Lot-to-lot variation: no longer a neglected issue

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The 99th percentile of reference population for cTnI and cTnT assay: Methodology, pathophysiology and clinical implications

According to recent international guidelines, including the 2012 Third Universal Definiton of Myocardial Infarction by the Joint ESC/ACCF/AHA/WHF Task Force, an increase in cardiac troponin (cTn) levels over the 99th percentile upper reference limit (99th URL) should be considered clinically relevant, this cut-off being measured with an imprecision â\u89¤10 CV%. In theory 99th URL values strongly depend not only on demographic and physiological variables (i.e. criteria for considering the reference population "healthy"), but also on the analytical performance of cTn methods and mathematical algorithms used for the calculation. The aim of the present article was therefore to review the methodological and pathophysiological factors affecting the evaluation and calculation of the 99th URL for cTn assay. The critical analysis made showed that no uniform procedure is followed, and nor have experts or regulatory bodies provided uniform guidelines for researchers or cTn assays manufacturers as an aid in "their quest to define normality". In particular, little attention has been paid to the way in which a healthy reference population is to be selected, or the criteria for calculating the 99th URL value for cTn assays, thus highlighting the need for international recommendations not only for demographic and physiological variables criteria for defining a healthy reference population, but also for calculating mathematical algorithms for establishing/calculating clinical decision values. An expert consensus group, comprising laboratory and clinical scientists, biomedical statisticians, industrial and regulatory representatives, should be responsible for drawing up these guidelines

Point: high-sensitive troponin assays – a valuable tool for astute physicians

This system is based on two criteria: i) the total imprecision at the 99 th percentile, and ii) the ability to measure normal values below the 99 th per- centile. Both criteria are supported by a clini- cal rationale, as the low CV at the cut-off level reduces the analytical uncertainty around the decision level. This, in turn, appears to be an essential issue as any increase of troponin lev- els is an index of myocardial damage. In addi- tion, a growing body of evidence demonstrates that detectable levels of troponins under the cut-off are associated with chronic myocardial diseases and poor clinical outcomes. 1

Definition of the upper reference limit of glycated albumin in blood donors from Italy

Glycated Albumin (GA) has been proposed as a short-term indicator of glycemic homeostasis. The aim of this study is to describe the distribution of GA in a large sample of blood donors from Italy to evaluate whether demographic features, namely age and sex, could influence GA levels and define specific reference limits. The study included 1334 Italian blood donors. GA was measured using an enzymatic method (quantILab Glycated Albumin, IL Werfen, Germany). The upper reference limit (URL) was calculated using the non-parametric percentile method. A modest, although significant, increase of GA was observed in relation to age (p14.5% presented a mean age of 48.4±12.2 years, 66.7% were males and the mean glucose was 6.88±2.5 mmol/L. GA in Caucasians shows a similar increasing trend at older ages documented in other ethnicities. The definition of the URL in this population could be useful for both clinical studies, which will clarify the role of GA for diagnosing and monitoring diabetes, and will encourage the introduction of GA in clinical practice

Enhanced osteogenic differentiation in zoledronate-treated osteoporotic patients

Bisphosphonates are well known inhibitors of osteoclast activity and thus may be employed to influence osteoblast activity. The present study was designed to evaluate the in vivo effects of zoledronic acid (ZA) on the proliferation and osteoblastic commitment of mesenchymal stem cells (MSC) in osteoporotic patients. We studied 22 postmenopausal osteoporotic patients. Densitometric, biochemical, cellular and molecular data were collected before as well as after 6 and 12 months of ZA treatment. Peripheral blood MSC-like cells were quantified by colony-forming unit fibroblastic assay; their osteogenic differentiation potential was evaluated after 3 and 7 days of induction, respectively. Circulating MSCs showed significantly increased expression levels of osteoblastic marker genes such as Runt-related transcription factor 2 (RUNX2), and Osteonectin (SPARC) during the 12 months of monitoring time. Lumbar bone mineral density (BMD) variation and SPARC gene expression correlated positively. Bone turnover marker levels were significantly lowered after ZA treatment; the effect was more pronounced for C terminal telopeptide (CTX) than for Procollagen Type 1 N-Terminal Propeptide (P1NP) and bone alkaline phosphatase (bALP). Our findings suggest a discrete anabolic activity supported by osteogenic commitment of MSCs, consequent to ZA treatment. We confirm its anabolic effects in vivo on osteogenic precursors

Analytical performance evaluation of the new GEM® Premier™ 5000 analyzer in comparison to the GEM® Premier™ 4000 and the RapidPoint® 405 systems

Abstract Aim of the study Blood gas analysis (BGA) is essential for the diagnosis and management of acid-base imbalances. We evaluated and compared the analytical characteristics of the new GEM® Premier™ 5000 (GP5000) (Instrumentation Laboratory, Bedford, MA, United States) BGA point-of-care (POC) device with those of the GEM® Premier™ 4000 (GP4000) (Instrumentation Laboratory, Bedford, MA, United States) and RapidPoint® 405 (RP405) (Siemens Healthcare, Milan, Italy) POC analyzers. The effect of sample mixing on patient results was also studied. Material and methods Quantitative measurement of pH, pCO2, pO2, Na+, K+, Cl−, iCa2+, glucose, lactate, tHb, COHb, MetHb, O2Hb, HHb and Hct were carried out. The imprecision study (IS) and method comparison study (MS) were performed according to CLSI EP guidelines, using respectively internal as well as external quality controls (IS) and whole blood samples collected from the routine analysis (MS). Results GP5000 demonstrated satisfactory characteristics in the IS showing comparable (GM4000) or even better (RP405) imprecision results than the routine POC devices. Good performance was observed in the MS both using GP4000 and RP405 as reference instruments. Pre-analytical sample management can heavily affect the accuracy of BGA results. In the specimen mixing evaluation, a significant improvement in results accuracy was observed when mixing procedures were more meticulous. Conclusions Considering the overall analytical performance observed, the ease of use of the system, the rapid time-to-results and the innovative Intelligent Quality Management technology (iQM2®), GP5000 seems suitable to be used in clinical care for safe patient management. Additionally, effective sample mixing upon draw and before analysis is strongly advisable in order to ensure the most clinically reliable BGA results

A new sampling device for faecal immunochemical testing: haemoglobin stability is still an open issue

Abstract Background: The detection of faecal occult blood is a fundamental step in making an early diagnosis of colorectal cancer. The aim of the present study was to evaluate the stability of haemoglobin in faeces collected with two sampling devices specific for faecal immunochemical testing (FOB Gold Tube Screen and FOB Gold Tube NG) that contain different preservative buffers (buffer H, BH, and buffer N, BN, respectively). Methods: Fifteen true positive faecal samples were collected with both devices. A pool from each sample was made. Each pool was portioned and stored at +4\ub0C, +21\ub0C and +32\ub0C for 10 days. One aliquot of each pool stored at each of the respective temperatures was tested at five time intervals between sampling and analysis. The same procedure was followed for three synthetic haemoglobin solutions in both buffers. Results: The percentage of cumulative faecal haemoglobin decrease (HbCD%) was evaluated. No significant difference was found between BH and BN in HbCD% at +4\ub0C (p=0.106); at +21\ub0C and +32\ub0C, HbCD% was lower in BH than in BN samples (p=0.002 and

Therapeutic drug monitoring of monoclonal antibodies in chronic inflammatory diseases: A snapshot of laboratories and applications across Europe

The European Cooperation in Science and Technology (COST) action ENOTTA (The European Network on Optimising Treatment with Therapeutic Antibodies in chronic inflammatory diseases) was launched in 2022. To pave the way for harmonization of analytical methods for quantitation of serum levels of therapeutic antibodies in research and clinical settings, ENOTTA recently performed an online survey mapping laboratories in the field. The survey, which contained 30 questions surrounding therapeutic drug monitoring of relevant drugs and anti-drug antibodies, was distributed via the ENOTTA and European Federation of Clinical Chemistry and Laboratory networks. Among 63 respondents across Europe, 45 reported analytical activity, with a range of utilized methods. Future engagement of as many sites as possible will enable comparison of methodologies and facilitate progress in the field

Copeptin levels are associated with organ dysfunction and death in the intensive care unit after out-of-hospital cardiac arrest

Introduction: We studied associations of the stress hormones copeptin and cortisol with outcome and organ dysfunction after out-of-hospital cardiac arrest (OHCA). Methods: Plasma was obtained after consent from next of kin in the FINNRESUSCI study conducted in 21 Finnish intensive care units (ICUs) between 2010 and 2011. We measured plasma copeptin (pmol/L) and free cortisol (nmol/L) on ICU admission (245 patients) and at 48 hours (additional 33 patients). Organ dysfunction was categorised with 24-hour Sequential Organ Failure Assessment (SOFA) scores. Twelve-month neurological outcome (available in 276 patients) was classified with cerebral performance categories (CPC) and dichotomised into good (CPC 1 or 2) or poor (CPC 3 to 5). Data are presented as medians and interquartile ranges (IQRs). A Mann-Whitney U test, multiple linear and logistic regression tests with odds ratios (ORs) 95% confidence intervals (CIs) and beta (B) values, repeated measure analysis of variance, and receiver operating characteristic curves with area under the curve (AUC) were performed. Results: Patients with a poor 12-month outcome had higher levels of admission copeptin (89, IQR 41 to 193 versus 51, IQR 29 to 111 pmol/L, P = 0.0014) and cortisol (728, IQR 522 to 1,017 versus 576, IQR 355 to 850 nmol/L, P = 0.0013). Copeptin levels fell between admission and 48 hours (P Conclusions: Admission copeptin and free cortisol were not of prognostic value regarding 12-month neurological outcome after OHCA. Higher admission copeptin and cortisol were associated with ICU death, and copeptin predicted subsequent organ dysfunction.Peer reviewe