LabMedica International November 2018 by Globetech

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WORLD’S CLINICAL LABORATORY NEWS LEADER ISSN 1068-1760

Vol. 35 No.7 • 11/2018

DAILY CLINICAL LAB NEWS

Treponemal Subspecies Discriminated by LAMP uman yaws is a tropical skin disease of children caused by the bacterium Treponema pallidum subsp. pertenue (TPE). Skin ulcers are the most characteristic clinical manifestations associated with infection in all three active disease stages, primary, secondary,

New Protein Analysis Tool Improves Diagnostic Accuracy he abundance of proteins in the body that correspond with disease or pharmaceutical reactions can provide physicians with vital clues for accurately diagnosing a condition, and for developing potential therapies and evaluating drug effects. Protein

analysis tools are used to quantify and compare the abundance of proteins in groups of healthy individuals with those who are ill or treated with a drug. Changes in protein abundances, when analyzed together, often reveal novel biomarkers.

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Image: Courtesy of The Centers for Disease Control and Prevention (CDC)

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Blood Test Predicts Death Risk from Coronary Disease

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ung nodules are a diagnostic challenge with an estimated yearly incidence of 1.6 million in the USA. The majority of these patients have benign lung nodules; however, there are significant costs, morbidity and mortality associated with the invasive biopsies needed to determine which nodules are cancerous. It has been found that of these pulmonary nodules detected each year more

Automated Clinical LC-MS/MS Driving Faster, More Reliable Results

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iquid chromatography-tandem mass spectrometry (LC-MS/MS) has rapidly emerged as an important tool for the analysis of clinical samples. Offering superior sensitivity, accuracy and precision,

Clinical News . . . . 4-60 IFCC News . . . . . . . . 61 Product News . . . 8-60 Industry News . . . . .65 Events Calendar . . . 66

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Molecular Test Device Developed for RNA Viral Detection

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rapid, point-of-care PCRbased diagnostic test will allow for the detection of occult hepatitis C virus (HCV) infections under both laboratory and field conditions. Chronic infection with the hepatitis C virus affects approximately 1% of the global population (an estimated 71 million people) and claims about 400,000 lives every year. PCR screening for the disease requires

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Rapid Test Developed for Hepatitis C Infections

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Liquid Biopsy Can Rule Out Early-Stage Lung Cancer

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he finding that elevated plasma ACE2 activity is an independent predictor of major adverse cardiovascular events (MACE) in patients with obstructive coronary artery disease (CAD), enables a new blood test that can detect heart patients who should undergo more aggressive treatment.

microfluidic, continuous-flow, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) system to detect viral RNA targets has been developed and its creator have been working to reduce manufacturing costs and identify potential part-

ners for commercialization. The qRT-PCR system has been used to detect the RNA-directed RNA polymerase L (L-gene), a bio marker for the Ebola virus, in a spiked liquid sample. The present aim is to develop point-ofcare (POC) devices based on the Cont’d on page 5

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Blood Test Predicts Death Risk From Coronary Disease ardiovascular (CV) disease is a major cause of morbidity and mortality, and is associated with activation of the renin-angiotensin system (RAS). Angiotensin converting enzyme 2 (ACE2) is an endogenous regulator of the renin angiotensin system. Increased circulating ACE2 predicts adverse outcomes in patients with heart failure (HF), but it is unknown if elevated plasma ACE2 activity predicts major adverse cardiovascular events (MACE) in patients with obstructive coronary artery disease (CAD). Scientists at the University of Melbourne (Parkville, Australia; www.unimelb.edu.au) and their international colleagues prospectively recruited 79 consecutive patients aged >18 years between November 2004 and January 2006 after referral to a tertiary cardiovascular center for a coronary angiogram to investigate suspected CAD. Fasting blood samples were collected at the time of admission for measurement of kidney function, lipids, and troponin. The Access AccuTnI assay (Beckman-Coulter, Chaska, MN, USA; www.beckmancoulter. com) was used to measure plasma troponin. For plasma ACE2 measurement, blood was collected within 48 hours of presentation into lithium heparin tubes, and plasma was obtained by centrifuging blood at 3,000 rpm at 4 °C for 10 minutes and stored at –80 °C until tested. Plasma ACE2 activity was measured within two years after all samples were collect-

ed. The catalytic activity of ACE2 was measured using a validated, sensitive quenched fluorescent substrate-based assay. The rate of substrate cleavage was determined by comparison to a standard curve of the free fluorophore. The scientists reported that the median (IQR) plasma ACE2 activity was 29.3 pmol/ mL/min (range: 21.2–41.2). Over a median follow up of 10.5 years, MACE occurred in 46% of patients (36 events). Above median levels of ACE2 (>29.3 pmol/mL/min) were significantly associated with a higher incidence of MACE and HF hospitalization compared with those with below-median ACE2. Over the follow-up period, there were 18 deaths, 19 myocardial infarcts and 16 hospitalizations with HF. The primary endpoint of MACE, a composite of CV mortality, HF hospitalization or MI occurred in 36 patients. The authors concluded that elevated plasma ACE2 activity is an independent predictor of MACE in patients with obstructive CAD. Louise M. Burrell, MBChB, MRCP, MD, FRACP, a professor of Cardiology and senior author of the study, said, “We have come a long way in treating coronary artery disease but certain patients continue to be at high risk of dying. This new blood test helped identify such patients who may derive benefit from more aggressive treatment.” The study was published on June 13, 2018, in the journal Public Library of Science ONE.

Automated Clinical LC-MS/MS Driving Faster, More Reliable Results cont’d from cover

the technology is capable of delivering powerful insights into patient health. However, conventional LC-MS/MS workflows have typically involved a large number of manual and time-consuming processes, including sample preparation, data collection and results analysis steps. As a result, the operation of LCMS/MS systems has traditionally required highly skilled technicians with the specialist knowhow necessary to obtain clinically useful data. Even when analyses are performed by the most experienced laboratory scientists, these multi-step workflows are vulnerable to errors that require repeat experiments, delaying timely patient treatment decisions. By eliminating and/or automating many of the error-prone manual steps involved in traditional workflows, a fully automated LCV

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MS/MS system could simplify and accelerate the collection of high quality, reliable data that’s right the first time. Consequently, such an advanced system would significantly reduce the need to perform repeat runs, driving faster decisions and giving clinical scientists added confidence in the validity of their results. Moreover, as this system could be operated by non-LC-MS/MS experts, more experienced scientists would have more time to pursue other laboratory tasks. This clear need for a fully automated LCMS/MS system that is designed specifically for the clinical laboratory has driven the development of the new Thermo Scientific™ Cascadion™ SM Clinical Analyzer (Thermo Fisher Scientific, Waltham, MA, USA; www.thermo fisher.com). The system has been designed to push the limits of what’s possible. Where sample preparation and analysis were once complex and time-consuming, this automated instrument has been developed to deliver consistent, high quality results in the shortest possible timeframe, allowing clinical scientists to focus on what they do best – driving ongoing improvements in human health. It should be noted that this product is IVD/CE-marked, but it is not 510(k) cleared and not yet available for sale in the USA.

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ISSN 1068-1760 Vol.35 No.7. 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: Postkom A.Ş. • İpkas Sanayi Sitesi 3. Etap C Blok • 34490 Başakşehir • İstanbul Yerel süreli yayındır. Yılda sekiz kere yayınlanır, ücretsiz dağıtılır.

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Liquid Biopsy Can Rule Out Early-Stage Lung Cancer cont’d from cover

than 90% of those smaller than two centimeters (around 3/4 inch) in diameter are benign, and current detection methods include positronemission tomography (PET) scans, bronchoscopy, needle biopsy, and surgery. A new study has confirmed the accuracy of a liquid biopsy

Molecular Test Device Developed For RNA Viral Detection cont’d from cover

technology to diagnose infectious disease in low-resource areas. Scientists at The Fraunhofer USA Center for Molecular Biotechnology (Newark, DE, USA; www.fraunhofer-cmb.org) developed the microfluidic chip that contains a syringe pump, heaters, and an optical detection system. The team used the syringe pump to introduce the liquid sample and PCR reagents into the system through a microfluidic connector. The purified RNA solution enters a mixing chamber and is then combined with the master mix, which contains the enzymes and other reagents required to conduct amplification. The mixture travels through a reverse transcription zone, where reVisit us at verse transcription enzymes convert RNA to complementary DNA. MEDICA The investigators tested two one2018 step reverse transcription PCR (qRTHall 3A-74 PCR) mastermixes. The team first used the commercial Affymetrix VeriQuest master mix ((Thermo Fisher Scientific, Santa Clara, CA, USA; www.thermo fisher.com), which is composed of reverse transcriptase and DNA polymerase. The team also developed a custom-made one-step master mix that combines Affymetrix’s VeriQuest master mix and the fast DNA polymerase included in Affymetrix’s USB fast quantitative PCR probe master mix. The newly formed complementary DNA and reagents travel through a 95° Czone, where DNA polymerase activates and the double-stranded DNA is melted. The sample then travels to the thermal cycling area, moving through 40 repetitive cycles and between areas heated to 95 °C and 62 °C. The DNA undergoes melting at the higher temperature zone portion of each loop, whereas annealing and polymerization occurs at the lower temperature zone. The optical detection system can then be used to measure fluorescence and real-time DNA amplification. The team demonstrated that that the system performs qRT-PCR in 30 minutes, compared to 80 minutes for standard conventional benchtop thermocyclers. Although they determined that their custom master mix generally delivered better results, they determined the assay’s limit of detection using the commercial mix because it would be more readily translated to the market. Using the commercial mix and the Ebola virus RNA as the target, the team achieved a limit of detection of 10 RNA copies per microliter.

that can help rule out early-stage lung cancer. A large team of medical scientists working with those at the Medical University of South Carolina, Charleston, SC, USA; www.musc.edu) carried out a prospective multicenter observational trial of 685 patients with 8-30 mm lung nodules at 33 sites in the USA and Canada. Multiple reaction monitoring mass spectrometry measured the relative abundance of two plasma proteins, galectin-3 binding protein (LG3BP) and scavenger receptor cysteinerich type 1 (C163A). The liquid biopsy used in the study was the Xpresys Lung 2 (‘XL2’) a second-generation diagnostic test Integrated Diagnostic (Seattle, WA, USA; www.indidx.com). A subgroup of 178 patients had a 16% prevalence of lung cancer. The integrated classifier demonstrated a sensitivity of 97% a specificity of 44% and a negative predictive value (NPV) of 98% in distinguishing benign from malignant nodules. The classifier performed better than positron emission tomography (PET), validated lung nodule risk models, and physician cancer probability estimates. If the integrated classifier results were used to direct care, 40% fewer procedures would be performed on benign nodules while 3% of malignant nodules would be misclassified. The study was published on March 1, 2018, in the journal Chest.

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New Protein Analysis Tool Improves Diagnostic Accuracy cont’d from cover

Scientists at the University at Buffalo (Buffalo, NY, USA; www. buffalo.edu) and their colleagues developed a new protein analysis tool that could vastly increase the speed and precision with which disease and drug effects are analyzed. The groundbreaking tool, called IonStar, is the first to provide near-perfect accuracy when quantifying and comparing the abundance of proteins in the bodies of people who are healthy and ill. The team used IonStar to quantify proteins in rats with traumatic brain injury, a debilitating condition that accounts for 2.2 million emergency room visits annually in the USA. Using 100 tissue samples, IonStar identified 7,000 proteins, including 1,000 that differed in abundance, without missing data. The team has used IonStar and similar techniques to analyze protein variation in cancer, diabetes, cardiovascular disease, neurodegeneration and retina degeneration as well. IonStar increases accuracy and precision and lowers missing data by improving on sample preparation methods, alignment and feature detection designs for mass spectrometry analysis.

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Several other unique features of IonStar are also included for removal of shared peptides, detection and rejection of outliers, and experimental estimate and control of false altered protein discovery rate (FADR). This well-optimized protocol enables global quantification of more than 5,000 proteins in ~50 replicated with high quantitative accuracy and precision, plus extremely low level of missing data. Additionally, extensive proteome coverage as well as much improved quantification of lowabundance proteins could be achieved. Jun Qu, PhD, a professor in the UB School of Pharmacy and Pharmaceutical Sciences and lead investigator, said, “IonStar will totally change the face of clinical and pharmaceutical studies and industry, where large investigations are often critical. For example, in clinical trials, comparing a handful of patients gets you nowhere. If you can analyze a large number of patients with high-quality data, you can discover and track biomarkers much more accurately and reliably. The same is true for pharmaceutical investigations.” The study was published on May 9, 2018, in the journal Proceedings of the National Academy of Sciences. Image: Compared to OpenMS and industry standard MaxQuant, IonStar lowered the amount of missing data in test results from 17% to 0.1%. White area indicates missing data (Photo courtesy of Professor Jun Qu, PhD).

Rapid Test Developed for Hepatitis C Infections cont’d from cover

dedicated infrastructure and qualified staff. In countries with limited resources, this type of assay is only available in centralized laboratories. Therefore, a major clinical challenge remains to identify undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of the current project was to develop and validate a point-ofcare (POC) assay for the qualitative detection of HCV RNA. For this endeavor, investigators at the Pasteur Institute (Paris, France; www.pasteur.fr) developed a POC assay for the qualitative detection of HCV RNA on the PCR Genedrive (Manchester, United Kingdom; www. genedriveplc.com) instrument. The Genedrive instrument is a 600-gram portable device that can be battery operated, thus making it highly suitable for decentralized testing in field settings, and requires only 30 microliters of sample. The investigators validated the Genedrive one hour HCV assay through a case–control study comparing results with those obtained with the Abbott (Lake Bluff, IL, USA; www.abbott.com) RealTime HCV test. Results revealed that the Genedrive PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/milliliter. Assessing 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity and 100% specificity to HCV. The Genedrive HCV diagnostic kit has obtained CE certification for distribution in Europe and will be available for sale in the Middle East, Africa, South-East Asia, and India once local regulatory clearance is obtained. The study was published in the April 3, 2018, online edition of the journal Gut. LINKXPRESS COM

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Treponemal Subspecies Discriminated by LAMP cont’d from cover

and tertiary yaws. Although it is possible to distinguish current infection, active or latent, from past infection when non-treponemal and treponemal tests are used in combination, it remains impossible based on serology and in some instances clinical manifestations, to differentiate yaws infection (TPE) from syphilis, caused by subsp. pallidum (TPA) or bejel, caused by the subsp. endemicum (TEN). A team of scientists working with the Institute for Primate Research (Göttingen, Germany; www.leibniz-gemeinschaft.de) used loop-mediated isothermal amplification (LAMP) assays to rapidly differentiate infection with any of the three Treponema pallidum subspecies (pallidum (TPA), pertenue (TPE), and endemicum (TEN)) and which are known to infect humans and nonhuman primates (NHPs). Four TPA, six human, and two NHP TPE strains, as well as two human TEN strains were used to establish and validate the LAMP assays. Three different LAMP assays were designed. First, the team generated a LAMP assay that is able to detect DNA of all three TP subspecies (TPA, TPE, and TEN). Another LAMP assay was designed to distinguish TPE Visit us at strain infection from infection with TPA or TEN strains. A third LAMP asMEDICA say that differentiates between infec2018 tion with TPE or TEN and infection Hall 3A-74 with TPA strains was established. LAMP reactions were performed using the Mast Isoplex DNA Kit (Mast Diagnostica GmbH, Reinfeld, Germany; www.mast-diagnostica.com). All reactions were run on a MircoAmp Fast Optical 96-well reaction plate (Thermo Fisher, Waltham MA, USA; www.thermofisher.com). The scientists reported that all three LAMP assays were highly specific for the target DNA. Amplification was rapid from 5 to 15 minutes, and within a range of 10E+6 to 10E+2 of target DNA molecules. Performance in non-human primate (NHP) clinical samples was similar to the one seen in human TPE strains. The LAMP assay targeting the gene was positive for all tested TP strain samples including the four TPA, six human TPE, two simian TPE, and the two human TEN strains. The LAMP assay that uses a part of the TP_0619 gene generated positive results for all TPE strains including simian TPE strains as well as the two human TEN strains. The authors concluded that the newly designed LAMP assays provide proof of concept for a diagnostic tool that enhances yaws clinical diagnosis. It is highly specific for the target DNA and does not require expensive laboratory equipment. Test results can potentially be interpreted with the naked eye, which makes it suitable for the use in remote clinical settings. The study was published on April 12, 2018, in the journal Public Library of Science Neglected Tropical Diseases.

Image: The MAST ISOPLEX DNA kit by Mast Diagnostica

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Sensitive Blood Test Speeds Up Heart Attack Diagnosis high-sensitivity (hs) troponin T (cTnT) assay that has greater sensitivity and precision than the conventional fourth-generation cTnT assay currently in use in the USA has been recently approved. The new high-sensitivity blood test for cardiac troponin, given in a hospital emergency room, was also found to be safe and effective. When patients present to emergency rooms with heart attack symptoms, doctors assess them in part by using a cardiac troponin test to measure a protein released into the blood when the heart is damaged. Scientists at the University of Texas (UT) Southwestern Medical Center (Dallas, TX, USA; www.utsouthwestern.edu) and their colleagues developed a procedure for assessing the results of the new test and compared it to existing practice using a conventional troponin test, which takes three hours to complete. Study participants were 536 patients admitted to an emergency room with heart attack symptoms, including chest pains and shortness of breath. The team reported that in the cohort (mean age 55 years, 44% women), the final adjudicated diagnosis was myocardial infarction (MI) in 2.1%, unstable angina in 0.4%, and nonischemic myocardial injury in 17.0%. With the conventional assay, 80.4% of patients ruled out for MI at three hours. With the new hs-cTnT protocol, 83.8% ruled out by three hours, including 30.0% at baseline, 24.8% at one hour, and 28.9% at three hours. Compared with 19.6% of patients considered abnormal by the conventional assay, 16.2% of patients were abnormal under the new protocol. Rebecca Vigen, MD, a cardiologist and lead author of the study, said, “We did not miss any heart attacks using this test in this population. The test also allowed us to determine faster that many patients who had symptoms of a heart attack were not having a heart attack than if we

had relied on the traditional test. We anticipate that this procedure will allow many patients with chest pain to be given a ‘yes’ or ‘no’ diagnosis of whether they are having a heart attack faster.” The study was published on August 6, 2018, in the journal Circulation. Image: The Elecsys high-sensitivity cardiac troponin T (hs-cTnT) assay (Photo courtesy of Roche Diagnostics).

Biomarker-Based Blood Test Developed for Early Cancer Diagnosis blood test for early detection of kidney cancer is based on the KIM-1 (Kidney-injury-molecule-1) protein biomarker. Renal cell carcinoma (RCC) has the potential for cure with surgery when diagnosed at an early stage. To this end, KIM-1 has been shown to be elevated in the plasma of RCC patients. In the current study, investigators at Brigham and Women’s Hospital (Boston, MA, USA; www.brighamandwomens.org) examined whether plasma KIM-1 could represent a means of detecting RCC prior to clinical diagnosis. The investigators measured KIM-1 concentrations in samples from patients enrolled in the European Prospective Investigation into Cancer and nutrition (EPIC). KIM-1 levels from 190 participants who went on

to develop RCC within the next five years were compared to those from 190 matched participants (same age, body mass index, smoking status, etc.) who remained healthy. In samples with detectable levels of KIM-1, the average concentration was double in those who would develop kidney cancer. Furthermore, compared with a risk model including known risk factors of RCC (age, sex, country, body mass index, and tobacco smoking status), a risk model that additionally included KIM-1 substantially improved discrimination between cases and controls. In addition, high plasma KIM-1 concentrations were associated with poorer survival. The KIM-1 study was published in the July 23, 2018, online edition of the journal Clinical Cancer Research. LabMedica International November/2018

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Rapid Diagnostic Test Evaluated for Tuberculosis he diagnosis of smear-negative and extrapulmonary Tuberculosis (TB) remains challenging in resource-limited settings. Confirmation of smear-negative and extrapulmonary TB cases requires a positive Mycobacterium tuberculosis culture, which may take up to eight weeks. The feasibility of the implementation of a commercial rapid molecular diagnostic test for the routine diagnosis of smear-negative or extrapulmonary tuberculosis (TB) and its diagnostic accuracy, and to assess HIV prevalence in a real-life setting has been evaluated. A team of international scientists collaborating with those at the University Hospitals of Geneva (Geneva, Switzerland; www.hug-ge.ch) conducted a prospective cohort study of all consecutive cases with suspected smear-negative and/or extrapulmonary TB over a two-year period. Cases were classified as proven, probable, or possible TB cases, or as having an alternative diagnosis. For suspected pulmonary TB patients, direct microscopic examination of sputum smears after Ziehlâ&#x20AC;&#x201C;Neelsen staining was performed at the local hospital in Madagascar. All negative sputum acid-fast bacillus (AFB) smears from pulmonary TB patients and specimens from extrapulmonary TB patients were sent to the Mycobacteria Laboratory for a second smear examination, culture, and Xpert MTB/RIF screening (Cepheid, Sunnyvale, CA, USA; www.cepheid.com). Standard analyses (cytological and biochemical) for biological fluids (cerebrospinal fluid, peritoneal fluid, pleural effusion) and the pathological examination of tissue samples (lymph nodes, cutaneous biopsies, pleural and synovial biopsies) were also performed. HIV serology testing was offered to all patients. HIV status was confirmed using three different conformational rapid tests. The scientists found that of the 363 patients included, 183 (50.4%)

had suspected smearnegative pulmonary TB and 180 (49.6%) had suspected extrapulmonary TB. For proven cases, the sensitivity, specificity, positive and negative predictive values of Xpert MTB/RIF were 82.4%, 98.8%, 98.3%, and 86.6%, respectively; for proven and probable cases grouped together, these values were 65%, 98.8%, 98.5%, and 64%, respectively. The diagnostic accuracy was slightly lower for extrapulmonary TB compared to smear-negative pulmonary TB. The prevalence of HIV infection was 12.1%, but almost half of these cases did not have TB (alternative diagnosis group). The authors concluded that the implementation of a rapid diagnosis programme for TB in a resource-poor setting is feasible. The performance of the Xpert-MTB/RIF was remarkable in this difficult-to-diagnose population. HIV prevalence in this study was much higher than the prevalence reported in the general population in Madagascar, in patients with TB and patients with conditions other than TB. The study was published in the April 2018 issue of the International Journal of Infectious Diseases. Image: The Xpert MTB/RIF assay loaded into the GeneXpert 4-module machine (Photo courtesy of Cepheid).

Two-Stage Algorithm Evaluated For Respiratory Viral Infections ew on-demand multiplex molecular respiratory viral diagnostics offer superior performance although can be expensive and some platforms cannot process multiple specimens simultaneously. The recent development of commercial panel-based molecular diagnostics for the rapid detection of pathogens in positive blood culture bottles, respiratory specimens, stool, and cerebrospinal fluid has resulted in a paradigm shift in clinical microbiology and clinical practice. Scientists from Tufts Medical Center (Boston, MA, USA; www.tuftsmedicalcenter.org) performed a retrospective study reviewing results of patients tested for respiratory viruses following introduction of a two-stage testing algorithm incorporating an initial screen with Sofia immunoassay (Quidel, San Diego, CA, USA; www.quidel.com) and then secondary Biofire FilmArray (bioMĂŠrieux, Inc. Durham, NC, USA; www.biomerieux-usa.com), and compared to a period when only FilmArray was used. Specifically, 1,814 samples were processed with the two-stage method during the winter influenza season. The protocol was then compared to 1,162 samples processed by FilmArray alone in the summer months. The team was able to diagnose 282 cases of influenza with the Quidel Sofia influenza immunoassay using the two-stage approach. It then tested all nasopharyngeal specimens that were shown to be negative for influenza by immunoassay with the FilmArray panel, picking up an additional 163 influenza cases that would otherwise have been missed by immunoassay alone. The two-stage approach also included a respiratory syncytial virus (RSV) immunoassay test in children under age five and in adults upon physician request, testing 363 patients. Approximately 28% of samples were Sofia RSV negative, but FilmArray RSV positive, and an additional 71 RSV cases were discovered by FilmArray in patients who did not have the immunoassay. Significantly more patients received their diagnosis within 90 minutes in winter despite testing more samples, and approximately USD 36,000 was saved. The study was published on March 12, 2018, in the journal Diagnostic Microbiology and Infectious Disease.

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Methods Discriminate Dengue Severity During Acute Infection engue is the most widely distributed mosquito-borne human viral disease and represents a major public health burden globally. An estimated 390 million infections occur each year, of which around 100 million are symptomatic. Although prior infection with another viral serotype, such as secondary dengue, is known to be an important factor influencing disease severity, current methods to determine primary versus secondary immune status during the acute illness do not consider the rapidly evolving immune response, and their accuracy has rarely been evaluated against an independent gold standard. An international team led working at the Hospital for Tropical Diseases (Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; www.ndm.ox.ac.uk) enrolled 293 laboratory confirmed dengue patients aged 5 to 25 years who had registered in one of several clinical studies carried out at the Hospital for Tropical Diseases. Daily plasma samples obtained during the acute illness were assayed using the Panbio anti-dengue indirect immunoglobulin-G (IgG) enzyme-linked immunosorbent assay (ELISA) (Alere, Waltham, MA, USA; www.alere.com), as well as in-house anti-dengue IgG and IgM capture ELISAs. Plaque reduction neutralization tests (PRNTs) were performed six months after the acute illness episode to define immune status. The study was published on August 7, 2018, in the journal BMC Infectious Diseases.

Genetic Testing for Hypercholesterolemia Improves Diagnosis

amilial Hypercholesterolemia (FH) is caused by a genetic defect that hinders the body’s ability to remove low-density lipoprotein (LDL) cholesterol from the blood. High LDL levels in the blood are more likely to result in narrowing of the arteries, which puts patients at substantially higher lifetime risk for heart disease and stroke at an early age. The condition occurs in around 1 out of 220 people and it is estimated that there are 30 million people with FH worldwide. However, FH is significantly underdiagnosed, largely due to the wide spectrum of phenotypes caused by a range of pathogenic variants. It is reported that more than 90% of patients worldwide and more than one million in the USA remain undiagnosed. An expert panel led by the Geisinger Genomic Medicine Institute (Danville, PA, USA; www.geisinger.org) has recommended that genetic testing should be the standard of care for patients who have a definite or probable diagnosis for FH based on clinical factors and family history. Wider use of genetic testing to identify FH patients is necessary, according to the expert panel, since cardiovascular conditions and other disease phenotypes might show up in a minority of patients, and there might be incomplete information on the prevalence of such conditions among relatives. Moreover, while patients with pathogenic FH variants generally have higher LDL-C levels, studies have shown a wide range of levels among patients. PREMIER MULTIMEDIA PLATFORM The scientists recommended that those with very high LDL cholesterol SERVING THE WORLD’S and a positive family history of high cholesterol or early heart attack should CLINICAL LABORATORY COMMUNITY be evaluated for pathogenic variants in at least three genes: low density Anytime, Anywhere, On the Go... lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein PRINT MAGAZINE convertase subtilisin/kexin type 9 (PCSK9), though doctors may assess other genes based on a patient’s specific phenotype. More than 2,000 unique geVisit us at netic variants associated with FH have been identified to date, with around MEDICA 2018 half being classified as pathogenic or likely pathogenic. More than 90% of Hall 11-J71 pathogenic variants are in LDLR, beINTERACTIVE tween 5% and 10% are in APOB, and DIGITAL EDITION less than 1% are in PCSK9. Genetic testing doesn’t always detect a pathoWEB PORTAL genic variant in one of these genes, and the authors noted that FH should be diagnosed clinically in the event of a negative test result. Daniel J Rader, MD, a Professor of Molecular Medicine and a senior coauthor of the study said, “In this era NEW: of precision medicine, genetic testing RUSSIAN EDITION is an important tool to identify people at high risk for FH and guide the management of their LDL cholesterol to reduce long-term morbidity and mortality from early and aggressive CAD. Physicians should entertain the diagnosis of FH in their patients who Website Editions: have a family history of early heart disease and/or high LDL cholesterol, English Spanish Russian and consider offering a genetic test in those who may have FH.” The study was published in the August 2018 issue of the Journal of the American College of Cardiology.

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LabMedica International November/2018

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LabMedica International

Procalcitonin Guides Use of Antibiotics for Respiratory Infections he overuse of antibiotic agents is a public health problem associated with increased health care costs and antibiotic resistance. Overuse of antibiotics is common in infections of the lower respiratory tract, where bacterial and viral infections manifest similarly. Procalcitonin is a peptide with levels that are more typically elevated in bacterial than in viral infections; the magnitude of the elevation correlates with the severity of infection, and decreasing levels over time correlate with the resolution of infection. Medical scientists at the University of Pittsburgh (Pittsburgh, PN, USA; www.pitt.edu) enrolled adult patients (≥18 years old) in the emergency department for whom the treating clinician had given an initial diagnosis of acute lower respiratory tract infection (<28 days in duration) but had not yet decided to give or withhold antibiotics and about whom there was uncertainty regarding the need for antibiotics, such that procalcitonin data could influence the prescribing decision. The team measured procalcitonin using a rapid assay with an analytic range of 0.05 to 200 μg/L (VIDAS BRAHMS Procalcitonin, bioMérieux, Marcy l’Etoile, France; www.biomerieux-diagnostics). They randomly assigned patients who presented to the emergency department with a suspected lower respiratory tract infection and for whom the treating physician was uncertain whether antibiotic therapy was indicated to one of two groups: the procalcitonin group, in which the treating clinicians were provided with realtime initial (and serial, if the patient was hospitalized) procalcitonin assay results and an antibiotic use guideline with graded recommendations based on four tiers of procalcitonin levels, or the usual-care group. The scientists included a total of 1,656 patients in the final analysis cohort (826 randomly assigned to the procalcitonin group and 830 to the usualcare group), of whom 782 (47.2%) were hospitalized and 984 (59.4%) received antibiotics within 30 days. The treating clinician received procalcitonin assay results for 792 of 826 patients (95.9%) in the procalcitonin group (median time from sample collection to assay result, 77 minutes) and for 18 of 830 patients (2.2%) in the usual-care group. In both groups, the procalcitonin-level tier was associated with the decision to prescribe antibiotics in the emergency department. There was no significant difference between the procalcitonin group and the usual-care group in antibiotic-days (mean, 4.2 and 4.3 days, respectively; difference, -0.05 day); or the proportion of patients with adverse outcomes of 96 patients (11.7%) and the other 109 patients (13.1%); (difference, -1.5 percentage points, for noninferiority) within 30 days. In the analysis of secondary outcomes, there was no significant difference between the procalcitonin group and the usual-care group in the percentage of patients receiving any antibiotics within 30 days. The study was published on May 20, 2018, in the New England Journal of Medicine.

LabMedica International November/2018

Image: The Vidas BRAHMS procalcitonin assay is performed on the benchtop Vidas multiparametric immunoassay instrument (Photo courtesy of bioMérieux).

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PRODUCT NEWS DIAGNOSTIC ASSAY

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PS/PT ELISA

CHEMISTRY ANALYZER

DiaSorin Molecular

Inova Diagnostics

Jeol

The Simplexa VZV Direct assay enables the direct detection of varicella-zoster virus DNA from CSF. The assay was designed for use on the LIAISON MDX instrument and intended for use with patients with suspected infections of the CNS.

The QUANTA Lite PS/PT helps identify patients at risk for thrombotic or pregnancy morbidity events. PS/PT serves as a good alternative when LAC results are ambiguous or for patients on anti-coagulation therapy.

The JCA-BM6070/C features a 2,400T/H throughput for ultrafast processing capability in a 2-second cycle time. While realizing minimum reaction volume of 60μl with a pre-dilution mechanism, it offers high reliability and excellent cost benefit.

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Exhaled Breath Test Diagnosis of Cancer Assessed n the United Kingdom, upper gastrointestinal symptoms account for at least 3% of consultations in primary care and many patients present with advanced-stage disease and only 38% of cases can be treated with a curative intent. Early esophagogastric cancer (OGC) stage presents with nonspecific symptoms. Volatile organic compounds (VOCs) emitted from the human body have been of interest to scientists for several decades, with associations previously suggested between specific VOCs and breath and lung, bladder, and breast cancers. In a multicenter diagnostic study, led by those at Imperial College London (UK; www.imperial.ac.uk), scientists recruited 335 patients, including 172 patients with esophagogastric cancer; a breath test demonstrated good diagnostic accuracy. Patients 18 years or older with upper gastrointestinal symptoms attending for endoscopy or surgery were eligible. In the cancer cohort only patients with histologically confirmed nonmetastatic esophagogastric adenocarcinoma (stage I-III) were included. All patients in the cancer cohort were sampled when they were neoadjuvant naive. Patients were asked to perform a single deep nasal inhalation followed by complete exhalation via their mouth into secure 500-mL steel breath bag (GastroCHECK, coVita, Santa Barbara, CA, USA; www.covita. net) via a 1-mL Luer-lok syringe. Patients in the cancer and control groups were recruited consecutively. Breath samples were returned to a central laboratory for selected ion flow tube mass spectrometry (SIFTMS) analysis. Histopathology examination of tissues obtained via en-

doscopy or from surgically resected specimens was carried out. The reference test was considered positive on OGC histopathology diagnosis. The authors concluded that their study shows the potential of breath analysis in noninvasive diagnosis of OGC in the clinical setting as the validation study showed a sensitivity of 80% and a specificity of 81% for the breath test to diagnose esophagogastric cancer. The study was published May 17, 2018, in the journal JAMA Oncology. Image: The GastroCHECK Gastrolyzer breath test monitor (Photo courtesy of coVita).

Portable Device for Early-Stage Malaria Detection ver 216 million people were infected with malaria in 2016, and 445,000 individuals died from the disease. The key to solving this health crisis is early-stage diagnosis when malaria therapeutics are most effective. There are two standard ways of diagnosing malaria, yet both have limitations. The first involves taking a blood sample from a person and looking at it underneath a microscope for red blood cells that have been infected with the malaria parasite. Another method are the rapid diagnostic tests. Bioengineers at the University of Southern California (Los Angeles, CA, USA; www.usc.edu) have developed a portable, magneto-optic technology for early stage malaria diagnosis based on the detection of the malaria pigment, hemozoin. The portable optical diagnostics system (PODS) prototype detects a byproduct generated by all species of the malaria parasite, as such; it is a rapid screening for all malaria strains. Because the amount of hemozoin in the blood is directly relat-

ed to how far the malaria infection has progressed, it is an ideal indicator of infection. By applying a magnet, it is possible to manipulate and move the hemozoin particles within a test tube around, or move them in and out of the laser beam. In this way, a single sample can be used to perform two measurements, and every diagnosis is personalized. If hemozoin is present, even in minute concentrations, the signals change. On average, it takes between 10 to 15 minutes for the signal to stabilize, and a larger difference between the two measurements indicates that the malaria has progressed farther. Andrea Martin Armani, PhD, a professor of Chemical Engineering and Materials Science, and senior author of the study, said, “Malaria primarily impacts low-resource environments where supply chain management is difficult and access to power can be unreliable. Therefore, an effective malaria diagnostic must be independent of these.” The study was published on May 21, 2018, in the journal ACS Sensors. LabMedica International November/2018

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COAGULATION ANALYZER

ESR ANALYZER

Karl Hecht

Erba Mannheim

Streck Laboratories

The Assistent digital stirrers feature an adjustable speed from 200-2200 rpm and run time up to 999 minutes of continuous operation. Other benefits include adjustable temp, optional heating plate and memory function with last settings used on restart.

The ECL 760 allows a wide range of clotting and chromogenic tests and immunological assays to be performed. It can accept 23 reagents at a time, trace samples to rack and position and onboard cooling and stirring is available for 20 reagents.

The CUBE 30 Touch produces ESR results directly from EDTA tubes without consuming the patient sample. It prepares up to 30 samples per batch, and delivers results in 20 minutes with automatic printing and transmission to LIS.

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Sampling Device Increases Detection of Barrett’s Esophagus sophageal adenocarcinoma, one of the most fatal and fastest growing cancers in the USA, can be prevented if detected at a precancerous stage. In Barrett’s esophagus (BE), esophageal squamous mucosa is replaced by metaplastic columnar mucosa predisposed to developing esophageal adenocarcinoma (EAC). Gastroenterologists perform more than five million upper endoscopies each year on patients with chronic heartburn and Barrett’s

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esophagus in an effort to find these precancerous cells before they can progress to cancer. Despite the inability to accurately predict which patients have BE prior to endoscopy, BE is known to develop more frequently in men than women. Scientists working with the University of Rochester Medical Center (Rochester, NY, USA; www.urmc.rochester.edu) conducted a multicenter prospective trial, and enrolled 4,203 patients screened for suspected BE and those with known BE undergoing surveillance in 25 community-based gastrointestinal (GI) centers across the USA. Barrett’s esophagus (BE) and esophageal dysplasia (ED) are frequently missed during screening and surveillance esophagoscopy because of sampling error associated with four-quadrant random forceps biopsy (FB). The scientists used Wide Area Transepithelial Sampling with 3D Tissue Analysis ( WATS3D, CDx Diagnostics, Suffern, NY, USA; www.cdxdiagnostics.com) and were able to rapidly collect a sample from a much larger surface area of the esophagus. By combining a larger sampling area with patented 3D imaging and expert cytopathology, WATS3D has far reaching implications for protecting a patient’s health. If precancerous cells are present, they can now be easily detected and removed or destroyed before they become cancerous, essentially preempting esophageal cancer. The authors reports that of 4,203 patients, 594 were diagnosed with BE by FB alone, and 493 additional cases were detected by adding WATS, increasing the overall detection of BE by 83% (493/594, 95% CI 74%–93%). Low-grade dysplasia (LGD) was diagnosed in 26 patients by FB alone, and 23 additional cases were detected by adding WATS, increasing the detection of LGD by 88.5% (23/26, 95% CI 48%–160%). The study was conducted predominantly on gastroesophageal reflux disease (GERD) patients who did not have a history of BE, the average BE length diagnosed in the study was less than 1.5 cm, which may result in lower endoscopic diagnostic accuracy. Seth Gross, MD, a gastroenterologist and lead author of the study said, “These data confirm findings from previous clinical trials showing that WATS3D biopsy significantly increases the detection rate of Barrett’s Esophagus as well as precancerous changes in esophageal tissue in GERD patients. Ultimately, WATS3D revolutionary technology is making esophageal cancer a potentially preventable disease.” The study was originally published on November 28, 2017, in the journal United European Gastroenterology Journal. The WATS3D study was also highlighted as part of the ASGE’s Scope Tech Talk video series and distributed to over 15,000 members in January 2018. LabMedica International November/2018

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LabMedica International

Multiplex Testing Speeds Up Central Nervous System Infection Diagnosis variety of viral, bacterial, and fungal pathogens cause infections of the central nervous system (CNS), which range in severity from mild and self-limiting to severe and life-threatening. Initial symptoms like headache, fever, photophobia, and neck stiffness are not organism-specific so cannot be used to guide therapy. Current microbiologic methods identify a specific organism in only 30%-50% of patients with presumed CNS infections, largely due to poor culture sensitivity stemming from the low concentration of organism in cerebrospinal fluid (CSF) and low volume of CSF collected for microbiologic analysis. An assistant professor of pathology at the Medical College of Wisconsin (Milwaukee, WI, USA; www.mcw.edu) has suggested that a multiplex testing approach simplifies ordering for clinicians and provides a relatively comprehensive result in as little as 60 minutes. Using multiplexed tests to analyze CSF resulted in a 44% to 600% increase in specimens with an identified organism, mostly due to nucleic acid amplification tests (NAATs’) increased sensitivity compared to culture. While potentially beneficial, the significance of detecting these additional organisms needs to be considered in the context of other laboratory values and a patient’s clinical status. The FilmArray ME panel (FAME, BioFire Diagnostics, Salt Lake City, UT, USA; www.biofiredx.com) identified Streptococcus pneumoniae in an additional 12 CSF specimens when compared to culture; however, seven of these patients had no clinical or laboratory evidence of S. pneumoniae suggesting a false positive result potentially due to external contamination of the specimens. Consequently, despite having a specificity of more than 99% for S. pneumoniae the test’s positive predictive value was just 60%. Similarly, a definitive diagnosis of CNS infection was made in only 11% of human herpesvirus-6 and 33% of CMV-positive specimens, possibly due to latent virus present within leukocytes in CSF rather than an indication of active disease. Combined, these data underscore the need to correlate FAME results with other laboratory values and host factors to validate a result, especially in cases with results unexpected or inconsistent with a patient’s risk factors and clinical course.

LabMedica International November/2018

The FA-ME test identifies 14 microorganisms frequently associated with community acquired CNS infections. However, other patient populations including those with traumatic injury or surgery involving the CNS are susceptible to pathogens that are not part of the FA-ME panel. In these patients, FA-ME lacks broad utility, and a negative FA-ME result could be misleading. Blake W. Buchan, PhD, D(ABMM), the author of the study concluded that for these reasons, laboratories need to develop criteria to optimize the benefit from FA-ME testing including selecting appropriate patient populations and rejecting specimens. The study was published on August 1, 2018, in the journal Clinical Laboratory News.

Image: The FilmArray System is the new standard for syndromic infectious disease diagnostics (Photo courtesy of BioFire Diagnostics).

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LabMedica International

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Breath Test Detects Early-Stage Parkinson’s arkinson’s disease (PD) is a degenerative disease that destroys brain tissue and affects movement. It has four main symptoms: stiffness, shaking, slowness, and problems with coordination and balance. Other problems can also develop as the disease progresses, including fatigue, speech difficulties, disrupted sleep, memory problems, and depression. The disease is complex and diverse and arises differently in different people. However, there are some common features, the main one being the dead dopamine-producing cells in a brain area called the substantia nigra. Dopamine is a brain chemical that carries messages that control movement and other functions. There are around 10 million people living with Parkinson’s disease worldwide, including one million in the USA. Scientists at the Technion – Israel Institute of Technology (Haifa, Israel; www.technion.ac.il) described for the first time a clinical trial to distinguish between de novo PD and control subjects using an electronic system for the detection of volatile molecules in exhaled breath (sensor array). They further determined for the first time the association to other common tests for PD diagnostics as smell, ultrasound, and nonmotor symptoms. The test group consisted of 29 PD patients after initial diagnosis by an experienced neurologist, compared with 19 control subjects of similar age who did not have the disease. The breath-testing device contains an array of 40 sensors made of carbon nanotubes or gold nanoparticles. Each sensor had a different chemical attached that could bind certain volatile molecules in the breath, and this binding changed the electrical resistance of the sensor. The authors reported that the test was able to detect early-stage Parkin-

son’s patients before medication and showed sensitivity, specificity, and accuracy values of the sensor array to detect PD from controls were 79%, 84%, and 81% respectively, in comparison with midbrain ultrasonography (93%, 90%, 92%) and smell detection (62%, 89%, 73%). The study was published online on July 10, 2018, in the journal ACS Chemical Neuroscience. Image: Early diagnosis of Parkinson’s disease is important because it affects the choice of therapy and is subject to a relatively high degree of error (Photo courtesy of Technion - Israel Institute of Technology).

Specific Biomarker Discovered for Rheumatoid Arthritis heumatoid arthritis (RA) is an autoimmune disorder that occurs when the immune system mistakenly attacks the body’s tissues. Unlike the wear-and-tear damage of osteoarthritis, rheumatoid arthritis affects the lining of the joints, causing painful swelling that can eventually result in bone erosion and joint deformity. Most RA patients are positive for anti-citrullinated protein antibodies (ACPA), and these antibodies are highly specific for RA diagnosis. ACPA recognizes various citrullinated proteins, such as fibrinogen, vimentin and glucose- 6-phosphate isomerase. Citrullinated proteins are proteins that have the amino acid

arginine converted into the citrulline, which is not one of the 20 standard amino acids encoded by DNA in the genetic code. Scientists at the University of Tsukuba (Tsukuba, Japan; www.tsukuba.ac.jp) collected serum samples from 60 Japanese patients with RA (mean age 52.2 years, range 20–73 years, 80% females) and from 30 healthy subjects (HS); (mean age 49.0 years, range 34–65 years, 80% females). Serum samples were also collected from 17 patients with RA before and 24 weeks after treatment with biologic drugs. A murine model was used to test the methodologies. The investigators used a variety of tech-

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niques to explore the expression and commonality of citrullinated proteins in peptide glucose-6-phosphate isomerase-induced arthritis (pGIA) and patients with RA, and went one step further to investigate its correlation with RA disease activity. These included the measurement of anti-citrullinated peptide (CCP) antibodies in pGIA using the Immunoscan CCPlus test kit (Euro Diagnostica, Malmö, Sweden; www.eurodiagnostica.com); measurement of anti-inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) antibodies with an ELISA test in patients with RA. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis carried out using an ABI 7500 analyzer (Applied Biosystems, Foster City, CA, USA; www.appliedbiosystems. com). Sera from pGIA mice, control mice, patients with RA, and HS were separated by 2DPAGE, and gels were stained. The resultant peptides were analyzed with the nanoACQUITY ultrahigh-performance liquid chromatography (UPLC) system (Waters, Milford, MA, USA; www.waters.com). The scientists found that citrullinated ITIH4 was highly specific to patients with RA, compared with patients with other autoimmune and arthritic diseases or in healthy subjects, indicating a potential role for citrullinated ITIH4 in RA pathogenesis. Notably, its levels were decreased in correlation with the reduction of disease activity score after effective treatment in patients with RA. Moreover, antibody response to citrullinated epitope in ITIH4 was specifically observed in patients with RA. The study was published on April 10, 2018, in the journal Arthritis Research & Therapy. LabMedica International November/2018

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PRODUCT NEWS CD4 T-CELL ANALYZER

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URINE ANALYZER

COAGULATION ANALYZER

Alere

Erba Mannheim

Sunostik

The Alere Pima enables CD4 T-cell analysis at the POC from a fingerstick or venous whole-blood sample in only 20 minutes. It is specifically designed to serve the needs of healthcare professionals in the field, lab or office.

The Laura M features an evaluation time of 60 seconds and a capacity of 600 strips per hour. Additional benefits include a memory capable of saving the last 2,000 measurements, making it ideal for use in clinical laboratories.

The SCLOT SERIES uses the optical detection method to detect the change in turbidity of blood during the coagulation process as the change in scattered light intensity. The series is available in 1-, 2-, and 4-channel semi-automatic options.

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New Test Predicts Risk of Preterm Birth test has been developed to predict a woman’s risk of preterm birth when she is between 15 and 20 weeks pregnant, which may enable doctors to treat them early and prevent severe complications later in the pregnancy. Preterm birth is the leading cause of death for children under five in the USA, and rates are increasing both in the USA, and around the world. It is often associated with inflammation and has many potential causes, including an acute infection in the mother, exposure to environmental toxins, or chronic conditions like hypertension and diabetes. Collaborating scientists from different institutions working with the University of California - San Francisco (San Francisco, CA, USA; www.ucsf.edu) built a comprehensive test that would capture both spontaneous preterm births, which occurs when the amniotic sac breaks or contractions begin spontaneously, and “indicated” preterm birth, in which a physician induces labor or performs a cesarean section because the health of the mother or baby is in jeopardy. The scientists also wanted to be able to identify risk for preeclampsia, which is not included in current tests for preterm birth. The study included 400 women with singleton deliveries in California in 2009–2010 (200 preterm births PTB and 200 full term) divided

into training and testing samples at a 2:1 ratio. Sixty-three markers were tested in 15 to 20 serum samples using multiplex technology. The new test screens for 25 biomarkers of inflammation and immune system activation, as well as for levels of proteins that are important for placenta development. Combined with information on other risk factors, such as the mother’s age and income, the test can predict whether a woman is at risk for preterm birth with more than 80% accuracy. In the highest risk pregnancies, preterm births occurring before 32 weeks or in women with preeclampsia, a potentially fatal pregnancy complication marked by high blood pressure in the mother, the test predicted nearly 90% of cases. Laura Jelliffe-Pawlowski, PhD, an associate professor of epidemiology and first author of the study, said, “There are multifactorial causes of preterm birth, and that’s why we felt like we needed to build a model that took into account multiple biological pathways. The model works especially well for early preterm births and preeclampsia, which suggests that we’re effectively capturing severe types of preterm birth.” The study was published on May 24, 2018, in the Journal of Perinatology.

Mutations Missed in Congenital Disease Screening type of genetic aberration has been identified as the cause of certain neurodevelopmental disorders and congenital diseases, such as autism and congenital heart disease, which are undetectable by conventional genetic testing. The discovery that genetic mutations called epivariations are involved in these diseases could lead to more advanced diagnostic tools for many congenital and neurodevelopmental disorders. Epivariations are variations in the DNA molecule that do not affect the basic composition of the DNA molecule, called the DNA sequence, but result in a change in gene function. An international team of scientists led by those at Icahn School of Medicine (New York, NY, USA; www.icahn.mssm.edu) studied the genetic profiles of 489 patients with known neurodevelopmental or congenital disorders, who had all previously undergone genetic testing that identified no DNA mutations. These disorders had long been thought to have genetic origins, so the scientists suspected that even though conventional testing had not discovered a genetic cause for them, epivariations in their DNA could be present, resulting in gene dysfunction leading to disease. To assess for epivariations, the team conducted methylation profiling,

determining the DNA methylation within each patient’s genome, finding epigenetic mutations that could be the cause of disease in approximately 20% of the studied cohort. Genome-wide DNA methylation profiling was performed using Human Methylation 450k BeadChips (Illumina Inc., San Diego, CA, USA; www.illumina.com). Furthermore, in analyzing more than 5,000 genome profiles of individuals with no known diagnosis of congenital disease or neurodevelopmental disorder, the team discovered epigenetic mutations to be relatively common, and that they could typically be identified via a blood test. The authors concluded that their study showed that epivariations are a relatively common feature in the human genome, that some are associated with changes in the local gene expression, and raise the possibility that they may be implicated in the etiology of developmental disorders. Andrew Sharp, PhD, an Associate Professor and lead investigator of the study, said, “These findings can open up a whole new world in what we know about disease and genetic profiling. Investigating DNA methylation when profiling genomes for disease mutations could help us uncover causative defects in congenital and neurodevelopmental diseases that have eluded us for years.” The study was published on May 25, 2018, in the journal Nature Communications. LabMedica International November/2018

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LabMedica International

Molecular Subtype Identified For CRCs Metastasized to Liver etastases are the leading cause of cancer-related deaths and frequently are widely disseminated, which has led to the prevailing view that metastases are always widespread. A form of colorectal cancer (CRC) forming a localized metastatic tumor in the liver, that is highly treatable, has been identified. Patients with limited liver metastases from CRC have been consistently demonstrated to achieve prolonged survival after hepatic resection and provide an opportunity to investigate the molecular basis for oligometastasis. An integrated team of scientists from the University of Chicago (Chicago, IL, USA; www.uchicago.edu) used a combination of RNA sequencing, targeted panel sequencing, microRNA analyses, and/or microsatellite instability assays, to profile samples from as many as 121 individuals with liver metastases stemming from primary CRC. Along with Affymetrix array-based miRNA (Affymetrix, Santa Clara, CA, USA; www.affymetrix.com) profiling on 116 samples, they used HiSeq instruments (Illumina, San Diego, CA, USA; www.illumina.com) to perform transcriptome sequencing on 95 metastatic tumors. The team added OncoPlus panel sequencing on matched tumor and normal samples from 59 of the cases, and used Promega MSI 1.2 clinical assays (Promega Corporation, Madison, WI, USA; www.promega.com) to assess microsatellite instability patterns in 89 of the metastatic tumor samples. The subset tumor classification strategy was informed by available CRC genomic data generated for efforts such as the Cancer Genome Atlas. The investigators identified three molecular subtypes for the CRC metastases in the liver, including a form of oligometastatic disease that coincided with better overall survival times. A subset of more favorable CRC liver metastasis cases showed “microsatellite instability-independent” activation of interferon and other immune signaling pathways, paired with mutations in genes such as NRAS, CDK12, and EBF1. The team reported, while an intermediate tumor subtype had VEGFA amplifications in combination with NOTCH1 mutations, PIK3C2B mutations, and E2F/MYC pathway activation, a molecular profile dubbed “canonical.” Riskier, “stromal” CRC liver metastatic tumors contained VEGFA amplifications coupled with stromal, mesenchymal, and angiogenic molecular signatures. The team noted that individuals with favorable or intermediate tumor types and low clinical risk scores appeared to have 10-year average survival rates of 94%. In contrast, 45% of individuals survived for 10 years when their metastases fell in the intermediate canonical subtype and had high clinical risk scores or belonged to the unfavorable stromal tumor subtypes with low clinical risk. The 10-year survival rates were even

LabMedica International November/2018

more dire, just 19% for cases with stromal CRC liver metastases paired with high clinical risk scores. The study was published on May 4, 2018, in the journal Nature Communications. Image: The MSI Analysis System, Version 1.2, is a fluorescent multiplex PCR-based method to detect microsatellite instability (MSI), a form of genomic instability (Photo courtesy of Promega).

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HAEMOSTASIS ANALYZER

PROTEIN ANALYZER

The Binding Site

Diagnostica Stago

Genrui Biotech

The MININEPH PLUS enables labs to offer a cost-efficient service for lower volume specialist protein assays. The assay starts when the pipette is activated, reducing the chance of false starts due to reagent sensing errors.

The STA Compact Max 3 delivers sample integrity verification via an EPC module providing fill volume check for any tube, detection of haemolysis, icterus and lipemia. It offers a viscosity-based detection system, ensuring reliable results.

The PA120 uses latex Nephelometry and processes up to 60 samples per hour, increasing efficiency and reducing labor costs. It allows for direct processing of whole blood samples, eliminating the need for pretreatment.

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NE DES W IGN

WORLD’S MEDICAL PRODUCT MARKETPLACE

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Thyroid Cancer Genetics Study Finds New Mutations naplastic thyroid cancer (ATC) is a form of thyroid cancer, which has a very poor prognosis due to its aggressive behavior and resistance to cancer treatments. Its anaplastic cells have poor differentiation, including dedifferentiation. A new study has defined the genetic landscape of advanced differentiated and anaplastic thyroid cancer and identified genetic alterations of potential diagnostic, prognostic and therapeutic significance. Scientists at the University of Colorado Cancer Center (Aurora, CO, USA; www. ucdenver.edu) and their colleagues recently completed the largest-ever study of thyroid cancer genetics, mining the data of 583 patient samples of advanced differentiated thyroid cancer and 196 anaplastic thyroid cancers. Genetic profiles were generated and analyzed with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT (Memorial Sloan Kettering Cancer Center, New York, NY, USA; www.mskcc.org) and FoundationOne (Foundation Medicine, Cambridge, MA, USA; www.foundationmedicine.com). Nikita Pozdeyev, MD, PhD, an assistant professor and lead author of the study, said, “Genetic analysis of earlystage thyroid cancers is most often not necessary as we successfully treat these tumors with surgery and radioactive iodine. But with distant metastases, genetic information becomes important for treatment. Because oncologists had sought this genetic information, our study is enriched for advanced cases.” The study was published on April 3, 2018, in the journal Clinical Cancer Research.

LabMedica International November/2018

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LabMedica International

Coherent Fluctuation Nephelometry Used to Diagnose Bacteriuria rinary tract infections (UTI) belong to the most common infectious diseases, making 20% to 49% of all nosocomial infections. For correct UTI diagnosis, the knowledge about the presence of microorganisms in urine is needed and such diagnosis is traditionally carried out by culture methods using solid nutrient media. Specialized analyzers are used to automate the diagnosis of bacteriuria in laboratory practice. They are based on analysis of microorganisms concentration in urine samples or recording the growth of urine microflora. Coherent fluctuation nephelometry (CFN) has high sensitivity and allows analyzing both parameters simultaneously. Scientists at the M.F. Vladimirsky Moscow Regional Clinical and Research Institute (Moscow, Russian Federation; www.monikiweb.ru) collected 117 urine samples for routine microbiological testing in hospital and outpatient departments. Every urine sample was divided into three parts. One part was used for culturing on Uriselect chromogenic agar (Bio-Rad, Hercules, CA, USA; www.bio-rad.com). The second part was tested using the CFN-analyzer; and the third part was analyzed using UF-1000i (Sysmex Corporation, Kobe, Japan; www.sysmex.com). Urine samples were centrifuged for 60 seconds at 3,000 rpm (1,700 g) to sediment large impurities (such as cells, salts, mucus). During such centrifugation, microorganisms do not sediment onto the bottom of the test tube and stay in the volume of the liquid. Then 0.5 mL of the supernatant was mixed with 0.5 ml sugar broth, placed into disposable 1 mL semi-micro cuvettes, and closed with disposable stoppers (LP ITALIANA SPA, Milan, Italy; www.lpitaliana.com). The team placed the cuvettes into CFN-P12 analyzer (Medtechno-park Ltd., Russian Federation, Moscow; www. medtechnopark.by) and incubated for eight hours. The scientists reported that in 21 urine samples (18%), significant bacteriuria was determined (equal to or greater than 104 CFU/mL). The best diagnostic indicators were obtained while testing urine samples using the CFN-analyzer. The most efficient bacteriuria diagnosis was achieved by simultaneous analyses of microorganisms concentration in urine and growth of urine microflora. The CFN-analyzer allows the preliminary selection of negative urine samples, which do not require further analysis by conventional microbiological methods, thereby decreasing the number of cultures by 80.3%. The authors concluded that their study suggests that the CFN-analyzer is the effective tool for bacteriuria screening in children. The study was published online on July 18, 2018, in the journal Practical Laboratory Medicine.

LabMedica International November/2018

Image: Coherent fluctuation nephelometry analyses microbiological concentrations in urine (Photo courtesy of Medtechnopark).

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LabMedica International

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Performance of Blood Culture Molecular Panels Evaluated igh accuracy of direct identification of pathogens from positive blood culture molecular panels is imperative, particularly for the detection of resistance determinants as it allows for antimicrobial optimization prior to conventional susceptibility testing. In general, when patients are suspected of having bacteremia or sepsis, clinicians immediately prescribe a broad-spectrum antibiotic aimed at killing most bacteria known to cause the infection. They start de-escalating use of the drugs when they deem it appropriate. Scientists at the Children’s Hospital Los Angeles (Los Angeles, CA, USA; www.chla.org) and their colleagues have provided extensive data of a five-year study since implementation of the Verigene Gram-positive blood culture panel (BC-GP, Luminex Corporation, Austin, TX, USA; www.luminexcorp.com) in 2013. Within five years, 1,636 blood culture bottles positive for a Grampositive organism were tested on the BC-GP panel. The BC-GP panel identified 1,520 Gram-positive organisms in 1,636 (92.9%) blood cultures tested. For positive blood cultures, they observed 96.4% (806/834) concordance to the species level. Compared with conventional antimicrobial susceptibility testing, the positive percent agreement (PPA) of methicillin-resistant Staphylococcus aureus, SA (MRSA) (50) and methicillin-resistant Staphylococcus epidermidis, SE (MRSE) (365) was 100%. The mecA gene was detected in two methicillin-susceptible Staphylococcus aureus (MSSA) and one methicillin-susceptible S. epidermidis (MSSE) with a negative percent agreement (NPA) of 99.1% (221/223) and 99.2% (120/121), respectively. The PPA and NPA for vancomycin-

resistant Enterococcus faecium (VRE) was 100%. The BC-GP panel demonstrated excellent performance and clinicians can confidently deescalate antimicrobial therapy in the absence of mecA and vanA/B gene. The panel also identifies coagulase-negative staphylococci that are usually contaminants obtained from a patient’s skin at the time of a blood draw, and that can enable clinicians to discontinue antibiotics if the patient is stable and the clinician is comfortable that an infection is not present. The study was published on August 11, 2018, in the European Journal of Clinical Microbiology & Infectious Diseases. Image: The Verigene Gram-positive blood culture test detects 12 Grampositive targets and three resistance markers (Photo courtesy of Luminex).

Rapid Diagnostic Tests for Malaria Compared alaria case management, consisting of early diagnosis and prompt effective treatment, remains a vital component of malaria control and elimination strategies. Although microscopy is a standard diagnostic tool for malaria and the gold standard, it is infrequently used because of unavailability of laboratory facilities and the absence of skilled readers in poor resource settings. Rapid diagnostic tests (RDTs) are being advocated and used as alternative, or as an adjunct to microscopy at health facilities because they can be easily used by health workers with less training and equipment, and can be per-

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formed by non-specialists in remote settings. The RDTs provide fast test results for initiating or maintaining treatment of patients. An international team of scientists working with the Kilimanjaro Christian Medical University College (Moshi, Tanzania; http://kcmuco.ac.tz) recruited a total of 1,293 among 1,423 outpatients with axillary temperature ≥ 37.5 °C, reported fever in the past 24 hours and/or other symptoms suggestive of malaria. The median age for study participants was 21 years and the majority of the participants (71.4%; 923/1293) were aged 18 to 24 years. More than two thirds (69.1%; 893/1293) of

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study participants were male. In this study, the SD Bioline Malaria Antigen Pf/pan RDT (Standard Diagnostic Inc., Yongin, Republic of Korea; www.alere.com) that detects PfHRP2 (Plasmodium falciparum) and pLDH (pan) was used for malaria diagnosis alongside microscopy. Stained smears were examined by experienced senior microscopists. The Deki Reader (DR, Fio Corporation, Toronto, ON, Canada; http://fio.com) provided automated sequential procedures to guide personnel on how to conduct the RDT test. After capturing an image and recognizing the brand of the RDT, the device prompts the user to remove the RDT from the device to proceed with taking blood samples from the patient. The sensitivity of malaria rapid diagnostic test results interpreted by the Deki Reader was 94.1% and that of visual interpretation was 93.9%. The specificity of malaria rapid diagnostic test results was 71.8% and that of human interpretation was 72.0%. The positive predictive value of malaria RDT results by the Deki Reader and visual interpretation was 75.8 and 75.4%, respectively, while the negative predictive values were 92.8 and 92.4%, respectively. The accuracy of RDT as interpreted by DR and visually was 82.6 and 82.1%, respectively. The authors concluded that there was no significant difference in performance of RDTs interpreted by either automated DR or visually by unskilled health workers. However, despite the similarities in performance parameters, the device has proven useful because it provides stepwise guidance on processing RDT, data transfer and reporting. The study was published on May 29, 2018, in the Malaria Journal. LabMedica International November/2018

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PRODUCT NEWS PCT ASSAY

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LAB AUTOMATION SYSTEM

GLUCOSE/KETONE MONITOR

Fujirebio Diagnostics

Beckman Coulter

Nova Biomedical

The Lumipulse G BRAHMS PCT is a CLEIA for the quantitative determination of PCT in human serum and plasma. It offers results in 35 minutes, making it an ideal for patients with suspected or confirmed lower respiratory tract infection.

The Power Express maximizes uptime, minimizes errors and optimizes workflow. Combined with analyzers and transformative clinical IT solutions, it gives labs the ability to connect all core disciplines into a single line‚ from sample entry to archive.

The StatStrip Express GLU/KET uses glucose measurement technology proven safe and effective throughout all healthcare settings. It offers bidirectional wireless connectivity to hospital HIS or LIS and can transmit patient results directly from the bedside.

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Fluorescent-Polymer Sensor Test Detects Liver Fibrosis novel method has been developed that can detect liver fibrosis from a blood sample in 30-45 minutes. Liver disease is the fifth most common cause of premature death in the Western world, with the irreversible damage caused by fibrosis, and ultimately cirrhosis, a primary driver of mortality. Early detection of fibrosis would facilitate treatment of the underlying liver disease to limit progression. Unfortunately, most cases of liver disease are diagnosed late, with current strategies reliant on invasive biopsy or fragile laboratory based antibody technologies. To upgrade the laboratory’s ability to detect liver fibrosis, investigators at the University of Massachusetts (Amherst, USA; www.umass.edu) and University College London (United Kingdom; www.ucl.ac.uk) developed a robust, fully synthetic fluorescent polymer sensor array. The array uses polymers coated with fluorescent dyes that bind to blood proteins based on specific chemical processes. The dyes vary in brightness and color, presenting different signatures or blood protein patterns. The sensor procedure, which was completed in only about 45 minutes, was evaluated by comparing results from 65 finger-prick volume blood samples taken from three balanced groups of healthy patients and from a group with early-stage and late-stage fibrosis patients. The test distinguished fibrotic samples from healthy blood 80% of the time, reaching the standard threshold of clinical relevance on a widely used metric and comparable to existing methods of diagnosing and monitoring fibrosis. The test distinguished between mild-moderate fibrosis and severe fibrosis 60% of the time.

“This platform provides a simple and inexpensive way of diagnosing disease with potential for both personal health monitoring and applications in developing parts of the world,” said senior author Dr. Vincent Rotello, professor of chemistry at the University of Massachusetts. “A key feature of this sensing strategy is that it is not disease-specific, so it is applicable to a wide spectrum of conditions, which opens up the possibility of diagnostic systems that can track health status, providing both disease detection and monitoring wellness.” Use of the fluorescent polymer sensor array was described in the May 24, 2018, online edition of the journal Advanced Materials. Image: A micrograph showing cirrhosis of the liver. The tissue in this example is stained with a trichrome stain, in which fibrosis is colored blue. The red areas are the nodular liver tissue (Photo courtesy of Wikimedia Commons).

Urinary Markers Predict Bone Problems After Hip Replacement steolysis is an active resorption of bone matrix by osteoclasts and can be interpreted as the reverse of ossification. Although osteoclasts are active during the natural formation of healthy bone the term “osteolysis” specifically refers to a pathological process. Peri implant osteolysis is commonly diagnosed after substantial bone loss has occurred, making revision surgery more challenging. A method has been developed was to identify urinary biomarkers that differentiate total hip replacement patients who eventually develop osteolysis from patients who do not. Scientists at Rush University Medical Center (Chicago, IL, USA; www.rush.edu) used a repository of 24 hour urine samples collected prior to surgery and annually thereafter in 26 patients, 16 who developed osteolysis, and 10 who did not. They examined the markers at radiographic diagnosis, annually for six years preceding diagnosis, at the first

post operative sampling point, and pre operatively. Patients in the osteolysis and non osteolysis groups were matched according to time post surgery and did not differ in the male:female ratio or age at surgery. The team measured seven candidate biomarkers, including free deoxypyridinoline (DPD), cross linked N telopeptides (NTX), interleukin 6 (IL 6), interleukin 8 (IL 8), osteoprotegerin (OPG), α crosslaps (α CTX), and β crosslaps (β CTX). The scientists found that as an individual biomarker, DPD demonstrated the highest ability to predict osteolysis, with an area under the curve (AUC) in Receiver Operating Characteristic (ROC) analyses of 0.844 at six years prior to diagnosis. A panel of α CTX and IL 6 was able to identify at risk patients with an AUC of 0.941 or greater at all post operative time points and an AUC of 1.000 pre operatively. The study was published on June 5, 2018, in the Journal of Orthopaedic Research. LabMedica International November/2018

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LabMedica International

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Female Bladder Bacteria Reveal Urogenital Microbiota ontrary to medical dogma, urine is not sterile, even in asymptomatic individuals. For over 60 years, the standard urine culture protocol has represented the primary tool for detecting bacteria in clinical microbiology laboratories. Culture-independent analysis of urine obtained by suprapubic aspirate, which bypasses the vulva, vagina, and urethra, demonstrates the presence of bacteria in the bladders of women. A new study has found that the female bladder not only contains bacteria, but the microbes are similar to those found in the vagina. Scientists from the Loyola University Chicago (Maywood, IL, USA; www.luc.edu) and their international colleagues collected urine samples by transurethral catheter from female that were recruited from a separate study. Four patients were chosen to sample both the bladder and vaginal environments. All samples underwent standard

urine culture (SUC) as well as expanded quantitative urine culture (EQUC). Each morphologically distinct colony type was isolated on a different plate of the same medium to prepare a pure culture that was used for identification. Matrixassisted laser desorption ionization–time of flight mass spectrophotometry with the MALDI Biotyper 3.0 software program (Bruker Daltonics, Billerica, MA, USA; www.bruker.com) was used to identify the bacterial strains. Genomic DNA was extracted from pelleted cells using a phenol–chloroform method. DNA was prepared and sequenced using the Illumina Hi-Seq platform (Illumina, San Diego, CA, USA; www.illumina.com) with library fragment sizes of 200–300 bp and a read length of 100 bp. Whole-genome metagenomic sequencing was performed on the Illumina HiSeq 2500. The phylogenetic analysis was conducted by extracting amino acid sequence of 40 universal single copy marker genes from bacterial collections. The team isolated and genome-sequenced 149 bacterial strains from catheterized urine

of 77 women. This culture collection spans 78 species, representing approximately two thirds of the bacterial diversity within the sampled bladders, including Proteobacteria, Actinobacteria, and Firmicutes. Whole-genome phylogenetic analysis of bacterial strains isolated from the vagina and bladder in the same women identifies highly similar E. coli, Streptococcus anginosus, Lactobacillus iners, and Lactobacillus crispatus, suggesting an interlinked female urogenital microbiota that is not only limited to pathogens but is also characteristic of health-associated commensals. The author concluded that this unique genome-sequenced culture collection should alter the way doctors view the bacteria of the female pelvic floor both by providing new diagnostic and treatment options for urinary tract infections (UTIs), urgency urinary incontinence, and other associated urinary tract disorders. The study was originally published online on April 19, 2018, in the journal Nature Communications.

Molecular Diagnostic Tool Developed for Chronic Endometritis hronic endometritis is a persistent inflammation of the endometrial mucosa caused by bacterial pathogens. Although chronic endometritis can be asymptomatic, it is found in up to 40% of infertile patients and is responsible for repeated implantation failure and recurrent miscarriage. Diagnosis of chronic endometritis is based on hysteroscopy of the uterine cavity, endometrial biopsy with plasma cells being identified histologically, while specific treatment is determined based on microbial culture. However, not all microorganisms implicated are easily or readily cultured needing a turnaround time of up to one week. A team of international scientists working with those at Stanford University (Stanford, CA, USA; www.stanford.edu) assessed endometrial samples from 113 patients assessed for chronic endometritis using at least one or several conventional diagnostic methods namely histology, hysteroscopy, and/or microbial culture. These samples were evaluated by reverse transcription polymerase chain reaction (RT-PCR) for the presence of nine chronic endometritis pathogens: Chlamydia trachomatis, Enterococcus, Escherichia coli, Gardnerella vaginalis, Klebsiella pneumoniae, Mycoplasma hominis, Neisseria gonorrhoeae, Staphylococcus, and Streptococcus. The sensitivity and specificity of the molecular analysis versus the classical diagnostic techniques were compared in the 65 patients assessed by all three-recognized classical methods. The molecular method showed concordant results with histological diagnosis in 30 samples (14 double positive and 16 double negative) with a matching accuracy of 46.2%. Concordance of molecular and hysteroscopic diagnosis was observed in 38 samples (37 double

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positive and one double negative), with an accuracy of 58.5%. When the molecular method was compared to microbial culture, concordance was present in 37 samples (22 double positive and 15 double negative), a matching rate of 56.9%. When cases of potential contamination and/or non-cultivable bacteria were considered, the accuracy increased to 66.2%. Of these 65 patients, only 27 patients had consistent histological plus hysteroscopic diagnosis revealing a 58.6% of non-concordant results. Only 13 out of 65 patients (20%) had consistent histology plus hysteroscopy plus microbial culture results. In these cases, the molecular microbiology matched in 10 cases showing a diagnostic accuracy of 76.9%. The molecular microbiology confirmed over half of the isolated pathogens and provided additional detection of non-culturable microorganisms. In the endometrial samples with concordant histology plus hysteroscopy plus microbial culture results, the molecular microbiology diagnosis demonstrates 75% sensitivity, 100% specificity, 100% positive and 25% negative predictive values, 0% false positive and 25% false negative rates. The authors concluded that the molecular microbiology method is a fast, and inexpensive diagnostic tool that allows for the identification of culturable and non-culturable endometrial pathogens associated with chronic endometritis. The results obtained were similar to all three classical diagnostic methods together with a degree of concordance of 76.9% providing an opportunity to improve the clinical management of infertile patients with a risk of suffering from this ghost endometrial pathology. The study was published on February 22, 2018, in the American Journal of Obstetrics and Gynecology. LabMedica International November/2018

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LabMedica International

Acute Myeloid Leukemia Risk Predicted in Healthy Individuals he incidence of acute myeloid leukemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukemic hematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal hematopoiesis (ARCH). An international team of scientists led by those at the Princess Margaret Cancer Centre (Toronto, ON, Canada; www.uhn.ca) analyzed peripheral blood samples from 95 pre-AML cases and 414 age- and gender-matched controls. The pre-AML samples were obtained an average 6.3 years before diagnosis. The team validated their findings in an additional cohort of 29 cases and 262 controls. The team used use deep sequencing to analyze genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. The scientists reported that preAML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival. In the combined discovery and validation cohorts, 73.4% percent of the preAML cases had ARCH, while 36.7% of the controls did. In both groups, DNMTA3A and TET2 were commonly mutated. The group noted that they did not observe any canonical NPM2 mutations or FLT3-internal tandem duplication mutations, which they said was consistent with these mutations cropping up late in disease development. The investigators also found that mutations in some genes conferred a greater risk of developing AML than others. For instance, mutations in DNMTA3A and TET2 confer a low risk of AML progression, while mutations in TP53 and U2F1 gave a much higher risk of disease progression. The scientist also developed a predictive test for AML into which they then folded additional data from patients’ electronic health records. This test could predict

LabMedica International November/2018

AML six to 12 months before diagnosis with a sensitivity of 25.7% and a specificity of 98.2%. George S. Vassiliou, FRCPath, MRCP, PhD, a cancer research senior fellow and a senior co-author of the study, said, “We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML.” The study was published on July 9, 2018, in the journal Nature. Image: A blood smear from a patient with acute myeloid leukemia showing very large, immature myeloblasts with many nucleoli. A distinctive feature of these blasts is a linear red “Auer rod“ composed of crystallized granules (Photo courtesy of University of Utah Medical School).

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POC COLLECT KIT

HBA1C ASSAY

Roche Diagnostics

Sarstedt

Sekisui Diagnostics

The Hydrocodone (HYD), Buprenorphine (BUP), and 6-Acetylmorphine (6-AM) screening assays are available on cobas c 501 & 502 analyzers. HYD and BUP detect specifically one parent drug, while 6-AM detects the metabolite of heroin.

The S-Monovette offers precise and controlled venous sample collection from an IV or indwelling catheter and dispensing into test cartridges. It helps reduce test cartridge rejection while minimizing the risk of blood aerosols and exposure.

The SEKURE measures the percent concentration of HbA1c or the HbA1c fraction mmol/mol in human venous whole blood and hemolysate. It uses a pretreatment step to eliminate time-consuming manual preparation prior to testing.

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Persistent Trichomoniasis Infection Found in Pregnant Women richomoniasis is a very common sexually transmitted disease (STD). It is caused by infection with a protozoan parasite called Trichomonas vaginalis. Although symptoms of the disease vary, most people who have the parasite cannot tell they are infected. Trichomoniasis is the most common curable STD. In the USA, an estimated 3.7 million people have the infection. However, only about 30% develop any symptoms of trichomoniasis. Infection is more common in women than in men. Older women are more likely than younger women to have been infected with trichomoniasis. Scientists at the Medical University of South Carolina (Charleston, SC, USA; www.musc.edu) determined the rate of persistent T. vaginalis infection among pregnant women post-treatment. Their secondary objective was to determine if oral multi-dose metronidazole was associated with fewer cases of persistent T. vaginalis compared to single dose treatment. The team carried out a retrospective cohort study of women diagnosed with genital T. vaginalis from 2008 to 2017. They calculated the rate of persistent trichomoniasis by dividing the number of positive Trichomonas tests collected ≥ 21 days post-treatment by the total number of women treated and retested. The physicians reported that 542 women with 565 pregnancies were diagnosed with T. vaginalis infection. The majority of subjects were prescribed either single dose (n=352) or multi-dose metronidazole (n=74). Post-treatment Trichomonas tests were collected ≥ 21 days in 326 sub-

jects and 44% (143) were positive. Rates of positive Trichomonas tests among women receiving single dose and multi-dose regimens were similar (45% versus 40%). Women who had ≥ 1 pregnancy affected by Trichomonas infection were more likely to have a positive test post-treatment. Obese women were less likely to have a positive test post-treatment. The study was published on July 31, 2018, in the journal Sexually Transmitted Diseases. Image: Trichomonas vaginalis protozoan flagellates that cause a common sexually transmitted disease (Photo courtesy of David M. Raymondo).

Testing Device Integrates Robotic Phlebotomy with Sample Processing iagnostic blood testing is the most commonly performed clinical procedure in the world and influences the majority of medical decisions made in hospital and laboratory settings. However, manual blood draw success rates are dependent on clinician skill and patient physiology. Results from such tests are generated almost exclusively in centralized laboratories from large-volume samples using labor-intensive analytical techniques. An end-to-end blood-testing device has been developed that integrates robotic phlebotomy with downstream sample processing. This platform device performs blood draws and provides diagnostic results in a fully automated fashion at the point-of-care. Biomedical engineers at Rutgers University, Piscataway NJ, USA; www.rutgers.edu) created a device that includes an image-guided venipuncture robot, to address the challenges of routine venous access, with a centrifuge-based blood analyzer to obtain quantitative measure-

ments of hematology. The team first demonstrated a white blood cell assay on the analyzer, using a blood mimicking fluid spiked with fluorescent microbeads, where the area of the packed bead layer is correlated with the bead concentration. Next the scientists performed studies to evaluate the pumping efficiency of the sample-handling module. Finally, studies were conducted on the integrated device from blood draw to analysis, using blood vessel phantoms to assess the accuracy and repeatability of the resulting white blood cell assay. Martin Yarmush, MD, PhD, a Distinguished Professor of Biomedical Engineering and the senior author of the study said, “This device represents the holy grail in blood testing technology. Integrating miniaturized robotic and microfluidic systems, this technology combines the breadth and accuracy of traditional laboratory testing with the speed and convenience of point-of-care testing.” The study was published on May 30, 2018, in the journal Technology. LabMedica International November/2018

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CHEMISTRY ANALYZER

Sclavo Diagnostics

ELITech Group

Rayto Life and Analytical Sciences

The SCLAVO PALIO 200N features a throughput of up to 360 tests/hour with ISE module and automatic sample dilution. It also offers an onboard reagent cooling system, continuous sample loading, barcode reader and walk-away capacity.

The Selectra Pro XS is an easy-to-use analyzer with a discrete random access throughput of up to 75 tests per hour. The system offers minimal maintenance and effective use of consumables to provide a truly costeffective operation.

The Chemray-240 features an automatic eight-step washing system and low carry over. It offers a 24hour, non-stop reagent cooling compartment, pre-diluent function for samples, low reagent consumption and real walk-away capability.

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Blood Test Predicts Lymphoma Therapy Success blood test can predict which patients with a type of cancer called diffuse large B cell lymphoma are likely to respond positively to initial therapy and which are likely to need more aggressive treatment. Diffuse large B cell lymphoma, a blood cancer, is the most common type of non-Hodgkin lymphoma and because it is highly biologically variable, patients vary widely in their response to treatment. Although most people are cured by conventional therapy, about one-third are not. Being able to predict early in the course of treatment those who will need additional or more aggressive therapies would be a significant boon to both clinicians and patients. A large team of scientists led by Stanford Medicine (Stanford, CA, USA; http://med.stanford.edu) tracked circulating tumor DNA (ctDNA) levels in 217 people with diffuse large B cell lymphoma that were treated at six medical centers, three in the USA and three in Europe. For each patient, they compared levels of ctDNA before treatment began with the levels after the first and second rounds of conventional chemotherapy. They then correlated those changes with each patientâ&#x20AC;&#x2122;s outcome. The scientists found that ctDNA was detectable prior to the initiation of therapy in 98% of the people studied, and, as would be expected, the amount of ctDNA in the blood dropped in all patients once treatment began. However the precipitousness of the decline varied. Those people

whose ctDNA levels dropped a hundredfold after the first round or three-hundredfold by the second round were much more likely to live 24 months or more without experiencing a recurrence of their disease than those whose ctDNA levels declined more slowly. The study was published on August 20, 2018, in the Journal of Clinical Oncology. Image: Bone marrow aspirate from a patient with diffuse large B cell lymphoma (Photo courtesy of Peter Maslak).

Molecular Test Developed for Nasopharyngeal Carcinoma he prevalence of nasopharyngeal carcinoma (NPC) is higher in Southeast Asia than other parts of the world, around 35 cases per 100,000. Five-year survival rate of the disease is as high as 95% when it is detected early, but drops to 60% if detected at later stage. Most patients are asymptomatic, and so 80% are diagnosed with advanced disease. Liquid biopsies via circulating cell-free DNA (cfDNA) analysis have been shown to be of value in noninvasive monitoring of cancer treatment response and for the detection of cancer recurrence. To extend the application of circulating cell-free DNA to cancer screening, investigators have to face the challenge of developing assays that are sufficiently sensitive for detecting the expectedly low concentrations of circulating tumor DNA in early stages of cancer. Scientists at The Chinese University of Hong Kong (Sha Tin, Hong Kong; www.cuhk.edu.hk) analyzed a target population that was asymptomatic, ethnically Chinese males aged between 40 and 62 years. This

group has the highest age-specific incidence of NPC. All of the participants provided a venous blood sample of 20 mL at enrollment. The team used 800 mL of plasma for Epstein - Barr virus (EBV) DNA analysis by a real-time polymerase chain reaction (RT-PCR) assay, which targeted the BamH1-W fragment of the EBV genome. For enrichment of viral DNA molecules from the plasma DNA samples for subsequent sequencing analysis, target enrichment with EBV capture probes was performed. DNA libraries from five samples were multiplexed in one capture reaction. Equal amounts of DNA libraries for each sample were used. The team also included probes to cover human autosomal regions for reference. The captured autosomal DNA sequences were used for normalization of the viral DNA reads. The multiplexed DNA libraries were sequenced using either the NextSeq 500 or the HiSeq 2500 Sequencing platforms (Illumina, San Diego, CA, USA; www.illumina.com). The study was published on May 14, 2018, in the journal Proceedings of the National Academy of the Sciences. LabMedica International November/2018

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LabMedica International

Urine and Blood Tests Better At Diagnosing Myeloma creening and diagnosis of monoclonal agnostics.fi). gammopathies is generally based on The investigators report that the findings electrophoretic examination of serum from samples with detectable free homogeand urine proteins, namely serum protein elecnous light chains in the urine favor systematic trophoresis (SPEP)/serum protein immunofixunder-detection of serum free lambda light ation electrophoresis (SIFE), urine protein chains by the Binding Site assay, or an underelectrophoresis (UPEP)/urine protein imdetection of lambda dominant κ/λ ratio due to munofixation electrophoresis (UIFE), and general over production of serum free polybone marrow examination. clonal kappa light chains in tertiary care paThe assay for serum free light chains is tients, thus affecting the κ/λ ratio. Nearly 40% based on the biological observation that imof patients have an abnormal ratio without munoglobulin light chains are produced in exhaving monoclonal gammopathy and these cess of the corresponding heavy chains. The variabilities mean some patients, particularly excess free light chains can be quantified in those with the less-common lambda chain-asserum and are also excreted in urine. Serum sociated lesions, could go undiagnosed. free kappa and lambda light chains are normalThe authors concluded that there is systemly present in a ratio of about 0.26 to 1.65. In atic under-detection of lambda dominant κ/λ patients with lambda chain producing monoclonal gammopathies, the ratio is depressed and in patients with kappa chain lesions the ratio is elevated. Medical laboratory Scientists at the Medical College of Georgia at Augusta University (Augusta, GA, USA; www.augusta.edu) retrospectively examined data from 482 patients comprising 2,448 observations from January 2010 through September 2017. In 193 patients with a monoclonal immunoglobulin, with a total of 279 observations, and results of SPEP/SIFE, UPEP/UIFE and serum free light chain assay (SFLCA) Visit us at were available. Of these 193 patients, 175 patients with 249 obserMEDICA 2018 vations had a diagnosis of monoclonal gammopathy of undetermined sigHall 3-D36 nificance (MGUS), smoldering multiple myeloma (SMM) or multiple/ plasma cell myeloma (MM), such as neoplastic monoclonal gammopathies (NMG). Serum and urine protein electrophoreses were carried out using a Helena SPIFE 3000 instrument (Beaumont, TX, USA; www.helena.c om), and by using gels procured from Helena. UPEP and UIFE were also carried out with Helena SPIFE 3000. Urine samples were concentrated with Minicon clinical sample concentrators from Millipore (Burlington, MA, USA; www.merckmillipore. com). The method achieved a concentration of 5 to 50-fold, depending on the protein concentration in the neat sample. Samples with low protein concentration in the neat state achieved higher levels of volume reduction. Serum free light chains were more recently assayed using an Optilite Protein Analysator (AH Diagnostics Oy, Helsinki, Finland; www.ahdi-

ratio. In about 25% of the patients, with false negative κ/λ ratio, under-detection of the serum free lambda light chains may account for the false negative SFLCA result, as documented by the presence of monoclonal lambda light chains in urine. The study was published in the July 2018 issue of the Journal of Clinical Medicine Research. Image: The SPIFE Touch electrophoresis analyzer (Photo courtesy of Helena).

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LabMedica International

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Biochip Can Detect Prostate Cancer Cells n men with prostate cancer, some tumor cells exit the prostate gland and circulate in the blood. Detecting these cells could enable diagnosis at an earlier stage or help doctors assess whether treatment is effective. A new type of sensor has been developed that acts like Velcro for prostate cancer cells, sticking them to a modified frosted glass slide, like those used in medical laboratories, so that they can be identified from blood samples. The low-cost method could help doctors better diagnose and monitor the disease. Scientists at the Chinese Academy of Sciences (Beijing, China; www. cas.cn) and their colleagues developed a simpler, more cost-effective way to monitor prostate cancer cells in the blood. The team based their device on frosted glass microscope slides. The frosted area, which is used to hold and label the slide, is a sandblasted surface with tiny depressions. They added a solution to the frosted slides that caused silica nanowires to grow on their surfaces, and then they suspended antibodies that recognized prostate cancer cells from the nanowires. After getting captured by the antibodies, circulating tumor cells became trapped in the depressions on the slide and tangled up within the nanowires, similar to the interlocking surfaces of Velcro. The team could then visualize the cancer cells with microscopy, and found that the device had a capture efficiency on par with other approaches. When the scientists tested blood samples from prostate cancer patients, the devices detected as few as 10 tumor cells in 1 mL of blood. The biochip showed the specificity and high capture efficiency of 85.4 ± 8.3% for prostate cancer cell line (PC-3). The micro-sized frosted slides and silica nanowires allow enhanced efficiency in capture ep-

ithelial cell adhesion molecule (EpCAM) positive cells by synergistic topographic interactions. The capture efficiency of biochip increased with the increase of silica nanowires length on frosted slide. The biochip shows that micro/nanocomposite structures improve the capture efficiency of PC-3 more than 70% compared to a plain slide. The authors concluded that the nanobiochip has been successfully applied to identify circulating tumor cells (CTCs) from whole blood specimens of prostate cancer patients. Thus, this frosted slide-based biochip may provide a cheap and effective way of clinical monitoring of CTCs. The study was published on May 17, 2018, in the journal ACS Applied Materials & Interfaces. Image: A scanning electron micrograph (SEM) of a prostate cancer cell captured on frosted slide with silica nanowires (Photo courtesy of the American Chemical Society).

Diagnostic Methods Compared for Fecal Helminth Eggs or estimating prevalence of soil-transmitted helminthiasis, assessing infection intensities, evaluating drug efficacy and monitoring drug resistance, accurate diagnostic methods are essential. The currently recommended Kato-Katz method has already been in use for decades. A comparison has been made between the Kato-Katz method and a novel method, which is an online, remote location, parasite diagnostic system previously used in veterinary medicine. The new method is based on the flotation-dilution principle and its novelty is the ac-

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cumulation of parasite eggs into one viewing area within a fluid meniscus. An international team of scientists working with the Swiss Tropical and Public Health Institute (Basel, Switzerland; www.swisstph.ch) collected two stool samples from adolescent participants (age 15–18 years) at baseline and 14 to 21 days after treatment in the framework of a randomized clinical trial on Pemba Island, Tanzania. Stool samples were analyzed with different diagnostic efforts: i) one or ii) two Kato-Katz thick smears from the first sample, iii) two Kato-Katz thick smears from two

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samples and iv) FECPAKG2 (Techion Group Ltd, Dunedin, New Zealand; www.techion group.com) from the first sample. For FECPAKG2 an image of the fecal sample was then captured, and stored offline on a computer and uploaded onto a cloud once connected to the Internet. Subsequently, the image can be analyzed at any time by specialists around the world. The team reported that complete data for all diagnostic efforts were available from 615 participants at baseline and 231 hookworm-positive participants at follow-up. At baseline FECPAKG2 revealed a sensitivity of 75.6% (72.0–77.7) for detecting Ascaris lumbricoides, 71.5% (67.4–95.3) for hookworm and 65.8% (64.9–66.2) for Trichuris trichiura, which was significantly lower than any of the Kato-Katz methods and highly dependent on infection intensity. Despite that the egg counts based on FECPAKG2 were relatively lower compared to Kato-Katz by a ratio of 0.38 (0.32–0.43) for A. lumbricoides, 0.36 (0.33–0.40) for hookworm and 0.08 (0.07–0.09) for T. trichiura, the egg reduction rates (ERR) were correctly estimated with FECPAKG2. The authors concluded that the sensitivity to identify any soil-transmitted helminthes (STH) infection was considerably lower for FECPAKG2 compared to Kato-Katz. Following rigorous development, FECPAKG2 might be an interesting tool with unique features for epidemiological and clinical studies. The study was published on June 4, 2018 in the journal Public Library of Science Neglected Tropical Diseases. LabMedica International November/2018

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LabMedica International

FDA Recommends Pooled Blood Testing Of Zika Screening he US Food and Drug Administration (Silver Springs, MD, USA; www.fda.gov) said today that it has revised its recommendations for testing blood donations for the Zika virus. In a revised final guidance, the agency said that pooled testing of donations using a screening test that it has licensed is a sufficient method for complying with its testing regulations and effectively reducing the risk of Zika virus transmission. The new approach is usually more cost effective and less burdensome for blood establishments, and will continue to monitor the situation closely, and as appropriate, reconsider what measures are needed to maintain the safety of the blood supply. The revised guidance replaces a guidance announced in August 2016 that recommended universal nucleic acid testing for Zika virus of individual units of blood donated in US states and territories. Following outbreaks of the Zika virus, US blood centers in 2016 began implementing individual donation nucleic acid testing under investigational new drug applications. They used the Roche Cobas Visit us at (Roche Molecular Diagnostics, Pleasanton, CA, USA; https:// MEDICA molecular.roche.com) or Grifols 2018 Procleix Zika virus assays (Grifols, Hall H18-C23 Barcelona, Spain; www.grifols. com). In May this year, the FDA approved an additional claim for Rocheâ&#x20AC;&#x2122;s Cobas Zika test for use on the Cobas 6800 and 8800 PCR systems that enables streamlined screening of multiple individual blood or plasma donations that have been pooled together. Cobas Zika is a qualitative in vitro nucleic acid screening test for the direct detection of Zika virus RNA in plasma specimens from individual human blood donors. It enables blood services to ensure that potentially infected blood units are not made available for transfusion. In an exception to pooled testing in its revised guidance, the FDA said that an increased risk of local mosquito-borne transmission of Zika virus in a specific geographic area would require individual donation testing in that location. The overall change, announced in a revised guidance document entitled Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood and Blood Components, comes after careful consideration of all available scientific evidence, including consultation with other public health agencies, and following the recommendations of a December 2017 meeting of the Blood Products Advisory Committee.

ticles, here colored blue, are 40nm in diameter, with an outer envelope, and an inner dense core (Photo courtesy of Cynthia Goldsmith).

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Image: A digitally colorized transmission electron microscopic (TEM) image of Zika virus, which is a member of the family, Flaviviridae. Virus par-

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PRODUCT NEWS IMMUNOASSAY ANALYZER

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IMMUNOASSAY ANALYZER

DETECTION SYSTEM

Euroimmun

Siemens Healthineers

Biomérieux

The EUROBlotMaster offers precision and reproducibility from the first incubation step to the incubated immunoblot strips. It is available with over 90 validated profiles and in two models for up to 30 or 44 strips per test run.

The IMMULITE 1000 bench top system offers an extensive menu, low cost of operation, reliability and ease of use. With over 100 assays for routine and esoteric testing, it is ideal for laboratories with low-volume immunoassay tests.

The BACT/ALERT VIRTUO features RT notification of blood volume, quicker time to detection and no hands-on time. The motion-activated loading lets any skill level load the instrument, while the flexible platform fits into nearly any size lab.

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Two Viral Blood Screening Assays Get FDA Clearance global producer of plasma-derived medicines and a developer of diagnostic solutions announced today that it has received approval from the U.S. Food & Drug Administration (FDA, Silver Springs, MD, USA; www.fda.gov) for two blood screening assays. One assay that allows for increased blood safety by screening and delivering simultaneous results for human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV), and hepatitis B virus (HBV) as well as detecting HIV type 2 (HIV-2). The Procleix Ultrio Elite assay (Grifols Diagnostics, Barcelona. Spain; www.grifols.es) can be used to test pools of plasma composed of up to 96 individual donations from donors of source plasma. Procleix WNV assay is a highly sensitive, qualitative in vitro nucleic acid assay for the detection of West Nile virus RNA in plasma and serum of human blood donors. Both assays will run on the fully automated nucleic acid testing (NAT) blood screening platform Grifols’ Procleix Panther system. The device is an integrated nucleic acid testing system that fully automates all necessary steps to perform Procleix assays, from sample processing through amplification, detection, and data reduction. The Procleix Panther system was created to be a fully automated sample-to-result instru-

ment that eliminates the need for batch processing. Grifols will begin commercializing the Procleix Ultrio Elite and Procleix WNV assays in the USA later this year. The system received CE marking and launched in Europe in 2012 and in 2016, the FDA allowed blood centers to use the Grifols’ Procleix Zika virus assay with the Procleix Panther system under an Investigational New Drug (IND) study protocol to screen donated blood nationwide. The firm has since launched an IND Babesia screening test on the platform. Carsten Schroeder, BA, MBA, the president of Grifols’ diagnostic division, said, “The addition of the Procleix Panther system with these assays will allow blood centers to efficiently screen for infectious diseases on one simple, automated platform while adapting to changes in donation volume and regulatory requirements.”

Hematological Parameters Predict Severity of Acute Pancreatitis cute pancreatitis (AP) is an acute inflammation of the pancreatic parenchyma induced by activated pancreatic enzymes due to multiple causes. Current severity scores include multiple variables and some of them are only complete within 48 hours of admission. Until now, no single serum marker is able to predict severity or mortality in AP at admission. Red cell distribution width (RDW) is a routine parameter of the complete blood count test, described as simple, easy, inexpensive and quantitative that measures the size heterogeneity of peripheral red blood cell (RBC), known as anisocytosis. Gastroenterologists at the University of Coimbra (Coimbra, Portugal; www.uc.pt) conducted a retrospective case-control study from January 2014 to December 2016, including a total of 312 consecutive admissions with AP. Ninety-one patients with severe AP were identified during the study period (cases) and were compared with patients with mild AP (controls), in the 1:1 proportion. The authors concluded that RDW is a simple routine parameter, available at admission. The AP cohort showed that RDW0h of greater than 13.0 and RDW0h-to-total serum calcium ratio greater than 1.4 were excellent predictors for severity and RDW0h greater than 14.0 and RDW0h-to-total serum calcium ratio of greater than 1.7 were very-good predictors for mortality, being superior to conventional prognostic scoring systems. The study was published on July 5, 2018, in the journal BMC Gastroenterology.

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Obesity Affects Prostate Cancer Test Results levated levels of prostate specific antigen (PSA) in the blood can be an indicator of prostate cancer and lead to further diagnostic investigations. Obese men have lower serum prostate-specific antigen (PSA) than comparably aged lean men, but the underlying mechanism remains unclear. A recent study determined the effect of obesity on PSA and the potential contributing mechanisms. Scientists at the University of Adelaide (Adelaide, Australia; www.adelaide.edu.au) and their colleagues recruited a cohort of 1,195 men aged 35 years and over, with demographic, anthropometric (body mass index (BMI), waist circumference (WC) and serum hormone (serum testosterone (T), estradiol (E2), PSA and hematology assessments obtained over two waves was assessed. Men with a history of prostate cancer or missing PSA were excluded, leaving 970 men for the final analysis. Mixed-effects regressions and mediation analyses adjusting for hormonal and volumetric factors explore the potential mechanisms relating obesity to PSA. The scientists reported that after adjusting for age, PSA levels were lower in men with greater WC. In a multivariable model including WC, age, E2/T and PlasV as predictors, no statistically significant associations were observed between with PSA and either WC or PlasV, while strong associations were observed with both E2/T and age. In the mediation analyses with PlasV as the mediator, the average causal mediation effect (ACME) explained roughly 0.2 of the total effect of WC on PSA, while when E2/T is a mediator; the ACME explained roughly 0.5 of the effect. The authors concluded that their findings indicate that lower PSA levels in obese men, as compared to normal weight men, can be explained both by hormonal changes (elevated E2/T ratio) and haemodilution. Hormonal factors therefore represent a substantial but underappreciated mediating pathway. Adel Aref, MBBch, MSc, a Clinical Oncologist, and first author of the study, said, â&#x20AC;&#x153;PSA is increased by the male sex steroid hormone, testosterone. We have shown for the first time that the concentration of PSA in the blood is lower in men with severe obesity (with a body mass index or BMI of 30 or higher) than in lean men, and that this can be attributed to lower concentrations of circulating testosterone.â&#x20AC;? The study was published on June 25, 2018, in the journal EndocrineRelated Cancer.

Image: Elevated levels of prostate specific antigen (PSA) in the blood can be an indicator of prostate cancer and lead to further diagnostic investigations (Photo courtesy of KeraNews).

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LabMedica International

PRODUCT NEWS COAGULATION MONITOR

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PLATELET TESTING SYSTEM

HEMATOLOGY ANALYZER

Instrumentation Lab

Mindray

The Hemochron Response for whole blood anticoagulant monitoring offers a test menu that standardizes testing and improves efficiencies. It offers dual test well capabilities and displays results as whole blood, plasma equivalent or INR.

The ROTEM measures platelet aggregation in whole blood samples and allows testing of samples with low hematocrit. With single-use cuvettes and three reagents, it measures three parameters and provides results in six minutes.

The BC-6000 can load up to 50 samples at a time and offers a throughput of up to 110 tests per hour. It requires only small amounts of whole blood and capillary blood for a CBC+DIFF test with NRBC result.

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Measurement of Two Biomarkers Predicts Diabetes Risk esults presented in a recently published study indicated that it is possible to predict likelihood of developing diabetes by measuring the levels of two biomarkers in a single blood sample. Current clinical definitions of diabetes require repeated blood work to confirm elevated levels of glucose or glycosylated hemoglobin A1c (HbA1c) to reduce the possibility of a false-positive diagnosis. The possibility that two different tests from a single blood sample would provide adequate confirmation had not been evaluated. To address this question, investigators at Johns Hopkins University (Baltimore, MD, USA; www.jhu.edu) examined analytical data from the long-running (more than 35 years) Atherosclerosis Risk in Communities (ARIC) Study that had been accumulated for 13,346 Americans (12,268 without diagnosed diabetes). For the current study, confirmed undiagnosed diabetes was defined as elevated levels of fasting glucose (higher than 126 milligrams per deciliter) and HbA1c (more than 6.5%) from a single blood sample. Results revealed that among 12,268 participants without diagnosed diabetes, 978 had elevated levels of fasting glucose or HbA1c at baseline (1990 to 1992). Among these, 39% had both (confirmed undiagnosed diabetes), whereas 61% had only one elevated measure (unconfirmed

undiagnosed diabetes). The confirmatory definition had moderate sensitivity (54.9%) but high specificity (98.1%) for identification of diabetes cases diagnosed during the first five years of follow-up, with specificity increasing to 99.6% by 15 years. The 15-year positive predictive value was 88.7% compared with 71.1% for unconfirmed cases. “The results of our study suggest that the two tests from one blood sample can provide adequate confirmation of diabetes, potentially allowing a major simplification of current clinical practice guidelines,” said lead author Dr. Elizabeth Selvin, professor of epidemiology at Johns Hopkins University. “Doctors are already doing these tests together – if a patient is obese, for example, and has other risk factors for diabetes, the physician is likely to order tests for both glucose and HbA1c from a single blood sample. It is just that the guidelines do not clearly let you use the tests from that one blood sample to make the initial diabetes diagnosis.” The study was published in the June 19, 2018, online edition of the journal Annals of Internal Medicine.

Urinary Tract Infections Diagnosed with Genetic Analysis of Cell-Free DNA enetic analysis of cell-free DNA (cfDNA) in urine samples reveals valuable information, which enables comprehensive monitoring of host and pathogen dynamics in bacterial and viral urinary tract infections (UTIs). Investigators at Cornell University (Ithaca, NY, USA; www.cornell.edu) isolated cfDNA from 141 urine samples from a cohort of 82 kidney transplant recipients and performed nextgeneration sequencing. The analysis revealed that urinary cfDNA was highly informative about bacterial and viral composition of the microbiome, antimicrobial susceptibility, bacterial growth dynamics, kidney allograft injury, and host response to infection. These different layers of information were accessible from a single assay and individually agreed with corresponding clinical tests based on quantitative PCR, conventional bacterial culture, and urinalysis. Furthermore, cfDNA revealed the frequent occurrence of diseases that remained undiagnosed with conventional diagnostic protocols. “We found that we could deduce the fraction of the bacterial population that is growing, by carefully looking at the places in the genome where the cell-free DNA was derived from” said senior author Dr. Iwijn De Vlaminck, professor of biomedical engineering at Cornell University. “Metagenomic analysis of the cell-free DNA can also be used to infer which antimicrobial drugs may work best against a particular infection.” The paper describing genetic analysis of cell-free DNA in urine specimens was published in the June 20, 2018, online edition of the journal Nature Communications.

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LabMedica International November/2018

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LabMedica International

Lateral-Flow Assay Rapidly Detects Plague Bacteria lague caused by Yersinia pestis is a known flea-borne disease that can trigger large epizootics among the rodent population. Humans that live in environments close to these rodents can contract the bubonic plague either through direct contact with infected animals or through transmission by infective flea bites. Over the last decade, thousands of cases of plague have been reported annually, indicating that the plague has not been eliminated. This is especially true in places where public health and living conditions are poor. Several well-established assays have been applied to detect Y. pestis/F1 protein, such as the indirect hemagglutination assay (IHA), which is the current gold standard for Y. pestis detection. Scientists at the National Defense Medical Center (Taipei, Taiwan; www.ndmctsgh.edu.tw) developed a rapid, cheap, sensitive, and specific technique, the lateral flow assay (LFA -F1 strips), to detect this pathogen, by using paired monoclonal antibodies (MAbs) against Y. pestis capsule like fraction 1 (F1) protein. Compared with the polyclonal antibody (PAb) based F1 strips, the MAb-based F1 strips have a remarkable increased detection limitation (10 to 100 fold). Furthermore, besides the limitation and specificity evaluation, the application of this F1 strip on simulated clinical samples indicate the LFA can be a good candidate to detect plague. Recombinant F1 antigen was expressed and purified from a series of studies. The various anti-F1 monoclonal antibodies (MAbs) generated from hybridoma cells were screened with the enzyme-linked immunosorbent assay (ELISA) technique. To evaluate the feasibility of this Y. pestis F1 test strip, the F1 protein/Y. pestis was spiked into simulated clinical samples such as human serum, mouse bronchoalveolar lavage fluids, and mouse blood to mimic natural infection status. Additionally, this technique was applied to detect the Y. pestis in the environment-captured rats, to evaluate the practical usefulness of the strips. The scientists reported that by using this MAb-based-LFA technique, 4 ng/mL of recombinant F1-protein and 103 CFU/mL of Y. pestis could be detected in less than 10 minutes, which is at least 10-folds than that of the polyclonal antibody (PAb) format. On the other hand, although various Yersinia strains were applied to the strips, only Y. pestis strain showed a positive result; all other Yersinia species did not produce a positive signal, indicating the high efficiency and specificity of the MAb-based F1-strips. The authors concluded that the MAb-format-LFA will be valuable as a diagnostic tool for the detection of Y. pestis. This report shows that the F1 strip is sufficient to support not only the detection of plague in simulated clinical samples, but also it may be a good candidate to meet the epidemiological surveillance during an

LabMedica International November/2018

outbreak of the biological warfare. The study was published on August 14, 2018, in the journal BMC Infectious Diseases. Image: Specificity assay of Yersinia F1-strips. Six Yersinia strains (105ÂŹâ&#x20AC; CFU/mL each) were applied on Yersinia-F1-strips. Strip 1: Y. pestis yreka; 2: Y. mollaretii; 3: Y. frederiksenii; 4: Y. pseudotuberculosis; 5: Y. enterocolitica; 6: Y. intermedia; 7: PCB buffer (Photo courtesy of National Defense Medical Center).

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LabMedica International

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Blood Separation Tubes Combine Serum Analysis With Plasma Analysis new line of blood separation tubes combines the quality of serum analysis with the speed of plasma analysis. Greiner BioOne (Kremsmünster, Austria; www.gbo.com) has released the Vacuette Serum Fast Tube, which with coagulation time of only five minutes enables serum to be analyzed as quickly as plasma. The inside of the Vacuette tube wall is spray-coated with a Blood Clotting Activator (BCA)-thrombin additive mixture, which accelerates the coagulation process. With the Vacuette Serum Fast Tube, the total processing time is just 10 minutes (coagulation + centrifugation), compared to 40 minutes with conventional serum tubes, enabling easy and effective improvement of the turnaround time (TAT). The tube also contains a gel that forms a stable barrier between the serum and the cellular components of the whole blood after centrifugation (five minutes at 3000 x g or 10 minutes at 1800 x g at 20 degrees Celsius). To protect against contamination Vacuette Serum Fast Tubes are made of shatterproof PET (polyethylene terephthalate). They incorporate proven vacuum technology and have an easy-to-open safety cap. This promotes maintenance of hygienic working procedures without the risk of splatters, which can occur with standard rubber stoppers. “Owing to the fast turnaround time, plasma tubes continue to be used for many analyses. However, determination of certain parameters on the basis of plasma is not appropriate for some tests,” said Dietmar Leichtfried, team leader research & development / preanalytics at Greiner Bio-One. “In some cases, incorrect values may result from the presence of anticoagulants or fibrinogen in the plasma tube. The use of serum is therefore indispensable in many cases.”

Image: The Vacuette Serum Fast Tubes, which offer a coagulation time of only five minutes (Photo courtesy of Greiner Bio-One).

Optimization of Analytical Procedures Reduces Variability of Results team of Spanish researchers recently described the development and optimization of several “quantitative suspension array” assays (qSAT) designed to assess natural and vaccine-induced responses to malaria and other parasites. Reducing variability of quantitative suspension array assays is critical to the success of multi-center and large sero-epidemiological studies. Towards this end, investigators at the Barcelona Institute for Global Health (Spain; www.isglobal.org) analyzed the effect of various procedural conditions on the variability of an in-house IgG multiplex assay designed to detect different types and classes of antibodies against multiple P. falci-

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parum antigens. The assay comprised different parasite antigens coupled to microspheres. These beads were tested to determine if they were recognized by plasma samples from individuals who may have been exposed to malaria. The assay was designed to detect different types and classes of antibodies against multiple P. falciparum antigens, in a sensitive and specific manner. The simple multiplex assay was found to be highly reproducible not only between experiments but also between operators and laboratories. The investigators identified the key factors requiring optimization to reduce variability of the assay. Then, they used the assay to better characterize the antibody profile of the anti-malaria human plasma pool provided by the WHO as reference reagent. IgG levels against seven P. falciparum antigens with heterogeneous immunogenicities were measured in test samples, in a positive control, and in blanks. Variability associated with each combination of conditions and their interactions was assessed, and the minimum number of samples and blank replicates required to achieve good replicability was determined. Results showed that antigen immunogenicity and sample seroreactivity defined the optimal dilution for assessing the effect of assay conditions on variability. Furthermore, unique antigen-bead coupling, pre-dilution of samples, incubation at 22 degrees Celsius, and an automated washing procedure reduced variability. “These simple and reproducible multiplex protocols will allow us to analyze in detail natural and vaccine-induced antibody responses to large panels of P. falciparum antigens, and elucidate correlates of malaria protection,” said senior author Dr. Carlota Dobaño, an associate research professor at the Barcelona Institute for Global Health. “Furthermore, the assay is highly versatile and can be adapted to study responses to antigens from other microbes or vaccines. We are currently collaborating with several groups outside the malaria field.” The study was published in the July 2, 2018, online edition of the journal PLOS One. LabMedica International November/2018

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LabMedica International

Hereditary Breast Cancer Tests Double Detection Rate ermline genetic testing in patients newly diagnosed with cancer has the potential to reduce disease burden through secondary prevention and targeted therapies. There is a prerequisite to understand how genetic testing is being integrated into practice for patients newly diagnosed with cancer and the impact of results on treatment decisions. As clinical whole-genome sequencing becomes increasingly feasible, it is crucial to understand the implications of expanded genetic testing on practice and patient experiences. Yet virtually nothing is known about the uptake, results, or consequences of multiple-gene sequencing in community practice. Multi-institutional scientists led by Stanford University (Stanford, CA, USA; www.stanford.edu) surveyed a population-based retrospective cohort study of 5,080 patients with breast cancer diagnosed from January 2013 to December 2015 and accrued from Surveillance, Epidemiology, and End Results (SEER) registries across Georgia and in Los Angeles, California and the response rate was 70%. The patients were racially diverse group that included 51% white, 18% black, 19% Hispanic, 9% Asian, and 2.5% unknown-ethnicity patients. Testing was performed by four laboratories: Ambry Genetics (Aliso Viejo, CA, USA; (www.ambrygen. com); GeneDx (Gaithersburg, MD, USA; www.genedx.com); Invitae (San Francisco, CA, USA; www.invitae. com); and Myriad Genetics (Salt Lake City, UT, USA; https://myriad.com) and the results were merged with the SEER clinical data and survey responses. Testing switched from BRCA1/2only to multi-gene panels: at the beginning, multi-gene sequencing accounted for 25.6 %, and BRCA1/2-testing for 74.4% of tests, which switched to 66.5% for multi-gene panels and 33.5% for BRCA1/2-testing at the end. Pathogenic variants for which guidelines advise a change in care were detected twice as often in patients who had multi-gene sequencing than in those who only had BRCA1 and BRCA2 analyzed. Those variants occurred in a variety of genes, including CHEK2, ATM, PALB2, APC, BRIP1, PMS2, and RAD51C. However, variants of uncertain significance (VUS) were also ten times more frequent in multigene-testers; about 30% received one, than in BRCA1/2-only testers, who only had a 3% VUS rate. This was especially true for certain groups: 51% of Asian patients tested with a multi-gene panel, for example, had a VUS, and 45% of black patients. The authors concluded that multiple-gene sequencing rapidly replaced BRCA1/2-only testing for patients with breast cancer in the community and enabled two-fold higher detection of clinically relevant pathogenic variants without an associated increase in prophylactic mastectomy. However, important targets for improvement in the clinical utility of

LabMedica International November/2018

multiple-gene sequencing include postsurgical delay and racial/ethnic disparity in variants of uncertain significance. The study was published on May 10, 2018, in the journal JAMA Oncology. Image: A photomicrograph of breast cancer cells in purple surrounded by healthy tissue in pink (Photo courtesy of US National Institute of Health).

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PRODUCT NEWS IMMUNOASSAY ANALYZER

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BLOOD GAS ANALYZER

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Tosoh Bioscience

Fortress Diagnostics

Grifols Diagnostic

The AIA-CL1200 utilizes the CL-AIA Pack twin cup format and has a throughput of up to 120 results per hour. It offers the first result within 15 minutes for most assays, making it suitable for a medium to high level of workload.

The BloodPro-100 analyzes blood gas, electrolyte, hemoglobin and metabolites that measures pO, pCO, K+, Ca++ Li+, Na+, Cl-, pH, GLU, LAC, Ref. & Hb. It features an illuminated LCD screen and comes with a 56mm thermal printer.

The Q Next is designed for in-vitro diagnostics clinical use in medium- to high-scale labs. It automatically performs all stages of hemostasis testing and tests parameters by means of clotting, chromogenic and immunoturbidimetric methods.

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Rapid Hepatitis C Virus POC Test Evaluated urrent hepatitis C (HCV) testing includes two clinical visits. In the first visit, clinicians test for HCV antibodies, which would confirm only that the patient has been exposed to the virus. A second visit includes testing for HCV RNA to determine the presence of active infection. Point-of-care hepatitis C virus (HCV) RNA testing is advantageous enabling diagnosis of active infection in a single visit. Previous studies have shown that patients are lost to follow up because they do not return for subsequent visits, and that the process can be difficult without a phlebotomist and for people who inject drugs (PWID), whose veins can be difficult to access. Scientists at the University of New South Wales (Sydney, Australia; www.unsw.edu.au) and their colleagues enrolled participants between August 3, 2016, and December 13, 2016, at three drug treatment clinics and a service for homeless people in Australia. A total of 223 participants enrolled, 72% had a history of injection drug use, and 46% had injected within the previous month of enrollment. The investigators evaluated the sensitivity and specificity of the Xpert

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HCV Viral Load Fingerstick assay (Xpert HCV VL FS, Cepheid, Sunnyvale, CA, USA; www.cepheid.com) for HCV RNA detection (finger-stick) and the Xpert HCV Viral Load assay (plasma) compared with the Abbott RealTime HCV Viral Load assay (Abbott Laboratories, Abbott Park, IL, USA; www.molecular.abbott) by venipuncture. The authors found that of 223 participants enrolled, HCV RNA was detected in 40% of participants (85 of 210) with available Xpert HCV Viral Load testing. Participants receiving HCV therapy were excluded from subsequent analyses. Sensitivity of the Xpert HCV Viral Load assay for HCV RNA quantification in plasma collected by venipuncture was 100% and specificity was 100%. Sensitivity of the Xpert HCV VL FS assay for HCV RNA quantification in samples collected by finger-stick was 100% and specificity was also 100%. The authors concluded this test provides a major advance over antibodybased point-of-care tests, which only indicate HCV exposure. Further, the novel Xpert VL FS assay provides a substantial advance over the [current] Xpert HCV Viral Load assay, avoiding the need for plasma separation and enabling testing and diagnosis in one hour as compared to two hours, increasing the potential to move toward a single-visit diagnosis. The study was published on March 9, 2018, in The Journal of Infectious Diseases. Image: The Xpert hepatitis C (HCV) Viral Load Assay cartridge (Photo courtesy of Cepheid). LabMedica International November/2018

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Protein Biomarker Found for Early-Stage Lung Cancer he American Cancer Society (ACS) estimate that in 2018, 154,050 people in the USA will have died from lung cancer and the World Health Organization (WHO) suggest that 1.69 million deaths are brought about by lung cancer worldwide. Most lung cancers are initially diagnosed at an advanced stage, and so the disease is associated with a poor prognosis, being the leading cause of cancer-related death worldwide. The identification of patients at a resectable early stage of cancer is therefore extremely important. Scientists at the Kitasato University School of Allied Health Sciences (Kanagawa, Japan; www.kitasato-u.ac.jp) obtained frozen fresh lung cancer tissues and kept at 80 °C until use for proteomic analysis. Sera from 271 patients with lung cancer and 100 healthy controls were used as the training set. In addition, a validation set consisting of sera from 100 patients with lung cancer and 38 healthy controls was also studied. The team developed monoclonal antibodies to validate their studies. They also performed immunoblotting and the immunoreactive bands on the membranes were detected with Immobilon Western Chemiluminescent HRP Substrate (Merck, Burlington, MA, USA; www.merckmillipore. com) and captured with ATTO Cool Saver System (ATTO, Tokyo, Japan; www.atto.co.jp). The team also carried out immunohistochemical staining and for reverse-phase protein array (RPPA) the stained slides were scanned on a microarray scanner Genepix 4000B (Molecular Devices, Sunnyvale, CA, USA; www.moleculardevices.com). Of the monoclonal antibodies generated, one antibody designated as KU-Lu-1, recognized cytoskeletonassociated protein 4 (CKAP4). CKAP4 was detected in lung cancer cells and tissues, and its secretion into the culture supernatant was also confirmed. The serum CKAP4 levels of lung cancer patients were significantly higher than those of healthy controls. Furthermore, the serum CKAP4 levels were also higher in patients with stage I adenocarcinoma or squamous cell carcinoma than in healthy controls. Serum CKAP4 levels may differentiate lung cancer patients from healthy controls, and they may be detected early even in stage I non–small cell lung cancer. Serum CKAP4 levels were also significantly higher in lung cancer patients than in healthy controls in the validation set. Yuichi Sato, PhD, a professor of Molecular Diagnostic, and senior author of the study, said, “The use of CKAP4 as a biomarker could change current practices regarding the treatment of lung cancer patients, and the diagnostic accuracies may be markedly improved by the combination of CKAP4 and conventional markers.” The study was published on May 8, 2018, in The American Journal of Pathology.

LabMedica International November/2018

Image: The Genepix 4000B microarray scanner (Photo courtesy of Molecular Devices).

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Image Analysis System Quantifies NASH Disease Activity on-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD), in which excessive fat accumulates in the liver of individuals who do not have a history of alcohol abuse. NAFLD is regarded as a hepatic manifestation of metabolic syndrome, with the number of individuals with NAFLD/NASH increasing rapidly worldwide, in parallel with the increasing prevalence of obesity. Although clinical algorithms based on blood test results are being developed to identify patients with progressive NASH, liver biopsy remains essential to establish both the diagnosis of NASH and the severity of the disease. In a study, a murine model fed a choline-deficient, L-amino-acid-defined diet supplemented with cholesterol was used to evaluate hepatocellular ballooning and lobular inflammation in liver biopsy samples. An expert histopathologist determined the ballooning and inflammation scores for all the animals included in the study, and deep-learning models were constructed to detect and analyze these histological features. An initial training set of 31 was used to calibrate ballooning and inflammation for subsequent prediction of these histological features in four independent cohorts (n=271). The study found that deep-learning algorithms applied using opensource pathology software QuPath1 (GENFIT, Loos, France; www. genfit.com), could accurately identify cell histology patterns consistent with lobular inflammation and hepatocellular ballooning – markers of disease activity that are essential to establish the diagnosis and severity of NASH. The deep-learning system was able to predict cell histological patterns relating to ballooning and inflammation with accuracies of 98% and 91%, respectively. Excellent agreement was observed between the

expert and fully automated scores of ballooning at a cellular level for each of the cohorts. An excellent correlation was also observed with the full tissue samples, and between whole slide imaging-based automatic scoring of inflammation on the training cohort. John Brozek, Chief Data and Information Officer at GENFIT, said, “Deep-learning-based scoring systems allow an exhaustive and reproducible analysis of all cells in a biopsy sample, and they can analyze specific regions of cells that can be difficult to interpret manually, even if you are an expert’. Automated scoring system for ballooning and inflammation showed a high correlation with expert evaluation and it is ready to be used for high-throughput activity scoring in pre-clinical studies or, in the near future, as a companion diagnostic tool for clinical application.” The study was presented at The International Liver Congress held April 11-15, 2018, in Paris, France. Image: A histopathology micrograph of a liver biopsy showing of steatohepatitis showing balloon degeneration of hepatocytes, a form of apoptosis (Photo courtesy of Nephron).

Molecular Technology Identifies Potential Biomarker for Cancer or patients with early-stage non-small cell lung cancer (NSCLC), the only recommended treatment option is surgery. After complete resection patients with disease at the same stage experience different outcomes, and within five years a third of patients relapse. Prognostic biomarkers are urgently needed to more accurately predict recurrence following surgery and potentially guide the decision to administer adjuvant chemotherapy for

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high-risk patients. The use of droplet digital polymerase chain reaction (ddPCR) technology in the clinic is increasing due to the technology’s ability to reliably detect and quantify these biomarkers, as well as ddPCR’s technical simplicity, speed, and cost-effectiveness. Scientists collaborating with the National Cancer Institute (Bethesda, MD, USA; www.cancer.gov) evaluated the prognostic significance of two biomarkers, namely Home-

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obox A9 (HOXA9) promoter methylation and blood vessel invasion (BVI), for risk stratification of stage I lung adenocarcinoma patients. The type of biospecimens and the choice of assay platform are key issues to foster translation of biomarkers to the clinic. The team demonstrated the application of a ddPCR-based assay (Bio-Rad, Hercules, CA, USA; www.bio-rad. com) to analyze HOXA9 promoter methylation in formalin-fixed, paraffin-embedded (FFPE) tumor specimens, generated during routine pathologic assessment of resected patients. The investigators used 177 formalin-fixed, paraffin-embedded (FFPE) tumor samples, and showed that high methylation was associated with worse cancer-specific survival (Hazard Ratio [HR], 3.37) and identified high-risk stage IA and IB patients. Importantly, addition of this molecular marker improved a risk model comprising clinical and pathologic parameters. HOXA9 promoter methylation was associated with a transcriptome signature enriched in genes marked by Polycomb in Embryonic Stem Cells, a signature previously associated with poor differentiation and worse overall patient survival. Moreover, BVI was independently associated with poor outcome (HR, 2.62) and a score that combined BVI with HOXA9 promoter methylation further stratified high-risk patients. The study was presented at the American Association for Cancer Research (AACR) Annual Meeting, held April 1418, 2018, in Chicago, IL, USA. LabMedica International November/2018

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Sequencing Improves Diagnostics for Pediatric Genetic Disease urrently, chromosomal microarrays are the recommended firstline genomic tests for children with certain genetic diseases, which can be difficult to diagnose. However, whole-genome and whole-exome sequencing have become more common testing approaches in recent years. Establishing an etiologic diagnosis in children with suspected genetic diseases is important for timely implementation of precision medicine and optimal outcomes, particularly to guide weighty clinical decisions such as surgeries, extracorporeal membrane oxygenation, therapeutic selection, and palliative care. Scientists at the Rady Children’s Institute for Genomic Medicine (San Diego, CA, USA; www.radygenomics.org) sifted through PubMed to uncover 37 studies that were published between January 2011 and August 2017 that included 20,068 children and evaluated the diagnostic utility of whole-genome sequencing (WGS) and whole-exome sequencing (WES) in comparison to chromosomal microarrays (CMA). One of these studies was a randomized controlled trial and 36 were case studies. The pooled diagnostic utility of WGS in these studies of 0.41 was qualitatively larger than for WES, which was 0.36, or CMA, which was 0.10. Additionally, over time, WES and WGS had increasing diagnostic rates of about 16% per year, while the odds of diagnosis via CMA decreased 14% each year. Still, within 11 studies of nearly 2,000 children, all published in 2017, the pooled diagnostic utility of WGS was 0.42, while it was 0.05 for CMA. Few studies, the investigators noted compared WES and WGS within cohorts. The two that did, involving 138 children, found no significant differences in the approaches’ diagnostic utility. When the team pooled WES and WGS together to compare them together versus CMA, they found that the odds of getting a diagnosis through a sequencing approach were 8.3 times greater than it was for CMA. The inference was that CMA should no longer be considered a first-line genomic test. More than a quarter of children analyzed by whole-genome sequencing had a change in their clinical management in light of their results, while only 6% of those who underwent CMA did. They also noted that WGS is about twice as expensive as WES, which is itself twice as expensive as CMA. Michelle M. Clark, PhD, a Statistical Scientist and first author of the study said, “What we learned is that WGS and WES offer greater diagnostic and clinical utility than CMA, leading us to conclude that WGS and WES should be considered first-line

LabMedica International November/2018

genomic tests for children with suspected genetic diseases.” The study was published on July 9, 2018, in the journal npj Genomic Medicine. Image: Genomic sequencing trajectory from the 1990s to the present (Photo courtesy of Mayo Clinic).

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The Tissue-Tek Xpress x120 offers an improved reagent system, enhanced QC possibilities and software, and an hourly throughput of up to 120 specimens. It uses molecularfriendly reagents and traditional vacuum infiltration techniques.

The ParaSys system is designed for the rapid analysis of intestinal parasites from fecal samples. It provides laboratories with a higher throughput and reduces labor costs, while its self-cleaning system ensures no cross-contamination.

The AltoStar AM16 is for the automated purification of NAs and automated assay setup for IVD purposes. It can process all samples, analyze up to four pathogens from a single sample and combine up to 8 RTPCR assays on a 96-well plate.

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Tissue-Imaging Technology Enables Real-Time Diagnostics new microscope system can image living tissue in real time and in molecular detail, without any chemicals or dyes. The system is called simultaneous label-free autofluorescence multi-harmonic microscopy (SLAM). The system uses precisely tailored pulses of light to simultaneously image with multiple wavelengths. This enables scientists to study concurrent processes within cells and tissue, and could give those studying cancer a new tool for tracking tumor progression and physicians new technology for tissue pathology and diagnostics. Scientists at the University of Illinois at Urbana-Champaign, Urbana, IL, USA; https://beckman.illinois.edu) designed an optical imaging platform that performs simultaneous label-free autofluorescence-multiharmonic (SLAM) microscopy, featuring fast epi-detection of nicotinamide adenine dinucleotide (NADH) from three-photon autofluorescence (3PAF) and simultaneous, and efficient acquisition of autofluorescence (FAD) from two-photon autofluorescence (2PAF), combined with noncentrosymmetric structures from second-harmonic generation (SHG) and interfacial features from third-harmonic generation (THG). The team saw that the cells near the mammary tumors in rats had differences in metabolism and morphology, indicating that the cells had been recruited by the cancer. In addition, they observed surrounding tissues creating infrastructure to support the tumor, such as collagen and blood vessels. They also saw communication between the tumor cells and the surrounding cells in the form of vesicles, tiny transport packages released by cells and absorbed by other cells. The authors concluded that they had demonstrated the versatility and efficiency of SLAM mi-

croscopy for tracking cellular events in vivo, and are a major enabling advance in label-free intravital microscopy (IVM). Stephen A. Boppart, MD, PhD, a professor and head of the Biophotonics Imaging Laboratory, and senior author of the study, said, â&#x20AC;&#x153;With advances in microscopy techniques such as ours, we hope to change the way we detect, visualize and monitor diseases that will lead to better diagnosis, treatments and outcomes.â&#x20AC;? The study was published on May 29, 2018, in the journal Nature Communications. Image: A tissue-imaging microscope has been developed that can image living tissue in real time and molecular detail, allowing them to monitor tumors and their environments as cancer progresses (Photo courtesy of Professor Stephen Boppart).

Loop-Mediated Isothermal Amplification Identifies Malaria Species alaria is an infectious disease caused by different species of Plasmodium, of which, five species are reported to infect humans. Since malaria caused by P. falciparum is the most serious, with high mortality, accurate and prompt diagnosis is especially important to effective management. The current gold standard for malaria diagnosis is microscopic examination of Giemsa-stained blood smears. Since the parasite species are identified by microscopists who manually search for the parasite-infected red blood cells (RBCs), misdiagnosis due to human error tends to occur in case of low parasitaemia or mixed infection. Scientists at the National Institute of Advanced Industrial Science and Technology (Takamatsu, Japan; www.aist.go.jp) performed in situ LoopMediated Isothermal Amplification (LAMP) in infected red blood cells

(iRBCs) on hydrophilic-treated plates to analyze as many iRBCs as possible on a slide. The identification of malarial parasite at cellular levels using in situ LAMP assay was able to be completed. The team used fresh RBCs from a healthy donor with blood type O were infected with P. falciparum, which contained more than 60% of ring-stage, more than 20% of late trophozoite-stage, and less than 20% of schizont-stage parasites. The authors concluded that their study showed the potential of in situ LAMP for the identification of Plasmodium species at the single cell level on hydrophilic-treated COC palates, allowing highly sensitive and accurate malaria diagnosis. The findings will improve the efficacy of the gold standard method for malaria diagnosis. The study was published on June 19, 2018, in the Malaria Journal. LabMedica International November/2018

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Blood-Based Test Predicts Benefits of Lung Cancer Treatment lthough programmed death-ligand 1–programmed death 1 (PDL1–PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. A large team of scientists led by those at UC Davis Comprehensive Cancer Center (Sacramento, CA, USA; www.ucdmc.ucdavis.edu) have developed a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB, Foundation Medicine, Cambridge, MA, USA; www.foundationmedicine.com) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, they showed that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from an anti-PD-L1atezolizumab in second-line and higher NSCLC. Investigators reported on the retrospective application of the test to more than 1,000 samples from paVisit us at tients with advanced NSCLC who participated in Genentech’s Phase II MEDICA POPLAR and Phase III OAK clinical 2018 trials (Genentech, South San FrancisHall 3-B95 co, CA, USA; www.gene.com). The POPLAR trial samples were used first, to identify blood-based TMB thresholds that reflect the discriminatory ability of tissue-based TMB. The positive predictive agreement for different cutoff points ranged from about 86% to 100%, and negative predictive agreements were spread between 82% and 100%. Overall, investigators calculated that the assay’s performance was optimized at three different cut-points: bTMB of ten or more, 16 or more, and 20 or more mutations. Based on results in the POPLAR cohort, the investigators narrowed down to the 16-mutation cutoff point for analysis in the OAK study. According to the authors, OAK study patients with at least 16 total mutations as calculated by the bTMB assay had significantly improved progression-free survival when treated with atezolizumab versus docetaxel chemotherapy with a hazard ratio of 0.65. In addition, patients’ bTMB results did not appear to correlate with PD-L1 expression levels, suggesting that the test provides independent predictive information that cannot be determined using PDL1. They concluded that their data shows that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC. David R. Gandara, MD, a professor and the lead author of the study, said, “These are exciting times in lung cancer immunotherapy. Having a blood test that can identify those

patients most likely to benefit would be a huge advantage for both physicians and patients. This publication is the first step toward what I anticipate will be full clinical application of this assay.” The study was published on August 6, 2018, in the journal Nature Medicine. Image: A colorized scanning electron micrograph (SEM) of two lung cancer cells (Photo courtesy of Anne Weston/Cancer Research UK).

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Cardiac Infarction Diagnosed With Sensitive Method hest pain is one of the most common reasons people seek emergency medical care. To determine if a person has suffered a cardiac infarction, symptoms are assessed partly on the basis of chest pain and partly with an electrocardiogram taken to detect typical changes consistent with a heart attack. In addition, a blood test is taken to measure levels of the protein troponin or else high-sensitive troponin T, both of which are biomarkers for heart damage. Elevated troponin values indicate that cells in parts of the heart have died from lack of oxygen after a heart attack impeded the flow of blood. Scientists at the Sahlgrenska Academy (Gothenburg, Sweden; https://sahlgrenska.gu.se) and their colleagues carried out a study that encompassed all patients who suffered heart attacks in Sweden during the 2009-2013 period. A total of 87,879 people were studied, of which 40,746 were diagnosed using high-sensitive troponin T (hs-cTnT) and 47,133 were tested using conventional troponin (cTn). The groups were similar in terms of gender and age distribution and other types of

illness in the patientsâ&#x20AC;&#x2122; history. From 2009 to 2012, the current iteration of the hs-cTnT assay (Roche Diagnostics, Basel, Switzerland; www.roche.com) was the only higher-precision method used in Sweden. For this assay, the lowest concentration measurable with a 10% coefficient of variation is 13 ng/L, the limit of detection is 5 ng/L and the 99th percentile value among healthy controls is 14 ng/L. However, some hospitals in Sweden initially used higher diagnostic cutoffs, in the range of 30 to 40 ng/L, for myocardial infarction (MI). The investigators showed that the more sensitive marker, hs-cTnT, detected 5% more heart attacks, although with no impact on survival. On the other hand, the number of heart attack victims suffering a relapse was 11% lower in that group. When high-sensitive troponin T started being introduced in 2009, there was concern about spending of health care resources in general and that interventions and treatments for the group of patients with suspected heart attacks would increase. The study was published in the June 2018 issue of the Journal of the American College of Cardiology. Image: The Elecsys high-sensitivity cardiac troponin T (hs-cTnT ) assay (Photo courtesy of Roche Diagnostics).

New Heart Attack Test Better Informs Underlying Condition he serum troponin assay is the biochemical gold standard for detecting myocardial infarction (MI). A major diagnostic issue is that some believe troponin levels can rise with reversible injury, in the absence of radiologically detectable infarct. Cardiac troponin is a protein unique to the heart, so elevated levels in the blood indicate that the heart has been damaged. The cardiac troponin blood test is still the current gold standard test used for the clinical diagnosis of MI or death of heart muscle due to lack of blood supply, but the test does not indicate the extent of cardiac damage. The team analyzed serum or plasma samples from 29 patients with cardiac troponin I elevations for proteolytic degradation, using three different sandwich enzyme-linked immunosorbent assays (ELISAs) designed to specifically detect the N-terminal, core, or C-terminal regions of cardiac troponin I (HyTest, Turku, Finland; www.hytest.fi). As predicted, the degree of proteolytic digestion increased with increasing severity of injury, as estimated by the total troponin level, and this trend was more pronounced for C-terminal versus N-terminal degradation. The authors concluded that the proteolytic degradation pattern of cardiac troponin I may be a better indicator of clinically significant MI than total serum troponin level. Distinguishing between intact and degraded forms of troponin may be useful for (a) identifying those patients with clinically significant infarct in need of revascularization, (b) monitoring intracellular proteolysis as a possible target for therapeutic intervention, and (c) providing an impetus for standardizing the epitopes used in the troponin I assay. The study was published in the February 2018 issue of the Journal of Applied Laboratory Medicine.

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Next-Gen Sequencing of CSF Diagnoses Neurobrucellosis rucellosis is the most common zoonotic infection in the world with more than 500,000 new cases are reported annually worldwide. It is a multisystem infection, with variable clinical presentations and brucellosis with nervous system involvement is known as Neurobrucellosis (NB). The clinical features and cerebrospinal fluid (CSF) findings of NB are usually non-specific, and the sensitivity and specificity of routine culture and serological tests vary, making the diagnosis of NB difficult. In endemic areas, NB should be considered in the differential diagnosis of patients presenting with neurological symptoms and concomitant fever. Scientists at the Peking Union Medical College Hospital (Beijing, China; www.pumch.cn) and their colleagues studied a case series that included four consecutive patients admitted to the Neurology Department between June 1, 2016 and June 1, 2017. The team used a 300- L CSF sample from each patient or a negative ‘no-template’ control (NTC), which was transferred to a new sterile tube, and the DNA was extracted directly with the TIANamp Micro DNA Kit (Tiangen Biotech, Beijing, China; www.tiangen.com). Extracted DNA was used for the construction of DNA libraries. The DNA libraries were constructed according to the standard protocol of the

BGISEQ-100 sequencing platform (BGI-Tianjin, Tianjin, China; www.genomics.cn). To measure the adapters before sequencing, quality control was performed with the Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA; www.agilent.com) combined with quantitative polymerase chain reaction (qPCR). Agarose gel electrophoresis was used to analyze the PCR products, and Sanger sequencing with an ABI PRISM 3730 DNA Analyzer (Applied Biosystems, Foster City, CA, USA; www.appliedbiosystems.com) was used to validate the sequencing results. The four patients were rapidly diagnosed with NB using next-generation sequencing (NGS) of the CSF in patients with clinically suspected CNS infections, although the clinical manifestations varied dramatically between these patients. NGS of the CSF revealed that the sequence reads identified that corresponded to Brucella species ranged from 11 to 104, with genomic coverage ranging from 0.043% to 0.4%. Rapid diagnosis led to prompt treatment with the appropriate antibiotics. The authors concluded that their study demonstrated the power of NGS of the CSF coupled with a bioinformatic pipeline in the diagnosis of NB. The study was published in the February 2018 issue of the International Journal of Infectious Diseases.

Multiple Myeloma Risk Genes Revealed wo genes have been uncovered with apparent ties to inherited multiple myeloma risk, starting from analyses of several large American families that are frequently affected by the complex blood plasma cell cancer. The high-risk pedigree (HRP) design is an established strategy to discover rare, highly penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. An international team of scientists led by those at the University of Utah School of Medicine (Salt Lake City, UT, USA; www.medicine.utah.edu) used an updated version of a gene mapping method known as shared genomic segment (SGS) to narrow in on commonly altered regions in the genomes of multiple myeloma-prone families or “highrisk pedigrees” (HRP) from Utah. The team used OmniExpress highdensity SNP arrays (Illumina, San Diego, CA, USA; www.illumina.com) and sequenced individuals from 11 multiple myeloma HRPs, identified through the Utah Cancer Registry, and applied SGS to find shared regions of the genome on chromosomes 6 and 1 with potential ties to multiple myeloma. The team noted that “Our myeloma findings demonstrate our high-risk pedigree method can identify genetic regions of interest in large, high-risk pedigrees that are also relevant to smaller nuclear families and overall disease risk.” The study was published on February 1, 2018, in the journal Public Library of Science Genetics.

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EBV Protein Implicated In Autoimmune Diseases pstein-Barr Virus (EBV) infection is common and more than 90% of people in the USA become infected by age 20. While resulting in mild disease or no symptoms in children, EBV causes mononucleosis in adolescents and young adults, with symptoms that include fever and extreme fatigue. EBV had already been implicated in systemic lupus erythematosus (SLE), increasing the risk for the disease by up to 50-fold in children, but the molecular mechanism by which the virus contributes to SLE had been unknown. In addition, genome-wide association studies had previously identified more than 50 SLE risk loci in cohorts with European ancestry. Scientists at the Cincinnati Children’s Hospital Medical Center (Cincinnati, OH, USA; www.cincinnatichildrens.org) developed the Regulatory Element Locus Intersection (RELI) algorithm, which looks for overlap between disease-associated genetic variants and transcription factor binding sites, as determined by ChIP-seq studies. They investigated whether RELI could recapitulate already known relationships between transcription factors and diseases and found that it correctly iden-

tified links between the androgen receptor and prostate cancer, between GATA3 and breast cancer, and between EBV-encoded EBNA2 and multiple sclerosis. They then analyzed 53 SLE risk loci in European-ancestry individuals together with ChIP-seq data for several EBV-encoded transcription factors, gathered from EBV-infected B cells, and found that EBNA2 binding sites overlap significantly with SLE risk loci, whereas other EBV protein binding sites do not. Next, they applied RELI to a large number of human transcription factor ChIP-seq datasets and found that 60 transcription factors also intersected with SLE loci. Further studies showed that several of these transcription factors bound SLE risk loci only in the presence of EBV and suggested a role for EBV-infected B cells in the disease. The study was published on April 16, 2018, in the journal Nature Genetics. Image: An Epstein-Barr virus budding in a B cell (Photo courtesy of Kenyon College).

Subthreshold Amyloid Predicts Tau Deposition in Aging he progressive nature of Alzheimer’s disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. The rate at which the protein beta-amyloid (Aβ) accumulates into the sticky plaques associated with Alzheimer’s disease (AD) is already slowing by the time a patient would be considered to have preclinical AD. Determining how early to intervene is a central challenge in slowing the progression of AD. Clinical trials of drugs for lowering amyloid levels typically involve individuals who do not yet have symptoms but are considered “amyloid positive” and at risk for developing AD. These trials have been largely unsuccessful, perhaps because they begin too late. Scientists at the University of California, Berkeley (Berkeley, CA, USA; www.berkeley.edu) studied 71 healthy men and women between the ages of 61 and 88 over a five-year period. They used longitudinal [11C] Pittsburgh Compound B (PIB) PET and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans. They used [18F] AV-1451 PET at the end of the observation period to measure subsequent tau deposition in a subset of the sample of 37. The investigators found evidence for an inverted-U relationship between baseline Aβ and Aβ slope in asymptomatic older adults, suggesting a slowing of Aβ accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of Aβ predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of Aβ increased, suggesting pathological accumulation occurs before impacting memory. The study was published on April 23, 2018, in the Journal of Neuroscience.

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Biomarker Panel Distinguishes Tuberculosis from Other Infections small proof-of-principle study confirmed the validity of a 20gene biomarker panel able to distinguish individuals with active or latent tuberculosis (TB) from those with viral or bacterial infections. While whole blood transcriptional signatures distinguishing active tuberculosis patients from asymptomatic latently infected individuals exist, consensus has not been achieved regarding which optimal reduced gene sets could be used as diagnostic biomarkers that also achieve discrimination from other diseases. To establish a reliable biomarker panel to distinguish between TB from other viral or bacterial infections, investigators at The Francis Crick Institute (London, United Kingdom; www.crick.ac.uk), the biotechnology firm BIOASTER (Lyon, France; www.bioaster.org), and other British, French, and South African research groups analyzed blood samples from patients across London and Africa with latent and active TB using RNA sequencing (RNA-Seq) technology. The investigators then used an advanced modular approach to develop a 20-gene signature that discriminated active tuberculosis patients from latently infected individuals or those with acute viral and bacterial infections. This panel was used to monitor 53 TB patients in Leicester, United Kingdom, and to follow 108 of their close contacts over two years to see who developed active TB. The investigators found that those who remained healthy showed no sustained gene signature, while six of the nine who went on to develop active TB maintained a strong, sustained signature. Development of the biomarker panel was described in the July 19, 2018, online edition of the journal Nature Communications.

Image: A photomicrograph of a sputum specimen showing the presence of numerous Mycobacterium tuberculosis bacteria (Photo courtesy of the CDC).

Biochemical Markers Predict Risk of Incident Diabetes ow osteocalcin and C-telopeptide of type 1 collagen levels in postmenopausal women are associated with an increased risk for insulin resistance and incident diabetes. A recent study investigated the relationship of osteocalcin (OC), which is a marker of bone formation, and C-telopeptide of type I collagen (CTX), which a marker of bone resorption, with incident diabetes in older women. A multi-institute team of scientists led by those at the Albert Einstein College of Medicine and Montefiore Medical Center (Bronx, NY, USA; www.einstein.yu.edu) analyzed 1,455 female participants from the population-based Cardiovascular Health Study (mean age 74.6 Âą 5.0 years). The cross-sectional association of serum total OC and CTX levels with insulin resistance (HOMA-IR) was examined using multiple linear regressions. The longitudinal association of both markers with incident diabetes, defined by follow-up glucose measurements, medications, and ICD-9 codes, was examined using multivariable Cox proportional hazards models. The investigators reported that continuous levels of osteocalcin were significantly inversely related to insulin resistance. Continuous C-telopeptide of type 1 collagen levels, though marginally insignificant, showed a similar relationship to insulin resistance. At median follow-up of 11.5 years, 196 cases of incident diabetes were discovered among the participants. After adjustment, both biomarkers still showed inverse associations with incident diabetes (osteocalcin: hazard ratio 0.85 per SD); C-telopeptide of type 1 collagen: hazard ratio 0.82 per SD). The authors concluded that osteocalcin and C-telopeptide of type 1 collagen are strongly associated with insulin resistance and incident diabetes in late postmenopausal women. The findings also suggest that bone health may be a factor in glucose maintenance in the same postmenopausal demographic. The study was published in the August 2018 issue of the journal Diabetes Care.

LabMedica International November/2018

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Genetic Predisposition Validated in Medulloblastoma edulloblastoma is a rare malignant tumor of the brain and occurs predominantly in children and is associated with rare hereditary cancer predisposition syndromes. It is believed that in many cases hereditary gene defects trigger the development of this malignant disease. The cause of medulloblastoma is largely unclear and most cases are presumed to arise sporadically. Medulloblastoma is an embryonal brain tumor of the cerebellum, with an annual age-adjusted incidence ranging from 2/1,000,000 cases to 5.8/1,000,000 cases worldwide. A large team of scientists led by those at the Heidelberg University Hospital (Heidelberg, Germany; www.heidelberg-university-hospital. com) analyzed patients with medulloblastoma from retrospective cohorts and from prospective cohorts from four clinical studies. These included a total of 1,022 patients with medulloblastoma, 673 from the retrospective cohorts and 349 from the four prospective studies from

whom 1,022 blood samples and 800 tumor samples were analyzed for germline mutations in 110 cancer predisposition genes. The scientists generated whole-genome and whole-exome sequencing data for germline and tumor samples at different institutes. To ensure standardization of genomic data processing, they used the same uniform computational analysis workflows for all germline and tumor samples. DNA methylation profiling was implemented to determine consensus molecular subgroups. The scientists were able to characterize medulloblastoma more accurately and to derive recommendations for genetic testing based on analysis of the patients with medulloblastoma. Stefan M. Pfister, MD, a professor of Pediatric Neurooncology and senior author of the study said, “Hereditary disease factors usually have a significant impact on the whole family of the patient. We want to make genetic analysis available as a standard of care for patients with specific medulloblastoma.” The study was published on May 9, 2018, in the journal Lancet Oncology.

Serum S-100β Elevated in Septic Shock Patients with Delirium high prevalence of delirium is observed in sepsis, yet specific markers for this brain dysfunction in sedated patients are still lacking. Cytoplasmic low molecular weight calcium-binding protein, S-100 , is a commonly used nonspecific marker for brain injury. S-100 is glial-specific and is expressed primarily by astrocytes, but not all astrocytes express S-100 . It has been shown that S-100 is only expressed by a subtype of mature astrocytes that ensheath blood vessels and by NG2-expressing cells. Increases in S-100 levels have been evaluated whether there is an association in patients with delirium. Scientists at the University of Oulu (Oulu, Finland; www.oulu.fi) carried out an observational study included 22 patients with septic shock. Delirium was assessed by the Confusion Assessment Method (CAM) score for use in intensive care unit patients (CAM-ICU). Blood samples were obtained to measure inflammatory biomarkers: C-reactive protein

(CRP), Procalcitonin (PCT), interleukin-6 (IL-6), IL-17, Tumor necrosis factor-alpha (TNF- ) and cerebral biomarkers such as S-100 , neuronspecific enolase (NSE), and two others. Patients were categorized according to the presence of delirium. The scientists found that delirium was present in 10/22 of the patients (45.5%). Serum S-100 levels were above the laboratory cutoff value of 0.15 g/L in 13/22 (59.1%) of the patients. The odds ratio for risk of developing delirium in cases with an S-100 greater than 0.15 g/L was 18.0. Patients with delirium had higher plasma levels of IL-6 compared to those without; 138.3 pg/mL (range: 28.0-296.7) versus 53.6 pg/mL (range 109.3-505). There was a positive correlation between S100- and IL-6 levels. Delirium patients had higher SOFA scores; 10 versus 7. The study was published on August 5, 2018, in the journal Acta Anaesthesiologica Scandinavica.

Biomarkers Explored in Patients with Acute Coronary Syndromes ell-developed coronary collateral arteries are associated with improved survival in patients with coronary artery disease. A key process in forming new blood vessels is attraction to occluded arteries of monocytes with their subsequent activation as macrophages. Vascular endothelial growth factor (VEGF) signaling is a critical step in angiogenesis. VEGF-A is one of five related growth factors,

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which bind primarily to three tyrosine kinase receptors with different affinity. Cardiac ischemia modulates the regulation and expression of several VEGF family ligands and receptors via Hypoxia Inducible Factor-1 (HIF-1). A large team of scientists working with those at the University of Otago (Christchurch, New Zealand; www.otago.ac.nz) recruited 2,067 patients after admission to Christchurch or Auckland City Hospitals with a diagnosis of acute coronary syndrome (ACS), from July 2002 to January 2009. In the Christchurch subgroup of the cohort collateral vessels were graded according to the Rentrop classification. Coronary artery anatomy, severity of coronary stenoses and the myocardium at risk were assessed according to the Brandt score in the same subgroup. Plasma samples were collected and stored at −80 °C. Soluble fmslike tyrosine kinase-1 (sFlt-1) and soluble vascular endothelial growth factor receptor (sKDR) were analyzed using chemiluminescent quantitative sandwich enzyme immunoassays (R&D Systems, Minneapolis, MN, USA; www.rndsystems.com) detection limits, sFlt-1 3.5 pg/mL and sKDR 4.6 pg/mL. High performance liquid chromatography (HPLC) measurement of pterins was performed using a, Sil-20A HPLC with auto-sampler (Shimadzu Corporation, Kyoto, Japan; www.shimadzu.com), with a RF-20Axls fluorescence detector. Genomic DNA was extracted for genotyping was performed by real-time polymerase chain reaction (RT-PCR). Circulating levels of Brain natriuretic peptide (BNP) and Nterminal proBNP (NT-proBNP) were also assayed. The authors concluded that there was an independent association of both plasma sFlt-1 and total pterin levels with all-cause and cardiovascular mortality in a cohort of patients with coronary artery disease followed up for several years after an index acute coronary event. The study was published on August 15, 2018, in the journal BMC Cardiovascular Disorders. LabMedica International November/2018

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Smart Phone Reader Detects Common Pathogens n rural or low resource areas, doctors sometimes must rely on a patient’s symptoms or use their own judgement in looking at test sample color results to determine whether a patient has an infection. A low-cost, portable laboratory on a phone has been developed that works nearly as well as clinical laboratories to detect common viral and bacterial infections. The work could lead to faster and lowercost laboratory results for fast-moving viral and bacterial epidemics. Bioengineers at Washington State University (Pullman, WA, USA; https://wsu.edu) and their colleagues developed an ultra-low-cost clinically accurate mobile phone microplate reader (mReader), and clinically validated this optical device for 12 infectious disease tests. The mReader optically reads 96 samples on a microplate at one time. The team tested 771 de-identified patient samples for 12 serology assays for bacterial/viral infections. The mReader and the clinical instrument blindly read and analyzed all tests in parallel. The scientists evaluated the analytical accuracy and the diagnostic performance of the mReader across the clinical reportable categories by comparison with clinical laboratorial testing results. The mReader exhibited 97.6% to 99.9% analytical accuracy and <5% coefficient of variation (CV). The positive percent agreement (PPA) in all 12 tests achieved 100%, negative percent agreement (NPA) was higher than 83% except for one test (42.9%), and overall percent agreement (OPA) ranged 89.3% to100%. The team was able to build the device for about USD 50, but the manufacturing cost would probably be lower than that.

The authors envision the mReader can benefit underserved areas/populations and low-resource settings in rural clinics/hospitals at a low cost with clinical-level analytical quality. It has the potential to improve health access, speed up healthcare delivery, and reduce health disparities and education disparities by providing access to a low-cost spectrophotometer. The study was published on March 23, 2018, in the journal Clinica Chimica Acta. Image: The low-cost, portable laboratory on a phone that can interpret results from a microplate assay (Photo courtesy of Washington State University).

Cancer Blood Test Engineered to Detect Tumors Early new innovative microfluidic device has been developed that uses magnetic particles and wavy-herringbone design to capture and release circulating tumor cells (CTC) with a high capture efficiency rate at different tumor cell concentrations. The microfluidic device achieves two key standards by which the success of CTC devices is measured: high capture efficiency and high selectivity. Capture efficiency refers to the percentage of CTCs that the device collects. Selectivity measures how well it rejects unwanted cells, such as red and white blood cells. Scientists at Lehigh University (Bethlehem, PA, USA; www. lehigh.edu) designed a device to create passive turbulence and increase the possibility of tumor cells colliding with the device wall. The rectangular chip, which is less than a few square centimeters and using as little as a few milliliters of blood, is made of the polymer PDMS. Under an external magnetic field, magnetic particles (MPs) coated with anti-epithelial cell adhesion molecules (EpCAM) against a tumor cell surface protein (EpCAM) were immobilized over the wavy-herringbone (wavy-HB) surface to capture tumor cells. After removing the magnetic field, the captured cells with surplus MPs were released from the device and collected; thus, these cells could be re-cultured for further analysis. Under optimized conditions, the capture efficiency of the tumor cells can be as high as 92% ± 2.8%. Capture experiments were also performed on whole blood samples, and the capture efficiency was in a high range of 81% to 95%, at different tumor cell concentrations. The authors concluded that such a method can potentially be used for CTC sorting from patient blood samples, CTC concentration monitoring, therapeutic guidance and drug dosage choice, and further study of tumors, such as drug screening and tumor mutations. Yaling Liu, PhD, an associate professor and the senior author of the study, said, “With metastatic cancers accounting for around 90% of deaths from solid tumors, the hope is that one day a device that can enable the analysis of single tumor cells circulating in the blood could make a big difference in early diagnosis, detection and monitoring of numerous types of cancer, without invasive biopsies.” The study was presented April 18, 2018, at Royal Academy of Science International Trust’s The Future of Medicine conference held in Istanbul, Turkey.

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HBA1C ANALYZER

CENTRIFUGE

Quotient Diagnostics

Labnovation Technologies

Medicus Health

The MosaiQ allows for rapid, extensive antigen typing/antibody identification of donor and patient blood utilizing a single microarray or consumable. It offers walk-away processing of approximately 1,000 samples in an eight-hour shift.

The LD-600 has a sample loading capacity of 110 samples with continuous loading capability and a speed of 65 seconds per test. It features an all-in-one 10-inch LED touch screen, and a column for 3,000+ tests.

The Microhematocrit Centrifuge features a metal housing for easy cleaning and disinfection and paint that is acid- and reagent-resistant. Rubber mounts provide less vibration, and a safety switch disconnects power when the latch is lifted.

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Interoperable Glucose Monitoring System Gets FDA Clearance n integrated continuous glucose monitoring (iCGM) system for determining blood glucose levels in children aged two years and older and adults with diabetes has been authorized. This is the first type of continuous glucose monitoring system permitted by the government agency to be used as part of an integrated system with other compatible medical devices and electronic interfaces, which may include automated insulin dosing systems, insulin pumps, blood glucose meters or other electronic devices used for diabetes management. The US Food and Drug Administration (FDA, Silver Springs, MD, USA; www.fda.gov) evaluated data from two clinical studies of the iCGM, which included 324 adults and children aged two years and older with diabetes. Both studies included multiple clinical visits within a 10-day period where system readings were compared with a laboratory test method that measures blood glucose values. No serious adverse events were reported during the studies. The Dexcom G6 (DEXCOM, San Diego, CA, USA; www.dexcom. com) is a patch device, about the size of a quarter that is applied to the skin of the abdomen and contains a small sensor that continuously measures the amount of glucose in body fluid. The device transmits real-time glucose readings every five minutes to a compatible display device such as a mobile medical app on a cell phone and will trigger an alarm when a patient’s blood glucose enters a danger zone soaring too high or dropping too low. If it’s integrated with an automated insulin dosing system, a rise in blood sugar would trigger the release of insulin from the pump. The patch device should be replaced every 10 days.

Donald St. Pierre, MD, FDA’s Center for Devices and Radiological Health, said, “The ability of this device to work with different types of compatible devices gives patients the flexibility to tailor their diabetes management tools to best meet personal preferences. In addition, the FDA has taken steps to expedite the review process for similar, integrated CGMs and make these types of systems available to patients as quickly as possible while also helping to ensure their safety and reliability.” Image: The Dexcom 6 is an integrated continuous glucose monitoring (iCGM) system for determining blood glucose (Photo courtesy of DEXCOM).

New Glioma Test Provides Answers During Surgical Procedures new diagnostic test detects certain mutations in glioma tumors during brain surgery and identifies those sensitive to metabolic chemotherapeutic agents. A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30% of all brain tumors and central nervous system tumors, and 80% of all malignant brain tumors. Lower-grade gliomas are often characterized by mutations in the metabolism-related genes IDH1 (isocitrate dehydrogenase 1) and IDH2 (isocitrate dehydrogenase 2). Patients with glioma carrying mutations in either IDH1 or IDH2 have a relatively favorable survival, compared with patients with glioma with wild-type IDH1/2 genes. Treating brain cancer and preventing recurrence has proven to be difficult, as the blood-brain barrier represents a considerable hurdle. To get around the blood brain barrier issue, investigators at Brigham and Women’s Hospital (Boston, MA, USA; www.brighamandwomens.org), Massachusetts General Hospital (Boston, USA; www.massgeneral.org) and the Massachusetts Institute of Technology (Cambridge, MA, USA;

www.mit.edu) hypothesized that application of metabolism-altering therapeutics at the surgical margin would improve tumor control and minimize toxicity. To facilitate this process, they developed an intraoperative diagnostic assay to identify IDH mutations. The rapid multiplexed genotyping tool they developed was used to analyze previously collected patient samples. Results demonstrated that the assay could detect mutations within 27 minutes. For 75 of the 87 clinically annotated brain tumor specimens tested, the assay detected the presence of one or more mutations. “The first and perhaps most important step in treatment of brain tumors is the initial operation, or craniotomy, which obtains tissue to make the diagnosis, and, for lower grade lesions, provides a therapeutic benefit from removal of the tumor mass,” said senior author Dr. Daniel Cahill, associate professor of neurosurgery at Massachusetts General Hospital. The glioma diagnostic test was described in the August 6, 2018, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America. LabMedica International November/2018

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Biomarker Used for Febrile Intracranial Hemorrhage Patients rocalcitonin (PCT) is a biomarker that exhibits greater specificity than other proinflammatory markers, such as cytokines, in identifying patients with sepsis and can be used in the diagnosis of bacterial infections. Intracerebral hemorrhage (ICH) is caused by bleeding within the brain tissue itself, a life-threatening type of stroke. A stroke occurs when the brain is deprived of oxygen and blood supply. ICH is most commonly caused by hypertension, arteriovenous malformations, or head trauma. Scientists at North Shore University Hospital (Manhasset, NY, USA; www.northwell.edu) and their colleagues enrolled in a prospective observational study 104 patients with intracranial hemorrhage (ICH) and fever above 38.3 C admitted to Intensive Care Units (ICUs) of a tertiary care hospital. PCT was measured on day one (PCT1) of fever and 48-72h later (PCT2). Patients were determined to have an infection (pneumonia, urinary tract infection or bacteremia) based on cultures, imaging and clinical impression of treating clinicians. The team used statistical analysis that indicated significant mean differences in PCT1 between patients with no, probable and definite infection. Patients with probable infection had the highest mean PCT1 and those with definite infection had higher PCT2. Additional analyses of univariable mean differences showed a mean PCT1 that was significantly higher in the probable-infection group compared with the no-infection group and mean PCT that was significantly higher at both time points in the definite-infection group compared with the no-infection group; however, there were no significant differences between the probable and definite-infection group. The authors concluded that PCT levels were higher in patients with

ICH and infections, and may be a useful marker to differentiate between infectious and noninfectious etiologies of fevers in these patients. Further studies including randomized control trials will help in establishing the utility of this marker in optimal management of febrile patients with ICH. The study was published on May 29, 2018, in the journal World Neurosurgery. Image: Histology of the brain, showing infarct and hemorrhage due to ruptured saccular aneurysm and thrombosis of right middle cerebral artery (Photo courtesy of Peter Anderson).

Immunoblot Test Differentiates Pollen Allergy Diagnoses pecific immunoglobulin E (IgE) antibodies against inhalation allergens that commonly occur in Southern Europe can be detected and differentiated using a new multiparameter immunoblot test. The test is based on defined partial allergens (DPA, allergen components) and the detailed profile identifies the precise allergy-causing proteins, distinguishing primary sensitizations from cross-reactions and thus aiding therapy decision-making. The test is based on a unique combination of species-specific marker molecules, cross-reactive components and whole extracts, encompassing tree pollens (birch, olive, cypress, hazel, oak), grass pollens (timothy grass, wall pellitory) and the fungus Alternaria alternata. The native extracts provide a general screening for IgE antibodies against the respective pollen/fungus. The multiparameter immunoblot EUROLINE DPA-Dx Pollen Southern Europe 1 test (EUROIMMUN AG, 23560 Luebeck, Germany; www. euroimmun.com) is a combination of the Southern European species-specific marker molecules together with common panallergens, such as PR-10 proteins and profilin, enables precise discrimination between a putative primary sensitization and a persistent cross reaction. Positive reactions with species-specific markers are an indication for specific immunotherapy. Positive reactions with panallergens on the other hand indicate cross-reactions. Cross-reactive molecules are prevalent among different types of plants, which often results in a high sensitization rate. An insufficient differentiation between primary sensitization and cross-reactions often results in a less effective desensitization during specific immunotherapy. The test also includes a band of cross reactive carbohydrate determinants (CCD), which aids the differentiation of clinically relevant reactions from unspecific anti-CCD reactions and thus the interpretation of results. With this in-depth profile, true sensitizations can be reliably identified, enabling targeted selection of the most suitable specific immunotherapy and improved prognosis of the therapy success. The test is easy to perform and requires only a small sample volume. The high analytical and clinical value of the profile has been verified in an independent study. Automated processing and evaluation are available for the assay.

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PRODUCT NEWS HEMATOLOGY ANALYZER

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DENGUE RAPID TEST

ESR SYSTEM

Samsung

CTK Biotech

Human

The LABGEO HC10 provides results based on 18 parameters and has a test speed of 45 seconds per sample. It performs tests using 25µL of whole blood or 50µL of whole blood in pre-diluted mode, and provides results within 45 seconds.

The OnSite Dengue Ag is for the qualitative detection of dengue NS1 antigen (DEN1, 2, 3, 4) in human serum, plasma or whole blood. The test is designed for use by professionals and provides a preliminary result to aid the diagnosis of infection.

The HumaSRate 24PT uses primary EDTA tubes for ESR reading, and offers the flexibility to run ERS tests at anytime without the need for an extra blood collection. It has a throughput of up to 24 samples per hour and features eight channels.

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New Method Can Quickly and Accurately Detect Infections method has been developed that can show quickly and accurately whether a person has been infected with harmful bacteria or other pathogens and additionally, this new method shows the exact severity of infection in a person. The most common method of testing for infection in medical facilities is currently a strip that turns a certain color when infected fluids come into contact with it. Other methods include microbiology or examining body fluid samples under a microscope and counting white blood cells, also known as leukocytes, which are an indicator of an infection. However, these can be slow processes and require more highly trained personnel. Biochemists at the University of Texas at San Antonio (TX, USA; www.utsa.edu) sought out an easier and more rapid method of testing for infection, resolved to test an electrochemical approach. They created molecules that bind to leukocyte enzymes and produce an electrical current to signal the presence of an infection. Their new molecules are housed on a testing strip. After being contacted with infected bodily fluids, the strip is connected to a computer monitor that displays a clear range of electrochemical responses demonstrating the severity of an infection. The team introduced a new class of substrates (compounds I–III) for leukocyte esterase (LE) that react with LE yielding anodic current in direct proportion to LE activity. The kinetic constants Km and kcat for the enzymatic reactions were determined by amperometry at a glassy carbon electrode. The binding affinity of I–III for LE was two orders of magnitude better than that of existing optical LE substrates. The average enzymatic activity of LE released from a single leukocyte was equal to 4.5 nU when measured with the compound (methoxycarbonyl)pyridine.

Stanton F McHardy, PhD, a professor of Medicinal Chemistry, said, “The signs and symptoms people demonstrate aren’t always reflective of the level of the infection they have. This device could very easily show just how serious an infection is and make diagnosis a much quicker process, possibly preventing a more serious illness.” The study was originally published online n April 20, 2018, in the journal ChemBioChem. Image: A new electrochemical method developed to test the presence of a bacterial infection using strips is faster and more accurate than methods currently on the market (Photo courtesy of the University of Texas at San Antonio).

Potential Shortcoming of Antibiotic Lab Tests Determined s multidrug-resistant organisms continue to emerge, specific tests, called antibiotic susceptibility assays, are increasingly critical. Clinicians depend on reliable results when choosing the right drug to treat patients. To determine which antibiotics reliably treat which bacterial infections, diagnostic laboratories that focus on clinical microbiology test pathogens isolated from patients for antibiotic sensitivity. However, a recent study reveals that one aspect of these tests may fall short and not be stringent enough. Microbiologists at the Beth Israel Deaconess Medical Center (Boston MA, USA; www.bidmc.org) and their colleagues examined pathogens cited by the US Centers for Disease Control and Prevention (Atlanta GA, USA; www.cdc.gov) and the World Health Organization (Geneva,

Switzerland; www.who.int) as urgent and concerning drug resistance threats. To obtain consistently reliable results, scientists conducting antibiotic susceptibility assays follow national guidelines with standardized methods, including the use of a specific number of organisms, or “inoculum” that is added to each assay. There is a target inoculum, and then a range of an allowable inoculum, or acceptable upper and lower bounds around the target inoculum. James Kirby, MD, the Director of the Clinical Microbiology Laboratory and senior co-author, said, “Our question was whether this wiggle room impacts results. Our findings were clear: inoculum matters.” The study was published on May 21, 2018, in the journal Antimicrobial Agents and Chemotherapy. LabMedica International November/2018

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Biomarker Low Predictive Power Validated for eGFR Decline lomerular filtration rate (GFR) is a measure of the function of the kidneys. This test measures the level of creatinine in the blood and uses the result in a formula to calculate a number that reflects how well the kidneys are functioning, called the estimated GFR or eGFR. The decline of estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes is variable, and early interventions would likely be cost-effective. The contribution of 17 plasma biomarkers to the prediction of eGFR loss on top of clinical risk factors has been elucidated. A large team of scientists collaborating with the Medical University of Vienna (Vienna, Austria; www.meduniwien.ac.at) studied participants in PROVALID (PROspective cohort study in 2,560 patients with type 2 diabetes mellitus for VALIDation of biomarkers), a prospective multinational cohort study of patients with type 2 diabetes and a followup of more than 24 months; (baseline median eGFR, 84 mL/min/1.73 m2; urine albumin-to-creatinine ratio, 8.1 mg/g). The 17 biomarkers were measured at baseline in 481 samples using Luminex (Luminex Corporation, Austin, TX, USA; www.luminexcorp.com) and enzymelinked immunosorbent assays (ELISA). The prediction of eGFR decline was evaluated by linear mixed modeling. The investigators reported that in univariable analyses, nine of the 17 markers showed significant differences in median concentration be-

tween stable and fast-progressing patients. A linear mixed model for eGFR obtained by variable selection exhibited an adjusted R2 of 62%. A panel of 12 biomarkers was selected by the procedure and accounted for 34% of the total explained variability, of which 32% were due to five markers. These five biomarkers include Kidney injury molecule 1 (KIM1), Fibroblast growth factor 23 (FGF23), N-terminal pro b-type natriuretic peptide (NTproBNP), hepatocyte growth factor (HGF), and matrix metalloproteinase-1 (MMP1). The individual contribution of each biomarker to the prediction of eGFR decline on top of clinical predictors was generally low. When included into the model, baseline eGFR exhibited the largest explained variability of eGFR decline (R2 of 79%), and the contribution of each biomarker dropped below 1%. The authors concluded that in their longitudinal of patients with type 2 diabetes and maintained eGFR at baseline, 12 of the 17 candidate biomarkers were associated with eGFR decline, but their predictive power was low. Given the inferior performance of this highly selected set of biomarkers in early-stage chronic kidney disease patients to predict future eGFR loss, these markers are not likely to be useful for clinical decision-making. The study was published in the September 2018 issue of the journal Diabetes Care.

Analysis of Nasal Polyps Suggests Mechanisms of Inflammation llergic inflammation can develop from persistent activation of type 2 immunity in the upper airway, resulting in chronic rhinosinusitis, which ranges in severity from rhinitis to severe nasal polyps. Basal cell hyperplasia is a hallmark of severe disease, but it is not known how these progenitor cells contribute to clinical presentation and barrier tissue dysfunction in humans. In an effort to elucidate molecular mechanisms of chronic inflammatory diseases, scientists have profiled the transcriptomes of human nasal polyps and nasal scrapings by single-cell RNA sequencing. Scientists at Brigham and Womenâ&#x20AC;&#x2122;s Hospital (Boston, MA, USA; www.brighamandwomens.org) and their colleagues performed singlecell RNA sequencing on more than 18,000 cells from 12 surgically removed nasal polyps spanning the disease spectrum. They used Seq-Well for massively parallel single-cell RNA sequencing, report transcriptomes for human respiratory epithelial, immune and stromal cell types and subsets from a type 2 inflammatory disease, and map key mediators. Seq-Well is a portable, low-cost platform for single-cell RNA sequencing

designed to be compatible with low-input, clinical biopsies. The investigators found that the diversity of epithelial cell types was reduced in the nasal polyps, which contained few glandular and ciliated cells and were enriched in basal cells. The latter appeared to be stuck in their ability to differentiate into other cell types. This reduction in cellular diversity might be explained by differences in gene expression the scientists found between polyp and non-polyp basal progenitor cells. In addition, they revealed that a transcriptional program that is activated by cytokines interleukin-4 (IL-4 ) and IL-13 is strongly induced in basal progenitor cells from polyps, suggesting a possible treatment with an antibody that blocks the shared IL-4/IL-13 receptor subunit. The authors concluded that that reduced epithelial diversity stemming from functional shifts in basal cells is a key characteristic of type 2 immune-mediated barrier tissue dysfunction. Their results demonstrate that epithelial stem cells may contribute to the persistence of human disease by serving as repositories for allergic memories. The study was published on August 22, 2018, in the journal Nature.

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CHEMISTRY ANALYZER

RAPID TEST

DIALAB

Randox Laboratories

Operon

The Autolyser ISE offers a throughput of 250 tests per hour (chemistry), 200 tests per hour (ISE) and 220 tests per hour (chemistry + ISE based on 20 ISE samples). Key benefits include cooled reagent tray and nondisposable optical glass cuvettes.

The RX misano features an ergonomic design, responsive touch screen display and intuitive userfriendly software. It offers the option to run flow cell or cuvette mode and uses flow cell washing to avoid contamination for accurate results.

The Stick HB test provides fast diagnosis of Hepatitis B by detection of HBsAg in human serum or plasma. The one-step immunochromatographic test is easy to use and only requires placing the sample in the test and waiting for the result.

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Gut Microbiome Analysis Predicts Hospitalization in Cirrhosis irrhosis is a leading cause of mortality and healthcare expenditure due to hospitalizations worldwide. Bacterial products such as endotoxin play a key role in the development of a proinflammatory milieu and disease progression in cirrhosis. Specifically, the development of hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP) has a strong gut-based origin. A growing body of literature has linked gut microbial DNA results with negative outcomes in cirrhosis. Scientists at the Virginia Commonwealth University (Richmond, VA, USA; www.vcu.edu) and their colleagues carried out a prospective study of patients with cirrhosis defined through biopsy, features of decompensation, endoscopic or radiological evidence of varices or cirrhosis in the setting of chronic liver disease. Stool collection for DNA and RNA was performed using Parapak (Meridian Bioscience, Inc, Cincinnati, OH, USA; www.meridianbioscience.com) and stool was stored in RNAlater until it was ultimately extracted. The reverse bacterial 16S primer (1492R) was used to make the cDNA. Both DNA and cDNA were used in polymerase chain reaction (PCRs) with universal bacterial primers for the first two variable regions L27F and 355R. DNA or cDNA was amplified by PCR for sequencing using Ion Tor-

rent technology (Thermo Fisher Scientific, Waltham, MA, USA; www.thermofisher.com). Prepared diluted samples were separated on an ABI 3130xl fluorescent capillary sequencer (Applied Biosystems, Foster City, CA, USA; www.appliedbiosystems.com). The team included 26 controls and 154 cirrhotics including 54 infected, 62 decompensated, 20 renal dysfunctions, and 18 treated with rifaximin in the study. RNA and DNA analysis showed differing potentially pathogenic taxa but similar autochthonous taxa composition. Thirty subjects underwent the omeprazole study, which demonstrated differences between RNA and DNA changes. Thirty-six patients were hospitalized within 90 days. In the RNA model, Model for End-Stage Liver Disease (MELD) score and Enterococcus were independently predictive of hospitalizations, while in the DNA model MELD was predictive and Roseburia protective. In both models, adding microbiota significantly added to the MELD score in predicting hospitalizations. The study was published on March 8, 2018, in the journal JCI Insight. Image: The Ion Personal Genome Machine (PGM) System combines semiconductor sequencing technology with natural biochemistry to directly translate chemical information into digital data (Photo courtesy of Thermo Fisher Scientific). LINKXPRESS COM

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LabMedica International November/2018

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LabMedica International

Continuous Glucose Monitoring System Offers Improved Accuracy

Multi-Omics Approach Guides Relapsed Multiple Myeloma Treatment

requent use of continuous glucose monitoring systems is associated with improved glycemic outcomes in persons with diabetes, but the need for calibrations and sensor insertions are often barriers to adoption. A newly improved, factory-calibrated, continuous glucose monitoring (CGM) system provided accurate glucose readings for 10 days (240 hours) and removed a number of clinical barriers to widespread CGM use, such as acetaminophen interference and complicated adjustments. Scientists at the University of Colorado Denver (Aurora, CO, USA; www.ucdenver.edu) and their colleague tested the accuracy of the improved G6 CGM system, which includes a thinner and smaller transmitter, predictive low glucose alert, sensor membrane to block acetaminophen, and 10-day sensor wear. The current study enrolled 151 youth (age 6 to 17) and 139 adults with type 1 and 2 diabetes from 11 sites within the USA. Youth participants returned for one clinic session of six hours, and adults for three clinic sessions of up to three hours, during which CGM readings were compared with venous glucose concentrations in a laboratory setting. Glucose levels were manipulated for the 202 participants over the age of 13 to determine that the G6 CGM system (Dexcom, San Diego, CA, USA; www.dexcom.com), was adequately covering the entire reportable 40-400 mg/dL range. Performance evaluation included the proportion of CGM values that were within ±20% of reference glucose values greater than 100 mg/dL or within ±20 mg/dL of reference glucose values ≤100 mg/dL (%20/20), the analogous (%15/15), and the mean absolute relative difference (MARD, expressed as a percentage) between temporally matched CGM and reference values. The data from 262 study participants (21,569 matched CGM reference pairs) were analyzed. The overall %15/15, %20/20, and MARD were 82.4%, 92.3%, and 10.0%, respectively. Matched pairs from 134 adults and 128 youth of ages 6–17 years were similar with respect to %20/20 (92.4% and 91.9%) and MARD (9.9% and 10.1%). Overall %20/20 values on days 1 and 10 of sensor wear were 88.6% and 90.6%, respectively. The system’s “Urgent Low Soon” (predictive of hypoglycemia within 20 minutes) hypoglycemia alert was correctly provided 84% of the time within 30 minutes before impending biochemical hypoglycemia (<70 mg/dL). The 10day sensor survival rate was 87%. The authors concluded that the new factory-calibrated G6 real-time CGM system provides accurate readings for 10 days and removes several clinical barriers to broader CGM adoption. The study was published online on June 1, 2018, in the journal Diabetes Technology & Therapeutics.

any patients with relapsed multiple myeloma are not often matched with correct treatment options in a timely or personalized manner, and most patients have a median survival rate of six years. With standard diagnosis and treatment, relapses are usually inevitable and fatal for most patients. Scientists at the Mount Sinai Hospital (New York, NY, USA; www.mountsinai.org) and their colleagues performed a precision medicine trial using a group of 64 relapsed multiple myeloma patients. They collected 4 to 10 mL of bone aspirate, as well as peripheral blood samples, and extracted tumor genomic DNA and RNA from BM CD138+ cells. Whole-exome sequencing (WES) and RNA sequencing libraries were submitted to Illumina HiSeq2500 (Illumina, San Diego, CA, USA; www.illumina.com) for paired-end sequencing (100 base pairs). Targeted sequencing was performed using the Lymphoma Extended targeted next-generation sequencing panel from Cancer Genetics (Rutherford, NJ, USA; www.cancergenetics.com). The study was published in the August 2018 issue of the journal JCO Precision Oncology.

LabMedica International November/2018

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Diagnostic Accuracy In H. Pylori Fecal Test Assessed elicobacter pylori (H. pylori) infection occurs among 48.5% of the general population worldwide, with high geographic variability. It is the leading cause of chronic/atrophic gastritis, peptic ulcer, gastric lymphoma, gastric carcinoma, and some extra-gastric disorders. Molecular testing is a promising approach for diagnosing H. pylori infection and has the added advantage of identifying bacterial DNA mutations associated with antibiotic resistance and the application of these tests on fecal samples is gaining interest. Gastroenterologists at the University of Bari (Bari, Italy; www.uniba.it) and their colleagues enrolled consecutive people 18 years or older without previous diagnosis of H. pylori infection, referred for dyspepsia between February and October 2017. At enrollment, all participants underwent 13C-urea breath test. Participants aged over 50 years were scheduled to undergo upper endoscopy with histology. Participants collected stool samples 1 to 3 days after enrollment for a new fecal investigation. The authors concluded that their results indicated that the THD fecal test has high diagnostic performance for non-invasive detection of H. pylori infection in patients with dyspeptic symptoms while enabling identification of bacterium resistance to clarithromycin and levofloxacin. On these bases, the THD fecal test may inform clinical decision-making and guide individualized treatments for H. pylori infection. The study was published on July 21, 2018, in the World Journal of Gastroenterology.

LabMedica International November/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

NEWS

IFCC Speakers Attend South African Society's Annual Meeting at Historic Wine Estate Near Cape Town by Tahir Pillay, President, SAACB s a daughter society of the Federation of South African Societies of Pathology ( FSASP), the SAACB held its annual meeting on 16-18 August 2018 during the FSASP Pathcape 2018 conference at the Spier Wine Estate, Stellenbosch South Africa. The invited overseas IFCC speakers included the IFCC Committee on Clinical Laboratory Management, chaired by Prof. Sedef Yenice (Turkey) with Prof. Mathias Orth (Germany); Prof. Phillipe Gillery (France), chair of the IFCC Scientific Division ; Prof. Tomáš Zima (Czech Republic); Prof. Joris De Langhe, Editor-in-Chief of Clinica Chimica Acta (the official IFCC journal) and Prof. Steven Soldin (USA), from the NIH. In keeping with tradition, the first session of the first day was a trainees day devoted to discussion on topics pertinent to training. Prof. Pillay, President of the SAACB and Senator, College of Pathologists, South Africa held an interactive session with residents (registrars) in chemical pathology to discuss the qualifying postgraduate examinations. This was attended by other senior academics including Prof. Johnny Mahlangu, president of the College of Pathologists. A lively and interactive discussion ensued. Prof. Soldin presented a session on interesting cases in chemical pathology. One of the plenary lectures was delivered by Prof. Robert Millar from the University of Pretoria who is an internationally renowed for his work on gonadotrophins. Prof. Millar’s group cloned the first GnRH and GnRH receptor. His lecture was on “Functional rescue of inactivating mutations in human G-protein-coupled receptors: a novel pharmacology”. The IFCC Committee on Clinical Laboratory Management (C-CLM) also held Leadership Workshop chaired by Prof. Sedef Yenice and the topics included Organizational culture and change (Yenice), Strategic planning and laboratory medicine and leading and managing the lab team (Orth). There were also selected oral presentations on research and clinical cases. Prof. Tomáš Zima chaired an Endocrine update session which included talks on Endocrine disruptors and the role of mass spectrometry in the diagnosis of adrenal and thyroid diseases. There was also a symposium on biomarkers for diabetes and its complications, chaired by Prof. Zima and included talks on Protein carbamylation (Gillery) and Glycated keratins (Delanghe). Additional symposia include one on personalised medicine and pathology supported genetic testing. The feedback from delegates was very positive with the meeting being hailed as a great success and delegates hoped that the SAACB will continue to organise such meetings. The last such annual meeting was held in 2014 and preceded a 4 year hiatus in the organisation of the FSASP national pathology congresses in South Africa.

LabMedica International November/2018

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15th Arab Conference of Clinical Biochemistry and 10th International Palestinian Conference of Laboratory Medicine Held Jointly in Ramallah By Dr Bernard Gouget, SFBC-International Committee, IFCC Chair, Committee on Mobile Health and Bioengineering in Laboratory Medicine (C-MHBLM) and past-Chair Nominations Committee; and Dr Rania Abu Seir, PhD; IPCLM-10 and AFCB-15 Scientific Committee Chair; Cancer Research Activist; Assistant Professor in Hematology, Department of Medical Laboratory Sciences, Al-Quds University, Abu Dis, Palestine he 10th International Palestinian Conference of Laboratory Medicine (IPCLM-10) and the 15th Arab Conference of Clinical Biology entitled “Enabling Laboratory Expertise in the Era of Automation and Accreditation” were held on April 18-21, 2018 in Ramallah, capital of the Palestinian Administration, located about 15 km north of Jerusalem. The international event was conducted under the patronage of His Excellency President of Palestine, Dr. Mahmoud Abbas, and under the aegis of the International Federation for Clinical Chemistry (IFCC), the Arab Federation of Clinical Biology (AFCB), and the Palestinian Medical Technology Association (PMTA). Generally speaking, Ramallah is relatively stable and safe for foreigners. The Arab colleagues came from Amman, Jordan, and for the European citizens, it was easy to reach Ramallah with their passport and Israel visa given at Ben Gurion Airport. Once through the checkpoint, it is a short drive to downtown Ramallah. The city is known for its relaxed religious atmosphere and as the cultural capital with an educated population. Before the stop at the Carmel Hotel, the delegations were invited to visit the new Yasser Arafat Mausoleum, in the proximity of the tiny Old City called Ramallah Tahta and spend a few minutes at the new museum near to the faculty of Bir Zeit, the place where the Palestinian Conference (PCLM) was established in 1997 to discuss updates on the medical biology profession. Since 2014, the PCLM has gone international (IPCLM) and has gathered momentum, size and strength for international dialogue and cooperation in order to address more challenging questions in the Laboratory Medicine field. Upon arriving at the Palestinian Red Crescent Society convention centre, we saw the spacious exhibition area and auditorium, and realized that Ramallah is really a vibrant Palestinian scientific and business hub. The conference was held at an international level with participation from all the Arab Federation countries as wellas from Sweden, Italy, Portugal, Greece, USA, and France. The number of attendants exceeded 1600 in addition to 72 Palestinian speakers, 10 Arab speakers and 14 international speakers. More than 140 abstracts were submitted to the scientific committee, brilliantly chaired by Dr Rania Abu Seir. From those, 33 were accepted for oral presentations and 50 for posters. The posters included microbiology, bioinformatics, cancer research, hematology, public health and epidemiology, blood transfusion, infectious diseases, molecular biology, immunology and serology, endocrinology, clinical chemistry, clinical toxicology, genetics and cytogenetics, and quality control and assurance. At the opening ceremony, Prof. M. Ferrari, IFCC Past-President, congratulated warmly Osama Najjar, AFBC and Palestine Medical Technology Association (PMTA) President. O. Najjar recalled that the aim of the conference is to suggest challenging topics in cutting-edge research in order to produce recommendations for the profession. He also mentioned that since the last conference in 2014, the Palestinian Ministry of Health established an advisory strategic council for the development of Laboratory Medicine in coordination with the universities and with PMTA. The scientific program started with a plenary lecture on the “Interpretation of the genome through NGS” by Prof Paolo Fortina, followed by a session dedicated to microbiology on Echinococcosis, Enterobacteriae, antifungal susceptibility, antimicrobial profile of methicillin-resistant Staphylococcus. The second part of the afternoon session, after a keynote on "Noninvasive prenatal testing" by Prof. M. Ferrari, had topics on osteoporosis, phenylketonuria, fetal lung immaturity, and vascular endothelial

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growth factor. At the end of the day, the IFCC session focused on digitalization of Lab Medicine, topics presented by Prof S. Bernardini, Dr. A. Haliassos and myself, as speakers. Prof. L. Chabraoui opened the second day with a plenary lecture on “Diagnosis of inborn errors of metabolism”, followed by topics on pesticides and cancer, thalassaemia, allo-immunization. Biomarkers in the era of genomics were discussed during the first part of the afternoon session. The second IFCC symposium addressed questions on health, drug abuse and environment. On Saturday, the last morning session raised the issues of quality management and the importance of proficiency testing. It was a great honor to chair the Awards Committee with Prof. S. Bernardini (IFCC, Italy), Prof. A Hedhili (AFCB, Tunisia), Prof. L Chabraoui (IFCC-AFBC EB representative) and and Dr. Khaled Qabaha (Arab American University, Palestine). Three different awards were given which included a certificate, a souvenir with a prize code, and a budgetary one. They were distributed as follows: Dr. Atallah Rashmawi Award for best oral Palestinian presentation in Laboratory Medicine: First place, Rashail Faraon; second place, Assalla Abu Shamseye; third place, Etaf Hadyeh. AFCB Award for best Arab oral presentations: First place Award, Entisar Al-Hallaq; second place, Raed Ghneim; third place, Mohammad Manassra. Best Poster Presentation Award: First place, Anas Sabarnah; second place, Nurah Ayesh; third place Sharehan Ariqa. At the end of the congress, the young awardees and other young scientists celebrated their reward in super cool and trendy places. Ramallah is also well known as a very fashionable spot for nightlife! On Saturday afternoon, President Abbas greeted, at the Palestinian Presidency’s office, Arab and International delegations participating in the conference (photo 1). We were told that Palestine, as the birthplace of monotheistic religions and multiple civilizations, is and will remain an important home for religious tolerance and coexistence. Palestine has always sought to ensure cultural integration, inclusiveness and diversity within all components of society. Palestinian leadership is firmly committed to maintaining social justice and safeguarding fundamental freedoms, human dignity and democracy in compliance with the Palestine Declaration of Independence which calls for equal rights, free of ethnic, sectarian, racial or gender discrimination. In spite of enduring severe hardships, Palestine will remain committed to building an inclusive, democratic and humanitarian state consistent with the norms and values of contemporary civilized behavior and the body of laws adopted by the international community. Palestine is a Holy Land with many faces: grandiose vestiges, majestic landscapes, gastronomy and contemporary art. Ramallah was the perfect place for the congress and to have the chance to explore the area. Religious or festive, the heart of the city beats day and night. It was difficult to forget the view from the hotel roof top of Jerusalem and surroundings. Osama Najjar reserved many surprises, both scientific and cultural, plunging us into a mosaic of cultures.This congress really contributed to reinforce regional networks of scientific excellence. Thanks to him and to all for this opportunity! LabMedica International November/2018

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

NEWS

Tunisian National Congress Dedicates Research Award in Honor of Prof. Abderraouf Mebazaa by Prof Taieb Messaoud, President STBC; Prof Abderrazeak Hedhili, IFCC-EB AFCB representative; Dr Bernard Gouget, General Secretary FIFBCML he 32nd National Congress of the “Société Tunisienne de Biologie Clinique” (STBC) on 7-12 May 2018 brought together more than 900 participants over three days and 287 posters at the Royal Hotel Yasmine Hammamet Convention centre. The International Francophone Federation (FIFBCML) and the Arab Federation of Clinical Biochemistry (AFBC) delegations were largely represented including Presidents of the National societies and international speakers. The 10th Molecular Biology Course is a tradition preceding the congress. This year, it was devoted to haemoglobinopathies. The aim is to become familiar with the new technologies and to get a better understanding of the cause and mechanisms of these pathologies. The pre-congress workshops were devoted to antimicrobial resistance and method validation. The multidisciplinary scientific programme was rich and varied. The 2018 congress was placed in a spirit of ethics in Laboratory Medicine brilliantly illustrated by Prof. Nouzha Guessous at the Opening. The IFCC session was dedicated to Clinical Laboratory informatics and automation, how to manage clinical laboratory variability and laboratory accreditation. Many thanks to Prof. Sunil Sethi (SG), Prof. Sergio Bernardini (IT) and Dr. David Kinninburg (CA) for their participation. This was an excellent time to exchange with the Tunisian colleagues and to make a small escapade to Tunis which is a captivating destination. The national Bardo Museum, was the first stop. This jewel of Tunisian heritage, is located at the old Beylic palace; through its collections, the museum represents a big part of Tunisia’s history and it contains the largest collection of mosaics in the world. It was impossible to miss the site of Carthago, designated as a UNESCO World Heritage. Sidi Bou Said located on top of a steep cliff, overlooks the Mediterranean sea with a absolutely phenomenal view. This town has inspired famous artists such as Paul Klee, and André Gide, a French writer. It was the right place for a short lunch. Friday's sessions included four major themes around thrombotic microangiopathies, growth hormone deficiency in children, invisible fungal infections, and food contamination by microorganisms. The two plenary lectures were dedicated one to “the future developments in Genetics” illustrated by Prof. Etienne Crevier and the other on: “Past, present and future of the bacteriological diagnosis”. A special session on quality management was organized for technicians. On Saturday, the scientific morning session was on the biological exploration of inflammatory demyelinating diseases of the central nervous system. Several workshops were devoted to the diagnosis of sepsis, and the New Generation Sequencing

techniques in oncology. A professional session on the revision of the law from 2002 in relation to the clinical biology exercise was the occasion of very animated discussions. For the first time, the "Abderraouf Mebazza Research Award in Clinical Biology" was given to the best research work of two young biologists. Prof. Abderraouf Mebazaa (1937-2011) was a famous colleague. He was cofounder of the STBC; his human qualities and his scientific skills have left an indelible trace in everyone's memory. He received a medical doctorate, a master's degree and a doctorate in sciences before returning to Tunisia in 1973 to serve his country and to start a brilliant academic career at the university and at the hospital. He was a visionary man. He never ceased to integrate innovation for establishing a modern organization of automated medical laboratories. He established national quality control in Tunisia. The acquisition of chromatography equipment and the introduction of molecular biology techniques allowed him to explore metabolic diseases. He held several positions, Vice-Dean, Chairman of the Board of National Health, Chairman of the Ethics Committee, and Head of Biology Department. "Raouf" was an honest, faithful man with a keen sense of fairness. His integrity, his sense of duty, and his scientific curiosity make him an exceptional man whom everyone respects and loved deeply. The 2018 Laureates of the "Abderraouf Mebazza Research Award in Clinical Biology" were: Sondess Hadj Fredj: Contribution to the study of genetic markers in the variability of the clinical expression of cystic fibrosis in Tunisia (experience over a period of 8 years); Imen Ben Mustapha: Contribution of molecular and functional study of lymphoproliferative syndrome with autoimmunity in highly consanguineous populations. Photo: Prof. Taieb Ben Messaoud, President STBC, together with Mme Mebazaa, the awardees and representatives from the Award Committee and from STBC-EB.

New Affiliate IFCC Member: Federation of Laboratory Medicine of Kazakhstan he public association "Federation of Laboratory Medicine" is a professional community of laboratory diagnostics specialists whose main goal is to provide comprehensive assistance to the development of the laboratory service of the Republic of Kazakhstan, improvement of professional and scientific activities of specialists in the field of laboratory diagnostics and related disciplines. The "Federation of Laboratory Medicine" is registered with the Ministry of Justice of the Republic of Kazakhstan under BIN 170140002855 and has been operating in Astana since January 2017. The executive body of the "Federation of Laboratory Medicine" is a general meeting of participants under the leadership of the President, who is elected by direct open ballot. The Federation of Laboratory Medicine includes 163 members, of which 15% are research workers, 82.6% are practicing laboratory specialists (doctors and technologists), and 2.4% are specialists in related fields (pharmaceuticals, management, IT technologies in the field of laboratory diagnostics). Honorary members of the Federation are academics and leading experts in the field of laboratory diagnostics of the Russian Federation, the Republic of Kazakhstan, the Republic of Uzbekistan, the Republic of Tajikistan, and other countries that made a significant contribution to the development of the laboratory service. In addition, the associated members of the Federation are manufacturers and suppliers of reagents and laboratory equipment. The Federation of Laboratory Medicine, a member of the Association of Legal Persons "National Chamber of Health of the Republic of Kazakhstan", actively cooperates with the Association of Specialists and Organizations of

LabMedica International November/2018

the Laboratory Service "Federation of Laboratory Medicine" of the Russian Federation and is a consultant of the Republican Centre for Health Development, the Ministry of Health of the Republic of Kazakhstan in the project of improving the laboratory service , actively participating in solving urgent problems of laboratory diagnostics in the country. Within a short period of its operation, the Federation of Laboratory Medicine made a great contribution to the development of the laboratory service: from 2017, the introduction Photo: Suleimenova Zhanar Nurlanovna, of interlaboratory test trials proPresident of the Federation of Laboratory grams in Astana and the ReMedicine public of Kazakhstan and a number of agreements on bilateral cooperation in the field of laboratory diagnostics and "Laboratory Management. Diagnostics. Practice schools “ for young specialists were held for the purpose of teaching practical workshops and seminars, including visiting cycles.

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

NEWS VIEWPOINT

The Evolving Digital Era and Ethics by Dr. Bernard Gouget Chair, IFCC Committee on Mobile Health and Bioengineering in Laboratory Medicine (C-MHBLM), SFBC-International Committee, General Secretary of the International Francophone Federation of Clinical Biology and Laboratory Medicine (FIFBCML); Counselor for Public Health-FHF; Chair-Human Health Care Committee-COFRAC

ny health system today is confronted with new societal and ethical challenges and the growing pace of scientific development. The great increase in chronic diseases as well as technical progress, the emergence of new therapies and the acceleration of the digital revolution will change healthcare needs and approaches to care. Digital technology is fundamentally positioned at the heart of all healthcare systems. Its development is part of an extremely active interna-

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tional context. It is a major and irreversible element for the organization of care and a source of progress for improving quality and efficiency in health. The expected benefits in the field of teaching and research are also considerable. All professionals and citizens are directly concerned with this movement of technological innovation and the democratization of digital technology in health. The French National Ethics Advisory Council reported in a recent opinion piece that digital technology also concerns data collection, the development of learning algorithms (AI), and their applications, as well as in-silico modeling of diseases and modeling the action of new drug molecules. Today, the human part in medical practice is constantly being reduced by robotization in the medical technology sectors. The future becomes the present with algorithms already validated by peers. Their developments in medical decision making assistance or prescription assistance software allow diagnoses and therapeutic approaches to be facilitated and refined thanks to computing potential multiplied via big data or international registers collating the data of rare patients. Digital innovations in health have become essential and the quality of care is improved to the benefit of patients through more personalized and predictive management and care is more secure, with better traceability. The gains that can be obtained also concern prevention and screening, care, support and healthcare governance more generally. The use of digital technology can constitute a source of concern for professionals and users, especially regarding the use of data and associated services. It is therefore essential that the shift to digital technology is done in the context of ethical values and standards in order to structure and set limits for use. Respecting the rights and freedoms of individuals and protecting health data and the extent they are shared to improve clinical and biological quality are imperative. Algorithmic medicine must not deprive patients of their ability to participate in the process of constructing the management of their disease. It is also necessary to be vigilant that the digital revolution does not create new inequalities and does not penalize non-digital citizens, who are fragile populations with significant health needs. The objective of e-health is to reduce the risks of disease, obtain better treatment and care with a patient who is no longer an object of care, but rather an actor in their healthcare. In this context, ethical reflection on data, algorithms, practices and AI must be undertaken very early in the conception and development of solutions. For this purpose, research into digital ethics should be increased. The digital transformation is a source of motivation; it is urgent to take action to anticipate changes in jobs and possibilities for new functions and professions in health. The appeal of our profession also depends on training in the necessary skills to respond to the challenges of digital health. Preparing for the future means training future professionals and preparing them to understand the everfaster progress in medical know-how. Laboratory medicine is diversifying. Professionals are in demand to work more collectively in a comprehensive approach to care and share the same engagement and professional culture. Dialog, responsiveness, collective deliberation, and cross-referencing are all useful to further improve the quality of care in an ethical framework and get the most out of the added value of laboratory medicine. Bioethics and digital technology are increasingly the subject of practical and theoretical training. Ethical considerations at the international level are inseparable from the dissemination of tools. The organizational and cultural heterogeneity of the various national ethics committees with different regulatory or legislative responses leads to the creation of coordinated digital committees to better communicate and understand our cultural differences. The digital revolution penetrates all healthcare sectors and requires unprecedented ethical reflections driven by scientific advances. Our Federation can doubtlessly be a place for transcultural sharing and reflection to study and debate new ethical problems in laboratory medicine. LabMedica International November/2018

Industry News

Global Medical Gas Analyzer Market To Reach USD 325 Million by 2025 he global medical gas analyzer market was valued at USD 235 million in 2017 and is expected to grow at a compound annual growth rate (CAGR) of 4.1% from 2018 to 2025 to reach USD 325 million by 2025, driven by an upsurge in the adoption of medical gas analyzers, stringent regulations for medical gas systems, and increase in demand for advanced medical gas analyzing systems. An increase in the number of medical gas therapies due to a surge in the number of patients treated in intensive care units (ICUs), neonatal intensive care units (NICUs), and emergency departments, as well as a surge in number of hospitals & surgery centers will further support the market growth. These are the latest findings of Research and Markets, (Dublin, Ireland; www. researchandmarkets.com), a global market research company. Based on product, the multiple gas analyzers segment is expected to grow at a CAGR of 4.5% during the forecast period. On the basis of modality type, the portable analyzers segment held more than half the share of the medical gas analyzers market in 2017 and is expected to continue dominating the market throughout the forecast period.

MEDLAB Europe 2018 Showcases Latest Advances EDLAB Europe 2018, which took place in Barcelona, Spain, from October 2-4, 2018, featured over 150 exhibitors showcasing the latest cutting-edge technologies and recent developments in the medical laboratory industry. The second edition of the show welcomed more than 2,600 international visitors and delegates, offering international manufacturers a chance to network with over 1,000 medical dealers and distributors from Spain, Italy, France, Germany, Portugal and other countries. Alongside the exhibition, the show hosted multi-disciplinary CMEaccredited conferences over three days that covered a range of topics, including point-of-care testing (POCT), immunology, laboratory management anatomic pathology, clinical microbiology and hematology. The conferences tackled current challenges and developments key to the European laboratory and diagnostics market. These areas included the latest in clinical diagnostics development to review the expanding role of laboratory medicine and discuss the key aspects in improving overall patience care and delivery, from new methods of effective lab management to the development of techniques in detecting diseases. This provided an opportunity to learn about advances in science and their applications in laboratory medicine that will improve practice through improving patient outcomes.

Global Hemostasis/ Coagulation Analyzer Demand Projected To Grow at 10% Annually he global hemostasis/coagulation analyzers market was valued at USD 3.65 billion in 2017 and is expected to grow at a compound annual growth rate (CAGR) of 9.9% over the period 2018 to 2026 to reach USD 9.55 billion by 2026, driven mainly by the growing incidence of blood disorders. Technological innovations and miniaturization has led to the commercialization of several novel devices that have quick turnaround time and can also be used in point of care (POC) settings. Additionally, growing awareness and demand for technologically advanced medical treatments, government support and increasing adoption of laboratory automation are driving the demand for novel coagulation analyzers. These are the latest findings of Research and Markets, (Dublin, Ireland; www.researchandmarkets.com), a global market research company. Based on test types, the routine coagulation tests segment holds the largest share of the global hemostasis/coagulation analyzers market, due to a large number of these tests being performed for almost all surgical procedures and treatments.

LabMedica International November/2018

Events Calendar For a free listing of your event, or a paid advertisement in this section, contact:

International Calendar, LabMedica International P.O.Box 801932, Miami, FL 33280-2214, USA Fax: 1-954-893-0038 • E-mail: info@globetech.net JANUARY 2019 Fertility 2019 – 12th Joint Conference of the UK Fertility Societies. Jan 3-5; Birmingham, UK; Web: fertilityconference.org

FEBRUARY 2019 EWCPS 2019 – European Winter Conference on Plasma Spectrochemistry. Feb 3-8; Pau, France; Web: winterplasma19.sciencesconf.org MEDLAB 2019. Feb 4-7; Dubai, UAE; Web: www.medlabme.com SLAS 2019 – Society of Laboratory Automation and Screening. Feb 2-6; Washington, DC, USA; Web: www.slas.org Labqaulity Days 2019: International Congress on Quality in Laboratory Medicine. Feb 7-8; Helsinki, Finland; Web: www.labqualitydays.fi Annual Mayo Clinic Endocrine Update 2019. Feb 11-15; Kohala Coast, HI, USA; Web: ce.mayo.edu 14th Annual Biomarkers Congress. Feb 21-22; Manchester, UK; Web: biomarkers-congress.com Medical Fair India & Clin Lab India 2019. Feb 21-23; New Delhi, India; Web: www.medicalfair-india.com CHINALAB 2019. Feb 26-28; Guangzhou, China; Web: www.chinalabexpo.com

MARCH 2019 ARABLAB 2019. Mar 12-14. Dubai, UAE; Web: www.arablab.com KIMES 2019. Mar 14-17; Seoul, Korea; Web: www.kimes.kr PITTCON 2019. Mar 17-21; Philadelphia, PA, USA; Web: pittcon.org 5th EFLM-BD European Conference on Preanalytical Phase. Mar 22-23; Zagreb, Croatia; Web: www.preanalytical-phase.org ENDO 2019 – Endocrine Society Annual Meeting. Mar 23-26; New Orleans, LA, USA; Web: www.endocrine.org MEDLAB Asia Pacific. Mar 27-29; Singapore; Web: www.medlabasia.com ExpoMED Eurasia 2019. Mar 28-30; Istanbul, Turkey; Web: expomedistanbul.com

APRIL 2019 Analytica Vietnam 2019. Apr 3-5; Ho Chi Minh City, Vietnam; Web: www.analyticavietnam.com SEACare 2019 – 22nd Southeast Asian Healthcare & Pharma Show. Apr 9-11; Kuala Lumpur; Malaysia; Web: abcex.com ECCMID 2019 – 29th European Congress of Clinical Microbiology and Infectious Diseases. Apr 13-16; Amsterdam, Netherlands; Web: www.eccmid.org World Vaccine Congress 2019. Apr 14-17; Washington, DC, USA; Web: www.terrapinn.com India Lab Expo & Analytica Anacon India. Apr 16-17; Mumbai, India; Web: www.indialabexpo.com KoreaLab 2019. Apr 16-19; Seoul, Korea; Web: www.korealab.org AACE 2019 – 28th Annual Scientific and Clinical Congress of the American Association of Clinical Endocrinologists. Apr 24-28; Los Angeles, CA, USA; Web: www.aace.com ECV 2019 – European Congress of Virology. Apr 28 – May 1; Rotterdam, The Netherlands; Web: www.ecv2019.com

MAY 2019 International Congress of Cytology 2019. May 5-9; Sydney, Australia; Web: www.cytology-iac.org ESPID 2019 – 37th Annual Meeting of the European Society for Paediatric Infectious Diseases. May 6-11; Ljubljana, Slovenia; Web: espidmeeting.org ISLH 2019 – International Society of Laboratory Hematology. May 9-11; Vancouver, Canada; Web: www.islh.org AAI Immunology 2019 – 103rd Annual Meeting of the American Association of Immunologists. May 9-13; San Diego, CA, USA; Web: www.aai.org CMEF Spring 2019 – China International Medical Equipment Fair. May 14-17; Shanghai, China; Web: www.cmef.com.cn AMP Global 2019 – Association for Molecular Pathology. May 16-18; Hong Kong; Web: ampglobal-congress.com 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.euromedlab2019 barcelona.org LABVOLUTION 2019. May 21-23; Hannover, Germany; Web: www.labvolution.de HOSPITALAR 2019. May 21-24; Sao Paulo, Brazil; Web: www.hospitalar.com ASCO 2019 – Annual Meeting of the American Society of Clinical Oncology. May 31-Jun 4; Chicago, IL, USA; Web: am.asco.org

JUNE 2019 EAACI Congress 2019 – European Academy of Allergy & Clinical Immunology. Jun 1-5; Lisbon, Portugal; Web: www.eaaci.org BIO International Convention 2019. Jun 3-6; Philadelphia, PA, USA; Web: convention.bio.org ESGH 2019 – European Human Genetics Conference. Jun 15-18; Gothenburg, Sweden; Web: www.eshg.org EHA24 – 24th Annual Congress of the European Hematology Association. Jun 13-16; Amsterdam, The Netherlands; Web: http://ehaweb.org ECC 2019 – 42nd European Congress of Cytology. Jun 16-19; Malmo, Sweden; Web: cytology2019.com 15th Annual Biomarkers & Immuno-Oncology World Congress. Jun 17-21; Boston, MA, USA; Web: www.biomarkerworldcongress.com FOCIS 2019 – Annual Meeting of the Federation of Clinical Immunology Societies. Jun 1821; Boston, MA, USA; Web: www.focisnet.org ASM Microbe 2019 – American Society for Microbiology. Jun 20-24; San Francisco, CA, USA; Web: www.asm.org 29th Regional Congress of the International Society of Blood Transfusion (ISBT). Jun 2226; Basel, Switzerland; Web: isbtweb.org ESHRE 2019 – 35th Annual Meeting of the European Society of Human Reproduction and Embryology. Jun 23-26; Vienna, Austria; Web: www.eshre.eu FIME 2019 – Florida International Medical Exhibition. Jun 26-28; Miami Beach, FL, USA; Web: www.fimeshow.com

JULY 2019 FEMS 2019 – 8th Congress of European Microbiologists. Jul 7-11; Glasgow, UK; Web: http:// fems2019.org Analytica Lab Africa. Jul 9-11; Johannesburg, South Africa; Web: analytica-africa.com

AUGUST 2019 71st AACC Annual Scientific Meeting & Clinical Lab Expo. Aug 3-8; Anaheim, CA, USA; Web: www.aacc.org

SEPTEMBER 2019 ECP 2019 – 31st European Congress of Pathology. Sep 7-11; Nice, France; Web: www. esp-congress.org EUROTOX 2019 – 55th Congress of the European Societies of Toxicology. Sep 8-11; Helsinki, Finland; Web: www.eurotox-congress.com COLABIOCLI 2018 – 24th Latin American Congress of Clinical Biochemistry. Sep 10-13; Panama City, Panama; Web: http://colabiocli panama2019.com ASCP 2019 -Annual Meeting of the American Society for Clinical Pathology. Sep 11-13; Phoenix, AZ, USA; Web: www.ascp.org Medical Fair Thailand. Sep 11-13; Bangkok, Thailand; Web: www.medicalfair-thailand.com ESCV – 22nd Annual Meeting of the European Society for Clinical Virology. Sep 11-14; Copenhagen, Denmark; Web: escv2019.com ESPE 2019 – 58th Annual Meeting of the European Society of Paediatric Endocrinology. Sep 19-21; Vienna, Austria; Web: www.eurospe.org India Lab Expo & analytica Anacon India. Sep 19-21; Hyderabad, India; Web: www.indialabexpo. com ASHI 2019 – 45th Annual Meeting of the American Society for Histocompatibility & Immunogenetics. Sep 23-27; Pittsburgh, PA, USA; Web: www.ashi-hla.org Analitica Latin America 2019. Sep 24-26; Sao Paulo, Brazil; Web: www.analiticanet.com.br ExpoMedical 2019. Sep 25-27; Buenos Aires, Argentina; Web: www.expomedical.com.ar

OCTOBER 2019 ASHG 2019 – American Society of Human Genetics. Oct 15-19; Houston, TX, USA; Web: www.ashg.org

NOVEMBER 2019 AMP 2019 –Annual Meeting & Expo of the Association for Molecular Pathology. Nov 7-9; Baltimore, MD, USA; Web: www.amp.org 30th Regional Congress of the International Society of Blood Transfusion (ISBT). Nov 1619; Bangkok, Thailand; Web: isbtweb.org 40th Annual Meeting of the American College of Toxicology. Nov 17-20; Phoenix, AZ, USA; Web: www.actox.org APFCB 2019 – 15th Congress of the Asian-Pacific Federation for Clinical Biochemistry and Laboratory Medicine. Nov 17-20; Jaipur, India; Web: www.apfcbcongress2019.org MEDICA 2019. Nov 18-21; Dusseldorf, Germany; Web: www.medica-tradefair.com

LabMedica International November/2018

Advertising Index

LabMedica International Inq.No.

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Vol. 35 No.7 • 11/ 2018 Advertiser

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155 77 Elektronika . . . . . . . . . .55

117 Diasys . . . . . . . . . . . . . . . .17

158 Mast Group . . . . . . . . . . . .58

– AACC . . . . . . . . . . . . . . . . .61

152 Diestro . . . . . . . . . . . . . . . .52

150 Medix Biochemica . . . . . . .50

145 Agappe . . . . . . . . . . . . . . .45

124 DRG . . . . . . . . . . . . . . . . . .24

– MEDLAB 2019 . . . . . . . . . .60

106 Alcor . . . . . . . . . . . . . . . . . . .6

148 DxGen . . . . . . . . . . . . . . . .48

– APFCB 2019 . . . . . . . . . . .66

140 Dymind . . . . . . . . . . . . . . . .40

153 Awareness Technology . . .53

151 EKF . . . . . . . . . . . . . . . . . .51

128 Biohit . . . . . . . . . . . . . . . . .28

105 Erba . . . . . . . . . . . . . . . . . . .5

159 Biokit . . . . . . . . . . . . . . . . .59

107 Erba . . . . . . . . . . . . . . . . . . .7

110 Orion . . . . . . . . . . . . . . . . .10

138 Bioron . . . . . . . . . . . . . . . .38

– EuroMedLab 2019 . . . . . . .65

115 Quantimetrix . . . . . . . . . . .15

129 Boule . . . . . . . . . . . . . . . . .29

– ExpoMed 2019 . . . . . . . . .66

102 Randox . . . . . . . . . . . . . . . .2

118 Buhlmann . . . . . . . . . . . . . .18

143 Genrui . . . . . . . . . . . . . . . .43

144 SSI Diagnostica . . . . . . . . .44

134 Caretium . . . . . . . . . . . . . .34

157 Hecht, Karl . . . . . . . . . . . . .57

103 SNIBE . . . . . . . . . . . . . . . . .3

168 Cellavision . . . . . . . . . . . . .68

133 HiMedia . . . . . . . . . . . . . . .33

135 Chemclin . . . . . . . . . . . . . .35

– IFCC WorldLab 2020 . . . . .65

136 Coris BioConcept . . . . . . . .36

109 Instrumentation Laboratory .9

137 Denka Seiken . . . . . . . . . .37

127 Instrumentation Laboratory 27

113 Diagnostica Stago . . . . . . .13

122 JEOL . . . . . . . . . . . . . . . . .23

164 Vicotex . . . . . . . . . . . . . . . .64

149 Diagnostica Stago . . . . . . .49

142 Labex . . . . . . . . . . . . . . . . .42

141 Vircell . . . . . . . . . . . . . . . . .41

147 DIASource . . . . . . . . . . . . .47

– LabMedica.com . . . . . . . . .12

131 Zivak . . . . . . . . . . . . . . . . .31

119 Mindray . . . . . . . . . . . . . . .19 139 NG Biotech . . . . . . . . . . . .39 111 Nova Biomedical . . . . . . . .11

125 SNIBE . . . . . . . . . . . . . . . .25 – TradeMed.com . . . . . . . . . .22 121 VEDA.LAB . . . . . . . . . . . . .21

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