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Jacob S.L.,Seacroft Hospital | Brewer C.,Seacroft Hospital | Tang T.,Royal Maternity Hospital | Picton H.M.,Seacroft Hospital | And 2 more authors.
Human Reproduction | Year: 2016

STUDY QUESTION: Does 'metformin' reduce the incidence of ovarian hyperstimulation syndrome (OHSS) for women with polycystic ovary syndrome (PCOS) undergoing a GnRH antagonist assisted conception treatment cycle? SUMMARY ANSWER: A short course of metformin does not reduce the incidence of OHSS for women with PCOS undergoing a GnRH antagonist treatment cycle. WHAT IS KNOWN ALREADY: Metformin does reduce the incidence of OHSS in a GnRH-Agonist treatment cycle. STUDY DESIGN, SIZE, DURATION: A randomised placebo-controlled trial (RCT) using metformin or placebo. Randomisation was blinded to both patient and investigator, using a random permuted blocks method with a 50:50 allocation ratio. The study was completed over 5 years (2009-2014) with 153 randomised patients. A sample size calculation based on the incidence of OHSS was completed prospectively suggesting a minimum of 146 recruits was required for the trial with a power of 80% and a type 1 error of 0.05. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients met the Rotterdam criteria for PCOS and were treated with a standard GnRH antagonist IVF/ICSI treatment cycle in a tertiary infertility clinic. The study medication was started prior to stimulation and continued to oocyte retrieval. Of the 153 patients, 77 received metformin and 76 placebo. MAIN RESULTS AND THE ROLE OF CHANCE: There was no reduction in the incidence of moderate-severe OHSS (Placebo (PLA) 12.2%, metformin (MET) = 16%, 95% CI -0.08-0.16, P = 0.66). There was no difference in total gonadotrophin dose (PLA = 1200, MET = 1200, 95% CI -118.67-118.67, P = 0.75), oocytes retrieved (PLA = 15, MET = 14, 95% CI -2.37-4.37, P = 0.66) or fertilisation rate (PLA = 60.7%, MET = 53.3%, 95% CI -0.96-14.94, P = 0.07). However, using metformin resulted in a reduced clinical pregnancy rate (CPR) per cycle started (PLA = 48.7%, MET = 28.6%, 95% CI 0.04-0.35, P = 0.02) and live birth rate (PLA = 51.6%, MET = 27.6%, 95% CI 0.05-0.40, P = 0.02). Furthermore, when ethnicity was taken into account there was a significant reduction in pregnancy outcome for the South Asian population irrespective of metformin or placebo use (CPR per cycle started,White Caucasian = 44.4%, South Asian = 19.4%; 95% CI 0.06-0.39, P = 0.01). LIMITATIONS, REASONS FOR CAUTION: This study was only undertaken on an infertility population with PCOS with a limited duration of study medication use. WIDER IMPLICATIONS OF THE FINDINGS: This is the first adequately powered RCT to assess the impact of metformin on OHSS in a high-risk group (women with PCOS) undergoing a GnRH antagonist cycle. It does not support the empirical prescribing of metformin as an adjunct to a GnRH antagonist treatment cycle. © The Author 2016.


Chandrajay D.,Blood science | Narayanan D.,Blood science | Barth J.H.,Blood science
Annals of Clinical Biochemistry | Year: 2016

Aim: The aim of the study was to review the clinical validation process of out of hours critical biochemistry results by a clinical biochemist and its effect on primary care services. Methods: A prospective study was conducted of all critical results for primary care patients who were analysed out of hours. The nine-month study period was conducted between June 2013 and February 2014. The data collected include patients’ age, clinical details, critical results and the urgency of result communicated. The patients’ subsequent attendance rate at the emergency department in the local hospital was reviewed. Results: A total of 311 out of hours critical results were identified in the laboratory. After clinical validation, 110 (35.4%) results were telephoned urgently and 155 (49.8%) results were deferred to the next day. Forty-six (14.8%) results were not telephoned. Following the urgent result communication, 53/110 (48.2%) patients attended the hospital emergency department within 24 h and 17/110 (15.5%) had their repeat blood test by their general practitioner surgery within 48 h. When the result was telephoned during working hours the next day, only 15/155 (9.7%) attended the hospital acute services within 48 h and 16/155 (10.3%) had repeat blood test at their general practitioner surgery. Conclusion: In our practice, the clinical validation of out of hours critical results by a clinical biochemist is associated with a reduction in the number of results telephoned when compared against the critical limits list recommended by the Royal College of Pathologists and may focus out of hours clinical activity on more suitable patients. © 2015, The Author(s) 2015.


Carless D.R.,Blood science | Wnek M.,Blood science | Knox C.,Blood science | Harrison K.R.,Blood science | And 3 more authors.
Scandinavian Journal of Clinical and Laboratory Investigation | Year: 2013

Background. Heart-type fatty acid-binding protein (H-FABP) is a low molecular weight protein involved in the intracellular uptake and buffering of long chain fatty acids in the myocardium. It is an early marker for ACS. We have evaluated the Randox Laboratories immunoturbidimetric assay on a Siemens Advia 1800 analyzer. The assay employs latex particles coated with mouse monoclonal anti-HFABP antibodies to generate turbidity. Methods. We used redundant patient samples and pools to assess precision, functional sensitivity, limit of detection, linearity, recovery of recombinant H-FABP and interference. We evaluated the 99th centile values and compared H-FABP with troponin in samples routinely received from chest pain patient samples. Results. Precision was typically < 10% and 12.5% at all concentrations for within and between batches. The functional sensitivity was 2.4 μg/L. The assay was linear on dilution over the range 2.76-115 μg/L. Recovery of recombinant H-FABP was approximately 20-25%. No interference was seen with haemoglobin concentrations <1.5 g/L, bilirubin < 250 μg/L and triacylglycerol < 5 mmol/L or rheumatoid factor. The 99th centile value in a reference population with eGFR > 60mL/min/1.73m2 was 9.1 μg/L with no significant gender difference. H-FABP was measured in routine clinical samples (N = 1310) received for troponin I measurement. Using Siemens TnI > 50 ng/L as an indicator of myocardial damage, the ROC area under curve for H-FABP was 0.82. Conclusions. The immunoturbidimetric H-FABP assay is robustly designed and shows good analytical performance. It is therefore well suited for use in a routine clinical laboratory. © 2013 Informa Healthcare.


Ozarda Y.,Uludag University | Ichihara K.,Yamaguchi University | Barth J.H.,Blood science | Klee G.,Rochester College
Clinical Chemistry and Laboratory Medicine | Year: 2013

The reference intervals (RIs) given in laboratory reports have an important role in aiding clinicians in interpreting test results in reference to values of healthy populations. In this report, we present a proposed protocol and standard operating procedures (SOPs) for common use in conducting multicenter RI studies on a national or international scale. The protocols and consensus on their contents were refined through discussions in recent C-RIDL meetings. The protocol describes in detail (1) the scheme and organization of the study, (2) the target population, inclusion/ exclusion criteria, ethnicity, and sample size, (3) health status questionnaire, (4) target analytes, (5) blood collection, (6) sample processing and storage, (7) assays, (8) cross-check testing, (9) ethics, (10) data analyses, and (11) reporting of results. In addition, the protocol proposes the common measurement of a panel of sera when no standard materials exist for harmonization of test results. It also describes the requirements of the central laboratory, including the method of cross-check testing between the central laboratory of each country and local laboratories. This protocol and the SOPs remain largely exploratory and may require a reevaluation from the practical point of view after their implementation in the ongoing worldwide study. The paper is mainly intended to be a basis for discussion in the scientific community.


Baddams E.L.,Blood science | Degg T.,Blood science | Barth J.H.,Blood science
Annals of Clinical Biochemistry | Year: 2014

Introduction: Serum ferritin is routinely used as a first line test for iron status. Testing subjects with low pre-test probability often results in unexpected abnormal results. Raised ferritin is typically found in subjects with iron overload, liver disease, malignancy or inflammation. We sought to determine whether primary care patients with high ferritin had either porphyria cutanea tarda (PCT) or hereditary haemochromatosis (HH). Methods: Redundant serum samples were collected from consecutive specimens with high ferritin (>500 μg/L) which had been received from primary care sources. Samples were analysed for serum iron and iron-binding capacity and for porphyrins by fluorescence scanning and HPLC. Results: There were 240 samples (91 females, 149 males) which represented 2.7% of total over the collection period. Serum iron was 17.3 (18.9) mmol/L (median (IQR)), TIBC 47.3 (14.2) mmol/L and transferrin saturation 35.7 (41.1) %. There were 87/240 (36%) with transferrin saturation >45% (57 males, 30 females). Of the samples 19/236 (8%) were positive for porphyrins by spectrofluorimetry and 14/15 (4 insufficient sample) had total porphyrins >11.2 nmol/L (40(63) median (IQR)) with 3/15 (1.25%) having a typical pattern for PCT. Discussion: This study demonstrates the feasibility of cascading tests using laboratory protocols and confirms the ability to identify potential cases. However, further studies for HH genotype and urine and stool porphyrin analysis will be necessary to confirm the diagnoses. © The Author(s) 2013 Reprints and permissions.


Davies J.,Blood science
Journal of Clinical Pathology | Year: 2015

Procalcitonin (PCT) is the 116 amino acid precursor of the hormone calcitonin, produced by the C cells of the thyroid. Its synthesis is upregulated in bacterial infection and downregulated by viral infection. Consequently, with the increasing development of antibiotic resistance, interest has focused on the ability of this marker to not only diagnose infection but to tailor antibiotic treatment and help reduce the development of antibiotic resistance. The value of PCT depends on the specific clinical situation and pretest probability of disease. This article discusses the role of PCT in these different situations, namely primary care, the emergency department and the intensive care unit. The true cost effectiveness of this test remains difficult to prove as evidence for the potential impact of using PCT on slowing the development of bacterial resistance remains largely circumstantial.


PubMed | Blood science
Type: Journal Article | Journal: Annals of clinical biochemistry | Year: 2016

Laboratories are recommended to determine their own local reference intervals (RIs) to embrace the variations in local populations. We have assessed local RIs for thyroid function tests using two different approaches to selection of reference populations and also searched the literature for studies using the Advia Centaur methods.Two independent populations were made of redundant serum samples from primary care in which exclusion criteria were used to reduce the inclusion of patients with thyroid disease. A further population of healthy subjects were recruited. All groups were restricted to 18-65 years and thyroid peroxidase antibodies (TPOabs) positive subjects were excluded. All samples were analysed using Advia Centaur reagents. A literature search was made for RI studies on non-pregnant adults using Advia Centaur.Redundant data sets consisted of 219 and 222 subjects and a healthy population of 280. Comparison of variance of all three groups showed differences for free T4 (fT4) and total T3 (TT3) (analysis of variance P<0.0001) but thyroid-stimulating hormone (TSH) was similar across all three groups (P=0.7656). RI for TSH, fT4 and TT3 all fell within the 95% confidence interval for each other for all three analytes. Published RIs give wide variation although their mean is similar to the prospective data reported here.Our data suggest that a consensus set of RIs for Advia Centaur can be adopted from the prospective studies and literature search in this paper and we would suggest the following RIs: TSH 0.5-4.4mIU/L; fT4 10-20pmol/L; and TT3 1.1-2.4nmol/L.


PubMed | University of Buenos Aires, Uludag University, Peking Union Medical College, Blood science and 12 more.
Type: | Journal: Clinica chimica acta; international journal of clinical chemistry | Year: 2016

The IFCC Committee on Reference Intervals and Decision Limits coordinated a global multicenter study on reference values (RVs) to explore rational and harmonizable procedures for derivation of reference intervals (RIs) and investigate the feasibility of sharing RIs through evaluation of sources of variation of RVs on a global scale.For the common protocol, rather lenient criteria for reference individuals were adopted to facilitate harmonized recruitment with planned use of the latent abnormal values exclusion (LAVE) method. As of July 2015, 12 countries had completed their study with total recruitment of 13,386 healthy adults. 25 analytes were measured chemically and 25 immunologically. A serum panel with assigned values was measured by all laboratories. RIs were derived by parametric and nonparametric methods.The effect of LAVE methods is prominent in analytes which reflect nutritional status, inflammation and muscular exertion, indicating that inappropriate results are frequent in any country. The validity of the parametric method was confirmed by the presence of analyte-specific distribution patterns and successful Gaussian transformation using the modified Box-Cox formula in all countries. After successful alignment of RVs based on the panel test results, nearly half the analytes showed variable degrees of between-country differences. This finding, however, requires confirmation after adjusting for BMI and other sources of variation. The results are reported in the second part of this paper.The collaborative study enabled us to evaluate rational methods for deriving RIs and comparing the RVs based on real-world datasets obtained in a harmonized manner.


PubMed | Cape Peninsula University of Technology, University of Buenos Aires, Uludag University, Peking Union Medical College and 9 more.
Type: | Journal: Clinica chimica acta; international journal of clinical chemistry | Year: 2016

The intent of this study, based on a global multicenter study of reference values (RVs) for serum analytes was to explore biological sources of variation (SVs) of the RVs among 12 countries around the world.As described in the first part of this paper, RVs of 50 major serum analytes from 13,396 healthy individuals living in 12 countries were obtained. Analyzed in this study were 23 clinical chemistry analytes and 8 analytes measured by immunoturbidimetry. Multiple regression analysis was performed for each gender, country by country, analyte by analyte, by setting four major SVs (age, BMI, and levels of drinking and smoking) as a fixed set of explanatory variables. For analytes with skewed distributions, log-transformation was applied. The association of each source of variation with RVs was expressed as the partial correlation coefficient (rObvious gender and age-related changes in the RVs were observed in many analytes, almost consistently between countries. Compilation of age-related variations of RVs after adjusting for between-country differences revealed peculiar patterns specific to each analyte. Judged fromtherThe features of sex, age, alcohol, and smoking-related changes in RVs of the analytes were largely comparable worldwide. The finding of differences in BMI-related changes among countries in some analytes is quite relevant to understanding ethnic differences in susceptibility to nutritionally related diseases.


PubMed | Imperial College London, University of Bergen, Ghent University, Laboratoire Of Biologie Polyvalente and 2 more.
Type: Journal Article | Journal: EJIFCC | Year: 2016

Clinical practice guidelines (CPGs) relating to laboratory diagnostic testing are increasingly produced with the aim of standardizing practice and improving patient care based on the best available evidence. However, the production of a CPG is merely the first step in the process of getting evidence into practice, to be undertaken by laboratories and other stakeholders. This process should evaluate the information provided in the guidelines on laboratory tests, devise a strategy for implementing the CPG or the laboratory aspects of the CPG and finally, once implemented, assess the impact of the CPG on clinical practice, patient outcomes and costs of care. The purpose of CPG evaluation by the laboratory is to determine whether sufficient information is provided on the particular test recommended. CPGs may not always be written with the involvement of a laboratory specialist and this underlies the paucity of relevant information in some national guidelines. When laboratory specialists are involved, CPGs can provide practical information which supports local laboratories as well as clinicians in the implementation and appropriate use of recommendations. Implementation of CPGs is an often neglected area that needs attention and thought. There are many barriers to successful implementation, which may vary at local level. These need to be identified early if CPGs are to be successfully adhered to. The effectiveness of CPGs also needs to be audited using process and health outcome indicators. Clinical audit is an effective tool for assessing adherence to recommendations and for measuring the impact and success of the CPG.

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