LabMedica International July 2018 by Globetech

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WORLD’S CLINICAL LABORATORY NEWS LEADER ISSN 1068-1760

Vol. 35 No.4 • 6-7/2018

DAILY CLINICAL LAB NEWS

Test Reports Antibiotic Resistance in 2 Hours

Assay Detects Hepatitis B In Multiple Specimens

esistant bacteria are spreading worldwide, which makes fast antibiotic susceptibility testing and determination of the minimal inhibitory concentration (MIC) urgently necessary to select appropriate antibiotic therapy in time.

epatitis B virus (HBV) infection has led to more than 686,000 deaths worldwide per year. Approximately two billion individuals worldwide are infected with HBV and are at risk of developing cirrhosis and hepatocellular carcinoma, which ranks fifth

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Image: Courtesy of The Children’s Lyme Disease Network

Chip-Based Blood Test Could Make Bone Biopsies Unnecessary

test protocol based on liquid chromatography-mass spectrometry (LC-MS) analysis accurately detects levels of illegal drugs in a single fingerprint from drug users, while eliminating those who had only passive contact with a drug user. In an earlier study, investigators at the University of Surrey (UK; www.surrey.ac.uk) described a test that used a fingerprint to detect

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recently-released line of ELISA tests for neonatal screening is based on Dry Blood Spot (DBS) technology and comprises a menu of eight kits. The kits are the newest diagnostic assays being introduced by Calbiotech (Spring

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Cervical Fluid Test Developed For Gynecological Cancers

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uberculosis, caused by infection with Mycobacterium tuberculosis (TB), is the world’s leading cause of death brought on by a single pathogen. More than 10 million new cases of TB are diagnosed each year, and almost two million people die from the disease. Those living with someone with active TB are at highest risk for developing the disease, yet

Fingerprint Test Detects Heroin and Cocaine Users

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he days of subjecting patients to painful bone biopsies, in order to guide treatment for multiple myeloma and other cancers such as leukemia, may be numbered. A low-cost reliable blood test, that uses a small plastic chip about the size of a credit card, can now deliver the same diagnostic information, but using a simple blood draw instead.

Blood Test Predicts Onset of TB in Advance

in terms of malignant cancer mortality. A novel HBV assay that offers advantages over currently used methods because it has the capability to detect closed circular DNA (cccDNA) in serum, single cells, and preserved tissue samples. This

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ogether, endometrial and ovarian cancers account for about 25,000 deaths each year and are the third leading cause of cancer-related mortality in women in the USA. Most of these deaths are caused by high-grade tumor subtypes, which tend to metasta-

size before the onset of symptoms. Cervical fluid samples gathered during routine Papanicolaou (Pap) tests are the basis of a new screening test for endometrial and ovarian cancers. The new screening test called PapSEEK detects mutations in DNA that have been Cont’d on page 4

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Test Reports Antibiotic Resistance in 2 Hours cont’d from cover

The often unnecessary and mass use of antibiotics causes the resistance of pathogens against drugs and infections that were easily curable up to now may become life threatening. A new rapid test will give information on which available antibiotics are still effective and faster diagnostics allows for personalized therapy and saves lives. Scientists at the Jena University Hospital (Jena, Germany; www.uni-jena.de) and their colleagues have developed a simple and fast Raman spectroscopy-based procedure to identify antimicrobial susceptibilities and determine the MIC within only two hours total analysis, marking a huge time savings compared to established phenotypic methods nowadays used in diagnostics. The sample preparation was fast and easy as well as comparable to currently established tests. The use of a dielectrophoresis chip allows automated collection of the bacteria in a micron-sized region for high-quality Raman measurement directly from bacterial suspensions. The new Raman spectroscopic MIC test was validated with 13 clinical Escherichia coli isolates that show a broad range of ciprofloxacin resistance levels and were collected from patients with blood-stream infection. Micro-Raman spectroscopy was able to detect ciprofloxacin-induced changes in E. coli after only 90 minutes interaction time. Princi-

pal component analysis as well as a simple computed ratio of the Raman marker bands at 1458 and 1485 cm–1 showed a clear concentration-dependent effect. The MIC values determined with the new Raman method are in good agreement with MICs obtained by reference methods such as broth microdilution, Vitek-2 and E-test (bioMérieux, Marcy l’Etoile, France; www.biomerieux.com) and can be used to provide a classification as sensitive, intermediate, or resistant. Ute Neugebauer, PhD, a professor of Physical Chemistry and senior author of the study said, “We combine light-based analytical methods with microfluidic sample processing. With our Lab-on-a-Chip system, thus a miniaturized lab, we are able to clearly identify bacterial strains and their resistances, in less than three hours.” The study was published in the February 2018 issue of the journal Analytical Chemistry. Image: The Lab-on-a-Chip system used with Raman spectroscopy to identify antibiotic resistance (Photo courtesy of Leibniz-Institute of Photonic Technology).

Cervical Fluid Test Developed For Gynecological Cancers cont’d from cover

identified for specific cancers sooner. Earlier detection of cancer could lead to earlier treatment and potentially better outcomes for patients. An international team of scientists working with those at Johns Hopkins University School of Medicine (Baltimore, MD, USA; www.hopkinsmedicine.org) carried out a retrospective study with samples collected from 1,658 individuals, including 656 patients with endometrial or ovarian cancers and 1,002 healthy controls. The average age of 714 women without cancer who underwent Pap brush analysis was 34 (range, 17 to 67 years). The average age of 125 women without cancer who underwent Tao brush analysis was 29 (range, 18 to 74 years). For intrauterine sampling, the Tao Brush IUMC Endometrial Sampler (Cook Medical, Bloomington, IN, USA; www.cookmedical. com) was used. For each sample, a single primer pair was used to amplify ~38,000 loci of LINEs throughout the genome. Massively parallel sequencing was performed on Illumina instruments (San Diego, CA, USA; www. illumina.com). DNA from Pap brush samples, Tao brush samples, or primary tumors was amplified in three multiplex polymerase chain reactions (PCRs) with 139 primer pairs that

were designed to amplify 110- to 142-bp segments. DNA from plasma was amplified in two multiplex PCRs consisting of 61 primer pairs that were designed to amplify 67- to 81bp segments. The investigators found that PapSEEK was nearly 99% specific for cancer, and it detected 81% of endometrial cancers and 78% were early-stage cancers and 33% of ovarian cancers and 34% were early-stage cancers. Of the 123 endometrial cancer patients studied using Tao brush samples, PapSEEK identified cancer 93% of the time. Of the 51 ovarian cancer patients studied, 45% tested positive for cancer with PapSEEK. There were no false-positive results. When the plasma and Pap brush samples were both tested, the sensitivity of the test for ovarian cancer increased to 63%. Lucy Gilbert, M.D. MSc FRCOG, director of gynecologic oncology at McGill University Health Centre, (Montreal, QC, Canada; https://muhc.ca) and a senior author of the study, said, “This allows sampling closer to where the cancers originated. Intrauterine sampling proved particularly important for increasing the detection of ovarian cancer.” The study was published on March 21, 2018, in the journal Science Translational Medicine.

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ISSN 1068-1760 Vol.35 No.4. Published, under license, by Globetech Media LLC; Copyright © 2018. All rights reserved. Reproduction in any form is forbidden without express permission. Opinions expressed are solely those of the authors, and do not represent an endorsement, or lack thereof, by the Publisher of any products or services. Teknopress Yayıncılık ve Ticaret Ltd. Şti. adına İmtiyaz Sahibi: M. Geren • Yazı işleri Müdürü: Ersin Köklü Müşir Derviş İbrahim Sok. 5/4, Esentepe, 34394 Şişli, İstanbul P. K. 1, AVPIM, 34001 İstanbul • E-mail: Teknopress@yahoo.com Baskı: Promat Web Ofset Tesisi • Orhangazi Mahallesi 1673. Sokak, No: 34 • 34510 Esenyurt, B. Çekmece • İstanbul Yerel süreli yayındır. Yılda sekiz kere yayınlanır, ücretsiz dağıtılır.

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Chip-Based Blood Test Could Make Bone Biopsies Unnecessary he diagnosis of multiple myeloma, a cancer affecting plasma cells, traditionally forces patients to suffer through a painful bone biopsy. Doctors insert a bone-biopsy needle through an incision to get a bone marrow sample or make a larger incision and remove a section of bone via surgery. However, the days of using bone biopsies to guide treatment for multiple myeloma and other cancers, such as many types of leukemia, may be numbered. A low-cost, reliable blood test that uses a small plastic chip about the size of a credit card that can deliver the same diagnostic information as a bone biopsy, but using a simple blood draw instead. Scientists collaborating with those at the University of Kansas (Lawrence, KS, USA; www.ku.edu) took blood samples from patients with plasma cell disorders, which were analyzed for the presence of circulating plasma cells (CPCs) using a microfluidic device modified with monoclonal anti-CD138 antibodies. CPCs were immuno-phenotyped using a CD38/CD56/CD45 panel and identified in 78% of patients with monoclonal gammopathy of undetermined significance (MGUS), all patients with festering and symptomatic multiple myeloma (MM), and none in the controls.

The burden of CPCs was higher in patients with symptomatic MM compared with MGUS and festering MM. Fluorescence in situ hybridization (FISH) analysis revealed the presence of chromosome 13 deletions in CPCs that correlated with bone marrow results. Point mutations in KRAS were identified, including different mutations from sub-clones derived from the same patient. The authors concluded that the microfluidic assay represents a highly sensitive method for enumerating CPCs and allows for the cytogenetic and molecular characterization of CPCs. Steven A. Soper, PhD, the Distinguished Professor of Chemistry and Mechanical Engineering, and the senior author of the study, said, “The chip we’re using, because it is made from a plastic, can be injection molded, the same method that is used to produce CDs, DVDs and Blu-ray Discs. What’s really nice is we can produce these chips for a couple of dollars per chip, which makes it really appropriate for testing in a clinical setting.” The new test will be brought to market by BioFluidica (San Diego, CA, USA; www.biofluidica.com). The study was originally published on January 22, 2018, in the journal Integrative Biology.

ELISA-Based Neonatal Screening Line Offers Menu of Eight Kits cont’d from cover

Valley, CA, USA; www.calbiotech. com). The Calbiotech catalog features over 200 diagnostic products including a full range of ELISA-based immunoassay kits focused on areas such as: thyroid hormones, fertility, steroids, diabetes, allergy, anemia, growth markers, bone metabolism, inflammatory diseases, cancer, cardiac diseases, drugs of abuse, autoimmune disorders, infectious diseases, and neonatal screening. In addition, Calbiotech's Custom Development team crafts custom assays in a "Pipeline to Production" approach. To this end, the company has developed coated microplates, reagents, buffers, and other components for pharmaceutical companies, universities, and research centers in the United States and around the world. Rounding out its contribution to the diagnostics industry, Calbiotech also offers contract-manufacturing services that cover immunoassay development (microplates and magnetic beads), bulk coating of microplates, reagent preparation, including bottling, labeling and packaging. V

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Fingerprint Test Detects Heroin and Cocaine Users cont’d from cover

cocaine use. Now, in a recent study, the group has improved on the earlier test by developing a new fingerprint protocol that detects both cocaine and heroin. For this study, 100 fingerprint samples were collected from the hands of 50 nondrug users before and after handwashing to establish separate environmental cutoff values and testing protocols for cocaine, benzoylecgonine, heroin, and 6-monoacetylmorphine. The cutoff was challenged by testing the fingerprints of drug-free volunteers after shaking hands with drug users. Fingerprints from patients who testified to taking cocaine (n = 32) and heroin (n = 24) were also collected and analyzed. Analysis was carried out using the LC-MS gold standard drug testing method. Results revealed that this protocol identified 100% of heroin users even after handwashing and gave a false positive for only one non-drug user who shook hands with a drug user. The investigators also used LCMS to test for cocaine and its metabolite benzoylecgonine, which identified 85% of cocaine users after handwashing and produced no false positives for the non-drug users who came in contact with drug users. For both heroin and cocaine the fingerprint test correctly identified more

drug users than saliva testing. “The possibility of drug testing from a fingerprint has become the subject of many recent research articles, due to the ease and noninvasive nature of sample collection, as well as the fact that the donor’s identity is embedded within the ridge detail of the fingerprint itself,” said senior author Dr. Melanie Bailey, lecturer in chemistry at the University of Surrey. “This provides … the possibility of rapidly and noninvasively carrying out drug testing in a way that is difficult to falsify. This is, we believe, the first study to explore the significance of testing for drugs from a fingerprint, and therefore, the first effort dedicated to establishing an environmental cutoff.” The study was published in the March 22, 2018, online edition of the journal Clinical Chemistry. Image: The friction ridges on a finger (Photo courtesy of Wikimedia Commons).

Assay Detects Hepatitis B in Multiple Specimens cont’d from cover

assay can be used to diagnose hepatocellular carcinoma (HCC) at an earlier stage to manage treatment more effectively. Scientists at the Wuhan University (Wuhan, China; www.whu.edu.cn) enrolled a total of 168 patients with HBV infection (HBsAg/HBV-DNA positive) in a study between December 2013 and November 2015 at the Zhongnan Hospital. The study included 79 cases of non-HCC patients, 56 without and 23 with cirrhosis; 50 males and 29 females; mean age, 41.7 ±12.8 years, and 89 cases of HCC patients, 75 males and 14 females; mean age, 53.4 ±15.3years. In total, 79 serum samples were collected from non-HCC patients, 68 preoperative serum samples on the first day after hospital admission and 14 paired formalin-fixed paraffin embedded (FFPE) tumor tissues, as well as 21 non-paired FFPE tumor tissues from HCC patients. Serum HBV-DNA copy number was assayed with COBAS TaqMan 48 kit (Roche Diagnostics, Basel, Switzerland; www.roche.com). The serological HBsAg, hepatitis B s antibody (HBsAb), HBeAg, hepatitis B e antibody (HBeAb), hepatitis B c antibody (HBcAb), and anti-HCV were detected by Architect chemiluminescent enzyme immunoassays (Abbott Architect i system; Abbott Diagnostics, Lake Bluff, IL, USA; www.abbott.com). The cccDNA copy number was quantified using the

QX200 Droplet Digital PCR system (Bio-Rad, Hercules, CA, USA; www.bio-rad.com). Clinical biochemical parameters and tumor biomarkers were measured by an automatic chemistry analyzer. The team found ddPCR was useful to identify which patients might be harboring hepatocellular carcinoma and found that almost 90% of 68 HCC patients were cccDNA-positive compared to 53% of 79 non-HCC patients. Serum cccDNA copy number was found to be higher in HCC patients compared to non-HCC patients. The combined analysis of serum cccDNA and HBV-DNA distinguished HCC patients from non-HCC patients. The investigators were also able to confirm that serum cccDNA was positively correlated with levels of cccDNA measured in liver samples. Song-Mei Liu, MD, PhD, the lead investigator, said, “The development of HCC is strongly associated with HBV. Recently, several new antiviral strategies targeting cccDNA have been established to improve HBV clearance. It is of great clinical significance to provide an accurate and sensitive approach for cccDNA detection. With this method, more and more patients with chronic HBV will have precision treatment available to prevent or delay HCC occurrence, and HCC in patients could be diagnosed at an earlier stage.” The study was published on April 12, 2018, in The Journal of Molecular Diagnostics. LabMedica International June-July/2018

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Blood Test Predicts Onset of TB in Advance cont’d from cover

only about 5% to 20% of people infected with tuberculosis actually develop the disease. A blood test that predicts the development of TB without putting large numbers of lower-risk people through unnecessary preventative treatment is not currently available. An international consortium of scientists working with those at Stellenbosch University (Stellenbosch, South Africa; www.sun.ac.za) enrolled 4,466 HIV-negative, healthy study participants from the households of 1,098 index cases, that were people with active TB, who allowed the teams to enroll members of their household who did not have TB in its active stage. Blood samples were taken from the 4,466 study participants, and stored. At the end of the initial study period, when it was apparent who had progressed to TB and who had not, the blood samples of 79 individuals who progressed to active TB between three and 24 months following exposure, and 328 who remained healthy during the two years of follow up, were analyzed. Various biosignatures, combinations of gene or protein levels, that together result in a test readout that relates to current or future risk for developing the condition, were measured. The scientists employed RNA sequencing, polymerase chain reaction (PCR) and the Pair Ratio algorithm in a training/test set approach. The consortium found that a fourVISIT US AT: transcript signature (RISK4) which is a combination of four genes associated with inflammatory responses, de2018 ANNUAL rived from samples in a South African MEETING and Gambian training set, predicted Booth: 325 progression up to two years before onset of disease in blinded test set samples from South Africa, The Gambia and Ethiopia with little population-associated variability and also validated on an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic tuberculosis signatures predicted on samples from some but not all three countries, indicating site-specific variability. Post-hoc meta-analysis identified a single gene pair, Complement C1q C Chain/ T Cell Receptor Alpha Variable 27 (C1QC/ TRAV27) that would consistently predict TB progression in household contacts from multiple African sites, but not in infected adolescents without known recent exposure events. Gerhard Walzl, MMed, PhD, a professor and lead study author, said, “This signature, known as ‘RISK4,’ was found to be present in all cohorts in the study, from South Africa, Gambia and Ethiopia. The individual components of this signature may not be sufficient to deliver an accurate diagnosis of prediction, but a combination of these markers improves its accuracy. We are hoping that primary health clinics will be able to use such a test and the reagents would then be read-

LabMedica International June-July/2018

ily available in that format, similar to the tests that are currently used to diagnose TB.” The study was published on April 6, 2018, in the American Journal of Respiratory and Critical Care Medicine. Image: Computer-generated illustration of Mycobacterium tuberculosis bacteria, Ziehl-Neelsen stain. Acid-fast bacilli stain red and the background is blue (Photo courtesy of Microbiology Pictures).

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New Cholesterol Calculation May Avoid Fasting n a direct comparison study, scientists have added to evidence that a newer method of calculating low-density lipoprotein-cholesterol levels in the blood is more accurate than the older method in people who did not fast before blood was drawn. Recent recommendations favoring non-fasting lipid assessment may impact low-density lipoprotein-cholesterol (LDL-C) estimation. The novel method of LDL-C estimation (LDL-CN) uses a flexible approach to derive patient-specific triglyceride (TG) to very low-density lipoprotein-cholesterol ratios. Blood lipid specialists and their colleagues at Johns Hopkins School of Medicine (Baltimore, MD, USA; www.hopkinsmedicine.org) used a USA cross-sectional sample of 1,545,634 patients (959,153 fasting ≥10-12 hours; 586,481 non-fasting) from the second harvest of the Very Large Database of Lipids study to assess for the first time the impact of fasting status on novel LDL-C accuracy. Rapid ultracentrifugation was used to directly measure LDL cholesterol con-

tent (LDL-CD). Accuracy was defined as the percentage of LDL-CD falling within the novel method of LDL-C estimation (LDL-CN) or the classical Friedewald method (LDL-CF) category by clinical cut-point. For low estimated LDL-C (<70 mg/dL), they evaluated accuracy by TG levels. The magnitude of absolute and percent differences between LDL-CD and estimated LDL-C (LDL-CN or LDL-CF) was stratified by LDL-C and TG categories. The scientists reported that in both fasting and non-fasting samples, accuracy was higher with the novel method across all clinical LDLC categories (range: 87-94%) compared to Friedewald estimation (range: 71-93%). Approximately 30% of the non-fasting participants had greater than 10 mg/dL inaccurate cholesterol measurements using the Friedewald method compared with only 3% error from the actual measured value with the new method. The investigators reported that the overall accuracy of LDL calculations decreased

as levels of triglycerides increased, particularly when using the Friedewald method. For example, in 6,168 non-fasting participants with high triglycerides between 200 to 399 mg/dL, the accuracy of the calculation among those in the less than 70 mg/dL LDL range was 82% with the new method versus 37% using the Friedewald method. The study was published on January 2, 2018, in the journal Circulation. Image: New accurate cholesterol test may allow patients to pass on fasting (Photo courtesy of Johns Hopkins School of Medicine).

Mutation Found in Families with Contradictory Blood Sugars nsulinomatosis is a condition characterized by the occurrence of multicentric insulinomas, pancreatic neuroendocrine tumors with β-cell–like features causing hyperinsulinemic hypoglycemia. Insulinomatosis usually occurs sporadically, although it had also been described to occur in a familial setting in one single kindred where hyperinsulinemic hypoglycemia was paradoxically associated with a strong family history of diabetes mellitus. Due to the multicentric nature of the disease, patients with insulinomatosis have a significantly higher chance of persistent or recurrent disease post-surgery. A collaborating group of international scientists working with those at the Queen Mary University of London (London, UK; www.qmul. ac.uk) recruited two families with autosomal dominant insulinomatosis and diabetes mellitus (36 subjects, 19 females), and nine patients with sporadic insulinomatosis (eight females). The two families in which some people have contradictory conditions due to high blood sugar and low blood sugar levels share a missense mutation. Both families contain members with diabetes and others with insulinomatosis, multiple pan-

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creatic tumors that produce insulin and lower blood sugar levels. The team performed immunohistochemistry on archival pancreatic tissue for neuroendocrine markers, Ki-67, and pancreatic hormones (insulin, gastrin, glucagon, and pancreatic polypeptide). Genomic DNA was extracted from peripheral blood leukocytes, saliva, or formalin-fixed archival tissue using commercially available kits. Other techniques employed by the scientists were protein mobility analysis, luciferase assays, and cycloheximide chase experiments. The quantitative polymerase chain reaction (qPCR) reactions were performed with MAFA-Myc, MAFA (endogenous), and GAPDH gene primers on a LightCycler 480 II (Roche, Molecular Diagnostics, Pleasanton, CA, USA; https://molecular.roche.com). The team sequenced the exomes of four affected people from the first family to find they all shared a missense mutation in the MAFA gene. When they tested all 25 members of that family for the mutation, they found an additional 14 members who were heterozygous for it and two who were homozygous. The study was published on January 16, 2018, in the journal Proceedings of the National Academy of Sciences.

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Blood Test Plus Ultrasound Enhances Liver Cancer Detection hile the incidence of most cancers is decreasing in the USA the incidence of liver cancer has increased by 2.7% a year over the last 10 years, which is estimated at about 40,700 new cases of liver cancer that will be diagnosed in the USA in 2018. Risk factors for liver cancer, also known as hepatocellular carcinoma or HCC, include hepatitis C infection, chronic heavy alcohol consumption, and nonalcoholic fatty liver disease related to diabetes and obesity. Symptoms can include upper abdominal pain or swelling, loss of weight or appetite, white chalky stools, and general fatigue. Hepatologists at the UT Southwestern Medical Center (Dallas, TX, USA; www.utsouthwestern.edu), carried out a meta-analysis of 32 previous studies comprising 13,367 patients, that characterized sensitivity of imaging with or without alpha fetoprotein (AFP) measurement for detection of HCC in patients with cirrhosis. They searched for data from January 1990 through August 2016 to identify published sensitivity and specificity of surveillance strategies for overall and early detection of HCC. AFP is a plasma protein that is produced in abundance by the liver cells in the fetus. In adults, AFP levels are normally low, but liver can-

cer can cause AFP levels to rise. They found that ultrasound detected any stage HCC with 84% sensitivity, but early-stage HCC with only 47% sensitivity. In studies comparing ultrasound with versus without AFP measurement, ultrasound detected any stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (relative risk [RR], 0.88) and early-stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (RR, 0.81). However, ultrasound alone detected HCC with a higher level of specificity than ultrasound plus AFP measurement (RR, 1.08). Ultrasound with versus without AFP detected early-stage HCC with 63% sensitivity and 45% sensitivity, respectively. The study was published on February 6, 2018, in the journal Gastroenterology. Image: An immunohistochemistry of anti-Alpha-Fetoprotein (AFP) antibody on liver tissue from a human hepatocellular carcinoma patient (Photo courtesy of Arigo Biolaboratories).

New Staining Method Enables Nano-CT Imaging of Tissue issue sectioning is a routine procedure in hospitals, for instance to investigate tumors. As the name implies, it entails cutting samples of body tissue into thin slices, then staining them and examining them under a microscope. The most obvious way forward for three-dimensional examination of the tissues lies in computed tomography (CT) scanning, also a standard method used in everyday clinical workflows. Soft tissue is notoriously difficult to examine using CT equipment. Samples have to be stained to render them visible in the first place. Stains for CT scanning are sometimes highly toxic, and they are also extremely time-consuming to apply. Scientists at the Technical University of Munich (Garching, Germany; www.tum.de) have developed a cytoplasm-specific staining method tailored for X-ray CT that enables a routine and efficient 3D volume screening at high resolutions. The technique is fully compatible with conventional histology and allows further histological investigations, as demonstrated for a mouse kidney. The team described an eosin-based preparation overcoming the challenges of contrast enhancement and selectivity for certain tissues. The eosin-based staining protocol is suitable for whole-organ staining, which then enables highresolution microCT imaging of whole organs and nanoCT imaging of smaller tissue pieces retrieved from the original sample. The nano-CT system delivers resolutions of up to 100 nm and is suitable for use in typical laboratory settings. The results of the study demonstrate suitability of the eosin-based staining method for diagnostic screening of 3D tissue samples without impeding further diagnostics through histological methods. Madleen Busse, PhD, a chemist and lead author of the study, said, â&#x20AC;&#x153;Our approach included developing a special pre-treatment so that we can use eosin anyway. The staining method is so time-efficient that it is also suited to everyday clinical workflows. Another important benefit is that there are no problems using established methods to examine the tissue sample following the scan.â&#x20AC;? The study was published on February 20, 2018, in the journal Proceedings of the National Academy of Sciences (PNAS).

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ELISA Methods Developed for Analyzing Immunotherapy new enzyme-linked immunosorbent assay (ELISA) with high sensitivity and selectivity for bioanalysis of bevacizumab (BEV), a monoclonal antibody used for immunotherapy of different types of cancer, has been developed. Bevacizumab is a recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF), a pro-angiogenic cytokine. Bevacizumab binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels. Scientists at King Saud University (Riyadh, Saudi Arabia; www.ksu. edu.sa) captured BEV by specific antigen human vascular endothelial growth factor protein; (VEGF) immobilized onto a 96-well assay plate. The BEV-VEGF complex formed onto the plate wells were quantified using horseradish peroxidase labeled anti-human immunoglobulin-G (HRP-IgG) and 3,3`,5,5`-tetramethylbenzidine (TMB) as a chromogenic substrate for peroxidase enzyme. The optimum conditions for conducting the proposed ELISA were es-

tablished and its analytical performance was evaluated as per the guidelines for the validation of immunoassays for bioanalysis of therapeutic monoclonal antibody. The assay limit of detection was 1.01 ng /mL and the effective working dynamic range was 3.07 to100 ng/mL. The accuracy and precision of the assay were proven. The present assay with high throughput analysis was very easy to perform in a 96-well plate and permits an operator to analyze a batch of about 200 samples, in triplicate. This facilitates the processing of a large number of samples in a clinical setting. ELISA eliminated the need for pretreatment of plasma samples by affinity chromatography or other sophisticated equipment. The studies were published on January 31, 2018, in the journal Current Pharmaceutical Analysis. Image: Bevacizumab (Avastin) is approved for immunotherapy use in metastatic renal cell carcinoma, glioblastoma, non-squamous nonsmall-cell lung cancer, and metastatic colorectal cancer, and cervical cancer (Photo courtesy of Genentech).

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Yellow Fever Virus Detected in Urine of Convalescent Patient

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ellow fever virus (YFV) is a member of the genus Flavivirus and causes yellow fever in humans, characterized by fever, prostration, and hepatic, renal, and myocardial complications that lead to death in 20% to 50% of cases. According to the current model, yellow fever virus transmissibility begins between 24 and 48 hours before the appearance of the first symptoms and lasts until between three and seven days thereafter. In most cases, the symptoms disappear after three or four days. A small percentage of those infected enter a second, more toxic stage within 24 hours of recovery from the initial symptoms, and half of these die within a period of seven to 10 days. Brazilian scientists at University of São Paulo (São Paulo, Brazil; www.fearp.usp.br) and their colleagues tested the urine and semen of a patient who survived the disease almost a month after the patient was infected. The patient showed a moderate clinical presentation: anicteric form and mild spontaneous hemorrhage (ecchymosis in the right eye). High fever, gastrointestinal symptoms (vomiting and diarrhea), weakness, adynamia, and generalized myalgia were also observed. The patient had a weight loss of 4 kg over eight days and the patient also had severe thrombocytopenia (platelet count 77,000/mm3). The team obtained serum, urine, and semen samples and extracted virus RNA by using the NucliSENS EasyMag Kit (bioMérieux, Marcy l’Étoile, France; www.biomerieux.com). They tested samples for YFV RNA by using a real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and primers specific for YFV and a conventional PCR and pan flavivirus primer. Serum samples showed negative results for both PCRs. However, a urine sample obtained 10 days after initial symptoms was positive for YFV RNA (cycle threshold [Ct] 17.42, 9.3 × 106 RNA copies/mL) by qRT-PCR. The authors concluded that semen can be a useful clinical material for diagnosis of yellow fever and indicate the need for testing urine and semen samples from patients with advanced disease. Such testing could improve diagnostics, reduce false-negative results, and strengthen the reliability of epidemiologic data during ongoing and future outbreaks. The study was published in the January 2018 issue of the journal Emerging Infectious Diseases.

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Amplification Tests Evaluated For Pelvic Inflammatory Disease exually transmitted Chlamydia trachomatis (chlamydia) is the most prevalent sexually transmitted infection (STI) with an estimated 68,455,000 incident cases globally in women in 2012. Chlamydia is the subject of intensive control efforts in many high-income settings. Nucleic Acid Amplification Tests (NAATs) are the recommended test type for diagnosing C. trachomatis; however, less sensitive diagnostic methods, including direct immunofluorescence (IF) and enzyme-linked immunoassay (ELISA), remain in use in lower resourced settings. Danish and British scientists led by those at the Imperial College London (London, UK; www.imperial.ac.uk) extracted from the Denmark’s national Chlamydia Study dataset all chlamydia test records from women aged 15 to 34 years that were performed between January 1, 1998 and December 31, 2001, the interval when non-NAATs were replaced by NAATs as the most common test type. Tests were categorized as non-NAAT (IF/ELISA) or NAAT and limited to each woman’s first test in the study period. They linked test data to hospital presentations for pelvic inflammatory disease (PID) within 12 months.

The study included 272,105 women with a chlamydia test, just under half (44.78%) were tested using NAATs. Overall, 17,353 (6.38%) tested positive for chlamydia and 1,732 (0.64%) were diagnosed with PID within 12 months. The risk of PID following a positive chlamydia test did not differ by test type (NAAT 0.81%, non-NAAT 0.78%). The risk of PID following a negative test was significantly lower in women tested with NAATs compared to non-NAATs (0.55% compared to 0.69%). The team estimated that 18% of chlamydia infections in women tested with a non-NAAT were undiagnosed and that the risk of progression from undiagnosed chlamydia infection to PID within 12 months was 9.52%. The use of non-NAATs could lead to an excess of 120 cases of PID per 100,000 women tested compared to using NAATs. The study was published on January 2, 2018, in the journal Public Library of Science Medicine. Image: Chlamydia trachomatis, the most prevalent sexually transmitted infection (STI) (Photo courtesy of Getty Images).

Genetic Biomarkers Determine Risk of Developing Endometriosis ndometriosis is one of the most common women’s health disorders, causing up to 10% of reproductive-age women to experience painful periods and potential infertility. Diagnosis can elude patients for decades, in part because exploratory surgery is considered the ultimate diagnostic method. Endometriosis is a condition in which the layer of tissue that normally covers the inside of the uterus grows outside of it. Most often this is on the ovaries, fallopian tubes, and tissue around the uterus and ovaries; however, in rare cases it may also occur in other parts of the body. Predictive Technology (Salt Lake City, UT, USA; www.predictive technologygroup.com), a biotech holding corporation, is commercializing an assay that uses genetic biomarkers to determine whether a woman is at risk of developing endometriosis as well as to diagnose the disease and personalize treatment guidance. The assay uses both blood or saliva samples and employs polymerase chain reaction (PCR) to detect a set of biomarkers that the firm purports to be both diagnostic and prognostic of endometriosis. The assay was originally developed by Juneau Biosciences (Salt Lake City, UT, USA; www.juneaubiosciences.com). An earlier genome-wide association study (GWAS) study had shown a relationship with some single-nucleotide polymorphisms (SNPs), while an article published last year described a panel of four genes associated with endometriosis that are potential regulators of mesothelial barrier integrity, suggesting a mechanism for the disease. The Predictive Technology test will enable the firm to predict how well patients are going to respond to different therapies, similar to a pharmacogenomics test. Specifically, the company will use data analytics to gauge the interaction between the individual and the type of disease to guide treatment more appropriately, both its own therapeutic as well as other treatments like hormonal birth control, GnRH agonists such as Lupron, or possibly a GnRH antagonist from AbbVie called Elagolix that is currently before the US Food and Drug Administration (FDA, Silver Springs, MD, USA; www.fda.gov).

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Rapid Diagnostic Test for RSV Evaluated espiratory syncytial virus (RSV) is a common ubiquitous pathogen responsible for mild upper respiratory tract infection in most children and healthy adults. In infants, RSV is mainly associated with acute lower respiratory infections. In elderly and immunocompromised patients, RSV has been known to cause severe respiratory failure, extended hospitalizations, higher mortality, with symptoms similar to those associated with seasonal influenza. Respiratory syncytial virus is responsible for severe respiratory infections and higher costs in medical care. Scientists at Normandy University (Caen, France; www.unicaen.fr) carried out two studies, one which focused on fresh nasopharyngeal swabs sent to the virology laboratory of Caen University Hospital for virological diagnosis and the second was conducted over a 20 weeks winter period from November 13, 2013 (week 46) to March 31, 2014 (week 13) for point-of-care testing (POCT), in the pediatric emergency department (ED) of the same hospital. In the first study all the respiratory samples were tested using SOFIA RSV, Direct Immunofluorescence Assay (Quidel, San Diego, CA, USA; www.quidel.com), that detects eight viral targets (direct fluorescent anti-

body, DFA): influenza virus type A, B (FluA, FluB), human RSV (hRSV), human metapneumovirus (hMPV), human adenovirus (hAdV), and human parainfluenza viruses 1, 2, 3 (hPIVs). In the second study two SOFIA RSV analyzers were set up and nurses performed the rapid diagnostic tests on fresh respiratory specimens, After a sample extraction, an aliquot was pipetted onto the test cassette. An incubation of 15 minutes and one-minute reading phase were performed as per mandatory protocol within the SOFIA RSV analyzer. Rapid positive and negative results were provided after 15 minutes. The team found that that among 401 samples in the first study, 123 (30.7%) tested RSV positive using the molecular method, 101 (25.2%) using SOFIA RSV, 80 (19.9%) using RSV DFA, and 53 (13.2%) using cell culture. The sensitivities of SOFIA RSV in infants (aged less than 24 months) performed in the laboratory and in the pediatric ED were respectively 95% and 74.8% to polymerase chain reaction (PCR). In the first study, the sensitivity among children (from 2 to 15 years old) and adults (above 15 years old) dropped to 45% and 59%, respectively. In the second study there were some differences in bed-management of SOFIA RSV positive compared to SOFIA RSV negative infants.

The authors concluded that SOFIA RSV tests performed in the laboratory and in the pediatric ED show high and satisfactory sensitivities among young children less than 24 months, which supports its robustness and reliability. SOFIA RSV tests will be very useful when new specific treatments become available, for example antiviral or immunomodulators, to reduce viral load and clinical severity scores. The study was published on June 26, 2017, in the journal BMC Infectious Diseases. Image: The Sofia respiratory syncytial virus (RSV) point of care diagnostic kit (Photo courtesy of Quidel).

Blood Test Detects Heart Attack Risk in Lupus Patients ystemic Lupus Erythematosus (Lupus) is a genetically complex chronic relapsing immune mediated rheumatic disease characterized by inflammation that may affect different tissues, including the skin, joint linings, lungs, kidneys and other organs. A specific biomarker detected in the blood of lupus patients with no symptoms of cardiovascular disease (CVD), thought to be at low risk of CVD based on traditional risk factors, is associated with the presence of atherosclerosis. Premature CVD is much more common in young premenopausal women with lupus than healthy women of a similar age. A team of scientists at the Bichat Hospital (Paris, France; www. aphp.fr) used vascular ultrasound, and found 23 out of 63 (36.5%) consecutive lupus patients to have signs of carotid plaques compared to only two out of 18 (11.1%) of a control group. None of these patients nor the controls had symptoms of CVD and they all had a low Framingham risk factor score. Only age and lupus disease status were independently associated with the presence of carotid plaques. The percentage of lupus patients with carotid plaques who had a detectable high-sensitivity cardiac troponin T (HS-cTnT) was 87%; only 42.5% of lupus patients without plaques had a detectable blood level of HS-cTnT. The authors concluded that the risk of having fatty deposits (plaques) in the carotid arteries that deliver blood to the brain due to atherosclerosis was increased by a factor of eight times in those lupus patients who had a biomarker known as High Sensitivity Cardiac Troponin T (HS-cTnT) in their blood. Karim Sacre, MD, a professor and lead author of the study, said, “The results of our study raise the possibility that this easily measured biomarker could be introduced into clinical practice as a more reliable way of evaluating CVD risk in lupus patients. This in turn will enable more effective primary prevention measures such as treating abnormally raised blood lipids to be implemented.” The study was presented at the Annual European Congress of Rheumatology (EULAR) held June 14-17, 2017, in Madrid, Spain.

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Liquid Biopsy Platform Isolates Circulating Disease Biomarkers new platform has been created with the potential to extract tiny circulating biomarkers of disease from patient blood. This simple, fast and convenient technique could help realize liquid biopsy diagnostics, which is a less invasive procedure than the current gold standard tumor biopsies. Extracellular vesicles are cell messengers that can be found in the blood. In cancer, cardiovascular and blood diseases, vesicles transport specific disease-related molecules (biomarkers) that can be used to diagnose these diseases. However, it is difficult to isolate vesicles from blood, because they are miniscule particles, only 30 nm -1,000 nm in size. Scientists at the National University of Singapore (Singapore; www.nus.edu.sg) utilized a microfluidic centrifugal technique, where a spinning rotor generates pressure, forcing the patient’s blood sample to flow through microscopic channels of a specially designed microfluidic chip. The centrifugal platform utilizes a gentle and efficient size-based separation without the requirements of syringe pump and other accessories. A biological sample is first added to the chip’s inlet, and then the chip is placed into the centrifugal nanoparticle separation and ex-

traction called the CENSE platform. The CENSE is then loaded into a standard laboratory benchtop centrifuge and spun. It takes less than eight minutes for the blood and vesicles to separate, and the extract can be removed from the chip outlet. This is a hundredfold faster than the high speed ultracentrifugal method that has been used in the past. The CENSE platform was designed to increase the external force field within a smaller radius, minimizing the centrifugal force and time requirements. Once isolated the vesicles molecular content can be tested for certain biomarkers of disease. This process includes examining the nucleic acid and protein content. For this study, the group successfully demonstrated that the CENSE was capable of separating and enriching vesicles from liquid medium exposed to cells grown in a laboratory, by showing that the protein biomarker for vesicles, CD63, was present. The team reported a high separation efficiency of 90% and an extraction purity of 85% within a single platform. The CENSE platform is highly versatile for multiple microscale manipulations, as the microfluidic chip can be redesigned for the nanoparticle that needs to be extracted.

Chwee Teck Lim, PhD, a professor and the lead investigator of the study, said, “As we spin the microfluidic chip, the sample in the inlet starts to migrate or move into this curved channel. Once there, the centrifugal forces start to separate the smaller vesicles from the larger particles, because the forces acting on the different sized vesicle are different. So, as they move from inlet to outlet, they start to separate into different zones. The smaller particles remain near the inner wall of the channel and the larger particles move towards the outer wall of the channel, and this separates them into two outlets.” The study was published in the March 2018 issue of the journal Biomicrofluidics. Image: The μCENSE chip with the benchtop centrifugal platform in the background (Photo courtesy of Dr. Joo Chuan Yeo, PhD).

Genetic Test May Improve Post-Stent Treatment Outcome test for specific genetic mutations successfully informed blood-thinner treatment selection following stent placement to open clogged blood vessels, leading to significantly fewer complications. Genetic testing identified patients with specific mutations that render the widely used blood thinner clopidogrel ineffective. Patients with the genetic mutations who received alternative medications were much less likely to die or have a heart attack, stroke or other complications than patients with the mutations who received clopidogrel. Medical scientists at University of North Carolina at Chapel Hill (NC, USA; www.unc.edu) included 1,193 patients in a study at the University of North Carolina Cardiac Catheterization Laboratory who received stent placement between July 1, 2012, and June 30, 2014. Their average age was 63 years and more than two-thirds were male. Most were white, 21% were black, and 1% was Asian. Patients identified as high risk, due to decreased blood flow to the heart, received the genetic testing and the follow up was 12 months. The scientists used the polymerase chain reaction-based TaqMan allelic discrimination assays (Life Technologies, Foster City, CA, USA; www.thermofisher.com), The team found genetic testing for cytochrome P450 family 2 subfamily C member 19 (CYP2C19) mutations could be used to guide blood-thinner treatment after stent placement. Furthermore, patients with the mutations who received one of two clopidogrel alternatives compared to clopidogrel were more than three times less likely to die or have a heart attack, stroke or other major complications 12 months after treatment. George Andrew Stouffer, III, MD, FAHA, chief of cardiology and codirector of the McAllister Heart Institute at UNC, said, “We are using CYP2C19 genetic testing on a daily basis at our institution to help decide in a timely manner which drug to prescribe.” The study was published on April 3, 2018, in the journal Circulation: Genomic and Precision Medicine.

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Smartphone Microscopes Transformed into Lab Devices obile phones have facilitated the creation of field-portable, costeffective imaging and sensing technologies that approach laboratory-grade instrument performance. However, the optical imaging interfaces of mobile phones are not designed for microscopy and produce distortions in imaging microscopic specimens. It has recently been demonstrated that deep learning, a powerful form of artificial intelligence, can discern and enhance microscopic details in photos taken by smartphones. The technique improves the resolution and color details of smartphone images so much that they approach the quality of images from laboratory-grade microscopes. Bioengineers at the Samueli School of Engineering, University of California (Los Angeles, CA; USA; https://samueli.ucla.edu) photographed images of lung tissue samples, blood and Papanicolaou smears, first using a standard laboratory-grade microscope, and then with a smartphone with the 3D-printed microscope attachment. The scientists then fed the pairs of corresponding images into a computer system that “learns” how to rapidly enhance the mobile phone images. The process relies on a deep-learning-based computer code, which they had developed. The use of deep learning to correct such distortions introduced by mobile-phone-based microscopes, facilitating the production of high-resolution, denoised, and color-corrected images, matching the performance of benchtop microscopes with high-end objective lenses, also extending their limited depth of field. After training a convolutional neural network, they successfully imaged various samples, including human tissue sections and Papanicolaou and blood smears, where the recorded images were highly compressed to ease storage and transmission. The technique uses attachments that can be inexpensively produced with a

3D printer, at less than USD100 a piece, versus the thousands of dollars it would cost to buy laboratory-grade equipment that produces images of similar quality. Aydogan Ozcan, PhD, a Professor of Electrical and Computer Engineering and Bioengineering, said, “Using deep learning, we set out to bridge the gap in image quality between inexpensive mobile phonebased microscopes and gold-standard bench-top microscopes that use high-end lenses. We believe that our approach is broadly applicable to other low-cost microscopy systems that use, for example, inexpensive lenses or cameras, and could facilitate the replacement of high-end bench-top microscopes with cost-effective, mobile alternatives.” The study was published online on March 15, 2018, in the journal ACS Photonics. Image: The 3D-printed devices can capture microscopic images, when attached to a smartphone camera lens (Photo courtesy of Ozcan Research Group/UCLA).

Genetic Variant Identified As Better Marker for CV Disease newly identified subset of a known genetic variant found primarily in individuals of South Asian descent may be a better marker for carriers of heart dysfunction in this population and that individuals with this genetic variant are more likely to develop early signs of hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy occurs when heart muscle cells enlarge and cause the walls of the ventricles to thicken. The ventricle size often remains normal, but the thickening may block blood flow out of the ventricle and cause the heart to work harder. Hypertrophic cardiomyopathy, also commonly referred to as enlarged heart, can lead to sudden cardiac arrest. An international team of scientists collaborating with the University of Cincinnati (Cincinnati, OH, USA; www.uc.edu) screened 2,401 South Asians living in the USA for the genetic variant of myosin-binding protein C, cardiac-type (MYBPC3 25bp). In this genotype-phenotype study, individuals of South Asian descent living in the USA from both sexes (36.23% female) with a mean population age of 48.92 years (range, 18-84 years) were recruited. Next-generation sequencing of 174 cardiovascular disease genes was applied to identify additional modifying gene mutations and correlate genotype-phenotype parameters. Cardiomyocytes derived from human-induced pluripotent stem cells were established and examined to assess the role of MYBPC3 25bp. The investigators found that 6%, or 144 individuals, carried the genetic variant. Of that population, 9.6% or 13 individuals also carried the novel MYBPC3 variant D389V on the same single allele. Scientists think the prevalence of both the variant and subset occurring in the population of people of South Asian descent to be 1 in 200 individuals. A higher frequency of missense titin (TTN) variation was found in MYBPC3 25bp carriers compared with noncarriers, identifying distinct genetic backgrounds within the MYBPC3 25bp carrier group. The study was published on April 11, 2018, in the journal JAMA Cardiology.

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PRODUCT NEWS URINE CHEMISTRY ANALYZER

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Antihypertensive Agents Reduce Heart Biomarkers Levels igh blood pressure (BP) is associated with an increased rate of cardiovascular events and mortality. Cardiovascular biomarkers are able to predict longterm risk in the general population, particularly in diseased cohorts. Two different antihypertensive regimens had the effect of lowering blood pressure levels in patients while reducing both cardiac troponin levels measured by a high-sensitivity assay (hs-cTn) and B-type natriuretic peptide (BNP) concentrations. Scientists at University Heart Center Hamburg (Hamburg, Germany; www.uke. de) randomized into two cohorts of hypertensive patients at one healthcare center. In one group, 251 individuals received 80 mg telmisartan and 5 mg amlodipine, while in the other, 230 received 40 mg olmesartan and 12.5 mg hydrochlorothiazide. Patients prior to randomization and after six months had measurements of their blood pressure,

hs-cTn I and T, BNP, and N-terminal-pro-BNP (NT-proBNP). Various assays from Roche (Basel, Switzerland; www.roche.com) and Abbott Laboratories (Abbott Park, IL, USA; www.abbott.com) were used to measure the cardiovascular biomarkers. The team reported that hs-cTnI concentrations declined markedly in both study groups and in the overall population dropped from 4.6 ng/L to 4.2 ng/L. In a subgroup analysis, the investigators discovered that male patients experienced a much higher reduction in hs-cTnI concentrations than their female counterparts. By comparison, hs-cTnTâ&#x20AC;&#x2122;s measurability was just 26.2% in the overall study population. Concentrations for this biomarker did not change after the intervention. BNP and NT-proBNP concentrations also were reduced after six months: from 15.0 ng/L to 12.4 ng/L and from 64.8 ng/L to 53.3 ng/L, respectively. The authors concluded that they had de-

termined that reducing blood pressure in patients led to a reduction in hs-cTnI, BNP, and NT-proBNP concentrations after half a yearâ&#x20AC;&#x2122;s treatment with antihypertensive therapies. This effect was stronger when the combination of an angiotensin-receptor blocker with a calcium-channel blocker was used as compared to an angiotensin-receptor blocker and a diuretic. The study was published in the December 2017 issue of the journal Clinical Chemistry. Image: The Troponin T hs assay kit improves the detection and exclusion of myocardial injury in the early stages (Photo courtesy of Roche Diagnostics).

Loss of Myosin Prognostic for Colorectal Cancer Recurrence oss of the protein Myosin Vb in colorectal cancer (CRC) patients has been identified as a strong prognostic factor for recurrence of the disease. Early detection and classification of CRC is of great importance, since not all Stage II patients benefit from chemotherapy. There are few known prognostic markers for CRC so that many patients suffer needlessly from side effects of the chemotherapy without having real benefits. Members of the Myosin family, proteins recognized to have a major role in trafficking and polarization of cells, have recently been reported to be closely associated with several types of cancer and might thus serve as potential prognostic markers in the context of CRC. Myosin V is an unconventional myosin motor, which translocates along actin filaments traveling towards the barbed end of the filaments. Myosin V is involved in the transport of cargo (e.g. RNA, vesicles, organelles, mitochondria) from the center of the cell to the periphery, but has been furthermore shown to act like a dynamic tether, retaining vesicles and organelles in the actin-rich periphery of cells. Investigators at the University of Luxembourg (Belvaux;

www.uni.lu) used a previously established meta-analysis of publicly available gene expression data to analyze the expression of different members of the Myosin V family, namely MYO5A, 5B, and 5C, in CRC. Using laser-microdissected material as well as tissue microarrays from paired human CRC samples, they validated both RNA and protein expression of Myosin Vb (MYO5B) and its known adapter proteins (RAB8A and RAB25) in an independent patient cohort. Finally, they assessed the prognostic value of both MYO5B and its adapter-coupled combinatorial gene expression signatures. Results revealed methylation-independent loss of MYO5B expression in CRC that matched disease progression. Significantly, CRC patients with low MYO5B expression displayed shorter overall, disease-, and metastasis-free survival, a trend that was further reinforced when RAB8A expression was also taken into account. These findings identified MYO5B as a powerful prognostic biomarker in CRC, especially in early stages (stages I and II), which could help stratifying patients with stage II for adjuvant chemotherapy. LabMedica International June-July/2018

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Lipidome Tested as Predictor in T2DM Progression ype 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by hyperglycemia, which results from impaired insulin secretion of pancreatic -cells and from ineffective cellular response to insulin. Prediabetes is currently characterized, once glucose has become elevated, by impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or both. IFG and IGT are not equivalent by metabolic terms and, most likely, reflect different pathophysiological states leading to T2DM. Scientists at the Steno Diabetes Center Copenhagen (Denmark; www.sdcc.dk) and their colleagues applied global lipidomic profiling on plasma samples from well-phenotyped men (107 cases, 216 controls) participating in a longitudinal study at baseline and at five-year follow-up. To validate the lipid markers, an additional study with a representative sample of 631 adult males was also conducted. A total of 277 plasma lipids were analyzed using the lipidomics platform based on ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. Lipid extracts were then analyzed on the Q-Tof Premier mass spectrometer with the Acquity ultra performance liquid chromatography (UPLC) (Waters, Inc., Milford, MA, USA; www.waters.com). Lipids with the highest predictive power for the development of T2DM were computationally selected, validated and compared to standard risk models without lipids. Glucose tolerance status was assessed on plasma glucose levels in OGTT and HbA1c measurements. The investigators found that a persistent lipid signature with higher levels of triacylglycerols and diacyl-phospholipids as well as lower levels of alkylacyl phosphatidylcholines was observed in progressors to T2DM. Lysophos-

phatidylcholine acyl C18:2 (LysoPC(18:2)), phosphatidylcholines PC(32:1), PC(34:2e) and PC(36:1), and triacylglycerol TG(17:1/18:1/18:2) were selected to the full model that included metabolic risk factors. When further adjusting for body mass index (BMI) and age, these lipids had respective odds ratios of 0.32, 2.4, 0.50, 2.2 and 0.31 for progression to T2DM. The authors concluded that their study indicates that a lipid signature characteristic of T2DM is present years before the diagnosis and improves prediction of progression to T2DM. Molecular lipid biomarkers were shown to have predictive power also in a high-risk group, where standard risk factors are not helpful at distinguishing progressors from non-progressors. The study was published in the January 2018 issue of the journal Metabolism Clinical and Experimental. Image: The ACQUITY UPLC I-Class / Xevo TQ-S IVD system (Photo courtesy of Waters).

Caffeine Levels Prove Diagnostic for Early Parkinson’s team of Japanese researchers demonstrated that serum caffeine and its metabolites were reliable biomarkers for detection of early Parkinson’s disease (PD). A 2013 paper evaluated a total of 13 articles involving 901,764 participants for coffee, eight articles involving 344,895 participants for tea, and seven articles involving 492,724 participants for caffeine. Results revealed a linear dose-relationship for decreased PD risk with tea and caffeine consumption, whereas the strength of protection reached a maximum at approximately three cups/day for coffee consumption overall. Based on the established link between PD and caffeine, investigators at Juntendo University School of Medicine (Tokyo, Japan; www.juntendo. ac.jp) conducted a study on 108 people who had Parkinson’s disease for an average of about six years and 31 people of the same age who did

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not have the disease. Liquid chromatography–mass spectrometry was used to determine serum levels of caffeine and of 11 byproducts the body makes as it metabolizes caffeine. Participants were also tested for mutations in genes that can affect caffeine metabolism. Results revealed that Parkinson’s disease patients had significantly lower blood levels of caffeine and nine of the 11 caffeine byproducts. The caffeine level was an average of 79 picomoles per 10 microliters for people without Parkinson’s disease, compared to 24 picomoles per 10 microliters for patients. Measurement of caffeine correctly identified patients with early PD with 98% accuracy. No differences were found in the activity of caffeine-related genes between the two groups. The caffeine study was published in the January 3, 2018, online edition of the journal Neurology.

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Molecular Test Adapted for Parkinson’s and Lewy Body Dementia arkinson’s disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB) (or Lewy body dementia) are called α-synucleinopathies due to the abnormal accumulation of aggregates of a protein called α-synuclein (αSyn) in the brain. Many neurodegenerative diseases are related to the accumulation of specific misfolded proteins. These deposits are identified upon postmortem analysis of brain tissue, allowing definite diagnoses to be made based on specific neuropathological and molecular findings. A team of scientists led by those at the National Institutes of Health (Hamilton, MT, USA; www.niaid.nih.gov) tested 60 cerebral spinal fluid (CSF) samples, including 12 from people with Parkinson’s disease, 17 from people with dementia with Lewy bodies, and 31 controls, including 16 of whom had Alzheimer’s disease. A sample was sent for analysis of cell count, total protein and glucose to a local laboratory. Autopsy brain analysis was performed with formalin-fixed left hemibrain is serially sectioned in 1 cm slices and tissue blocks and processed for histopathological examination by H&E, and Thioflavin-S (Thio-S) to detect tau and -amyloid deposits. Lewy body pathology is evaluated using phosphorylated α-synuclein immunoreactivity with a mouse monoclonal antibody. The team used an improved αsynuclein real time quaking-induced conversion ( Syn RT-QuIC) assay that has similar sensitivity and specificity to prior assays, but can be performed in 1 to 2 days with quantitation. RT-QuIC reactions were performed in black 96well plates with a clear bottom. After processing the plates were then sealed with a plate sealer film (Nalgene Nunc International, Rochester, NY, USA; www.nalgene.com) and incubated at 42 °C in a BMG FLUOstar Omega plate reader (BMG Labtech, Ortenberg. Germany; www.bmglabtech. com) with cycles of 1 minute shaking (400 rpm double orbital) and 1 minute rest throughout the indicated incubation time. VISIT US AT: Blinded analysis of cerebrospinal fluid from 29 synucleinopathy cases 2018 (12 Parkinson’s and 17 dementia ANNUAL MEETING with Lewy bodies) and 31 non-synuBooth: 623 cleinopathy controls, including 16 Alzheimer’s cases, yielded 93% diagnostic sensitivity and 100% specificity for this test so far. End-point dilution analyses allowed quantitation of relative amounts of pathogenic disease-associated forms of α-synuclein ( SynD) seeding activity in cerebrospinal fluid samples, and detection in as little as 0.2 L. These results confirm that SynD seeding activity is present in cerebrospinal fluid. The team also demonstrated that it can be rapidly detected, and quantitated, even in early symptomatic stages of synucleinopathy. The study was published on February 9, 2018, in the journal Acta Neuropathologica Communications.

Image: The FLUOstar Omega multimode microplate reader with six detection modes (Photo courtesy of BMG Labtech).

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Immune Response Tests Enable Rapid Antibiotic Decisions novel test uses quantitative multiplex gene expression to analyze a patient’s immune system, or the host response, rather than looking for the presence of a pathogen that indicates whether there is an infection in the blood. The assays run on a molecular, multiplex platform, read patterns of gene expression from white blood cells as an indicator of the immune system’s response to infection. The multigene sepsis diagnostic panel would be able to tell from a blood sample whether a hospitalized patient has a bacterial, viral, or no infection so that physicians would be able to administer more appropriate treatments earlier. The HostDx Sepsis test (Inflammatix, Burlingame, CA, USA; (https://inflammatix.com) has been validated in 20 cohorts of 1,057 patients. It has also demonstrated its performance in five cohorts of 189 patients diagnosed with sepsis at the time of hospital admission and four cohorts of 282 patients with hospital-acquired sepsis. In developing its tests, Inflammatix analyzes microarray and RNA-sequencing data that reside in public and private databases and that are derived from several patient cohorts around the world. Its data science team observes patterns or fingerprints of gene expression across different cohorts. For its fever assay, the firm has reported 94% sensitivity and 76% specificity for bacterial infection. For its sepsis assay, it has reported 94% sensitivity for bacterial infection, 91% specificity for viral infection, and 95% sensitivity for 30-day mortality related to sepsis. While diagnosing infections, clinicians frequently use blood culture testing to find pathogens, which can take up to 72 hours to get a positive test result, compared to one hour with HostDx.

Timothy E. Sweeney, MD, CEO and founder of Inflammatix, said, “Inflammatix has developed a method that is broadly applicable and gives us the ability to not only discover the best gene sets for specific applications, but also the best algorithms that sit on top of those gene sets to make sure that the diagnostic tools are accurate. The firm has prospectively validated eight sets of genes for different clinical applications. By reading the immune response, you can tell whether a bacterial or viral infection is causing a patient’s symptoms, and fundamentally that’s what a physician needs to know up front.” Image: The diagnostic accuracy of the HostDx Sepsis assay compared to other methods (Photo courtesy of Inflammatix).

Residual Disease in Leukemia Patients Identified by ddPCR urrently, minimal residual disease for chronic myeloid leukemia (CML) patients is typically monitored using real-time quantitative polymerase chain reaction (RT-qPCR), but often leukemic stem cells with the BCR-ABL1 rearrangement are present below the limit of detect of RT-qPCR. While DNA-based approaches have previously been shown to be more sensitive identifying the breakpoint of the BCR-ABL1 rearrangement can be challenging because it is highly repetitive. In addition, many diagnostic laboratories do not have next-generation sequencing

capabilities. Nanopore sequencing in combination with droplet digital PCR can be used to identify minimal residual disease in some leukemia patients. Scientists at the University of Bari, (Bari, Italy; www.uniba.it) included 10 patients with CML in their study. The team designed amplicons to span the BCR-ABL1 junction for 10 patients and then barcoded and sequenced them on the MinION, a portable real-time device for DNA and RNA sequencing (Oxford Nanopore Technologies, Oxford Science Park, UK; http://nanoporetech.com). Sequencing took

around 24 hours and generated more than 21,000 reads. Average sequencing depth was 400× and the error rate around 8%. For all 10 patients, MinIon sequencing was able to identify the breakpoint and was concordant with Sanger sequencing. Next, the team used ddPCR to quantify the number of cells that contained the rearrangement. For each patient, they designed a personalized assay based on the sequence of the BCRABL1 region. At diagnosis, a median of 87% of the patients’ cells contained the rearrangement. Chia-Lin Wei, PhD, director of genome technologies at the Jackson Laboratory (Farmington, CT, USA; www.jax.org), said, “The study demonstrated a very suitable application for nanopore sequencing. Although the MinION does not yet have the accuracy to evaluate somatic point mutations in a diagnostic setting, sequencing through translocations is a very ideal type of data for the system. The MinIon’s long reads are particularly valuable since they enable the entire region to be sequenced through in one read, which is important because breakpoint location can vary patient to patient.” The study was published on January 5, 2018, in the journal Oncotarget. Image: The MinION is the only portable realtime device for DNA and RNA sequencing (Photo courtesy of Oxford Nanopore Technologies).

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LabMedica International

Comprehensive Metabolic Profiling Assessed for Chronic Inflammation nflammation is a corporeal response to damaging stimuli associated with the activation of various molecular mechanisms. Both the local and systemic responses initiated by an inflammatory process indicate an imbalance in metabolism in the tissues affected. Inflammation occurs as an immediate protective response of the immune system to a harmful stimulus, whether locally confined or systemic. In contrast, a persisting chronic, inflammatory state, even at a low-grade, is a well-known risk factor in the development of common diseases like diabetes or atherosclerosis. Scientists at the University Medicine Greifswald (Greifswald, Germany; www.uni-greifswald.de) assessed the metabolic patterns associated with alterations in inflammatory markers. Based on mass spectrometry and nuclear magnetic resonance spectroscopy they determined a comprehensive panel of 613 plasma and 587 urine metabolites among 925 apparently healthy individuals. Associations between inflammatory markers, namely high-sensitivity Creactive protein (hsCRP), white blood cell counts (WBC), and fibrinogen, and metabolite levels were tested by linear regression analyses controlling for common confounders. Fibrinogen concentrations were determined in citrate plasma samples, using a BCS-XP system (Siemens Healthineers, Tarrytown, NY; www.healthcare.siemens.com). WBC concentration was determined in EDTA whole blood samples using the Sysmex XT 2000, XE 5000, or SE9000 analyzers (Sysmex Corporation, Kobe, Japan; www.sysmex. com) or the Siemens Healthcare Diagnostics Advia 2120i. Targeted metabolomics profiling of the plasma samples was performed using the AbsoluteIDQ p180 Kit (BIOCRATES LifeSciences AG, Innsbruck, Austria; www.biocrates.com). This approach allows simultaneous absolute quantification of 188 metabolites using a combination of liquid chromatography (Agilent 1260 Infinity Binary LC, Santa Clara, CA, VISIT US AT: USA; www.agilent.com) and mass spectrometry (AB SCIEX 5500 QTrap mass spectrometer; AB SCI2018 EX, Darmstadt, Germany; https:// ANNUAL MEETING sciex.com). Urine samples were Booth: 4041 measured on a Bruker DRX-400 NMR Spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany; www.bruker. com). The team found that HsCRP, WBC, and fibrinogen were significantly associated with 71, 20, and 19 plasma and 22, 3, and 16 urine metabolites, respectively. Identified metabolites were related to the bradykinin system, involved in oxidative stress (e.g., glutamine or pipecolate) or linked to the urea cycle (e.g., ornithine or citrulline). In

LabMedica International June-July/2018

particular, urine 3’-sialyllactose was found as a novel metabolite related to inflammation. Prediction of an advanced inflammatory state based solely on 10 metabolites was completely feasible. The study was published on November 30, 2017, in the journal BMC Medicine. Image: The BCS XP System, one of the most widely used fully automated hemostasis analyzers (Photo courtesy of Siemens Healthineers).

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PRODUCT NEWS IMMUNOASSAY TEST

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CHEMISTRY ANALYZER

ASSAY TEST KIT

Denka Seiken

Erba Mannheim

Maccura Biotechology

The CysC-Latex is for the accurate measurement of Cystatin C in blood and can be used in various chemistry analyzers. It uses latex particles coated with anti-human Cystatin C, which form a complex with the Cystatin C present in a blood sample.

The XL 180 features a compact bench top design with a wide test menu. It offers reagent savings and comes with features such as auto dilution and auto rerun, and Levey Jennings program and QC rules.

The Thrombin Time kit can remain stable for 12 months when stored at the required temperature in airtight conditions. Also depending on temperature, the reagent can be stable after re-dissolved for seven days, for 24 hours or for one hour.

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Exhaled Nitrous Oxide Adjunct Test Diagnoses Asthma lthough about 24 million Americans are diagnosed with asthma every year, there is no single test that can diagnose the disease and common symptoms, such as shortness of breath, wheezing, and cough, are relatively nonspecific. Various tests, including bronchodilator response and positive results on bronchial challenge, may be used by clinicians to aid in the diagnosis of asthma in the appropriate clinical context, but no single criterion standard diagnostic test exists. More recently, fractional exhaled nitric oxide (FeNO) concentration has been added to the list of tests that clinicians may use to diagnose asthma. A team of scientists from the Mayo Clinic (Rochester, MN, USA; www.mayoclinic.org) conducted a comprehensive literature search of six databases. The search included randomized clinical trials and observational studies that (1) enrolled patients aged five years and older with suspected asthma, (2) compared FeNO testing (diagnostic test) to standard diagnostic testing of asthma by health care professionals based on history, clinical course, or other diagnostic tests (clinical diagnosis, bronchodilator response, and positive results on bronchial challenge) (reference test), and (3) reported FeNO diagnostic accuracy. The team included 43 studies with a total of 13,747 patients. In adults, using FeNO cutoffs of less than 20, 20 to 29, 30 to 39, and 40 or more parts per billion (ppb), FeNO testing had sensitivities of 0.80, 0.69, 0.53, and 0.41, respectively, and specificities of 0.64, 0.78, 0.85,

and 0.93, respectively. In children, using FeNO cutoffs of less than 20 and 20 to 29 ppb, FeNO testing had sensitivities of 0.78 and 0.61, respectively, and specificities of 0.79 and 0.89, respectively. Depending on the FeNO cutoff, the posttest odds of having asthma with a positive FeNO test result increased by 2.80-fold to 7.00-fold. Diagnostic accuracy was modestly better in corticosteroid-naive asthmatics, children, and nonsmokers than in the overall population. M. Hassan Murad, MD, MPH, the lead investigator of the study, said, “Asthma can sometimes be difficult to diagnose, and FeNO can be helpful to make therapeutic decisions more evidence based. In addition to a patient’s history, the initial test is usually spirometry with an assessment of bronchodilator response.” The study was published on December 20, 2017, in the journal Mayo Clinic Proceedings. Image: The fractional exhaled nitric oxide (FeNO) concentration test is a quick and simple test and a valuable tool to assist in the diagnosis of asthma (Photo courtesy of Talkhealth Partnership).

Cancerous Tissue Analysis Introduced Using On-Chip Technology novel gene expression analysis technique has been introduced that can accurately measure levels of RNA quickly and directly from a cancerous tissue sample while preserving the spatial information across the tissue. The new technique performs on-chip picoliter real-time reverse transcriptase loop mediated isothermal amplification (RT-LAMP) reactions on a histological tissue section without any analyte purification while preserving the native spatial location of the nucleic acid molecules. LAMP is an isothermal nucleic acid amplification technique, which in contrast to polymerase chain reaction (PCR) technology in which the reaction is carried out with a series of alternating temperature steps or cycles, is carried out at a constant temperature and does not require a thermal cycler. In LAMP, the target sequence is amplified at a constant temperature of 60–65 degrees Celsius using either two or three sets of primers and a polymerase with high strand displacement activity in addition to a replication activity. An additional pair of “loop primers” can

further accelerate the reaction. Due to the specific nature of the action of these primers, the amount of DNA produced in LAMP is considerably higher than PCR based amplification. The new technique developed through collaboration between the University of Illinois (Champaign-Urbana, USA; www.illinois.edu) and the Mayo Clinic (Rochester, MN, USA; www.mayoclinic.org) is conducted on a fingernail-size silicon chip that contains an array of more than 5,000 pyramid-shaped wells with razor-sharp edges. When a centimeter-sized cancer tissue sample is placed on the chip it is automatically cut up into hundreds or thousands of tiny pieces (in a two minute process called “tissue pixelation”). This step is followed by tissue fixation (10 minutes), permeabilization (30 minutes), loading of wells with amplification reagents (two minutes), and finally on-chip picoliter RTLAMP reaction on a hot plate (45 minutes). Details of the new technique were published in the January 15, 2018, online edition of the journal Nature Communications. LabMedica International June-July/2018

International Federation of Clinical Chemistry and Laboratory Medicine

2017 ANNUAL REPORT HIGHLIGHTS OF THE YEAR EuroMedLab Congress, Athens, Greece – June 2017 (http://euromedlab.org) WorldLab Congress, Durban, South Africa – October 2017 (http://durban2017.org) 23rd Congreso Latinoamericano de Bioquímica Clínica COLABIOCLI Congress, Punta del Este, Uruguay – September 2017 (http://www.colabiocli2017uy.com/index.html) IFCC VLP Program (www.ifcc.org/ifcc-education-division/emd-special-projects) IFCC Speakers Bureau (www.ifcc.org/ifcc-education-division/speaker-s-bureau) Roche/IFCC Travel Scholarship

IFCC Travel Scholarships WorldLab Durban Webinars and Distance Learning Modules (www.ifcc.org/ifcc-education-division/webinars/ifcc-webinars) e-Academy, Open Educational Resources (http://eacademy.ifcc.org) IFCC Expert Database (www.ifcc.org/ifcc-education-division/experts) IFCC FEN – Foundation for Emerging Nations (www.ifccfoundation.org) Implement Cooperation and Agreements with IFCC Regional Federations

PRESIDENT’S MESSAGE

by Maurizio Ferrari, IFCC President

he IFCC represents clinical chemistry and laboratory medicine organizations throughout the world, and brings together that vast combined knowledge and experience to address the important challenges that face our profession. 2017 marked the last year of my three year term as President of the IFCC, and it was a unique privilege and an honor to lead such a vital and progressive organization. There were a number of significant achievements in 2017, as a result of the efforts of the Divisions, Committees, Working Groups and Task Forces made up of volunteers from our member organizations. These achievements are summarized in the various reports from the functional groups below. My thanks to all of these groups and their volunteers

for the excellent work they have done. It is the responsibility of the Executive Board, reporting to the IFCC Council, to ensure that the functional groups have the direction, resources and support to operate as efficiently and effectively as possible. I am extremely thankful for the excellent work that the EB has done over my term as President. My sincere thanks also to the member organizations: full, associate and corporate members, for their continued support of the IFCC and for the individuals that they nominate to the IFCC functional groups. I wish to thank the Head Office Staff, Paola Bramati, Silvia Cardinale and Silvia Colli Lanzi for their dedicated efforts in managing the day to day business of the IFCC, and for their personal assistance to me as President. Finally, my very best wishes for continued success go to the new EB, the first under the new format with representation from the Federations. I look forward to my participation as Past-President.

EXECUTIVE BOARD (EB)

TREASURER’S REPORT

The Executive Board held three meetings during 2017. The first meeting was held in Milan on February 24-25; the second EB meeting was held in Athens in connection with the EuroMedLab Congress on June 9-10; the third EB meeting was held in Durban in connection with the WorldLab Congress on October 20-21. The 23rd Meeting of the IFCC Council was held in Durban, with a good attendance. A general discussion ensued with a focus on the future of Laboratory Medicine and the role of IFCC in managing the incoming challenges. The National Representatives agreed that technological advances have led to integrated diagnostics while increasing use of Informatics and Management of Knowledge will be required to optimize the patient diagnostic pathway. In the near future IFCC will face significant threats including: restricted financial resources due to financial pressures on national society and corporate members including the discontinuation of direct sponsorship of congress delegates and speakers by the IVD industry, the aging of the IFCC workforce and need to establish relevance to Young Scientists, and challenges to retaining our current status with global clinical organizations. It was suggested that IFCC should seek closer collaboration with clinical societies, organizations involved in guideline development, and regulators, to increase the influence of the federation on guidelines, at the same time avoiding duplication and inconsistency. During 2017 new full members joined IFCC: the “Kosovo Association of Clinical Chemistry (KACC)”, the new Russian Full Member Society ”Federation of Laboratory Medicine (FLM)” replacing the previous member “Russian Scientifically-Practical Society of Specialists in Laboratory Medicine (RSPSSLM)”; the “Association of Clinical Chemistry and Laboratory Medicine of Ukraine (ACCLMU)” formed by merging the “Ukrainian Society of Clinical Laboratory Diagnostics (USCLD)” and the Affiliate Member “Association of Clinical Chemistry and Laboratory Medicine of Ukraine (ACCLMU)”; the “Belarus Society of Clinical Laboratory Diagnosticians”, the “Colegio Nacional de Laboratoristas Clínicos de Panamá” and the “Palestine Medical Technology Association-PMTA” In addition, the "Lab Medicine Committee, branch of China Association of Medical Equipment”, the ”Association for Quality Assurance of Laboratory Medicine – AQALM” and the “Egyptian Association of Healthcare Quality and Patient Safety” joined as Affiliate Members. The EB decided that the EuroMedLab 2021 will be held in Munich and that the WorldLab/EuroMedLab 2023 will be held in Rome. A letter was sent to National Societies Full and Affiliate members requesting their annual report. More than forty reports were received to be included in the IFCC Annual report for 2017 which is available on the IFCC Website (www.ifcc.org). Finally 2017 has been the last year of my 2nd term as Secretary of the IFCC and I’d like to thank all the IFCC officers and friends me serve six extraordinary years as IFCC Secretary. It has been a great opportunity for my professional growth in Laboratory Medicine as well as the chance to meet and make new friends from different countries and cultures. Thanks to the members of the EBs 2012-2014 and 20152017 for their support and friendship, thanks to the staff of Emmezeta-MZ Congressi in Milan (Paola Bramati, Silvia Cardinale and Silvia-Colli-Lanzi). Sergio Bernardini, Executive Board Secretary

During the third year of my term as the IFCC treasurer, with the valuable help and assistance of the IFCC office, the annual dues of Full, Affiliate and Corporate Members were received, the adherence of IFCC operating units to their allocated budgets was monitored and detailed records of all transactions were kept, reimbursements were processed within two days after the receipt of the claims from the IFCC office. Close collaboration was achieved with the IFCC investment bank (Credit Suisse) to optimise the financial return on IFCC investments. The annual accounts and financial actions were reviewed by an external independent auditor in order to finalize the actual income and expenses as of 31st December 2017.

COMPARISON OF 2017 PROPOSED BUDGET WITH ACTUALS AT DECEMBER 31, 2017: IFCC NET INCOME. The 2017 budget was expected to be closed with a deficit of CHF -725.655. Instead, it was closed with a positive balance of CHF 478.624 (Fig. 1).

Figure 1. 2017 proposed budget versus actual as of 31st December 2017 IFCC MEMBERSHIP DUES: Table 2 below shows the major income of IFCC from the annual dues of Full, Affiliate and Corporate Members collected during 2017 (Fig. 2). Thanks to all the member Societies and Corporate members that supported the IFCC throughout the past years. Their continuous contribution has made possible the accomplishment of numerous IFCC tasks and projects. IFCC is grateful to the IVD industry for their support and active participation in the IFCC scientific events. We also thank the members for their loyalty and attention in paying dues at the start of the year, which helps the cash flow.

Figure 2. IFCC membership dues collected in 2017 IFCC MEETINGS INCOME PARTITION: IFCC meetings’ revenues are not a regular yearly income. The average yearly income arising from the meetings can be calculated by dividing the total revenue by the frequency of the event. The yearly income of IFCC from the recent meetings (EuroMedLab2017 Athens and WorldLab 2017 Durban) calculated per year is indicated below (Fig. 3).

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2017 Annual Report

Figure 3. IFCC annual meetings income from EML Athens and WL Durban. The income of IFCC from the membership dues and annual meetings income (excluding sponsorships and other revenues) in 2017: CHF 527.175 (dues) + CHF 346.798 (annual meeting income) = CHF 873.973

IFCC

IFCC INVESTMENT AT LGT IN 2017 Due to the high investment charges, IFCC EB decided to move its investment from LGT Bank to Credit Suisse. The transfer of the securities from LGT to Credit Suisse was completed on January 12, 2017 (35 assets). The important features of the agreement with Credit Suisse are outlined as below: • Investment strategy: Income oriented • Risk Profile: Moderate • Risk Budget: Moderate • Reporting currency: CHF (with investments in three currencies: CHF, EUR, USD) • Ticket fee model: 0.20% for the safekeeping fee (no investment fee, only 0.20% p.a. for the safekeeping fee when invested in CS Portfolios). Plus brokerage fees. Remuneration will be given to IFCC for the transactions.

TOTAL OPERATIONAL REVENUES AND FINANCIAL INCOME. The actual total operational revenues and financial income were CHF2 027.641(Fig. 4).

Figure 4. Income as of 31st December 2017: CHF 2,027.641. SPONSORSHIP Divisions and some Functional Units raise sponsorship funds which give them a certain flexibility in conducting projects. These sponsorship funds are used only for specific projects. The unspent sponsorship funds are carried over to the next years. The total amount of sponsorships available for specific projects as of 31 December 2017 to be carried to 2018 is CHF 423.931. TOTAL OPERATIONAL COSTS AND FINANCIAL CHARGES The actual total operational costs and financial charges in 2017 were CHF 1.549.017 (Fig.5).

Figure 5. IFCC General Expenses – Actual as of 31 December 2017

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Tomris Ozben, Treasurer

IFCC

2017 Annual Report CORPORATE MEMBERS

Rolf Hinzmann, MD, PhD (Roche), Corporate Representative at IFCC Executive Board (2nd term 2018-2020) In 2017, a new Corporate Representative was elected to represent the Corporate Members at IFCC's Executive Board. Slightly more than half of the Corporate Members participated in the election, and I received 80% of their votes. I would like to thank the Corporate Members for re-electing me for a second term. I feel honored by the trust and confidence in me and I will continue to foster collaboration between IFCC and its Corporates Members for mutual benefit. The Corporate Members make several important contributions to IFCC activities: Numerous delegates from Corporate Members are actively engaged in most of the scientific workgroups in all of IFCC's divisions and in their Executive Committees, either as full members or as corresponding members, as well as in the Congresses & Conferences Committee. By the end of 2017, the total number of IFCC's Corporate Members was 43, providing the IFCC with annual fees of CHF 340,000 which was approximately 65 % of IFCC's total direct annual income from its members (which comprise National Societies and Affiliate Member Societies as well). In addition, Corporate Members continued sponsoring IFCC conferences, workgroups, scientific awards, e-learning programs and travel scholarships. In return, IFCC provides value to its Corporate Members by: • emphasizing the importance of quality and providing expertise in standardization, • providing opportunities for exhibitions, industry symposia and networking with lab professionals during high-level academic conferences, • conducting educational programs, in particular in countries and regions with limited resources. In 2017 the IFCC was pleased to welcome Beijing Dream Diagnostic Medicine as a new Corporate Member and Hemas Hospitals Sri Lanka joined at the beginning of 2018. Regrettably seven companies left IFCC in 2017: Response Biomedical, Sonic Healthcare Europe, Philips, Axis Shield, Unilabs, Elga Labwater and Instrumentation Laboratory. During the past years we have made progress with regard to strengthening the role of Corporate Members within IFCC. However, the decline in membership poses a challenge for IFCC to further enhance the value of IFCC for its Corporate Members, e.g. by • better serving the needs of the Corporate Members instead of regarding Corporate Members mainly as a source of income, • making it easier for employees of Corporate Members to actively participate in IFCC working groups and committees (and not only as corresponding members), • collaborating better with clinical societies to harmonize guidelines and support medical claims leading to reimbursement for lab tests, • aligning stronger with others (CLSI, FDA, clinical societies, etc.) to avoid inconsistency and duplication of regulatory guidelines and recommendations, • complying with the "MedTech Europe Code of Ethical Business Practice" and other codes to avoid that Corporate Members face challenges when sponsoring and exhibiting at congresses, • pursuing the opportunities of data analytics in laboratory diagnostics. For most of these topics, first steps have been taken and first results have been achieved. However, all of these requirements of Corporate Members need to receive more emphasis in the future. The last item will be a major task to be pursued by a new division within IFCC which is called the Emerging Technologies Division. Please find below some helpful contact information: The following Corporate Representatives were / are members of the Executive Committees of three of the IFCC's divisions and the Congresses & Conferences Committee: • Scientific Division: James Pierson-Perry (Siemens) (1st term 2015-2017, 2nd term 2018-2020), • Emerging Technologies Division: This newly established division will have two Corporate Representatives: Peng Yin (Abbott) (1st term 2018-2010) and Markus Roessler (Roche) (1st term 2018-2020), • Education & Management Division: André Ziegler (Roche) (1st term 2017-2019), • Communications & Publications Division: Peter Bialk (Roche) (1st term 20172019), • Congresses & Conferences Committee: Peng Yin (Abbott) (2nd term 20152017), Cheryl Jackson (Beckman Coulter) (1st term 2018-2020). The following persons were / are Corporate Members of the respective Congress Organizing Committees (COCs): • IFCC / EuroMedLab 2017, Athens, Greece: Angelos Evangelopoulos (Roche) and Thomas Brinkmann (Sonic Healthcare). • IFCC / WorldLab 2017, Durban, South Africa: Beth Slavic (Ortho Clinical Diagnostics) • IFCC / EuroMedLab 2019, Barcelona, Spain: Jaime Vives (Roche) • IFCC / WorldLab 2020, Seoul, South Korea: Douglas Chung (Abbott) Out of approximately 3,300 delegates at EuroMedLab in Athens, 2,400 were sponsored by the IVD industry. In addition, more than 2,000 visitors were registered for the exhibition only. IFCC successfully sold all exhibition space at EuroMedLab; however, the distribution of the exhibition over several floors was not optimal for many of the exhibiting companies, particularly those on the upper floors. Those responsible to organize future events are working on means to prevent this for upcoming conferences. Approximately 660 delegates attended WorldLab in Durban (around 50 of them sponsored by the IVD industry), and 330 visitors came for the exhibition only. The exhibition space had to be reduced due to a limited number of exhibitors. It remains to be seen what the outcome will be for Barcelona since this will be the first EFLM/IFCC conference where the transition period of the MedTech Europe Code has expired and IVD industry can no longer sponsor delegates or speakers to attend conferences: • For third-party organized conferences (main program): Companies may not directly support a healthcare professional, neither as a delegate, nor as a speaker. • For company-organized events in the framework of third-party organized confer-

ences (e.g. satellite symposia): Companies may directly support speakers (i.e. their consultants) but not delegates. • Educational grants are still possible. They can only be provided to legal entities but never to individuals. • Companies will be able to define the type of recipients who should be eligible for the grant but will not be able to identify individual recipients. • Companies must have an internal and independent process based on objective criteria to assess grant requests. For more information please check out the MedTech Europe website. Similar codes are expected to come into place in various other regions of the world. The next Corporate Members Meeting will be held during AACC in Chicago, USA, on July 31st, 2018. In general, attendance from Corporate Members at these meetings is rather low and I would like to encourage all members to take part in the meeting. The exact meeting details will be communicated soon. Corporate Members fully support IFCC's recently developed new vision to advance excellence in laboratory medicine for better healthcare worldwide. Rolf Hinzmann, Corporate Members Representative

COMMITTEE ON CONGRESSES AND CONFERENCES (C-CC) International Congresses of Clinical Chemistry & Laboratory Medicine (ICCCLM) IFCC ICCCLM (WorldLab) Durban, South Africa 2017 (October 22-25) Congress Chair: Prof. RT Erasmus; Scientific Chair: Prof. TS Pillay Through diligent planning and management the Congress was an academic and financial success. IFCC ICCCLM (WorldLab) Seoul, Korea 2020 (May 24-28) Congress President: Prof. Won-Ki Min; Congress Chair: Prof. Junghan Song Planning for this Congress is progressing on schedule. IFCC ICCCLM (WorldLab) Rome, Italy 2023 (May 21-25) Congress Chair: Prof. Sergio Bernardini Regional Congresses of Clinical Biochemistry and Laboratory Medicine APFCB, Jaipur, India, 2019 (November 17-20) Congress Chair: Prof. Praveen Sharma This Congress will be held at the Jaipur Exhibition and Convention Centre. EuroMedLab, Athens, Greece, 2017 (June 11-15) Congress Chair: Prof. Alexander Haliassos This successful Congress was held at the Megaron Athens International Conference Centre. EuroMedLab, Barcelona, Spain, 2019 (May 18 - 23) Congress Chairs: Prof. Maurizio Ferrari and Dra. Imma Caballé Planning for this Congress is progressing on schedule. EuroMedLab, Munich, Germany, 2021 (May 16 – 20) Congress Chair: Dr. Michael Vogeser COLABIOCLI, Punta del Este, Uruguay, 2017 (September 17 – 20) Congress Chair: Dra. Stella Raymondo This successful Congress received widespread support. COLABIOCLI, Panama City, Panama, 2019 (September 10 - 13) Congress Chair: Lizbeth Campillo, Jovanna Borace The Congress will be held at the Megapolis Convention Center, located in the center of Panama City in Multicentro. Planning is underway. AFCB, Ramallah, Palestine, 2018 Congress Chairs: Dr. M H Kamil and Dr. Osama Najjar Planning is ongoing. AFCC, Durban, South Africa 2017 Congress Chair: Prof. Vanessa Steenkamp The 5th AFCC congress was held concurrent with WorldLab 2017. IFCC Specialized Conferences Roche Diagnostics Bergmeyer Conference 2018 The 16th IFCC – Roche Diagnostics Bergmeyer Conference has been proposed to 2019 in Eisbee, Germany. The proposed title is “Coagulation”. A decision is pending further discussions between the IFCC EB and Roche Diagnostics. A significant concern is compliance with the MedTech Europe Code of Ethical Business Practice. Congress Guidelines and Other Documents Guidance for National and International Congresses Revisions to the 2013 version of this document were completed by the C-CC and MZ Congressi. The revised document has been submitted for approval by the IFCC EB early in 2018. IFCC Guidelines for Compliance with Applicable Codes of Ethical Business Practice This new document was developed to create awareness of the revised MedTech Europe Code of Ethical Business Practice and the EthicalMedTech – Conference Vetting System. IFCC General Conference The next IFCC General Conference will be held in Budapest, Hungary, November 10 – 11, 2018. Congresses with IFCC Auspices: 54 events A significant concern is the occasional request for IFCC auspices from corporations in the business, presumably for profit, of organizing congresses, conferences and other educational events. These corporations also approach IFCC officers and other laboratory professionals for their endorsement and participation. These educational events potentially represent competition for funding / sponsorship from the IVD Industry; participation in the commercial exhibition by the IVD Industry, and the competition for delegates. The EB is considering this matter. James Wesenberg, C-CC Chair

Special Supplement to Lab Medica International • 31

2017 Annual Report SCIENTIFIC DIVISION (SD)

During 2017, the following members served on the SD Executive Committee: Philippe Gillery (France) (Chair), Christa Cobbaert (the Netherlands) (Vice-Chair), Joseph Passarelli (United States) (Secretary), Konstantinos Makris (Greece), Tsutomu Nobori (Japan), Mario Plebani (Italy) (members) and James Pierson-Perry (United States) (corporate representative). Four representatives of International Organizations are invited to attend the SD meetings as consultants: Gary Myers (JCTLM), Heinz Schimmel (JRC) Karen Phinney as replacement for David Bunk (NIST) and Chris Burns (NIBSC). Two meetings were held during 2017: June 9 – 10 (Athens, Greece in conjunction with EuroMedLab) and October 20 - 21 (Durban, South Africa in conjunction with WorldLab). Relationship with International Organizations The SD continues to pursue the expansion of its activities to partner with international organizations to promote the implementation of the concept of traceability in laboratory medicine and the implementation of reference measurement systems. • Joint Committee on Traceability in Laboratory Medicine (JCTLM) The JCTLM continues its work which is available for review on its database at www.bipm.org/jctlm. Governance: 1. Dr. Anja Kessler was appointed as the new representative from the IFCC to the JCTLM Executive Committee replacing Prof Lothar Siekmann. 2. Ms. Regina Robertson informed the Executive Committee that she will no longer serve as one of the two ILAC liaisons to the JCTLM Executive. Ms. Robertson is replaced by Ms. Martina Bednarova, Director, Czech Accreditation Institute Department for Medical Laboratories. Dr. Graham Jones will continue to also serve as ILAC liaison to the JCTLM Executive. 3. JCTLM Executive Committee Meetings were held as follows: • 11 June 2017 Athens, Greece in conjunction with the EuroMedLab Congress. • 7-8 December 2017 at BIPM JCTLM Membership: 1. Progress with identifying potential JCTLM Executive Committee Organizations. The JCTLM Executive Committee continued its efforts to engage the International Council for Standardization in Haematology (ICSH) in collaborative programing activities in traceability. 2. JCTLM Membership Applications. The Executive Committee approved the following applications in 2017 for JCTLM National and Regional Membership: 1. AllRussian Scientific Research Institute for Metrological Service, Rosstandart [VNIIMS], Moscow; 2. All-Russian Scientific Research Institute for Optical and Physical Measurements, Rosstandart [VNIIOFI], Moscow The Executive Committee approved 14 applications in 2017 for JCTLM Stakeholder Membership. JCTLM Members’ and Stakeholders’ Meeting: The biennial JCTLM Members’ and Stakeholders’ Meeting; Accurate Results for Patient Care Workshop, was held 4-5 December, 2017 at BIPM. 117 persons from 27 different countries attended the meeting. Posters were accepted and displayed for the first time. JCTLM Database: 1. There were 79 nominations submitted by 30 May 2017 for the 2017 review cycle. 46 certified reference materials; 11 reference measurement procedures, 22 reference measurement services provided by 4 reference laboratories. 2. The Executive Committee appointed Professor Mauro Panteghini (CIRME) as Vice-Chair of the Database WG for Analyte Group 2 covering Blood Cell Counting and Typing, Coagulation Factors, Enzymes, Infectious Diseases, Nucleic Acids, and Proteins. He replaces Dr. Heinz Schimmel who stepped down as Vice-Chair due to other professional responsibilities. 3. JCTLM Database Content: As of March 2017, the JCTLM Database contains: • 293 available certified reference materials; • 184 reference measurement methods or procedures that represent about 80 different analytes in nine categories of analytes; • 161 reference measurement services delivered by 17 reference laboratories. JCTLM WG on Traceability Education and Promotion: 1. Definitions – The completed output of this work is available as a glossary on www.jctlm.org 2. Mini-presentations – Eight webinars are now published on the IFCC e-academy with direct links from www.jctlm.org. The remaining two webinars (on commutability) will be published in 2018. 3. Importance of traceability in laboratory medicine (TLM) to IVD manufacturers – Complete. 4. Importance of TLM to Patients and the Public – Presentations on this topic were given in Athens (June 2017), Durban (October 2107) and at the JCTLM Members’ and Stakeholders’ Meeting (December 2017). 5. Global significance of TLM – A review article has been published in Clinical Chemistry and Laboratory Medicine. “Traceability in laboratory medicine: a global driver for accurate results in patient care”. Beastall GH, Brouwer N, Quiroga S, Myers GL. Clin Chem Lab Med 2017; 55(8): 1100-1108. 6. Tools for promoting TLM – Ongoing 7. Involving TLM in meetings – Raising the profile of TLM in national and international scientific meetings. JCTLM Symposia at Scientific Meetings: • EuroMedLab – Athens, Greece, 14 June, 2017 Title: Traceability in laboratory medicine: what is it and why is it important? A. Traceability in laboratory medicine: what every laboratory specialist should know. Gary Myers (USA); B. Traceability and harmonization - powerful tools for trueness of laboratory results. Elvar Theodorsson (Sweden); C. Why traceability in laboratory medicine is important for patients. Graham Jones (Australia); D. Traceability, education and promotion: getting the message out. Graham Beastall (UK)

IFCC

• IFCC WorldLab Congress – Durban, South Africa, 24 October, 2017 Title: Traceability in Laboratory Medicine: what is it and why is it important? A. Traceability in Laboratory Medicine: what every laboratory specialist should know. Gary Myers (USA); B. Traceability and harmonization - powerful tools for trueness of laboratory results. Elvar Theodorsson (Sweden); C. Traceability, education and promotion: getting the message out. Graham Beastall (UK) WG-TEP website: The new JCTLM website was launched in early February 2017 as www.jctlm.org. JCTLM Newsletter: This fourth issue of the Newsletter was released in March 2017 and can be downloaded from the following link: http://www.bipm.org/utils/common/ pdf/JCTLM/JCTLM-Newsletter-2017.pdf • Joint Committee for Guide in Metrology (JCGM) Working Group 1 (GUM): The draft revision of the GUM (JCGM 100) is still in process. JCGM 103: Modelling measurement data is still in development. Working Group 2 (VIM): Joint Committee for Guides in Metrology Working Group 2: International Vocabulary of Metrology met 16-19 May, 2017, Paris. The major focus of the meeting was a detailed consideration of items proposed for inclusion in VIM4. A considerable amount of time was spent on discussion of the term “unit of measurement”. The WG agreed on a position statement. • Joint Research Center (JRC – formerly the Institute for Reference Materials and Measurements (IRMM)) Close collaboration with JRC continues through a number of joint ventures involving SD Committees and Working Groups. • Clinical and Laboratory Standards Institute (CLSI) (Formerly NCCLS) An updated list of joint CLSI/IFCC documents is available on the IFCC web site at: http://www.ifcc.org/index.asp?cat=Publications&scat=CLSI_(Clin_Lab_Stand_Inst)_-_IFCC_Joint_Projects&rif=6&dove=1. • National Institute of Standards and Technology (NIST) NIST continues to undertake a large number of projects, many of which are of considerable interest to IFCC. The NIST website (www.nist.gov) can provide information on materials and services available today. • National Institute of Biological Standards and Control (NIBSC) NIBSC, previously part of the Health Protection Agency (HPA), is now a new Centre of the Medicines and Healthcare Products Regulatory Agency (MHRA) alongside the Clinical Practice Research Datalink (CPRD). The MHRA is an executive agency of the Department of Health, UK. Collaboration with NIBSC continues through joint activities involving SD Committees and Working Groups. • European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) The EFLM Science Committee and SD leadership once again agreed there should be close liaison and communication between the two groups. Within the EFLM SC there are working groups on cardiac biomarkers, biological variation, test evaluation, personalized laboratory medicine and a number of others but the general consensus of the SD are that these activities do not overlap with the IFCC SD. Approaches to avoid overlap and work collaboratively are periodically discussed and explored. World Health Organization (WHO) Philippe Gillery attends and participates as the liaison from the SD. The most recent WHO meetings occurred on October 16-19, 2017. There may be a significant decision on HbA2 with respect to a reference measurement procedure which then might lead to a proposal for a new reference material. Commutability of the WHO material will need to be carefully considered. Beyond this, the SD decided that there were no new projects or collaborations to consider. Congresses (WorldLab, Regional and other congresses) EuroMedLab 2017 - 22nd IFCC-EFLM European Congress of Clinical Chemistry and Laboratory Medicine – Athens, Greece: June 11-15, 2017: Standardization in Endocrinology (Chair: P. Gillery): 1. Clinical needs for standardization in endocrinology (P. Gillery); 2. Standardization of Growth hormone (E. Lentjes); 3. Standardization of Parathyroid Hormone (C. Sturgeon); 4. Standardization of thyroid function tests (L. Thienpont) XXIII International Congress of Clinical Chemistry and Laboratory Medicine, Durban, South Africa, October 22-25, 2017: A) Standardization in laboratory medicine beyond clinical chemistry (Chair: P. Gillery): 1.Standardization: a universal need (P. Gillery); 2.Standardization of Hb A2 (A. Mosca); 3.Standardization of autoimmune tests (J. Sheldon); 4.Standardization in molecular diagnostics (D. Payne) B) Recent advances in standardization (Chair G. Miller): 1.Commutability issues in standardization of laboratory measurement procedures (G. Miller); 2.Standardization of Pregnancy- Associated Plasma Protein A (S. Wittfooth); 3.Standardization of urine albumin assays (L. Bachman); 4.Standardization of CSF proteins (K. Blennow) Activities of Committees and Working Groups The Committees (Cs), which are theme-oriented, carry out much of the scientific and professional activities of the SD. Their work is often in close collaboration with other international organizations. For more specific tasks, the activities are usually accomplished through Working Groups (WGs). Committees • C-Nomenclature, Properties and Units (C-NPU); Chair: Robert Flatman (AU) During 2017 ongoing progress towards C-NPU terms of reference included: Term of Reference 1. To continuously provide advice for the management, updating and publishing of the NPU terminology. Accomplishments include: 1. The NPU Steering Committee continues to provide governance for the NPU terminology through representation from key stakeholders consisting of IFCC, IUPAC and National Release Centre representative, while the C-NPU functions as the technical and

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IFCC

2017 Annual Report

scientific expert committee; 2. Karin Toska has now taken over from Robert Flatman as the C-NPU Chair (who had reached the end of 2 terms in the role of Chair). Robert will act as secretary of the NPU Steering Committee, and continues to consult with the C-NPU; 3. The NPU Steering Committee website continues to act as the main governance site (http://www.npu-terminology.org), while the NPU terminology itself can be searched from (http://www.ifcc.org/ifcc-scientific-division/sd-committees/cnpu/npusearch/). The NPU also holds a Wikipedia page at https://en. wikipedia.org/wiki/NPU_terminology Term of Reference 2. To make recommendations on NPU for reporting clinical laboratory data that conform to or adapt current standards of authoritative organizations and that will improve their utilization for health care. Accomplishments include: 1. Project on Molecular Biology terms for the NPU terminology continues; 2. A new project aim to create an online “dynamic” manual for the NPU terminology is in development. This is expected to act as both a user manual and reference, but also as repository for NPU decisions made during NPU scientific meetings. Term of Reference 3. To provide a connection with other organizations concerned with NPU, such as the Bureau International des Poids et Mesures (BIPM), the European Committee for Standardization (CEN) and the International Organization for Standardization (ISO), and, by extension, clinical laboratory sciences societies, such as the International Union of Pure and Applied Chemistry (IUPAC), and the in vitro diagnostics industry, to ensure that problems encountered by health care professionals in the area of NPU are considered by those organizations. Accomplishments include: 1. C-NPU remains a joint committee with both IFCC and IUPAC representation; 2. Gunnar Nordin continues to attend BIPM WG2 meetings and provide input into the upcoming VIM4 (International Vocabulary of Metrology); 3. Daniel Karlsson reports to the NPU on IHTSDO/SNOMED-CT related matters; 4. The National Release Centres of Denmark, Norway and Sweden provide national NPU support for those countries, and are represented both on the SC NPU and C-NPU. Term of Reference 4. To act as a consultant group on NPU in clinical chemistry and, by extension, in the rest of clinical laboratory sciences to international scientific panels, regional and national clinical laboratory sciences organizations, editors of scientific journals, manufacturers of clinical laboratory instrumentation and products, and to individual clinical laboratory professionals and other health care professionals. Accomplishments include: Individual NPU members continue to be active with their societies, particularly in the informatics and terminology arenas. • C-Molecular Diagnostics (C-MD), Chair: Deborah Payne (US) During 2017 ongoing progress towards C-MD’s terms of reference included: Term of Reference 1. Foster dynamic exchanges between IFCC and molecular diagnostic laboratories and industry. Accomplishments Include: 1. Updated website on EQA programs with input from various EQA suppliers; 2. Added more laboratories for the Molecular Centres; 3. Developed and circulated questionnaire geared to evaluate current state of reporting practices for molecular laboratories; 4. Sent out survey to network laboratories and other laboratories; 5. Compiled data and submitted paper to CCLM Term of Reference 2. To produce guidelines on clinical validation of tests, conduct and report on molecular diagnostic tests. Accomplishments Include: 1. Submitted research article to CCLM entitled “Toward harmonization of Clinical Molecular Diagnostic Reports: Findings of an international Survey; 2. The chair (Dr.Payne) presented findings on the Standardization of Molecular Diagnostics in Durban, South Africa Term of Reference 3. Creation of a network of locus-specific IFCC Molecular Diagnostics Centres. Accomplishments Include: 1. Engage Network laboratories in surveys; 2. Identified candidate Expert Laboratories and reviewing applications of 10 laboratories; 3. Revise requirements for expert laboratories; 4. Engaged C-MD members to review articles in for CCLM. Additional Information: The C-MD will merge with the Pharmacogenetics Task force for 2018. • C-Traceability in Laboratory Medicine (C-TLM), Chair: Lothar Siekmann (DE) During 2017 ongoing progress towards C-TLM terms of reference included: Term of Reference 1. To Support activities regarding Traceability in Laboratory Medicine, permitting IFCC to continue its international role in this area and providing an operating link between the SD and the WGs of the Joint Committee on Traceability in Laboratory Medicine (JCTLM), concerning identification of reference measurement procedures, reference materials and reference laboratories. Accomplishments include: JCTLM structure and activities: The JCTLM has about 40 member organizations spread across three categories: Executive Committee Members: BIPM, IFCC, and ILAC; National and Regional NMIs; Stakeholder Members. JCTLM Database WG: The JCTLM Database WG has been restructured. Three analyte groups were formed: Analyte Group 1: drugs, metabolites and substrates, non-peptide hormones (chair: Qinde Liu); Analyte Group 2: blood cell counting and typing, coagulation factors, enzymes, infectious diseases, nucleic acid, proteins (chair: Mauro Panteghini); Analyte Group 3: electrolytes and blood gases, non-electrolyte metals, vitamins and micronutrients (chair: Karen Phinney). The main output of the JCTLM is the global database of: higher order reference materials; Reference measurement methods/ procedures; Reference measurement services. This database is freely available: www.bipm.org/jctlm/ JCTLM Education and Promotion WG: JCTLM WG-TEP was founded in 2016. A website (http://www.jctlm.org) has been created. Review Teams: The judgment of nominations of reference methods, materials and reference measurement services is the mandate of JCTLM Review Teams. Each Review Team is responsible for a particular group of measurands, e.g. electrolytes, metabolites and substrate, hormones, proteins, etc... The C-TLM supports the JCTLM, which was established about 14 years ago by the IFCC, the BIPM, and the ILAC. All details are available on the JCTLM website: www.bipm.org/jctlm. Term of Reference 2. RELA - External Quality Assessment Scheme for Reference Laboratories. The C-TLM supports reference laboratories in the context of complete reference systems (accepted reference measurement procedures of higher order, reference materials, and reference laboratories) by establishing an External Quality Assessment Scheme (EQAS) for reference laboratories in order to monitor their

competence. Accomplishments include: IFCC External Quality Assessment for Reference Laboratories: RELA ring trials are currently provided for 36 measurands. The results of RELA 2016 were published on the website (www.dgkl-rfb.de:81) in July 2017. 48 laboratories participated in RELA 2016 and the organizer received 361 results from these laboratories.The question that has been asked is what options exist for dealing with discrepant results or outliers and how the quality level of reference systems could be ensured. Various ideas were discussed (contacting, exchange of calibrators) and should be substantiated in 2018. Term of Reference 3. To promote establishment and maintenance of IFCC reference laboratory networks for clinically relevant measurands. Accomplishments include: HbA1c Network: As in previous years the network organized 2 inter-comparison studies with participation of the approved and candidate network laboratories and the designated comparison method networks in the US, Japan and Sweden. All approved network laboratories kept their approval, and master equations were confirmed. Candidates Reference Institute for Bioanalytics in Bonn, Germany and Fleury Laboratories in Sao Paulo, Brazil passed criteria and gained the status of “approved network laboratory”. There are now 18 approved network laboratories. For educational activities the network collaborates with the IFCC C-EUBD. Some of the activities are a) symposium on HbA1c in Shanghai, China, b) satellite symposium EuroMedLab in Sounio, Greece) satellite Symposium IFCC WorldLab, Cape Town, South Africa. Also a multinational project was organized in 2016: national EQA organizers in 15 European countries shared 2 samples in the so called EurA1c project. Results allow comparisons per country or even per manufacturer. The study was repeated in 2017. Results reveal that the differences per country are limited and confirmed that performance in terms of bias and between laboratory CV improved throughout the years. Term of Reference 4. Traceability of total protein measurement results. Accomplishments include: No update is available at this time. Additional Information: CDT Network: In 2016 the mission of the IFCC Working Group on standardization of CDT (an alcohol of abuse biomarker) was completed and the WG was disbanded. To warrant sustainability of the reference measurement procedure and to implement standardization of patient results, the IFCC Scientific Division asked to start a network similar to HbA1c. This was initiated in an airport meeting in Amsterdam in January 2017 and confirmed during EuroMedlab in June 2017. A first inter-comparison study with participation of 7 potential network labs and 6 manufacturers was organized and results were discussed during a meeting at EuroMedLab. The manufacturers expressed commitment to the reference measurement procedure. The analytical aspects of the network are supervised by IFCC C-TLM (the network coordinator will report to C-TLM). • C-Reference Intervals and Decision Limits (C-RIDL), Chair: Yesim Ozarda (TR) During 2017 ongoing progress towards C-RIDL terms of reference included: Term of Reference 1. Review current concepts of establishing reference intervals (RIs) and decision limits and to prepare state-of-the-art position statements regarding new avenues. Accomplishments include: An indirect reference interval study of biochemical parameters was conducted in Turkey to compare alternative approaches (conventional and big data) for the determination of reference intervals and presented in Athens in June in conjunction with EuroMedLab. The direct reference intervals study in Nepal was completed as a part of global reference interval study. A reference interval study in Canada was conducted to determine ‘Harmonized reference intervals for 24 common biochemical parameters’ with the support of the Canadian Society of Clinical Chemists. Another important issue discussed in Athens was whether or not the reference interval is required when the clinical decision limit is available in clinical guidelines. To avoid confusion, it was concluded that it is necessary to clarify the differences between reference intervals and clinical decision limits. Term of Reference 2. To make available reference intervals and decision limits that respects the requirements of international directives such as the European IVD Directive 98/79, and relevant ISO standards. Accomplishments include: Two papers were published in Clinica Chimica Acta about the results of Global Reference Intervals Study performed by C-RIDL: "A global multicenter study on reference values": Part 1: Assessment of methods for derivation and comparison of reference intervals, Part 2: Exploration of sources of variation across the countries. (see Publications). Term of Reference 3. To determine priority list of measurands (analytes) for which reference intervals and/or decision limits have to be developed, considering various factors, such as age, gender, ethnicity, and for which the greatest improvements in medical decision making are anticipated. Accomplishments include: The previous studies performed by C-RIDL were on the most commonly used tests in the clinical laboratories for the adult age group. The main age was 18-65 years, although older healthy individuals were also included. The list of analytes was published by CCA and age-related changes in the reference values were nearly consistent across the countries. Term of Reference 4. To monitor and evaluate currently proposed reference intervals for selected measurands (analytes) in the light of the concept of traceability and of the identification of the uncertainty. Accomplishments include: No action was taken on this Term of Reference. Term of Reference 5. Establish transferability protocols of reference intervals and decision limits, which take into consideration inter-routine laboratory method variations and achieve better applicability in clinical practice. Accomplishments include: At the Athens (EuroMedLab) and Durban (WorldLab) 2017 meetings, the transference and verification protocols of reference intervals were discussed which take into consideration inter-routine laboratory method variations and achieve better applicability in clinical practice. Term of Reference 6. Collaborate with other organizations and/or to undertake establishment of reference intervals or decision limits for measurands (analytes) identified as a priority. Accomplishments include: A new member of C-RIDL, Thomas Streichert from Germany, is also a member of the German Association of Clinical Chemistry and Laboratory Medicine (DKLG), and introduced their current projects namely, ‘Integration of indirect reference intervals into laboratory information systems and pediatric reference intervals using Reference Limit Estimator’ at the Athens meeting. The other new member of C-RIDL, Ken Sikaris from Australia, is also a

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member of the Australasian Association of Clinical Biochemists (AABC) and introduced their previous studies entitled ‘Harmonizing Adult and Paediatric Reference Intervals in Australia and New Zealand’. Term of Reference 7. Work in close collaboration with other Cs and WGs of SD and other IFCC Divisions for the development and appropriate clinical utilization of reference intervals and decision limits. Accomplishments include: No action was taken on this Term of Reference. • C-Standardization of Thyroid Function Tests (C-STFT), Chair: Linda Thienpont (BE) During 2017 ongoing progress towards C-STFT terms of reference included: Term of Reference 1. To develop reference measurement systems for free thyroid hormones and TSH. Accomplishments include: 1. Two manuscripts describing the results of the final method comparisons, the outcome of the recalibration exercises and proof-of-concept studies (= reference interval (RI) studies), one for TSH, one for free T4 have been published in Clin Chem. (see http://clinchem.aaccjnls.org/ content/63/7/1248 and http://clinchem.aaccjnls.org/content/63/10/1642); 2. The last new company (Wako-Sanyo (joint-venture), Japan) has successfully finished the Phase IV study and received its final reports. The results were included in the presentations given by the chair in the annual meeting at EuroMedLab Athens. Note that this brings a total of 15 IVD companies in collaboration with C-STFT; 3. The first phase of the isochronous stability study of the free T4 standardization and TSH harmonization panels ended in June 2017 (24 months of storage), but the monitoring will be pursued (36, 48 and 60 months of storage). The measurements for the first phase study were done by one of the participating manufacturers. They showed that the samples can be considered stable when stored at -70°C up to 24 months; 4. The certificates for both the FT4 and TSH follow-up panels have been written. They also include guidance on how to use the panels and the targets for recalibration of new FT4 and TSH assays. Term of Reference 2. To establish a network of laboratories competent to offer reference measurement services for thyroid hormones. Accomplishments include: 1. The four potential partners within the network met during EuroMedLab Athens. These are: Ref4U (K. Van Uytfanghe), CDC (H. Vesper), Radboud University Medical Center of Nijmegen (T. Van Herwaarden), the Reference Material Institute for Clinical Chemistry Standards (ReCCS) of Japan (H. Umemoto). They discussed the organization of the network itself, the implementation of the IFCC RMP and the road ahead. A report of the discussion was sent out for review to all participants; 2. To evaluate the implementation of the IFCC RMP in the different partner labs, UGent has assembled a panel of 20 frozen sera from presumably healthy subjects, and assigned it with free T4 concentrations by the IFCC RMP. The samples are stored at 70°C. These samples were shipped to the above potential partners within the network for validation of their performance; 3. The above mentioned samples were used in a first method comparison with the laboratory of the Radboud University Medical Center. The outcome looks promising; however, the lab of the candidate network member still has day to day variation that is too high. The laboratory agreed to further optimize the implementation of the IFCC RMP. UGent is involved in the optimization experiments; 4. Also at CDC and ReCCS the implementation of the FT4 IFCC RMP has been initiated. Results for the preliminary method comparison (on the aforementioned samples) are still to be expected; 5. The design of the factual inter laboratory comparison (final proof-of-concept) amongst the 4 members has also been fixed during the aforementioned meeting. The comparison is planned early 2018. A set of 40 samples, comprising hypo-, eu- and hyperthyroid donors will be measured by all partners. Term of Reference 3 and 4. Term of ref 3: To provide an infrastructure for procurement of serum panels and Term of ref 4: Demonstrate that the traceable assays can use a common reference interval; use this as a basis for further elaboration of the reference intervals by the IVD manufacturers; consult with clinicians about the need for ethnic, age- or sub-population-specific reference intervals in co-operation with CRIDL. Accomplishments include: Term of ref. 3: In order to source samples for the final method comparisons (Phase IV) and the samples for the RI studies, the C already established in 2015 a relationship with 2 commercial vendors but also with several clinicians. It is the aim to sustain this infrastructure. A questionnaire was sent out to all participating manufacturers to find out their view on the destination of the FT4 standardization and TSH harmonization panels (there are some leftovers), the FT4 and TSH follow-up panels, and the leftovers of the RI panels. The questionnaire asked the manufacturers whether they think that the fact that they funded the panels gives them the proprietary rights (=option 1), or whether they agree that the samples can be made available to new manufacturers who want to join the C-STFT activities (+ how much should be charged?) (=option 2). Another question was about their view whether storage of the samples (panels and 2nd aliquot of the RI study) should be continued at the NIBSC or at their own facilities (in case they opted for option 1). The majority of the companies (66% of the replies received) consider that the follow-up panels belong in first instance to the companies-sponsors of the C-STFT activities (= option 1); however, most (again 66%) also consider that the panels should be within reach of potentially new company entrants (= option 2). The final conclusions can be summarized as follows: 1) as per advice of the majority, at least one set of samples of each of the follow-up panels should be reserved for the companies-sponsors; 2) sets should be made available to new company entrants; 3) sufficient aliquots should be set aside for making the link between the 1st and 2nd TSH follow-up panel; 4) a fair price should be fixed for the new companies to obtain a set of the follow-up panels, e.g., representing only a part of the original cost, but not prohibitive for small companies to purchase them. 5) storage of the follow-up and RI panels will be continued in the facilities of the NIBSC. Term of ref. 4: The pilot RI study is completed and the results are incorporated in the above mentioned manuscripts. The message in the manuscript is that our studies provided the proof-of-concept that common RIs are feasible for assays with calibration traceability to the free T4 and TSH reference measurement systems. Particularly, the TSH proof-of-concept was convincing, while that for free T4 might need some improvement.

IFCC

Term of Reference 5 and 6. Term of ref. 5: Liaise with key stakeholders to implement the use of the traceable assays in routine clinical practice. Term of ref. 6: Through collaboration with IFCC EMD, provide educational materials for manufacturers, clinicians and patients which will support the implementation of traceable assays. Accomplishments include: Term of ref. 5: C-STFT identified who is involved as stakeholder, i.e., IVD manufacturers laboratories (and their societies/associations), clinicians/nurses (& their societies/associations), patients (Thyroid Federation International), international/national regulators (in the broader sense). First contacts were established, among others with representatives of the clinical laboratory profession, regulatory agencies (e.g., the US FDA, the Chinese FDA), professional societies, physicians and their patients. A letter was published in several journals and on the website of clinical and laboratory societies, as well as a survey among the members of AACC Endocrine Division. Input was requested from physicians, laboratory directors and patients regarding their views on the benefits and risks arising from TSH harmonization and FT4 standardization and thus changes in RIs. In addition, questionnaires were sent to all levels of stakeholders: manufacturers, laboratories, endocrinologists and general practitioners. It can be cautiously concluded that, when important changes in RI occur (i) there are well-established communication chains amongst all stakeholders, (ii) all sources of communication are used (reviewed literature, newsletters, circulars, oral communications …), (iii) all opportunities to communicate (in meetings and workshops, through the intranet, the LIS …). In addition, it seems that (iv) the benefits of standardization/harmonization are understood and considered valuable by all stakeholders, (v) the potential risks are mainly related to patient safety and clinical outcomes (issues may arise as a consequence of changes in the numerical values for patients with thyroid diseases, despite appropriate adjustments of the RIs), however, (vi) users are in general familiar with handling changes in numbers and RIs, so that they consider it unlikely that changes will not be captured, hence, that there is minimal risk for the patient. Two new tools were developed to monitor the stability of the post-standardization/harmonization calibration basis of the assays (called the Percentiler and Flagger). They are intended to prevent risks due to non-sustainability of the new calibration basis. Efforts to recruit more laboratories to have reliable peer groups of all systems involved in the C-STFT activities are ongoing. At this point in time there are 79 participants. The C-STFT relies on the support from manufacturers to increase the number of participants. In addition, C-STFT and IVD industry are in close contact with the FDA to comply with the regulatory requirements upon implementation of the recalibrated immunoassays. For most TSH assays the changes after harmonization will be within 10% and within the limits for acceptable changes currently set by the manufacturers. In this case, internal documentation will be sufficient to obtain a new FDA clearance. For this purpose the TSH manuscript discussing the harmonization effort and the establishment of a common RI, can be part of the documentation. No date for final implementation has been fixed. With regard to the dissemination of our work, the AACB organized a harmonization workshop, 17-18 May 2017, Sydney, Australia. It was entitled: “Thyroid harmonization symposium: changes in thyroid function tests – values and RIs”. They invited several representatives of our industry partners, among others Dr. M. Patru, to represent the C-STFT. All gave their view on the future actions they will undertake. The discussion also included the view of the audience of pathologists and scientists. In a final vote the latter were supportive of TSH harmonization and FT4 re-standardization. However, a matter of concern remains with standardization/harmonization of the assays for use in thyroid testing of special patient populations like pregnant females and patients with the NTI syndrome. • C-Harmonization of Autoantibody Test (C-HAT), Chair: Joanna Sheldon (UK) During 2017 ongoing progress towards C-HAT terms of reference included: Term of Reference 1. To evaluate what are the main causes of variability for a number of diagnostically critical autoantibodies. Accomplishments include: This is a complex task for the C-HAT but will need to be addressed otherwise there will be no evidence based progression for autoantibody measurements, or harmonization or standardization. It is also a technically difficult area and current members do not have the epitope mapping (the most likely source of variation) capability within the committee. Xavier Bossuyt reported on his large study on the potential impact of the reference materials on comparability of IgG anti MPO and IgG anti PR3 measurements. It was reported that some methods did show comparability but others did not; they concluded that it would not be possible for all assays to show the same cut-off values. Term of Reference 2. To identify autoantibodies where a common calibrator could reduce the inter-assay variability. Accomplishments include: IgG anti glomerular basement membrane and IgG and IgA anti TTG antibodies are generally considered to be the next important antigens where a common reference material would be beneficial. Term of Reference 3. To identify or produce commutable materials that could be used as interim calibration material for autoantibody assays. Accomplishments include: ERM DA 483/IFCC IgG anti proteinase 3 antibodies was certified in February 2017. A further commutability study for B2GP1 candidate reference material is in progress (Jan 2018). Term of Reference 4. To produce well-characterized pure antibody preparations with known concentration and identity and use these to transfer values to a matrix preparation. Accomplishments include: The preparation of pure antibody preparations with known concentration is embedded in the value assignment process. Term of Reference 5. To evaluate the impact of new reference material on the variability of autoantibody tests and identify areas where further harmonization would improve diagnostic accuracy. Accomplishments include: The C is in discussion with UKNEQAS and the Royal College of Pathologists of Australasia Quality Assurance Programs. Working Groups • WG - Standardization of Hemoglobin A2 (WG-SHbA2), Chair: Andrea Mosca (IT) During 2017 ongoing progress towards WG-HbA2 terms of reference included: Term of Reference 1. To promote the standardization of hemoglobin A2 measure-

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ment through the definition of an international reference system, including a reference measurement procedure and primary and secondary reference materials. Accomplishments include: All the experimental validation measurements have been accomplished. A draft of the paper to be submitted to the IFCC Scientific Division for the publication in Clin Chim Acta is almost ready. Term of Reference 2. Development of a secondary certified reference material for hemoglobin A2 (in cooperation with the IRMM). Accomplishments include: Experimental work has been accomplished, proving that the present routine methods are not aligned and that the inter-method variability could be improved by performing a common calibration using commutable control materials, such as those planned to be produced in collaboration with the JRC (Geel, BE). The only presently available control material from WHO has been proven not to be commutable for the majority of routine methods. • WG - Standardization of Carbohydrate-Deficient Transferrin (WG-SCDT), Chair: Jos Wielders (NL) During 2017 ongoing progress towards WG-CDT terms of reference included: Term of Reference 1. Definition of the analyte and standardization of the nomenclature. Accomplishments include: In 2017 several manuscripts were published outlining standardized CDT-IFCC. Term of Reference 2. Preparation of reference material and selection of reference method Accomplishments include: The reference material was developed in 2014. No further actions in 2017. Term of Reference 3. Establishment of appropriate reference intervals. Accomplishments include: The reference interval and a decision limit in forensic use have been formally established and explained in the 2017 publications. Term of Reference 4. Supporting the development of guidelines for clinical use of CDT assays. Accomplishments include: This is a local activity and responsibility of medical societies, which can only be supported or influenced by WG members. Additional Information: Current Projects: 1. Promoting the use of the HPLC reference measurement procedure (RMP) as the accuracy base for CDT test standardization; 2. Maintaining an international network of reference laboratories; 3. Supporting the worldwide standardization of commercial methods against the RMP; 4. Promoting the incorporation of the use of CDTIFCC in guidelines concerning prolonged excessive alcohol consumption • WG-Standardization of Albumin Assay in Urine (WG-SAU) (a joint committee with the Laboratory Working Group (LWG) of the National Kidney Disease Education Program (NKDEP), USA); Chair: Lorin Bachmann (US) During 2017 ongoing progress towards WG-SAU terms of reference included: Terms of Reference 1. Status of harmonization among commercial immunoassays for UA (funded by NKDEP). Accomplishments include: A joint NKDEP/IFCC WGSAU meeting on August 1st, 2017 held in conjunction with the AACC annual meeting in San Diego, CA took place. A manuscript describing recommended total allowable error, precision and bias goals for UA was published (see Publications). The recommendations are based on published data for intra-individual variation, and precision/bias data generated from the WG-SAU urine albumin harmonization study. Between-day CV goals of ≤6% above 15 mg/L, specimen-specific influences ≤6% were based on performance observed in the harmonization study and total allowable error was based on intra-individual variation estimates. Bias goals of ≤7% (optimal) and ≤13% (desirable) were recommended. Terms of Reference 2.Reference measurement procedure for UA (funded by NKDEP and NIST). Accomplishments include: Candidate isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) reference measurement procedures for UA are under development by the Mayo Clinic Renal Function Laboratory (John Lieske) and NIST. It is anticipated the NIST procedure will enable assessment of the molecular forms of albumin in urine that may be of importance in the specificity requirements for routine measurement procedures. There were some unexplained discrepancies that are under investigation. A team from the University of Minnesota has expressed interest in developing a publically available reference measurement procedure for UA. To pursue this goal, Univ of Minn has received NKDEP funding to purchase 15N human albumin for use as an internal standard for method development. NIST and Mayo continued to perform development of their candidate reference measurement procedures. Updates, coordination and future planning for these activities were the main topics of discussion at the 2017 WG-SAU meeting held in conjunction with the NKDEP Lab Working Group during the AACC annual meeting on August 1st, 2017. Minutes of the meeting can be found at https://www.niddk.nih.gov/ health-information/communication-programs/nkdep/workinggroups/laboratory/meeting-summaries. Term of Reference 3. Reference materials for UA and urine creatinine. Accomplishments include: SRM 2925 Human Serum Albumin is a primary certified reference material for use with higher order reference measurement procedures for albumin. It is solid recombinant human serum albumin (~1 g/L). Value assignment is by amino acid analysis using ID-LC-MS/MS. The material is not yet available on the NIST website. To facilitate standardization of routine methods, NIST SRM 3666 is currently being developed based on the specifications recommended by the WGSAU and the LWG of the NKDEP. Once developed, a commutability assessment of the materials will be conducted. • WG - Standardization of Pregnancy-associated Plasma Protein A (WG-PAPP A), Chair: Saara Wittfooth (FI) During 2017 ongoing progress towards WG-PAPPA terms of reference included: Term of Reference: Develop a reference system for standardization of PAPPA measurement employed as marker for prenatal screening. Accomplishments include: Reactivation of the work of the WG: work continued with a study to investigate the commutability of materials of pooled pregnancy sera from 2nd and 3rd trimester diluted in different diluents with commercial PAPP-A tests aimed for prenatal screening. For this study plan sample materials have been prepared and shipped to the participating companies.

• WG - Growth Hormone (WG-GH), Chair: Eef Lentjes (NL) During 2017 ongoing progress towards WG-GH terms of reference included: Term of Reference: To achieve standardization of growth hormone through secondary reference materials and a reference measurement procedure. Accomplishments include: A pilot study was started testing commutability of potential GH calibrators among 25 individual patient samples. Several potential calibrators were included: pools of patient sera and the WHO standard IS 98/574 in a serum matrix. All available routine methods were included and also a LCMS-MS method. The results of the LCMS-MS have not yet been completed, but all other results have. It can be concluded so far that for the analysis with the immunoassays only a single pool was commutable. Patient pools are probably not a good basis for obtaining commutable calibrators.The next step is to obtain individual serum samples from donors, which will be obtained after exercise (cycling) in order to get measurable GH levels. • WG - Standardization of Insulin Assays (WG-SIA), Chair: Amy Saenger (US) During 2017 ongoing progress towards WG-SIA terms of reference included: Term of Reference 1. To improve the standardization of assays for insulin by the development of a candidate reference method and materials. Accomplishments include: 1. Ongoing development and validation of MS/MS method for intact insulin at University of Minnesota; 2. Continued collaboration with other laboratories developing insulin methods by mass spectrometry and sustain efforts to evolve reference method procedures in these laboratories; 3. Evaluation of “wild card” serum pools with routine proficiency testing sent to US laboratories, demonstrated current state (lack of harmonization) of insulin assays; 4. Established connection with NIBSC to evaluate candidate reference material and will ultimately utilize that to calibrate the mass spec method and establish it as a higher order reference method. • WG - Standardization of Troponin I (WG-TNI), Chair: Robert Christenson (US) During 2017 the WG-TNI continued ongoing progress towards its terms of reference. • Development of a candidate secondary reference measurement procedure and candidate secondary reference material for cardiac troponin I (cTnI) • Testing for cTnI standardization and clinical validation by comparison with validated commercial assays in a round robin study Accomplishments include: Recruited Dr. Amy Saenger, University of Minnesota, Minneapolis, MN to the WG-TNI. Dr. Saenger holds a key position with the College of American Pathologist and has a keen interest in standardization, cardiac troponin physiology, guidelines and use in laboratory medicine. Recruited Dr. David Armbruster to join the WG-TnI. Dr. Armbruster is an expert in characterizing assays and has a keen interest in cardiac troponin. Named Dr. Mark Lowenthal from NIST as a key member of the WG-TNI. The C’s goal has been development of a commutable cTnI reference material (RM). This RM will be serum based and will be termed RM 2922 and it will be maintained and publically available NIST. Using earlier work of the WG-TNI, Dr. Lowenthal and the chair finished drafting the protocol for collection of the human material for the RM. This draft has been distributed to the WG-TNI members, and comments are due back in Q1 2018. • WG - Parathyroid Hormone (WG-PTH) During 2017 the ongoing progress towards WG-PTH terms of reference included: The WG continues to work on developing a reference system for PTH. Currently, activities are focused in three areas: Term of Reference 1. Collaborative educational effort to encourage worldwide implementation of PTH IS 95/646 and to assess the effect of this on between-method agreement. Accomplishments include: There has been further discussion regarding the importance of implementing an internationally recognized standard for PTH (preferably IS 95/646 if commutable). The IFCC initiative received wide publicity through a cover page article entitled “Variability in parathyroid hormone assays: Better standardization on the way?” in Kidney News, a journal of the American Society of Nephrology. Further publicity was generated by another cover page article entitled “On the path to standardizing parathyroid hormone testing” in the June issue of the AACC’s Clinical Laboratory News. Term of Reference 2. Definition of inclusion/exclusion requirements for an appropriate panel of sera and plasma with which to establish reference intervals and establishment of such a panel with support from the clinical community and diagnostics manufacturers. Accomplishments include: Inclusion/exclusion requirements based on results of the systematic review previously undertaken by the Working Group were reviewed in some detail at an open meeting of the Working Group held during the AACC conference (July 2017). Practical arrangements are being made with UK nephrologists who have agreed to provide plasma for the commutability study. Term of Reference 3. Development of a reference measurement procedure for PTH(1-84) to a standard that would enable its adoption by the IFCC reference laboratory network. Accomplishments include: Work is being undertaken at the CDC and NIST laboratories with the aim of increasing the analytical sensitivity of available mass spectrometric methods for PTH, such that these are closer to that of routine automated PTH immunoassays. Some progress has been made. • WG - CSF Proteins (WG-CSF), Chair: Kaj Blennow (SE) During 2017 ongoing progress towards WG-CSF terms of reference included: Term of Reference 1. Develop an international reference material for cerebrospinal fluid (CSF). The project aims to: • Collect CSF material, test stability, and assign values, to establish a Certified Reference Material (CRM); • Establishment of Reference Measurement Procedure (RMP) for the key measurands (Aβ1-42 and tau) for assignment of values to the reference material. Accomplishments include: - Several of the labs in the WG have initiated work to develop a SRM method for total tau (T-tau) in CSF. Experiments show that this will need to be based on direct trypsination of CSF proteins. The method will probably be more complicated than for Aβ1-42, one reason is that there are six isoforms of tau, and several phosphorylation sites, and probably also endogenous fragments of the protein. A first preliminary version of the method has been developed in UGOT (Dr. J Pannee), based on the quantification of the tryptic tau peptide GAAPGQK making use of a centrifugal filter system for sample preparation. The method shows good linearity, sensitivity and repeatability; - A third com-

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mutability study where the 3 final CRMs will be included is now ongoing. Commutability studies for tau in the candidate reference materials for Aβ42 show these are quite commutable also for tau. Additional commutability studies will be needed to produce a material with high tau concentration, either by spiking or by using ventricular CSF with high tau concentrations, and spike this into a pool of normal CSF. There is a growing use of Aβ40, and it had previously been discussed that a reference material would be useful. The consensus of the WG is that an indicative value for Aβ40 would not be useful, but the existing LS-MS method for Aβ42 could be adapted for Aβ40, and submitted as reference method to IFCC and JCTLM. In the meantime JRC has assessed homogeneity and stability (including one-year stability) in for Aβ40 in the materials produced for Aβ42. Therefore the certification of Aβ40 in one of these materials would require only the value assignment measurements. • WG - Standardization of Bone Marker Assays (WG-SBMA), Chair: Howard Morris (AU) This is a joint activity with the International Osteoporosis Foundation. During 2017 ongoing progress towards WG-SBMA terms of reference included: Term of Reference 1: Standardize or harmonize (as technically feasible or appropriate at this time) clinical assays available for routine and research use for the serum assay for C-telopeptide fragments of collagen type I α1 chains containing the epitope GluLys-Ala-His-Asp-s-Gly-Gly-Arg in an isomerised form (also known as serum Crosslaps (CTx)). Accomplishments include: The comparability study of the two major clinical assays for CTX has been completed at four European centres including data on the effects of serum or plasma specimen, fasting or non-fasting subjects and males and females presenting to osteoporosis clinics on the comparability of the results of assays from two manufacturers used by clinical laboratories. A draft manuscript is being finalized in preparation for submission to an appropriate peer-reviewed journal. Term of Reference 2: Standardize or harmonize (as technically feasible or appropriate at this time) clinical assays available for routine and research and the serum assay for N-terminal Propeptide of Type I Procollagen (P1NP). Accomplishments include: The comparability study of the two major clinical assays for PINP has been completed at four European centres including data on the effects of serum or plasma specimen, fasting or non-fasting subjects and males and females presenting to osteoporosis clinics on the comparability of the results of assays from two manufacturers used by clinical laboratories. A preliminary report has been presented at the annual meeting of the WG held in conjunction with the World Congress of Osteoporosis in Florence, 24 March 2017. A draft manuscript is to be prepared. Additional Information: The current Chair of the WG will step down immediately since he is the incoming IFCC President and Professor Etienne Cavalier is recommended by the WG to be appointed the new Chair. Analyses of data on bone turnover markers, concerning their clinical utility, collected under the aegis of previous osteoporosis therapy clinical trials is likely to be concluded in early 2018. These data will be valuable in informing future work in this field. Studies of other bone turnover markers may be considered for standardization or harmonization as technically feasible. A major issue is bone-specific alkaline phosphatase as many assays are in use in clinical laboratories. • WG - Commutability (WG-C). Chair: Greg Miller (US) During 2017 ongoing progress towards WG-C terms of reference included: Term of Reference 1: Establish operating procedures for the formal assessment of the commutability of a reference material intended for use as a calibrator, trueness control or EQA sample, taking into account different measurement procedure properties and categories of traceability described in ISO 17511. Accomplishments include: Three papers have been accepted by Clinical Chemistry and are scheduled for the March 2018 issue (see Publications at the end of this report). Term of Reference 2: Establish how to define the degree of commutability which is required for a given reference material, taking into account its intended use and the intended use of the measurand. The degree of commutability becomes the criteria used in the assessment process. Accomplishments include: Described in term of reference #1. Term of Reference 3: Propose standard terminology to describe the degree of commutability of a reference material, taking into account its intended use. Accomplishments include: Included in the part 1, 2 and 3 papers to be published in Clin Chem. Term of Reference 4: Provide guidance to manufacturers and laboratories about what information should be provided by manufacturers in relation to the commutability of reference materials used to establish the calibration traceability of a measurement procedure. Accomplishments include: Included in the part 1 paper to be published in Clin Chem. • WG - Apolipoproteins by Mass Spectrometry (WG-APO MS), Chair: Christa Cobbaert (NL) During 2017 ongoing progress towards WG-APO MS terms of reference included: Term of Reference 1. To achieve standardization of a panel of clinically relevant serum apolipoproteins (apo) A-I, B, C-I, C-II, C-III, E and apo (a) (including qualitative phenotyping where needed). Standardization is done in such a way that measurement results are traceable to SI as outlined in ISO 17511. Other traceability chains will be used in cases where traceability to SI cannot be achieved. Accomplishments include: It was decided to work on two routes: a. Development of a common Reference Measurement Procedure (RMP) with calibration labs that have Mass Spec-resources and skilled personnel. Three calibration labs volunteered: the CDC lab, the Leipzig university lab and the Leiden LUMC lab. All three labs have inhouse LC-MS methods for serum / plasma apolipoprotein quantitation and profiling, which have been published. Work plans were set up using a step-by-step approach in order to develop a common accuracy base across the three calibration labs. Based on the findings, transparent and consensus-based decisions will be taken regarding the characteristics of the entire RMP; b. Search for commutable Candidate Reference Materials. The WG currently focuses on the acquirement of apo(a) candidate Reference Material. To that end, negotiations with a research group from a Japanese university are ongoing. The first preliminary commutability experiment with some of the pig-derived transgenic apo(a) across different immunoassays and the

IFCC

LC-MS test seems to be promising. Negotiations are ongoing to receive additional material. The lab of Professor Kostner performed the immunoassays; the Leiden lab further developed the LCMS test, including apo(a). Term of Reference 2: To evaluate clinical performance and clinical utility of serum apolipoprotein panel(s) for CVD risk stratification and treatment, in comparison to or together with contemporary blood lipids. Accomplishments include: Developing cohesion and a good relation between the group members: An excellent meeting took place in December in Leiden with representatives from the three calibration labs and the Austrian lab, as well as the IVD rep. • WG - Pancreatic Enzymes (WG-PE), Chair: Denis Grote-Koska (DE) During 2017 ongoing progress towards WG-PE terms of reference included: Term of Reference 1. To develop a primary reference method for pancreatic Amylase in Serum. Accomplishments include: At the meeting in Athens in conjunction with EuroMedlab 2017, the group decided to base the method on Roche’s antibodies inhibiting salivary amylase. Roche recently (11/2017) provided the desired antibodies for first experiments without costs. Term of Reference 2: To develop a primary reference method for pancreatic Lipase in Serum. Accomplishments include: Development of Lipase procedure has paused, due to insufficient results and lack of additional and reasonable ideas from the group. Several improvements were previously made, but not sufficient for a RMP. Term of Reference 3: To support EC-JRC (Joint Research Centre, Directorate F – Health, Consumers and Reference Materials, formerly IRMM) in case of studies and certification of reference materials for enzymes Accomplishments include: A commutability study of JRC of 5 candidate CRMs was performed in the Hannover calibration laboratory. • WG - Fecal Immunochemical Testing (WG-FIT), Chair: Sally Benton (UK) During 2017 ongoing progress towards WG-FIT terms of reference included: Term of Reference 1. To harmonize and/or standardize analysis of haemoglobin in faecal samples by immunochemistry (FIT). Accomplishments include: A survey compiled by Ingrid Zegers from the Reference Materials Unit at the Joint Research Centre in Geel has been completed by all quantitative FIT manufacturers. The data has been collated and presented to the group to aid discussions in terms of appropriate candidate reference materials for FIT. Term of Reference 2. To standardize the pre-analytical phase. Accomplishments include: A review has been carried out by Natasha Djedovic of all pre-analytical factors that impact FIT. This review has been distributed around the group. Term of Reference 3. To establish EQA and 3rd party IQC programmes. Accomplishments include: A document has been produced by Samantha Jones summarizing all known EQA schemes available for quantitative FIT, and qualitative FIT, around the world. Term of Reference 4. To determine impact of assay interference of Hb variants and other factors. Accomplishments include: The group has shared information on work being carried out and due for publication. Philippe Gillery, SD Chair and Joseph Passarelli, SD Secretary

EDUCATION AND MANAGEMENT DIVISION (EMD) COMMITTEES activities: • Clinical Molecular Biology Curriculum (C-CMBC) - Chair: Evi Lianidou 1. A symposium entitled “The Liquid Biopsy approach: Following the tumor in peripheral blood” was held on June 15th 2017 during the Athens EuroMedLab Congress; 2. The 2017 molecular biology course has had to be postponed to February 2018. • Analytical Quality (C-AQ) – Chair: Annette Thomas 1. Updating of the “Directory of EQA Services” was completed in 2017 and the site will be maintained by Alexander Haliassos as an IFCC Task Force on Proficiency Testing (TF-PT) and C-AQ venture. This will be updated on a regular basis. 2. The “EQA Setup Checklist” in the C-AQ section of the IFCC website was reviewed by Annette Thomas in January 2017 and tested at a workshop in South Africa. The existing checklist was deemed suitable by the audience. 3. Updating of the existing “Resource table for EQA” database will be completed in January 2018. 4. Development of eLearning presentations for the IFCC eAcademy as follows: A power point presentation on the Principles of EQA has been reviewed and updated by Annette Thomas. ‘Principles of IQC’ has been developed by Alexander Haliassos. Quality Planning has been completed by Annette Thomas. Risks and IQC principles are to be developed by Qing Meng. David Grenache is going to inquire as to whether additional relevant material may be available from AACC Clinical Chemistry Trainee Council, Pearls of Laboratory Medicine. 5. Development of a joint C-AQ / C-CLM publication on “Developing a Quality System” aimed at developing countries is in progress. A detailed plan of contributors and content was discussed and agreed between C-AQ and C-CLM at a meeting in Durban. An update of the outline chapters for the joint monograph was distributed by the C-CLM chair in November 2017. Following discussion in Durban, the title of the monograph was changed to "Practical Approaches to Quality Systems Set-up for Resource Strained Clinical Laboratories". 6. Annette Thomas conducted a workshop on 27th to 28th January 2017 in South Africa organized by the Chair of the C-EUBD. 7. To develop a Quality Ladder - a series of monographs covering the basic concepts of Quality that can be used by developing countries. • Evidence-Based Laboratory Medicine (C-EBLM) - Chair: Chris Florkowski 1. Although only two units have been uploaded so far, other topics have been allocated to C-EBLM members for recording as follows: - Audits of laboratory tests. Diagnostic accuracy studies; - POCT, pitfalls and advantages, STARD criteria, Tools for appraisal; - Diagnostic performance. EBLM process and examples; Searching the evidence, Appraisal of guidelines, Cochrane; - Meta-analysis (PHI practical example; from published paper); - Improving clinical decision making; ROC curve analysis and its application.

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2. The Endocrine Guidelines evaluated to date were reviewed in Durban, October 2017: A realistic goal is to appraise guidelines with a 1 page summary pertinent to laboratory medicine. A problem to highlight is the different assays and reference intervals and the need to let clinicians know of limitations of coverage of laboratory aspects. 3. At the Durban face-to-face meeting, the results of the global survey of perceptions of competence in EBLM and learning requirements and also in the IFCC Symposium on the IFCC Worldlab Programme were presented and discussed. 4. Invited review on POCT and clinical decision making. 5. The committee organised and conducted symposia for COLABIOCLI and IFCC WorldLab. 6. A proposal has been submitted for an educational session at AACC in Chicago in 2018. Interactive sessions: Julien Wils – How to appraise guidelines; Karina Rodriguez-Capote – Perceptions of EBLM based on an international survey (needs assessment); Annalise Zemlin – EBLM and how to appraise the literature; Hernan Fares Taie – Getting the EBLM message across; new initiatives. • Clinical Laboratory Management (C-CLM) - Chair: Sedef Yenice 1. Development of a monograph on “Project Management Basics for Laboratory Leaders” is in progress and will be finalized in the first quarter of 2018. 2. C-CLM held a Satellite Educational Workshop on "Intelligent Clinical Laboratory Management: Impacts on Quality System Improvement" at the Hilton Durban Hotel on 22nd October 2017. This event was sponsored by industrial partners as well as the Federation of South African Societies of Pathology (FSASP). A survey activity by means of speaker evaluation forms was performed at the Satellite Educational Workshop. 3. A symposium entitled "Improvement in Clinical Laboratory Services: Approaches to Adding Value" at the IFCC WorldLab, on October 25, 2017. 4. Power Point presentations of the lectures delivered at the Satellite Educational Workshop as well as the symposium at the IFCC WorldLab, Durban were uploaded onto the C-CLM website on 22nd November 2017. 5. A guide entitled “A Training Manual on Leadership Basics for Clinical Laboratory Professionals" is about to be finalized and ready to be published by the end of February 2018. 6. A joint C-AQ/C-CLM publication on “Developing Quality Systems in the Clinical Laboratory” aimed at developing countries is being developed. 7. The power points of the Leadership Training Module were uploaded onto the CCLM website on 30th January 2017. 8. Sedef Yenice was an IFCC-Abbott VLP speaker at the 2nd Conference of the Romanian Association of Laboratory Medicine (RALM) with international participation in Timișoara, from 10th till 13th May 2017. Sedef Yenice chaired the session on Quality Management with Prof.Dr.Minodora Dobreanu on 11th May 2017 and delivered two talks entitled: “Understanding quality management system: Essential strategies to improve laboratory performance” and “Role of proactive measures in clinıcal laboratory practice”. • Distance Learning (C-DL) - Chair: Janet Smith 1. The approval of educational material to be made available on or through the IFCC website, to ensure quality, continues. 2. Considerable work has been done on the curriculum. Janet Smith has completed the sections covering clinical aspects of our specialty and Ronda Greaves has completed the analytes section and working closely with Silvia Colli-Lanzi, has produced a formatted IFCC document. Version 1 of the curriculum will be published as part of the eAcademy in 2018. 3. A successful joint CPD/EMD symposium was held at the COLABIOCLI Congress in September 2017. 4. The development of the mass spectrometry area of the eAcademy is now complete and includes learning objectives. 5. The commissioning of webinar development on topics recommended by National Societies and, where appropriate, identification of relevant presentations from IFCC and National Society conferences for recording to populate the eAcademy continues. 6. Number of published modules: 118 / Number of modules pending publication: 3 7. With the appointment of Eduardo Freggiaro as the new Chair of C-IeL, more focus has been put to provide learning objectives and multiple choice questions for published webinars for which these were not originally provided. This comprehensive task is currently being undertaken by C-DL and C-IeL members and IFCC experts. This exercise will enable the next phase of the eAcademy to be successfully launched. 8. It was agreed by IFCC EB that the C-DL and C-IeL will combine to form a single committee, as of 1 January 2018, known as the Committee for Internet and Distance Learning (C-IDL). There will be two co-Chairs, one from each of the current committees. Eduardo Freggiaro (for CPD) and Loralie Langman (for EMD) will take on these roles. • Education in the Use of Biomarkers in Diabetes (C-EUBD) - Chair: Garry John 1. Committee members (CW, EE and GJ) will finalise the WHO ‘Compendium of diagnostic tests associated with diabetes’. This will be published as a joint WHO/IFCC document. WHO has returned comments; not all can be addressed. An updated document will be finalized in 2018 2. The results of the joint IFCC, WHO and IDF worldwide questionnaire on use of glucose and HbA1c testing will be finalized and submitted for publication within the next three months (preliminary findings were presented at the IDF congress in Vancouver in 2015). 3. The committee will collaborate in a project to look at the diagnostic cut-points for type 2 diabetes diagnosis using HbA1c. Currently, there is representation from IFCC, IDF and ACB. Further links will be developed with ADA and EASD and an evidence gathering project launched. 4. A project to investigate a European-wide evaluation of HbA1c EQA programmes in different countries using fresh whole blood and lyophilised samples with the aim of being able to evaluate cross National network performance has been complet-

ed successfully. The outcome can be used to educate users on the analytical variability of HbA1c measurements. The results were presented in the satellite symposium on diabetes held at the end of the Athens EuroMedLab Congress in June 2017. Additionally, a publication is being written; this will be submitted in the first instance to Clinical Chemistry. 5. Members of the C-EUBD were part of the Scientific Committee for a satellite symposium on diabetes held at the end of the Athens EuroMedLab Congress in June 2017. On 15-16 June 2017, a meeting on Diabetes was organised in Sounio as a satellite meeting of EuroMedLab in Athens. This was a very successful meeting based on participants’ feedback. 6. Committee members will work with National societies and with manufacturers to deliver educational meetings in countries that would benefit from scientific updates; this year educational meetings were held in South America, India and China and also in South Africa for delegates from Ethiopia and Kenya. 7. C-EUBD was successful in obtaining a EPSRC-IAA funding award. This funded a two day meeting in Cape Town with participants from Ethiopia, Nigeria, Kenya. The meeting was highly successful with the goal to build a network between these three countries; but principally focusing on Ethiopia. As a major focus was on POCT and improving quality procedures Annette Thomas, Chair of C-AQ, was invited to participate. Working with other IFCC committees is one of the objectives of the C-EUBD committee. Further funding (GCRF – AMD) for £20.000 has been applied for and if successful will fund two further educational meetings in Ethiopia and Cape Town. The outcome of this funding application will be out soon. 8. The Diabetes Biomarker meeting in Paarl, October 26-27, 2017 (held in conjunction with IFCC WorldLab Durban) had a good range of international speakers with high quality presentations and good interaction from the clinical and laboratory perspective. There was excellent feedback. 9. Following a successful research project by C-EUBD committee members which assessed HbA1c results in 30 Chinese Laboratories, the committee has been approached to develop an IFCC-Chinese Diabetes Society committee to improve Diabetes Services in China. 10. The C-EUBD committee provides a clinical steering committee for the IFCC international Network of Reference Laboratories. The Network continues to perform at a very high standard with all laboratories passing agreed quality standards. WORKING GROUPS activities: • Laboratory Errors and Patient Safety (WG-LEPS) - Chair: Laura Sciacovelli 1. The following activity has been concluded: - Updating of the Model of Quality Indicators on the basis of the findings of a Consensus Conference “Harmonization of quality indicators in Laboratory Medicine: two years later?” held in Padova (Italy) on 26th October 2016; - A new procedure has been introduced for data inputting of Quality Indicators by laboratories in the dedicated website (www.ifcc-mqi.com). 2. Selection and appointment of a National Leader in each country who should coordinate and manage the Model of Quality Indicators project is in progress. It is expected that the National Leader should (i) encourage the use of MQI; (ii) “personalize” the use of QIs in daily practice according to national practices, requirements and regulations; (iii) cooperate with members of the WG-LEPS providing valuable suggestions for improving the project. 3. Involvement of national scientific societies, accreditation bodies and EQA/PT providers of different countries in disseminating the MQI project and promoting participation of laboratories is in progress. 4. Identification of automated and computerized systems for easy and systematic data collection and recording is in progress. 5. Invited talk entitled “Quality indicators in laboratory medicine” at MEDLAB EUROPE in Barcelona on 14th September 2017. • Cancer Genomics (WG-CG) - Chair: Jason Park (Resigned 30 June 2017) Co-Chair: Paolo Fortina 1. The IFCC EMD symposium entitled “Implementing Cancer Genomics in Low Resource Settings” to be held at the IFCC WorldLab Durban 2017, South Africa, was as follows: Chair: Larry J. Kricka (US): 1) Genomic medicine: learning how to walk before we run – M. Ferrari; 2) Pharmacogenetic applications in oncology - RHN van Schaik; 3) Advanced laboratory techniques for low resource - L. Kricka (US) 2. At the VIII Baltic Transfusion Medicine Congress and the I Latvian Congress in Laboratory Medicine Congress held in Riga, Latvia, Paolo Fortina delivered “Technologies for Personalized Medicine” and “Clinical Applications of Cancer Molecular Biomarker” talks on 11th and 12th May 2017, respectively. 3. On 14th June 2017, a presentation entitled “Personalized Genomic Medicine Approaches in the Study of Cancer” was delivered by Paolo Fortina at the IFCC EMD Symposium “Personalized Medicine” held at the EuroMedLab 2017 in Athens. • Harmonization of Interpretive Comments External Quality Assurance (WGICQA) - Chair: Samuel Vasikaran 1. A workshop was organized for the IFCC WorldLab, Durban. Title of workshop: Interpretation and Commenting on Clinical Chemistry Results: An interactive workshop, Chair: Samuel Vasikaran; Speakers: E Kilpatrick: Case presentation and discussion; M Turzyniecka: Case presentation and discussion; K Sikaris: Case presentation and discussion. 2. A patient report comment EQA program in Africa, locally led, was initiated in Durban during IFCC WorldLab. 3. The working group is working with ISO in order to include quality assessment of interpretive commenting in ISO 15189. Submission will be put forward for the revision phase of ISO 15189. SPECIAL PROJECTS activities: • IFCC Visiting Lecturer Programme (IFCC-VLP) - Chair: Elizabeth Frank Eleven VLP applications, with a total of 21 Visiting Lecturers, were approved in 2017.

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• Working Group on Flow Cytometry (WG-FC) - Chair: Ulrich Sack 1. One course was conducted in Europe in Munich (18th - 22nd September 2017). 2. A winter school was held in St-Etienne/France (6th-10th March 2017). 3. One course was conducted in Montevideo/Uruguay sponsored by Beckman (29th -31st March 2017). 4. Ulrich Sack gave lectures in Bahir Dar, Ethiopia, as an IFCC-Abbott Visiting Lecturer. 5. Communication with India and Turkey has been initiated for future courses. • Developing Quality Competence in Medical Laboratories (DQCML) Chair: Egon Amann 1. An Open Session of the DQCML took place during the IFCC WorldLab 2017 Congress on 23rd October 2017 to facilitate meeting National Representatives who may wish to seek the support of the Project for future Quality Systems initiatives. Twelve visitors participated (1 from Nepal, 1 from Russia, 1 from Zambia, 3 from Malawi, 4 from Nigeria, plus Ronda Greaves (Australia), and Graham Beastall (UK). 2. A DQCML application for a workshop on IQC and EQA has been received from NAMLS (Nepal Association for Medical Sciences), a full IFCC member. • Workshop time frame: May / June 2018. 3. On November 11, 2017 an application for a workshop on IQC and EQA was received by MAMLS (Malawi Association of Medical Laboratory Sciences). • Two workshops will be conducted, one in Blantyre, and one in Lilongwe. • Visit dates: Monday, February 26 till Wednesday, February 28, 2018. • Lecturers & workshop moderators: Annette Thomas, Graham Beastall, Egon Amann. • An EQA program with likely material sponsorship by BioRad has been planned to be implemented immediately after the workshop. • IFCC Mentoring Programme (MENT) - Chair: Donald Young 1. The number of Mentors and Associates has been expanded: There are now 25 mentors enrolled, although not all are active. There are 46 Associates on file although several do not actively participate. Expansion of both categories continues. 2. Recruitment of Spanish speakers as mentors has been completed with the help of Rosa Sierra Amor. 3. A proposal was approved by both EMD and EB to merge the Mentoring Programme and Register of Experts into a single Working Group for Personal Support. With the implementation of this in 2018 Graham Beastall will assume overall responsibility for the newly merged WG. Leslie Lai, Chair EMD

COMMUNICATIONS AND PUBLICATIONS DIVISION (CPD) In 2017, the following members served on the CPD Executive Committee: Khosrow Adeli (CA, Chair), Edgard Delvin (CA, Vice Chair/Public Relations Coordinator), Eduardo Freggiaro (AR, Publications/Distance Learning Coordinator), Tahir Pillay (ZA, News Editor), G. L. Kovács (HU, Editor eJIFCC), and Peter Bialk (CH Corporate Representative). Janine Grant (AU, Website Editor), Maria del Carmen Pasquel (EC, WG- IANT Chair), Ellis Jacobs (US, IFCC Labs are Vital representative), Anthony Newman (NL, Publications consultant) and Ion Toporan (DK, Insoft, IT provider) were invited to attend the CPD meeting in Athens, on occasion of the IFCC EuroMedLab Congress 2017. The following is a summary list of the key CPD activities in 2017: • Three face-to-face committee meetings were held in 2017: Milan, (IT) in February, Athens (GR) in June and Durban (ZA) in October; Informal CPD meeting in San Diego on occasion of AACC. • Actions to implement the IFCC Strategic plan in support to our IFCC Membership a) Maintaining support materials and web-based tools to demonstrate the benefits of IFCC membership to all countries, with: - focus on improvement of internal communications within IFCC and its Member Societies; - major improvements for both the IFCC eNewsletter and the eJournal. Publication formats as well as news/scientific content have been enhanced considerably over the past year. b) Use and evaluate effectiveness of new support materials; - new agreement with Insoft has been reached for eNews, allowing to increase eNews frequency in 2018 and to publish it monthly; - IFCC social presence (FB, LinkedIn, Twitter) is lively and well managed: we run a paid promotion for IFCC Facebook page. During the period, we got more than 15.400 new followers. Now the total followers of the page are 23.5 K boosting IFCC page in 2nd position in the list of the similar page (next to Clinical Chemistry). And: a) Deliver the e-academy as the platform to support IFCC educational materials: - renewal of Siemens support to the initiative; - increased communication with the Spanish speaking countries with AMARA collaboration initiative b) Develop and present a series of webinars to meet the needs of Members: - Promotion of Distance Learning Opportunities for Member Societies & their Membership via eAcademy. • Enhancement of IFCC Organization’s Public Relations/Visibility. • Social Media enhanced presence. • IFCC App continues to be updated with IFCC initiatives and activities. A new update is planned for 2018 • New initiatives to promote the image of the IFCC to its individual members, to the biomedical industry and to the worldwide health care community at large. • Contribution to IFCC congresses with organization of CPD Sessions and Symposia in 2017 • Completion of Electronic Journal of IFCC (eJIFCC) renumbering and ordering of all archived issues for indexing by MEDLINE/PUBMED. • Communications to list eJIFCC into Google Scholar, Thomson Reuters, Scopus, and Web of Sciences, continue. CPD Symposia at 2017 Meetings: • Athens, Greece, IFCC/EFLM EuroMedLab, 11-15 June 2017 CPD Symposium: Role of Communication in P4 Laboratory Medicine - Chair: Khosrow Adeli (CA): Online Resources for Patients and Healthcare Professionals

IFCC

– T.Pillay (ZA); eLearning and Online Educational Tools in Laboratory Medicine – P. Vervaart (AU); Electronic Apps and Medical Diagnostics Data Management – K. Adeli (CA). • Punta Del Est, Uruguay, XXIII COLABLIOCLI, 17-20 September 2017 C-DL and C-IeL Joint Symposium: The IFCC eAcademy: Progress and the future Chair: Janet Smith (UK): The IFCC Curriculum – J. Smith (UK); The eAcademy: technical aspects and the present.me software - P Vervaart (AU); Translation of eAcademy material – E.L. Freggiaro (AR). • Durban, South Africa, IFCC WorldLab, 22-25 October 2017 CPD Symposium: "Value of Laboratory Medicine in Healthcare Delivery" - Chair: Khosrow Adeli (CA): Anatomy of a value proposition for laboratory medicine - H. Morris (AU); Critical review of the evidence supporting the value of lab medicine in clinical care - K Adeli (CA); Demonstrating the value of laboratory tests: a clinical and economic perspective – W. van der Helm (CH). Committee on Public Relations (C-PR), Chair: Edgard Delvin (CA) A Committee Meeting was held in Athens, to which most members attended. The 2017 SURVEY directed towards the individual members of the National Societies and Regional Federations was conducted and results presented on the eNews. The C-PR contributed to the PROMOTION OF EJIFCC INDEXING, THE IFCC APP AND THE WEBSITE. It is developing new POSTERS and BROCHURES, so to reflect the new IFCC value to members. The C-PR re-wrote its TERMS OF REFERENCE so to broaden its reach. As for the LABS ARE VITAL CONSORTIUM, the collaboration continued. The projects for the incoming year include the preparation of a new action plan, along with the continuation of development of promotional tools targeting the lay audience inspired by the initial document “Understanding Laboratory Medicine”. The C-PR is presently developing a series of multi-panel posters on different clinical subjects that could be adapted to the local needs/policies, printed by National Societies or displayed on TV screens. To this end, template PowerPoint presentations will be developed in the course of next year. Committee on Internet and e-Learning (C-IeL), Chair: Eduardo Freggiaro (AR) A Committee Meeting was held in Athens, along with a C-IeL and C-DL joint meeting. Among the C-IeL accomplishments, the Content Management Software (CMS) used to maintain the IFCC website was updated, although no changes were made to the IFCC website layout. The C-Iel will work on RIA and DIV pages layout to harmonize them with the IFCC website design. IFCC eAcademy: thanks to Siemens, that will continue providing funds for the project in general the eAcademy project continued its growth, with 117 resources published, 24 of them already completed with Learning Objectives and Multiple Choice Questions ready to be deployed in eAcademy phase 2. New experts are joining so to add original content. A consultant will be hired to coordinate the eAcademy activities so to fulfil Phase 2 deployment, including User’s profile, self-testing and certificate production, along with a significant increase in the number of available learning modules. C-DL and C-IeL held a JOINT SYMPOSIUM on EACADEMY AT COLABIOCLI CONGRESS, which was very well received: Dr Michael Bennett (AACC president) attended the symposium and expressed his interest in eAcademy. WG-IANT Meeting: presentation of the eAcademy Translation Project. This working group has a meeting in Punta Del Este during the COLABIOCLI congress. C-IeL chair gave a detailed presentation about the Amara platform for collaborative translation. This idea was very well received by WG members. Originally, this project was under the C-IeL umbrella. In this meeting the project was officially assigned to WG-IANT and María del Carmen Pasquel will continue leading the initiative. At the moment, 26 members have joined the translation team. Website: The website continues to develop in ‘real time’ and it continues to be a major communication tool, a repository of resources, a window for IFCC members and Functional Units and a hosting platform for IFCC initiatives and projects. Several major and minor updates have been performed in 2017. Policy and Procedure for IFCC functional unit web pages have been prepared and final version will be ready for circulation shortly. Social Media: Thanks to a promotion campaign, IFCC has now more than 23.5 K followers in Facebook, with which we are in 2nd position in the list of the similar pages (next to Clinical Chemistry). Working Group on Electronic Journal of the IFCC (WG-ejIFCC) Chair: Gabor Kovacs (HU) Major accomplishment: All archived issues of eJIFCC, published online by PubMed since October 2016, have been fully reorganized and converted in accepted format for indexing in PMC. The process will continue in 2018 until the full eJIFCC archive will be published in PMC. Next steps: follow up of our application to WoS and Scopus for indexing of eJIFCC. A new editor in chief will take over the role, as prof. Gabor Kovacs has completed his second term in December 2017. Many thanks to him for his commitment to increase further the eJIFCC quality level, and valuable efforts to bring our Journal in the renown international scientific publications arena. A new editorial board member joined the WG: Tamas Kőszegi (HU). The CPD will identify a few associate or deputy editor/s to support the future, increasing work of the eJFCC Editor. The eJIFCC collection is available at: http://www.ifcc.org/ifcc-communications-publications-divisioncpd/ifcc-publications/ejifcc-journal/e-journal-volumes/ Volume 28 no 1/ 2017 – Feb 2017. The issue contains 9 manuscripts, 7 of them guest-edited by Prof. Edgard Delvin (CA), on “Recent Advances in Pediatric Laboratory Medicine” - Volume 28 no 2/2017 – May 2017. The issue contains 7 manuscripts (+foreword), 5 of them guest-edited by Prof. Tamas Kőszegi (HU) on “Advances in the diagnosis of sepsis” Volume 28 no 3/2017 – Oct 2017. The issue contains 7 manuscripts - Volume 28 no 4/2017, the last published under Prof. Kovacs’ chairmanship, Dec 2017. The issue is a TF-CKD special issue on “The laboratory diagnostics of chronic kidney diseases”. It contains 11 manuscripts, (+foreword and farewell article), 8 of them guest-edited by Dr Flavio Ferraz de Paes de Alcantara (BR) and Dr. Vanja Radišić Biljak (HR).

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Working Group on IFCC NEWS (WG-e-NEWS), Chair: Tahir Pillay (ZA) The WG membership consists of representatives from Spain, Serbia, Morocco, Nigeria, South Africa, Greece, Brazil, Canada, Cyprus, Malaysia, Mexico, Morocco, Nepal, Poland, Slovenia, Tunisia, Uruguay & Vietnam. Additionally, there are National Society liaisons from Australasia, Chile, Serbia, UK, USA, Paraguay, Spain, Taiwan, Pakistan, Latvia & Vietnam. The working group meeting was held in Athens on occasion of the EuroMedLab Congress Newsflash: A number of “eNewsflash” items were sent between issues of the newsletter and this has contained items of special and urgent interest. The schedule of 6 issues per year has been maintained with good content and we plan to increase the rate of publication to monthly in 2018 as the IFCC board has requested a shorter and more frequent newsletter. Requests for articles are sent to all eNewsletter WG members, National Societies liaisons and National Representatives (through the IFCC Office) with a reminder of the deadlines. The reports of the IFCC Young Scientists task force and the PSEP reports from awardees tend to feature prominently. This helps to highlight the contribution of the IFCC to international clinical chemistry across the world and has also ensured that contributions from members continue to come to the newsletter. The eNews continue to coordinate with Social Media editor to post most popular articles on IFCC Social accounts. The newsletter provides regular updates of the structure and strategy of the IFCC, Working groups, and Divisions and several of these have now appeared. The eNews collection is available at: http://www.ifcc.org/ifcc-communicationspublications-division-cpd/ifcc-publications/enewsletter/enews-volumes/ The eNews Flash collection is available at: http://www.ifcc.org/ifcc-communications-publications-division-cpd/ifcc-publications/enewsletter/enews-flash-archive/ Relationship with LabMedica International. LMI prints a selection of the articles. The eNews editor is on the editorial board of LabMedica. Working Group – Spanish (Ibero-American) Nomenclature and Transaltions (WG-IANT), Chair: Maria Del Carmen Pasquel (EC) Membership: New members are participating into the WG activities representing all Ibero American IFCC countries. The RIA section of IFCC website is continuously updated. New programs and initiatives are planned, mainly focused on updating the RIA section of the website. DiV, Diagnostico in Vitro continues to be a major product of the WG-IANT activity, Three issues have been published in 2017. DiV main sections are: Editorial, News and Updates, Scientific Articles, Letters to the Editor, Young Scientists corner, Radio Interview El Microscopio. The DiV collection is available at: http://www.ifcc.org/div/ El Microscopio: Programmes are regularly broadcasted and some of them are in English, for a broader circulation. This successful initiative is in search of additional funding and tools for promotional purposes. Corporate Member Activities - Dr. Peter Bialk Peter Bialk (Roche Diagnostics) has provided great support for IFCC public relations. His recent activities included supporting recording of ICPLM Congress presentations for the eAcademy. Khosrow Adeli, CPD Chair

IFCC TASK FORCES • TASK FORCE ON ETHICS (TF-E) Achievements during 2017: • Created ethics teaching modules "Pearls" for Clinical Chemistry Trainee Council website. "Ethical Issues in Biobanking" by Ann Gronowski and Gwen Clark was completed and is now posted on the CCTC website. The Pearl has been shared with IFCC to post on the IFCC website. • "Ethical Issues in Laboratory Medicine" Symposium was presented at the EuroMedLab meeting, Athens 2017. Symposium included three talks: "A primer in biomedical ethics", Ann M. Gronowski; "Ethics in publishing", Nader Rifai; "Case studies in ethics in laboratory medicine", Trefor Higgins. • Updated TF-Ethics website. • TF-Ethics held a committee meeting in Athens during WorldLab. • IFCC enews article on TF accomplishments and future plans was published February 2017. Plans for 2018: • Create a survey to send all IFCC member societies regarding their current ethics documents and future needs regarding ethics. Survey will request society documents on COI, code of ethics and relationship with industry. TF will then review all documents and create a list of suggested elements for each as a guide for member societies wishing to create their own documents. • Create Ethics "toolbox" for Member Societies (starting with example COI and code of ethics from member societies) based on results from above survey. Ann Gronowski, Chair • TASK FORCE ON PEDIATRIC LABORATORY MEDICINE (TF-PLM) Activities: The TFPLM has held 5 teleconferences during 2017 through the provision of GoToMeeting, kindly provided by the AACB contacts. The majority of these meeting focused on the organisation of the 14th ICPLM being held in Durban in October. A report of the ICPLM can be found be found in the February’s IFCC news detailing the congress. There were 120 registered participants from around the world attending this satellite meeting which preceded the IFCC WorldLab conference. The four Plenary Lectures and nine Symposia were delivered by 30 speakers, with over 25% of delegates from sub Saharan Africa. For first time the Congress was able to offer a large number of travel scholarships funded by sponsorship from the Society for the Study of Inborn Errors of Metabolism, which the organisers and successful applicants were truly grateful. In total 22 scholarships were awarded to delegates with 50% going to delegates from Africa and 50% the rest of the world. Update of Reference Intervals: A summary of the TF activities in this theme were presented in the reference intervals symposium at ICPLM.

Update on Critical Values: A summary of the TF activities in this theme were presented in the Panel discussion of critical values during the ICPLM. Update of Educational Activities: The main education activity of the ICPLM was as expected the ICPLM. A large proportion of the lectures delivered were recorded for the IFCC e-Academy, but currently none have been published on the website. Three members recorded interviews for the El-Microscopio audio website discussing the ICPLM and WorldLab congress. The TFPLM gave auspices to the EuroMedLab 2017 Satellite meeting on Inborn Errors of Metabolism held from 10-11/06/2017 in Athens and was organised by two of the TF members ( MH and IP). Several members of the TF were invited to prepare a consensus paper of paediatric biochemistry for the journal Clinical Biochemistry. • Paediatric Laboratory Medicine – Some reflections on the sub-specialty. Grey VJ et al (2017) Clin Biochem 50 (12), 648-650. The TF has collected and collated several curriculums covering the pre and post registration/graduate training of laboratory and clinical staff in the area of paediatric biochemistry and inborn errors of metabolism. It is hope that this can be used to assess and prepare the content of future curriculum to ensure that important areas are covered and there is consistency across the board. The TF has commented on recently published curriculum in the UK and that of the IFCC education committee. Michael Metz (Chair) and Tim Lang (Vice-Chair) • TASK FORCE ON PHARMACOGENETICS (TF-PG) The TF-PG will merge with the Committee on Molecular Diagnostics (C-MD) under the Scientific Division for 2018. The Co-Chairs will be D. Payne and M. Linder. Mark W. Linder (Chair) • TASK FORCE ON CHRONIC KIDNEY DISEASE (TF-CKD) (JOINT WITH WASPALM) Volume 28 no 4/2017 of the eJIFCC, the last published under Prof. Kovacs’ chairmanship, Dec 2017 was a TF-CKD special issue on “The laboratory diagnostics of chronic kidney diseases”, conataining 11 manuscripts, (plus foreword and farewell article), 8 of them guest-edited by Dr Flavio Ferraz de Paes de Alcantara (BR) and Dr. Vanja Radišić Biljak (HR). The TF-CKD will become the C-CKD, under the Education and Management Division in 2018, and Chaired by F. Alcantara. Flavio F Alcantara, (Chair) • TASK FORCE FOR YOUNG SCIENTISTS (TF-YS) Achievements during 2017: IFCC-TF YS is devoted to the preparation of young scientists for the ongoing challenges in laboratory medicine and healthcare practices. The TF creates a strong young scientists support group involving 1 chair; 5 core members; 1 consultant; 35 corresponding members; 1 corporate member. About 1500 members make up a large network at Google group, LinkedIn, Facebook and Twitter with regular exchange of information. More than 600 registered users at Lab-Surfing.com; Creation of a Discussion Forum for fast and easy communication (Q&A). Meetings conducted at IFCC-EFLM EuroMedLab Athens 2017, June 11-15: “Meet the Experts” Sessions, Open meeting with Quiz, Social Gathering followed by Dinner; COLABIOCOLI, Uruguay 2017, Sep 17-20: “Workshop for Young Scientists Networking”; IFCC WorldLab, Durban 2017, Oct 22-25: Symposium theme “ISO Accreditation & Quality Assurance” focusing African Regions and networking with young scientists; AMBICON, India 2017, Nov 17-19: Symposium theme ”IFCC Young Scientists Forum”; ACBICON, India 2017, Dec 4-6: Symposium theme “Leadership Skills: Essential for Career & Organisational Success”, ACBI-IFCCTFYS Awards 2017 to 5 young scientists; Online webinars for YS; Promotion of the “Mentorship Programme” and “Research Booklet”; New interviews published. The TF-YS webpage was updated throughout the year to reflect recent and forthcoming activities. Plans for 2018: Extend the YS network and encourage participation amongst each other the YS members. Symposiums at 1st IFCC, EFLM, AFCB Conference "Laboratory Medicine: Meeting the needs of Mediterranean Nations"– Rome, July 2018; Joint Symposium with SYCL at AACC Chicago, July 2018; IFCC General Conference Budapest, November 2018; Session and YS awards at National Conference, India; 3 Online Webinars; publishing Global “IFCC TF-YS Survey “results and initiating new needs based survey; Promotion of: Mentorship Programme, Lab-Surfing.com, Research Booklet, Radio “EI Microscopio” and uniting YS globally. Pradeep Kumar Dabla (Chair) • TASK FORCE ON CLINICAL APPLICATIONS OF CARDIAC BIOMARKERS - (TF-CB) Educational materials describing the properties of high sensitivity cardiac troponin activities were produced, including a poster and a mouse pad. At each of the IFCC Athens and AACC San Diego meetings, 3000 posters and 1000 mouse pads were distributed to attendees at the IFCC booth. The TF completed the first of 2 tasks regarding updating educational tables for both cardiac troponin assays and natriuretic peptide tables. Three tables were posted in June for high sensitivity, contemporary and POC troponin assays, representing commercial package inserts globally on our webpage. These tables will be referenced as a link to the ‘Fourth Universal Definition of Myocardial Infarction’ paper that will be published next spring 2018. A fourth table on natriuretic peptides was posted in August. The TF established a joint venture with the AACC Academy, to draft updated educational guidelines regarding cardiac troponin, which has resulted in a manuscript that is under review at Clinical Chemistry. At the December 2017 meeting in London, manuscript preparations will begin for two papers addressing the characteristics of the tables (troponin and NP) posted on the IFCC website. The Chair has submitted proposals to the 2018 IFCC meeting in Barcelona and the 2018 AACC meeting in Chicago, to present TF-CB activities. The Chair has been in communication with the Chair of the POCT group (Chair Rosy Tirimacco), to improve the harmonization of cardiac biomarker educational documents and educational materials. Rosy will be invited to the December meeting in London. The TF has a 2017-2018 goal of developing a smart-phone APP to assist laboratorians and clinicians in better understanding cardiac biomarker as-

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says based on data contained in the web-based tables and published educational documents in collaboration with the IFCC office and industry colleagues. This is a high priority agenda item for December meeting. Fred Apple (Chair) • TASK FORCE ON POINT OF CARE TESTING (TF-POCT) The TF-POCT will become the C-POCT under the Education and Management Division, with Rosy Tirimacco as the Chair. The EB agreed to a request from the Chair, Rosy Tirimacco, for a 12 months extension to find a new Chair and nominate two new members. Rosy Tirimacco (Chair) • TASK FORCE ON PROFICIENCY TESTING (TF-PT) Organization, history and previous achievements: The TF-PT is a multidisciplinary effort focused on the analysis and the exploration of Proficiency Testing issues. The main project of the TF-PT is the creation of an online database - web application (PTDB) accessible via web browsers also as via specific applications, for the major mobile platforms, offering much more functionality and ease of use. The contents of this database are the analytes (tests, measurands) that have to be filed with all possible synonyms, and the methods (assays, instruments, reagents etc) also with all possible synonyms. Another part of the database, maintained with the cooperation of the IFCC C-AQ and of EQALM, is the PT providers section containing all their contact information, their programs with the analytes, frequencies, type of statistics, commutability of control materials, and their accreditation or certification status etc. During 2014, the TF-PT had his kick-off meeting at the WorldLab 2014 in Istanbul; afterwards at the EuroMedLab 2015 congress in Paris the members of the TF-PT had their second annual meeting. The result of this meeting was the production of two draft documents: one entitled “Exploration and Clarification of Specifications for the TF-PT Project” containing the analytical terminology of the project, and one entitled “Webpage IFCC Market Place Forum Supply and Demand EQA” describing the basic workflow diagram of the proposed application-database with various examples in a table form. InSoft, the IT provider of the IFCC, appointed in November 2014, using the preliminary workflow and schematic of the PTDB started the implementation of this project and a functional prototype which was presented at the Madrid General Conference of IFCC. During this meeting the Chair of the TF-PT presented an interactive workshop entitled “Meeting the clients with the producers on Proficiency Testing of rare analytes” describing the aims, the projects, and the prototype of the PTDB. The presentation can be found at http://www.ifcc.org/media/412855/S6.12.Haliassos_WS_GC2016.pdf. Moreover, at the Madrid GC, the members of the TF-PT had their third annual meeting. Following this meeting, the TF-PT chair in cooperation with the chair of the C-AQ, prepared two emails, approved by the President of IFCC, to be sent automatically by the PTDB when this project will be rolled out, to the scientific community. These emails will invite the PT-EQA providers to cooperate in this project and register or update the data of their organizations in the database. Moreover, will request the cooperation of the National Representatives of the IFCC in order to spread the word about the functionalities of the PTDB project to the PT-EQA providers of their countries. During the fall of 2016 the chair of TF-PT participated at the EQALM EB meeting (Barcelona, October 13th & 14th, 2016) where was finalized the participation and the help of the EQALM members for the implementation, updating and maintenance of the TF-PT database, especially the “P”roviders section. During the last quarter of the 2016 another four (4) corresponding members, nominated by National Societies (3) or by Corporate Members (1), were added to the TF-PT. Achievements during 2017: The roll out of the “P”roviders database by InSoft was achieved by the middle of February 2017 and the, previously mentioned, letters to the PT providers and the National Representatives were sent during March 2017. As a result, the PTDB has been updated by the organizations already included and amended by new PT providers listing their schemes. As of today (January 2018) we have 68 providers from all around the world registered in the PTDB and the latest additions are from Mexico, Russian Federation, Iran and India. The PTDB can be consulted directly at http://ptdb.ifcc.org/providers During the EuroMedLab 2017 congress in Athens, the members of the TF-PT had their fourth annual meeting and decided to start the development and the implementation of the “A”nalytes section and to start adding all the common analytes from the already registered EQA-PT providers. In order to continue this effort we decided to produce a document describing all the fields required for the creation of an Analyte record and documenting this procedure, starting from the biomarkers of neurodegenerative diseases as they are quite complicated, but well documented and we have members at the committee with expertise in these markers. During the EuroMedLab 2017 congress in Athens, the symposium on EQA-PT issues entitled: “External quality assurance - just a necessary evil or a valuable tool in laboratory management?” was co-organized with the EQALM and, although scheduled on the last day of the Congress, had great success. During the fall of 2017 the chair of TF-PT participated at the EQALM EB meeting (Dublin, October 19th & 20th, 2017) where the next steps of the participation and the help of the EQALM members for the implementation, updating and maintenance of the PTDB, especially now including the new “A”nalytes section was discussed, and the PTDB was advertised among the EQALM members. From January 2018, according to the re-organization plan of the IFCC TFs, the TF-PT has become a committee, the C-PT, under the Education and Management Division (EMD). Plans for 2018: After the implementation of the above-discussed document, describing all the fields required for the creation of an “A”nalyte record and documenting this procedure, the development of the “A”nalytes database will be started by InSoft. At the same time, the C-PT with the help and cooperation of the InSoft will start the development of e-documents on the use of the PTDB (manuals). During the fall of 2018 the chair of the C-PT plans to participate at the EQALM EB meeting (Zagreb, October 18th & 19th, 2018) where the next steps of the participation and the help of the EQALM members for the implementation, updating and maintenance of the C-PT database and the planning of a new co-organized symposium during EuroMedLab Barcelona 2019 congress. Alexander Haliassos (Chair)

IFCC

FOUNDATION FOR EMERGING NATIONS - FEN Introduction: The FEN) is established under Swiss law as a non-profit making charitable trust, which is devoted to fund raising and to supporting programmes that help to improve the quality and delivery of laboratory medicine services, particularly in emerging nations. Board of Directors: There are five members of the FEN Board of Directors. Dr Graham H Beastall (UK) Chair; Dr Michelle Rossier (CH); Prof Thomas Brinkmann (DE); Ms Lucia Monaco (IT); Prof Tomris Ozben (TR). Biographies of the Board of Directors are available from www.ifccfoundation.org Board Meetings: During 2017 the Board met (by Skype) on four occasions (April, July, October and December). There was a high level of participation by Directors. Confirmed and signed Minutes of those meetings are available on request. Achievements: During 2017 the FEN achieved the following: • Compliance with the Handelsregister des Kantons Schwyz and the Swiss Foundation Supervisory Authority • Publication of the annual report for 2016 • Approval of audited accounts for 2016 • Operation of the FEN website www.ifccfoundation.org • Publication of two newsletters • Promotion of the FEN through various IFCC media outlets • Liaison with the AACC Global • Fundraising initiatives • Support for and monitoring of four funded projects Completed Projects: • ‘Lab Surfing’: A resource to facilitate global exchange between young scientists: ‘Lab Surfing’ is a project designed and operated by the IFCC Task Force for Young Scientists (TF-YS). ‘Lab Surfing’ is a website that connects YS from around the world and facilitates self-organised exchange programmes between YS trainees in laboratory medicine. Several hundred YS are engaged with ‘Lab Surfing’. A report is on the FEN website. Details are available from www.lab-surfing.com • ‘Adopt a Professional’: Collaboration to support the training of laboratory medicine: specialists The ‘Adopt a Professional’ programme is a collaboration between the FEN and the Società Italiana di Biochimica Clinica e Biologia Molecolare Clinica (SIBioC) to support training in laboratory medicine to scientists from designated emerging nations. Trainees are selected on merit to spend time training in an Italian centre of excellence. During 2017 two trainees participated in the ‘Adopt a Professional’ programme: • From June to August Lumbani Phiri from Zambia trained in Palermo under the supervision of Prof M. Ciaccio. A report is on the FEN website • From December José Guillermo Pereira Brunelli from Paraguay trained in Rome under the supervision of Prof. S. Bernardini. A report is awaiting approval. Ongoing Projects: • ‘Africa LabMed Radio’: The FEN supported the purchase of equipment to enable an internet radio station to be established for all countries in Africa. Interviews and news items will be archived. Young scientists have been recruited as reporters. The project will reach maturity in 2018. • Proficiency of malaria microscopists in Ethiopia: The Ethiopian Public Health Institute has an ambitious programme to eliminate malaria from areas of the country. The proficiency of the microscopists who make the diagnosis requires improvement if this is to be achieved. The FEN is working with EPHI to develop training support for microscopists. The project will be implemented during 2018. Challenge: The greatest challenge faced by the FEN during 2017 was raising funds to support the ongoing work of the Foundation. Acknowledgement: The FEN acknowledges expert administrative support from Ms. Paola Bramati of IFCC. Graham Beastall (Chair)

ORGANIZATIONS (REGIONAL) AFFILIATED WITH IFCC There are six main Regional Professional Laboratory Medicine organizations which can be considered IFCC regional partners: • AFCB - Arab Federation of Clinical Biochemistry • AFCC - African Federation of Clinical Chemistry • APFCB - Asia-Pacific Federation of Clinical Biochemistry • COLABIOCLI - Latin-American Confederation of Clinical Biochemistry • EFLM - European Federation Clinical Chemistry and Laboratory Medicine • NAFCC - North American Federation of Clinical Chemistry and Laboratory Medicine More information about these affiliate organizations and their activities can be found on our website (www.ifcc.org) and are included in the IFCC Annual report 2016, web edition.

FOR MORE INFORMATION ON THE IFCC CONTACT: IFCC Office • Via Carlo Farini 81, 20159 Milan, ITALY Tel: (39) 02-6680-9912 • Fax: (39) 02-6078-1846 E-mail: ifcc@ifcc.org • Web: www.ifcc.org

Special Supplement to Lab Medica International • 40

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LabMedica International

Mycobacterium Mutations Associated with Clarithromycin Resistance ycobacterium abscessus is a leading cause of respiratory diseases and soft tissue infections and it is naturally resistant to many antibiotics in vitro, which complicates clinical treatment and leads to unsatisfactory results. Macrolides, such as clarithromycin and azithromycin, were regarded as the foundation for the therapeutic regimen for M. abscessus complex infections. However, clarithromycin resistance is increasing dramatically among M. abscessus complex. Microbiologists at Tongji University School of Medicine (Shanghai, China; www.med. tongji.edu.cn) collected specimens from the affiliated Shanghai Pulmonary Hospital and a collection of 139 M. abscessus subsp. abscessus and 36 M. abscessus subsp. massiliense clinical isolates was used to explore the utility of the polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) technique for the rapid identification of 23S rRNA (Adenine(2058)-N(6))methyltransferase Erm(41) (erm(41) and the 23S ribosomal RNA (rrl) gene mutations. The team designed four primer sets to scan for mutations in the erm(41) and rrl genes using DGGE. PCR reactions and electrophoresis, as well as band retrieval and gel analysis, were performed according to previously described protocols. A Sensititre RAPMYCO panel (TREK Diagnostic Systems, East Grinstead, UK; www.trekds.co) was used to test the susceptibility of various antibiotics including clarithromycin against the 175 M. abscessus complex isolates. The authors found a combination of 16 different DGGE patterns were observed for erm(41) gene, including 16 in M. abscessus subsp. abscessus and one in M. abscessus subsp. massiliense. Six DGGE patterns were obtained for rrl gene. Mutations in the erm(41) and rrl detected by DGGE were 100% identical to mutations detected by DNA sequencing. Among the 139 M. abscessus subsp. abscessus isolates, 36 isolates exhibited clarithromycin resistance on day 5. The other 103 were sensitive to clarithromycin on day 5, and 83 of these exhibited inducible resistance after 14 days incubation. Of the 36 M. abscessus subsp. massiliense isolates, 27 were sensitive and eight were resistant to clarithromycin on both days 5 and 14. Notably, one of the isolates was sensitive to clarithromycin on day 5, but displayed

LabMedica International June-July/2018

inducible resistance on day 14. The authors concluded that their results demonstrated that DGGE technology is very sensitive to point mutations, as well as to small insertions and deletions in DNA sequences. The accuracy was essentially 100% among targeted fragments of the erm(41) and rrl genes. The results of whole genome sequencing confirmed DGGE efficacy, all distinct nucleotides polymorphisms were detected. PCR-based DGGE is a practical technique for the rapid detection of mutations in the erm(41) and rrl genes associated with clarithromycin resistance in M. abscessus complex. The study was published in the December 2017 issue of the Journal of Microbiological Methods.

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Image: The Sensititre OptiRead automated fluorometric plate reading system for use with Sensititre microtiter plates in antibiotic-susceptibility tests (Photo courtesy of Thermo Fisher Scientific).

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Test Identifies BRCA2 Gene Mutations for Cancers any variants of uncertain significance (VUS) have been identified in breast cancer 2 (BRCA2) through clinical genetic testing. VUS pose a significant clinical challenge because the contribution of these variants to cancer risk has not been determined. A new test recently developed shows which mutations in the BRCA2 gene make women susceptible to developing breast or ovarian cancers. The laboratory-based test can establish which inherited mutations called VUS in the BRCA2 gene are involved in cancer. Scientists at the Mayo Clinic (Rochester, MN, USA; www.mayoclinic. org) and their colleagues conducted a comprehensive assessment of VUS in the BRCA2 C-terminal DNA binding domain (DBD) by using a validated functional assay of BRCA2 homologous recombination (HR) DNA-repair activity and defined a classifier of variant pathogenicity. Among 139 variants evaluated, 54 had equal to or greater than 99% probability of pathogenicity, and 73 had equal to or greater than 95% probability of neutrality. Functional assay results were compared with predictions of variant pathogenicity from the Align-GVGD protein-sequencebased prediction algorithm, which has been used for variant classification. Relative to the HR assay, Align-GVGD significantly over-predicted pathogenic variants. The team subsequently combined functional and Align-GVGD prediction results in a Bayesian hierarchical model (VarCall) to estimate the over-

all probability of pathogenicity for each VUS. In addition, to predict the effects of all other BRCA2 DBD variants and to prioritize variants for functional studies, they used the endoPhenotype-Optimized Sequence Ensemble (ePOSE) algorithm to train classifiers for BRCA2 variants by using data from the HR functional assay. The study was published on January 25, 2018, in the American Journal of Human Genetics. Image: Endometrioid ovarian carcinoma cells show nuclear staining for BRCA2 (right panel); BRCA2-negative staining in endometrioid ovarian carcinoma (left panel) (Photo courtesy of The University of Texas MD Anderson Cancer Center).

Nanowire Technology Developed to Detect Cancer Biomarkers in Urine nalyzing microRNAs (miRNAs) within urine extracellular vesicles (EVs) is important for realizing miRNA-based, simple, and noninvasive early disease diagnoses and timely medical checkups. A new approach for detecting cancer biomarkers in urine has been developed using a device composed of nanowires anchored into a microfluidic substrate. This device enables EV collections at high efficiency and in situ extractions of various miRNAs of different sequences (around 1,000 types) that significantly exceed the number of species being extracted by the conventional ultracentrifugation method. Scientists at Nagoya University (Furo-cho, Japan; http://nagoya-u. ac.jp) and their colleagues fabricated nanowire-anchored microfluidic device for in situ extraction of urine EVâ&#x20AC;&#x201C;encapsulated miRNAs was fabricated by bonding the nanowire-embedded polydimethylsiloxane (PDMS) substrate and a herringbone-structured PDMS substrate. This new approach relies on playing the forces of negatively charged EVs off of positively charged nanowires to extract the miRNAs from the urine of patients with a variety of diseases. The team looked at samples from

patients with pancreatic, liver, bladder, and prostate cancer, in addition to healthy subjects. The scientists used a syringe pump to flow urine into the device, and then transferred the extracted samples on Torayâ&#x20AC;&#x2122;s 3D-Gene microarray platform (Toray Industries, Tokyo, Japan; www.toray.com) for miRNA analysis by pipetting. Using the device, they were able to detect 1,106 different types of miRNAs in a single milliliter, versus an average yield of 200 to 400 miRNAs in total obtained using conventional methods, such as centrifugation. The mechanical stability of the anchored nanowires during the buffer flow, as well as to the electrostatic collection of EVs onto the nanowires attributed to the success of the device. The approach yielded potential cancer-related miRNAs in urine for not only urological malignancies such as prostate cancer and bladder cancer, but also non-urological ones such as liver cancer and pancreatic cancer, the scientists believe it will be widely applicable. The study was published on December 15, 2017, in the journal Science Advances. LabMedica International June-July/2018

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LabMedica International

Esophageal Cancer GWAS Leads to Risk Variants enome-wide association studies have identified common variants associated with risk of esophageal squamous cell carcinoma; however, these common variants cannot explain all heritability of esophageal cancer. New germline contributors to esophageal squamous cell carcinoma (ESCC) risk have been revealed, including a low-frequency change to the Cytochrome P450 Family 26 Subfamily B Member 1, (CYP26B1) drug metabolism gene that appears to affect blood serum levels of a tumor suppressor called all-trans retinoic acid (atRA). Scientists at the Chinese Academy of Medical Sciences (Beijing, China; www.cams.cn) and their colleagues used exome sequences for more than 3,700 individuals with ESCC and nearly 3,900 individuals without. They looked for single-nucleotide polymorphisms (SNPs) or low-frequency variants associated with risk of the disease, which is especially common in parts of China. From these data, they narrowed in on half a dozen risk sites that could be replicated in another 7,002 cases and 8,757 controls, including three common SNPs and three low-frequency variants. The team used Illumina HumanExome BeadChip arrays (San Diego, CA, USA; www.illumina. com) to profile low-frequency protein-coding variants in the ESCC cases and the controls from Beijing. After excluding samples with insufficient or low-quality data, they were left comparing exome patterns for VISITâ&#x20AC;&#x2C6;USâ&#x20AC;&#x2C6;AT: 3,714 of the ESCC cases and 3,880 controls, an analysis that led to 30 suspicious variants. The team at2018 ANNUAL tempted to verify the potential ESCC MEETING risk variants with OpenArray- or TaqBooth: 3048 Man-based genotyping on individuals from two replication cohorts: 3,120 ESCC cases and 3,919 controls from Wuhan province and another 3,882 individuals with ESCC and 4,838 without from the Chinese province of Hebei. The scientists uncovered six new risk variants at four sites in or around the CCHCR1, TCN2, TNXB, LTA, CYP26B1, and FASN genes. Three of the associations at the TCN2, CYP26B1, and FASN gene loci, were based on low-frequency variants that appeared to have higher-than-usual effect sizes. An ESCC-associated variant at CYP26B1, called rs138478634, had particularly close ties to ESCC risk in individuals with a history of smoking and/or drinking, although the team noted that rs138478634 was not linked to smoking or drinking status in control individuals. Through a series of follow-up cell line and patient serum expression profiling experiments, the group saw lower-thanusual levels of the atRA tumor suppressor in cells or individuals pumping out the rs138478634 variant-containing version of CYP26B1. The authors concluded that results of the new study extended previous findings and advanced our under-

LabMedica International June-July/2018

standing of the genetic etiology of ESCC, which might be useful for risk assessment, early detection, and targeted treatment of ESCC. The study was published on January 29, 2018, in the journal Nature Genetics. Image: A histopathology of esophageal squamous cell carcinoma with keratin pearl formation (Photo courtesy of Dr. Dharam Ramnani, MD).

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Glycan-Attaching Enzyme Defines Colon Cancer n enzyme that is absent in healthy colon tissue but abundant in colon cancer cells and this enzyme appears to drive the conversion of normal colon tissue into cancer by attaching sugar molecules, or glycans, to certain proteins in the cell. A group of 20 enzymes have been studied that initiate the first step in a particular kind of glycan modification, called N-acetylgalactosamine (GalNAc)-type O-glycosylation, found on diverse proteins. These enzymes, called GalNAc transferases (GalNAc -Ts) are variously found in different amounts in different tissues, but their functions are poorly understood. Biochemists at the University of Copenhagen (Denmark; www.ku.dk) obtained tissue microarrays from frozen tissue samples were from colorectal adenocarcinoma patients. Healthy control samples were evaluated from frozen multiple organ normal tissue array. The sections were fixed in cold 10% buffered neutral formalin for 15 minutes or in cold acetone for 10 minutes. Immunohistochemistry was

performed and processed and fluorescence micrographs were obtained on a Leica wide-field fluorescence microscope or a LSM710 confocal microscope (Zeiss, Oberkochen, Germany; www.zeiss.com). The team used the EASY-nLC 1000 UHPLC interfaced via nanoSpray Flex ion source to an LTQ-Orbitrap Velos Pro mass spectrometer (Thermo Fisher Scientific, Waltham, MA. USA; www.thermofisher.com) to categorize the proteins that GalNAc-T6 acted on cancer cells. The team used CRISPR/Cas engineering of a colon cancer cell line with and without GalNAc-T6 to understand which proteins the enzyme helped attach sugars to, and what effect this had on the cells. They found that one of the GalNAc-Ts, called GalNAc-T6, was absent in healthy colon tissue but abundant in colon cancer cells. Understanding the role that sugar-modified (glycosylated) proteins play in healthy and cancerous cells is an emerging area of cancer biology that may lead to new therapies. Hans H. Wandall, PhD, a professor and

lead investigator, said, “When we look at the 3D growth of a cancer cell line that has GalNAc-T6, it can form tubular structures with formation of something that looks like colon cancer tissue. When we take out GalNAc-T6, then suddenly the tissue formation changes to look more like the crypt structures that you would find in a healthy colon.” The study was published on January 26, 2018, in the Journal of Biological Chemistry. Image: The LSM 710 confocal microscope (Photo courtesy of Carl Zeiss).

Stability of Cardiac Biomarkers Tested in Different Samples lood-based biomarkers, such as cardiac troponin (cTn) and galectin-3, are widely used in clinical trials and/or in clinical routines as an aid for the diagnosis and risk stratification of patients with heart disease. When blood samples are used for biomarker measurements in clinical routine analyses, efforts should be made to process these samples immediately after blood collection to provide immediate results for timely diagnosis and therapy and to avoid any pre-analytical errors. Doctors at Konventhospital Barmherzige

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Brueder Linz, (Linz, Austria; www.barmherzige -brueder.at) tested the hypothesis that the analytes hs-cTnI, hs-cTnT and galectin-3 are stable in vitro at a storage temperature of −80 °C for at least one year, and they used blood samples from clinical routine analyses. The analyte concentrations of 30 patients were measured in heparin-treated plasma, EDTA-treated plasma and serum samples after the following storage conditions: 1) samples used immediately after blood collection for baseline measurements; 2) samples stored for six months at −80 °C after one freeze-thaw cycle; 3) samples stored for one year at −80 °C after two freeze-

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thaw cycles; and 4) samples stored for one year at −80 °C after one freeze-thaw cycle. Circulating concentrations of high-sensitivity cardiac troponin I (hs-cTnI) were measured with the STAT High Sensitive Troponin-I assay (Abbott Diagnostics, Vienna, Austria; www. corelaboratory.abbott) on the Abbott ARCHITECT i2000SR analyzer. The team measured hs-cTnT concentrations with the Troponin T hs assay (Roche Diagnostics, Vienna, Austria; www.roche.com) on the Roche cobas e 411. The scientists also measured galectin-3 with the Abbott Diagnostics routine Galectin-3 assay on an ARCHITECT i2000SR analyzer. The investigators reported that baseline hscTnI, hs-cTnT and galectin-3 concentrations ranged from 2.3 to 5,436 ng/L, from 5.3 to 850 ng/L, and from 8.3 to 79.3 ng/mL, respectively. After applying the default criterion for analyte stability, the three analytes were stable for at least one year even after two freeze-thaw cycles for each sample type. They observed the following variation in analyte concentrations after storage relative to the baseline values: the interquartile range (IQR) of cardiac troponin results extended from approx. 80% to 115%, and the IQR of galectin-3 results extended from approx. 90% to 110%. The authors concluded that hs-cTnI, hs-cTnT and galectin-3 were stable under the reported storage conditions irrespective of the sample type used. However, they observed a considerable variation in analyte concentrations after sample storage, which might affect the diagnostic/prognostic value of these analytes in individual patients using frozen blood samples. The study was published in the January 2018 issue of the journal Clinica Chimica Acta. LabMedica International June-July/2018

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Ovarian Cancer Risk May Be Paternally Inherited history of ovarian cancer among first-order relatives remains the strongest and best-characterized predictor of ovarian cancer risk and a main determinant of genetic testing referral. The evidence for a monogenic, autosomal dominant mode of inherited risk dates to the prebreast cancer 1, early onset gene (BRCA) era where studies focused on assessing heritability using affected first-order and second-order female relatives. Scientists at Roswell Park Cancer Institute (Buffalo, NY, USA; www.roswellpark.org) and their colleagues first identified 3,499 grandmother-granddaughter pairs from a familial ovarian cancer registry that encompassed information on more than 50,000 individuals from 2,600 families collected over several decades. They whittled this set down to the 892 pairs, providing clues to ovarian cancer risk transmission, which included 157 granddaughters with ovarian cancer. In an effort to tease out the basis of this X-linked inheritance, the scientists did exome sequencing on 159 BRCA1/2 mutation-negative women from the registry, focusing on germline X chromosome and BRCA1 coding sequences. The group included 49 ovarian cancer-affected women with affected mothers, 46 cases who had an affected sister and unaffected mother, and seven ovarian cancer-affected women with an affected sister and mother. The team found that overlapping ovarian cancer diagnoses were more common in the paternal grandmother-granddaughter pairs, where the cancer rate was more than 28% than in the pairs involving maternal grandmothers and their granddaughters. The latter pairs had an ovarian cancer rate just shy of 14%. The presence of ovarian cancer in a paternal grandmother, but not a maternal grandmother, coincided with earlier age of onset in affected granddaughters. They tracked down a missense mutation in the MAGE Family Member C3 (MAGEC3), a gene previously put forward as a potential X-linked tumor suppressor. The variant was in linkage disequilibrium with other nearby variants, suggesting there might be an alternative causal variant or a related haploblock in the X chromosome region identified. The authors concluded that they had demonstrated that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An Xlinked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. The study was published on February 15, 2018, in the journal PLOS Genetics.

Image: Diagrams for X-linked inheritance when cancer status is specific to women (all carrier men are effectively disease censored). Two family patterns with a pair of first-degree affected women are the maternal grandmother (MGM) family and the paternal grandmother (PGM) family (Photo courtesy of Roswell Park Cancer Institute).

LabMedica International June-July/2018

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LabMedica International

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KRAS Mutations Revealed in Rare Brain Condition poradic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The underlying cause of sporadic arteriovenous malformations of the brain is unknown, but similar lesions are found in rare genetic syndromes, such as hereditary hemorrhagic telangiectasias and and in the capillary malformationâ&#x20AC;&#x201C;arteriovenous malformation syndrome. An international team of scientists led by those at the University of Geneva (Geneva, Switzerland; www.unige.ch), used exome sequencing and/or droplet digital polymerase chain reaction (ddPCR) to search for recurrent mutations in brain samples from dozens of individuals with sporadic arteriovenous malformations of the brain, a condition that can increase a childâ&#x20AC;&#x2122;s hemorrhagic stroke risk. Across the 72 cases considered in the discovery and validation stages of the study, they identified somatic KRAS mutations in 45 individuals. The team obtained freshly resected tissue samples of arteriovenous malformations of the brain or control samples of normal tissue from temporal lobectomy specimens. Endothelial-cell cultures were established and

were enriched and depleted with the use of anti-CD31 magnetic beads. Cell cultures were isolated from freshly resected tissue. Frozen tissues were used for exome sequencing and ddPCR assays. Detection of rare variants in KRAS was performed on the QX200 Droplet Digital PCR system (Bio-Rad Laboratories, Inc., Hercules, CA, USA; www.bio-rad.com). The cell cultures were used for the ddPCR assays and Western blotting. The investigators also tested matched normal blood samples from 17 of those patients and used ddPCR to find and verify mutations in all 39 arteriovenous malformation cases in their discovery group. A dozen of the exome-sequenced malformation samples contained activating KRAS mutations not found in matched normal samples, the team reported, while ddPCR unearthed six KRAS mutations missed in the malformation exomes. Eleven more KRAS mutations turned up in malformation samples tested by ddPCR alone. They detected KRAS mutations by ddPCR that were not found in post-mortem samples from individuals who experienced other vascular malformations in the brain or central nervous syndrome. Nearly half of the arteriovenous malformations in the validation set (48%) contained suspicious KRAS variants. The authors concluded that their findings of increased MAPK-ERK signaling in endothelial cells from arteriovenous malformations of the brain without a KRAS variant suggests that activation of the MAPK-ERK pathway may be a defining feature of arteriovenous malformations of the brain. In the absence of available direct pharmacologic inhibitors of KRAS, small-molecule mitogen-activated protein kinase enzymes (MEK) inhibitors, which are used in clinical practice for treating cancers, represent candidates for testing in clinical trials to treat arteriovenous malformations of the brain. The study was published on January 3, 2018, in the journal New England Journal of Medicine. Image: The QX200 droplet digital polymerase chain reaction (ddPCR) system (Photo courtesy of Bio-Rad Laboratories).

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LabMedica International

TB-LAMP Assay Evaluated in Reference Labs mear microscopy, the first line in tuberculosis (TB) detection, has a low and variable sensitivity of 30% to 70%. Conventional culture on solid media has a sensitivity of 80% to 90%, but requires two to eight weeks for a result. The use of molecular methods such as nucleic acid amplification tests (NAAT) may promise faster results with high sensitivity and specificity. Novel loop-mediated isothermal amplification (LAMP) is an attractive diagnostics platform because it takes less than two hours to perform, requires minimal instrumentation, and generates a fluorescent result that can be detected with the naked eye. In a large multicenter study led by those at the Foundation for Innovative New Diagnostics (Geneva, Switzerland; www.finddx.org), two sputum samples were collected from participants with TB symptoms in reference laboratories in Peru, South Africa, Brazil, and Vietnam. Each sample was tested with TB-LAMP (Eiken Chemical Company, Tokyo, Japan; www.eiken.co.jp). The reference standard consisted of four direct smears, four cultures, and clinical and radiological findings. Individuals negative on conventional tests were followed up after 8 weeks. The Xpert MTB/RIF assay (Cepheid Inc, Sunnyvale, CA, USA; www.cepheid.com) was performed on fresh or

frozen samples as a molecular test comparison. The teams enrolled a total of 1,036 adults with suspected TB between January and December 2012. Among 375 culture-confirmed TB cases with 750 sputum samples, TB-LAMP detected 75.6% (95% confidence interval (CI) 71.8–79.4%), including 97.9% (95% CI 96.4–99.4%) of smearpositive TB samples and 46.6% (95% CI 40.6–52.7%) of smearnegative TB samples. Specificity in 477 culture-negative participants not treated for TB (954 sputum samples) was 98.7% (95% CI 97.9–99.6%). TBLAMP test results were indeterminate in 0.3% of cases. The authors concluded that the finding in this study that laboratory performance of TBLAMP approaches that of Xpert MTB/RIF, further studies are recommended in settings of intended use to evaluate these expected benefits. The use of a manual technique may give TB-LAMP the potential to enter the market at a lower cost than its automated counterpart. The study was published in the March 2018 issue of the journal International Journal of Infectious Diseases.

Image: Results of a LAMP test showing positive samples that emit green fluorescence (Photo courtesy of Foundation for Innovative New Diagnostics).

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Streamlined Approach Discovered for Treating Bowel Cancer ore than 4,000 Australians die from bowel cancer each year, and more than 17,000 new cases of this cancer will be diagnosed in 2018. Scientists are working to understand the genetic drivers of bowel cancer, with a special interest in those cancers which are the hardest to treat, and which have the poorest prognosis. A new method helps determine which DNA changes are important to the cancer, in a fraction of the time, at less expense and using fewer animals than traditional genetically-engineered models that are used in cancer research. Analysis of the models, combined with patient data, has suggested potential drug vulnerabilities that are being tested. An international team of scientists led by those at the University of Adelaide (Adelaide, Australia; www.adelaide.edu.au) have discovered a faster, more cost-effective way to determine which DNA mutations cause human bowel cancer. Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumors that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen-activated kinase pathway gene, BRAF, and epigenetic modifications termed the CpG Island Methylator Phenotype, leading to epigenetic silencing of key tumor suppressor genes. The team used organoid culture combined with CRISPR/Cas9 genome engineering to sequentially introduce genetic al-

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2018

ANNUAL MEETING

terations associated with serrated CRC and which regulate the stem cell niche, senescence and DNA mismatch repair. The scientists reported that targeted biallelic gene alterations were verified by DNA sequencing. Organoid growth in the absence of niche factors was assessed, as well as analysis of downstream molecular pathway activity. Orthotopic engraftment of complex organoid lines, but not BrafV600E alone, quickly generated adenocarcinoma in vivo with serrated features consistent with human disease. Loss of the essential DNA mismatch repair enzyme, MutL Homolog 1(Mlh1), led to microsatellite instability. Sphingolipid metabolism genes are differentially regulated in both our mouse models of serrated CRC and human CRC, with key members of this pathway having prognostic significance in the human setting. The authors concluded that they had generated rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of the models alongside patient data has led to the identification of a potential susceptibility for this tumor type. Susan L. Woods, PhD, a Senior Research Fellow and a study co-leader, said, “Now, we have rapidly made new models of bowel cancer that mimic the complex genetic (DNA) changes that we see in human tumors and recapitulate features of the human disease.” The study was published on April 17, 2018, in the journal GUT.

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URINE ANALYZER

Mast Group

Acon Laboratories

Analyticon Biotechnologies

The Mast UriPlus automates the reading/ analysis of Mast Uri plates to generate identification and antibiotic susceptibility reports. Each plate can be read in 30 seconds, meaning an average 10-plate set can be recorded in less than five minutes.

The U120 Ultra can read strips with up to 14 parameters and comes with lockout functions that offer confidence in results and patient information privacy. It has a throughput 55 or 120 tests/hour, and features a large color touch screen.

The Urilyzer Flex combines the Urilyzer 500 Pro and Urilyzer Sed to offer an affordable analyzer for sediment analysis. With a sample throughput of 50-150 sediment and 50250 chemistry per day, it is ideal for labs with medium sample throughput.

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New Guidelines Issued For Diabetes Testing he American Diabetes Association (ADA) in its 2018 Standards of Medical Care in Diabetes is recommending continuous glucose monitoring (CGM) to all adults 18 and over who are not meeting glycemic targets, as well as screening high-risk youths for type 2 diabetes. Two sections in this guidance, classification and diagnosis of diabetes and glycemic targets, specifically address the limitations of glycemic hemoglobin (A1C) measurements. A number of different factors can affect the results of this test, including assay interference, hemoglobin variants, and variations in red blood cell turnover rates, as well as age, pregnancy, and ethnicity. Scientists working with the ADA (Arlington, VA, USA; www.diabetes. org) suggested that A1C testing take place just twice a year in patients who are successfully managing their diabetes, compared with those not meeting glycemic goals or who have experienced changes in their therapy. For these patients, A1C testing should take place quarterly. “Point-of-care testing for A1C provides the opportunity for more timely treatment changes,” the scientists recommended. ADA’s 2018 update also refines screening recommendations for certain

populations. As an example, the document recommends type 2 screening in children and adolescents younger than age 18 who qualify as overweight or obese with body mass index greater than the 85th percentile for age and sex, weight for height greater than the 85th percentile, or weight greater than 120% of ideal for height and one or more additional risk factor(s). The latter include: family history of type 2 diabetes in first or second degree relatives; any history of diabetes during a child’s gestation; Native American, African American, Latino or Asian American Pacific Islander descent; and signs of insulin resistance or conditions associated with insulin resistance such as hypertension or dyslipidemia. The 2018 standards also include language about new CGM technology, highlighting a newly approved “flash” CGM device (Abbott Diabetes Care, Alameda, CA, USA; www.diabetescare.abbott) for adults that provide on-demand glucose readings. ADA provided additional information about devices that no longer require confirmation from fingerstick testing to make treatment decisions. It also modified language to align with recent data showing that CGM helps improve glycemic control for adults with type 1 diabetes. The guideline authors stated, “A study in adults with well-controlled type 1 diabetes found that flash CGM users spent less time in hypoglycemia than those using self-monitoring of blood glucose devices. However, due to significant differences between flash CGM and other CGM devices, more discussion is needed on outcomes and regarding specific recommendations.” The guidelines were published in the January 2018 issue of the Standards of Medical Care in Diabetes. Image: The FreeStyle Libre continuous glucose monitoring system (Photo courtesy of Abbott).

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Omega-3 Levels Predict Death Risk Better Than Serum Cholesterol he value of measuring blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 fatty acids to assess an individual’s risk for developing certain disease has been investigated. EPA and DHA, called for simplicity the Omega-3 Index, have been proposed as a risk factor for death from cardiovascular disease (CVD). Consistent with these observations, there is an inverse relationship between the Omega-3 Index and the rate of telomere attrition, a marker of cellular aging. Scientists at the Sanford School of Medicine (University of South Dakota, Vermillion, SD, USA; www.usd.edu) and their colleagues measured in 2,500 participants in the Offspring cohort of the Framingham Heart Study the EPA+DHA content of red blood cell membranes (Omega-3 Index). All of the individuals in present study were free of known cardiovascular disease (CVD) at baseline. The team primarily focused on total mortality (death from any cause) as an endpoint, but also tracked death from CVD, cancer and other causes. The population was 66 years of age at baseline and there were a few more females than males. The study followed these individuals for disease outcomes until about age 73. Blood was drawn after a 10- to 12hour fast into an EDTA tube, and red blood cells (RBCs) were separated from plasma by centrifugation. The RBC fraction was frozen at −80 °C immediately after collection. RBC fatty acid (FA) composition was determined. Briefly, RBCs were incubated at 100 °C using boron trifluoride methanol and hexane to generate FA methyl esters that were then analyzed by gas chromatography with flame ionization detection (GC-2010 Gas Chromatograph, Shimadzu Corporation, Kyoto, Japan; www.shimadzu. com). N-3 FAs analyzed included linolenic acid (ALA; 18:3n3), EPA (20:5n3), docosapentaenoic acid (DPA; 22:5n3), DHA (22:6n3), and the Omega-3 Index (EPA + DHA). William S. Harris, PhD, the lead author of the study, said, “We all know that the serum cholesterol level is a major risk factor for CHD, and since the latter is a major cause of death in the Western world, it would be reasonable to expect that a high cholesterol level would portend higher risk for premature death. This did not turn out to be the case here. When baseline serum cholesterol levels were substituted for the Omega-3 Index in the same multi-variable models, the former was not significantly associated with any of the tracked outcomes whereas the latter was related to four of the five outcomes assessed.” The study was published online on February 24, 2018, in the Journal of Clinical Lipidology.

LabMedica International June-July/2018

Image: The GC-2010 gas chromatograph used for calculating the Omega3 Index (Photo courtesy of Shimadzu).

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PRODUCT NEWS ROBOTIC CENTRIFUGE

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BIOCHEMISTRY ANALYZER

CHEMISTRY ANALYZERS

Andreas Hettich

AXA Diagnostics

Beckman Coulter

The Mikro 220 Robotic can spin tubes up to 2.0 ml quickly and safely. With its swing-out rotors for microliter tubes, the centrifuge is suitable for HTP-laboratories in many applications, including the evaluation of clinical samples.

The ChemRead 3000 offers high reliability and anti-interference, and allows up to 112 test profiles to be programmed. It features a large LCD touch screen display, built-in recorder and internal memory for storing 112 profiles or 3,200 results.

The AU5800 series offers a throughput ranging from approximately 2,000-9,800 tests per hour. Available in four different scalable models, it offers a comprehensive AU test menu consists of more than 125 convenient, barcoded, liquid reagents.

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Novel Biomarkers Revealed For Future Dementia Risk

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ementia, including Alzheimer’s disease (AD), is a major public health problem with devastating physical, financial, and social consequences for patients, their caregivers, families, and society. Dementia is increasingly recognized as a heterogeneous syndrome that would be best addressed with a multipronged approach to prevention and treatment, analogous to the multipronged and individually tailored use of statins, anti-hypertensives, antiplatelet agents, and vasodilators in persons with coronary artery disease. An international team of scientists collaborating with those at the University of Texas Health Sciences Center (San Antonio, TX, USA; www.uthscsa.edu) analyzed small molecules called metabolites in blood samples drawn from 22,623 individuals, including 995 who went on to develop dementia. The participants who were all of European ancestry were enrolled in eight research cohorts in five countries. A serum nuclear magnetic resonance (NMR) metabolomics platform (Nightingale Health Ltd, Helsinki, Finland; https:// nightingalehealth.com) was used to quantify 228 circulating metabolites, lipid or lipoprotein lipid measures in seven of the eight cohorts. Liquid chromatography-tandem mass spectrometry (LC-MS) was also used. LC-MS data were acquired using either an AB SCIEX 4000 QTRAP triple quadrupole mass spectrometer (Sciex, Concord, ON, Canada; https://sciex.com) for positively charged polar compounds and lipids) or an AB SCIEX 5500 QTRAP triple quadrupole mass spectrometer for negatively charged polar compounds. The team found that found that higher blood concentrations of molecules called branched-chain amino acids (BCAAs) were associated with lower risk of future dementia. All three BCAAs, isoleucine, leucine, and valine, were inversely associated with incident dementia. Another molecule, creatinine, and two very low-density lipoprotein (VLDL)-specific lipoprotein lipid subclasses also were associated with lower risk of dementia. One high-density lipoprotein (HDL) and one VLDL lipoprotein subclass were associated with increased dementia risk. The authors concluded that their large prospective study identified lower BCAA levels to be associated with an increased risk of incident dementia, independent of other conventional risk factors. Moreover, creatinine, one HDL, and three VLDL lipoprotein subclasses were also associated with dementia risk, but these associations disappeared when adjusted for BMI and cholesterol-lowering medication. The study was published on March 5, 2018, in the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

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LabMedica International

CKD May Occur Before Diabetes Diagnosis octors have long known that patients with diabetes are at risk for kidney disease, and while chronic kidney disease (CKD) is regularly evaluated among patients with diabetes, kidney function may be significantly impaired before diabetes is diagnosed. Approximately 10% of the general population in the USA, more than 20 million people, has chronic kidney disease (CKD), and this condition is especially prevalent among patients with diabetes mellitus (DM). Specifically, an estimated one-third of adults with DM have CKD, and DM is the leading cause of CKD and end stage renal disease. Scientists working with the University of Tennessee Health Science Center (Memphis, TN, USA; www.uthsc.edu) assessed the risk of kidney damage from undiagnosed diabetes, and looked at data on 36,794 veterans who were diagnosed with diabetes between 2003 and 2013. They found that 31.6% of these veterans had evidence of CKD prior to the diabetes diagnosis, based on estimated glomerular filtration rate (eGFR) and urine-albumin-creatine ratios, two common measures of kidney function. Veterans with higher age, hemoglobin A1C, blood pressure, and body mass index (BMI) also had a greater risk of CKD. All of these factors are themselves risk factors for diabetes. Those with cerebrovascular disease, congestive heart failure, or peripheral artery disease, conditions that are frequently seen alongside diabetes had higher kidney disease risk as well. The study also revealed disparities in the rates of CKD based on race. Asian Americans and African Americans had higher rates of chronic kidney disease than whites. However, the proportion of patients who were minorities decreased as disease severity increased. The results suggest that kidney damage often occurs before diabetes is diagnosed. The authors propose two possible reasons for this early kidney damage: Type 2 diabetes can be undiagnosed for a long time, meaning the kidneys are being damaged without the patient or doctors being aware, or, kidney damage could come from other conditions common in the population at risk for diabetes. The results highlight an opportunity for broadening screening among patients with increased risk of CKD. More screening of at-risk populations could lead to earlier identification of diabetes, which could in turn prevent organ damage.

LabMedica International June-July/2018

Csaba P. Kovesdy, MD, FASN, a professor of Medical Nephrology and senior author of the study, said, “Chronic kidney disease is silent, so patients can develop even advanced stages of chronic kidney disease before noticing anything. The only way to detect it in most affected individuals is through laboratory measurement, i.e., serum creatinine and urine albumin. Serum creatinine is measured very frequently among veterans, but an abnormal value would only diagnose stage 3 and above of chronic kidney disease. Urine albumin screening would be a way to identify early stages, but the use of this screening test is mostly limited to diabetics.” The study was published on February 9, 2018, in the journal Public Library of Science ONE.

Image: A histopathology of the diabetic kidney showing the thickening of the mesangial basement membrane and matrix with nodular glomerular sclerosis and intercapillary sclerosis (Photo courtesy of the University of Antioquia).

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URINE ANALYZER

HEMOGLOBIN TEST SYSTEM

Auotobio Diagnostics

Biocare

Bio-Rad Laboratories

The LUmo is designed to meet the demanding requirements of today's microplate-based photometric applications. It has a spectral sensitivity range of 300-650nm and an impressive measurement time.

The Nuancer SR-III has an analysis time of 69 tests per hour and features automatic calibration. It comes with a built-in, two-line LCD with backlight, start function button for easy operation, and internal memory with a 150test storage capacity.

The D-10 combines diabetes and ß-thalassemia testing on a single platform and features an automatic startup checklist and touch screen operation. Its one-step cartridge switching and automatic barcode reading increase workflow efficiency.

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Genetic Factors Responsible for Alzheimer’s Identified everal new genes have been identified that are responsible for Alzheimer’s disease (AD) including those leading to functional and structural changes in the brain and elevated levels of AD proteins in cerebrospinal fluid (CSF). A new study focused on individual groups across specific on the cognitive spectrum: normal cognitive functioning or controls, mild cognitive impairment (MCI) and AD cases. As opposed to the typical study design, which combines all such persons into a single group or focuses only on cognitively healthy persons, a new study identified several novel genetic associations within multiple subgroups. A team of scientists led by those at Boston University School of Medicine (Boston, MA, USA; www.bmc.org) conducted genome-wide association studies for AD-related endophenotypes including hippocampal volume, logical memory scores, and CSF. They tested the association between AD-related brain MRI measures, logical memory test scores and CSF levels of two AD proteins amyloid-beta (A 42) and tau with several million genetic markers called single-nucleotide polymorphisms (SNPs) across the genome in a sample of 1,189 participants of the Alzheimer Disease Neuroimaging Initiative (ADNI) study. They then examined the biological significance of the top-ranked associated SNPs and genes using several datasets containing information about gene expression in parts of the brain most affected by AD. The scientists found that two of the study-wide significant genes identified in the normal cognitive functioning group, Serine/Arginine Repetitive Matrix 4 (SRRM4) and Microtubule Associated Scaffold Protein 1(MTUS1), are involved in neuronal signaling, development and loss. Another gene identified in this group, Glutamate Ionotropic Recep-

tor NMDA Type Subunit 2B (GRIN2B), encodes a subunit of a receptor that has roles in resilience of neurons and memory. They found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls. The study was published on December 20, 2017, in the journal Alzheimer’s & Dementia. Image: Researchers have identified genes that could be precursors to Alzheimer’s disease, which could be targets for new treatments that may delay or prevent the onset of the disease (Photo courtesy of Medical News Today).

Lipid Biomarker Concentrations Associated with Cardiovascular Disease Risk irculating concentrations of lipid biomarkers are consistently associated with cardiovascular disease (CVD) events and thus are considered major indicators of metabolic health, but the evidence for a relationship with cancer risk, however, is not entirely consistent. High levels of low-density lipoprotein cholesterol (LDL-C) have been consistently associated with up to 1.7-fold increases in risk of CVD in observational studies. Other lipid parameters, such as high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), or lipoprotein (a) (Lp(a)), have also been increasingly investigated in relation to risk of atherosclerotic CVD or coronary heart disease. Scientists at the German Cancer Research Center (DKFZ, Heidelberg, Germany; www.dkfz.de) selected a case-cohort sample out of the prospective EPIC–Heidelberg study, including a random sub-cohort of 2,739, and 1.632 cases of cancer, 761 cancer mortality, 1,070 CVD and

381 CVD mortality. Concentrations of lipid biomarkers were measured in pre-diagnostic blood samples. Participants were recruited between 1994 and 1998 and were aged between 35 and 65 years. Basic clinical chemistry measurements were performed including serum concentrations of total cholesterol (TC), HDL-C, TG, apo(a), Apolipoprotein B100 (apoB-100), and Lp(a). All measurements were made using the Roche Cobas 6000 analytical system (Roche, Basel, Switzerland; www.roche.com). The Friedewald formula (LDL = TC – HDL – TG/5) was applied to calculate LDL-C values. High levels of circulating apoB-100 and TG were inversely associated and high HDL-C levels were positively associated with breast cancer risk. Higher levels of Lp(a) were associated with an increase in prostate cancer risk and high levels of apo(a) were associated with a decrease in lung cancer risk. The study was published on December 19, 2017, in the journal BMC Medicine. LabMedica International June-July/2018

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LabMedica International

Unusual Blood Clots Characterized in Leprosy Patients eprosy is a chronic infection by Mycobacterium leprae and causes body-wide symptoms, deformities, and disability. It remains a public health problem worldwide, despite the existence of antibiotic combinations that can cure it. Hemostatic disorders are frequently associated with acute and chronic infections due to the fact that platelet functions, blood coagulation and fibrinolysis are intimately correlated with the immune system. For years, doctors have observed that some patients with leprosy develop unusual blood clots, which can lead to stroke or heart attack. Scientists at the Oswaldo Cruz Institute (Rio de Janeiro, Brazil; https://portal.fiocruz.br) analyzed two groups of patients: a prospective group, which plasma samples were collected before multidrug therapy against leprosy, composed of 11 non-reactional (multibacillary leprosy; MB-NR), being 10 lepromatous leprosy (LL) and one borderline lepromatous (BL). The erythema nodosum leprosum patients group (MBENL) included 13 LL and one BL individuals. These two groups include six females, 19 males with median age of 45.2 years, ranging from 23 to 80. The retrospective cohort was composed of 638 leprosy outpatients at an Outpatient Unit, from 2012 to 2014, where 35 patients presented the leprosum clot during serum harvesting. The team performed SDS-PAGE and protein content was measured with the commercially available 2D Quant-Kit (GE Healthcare, Aurora, OH, USA; www.gehealthcare.com). Spots were taken from the gel, digested with trypsin and analyzed by spectrometry using the MALDITOF/TOF 5800 (AB SCIEX, Framingham, MA, USA; https://sciex. com). The mass spectrometry protein identifications were obtained with a 5800 Proteomics Analyzer (Applied Biosystems, Foster City, CA, USA; www.appliedbiosystems.com). The scientists applied the STA-R Evolution instrument (Stago, Asnières sur Seine, France; www. stago.fr) to determine partial thromboplastin time (aPPT) and prothrombin time (PT) in all plasma samples. The levels of von Willebrand and solVISIT US AT: uble tissue factor, C4 complement, and anti-cardiolipin IgM antibody in the serum of leprosy patients were 2018 determined using the following comANNUAL MEETING mercial kits: Human von Willebrand Booth: 1440 Factor ELISA kit and Human Tissue Factor ELISA kit (Abcam, Cambridge, UK; www.abcam.com) and C4 turbiquest (Labtest, Minas Gerais, Brazil; https://labtest.com.br), respectively. The authors propose that multibacillary patients with high levels of fibrinogen could be beneficiated from a prophylactic use of xanthine derivatives such as pentoxifylline, in order to prevent some of the acute clinical symptoms observed during severe cases of leprosy reactional episodes, such as cyanosis and tissue necrosis, probably related with superficial vein thrombosis. The study was published on March 22, 2018, in the journal PLOS Neglected Tropical Diseases.

LabMedica International June-July/2018

Image: A histopathology of a deep vein inflammatory infiltrate with wall dissociated by edema, observed in a skin lesion of a leprosy patient suffering an erythema nodosum leprosum episode (Photo courtesy of Oswaldo Cruz Institute).

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IMMUNOASSAY ANALYZER

HBA1C ANALYZER

The Binding Site

Tosoh Bioscience

Trinity Biotech

The SPA PLUS consistently delivers high quality results and achieves an impressive throughput of up to 240 tests per hour. It has a large assay menu that enables labs to run more of their special protein assays on a dedicated platform.

The AIA-600II features a throughput of 60 tests per hour and reports first results in 19 minutes. It has a comprehensive menu and is an excellent stand-alone solution for midsized or small labs, as well as an ideal backup system for larger labs.

The Tri-stat 2 HbA1c analyzer delivers results within minutes, using boronate affinity technology and a two-phase optical system. It can run up to three samples simultaneously in 10 minutes and is ideal for small labs with a lowvolume throughput.

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Polygenic Score Predicts Prostate Cancer Development urrently, detection of prostate cancer relies primarily upon the prostate-specific antigen (PSA) screening blood test, but PSA testing is not very good as a screening tool. While it reduces deaths from prostate cancer, indiscriminate PSA screening also produces false positive results and encourages over-detection of non-aggressive, slow-growing tumors. Because of concerns over a high rate of false positive results, in addition to aggressive treatment of apparently indolent disease, however, many clinical guidelines do not endorse universal screening and instead stress the importance of taking into account individual patient risk factors to decide whether to screen. An international multidisciplinary team of scientists led by those at University of California, San Diego (La Jolla, CA, USA; www.ucsd.edu) used genome-wide association studies (GWAS) to determine whether a man’s genetic predisposition to developing prostate cancer could be used to predict his risk of developing the aggressive and lethal form of the disease. GWAS search individual genomes for small variations, called singlenucleotide polymorphisms (SNPs) that occur more frequently in people with a particular disease than in people without the disease. The development dataset comprised 31,747 men; the validation dataset comprised 6,411 men. The team found that in the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly

significant predictor of age at diagnosis of aggressive cancer. When men in the validation set with high scores were compared with those with average scores, the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive prostate cancer and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive prostate cancer was increased with increasing polygenic hazard score. The study was published on January 10, 2018, in the journal BMJ. Image: Cell division of a prostate-cancer cell, captured in a colored scanning electron micrograph (SEM) (Photo courtesy of Getty Images).

Device Leads to Lower Blood Culture Contamination Rates he use of a mechanical initial specimen diversion device and staff education has led to a nearly four-fold decrease in contaminated blood cultures that was sustained over 20 months. Blood cultures help physicians determine whether patients have serious and potentially life-threatening blood infections such as sepsis. These blood draws may become contaminated with bacteria-containing fragments of a patient’s skin that enter the needle during the blood collection process. Studies have shown that conventional techniques can lead to false positives which in turn may lead to patients receiving more blood draws, extended length of stay, increased exposure to hospital-acquired conditions, and unnecessary antibiotic treatment. Scientists at the Medical University of South Carolina (MUSC, Charleston, SC, USA; www.musc.edu) used the mechanical initial specimen diversion device (ISDD) called SteriPath (Magnolia Medical Technologies, Seattle, WA, USA; https://magnolia-medical.com), which is a sterile, closed blood

culture collection system that diverts, sequesters, and isolates the first 1.5-2 mL of blood, the portion that is known to contain contaminants, during the blood draw. The study also showed that use of the mechanical ISDD could reduce costs and use staff time more efficiently. The investigators suggested that MUSC would have saved USD 744,955 if the ISDD had been used for every blood draw in the emergency department during the study, based on a conservative estimate (USD 4,850) for the cost of a contaminated culture. Lisa Steed, PhD, a professor of Pathology and Laboratory Medicine, said, “Working on this study and seeing such strong results speaks to the great things that can happen for patients when clinicians join forces on these issues. Blood cultures, and the accuracy of those cultures, are incredibly important in making sure that patients are getting the right care, at the right time, and with the right process in place.” The study was presented at The Institute of Healthcare Improvement National Forum was held December 11, 2017, in Orlando, FL, USA. LabMedica International June-July/2018

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LabMedica International

Potential Genetic Link Identified in Sudden Infant Death Syndrome udden infant death syndrome (SIDS) is the unexpected death of a seemingly healthy infant. It is the leading cause of post-neonatal infant death in high-income countries and accounts for 2,400 deaths per year in the USA alone and around 300 in the UK. Death from SIDS commonly occurs at two to four months of age. Although the cause of death is unknown, several intrinsic and extrinsic risk factors have been identified, including prematurity, male sex, prone sleeping position, and bed sharing. A failure to rouse and respond appropriately to a life-threatening hypoxic event is considered to be a common final pathway. A large team of scientists working with the University College London (London, UK; www.ucl.ac.uk) studied two cohorts of children of Caucasian European ancestry who had died from sudden infant death syndrome in the UK and USA, including 278 children overall (84 from the UK and 194 from the USA). All deaths were unexplained after thorough post-mortem investigations. These were matched with 729 adults who had no history of cardiovascular, respiratory or neurological disease. The investigators used tissue from each group and their genes were analyzed to identify whether they had a mutation in the Sodium Voltage-Gated Channel Alpha Subunit 4, (SCN4A) gene, and to confirm whether the mutations affected the cell surface receptor that the gene codes for. Whole exome sequencing for both cases and controls was done using 1.5 to 3 g of genomic DNA and in the UK sequencing was performed using the Sure Select XT Human All Exon v5 Target Enrichment System (Agilent Technologies, Santa Clara, CA, USA; www.agilent.com). DNA libraries were prepared according to manufacturer’s protocols and 100 base pair paired end sequencing was performed on the Illumina HiSeq 2500 platform (Illumina, San Diego, CA, USA; www.illumina.com). The authors found general mutations in the SCN4A gene in six of the 284 infants who died, and in nine of the 729 controls. Specific mutations that disrupted the cell surface receptor were only found in four of the children who had died of sudden infant death syndrome, and none of the controls. The authors conclude that the disruptive variants are overrepresented in this group, and could indicate a genetic element of sudden infant death syndrome. The authors suggest that this may increase sus-

LabMedica International June-July/2018

ceptibility to sudden infant death syndrome in some cases as the cell receptor becomes more commonly used. During this period, the mutation could potentially leave these children with weaker breathing muscles, and, if an external stressor impacts their breathing, such as tobacco smoke, getting tangled in bedding, a minor illness or a breathing obstruction, they may be less able to correct their breathing, cough or catch their breath in response. Michael Hanna, MD, FRCP, a professor of Clinical Neurology and a senior author of the study, said, “Our study is the first to link a genetic cause of weaker breathing muscles with sudden infant death syndrome, and suggests that genes controlling breathing muscle function could be important in this condition. While

there are drug treatments for children and adults with genetic neuromuscular disorders caused by SCN4A gene mutations, it is unclear whether these treatments would reduce the risk of sudden infant death syndrome.” The study was published on March 28, 2018, in the journal The Lancet. Image: The SureSelect All Exon kits are the most widely used target enrichment solution for exome sequencing (Photo courtesy of Agilent Technologies).

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Erba Mannheim

The Heama T4 monitors blood coagulation and assists physicians in making a diagnosis of coagulation/fibrinolysis status. It can be applied in various surgical applications, as well as in prevention of post-operative bleeding and thrombosis.

The URIT-920 has a measuring time of 60 seconds for sample introduction, measuring, cleaning and printing. Other key features include an auto-sampling tray, 5-inch TFT LCD touch screen and 25 sample positions.

The Laura M urine analyzer features an evaluation time of 60 seconds and a capacity of 600 strips per hour. It also offers a memory capacity to save the last 2,000 measurements, making it ideal for use in clinical labs.

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New Biosensor Monitors Glucose in Tears and Sweat he diagnosis and tracking medical conditions are often done by analyzing a sample of blood. The pain of pricking fingers or drawing blood, however, can deter people from vigilantly monitoring conditions such as diabetes that require regular checks. The use of wearable sensors are part of an increasingly digitized world. An ultra-thin, flexible sensor has been developed that could be incorporated into contact lenses or on the backs of watches for real-time glucose tracking. Scientists at the University of Southern California (Los Angeles, CA, USA; www.usc.edu) and their colleagues created a biosensor using nanoribbons of indium oxide, an enzyme glucose oxidase, a natural chitosan film and single-walled carbon nanotubes. When glucose is present in a test sample, it interacts with the enzyme, setting off a short chain of reactions and ultimately creating an electrical signal. Testing showed that the device could detect a range of glucose concentrations from 10 nanomolar to 1 millimolar, which is sensitive enough to cover typical glucose levels in sweat, saliva and tears in people with and without diabetes. Bending the film 100 times did not noticeably affect its performance. The shadow-mask-fabricated devices show good electrical performance with gate voltage applied using a gold side gate electrode and through an aqueous electrolyte. The biosensor aims to track glucose levels through tears and sweat and could be incorporated into contact lenses or watches for real-time

monitoring. The authors concluded that their high-performance indium oxide (In2O3) nanoribbon sensing platform has great potential to work as indispensable components for wearable healthcare electronics. The study was published on January 17, 2018, in the journal ACS Nano. Image: The biosensor uses nanoribbons of indium oxide, an enzyme glucose oxidase, a natural chitosan film and single-walled carbon nanotubes to track glucose levels (Photo courtesy of University of Southern California).

RNA Analysis of Nasal Swabs Diagnoses Respiratory Virus Infection panel of three mRNAs has been shown to be able to predict presence of respiratory virus infection in nasal samples with an accuracy of 97%. Despite the high burden of respiratory infection and the importance of early and accurate diagnosis, there is at this time no simple diagnostic test to rule in viral infection as a cause of respiratory symptoms. To fill this gap, investigators at Yale University (New London, CT, USA; www.yale.edu) performed RNASeq on human nasal epithelial cells following stimulation of the intracellular viral recognition receptor RIGI. Next, they evaluated whether measuring identified host mRNAs and proteins from patient nasopharyngeal swabs could predict the presence of a respiratory virus in the sample. Samples were obtained from patients who were primarily older adults or young children, reflecting the population tested for respiratory viruses in the healthcare system. RNASeq (RNA sequencing) uses next-generation sequencing (NGS) to reveal the presence and quantity of RNA in a biological sample at a

given moment in time. This technique is used to analyze the continuously changing cellular transcriptome. Specifically, RNASeq facilitates the ability to look at alternative gene spliced transcripts, post-transcriptional modifications, gene fusion, mutations/SNPs, and changes in gene expression over time, or differences in gene expression in different groups or treatments. In addition to mRNA transcripts, RNASeq can look at different populations of RNA to include total RNA, small RNA, such as miRNA, tRNA, and ribosomal profiling. The investigators initially showed that a signature of three mRNAs, CXCL10, IFIT2, and OASL, predicted respiratory virus detection with an accuracy of 97% and identified proteins correlating with virus detection. In a follow-up study, elevated CXCL11 or CXCL10 protein levels identified samples containing respiratory viruses, including viruses not on the initial test panel. The respiratory virus test was described in the December 21, 2017, online edition of The Journal of Infectious Diseases. LabMedica International June-July/2018

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LabMedica International

Nanopore Method Developed for Genetic Screening apid sequencing of short DNA reads may be useful for a wide range of clinical applications including targeted mutation analysis, cancer-panel testing, and aneuploidy screening. Fast, point-of-care preimplantation genetic screening could improve the success of in vitro fertilization procedures by not requiring embryos to be frozen. However, the time and skill required for library preparation and sequencing using existing DNA sequencing methods limits their widespread clinical use. Nanopore sequencing technology is one of the fastest growing third generation next-generation sequencing (NGS) technologies. A new method that simplifies and accelerates nanopore-based shortlength DNA library preparation and sequencing has been applied to test a panel of normal and aneuploid genomic DNA samples. Scientists at the Columbia University Medical Center (New York, NY, USA; www.cumc.columbia.edu) tested the new protocol on nine blinded samples. The nine samples included both diploid and aneuploid samples and one normal reference male sample. Trophoectoderm biopsy samples were taken from fresh, day-five embryos and sent to a reference laboraVISIT US AT: tory for clinical preimplantation genetic screening (PGS) testing. 2018 PGS screening was performed usANNUAL MEETING ing the VeriSeq PGS assay (Illumina, San Diego, CA, USA; www.illumina. Booth: 1952 com) with excess DNA used to run the MinION-based workflow (Oxford Nanopore technologies, Oxford Science Park, UK; https://nano poretech.com). After sequencing, the scientists used only reads that were assigned to a barcode and uniquely matched to the reference genome for analysis. More than 70% of reads were assigned to a unique barcode, and of those, between 75% and 95%were uniquely assigned to the reference. The investigators determined that to detect whole chromosome aneuploidy, 30,000 reads were needed. In the study, their results were concurrent with the VeriSeq PGS test. Of the nine samples, five were abnormal, including a female monosomy 22, female trisomy 19, female trisomy 22 and monosomy X, female trisomy 13 and monosomy 14, a male with an extra X chromosome and trisomy 15, and a female with trisomy 15 and monosomy 18 that was also mosaic for trisomy 6. S. Zev Williams, MD, PhD, an Associate Professor of Obstetrics and Gynecology, and senior author of the study, said, “One limitation of nanopore sequencing has been its accuracy. However, since aneuploidy detection does not rely on calling point mutations, base-level accuracy is not as important. We want to have an accuracy of over 99%, and to test enough samples to be sure that’s what it is will take time. Nonethe-

LabMedica International June-July/2018

Image: The MinION is the only portable real-time device for DNA and RNA sequencing (Photo courtesy of Oxford Nanopore Technologies).

less, I think the potential is there.” The study was published in the April 2018 issue of the journal G3: Genes, Genomes, Genetics.

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The BIOSSAYS 240 allows up to 90 sample positions to be loaded continuously on the sample disk with barcode label recognition. Its reagent disk has up to 90 reagent positions, and it offers a constant throughput of 240 tests per hour.

The Quick Test Reader is intended to provide a confirmation of the visual reading of the test line. It comes with a power supply for charging, combo adapter supporting both the ColonView and the Celiac Quick Tests and optional printer.

The Cytation readers are available with UVVis absorbance, fluorescence and luminescence detection modes. They also allow the addition of fluorescence microscopy to expand the range of applications in a single instrument.

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Genetic Study Predicts Stomach Cancer Progression lthough stomach cancer is treatable if detected early, diagnosis often occurs at an advanced stage, resulting in high mortality. Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Stomach cancer is the third deadliest cancer in the world according to statistics, and claims more than 300 lives yearly in Singapore. The disease is believed to be caused by infection with Helicobacter pylori but is potentially treatable if detected early. Unfortunately, more than two-thirds of stomach cancer patients are only diagnosed at an advanced stage. A large team of scientists led by those at the National University of Singapore (Singapore; http://nusmedicine.nus.edu.sg) performed genomic profiling of 138 IMs from 148 cancer-free patients, recruited through a 10-year prospective study. The team leveraged the near 3,000 participants-strong Gastric Cancer Epidemiology Programme (GCEP) cohort, recruited with the support of patients and doctors to show that a comprehensive analysis of the genetic patterns of IM can predict its subsequent progression towards stomach cancer. The investigators found that compared with GCs, IMs exhibit low mutational burdens, recurrent mutations in certain tumor suppressors (F-Box And WD Repeat Domain Containing 7, [FBXW7]) but not others (Tumor Protein P53, [TP53], AT-Rich Interaction Domain 1A [ARID1A]), chromosome 8q amplification, and shortened telomeres. Sequencing identified more IM patients with active H. pylori infection compared with histopathology (11% to 27%). Several IMs exhibited hypermethylation at DNA methylation valleys; however, IMs generally lack intra-

genic hypomethylation signatures of advanced malignancy. IM patients with shortened telomeres and chromosomal alterations were associated with subsequent dysplasia or GC; conversely patients exhibiting normallike epigenomic patterns were associated with regression. Yeoh Khay Guan, MBBS, MMed, FRCP, Deputy Chief Executive, NUHS as well as Dean, NUS Yong Loo Lin School of Medicine and colead investigator of the study said, “Our study is the largest series of IM to be studied in detail by genetic analysis. These new findings help us understand why some people have a higher risk of progression to stomach cancer, and identify those who may benefit from closer follow-up to prevent cancer or to detect it early so that it can be cured.” The study was published on December 28, 2017, in the journal Cancer Cell. Image: Scientists analyzed the genomes of nearly 3,000 patients to identify genomic signatures associated with higher risk of developing stomach cancer (Photo courtesy of Shutterstock).

CSF MicroRNA Levels Investigated for Prodromal HD untington disease (HD) is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition). Adult-onset HD is the most common form of this disorder and the mean age of onset of HD is 35 to 44 years and the median survival time is 15 to 18 years after onset. A genetically confirmed diagnosis of HD requires molecular genetic testing to determine the number of CAG repeats in exon 1 of the huntingtin (HTT) gene. The feasibility of microRNA (miRNA) levels in cerebrospinal fluid (CSF) as biomarkers for prodromal Huntington disease (HD) has been investigated. Scientists at the Carver College of Medicine, (University of Iowa, Iowa City, IA, USA; https://medicine.uiowa.edu) and their colleagues profiled miRNA levels in CSF from 30 not-yet-diagnosed individuals car-

rying the type of huntingtin gene expansions linked to the neurodegenerative condition. By looking at levels of more than 2,000 miRNAs patterns and comparing them with those in CSF samples from 15 individuals previously diagnosed with HD and 15 unaffected controls, they searched for telltale miRNAs with ties to eventual HD development. The team processed 15 μL of CSF was for miRNA levels using the miRNA whole transcriptome protocol HTG EdgeSeq system (HTG Molecular Diagnostics, Tucson, AZ, USA; www.htgmolecular.com). This process includes specific probes for 2,083 miRNAs, producing both raw small-RNA sequencing files and pre-quantified data. A maximum of 24 samples can be processed in a single run and samples were randomly assigned to each of three batches. The study was published on December 27, 2017, in the journal Neurology. LabMedica International June-July/2018

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LabMedica International

Protein Signature Associated with Outcome In Metastatic Melanoma linical results in metastatic melanoma with the antibodies nivolumab and pembrolizumab to anti– programmed cell death protein 1 (PD-1) have led to clinically and statistically significant improvements in progression-free and overall survival compared to alternative first- and second-line therapies. Three tests of programmed cell death protein ligand 1(PD-L1) expression by immunohistochemistry are approved to guide treatment decisions in bladder and non-small cell lung cancer as well as melanoma, with different assays using different screening thresholds for PD-L1 positivity, but there is a lack of standardization. A team of scientists led by those at the Perlmutter Cancer Center (New York, NY, USA; www.nyulangone.org) obtained pretreatment serum from a development set of 119 melanoma patients on a trial of nivolumab with or without a multi-peptide vaccine and from patients receiving pembrolizumab, nivolumab, ipilimumab, or both nivolumab and ipilimumab. Spectra were obtained using matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDITOF). These data combined with clinical data identified patients with better or worse outcomes. The test was applied to five independent patients. Samples were processed using standardized operating procedures and the team used the Deep MALDI method of mass spectrometry on a SimulToF mass spectrometer (Virgin Instruments, MA, USA; www.simultof.com) to generate reproducible mass spectra from small amounts of serum, showing peaks from a higher abundance range than previously possible by exposing the samples to 400,000 MALDI laser “shots” compared to several thousand employed in standard applications. An additional independent reference set of 49 serum samples with matched mass spectrometry data and protein expression data from the panel of 1,129 proteins measured by SomaLogic (Boulder, CO, USA; www. somalogic.com) was used for this analysis. The scientists found that a signature consisting of 209 proteins or peptides was associated with progression-free and overall survival in a multivariate analysis. The test performance across validation cohorts was consistent with the development set results. A pooled analysis, stratified by set, demonstrated a significantly better overall survival for ‘sensitive’ relative to ‘resistant’ patients. The test was also associated

LabMedica International June-July/2018

with survival in a cohort of ipilimumab-treated patients. Test classification was found to be associated with acute phase reactant, complement and wound healing pathways. Heinrich Roder, PhD, chief technical officer at Biodesix (Boulder, CO, USA; www.biodesix. com), said, “Adapting Gene Set Enrichment Analysis (GSEA) to protein data allowed identification of biological processes associated with test classifications. The information derived from protein set enrichment analysis could help develop treatments overcoming primary antiPD-1 resistance by adding inhibition of complement activation, suppression of wound healing, or down-modulation of acute phase pathways by blocking IL6 and IL1. These data may indicate that similar resistance mechanisms might be at

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work in other tumor types and increase the likelihood that Biodesix can develop tests outside of melanoma.” The study was published on December 5, 2017, in the journal Cancer Immunology Research. Image: The SimulToF matrix assisted laser desorption/ionization time of flight mass spectrometer (Photo courtesy of Virgin Instruments).

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The CUBE 30 Touch for ESR testing in EDTA tubes is compatible with standard 4.0 mL K2EDTA tubes. Its internal mixing function prepares up to 30 samples per batch, and it delivers results in 20 minutes with printing and transmission to LIS.

The Freedom EVO Clinical is supported by a range of features and options that improve safety, security and efficiency. It enhances the quality, safety and performance of the clinical diagnostic environment in a wide range of applications.

The SUNMATIK-6020 features automatic sample dilution, liquid level detection and collision protection. It offers 44 sample positions and 44 positions for single and dual reagents in a compartment with a 24-hour cooling system.

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Novel Molecular Test For H. pylori Evaluated elicobacter pylori is a Gram-negative bacterium that can cause chronic stomach infections and is therefore known as the main cause of gastric ulcers and subsequently for the development of gastric cancer if untreated. In times of increasing antibiotic resistance, the need for more rapid resistance screening procedures that replace conventional cultural methods gain importance as H. pylori is a fastidious and slow growing bacterium that can make susceptibility testing from culture a time consuming and challenging task. Medical microbiologists at the University of Zurich (Switzerland; www.uzh.ch) used a set of 60 H. pylori strains from the culture collection of their Institute of Medical Microbiology. These strains were isolated between 2013 and 2015 from gastric biopsies that were sent to the laboratory for susceptibility testing after clarithromycin (CLR) treatment failure. The strains were intentionally selected based on their phenotypic resistance status to get an evenly distributed number of CLR susceptible (minimum inhibitory concentrations (MIC) ≤0.25 mg/L) and CLR resistant strains (MIC from 0.016 to 256 mg/L). The scientists compared the CLR susceptibility testing by E-Test (bioMérieux, Marcy l’Etoile, France; www.biomerieux.com) and the Lightmix Real-Time Polymerase Chain Reaction assay (RT-PCR, Roche, Basel, Switzerland; www.lifescience.roche.com). A Veriti Thermal Cycler (Applied Biosystems, Forster City, CA, USA; www.appliedbiosystems. com) was used for the cycle sequencing program. The team found high

concordance (95%) between phenotypical CLR resistance screening by E-Test and the Lightmix RT-PCR. Discrepant results were verified by sequencing of the 23S rRNA gene that always confirmed the results obtained by Lightmix RT-PCR. Furthermore, H. pylori was detected in clinical biopsy and stool specimens by Lightmix RT-PCR that identified the correct H. pylori genotype. The authors concluded that their data showed that there is a strong association between specific mutations in the 23S rDNA and CLR resistance. The RT-PCR proved to be an exceptional tool for a fast and reliable detection of H. pylori. Furthermore, it allows for CLR resistance screening within a few hours prior to the prescription of an antibiotic therapy and should drastically reduce the cases of treatment failure. The study was published in the January 2018 issue of the journal Diagnostic Microbiology and Infectious Disease. Image: An artist’s rendition of H. pylori (Photo courtesy of Medical News Today).

Key Mechanism of Autoimmune and Inflammatory Diseases Revealed he prevalence of psoriasis, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis, has been rapidly expanding over the last few decades. A crucial aspect of the molecular basis of these autoimmune and inflammatory has been unraveled. For instance, an estimated 125 million people worldwide are affected by psoriasis and another 100 million by rheumatoid arthritis, while the presence of inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) in ethnic populations and previously unaffected geographical regions is growing at alarming rates. Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. Scientists at the Flanders Institute for Biotechnology (VIB, Ghent, Belgium; www.vib.be) and their colleagues discovered that the immunomodula-

tory cytokine IL-23 pro-inflammatory activity, which underlies a wide range of inflammatory diseases, critically depends on structural activation of the cytokine by its receptor, IL-23R. The team determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12R 1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23 antibody complexes, they proposed a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit. The study was published in the January 2018 issue of the journal Immunity. LabMedica International June-July/2018

Edited by Tahir Pillay MBChB, PhD, FRCPath(Lon), FCPath(SA) IFCC members may send news to: Tahir Pillay MBChB, PhD, Head, Dept of Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Private Bag Bag x323, Arcadia, 0007, South Africa Tel: (27) 012-319-2114; Email: enews@ifcc.org

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Changing the Agenda from Cost to Value Background to the Formation of the IFCC-WASPaLM Committee for the Value Proposition in Laboratory Medicine By Andrew St John, Chair IFCC C-VPLM, ARC Consulting or many years laboratory professionals proudly made the claim that the value of laboratory medicine was demonstrated by the fact that 70% of clinical decisions depended upon the lab. In recent years we have realised that this claim has very little foundation and we need to generate and promote more substantive measures of value. The case for a need to move from a focus on the costs of testing to one which is more value based was documented by the IFCC Task Force on the Impact of Laboratory Medicine on Clinical Management and Outcomes and is now widely acknowledged throughout the profession and industry. In order to reflect this new awareness of the importance of value, various groups within laboratory medicine are developing specific initiatives that are aimed at changing practice in ways that will generate better value for patients and for the community at large. These groups include the Test Evaluation Working Group of the European Federation of Laboratory Medicine (www.eflm.eu/site/page/a/1158) and the US-based group Society to Improve Diagnosis in Medicine (www.improve diagnosis.org/page/Diagnosis). A third and somewhat different approach to determine value has just been formalised into the IFCC-WASPaLM Committee for the Value Proposition in Laboratory Medicine (VPLM). It aims to address the problem that even when we have tests accompanied by a substantial evidence base to support their effectiveness, experience shows that this evidence often does not always translate into routine practice. In other words there are serious problems with the implementation of new tests, a problem which exists in healthcare generally. The value proposition concept has been borrowed from business and can be defined simply as a “statement that describes the benefits of a service, to whom, and how the benefits can be delivered”. Translating that to laboratory medicine and the use of a particular test, means that we must define the care pathway where the test will be used, document the evidence, and measure the impact and outcomes on all the stakeholders including patients. In work completed to date we have described a theoretical framework which lists all the key components of the value proposition that need to be determined for a test to be clinical and economically effective. The most recent publication describes the application of the value proposition to the implementation of high sensitive troponin testing. The VPLM Committee will be working on extending the value proposition to several different tests and evaluating

IFCC OFFICE Via Carlo Farini 81, 20159 Milan, ITALY Tel: (39) 02-6680-9912 • Fax: (39) 02-6078-1846 E-mail: ifcc@ifcc.org • Web: www.ifcc.org Office Hours: 8.30-13.00 and 13.30-17.30 Staff Members: Paola Bramati, Silvia Cardinale, Silvia Colli-Lanzi

LabMedica International June-July/2018

the concept in laboratory sites. Another key task will be to assess the relevance and applicability of the concept in different health care systems where funding systems will vary, and value may be quantified differently. The international composition of the Committee will facilitate such work, as also will the involvement of members from the profession and industry. Further details on the composition and terms of reference for the Committee can be found at: www.ifcc.org/ifcc-education-division/emd-committees/c-vplm

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News from the World of the International Federation of Clinical Chemistry and Laboratory Medicine Visit www.ifcc.org for more information

Report from Chinese Association for Clinical Biochemistry (Taiwan) by Dr. Woei-horng Fang, National Representative his brief report summarizes some of the highlights of activities for CACB during the first half Year of 2018. CACB held its annual meeting during the 33rd Joint Annual Conference of Biomedical Science (JACBS) held at the National Defense Medical University Campus, Taipei on 24-25 March 2018. We invited Dr. Jozica Habijanic, Head, Strategic Development Asia Pacific, Roche Diagnostic Asia Pacific, to deliver a special lecture on “The Future of Healthcare and Diagnostics: AI Application.” She shared valuable experiences with us from the vision of corporate sector ranging from recent advances to the future developments in health care and diagnostics. CACB also organized a symposium “Metabolism and Disease from Research to Clinical Diagnosis” . Three speakers shared their experiences in recent development of in vitro diagnostic technology. Ching-Hua Kuo, Professor of School of Pharmacy, National Taiwan University, presented “Development of analytical methods for metabolomics studies and therapeutic drug monitoring.” Dr. Ching-Ying Kuo, Professor of Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, presented “Altered mitochondrial metabolism regulates breast cancer tumorigenicity.” Mei-Ling Cheng, Professor of Healthy Aging Research Center, Metabolomics Core Laboratory, Chang Gung University, presented “Metabolomics in human health.” Following the symposium, the student research oral presentation competition and poster contest were also held. Overall, the two-day conference was very successful and truly an enjoyable academic gathering for the attending members of CACB. Election for CACB Executive Board 2018-2021: Ms. Hsiao-Chen Ning (ning@cgmh.org.tw), Chief Technologist, Department of Laboratory Medicine, Chang Gung Memorial Hospital, was elected as the President. The immediate past-president Dr. Woei-horng Fang will serve as

Photo: CACB newly elected president Ms. Hsiao-Chen Ning (center in the front) and Board members of 2018-2021.

Executive Board member and National Representative to IFCC for the same period. The new Secretary General is Dr. Ching-Ying Kuo (cykuo27@ntu.edu.tw), Assistant Professor of Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University. CACB in conjuction with Dept CLSMB, NTU, and Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute organized a special lecture to invite Dr. Alan Wu, Professor Laboratory Medicine, Chief, Clinical Chemistry Laboratory, San Francisco General Hospital, to deliver a speech of “Promoting the value of the clinical lab to students, patients and the general public.” CACB members and students from Dept CLSMB, NTU enjoyed the talk followed by an enthusiastic discussion. This special lecture also served as the official launch of tranditional Chinese edition for Dr. Wu’s book: “The Hidden Assassin: When Clinical Lab Tests Go Awry.” All the fans were very happy to have Dr. Wu’s signature on the front page of the books.

In Memoriam: Dr. Norbert Tietz A Giant in Clinical Chemistry Has Died by Nader Rifai, Boston Children’s Hospital Department of Laboratory Medicine, Boston USA; IFCC EMD EC, VLP Chair n the morning of May 23, 2018, Dr. Norbert Tietz, a major figure in the field of clinical chemistry and laboratory medicine, died peacefully in Georgia, aged 91. Norbert was born in Stettin, Germany in 1926; one of seven children who all pursued a career in science. Two of his siblings became physicians but Norbert believed that a PhD was a harder goal to achieve, so that is what he pursued. As a World War II veteran and a prisoner of war, Norbert immigrated to America in 1954 to join his brother and to start a new life. He returned home briefly to convince Gertrud to marry him; they met in Munich just before he left Germany. Shortly after, they got married in Chicago and had four children. His first job was at Rockford Memorial Hospital in Illinois, working under the guidance of Dr. Samuel Natelson, an early pioneer in the development of clinical laboratory methods. At the time, the field of clinical chemistry was undergoing a transformational change driven by people like Otto Folin, Donald Van Slyke, and Michael Somogyi. In the 1950’s, instrumental methods of analysis such as flame photometers and UV spectrophotometers as well as systems such as the Coulter electronic cell counter and the Technicon Auto Analyzer had been introduced and changed forever the landscape of the clinical laboratory. In 1959, he was offered a position at Mount Sinai Hospital Medical Center in Chicago with a faculty appointment at the Chicago Medical School. During his interaction with clinicians, he realized their great dependence on laboratory tests and the need for having a book that bridges modern automated technology and pathophysiology to better connect the medical staff with the clinical laboratorians. Hence he published the first edition of the Fundamentals of Clinical Chemistry in 1969; the 8th edition of this book is scheduled to appear later this year. The Tietz Textbook of Clinical Chemistry followed almost two decades

later to become the main reference book in the field. In 2014, I was asked to assume responsibility for both the Tietz Textbook of Clinical Chemistry and Molecular Diagnostics and the Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics and to build on the excellent work that Norbert had started and Carl Burtis, Edward Ashwood and David Bruns continued; Carl Wittwer and Rita Horvath joined me to accomplish this task. Jerry Gallwas, a dear and a mutual friend, visited Norbert regularly in his home in La Jolla to share a meal. During each visit, the three of us conversed on FaceTime. I recall once describing to Norbert the vision for the 6th edition of the Textbook and the desire to convert it from a book to a primarily cloud-based platform. He was quite pleased with this and intrigued by the concept and inquired about the publication date. When I informed him that it would be in one and a half year, he said disappointedly “Oh, I will be dead by then” and I immediately answered “that is totally out of the question, you have to stay alive to see it”. His reply was simply “Okay”. I am glad that he lived to see it and for us to have several conversations about it. Norbert dedicated his book “My Life: From Refugee to Teacher & Scientist” to his “Family, Colleagues, and Students”, those who meant the most to him. His passion for teaching was exceptional and his dedication to education was recognized by both the IFCC and AACC as they bestowed on him their highest honors. Norbert Tietz was an unusual man who contributed greatly to our profession and left an indelible and a long-lasting impression. His legacy in his books and publications will be appreciated for generations to come. LabMedica International June-July/2018

News from the World of the International Federation of Clinical Chemistry and Laboratory Medicine Visit www.ifcc.org for more information

THE WORLD OF IFCC

NEWS

Spanish Society of Laboratory Medicine (SEQCML)

Lab Tests Online (LTO) Website Brings Work of Clinical Laboratory Professionals Closer to Spanish Public The initiative aims to offer information about clinical analyses to the general public Adapted to Spain by an Editorial Committee, it includes information on some 1,200 tests, news, and other resources LTO ES (www.labtestsonline.es) exceeds 300,000 monthly users from all Spanish-speaking countries The Internet has made available to the entire world a great deal of information on any subject, including health. The problem now is to distinguish serious and reliable information from unverified data. Lab Tests Online (LTO) was created with this objective in mind, and is a website that offers rigorous and quality information in the specific field of medical tests. It is an initiative backed in Spain by the Spanish Society of Laboratory Medicine (SEQCML), which was charged with developing the version of this site for Spanish-speaking countries, LTO ES (www.labtestsonline.es). LTO ES has the WMA (Accredited Medical Web) seal and follows the principles of the HON Code (Health on Internet Foundation). "In today's society, people are increasingly concerned about their health and seek out information on how to stay healthy longer," explains Dr. Marià Cortés, director of the Editorial Board of LTO ES. She notes that, with this in mind, the tool was designed to help provide better understanding of the work performed by clinical laboratory professionals. The website is aimed at the general public, but it can also be useful for health professionals. "The clinical laboratory is usually unknown to the general public, despite the fact that around 70-75% of medical decisions are made taking laboratory data into account," says Dr. Cortés. Thus, Dr. Cortés believes that LTO can be a great help in the interpretation of laboratory tests. "Knowing what is analyzed, what it is used for, how the result is interpreted, etc. ... can help users understand better the report they receive from the laboratory and why the included tests were requested", she explains. "We also believe that it can be a practical source of information for general practitioners, especially for more specialized laboratory tests," adds the specialist. The LTO ES website includes information on around 1,200 tests and is constantly updated. The site allows access to the information by searching for the name of the test or the associated physiological condition. It also offers an information section. "We try to maintain a periodic frequency of publication of health news related to the clinical laboratory that is aimed at the general public, so that they can become aware of the importance of the laboratory in the overall context of health care," says Dr. Cortés. In 2017 the website was visited by more than 3.7 million users, with an average of 310,500 visits per month; this usage data is four times higher than in 2014. Although the website is managed in Spain and adapted to its specificities, a significant number of visits come from other Spanish-speaking countries. In fact, Spain is the country with the largest audience (28.14%), followed by Mexico (20.98%).

of LTO ES. Over the past 11 years, LTO ES has been enriched by the progressive incorporation of the American website´s content. In recent years, in addition, its presence in social networks has been enhanced by the publication of news items prepared in Spain, and related to various aspects of health or disease prevention, which were published on the LTO ES website and shared on different social networks. This, according to Dr. Panadero, is aimed at attracting a younger audience. In addition, the doctor notes that the website has recently been migrated to the American website´s management system, which was in the redesign phase. This has not only improved the management of the website but also its design. "The current www.labtestsonline.es not only looks much more attractive, but is also more user-friendly and simple to use; it is also 'responsive', that is, adaptable to all types of devices."

The SEQCML The Spanish Society of Laboratory Medicine (SEQCML) – founded in 1976 – now includes more than 2,500 professionals and has as its main objective to bring together all interested scientists in the field of the Clinical Laboratory, to promote the dissemination of scientific and technical publications, to organize meetings, courses, and congresses of national and international character, and to cooperate with other Scientific Societies. Likewise, the Society aims to contribute to the study and recommendation of standardized methods and establish guidelines and recommendations for training in the field of Laboratory Medicine. For more information: www.seqc.es

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11 years of LTO ES Lab Tests Online (LTO) began as an initiative of the American Association for Clinical Chemistry (AACC) at a time when the Internet was beginning to become popular, in 2001. Starting the following year, the Spanish Federation of Health Technology (FENIN) and the Spanish Society of Laboratory Medicine (SEQCML) tried to reach an agreement with the AACC to develop a Spanish version of this website. An agreement was not reached until 2006, and was signed between the AACC and the European Diagnostic Manufacturers Association (EDMA), allowing the Scientific Societies of European countries to translate the content of the website, adapting it to the specific circumstances of each country. This is how Lab Tests Online began in Spain, Germany, France, Italy, and Greece, with a common content management system managed by Engitel. The Spanish version of Lab Tests Online first appeared in March 2007. "For its development, we had a large team of laboratory medicine professionals who, under the tutelage of the Editorial Committee, were in charge of translating the content of the American website and adapting it to the characteristics of our country", explains Dr. Maite Panadero, member of the editorial committee

LabMedica International June-July/2018

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News from the World of the International Federation of Clinical Chemistry and Laboratory Medicine Visit www.ifcc.org for more information

VIEWPOINT

What Kind of World Do We Want for Tomorrow? by Dr. Bernard Gouget Counselor for Public Health FHF; Chair-Human Health Care Committee-COFRAC; IFCC Chair-Nominations Committee; General Secretary of the International Francophone Federation Of Clinical Biology and Laboratory Medicine (FIFBCML)

dvances in biology and medicine pose a certain number of moral problems to reconcile the respect due to human beings with scientific progress. There are two conflicting conceptions of bioethics. For some, it is a framework that moves to adapt to scientific advances according to the expectations of society. For others, it is the application of intangible benchmarks to new situations. Reflecting on the model for the society we want to have tomorrow is the question which has guided the French National Consultative Ethics Committee which, after several months of civic debate, is preparing a synthesis before the promulgation of the new bioethics law. The program is very broad, with nine societal themes or themes dictated by scientific progress: medically-assisted reproduction (MAR) and gestational surrogacy, end of life, research in the fields of reproduction, genetics, organ donation, health data, artificial intelligence, neuroscience and health/environment relationship. MAR is at the forefront of controversial subjects. It has given rise to the hope of having a child in many people who cannot procreate naturally, posing a major question for society. Can MAR be considered as a new method of reproduction, alleviating the inability to procreate in the broad sense for infertile couples, same-sex couples and single women? The techniques used are: artificial insemination, including via a donor, considered the simplest, which aims to remedy certain types of sterility, male or female, often associated with ovarian stimulation, and in vitro fertilization including assisted fertilization or via a donor. In France, it is currently reserved for heterosexual couples in the event of male or female infertility, or both, or where there is a risk of transmission of a serious disease to the spouse or child. The beneficiaries of medically-as-

IFCC Annual Report 2017 o you want to know about the activities that were carried out in 2017 by IFCC and its members? The IFCC Annual Report 2017 compiled by Dr David Kinniburgh, IFCC Secretary, is now available on the IFCC website (www.ifcc.org). A message from the IFCC past President, Prof. Maurizio Ferrari, welcomes the reader, followed by reports from IFCC Officers on key projects covering a wide range of clinical, scientific, educational and communication related topics. National or Area Societies and Regional Federation reports are also included, allowing the opportunity to communicate their activities to other members. www.ifcc.org/media/477298/ifcc_2017_annual_report-web.pdf

eJIFCC Volume 29 No 1 - April 2018 he first issue of eJIFCC for 2018 is now available - the first edited by Prof. János Kappelmayer, director of a large clinical laboratory at the University of Debrecen, Hungary. eJIFCC, indexed on PubMed Central, has become an increasingly recognized journal, greatly due to the dedicated efforts of the former Editor-in-Chief Prof. Gábor L. Kovács. Prof. Kappelmayer's intention is to continue to publish thematic issues, along with research articles, free communications, letters, and book reviews. Articles in this first issue for 2018 will definitely be of interest to all practicing laboratory specialists. Topics include next generation sequencing for diagnosis of human disease, the investigation of leptin receptor polymorphism in rheumatoid arthritis, hematological parameters in HIV infected patients, and the new IFCC clinical chemistry curriculum developed a guide for trainees in clinical laboratory medicine. www.ifcc.org/ifcc-communicationspublications-division-cpd/ifcc-publications/ejifcc-journal/e-journalvolumes/ejifcc-2018-vol-29/ejifcc-vol-29-no-1

sisted reproduction (MAR) must be of childbearing age. MAR also covers practices such as storage of gametes, germinal tissues and embryos. Some practices can be implemented when the future fertility of a person (child, adolescent or adult) is at risk of being impaired after a treatment or disease. In MAR internationally, policies differ from one country to another. Also, some women choose to go to another country since MAR is not always allowed for lesbian couples and single women. Other methods such as surrogacy, post-mortem MAR and double gamete donation and preservation of oocytes with no medical indication, prohibited in France, are allowed in other countries. Surrogacy, an agreement according to which a woman agrees to become pregnant by artificial insemination or embryo transfer and to give birth to a child that she gives up at birth, and in exchange for payment, to its "contractual parents” is prohibited by bioethics law and the French penal code. But it is allowed partly abroad and in several European countries (BE, PT, NL, IE, UK, PL, SK, RO, etc.). While some would like to allow surrogacy under strict conditions, for women who lack a uterus for medical reasons, for example, others are against it, in the name of the interest of the unborn child and the risk of instrumentalization of women's bodies, highlighting legal and ethical difficulties. In a context relating to “children’s rights”, we need to consider the future of the unborn child when applying certain medical technologies. Numerous questions are raised: related to descent, the gratuitousness and anonymity of gamete donations, the opening of MAR to lesbian couples and single women, to surrogacy itself which attributes a market value to the child and to the organic life of the surrogate mother. The anonymity and gratuity of donations is a principle set down in French law that is common to all elements issued from the human body: the donor cannot know the identity of the receiver, nor the receiver that of the donor. Gametes, as cells issuing from the human body, are subject to these same provisions. However, regulations applying to gamete donation vary greatly within the EU. Should we reconsider or update this principle of anonymity? Associations of people born from MAR with donation claim their right to know their origins. Today, major technological advances, which have led to the appearance of vast genetic databases, risk undermining this principle of anonymity insofar as these data may become accessible to everyone. Debate around surrogacy is lively; infertility treatment associations believe that we can no longer ignore children born from surrogacy. Should the possibility of gestation in a non-commercial context be open to women with serious uterine anomalies? Male couples also wish to use surrogacy to become parents. Should access to gestation be allowed for others outside a therapeutic indication? The question is even more pressing since currently some major nations including India, Russia, and part of the US allow surrogacy. Other countries such as Sweden are banning all surrogacy, commercial as well as altruistic because the social acceptance of this practice will perpetuate the notion that the wombs of women can be used as a service. It has become the subject of a growing globalized reproductive market which includes the sale of sperm and oocytes. However, since the commercial surrogacy industry kicked off, it has been awash with scandals, exploitation and abuses. The ethics of outsourcing pregnancy is an issue that deeply divides citizens. According to Prof. René Frydman, father of the first test-tube baby, “Today people are rising up to denounce violence against women and tackle gender stereotypes, and the claim to gender equality has taken center stage. Now should be the time to mobilize public opinion and the media about the use made of women’s bodies in the reproductive industry”. National and international legislative decisions in this area are of great importance, faced with the pressure of those who have financial interests in the business, as well as those who want a child at any cost. Society must mobilize via an international agreement to resist commodification of bodies on an international scale and effectively condemn any attacks on fundamental human rights, the only way of combatting situations where the dignity of women and the safety of children are not respected. The ethical issues related to the life and health sciences pose questions that transcend borders with a need to be shared internationally. We must ceaselessly ask ourselves whether what is "technically" possible is desirable. This is the evolution from the medical to the societal that we are living through. LabMedica International June-July/2018

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Industry News

Global PCR Market to Surpass USD 7 Billion by 2025 he global polymerase chain reaction market (PCR) was valued at USD 3.7 billion in 2017 and is projected to grow at a CAGR of 8.8% over the forecast period (2017 â&#x20AC;&#x201C; 2025) to surpass USD 7.4 billion by 2025. The extensive applications of the PCR laboratory technique in various fields, rising prevalence and incidence of infectious and chronic diseases, and growing need to develop advanced PCR systems for the rapid and inexpensive quantitative detection of target samples are expected to be the key growth drivers of the PCR market during the forecast period. These are the latest findings of Coherent Market Insights (Seattle, WA, USA; www.coherentmarketinsights.com), a market research and consulting firm. Based on product type, reagents and consumables hold the largest share of the PCR market due to the need to run the sample and amplify the target DNA sequence in PCR instruments. Based on end-user, academic and research laboratories account for the largest market share, on account of the increasing need for PCR systems in advanced laboratory testing and research services. The use of PCR is increasing in the clinical diagnosis of infectious disease, nucleic acid amplification, paternity testing, DNA fingerprinting, detection and diagnosis of infectious disease,

CerTest Biotec Opens New Facility for Diagnostic Products erTest Biotec (Zaragoza, Spain; www.certest.es), a biotechnology company focused on the development and manufacturing of IVD diagnostic products, has opened a new facility in Spain for the research, development and manufacture of molecular diagnostics products. CerTest develops, manufactures and sells a wide range of products for the identification of the agents causing infectious diseases in health facilities, laboratories and hospitals. The company develops and provides clinical diagnostics products with high standards of quality, sensitivity, specificity and reproducibility, allowing the identification of pathogens at early stages of infection. It also collaborates with a large number of hospitals and research institutes in Spain and abroad. The new facility, with a surface area of 4,500 square meters, comprises state-of-the-art laboratories, offices, warehouse and production and quality control areas, among others and has been set up at an investment of 5 million Euros. With this facility, CerTest Biotec will now have a total floor space of 7,000 square meters and will continue to expand in the field of molecular biology, which is one of the companyâ&#x20AC;&#x2122;s specialties.

Global Molecular Diagnostics Market To Reach USD 11 Billion by 2023 he global molecular diagnostics market is expected to grow at a CAGR of 8.4% from USD 7.71 billion in 2018 to USD 11.54 billion by 2023, driven by the increasing prevalence of infectious diseases and various types of cancers, rising awareness and acceptance of personalized medicine and companion diagnostics, growth of the biomarker identification market, and advancements in molecular techniques. These are the latest findings of MarketsandMarkets (Northbrook, IL, USA; www.marketsandmarkets.com), a global market research company. Based on technology, the PCR segment is expected to account for the largest share of the molecular diagnostics market in 2018 due to the increasing use of PCR in proteomics and genomics, automation of PCR instruments, and emergence of advanced technologies such as qRT-PCR. On the basis application, the molecular diagnostics market is expected to be dominated by the infectious diseases segment in 2018, owing to the development of advanced assays for various diseases and conditions, sharp rise in the prevalence of infectious diseases, and growing awareness about the effective use of molecular diagnostic technologies to control the occurrence and spread of infectious diseases. Based on end-user, the hospital & academic laboratories is expected to account for the largest share of the molecular diagnostics market in 2018 primarily on account of the large number of diagnostic tests conducted in hospitals.

LabMedica International June-July/2018

quality control, and personalized medicine. However, R&D advancements are resulting in the creation of various alternative nucleic acid amplification methods, such as loop medicated isothermal amplification, nucleic acid sequence based amplification, strand displacement amplification, and multiple displacement amplification. These methods offer better applicability and sensitivity in nucleic acid amplification, as compared to PCR, which has limitations such as contamination, sensitivity to certain classes of contaminants and inhibitors, and requirement of thermal cycling. These alternative nucleic acid amplification methods could hamper the growth of the PCR market during the forecasted period.

Global POC Coag Test Market Driven by Increasing Geriatrics he global point-of-care (POC) coagulation testing market is projected to grow at a CAGR of over 6% during the period 20182022, driven by the growing geriatric population, worldwide, and increasing focus on personalized medicine. These are the latest findings of Technavio Research, (London, UK; www.technavio.com), a global technology research and advisory company. The aging population is increasing gradually across the world. In 2015, people over the age of 65 years comprised about 7-8% of the global population and are estimated to grow by 50-55% with 1.2-1.4 billion people likely to be aged above 65 years by 2030. This increase in the aging population is leading to the rising prevalence of lung disease, stroke, and cancer among people over the age of 65 years as their immune systems and functioning of organs become weaker and more susceptible to infections. This is driving an increase in the number of blood coagulation disorders, thereby propelling the demand for blood coagulation testing and POC coagulation analyzers.

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SEPTEMBER 2018 Eurotox 2018 – 54th Congress of the European Societies of Toxicology. Sep 2-5; Brussels, Belgium; Web: www.eurotox-congress.com ESP 2018 – 30th European Congress of Pathology. Sep 9-12; Bilbao, Spain; Web: www.esp-pathology.org MSACL 2018 EU – 5th Annual European Congress & Exhibits for Clinical Mass Spectrometry. Sep 11-13; Salzburg, Austria; Web: www.msacl.org ESCV 2018 – 21th Annual Meeting of the European Congress of Virology. Sep 23-26; Athens, Greece; Web: www.escv.org ESPE 2018 – 57th Annual Meeting of European Society of Paediatric Endocrinology. Sep 27-29; Athens, Greece; Web: www.espe2016.org BSACI 2018 – British Society of Allergy & Clinical Immunology Annual Meeting. Sep 30-Oct 2; Telford, UK; Web: www.bsaci.org OCTOBER 2018 ASHI 2018 – 44th Annual Meeting of the American Society for Histocompatibility and Immunogenetics. Oct 15; Baltimore, MD, USA; Web: www. ashi-hla.org ASCP 2018 – American Society for Clinical Pathology. Oct 3-5; Baltimore, MD, USA; Web: www.ascp.org BCLF 2018 – Meeting of Balkan Clinical Laboratory Federation. Oct 3-5; Skoplje, Macedonia; Web: www.bclf.info 5th Joint EFLM-UEMS Congress Lab-

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14-17; Shanghai, China; Web: www. cmef.com.cn ECE 2019 – 21st European Congress of Endocrinology. May 18-21; Lyon, France; Web: www.ese-hormones.org 23rd IFCC/EFLM EuroMedLab. May 19-23; Barcelona, Spain; Web: www. euromedlab2019barcelona.org Hospitalar 2019. May 21-24; Sao Paulo, Brazil; Web: www.hospitalar.com

– 110 – 116 102 121 147 125 145 126 168 146 143 149 151 141 127 148 114 112 105 107

30th Eur. Cong. of Path. . . . . . . .65 77 Elektronika . . . . . . . . . . . . . . .10 AACC . . . . . . . . . . . . . . . . . . . . .61 Aalto Medical . . . . . . . . . . . . . . . .16 Beckman Coulter . . . . . . . . . . . . . .2 Biofire . . . . . . . . . . . . . . . . . . . . .21 Biohit . . . . . . . . . . . . . . . . . . . . . .47 Biokit . . . . . . . . . . . . . . . . . . . . . .25 Boule . . . . . . . . . . . . . . . . . . . . . .45 Caretium . . . . . . . . . . . . . . . . . . .26 Cellavision . . . . . . . . . . . . . . . . . .68 Coris Bioscience . . . . . . . . . . . . .46 Denka Seiken . . . . . . . . . . . . . . .43 Diagnostica Stago . . . . . . . . . . . .49 Diagnostica Stago . . . . . . . . . . . .51 Diasource . . . . . . . . . . . . . . . . . .41 DiaSys . . . . . . . . . . . . . . . . . . . . .27 Dymind . . . . . . . . . . . . . . . . . . . .48 EKF . . . . . . . . . . . . . . . . . . . . . . .14 Drucker . . . . . . . . . . . . . . . . . . . .12 Erba . . . . . . . . . . . . . . . . . . . . . . . .5 Erba . . . . . . . . . . . . . . . . . . . . . . . .7

– 153 108 118 122 128 155 124 115 120 113 – 111 109 117 103 119 144 – 157 150 159

ExpoMedical 2018 . . . . . . . . . . . .66 Greiner . . . . . . . . . . . . . . . . . . . .53 Hecht, Karl . . . . . . . . . . . . . . . . . .8 HiMedia . . . . . . . . . . . . . . . . . . . .18 Instrumentation Laboratory . . . . .23 JS Medicina . . . . . . . . . . . . . . . . .24 Maccura . . . . . . . . . . . . . . . . . . .55 Mast Group . . . . . . . . . . . . . . . . .24 Mayo Clinic . . . . . . . . . . . . . . . . .15 Medix Chemica . . . . . . . . . . . . . .20 Mindray . . . . . . . . . . . . . . . . . . . .13 MSACL 2018 . . . . . . . . . . . . . . . .67 Nova Biomedicals . . . . . . . . . . . .11 Randox . . . . . . . . . . . . . . . . . . . . .9 Randox . . . . . . . . . . . . . . . . . . . .17 SNIBE . . . . . . . . . . . . . . . . . . . . . .3 SNIBE . . . . . . . . . . . . . . . . . . . . .19 SSI . . . . . . . . . . . . . . . . . . . . . . .44 TradeMed.com . . . . . . . . . . . . . .63 VEDALAB . . . . . . . . . . . . . . . . . .57 Vicotex . . . . . . . . . . . . . . . . . . . .50 Vircell . . . . . . . . . . . . . . . . . . . . .59

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