Applying clinical decision aids for the assessment and management of febrile infants presenting to emergency care in the UK and Ireland: Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study protocol.

INTRODUCTION: Febrile infants 90 days and younger are at risk of invasive bacterial infections (bacteraemia and meningitis) and urinary tract infections. Together this is previously termed serious bacterial infection with an incidence of approximately 10-20%. The National Institute for Health and Care Excellence guidance advocates a cautious approach with most infants requiring septic screening, parenteral broad-spectrum antibiotics and hospital admission. Internationally, variations exist in the approach to febrile infants, with European and North American guidance advocating a tailored approach based on clinical features and biomarker testing. None of the available international clinical decision aids (CDAs) has been validated in the UK and Irish cohorts. The aim of the Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study is to prospectively validate a range of CDAs in a UK and Irish population including CDAs that use procalcitonin testing. METHODS AND ANALYSIS: The FIDO Study is a prospective multicentre mixed-methods cohort study conducted in UK and Irish hospitals. All infants aged 90 days and younger presenting with fever or history of fever (≥38°C) are eligible for inclusion. Infants will receive standard emergency clinical care without delay. Clinical data and blood samples will be collected, and consent will be obtained at the earliest appropriate opportunity using research without prior consent methodology. The performance and cost-effectiveness of CDAs will be assessed. An embedded qualitative study will explore clinician and caregiver views on different approaches to care and perceptions of risk. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Office for Research Ethics Committees Northern Ireland-Health and Social Care Research Ethics Committee B, Public Benefit and Privacy Panel for Health and Social Care Scotland, and Children's Health Ireland Research and Ethics Committee Ireland. The results of this study will be presented at academic conferences and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05259683.

How to interpret cardiac biomarkers in children?

Cardiac biomarkers are used as first-line diagnostic tools in suspected myocardial injury and heart failure in adult patients. Their use in paediatric patients has been limited by variability caused by age, gender and the presence of an underlying congenital cardiac condition. There are established reference ranges for both NT-proBNP and troponin in healthy children, but these cannot be applied to all paediatric patients because of limited large studies focusing on children with congenital heart disease and/or cardiomyopathy.This article will focus on the pathophysiology of myocardial injury and heart failure in children and the subsequent cardiac biomarker correlation. It will explain how to interpret the biomarker assay levels obtained for both troponin and NT-proBNP and highlights the importance of a clear clinical question prior to requesting a cardiac biomarker assay level.Clinical cases outline scenarios that may prompt consideration of biomarker analysis in children and aims to equip the reader with an understanding of how to interpret the results.

Investigating the effects of endogenous lipaemia on the measurement of sodium by indirect ion specific electrode potentiometry.

BACKGROUND: The widely automated method using indirect ion specific electrodes (ISE) potentiometry for determination of sodium concentration is prone to interference from lipaemia. Manufacturer-specified lipaemic (L)-index cut offs may underestimate the effects of endogenous lipaemia. METHODS: We assessed the interference on sodium concentration caused by endogenous lipaemia in 32 residual samples (from 13 patients) using indirect ISE (Cobas® 8000 modular analyser with c702 module, Roche diagnostics) and direct ISE (GEM 4000 premier, Werfen) potentiometric methods. Regression analysis (linear and non-linear) was used to determine a reliable (L)-index cut off for reporting sodium concentration. RESULTS: There was a poor correlation observed between triglyceride concentration and (L)-index. There was significant negative interference caused by endogenous lipaemia within analysed samples. Non-linear regression demonstrated a negative interference of approximately 5% at an (L)-index of 250. CONCLUSION: At present, the manufacturer advises not to report sodium concentration by indirect ISE on the Cobas® 8000 modular analyser if the (L)-index is >2000. However, this has been determined by the addition of exogenous lipids (Intralipid®) and it is clear that this is not comparable to endogenous lipaemia. To ensure patient safety, clinical laboratories should consider lowering the cut off for (L)-index that they use for reporting sodium concentration.

Stabilization of Plasma Glucose: The Use of Newer Technology and Pragmatic Laboratory Practice.

BACKGROUND: The target values for plasma glucose concentrations for the investigation and diagnosis of diabetes and impaired fasting glucose, and the realization that small incremental changes in glucose concentration increase the risk of adverse events, has led to greater focus on laboratory glucose results. Although analytical methods show acceptable precision, the control of preanalytical error due to the stability of glucose remains problematic. The aim of this study was to compare glucose concentrations in 3 different and commercially available blood tubes, with analysis and storage under current practices and conditions. METHODS: Blood samples for glucose were obtained from consenting patients attending the Diabetic Clinic at the Royal Victoria Hospital, Belfast. Blood was collected into BD Vacutainer® Barricor™ Lithium Heparin tubes, BD Vacutainer Fluoride EDTA tubes, and Greiner Vacuette® FC-Mix (sodium fluoride/citrate/Na2EDTA) tubes in that order. The Barricor tubes were immediately centrifuged at 4000g for 3 min. All samples were then sent to the Biochemistry Laboratory for analysis on the same day, and again the following day after storage at 4 °C. RESULTS: There was no significant difference in mean glucose concentrations between immediately centrifuged Barricor and FC-Mix tubes when analyzed on day 0. Both tube types demonstrated higher mean glucose concentrations than traditional fluoride EDTA (F/EDTA) samples. CONCLUSIONS: Both immediately separated Barricor and citrated FC-Mix plasma preserve glucose concentrations to the same extent, and better than F/EDTA preservative. These newer technologies involved offer pragmatic solutions to improved glucose analysis, allowing laboratories to choose the best option given the source of their samples.

Neonatal TSH levels in Northern Ireland from 2003 to 2014 as a measure of population iodine status.

OBJECTIVE: The re-emergence of iodine deficiency in the UK has recently been reported in a large cohort of teenage girls including from Northern Ireland (NI) using the gold standard spot urinary iodine concentration. We wished to explore and confirm this by analysing neonatal thyroid-stimulating hormone (nTSH) levels in the NI population. DESIGN: We analysed the nTSH heel prick tests results from the NI national screening database between 2003 and 2014. The WHO proposes a definition for population iodine sufficiency at <3% of the population with nTSH results >5 mIU/L. METHODS: Anonymized results from 288 491 nTSH tests were retrieved, and prevalence rates of results at increasing cut-offs including >2 mIU/L and >5 mIU/L calculated. We also assessed for possible seasonal variation in nTSH results. RESULTS: An overall population prevalence of 0.49% with TSH >5 mIU/L was found, indicating population iodine sufficiency with no year attaining a prevalence >3%. The prevalence of nTSH >2 mIU/L decreased to 4.1% in 2007 and subsequently increased to 9.8% in 2014. Modest seasonal variation was also detected, with higher levels among April/May births. CONCLUSIONS: The neonatal TSH database suggests iodine sufficiency in the NI population. However, the rising frequency of results >2 mIU/L may indicate an emerging mild iodine deficiency. This is one of the largest and longest studies of its kind in the UK and the first carried out in NI. The summer months may be a time of increased risk of iodine deficiency in our pregnant women whose requirements are increased and who are not currently targeted by any iodine fortification programme in the UK.

A national survey of troponin testing and recommendations for improved practice.

BACKGROUND: The introduction of troponin assays with higher analytical sensitivity and enhanced performance has produced new challenges for both laboratory and clinician in the optimal investigation of patients with cardiovascular disease. After some years of collective experience with this new generation of assays, this survey aimed to assess the level of consensus that exists regarding their application. METHODS: A questionnaire was designed, based on a review of published evidence and current opinion, to obtain information on a number of key areas relating to troponin analysis and reporting and was circulated to lead laboratory consultants across the UK and Ireland. RESULTS: Completed questionnaires were received from 94 laboratory contacts. Sixty per cent of those who responded had implemented a high-sensitivity troponin assay, with the Roche Cobas troponin T high sensitivity assay the most widely used. It is evident that some confusion remains regarding the definition of high-sensitivity assays and there was considerable variation in practice, even among those using the same manufacturer's assay. CONCLUSIONS: There is a need for greater consensus in the approach to the clinical utilization of troponin assays with improved sensitivity and it is important that laboratories are fully aware of the capabilities of their assay and provide useful guidance to users. On the basis of survey findings and the existing evidence base, a number of recommendations have been proposed to improve current practice and enhance patient safety.

Vitamin C prophylaxis promotes oxidative lipid damage during surgical ischemia-reperfusion.

Reactive oxygen species (ROS) have been implicated in the cellular membrane damage and postoperative morbidity associated with obligatory ischemia-reperfusion (I-R) during vascular surgery. Thus, a clinical study was undertaken to evaluate the effects of ascorbate prophylaxis on ROS exchange kinetics in 22 patients scheduled for elective abdominal aortic aneurysm (AAA) or infra-inguinal bypass (IIB) repair. Patients were assigned double-blind to receive intravenous sodium ascorbate (2 g vitamin C, n=10) or placebo (0.9% saline, n=12) administered 2 h prior to surgery. Blood samples were obtained from the arterial and venous circulation proximal to the respective sites of surgical repair (local) and from an antecubital vein (peripheral) during cross-clamping (ischemia) and within 60 s of clamp release (reperfusion). Ascorbate supplementation increased the venoarterial concentration difference (v-adiff) of lipid hydroperoxides (LH), interleukin (IL)-6 and vascular endothelial growth factor (VEGF) protein during ischemia. This increased the peripheral concentration of LH, total creatine phosphokinase (CPK), and VEGF protein during reperfusion (P<0.05 vs placebo). Electron paramagnetic resonance (EPR) spectroscopy confirmed that free iron was available for oxidative catalysis in the local ischemic venous blood of supplemented patients. An increased concentration of the ascorbate radical (A.-) and alpha-phenyl-tert-butylnitrone (PBN) adducts assigned as lipid-derived alkoxyl (LO.) and alkyl (LC.) species were also detected in the peripheral blood of supplemented patients during reperfusion (P<0.05 vs ischemia). In conclusion, these findings suggest that ascorbate prophylaxis may have promoted iron-induced oxidative lipid damage via a Fenton-type reaction initiated during the ischemic phase of surgery. The subsequent release of LH into the systemic circulation may have catalyzed formation of second-generation radicals implicated in the regulation of vascular permeability and angiogenesis.

Retinal vein occlusion, homocysteine, and methylene tetrahydrofolate reductase genotype.

PURPOSE: The aim of this case-control study was to investigate the relationship between homocysteine (tHcy), 5,10 methylene tetrahydrofolate reductase (MTHFR) C677T genotype, folate and vitamin B12 status, and retinal vein occlusion (RVO). METHODS: Subjects with RVO (n = 106) were recruited from outpatient and inpatient sources. Controls (n = 98) were selected to achieve a similar age and sex distribution. Full ocular examination was performed and medical history was taken for each study participant. Plasma and serum samples were analyzed for tHcy level and folate and vitamin B12 status, and extracted DNA was assessed for the MTHFR C677T genotype. RESULTS: There was no significant difference in plasma tHcy level or thermolabile MTHFR allele frequency between subjects and controls. Similarly, there was no significant difference in folate or vitamin B12 status between subjects and controls. MTHFR genotype did not affect folate or vitamin B12 concentrations in subjects or controls. However, tHcy was significantly higher in thermolabile homozygotes than in nonthermolabile homozygotes (ratio of geometric means, 1.35; 95% confidence interval [CI], 1.04-1.74; P = 0.024). CONCLUSIONS: Hyperhomocysteinemia, the MTHFR C677T mutation, and folate and vitamin B12 status are not important risk factors for RVO in this population.

Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop.

OBJECTIVE: This study was undertaken to analyze prospectively circulating vascular endothelial growth factor (VEGF) and its soluble receptor, (s) Flt-1, throughout normotensive and preeclamptic pregnancies and to assess the importance of these proteins in the development of preeclampsia. STUDY DESIGN: In this longitudinal cohort study, serum samples were collected from recruited subjects throughout pregnancy at 12, 20, 30, and 37 weeks and in the 24 hours before and after delivery. Subjects were divided retrospectively into normotensive and preeclamptic groups. Circulating VEGF and sFlt-1 concentrations were analyzed by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. RESULTS: Circulating sFlt-1 and VEGF significantly increased as gestation progressed and both were further elevated in preeclampsia compared with normotensive pregnancy. Soluble Flt-1 concentrations were elevated early in gestation and were significantly increased at 30 weeks' gestation in those who subsequently developed preeclampsia. CONCLUSION: These results indicate a definite association between elevated sFlt-1 concentrations and the onset of preeclampsia suggesting that sFlt-1 is linked with disease pathogenesis.