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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.

Background: Impaired postprandial remnant cholesterol (RC) metabolism results in high triglyceride (TG) in plasma and may intensify the risk of atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolaemia (FH). However, routine assessment of postprandial lipaemia in FH has not been previously investigated. Objective(s): We aimed to assess postprandial lipaemia and chylomicron metabolism by implicating a simplified oral fat tolerance test (OFTT). Method(s): Thirty consecutive subjects with phenotypical FH (N1 = 20 with ASCVD and N2 = 10 without ASCVD) prospectively underwent a simplified OFTT (0,4 h) using a dietary supplement containing 75.0 g monosaturated fat, 41.9 g carbohydrate and 7.2 g protein. FH was diagnosed using the Dutch Lipid Clinic Network criteria. Total cholesterol, TG and high-density lipoprotein (HDL)-cholesterol were measured with enzymatic, colorimetric assays on a Beckman Coulter AU 5800 analyser. RC was calculated as (Total cholesterol-LDL cholesterol-HDL cholesterol). Result(s): Delta plasma TG for cases [mean age 49.9 +/- 11.6yr, median LDL 2.3 (1.7-4.4), median TG 1.2 (0.95-1.40) mmol/L], and 10 FH patients without ASCVD [mean age 46.4 +/- 13.8 yr, LDL 3.5 (2.4-4.5), TG 1.0 (0.60-1.30)] was measured. In cases with ASCVD, there was significant increased postprandial delta TG [1.50 (0.75-2.0) vs 0.35 (0.18-1.56), p = 0.01] and RC [1.2 (0.85-1.55) vs 0.35 (0.18-1.56), p = 0.01]. Postprandial dyslipidaemia in FH with and without ASCVD was independent to conventional risk factors, lipoprotein (a) level [0.18 (0.06-1.14) vs 0.23 (0.15-0.40) p = 0.54], body mass index [(27.3 (3.7) vs 24.4 (4.2), p = 0.06], HbA1C [5.8 (0.4) vs 5.6 (0.8), p = 0.29] and insulin plasma level [(11.5 (6.3) vs 7.0 (2.4), P = 0.06]. Conclusion(s): Our results suggest that postprandial lipaemia is significantly higher in FH subjects with ASCVD. Further trial is required to evaluate implications for additional lipid lowering therapy for further reduction

Paracetamol overdose is common and microRNA (miR)-122 expression is increased with liver injury. We aimed to measure miR-122 in the setting of an abbreviated paracetamol overdose treatment regimen. We compared miRNA expression in patients treated for paracetamol poisoning with an abbreviated 12-h intravenous acetylcysteine regimen (200 mg/kg over 4 h, 50 mg/kg over 8 h) or a 20-h regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) (NACSTOP trial). miR-122 expression is increased (decreased cycle threshold (Ct) values) with paracetamol liver injury. We assessed miR-122 expression in patients receiving the two acetylcysteine regimens and in a separate group with acute liver injury (ALI). We examined 121 blood samples in 38 patients. After 20 h of acetylcysteine, median alanine transaminase (ALT) was 12 U/L (18, 14) versus 16 U/L (11, 21) (p = 0.17) and median miR-122 Ct was 30.1 (interquartile range (IQR): 28.9, 33.3) versus 31.4 (28.9, 33.9) (p = 0.7) in the NACSTOP abbreviated and control groups, respectively. Median normalized miR-122 Ct after 20 h of acetylcysteine was 2.2 (IQR 1.9, 6.4), 1.1 (0.7, 2.9), 63.9 (2.5, 168), 123.2 (40.9, 207.8) in the NACSTOP-abbreviated, NACSTOP-control, ALI and hepatotoxicity groups, respectively. There was no significant difference in ALT or miRNA between NACSTOP treatment groups and no signal of increased liver injury from an abbreviated 12-h acetylcysteine regimen. These findings suggest that an abbreviated acetylcysteine regimen in low-risk patients who have overdosed on paracetamol is safe. Further study is required to validate this finding utilizing miRNA as a comparative biomarker.Copyright © The Author(s) 2019.

Context: To compare degree of liver injury and paracetamol metabolite concentrations after treatment with standard of care (20-h) vs. abbreviated (12-h) acetylcysteine regimens used in paracetamol overdose (NACSTOP trial). Method(s): Timed blood samples from a cohort of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-h acetylcysteine regimen (200 mg/kg over 4 h, 50 mg/kg over 8 h) were assayed for paracetamol metabolites as a pilot study, using liquid chromatography/mass spectrometry. Control group subjects received a 20-h course of acetylcysteine (200 mg/kg over 4 h, 100 mg/kg over 16 h). The intervention group received a 12-h acetylcysteine regimen (stopped after at least 12 h of treatment). Positive control groups not in the trial with acute liver injury (ALI) or hepatotoxicity were also studied. Result(s): One hundred and forty-one blood samples were collected from 40 patients receiving acetylcysteine after paracetamol overdose. Median ALT after 20 h of acetylcysteine was 12 U/L (IQR 8.14) in the abbreviated regimen group, compared to the control group 16 U/L (IQR 11.21) (p =.46). There was no significant difference in median metabolite concentrations on presentation and after 20 h of acetylcysteine between these two groups (p >.05). Presentation median sum CYP-metabolite/total metabolite percentages were 2.5 and 3.0 in the abbreviated and control NACSTOP groups, respectively. Conclusion(s): An abbreviated 12-h acetylcysteine regimen for paracetamol overdose used in the NACSTOP trial had similar circulating metabolite concentrations compared to a 20-h regimen in selected subjects with low risk of hepatotoxicity. This suggests that further acetylcysteine may not be needed in the abbreviated group at time of cessation.Copyright © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

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. All TSH, FT4 and FT3 results with date and time of collection from neonates aged <7 days during 2005-2015 were extracted from the Monash Pathology database. Neonates with more than one episode of testing or with known primary hypothyroidism, identified by treating physicians or from medical records, were excluded from the analysis. The date and time of birth were obtained from the medical records. 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. 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.Copyright © 2018 2018 Walter de Gruyter GmbH, Berlin/Boston.

Introduction: Prompt intervention can prevent permanent adverse neurological effects caused by neonatal hypothyroidism. Thyroid function changes rapidly in the first few days of life but age-related reference intervals (RIs) for TSH, FT4 and FT3 are not available to aid interpretation. This is further complicated by the imprecision of how the days of life are classified, e.g., a neonate who was born just before midnight would be classified as day-1 a few minutes after midnight rather than day-0. We have developed hour-based RIs using data mining. Method(s): All TSH, FT4 and FT3 results (Beckman) with date and time of collection from neonates aged Results: Of the 728 neonates qualifying, 569 had time of birth available. All 569 had TSH, 415 had FT4 and 146 had FT3 results. For age <=24h, 24.1-48.0h, 48.1-72.0h, 72.1-120.0h and 120.0-168.0h of life, the TSH RIs (2.5th-97.5th) (mIU/L) were 4.1-40.2, 3.2-29.6, 2.6-17.3, 1.0-10.3 and 1.0-8.2 respectively; the FT4 RIs (mean +/- 2SD) (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, 13.9-30.9 and 14.4-28.6 respectively; and the FT3 RIs (mean +/- 2SD) (pmol/L) were 5.0-9.4, 4.1-9.0, 2.8-7.8, 3.5-7.2, 3.4-8.0, 3.8-7.9 and 3.8-7.2 respectively. Conclusion(s): In most babies, there is a substantial surge in TSH and FT4 shortly after birth followed by a rapid decline over the subsequent 168 hours. The upper limits are manyfold higher than the values for adults. Use of method- and hour-based RIs in newborns allows for correct identification of neonates who are at risk of hypothyroidism. Due to current lack of analytical harmonisation, these RIs must necessarily be method-specific.

Background: The saline suppression test (SST) is conducted to confirm the diagnosis of primary aldosteronism (PA) in patients with an elevated aldosterone:renin ratio. Studies have speculated that SST can predict PA subtype as either unilateral (predominantly an aldosterone-producing adenoma) or bilateral (adrenal hyperplasia) [1]. An accurate prediction of bilateral disease may reduce the need for adrenal vein sampling (AVS). Aim(s): To identify SST parameters that distinguish bilateral from unilateral PA. Method(s): A retrospective analysis was performed on 89 patients who underwent the SST at Monash Health (February 2011-May 2017). Clinical information collected included patient demographics, SST, AVS and histology results. A positive SST was defined as plasma aldosterone concentration (PAC) >140 pmol/L at 4 hours post-infusion of 2 L normal saline in the recumbent position [2]. Patients with positive SST results were categorized into three PA subtypes: unilateral, bilateral and undetermined (unsuccessful AVS or no AVS). Results were expressed as median (lower and upper quartiles). Result(s): 84 patients had a positive SST: 25 unilateral, 25 bilateral and 34 undetermined. The unilateral group had significantly higher PAC compared to the bilateral group both at 0 hours, 538 pmol/L (441-748) vs 323 pmol/L (250-429) (P = .004), and at 4 hours, 462 pmol/L (280-764) vs 230 pmol/L (195-298) (P = 0.05). Compared to the bilateral group, the PAC in the unilateral group demonstrated a lower absolute reduction at 4 hours, -69 pmol/L (-178-30) vs -87 pmol/L (-142-44) and a smaller percentage decrease at 4 hours, -17% vs -27%, however these were not statistically significant. Conclusion(s): Unilateral causes of PA had a higher PAC during the SST both at 0 and 4 hours. However, we did not identify a clear SST parameter which differentiated unilateral from bilateral PA. A seated SST which is more sensitive for bilateral PA [3] may be better for predicting PA subtypes.

Objective: MicroRNA (miR)-122 expression increases, and miR-483 decreases with paracetamol liver injury. We compared the clinical safety of an abbreviated 12 hour IV acetylcysteine protocol (200 mg/kg over 4 hours, 50 mg/kg over 8 hours) with a 20-hour regimen (200 mg/kg over 4 hours, 100 mg/kg over 16 hours) in patients with low risk of liver injury after acute paracetamol poisoning (NACSTOP-trial). Method(s): A convenience sample of patients treated with acetylcysteine following paracetamol overdose was recruited from NACSTOP. Patients with a normal ALT at presentation and low paracetamol (<20 mg/L) and normal ALT 12 and 20 hours from the start of acetylcysteine were included. Two comparative groups not enrolled in NACSTOP with acute liver injury (ALI: ALT >50 IU/L and double baseline) or hepatotoxicity (ALT >1000 IU/L) were also included. miR-122 expression (quantification cycle, Cq), miR-483 and a miR-ratio (2-deltaCq miR-122/483) were determined from patient samples. Cq results are inversely proportional to miR-expression. Result(s): Of the 38 patients, eight received the 12-hour (abbreviated) and 20 received the 20-hour (control) NACSTOP acetylcysteine regimens; seven patients with ALI and three with hepatotoxicity were also included. The overall median age was 22 years (IQR 18,32) and 70% were female. Median acetylcysteine duration was 13 hours in those receiving the abbreviated regimen, 20 hours in the control and ALI groups and 60 hours in those with hepatotoxicity. Median time to starting acetylcysteine was 6 hours (IQR 5.5,12), 6.5 (5.6,10.5), 7 (5,12), 24 (12,31); median peak ALT was 13 (IQR 10,20) IU/L, 20 (14,22), 83 (61,100), 2365 (2035,15601); and median peak miR-122 Cq was 29.6 (IQR 28.7,31.0), 29.7 (28.6,32.7), 29.0 (23.1,32.4), 23.7 (21.1,23.8) in the abbreviated, control, ALI, and hepatotoxicity groups, respectively. There was no significant difference in median peak ALT or miR-122 Cq between abbreviated and control NACSTOP groups (p > .05). Ther

Aims: Disorders of puberty are diagnosed and monitored by measurement of hormones of the hypothalamic-pituitary-gonadal (HPG) axis. As growth and development can influence normal circulating concentrations of these hormones, gender- and Tanner stage-specific gonadotropin ranges are more meaningful than age-specific values. In particular, given the pulsatile nature of gonadotropin release, are baseline luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels using a sensitive assay able to distinguish between prepuberty and the onset of puberty? Methods: LH and'sH results (measured on Beckman Coulter UniCel DxI 800 analyser) betweeen March 2011 and October 2015 were extracted from Monash Pathology laboratory information system. Patients were included where data on Tanner staging were available. Patients with primary gonadal failure and on treatments influencing the HPG axis were excluded. The remaining data were used to calculate genderand Tanner stage-specific LH and'sH ranges (mean +/- 2SD). Result(s): Of 724 records of paired LH and'sH measurements Tanner staging for 185 was available. See table below for gender- and Tanner stage-specific LH and'sH ranges (mean +/- 2SD). Conclusion(s): Results from a cohort of healthy children and adolescents are ideal for calculation of paediatric reference intervals for gonadotropins. Nevertheless, our data from hospital outpatients (after exclusion of any intervention that might alter HPG axis) still provided a useful picture of gonadotropin levels across Tanner stages. More data points are required to establish reference ranges for routine clinical use. There is significant overlap between gonadotropin results between Tanner Stages I and II suggesting that diagnosing the onset of puberty is difficult using baseline measurements, particularly in females, suggesting the need for gonadotropin-releasing hormonestimulated gonadotropins to assess maturity of the HPG axis.

Background: Familial hypercholesterolemia (FH) is a common hereditary lipid disorder associated with high risk of cardiovascular disease. Emerging evidence suggests, FH is often both underdiagnosed and undertreated by health care providers. The prevalence of identified FH in a tertiary laboratory was assessed in this study. Method(s): We reviewed serum LDL-C level measured by a tertiary laboratory in Melbourne Australia over a six months period (July to December 2016). The prevalence of possible FHbasedonrecommendedLDL-Cthresholdsof5mmol/Las employed by the Dutch Lipid Clinic Network (DLCN) score was evaluated. Result(s): 4943 individuals had serum LDL-C assessment within this period, 106 patients; male/female ratio of 46/60 and mean age of 56, had LDL cholesterol of >= 5mmol/L after exclusion of five patients (0.1%) with secondary causes. Despite a poor documentation of family history and physical examination, 1.8% had DLCNS of 3-5, 0.3% a score of 6-8 and 0.1% a score of >8 indicating a possible, probable and definite diagnosis of FH respectively. The cumulative prevalence of likely phenotypical FH based on an LDL-C >=5.0mmol/L was 2.1% (1: 50). General practitioners referred 37.1% of the total patients followed by cardiologists and endocrinologists equally 12.2% and remaining 38.5% by other specialists. Conclusion(s): This study highlights the potential role of a tertiary laboratory in an opportunistic screening for index cases of FH. These data support the benefit of establishing an efficient "alert system" along with a trigger "reflex testing" to facilitate screening and ensuring further referral to a lipid disorder specialist.

Objective: Circulating CYP450-metabolites have been investigated previously to ascertain risk of liver injury. We investigated the clinical safety of an abbreviated 12-hour IV acetylcysteine protocol (200 mg/kg over 4 hours, 50 mg/kg over 8 hours) with a control group, 20-hour regimen (200 mg/kg over 4 hours, 100 mg/kg over 16 hours) in patients with acute paracetamol poisoning and low-risk of liver injury (NACSTOP-trial) using paracetamol metabolites to predict liver injury. Method(s): A convenience sample, treated with acetylcysteine, following paracetamol overdose was recruited from NACSTOP. Patients with normal ALT at presentation and low paracetamol (<20 mg/L) and normal ALT after 12 hours of acetylcysteine were included. Two comparative groups not enrolled in NACSTOP, with acute liver injury (ALI: ALT >50 IU/L and double baseline) or hepatotoxicity (ALT >1000 IU/L), were also included. Paracetamol metabolites (APAP-Cys, APAP-GSH, APAP-Mer, APAP-Sul, APAPGlu) were assayed. Sum CYP-metabolite percentage (CYS, Mer, GSH)/Total metabolites was calculated. Result(s): Paracetamol metabolites were examined in 40 patients; eight received the 12-hour regimen and 21 received 20-hours of acetylcysteine (NACSTOP-control). Nine patients with ALI and two with hepatotoxicity were also recruited. The overall median age was 22 years (IQR 18,32) and 70% were female. Median acetylcysteine duration was 13 hours in those receiving the 12-hour regimen, 20 hours in the NACSTOP-control and ALI groups and 60 hours in those with hepatotoxicity. Median times to starting acetylcysteine were 6 hours (IQR 5.5,12), 6.5 (5.6,11), 9 (5.5,16), 21 (12,31); median peak ALT was 13 IU/L (IQR 10,20), 19 (14,22), 67 (59,94), 8983 (2365,15601); and presentation sum CYP-metabolites percentage 2.5, 3.0, 2.8, 14.9 in the abbreviated, NACSTOP-control, ALI and hepatotoxicity groups, respectively. There was also a significant difference between presentation sum CYP-metabolite percentage in those with and wi

Background: A large body of evidence suggests a low-fat diet is an essential element of primary prevention in cardiovascular disease and heart failure (HF). Current HF guidelines do not have an endorsed dietary fat advice for patients with established HF; therefore most clinicians apply the same restricted fat diet for prevention of atherosclerotic disease to HF patients. Objective(s): To determine the current evidence of effectiveness and a review of a low-fat diet in HF. Method(s): This review was performed by a comprehensive literature searching in PubMed and Embase in a range of subjects from basic to clinical studies, addressing the role of dietary fat in myocardial contractility and clinical outcomes in both animal and human models. We selected 13 studies (8 human and 5 animal) satisfying the eligibility and the out-comes of interest. Result(s): There were 51874 human and 102 animal subjects included in this review. Substantial role of fatty acids (FA) as the primary source of energy for the myocardium is well established. Several animal-based laboratory studies suggested high FA improves cardiac contractility and prolongs survival in rodents with HF. Evidence shows a low concentration of low-density lipoprotein in plasma is associated with a poor prognosis in HF patients. (Fig. 1) [Figure Presented]. Conclusion(s): This review has identified a deficiency in current dietary fat advice in HF clinical guidelines, particularly those with severely reduced LV ejection fraction. Need for a large randomised clinical trial to assess the cause-effect of fat diet on myocardial function and long-term prognosis in this subset is highly demanded.

Objective: Adrenal vein sampling (AVS) is crucial for differentiating between unilateral and bilateral causes of primary aldosteronism (PA). However, there is a lack of uniform agreement regarding the use of adrenocorticotropic hormone (ACTH) stimulation during AVS. This study compares basal and post-ACTH aldosterone and cortisol values to evaluate the role of ACTH stimulation in AVS. Method(s): An audit was conducted of 127 AVS procedures performed at Austin Health (Jan 2001-Dec 2015) and Monash Health (Jan 2010-Dec 2015). Both centres performed AVS pre- and post-ACTH using sequential catheterization. Patient demographics, screening aldosterone and renin concentrations, AVS aldosterone and cortisol levels pre- and post-ACTH stimulation, adrenal imaging and surgical outcomes including adrenal histology were retrieved. Successful cannulation and lateralization were defined by the selectivity index (SI) and the lateralization index (LI) respectively. Suppression of the non-dominant adrenal site was defined as contralateral suppression index (CSI) <1. Result(s): ACTH significantly increased the rate of successful cannulation (SI > 2 pre- or > 3 post-ACTH), from 70% to 95% on the left (p<0.001), and from 54% to 68% on the right (p=0.029). However, ACTH stimulation significantly lowered the LI (p=0.03). Using LI> 3 pre-ACTH and LI > 4 post-ACTH as thresholds for lateralization, the number of unilateral cases decreased from 71% pre-ACTH to 52% post-ACTH. 6 cases were discordant, whereby the cases would have been re-classified as bilateral despite basal lateralization. Despite being discordant, all underwent unilateral adrenalectomy, 4 of those had adrenal adenomas confirmed on histology and had clinical improvement and normalization or improvement in blood pressure. All 4 patients had post-ACTH LI > 2 and basal CSI<1. Conclusion(s): ACTH stimulation increased the rate of successful cannulation in AVS but masked lateralization in four cases of proven adenoma. Basal LI appe

Objective: Maternal vitamin D deficiency during pregnancy has been linked to impaired neurocognitive development in childhood. The mechanism by which vitamin D affects childhood neurocognition is unclear but may be via interactions with serotonin, a neurotransmitter involved in foetal brain development. In this study, we aimed to explore associations between maternal and foetal vitamin D concentrations, and foetal serotonin concentrations at term. Study design and measurements: Serum 25-hydroxyvitamin D (25(OH)D, nmol/l) and serotonin (5-HT, nmol/l) concentrations were measured in maternal and umbilical cord blood from mother-infant pairs (n = 64). Association between maternal 25(OH)D, cord 25(OH)D and cord serotonin was explored using linear regression, before and after adjusting for maternal serotonin levels. We also assessed the effects of siRNA knockdown of the vitamin D receptor (VDR) and administration of 10 nm 1,25-dihydroxyvitamin D3 on serotonin secretion in human umbilical vein endothelial cells (HUVECs) in vitro. Result(s): We observed an inverse relationship between both maternal and cord 25(OH)D concentrations with cord serotonin concentrations. The treatment of HUVECs with 1,25-dihydroxyvitamin D3 in vitro decreased the release of serotonin (193.9 +/-14.8 nmol/l vs 458.9 +/- 317.5 nmol/l, control, P < 0.05). Conversely, inactivation of VDR increased serotonin release in cultured HUVECs. Conclusion(s): These observations provide the first evidence of an inverse relationship between maternal 25(OH)D and foetal serotonin concentrations. We propose that maternal vitamin D deficiency increases foetal serotonin concentrations and thereby contributes to longer-term neurocognitive impairment in infants and children.Copyright © 2016 John Wiley & Sons Ltd

OBJECTIVE: Maternal vitamin D deficiency during pregnancy has been linked to impaired neurocognitive development in childhood. The mechanism by which vitamin D affects childhood neurocognition is unclear but may be via interactions with serotonin, a neurotransmitter involved in foetal brain development. In this study, we aimed to explore associations between maternal and foetal vitamin D concentrations, and foetal serotonin concentrations at term. STUDY DESIGN AND MEASUREMENTS: Serum 25-hydroxyvitamin D (25(OH)D, nmol/l) and serotonin (5-HT, nmol/l) concentrations were measured in maternal and umbilical cord blood from mother-infant pairs (n = 64). Association between maternal 25(OH)D, cord 25(OH)D and cord serotonin was explored using linear regression, before and after adjusting for maternal serotonin levels. We also assessed the effects of siRNA knockdown of the vitamin D receptor (VDR) and administration of 10 nm 1,25-dihydroxyvitamin D3 on serotonin secretion in human umbilical vein endothelial cells (HUVECs) in vitro. RESULTS: We observed an inverse relationship between both maternal and cord 25(OH)D concentrations with cord serotonin concentrations. The treatment of HUVECs with 1,25-dihydroxyvitamin D3 in vitro decreased the release of serotonin (193·9 ±14·8 nmol/l vs 458·9 ± 317·5 nmol/l, control, P < 0·05). Conversely, inactivation of VDR increased serotonin release in cultured HUVECs. CONCLUSIONS: These observations provide the first evidence of an inverse relationship between maternal 25(OH)D and foetal serotonin concentrations. We propose that maternal vitamin D deficiency increases foetal serotonin concentrations and thereby contributes to longer-term neurocognitive impairment in infants and children.

Background: Supplementation of newborns at risk of vitamin D deficiency is varied across tertiary perinatal centres. There is no published data to demonstrate the efficacy and safety of a single bolus dose vitamin D in infants. We aim to evaluate the efficacy and safety of this alternative approach. Method(s): The single centre study was conducted from Aug 2013 to May 2014. Of 307 pregnant women diagnosed with vitamin D deficiency (vit D <50 nmol/L) 70 were recruited. Their newborn infants were randomly assigned a daily dosing of 400 IU vitamin D for 4 months or a single dosing of 50,000 IU Cholecalciferol. The primary objective was to ascertain which treatment was more effective in achieving repletion (vit D >50 nmol/L). The secondary objective was to determine safety using corrected calcium. Result(s): Of 70 eligible infants, 36 received daily low dose and 34 received single high dose Cholecalciferol. The mean vitamin D3 in the bolus group was significantly higher than the daily group at 1-2 weeks of age; however, this was not seen at 3-4 months (Table 1). Significantly more infants in the single bolus group achieved vitamin D replete status compared to the daily group at 1-2 weeks. By 3-4 months, both groups achieved similar vitamin D repletion status (Table 2). Mean Corrected Calcium levels in the bolus group were within the normal range at 1-2 weeks and 3-4 months (Table 2). No infant had toxic vitamin D3 levels including those changed from breastfeeding to mixed and formula feeding. Conclusion(s): Single bolus dosing of 50,000 IU Cholecalciferol achieves higher repletion rates of Vitamin D3 at 1-2 weeks of age compared to daily dosing, but were similar by 3-4 months. Single bolus dosing did not cause significant hypercalcaemia. (Table Presented).

Background: Measurement of umbilical cord blood and fetal scalp lactate is useful in the assessment of fetal metabolic status. Point of Care (POC) meters have the advantage of delivering immediate results on very small whole blood specimens. However, results may be affected by both meter performance and the effect of highly variable haematocrits. We aimed to evaluate the effect of haematocrit on POC lactate measurement. Method(s): Laboratory experiment: Venous heparinised blood was collected from a volunteer and haematocrit was adjusted to 24%, 40% and 63% using CLSI protocol. Specimens were then placed on a roller for several hours at room temperature while the lactate levels increased (for further measurements). All specimens were analysed on two hand held lactate meters (Adams Akray Lactate Pro and Nova Biomedical Statstrip Express) and a blood gas analyser (Radiometer ABL825). Three replicate measurements were done for each specimen. Results were compared to the Laboratory Beckman DxC800 analyser. Comparison of cord blood: Fresh cord blood was measured on the same lactate meters in the Birth Suite. The samples were immediately taken to the laboratory where haematocrit was measured on the Abbott Cell- Dyn3700 haematology analyser and lactate on the Beckman DxC analyser. Result(s): Laboratory experiment: The Lactate Pro meter gave high results at a haematocrit of 24%. Lactate results were significantly lower on Lactate Pro at the haematocrit of 63% ie: difference is -4.4 mmol/L for Lactate Pro, -0.9 mmol/L for Statstrip and -0.3 for Radiometer. Comparison of cord blood: Compared to Beckman, both meters gave lower results. The difference is more on Lactate Pro meter compared to Statstrip. Conclusion(s): Different POC devices give different lactate results depending on the haematocrit. This could be dangerous especially evaluating fetal or neonatal specimens with high or low haematocrits. Clinicians need to be aware of this to prevent mismanagement of the newborns.

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. © 2008 The Authors.

This study was a randomized controlled trial of a smoking cessation intervention for pregnant smokers. Women who reported smoking at their first antenatal visit and satisfied the inclusion criteria were asked to participate in the trial. Analysis was restricted to 393 evaluable women in the control group (received usual antenatal care) and 339 women to the study group (received usual antenatal care plus the intervention). The primary hypotheses were that the intervention would result in a higher proportion of quitters and that the mean birth-weight of babies born to women receiving the intervention would be greater than that of babies born to women in the control group. The outcome measures were smoking status based on self-report combined with a urinary cotinine level of < 115 ng/mL, and birth-weight. There was no significant difference in quit rate between women receiving the intervention and women in the control group (11.9% versus 9.8% p = 0.41). Babies born to women receiving the intervention were on average 84 g heavier than babies born to controls (p = 0.04). The factors that contribute to the lack of a significant increase in smoking cessation in the intervention group and the possible explanation for the changes in birth-weight are discussed.

Background and objective: Growth failure in homozygous beta-thalassaemia has been recognized for many years, and has persisted despite major treatment advances. In this cross-sectional study, sitting and standing height were measured to determine whether growth failure was disproportionate. Design(s): Patient data were analysed in three age groups, 2-10 years, 11-18 years and 19 and over. Sitting height and subischial leg length were also determined in a cohort of parents (n = 19) and normal Greek adolescents (n = 32). Patients and measurements: Of the known 156 patients with homozygous P-thalassaemia in the State of Victoria, 154 (98.7%) attend our institution. Sitting and standing heights were measured, using Harpenden stadiometers, in 57 of 60 (95%) patients aged 2-18 years and in a random selection of 51 of 89 patients aged 19 and over (57%). Measurements are expressed as mean+/-SDS. Other data analysed included serum concentrations of ferritin, zinc, copper, FSH, LH, oestradiol and testosterone, according to standard laboratory assays, together with pubertal status and bone age in patients aged less than 19 years. Result(s): Standing height standard deviation scores in the 2-10 age group were -0.687 +/- 0.861 (n = 9), in the 11-18 age group were -1.838 +/- 1.413 (n = 48) and in the age group 19 and over were -1.175 +/- 1.126. In individuals aged 2-10 years, sitting height standard deviation scores (SDS) were -1.56 +/- 1.02, in individuals 11-18 years were -3.76 +/- 1.51 (n = 48), and in individuals 19 years and over were -2.77 +/- 1.20 (n = 51), compared with subischial leg length SDS which were, in individuals aged 2-10 years 0.214 +/- 0.91; in 11-18 years, -0.063 +/- 1.347, and in individuals 19 and over, 0.37 +/- 1.18. These data show that the reduction in standing height was the result of truncal shortening. Mean sitting height SDS was significantly lower in children with homozygous beta-thalassaemia, compared with their parents (P < 0.001), and in a subgro

A 28-year-old woman with transfusion-dependent beta-thalassemia major and a history of renal calculi one year earlier presented with a progressive decline in bone mineral density (BMD). The patient reported several months of hip pain following a snow-boarding accident in the preceding year and BMD monitoring with DXA showed a 28% and 34% loss in lumbar spine and femoral neck BMD respectively over the past 3 years. Her medical history included hepatitis C and diet-controlled diabetes. Current medications were vitamin D3 1000 IU daily and the iron-chelating therapy desferasirox (Exjade) 1 g daily. Biochemical testing revealed a low serum phosphate (0.39 mmol/L) with normal renal function (serum creatinine 56 mumol/L) and normal serum calcium, magnesium, 25OH vitamin D and PTH. Alkaline phosphatase was 2-3 times the upper limit of normal. Tubular reabsorption of phosphate (TRP) was abnormal at 47.2% in the setting of low serum phosphate. Diffuse demineralisation was reported on thoracolumbar X-ray. A bone scan demonstrated healing fractures of the right superior and inferior pubic rami and two older rib fractures. A diagnosis of hypophosphataemic osteomalacia was made. Given a case report1 of proximal tubular injury and acute renal insufficiency with desferasirox therapy, a urine metabolic screen was performed and demonstrated generalised mild aminoaciduria and glycosuria. Intermittent hypercalciuria was also noted. Following cessation of desferasirox, rapid normalisation of the serum phosphate, TRP and aminoaciduria occurred and significant improvement in BMD was seen four months later. This is the first case of hypophosphataemic osteomalacia secondary to desferasirox treatment. We report the clinical monitoring of this patient following the necessary reintroduction of desferasirox at reduced doses. Subsequent screening of 86 patients with beta-thalassemia major on desferasirox is planned.

Aim: To evaluate the effect of exercise on albuminuria in subjects at various stages of diabetic nephropathy and healthy control volunteers. Background(s): Spot urine measurement of albumin is now the most commonly accepted approach to assessing proteinuria. Exertion prior to the collection may potentially influence the result of spot urine albumin estimation. Method(s): Thirty-Five diabetic subjects (19 with normoalbuminuria (NA), 9 with microalbuminuria (MA) and 7 with overt proteinuria (OP)) and nine control subjects were assessed. A 1 km treadmill walk was performed. Four Spot urine specimesn were collected; first morning void, immediately prior to exercise, and 1 and 2 hours after of exercise. A random effect linear regression mixed model was used to assess the effect of exercise on uACR. Results are presented separately for males and female diabetic subjects due to a significant exercise/gender interaction (p <0.05). Result(s): No significant effect of exercise on uACR was seen in control subjects. In NA diabetic males no effect of exercise was seen while in females uACR 1 hour post exercise was significantly higher than the early morning sample (3.55 mg/mmol (96% CI 0.27-6.83)). uACR increased 1 hour post exercise in MA subjects although the effect was more marked in females (87.8, -24.3-199.4) compared to males (6.7, 2.1-11.3). For both males and females with OP, uACR was significantly increased 1 hour post exercise (67.5, 22-113 & 21.6, 8.4-34.8 respectively). In all groups uACR at 2 hours post exercise was not significantly different to the early morning sample. Conclusion(s): Exercise increased uACR estimation in subjects with diabetes with a larger effect in females. Whether exercise unmasks early diabetic nephropathy in NA subjects requires further study.