Pediatric reference intervals for endocrine markers in healthy children and adolescents on the Liaison XL (DiaSorin) immunoassay system.

OBJECTIVES: Prominent physiological changes occurring throughout childhood and adolescence necessitate the consideration of age and sex in biomarker interpretation. Critical gaps exist in pediatric reference intervals (RIs) for specialized endocrine markers, despite expected influence of growth and development. The current study aimed to establish and/or verify RIs for six specialized endocrine markers on a specialized immunoassay system. METHODS: Samples were collected from healthy children and adolescents (5 to <19 years) and apparently healthy outpatients (0 to <5 years) as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER). Serum samples were analysed for aldosterone, renin (plasma), thyroglobulin, anti-thyroglobulin, growth hormone, and insulin-like growth factor-1 (IGF-1) on the Liaison XL (DiaSorin) immunoassay platform. RIs (2.5th and 97.5th percentiles) were established for aldosterone, renin, thyroglobulin, anti-thyroglobulin, and growth hormone. Manufacturer-recommended pediatric RIs for IGF-1 were verified. RESULTS: Age-specific RIs were established for aldosterone, renin, and thyroglobulin, while no age-specific differences were observed for anti-thyroglobulin or growth hormone. IGF-1 was the only endocrine marker studied that demonstrated significant sex-specific differences. Manufacturer-recommended IGF-1 RIs were verified for children aged 6 to <19 years, while those for children aged 0 to <6 years did not verify. CONCLUSIONS: This study marks the first time that pediatric RIs for aldosterone and renin were established in the CALIPER cohort and highlights the dynamic changes that occur in water and sodium homeostasis during the first years of life. Overall, these data will assist pediatric clinical laboratories in test result interpretation and improve clinical decision-making for patients tested using Liaison immunoassays.

Stillbirth: are we making more progress than we think? A retrospective cohort study.

OBJECTIVE: To quantify how the changing stillbirth risk profile of women is affecting the interpretation of the stillbirth rate. DESIGN: A retrospective, population-based cohort study from 1983 to 2018. SETTING: Victoria, Australia. POPULATION: A total of 2 419 923 births at ≥28 weeks of gestation. METHODS: Changes in maternal characteristics over time were assessed. A multivariable logistic regression model was developed for stillbirth, based on maternal characteristics in 1983-1987, and used to calculate individual predictive probabilities of stillbirth from the regression equation. The number of expected stillbirths per year as a result of the change in maternal demographics was then calculated, assuming no changes in care and in the associations between maternal characteristics and stillbirth over time. MAIN OUTCOME MEASURE: Stillbirth. RESULTS: Compared with 1983-1987, there were more women in older age groups giving birth, more nulliparous women, more indigenous women and women born in Oceania, Asia and Africa, more multiple pregnancies and more women with pre-existing diabetes in 2014-2018. Despite this, the rate of stillbirth fell from 5.42 per 1000 births in 1983 to 1.72 per 1000 births in 2018 (P < 0.001). Applying the multivariable logistic regression equation, derived from the 1983-87 data, to each year, had there been no changes in care or in the associations between maternal characteristics and stillbirth, the rate of stillbirth would have increased by 12%, from 4.94 per 1000 in 1983 to 5.54 per 1000 in 2018, as a result of the change in maternal characteristics. CONCLUSIONS: Population rates of stillbirth are falling faster than is generally appreciated. TWEETABLE ABSTRACT: Population reductions in stillbirth have been underestimated as a result of changing maternal characteristics.

Analytical performance evaluation of thyroid-stimulating hormone receptor antibody (TRAb) immunoassays.

BACKGROUND: Thyroid-stimulating hormone receptor (TSHR)-activating autoantibodies stimulate thyroid growth and hormone synthesis/secretion, causing hyperthyroidism of Graves' disease (GD). TRAb measurement helps diagnose GD and is an important first test in evaluating hyperthyroidism according to the recent American Thyroid Association guidelines. We compared the performance of the BRAHMS TRAK Kryptor (Thermo Scientific) and Roche cobas TRAb immunoassays for use in GD. METHOD: Method comparison (n = 40) and clinical agreement were assessed between the Kryptor, cobas e411, and cobas e601. The analytical performance of Kryptor and cobas e411 were assessed for within- and between-day imprecision across 20 days, linearity, functional assay sensitivity (FAS), dilution recovery, and cut-off verification. RESULTS: The Kryptor, e411, and e601 TRAb immunoassays correlated well (r > 0.95, overall percent agreement = 0.95, Cohen's kappa = 0.90). With a total allowable error of 20%, percent bias was within 13%, which was minimally negative at <20 IU/L, but highly positive (33%-34%) >20 IU/L. The Kryptor, but not e411, was linear across the claimed analytical measuring range (AMR). The claimed functional assay sensitivity (FAS), which was close to the clinical GD cut-off 1.8 IU/L, was verified for Kryptor and e411. CONCLUSION: Overall, our evaluation demonstrates acceptable comparability between TRAb immunoassays with in-house imprecision up to 13% and 10% on Kryptor and e411, respectively. While Roche has preferable calibration frequency and on-board reagent stability, both platforms demonstrate acceptable imprecision using patient samples at their claimed FAS, which is important for GD diagnosis. Diluted results (using a negative patient pool as diluent) exhibits proportional positive bias on the Kryptor relative to the Roche methods.

Increasing obstetric intervention for fetal growth restriction is shifting birthweight centiles: a retrospective cohort study.

OBJECTIVE: To assess the impact of increasing obstetric intervention on birthweight centiles. DESIGN: Retrospective cohort study of births in five 2-year epochs: 1983-84, 1993-94, 2003-2004, 2013-2014 and 2016-2017. POPULATION: 665 205 singleton births at ≥32 weeks' gestation. SETTING: All maternity services in Victoria, Australia. METHODS: For each epoch, we calculated the birthweight cutoffs defining each birthweight centile at 34, 37 and 40 weeks' gestation. We calculated rates of iatrogenic delivery over time. We then calculated the number of babies whose birthweight would have classified them as ≥3rd centile based on 1983-84 centile definitions but as <3rd centile based on 2016-2017 centile definitions. MAIN OUTCOME MEASURES: Birthweight centile, and gestation at delivery. RESULTS: From 1983-84 to 2016-2017, the rate of iatrogenic delivery for singleton pregnancies increased at all term gestations: 1.6-6.4% at 37 weeks', 4.5-18.3% at 38 weeks', 7.6-23.9% at 39 weeks' and 18.4-25.1% at 40 weeks' (all P < 0.001). Over the same period, the birthweight cutoffs defining the 3rd, 5th and 10th centiles increased significantly at term, but not preterm, gestations. This led to increasing numbers of term births being classified as small for gestational age (SGA). Of the 2748 babies born in 2016-2017 at 37-39 weeks' gestation with a birthweight <3rd centile in that period, 1478 (53.8%) would have been classified as ≥3rd centile based on 1983-84 centile definitions. CONCLUSION: Increasing intervention is shifting the birthweight cutoffs that define birthweight centiles and thereby redefining what constitutes SGA. This undermines the use of population-derived birthweight centiles to audit clinical care. TWEETABLE ABSTRACT: Increasing obstetric intervention is shifting birthweight centiles and therefore definitions of normality.

Does public reporting of the detection of fetal growth restriction improve clinical outcomes: a retrospective cohort study.

OBJECTIVE: To assess the impact of publicly reporting a statewide fetal growth restriction (FGR) performance indicator. DESIGN: Retrospective cohort study from 2000 to 2017. SETTING: All maternity services in Victoria, Australia. POPULATION: A total of 1 231 415 singleton births at ≥32 weeks of gestation. METHODS: We performed an interrupted time-series analysis to assess the impact of publicly reporting an FGR performance indicator on the rate of detection for severe cases of small for gestational age (SGA). Rates of perinatal mortality and morbidity and obstetric intervention were assessed for severe SGA pregnancies and pregnancies delivered for suspected SGA. MAIN OUTCOME MEASURES: Gestation at delivery, obstetric management and perinatal outcome. RESULTS: The public reporting of a statewide FGR performance indicator was associated with a steeper reduction per quarter in the percentage of severe SGA undelivered by 40 weeks of gestation, from 0.13 to 0.51% (P = 0.001), and a decrease in the stillbirth rate by 3.3 per 1000 births among those babies (P = 0.01). Of babies delivered for suspected SGA, the percentage with birthweights ≥ 10th centile increased from 41.4% (n = 307) in 2000 to 53.3% (n = 1597) in 2017 (P < 0.001). Admissions to a neonatal intensive care unit for babies delivered for suspected SGA but with a birthweight ≥ 10th centile increased from 0.8 to 2.0% (P < 0.001). CONCLUSIONS: The public reporting of an FGR performance indicator has been associated with the improved detection of severe SGA and a decrease in the rate of stillbirth among those babies, but with an increase in the rate of iatrogenic birth for babies with normal growth. TWEETABLE ABSTRACT: The public reporting of hospital performance is associated with a reduction in stillbirth, but also with unintended interventions.

Noradrenergic modulation of hypoglossal motoneuron excitability: developmental and putative state-dependent mechanisms.

Hypoglossal (XII) motoneurons (MNs) contribute to diverse behaviors. Their innervation of the genioglossus muscle, a tongue protruder, plays a critical role in maintaining upper airway patency during breathing. Indeed, reduced activity in these motoneurons is implicated in sleep related disorders of breathing such as obstructive sleep apnea (OSA). The excitability of these MNs is modulated by multiple neurotransmitter systems. The focus of this review is on the modulation of XII MN excitability by norepinephrine (NE), which increases MN excitability through a variety of mechanisms. The level of noradrenergic drive, however, is very dynamic, varying on developmental, sleep-wake and even millisecond timescales relevant to transitions between behaviours. Here we review and provide new data on the maturation of the noradrenergic modulatory system, focusing on those elements specifically relevant to XII MN excitability including the: i) ontogeny of the noradrenergic cell group that provides the majority of the noradrenergic innervation to the XII nucleus, the Locus subcoeruleus (LsC); ii) time course over which the XII nucleus is innervated by noradrenergic nerve fibres, and; iii) ontogeny of XII MN sensitivity to NE. In the context of state-dependent changes in noradrenergic cell activity, we review mechanisms of NE action most relevant to its role in the muscle atonia of REM sleep. We conclude with a discussion of the hypothesis that the dynamics of MN modulation by NE extend to the spatial domain and recent data suggesting that noradrenergic modulation of the dendritic tree is not uniform but compartmentalized. Implications for information processing are discussed.

Thrombolysis beyond 3 hours for acute ischaemic stroke.

Intravenous thrombolysis is an accepted form of treatment for acute ischaemic stroke when administered within 3 h of symptom onset. However, evidence for its benefit when given beyond this time continues to strengthen. The case history of a young woman is presented with an ischaemic stroke who was successfully thrombolysed with recombinant tissue-type plasminogen activator more than 3 h after presentation. Perfusion CT scanning was used to stratify the likelihood of benefit. Thrombolysis was administered through a combination of intravenous and intra-arterial routes. This case illustrates the advances being made both in the imaging techniques used and the forms of drug administration which can be applied to maximise benefit in this extended therapeutic window. These recent advances are reviewed and their possible impact on current and future practice assessed. While the drive remains the introduction of thrombolysis at a local level for ischaemic stroke within 3 h of symptom onset, it is necessary to consider treatment of subjects presenting beyond 3 h in tertiary centres with the appropriate facilities and expertise.

Nutritional status and productivity of Sri Lankan tea pluckers.

OBJECTIVE: To assess the impact of nutritional status on productivity of tea pluckers. DESIGN: Cross-sectional, analytical. SETTING AND PARTICIPANTS OF STUDY: All tea pluckers in five divisions of a tea estate in Hatton. MEASUREMENTS: A dietary survey was conducted using the 24 h dietary recall method. Nutritional status was assessed by measurement of body mass index (BMI) and haemoglobin (Hb) levels, and faeces were examined for helminth ova. The daily weight of tea leaves plucked and the number of days worked by each woman during the preceding month were noted from production records. RESULTS: Three hundred and four women (mean age 37.8 years, SD 8.4) were examined. The majority (59.9%) had evidence of chronic energy deficiency (BMI < 18.5). Almost all (94.4%) were anaemic (Hb < 13.3 g/dl, altitude adjusted cutoff). Mean daily iron intake was 8.7 mg (SD 2.3 mg), 45.9% of the national recommended dietary allowance. Only 10.1% had hookworm infection, all of light intensity. Multivariate regression analysis showed that dietary iron intake, the number of children and the number of children below 5 years, but not hookworm infection, were independently associated with Hb (p < 0.05). There was a strong positive correlation between monthly productivity and Hb, but not with BMI. Variation in Hb levels accounted for 65% of variation in productivity (adjusted R2 = 0.651). CONCLUSIONS: Most of the study population had chronic energy deficiency and anaemia. Dietary inadequacy of iron is a much more important causative factor than hookworm infection. Productivity was strongly associated with the degree of anaemia but not with BMI.