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Abstract: Background: Creatinine determination in serum is a key indicator of kidney glomerular function. A reference measurement system for its standardization is available and virtually all IVD manufacturers have aligned their assays to this system. In this study, we verified the impact of these standardization efforts on the results of an Italian EQAS involving about 430 laboratories. Method: We considered data obtained during 2006, 2010 and 2011 schemes of EQAS Prolarit for control materials with target values assigned by a traceable method (enzymatic assay calibrated against the NIST SRM 967). Results: The results showed a good alignment at concentrations ~170μmol/L, with 2011 results — except for one method group — well inside the desirable bias (±4%). At higher concentrations, whereas the bias was small in 2010, for some groups using alkaline-picrate (AP) methods it became significantly negative in 2011. The performance seems to worsen when measuring physiologic concentrations, where a significant positive bias (up to ~20%) is shown by most of the AP-based analytical systems. With few exceptions, no evident improvement in individual assay bias was noted from pre- (2006) to post-standardization (2011) periods. The enzymatic method groups were the only always presenting an acceptable bias at all creatinine concentrations, also showing the lowest between-laboratory variability. Conclusion: Our data seem to indicate that the standardization efforts are still having effects lower than expected. Even taking into consideration that some of the bias may derive from non commutability problems, most of the current “standardized” AP-based methods, at the lower creatinine concentrations, seem to present accuracy problems. This inaccuracy can adversely impact the estimation of GFR by equations and the evaluation of kidney function in pediatrics. [Copyright &y& Elsevier]

Context.—: A relevant portion of coronavirus disease 2019 (COVID-19) patients develop severe disease with negative outcomes. Several biomarkers have been proposed to predict COVID-19 severity, but no definite interpretative criteria have been established to date for stratifying risk., Objective.—: To evaluate 6 serum biomarkers (C-reactive protein, lactate dehydrogenase, D-dimer, albumin, ferritin, and cardiac troponin T) for predicting COVID-19 severity and to define related cutoffs able to aid clinicians in risk stratification of hospitalized patients., Design.—: A retrospective study of 427 COVID-19 patients was performed. Patients were divided into groups based on their clinical outcome: nonsurvivors versus survivors and patients admitted to an intensive care unit versus others. Receiver operating characteristic curves and likelihood ratios were employed to define predictive cutoffs for evaluated markers., Results.—: Marker concentrations at peak were significantly different between groups for both selected outcomes. At univariate logistic regression analysis, all parameters were significantly associated with higher odds of death and intensive care. At the multivariate analysis, high concentrations of lactate dehydrogenase and low concentrations of albumin in serum remained significantly associated with higher odds of death, whereas only low lactate dehydrogenase activities remained associated with lower odds of intensive care admission. The best cutoffs for death prediction were greater than 731 U/L for lactate dehydrogenase and 18 g/L or lower for albumin, whereas a lactate dehydrogenase activity lower than 425 U/L was associated with a negative likelihood ratio of 0.10 for intensive treatment., Conclusions.—: Our study identifies which biochemistry tests represent major predictors of COVID-19 severity and defines the best cutoffs for their use., (© 2020 College of American Pathologists.)

The objective of the study is to assess the prevalence of target organ damage (TOD) at carotid, cardiac, renal and peripheral vascular levels in a population at intermediate cardiovascular risk, with adjunctive major risk factors (AMRF). From March 2007 to July 2009 we examined 979 subjects at intermediate cardiovascular risk, as indicated by the Italian algorithm "Progetto Cuore"; the patients were aged 40-69 years, sensitized by one or more AMRF such as family history for cardiovascular disease (CVD), being overweight or obese, and smoking habit (more than 10 cigarettes/day). We measured common carotid intima-media thickness (cc-IMT) and plaque at any level, left ventricular mass index (LVMI), urine albumin/creatinine ratio (UACR), and ankle-brachial index (ABI). The prevalence of at least one TOD was 63% (617 subjects), cc-IMT was high in 48.2% (472), UACR abnormal in 14.1% (138), LVMI high in 12.6% (117) and ABI pathological in 9.1% (89). In those with carotid damage 423 had a plaque, amounting to 43.2% of the total population. Of note, carotid damage was present in all subjects with 3 TODs, and in 92% of subjects with 2 TODs. A multivariate logistic regression model including conventional factors and AMRF indicated that age 50-69 years, systolic blood pressure, relevant smoking and CV risk score ≥15 were independently and significantly associated with at least one TOD, and at least, with carotid damage. Among the AMRF, peripheral arterial disease was associated with relevant smoking, with an odds ratio (OR) of 3 [confidence interval (CI) 1.80-4.97, p < 0.0001]; overweight and obesity both had selective associations with cardiac damage with OR 2.75 (CI 1.2-6.3, p < 0.01) and OR 3.89 (CI 1.61-9.73, p < 0.01). A substantial proportion of people at intermediate risk, with at least one AMRF have at least one TOD, a major predictor of cardiovascular outcomes.

In 1999 the Centre of Biomedical Research (CRB) in co-operation with the Italian interdisciplinary and intersociety Working Group on Markers of Myocardial Damage proposed a national external quality assurance scheme that was granted in accordance with the UK Clinical Pathology Accreditation Standards in 2001. The scheme, which stresses the importance of educational aspects in quality assurance, was scientifically designed to ensure that it would provide an objective assessment of participants' performance and promote quality improvements to meet the needs of participants. The present paper reports on the data collected in EQA cycles conducted to evaluate improvements in the performance of participants and in related methods. The findings obtained demonstrate that during the 4-year experience the scheme provided opportunities to improve the performance of laboratories and promoted an efficient, more satisfactory approach to analytical aspects. The number of unacceptable performances decreased from 11.6% to 5.6% for troponin I, from 19.5% to 9.0% for myoglobin and from 13.2% to 4.3% for creatine kinase myocardial isoenzyme (CK-MB). During cycles in 2001 and 2002, inter-variability (coefficient of variation, CV%) data for all markers appeared satisfactory and showed a significant improvement (lower than 10%), in particular for procedures automated on Dade Behring Dimension and Beckman Access systems. However, reference values/decisional limits declared by laboratories and those suggested by the manufacturers are not comparable, even within the same diagnostic system. The findings demonstrate that participation in EQA schemes provided an opportunity for participating laboratories to continuously improve the quality of their services.

Objectives: More than 30 genetic variants of serum cholinesterase (butyrylcholinesterase, BChE) have been described. Some of them (the atypical and the fluoride-resistant variants) are well known because carriers are prone to develop prolonged apnea following the administration of the muscle relaxant succinylcholine. Genotype characterization is therefore important in order to prevent such episodes. Genetic studies have so far focused on selected individuals or families rather than on the random population., Methods: From a large group of healthy blood donors (n = 2609), we selected all the 58 individuals with low serum cholinesterase activity: among them 28 subjects had abnormal dibucaine and fluoride inhibition numbers. Twenty-five mutations in the coding region of the human cholinesterase gene were analyzed., Results: All individuals with abnormal inhibition numbers were homozygotes or double heterozygotes in several mutations. Asp70Gly (Atypical variant) and Ala539Thr (K variant) were the most frequently observed amino acid substitutions. The majority of subjects with low BChE activity but normal dibucaine and fluoride number presented only the K form. We analyzed 106 randomly chosen subjects for K and atypical variants. Carriers of these alleles were at risk of low BChE activity (OR = 9.55, 95%CI, 5.61-16.26 and OR = 30.33, 95%CI, 7.05-130.52 respectively)., Conclusions: Data obtained from this study help to better define the etiology of low BChE activity and the role of the rather common K allele. It is the first time that such a large population has been screened for so many mutations. BChE is also implicated in detoxifying cocaine; therefore genetic analysis could be useful in cases of cocaine toxicity in Italian subjects.

Background: The Joint European Society of Cardiology and the American College of Cardiology Committee has recently reviewed the criteria to diagnose myocardial infarction, focusing on the central role of biochemical criterium and indicating the cardiac troponins as the reference marker. However, at present, little is known upon how "old" and "new" biochemical markers of myocardial damage are utilized in daily clinical practice., Methods: We performed a survey across the whole set of Italian coronary care units (CCUs) to evaluate the actual behavior of the clinicians in detecting myocardial necrosis with the biomarkers. A simple and brief questionnaire was used to pursue such purpose., Results: The feedback from CCUs was positive in 87.6% (303/346). The creatine kinase-MB is the most frequently used biomarker, however the "mass concentration" method was utilized in a minority of centers (38%). More than 60% of the CCUs are still measuring obsolete biomarkers as lactic dehydrogenase or aspartate transaminase. Cardiac troponins are measured only in 70% of the centers, and almost always in conjunction with the "old" biomarkers. Additionally, 14.5% of the Italian CCUs had written guidelines upon how to use the biomarkers to pose diagnosis of myocardial infarction. Biochemical criteria widely differed from center to center, regardless of the biomarker selected as reference standard., Conclusions: The results of our survey show a high degree of difference in the choice as well as in the application criteria of biochemical markers for diagnosing myocardial infarction among the Italian CCUs. A great deal of confusion has been accumulating over the years among Italian cardiologists, and this situation was antecedent to the recently released revised criteria for detecting myocardial necrosis.

The recent document of the ESC/ACC Committee for the redefinition of myocardial infarction (MI) has introduced the measurement of cardiac troponin as the biochemical standard for the diagnosis of MI. This change has been mainly driven by the demonstration that any amount of myocardial damage, as detected by cardiac troponins, implies a worse long-term outcome of the patient. The results of several studies consistently show that there is a continuous relationship between the degree of troponin elevation and the patient's prognosis. The new definition has important consequences on the diagnostic and therapeutic approaches to patients with acute coronary syndromes; in fact, patients with increased troponins, i.e. patients with MI, necessitate more aggressive treatment than those without troponin elevations, i.e. patients with unstable angina. The application of the new definition is expected to increase the number of cases of MI by about 30% and to decrease mortality. We believe that several aspects of the new definition need to be discussed before the new criteria for MI are used in clinical practice in Italy. The most relevant issues are the following: 1) the definition of troponin elevation should meet the analytical performance of the available assays, the diagnostic cut-off of which is frequently too imprecise. We propose that troponin elevations be defined as values exceeding the concentration corresponding to a total analytical imprecision of 10%. We disclose such a concentration for the currently available assays and suggest its use in clinical practice to mitigate the possibility of false-positive values; 2) the number of samples required for the diagnosis should be sufficient for the assessment of the changes in concentration over time. When only one sample is available, or when the temporal pattern of the changes in marker concentration is not consistent with the time elapsed from the onset of symptoms, we suggest that objective evidence that myocardial ischemia is the likely cause of myocardial damage should be obtained; 3) the diagnosis of MI after a percutaneous coronary intervention represents a unique situation. In contrast with myocardial damage occurring during spontaneous ischemia, available data do not support the concept that any troponin elevation is associated with an adverse prognosis. In the absence of conclusive studies, we suggest that the diagnosis of MI after a percutaneous coronary intervention be based on conventional criteria. Finally, we propose this summary with the aim of overcoming some of the more controversial aspects of the ESC/ACC redefinition of MI: Criteria for acute, evolving or recent MI. Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI: 1) elevation of biochemical markers of myocardial necrosis (preferably troponin) with at least one of the following: a) ischemic symptoms; b) development of pathologic Q waves on the ECG; c) ECG changes indicative of ischemia (ST segment elevation or depression); d) coronary artery intervention (e.g., coronary angioplasty). Marker elevations should be accompanied by objective evidence that myocardial ischemia is the likely cause of myocardial damage when: a) only one blood sample is available; b) marker changes over time are not consistent with the onset of symptoms; 2) pathologic findings of an acute MI. Criteria for established MI. Anyone of the following criteria satisfies the diagnosis for established MI: 1) development of new pathologic Q waves on serial ECGs. The patient may or may not remember previous symptoms. Biochemical markers of myocardial necrosis may have normalized, depending on the length of time that has passed since the infarct developed; 2) pathologic findings of a healed or healing MI.