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The TRAPID-AMI (High Sensitivity Cardiac Troponin T assay for rapid Rule-out of Acute Myocardial Infarction) study evaluated a rapid "rule-out" acute myocardial infarction (AMI). We evaluated what symptoms were associated with AMI as part of a substudy of TRAPID-AMI. There were 1282 patients evaluated from 12 centers in Europe, the United States of America, and Australia from 2011 to 2013. Multiple symptom variables were prospectively obtained and evaluated for association with the final diagnosis of AMI. Multivariate logistic regression analysis was done, and odds ratios (OR) were calculated. There were 213/1282 (17%) AMIs. Four independent predictors for the diagnosis of AMI were identified: radiation to right arm or shoulder [OR = 3.0; confidence interval (CI): 1.8-5.0], chest pressure (OR = 2.5; CI: 1.3-4.6), worsened by physical activity (OR = 1.7; CI: 1.2-2.5), and radiation to left arm or shoulder (OR = 1.7; CI: 1.1-2.4). In the entire group, 131 (10%) had radiation to right arm or shoulder, 897 (70%) had chest pressure, 385 (30%) worsened with physical activity, and 448 (35%) had radiation to left arm or shoulder. Duration of symptoms was not predictive of AMI. There were no symptoms predictive of non-AMI. Relationship between AMI size and symptoms was also studied. For 213 AMI patients, cardiac troponins I values were divided into 4 quartiles. Symptoms including pulling chest pain, supramammillary right location, and right arm/shoulder radiation were significantly more likely to occur in patients with larger AMIs. In a large multicenter trial, only 4 symptoms were associated with the diagnosis of AMI, and no symptoms that were associated with a non-AMI diagnosis.

ISO15189:2012 requires medical laboratories to document metrological traceability of their results. While the ISO17511:2003 standard on metrological traceability in laboratory medicine requires the use of the highest available level in the traceability chain, it recognizes that for many measurands there is no reference above the manufacturer's selected measurement procedure and the manufacturer's working calibrator. Some immunoassays, although they intend to measure the same quantity and may even refer to the same reference material, unfortunately produce different results because of differences in analytical selectivity as manufacturers select different epitopes and antibodies for the same analyte. In other cases, the cause is the use of reference materials, which are not commutable. The uncertainty associated with the result is another important aspect in metrological traceability implementation. As the measurement uncertainty on the clinical samples is influenced by the uncertainty of all steps higher in the traceability chain, laboratories should be provided with adequate and appropriate information on the uncertainty of the value assignment to the commercial calibrators that they use. Although the between-lot variation in value assignment will manifest itself as part of the long-term imprecision as estimated by the end-user, information on worst-case to be expected lot- lot variation has to be communicated to the end-user by the IVD provider. When laboratories use ancillary equipment that potentially could have a critical contribution to the reported results, such equipment needs verification of its proper calibration and criticality to the result uncertainty could be assessed by an approach based on risk analysis, which is a key element of ISO15189:2012 anyway. This paper discusses how the requirement for metrological traceability as stated in ISO15189 should be met by the medical laboratory and how this should be assessed by accreditation bodies.

Laboratory diagnostics in the emergency setting encompasses the identification of appropriate testing according to specific acute conditions. Since the pathway of ordering tests in the Italian Emergency Departments (EDs) is rather heterogeneous, SIBioC-Medicina di Laboratorio and the Academy of Emergency Medicine and Care designed a survey aimed to generate consensus pertaining to appropriate laboratory tests in most frequent acute conditions. A questionnaire including a panel of laboratory tests was administered to 8 representative members of each of the two societies, who were asked to provide a score between 1 and 3 for the various tests, where a score of 1 entailed "highly recommended", 2 "recommended in specific conditions" and 3 identified "highly discouraged" tests. The results of the questionnaire are shown as mean (±SD) of individual responses, thus allowing to define a scale of priority comprised between "highly recommended" and "highly discouraged". Overall, 24 tests were classified as "highly recommended", whereas 6 were "highly discouraged". The remaining 16 tests were classified as "somehow recommended" or "somehow discouraged". In the expectations of the two societies, this document may represent a first step towards harmonizing the laboratory test ordering in Italian EDs.

To be accurate and equivalent, laboratory results should be traceable to higher-order references. Furthermore, their quality should fulfill acceptable measurement uncertainty as defined to fit the intended clinical use. With this aim, in vitro diagnostics (IVD) manufacturers should define a calibration hierarchy to assign traceable values to their system calibrators and to fulfill during this process uncertainty limits for calibrators, which should represent a proportion of the uncertainty budget allowed for clinical laboratory results. It is therefore important that, on one hand, the laboratory profession clearly defines the clinically acceptable uncertainty for relevant tests and, on the other hand, end-users may know and verify how manufacturers have implemented the traceability of their calibrators and estimated the corresponding uncertainty. Important tools for IVD traceability surveillance are quality control programmes through the daily verification by clinical laboratories that control materials of analytical systems are in the manufacturer's declared validation range [Internal Quality Control (IQ C) component I] and the organization of External Quality Assessment Schemes meeting metrological criteria. In a separate way, clinical laboratories should also monitor the reliability of employed commercial systems through the IQC component II, devoted to estimation of the measurement uncertainty due to random effects, which includes analytical system imprecision together with individual laboratory performance in terms of variability.

Chronic kidney disease (CKD) is a major public health issue worldwide and is associated with adverse health outcomes, especially in low- and middle-income countries. In a cash limited healthcare system, guidelines that improve the efficiency of health care free up resources needed for other healthcare services. This short review presents some examples from national acitivities in CKD testing, including countries throughout the globe: Mexico in North America, Uruguay in South America, Italy in Europe, Nigeria in Africa and India in Asia. Considering the fact that treatment of CKD is cost-effective and improves outcomes, this observation argue in favor of including CKD in national guidelines and noncommunicable chronic disease (NCD) programs. This diverse example of national activities fullfil the very first step in achieving this goal.

Recent single-center and retrospective studies suggest that acute myocardial infarction (AMI) could be immediately excluded without serial sampling in patients with initial high-sensitivity cardiac troponin T (hs-cTnT) levels below the limit of detection (LoD) of the assay and no electrocardiogram (ECG) ischemia.We aimed to determine the external validity of those findings in a multicenter study at 12 sites in nine countries.TRAPID-AMI was a prospective diagnostic cohort study including patients with suspected cardiac chest pain within 6 hours of peak symptoms. Blood drawn on arrival was centrally tested for hs-cTnT (Roche; 99th percentile = 14 ng/L, LoD = 5 ng/L). All patients underwent serial troponin sampling over 4-14 hours. The primary outcome, prevalent AMI, was adjudicated based on sensitive troponin I (Siemens Ultra) levels. Major adverse cardiac events (MACE) including AMI, death, or rehospitalization for acute coronary syndrome with coronary revascularization were determined after 30 days.We included 1,282 patients, of whom 213 (16.6%) had AMI and 231 (18.0%) developed MACE. Of 560 (43.7%) patients with initial hs-cTnT levels below the LoD, four (0.7%) had AMI. In total, 471 (36.7%) patients had both initial hs-cTnT levels below the LoD and no ECG ischemia. These patients had a 0.4% (n = 2) probability of AMI, giving 99.1% (95% confidence interval [CI] = 96.7% to 99.9%) sensitivity and 99.6% (95% CI = 98.5% to 100.0%) negative predictive value. The incidence of MACE in this group was 1.3% (95% CI = 0.5% to 2.8%).In the absence of ECG ischemia, the detection of very low concentrations of hs-cTnT at admission seems to allow rapid, safe exclusion of AMI in one-third of patients without serial sampling. This could be used alongside careful clinical assessment to help reduce unnecessary hospital admissions.

Background: Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) measurements are important for the assessment of liver damage. The aim of this study was to define the reference intervals (RIs) for these enzymes in adults, paying attention to standardization of the methods used and careful selection of the reference population. Methods: AST, ALT and GGT were measured with commercial analytical systems standardized to the IFCC-recommended reference measurement systems. Three centers (two in Italy and one in China) measured their own freshly collected samples; one of these centers also measured frozen samples from the Nordic Countries RI Project and from a Turkish center. RIs were generated using non-parametric techniques from the results of 765 individuals (411 females and 354 males, 18-85 years old) selected on the basis of the results of other laboratory tests and a specific questionnaire. Results: AST results from the four regions (Milan, Beijing, Bursa and Nordic Countries) were statistically different, but these differences were too small to be clinically relevant. Likewise, differences between the upper reference limits for genders was only 1.7 U/L (0.03 mu kat/L), allowing a single RI of 11-34 U/L (0.18-0.57 mu kat/L) to be defined. Inter-regional differences were not statistically significant for ALT, but partitioning was required due to significant gender differences. RIs for ALT were 8-41 U/L (0.13-0.68 mu kat/L) for females and 9-59 U/L (0.15-0.99 mu kat/L) for males, respectively. The upper reference limits for GGT from the Nordic Country population were higher than those from the other three regions and results from this group were excluded from final calculations. The GGT RIs were 6-40 U/L (0.11-0.66 mu kat/L) for females and 12-68 U/L (0.20-1.13 mu kat/L) for males, respectively. Conclusions: For AST and ALT, the implementation of common RIs appears to be possible, because no differences between regions were observed. However, a common RI for GGT that is applicable worldwide appears unlikely due to differences among populations. Clin Chem Lab Med 2010;48:1593-601. IFCC Abbott Laboratories Ortho-Clinical Diagnostics Inc. Sysmex Europe GmbH Binding Site Ltd.

Since the future role of Laboratory Medicine is strongly and equally challenged by economic and new technological pressures, it is essential to take a broad view of the discipline and present to the administrators and other decision-makers the full spectrum of activities and benefits Laboratory Medicine can provide. In particular, the importance and the true impact of Laboratory Medicine can only be achieved by adding value to laboratory tests, represented by their effectiveness in influencing the management of patients and related clinical outcomes.

Background: The mainstay of patient-oriented laboratory testing in emergency settings entails selecting a number and the type of tests according to valid criteria of appropriateness. Since the pattern of urgent tests requesting is variable across different institutions, we designed a joined survey between the Academy of Emergency Medicine and Care (AcEMC) and the Italian Society of Clinical Biochemistry and Clinical Molecular Biology (SIBioC) for reaching tentative consensus about the most informative diagnostic tests in emergency settings. Methods: A survey, containing the most commonly ordered urgent laboratory tests and the relative clinical indications, was disseminated to eight relevant members of AcEMC and eight relevant members of SIBioC. All contributors were asked to provide numerical scores for the different laboratory parameters, where 1 indicated “strongly recommended”, 2 “recommended in specific circumstances”, and 3 “strongly discouraged”. The mean results of the survey were presented as the mean of responders’ values, and the parameters were finally classified as “strongly recommended” (mean value, 1.00–1.49), “weakly recommended” (mean value, 1.50–1.99), “discouraged” (mean value, 2.00–2.49) and “strongly discouraged” (mean value, 2.50–3.00). Results: The results of the survey allowed defining a hierarchy of priority, wherein 24 tests were “strongly recommended”. The use of five common tests was instead “strongly discouraged”. For 16 additional parameters in the list, the consensus ranged between “weakly recommended” and “discouraged”. Conclusions: We hope that results presented in this joint AcEMC-SIBioC consensus document may help harmonizing panel of tests and requesting patterns in emergency setting, at least at a national level.

Background: Hepatocellular carcinoma (HCC) is the most common complication of liver cirrhosis. Screening of patients with cirrhosis is necessary to confirm the diagnosis of HCC in an early phase of the limited and small tumor. The recommended monitoring strategy in patients with cirrhosis is still based on ultrasound examination and determination of αfetoprotein (AFP) in the serum. The limitations of ultrasound diagnostics are the inability to distinguish HCC from hemangioma and cirrhotic nodules, limited sensitivity to detect small tumors as well as the impact of human factor. On the other hand, AFP tumor marker has a low specificity. Considering that, it is necessary to find and evaluate new serum and molecular markers for monitoring high risk population as well as for early diagnosis of HCC. The aim of this study was to evaluate whether the determination of AFPL3 isoforme can improve early non-invasive diagnosis of HCC. Materials and Methods: Sera samples from 32 patients with HCC with a background of alcoholic liver disease (ALD) as well as 28 sera samples from age adjusted alcohol related cirrhosis control group, were assessed by specific ELISA assay for AFPL3 (Cusabio Biotech CO., LTD. Wuhan, P.R.China). AFP concentrations were determined using Cobas e411 (Hitachi High Technologies Corporation, Tokyo, Japan) analyzer. The diagnostic accuracy of each biomarker was evaluated using receiver operating characteristic (ROC) curve analysis reporting the area under the curve (AUC) and its 95% confidence interval (CI). Results: Our results showed that AFP concentration of 14.62 ng/mL distinguishes patients with HCC and patients with liver cirrhosis with diagnostic sensitivity of 68, 75% and 100% diagnostic specificity. AFP-L3 concentration of 4.26 ng/mL distinguishes tested groups with diagnostic sensitivity of 75% and 100% diagnostic specificity. AUC (95% CI) for AFP was 0.888 (0.781-0.955), and for ALP-L3 0.929 (0.832-0.979). Conclusion: Our study indicates that AFP-L3 is an improvement in HCC screening of high risk ALD patients in relation to AFP due to better diagnostic sensitivity and higher AUC.

Consensus recommendations on the quality targets in laboratory medicine supports hierarchy quality model. In this concept, a model higher in the hierarchy should be preferred over lower one. The analytical performance in the majority of laboratories in our country is evaluated according to manufacturer recommendations, which is the lowest model in the hierarchy. Thus, we aimed to compare analytical coefficients of variation (CVa) against criteria for imprecision based on biological variation from five different laboratories. Imprecision of 17 biochemistry parameters (amylase, AST, ALT, bilirubin – total and conjugated, Ca, Cl, CK, CK-MB, creatinine, CRP, glucose, K, LD, Na, urea and total protein) was monitored by analyzing two levels of commercial quality control material, three times per day, over one year. CVa was monitored on four different platforms (AU2700, AU480, Architect ci 4100 and Cobas c501). Obtained CVa for each platform was evaluated against criteria for imprecision based on biological variation. Comparison against biological variation was as follows: all monitored parameters met the optimum quality specifications only on AU480, while CVa monitored on the rest of the platforms (AU2700, Architect ci 4100 and Cobas c501) did not meet quality specifications based on biological variation for four parameters (sodium, chloride, calcium and total protein). According to our results sodium, chloride, calcium and total protein did not meet quality requirements on three different platforms. One of the possible reasons is low within-subject biological variation which is difficult to achieve with available analytical methods.

Background: Sulfonylureas are used as first- line therapy drugs in type 2 diabetics ; however, therapy failure occurs in approximately 30% of patients. We hypothesize that at least one part of the cause lies in genetic factors. Sulfonylureas are insulin secretagogues that act by binding to pancreatic beta cells sulfonylurea receptor (SUR-1) encoded by two genes: ABCC8 and KCNJ11. The aim of this study was create a logistic regression model to identify patients with poor response to sulfonylurea therapy using demographic (age, gender), anthropometric (body mass index, BMI), biochemical (fasting and postprandial glucose and lipid concentration) and genetic (ABCC8 polymorphisms: SUR1 exon 16 (-3C/T), SUR-1 exon 31 (Arg1273Arg) and SUR-1 exon 33 (S1369A) and KCNJ11 polymorphism E23K) parameters. Methods: The study included 251 unrelated type 2 diabetics on sulfonylurea therapy. Polymorphisms were detected using polymerase chain reaction - restriction fragment length polymorphism. Biochemical parameters were determined on automatic analyzer Olympus AU 2700 (Olympus, Hamburg, Germany). Based on the HbA1c concentration, patients were divided into two groups: patients with HbA1c concentration over 53 mmol/mol Hb were classified as patients with poor outcome. All variables are analysed using univatiate regression analysis. Statistically significant variables were included into multivariate regression model. Results: Univariate regression analysis identified following variables as statistically significant: fasting glucose (OR (95% CI) = 1.60 (1.37-1.88)) ; postprandial glucose (1.28 (1.17-1.40)) ; SUR1 exon 16 polymorphism (1.58 (1.06-2.36)) and SUR-1 exon 31 polymorphism (0.51 (0.33-0.77)), while age, gender, BMI and lipid concentration didn't differ significantly across subgroups. After inclusion into stepwise multivariate regression model, fasting and postprandial glucose and SUR-1 exon 31 polymorphism remained significant (1.45 (1.22- 1.74) ; 1.14 (1.03-1.27) and 0.48 (0.30-0.80), respectively). Percent of correctly classified cases was 74.10%. Conclusion: Type 2 diabetics with high fasting and postprandial glucose and wild type allele of the SUR-1 exon 31 (Arg1273Arg) polymorphism are more likely to have poor glycemic control expressed as high HbA1c concentration.

Background. Posttraumatic stress disorder (PTSD) is a complex anxiety disorder caused by a traumatic experience. It is over represented in combat veterans from Croatian homeland war. The glutathione S-transferases (GSTs) belong to a group of major detoxifying enzymes responsible for eliminating of oxidative stress products. It is hypothesized that GSTs genetic isoforms together with oxidative stress biomarkers might contribute in pathogenesis of PTSD. Methods. 134 male combat veterans from Croatian homeland war were included in the study, 121 with PTSD diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), and 13 control subjects. Concentrations of serum lipid parameters were determined with standard enzymatic methods. Gluthatione peroxidase (GPx) and superoxide dismutase (SOD) catalytic concentrations were determined in hemolysates of erythrocytes by standard spectrophotometric methods. Anthropometric data were collected. GSTM1 and GSTT1 were determined by multiplex PCR. Results. GSTM1 genotype frequencies (functional vs. deleted) were 95 vs. 26 in PTSD, and 9 vs. 4 in controls, respectively, (P=0.487). GSTT1 genotype frequencies (functional vs. deleted) were 97 vs. 22 in PTSD, and 9 vs.4 in controls, respectively, (P=0.487). Waist-to-hip ratio (WHR), SOD and GPx were significantly lower in PTSD subjects (P=0.040, P