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In the initial stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, a plethora of new serology tests were developed and introduced to the global market. Many were not evaluated rigorously, and there is a significant lack of concordance in results across methods. To enable meaningful clinical decisions to be made, robustly evaluated, quantitative serology methods are needed. These should be harmonized to a primary reference material, allowing for the comparison of trial data and improved clinical decision making. A comprehensive evaluation of the new Abbott IgG II anti-SARS-CoV-2 IgG method was undertaken using CLSI-based protocols. Two different candidate primary reference materials and verification panels were assessed with a goal to move toward harmonization. The Abbott IgG II method performed well across a wide range of parameters with excellent imprecision (

Background: Most approved vaccines utilise a two-dose strategy. To enable larger groups of patients to receive the first dose, the UK government increased the gap between the two doses from three to 12 weeks. Here we report on the immunogenicity of the first dose, including effect of age and vitamin D status on these levels over an 8 week-period. Methods: Blood was collected from healthcare workers (HCW) receiving their first BNT162b2 vaccine dose between January and February 2021. Antibody production was measured, prior to and weekly for 4 weeks post immunization, and a final measurement was performed at 8 weeks. Vitamin D were also measured at baseline. Findings: Immunization of 97 HCW induced an Ab response that peaked 3·2 weeks post immunization to decrease thereafter. Ab levels remained positive at 8 weeks. The response was significantly modified by age (p 50nmol/L. No other variable showed significant effect. Interpretation: The first dose of BNT162b2 produced Ab levels that remained positive after 8 weeks. Peak was greater in younger subjects and 25(OH)D>50nmol/L was beneficial. Booster campaigns should take into consideration vitamin D status which is at its highest following a period of sunshine exposure or following oral supplementation (400-1000IU daily). Funding: Abbott Diagnostics Ltd supplied the kits used to quantify the anti-SARS -CoV-2 Spike IgG and technical support as well as provided financial support for sample collections. Declaration of Interest: Two of the authors (SR and MB) are employees of Abbott Diagnostics Ltd who supplied the kits used to quantify the anti-SARS -CoV-2 Spike IgG and technical support as well as provided financial support for sample collections. All other authors have no conflict of interest. Ethical Approval: The study was approved by the Health Research Authority Health and Care Research Wales ethical committee (IRAS#292799).

Objectives Point-of-care (POC) analyzers are playing an increasingly important role in diabetes management but it is essential that we know the performance of these analyzers in order to make appropriate clinical decisions. Whilst there is a growing body of evidence around the more well-known analyzers, there are many ‘new kids on the block’ with new features, such as displaying the presence of potential Hb-variants, which do not yet have a proven track record. Methods The study is a comprehensive analytical and usability study of six POC analyzers for HbA1c using Clinical and Laboratory Standards Institute (CLSI) protocols, international quality targets and certified International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and National Glycohemoglobin Standardization Program (NGSP) Secondary Reference Measurement Procedures (SRMP). The study includes precision (EP-5 and EP-15), trueness (EP-9), linearity (EP-6), sample commutability (fresh, frozen and lyophilized), interference of Hb-variants (fresh and frozen samples). Results Only two of the six analyzers performed to acceptable levels over the range of performance criteria. Hb-variant interference, imprecision or variability between lot numbers are still poor in four of the analyzers. Conclusions This unique and comprehensive study shows that out of six POC analyzers studied only two (The Lab 001 and Cobas B101) met international quality criteria (IFCC and NGSP), two (A1Care and Innovastar) were borderline and two (QuikReadgo and Allegro) were unacceptable. It is essential that the scientific and clinical community are equipped with this knowledge in order to make sound decisions on the use of these analyzers.

Background: Controlling the spread of the COVID-19 pandemic relies heavily on worldwide immunization programs. Most of the current approved vaccines utilise a two-dose strategy to prime-boost the immune system. To enable larger groups of patients to receive the first dose, the UK government increased the gap between the two doses from three to 12 weeks. Here we report on the immunogenicity of the first dose. Methods: Anti SARS-CoV-2 IgG production (quantitative Abbott immunoassays) and vitamin D (25-hydroxyvitamin D (25(OH)D; LCMS) and 1-α,25-dihydroxyvitamin D (1,25(OH) 2 D, LCMS)) were measured in a group of 105 HCW, post immunization with the Pfizer/BioNTech vaccine. Findings: The anti-Spike IgG Ab response showed minimal change within the first week, rapidly peaked 3·2 weeks post immunization, subsequently decreasing to the nadir at 8 weeks prior to the scheduled second dose being administered. All subjects who responded with positive anti-Spike IgG Abs, retained significant levels at 8 weeks. Response to immunization was significantly modified by age and replete vitamin D status (25(OH)D>50 nmol/L). Interpretation: The results indicate that in this cohort 1) Ab levels are greatest 3-4 weeks post the first dose of the Pfizer/BioNTech vaccine 2) Abs are still circulating eight weeks post first dose 3) age significantly modifies the initial Ab response, the youngest decile having a greater peak and faster decline, resulting in 4) no significant difference in Ab concentration with age at W8 and 5) baseline vitamin D affected the peak of response, with vitamin D replete individuals showing the strongest Ab response. Funding Information: Abbott Diagnostics Ltd supplied the kits used to quantify the anti-SARS -CoV-2 Spike IgG and technical support as well as provided financial support for sample collections. Declaration of Interests: Abbott Diagnostics Ltd provided the necessary immunoassay for analysis of the samples for SARS-CoV-2 IgG and financial support for collection of samples. SR and MB work at Abbott Diagnostics Ltd. All other authors have no conflict of interest. Ethics Approval Statement: All participants provided written informed consent. The study was approved by the Health Research Authority Health and Care Research Wales ethical committee (IRAS#292799).

IntroductionTo report the observations of point-of-care (POC) glycated hemoglobin (HbA1c) testing in people with non-diabetic hyperglycemia (NDH; HbA1c 42–47 mmol/mol (6.0%–6.4%)), applied in community settings, within the English National Health Service Diabetes Prevention Programme (NHS DPP).Research design and methodsA service evaluation assessing prospectively collected national service-level data from the NHS DPP, using data from the first referral received in June 2016–October 2018. Individuals were referred to the NHS DPP with a laboratory-measured HbA1c in the NDH range and had a repeat HbA1c measured at first attendance of the program using one of three POC devices: DCA Vantage, Afinion or A1C Now+. Differences between the referral and POC HbA1c and the SD of the POC HbA1c were calculated. The factors associated with the difference in HbA1c and the association between POC HbA1c result and subsequent attendance of the NHS DPP were also evaluated.ResultsData from 73 703 participants demonstrated a significant mean difference between the referral and POC HbA1c of −2.48 mmol/mol (−0.23%) (t=157, pConclusionPOC HbA1c testing in community settings was associated with significantly lower HbA1c values when compared with laboratory-measured referrals. Acknowledging effects of regression to the mean, we found that these differences were also associated with POC method, location, individual patient factors and time between measurements. Compared with POC HbA1c values in the NDH range, normoglycemic POC HbA1c values were associated with lower subsequent intervention attendance.

Point-of-care (POC) analyzers are playing an increasingly important role in diabetes management but it is essential that we know the performance of these analyzers in order to make appropriate clinical decisions. Whilst there is a growing body of evidence around the more well-known analyzers, there are many 'new kids on the block' with new features, such as displaying the presence of potential Hb-variants, which do not yet have a proven track record.The study is a comprehensive analytical and usability study of six POC analyzers for HbAOnly two of the six analyzers performed to acceptable levels over the range of performance criteria. Hb-variant interference, imprecision or variability between lot numbers are still poor in four of the analyzers.This unique and comprehensive study shows that out of six POC analyzers studied only two (The Lab 001 and Cobas B101) met international quality criteria (IFCC and NGSP), two (A1Care and Innovastar) were borderline and two (QuikReadgo and Allegro) were unacceptable. It is essential that the scientific and clinical community are equipped with this knowledge in order to make sound decisions on the use of these analyzers.

Background Diabetes mellitus is a major global issue and high quality testing is essential for the diagnosis and treatment of the disease. The IFCC Committee for the Education in the Utility of Biomarkers in Diabetes (C-EUBD) plays a global role in improving knowledge and understanding around diabetes testing. This paper describes a multi-stakeholder approach, to improving diagnostic and therapeutic testing for diabetes, using a multicentre study in China as an example of the global impact of the group. Methods Educational workshops were developed to support the scientific aims of the study in which 30 centres around China received identical, fresh frozen whole blood samples with values assigned using IFCC secondary reference methods and undertook precision (EP-5) and trueness studies. Performance was assessed using sigma metrics. Results A successful multi-stakeholder group was developed and sustained throughout the study through several educational workshops, which enabled the formation of a long-term collaboration with key opinion leaders and policy makers in China. All 30 centres showed good performance with within and between laboratory coefficient of variations (CVs) below 3% in SI units at both low and high haemoglobin A1c (HbA1c) levels. All individual laboratories met the criteria of a sigma of two or more at a total allowable error (TAE) of 5 mmol/mol (0.46% NGSP). Conclusions The study led to a successful multi-partner approach to improving diabetes testing in China. All centres involved in the study meeting the published IFCC quality criteria, paving the way for future clinical trials and an expanded role for HbA1c testing across the country.

Diagnosing and monitoring the treatment of people with diabetes is a global issue and uses considerable resources in laboratories and clinics worldwide. Hemoglobin A1c (HbA1c) has been the mainstay of monitoring glycemic control in people with diabetes for many years and more recently it has been advocated as a diagnostic tool for type 2 diabetes mellitus (T2DM). Good analytical performance is key to the successful use of any laboratory test, but is critical when using the test to diagnose disease, especially when the potential number of diagnoses could exceed 500 million people. Very small variations in bias or increased imprecision could lead to either a missed diagnosis or overdiagnosis of the disease and given the scale of the global disease burden, this could mean erroneous categorization of potentially millions of people. Fundamental to good performance of diagnostic testing is standardization, with defined reference materials and measurement procedures. In this review, we discuss the historical steps to first harmonize HbA1c testing, followed by the global standardization efforts and provide an update on the current situation and future goals for HbA1c testing.

Background: Point-of-care (POC) testing is becoming increasingly valuable in health care delivery, and it is important that the devices used meet the same quality criteria as main laboratory analyzers. While external quality assessment (EQA) provides a great tool for assessing quality, many POC devices are not enrolled in these schemes and standard laboratory evaluations are needed to assess performance. Methods: The Clinical and Laboratory Standards Institute (CLSI) protocols EP-5 and EP-9 were applied to investigate imprecision, accuracy and bias. We assessed bias using the mean of 4 certified secondary reference measurement procedures (SRMPs). Results: The Afinion2™ and the Quo-Lab had CVs of ≤1.7 and ≤2.4% respectively in IFCC SI units (≤1.2 and ≤1.7% NGSP) and a bias ≤2 mmol/mol (≤0.2% NGSP) at 48 and 75 mmol/mol (6.5 and 9.0% NGSP). Sigma for the Afinion2 was 5.8 and for the Quo-Lab 4.0. Both methods passed the NGSP criteria with 2 instruments when compared with 4 individual SRMPs. The HbA1c 501 had a CV of 3.4% and 2.7% in IFCC SI units (2.1% and 1.7% NGSP) and a bias ≤2.4 mmol/mol (≤0.2% NGSP) and passed the NGSP criteria with 2 instruments compared with 4 individual SRMPs except for instrument 2 compared with the Tosoh G8. Sigma was 2.1. The A1Care had a sigma of 1.4 and failed all criteria mainly due to a high CV (6.2% and 4.1% in IFCC SI units [4.1% and 2.9% NGSP] at 48 and 75 mmol/mol [6.5 and 9.0% NGSP]). Conclusions: The analytical performance was excellent for the Afinion2 and the Quo-Lab, acceptable for the HbA1c 501 and unacceptable for the A1Care according to different used criteria, demonstrating that whilst performance is improving there are still areas for considerable improvement.

There are a growing number of publications evaluating the performance of HbA1c point-of-care testing (POCT) devices when compared to routine laboratory instruments, but is this what we need from future studies? Here we describe the current understanding of the performance of POCT for HbA1c, which areas need further studies, and the key requirements for future publications based on performance evaluations of these devices. These include studies in clinical settings, performance measured against internationally standardized reference methods, and the need to evaluate new to the market devices that do not currently have a detailed performance history. In addition we highlight the need for external quality assessment schemes that are designed to support POCT in a wide range of clinical settings.

BACKGROUND A major objective of the IFCC Committee on Education and Use of Biomarkers in Diabetes is to generate awareness and improvement of HbA1c assays through evaluation of the performance by countries and manufacturers. METHODS Fresh whole blood and lyophilized hemolysate specimens manufactured from the same pool were used by 17 external quality assessment organizers to evaluate analytical performance of 2166 laboratories. Results were evaluated per country, per manufacturer, and per manufacturer and country combined according to criteria of the IFCC model for quality targets. RESULTS At the country level with fresh whole blood specimens, 6 countries met the IFCC criterion, 2 did not, and 2 were borderline. With lyophilized hemolysates, 5 countries met the criterion, 2 did not, and 3 were borderline. At the manufacturer level using fresh whole blood specimens, 13 manufacturers met the criterion, 8 did not, and 3 were borderline. Using lyophilized hemolysates, 7 manufacturers met the criterion, 6 did not, and 3 were borderline. In both country and manufacturer groups, the major contribution to total error derived from between-laboratory variation. There were no substantial differences in performance between groups using fresh whole blood or lyophilized hemolysate samples. CONCLUSIONS The state of the art is that 1 of 20 laboratories does not meet the IFCC criterion, but there are substantial differences between country and between manufacturer groups. Efforts to further improve quality should focus on reducing between-laboratory variation. With some limitations, fresh whole blood and well-defined lyophilized specimens are suitable for purpose.

This study uses three unique data sets to show the state of the art of hemoglobin A1c (HbA1c) analyzers in a range of settings and compares their performance against the international guidance set by the International Federation of Clinical Chemistry and Laboratory Medicine task force for HbA1c standardization. The data are used to show the effect of tightening those criteria, and the study serves as a guide to the practical implementation of the sigma-metrics approach in a range of clinical settings.

Background: As a reference laboratory for HbA1c, it is essential to have accurate and precise HbA1c methods covering a range of measurement principles. We report an evaluation of the Abbott Enzymatic (Architect c4000), Roche Gen.3 HbA1c (Cobas c513) and Tosoh G11 using different quality targets. Methods: The effect of hemoglobin variants, other potential interferences and the performance in comparison to both the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the National Glycohemoglobin Standardization Program (NGSP) reference systems was assessed using certified evaluation protocols. Results: Each of the evaluated HbA1c methods had CVs

Background: Point-of-care (POC) devices could be used to measure hemoglobin A1c (HbA1c) in the doctors’ office, allowing immediate feedback of results to patients. Reports have raised concerns about the analytical performance of some of these devices. We carried out a systematic review and meta-analysis using a novel approach to compare the accuracy and precision of POC HbA1c devices. Methods: Medline, Embase and Web of Science databases were searched in June 2015 for published reports comparing POC HbA1c devices with laboratory methods. Two reviewers screened articles and extracted data on bias, precision and diagnostic accuracy. Mean bias and variability between the POC and laboratory test were combined in a meta-analysis. Study quality was assessed using the QUADAS2 tool. Results: Two researchers independently reviewed 1739 records for eligibility. Sixty-one studies were included in the meta-analysis of mean bias. Devices evaluated were A1cgear, A1cNow, Afinion, B-analyst, Clover, Cobas b101, DCA 2000/Vantage, HemoCue, Innovastar, Nycocard, Quo-Lab, Quo-Test and SDA1cCare. Nine devices had a negative mean bias which was significant for three devices. There was substantial variability in bias within devices. There was no difference in bias between clinical or laboratory operators in two devices. Conclusions: This is the first meta-analysis to directly compare performance of POC HbA1c devices. Use of a device with a mean negative bias compared to a laboratory method may lead to higher levels of glycemia and a lower risk of hypoglycaemia. The implications of this on clinical decision-making and patient outcomes now need to be tested in a randomized trial.

Background Internal quality control (IQC) has a long and well-established role in clinical biochemistry laboratories. However, despite the duration of use, and the publication of several articles detailing best practice, the implementation and use of IQC vary significantly between institutions. Consequently, the North Thames Audit and Quality Assurance Group undertook a region-wide audit of current IQC practice in 2006. Methods On aspects of IQC testing, interpretation and laboratory processes, 54 laboratories in the region were audited. Results Audit data showed significant variability in all aspects of practice, including IQC frequency, use of appropriate material, statistical processing and grades of staff involved. Conclusions Some of the variation in practice may affect the effectiveness of laboratory IQC, and thus the adequacy of a laboratory to monitor system performance. Consequently, a set of proposed regional standards have been developed and disseminated, prior to re-audit at a future date.

Aims/hypothesis: The use of HbA1c for the diagnosis of diabetes is now widely advocated despite caveats to its use. Anaemia is cited as a major confounder to this use; however, the effect of erythrocyte indices and to what degree anaemia influences HbA1c levels is not known. Methods: A systematic electronic database search of MEDLINE, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL) and the Cochrane Library was conducted for relevant articles published between January 1990 and May 2014. Included studies had at least one measurement of HbA1c and glucose, and a least one index of haematinic deficiency, involving non-pregnant adults, not known to have diabetes. Results: A total of 12 articles from 544 were included. The majority of studies focused on iron deficiency anaemia (IDA) and, in general, demonstrated that the presence of iron deficiency with or without anaemia led to an increase in HbA1c values compared with controls, with no concomitant rise in glucose indices. Data on the effects of other indices of erythrocyte abnormalities on HbA1c are limited but show a possible decrease in HbA1c values with non-iron deficiency forms of anaemia. Conclusions/interpretation: HbA1c is likely to be affected by iron deficiency and IDA with a spurious increase in HbA1c values; conversely, non-IDA may lead to a decreased HbA1c value. This may lead to confusion when diagnosing diabetes using HbA1c. This review clearly identifies the need for more evidence, especially in identifying the types and degrees of anaemia likely to have significant impact on the reliability of HbA1c.

BACKGROUND A major objective of the IFCC Task Force on Implementation of HbA1c Standardization is to develop a model to define quality targets for glycated hemoglobin (Hb A1c). METHODS Two generic models, biological variation and sigma-metrics, are investigated. We selected variables in the models for Hb A1c and used data of external quality assurance/proficiency testing programs to evaluate the suitability of the models to set and evaluate quality targets within and between laboratories. RESULTS In the biological variation model, 48% of individual laboratories and none of the 26 instrument groups met the minimum performance criterion. In the sigma-metrics model, with a total allowable error (TAE) set at 5 mmol/mol (0.46% NGSP), 77% of the individual laboratories and 12 of 26 instrument groups met the 2σ criterion. CONCLUSIONS The biological variation and sigma-metrics models were demonstrated to be suitable for setting and evaluating quality targets within and between laboratories. The sigma-metrics model is more flexible, as both the TAE and the risk of failure can be adjusted to the situation—for example, requirements related to diagnosis/monitoring or international authorities. With the aim of reaching (inter)national consensus on advice regarding quality targets for Hb A1c, the Task Force suggests the sigma-metrics model as the model of choice, with default values of 5 mmol/mol (0.46%) for TAE and risk levels of 2σ and 4σ for routine laboratories and laboratories performing clinical trials, respectively. These goals should serve as a starting point for discussion with international stakeholders in the field of diabetes.

Background: The stability of parathyroid hormone (PTH) in whole blood has not been well characterized. Previous studies show EDTA plasma samples to be more stable than serum samples. Methods: Blood from 17 haemodialysis patients and five healthy volunteers was collected into serum separator tubes (SSTs) and potassium EDTA tubes (EDTA-Ts) and incubated at room temperature before separation and storage for PTH analysis using the Bayer Advia Centaur. Results: Initial PTH concentrations were 7% higher (95% confidence interval [CI] 2-16%, P=0.016) in EDTA-Ts compared to the SSTs in the renal cohort. PTH concentrations in SSTs were significantly lower after 8 (10%, 95% CI 3-17%) and 20 h (22%, 95% CI 11-31%) but did not change significantly in EDTA-Ts ( P=0.1543). PTH concentration in EDTA-Ts from healthy volunteers was also independent of incubation time ( P=0.1165). Conclusion: The greater stability of PTH in whole blood anticoagulated with potassium EDTA allows PTH analysis to be offered to sites such as satellite clinics and primary care sites which do not have centrifugation and refrigeration facilities.

Intrathyroidal parathyroid adenomas are rare and are often misdiagnosed as thyroid nodules. Accurate diagnosis and preoperative localization is important for a successful surgical outcome, especially in the context of minimally invasive parathyroid surgery. Nuclear medicine imaging has been invaluable in differentiating between thyroid and parathyroid pathologies, but ultrasound scanning also has a prominent role. Cases of intrathyroidal adenomas showing significant uptake of Tc-99m pertechnetate appearing as a hyperfunctioning thyroid nodule have previously been reported. Using sonographic as well as scintigraphic methods of localization, we describe an unusual case of a large intrathyroidal parathyroid adenoma (confirmed on surgery), which appeared “cold” on a Tc-99m pertechnetate scan falsely giving the impression of a hypofunctioning nodule, mimicking thyroid neoplasm. The decision to proceed to surgery without a fine needle aspiration was taken because the clinical picture was more suggestive of a parathyroid adenoma/carcinoma than thyroid malignancy.

It is fascinating to consider the analytical improvements that have occurred since glycated hemoglobin was first used in routine clinical laboratories for diabetes monitoring around 1977; at that time methods displayed poor precision, there were no calibrators or material with assayed values for quality control purposes. This review outlines the major improvements in hemoglobin A1c (HbA1c) measurement that have occurred since its introduction, and reflects on the increased importance of this hemoglobin fraction in the monitoring of glycemic control. The use of HbA1c as a diagnostic tool is discussed in addition to its use in monitoring the patient with diabetes; the biochemistry of HbA1c formation is described, and how these changes to the hemoglobin molecule have been used to develop methods to measure this fraction. Standardization of HbA1c is described in detail; the development of the IFCC Reference Measurement Procedure for HbA1c has enabled global standardization to be achieved which has allowed global targets to be set for glycemic control and diagnosis. The importance of factors that may interfere in the measurement of HbA1c are highlighted.