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Context The plasma aldosterone concentration (PAC), renin, and aldosterone-to-renin ratio (ARR) are used to screen for primary aldosteronism (PA). Substantial intra-individual variability of PAC and ARR using plasma renin activity in the context of usual antihypertensive therapy has been described, but there is no data on ARR variability calculated using direct renin concentration (DRC). Objective To describe the intra-individual variability of PAC, DRC, and ARR in the absence of interfering medications in patients with and without PA. Design Retrospective cohort study. Patients Hypertensive patients referred for investigation of PA, with at least 2 ARR measurements while off interfering medications. Setting Endocrine hypertension service of a tertiary center, from May 2017 to July 2021. Main outcome measures PAC, DRC, and ARR variability was calculated as coefficient of variation (CV) and percent difference (PD). Results Analysis of 223 patients (55% female, median age 52 years), including 162 with confirmed PA, demonstrated high variability with a sample CV of 22-25% in the PAC and sample CV of 41% to 42% in the DRC and ARR in both the PA and non-PA groups. The degree of variability was substantially higher than the assays’ analytical CV. Sixty-two patients (38%) with PA had at least one ARR below 70 pmol/L:mU/L (2.4 ng/dL:mU/L), a cut-off for first-line screening of PA. Conclusions Significant intra-individual variability in PAC, DRC, and hence ARR occurs in a large proportion of patients being investigated for PA. These findings support the need for at least 2 ARR before PA is excluded or further investigated.

High dietary phosphate intake may lead to adverse outcomes including cardiovascular disease (CVD). Urinary phosphate excretion, a marker of intestinal phosphate absorption, may be a more reliable marker of phosphate homeostasis in steady state than serum phosphate. Studies report good agreement between urine phosphate-to-creatinine ratio (uPiCr) and 24-hour urinary phosphate; however, whether uPiCr is associated with increased risk of CVD or mortality remains uncertain. This study aimed to assess the relationship between uPiCr and all-cause and CVD mortality.This is an observational longitudinal cohort study using data from the population-based national Australian Diabetes, Obesity and Lifestyle study (n = 10,014 participants). Non-linear association between uPiCr and all-cause and CVD mortality was assessed using fractional polynomial transformations. Cox proportional hazards regression models were used to estimate adjusted hazard ratios for all-cause and CVD mortality.Median age [interquartile range] was 50 [41-62] years, and 46% were male. Median uPiCr was 1.38 [1.02-1.79] mmol/mmol. Median follow-up time was 16.9 years with 1,735 deaths. uPiCr was associated with all-cause and CVD mortality in univariate models and when adjusted for age and gender. However, associations were not significant in multivariate models. Sensitivity analyses excluding participants with chronic kidney disease (CKD) revealed a significant J-shaped association between uPiCr and all-cause mortality. Urine phosphate alone showed an association with increased all-cause mortality in a similar J-shape relationship.Although no association between uPiCr and all-cause and CVD mortality was observed in multivariate analyses in the whole cohort, a significant relationship between uPiCr and mortality in those without CKD suggests that uPiCr may have predictive validity for future adverse outcomes in people with no CKD.

Type 2 diabetes (T2DM) is a major cause of morbidity and mortality globally. Carnosine, a naturally occurring dipeptide, has anti-inflammatory, antioxidant, and anti-glycating effects, with preliminary evidence suggesting it may improve important chronic disease risk factors in adults with cardiometabolic conditions. In this randomized controlled trial, 43 adults (30%F) living with prediabetes or T2DM consumed carnosine (2 grams) or a matching placebo daily for 14 weeks to evaluate its effect on glucose metabolism assessed via 2 hr, 75g oral glucose tolerance test. Secondary outcomes included body composition analysis by dual energy x-ray absorptiometry (DEXA), calf muscle density by pQCT and anthropometry. Carnosine supplementation decreased blood glucose at 90 minutes (−1.31mmol/L; p=0.02) and 120 minutes (−1.60mmol/L, p=0.02) and total glucose area under the curve (−3.30mmol/L; p=0.04) following an oral glucose tolerance test. There were no additional changes in secondary outcomes. The carnosine group results remained significant before and after adjustment for age, sex, and change in weight (all>0.05), and in further sensitivity analyses accounting for missing data. There were no significant changes in insulin levels. Likely mechanisms may include changes to hepatic glucose output explaining the observed reduction in blood glucose without changes in insulin secretion following carnosine supplementation. This study provides preliminary support for larger trials evaluating carnosine as a potential treatment for prediabetes and the early stages of T2DM.

BACKGROUND AND PURPOSE Nitrous oxide misuse is a recognized issue worldwide. Prolonged misuse inactivates vitamin B12, causing a myeloneuropathy. METHODS Twenty patients presenting between 2016 and 2020 to tertiary hospitals in Sydney with myeloneuropathy due to nitrous oxide misuse were reviewed. RESULTS The average age was 24 years, and mean canister consumption was 148 per day for 9 months. At presentation, paresthesias and gait unsteadiness were common, and seven patients were bedbound. Mean serum B12 was normal (258 pmol/L, normal range [NR] = 140-750) as was active B12 (87 pmol/L, normal > 35). In contrast, mean serum homocysteine was high (51 μmol/L, NR = 5-15). Spinal magnetic resonance imaging (MRI) showed characteristic dorsal column T2 hyperintensities in all 20 patients. Nerve conduction studies showed a predominantly axonal sensorimotor neuropathy (n = 5). Patients were treated with intramuscular vitamin B12, with variable functional recovery. Three of the seven patients who were bedbound at presentation were able to walk again with an aid at discharge. Of eight patients with follow-up data, most had persistent paresthesias and/or sensory ataxia. Mobility scores at admission and discharge were not significantly correlated with the serum total and active B12 levels or cumulative nitrous oxide use. There were no significant trends between serum active B12 level and cumulative nitrous oxide use (Spearman rho = -0.331, p = 0.195). CONCLUSIONS Nitrous oxide misuse can cause a severe but potentially reversible subacute myeloneuropathy. Serum and active B12 can be normal, while elevated homocysteine and dorsal column high T2 signal on MRI strongly suggest the diagnosis. Neurological deficits can improve with abstinence and B12 supplementation, even in the most severely affected patients.

Childhood lung infection is often associated with prominent neutrophilic airway inflammation and excess production of proteases such as neutrophil elastase (NE). The mechanisms responsible for this inflammation are not well understood. One potentially relevant pathway is the production of extracellular traps by neutrophils (NETs) and macrophages (METs). The aim of this study was to measure NET and MET expression in children and the effect of deoxyribonculease (DNase) 1 and α1-antitrypsin (AAT) on this process. We studied 76 children (median age of 4.0 years) with cystic fibrosis or chronic cough who underwent investigational bronchoscopy. NETs, METs and neutrophil elastase activity in bronchoalveolar lavage (BAL) samples were measured using confocal microscopy and functional assays. The effects of DNase 1 and AAT on NET/MET expression and neutrophil elastase activity were examined in vitro. Both subject groups had airway neutrophilia with prominent BAL production of NETs with neutrophil elastase co-expression; the mean %±standard error of the mean of neutrophils expressing NETs in the cystic fibrosis group was 23.3±2.8% and in the non-cystic fibrosis group was 28.4±3.9%. NET expression was higher in subjects who had detectable neutrophil elastase activity (p≤0.0074). The percentage of macrophages expressing METs in the cystic fibrosis group was 10.7±1.2% and in the non-cystic fibrosis group was 13.2±1.9%. DNase 1 decreased NET/MET expression (p, Prominent extracellular trap formation may be observed in young children with airway inflammation, with and without cystic fibrosis. This innate inflammatory response is down-regulated by a combination of currently available therapeutics. https://bit.ly/3bDaWyC

Background Interest in potential adverse outcomes associated with maternal subclinical hypothyroidism (normal free T4, elevated thyroid-stimulating hormone (TSH)) has increased significantly over recent years. In turn, the frequency of maternal thyroid function testing has risen, despite universal thyroid function screening not being recommended, leading to a marked increase in referrals to obstetric endocrinology clinics. In 2017 the American Thyroid Association revised their diagnostic and management guidelines. Although welcome, these new guidelines contain recommendations that may cause confusion in clinical practice. Aim To ensure uniform practice in the diagnosis and management of subclinical hypothyroidism in pregnancy across all Melbourne public hospitals. Methods Endocrinology and obstetric representatives from all Melbourne public hospital networks reviewed the 2017 American Thyroid Association guidelines and other relevant literature to develop a consensus for diagnosing and treating subclinical hypothyroidism during pregnancy in Melbourne. The consensus guidelines were then referred to the Endocrine Society of Australia for comment and endorsement. Results Consensus was achieved and the guidelines were endorsed by the Council of the Endocrine Society of Australia. Trimester and assay-specific TSH reference intervals derived from healthy local populations should be used, where available. When unavailable, a TSH cut-off of 4 mU/L (replacing the previously recommended 2.5 mU/L) should be used to initiate treatment, irrespective of thyroid auto-antibody status. The recommended starting dose of levothyroxine is 50 μg daily, with a therapeutic TSH target of 0.1-2.5 mU/L. Levothyroxine should generally be ceased after delivery, with some exceptions. Hospitals will ensure smooth transfer of care back to the woman's general practitioner with clear documentation of pregnancy thyroid management and a recommended plan for follow-up. Conclusion Fewer women will be classified as having subclinical hypothyroidism during pregnancy, which is likely to lead to reductions in emotional stress, hospital visits, repeated blood tests and financial costs. Uniform clinical practice will occur across Melbourne.

Background: In Australia’s Northern Territory, 33% of babies are born to Indigenous mothers, who experience high rates of hyperglycemia in pregnancy. We aimed to determine the extent to which pregnancy outcomes for Indigenous Australian women are explained by relative frequencies of diabetes type [type 2 diabetes (T2DM) and gestational diabetes (GDM)]. Methods: This prospective birth cohort study examined participants recruited from a hyperglycemia in pregnancy register. Baseline data collected were antenatal and perinatal clinical information, cord blood and neonatal anthropometry. Of 1135 women (48%Indigenous), 900 had diabetes: 175 T2DM, 86 newly diagnosed diabetes in pregnancy(DIP) and 639 had GDM. A group of 235 women without hyperglycemia in pregnancywas also recruited. Results: Diabetes type differed for Indigenous and non-Indigenous women (T2DM, 36 vs5%; DIP, 15 vs 7%; GDM, 49 vs 88%, p < 0.001). Within each diabetes type, Indigenous women were younger and had higher smoking rates. Among women with GDM/DIP,Indigenous women demonstrated poorer birth outcomes than non-Indigenous women:large for gestational age, 19 vs 11%, p ¼ 0002; neonatal fat 11.3 vs 10.2%, p < 0.001. Inthe full cohort, on multivariate regression, T2DM and DIP were independently associated(and Indigenous ethnicity was not) with pregnancy outcomes Conclusions: Higher rates of T2DM among Indigenous women predominantly contribute to absolute poorer pregnancy outcomes among Indigenous women with hyperglycemia.As with Indigenous and minority populations globally, prevention or delay of type 2 diabetes in younger women is vital to improve pregnancy outcomes and possibly to improve the long-term health of their offspring. Refereed/Peer-reviewed

Background Serum fibroblast growth factor 23 (FGF-23) levels are markedly elevated in haemodialysis patients and have been linked to mortality outcomes. Small studies in health and chronic kidney disease, have demonstrated marked intra- and inter-individual variability in measured FGF-23 levels, and variable degradation in serum as compared to plasma samples. In end-stage kidney disease (ESKD), the intra- and inter-individual variability of FGF-23 levels, and the optimal collection methods remain poorly characterized. In this study we assessed the variability of FGF-23 levels in a cohort of stable haemodialysis patients. Secondly, in a subset of patients, we assessed the effects of different collection methods on measured FGF-23 levels. Methods To assess the variability of FGF-23, pre-dialysis blood samples were collected over 3 consecutive weeks from 75 haemodialysis patients. The effects of different specimen collection methods were examined in a subset of patients (n = 23), with pre-dialysis blood collected into different tubes: plain (serum), EDTA (plasma) and EDTA with the addition of a protease inhibitor (EDTA-PI). All analyses were performed in the main cohort and repeated in each subgroup. Variability over a 3-week period was assessed using repeated measures ANOVA and random effects linear regression models. Intra-class correlation coefficients were calculated to assess agreement, and coefficients of variation were calculated to assess intra- and inter-individual variability. Results Over the 3-week study period the mean FGF-23 levels were not significantly different in the serum (p = 0.26), EDTA (p = 0.62) and EDTA-PI (p = 0.55) groups. FGF-23 levels demonstrated marked intra- and inter-individual variability with a CV of 36 and 203.2%, respectively. In the subgroup analysis, the mean serum FGF-23 levels were significantly lower than the EDTA (p

Summary Serum ferritin is currently the recommended laboratory test to investigate iron deficiency. There have been efforts to standardise serum ferritin assays with implementation of traceability to the World Health Organization reference standard. We evaluate the analytical bias among five widely used commercial ferritin assays in Australia. The relationship between serum ferritin and erythrocyte parameters was recently explored to derive functional reference limits. Residual patient serum specimens were analysed by five participating laboratories that utilised a different ferritin assay, Abbott, Beckman Coulter, Roche, Siemens, and Ortho. Using data mining approach, functional reference limits for Siemens, Abbott, and Ortho serum ferritin methods were derived and compared. At clinically relevant ferritin decision points, compared to the Beckman method, the Roche assay showed higher results ranging from 6 μg/L (31%) at the lowest decision point to 575 μg/L (57%) at the highest decision point. In contrast, the Ortho method underestimated ferritin results at lower decision points of 20 and 30 μg/L, with estimated ferritin results of 16 μg/L (–19%) and 27 μg/L (–12%), respectively. The Abbott and Siemens assays showed a positive bias which was introduced at differing decision points. The comparison of the Siemens and Ortho methods presents similar inflection points between the two assays in the establishment of functional reference limits for serum ferritin. There remain significant biases among some of the commonly used commercial ferritin assays in Australia. More studies are needed to assess if functional reference limits are a way to overcome method commutability issues.

Objectives Results can vary between different free thyroxine (FT4) assays; global standardization would improve comparability of results between laboratories, allowing development of common clinical decision limits in evidence-based guidelines. Content We summarize the path to standardization of FT4 assays, and challenges associated with FT4 testing in special populations, including the need for collaborative efforts toward establishing population-specific reference intervals. The International Federation of Clinical Chemistry and Laboratory Medicine Committee for Standardization of Thyroid Function Tests has undertaken FT4 immunoassay method comparison and recalibration studies and developed a reference measurement procedure that is currently being validated. Further studies are needed to establish common reference intervals/clinical decision limits. Standardization of FT4 assays will change test results substantially; therefore, a major education program will be required to ensure stakeholders are aware of the benefits of FT4 standardization, planned transition procedure, and potential clinical impact of the changes. Assay recalibration by manufacturers and approval process simplification by regulatory authorities will help minimize the clinical impact of standardization. Summary Significant progress has been made toward standardization of FT4 testing, but technical and logistical challenges remain. Outlook Collaborative efforts by manufacturers, laboratories, and clinicians are required to achieve successful global standardization of the FT4 assays.

Intravenous iodinated contrast is a commonly used diagnostic aid to improve image quality on computed tomography. There exists a small risk of post-contrast acute kidney injury in patients receiving IV contrast. One of the biggest risk factors for developing PC-AKI is the presence of pre-existing renal dysfunction, making it important to measure the renal function prior to contrast administration. Point of care (POC) devices offer a quick estimation of renal function, potentially improving workflows in radiology departments. Two POC devices were evaluated, the Nova StatSensor and Abbott iSTAT. Patients undergoing routine radiological investigations had blood collected and analysed by a POC method and the laboratory method (Beckman AU5800). The two values were analysed and compared. Renal function was calculated using eGFR via the CKD-EPI result. eGFR values were stratified as high risk (eGFR

Aims/hypothesis We aimed to assess associations between cord blood metabolic markers and fetal overgrowth, and whether cord markers mediated the impact of maternal adiposity on neonatal anthropometric outcomes among children born to Indigenous and Non-Indigenous Australian women with normal glucose tolerance (NGT), gestational diabetes mellitus (GDM) and pregestational type 2 diabetes mellitus.Methods From the Pregnancy and Neonatal Outcomes in Remote Australia (PANDORA) study, an observational cohort of 1135mother-baby pairs, venous cord blood was available for 645 singleton babies (49% Indigenous Australian) of women with NGT(n = 129),GDM(n = 419) and type 2 diabetes (n = 97). Cord glucose, triacylglycerol, HDL-cholesterol, C-reactive protein (CRP)and C-peptide were measured. Multivariable logistic and linear regression were used to assess the associations between cord blood metabolic markers and the outcomes of birthweight z score, sum of skinfold thickness (SSF), being large for gestational age(LGA) and percentage of body fat. Pathway analysis assessed whether cord markers mediated the associations between maternal and neonatal adiposity. Results Elevated cord C-peptide was significantly associated with increasing birthweight z score (β 0.57 [95% CI 0.42, 0.71]),SSF (β 0.83 [95% CI 0.41, 1.25]), percentage of body fat (β 1.20 [95% CI 0.69, 1.71]) and risk for LGA [OR 3.14 [95% CI 2.11,4.68]), after adjusting for age, ethnicity and diabetes type. Cord triacylglycerol was negatively associated with birthweight z score for Indigenous Australian women only. No associations between cord glucose, HDL-cholesterol and CRP >0.3 mg/l (2.9 nmol/l)with neonatal outcomes were observed. C-peptide mediated 18% (95% CI 13, 36) of the association of maternal BMI with LGAand 11% (95% CI 8, 17) of the association with per cent neonatal fat. Conclusions/interpretation Cord blood C-peptide is an important mediator of the association between maternal and infant adiposity, across the spectrum of maternal glucose tolerance. Refereed/Peer-reviewed

Central hypothyroidism is a condition where there is (qualitatively or quantitatively) TSH deficiency, leading to reduced thyroid hormone production. In such patients, serum TSH does not accurately reflect the adequacy of thyroxine replacement, as the log-linear relationship between thyrotropin (TSH) and free thyroxine (FT4) is lost. We aimed to prospectively determine the optimal physiological FT4 treatment range for children treated for primary hypothyroidism, based on their serum TSH concentrations. This information could be used to guide optimal therapy for all children on thyroxine replacement, including those with central hypothyroidism. In total, sixty children (median age: 11 years, range: 11 months to 18 years) were recruited over 21 months. They were prescribed a stable dose of thyroxine for at least 6–8 weeks prior to a thyroid function test that consisted of serum TSH, FT4 and free triiodothyronine (FT3) measurements. The serum sample for the thyroid function tests was collected before ingestion of the daily dose, i.e. the trough concentration, and measured using Beckman Coulter UniCel DxI 800 instrument, Siemens Advia Centaur, Roche Cobas, Abbott Architect, Ortho Clinical Diagnostics Vitros 5600 (Ortho-Clinical Diagnostics, Raritan, NJ) platforms. The FT4 and FT3 reference intervals showed significant inter-method difference. The lower limit of the FT4 reference intervals were generally shifted mildly higher when the TSH concentration of the children were restricted from 0.5–5.0 mIU/L to 0.5–2.5 mIU/L. By contrast, the upper limit of the FT3 and FT4 reference intervals were relatively stable for the different TSH concentrations. Assay-specific target ranges for optimal thyroxine therapy are required until FT4 assay standardisation is realised.

Aims: To determine among First Nations and Europid pregnant women the cumulative incidence and predictors of postpartum type 2 diabetes and prediabetes and describe postpartum cardiovascular disease (CVD) risk profiles. Methods: PANDORA is a prospective longitudinal cohort of women recruited in pregnancy. Ethnic-specific rates of postpartum type 2 diabetes and prediabetes were reported for women with diabetes in pregnancy (DIP), gestational diabetes (GDM) or normoglycaemia in pregnancy over a short follow-up of 2.5 years (n = 325). Pregnancy characteristics and CVD risk profiles according to glycaemic status, and factors associated with postpartum diabetes/prediabetes were examined in First Nations women. Results: The cumulative incidence of postpartum type 2 diabetes among women with DIP or GDM were higher for First Nations women (48%, 13/27, women with DIP, 13%, 11/82, GDM), compared to Europid women (nil DIP or GDM p < 0.001). Characteristics associated with type 2 diabetes/prediabetes among First Nations women with GDM/DIP included, older age, multiparity, family history of diabetes, higher glucose values, insulin use and body mass index (BMI). Conclusions: First Nations women experience a high incidence of postpartum type 2 diabetes after GDM/DIP, highlighting the need for culturally responsive policies at an individual and systems level, to prevent diabetes and its complications. Refereed/Peer-reviewed

Context: Vitamin D "insufficiency" and "deficiency" are defined as serum 25-hydroxyvitamin D [25(OH)D] levels < 75 and < 30 nmol/L, respectively. We aimed to determine whether these values signal hypocalcemia and hypophosphatemia, secondary hyperparathyroidism, high bone remodeling, low areal bone mineral density (aBMD), microstructural deterioration, or reduced matrix mineralization density (MMD) and so suggest whether bone fragility is present. Methods: Concentrations of 25(OH)D, calcium, phosphate, creatinine, and parathyroid hormone (PTH) were measured in 11,855 participants. Serum C-terminal telopeptide of type 1 collagen, procollagen type 1 N-terminal propeptide (P1NP), aBMD, and distal radius microstructure and MMD were measured in a second subset of 150 participants. Results: A breakpoint for calcium, PTH, and alkaline phosphatase was identified at a threshold 25(OH)D level < 30 nmol/L. There was no plateau beyond 75 nmol/L. In the subgroup with measurements of bone morphology, no associations were detectable between serum 25(OH)D concentration, aBMD, trabecular density, cortical porosity, or MMD. Among 1439 participants with serum 25(OH)D < 30 nmol/L, 6.1% had low serum calcium, 3.4% had low serum phosphate, 6.1% had high alkaline phosphatase, and 34.2% had elevated PTH. Most participants did not have any abnormalities. Conclusion: At a 25(OH)D threshold of ≤30 nmol/L, abnormalities in biochemical features support the notion of a "deficiency" state predisposing to bone disease. However, no deleterious effects were found in participants within an insufficiency threshold of a 25(OH)D level of 30 to 75 nmol/L, which challenges the rationale justifying vitamin D supplementation in these individuals.

It is unknown if high prolactin levels during pregnancy contribute to the development of gestational diabetes. We hypothesized that higher prolactin levels are associated with reduced glucose tolerance, as determined by higher 2‐h glucose level from an oral glucose tolerance test in pregnancy. The 75‐g oral glucose tolerance test was carried out at 28 weeks of gestation in 69 participants. A multiple regression analysis was used to determine the relationship between serum prolactin and 2‐h glucose levels. Multivariable regression analysis showed an independent and significant relationship between third trimester prolactin and 2‐h glucose levels post oral glucose tolerance test. Higher prolactin levels were associated with higher glucose levels independent of age, body mass index, gravidity and parity. Higher prolactin levels associated with reduced glucose tolerance in the third trimester of pregnancy suggests the possible independent role of prolactin in the pathogenesis of gestational diabetes.

AIMS Uncertainties about the role of cystatin C-based estimated glomerular filtration rate (eGFR) in the prediction of cardiovascular disease (CVD) beyond traditional CVD risk factors remain. We assessed contributions of eGFR to CVD and mortality in the general population. METHODS Using 14 year follow-up data on 9353 adults without a reported history of CVD from the Australian Diabetes, Obesity and Lifestyle study, we assessed the contributions of eGFR (assessed by cystatin C (eGFRcysC ) and serum creatinine (eGFRcr ) and albuminuria (uACR) to total and CVD mortality. RESULTS After adjusting for age, sex, CVD risk factors and uACR, compared with an eGFRcysC >90 mL/min per 1.73 m2 , eGFRcysC

Background: Prompt intervention can prevent permanent adverse neurological effects caused by neonatal hypothyroidism. Thyroid function changes rapidly in the first few days of life but well-defined age-specific reference intervals (RIs) for thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free tri-iodothyronine (FT3) are not available to aid interpretation. We developed hour-based RIs using data mining. Methods: All TSH, FT4 and FT3 results with date and time of collection from neonates aged Results: Of the 728 neonates qualifying for the study, 569 had time of birth available. All 569 had TSH, 415 had FT4 and 146 had FT3 results. For age ≤24 h, 25–48 h, 49–72 h, 73–96 h, 97–120 h, 121–144 h and 145–168 h of life, the TSH RIs (2.5th–97.5th) (mIU/L) were 4.1–40.2, 3.2–29.6, 2.6–17.3, 2.2–14.7, 1.8–14.2, 1.4–12.7 and 1.0–8.3, respectively; the FT4 RIs (mean ± 2 standard deviation [SD]) (pmol/L) were 15.3–43.6, 14.7–53.2, 16.5–45.5, 17.8–39.4, 15.3–32.1, 14.5–32.6 and 13.9–30.9, respectively; the FT3 RIs (mean±2 SD) (pmol/L) were 5.0–9.4, 4.1–9.1, 2.8–7.8, 2.9–7.8, 3.5–7.2, 3.4–8.0 and 3.8–7.9, respectively. Conclusions: TSH and FT4 were substantially high in the first 24 h after birth followed by a rapid decline over the subsequent 168 h. Use of hour-based RIs in newborns allows for more accurate identification of neonates who are at risk of hypothyroidism.

Background Biotin interference is a significant problem to which at-risk laboratories must now be attuned. We sought to systematically characterize the nature of this interference in Roche immunoassays. Methods Known concentrations of biotin were titrated into serum samples and the effects on competitive and sandwich immunoassays were analysed. The maximum and minimum concentrations examined reflect those likely to be achieved in individuals on 5 to 10 mg supplements at the lower end, and 100 to 300 mg biotin at the high end. Results A high variability in biotin tolerance was observed. Some assays, such as troponin T, TSH and antithyroid antibodies, were extremely sensitive to the lower concentrations of biotin (15.6 and 31.3 ng/mL), whereas the majority of assays were relatively resistant. At concentrations ≥500 ng/mL, all assays showed significant interference from biotin but, again, the magnitude of the interference was variable. The more sensitive assays showed profound analytical bias at biotin concentrations that occur with high-dose therapy. Conclusion Our data demonstrate high variability in biotin tolerance across Roche immunoassays. The shape of the dose–response curves provides more detailed information than the single manufacturer-quoted figure for biotin tolerance. Accordingly, these data may be used by laboratories for more accurate risk assessment in predicting the effects of biotin. Our data may also be extrapolated to guide timing of blood tests in patients on high-dose biotin therapy: it demonstrates the number of half-lives required to withhold biotin in order to decrease its concentration to below a given assay tolerance.

Background Biotin interference in streptavidin-based immunoassays causes widespread analytical distortions that may lead to clinical confusion, inappropriate patient management and, ultimately, adverse events. Its prevalence has increased recently due to the increased use of high-dose biotin therapy in specific patient groups (notably multiple sclerosis) and possibly the general community. Methods We have developed a method to deplete biotin from samples using the streptavidin-coated magnetic microparticles that are a component of most susceptible assays. Results We show that high concentrations of spiked biotin can be adequately depleted from serum using this approach, and that gross biochemical derangements can be restored to normality. We also show that biotin in samples derived from multiple sclerosis patients receiving 300 mg biotin daily can be adequately depleted to remove associated analytical interference and restore normal results. The method is applicable to competitive and sandwich immunoassays and importantly, because it does not change the volume of the sample, suitable for the measurement of free thyroid hormone assays. Application of the method does not significantly change the precision of measurement, and for the majority of analytes, the accuracy is not substantially altered. Conclusions Adopting this method enables laboratories to confirm biotin interference in the appropriate clinical setting. Moreover, it enables laboratories to remove the interference and report accurate and reliable results, without the need for patients to withhold beneficial therapy prior to blood tests. Until the biotin tolerance of susceptible assays is improved, our method gives laboratories a safe alternative for reporting results using streptavidin-based methods.

Osmolal gap is the difference between the measured osmolality and a calculated osmolality based on the major commonly measured osmotically active particles. The perceived gap indicates the presence of unmeasured osmotically active particles. The major use of osmolal gap today is to screen for the possible presence of exogenous toxic substances in patients in an emergency department or intensive care unit. There is a long history of osmolal gap calculations and it needs to be appreciated that the uncertainty of the osmolal gap will be determined by the sum of errors in the calculated osmolality, error in measured osmolality and variability in unmeasured analytes. Since 1958 there has been a constant trickle of papers proposing both simple and sophisticated formulae to calculate the ‘ultimate’ osmolal gap. A gap as close to zero as possible and with a low coefficient of variation across multiple clinical conditions and analytical platforms are also determinants of ‘fitness for purpose’ of any osmolal gap calculations. The Smithline-Gardner formula for calculated osmolality [2(Na) + Glu + Urea] is fit for purpose in both normal people and general hospital patients. It also performs well across different analytical platforms. This simple formula can be used for rapid mental calculation at the bedside and automated laboratory information system reporting whenever a measured osmolality is requested. In this era of harmonisation, we propose that this formula be adopted by all clinicians and laboratories.

Background Trimester-specific reference intervals (RIs) for thyroid function tests are lacking for Beckman Dxl 800 analysers. We aimed to establish RIs for thyroid stimulating hormone (TSH), free thyroxine (fT4) and to track intraindividual changes in thyroid function throughout pregnancy. Methods One hundred and thirty healthy women without antithyroid peroxidase antibodies were followed longitudinally. Thyroid function was determined at trimester-1 (T1): 9–13 weeks; trimester-2 (T2): 22–26 weeks; trimester-3 (T3): 35–39 weeks and postpartum (PP): 8–12 weeks. A subgroup ( n = 47) was used to track intraindividual changes using PP as non-pregnant state (baseline). Results For trimesters 1–3, TSH (median (2.5th, 5th, 95th and 97.5th percentile)) was 0.77 (0.03, 0.05, 2.33, 3.05), 1.17 (0.42, 0.47, 2.71, 3.36) and 1.35 (0.34, 0.42, 2.65, 2.83) mIU/L, respectively. Free T4 (mean (95%CI)) was 10.7 (5.9–15.5), 8.1 (4.9–11.3), 7.8 (4.5–11.0) pmol/L, respectively. In T2 and T3, 36% and 41% of the fT4 values, respectively, fell below the non-pregnancy lower normal limit. In the subgroup assessed for longitudinal changes, of the women with baseline TSH ⩽ median, 71–75% remained at or below the corresponding median for trimesters 1–3. Of the women with baseline fT4 ⩽ median, 69–81% also remained at or below the corresponding median for trimesters 1–3. High correlation was observed at different trimesters and baseline for TSH (Spearman’s r: 0.593–0.846, P Conclusions Use of trimester-specific RIs would prevent misclassification of thyroid function during pregnancy. In the majority of women, TSH and fT4 tracked on the same side of the median distribution, from a non-pregnant baseline, throughout pregnancy.

Background Low serum 25-hydroxyvitamin D (25[OH]D) levels have been associated with chronic kidney disease in cross-sectional studies. However, this association has not been studied prospectively in a large general population–based cohort. Study Design Prospective cohort study. Setting & Participants 6,180 adults 25 years or older participating in the baseline and 5-year follow-up phases of the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study. Predictor Serum 25(OH)D levels Outcomes & Measurements Incident chronic kidney disease was defined as being negative at baseline but positive after 5 years for (1) reduced estimated glomerular filtration rate (eGFR; 2 ) or (2) albuminuria (spot urine albumin-creatinine ratio ≥2.5 mg/mmol [≥22.1 mg/g] for men and ≥3.5 mg/mmol [≥30.9 mg/g] for women). Results 623 (10.9%) participants were vitamin D deficient, 161 developed incident reduced eGFR, and 222 developed incident albuminuria. In participants with and without vitamin D deficiency, annual age-standardized incidences were 0.92% (95% CI, 0.56%-1.30%) and 0.59% (95% CI, 0.51%-0.68%), respectively, for eGFR 2 and 1.50% (95% CI, 1.06%-1.95%) and 0.66% (95% CI, 0.56%-0.76%), respectively, for albuminuria. In multivariate regression models, vitamin D deficiency was associated significantly with the 5-year incidence of albuminuria (OR, 1.71; 95% CI, 1.12-2.61; P = 0.01), but not reduced eGFR (OR, 0.93; 95% CI, 0.53-1.66; P = 0.8). Limitations The observational nature of the study does not account for unmeasured confounders. Only baseline 25(OH)D level was measured and therefore may not accurately reflect lifetime levels. Differences in baseline characteristics of participants who were included compared with those excluded due to missing data or follow-up may limit the applicability of results to the original AusDiab cohort. Conclusions Our prospective cohort study shows that vitamin D deficiency is associated with a higher annual incidence of albuminuria and reduced eGFR and independently predicts the 5-year incidence of albuminuria. These associations warrant further exploration in long-term prospective clinical trials.

Objective Vitamin D deficiency is recognized as a global public health problem, but the population-based prevalence of deficiency and its determinants in Australian adults is not known. This study evaluated the vitamin D status of Australian adults aged ≥25 years and risk factors associated with vitamin D deficiency in this population. Design and Patients We studied a national sample of 11 247 Australian adults enrolled in the 1999/2000 Australian Diabetes, Obesity and Lifestyle (AusDiab) study drawn from 42 randomly selected districts throughout Australia. Measurements Serum concentrations of 25-hydroxyvitamin D [25(OH)D] were measured by immunoassay. Vitamin D deficiency was defined as a concentration Results The mean serum 25(OH)D concentration was 63 nmol/l (95% CI: 59–67 nmol/l). Only 4% of the population had a level 35°S); 42% of women and 27% of men were deficient during summer–autumn, which increased to 58% and 35%, respectively, during winter–spring. Conclusion Vitamin D deficiency is common in Australia affecting nearly one-third of adults aged ≥25 years. This indicates that strategies are needed at the population level to improve vitamin D status of Australians.

Context: Serum 25-hydroxyvitamin D [25(OH)D] concentration has been inversely associated with the prevalence of metabolic syndrome (MetS), but the relationship between 25(OH)D and incident MetS remains unclear. Objective: We evaluated the prospective association between 25(OH)D, MetS, and its components in a large population-based cohort of adults aged 25 yr or older. Design: We used baseline (1999–2000) and 5-yr follow-up data of the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Participants: Of the 11,247 adults evaluated at baseline, 6,537 returned for follow-up. We studied those without MetS at baseline and with complete data (n = 4164; mean age 50 yr; 58% women; 92% Europids). Outcome Measures: We report the associations between baseline 25(OH)D and 5-yr MetS incidence and its components, adjusted for age, sex, ethnicity, season, latitude, smoking, family history of type 2 diabetes, physical activity, education, kidney function, waist circumference (WC), and baseline MetS components. Results: A total of 528 incident cases (12.7%) of MetS developed over 5 yr. Compared with those in the highest quintile of 25(OH)D (≥34 ng/ml), MetS risk was significantly higher in people with 25(OH)D in the first ( < 18 ng/ml) and second (18–23 ng/ml) quintiles; odds ratio (95% confidence interval) = 1.41 (1.02–1.95) and 1.74 (1.28–2.37), respectively. Serum 25(OH)D was inversely associated with 5-yr WC (P < 0.001), triglycerides (P < 0.01), fasting glucose (P < 0.01), and homeostasis model assessment for insulin resistance (P < 0.001) but not with 2-h plasma glucose (P = 0.29), high-density lipoprotein cholesterol (P = 0.70), or blood pressure (P = 0.46). Conclusions: In Australian adults, lower 25(OH)D concentrations were associated with increased MetS risk and higher WC, serum triglyceride, fasting glucose, and insulin resistance at 5 yr. Vitamin D supplementation studies are required to establish whether the link between vitamin D deficiency and MetS is causal.

Background Our hypothesis was that both the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations would underestimate directly measured GFR (mGFR) to a similar extent in people with diabetes and preserved renal function. Methods In a cross-sectional study, bias (eGFR – mGFR) was compared for the CKD-EPI and MDRD equations, after stratification for mGFR levels. We also examined the ability of the CKD-EPI compared with the MDRD equation to correctly classify subjects to various CKD stages. In a longitudinal study of subjects with an early decline in GFR i.e., initial mGFR >60 ml/min/1.73 m2 and rate of decline in GFR (ΔmGFR) > 3.3 ml/min/1.73 m2 per year, ΔmGFR (based on initial and final values) was compared with ΔeGFR by the CKD-EPI and MDRD equations over a mean of 9 years. Results In the cross-sectional study, mGFR for the whole group was 80 ± 2.2 ml/min/1.73 m2 (n = 199, 75 % type 2 diabetes). For subjects with mGFR >90 ml/min/1.73 m2 (mGFR: 112 ± 2.0, n = 76), both equations significantly underestimated mGFR to a similar extent: bias for CKD-EPI: -12 ± 1.4 ml/min/1.73 m2 (p 90 ml/min/1.73 m2 as well as an early decline in GFR to a similar extent in people with diabetes. There is scope to improve methods for estimating an early decline in GFR.

Uncertainties about the role of cystatin C-based estimated glomerular filtration rate (eGFR) in the prediction of cardiovascular disease (CVD) beyond traditional CVD risk factors remain. We assessed contributions of eGFR to CVD and mortality in the general population.Using 14 year follow-up data on 9353 adults without a reported history of CVD from the Australian Diabetes, Obesity and Lifestyle study, we assessed the contributions of eGFR (assessed by cystatin C (eGFRAfter adjusting for age, sex, CVD risk factors and uACR, compared with an eGFRIn our community-based cohort, reduced eGFR

OBJECTIVE To examine whether serum 25-hydroxyvitamin D (25OHD) and dietary calcium predict incident type 2 diabetes and insulin sensitivity. RESEARCH DESIGN AND METHODS A total of 6,537 of the 11,247 adults evaluated in 1999–2000 in the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, returned for oral glucose tolerance test (OGTT) in 2004–2005. We studied those without diabetes who had complete data at baseline (n = 5,200; mean age 51 years; 55% were women; 92% were Europids). Serum 25OHD and energy-adjusted calcium intake (food frequency questionnaire) were assessed at baseline. Logistic regression was used to evaluate associations between serum 25OHD and dietary calcium on 5-year incidence of diabetes (diagnosed by OGTT) and insulin sensitivity (homeostasis model assessment of insulin sensitivity [HOMA-S]), adjusted for multiple potential confounders, including fasting plasma glucose (FPG). RESULTS During the 5-year follow-up, 199 incident cases of diabetes were diagnosed. Those who developed diabetes had lower serum 25OHD (mean 58 vs. 65 nmol/L; P < 0.001) and calcium intake (mean 881 vs. 923 mg/day; P = 0.03) compared with those who remained free of diabetes. Each 25 nmol/L increment in serum 25OHD was associated with a 24% reduced risk of diabetes (odds ratio 0.76 [95% CI 0.63–0.92]) after adjusting for age, waist circumference, ethnicity, season, latitude, smoking, physical activity, family history of diabetes, dietary magnesium, hypertension, serum triglycerides, and FPG. Dietary calcium intake was not associated with reduced diabetes risk. Only serum 25OHD was positively and independently associated with HOMA-S at 5 years. CONCLUSIONS Higher serum 25OHD levels, but not higher dietary calcium, were associated with a significantly reduced risk of diabetes in Australian adult men and women.

Thyroglobulin (Tg) measurement has become increasingly an important and integral part of the follow up and management of patients with differentiated thyroid cancer. Clinicians predominantly rely on Tg for decision-making for surveillance of patients with differentiated thyroid cancer, but despite this new reliance, issues regarding Tg measurement have not been appropriately addressed especially within a local context. In the process of developing an institutional protocol we have identified that there are significant clinical and technical issues regarding Tg measurement, and surprisingly Tg assessment is currently not part of an external quality control programme. We conducted a small pilot study to specifically emphasize some of the assay issues. We aim to inform endocrinologists, pathologists and nuclear medicine physicians, the need and urgency for these issues to be addressed to improve the ongoing surveillance of differentiated thyroid cancer.

A previously fit and well 5-year-old girl presented to the emergency department with right hip pain and limp following a minor fall from play equipment. X-ray imaging confirmed the presence of a femoral fracture as well as diffuse sclerosis in the sacrum, pelvis, and bilateral proximal femurs (Fig. 1). MRI scan revealed mild stenosis of auditory canals, optic canals, and foramen magnum with no neural compression. DEXA (dual energy X-ray absorptiometry) scan showed markedly increased bone density, with a total body age-matched z score of +14. Bone marrow aspirate was normal. The patient had no other significant medical history and she was not on any regular medications. There was no family history of note but her mother also has increased bone mineral density. Fig. 1. Hip X-ray. Diffuse sclerosis of the sacrum, pelvis, proximal femurs bilaterally, and distal right femur. Right femoral neck fracture is also identified, although alignment of the right hip is maintained. Results for serum electrolytes, urea, creatinine, total calcium, phosphate, parathyroid hormone, vitamin D, alkaline phosphatase, and alanine aminotransferase were all within reference intervals. However, other biochemistry investigations revealed aspartate aminotransferase (AST)7 89 U/L (reference interval, 20–80 U/L); lactate dehydrogenase (LD) 667 U/L (reference interval, 100–200 U/L); acid phosphatase (ACP) 32.1 U/L (reference interval