and local necrosis. Hepatic ischemia/hypoxia-reperfusion was also associated with significant changes in the hepatic extracellular and intracellular spaces., Discussion: The morphology and function of the liver associated with a range of hepatic ischemia/hypoxia-reperfusion models varies with the duration of the insult and between models. The choice of model is therefore an important consideration in seeking to resolve any particular hypothesis associated with hepatic ischemia/hypoxia-reperfusion., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To determine the potential of opportunistic glycated haemoglobin (HbA1c) testing of pathology samples to detect previously unknown diabetes., Design: Pathology samples from participants collected for other reasons and suitable for HbA1c testing were utilised for opportunistic diabetes screening. HbA1c was measured with a Biorad Variant II turbo analyser and HbA1c levels of ≥6.5% (48 mmol/mol) were considered diagnostic for diabetes. Confirmation of previously unknown diabetes status was obtained by a review of hospital medical records and phone calls to general practitioners., Setting: Hospital pathology laboratory receiving samples from hospital-based and community-based (CB) settings., Participants: Participants were identified based on the blood sample collection location in the CB, emergency department (ED) and inpatient (IP) groups. Exclusions pretesting were made based on the electronic patient history of: age <18 years, previous diabetes diagnosis, query for diabetes status in the past 12 months, evidence of pregnancy and sample collected postsurgery or transfusion. Only one sample per individual participant was tested., Results: Of the 22 396 blood samples collected, 4505 (1142 CB, 1113 ED, 2250 IP) were tested of which 327 (7.3%) had HbA1c levels ≥6.5% (48 mmol/mol). Of these 120 (2.7%) were determined to have previously unknown diabetes (11 (1%) CB, 21 (1.9%) ED, 88 (3.9%) IP). The prevalence of previously unknown diabetes was substantially higher (5.4%) in hospital-based (ED and IP) participants aged over 54 years., Conclusions: Opportunistic testing of referred pathology samples can be an effective method of screening for diabetes, especially in hospital-based and older persons.

Introduction: There is a paucity of data on the utilisation of the serum-free light chain (sFLC) and compliance with published guidelines., Methods: Serum-free light chain assays requested at our institute for the diagnosis, prognosis and monitoring of plasma cell dyscrasias from July 2008 to March 2010 were compared with the International Myeloma Working Group (IMWG) consensus guidelines., Results: In total, 1150 assays were performed (4.3 assays per patient, range 1-20). Eight hundred and forty-four (73%) of these were performed for multiple myeloma (MM), 188 (16%) for monoclonal gammopathy of undetermined significance, 72 (6%) for AL amyloidosis and 46 (4%) for smouldering myeloma. Of these, 49.6%, 22.9%, 1.4% and 69.6% of the monitoring assays were outside of IMWG recommendations, respectively. Of the 419 assays performed outside of guidelines for MM patients, 404 (96.4%) were due to monitoring of patients with a measurable M protein, while 24 (5.7%) were due to too frequent requesting (≤14 days) with 15 assays (3.6%) being noncompliant on both grounds., Conclusion: Utilisation of the sFLC assay shows reasonable adherence to guidelines within our centre. We propose to further optimise usage of the test with the help of administrative processes and education of clinicians., (© 2012 Blackwell Publishing Ltd.)

Objectives: To describe the distribution of hs-cTnI in a large cohort of healthy children., Design and Methods: As part of the LOOK study, blood was collected from a large cohort of healthy children on 3 separate occasions when the children were aged 8, 10 and 12years. Samples were stored at -80°C after collection and assayed after 1 freeze-thaw cycle using a pre-commercial release hs-cTnI assay from Abbott Diagnostics., Results: More than 98% of the 12year-old children had cTnI above the LoD of 1.0ng/L. For the 212 boys the central 95% of results was distributed in a Gaussian fashion. For the 237 girls, the initial analysis was non-Gaussian, but after the elimination of 2 results, the pattern for girls was also Gaussian., Conclusions: In healthy children, cTnI is present in a Gaussian distribution. Even minor illnesses can cause some troponin release, distorting this Gaussian distribution., (Copyright © 2012 Elsevier B.V. All rights reserved.)

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., (Copyright © 2013 S. Karger AG, Basel.)

Background: There is little information available on cardiac troponin concentrations in healthy young children., Methods: Using a precommercial high-sensitivity assay from Abbott Diagnostics, we measured cardiac troponin I (cTnI) in longitudinal blood samples collected at ages 8, 10, and 12 years from a cohort of healthy, community-dwelling children. The 99th percentile values were calculated and estimates of the long-term biological variation were made., Results: cTnI concentrations were above the limit of detection in 87%, 90%, and 98% of the children at ages 8, 10, and 12 years. The 99th percentiles were lower compared to a healthy adult population in both male and female children at all ages studied. At the 3 periods of study assessment, different children had cTnI concentrations above the 99th percentile. The calculated 99th percentile varied markedly depending upon whether the lowest or highest cTnI measurement for an individual child was included in the calculation. Biological variation varied markedly between 0% and 136%, the index of individuality was low at 0.36, and the reference change value was an increase of 147% or a decrease of 59%., Conclusions: In this longitudinal study of cTnI concentrations in healthy children as determined by a high-sensitivity assay, different children had concentrations of cTnI above the 99th percentile at the 3 episodes of assessment. These results suggest that in children the 99th percentile may not be a reliable index of silent cardiac disease, but rather may be indicating low-grade intercurrent illness., (© 2012 American Association for Clinical Chemistry)

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., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Aims: Whilst cardiac troponin is considered to be indicative of cardiac necrosis, the advent of new high sensitivity assays for troponin suggests that troponin may be present in the blood of healthy persons. We have examined a cohort of healthy children and measured TnT in their blood., Methods and Results: In this community-based prospective study, we collected blood samples from a large cohort of healthy children at ages 8, 10 and 12 years and measured hs-TnT on these samples. 727 children had at least one blood sample collected and of these 28.6% had at least one sample in which troponin was detected. The number of samples with a positive troponin at each period of blood collection varied between 14.0% and 20.3%. Statistical analysis showed that the prevalence of positive TnT varied between schools and the between school pattern was different in different years., Conclusions: Low concentrations of troponin may be seen transiently in healthy children with no evidence of cardiac injury. This between-school by year variation is highly significant and is suggestive of a transient infective agent., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Abbott Diagnostics have developed a new highly sensitive troponin I (hs-TnI) assay. We have assessed its analytical characteristics and applied the assay to a population of apparently cardio-healthy persons., Methods: We assessed imprecision, bias compared to the previous generation assay, matrix effects, and interferences and applied the assay to an apparently healthy population, deriving the 99th percentile limit of the distribution of values in reference populations for men and women separately., Results: The dynamic range of the assay was ranged from 0.5-50,000 ng/L (pg/mL). The 10% CV was at a concentration of 3.9 ng/L, and the 20% CV was at a concentration of 1.8 ng/L. The new and current version of the TnI assay were highly correlated [slope: 0.98 (95%CI:0.88-1.07), y-intercept:1.20 (95%CI:-2.35-4.75) r²=0.99]. The 99th percentile limit of the distribution of values in a reference population was different for males and females: for males 14.0 ng/L and for females 11.1 ng/L and at these concentrations the assay CV was 5.0%. TnI was detectable in nearly all patient samples from the healthy reference population (98.6%)., Conclusions: This new hs-TnI assay is able to measure to an order of magnitude lower than the current generation TnI assay from the same manufacturer. With TnI being detectable in nearly all apparently healthy subject samples this suggests that TnI presence does not always indicate cardiomyocyte necrosis.

Background: In a previous longitudinal analysis of our cohort as 8 to 10 year-olds, insulin resistance (IR) increased with age, but was not modified by changes in percent body fat (%BF), and was only responsive to changes in physical activity (PA) in boys. We aimed to determine whether these responses persisted as the children approached adolescence., Methods: In this prospective cohort study, 256 boys and 278 girls were assessed at ages 8, 10 and 12 years for fasting blood glucose and insulin, %BF (dual energy X-ray absorptiometry); PA (7-day pedometers), fitness (multistage run); and pubertal development (Tanner stage)., Results: From age 8 to 12 years, the median homeostatic model of IR (HOMA-IR) doubled in boys and increased 250% in girls. By age 12, 23% of boys and 31% of girls had elevated IR, as indicated by HOMA-IR greater than 3. Longitudinal relationships, with important adjustments for covariates body weight, PA, %BF, Tanner score and socioeconomic status showed that, on average, for every 1 unit reduction of %BF, HOMA-IR was lowered by 2.2% (95% CI 0.04-4) in girls and 1.6% (95% CI 0-3.2) in boys. Furthermore, in boys but not girls, HOMA-IR was decreased by 3.5% (95%CI 0.5-6.5) if PA was increased by 2100 steps/day., Conclusion: Evidence that a quarter of our apparently healthy 12 year-old Australians possessed elevated IR suggests that community-based education and prevention strategies may be warranted. Responsiveness of IR to changes in %BF in both sexes during late preadolescence and to changes in PA in the boys provides a specific basis for targeting elevated IR. That body weight was a strong covariate of IR, independent of %BF, points to the importance of adjusting for weight in correctly assessing these relationships in growing children.

Liver biopsy with histological examination of liver tissue was for many years the cornerstone of the diagnosis of haemochromatosis, allowing assessment of the degree of iron overload and examination of liver histology for the acute and chronic effects of iron overload. In the past two decades the role of liver biopsy in haemochromatosis has changed dramatically. Liver biopsy is rarely requested for two main reasons: (1) genetic testing for human haemochromatosis (HFE) mutations has proved to be very reliable in the diagnosis of haemochromatosis in Caucasian populations, and (2) the majority of patients with haemochromatosis are now diagnosed at an early stage well before permanent tissue damage occurs, so the need to assess tissue and organ damage has diminished. Liver biopsy continues to have a very important role in a small number of haemochromatosis patients for whom it has both diagnostic and prognostic implications. Liver biopsy is essential for the accurate assessment of patients with non-HFE haemochromatosis and in patients who have dual pathology. It is also useful where there appears to be a discrepancy between HFE genotypes and iron studies, particularly in HFE heterozygotes. Finally, liver biopsy is currently the 'gold standard' for the diagnosis of fibrosis and cirrhosis, although this is changing as non-invasive methods for assessing fibrosis become more reliable and available. Therefore, it is important that pathologists maintain their knowledge and skills in the use of liver biopsy in haemochromatosis and other iron storage disorders.

Background: High prevalence rates of suboptimal vitamin D levels have been observed in women who are not considered 'at risk'. The effect of behavioural factors such as sun exposure, attire, sunscreen use and vitamin D supplementation on vitamin D levels in pregnancy is unknown., Aim: To determine prevalence and predictive factors of suboptimal vitamin D levels in 2 antenatal clinics in Australia--Campbelltown, NSW and Canberra, ACT., Methods: A cross-sectional study of pregnant women was performed with a survey of demographic and behavioural factors and a mid-pregnancy determination of maternal vitamin D levels., Results: The prevalence of vitamin D deficiency (≤25 nmol/L) and insufficiency (26-50 nmol/L) was 35% in Canberra (n=100) and 25.7% in Campbelltown (n=101). The majority of participants with suboptimal D levels had vitamin D insufficiency. Among the vitamin D-deficient women, 38% were Caucasian. Skin exposure was the main behavioural determinant of vitamin D level in pregnancy in univariate analysis. Using pooled data ethnicity, season, BMI and use of vitamin D supplements were the main predictive factors of suboptimal vitamin D. Vitamin D supplementation at 500 IU/day was inadequate to prevent insufficiency., Conclusions: Behavioural factors were not as predictive as ethnicity, season and BMI. As most participants had one of the predictive risk factors for suboptimal vitamin D, a case could be made for universal supplementation with a higher dose of vitamin D in pregnancy and continued targeted screening of the women at highest risk of vitamin D deficiency., (© 2011 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology © 2011 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)