LabMedica International July 2017 by Globetech

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W O R L D ’ S C L I N I C A L L A B O R AT O R Y N E W S L E A D E R Annual Meeting & Clinical Lab Expo

ISSN 1068-1760

Vol. 34 No. 4 • 6-7/ 2017

DAILY CLINICAL LAB NEWS

Simple Urine Test Helps Track ALS Progression he continued failure of amyotrophic lateral sclerosis (ALS) clinical trials and the absence of therapeutic options for this fatal disease have fueled interest in the prospect that biomarkers may hold great promise for advancing therapy development efforts. Among the biological fluid–based biomarker candidates,

Panel Establishes Biomarker Guidelines for CRC Diagnostics fter reviewing more than 4,000 articles, an expert panel has issued recommendations for testing diagnostic biomarkers in patients with early and advanced colorectal cancer. The multi-disciplinary panel was established by The American Society for Clinical Pathology (ASCP), the College of American Pathologists

(CAP), the Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) with the objective of establishing standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens.

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Image: Courtesy of Stanford University Medical Center

Haptoglobin Test Enables New Diabetes Treatment A

Test for Earlier Detection Of Transplant Rejection method has been discovered that appears to provide earlier warning of organ transplant rejection compared to standard methods, and requires only a blood test rather than a more invasive and painful needle biopsy. Approximately 30,000 organ transplants occur in the USA each year. However, depending on the organ type of the transplanted organs, between 20% and 50% fail within five years, most often because the recipient’s

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Diagnosis of Skin Cancer without Biopsy

breakthrough ELISA kit, based on the Haptoglobin 2-2 (Hp 2-2) protein marker, identifies diabetics at higher risk of cardiovascular disease or renal failure, thereby enabling Vitamin E treatment beneficial to them but harmful to non HP 2-2 diabetics.

esearchers have developed a noninvasive method that accurately identified skin cancer by using multiphoton microscopy to quickly detect abnormal clusters of mitochondria in skin cells. Most types of skin cancer are highly treatable, especially if detected early. “The technology developed here has the potential to make the detection of skin cancers extremely rapid and feasible at very early stages,” said

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n innovative blood culture microbial detection system is now commercially available in countries that recognize CE marking and in the USA and is the first continuously monitoring blood culture microbial detection system to offer “Load & Go” technology.

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Blood Test Predicts Effectiveness of Anti-Depression Medication

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Automated Blood Culture System Receives FDA Clearance

epression and anxiety are two important mood disorders that are frequently associated with chronic diseases such as cardiovascular diseases (CVDs). Hyper-inflammation is related to both CVDs and psychological conditions such as depression and anxiety. A finger-prick blood test could help doctors to choose which medication is

most likely to succeed in treating depression as levels of C-reactive protein in the blood predict which antidepressant treatments are most likely to lead to successful outcomes in patients with depression. Scientists at the University of Texas Southwestern Medical Center (Dallas, Cont’d on page 8

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Haptoglobin Test Enables New Diabetes Treatment breakthrough ELISA kit, based on the Haptoglobin 2-2 (Hp 2-2) protein marker, can identify diabetes patients at higher risk of developing lethal cardiovascular or renal disease, thereby enabling them to take Vitamin E, a nutritional supplement shown to be of great benefit to them but posing harm to the remaining non HP 2-2 diabetic population. A CE mark application for the test is currently in progress, with FDA certification planned for the US market. Haptoglobin (Hp) is a plasma protein which every person carries in one of three variants: Hp 1-1, 2-1, or 2-2. With heart disease as the leading cause of death among diabetics, it has been shown that diabetes patients with the Hp 2-2 type, representing around onethird of all diabetics, face a much higher risk of heart disease compared to the remaining two-thirds of diabetics that have other Hp types. Conversely, studies have also shown that Vitamin E supplementation reduces heart attacks and death from cardiovascular disease by 50% in diabetes patients with HP 2-2, while having harmful effects on those with other Hp types. Now a novel test developed by BioRap Technologies (Haifa, Israel; www.bio-rap.com) brings a much-needed solution to this dilemma. By differentiating diabetes patients with the Hp 2-2 type from the general diabetic population, the new test allows them to receive the Vitamin E treatment, while excluding diabetics with other Hp types. The Hp test can indicate to the physician which of the three Hp types the patient carries, thus determining the risk of developing cardiovascular and renal diseases, and allowing for the application of appropriate treatment. BioRap's Hp typing test has been validated for 99% accuracy by eight different clinical studies, and is easily and rapidly performed from 20 μl of serum or plasma using the ELISA based kit (www. haptoglobintyping.com). BioRap's research team is headed by Prof. Andrew P. Levy, MD, PhD, FACC, whose record includes cuttingedge investigation for some 13 years in Haptoglobin Genomics and Therapeutics, and 25 years in Molecular Cardiology. Prof. Levy and other researchers have confirmed in 11 studies in the US, Europe, and Israel that diabetics (of both type I and II) carrying the Hp 2-2 genotype have up to a five-fold increased risk of developing cardiovascular disease and end-stage renal disease as compared to diabetics carrying the Hp 2-1 or Hp 1-1 genotypes. Nevertheless, Hp typing and Vitamin E treatment of Hp 2-2 diabetics still remain not part of standard clinical guidelines on diabetes treatment. However this could change if a major clinical trial replicates, on a wider scale, the findings of the two previous smallerscale trials. If such a trial were to be carried out by a pharmaceutical company, its costs could exceed USD

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40 million. However, since Vitamin E is not patentable medicine, no company or private investor would profit sufficiently to justify funding such a clinical trial. As to public health agencies such as NIH or EU, they do not have this level of funding available in the current environment. As a solution, Dr. Irit Hochberg with the Institute of Endocrinology, Diabetes & Metabolism at Rambam Health Care Center (Haifa, Israel; www.rambam.org.il/ englishsite), who was involved in the first diabetes Hp studies, is calling for HD-VERDICT, a pragmatic trial in which 6,000 diabetics with Hp 2-2 will be randomly assigned to Vitamin E at 400 IU/day or a placebo, and followed for heart events and deaths. According to Dr. Hochberg, "by way of existing infrastructure and avoiding heavy staff expenses of a clinical research organization, such a trial is expected to cost no more than USD 1 million". Dr. Hochberg added that, "over 150 million people in the world have both diabetes and Hp 2-2. Should the proposed study confirm results of the previous smallscale studies, the public health benefits would be enormous, justifying mass-scale Hp typing and Vitamin E treatment. Simulation of the previous results over 50 years at the Kaiser Permanente Healthcare System (Oakland, CA, USA; www.kp.org) demonstrated that such treatment would increase the diabetics' life expectancy by 2.5 years, compared with an increase of only 0.9 years after prevailing lipid-lowering therapy." According to Dr. Orit Shaked, chief executive officer of BioRap Technologies, "every year, diabetes causes 1.5 million deaths and costs USD 825 billion in worldwide healthcare spending. For every 1,000 diabetics of the Hp 2-2 type, treatment with Vitamin E could prevent 75 myocardial infarction admissions, 31 cardiac surgical procedures, plus 19 percutaneous coronary interventions. As a result of the new test gaining worldwide application, an extensive diagnostic and therapeutic potential could be unleashed, addressing the needs of a diabetic population of over 420 million worldwide – and growing by 10 million per year – of which 30 million are in the US." BioRap's Haptoglobin ELISA kit and indications for its use are covered by a wide portfolio of approved and pending patents. License for European distribution has been granted and the test is in midst of the CE approval process. BioRap is currently exploring a suitable licensing agreement covering the US market. The potential US licensee is envisaged as a nationwide distributor, or a manufacturer with similar distribution capabilities. BioRap Technologies Ltd. is a technology transfer company built upon innovations and patented technologies developed by research scientists at the Rappaport Family Institute for Research in the Biomedical Sciences, affiliated with Technion Israel Institute of Technology (Haifa, Israel; www.technion.ac.il/en). The company's approach, which identifies commercial opportunities emanating from scientific research and advanced technologies, has among others resulted in the development of Azilect (Rasagiline), a successful drug in the treatment of Parkinson's Disease, currently marketed worldwide by Teva Pharmaceuticals. BioRap offers a one-stop shop to advance the research and development of significant discoveries by fostering strategic collaborations with industry, through licensing, sponsored research, or new ventures.

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ISSN 1068-1760 Vol.34 No.4. Published, under license, by Globetech Media LLC; Copyright © 2017. 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. S¸ti. adına ˙Imtiyaz Sahibi: M. Geren • Yazı is¸leri Müdürü: Ersin Köklü Müs¸ ir Dervis¸ ˙Ibrahim Sok. 5/4, Esentepe, 34394 S¸is¸ li, ˙Istanbul P. K. 1, AVPIM, 34001 ˙Istanbul • E-mail: Teknopress@yahoo.com Baskı: Promat Web Ofset Tesisi • Orhangazi Mahallesi 1673. Sokak, No: 34 • 34510 Esenyurt, B. Çekmece • ˙Istanbul Yerel süreli yayındır. Yılda sekiz kere yayınlanır, ücretsiz dag˘ıtılır.

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Test for Earlier Detection of Transplant Rejection cont’d from cover

immune system attacks, or “rejects,” the donated organ. Scientists at the Perelman School of Medicine at the University of Pennsylvania (Philadelphia, PA, USA; www.med.upenn.edu) analyzed human blood and urine samples using a new method. The new method involves tiny, capsule-like structures known as exosomes, which normally are secreted from most types of cell. Precisely what exosomes evolved to do is not clear, but scientists know that these capsules contain proteins and other molecules from their mother cell that can influence the activities of neighboring cells. Like their mother cells, exosomes have protein markers on their surfaces, often called major histocompatibility complex (MHC) antigens that identify them to the immune system as part of the body. Just as donor and host cells usually differ in their MHC markers, so do donor and host exosomes. Human pancreas was processed for islet isolation, and highpurity (>80%) islets were used for xenoislet transplantation. Islet isolation was performed and the islets were cultured in CMRL media supplemented with albumin, without any exogenous exosome contamination. Islet culture supernatant (20 mL) was obtained 24 to72 hours after isolation for exosome analysis. Exosomes were isolated from human islet culture supernatants by size exclusion limit gel chromatography along with ultracentrifugation. Exosomes were analyzed on the NanoSight NS300 (405 nm laser diode) on the light scatter mode for quantification and scatter distribution (Malvern Instruments Inc, Malvern, UK; www.malvern.com). In an initial exploration of the transplant-exosome strategy in people, the team examined stored blood plasma samples from five recipients of transplanted islet cells in a clinical trial, and was able to detect donor exosomes in these samples following the transplants. They also found some preliminary evidence that their falling-exosome measure could be useful in predicting transplant rejection in people. For one patient who experienced a rejection of the transplanted islet cells, a steep drop in the level of donor exosomes was detectable in a blood sample taken six and a half months before the transplanted cells stopped working and the patient developed clinical signs of diabetes. The scientists showed that they could isolate and detect donor-tissue exosomes in a different type of transplant: kidney transplant, currently the most common type of organ transplant. In this case, the team found that they could isolate and quantify donor-kidney exosomes not just in blood but also in urine, thus potentially enabling urine tests which are even less invasive than blood tests. Ali Naji, MD, PhD, a Professor of Surgery and senior author of the study said, “I believe that analyses of exosomes from transplanted organs will ultimately provide a very powerful and unprecedented ability to understand the conditional state of the organ as a whole.” The study was published on March 20, 2017, in the Journal of Clinical Investigation. Image: The NanoSight NS300 instrument provides an easy-to-use, reproducible platform for nanoparticle characterization (Photo courtesy of Malvern Instruments). LabMedica International June-July/2017 LINKXPRESS COM

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Panel Establishes Biomarker Guidelines for CRC Diagnostics cont’d from cover

To accomplish this goal, the panel conducted a comprehensive literature search that included more than 4,000 articles. The members of the panel focused on the following list of key questions: (1) What biomarkers are useful to select patients with CRC for targeted and conventional therapies? (2) How should tissue specimens be processed for biomarker testing for CRC management? (3) How should biomarker testing for CRC management be performed? (4) How should molecular testing of CRC be implemented and operationalized? (5) Are there emerging genes/biomarkers that should be routinely tested in CRC? Following their review, the panel published its findings in the February 6, 2017, online editions of the American Journal of Clinical Pathology, Archives of Pathology & Laboratory Medicine, the Journal of Molecular Diagnostics and the Journal of Clinical Oncology, from each collaborating organi-

zation, respectively. The panel established 21 guideline statements (eight recommendations, 10 expert consensus opinions, and three “no recommendation”) and concluded that the evidence supported mutational testing of specific genes in the EGFR signaling pathway, since they provide clinically actionable information for targeted therapy of CRC with anti-EGFR monoclonal antibodies. Mutations in some of the biomarkers have clear prognostic value (BRAF, MMR), and at least two (KRAS and NRAS) have relatively strong evidence as negative predictors of benefit to anti-EGFR therapies and should be used to guide the use of these agents. BRAF mutations are consistently associated with poor outcomes in patients with metastatic CRC, including those who relapse after adjuvant therapy. “While many existing recommendations cover the application of individual molecular biomarkers in colorectal cancer, this guideline fills the need for

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an overarching set of recommendations spanning the breadth of current knowledge,” said contributing author Dr. Wayne W. Grody, professor of medicine at the University of California, Los Angeles (USA; www.ucla.edu) and project co-chair on behalf of ASCP. “This comprehensive guideline will prove useful for pathologists and oncologists to support decision-making on what molecular tests to order for patients with colorectal cancer.” Image: A scanning electron micrograph (SEM) of dividing colorectal cancer cells (Photo courtesy of MNT).

Blood Test Predicts Effectiveness of Anti-Depression Medication cont’d from cover

TX, USA; www.utsouthwestern.edu) and their colleagues analyzed remission rates in 106 patients with depression who were randomly allocated between two groups. One group of 51 patients was prescribed the selective serotonin reuptake inhibitor escitalopram alone and 55 patients in the other group were prescribed escitalopram plus bupropion. C-reactive protein (CRP), serum amyloid P component, and alpha-2-macroglobulin were measured using the Bioplex Pro human acute-phase 4-plex panel (Bio-Rad, Hercules, CA, USA; www.bio-rad.com). The reason CRP was chosen was because it is often used as a marker of inflammation in cardiovascular disease, diabetes, and other disorders. The team found that the treatment arms did not differ in depressive symptom or side effect outcomes. Most participants 74/106 (69.8%) had baseline CRP levels greater than 1 mg/L (indicative of systemic inflammatory activity). Higher baseline CRP levels were associated lower depression severity with bupropion-SSRI combination but not with SSRI monotherapy. The overall remission rate was 41.5%. The estimated remission rate with CRP threshold based assignment (SSRI monotherapy for less than 1 mg/L and Bupropion-SSRI for equal to or greater than 1 mg/L) was 53.1%. Side effect burden was unrelated to any baseline inflammatory marker. Madhukar Trivedi, MD, a professor and senior author of the study, said, “Both patients and primary-care providers are very desperately looking for markers that would indicate there is some biology involved in this disease. Otherwise, we are talking about deciding treatments from question-and-answer from the patients, and that is not sufficient.” The study was published in the April 2017 edition of the journal Psychoneuroendocrinology.

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Sensor Monitoring System Improves Glucose Control for Diabetics eople who scan more frequently using sensor monitoring system spend less time in hypoglycemia (low blood sugar) or hyperglycemia (high blood sugar) while having improved average glucose levels. The monitoring system consists of small, round sensor worn on the back of the upper arm for up to 14 days, measures glucose every minute in interstitial fluid through a small filament that is inserted just under the skin and held in place with a small adhesive pad. A reader is scanned over the sensor to get a glucose result painlessly in less than one second. A full data set had been generated from 50,831 readers, which were used to scan 279,446 sensors. This constituted 409.4 million glucose measurements, 86.4 million monitoring hours and 63.8 million scans representing more than 50,000 users across the Europe region. De-identified data was

collected over a period of 18 months when readers were connected to the PC-based software with an active internet connection. All information was aggregated. No personal data was utilized or shared. The key findings of the real-world data of the FreeStyle Libre sensor monitoring system (Abbott Laboratories, Abbott Park, IL, USA; www.abbott .com) were users checked their glucose levels an average of 16.3 scans per day; improved HbA1c: average glucose level decreased as scan rate increased with estimated HbA1c decreasing from 8.0% to 6.7%; there was a reduction in hypoglycemia: time spent below glucose levels of 70, 55 and 45 mg/dL decreased by 15%, 40% and 49%; there was a reduction in hyperglycemia: time above 180 mg/dL decreased from 10.5 to 5.9 hours per day; and there was an increased time in range: time

in glucose range (70-180 mg/dL) increased from 12.0 to 16.8 hours per day. The FreeStyle Libre system generates an Ambulatory Glucose Profile (AGP) that provides a visual snapshot of glucose levels, trends and patterns over time. The study was presented at the 10th International Conference on Advanced Technologies and Treatment for Diabetes (ATTD) congress held February 15-18, 2017, in Paris, France. Image: The FreeStyle Libre monitoring system for diabetes (Photo courtesy of Abbott).

Automated Blood Culture System Receives FDA Clearance

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Personnel of all skill levels can easily load bottles on the instrument at any time throughout the day or night, enabling prompt incubation and reducing hands-on time. Bottle unloading is fully automated with visual and audible alarms and alerts, helping laboratories to streamline their workflow. The US Food and Drug Administration (FDA, Silver Springs, MD, USA; www.fda.gov) has given 510(k) clearance to the blood culture microbial system. The BacT/ALERT VIRTUO system (bioMérieux, Marcy l'Etoile, France; www.biomerieux.com) that received FDA approval, offers powerful proprietary algorithms, high thermal stability and superior optics, which enhance blood culture performance for more rapid time to detection. This translates into faster identification of bloodstream infections. This unrivalled blood culture system further enriches the BacT/ALERT product line for blood culture. It offers an integrated configuration with scalable incubation capacity from 428 to 1,712 cells and facilitates the management of high volumes of blood cultures. A unique blood level detection technology measures the blood volume in each blood culture bottle at the time of loading. This feature helps laboratories track and ensure collection of the recommended blood volume in order to be compliant with accreditation and quality guidelines. This is a significant benefit to patient care, since the blood volume collected is a critical factor in detecting bloodstream infections. BacT/ALERT VIRTUO utilizes the FANPlus media, which are formulated to optimize antibiotic neutralization with optimal growth performance of microorganisms. François Lacoste, Vice President-Clinical Unit at bioMérieux, said, “We are proud to receive this FDA clearance for BacT/ALERT VIRTUO, which allows us to enhance our blood culture offer to our customers in the USA. This highly automated blood culture solution enables faster detection of pathogens by clinical microbiology laboratories, which is of crucial importance for optimal patient treatment, especially in life-threatening conditions such as bloodstream infections which may progress to severe sepsis.”

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Simple Urine Test Helps Track ALS Progression cont’d from cover

the cytoskeletal proteins neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) show great promise as prognostic markers and potential pharmacodynamics biomarkers. However, since neurofilament levels remain largely stable over time, they do not reflect disease progression. Scientists at Flinders University (Adelaide, Australia; www. flinders.edu.au) and their colleagues performed a prospective cohort study in which urine samples from patients with ALS and controls were collected. The population in the study comprised 45 healthy controls and 54 people with ALS, 31 of who were sampled longitudinally. Urinary creatinine and osmolarity measurements were performed using a Roche (Basel, Switzerland; www.roche.com) / Hitachi (Tokyo, Japan; www.hitachi.com) modular analyzer. To evaluate urinary neurotrophin receptor p75 extracellular domain (p75ECD) levels, the team used a sandwich enzyme-linked immunoassay (ELISA) and validation included intra-assay and inter-assay coefficients of variation, effect of circadian rhythm, and stability over time at room temperature, 48 °C, and repeated freezethaw cycles. Longitudinal changes in urinary p75ECD were examined by mixed model analysis, and the prognostic value of baseline p75ECD was explored by survival analysis. The ELISA assays were read using a Victor×4 plate reader PerkinElmer (Waltham, MA, USA; www.perkinelmer.com). The scientists confirmed that p75ECD was higher in patients with ALS (5.6 ± 2.2 ng/mg creatinine) compared to controls (3.6 ± 1.4 ng/mg creatinine). Assay reproducibility was high, with p75ECD showing stability across repeated freeze-thaw cycles, at room temperature and 48 °C 42 days, and no diurnal variation. Urinary p75ECD correlated with the revised ALS Functional Rating Scale at first evaluation and p75ECD also increased as disease progressed at an average rate of 0.19 ng/mg creatinine per month. The authors concluded that the assay for urinary p75ECD is analytically robust and shows promise as an ALS biomarker with prognostic, disease progression, and potential pharmacodynamic application. Baseline urinary p75ECD provides prognostic information and is currently the only biological fluid–based biomarker of disease progression. The study was published ahead of print on February 22, 2017, in the journal Neurology. Image: Research shows a simple urine test can help diagnose and track the progression of ALS (Photo courtesy of AdobeStock). V

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FDA Clears Assay for Herpes Simplex and Varicella-Zoster Viruses he US Food and Drug Administration (FDA) has given 510(k) clearance for a new molecular assay for herpes simplex virus (HSV) types 1 & 2 and varicellazoster virus (VZV), developed to run on the Solana platform. Quidel Corporation (San Diego, CA, USA; www.quidel.com) received the FDA clearance for its Solana HSV1+2/VZV Assay for qualitative detection and differentiation of HSV-1, HSV-2, and VZV DNA isolated and purified from cutaneous or mucocutaneous lesion samples obtained from symptomatic patients suspected of active HSV-1, HSV-2, and/or VZV infection. Herpetic lesions can be a result of the primary infection or from a reactivation of the latent virus, causing recurrent episodes. HSV-1 and HSV-2 are genetically and antigenically distinct. HSV-2 is the most common cause of genital infections, due to venereal transmission, often from an infected partner who does not have visible sores and who may not know that he or she is infected. HSV-1 is commonly associated with other disease locations, although both serotypes have been shown to cause disease in various locations of the body. VZV is a DNA virus of the family Herpesviridae. Primary infection results in chickenpox (varicella), which rarely results in complications (e.g. encephalitis or pneumonia). Latency occurs with VZV remaining dormant

in the nervous system of the infected person. In approximately 10-20% of cases, VZV reactivates later in life, producing shingles. With Solana HSV-1+2/VZV Assay, specimens submitted in a broad range of transport media can be tested. In addition to being compatible with many commonly used transport media, the easy-to-use assay requires no upfront extraction of DNA, and generates three accurate results within an hour. Solana can process up to 12 patient samples per run, and provides timesaving workflow advantages in moderately complex settings. Results are reported on the screen, stored in the instrument, can be saved to a USB drive, printed, and/or sent to the LIS. Supervisors can set access rights for higher security. Solana can also come with Virena, Quidel’s wireless data management and surveillance system. “Quidel has long been a leader in developing innovative Respiratory and Women’s Health assays. Our latest product introduction, the Solana HSV-1+2/VZV assay, broadens our molecular diagnostic offerings for Women’s Health assays in the moderately complex setting,” said Douglas Bryant, president and CEO of Quidel, “We believe that the Solana platform will provide the laboratorian with a fast and accurate method to diagnose many Women’s Health conditions.”

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HSV-1+2/VZV is Quidel’s fifth molecular diagnostic test to receive FDA 510(k) clearance in the Solana format, the other four being: Strep Complete, Influenza A+B, Trichomonas, and Group A Strep. With the Solana franchise, Quidel has broadened its molecular strategy to include instrumented systems, and grown the number of its available FDA-cleared platforms. Quidel’s other FDA-cleared molecular solutions include the AmpliVue non-instrumented system for lower-volume moderately complex labs, and Lyra

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reagents for higher throughput, highly complex laboratories that are compatible with existing PCR infrastructure. Solana HSV-1+2/VZV Assay is not intended for use in prenatal screening, nor for use with cerebrospinal fluid or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS). Image: The Solana platform leverages the Helicase-Dependent Amplification (HDA) technology to generate fast and accurate test results (Photo courtesy of Quidel).

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Diagnosis of Skin Cancer without Biopsy cont’d from cover

Behrouz Shabestari, PhD, of National Institute of Biomedical Imaging and Bioengineering (Bethesda, MD, USA; www.nibib.nih.gov), which largely funded the study, “Rather than taking a biopsy sample that must be processed and then examined under a microscope by a pathologist, this system involves simply looking through the microscope at the patient’s skin and determining whether it is cancerous or not, within minutes.” A group of international collaborators led by co-senior author Irene Georgakoudi, PhD, of Tufts University (Medford, MA, USA; www.tufts.edu), found that mitochondria behave very differently in healthy versus cancerous tissue. They used a laser microscopy technique that takes advantage of characteristics of the mitochondrial compound nicotinamide adenine dinucleotide (NADH), which naturally fluoresces without injecting any dye or contrast agent into the individuals being screened. They found that NADH can be detected using multiphoton microscopy to provide diagnostically useful information about the organization of the mitochondria in skin cells. “The system allows us to obtain very high-resolution images of individual cells without having to slice the tissue physically,” explained Dr. Georgakoudi, “we found that in normal cells the mitochondria are spread throughout the cell in a web-like pattern. Conversely, cancerous skin cells show a very different pattern with the mitochondria found in clumps or clusters typically at the center of the cell along the border of the nucleus.” In this study the technique was tested in 10 patients with skin cancer (melanoma or basal carcinoma) and 4 without skin cancer. When compared to the traditional biopsy results obtained from each patient, the results demonstrated that the imaging technique correctly identified skin cancer in all 10 cancer patients, and made no false diagnoses in the four individuals without skin cancer. Dr. Georgakoudi estimates that this test could be used routinely within five years, but the USD 100,000 price of the laser used in this microscope would limit the facilities that could make the investment. “Less-expensive lasers are on the horizon,” said Dr. Georgakoudi, “However, this approach would enable a doctor to make a quick diagnosis and begin treatment immediately, which could ultimately lower healthcare costs associated with these very common cancers.” The study, by Pouli D et al, was published November 30, 2016, in the journal Science Translational Medicine. Image: A diagram showing differences that can be observed in cell morphology in normal skin cells versus melanomas (Photo courtesy of Irene Georgakoudi, Tufts University).

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Quick Test Detects Inflammation in Diabetic Patients new kit has been developed that will allow doctors to find out within minutes if diabetic patients are suffering from inflammation. Current procedures require patients to wait for several hours for the results obtained from the conventional full blood count test. Type 2 diabetes is the most common and is usually treated with lifestyle changes, medication and insulin. If diabetic patients can be grouped based on their inflammation status in addition to glucose level, then doctors can better choose the treatment best suited for their patients. Scientists at the Nanyang Technological University (Singapore; www.ntu.edu.sg) and their colleagues have developed a rapid microfluidic neutrophil sorting and functional phenotyping strategy for type 2 diabetes mellitus (T2DM) patients using small blood volumes from a fingerprick of ~100 L. The developed inertial microfluidics technology enables single-step neutrophil isolation of greater

than 90% purity without immuno-labeling and sorted neutrophils are used to characterize their rolling behavior on E-selectin, a critical step in leukocyte recruitment during inflammation. Flow cytometry analysis was performed using BD LSR Fortessa flow cytometer (BD Biosciences, San Jose, CA, USA; www.bdbiosciences.com). The team discovered that neutrophils can be used as a biomarker to determine if diabetic patients are suffering from an inflammation. Using the new test kit, neutrophils can be easily extracted from a blood sample, and their behavior and function observed for more efficient inflammation profiling in additional to the cell count. In healthy individuals, neutrophils float free in the blood stream. When there is an acute inflammation such as during a bacterial or viral infection, they will slow down and roll along the vessel walls. Once near the site of infection, the neutrophils squeeze through the vessel walls and move to the

site of the injury. In diabetic patients, the neutrophils roll faster, which means that fewer of them will manage to squeeze through the vessel wall to tackle the infection. The increased rolling speeds of neutrophils correlate closely with cholesterol and C-reactive protein levels, a biomarker for inflammation, so it provides doctors with a better indicator of an individualâ&#x20AC;&#x2122;s immune status. The authors concluded that their results suggest a new point-of-care testing methodology, and neutrophil rolling speed as a functional biomarker for rapid profiling of dysmetabolic subjects in clinical and patient-oriented settings. This new test kit will advance diabetes management by providing real-time signals related to a cluster of risk factors faced by patients. It will lead the way to improvements in patient care, enabling chronic disease self-management and finally a healthier society. The study was published on September 27, 2016, in the journal Scientific Reports.

Optimal Rule-Out Biomarker Strategy Developed for Acute Myocardial Infarction ssessment of patients presenting to the Emergency Department (ED) with symptoms suggestive of acute coronary syndrome (ACS) represents a major clinical challenge, since the majority of patients do not have a final diagnosis of acute myocardial infarction (AMI). A multi-marker strategy, combining high-sensitivity troponins (hs-cTn) with an early cardiac marker may improve sensitivity and increase the proportion of low-risk patients suitable for early discharge by allowing a higher troponin threshold to be utilized. Heart Fatty Acid Binding Protein (HFABP), a highly myocardium-specific protein and early rise marker of ACS, is a potential candidate. Scientists at the University of Otago (Dunedin, New Zealand; www. otago.ac.nz) and their medical colleagues enrolled consecutive patients presenting acutely to the emergency department (ED) with symptoms suggestive of AMI. Patient assessment included blood sampling for contemporary TnI (c-TnI) at presentation and six to 12 hours later. The primary end point was AMI during initial hospital attendance. AMI diagnosis was based on evidence of myocardial necrosis, together with clinical features consistent with myocardial ischemia (ischemic symptoms, ECG changes or imaging evidence). Necrosis was diagnosed on the basis of a rising or falling pattern of the routine laboratory c-TnI (ARCHITECT c-TnI assay, Abbott Diagnostics, Lake Forest, IL, USA; www.

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abbottdiagnostics.com), with at least one value above 0.028 ng/mL. HscTnI concentrations were measured on the ARCHITECT STAT platform (Abbott Laboratories, Abbott Park, IL, USA; www.abbott.com). Hs-cTnT concentrations were measured with the Roche Elecsys hs-cTnT assay (Roche Diagnostics, Basel, Switzerland; www.roche.com). H-FABP concentrations were measured with an immunoturbidimetric H-FABP assay (Randox Laboratories Limited, Crumlin, UK; www.randox.com ) on the ARCHITECT platform. The team recruited 1,079 patients including 248 with AMI. H-FABP of less than 4.3ng/mL plus hs-cTnI of greater than 10.0 ng/L together with a negative ECG maintained more than 99% sensitivity for AMI whilst classifying 40.9% of patients as low-risk. The combination of H-FABP less than 3.9ng/mL and hs-cTnT of greater than 7.6ng/L with a negative ECG maintained the same sensitivity whilst classifying 32.1% of patients as low risk. The authors concluded that in patients requiring rule-out of AMI, the addition of H-FABP to hs-cTn at presentation in the absence of new ischemic ECG findings may accelerate clinical diagnostic decision making by identifying up to 40% of such patients as low-risk for AMI on the basis of blood tests performed on presentation. If implemented this has the potential to significantly accelerate triaging of patients for early discharge from the ED. The study was published on August 31, 2016, in the journal BMC Emergency Medicine. LabMedica International June-July/2017

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UTI Testing Technology Cuts Screening Time Significantly ost urinary tract infections (UTI) are mild, but serious cases can lead to hospitalization and at worst, bacteria can enter the bloodstream causing urosepsis, a life-threatening condition. In this case antibiotics are vital and must be given immediately. Faster prediction of whether the UTI is caused by a highly resistant type of bacteria will allow precise tailoring of treatment. The patient will get an antibiotic that is sure to be active against their pathogen, and society’s limited antibiotic resource will be better managed. This will help in the fight against increasing antibiotic resistance, one of the biggest challenges facing society today. Medical scientists at the University of East Anglia (Norwich, UK; www.uea.ac.uk) explored whether nanopore sequencing could accelerate di-

agnosis and resistance profiling, using complicated urinary tract infections as an exemplar. Bacterial DNA was enriched from 10 clinical urines and from five healthy urines ‘spiked’ with multiresistant Escherichia coli then sequenced. Sequences were analyzed using external databases and bioinformatic pipelines or, ultimately, using integrated real-time analysis applications. Results were compared with Illumina data and resistance phenotypes. The team used the MinION nanopore sequencing (Oxford Nanopore Technologies, Oxford, UK; https://nanoporetech.com) which correctly identified pathogens without culture and, among 55 acquired resistance genes detected in the cultivated bacteria by Illumina sequencing, 51 were found by MinION sequencing directly from the urines; with three of the four failures in an early run with low

genome coverage. Resistance-conferring mutations and allelic variants were not reliably identified. MinION sequencing comprehensively identified pathogens and acquired resistance genes from urine in a timeframe of four hours from sample to result similar to polymerase chain reaction (PCR). The study was published on September 25, 2016, in the Journal of Antimicrobial Chemotherapy. Image: The MinION nanopore sequencing device (Photo courtesy of Oxford Nanopore Technologies).

Groundbreaking Immune Approach Targets Humans Instead of Bacteria taphylococcal and streptococcal infections affect millions of individuals each year and they are a leading cause of sepsis and account for many cases of pneumonia and post-surgical infections. The ability of staphylococcal and streptococcal bacteria to cause disease is due to numerous virulence factors, among which a group called Superantigens play a prominent role. Several dozen superantigens are highly lethal in humans and are critical contributors to sepsis and progression to toxic shock. Scientists at the Hebrew University-Hadassah Medical School (Jerusalem, Israel; www.medicine.ekmd. huji.ac.il) developed describe a novel host-oriented therapeutic approach for preventing lethal immune responses. With major implications for medicine, the novel approach is both broad-acting and impervious to bacterial antibiotic resistance. While the inflammatory immune response is essential to protecting humans against viruses and bacteria, superantigen toxins cause an exaggerated response, called an immune storm, that can do a great deal of damage in the body and can result in multiple organ failure. Even with currently available treatment strategies, most of these diseases have high mortality rates. Complicating treatment of these bacterial infections are multi-drug resistant strains. A normal immune response is mediated by an antigen through the joining of cells through well-known receptors on their surface, a process that is

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helped by the so-called “costimulatory” receptors. Unexpectedly, the superantigen strongly promotes the interaction between the major costimulatory receptors, B7-2 and CD28, and this turns out to be critical for its ability to elicit an immune storm. Formation of the costimulatory axis was already known to be important for a full immune response, but the present findings propel this axis to the foreground as a key bottleneck. The investigators now show that in order to enhance B7-2/CD28 receptor engagement, superantigen molecules bind directly to both receptors. By binding not only CD28 but also its co-ligand B7-2 directly, superantigens potently enhance the B72/CD28 interaction, inducing thereby T-cell hyperactivation. Bacterial superantigens thus induce the pathogenic immune storm by strongly enhancing formation of the B7-2/CD28 costimulatory axis. Insight into this mechanism led the scientists to design new peptides, snippets of the human B7-2 receptor protein that powerfully block the binding of a superantigen to its costimulatory receptor targets, and thereby protect against lethal toxic shock, as they showed in animals. Each peptide mimics a small part of the site in B7-2 where the superantigen must bind. Acting as a decoy of the intact receptor, such a peptide will bind the superantigen toxin and thereby block its access to the receptor needed for toxicity. The study was published on October 4, 2016, in the journal Proceedings of the National Academy of Science. LabMedica International June-July/2017

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PRODUCT NEWS HEMATOLOGY SYSTEM

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ANAEROBIC JAR SYSTEM

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Abbott Diagnostics

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The CELL-DYN Emerald 22 allows programming of startup and shutdown to occur automatically each workday. It delivers a full CBC and five-part optical differential in a compact design, which is ideal for smaller laboratories seeking greater productivity under tighter space limitations.

The Anoxomat III features a new jar design that is easier to use and more secure, providing flexibility for lab techs, while maximizing incubator and lab space. The system can create exact and repeatable environmental conditions with low gas consumption, offering substantial cost savings.

The DF50 is a compact 5-Part hematology analyzer that provides 27 parameters, three histograms and four scattergrams. It also features a 10.4-inch TFT touch screen display, a throughput of up to 60 tests per hour, and supports capillary blood test mode.

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Zika Virus May Damage Fertility in Men n a study on mice, researchers have now found that Zika virus infection damages the testes, lowers testosterone, and reduces fertility. Human studies will determine if men are similarly affected. Most of the research to understand the consequences of Zika virus infection has focused on how the virus affects pregnant women and causes severe birth defects in their developing fetuses. The new study in mice suggests that Zika infection may have major consequences for men by interfering with their ability to have children. The results showed that the virus targeted the male reproductive system: three weeks after male mice were infected with Zika, their testicles had shrunk, sex hormone levels had dropped, and fertility was reduced. Overall, these mice were less likely to impregnate female mice. The virus is known to persist in men’s semen for months. The US Centers for Disease Control and Prevention (CDC) recommend that men who have traveled to a Zika-endemic region use condoms for 6 months, regardless of whether they have had symptoms of Zika infection. It is not known, however, what impact this lingering virus can have on men’s reproductive systems. To find out how the Zika virus affects males, the research team, led by co-senior authors Michael Diamond, MD, PhD, and Kelle Moley, MD, both professors at Washington University School of Medicine (St. Louis, MO, USA; http://medicine. wustl.edu), injected male mice with the Zika virus. After 1 week, the virus had migrated to the testes, which bore microscopic signs of inflammation. After 2 weeks, the testicles were significantly smaller, their internal structure was collapsing, and many cells were dead or dying. After 3 weeks, the mice’s testicles had shrunk to 1/10th of normal size and the internal structure was completely destroyed. The mice were monitored until 6 weeks post-infection, and in that time their testicles did not heal – even after the mice had cleared the virus from their bloodstreams. “We don’t know for certain if the damage is irre-

versible, but I expect so, because the cells that hold the internal structure in place have been infected and destroyed,” said Prof. Diamond. The structure of the testes depends Sertoli cells, which maintain the barrier between bloodstream and testes and nourish developing sperm cells. The researchers found that Zika infects and kills Sertoli cells, and Sertoli cells do not regenerate. Furthermore, as the mice’s testes sustained increasing levels of damage, their sperm counts and testosterone levels plummeted. By 6 weeks post-infection, the number of motile sperm was down 10fold, and testosterone levels were similarly low. When healthy females were mated with infected and uninfected males, the females paired with infected males were about 4 times less likely to become pregnant as those paired with uninfected males. “This is the only virus I know of that causes such severe symptoms of infertility,” said Prof. Moley, “There are very few microbes that can cross the barrier that separates the testes from the bloodstream to infect the testes directly.” No reports have been published linking infertility in men to Zika infection, but infertility can be a difficult symptom to pick up in epidemiologic surveys. “People often don’t find out that they’re infertile until they try to have children, and that could be years or decades after infection,” said Prof. Moley, “I think it is more likely doctors will start seeing men with symptoms of low testosterone, and they will work backward to make the connection to Zika.” Low testosterone can be diagnosed with a simple blood test. “If testosterone levels drop in men like they did in the mice, I think we’ll start to see men coming forward saying, ‘I don’t feel like my-

self,’ and we’ll find out about it that way,” said Prof. Moley said, “You might also ask, ‘Wouldn’t a man notice if his testicles shrank?’ Well, probably. But we don’t really know how the severity in men might compare with the severity in mice. I assume that something is happening to the testes of men, but whether it’s as dramatic as in the mice is hard to say.” Professors Diamond and Moley said human studies in areas with high rates of Zika infection are needed to help determine the impact of the virus on human male reproductive health. “The question is, what happens in men and at what frequency?” said Prof. Diamond, “We don’t know what proportion of infected men get persistently infected, or whether shorter-term infections also can have consequences for sperm count and fertility.” The study, by Govero J et al, was published on October 31, 2016, in the journal Nature. Image: Three weeks after Zika virus infection, some male mice sperm remained infected with the virus (shown circled with red outline). By this point these mice also had shrunken testicles, low levels of sex hormones, and reduced fertility (Photo courtesy of Prabagaran Esakky and Eric Young, Washington University School of Medicine). LabMedica International June-July/2017

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Early Signs of Alzheimer’s Detected in Cerebrospinal Fluid n early immune response has been found in individuals with a genetic predisposition to Alzheimer’s and their brains showed abnormal immune reactions as early as about seven years before the expected onset of dementia. Emerging evidence supports a role for innate immunity and microglia in Alzheimer’s disease (AD) pathophysiology. However, no marker related to microglia has been included in the temporal evolution models of AD. Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) is a transmembrane protein involved in innate immunity and is selectively expressed by microglia and genetically linked to AD and other neurodegenerative disorders. Scientists at the German Center for Neurodegenerative Diseases (Munich, Germany; www. dzne.de) have measured the amount of a secreted form of TREM2 (sTREM2) in cerebrospinal fluid (CSF) as a surrogate marker for microglial activation. Participants in the study were a unique cohort of 127 subjects with autosomal dominant AD and 91 healthy siblings. They were on average 40 years old and the vast majority showed no symptoms of

dementia or had only minor cognitive impairments. The team found that CSF’sTREM2 was abnormally increased five years before the expected onset of symptoms in the AD patients. They observed that CSF sTREM2 increased in mutation carriers (MCs) compared to non-carriers five years before the expected symptom onset and this difference remained significant until five years after the expected symptom onset. Changes in CSF’sTREM2 occurred after alterations were observed in markers for brain amyloidosis and neuronal injury. Michael Ewers, Dipl. Rel. Paed., MPH, Dr. PH, a professor and a senior author of the study, said, “There are many similarities between the inherited form of Alzheimer’s disease and the so-called sporadic variant, which is far more common. TREM2 levels could therefore be a biomarker used to track immune activity while Alzheimer’s is progressing, irrespective of whether the disease is genetic or

not. TREM2 may also serve as a therapeutic marker to monitor drug response.” The study was published on December 14, 2016, in the journal Science Translational Medicine. Image: A histology of immune cells of the brain, the microglia (brown), cluster around the beta-amyloid deposits (red) in an Alzheimer’s disease model (Photo courtesy of Frank Heppner/ Charité).

Multiple Sclerosis Associated with Leaked Hemoglobin in Brain n multiple sclerosis (MS), progressive disease develops in over half of those who present with an initial relapsing phase, known as secondary progressive MS (SPMS), but can also present as primary progressive MS (PPMS). Unlike relapsing-remitting MS (RRMS), where an inflammatory response involving the adaptive immune system leads to episodic neurological deficits, in progressive MS neuroaxonal loss leads to an increasing neurological deficit and brain atrophy. When red blood cells break down they release hemoglobin into the blood stream. Normally, the protein would then be prevented from entering the brain by the semi-permeable membrane between

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the bloodstream and the brain. Scientists at the Imperial College London (UK; www.imperial.ac.uk) analyzed blood samples of 140 patients with secondary progressive MS, taken over a two-year period, and looked for any proteins raised above normal levels. The team also analyzed brain scans of the patients, as well as blood samples from 20 healthy controls, and 40 patients with other medical conditions apart from MS. The scientists used surface-enhanced laser desorption-ionization time-of-flight (SELDI-TOF) mass spectrometry to analyze serial serum samples from the population that participated in the study, to identify proteins whose abundance was associated

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with Magnetic resonance imaging (MRI)-measured brain atrophy rate. Time-of-flight spectra were generated using a PCS-4000 mass spectrometer (BioRad, Hercules, CA, USA; www.bio-rad.com). Free hemoglobin levels were assayed by enzyme-linked immunosorbent assay (ELISA) and the absorbance was measured at 450 nm on a SpectraMax microplate reader (Molecular Devices, Sunnyvale, CA, USA; www.moleculardevices.com). Serum lactate dehydrogenase (LDH) activity was assayed by the conversion of lactate to pyruvate, using the absorption of light at 340 nm by the reaction product nicotinamide adenine dinucleotide (NADH). The team found that there was a significant correlation between the rate of brain atrophy and a rise in the concentration of proteins at 15.1 kDa and 15.9 kDa in the serum. Tandem mass spectrometry identified these proteins as alpha-hemoglobin and beta-hemoglobin, respectively. The abnormal concentration of free serum hemoglobin was confirmed by ELISA. The serum lactate dehydrogenase activity was also highly significantly raised in patients with secondary progressive multiple sclerosis. They calculated that a 30% increase in free hemoglobin levels resulted in an increased rate of brain shrinkage by 0.1%. This could make a significant difference to a patient’s symptoms. Charles R. M. Bangham, MRCP, PhD, ScD, a professor and lead author of the study said, “The iron escapes from the hemoglobin, and may then result in the cell damage and brain shrinkage we see in secondary progressive MS. We were amazed by the results, and we were surprised by the size of the apparent effect of hemoglobin on brain shrinkage. Over a number of years it could significantly impact a patient’s symptoms.” The study was published on December 23, 2016, in the journal Wellcome Open Research. LabMedica International June-July/2017

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PRODUCT NEWS TRIPLEX ASSAY

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PCR CYCLER

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The STI ELITe MGB Panel can simultaneously detect and differentiate Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium. It is intended for use with the InGenius system, which performs all steps of molecular diagnostics with minimal hands-on time.

The Mastercycler X50 features heating rates of 10°C/s average, a touch screen interface, and fast connectivity to VisioNize software. The 96-well cycler is compatible with standard format consumables, and offers 2D-Gradient, which allows new expectations for yields and specificity of PCR.

The KT6610 counts and differentiates WBC by triangle laser scattering without the use of PC, and processes 60 samples per hour. It is designed to fulfill and exceed the demands of small labs, clinics, and hospitals by providing accurate results in a more economic way.

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Skin Patch with Microneedles May Provide Improved Alternative for Various Applications esearchers have developed flexible and stretchable patches with rigid stainless steel microneedles for transdermal biointerfacing. Such microneedle patches could enable more comfortable yet effective delivery of drugs, extraction of physiological signals for fitness monitoring devices, extracting body fluids for real-time monitoring of glucose, pH level and other diagnostic markers, as well as skin treatments in cosmetics and bioelectric treatments. Designers of such patches must balance the need for flexible, comfortable-to-wear material with effective microneedle penetration of the skin. A team of researchers from KTH Royal Institute of Technology (Stockholm, Sweden; www.kth.se/en) may have cracked the problem. They have now reported successful initial testing of their microneedle patch. The soft polymer-based material made it comfortable to wear, while the stiff stainless steel needles ensured reliable skin penetration. Unlike epidermal patches, microneedles penetrate the upper layer of the skin, just enough to avoid touching the nerves.

“To the best of our knowledge, flexible and stretchable patches with arrays of sharp and stiff microneedles have not been demonstrated to date,” said Frank Niklaus, professor at KTH. He added that practically all microneedle arrays being tested today are “monoliths” in that the needles and their supporting base are made of the same, often hard and stiff, material. While that allows the microneedles to penetrate the skin, they are uncomfortable to wear. On the other hand, if the whole array is made from softer materials, they may fit more comfortably, but soft needles are less reliable for penetrating the skin. A successful microneedle product could have major implications for health care. For example, “the chronically ill would not have to take daily injections,” said co-author Niclas Roxhed, a research leader at KTH. Microneedles also offer a hygiene benefit: the World Health Organization (WHO) estimates that about 1.3 million people die each year due to improper handling of needles – “Since the patch does not enter the bloodstream, there is less

risk of spreading infections,” said Dr. Roxhed. The study, by Rajabi M et al, was published December 9, 2016, in the journal PLOS One. Image: The new microneedle patch was made more flexible by developing a base of molded thiolene-epoxy-based thermoset film. This version conformed well to deformations of the skin surface and each of its 50 needles penetrated the skin during a 30-minute test. A flexible base combined with stainless steel needles could make the patch an effective alternative for various applications (Photo courtesy of KTH Royal Institute of Technology).

Real-Time PCR Of Oropharyngeal Swabs Diagnoses Pneumonia in Adults lack of sensitive tests and difficulties obtaining representative samples contribute to the challenge in identifying etiology in pneumonia. Upper respiratory tract swabs can be easily collected and analyzed with real-time polymerase chain reaction (rtPCR). The microbial etiology of pneumonia often remains undetected despite extensive diagnostic testing. Blood cultures lack sensitivity and obtaining representative lower respiratory tract samples can be challenging. An etiologic diagnosis allows targeted antimicrobial treatment, a matter of increasing importance as resistance rates increase. Medical scientists at the University of Iceland (Reykjavik, Iceland; www.hi.is) prospectively collected oropharyngeal swabs from 239 adults admitted to hospital with pneumonia. Blood cultures

were collected, incubated and cultured using standard methods. Urine antigen testing (UAT) for Streptococcus pneumoniae (SP) was performed using a commercially available kit, the BinaxNOW Streptococcus pneumoniae (Alere, Waltham, MA, USA; www.alere.com). An oropharyngeal swab sample using sterile rayon tipped swabs, (COPAN Italia, Brescia, Italy; www.copangroup.com) was collected for rtPCR. The team extracted nucleic acid from 200 L specimens and rtPCR was performed with an ABI 7900 384-well system (Applied Biosystems, Foster City, CA, USA; www.appliedbiosystems.com). The specificity of rtPCR for SP and Haemophilus influenzae (HI) was tested using reference samples containing S. mitis, S. oralis and S. sanguinis, and H. haemolyticus and H. parainfluenzae respective-

ly. No cross-reaction was noted with either comparison. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of rtPCR for SP and HI were calculated using combined and separate results from sputum (SP and HI) and blood cultures (SP only), and urine antigen analysis (SP only) as a reference “gold standard.” The authors concluded that analysis of oropharyngeal swabs using rtPCR proved both reasonably sensitive and specific for diagnosing pneumonia caused by S. pneumoniae and H. influenzae. This method may be a useful diagnostic adjunct to other methods and of special value in patients unable to provide representative lower airway samples. The study was published online on November 7, 2016, in the European Journal of Clinical Microbiology & Infectious Diseases. LabMedica International June-July/2017

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Specific Gene Expression Differentiates Moles from Melanoma ost melanomas are driven by mutations that spur out-of-control cell replication, while nevi which are moles composed of non-cancerous cells at the skin surface, that harbor the same mutations do not grow wildly. Dermatologists surmise that 30% to 40% of melanomas, approximately 30,000 cases per year, may arise in association with a nevus. However, clinicians would like to be able to better distinguish between the two, especially in borderline cases when they examine skin tissue after a patient biopsy. Scientists at the University of Pennsylvania (Philadelphia, PN, USA; www.uphs.upenn.edu) stained human nevus and melanoma tissue samples with p15 and p16 antibodies. Staining was evaluated and graded for percentage and intensity to determine an “H score,” which correlates with the level of protein in the cells. This approach could also form the basis of a clinical determination, taking the form of an antibody test for p15 from a patient’s biopsy specimen. Ribonucleic acid (RNA) was also extracted from 14 nevus and melanoma tissue samples to determine levels of p15 messenger RNA (mRNA). The expression of p15 mRNA was significantly increased in melanocytic nevi compared with melanomas as determined by real-time quantitative real-time quantitative polymerase chain reaction (RT-PCR) analysis. John T. Seykora, MD, PhD, a professor of Dermatology and senior author of the study, said, “We showed that p15 expression is a robust biomarker for distinguishing nevus from melanoma. Making this distinction has been a longstanding issue for dermatologists. We hope that this new finding will help doctors determine if a nevus has transformed to melanoma. This could help doctors and patients in difficult cases. If the staining level is high then that would be most consistent with a benign nevus. If the staining level is low then that would be consistent with a melanoma.” The study was published in the December 2016 issue of the American Journal of Pathology.

Image: p15 expressed in nevi is a key factor mediating BRAF-induced growth arrest. A, p15 expression in a benign intradermal nevus and B, antibody control C, co-immunofluorescence of p15 and Melan-A in a representative intradermal benign nevus. D, nevus melanocytes express p15, whereas non- nevus melanocytes (white arrows) are p15-negative (Photo courtesy of University of Pennsylvania).

Change in Serum Bilirubin Level Predicts Incident Metabolic Syndrome etabolic syndrome (MetS) is a constellation of interlinked metabolic conditions that seem to accelerate the development of cardiovascular disease. Chronic inflammation, oxidative stress, and insulin resistance all play important roles in the initiation and advancement of MetS. Serum bilirubin level was negatively associated with the prevalence of MetS in previous cross-sectional studies; however, bilirubin variance preceding the development of MetS has yet to be investigated. An inverse association between mean bilirubin concentrations and the number of metabolic syndrome components in a population with athero-

genic dyslipidemia has been reported. Scientists at the Sungkyunkwan University School of Medicine (Seoul, Republic of Korea; www.skku. edu) conducted a retrospective longitudinal study of subjects who had undergone at least four yearly health check-ups between 2006 and 2012. Of 24,185 total individuals who received annual checkups, 11,613 non-MetS participants with a baseline bilirubin level not exceeding 34.2 mol/L were enrolled. Venous blood samples were obtained after an overnight fast and measurements included serum bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), fasting plasma glucose, plasma See us at Clinical Lab Expo, Booth #2345

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insulin, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), serum uric acid, and creatinine. Serum bilirubin concentrations were measured using the diazonium salt/diazonium ion with blank method on a Hitachi-7600, Modular DP-110 autoanalyzer (Hitachi, Tokyo, Japan; www.hitachi. com). Plasma glucose levels were determined using the hexokinase method on an Advia 1650 automated chemistry analyzer (Bayer Diagnostics, Leverkusen, Germany; www.bayer.com), and plasma insulin values were derived using an immunoradiometric assay (DIAsource Co., Louvain-la-Neuve, Belgium; www.diasource-diagnostics.com). Fasting HDL-C, LDL-C, and TG were measured using the enzymatic colorimetric method with a Modular D2400 (Roche Diagnostics, Basel, Switzerland; www.roche.com). The scientists found that during 55,407 personyears of follow-up, 2,439 cases of incident MetS developed (21.0%). There was an increased risk for incident MetS that was observed in higher percent change in bilirubin quartiles, with hazard ratios of 2.415 in men and 2.156 in women in the fourth quartile, compared to the lowest quartile, after adjusting for various variables. The hazard ratios per one standard deviation increase in percent change in bilirubin as a continuous variable were 1.277 in men and 1.366 in women. The authors concluded that an increase in bilirubin concentration, defined as PCB, was positively associated with incident MetS in a healthy Korean population, indicating that bilirubin increase might precede the development of MetS. Positive levels of PCB may reflect an increase in oxidative stress preceding new-onset MetS. The study was published on December 9, 2016, in the journal Public Library of Science ONE. LabMedica International June-July/2017

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LabMedica International

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DNA Levels in Blood Correlated With Ovarian Cancer Outcomes he development of blood biomarkers that can be used for early detection of cancer or to measure tumor burden and response to treatment is a major goal of translational cancer studies across all cancer types. Both tumor-derived proteins and DNA can be detected in circulating plasma and serum from cancer patients. Levels of circulating tumor DNA (ctDNA) detected in a blood test can be correlated with the size of ovarian cancers and can predict a patient’s response to treatment or time to disease progression. Scientists at the Cancer Research UK Cambridge Institute (Cambridge, UK; www.cambridgecancer.org.uk) measured levels of ctDNA carrying mutations in the tumor protein 53 gene (TP53), which are detected in 99% of patients with high-grade

serous ovarian cancer (HGSOC). They analyzed 318 blood samples from 40 HGSOC patients, taken before, during, and after standard-ofcare treatment were analyzed. Computerized tomography (CT) images of the patients’ tumors were collected, as well as data on the progression of their cancers. In order to quantify ctDNA levels, patient-specific TP53 TaqMan assays were designed to target mutations identified in formalin-fixed paraffinembedded (FFPE) tissue. Digital PCR using the Biomark microfluidic system (Fluidigm, South San Francisco, CA, USA; www.fluidigm.com) was used to measure ctDNA levels in cellfree DNA from plasma samples collected during courses of chemotherapy. Serum CA-125 level was routinely monitored using a two-site sandwich immunoassay on a Siemens Centaur

XP auto-analyzer (Malvern, PA, USA; Malvern, PA Malvern, PA (www. healthcare.siemens.com). The team found the fraction of mutated TP53 in ctDNA (TP53MAF) was correlated with volume of disease as measured by CT scan and unlike CA-125 pre-treatment TP53MAF levels were also correlated with each patient’s time to progression. While CA125 took 84 days to reflect the full extent of changes after chemotherapy, changes were reflected in TP53MAF in a median of just 37 days. In patients being treated for a relapse, a decrease in TP53MAF of more than 60% was associated with a longer time to progression, while a decrease of 60% or less was associated with poor response to chemotherapy and a time to progression of less than six months. The authors concluded that their findings have strong potential for clinical utility owing to the ease of assaying DNA in plasma and the low cost and speed of ctDNA testing. Having very

early information on response would empower patients and physicians to test alternative treatment options and have high utility in trials that link biomarkers to targeted therapy. The study was published on December 20, 2016, in the journal Public Library of Science Medicine. Image: The Biomark microfluidic system for polymerase chain reactions (Photo courtesy of Fluidigm).

Genetic Screening May Predict Risk of CMV Infection esearchers have found that the protein nucleotide-binding oligomerization domain 1 (NOD1) is involved in regulating cytomegalovirus (CMV) infection and that loss-offunction NOD1 variants may result in higher susceptibility to CMV infection, which can lead to devastating developmental defects in fetuses and severe disease in people with weakened immune systems. The new study, led by researchers Johns Hopkins University School of Medicine (Baltimore, MD, USA; www.hopkinsmedicine.org/som), provides what appears to be the first reported evidence that NOD1, a protein with a well-known role in inducing the innate immune response, has an integral

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role in control of CMV and that certain NOD1 variants may increase risk of susceptibility. CMV is transmitted from person to person through body fluids. Most people show no signs or symptoms of infection, while others develop symptoms such as a fever, sore throat, and fatigue. In addition, CMV causes colitis in individuals with Crohn’s disease and patients with suppressed immune systems, making it a significant risk to transplant recipients. Furthermore, CMV has not drawn the same attention in the medical and scientific community as the much less common Zika virus, despite causing similar neurological complications, said Prof. Boger. According to the US Centers for Disease Control

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and Prevention (CDC), 1 in 150 babies in the US is born with a congenital CMV infection, and of those, 1 in 5 suffers from complications, which can include hearing loss, vision loss, cerebral palsy, cognitive impairments, and microcephaly. “Our results suggest that this protein explains why not every person is at the same risk for CMV, and that we might someday be able to develop tests to identify and manage those who are at an increased risk for CMV-related disease,” said Ravit Boger, MD, associate professor at Johns Hopkins medical school. Using human fibroblasts that make up connective tissue, the team tested whether NOD1 activity could affect CMV replication in the cultured cells. They upregulated NOD1 by treating the cells with a bacterial fragment. They also tested genetically engineered cells that contain nonfunctional NOD1. The results showed that cells in which NOD1 was activated had decreased levels of CMV replication compared to controls. In mouse experiments, the researchers treated the animals with two doses of iE-DAP, another bacterial NOD1 activator, and subsequently infected them with mouse CMV. Two weeks later, organs and intracardiac blood were collected from the mice and cells were cultured. How mutations in NOD1 protein determine its function against CMV remains to be determined. Prof. Boger cautions that NOD1 is not the only factor in determining risk of CMV infection, rather it is one piece of a larger puzzle in determining risk. The team will now investigate the cell signaling pathways involving the NOD proteins to help pin down how NOD1 and NOD2 interact with CMV. The study, by Fan YH et al, was published November 14, 2016, in the journal Proceedings of the National Academy of Science (PNAS). LabMedica International June-July/2017

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New Monitoring System Evaluated for Antiphospholipid Syndrome Patients ntiphospholipid syndrome or antiphospholipid antibody syndrome (APS or APLS), or often also Hughes syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia. Patients on anticoagulant therapy with vitamin K antagonists (VKA) need frequent International Normalized Ratio (INR) monitoring. The reliability of point-of-care (POC) devices for measuring INR needs rigorous evaluation, particularly in patients with APS. Scientists at the University of Milan (Italy; www.unimi.it) compared a POC-INR device versus the laboratory INR measurement for blood samples from 29 APS-positive and 31 APS-negative patients consecutively enrolled. Chromogenic factor X assay was used

to evaluate anticoagulation. Bland–Altman difference plot for paired INR (POC versus laboratory) was used to evaluate agreement between the device and the laboratory method. The device INR relationship with factor X chromogenic assay was evaluated by orthogonal regression analysis. The team evaluated the accuracy of the ProTime InRhythm System (International Technidyne Corporation, Piscataway, NJ, USA; www.itcmed.com), which consists of an instrument and disposable cuvettes. Each cuvette consists of two PT microchannels containing human recombinant thromboplastin to analyze a patient’s sample in duplicate to ensure accurate results, and a third internal control channel that is activated each time a test is performed to verify the integrity of the reagents and proper test procedure. The scientists found that overall, 97% of the POC device INR measurements were similar to laboratory INR

values with an absolute difference less than 0.4 units. Correlation coefficient for the device INR versus factor X was −0.69, (CI 95% −0.80 to −0.52). The authors concluded that The ProTime InRhythm System is an accurate point-of-care device for measuring INR also in patients with

and without APS. The study was published in the October 2016 issue of the International Journal of Laboratory Hematology. Image: The Protime InRhythm microcoagulation system kit (Photo courtesy of International Technidyne Corporation).

Inflammation Test Developed Predicts Cardiovascular Disease hronic inflammation, a decline in immune responsiveness, and reduced cardiovascular function are all associated with aging, but the relationships among these phenomena remain unclear. An assessment blending several measures of immune-cell responsiveness predicted cardiovascular problems in individuals who likely would have slipped under the radar. A blood test produces a single number that strongly predicts the development of the world’s most prevalent medical disorder: cardiovascular disease. An international team of scientists led by those at Stanford University School of Medicine (Stanford, CA, USA; http://med.stanford.edu) longitudi-

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nally profiled a total of 84 signaling conditions in 91 young and older adults and observed an age-related reduction in cytokine responsiveness within four immune cell lineages, most prominently T cells. Testing for levels of C-reactive protein (CRP), a circulating protein linked to inflammation, has been shown to further enhance the prediction of cardiovascular risk, even among patients with normal cholesterol levels. A CRP reading is relatively simple to get, requiring only a blood draw and relatively straightforward laboratory tests. The new test developed is more complicated but appears to have superior diagnostic value to either the cholesterol or CRP test. Rather than testing circulating inflammatory proteins, it tests for the re-

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sponse of immune cells themselves to inflammation, a signal that appears to be more stable and hence a more robust diagnostic. In the study, it was able to detect early cardiovascular irregularities in otherwise asymptomatic individuals. The phenotype can be partially explained by elevated baseline levels of phosphorylated STAT (pSTAT) proteins and a different response capacity of naive versus memory T cell subsets to interleukin 6 (IL-6), interferon α (IFN-α), and, to a lesser extent, IL-21 and IFN-γ. When immune cells from young people were stimulated with certain cytokines, the activation levels of STAT proteins skyrocketed. When the same thing was done to immune cells from old people, STAT-protein activity increased a lot less. The investigators blended 15 separate cytokine-responsiveness measurements to generate a single number called a cytokine response score (CRS). This measure, which varied considerably among different older adults, was quite stable from year to year for any given individual. A higher CRS is better, as it indicates a more-responsive immune system and lower background inflammation. The team found that cytokine response scores were inversely correlated with clinical signs of atherosclerosis and with two measures associated with the heart’s ability to relax between beats. Importantly, the borderline subjects also had low cytokine response scores. Mark M Davis, PhD, professor of microbiology and immunology and the senior author of the study, said, “For too many men experiencing a heart attack or stroke, the first observed hint of cardiovascular risk is their death. The CRS may be a useful proxy for healthy aging and its predictive accuracy in cardiovascular disease further substantiates the inflammatory underpinnings of that prevalent, agerelated condition.” The study was published on October 13, 2016, in the Cell Systems. LabMedica International June-July/2017

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PRODUCT NEWS THERMOSTATIC WATER BATH

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SPECIMEN PROCESSING SYSTEM

HPLC SYSTEM

Hecht-Assistent

Hitachi

Lifotronic

The digital thermostatic water bath includes stainless steel bare metal parts capable of full immersion. Other features include fully electronic wearfree temperature control with digital display, and plexiglass tank. A cooling coil and connection for external use are also available as spare parts.

The LabFLEX2600 pre-analytical specimen-processing / aliquoting system is a space-saving, allin-one system. It handles pre-analytical specimen processing – from specimen arrival checks, decapping, aliquoting and labeling of the daughter specimen containers, to external transport.

The H8 features high operating pressure to realize a test in less than two minutes. It gives an alarm if any variant hemoglobin appears, so that the interference can be easily eliminated. The slim H8 fits into small lab spaces and offers a fully automated routine interface to avoid hands-on operation.

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Optical Sensor to Detect Vitamin B12 Deficiency esearchers have developed the first optical sensor that can detect vitamin B12 in diluted human blood – and a first step towards a low-cost, portable, broadscale B12 deficiency test that would overcome limitations of current methods for monitoring levels in high-risk individuals and populations. The device, developed by scientists at the University of Adelaide (Adelaide, Australia; www. adelaide.edu.au), was presented October 17, 2016, at the inaugural “SPIE BioPhotonics Australasia” international conference in Adelaide. “Vitamin B12 deficiency has been shown to be a potential modifiable risk factor for dementia and Alzheimer’s disease and is associated with cognitive decline,” said Dr. Georgios Tsiminis, research fellow at the University of Adelaide, “Older adults are particularly at risk of B12 deficiency due to age-related reduction in absorbing vitamin B12 received through their diet.

Currently at proof-of-concept stage, the sensor demonstrates feasibility of testing for vitamin B12 in human blood serum without the need for a full laboratory test. It could provide pointof-care B12 tracking in, for example, healthy ageing adults, enabling early treatment intervention as soon as deficiency is detected. “This is the first time a rapid technique based on optical spectroscopy has been shown to be able to detect vitamin B12 in human blood serum. We believe this is a very promising first step towards achieving this goal,” said Dr. Tsiminis. Currently, routine B12 testing is not being carried out due to time and cost limitations. “Our method provides a realistic basis for a system that is portable, cost-effective, and affords rapid results, along the lines of the pin-prick test for diabetes,”

said Dr. Tsiminis. The device uses Raman spectroscopy to produce the vitamin B12 optical fingerprint, takes under 1 minute to measure B12 in human blood, and requires minimal preparation. Image: Dr. Georgios Tsiminis in his photonics laboratory (Photo courtesy of the University of Adelaide).

Field Test Allows Rapid Diagnosis of Chikungunya Virus Infection hikungunya virus (CHIKV) infection causes symptoms that are similar to Dengue and Zika as well as other viral diseases, including influenza and accurate diagnosis of CHIKV is important for effective outbreak responses, including patient management and mosquito control. A reverse transcriptase (RT) recombinase polymerase amplification (RPA) assay has been developed for rapid detection of CHIKV in clinical samples. RPA-based detection of small amounts of DNA is an alternative to polymerase chain reaction (PCR) and based on reactions that can run at constant temperatures. An international team of scientists led by those at the Robert-Koch-Institute (Berlin, Germany; www.rki.de) included in their study 78 patients with a history of sudden onset of fever, headache, fatigue, nausea, vomiting, rash, myalgia and severe and very painful polyarthralgia suggestive of CHIK

infection. Fifty-eight plasma samples were provided by a group in Thailand and 20 CHIKV positive sera samples collected from patients suspected to be infected by CHIKV during routine medical examination, were provided by French scientists. The team designed a set of CHIKV-specific reagents and showed that the assay was able to detect very small amounts of CHIKV ribonucleic acid (RNA). The RT-RPA assay was slightly less sensitive than RTPCR, but both assays yielded identical results on clinical samples of 20 patients with known CHIKV infection and 58 samples from suspected cases. Testing the RT-RPA assay on different CHIKV strains and a panel of related alpha- and arboviruses, the scientists found, that the assay reliably detected all 18 different CHIKV strains tested. In addition, there was no cross-reactivity of the assay with any of the other tested viruses except for the very closely related O’nyong’nyong virus (ONNV).

Using a modified set of assay reagents, the scientists were able to eliminate the problem of false-positive results caused by ONNV. The diagnostic sensitivity and specificity of the CHIKV RT-RPA assay were determined at 100%. The investigators highlighted that RPA reagents are stable at ambient temperature (25-38 °C), meaning they do not need to be refrigerated. The authors concluded that the CHIKV RPA assay is a promising tool for CHIKV diagnostics at the point of need. Integration into a multimer or multiplex assay for simultaneous and detection of CHIKV, Dengue virus and Zika virus as well as an internal control would improve outbreak investigations, since the three viruses induce same clinical picture upon infection and increasingly co-circulate in many parts of world. The study was published on September 29, 2016, in the journal Public Library of Science Neglected Tropical Diseases. LabMedica International June-July/2017

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PRODUCT NEWS HEMATOLOGY ANALYZER

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RT-PCR KIT

CLIA ANALYZER

Maccura

Mediven

Mindray

The F 580 offers enhanced sensitivity to identify immature cells, and provides early detection of many blood diseases such as leukemia. The automatic system measures 28 parameters, requires only 20 Îźl of blood for each test, and features 34 diagnostic alarms.

The GenoAmp RT-PCR Flu-MERS kit is a realtime molecular diagnostic test for screening seasonal human influenza A, subtypes H1N1, H3N2, influenza B and Middle East respiratory syndrome coronavirus. Each kit contains 100 tests, and each test takes only 2.5 hours from sample to result.

The newly launched CL-1200i is the fastest benchtop CLIA analyzer with the largest onboard capacity. Key features of the system include 25 reagents and a maximum throughput of up to 180 tests per hour, making the CL-1200i ideal for the needs of medium-sized laboratories.

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Extended Multilocus Sequence Typing Developed for Leptospirosis eptospirosis is a zoonotic disease caused by pathogenic species of Leptospira that can be carried naturally by most mammalian species and transmission to humans most commonly occurs via direct animal contact or via water contaminated with animal urine. The gold standards for laboratory diagnosis of leptospirosis are culture or a four-fold rise in antibody titer between admission and convalescent samples by the microscopic agglutination test (MAT). Culture of Leptospira spp. is time consuming and diagnosis by MAT is retrospective by nature, hence both methods have disadvantages as diagnostic tools. A team of scientists led by those at

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Public Health England (London, UK; www.phe.gov.uk) modified an existing polymerase chain reaction (PCR) based on multilocus sequence typing (MLST) scheme by designing nested primers including anchors for facilitated subsequent sequencing. The assay was applied to various specimen types from patients diagnosed with leptospirosis between 2014 and 2015 in the United Kingdom (UK) and the Lao Peoples Democratic Republic (Lao PDR). Of 44 clinical samples (23 serum, six whole blood, three buffy coat, 12 urine) PCR positive for pathogenic Leptospira spp. at least one allele was amplified in 22 samples (50%) and used for phylogenetic inference.

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DNA from bacterial isolates and Lao PDR samples was extracted using the QIAmp DNA Mini Kit (Qiagen, Hilden, Germany; www.qiagen.com). DNA from UK samples was extracted on the MagNA Pure Compact (Roche Diagnostics, Mannheim, Germany, www.roche.com) using the DNA Bacteria Protocol. The PCR products were purified on a Biomek NXP automated liquid handling robot (Beckman Coulter Life Sciences, Indianapolis, IN, USA; www.beckman.com) using Beckman Coulter Ampure XP paramagnetic beads. Sanger sequencing was carried out on the 3730XL Genetic Analyzer (Applied Biosystems, Foster City, CA, USA; www.applied biosystems.com). The team obtained full allelic profiles from ten specimens, representing all sample types (23%). No nonspecific amplicons were observed in any of the samples. Of twelve PCR positive urine specimens three gave full allelic profiles (25%) and two a partial profile. Phylogenetic analysis allowed for species assignment. The

predominant species detected was L. interrogans (10/14 and 7/8 from UK and Lao PDR, respectively). All other species were detected in samples from only one country (Lao PDR: L. borgpetersenii [1/8]; UK: L. kirschneri [1/14], L. santarosai [1/14], L. weilii [2/14]). The authors concluded that typing information of pathogenic Leptospira spp. was obtained directly from a variety of clinical samples using a modified MLST assay. This assay negates the need for time-consuming culture of Leptospira prior to typing and will be of use both in surveillance, as single alleles enable species determination, and outbreaks for the rapid identification of clusters. The study was published on September 21, 2016, in the journal Public Library of Science Neglected Tropical Diseases. Image: A photomicrograph of Leptospirosis bacteria magnified 200x in a dark field optical microscope (Photo courtesy Dr. Steve H. Fisyh). LabMedica International June-July/2017

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Rapid Influenza Detection Tests Evaluated for Viral Antigens everse transcriptase polymerase chain reaction (RT-PCR) has a high sensitivity and a high specificity for the rapid diagnosis of influenza infection; however, the high cost and necessity of specialized equipment have limited the use of RT-PCR in the clinical setting. Immunochromatography-based rapid influenza virus antigen tests, in which the result appears within 15 minutes, have been used for the early diagnosis of influenza in the clinical setting in Japan. Rapid influenza detection tests (RIDTs) equipped with an instrument-based fluorescence reader system has recently been developed, and their performances have been validated. Scientists at the Tokyo Medical University (Japan; www.tokyo-med.ac.jp) enrolled a total of 123 participants consisting of 53 men (43.1%) and 70 women (56.9%). The mean age of the patients was 35.1 years (range 20–74 years). The median time to visiting the hospital after illness onset was 26.2 hours (ranging from a few hours to five days). The study was performed from December 2013 to March 2014. Nasopharyngeal swab specimens were collected by performing original swab samplings, which were composed of three swabs. After collecting the specimens from the participants, the swabs were separated for the tests. One swab was transferred in viral transport medium for virus isolation; the other two swabs were used for the rapid influenza virus antigen detection tests. In this study, the new RIDT GOLD SIGN FLU (Morinaga Milk Industry Co., Ltd, Tokyo, Japan; www.morinagamilk.co.jp) and the existing immunochromatographybased RIDT Quick Navi-Flu (Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan; www. otsuka.com) were evaluated as compared to viral isolation as the gold standard method. Among the 123 patients from whom nasopharyngeal swab specimens were collected, 59 tested positive by viral isolation as the gold standard method, 38 with influenza A; 21 with influenza B. For GOLD SIGN FLU, the sensitivities were 73.7% and 81.0%, and the specificities were VISIT US AT: 97.6% and 98.0% for influenza A and B, respectively. For Quick Navi-Flu, the sensitiv2017 ities were 86.8% and 85.7%, and the speciANNUAL ficities were 98.8% and 100% for influenza MEETING A and B, respectively. The time to the apBooth: 4951 pearance of the line on the test strip was less than three minutes for influenza A and less than two minutes for influenza B with both RIDTs in more than 90% of cases. The authors concluded that GOLD SIGN FLU was useful for diagnosing influenza A, and the result was readily available for influenza B particularly among adult patients. Quick Navi-Flu showed better sensitivities and specificities than GOLD SIGN FLU. The study was published in the November 2016 issue of the International Journal of Infectious Diseases.

Image: The rapid influenza detection test Quick Navi-Flu (Photo courtesy of Otsuka Pharmaceutical).

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PRODUCT NEWS RAPID TEST

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CHEMISTRY ANALYZER

LC-MS/MS ANALYZER

Operon

Pointe Scientific

Thermo Fisher Scientific

The improved S. PneumoStrip kit allows the easy and quick identification of 76 different serotypes of S. pneumoniae in DNA samples, with a 93.3% detection rate. The ready-to-use test can be performed manually or automatically, and includes all necessary reagents and internal controls.

The Pointe c2000 features minimal daily startup procedures; dual power switches; probe management system with liquid-level sensing and collision protection, and a reagent management system. The system is for small/medium-volume labs, and can be ordered with or without the ISE module.

The Cascadion SM brings together the ease of use of clinical analyzers with the selectivity and sensitivity of liquid chromatography-tandem mass spectrometry. The analyzer is designed for use in a variety of settings, including hospital labs and to provide results for a range of clinical tests.

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Genetic Cause Deciphered for Inherited Nerve Damage Afflicting Older Adults n international team of researchers has identified a gene, MME, with a causative link to late-onset autosomal dominant axonal polyneuropathies. Patients initially develop loss of sensation and pain, then the illness can advance rapidly and lead to paralysis, inability to walk, and wheelchair dependency. Rare loss-of-function mutations in the MME gene, encoding the metalloprotease neprilysin, underlying the disease were discovered by an international team under the guidance of researchers at Medical University Vienna (MedUni Vienna; Vienna, Austria; www.meduniwien.ac.at/web) and University of Munich (Munich, Germany; www.en. uni-muenchen.de/index.html). “The gene mutation leads to an enzyme deficiency which probably triggers nerve damage. In future, the balance of the reduced enzyme activity could represent a novel therapy approach,” said lead author and study manager Michaela Auer-

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Grumbach, MedUni Vienna. Polyneuropathy occurs in 2-3% of the population and in 7% of those over age 65. The cause is still unclear in up to 50% of affected people and a causal therapy is not yet available for this group of patients. The origin of this discovery was 3 unrelated Austrian families where several members between ages 55-80 initially noticed a loss of sensation and discomfort in the toes, which spread to the knees within just a few months. This was often accompanied by pain as well as a relatively quickly advancing muscle weakness when lifting toes and feet. “After a few years, walking freely was often no longer possible,” said M. Auer-Grumbach. Despite extensive research, initially the cause could not be clarified. “Due to the rapid deterioration of the symptoms, some patients were initially treated with unsuitable medication, which showed no improvement, but often caused considerable side-effects. Based on the poor response

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to anti-inflammatory medication, but also due to the familial accumulation of polyneuropathy, we ultimately assumed a genetic cause, even though the late start of the disease seemed rather atypical for inherited polyneuropathy,” explained M. Auer-Grumbach. “An analysis of the entire exome of the patients [i.e. the protein-encoding genes] resulted in a serious genetic deviation in the MME gene, which is responsible for the formation of the neprilysin enzyme,” she added. Together with Jan Senderek, University Munich, who was aware of similar patients in Germany, the MME gene was examined in other patients, and following additional collaborations with European and American work groups mutations could be identified in 28 patients from 19 families. Further confirmation was then provided by results of measurements of neprilysin in the blood and fatty tissue, which was significantly lower than in control persons. A study from Japan, that also describes severe polyneuropathy at a complete lack of neprilysin, confirmed the Vienna and Munich study results. “Discovery of the cause of this disease allows the specific genetic diagnostic and consultancy of afflicted patients and their families and shall avoid ineffective therapies, which are stressful due to undesirable side-effects”, said M. Auer-Grumbach, “If further studies confirm that the deficiency of neprilysin leads to the formation of polyneuropathy, there is justified hope that an effective therapy can be developed in the near future, either by enzyme replacement or with active ingredients, which are already known for raising the neprilysin level.” The researchers are planning further epidemiological examinations of patients with unclear polyneuropathy to discover whether mutations in MME are also of significance in the sporadic (not family-cumulative) appearance of polyneuropathy. The study, by Auer-Grumbach M et al, was published September 1, 2016, in the American Journal of Human Genetics. LabMedica International June-July/2017

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LabMedica International

Diagnostic Tool Designed for Familial Mediterranean Fever tool has been developed to diagnose Familial Mediterranean Fever (FMF) which is particularly common among populations originating from around Mediterranean Sea and this genetic disease is characterized by inflammation, fever and severe pain. FMF is usually diagnosed during childhood, after which a daily, lifelong treatment is necessary. However, accurate diagnosis is complicated by a number of factors: other auto-inflammatory diseases show similar symptoms, the clinical picture is often incomplete in young children, atypical signs may occur, and a suggestive family history is sometimes lacking. Wrong or late diagnosis often even leads to unnecessary surgery and, ultimately, kidney failure. A large group of scientists led by those at the Inflammation Research Center, VIB, Zwijnaarde, Belgium; www.vib.be) developed an alternative for today’s inadequate diagnosis, efficiently segregating FMF patients from people suffering from other auto-inflammatory diseases and healthy individuals. The tool detects changes in the body’s immune reaction to pyrin, a protein that is usually mutated in FMF. Following successful tests on mice, the tool has been validated in 13 patients in collaboration with physicians from Belgium and Italy. The team used many different techniques during the study that included identification of FMF disease gene variants using genomic DNA, Transfection, Immunoprecipitation, the eluted samples were analyzed by SDS/PAGE, Western Blotting, Cytokine Analysis, Microarray Data Analysis, and Confocal Microscopy that was performed on a Zeiss LSM 780 confocal microscope (Zeiss, Jena, Germany; www. zeiss.com) equipped with a Ti:Sa laser (Mai Tai DeepSee multiphoton laser; SpectraPhysics, Santa Clara, CA, USA; www. spectra-physics.com), an Ar laser, and two diode lasers (561 nm and 633 nm). The scientists established Clostridium difficile and its enterotoxin A (TcdA) as Pyrin-activating agents and show that wildtype and FMF Pyrin are differentially controlled by microtubules. Diverse microtubule assembly inhibitors prevented Pyrin-mediated caspase-1 activation and secretion of IL-1 and IL-18 from mouse macrophages and human peripheral blood mononuclear cells (PBMCs). Remarkably, Pyrin inflammasome activation persisted upon microtubule disassembly in PBMCs of FMF patients but not in cells of patients afflicted with other auto-inflammatory diseases. The team further demonstrated that microtubules control Pyrin activation downstream of Pyrin dephosphorylation and those FMF mutations enable microtubule-independent assembly of apoptosisassociated speck-like protein containing a caspase recruitment domain (ASC) mi-

LabMedica International June-July/2017

crometer-sized perinuclear structures. Mohamed Lamkanfi, PhD, a professor and a senior author of the study said, “As next steps, we are setting up clinical trials in Belgium for which we are actively seeking volunteers; both FMF patients and people suffering from related inflammatory disorders. We are also exploring possible collaborations with industrial partners in order to make our method available as a diagnostic kit.” The study was published on November 22, 2016, in the journal Proceedings of the National Academy of Sciences of the United States of America.

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Image: The LSM 780 laser scanning confocal microscope (Photo courtesy of Zeiss).

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DNA Signature Linked to Prostate Cancer Severity rom extensive genomic analyses of localized, non-indolent prostate cancer (PrCa), researchers have succeeded to identify differences in mutational profiles between localized intermediate risk and metastatic, castrate-resistant PrCa. The study, by a team from the Canadian Prostate Cancer Genome Network (CPC-GENE; Toronto, Ontario, Canada; www.prostatecancer.ca), uncovered a comprehensive set of mutations that can occur in PrCa. By cataloging these mutations, they were able to create a new signature that predicts at an early stage whether a prostate cancer tumor will become aggressive or not, allowing for more precise personalized treatment. The analyses included 200 whole-genome and 477 whole-exome sequences of localized PrCa tumors, and analyses of copy-number alterations, genomic rearrangements, and methylation. “We hope that this research mode of testing will now go into the clinical mode in the next two to five years, and really NE DES W change clinical practice for men with IGN prostate cancer in Canada and worldwide,” said study co-leader Dr. Robert Bristow, Princess Margaret Cancer Centre. Study co-leader Dr. Paul Boutros, Ontario Institute for Cancer Research, said, “This MARKETPLACE work really gives us a map to what is going on inside a prostate cancer cell, and will become the scaffold on which precision therapy will be built.” “Collaborations like this are key to drivSIGN UP ing scientific discoveries and ultimately deFOR FREE! livering better care for prostate cancer patients,” said Reza Moridi, Ontario Minister of Research, Innovation and Science. Through funding of approximately CAD 20 million (~ USD 15.3 million), research of this magnitude has been made possible through a partnership between the Movember Foundation, Prostate Cancer Canada, and the Ontario Institute for Cancer Research, who released a joint statement that included: “From the tireless work of researchers to the selfless giving of donors, we applaud the efforts of everyone who has played a role in helping make CPC-GENE possible. Since its beginnings as an ambitious undertaking that was massive in scope, the goal of this project has been to greatly improve personalized care for men with prostate cancer. The findings […] represent a monumental stride towards that goal.” The study, by Michael Fraser M et al, was published online January 9, 2017, in the journal Nature.

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Study Finds Myocarditis Caused by Infection Rising Globally new assessment of the global state of myocarditis examines diagnostics, treatments, and causes, the most common cause being viral infections. Myocarditis, an assortment of heart disorders often caused by infection and inflammation, is difficult to diagnose and treat. Dilated cardiomyopathy and cardiac sarcoidosis can result from myocarditis. Among the young, myocarditis accounts for about 5% of sudden cardiovascular infant deaths and up to 20% of sudden cardiovascular death in adolescents. It is responsible for up to 45% of heart transplants in the US. The new global assessment was conducted by a team led by Leslie Cooper Jr, MD, cardiologist, at the Mayo Clinic (Jacksonville, FL, USA; www.mayoclinic. org). Along with Dr. Cooper, researchers from the Netherlands, Switzerland, and Finland contributed to the study. Dr. Cooper and colleagues recently reported that cases of myocarditis have increased from about 1.5 million annually to 2.2 million cases from 2013 to 2015. The new study found that the rate of myocarditis and associated death is much higher in men than in women, likely due to testosterone-driven inflammation. The most common cause of myocarditis is infection – usually viral – that can damage heart muscle chronically or acutely in otherwise healthy people, said Dr. Cooper. Infections that affect the heart differ around the globe. In the US, a dozen common pathogens can be responsible. An example is coxsackie virus, which up to 70% of US residents have been exposed to age 30. “But only 1-2% of people with acute coxsackie virus infection develop cardiac symptoms,” said Dr. Cooper. Myocarditis can also have other causes, including autoimmune diseases, environmental toxins, and adverse reactions to medications. Early diagnosis is key to preventing long-term heart damage from myocarditis. If chronic disease results, scarring in the heart can promote heart failure. Although standard therapies are used to control symptoms of heart failure, new investigational therapies based on mechanistic advances may soon enter clinical trials, and new management of the disorder is being discussed. “We are on a quest for advances in treating this disorder,” said Dr. Cooper. To prevent the disorder from worsening in children, Dr. Cooper suggests that aerobic exercise be limited for several weeks after a suspected coxsackie virus infection, and “if a child or adolescent develops breathing difficulties or chest pain with evidence of myocarditis, my recommendation is to avoid competitive sports for at least 3 months,” said Dr. Cooper. Revised management recommendations regarding athletic participation after acute myocarditis have further height-

LabMedica International June-July/2017

ened the importance of early diagnosis. A cardiac MRI within 2 weeks of symptom onset is 80% effective in diagnosing cardiomyopathy, but diagnosis is difficult at more chronic stages. The sensitivity of endomyocardial biopsy may be increased, especially in suspected sarcoidosis, by the use of electrogram guidance to target regions of abnormal signal. The study, by Heymans S et al, was published November 29, 2016, in the Journal of the American College of Cardiology. Image: A new study assessing the global state of myocarditis examines diagnostics, treatments, and causes (Photo courtesy of the Mayo Clinic).

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The VD-200 UHPLC analyzer features high sensitivity with special D-UV-Detector developed for VitD2/D3 with 0.9 ng/mL LOQ, and direct LIS data transfer from automated reading to result. The low-maintenance system offers a test capacity of 240 tests in 12 hours.

The RESIST-3 O.K.N. is for the triple independent identification of OXA-48-like, KPC-like and NDMlike carbapenemase on bacterial colony. The ready-to-use kit offers the advantage of testing for three parameters in one test with the shortest time-to-result and without any equipment.

The EasyRA features a throughput of 150 tests per hour (>300 with integrated ISE), 24 sample positions, and 24 reagents on board. It features a unique, slide-out drawer for quick and easy maintenance and uses RFID technology to eliminate the need for manual programming of reagents.

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Lower Cut-Off Point of Blood Glucose May Define Prediabetes octors define prediabetes as impaired fasting glucose with a higher than normal blood sugar levels after a period of fasting, impaired glucose tolerance with a higher than normal blood sugar levels after eating, or raised glycosylated hemoglobin levels. Results of studies on the association between prediabetes and risk of cardiovascular disease and all-cause mortality are also inconsistent. Furthermore, whether raised glycosylated hemoglobin levels for defining prediabetes is useful for predicting future cardiovascular disease is unclear. Scientists affiliated with the Affiliated Hospital at Shunde, (Southern Medical University, Foshan, China; www.fimmu.com) analyzed the results of 53 studies involving over 1.6 million individuals to shed more light on associations between different definitions of prediabetes and the risk of cardiovascular disease, coronary heart disease, stroke, and all-cause mortality. Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (ADA, Arlington County, VA, USA; www.diabetes.org; IFG-ADA; fasting glucose 5.6-6.9 mmol/L), the World Health Organization expert group (WHO, Geneva, Switzerland; www.who.int ; IFG-WHO; fasting glucose 6.1-6.9 mmol/L), impaired glucose tolerance (two hour plasma glucose concentration 7.8-11.0 mmol/L during an oral glucose tolerance test), or raised hemoglobin A 1c (HbA 1c ) of 39-47 mmol/mol (5.7-6.4%) according to ADA criteria or 42-47 mmol/mol (6.0-6.4%). The scientists found that prediabetes, defined

as impaired fasting glucose or impaired glucose tolerance, was associated with an increased risk of cardiovascular disease and all-cause mortality. The risk increased in people with a fasting glucose concentration as low as 5.6 mmol/L (100.8 mg/dL), which was the lower cut-off point according to ADA criteria. Raised HbA1c levels to 39-47 mmol/mol or 42-47 mmol/mol were both associated with an increased risk of composite cardiovascular disease and coronary heart disease but not with an increased risk of stroke and allcause mortality. The authors concluded that prediabetes, defined as impaired glucose tolerance, impaired fasting glucose, or raised HbA1c, was associated with an increased risk of cardiovascular disease. The health risk might be increased in people with a fasting glucose concentration as low as 5.6 mmol/L or HbA1c of 39 mmol/mol. The study was published on November 23, 2016, in the journal BMJ. Image: Glycated Hemoglobin as an indicator for diabetes control (Photo courtesy of iStock). LabMedica International June-July/2017

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Gene Activity Mapping Points to Two Subtypes of Crohn’s Disease ene activity studies have found that there the right targets. We hope one day to be able to are two clinically relevant forms of Crohn’s test Crohn’s patients for the subtype of the disease disease that are defined by molecular sigthey have, and thus determine which treatment natures that are not linked to tissue sampling locashould work best. The idea is to find the best thertion, patient age, or treatment status. apeutic course for each patient as quickly and effiThe clinical presentation and course of Crohn’s ciently as possible.” disease (CD) is highly variable with the course and The study was published in the October 14, severity of the disease varying widely from one case 2016, online edition of the journal Gut. to the next. Investigators at the University of North Carolina (Chapel Hill, USA; www.unc.edu) sought Image: The discovery of two classes of Crohn’s to better understand the cellular and molecular has implications for scientists to deliver more targeted treatments (Photo courtesy of MNT). mechanisms that guide this heterogeneity, and characterize the cellular processes associated with disease phenotypes. To this end they examined both gene VISIT US AT: expression and gene regulation (chromatin accessibility) in non-inflamed colon 2017 tissue from a cohort of adult patients with ANNUAL MEETING CD and control patients. To support the generality of these findings, they analyzed Booth: 4951 previously published expression data from a large cohort of treatment-naïve pediatric CD and control ileum (the part of the small intestine that empties into the colon). The investigators found that adult patients with CD clearly segregated into two classes based on colon tissue gene expression – one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Furthermore, gene expression from the ilea of a treatmentnaïve cohort of 201 pediatric patients with CD could be similarly subdivided into colon-like and ileum-like classes. Expression patterns within these CD subclasses highlighted large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behavior, including rectal disease and need for colectomy (surgical removal of the colon). The results strongly suggested that these molecular signatures defined two clinically relevant forms of CD irrespective of tissue sampling location, patient age, or treatment status. “The one-treatment-fits-all approach does not seem to be working for Crohn’s patients,” said senior author Dr. Shehzad Z. Sheikh, assistant professor of medicine and genetics at the University of North Carolina. “It is plausible that this is because only a subset of patients has the type of disease that responds to standard therapy, whereas, for the rest of the patients, we are really not hitting

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DiagCor Bioscience

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The Taigen VacEZor enables direct binding and washing steps on a vacuum manifold without having to repetitively load spin columns on the centrifuge and discard the waste. It is designed for filtration-type DNA/RNA purification with low-tomedium throughput (36-sample capacity).

The STA-Edoxaban Calibrator/STA-Edoxaban Control reagents enable the quantitative determination of edoxaban plasmatic concentration. Specific, stable, and fully automated, it allows measurement in various settings such as prior to surgery or in emergency situations.

The Coag 4D D-Dimer + AT III offers four independent measuring channels (two parallel or four single test) for full-scope coagulation testing. It features a color touch screen with an innovative user interface that offers visual sample traffic guidance for easy and touch-less operation.

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New Genetic Factors Linked to HPV-Related Cancers new, large-scale genetic study of head and neck cancers shows why some individuals infected with human papillomavirus (HPV) may go on to develop oropharyngeal cancer while others do not. Head and neck cancers are a related group of cancers that involve the oral cavity, pharynx (oropharynx, nasopharynx, and hypopharynx), and larynx. The most significant causes of all head and neck cancers are tobacco use and alcohol consumption. These exposures account for the development of approximately 80% of such cancers globally, with some variation for different subsites with 65% for the oral cavity versus 86% for the larynx. An international team of scientists led by those at the International Agency for Research on Cancer (IARC, Lyon, France; www.iarc.fr) conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. The team conducted extensive DNA analysis of more than seven million variants for each individual. The scientists identified seven new genetic loci (locations of a gene on a chromosome): one that is linked to oropharyngeal cancer and six that are as-

sociated with oral cavity cancer, thus providing new insights into the development of these diseases. The most prominent finding was an association between oropharyngeal cancer and genetic variation in the human leukocyte antigen (HLA) region, a genetic region important for regulation of the immune system. One particular set of variants in the HLA region was associated with a more than 4-fold protective effect against developing oropharyngeal cancer associated with HPV infection. The same genetic variants have previously been shown to protect against cervical cancer, which is known to be associated with HPV infection. Paul Brennan, PhD, Head of IARC’s Section of Genetics and a senior author of the study said, “These results indicate that genes that control the immune system play a fundamental role in influencing whether an HPV infection goes on to develop into an HPV-related cancer. Understanding why this happens may help us to identify additional methods to protect against HPV-related cancers.”

The study was published on October 17, 2016, in the journal Nature Genetics. Image: Immunohistochemistry image of invasive squamous cell carcinomas of tonsil tissue showing overexpression of p16, which is a very good surrogate marker for HPV infection (Photo courtesy of David C. Hoak, MD).

Respiratory Tract Bacterium Triggers Serious Nervous System Disease uillain-Barré syndrome (GBS) is an acute post infectious immune-mediated polyneuropathy and an acute life-threatening disease of the nervous system that leads to sensory disturbances and acute flaccid paralysis. Although preceding respiratory tract infections with Mycoplasma pneumoniae have been reported in some cases, the role of M. pneumoniae in the pathogenesis of GBS remains unclear. Bacteria, which often cause pneumonia, can trigger the autoimmune disease GBS. Antibodies that not only attack the bacteria but also the outer layer of the body’s own nerve cells are a critical step in the pathogenesis of GBS after this respiratory infection. Scientists at the Erasmus University Medical Cen-

ter (Rotterdam, The Netherlands; www.erasmusmc. nl) and their colleagues investigated a total of 189 adults and 24 children with GBS for the presence of antibodies to mycoplasma, as an indication of a recent bacterial infection, and galactocerebroside (GalC) as the suspected trigger for GBS, and compared them with 677 healthy individuals as controls. Anti–M. pneumoniae immunoglobulin (Ig) M antibodies were detected in GBS patients and healthy controls in 3% and 0% of adults and 21% and 7% of children respectively. The anti-GalC antibodies immunoglobulins M and/or G (IgM and/or IgG) were found in 4% of adults and 25% of children with GBS. Anti-GalC-positive patients showed more frequent preceding respiratory symptoms, cra-

nial nerve involvement, and a better outcome. Anti-GalC antibodies correlated with anti–M. pneumoniae antibodies and cross-reacted with different M. pneumoniae strains. Anti-GalC IgM antibodies were not only found in GBS patients with M. pneumoniae infection, but also in patients without neurological disease whereas anti-GalC IgG was exclusively found in patients with GBS. Interestingly, the anti-GalC antibodies were also found in patients without GBS who had recently been infected with mycoplasma. However, these were all of the antibody isotype M (immunoglobulin M, IgM), the earliest antibody type elicited during an acute immune response. The study was published on September 26, 2016, in the journal Annals of Neurology. LabMedica International June-July/2017

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Zika Virus Detected in Conjunctival Fluid esearchers have found that Zika virus (ZIKV) can be detected in samples of conjunctival fluid from patients with ZIKV infection, suggesting the possibility for a simpler and safer noninvasive test for diagnosis and/or screening than blood testing. The results also add evidence about the cause of conjunctivitis in ZIKV-infected infants with microcephaly. Though over 80% of infections are asymptomatic, clinical symptoms are often joint pain, mild and self-limited rash, and conjunctivitis (“pink eye”). Severe eye damage in infants with microcephaly was associated with ZIKV infection; how-

Effectiveness of PD-L1 Tests Compared for Non-Small-Cell Lung Cancer

ever, it has not been clear whether the eye lesions are the result of the microcephaly or directly of ZIKV infection. A team led by researchers of the Guangzhou Province department of the Chinese Center for Disease Control and Prevention (China CDC; Beijing, China; www.chinacdc.cn/en) examined ZIKV could be detected from conjunctival swab samples of laboratory-confirmed ZIKV cases. Since February 2016, 11 ZIKV infection cases had been confirmed (by PCR) of Chinese travelers entering Guangdong from Venezuela. Serum and conjunctival swab samples were taken from 6 of 11 cases. The ZIKV RNA was detectable in serum no more than 5 days after symptom onset, but it was detected in conjunctival swab samples until day 7 in case 5. “Detection of ZIKV RNA is a gold standard of confirmation of ZIKV infection. In this study, we de-

scribed the direct detection and isolation of ZIKV from conjunctival swab samples. Although isolation of ZIKV in cell culture from urine, semen, saliva, and breast milk has been described, to our knowledge, detection and isolation of ZIKV from conjunctiva has not been reported so far,” the authors wrote. “These results, though, are not sufficient to recommend the use of conjunctival swabs as alternative samples for ZIKV diagnosis because of shorter persisting and shedding time of ZIKV in conjunctiva fluid (<7 days) compared with urine and saliva samples (<20 days),” they added, “It may have implications for transmission of ZIKV, e.g. through corneal graft donors, although this report does not provide direct evidence to support that indication. Nevertheless, epidemiological data and experimental studies are needed.” The study, by Sun J et al, was published online September 15, 2016, in the journal JAMA Ophthalmology.

n a recent study, clinical researchers compared performance of the 4 available assays for the tumor-promoting protein PD-L1 as a biomarker for assessing non-small cell lung cancer (NSCLC). They found that one assay failed to result in comparable levels of PD-L1, while the three other assays resulted in comparable levels. The assays are used to test expression of PD-L1 on a patient’s tumor to help customize treatment options using drugs that may be more effective against lung cancer than chemotherapy. Findings of the new study were presented September 26, 2016, by researchers from Yale Cancer Center (New Haven, CT, USA; http://yalecancercenter.org) at the International Association for the Study of Lung Cancer (IASLC) 2016 Chicago Multidisciplinary Symposium in Thoracic Oncology (Chicago, USA). The study was sponsored by Bristol Myers Squibb with the National Comprehensive Cancer Network (NCCN) Oncology Research Program. The team reviewed 90 surgically resected NSCLC cases (stages I-III) and sent a sample of each to four facilities for staining. A group of 13 pathologists at 7 institutions then reviewed the samples, using 4 different assays on each case, and scored them using a unified scoring system. A comprehensive statistical analysis was then performed on the scores collected. Currently available are four drugs with four PD-L1 assays: 22c3, 28-8, E1L3N, and SP142. However only the 22c3 test is required by the US Food & Drug Administration (FDA) for prescription of a targeted anti-PD-1 drug (pembrolizumab), while the other tests are not yet required for prescription of other PD1 axis drugs. The study revealed that SP142 systematically returned statistically lower levels of PD-L1 expression than the other three tests. This was true in both tumor and immune cells using any test. The other three available assays (28-8, E1L3N, and 22c3) showed no significant difference between them. “Our data shows that the SP142 assay shows significantly lower levels of PD-L1 expression. This observation may limit the use of this assay in PD-L1 testing moving forward,” said first author David L. Rimm, MD, PhD, professor at Yale School of Medicine, “However, the other three assays seem equivalent, which is good news for the future when other PD-1 axis drugs with assay-specific diagnostics gain FDA approval.”

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The Autolyser 450 uses glass cuvettes and an internal barcode reader for sample and reagents, and can store up to 500 tests plus unlimited relation tests in its internal memory. It offers a throughput of up to 450 tests/hour without I.S.E, and up to 690 tests/hour with I.S.E.

The io System is designed for detecting the presence of infectious diseases, such as Chlamydia and MRSA. It is specifically intended for use in decentralized laboratories, point-of-care and other near-patient settings, providing laboratory accurate test results in around 30 minutes.

The Stratec Gemini is designed for low-throughput applications and features an absorbance reader with up to eight different filters. It provides singleor dual-wavelength reading, offers scheduling of up to three plates, and has a loading capacity of up to 192 samples with continuous loading.

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Rapid Blood Test Can Rule Out Serious Childhood Infections he care for acutely ill children has traditionally been a primary care responsibility, but increasing numbers are being seen in secondary care, but a simple decision rule and a finger prick to test blood, general practitioners can now detect serious infections in children very quickly. The introduction of better diagnostic tests might strengthen the primary care management of acutely ill children and inflammatory markers such as Creactive protein (CRP) and procalcitonin can assist in diagnosing serious infections in hospital settings. Scientists at the University of Leuven (Belgium; www.kuleuven.be) and their colleagues assessed a whether performing point-of-care CRP testing should be done in all children presenting with acute infection in primary care or only in those deemed at high-risk of serious illness after initial clinical assessment. They also investigated how CRP results should be interpreted; specifically, whether a low CRP level can rule out infection and

the consequent need for hospital referral. A cluster randomized controlled trial was carried out involving acutely ill children presenting to 133 general practitioners (GPs) at 78 GP practices in Belgium. Practices were randomized to undertake point-of-care CRP testing in all children (1,730 episodes) or restricted to children identified as at clinical risk (1,417 episodes). In the “CRP only if at clinical risk” group, CRP testing was dependent on the presence of at least one of the following clinical features: breathlessness, body temperature of at least 40 °C, diarrhea in children 12–30 months of age, and clinician concern. The Afinion CRP Test Cartridge (Alere, Waltham, MA, USA; www.alere.com) was used, which has a measuring range for CRP of 5–200 mg/L and requires 1.5 L of blood obtained by finger prick, providing a result within four minutes. They trained all physicians to perform the CRP test. The investigators found that t restricting CRP testing to children at clinical risk (because of breathlessness, temperature equal to or greater than

40 °C, diarrhea and age 12 to 30 months, or clinician concern) substantially reduced the number of children tested to 285/1,417. The team reported that restricting CRP testing to those identified as at clinical risk increased the median CRP level of the children tested from 7 mg/L to 11 mg/L. Time from onset of fever did not influence the median point-of-care CRP level. The study was published on October 6, 2016, in the journal BMC Medicine. Image: The Afinion C-reactive protein (CRP) test cartridge and Afinion AS100 analyzer (Photo courtesy of Alere).

Liquid Biopsy Tests Identified Cell-Free Tumor DNA Mutations he feasibility of using cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS) from liquid biopsies as a complement or alternative to tissue NGS has been evaluated. The expanding number of targeted therapeutics for non-small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for NGS. Scientists at the University of Pennsylvania (Philadelphia, PA, USA; www.upenn.edu) obtained 112 plasma samples from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible between February 2015 and March 2016. Only 50 patients could only provide tissue

samples and liquid biopsy samples were sent to Guardant Health (Redwood City, CA; USA; www.guardanthealth.com) for testing. The team detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with epidermal growth factor receptor (EGFR) variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. While ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance. ctDNA sequencing identified eight pa-

tients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible. The authors concluded that therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Erica L Carpenter, MBA, PhD, the senior author of the study said, “The tissue biopsy sequencing result has been considered the gold standard against which one compares the ctDNA result. Our work suggests that one can act on a ctDNA result, even in the absence of the so-called gold standard, and get a clinical response in these patients,” The study was published on September 6, 2016, in the journal Clinical Cancer Research. LabMedica International June-July/2017

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Rapid Rabies Test Validated For Field Surveillance abies is a viral zoonotic encephalomyelitis transmitted to humans after exposure to infected mammals, mainly dogs, through bites, scratches or licks on damaged skin or mucous membranes. The high fatality and burden of rabies stands in contrast to the very low performance of laboratory-based surveillance in resource-challenged countries. The absence of reliable human and animal rabies incidence data ultimately result in neglect of disease prevention and control and the perpetuation of rabies virus (RABV) transmission despite the existence of powerful management tools. An international team of scientists led by those at the Swiss Tropical and Public Health Institute (Basel, Switzerland; www.swisstph.ch) tested 48 samples from dogs and in the reference laboratory setting, a total of 73 samples was tested, representing a wide diversity of RABV in terms of animal species tested (13 different species), geographical origin of isolates with special emphasis on Africa, and different phylogenetic clades. The team evaluated a rapid immunodiagnostic test (RIDT) in comparison with the standard fluorescent antibody test (FAT) and confirmed the detection of the viral ribonucleic acid (RNA) by real time reverse transcription polymerase chain reaction (RT-qPCR). The RIDT Anigen test, was a chromatographic immunoassay-based on lateral flow technology (BioNote, Inc, Hwaseong, Republic of Korea; www.bionote.co.kr). Viral RNA detection was performed using a one-step dual combine pan-lyssavirus RT-qPCR assay. The scientists reported that for the majority of the total sample size of 121 samples tested, the RIDT was successfully performed, with the presence of a line clearly visible in the control zone after five to 15 minutes of migration once the sample was deposited. Compared to the gold standard FAT, the RIDT demonstrated an accordance of 95%. The specificity was 93.3% with only two false positive results among the 30 FAT negative specimens. A total of 51 samples were tested for viral RNA detection using RT-qPCR on the Anigen test strip, which were previously found positive for the post-mortem diagnosis of rabies. When compared to the FAT Whatman card, RT-qPCR performed on the Anigen test strip exhibited a sensitivity of 80.6%. The authors concluded that the RIDT shows excellent performance qualities both in regard to user friendliness and reliability of the result. In addition, the test cassettes can be used as a vehicle to ship viral RNA to reference laboratories for further laboratory confirmation of the diagnosis and for epidemiological investigations using nucleotide sequencing. The potential for satisfactory use in remote locations is therefore very high to improve the global knowledge of rabies epidemiology. The study was published on October 5, 2016, in the journal Public Library of Science Neglected Tropical Diseases.

Image: The results from the rapid immunodiagnostic test (RIDT Ag) for rabies (Photo courtesy of the Swiss Tropical and Public Health Institute). V

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The CoaLyser performs clotting and immunoturbidimetric assays with a throughput of PT 137 tests/hour, APTT 60 tests/hour ¬± 20 tests/hour. It offers continuous loading of samples and features a color touch display, and internal sample barcode reader.

The HELMED can incubate from room temperature up to 45 degrees C, making it the only system that can process infectious serology slides, as well as autoimmunity. It has a processing capacity of up to 20 slides, four tests and 150 samples per run, and comes with a built-in BC reader.

The MISPA CLOG offers seven pre-programmed test positions along with auto cuvette detection feature. It offers one position for reagent incubation and four sample incubation positions, and requires a minimum cuvette volume of 150 ¬µL for one test.

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Point-of-Care Diagnostic Test for Diabetes Reviewed upporters of point-of-care (POC) HbA1c testing emphasized its advantages, particularly the increased access it affords patients and the potential for more timely treatment changes that could improve glycemic control. Such tests also enable clinicians to discuss the results with patients before they leave the examination room, rather than requiring a follow-up visit. The system is identical to one already used to monitor patients with diabetes. That test has received a Clinical Laboratory Improvement Amendments (CLIA) waiver and can be used in numerous POC clinical settings with no required training. The US Food and Drug Administration (FDA, Silver Springs, MD, USA; www.fda.gov) typically convenes panels to provide a recommendation on approval. Although it is not required to follow the advice of such panels, it typically does. In accuracy studies of the Alere Afinion HbA1c Dx, (Alere, Waltham, MA, USA; www.alere.com) the total error estimates for the test based on venous whole blood precision estimates ranged from

2.25% to 3.16%, within the acceptance criterion for total error. The total error estimates for the test based on fingerstick whole blood ranged from 1.41% to 4.05%, also within the acceptance criterion of less than 6%. POC diabetes diagnostics is somewhat controversial. The American Diabetes Association (ADA) did not recommend such assays for diagnostic purposes in its 2016 guidelines, citing a lack of required proficiency testing. The missing support is the main reason the FDA asked for the panel review. Robert E. Ratner, MD, the ADA chief scientific and medical officer, said, “Using the test to monitor patients already diagnosed with diabetes is appropriate because it doesn’t require the same degree of accuracy as a diagnostic test.” However, Richard Kahn, PhD, a clinical professor of medicine at the University of North Carolina in Chapel Hill, disputed that claim, arguing that POC testing could improve the diagnosis

of diabetes (currently about a third of people with diabetes are undiagnosed) with little risk of false positives or negatives. Image: The Afinion HbA1c assay tests for quantitative determination of glycated Hemoglobin (HbA1c) in human whole blood (Photo courtesy of Alere).

Method Simplifies Blood Biomarker Discovery and Analysis new gene expression analysis method has been developed to widen the usage of blood in biomarker discovery and analysis and the majority of the cells are erythrocytes that carry oxygen, causing 50% to 80% enrichment of globin ribonucleic acid (RNA) molecules among all blood RNA. As a type of liquid biopsy, blood is widely used in clinical studies due to its ease of sampling, its transport of biomolecules from all over the body and its rapid dynamics, but the high prevalence of globin complicates blood related gene expression biomarker studies, causing technical bias and leaving biologically relevant molecules undetectable. Scientists at the Karolinska Institute (Huddinge, Sweden; www.ki.se) and their colleagues developed the new method that consists of a pair of short

synthetic DNA strands that silence majority of globin RNA molecules by highly specific binding. The strands are introduced to purified RNA sample, and according to the team, being effective immediately after RNA denaturation and add only ten minutes of incubation time to the whole complementary DNA synthesis procedure. The locking DNA molecules bind specifically at globin RNA poly-A site that is needed for further analysis. Therefore the globin RNAs are “locked” prior downstream manipulations and are unavailable to cause technical biases in blood RNA biomarker applications. RNA concentrations and the RNA integrity number (RIN) were measured with an Agilent 2100 Bioanalyzer Total RNA Nano kit (Agilent Technologies, Santa Clara, CA, USA; www.agilent.com) or Qubit Fluorometer (Thermo Fisher Scientific,

Waltham, MA, USA; www.thermofisher.com). Kaarel Krjutškov, PhD, the lead author of the study, said, “The globin reduction rate of GlobinLock (GL) is sufficient for any applications. It reduces the globin prevalence from 63% before to 5% which makes it an effective tool for biotechnology companies as an additive to their kits.” The authors concluded that they had developed a simple and cost-effective method to overcome globin mRNA caused limitation in biomarker studies when whole-blood RNA samples are used. The data presented obtained by qPCR and RNAseq proofs the GL positive reduction effect with adult human whole-blood RNA samples and indicates its potential for species. The study was published on August 12, 2016, in the journal Scientific Reports. LabMedica International June-July/2017

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LabMedica International

Hypoglycemia in Hospitalized Patients Linked to Increased Mortality Risk pontaneous and insulin-related hypoglycemia is common among hospitalized patients with and without diabetes mellitus (DM). The definition of hypoglycemia in hospitalized patients is poorly defined and thus the true prevalence of hypoglycemia during hospitalization is variable. One complication of diabetes, hypoglycemia, occurs most often in people taking medications to manage their blood sugar. These treatments can raise insulin levels too high, which can in turn cause blood glucose levels to drop too low. Hypoglycemia can be dangerous and, depending on the severity, can lead to various symptoms, including dizziness, confusion,

Genetic Test Significantly Reduces Risk of Cardiovascular Events

anxiety, seizure or loss of consciousness. A team of medical scientists at the Rabin Medical Center (Petah Tikva, Israel; www.hospitals. clalit.co.il) conducted a study in a large 1,300-bed university-affiliated tertiary medical center collected historical prospectively observational data which were extracted from the medical records of all patients admitted for any cause to the hospital’s medical wards between January 1, 2011 and December 31, 2013. This study included nearly 3,000 patients with hypoglycemia, defined as blood glucose levels lower than 70 mg/dL. The team found that for patients with hypoglycemia, 31.9% had died at the end of the followup period. Mortality risk was higher in insulin-treated patients with moderate hypoglycemia (40-70 mg/dL), compared to patients without insulin treatment with similar glucose values. However, with severe hypoglycemia of less than 40 mg/dL, the in-

crease in mortality risk was similar with insulin-related and non-insulin related hypoglycemia. The cause of admission did not affect the association between glucose levels and mortality. Almost half the patients with hypoglycemia during hospitalization did not have preexisting DM (1,452/2,947 patients, 49%). However, most of the patients with severe hypoglycemia had pre-existing DM (236/342 patients, 69%). Amit Akirov, MD, the study senior author, said, “Hypoglycemia is common among hospitalized patients with and without diabetes mellitus. Our findings suggest that hypoglycemia, whether insulin-related or non-insulin related, is associated with short- and long-term mortality risk. These data are a timely reminder that hypoglycemia of any cause carries the association with increased mortality.” The study was published on November 17, 2016, in the Journal of Clinical Endocrinology & Metabolism.

quick, precise genetic test can significantly reduce the risk of cardiovascular events by helping to identify more effective medication for some heart patients. The genetic testing allows physicians to pinpoint the best anti-clotting medication for each patient. Decoding a patient’s genetic tendencies is not just about rapid treatment as many patients take an anti-clotting drug for a year or longer. Patients who had the genetic deficiency and received an alternative medication were less likely to have a major adverse cardiovascular event compared with those who received clopidogrel during the follow-up period of up to a year. A group of scientists led by those at the University of Florida Health (Jacksonville, FL, USA; https:// ufhealth.org) analyzed medical outcomes in 1,815 patients who had genetic testing at the time of their cardiac procedure. The test identifies a genetic deficiency that affects the body’s ability to activate clopidogrel, a common anti-clotting drug given after a coronary artery stent is inserted. The study examined the effect of genotype-guided treatment on cardiovascular outcomes after a heart procedure known as percutaneous coronary intervention, or PCI, in which a metallic stent is inserted into a heart artery to treat a blockage. More broadly, it shows the power and the promise of personalized medicine, which tailors medical decisions based on a patient’s genetic information and other unique characteristics. The study reported significant results as about 60% of patients with the genetic deficiency were given a different, more effective medication. Using the genetic data to guide changes in therapy reduced the percentage of deaths, heart attacks or strokes by nearly half compared with those who continued taking clopidogrel. Among those who had the genetic deficiency and continued taking clopidogrel, 8% of patients experienced one of those complications. About 30% of all patients have a genetic deficiency that impairs their ability to activate the drug, which can lead to decreased clopidogrel effectiveness and increased risk for adverse cardiovascular events such as strokes, heart attacks and death.

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The ACCENT-220S offers up to 33 positions for samples and up to 35 positions for reagents with flexible configuration, and liquid level detection and collision protection. It also features a throughput of up to 220 tests/hour without ISE and 385 tests/hour with ISE.

The EasyElectrolytes measures Na+, K+, Cl‚Äì, and Li+ in whole blood, serum, urine (not applicable for Li+), and plasma, with results displayed and printed in 35 seconds. It features precise control of calibrator volumes to ensure low-cost operation and faster test results.

The mLabs platform includes the mLabs ImmunoMeter and mLabs disposable microfluidic cartridges. The compact POCT system helps diagnose various cardiac diseases within minutes, including DVT, PEs, stroke, sepsis, heart attack, congestive heart failure, and angina.

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Simple Saliva Test Developed To Diagnose Asthma urrent clinical tests employed to diagnose asthma are inaccurate and limited by their invasive nature, but a new test that can diagnose asthma from a patient’s saliva has now been developed. To diagnose an asthmatic condition doctors usually measure a person’s airflow lung capacity, however lung function tests can be inaccurate and do not reflect underlying changes associated with asthma. Other tests, such as blood, urine or sputum analysis can be distressing, particularly for younger patients. Scientists at Loughborough University (UK; www.lboro.ac.uk) and their colleagues developed a rapid analytical method for metabolite profiling of saliva is reported using ultra-high performance liquid chromatography combined with high-resolution time-of-flight mass spectrometry (UHPLC-MS). The only sample pre-treatment required was protein precipitation with acetonitrile. The method has been applied to a pilot study of saliva samples obtained by passive drool from well phenotyped patients with asthma and healthy controls.

The team performed an assessment on the complex dataset obtained from the UHPLC-MS analysis to identify potential metabolomic biomarkers of asthma in saliva. Ten discriminant features were identified that distinguished between moderate asthma and healthy control samples with an overall recognition ability of 80% during training of the model and 97% for model cross-validation. The reported method demonstrates the potential for a non-invasive approach to the clinical diagnosis of asthma using mass spectrometry-based metabolic profiling of saliva. Colin Creaser, PhD, a professor of Chemistry and senior author of the study, said, “Unlike other sampling methods, such as expired breath analysis, saliva can be collected by passive drool from the very young to the very old without causing distress. We were therefore interested to know if techniques for metabolic profiling of saliva to iden-

tify physiological stress from exercise, which was developed by Loughborough University, could be applied to asthma diagnosis. We were very excited to discover that they could.” The study was published in the August 2016 issue of the journal Analytical Methods. Image: A saliva test for 10 biomarkers indicating asthma could prove to be more accurate and convenient than other methods of diagnosis, according to new research (Photo courtesy of Image Point Fr / Shutterstock).

DNA Analysis Clarifies Ancestry of Triple-Negative Breast Cancer Patients ge of onset and severity of triple-negative breast cancer are related to ethnic origin, which can be definitively established by analysis of mitochondrial DNA. Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and difficult to treat. Patients with TNBC tend to be younger and are more likely to be African-American. However, between 10 and 30% of Americans may not be aware of a mixed ancestry that increases their susceptibility to the disease. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. To assess the

value of mtDNA profiling to establish ethnic origin in TNBC patients, investigators at the University of Texas Southwestern Medical Center (Dallas, USA; www.utsouthwestern.edu) examined 92 patients: 31 self-described as African-American, 31 self-described as White, and 30 self-described as Hispanic. Results revealed that Hispanic patients had largest tumor size and youngest age of onset among the three groups. However, there was a discrepency between mtDNA analysis and self-described ethnicity in 13% of the 92 patients. The highest discordance (26%; eight patients) was noted in self-described Hispanic patients: three had Nigerian ancestry, and one individual demonstrated haplogroup K

mtDNA (Ashkenazi Jewish ancestry). “We found 12 differences among 92 patients, a significant amount,” said senior author Dr. Roshni Rao, associate professor of surgery at the University of Texas Southwestern Medical Center. “Some patients who self-identified as Hispanic had AfricanAmerican ancestry. One Hispanic woman was found to be Ashkenazi Jewish. Both African-Americans and some Ashkenazi Jewish populations have a higher risk for triple negative breast cancer. “If you know your ancestry, then you could be included in the group that gets screened at a younger age.” The study was published in the September 1, 2016, online edition of the journal Cancer. LabMedica International June-July/2017

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LabMedica International

Unique Assay Improves Cancer Diagnosis for Leukemia Patients new CE-IVD-marked assay for calreticulin (CALR) mutations, run on a well-established RT-PCR platform, aids in establishing the diagnosis of myeloproliferative neoplasms (MPN) in line with the latest WHO recommendations and clinical guidelines. The new ipsogen CALR RGQ PCR Kit (ipsogen CALR assay) from QIAGEN N.V. (Hilden, Germany; www.qiagen.com) is intended for detection of CALR mutations in genomic DNA from patients suspected of MPN. It enables identification of the two majors CALR mutations, Type 1 and Type 2, and detects additional mutations in the CALR exon 9 region. The ipsogen CALR assay simplifies CALR testing by covering various relevant mutations to deliver multiple clinical results within one working day. The test runs on QIAGEN’s QIAsymphony and Rotor-Gene (RGQ) platforms, employing the CE-IVD-marked Rotor-Gene Q MDx 5Plex HRM Platform real-time cycler with automated analysis and interpretation using the Rotor Gene AssayManager software. QIAsymphony is a highly flexible, widely available platform for medium throughput molecular testing. Throughput flexibility is achieved by DNA sample processing from peripheral blood using either the manual QIAamp DSP DNA Blood Mini Kit or the automated sample processing on the QIAsymphony SP instrument. VISIT US AT: The new ipsogen CALR RGQ PCR Kit is synergistic with the CE-IVD-marked ipsogen JAK2 RGQ 2017 PCR Kit, QIAGEN’s leading solution to detect the ANNUAL V617F mutation in the janus kinase 2 (JAK2) gene, MEETING as CALR mutations can be detected from the same Booth: 1647 patient sample. The ipsogen CALR assay is the latest addition to QIAGEN’s ipsogen portfolio of assays for both common and rare leukemia types. MPN are a group of blood cancers characterized by significant symptoms and complications such as thrombosis (blood clots) and a high risk of transformation into acute leukemia. MPN include polycythemia vera (PV), essential thrombocythemia (ET), and various forms of (primary) myelofibrosis (PMF). MPN affect nearly 250,000 patients in Europe and 300,000 patients in the US. The combined annual incidence rate for MPN worldwide is roughly 2.5 in every 100,000. “We are excited to announce the launch of our new ipsogen CALR assay to help improve and facilitate patient diagnosis of MPN. The CALR assay is a very important addition to QIAGEN’s market leading ipsogen portfolio of molecular assays that are advancing treatment standards for patients with blood cancers,” said Dr. Christoph Menzel, director Global Product Management Personalized Healthcare and Oncology, QIAGEN, “We strongly believe our IVD Sample to Insight workflows for biomarkers such as CALR and JAK2 will make it easier for hemato-oncologists to follow recommended diagnostic testing algorithms and international guidelines.” The importance of CALR mutations in MPN was first described in December 2013 in two important papers published in the New England Journal of Medicine (Klampfl T et al, and Nangalia J et al). Earlier in 2016, mutations in CALR were included in addition to JAK2 mutations as a major diagnostic criterion for MPN in the updated WHO guidelines for the classification of myeloid neoplasms and acute leukemia. Both CALR and JAK2 V617F mutations were recently described in clinical guidelines to have prognostic significance.

LabMedica International June-July/2017

Image: The new CALR RGQ PCR Kit tests for calreticulin (CALR) mutation to aid in diagnosis of myeloproliferative neoplasms (MPN), and is QIAGEN’s latest addition to its ipsogen portfolio of assays for hemato-oncology testing (Photo courtesy of QIAGEN).

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The range of kits includes a qualitative, immunochromatographic test for the rapid detection of RSV and influenza viruses, and RSV F-protein antigens in nasal wash, nasopharyngeal aspirate and swabs. It also includes a test indicated for measuring PCT with results in 15 minutes.

The KENZA MAX BioChemisTry features a built-in incubator and an automatic flow cell, making it ideal for medium workloads. A flow-cell storage hole makes it easy to arrange reading through disposable cuvettes, and a friendly interface allows the user to program 120 methodologies.

The Access 2 is a benchtop system delivers an extensive test menu, and runs up to 100 tests per hour. Other features include on-board refrigeration storage of up to 24 assays, up to 56-day reagent open-pack stability, and the capability to load up to 60 samples at one time.

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Students Developing Portable Device To Quickly Detect Bacterial Infections he new diagnostic tool, which uses genetically engineered bacteria to detect bacterial infections in blood samples, would lead to more informed decisions that would reduce the number of patients with viral infections being prescribed antibiotics, thus reducing unnecessary treatments and helping to tackle antibiotic resistance. The device is being developed by the University of Sheffield’s (Sheffield, UK; www.sheffield.ac.uk) team of students who participated in this year’s “International Genetically Engineered Machine Competition” – iGEM 2016 (October 27-31; Boston, MA, USA) in the field of synthetic biology. The team consists of students from a range of science, engineering, and medicine disciplines. They hope the device could be used after GP surgeries to potentially help prevent complications from sepsis, or in walk-in clinics to enable patients with flu-like symptoms to have a small blood sample tested and be promptly told whether they have a bacterial or non-bacterial infection and be treated

accordingly. The tool distinguishes between bacterial and viral infection by detecting levels of the protein lipocalin-2, which is produced in high levels by immune system cells in response to bacterial infections. Bacteria produce siderophores that scavenge iron (as Fe3+) from host blood. In response, the immune system produces lipocalin-2, which sequesters siderophores. Lipocalin-2 levels can increase 5-fold during a bacterial infection. The device detects lipocalin-2 levels using genetically engineered bacteria that report a fluorescent signal inversely correlated to lipocalin-2 levels (via repression of GFP, the fluorescent reporter protein). Therefore, patient blood with bacterial infection results in a weak GFP signal, in contrast to a strong signal without bacterial infection. The portable de-

vice, which includes a shoebox size fluorometer, potentially has the capability of rapidly determining the presence of any bacterial infection. Image: A new device capable of quickly diagnosing bacterial infections could help doctors improve the way they prescribe treatment for patients (Photo courtesy of the University of Sheffield).

Method Predicts Disease Activity in Multiple Sclerosis ultiple sclerosis, or MS, is an inflammatory disease of the central nervous system that mainly affects young adults and it is not currently possible to know which individuals with multiple sclerosis, a life-long condition, risk developing severe disease. Biomarkers are naturally occurring substances in the body that can be measured in, for example, blood and that mirror a condition in the body and they are used in medical care to follow the progression of a disease and measure the effect of a treatment. Scientists at the Linköping University (Sweden; https://liu.se) isolated CD4+ T cells were isolated from 16 women diagnosed with definite relapsingremitting MS. None of the patients had experienced a relapse within three months prior to blood sampling nor had received immunomodulatory or immunosuppressive treatment for at least two

months (one exception was intravenous immunoglobulin treatment given 15 days before treatment in one patient). 16 age-matched, healthy control women were recruited among blood donors. To validate the clinical classifying capacity at the protein level, plasma and cerebrospinal fluid (CSF) from a second cohort of 41 patients with early MS was used. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood by density centrifugation (Lymphoprep, Axis-Shield, Oslo, Norway; www.axis-shield.com). The scientists used a variety of techniques including cell culture, flow cytometry staining and analysis, ribonucleic acid (RNA) extraction and microarray analysis, and these arrays were scanned on an Agilent Microarray Scanner (Agilent Technologies, Santa Clara, CA, USA; www.agilent.com). Cytokines and chemokines

were also quantified. The scientists tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating their findings with genome-wide association studies, they constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in CSF and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after two years and distinguish low and high responders to treatment in two additional, independent cohorts. The study was published on September 13, 2016, in the journal Cell Reports. LabMedica International June-July/2017

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Next Generation Qualitative In Vitro MRSA Diagnostic Test Approved n accurate, on-demand, molecular test for methicillin-resistant Staphylococcus aureus (MRSA), which returns results within an hour, has been officially approved for use. Emerging MRSA strains tend to elude detection from traditional assays and threaten the progress made against hospital-acquired infections in recent years and this new next generation qualitative test aims to fill this gap. The new teat is based on a library of MRSA strains from around the world, covering more strains than existing tests. The test lowers the likelihood of false positives thanks to a new design incorporating updated polymerase chain reaction (PCR) primers and probes that detect different strains with mecA and mecC genes. The US Food and Drug Administration (FDA, Silver

Springs, MD, USA; www.fda.gov) has approved a substantial Equivalence Determination for the test. The Xpert MRSA NxG Assay (Cepheid, Sunnyvale, CA, USA; www.cepheid.com) is performed on the GeneXpert Instrument Systems, is a qualitative in vitro diagnostic test intended for the detection of methicillin-resistant Staphylococcus aureus (MRSA) DNA directly from nasal swabs in patients at risk for nasal colonization. The test utilizes automated real-time polymerase chain reaction (PCR) for the amplification of MRSA-specific DNA targets and fluorogenic target-specific hybridization probes for the real-time detection of the amplified DNA. The Xpert MRSA NxG Assay is intended to aid in the prevention and control of MRSA infections in healthcare settings.

Image: The Xpert Next generation methicillin-resistant Staphylococcus aureus (MRSA) assay cartridge (Photo courtesy of Cepheid).

Gene Activity Predicts Progression of Autoimmune Disease new diagnostic tool has been designed for a rare and deadly autoimmune disease called systemic sclerosis that affects the skin and internal organs and the disease affects about 100,000 people in the USA. The cause of systemic sclerosis (SSc) is unknown, and there are no drugs approved for treating it. Many patients are given drugs that are approved for use in other diseases, but each drug is clinically effective in only a fraction of patients. To find out if a patient is responding to treatment, clinicians use a test called the modified Rodnan skin score (mRSS), in which a doctor pinches the skin to see how thick it is. Scientists at the Stanford University School of Medicine (CA, USA; http://med.stanford.edu) and six other institutions performed an integrated, multicohort analysis of SSc transcriptome data across seven datasets from six centers composed of 515 samples. Using 158 skin samples from SSc patients and healthy controls recruited at two centers as a discovery cohort, they identified a 415-gene expression signature specific for SSc, and validated its ability to distinguish SSc patients from healthy controls in an additional 357 skin samples from five independent cohorts. The investigators defined the SSc skin severity score (4S). In every SSc cohort of skin biopsy samples analyzed in the study, 4S correlated significantly with mRSS, allowing objective quantification of SSc disease severity. Using transcriptome data from the largest longitudinal trial of SSc patients to date, they showed that 4S allowed them to objectively monitor individual SSc patients over time. The 4S test applied to the preexisting set of patient data could distinguish patients who were improving from those who were not 12 months after their treatment began. In contrast, the doctors’ skin pinch test from the same set of data took 24 months to identify, which patients were improving. The study also uncovered a gene-activity signal suggesting the involvement of epidermal growth factor receptors in the disease. The study was published on December 22, 2016, in the journal JCI Insight.

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The UF-1000i offers rapid sample processing to enhance laboratory workflow and improve turnaround times. It uses fluorescent flow cytometry to reduce testing variables for improved standardization and efficiency, and is designed for low maintenance and high reliability.

The MagNA Pure 24 offers walkaway automation, minimal intervention, and extraction-to-extraction variability. It extracts NAs with a single universal reagent kit, along with on-board primary sample handling for low- to medium-throughput users who require high-quality NA extractions.

The BP800 provides pre-programmed (optional) assay protocols for Biohit diagnostics, and its intuitive user interface allows new test protocols to be made fast and easily. Its extensive on-board data analysis includes several curve-fitting options, transformations and control validation.

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Electrophotonic Silicon Biosensor Speeds Up Blood Test Analyses new sensor has been developed that is capable of detecting multiple proteins and enzymes in a small volume of blood, which could significantly speed up diagnostic healthcare processes. The complexity and heterogeneity of many diseases, and their dependence on lifestyle and genetics, demand new in vitro diagnostic technology that can provide quantitative measurement of multiple disease biomarkers in real time and at low cost. Scientists at the University of York (Heslington, UK; www.york.ac.uk) have developed a biosensor that combines light and electricity, to detect multiple disease biomarkers in one smaller sample of blood. The technology could make blood tests more comfortable for patients and enable results to be processed quicker. The team is using the new technology in urine samples for urinary tract infections (UTIs), which has a high resistance to antibiotic treatment. If the biosensor can identify biomarkers of the infection and of resistance, it is more likely that the correct course of antibiotic treatment will

be prescribed the first time around, rather than on repeat visits, which is often the case with UTIs. The investigators created a device capable of multiplexed detection that consists of a pair of photonic electrode ring resonators in the same microfluidic chamber. To explore the dual sensing capabilities of the device, they used the electrophotonic technology to monitor and quantify electrochemical reactions occurring at the silicon surface. The combination of electrochemical and photonic sensing not only provides access to complementary information, but also the ability to regulate the local surface chemistry via electrochemical processes in situ. Thomas F Krauss, PhD, a professor and co-author of the study, said, “These sensors can give fast, real time results and at low cost. The length of time and money that it takes laboratory technicians to identify just one protein in a patient sample is a real challenge for the UK National Health Service

(NHS) and can result in emotional distress for patients. Not only can this new technology speed the process up, but it can test for a number of proteins and enzymes together in just one sample, increasing the chances of a successful and timely diagnosis.” The study was published on September 14, 2016, in the journal Nature Communications. Image: A single electro-optical device: ohmic contacts fabricated on the doped silicon substrate allow electrochemical control over the sensor surface (Photo courtesy of the University of York).

Reliability Reevaluated for Bladder Cancer Test Prognosis blood test that had shown promise in predicting how cancer will progress and what treatments will be most effective for a given patient may not be reliable for either, as results from previous studies are threatened by methodological limitations. Preoperative risk stratification is a major challenge in bladder cancer (BC) and a robust biomarker is needed. One emerging candidate is the neutrophil-to-lymphocyte ratio (NLR). NLR is easily calculated from a complete blood count (CBC) and is felt to reflect the systemic inflammatory state. Medical scientists at the University of Pennsylvania (Philadelphia, PA, USA; www.pennmedicine. org) and their colleagues analyzed data that was collected in real-time during a prospective clinical

trial, making it the first study of NLR in bladder cancer not to rely on observational data. The study analyzed SWOG 8710, which was a randomized Phase III trial of 317 patients with muscle-invasive bladder cancer. All patients were treated with radical cystectomies. Half had pre-surgery chemotherapy, while the other half did not. Of the 317 total patients, the team identified 230 for a prognostic analysis to see if NLR could serve as a predictor of how long patients would live after curative treatment. They identified 263 others for a predictive analysis to see if NLR could tell which patients would respond to chemotherapy. There was a median follow-up of 18.6 years. For the prognostic analysis, NLR was not a significant factor in overall survival. The important factors

were age and whether the patient received pre-surgery chemotherapy. For the predictive analysis, NLR did not predict which patients benefitted from chemotherapy. Eric Ojerholm, MD, the lead author of the study, said, “The trial we used has a few big advantages to study NLR. First, baseline blood samples were collected as part of the trial protocol. Second, the study’s long-term follow-up gave us adequate ‘statistical power,’ meaning that if NLR really was a biomarker, then we should be able to detect it. Third, the trial randomly assigned some patients to receive pre-surgery chemotherapy. This allowed us to test NLR both as a prognostic and predictive biomarker.” The study was published on October 27, 2016, in the journal Cancer. LabMedica International June-July/2017

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Lipoarabinomannan Assay Screens for Active Tuberculosis ymptom-based screening misses approximately one-quarter of active tuberculosis (TB) cases among human immunodeficiency virus (HIV)-infected adults, and a more recent study suggested this might be as high as 76% of active TB cases in western South Africa. A rapid urine lateral flow assay to detect lipoarabinomannan (LAM), a glycolipid released from the cell wall of TB, has been shown to reduce mortality among HIV-infected hospitalized patients with TB-related symptoms when used to guide anti-TB treatment. A team of scientists led by those at the University of Washington (Seattle, WA, USA; www.washington.edu) conducted a prospective, clinic-based study enrolling consecutive antiretroviral therapy (ART)-naïve HIV-infected adults in the ambulatory clinical areas of two hospitals and two municipal health centers in KwaZulu-Natal, South Africa from October 2011 to January 2014. They assessed TB-related symptoms (cough, fever, night sweats, weight loss), and obtained sputum specimens for mycobacterial culture. Specially trained study nurses tested urine samples for LAM using the Determine TB LAM assay (Alere Inc, Waltham, MA, USA; www.alere.com), and interpreted results after 25 minutes. Sputum samples were processed and inoculated into Bactec 960 mycobacterial growth indicator tubes (MGIT; BD, Franklin Lakes, NJ, USA; www.bd.com), and solid culture Middlebrook 7H11 agar medium. Mycobacterium tuberculosis was confirmed using niacin and nitrate testing. The investigators found that among 675 HIV-infected adults with median CD4 of 213/mm3 (interquartile range 85-360/mm3), 123 (18%) had culture-confirmed pulmonary TB. They reported that including the LAM assay improved sensitivity to 83%; and NPV to 91% while decreasing the negative likelihood ratio (0.45 versus 0.57). Among participants with CD4 of less than 100/mm3, including urine LAM testing improved the negative predictive value of symptom based screening from 83% to 87%. All screening algorithms with urine LAM performed better among participants with CD4 less than 100/mm3, compared to those with CD4 equal to or more than 100/mm3. The authors concluded that their results demonstrate a marginal benefit from the inclusion of rapid urine LAM screening to clinical symptom screening among ART-naïve HIV-infected adults in resourceconstrained TB-endemic regions. The current urine LAM assay is imperfect and does not solve the public health challenge of screening or diagnosing TB. However, since the principles behind the urine LAM assay are sound, an improved, next-generation urinary LAM assay could meet the criteria for a rapid, clinic-based TB screening test among HIV-infected adults in TB-endemic settings. The study was published on November 14, 2016, in the journal BMC Pulmonary Medicine.

Image: The Determine TB LAM Ag test is targeted for the most vulnerable and hard to diagnose patients (Photo courtesy of Alere). V

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LabMedica International

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New Genes Implicated in High Blood Pressure Regulation igh blood pressure, or hypertension, affects one in three adults in the USA, according to the government authorities. The condition increases the risk for heart disease and stroke, but most people with high blood pressure are not aware they have it. Several large international groups of scientists report data that more than doubles the number of sites in the human genome tied to blood pressure regulation. One of the studies turned up unexpected hints that biochemical signals controlling blood pressure may spring from within cells that line blood vessels themselves. In one study conducted by scientists at Johns Hopkins University School of Medicine (Baltimore, MD, USA; www.hopkinsmedicine.org) and the colleagues examined participants’ genomes on computer-chiplike devices known as microarrays, which had been customized to simultaneously analyze nearly 200,000 sites in the genome where variations from person to person were suspected to have some effect on blood pressure. They then compared variants at the sites with information on each individual’s blood pressure information to confirm likely associations. To dissect the genetic architecture of blood pressure

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and assess effects on target organ damage, they analyzed 128,272 single nuclear polymorphisms (SNPs) from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. The teams identified 66 blood pressure–associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney.

One surprising finding from the study was that many of the new sites identified were near genes that are active in cells that line the inside of blood vessels, suggesting those cells are somehow involved directly in blood pressure control. Aravinda Chakravarti, PhD, a professor of medicine and a lead investigator, said, “It is thought that about half the explanation for our blood pressure comes from environmental and lifestyle factors, like diet, exercise and smoking, and the other half is controlled by our genes, but as with many other complex, multigene traits, pinning down what those genes are is challenging.” The study was published on September 12, 2016, in the journal Nature Genetics. Image: A recent JHU study showed how the human genome relates to blood pressure regulation (Photo courtesy of Shutterstock). LabMedica International June-July/2017

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LabMedica International

New Genetic Variants Discovered in Blood Group Systems n the surface of the red blood cells are proteins and sugar molecules, in which small differences give rise to different antigens. The ability to identify and match blood group types is important for blood transfusions, but also in pregnancy and before certain types of transplantation. Next-generation sequencing (NGS) is rapidly moving toward routine practice for patient and donor typing and has the potential to remedy some of the limitations of currently used platforms. However, a large-scale investigation into the blood group genotypes obtained by NGS in a multiethnic cohort is lacking. Scientists at Lund University (Sweden; www.lunduniversity.lu.se) extracted data from the 1,000 Genomes Project, which provides information on genome variation among 2,504 individuals representing 26 populations worldwide. They extracted their NGS data for all 36 blood group systems to a customdesigned database. In total, 210,412 alleles from 43 blood group–related genes were imported and curated. They developed matching algorithms to compare them to blood group variants identified to date. The team found of the 1,241 non-synonymous variants identified in the coding regions, 241 are known blood group polymorphisms. Interestingly, 357 of the remaining 1.000 variants are predicted to occur on extracellular portions of 31 different blood group–carrying proteins and some may represent undiscovered antigens. Of the alleles analyzed, 1,504 were not previously described. The study showed that 89% of the genetic variants were previously known, but among the remaining 11% were a total of 1,000 different mutations which were absent from official catalogues of known blood group variants. The results were exported to an online search engine, www.erythrogene.com, which presents data according to the allele nomenclature developed for clinical reporting by the International Society of Blood Transfusion (Amsterdam, The Netherlands; www.isbtweb.org). Mattias Möller, a doctoral student who developed the program, said, “Never before has there been a worldwide mapping of blood group genes in healthy individuals. Most previously known blood group variants were discovered when a blood transfusion failed, i.e. when it didn’t work between the donor and the recipient. I started from the genes instead, to find variations in DNA which might give rise to a new antigen, likely to cause problems in case of transfusion, for example.” The study was published on December 27, 2016, in the journal Blood Advances.

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Image: Researchers discovered 1,000 new gene variants in blood group data (Photo courtesy of Fotalia).

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Blood Test Could Predict Best Treatment for Lung Cancer

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blood test could predict how well small-cell lung cancer (SCLC) patients will respond to treatment. In most patients with SCLC, a metastatic, aggressive disease, the condition is initially chemosensitive, but then relapses with acquired chemoresistance. In a minority of patients with SCLC, however, relapse occurs within three months of initial treatment; in these cases, disease is defined as chemorefractory. The molecular mechanisms that differentiate chemosensitive from chemorefractory disease are currently unknown. Scientists, based at the Cancer Research UK Manchester Institute at The University of Manchester (UK; www. cancerresearchuk.org) examined copynumber aberrations (CNAs) in circulating tumor cells (CTCs) from pretreatment SCLC blood samples to identify genetic features that distinguish chemosensitive from chemorefractory disease. After analysis of 88 CTCs isolated from 13 patients (training set), they generated a CNA-based classifier that they validated in 18 additional patients (testing set, 112 CTC samples) and in six SCLC patient-derived CTC explant tumors. The classifier correctly assigned 83.3% of the cases as chemorefractory or chemosensitive. Furthermore, a significant difference was observed in progression-free survival (PFS) between patients designated as chemorefractory or chemosensitive by using the base-

line CNA classifier. Notably, CTC CNA profiles obtained at relapse from five patients with initially chemosensitive disease did not switch to a chemorefractory CNA profile, which suggests that the genetic basis for initial chemoresistance differs from that underlying acquired chemoresistance. Caroline Dive, PhD, a professor and the lead investigator, said, “Our study reveals how blood samples could be used to anticipate how lung cancer patients may respond to treatments. Unfortunately, we have very few treatment options for patients with SCLC, and none at all for those whose cancer is resistant to chemotherapy. By identifying differences in the patterns of genetic faults between patients, we now have a starting point to begin to understand more about how drug resistance develops in patients with this aggressive form of lung cancer.” The study was published on November 21, 2016, 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). LabMedica International June-July/2017

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New Diagnostic Tests Improve Care for Heart Failure Patients or the first time, researchers have developed tests that could improve treatment for heart failure patients by diagnosing the condition with greater accuracy, as well as by detecting the onset of congestive heart failure earlier. Heart failure is a leading cause of hospitalization for people older than age 65 in developed “Western” countries. At present, the main blood tests used to aid in the diagnosis of heart failure are those for B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). However, natriuretic peptide tests have a high false positive rate and a limited ability to detect the early and asymptomatic stages of the disease. With the goal of overcoming the drawbacks of current heart failure tests, a group of researchers developed a diagnostic panel that provides a more comprehensive representation of the heart’s functioning by measuring multiple biological molecules. Led by Hugo A. Katus, MD, PhD, of Heidelberg University Hospital (Heidelberg, Germany; www. heidelberg-university-hospital.com/en/home), the researchers began by identifying 92 metabolites (metabolic byproducts) that changed significantly in heart failure patients compared with healthy individuals. They chose 3 of these metabolites, which belong to the lipid classes of sphingomyelins, triglycerides, and phosphatidylcholines, for their cardiac lipid panel (CLP). The researchers then tested the ability of CLP combined with NT-proBNP measurements to diagnose heart failure in 649 individuals who either had the condition, were healthy, or had pulmonary diseases (which can often be misidentified as heart failure). CLP plus NT-proBNP diagnosed heart failure with much greater certainty than NT-proBNP alone, even in the early and asymptomatic stages, demonstrating a high specificity of 97.6% while NT-proBNP by itself has a specificity of only 88.1%. “A low false-positive rate is particularly important in the outpatient setting and may prevent patients from unnecessary diagnostic workup and treatment, which in turn will save resources and avoid potential side-effects,” said Dr. Katus, “A more accurate diagnosis of patients […] may accelerate adequate pharmacological or behavioral treatments for the reduction of mortality and morbidity.” Heart failure can also progress to congestive heart failure, which occurs when fluid builds up in the limbs, lungs, and/or other organs as an indirect result of the heart’s weakened pumping. Systemic congestion is a major determinant of organ dysfunction and death in chronic heart failure patients. Currently, there is no reliable test that can diagnose congestion in its pre-symptomatic stages, which is needed so that healthcare providers can start or adjust decongestive therapy for patients before the condition worsens. In a second paper, a group of researchers led by Alexandre Mebazaa, MD, of Université Paris Diderot (Paris, France; www.univ-paris-diderot.fr) showed that a test for the protein soluble CD146 (sCD146) could potentially detect congestion early. One of the initial signs of congestion is a subclinical increase of venous pressures. To determine if sCD146 is released as a response to this, the researchers compressed the dominant arm of 44 stable chronic heart failure patients and measured sCD146 levels in both arms at the start time and after 90 minutes. In the compressed arm, sCD146 levels increased significantly by 60 μg/L compared with a small 16 μg/L increase in the control arm. These results indicate that, if validated in larger studies, sCD146 could serve as a marker of increased venous pressure that signals the onset of congestion. Both studies, by Mueller-Hennessen M et al and by Arrigo M et al, were published January 6, 2017, in the Cardiovascular Disease special issue of the journal Clinical Chemistry.

LabMedica International June-July/2017

Image: New tests could improve treatment for heart failure patients by increasing diagnostic accuracy and early detection (Photo courtesy of Getty Images).

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have some effect on blood pressure. They then compared variants at the sites with information on each individual’s blood pressure information to confirm likely associations. To dissect the genetic architecture of blood pressure and assess effects on target organ damage, they analyzed 128,272 single nuclear polymorphisms (SNPs) from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. The teams identified 66 blood pressure–associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent.

The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. One surprising finding from the study was that many of the new sites identified were near genes that are active in cells that line the inside of blood vessels, suggesting those cells are somehow involved directly in blood pressure control. Aravinda Chakravarti, PhD, a professor of medicine and a lead investigator, said, “It is thought that about half the expla-

nation for our blood pressure comes from environmental and lifestyle factors, like diet, exercise and smoking, and the other half is controlled by our genes, but as with many other complex, multigene traits, pinning down what those genes are is challenging.” The study was published on September 12, 2016, in the journal Nature Genetics. Image: A recent JHU study showed how the human genome relates to blood pressure regulation (Photo courtesy of Shutterstock).

Next-Generation Systems Introduced for Clinical Laboratories harmonized family of nextgeneration systems across immunoassay, clinical chemistry, point of care, hematology, blood and plasma screening and molecular diagnostics has been unveiled. Many institutions and laboratories use multiple diagnostic platforms, often within a larger health care network and as they serve more patients and try to improve service levels with fewer qualified technicians, institutions are looking for new technologies that can help maximize testing efficiencies and help better manage resources. The Alinity systems (Abbott Diagnostics, Abbott Park, IL, USA; www. abbottdiagnostics.com) will have the ability to work together, providing greater capacity and simplifying the user experience. Several of the platforms will be designed to run more tests in less space, generate test results faster and minimize human errors. By offering a comprehensive solution that addresses the challenges of using multiple diagnostics platforms, while continuing to provide quality results that positively impact patient care, Alinity could potentially change the industry’s testing paradigm. Abbott expects Alinity launches to

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begin later this year and continue into 2017. The systems are supported by Abbott’s AlinIQ, the first-of-itskind, combined professional services and informatics solution that assists laboratories in achieving greater operational productivity with their existing resources. AlinIQ launched worldwide in April 2016. To develop each next-generation platform, Abbott’s scientific and development teams engaged with thousands of clinicians, scientists, laboratory technicians and health care executives. Dennis Gilbert, Ph.D., vice president at Abbott Diagnostics Products, said, “Abbott’s Alinity systems are being built from the ground up based on customer insights, using the latest technologies suitable for testing today and in the future. Whether it’s an easy-to-use software interface, running more tests faster or the ability to run any test at any time, our Alinity platforms are designed to include these features and more without any compromise in performance or quality.” The Alinity System was unveiled during the 68th AACC Annual Scientific Meeting & Clinical Lab Expo held July 31 to August 4, 2016, in Philadelphia, PA, USA (www.aacc.org). LabMedica International June-July/2017

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New Version of Online QC Management Program Available he new version of a cloud-based quality control (QC) management program is faster than its predecessor, has a simplified user interface, and provides an enhanced user experience. The Randox Laboratories Ltd. (Crumlin, United Kingdom; www.randox.com) Acusera 24•7 Live Online program is an interlaboratory data management and peer group reporting package that complements the Acusera range of true third party quality controls. Being cloud-based, Acusera 24•7 Live Online Version 2.0 avoids the necessity of local installation and frequent back-ups. Acusera 24•7 Live Online Version 2.0 upgrades and replaces the successful version 1.6, which had introduced several features including the automatic calculation of Sigma Metrics and Measurement Uncertainty. The biggest update to Version 2.0 is the ability to review peer data in real time. Previously, peer group statistics would have been updated every 24 hours, however, with this new update, data will be available for instant review. The ability to generate peer data live in real-time will enhance the laboratory’s troubleshooting capabilities and allow labs to compare their data with others around the world. Other updates to the software include more comprehensive charts and reports, bidirectional connectivity, speed improvements, and a complete make over to the dashboard display. Acusera 24•7 Live Online is a valuable QC tool for laboratories of all sizes. By participating and implementing this software, the user laboratory will be able to do the following: quickly identify trends, system errors and reagent issues, minimizing expensive repeat tests; automatically calculate Measurement Uncertainty, Total Error and Sigma Metrics; bridge the gap between daily quality control and external quality assessment; improve EQA (external quality assessment) performance by eliminating any undetected bias; facilitate regulatory compliance; reduce false rejections through the use of QC multi-rules; increase confidence in assigned QC target values; and speed up troubleshooting processes, shortening delays in reporting. Acusera 24•7 was designed primarily for use with the Randox Laboratory Acusera range of true third party controls, however, the software is flexible and can therefore be used with any QC material. Performance limits, QC multi-rules, and peer groups can be customized to suit each individual laboratory depending on user preferences for each different analyte, instrument, or lot of control. Randox Laboratories, which operates under the accreditation of ISO 13485:2003, has more than 30 years’ experience in research and development of in vitro diagnostic products and processes.

Image: The Acusera 24•7 Live Online is designed to be a valuable QC tool for labs of all sizes (Photo courtesy of Randox Laboratories). V

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Automated Imaging Speeds Up Infectious Disease Diagnosis utomated Plate Assessment System (APAS) is a breakthrough artificial intelligence technology for the automated imaging, image analysis, interpretation and reporting of growth on microbiology culture plates after incubation. Thousands of agar plates are assessed in busy laboratories every day and currently each one has to be examined by a microbiologist for the presence of significant bacterial colonies. APAS automatically screens, interprets and sorts these plates, freeing up the plate reading bottleneck in laboratory workflows and microbiologists’ time and enabling faster time to patient results. The US Food and Drug Administration (FDA, Silver Springs, MD, USA; www.fda.gov) have given 510(k) de novo submission clearance for the APAS as a class II device. The 510(k) de novo submission used a manual version of APAS to test 10,000 patients in a series of clinical trials conducted in Australia and the USA over a 12-month period. In each trial, APAS achieved its target primary endpoints

and the results matched or exceeded the findings of a panel of experienced microbiologists. The APAS was developed by LBT Innovations (Adelaide, Australia; www.lbtinnovations.com), and has been licensed on a global, exclusive basis to Clever Culture Systems AG (CCS, Bäch, Switzerland; www.cleverculturesystems.com), which is integrating APAS with laboratory robotic instrumentation. CCS plans to bring APAS to market in 2017 as an automated stand-alone plate reader (APAS Independence) closely followed by the integrated incubator (APAS Incubot). Brent Barnes, CEO of LBT Innovations, said, “FDA clearance follows rigorous interrogation and validation of the capabilities of APAS. The successful clinical trial program completed in 2015 and clearance by FDA also validate the underlying technology that is the core platform of our Company’s vision to integrate imaging with interpretative intelligence to deliver faster and more secure diagnoses for patients. FDA clearance is a fitting tribute to the

many years of painstaking work by LBT’s staff and partners, who together have made our shared vision a reality.” Image: The Automated Plate Assessment System, or APAS, is a platform technology for the automation of culture-plate screening and interpretation (Photo courtesy of Clever Culture Systems).

Smartphone-Based Analyzer Offers Accurate Diagnostic Testing martphone technology has been adapted to create low-cost multi-channel analyzers for accurate measurement of proteins and biomarkers for diagnostic use. Investigators at Washington State University (Pullman, USA; www.wsu.edu) have converted a smartphone into a multi-channel optical spectral sensing device with nanometer resolution. A prototype instrument comprised a three-dimensional printed cradle that held the smartphone integrated with optical components. The multichannel spectrometer component was built to measure the results of up to eight different ELISA tests at once. A dedicated smartphone multi-view application was developed to control the optical sensing param-

eters and to align each sample to the corresponding channel. The captured images were converted to the transmission spectra in the visible wavelength range from 400 nanometers to 700 nanometers with the high resolution of 0.2521 nanometers per pixel. The investigators used the prototype device to measure human interleukin-6 (IL-6), a known biomarker for lung, prostate, liver, breast, and epithelial cancers. The optical sensor performed accurate and reliable spectral measurements by detecting optical intensity changes at specific wavelength or optical spectral shifts. In laboratory controlled tests the smartphone device obtained results with detection limits, accuracy, and sensitivity that compared favorably to those from a standard laboratory instru-

ment. “With our eight channel spectrometer, we can put eight different samples to do the same test, or one sample in eight different wells to do eight different tests. This increases our device’s efficiency,” said senior author Dr. Lei Li, assistant professor of mechanical and materials engineering at Washington State University. “The spectrometer would be especially useful in clinics and hospitals that have a large number of samples without on-site labs, or for doctors who practice abroad or in remote areas. They cannot carry a whole lab with them. They need a portable and efficient device.” The eight channel smartphone bio-analyzer was described in the September 9, 2016, online edition of the journal Biosensors and Bioelectronics.

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Miniaturized Clinical Test Rapidly Detects Antibiotic Resistance new microfluidic concept for multi-analyte testing in a dipstick format, termed “Labon-a-Stick”, that combines the simplicity of dipstick tests with the high performance of microfluidic devices has been developed. Lab-on-a-stick tests are ideally suited to analysis of particulate samples such as mammalian or bacterial cells and capable of performing multiple different parallel microfluidic assays when dipped into a single sample with results recorded optically and a portable power-free test for the rapid detection of bacterial resistance to antibiotics has been developed. Scientists at Loughborough University (UK; www.lboro.ac.uk) and their colleagues carried out different cellular tests to demonstrate the full potential of Lab-on-a-Stick devices for a range of clinical situations. The utility of this new diagnostics format was demonstrated by performing three types of multiplex cellular assays that are challenging to perform in conventional dipsticks: instantaneous ABO blood typing; microbial identification; and antibiotic minimum inhibitory (MIC) concentration measurement. Anti-microbial resistance was measured with Escherichia coli samples typical of common urinary tract infection (UTIs). UTIs can be hard to treat with antibiotics because antibiotic resistance is so common and laboratory testing takes at least two days. The team demonstrated the advantage of using the microcapillary film, which enables 10 differ-

Image: The versatile Lab-on-a-stick device that can perform multiplex cellular assays (Photo courtesy of Loughborough University).

ent concentrations of antibiotic per sample to be tested with a single test strip. To identify bacteria, many different tests must be performed on every sample, illustrating again the benefits of microcapillary film, which performs 10 tests per test strip. This study demonstrated a fourhour test to distinguish two very closely related bacteria, a harmless laboratory strain of E. coli from Salmonella enterica that causes food poisoning. For ABO blood typing, a simple blood test that takes only two minutes was miniaturized and the results

were recorded using an everyday digital camera. Alexander D. Edwards, PhD, an associate professor and co-author of the study, said, “This is the latest demonstration of our exciting new technology called microcapillary film. What we have done is to develop a low cost way of making thousands of miniature test tubes, so that we can use them for many important applications. Lab-on-a-Stick shows yet again how versatile these microscopic test tubes are.” The study was first published online on June 23, 2016, in the journal Lab on a Chip.

Simple Saliva Test Developed to Diagnose Asthma urrent clinical tests employed to diagnose asthma are inaccurate and limited by their invasive nature, but a new test that can diagnose asthma from a patient’s saliva has now been developed. To diagnose an asthmatic condition doctors usually measure a person’s airflow lung capacity, however lung function tests can be inaccurate and do not reflect underlying changes associated with asthma. Other tests, such as blood, urine or sputum analysis can be distressing, particularly for younger patients. Scientists at Loughborough University (UK; www.lboro.ac.uk) and their colleagues developed a rapid analytical method for metabolite profiling of saliva is reported using ultrahigh performance liquid chromatography combined with high-resolution time-of-flight mass spectrometry (UHPLC-MS). The only sample pre-treatment required was protein precipitation with acetonitrile. The method has been applied to a pilot study of saliva samples obtained by passive drool from well phenotyped patients with asthma and healthy controls. The team performed an assessment

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on the complex dataset obtained from the UHPLC-MS analysis to identify potential metabolomic biomarkers of asthma in saliva. Ten discriminant features were identified that distinguished between moderate asthma and healthy control samples with an overall recognition ability of 80% during training of the model and 97% for model crossvalidation. The reported method demonstrates the potential for a noninvasive approach to the clinical diagnosis of asthma using mass spectrometry-based metabolic profiling of saliva. Colin Creaser, PhD, a professor of Chemistry and senior author of the study, said, “Unlike other sampling methods, such as expired breath analysis, saliva can be collected by passive drool from the very young to the very old without causing distress. We were therefore interested to know if techniques for metabolic profiling of saliva to identify physiological stress from exercise, which was developed by Loughborough University, could be applied to asthma diagnosis. We were very excited to discover that they could.” The study was published in the August 2016 issue of the journal Analytical Methods. LINKXPRESS COM

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Innate Immune Sensor of Microbial Proteolysis Revealed he human immune system can quickly recognize and respond to bacterial infections, but sometimes this reaction can become skewed, leading to autoimmune diseases such as rheumatoid arthritis. In this case, a person’s own immune system attacks “self” proteins instead of just foreign invaders. Interleukin 1 beta (IL-1 ) is a molecule that stimulates an immune response, calling white blood cells to the site of an infection so they can engulf and clear away invading pathogens. The body first produces the molecule in a longer, inactive form that must be cleaved to be activated. Scientists at the University of California - San Diego (La Jolla, CA,USA; www.ucsd.edu) investigated IL-1 function, team by analyzing the US Food and Drug Administration (FDA, Silver Springs, MD, USA; www.fda.gov) database on adverse events in rheumatoid patients who took anakinra, a drug that dampens autoimmunity by inhibiting IL-1 . They found that patients receiving anakinra were more than 300 times more likely to experience invasive, flesh-eating group A Streptococcus (GAS) infections than patients not taking the drug. IL-1 inhibition increased susceptibility to GAS infection, but IL-1 was produced independent of canonical inflammasomes. Newly synthesized IL1 has an amino-terminal prodomain that blocks signaling activity, which is usually proteolytically removed by caspase-1, a protease activated within the inflammasome structure. In place of host caspases,

the secreted GAS cysteine protease SpeB generated mature IL-1 . During invasive infection, GAS isolates may acquire pathoadaptive mutations eliminating SpeB expression to evade detection by IL1 . Pharmacological IL-1 inhibition alleviates this selective pressure, allowing invasive infection by non-pathoadapted GAS. Christopher LaRock, PhD, a postdoctoral scientist and first author of the study said, “This finding may explain why some of the more invasive, flesheating strep strains have a genetic mutation that blocks SpeB production which helps them avoid

tripping the alarm and setting off an immune response. A likely explanation for this increased risk is that with IL-1 out of the picture, as is the case with patients taking anakinra, strep strains can progress to invasive infection even while producing SpeB, which goes unnoticed by the immune system.” The study was published in the August 2016 issue of the journal Science Immunology. Image: Immune molecule IL-1ß (the “hot spots” shown) senses bacterial infections (Photo courtesy of the UC San Diego Health).

Proteomic Testing May Enable NIV Diagnosis of Respiratory Pathologies in Preterm Newborns team of researchers is developing its new method for noninvasive diagnosis and therapeutic response monitoring of conditions in preterm newborns based on marker sets now identified by proteome analysis of urine samples. The majority of patients in neonatal intensive care units are premature babies, who often have respiratory conditions. It is important to distinguish whether their illness is due to infection or a failure in the developmental process. The composition of biological fluids (e.g. blood, urine, saliva) is highly complex, and most current diagnostic procedures for neonatal intensive therapy include sample collections that are invasive (e.g. biopsy) or semi-invasive (e.g. blood sampling). Using high-performance mass spectrometry (HPMS; more specifically LC-MS/MS), experts from the Moscow Institute of Physics and Technology (MIPT; Moscow, Russia; https://mipt.ru/english) are identifying different proteins and determin-

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ing their concentrations in target fluids. Studies of the urinary proteome in pediatrics, especially in neonatology, are limited. In the new study, the team investigated the urine proteome of preterm newborns with respiratory pathologies. In order to further specify the defined infant-specific dataset, proteins were compared with the urinary proteome of healthy adults (men and pregnant women). “In our pilot study, we succeeded in defining the core urinary proteome and proteins specific for infants and pathological conditions. We are pioneers in the non-invasive identification of urinary biomarkers diagnosing respiratory conditions in newborns. The results are optimistic and will serve as a platform to move forward in developing a method of monitoring conditions in newborns,” said team leader Prof. Evgeny Nikolaev, head of MIPT’s Laboratory of Ionic and Molecular Physics. The study, by Starodubtseva NL, Kononikhin AS, et al, was published June 14, 2016, online ahead of print in the Journal of Proteomics. LabMedica International June-July/2017

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; Fax: (27) 012-328-3600; Email: enews@ifcc.org

NEWS

EuroMedLab Athens 2017 Etched In Memory Amid Unique Setting Katherina Psarra, Aggeliki Grigoratou, Alexander Haliassos On behalf of the Editorial Committee of EuroMedLab Daily News he 22nd IFCC-EFLM European Congress of Clinical Chemistry and Laboratory Medicine “EuroMedLab Athens 2017” took place in Athens, the cradle of western civilization, the birth place of Philosophy, under the shadow of the Acropolis. Held every two years, the congress was organized by the Greek Society of Clinical Chemistry Clinical Biochemistry (GSCC-CB), the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM). This year’s conference was co-organized along with the 25th Balkan Clinical Laboratory Federation (BCLF) meeting and the 15th National Congress of GSCC-CB. This was the accomplished achievement of enthusiastic people and devoted committees working together for a long time. “EuroMedLab Athens 2017 contributed to the promotion and recognition of the academic and clinical work in the field of diagnostics”, as was pointed out by the president of the congress, Dr. Alexander Haliassos. Through creative dialogues it aimed to broaden the cognitive field and deepen the knowledge of cutting-edge matters, promoting reflection and exchanges on the latest developments and innovations in Laboratory Medicine. The scientific program included, inter alia, lectures whose speakers are visionaries of the future in healthcare and laboratory medicine, in particular – “New vaccines and immunotherapies for AIDS and cancer”, “Human gene editing: The dawn, the zenith and the dusk”, “The influence of stress in human disease risk“, “Whole genome sequencing in health and disease” and 33 symposia with aggregate participation, especially from young colleagues. For the first time in EuroMedLab congresses and in cooperation with the “Young Scientists” Task Force of the IFCC, we introduced the "Meet the Expert" sessions, referred to in general interest subjects. All six of these sessions “Accreditation and laboratory management: why and how to do it”, “Success in research – academic career: Lessons and opportunities a workshop on how to draw up a scientific paper”, “How to succeed in science and laboratory medicine as a woman”, “Assessing vitamin D status in the clinical laboratory: Assays and interpretation are the key issues”, “Established and emerging biomarkers in heart failure diagnosis and management”, “Existing and emerging technologies in PoCT: The laboratory tests from the central laboratory to clinic to family practitioner to patient” – gave the opportunity for interactive discussion among the audience and expert scientists. Another highlight of the congress program included the public debates. The choice of debates aimed to make

Cont’d on page 62

LabMedica International June-July/2017

Acropolis of Athens, Greece

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EuroMedLab Athens 2017 Etched in Memory Amid Unique Setting

Photo: Delegates at a social dinner at Vouliagmeni Nautical Club (Attica, Greece).

Cont’d from page 61 scientific achievements more understandable to the general public as well as to specialized journalists of the healthcare sector. They offered them the opportunity to estimate the difficulties, with emphasis on those subjects which raise moral dilemmas. The debates covered capturing and interesting topics such as : “Lessons from 30 years of cancer screening”, “The ethics of gene editing”, “Direct to consumer testing (DCT). Ethical issues and confidentiality, “Antidoping testing”. The program also included scientific workshops delivered by in-vitro diagnostic companies, which presented the Europe’s largest and most interesting commercial exhibition of related instruments and reagents. Delegates welcomed the opportunity to get in direct contact with them.

IFCC Medals for Outstanding Service FCC is happy and proud to announce that IFCC Medals for Outstanding Service have been awarded to Prof. Paivi H. Laitinen (FI), Prof. Paolo Mocarelli (IT), Dr. Cas Weykamp (NL), and in memory of Prof. Daniel Mazziotta (AR). The IFCC Executive Board has introduced the “IFCC Medal for Outstanding Service” to be awarded to an individual in recognition of sustained service to IFCC at the highest level in promoting the international practice of Clinical Chemistry and Laboratory Medicine worldwide. The recipients were selected among highly regarded nominations.

Prof. Paivi H. Laitinen

Prof. Paolo Mocarelli

Dr. Cas Weykamp

Prof. Daniel Mazziotta

EuroMedLab Athens 2017 was full of worldrenowned scientists, researchers and accomplished professionals that made it the exciting and unforgettable event that it was. More than 5778 scientists from Europe and elsewhere, altogether 117 countries all over the world, registered and actively participated in the EuroMedLab Athens 2017. We would like you to remember Greece with its glorious tradition and everactive myth, the Aegean waves and the hospitality of the people. We hope we will meet you again in IFCCEFLM EuroMedLab Barcelona, in May 2019. Meanwhile, as the poet says, “to protect you I placed three guards: the sun on the mountain, the eagle on the plain, and the fresh north wind on the ships.”* Until we meet again, Kali Adamosi! * George Seferis, Greek poet (Nobel Prize in Literature, 1963)

Faecal Immunochemical Test (FIT) Working Group nalysis of haemoglobin (Hb) in faecal samples by immunochemistry, the faecal immunochemical test (FIT) is becoming commonplace in screening programmes across the world and recently published evidence is supporting it’s potential as a rule out test for use in patients with low risk symptoms suggestive of colorectal cancer (CRC). Commercial immunoassays are available for this analysis and FIT is rapidly replacing the traditionally used guaiac faecal occult blood test. The antibody in FIT binds to the globin moiety of the Hb molecule and the test offers numerous benefits over the guaiac method; only a signal stool collection is required (compared to 3 for guaiac), it only detects human Hb and we can obtain quantitative results enabling risk stratification and the potential to incorporate the results in to risk algorithms. Both quantitative and qualitative FIT tests are available. The qualitative tests tend to use lateral flow technology, and many are marketed as home testing devices. In the first instance it is anticipated that these will not be covered as part of the scope of the FIT working group. For quantitative FIT, faecal samples are typically collected into a FIT sampling device by the patient at their home. A small amount of faeces is loaded onto a grooved or dimpled stick then inserted into a bottle containing a preservative buffer. Tubes are then transported to the laboratory, often by normal postal service, for analysis. There is currently no harmonisation or standardisation of the FIT tests. Manufacturers have developed different antibodies, they have different buffering systems in the collection tubes to stabilise the Hb and not all assays are standardised to the same reference material. There is no established international EQA or IQC programme and there is limited/ no data available on a number of important an-

alytical factors such as the impact of Hb variants on the assays. Additionally the heterogeneity of faecal samples and the nature of the collection process leads to high levels of pre-analytical variability. The IFCC FIT-WG has been established to begin to address some of these issues. There has been great support and engagement in this project from both leaders in the field of CRC and FIT as well as the manufacturers of the quantitative FIT analytical systems. The objectives of the group in the first instance include; Determine the pitfalls in FIT and possible solutions Determine the role of Hb variants as confounding factors Determine the feasibility of developing reference materials and/or commutable calibrators Determine prerequisites for preanalytical phase standardization Establish EQA programmes Establish 3rd party IQC material Investigate sample stability Chair: Sally C Benton (UK); Group Members: Marieke Fasa (NL), Barcey Levy (USA), Han Mo Chiu (Taiwan), Josep-Maria Auge (Spain), Erin Symonds (Australia), Petr Kocna (Czech Republic), Natasha Djedovic (UK), Judith Strachan (UK), Heinz Schimmel (Belgium), Shizuka Takehara (Japan), Samantha Jones (UK); Corporate members: Maurizio Gramegna (Sentinel, Italy), Takuo Ichiyanagi (Eiken, Japan), Tsuyoshi Fukuda (Kyowa, Japan), Yasunobu Masuda (Kyowa, Japan), Mr Yosuke Doi (Alfresa, Japan), Dr Tetsuya Kosaka (Alfresa, Japan). IFCC OFFICE Via Carlo Farini 81, 20159 Milan, ITALY Tel: (39) 02-6680-9912 • Fax: (39) 02-6078-1846 E-mail: ifcc@ifcc.org • Web: www.ifcc.org Office Hours: 8.30-13.00 and 13.30-17.30 Staff Members: Paola Bramati, Silvia Cardinale, Silvia Colli-Lanzi

LabMedica International June-July/2017

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THE WORLD OF IFCC

Spanish Society of Laboratory Medicine (SEQCML): An Update hen speaking in front of an audience, only 15% of what actually reaches the public corresponds to the spoken message. In contrast, more than half the information retained by listeners lies in nonverbal communication. Indeed, the lecturer’s posture, gestures and eye contact tell a lot more about how he/she feels than mere words. These courses organized by the Esteve Foundation on “How to perform oral presentations in biomedicine” attempt to address all the aspects directly related to this skill. No matter how good the content selection is, how clearly and orderly the data are presented and how reliable the audiovisual support is, they will all be clean forgotten if the speaker’s enunciation, eye contact, posture and audience interaction are poor. This 32nd edition, held on 8- 9 March 2017 in Barcelona, organized in collaboration with the Spanish Society of Laboratory Medicine (SEQCML) was again imparted by four teachers who combine the two approaches. On the one hand, family physician Elena Muñoz and Pharmacology professor Maria Isabel Martín unveiled the keys to a good biomedical presentation. On the other hand, professional actors Àlex Mañas and Aina Clotet provided some tricks for good vocal and bodily expression. Theory and practice were combined during these two work days. The attendants had to perform different exercises to put their communication skills to the test. The objective was to perfect hand movements and body posture, to profit from eye contact, to improve improvisational capacity, to overcome embarrassing situations, etc. In the last course session, which consisted of delivering a five-minute presentation, each participant had to put into practice the knowledge acquired during the previous hours. That was when the many factors involved in a presentation were made clear, from the size and colour of the letters in a slide to the pace and volume of the speaker’s voice. The golden rule, however, is self-confidence, particularly when facing an audience involves significant psychological erosion. In the survey taken, the students evaluated the course very positively, and considered its presentation and what it empowered to be of great interest, as well as the offering of this type of activity to SEQCML members.

New eAcademy JCTLM Webinars on Standardization and Harmonization f you are strong in the use of laboratory methods for medical diagnosis and monitoring and wish to improve your understanding of the basic principles of establishing and maintaining accuracy and trueness of measurement results, participate in the eAcademy JCTLM webinar. You can access this one and all IFCC eAcademy webinars visiting the IFCC website at: http://eacademy.ifcc.org

LabMedica International June-July/2017

Photo: Professors and students of the course “How to perform oral presentations in biomedicine” organized by the Esteve Foundation in collaboration with the SEQCML in the Society headquarters.

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

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SERBIS on Wave of New Energy by Sanja STANKOVIC; Director of Center for Medical Biochemistry, Clinical Center of Serbia, Belgrade, Serbia; eJIFCC Editorial Board Member; General Secretary of European Society of Pharmacogenomics and Personalized Therapy nd SERbian BIomarker Symposium (SERBIS) (www.serbis.rs) with the overall theme ‘Biomarkers in diabetes: analytical and clinical perspectives’ was held on 23-24 February 2017 in Belgrade (Serbia). This international symposium was organized by the Center for Medical Biochemistry and Clinic for Endocrinology, Diabetes and Metabolic Disorders of Clinical Center of Serbia supported by Serbian Diabetes Society, Board on Cardiovascular Pathology of the Serbian Academy of Sciences and Arts and Belgrade University School of Medicine. It was organized under the auspices of IFCC, EFLM, ESPT, Ministry of Health and Ministry of Education, Science and Technological Development of Republic of Serbia, and under honorary patronage of TRH Crown Prince Alexander and Princess Katherine Karadjordjevic. The two day symposium included 15 foreign (from 10 different countries) and 6 Serbian expert speakers who presented their lectures, and was attended by 1374 health care professionals from Serbia and abroad. This international symposium was arranged to bridge clinical and laboratory work, emphasizing the importance of teamwork and interactions between all professionals involved in the fight against diabetes mellitus as an increasing global problem for public health. The 2nd SERBIS was in-

tended to display the state of the availability of reliable biomarker use at the interface between Diabetes mellitus and Laboratory Medicine. The official opening included the official welcome of symposium directors Dr Sanja Stankovic and Academician Nebojsa Lalic, welcome address of Prof. Sverre Sandberg-EFLM President, Prof. Philippe Gillery-Chair of IFCC-SD, Prof. Garry John-Chair of IFCC-EMD C-EUBD, Prof. Ron van Schaik-ESPT President, welcome on behalf of the Ministry of Health Republic of Serbia, Serbian Health Council, and Serbian Academy of Sciences and Arts. The great honour to the 2nd SERBIS was made with the attendance and addressing by HRH Crown Princess Katherine of Serbia during the opening ceremony. At the end of opening ceremony, charter award and the statue of Serbian goodness of knowledge about biomarkers “SERBICA” was delivered to the honorable President of the 2nd SERBIS, Prof. Philippe Gillery (FR) in recognition of his outstanding contribution toward the success of this symposium. The working part of symposium included overview of the most recent advances in diagnosis and management of diabetes focusing on HbA1c (Prof. Garry John (UK), Dr David Sacks (US), Prof. Antionio Ceriello (IT), Academician Nebojsa Lalic (RS), Prof. Aleksan-

Photo: Speakers at the conference

dra Jotic (RS)) and especially on new biomarkers (Prof. Philippe Gillery (FR), Prof. Joris Delanghe (BE), Dr Michèle Fonfrede (FR)), advantages and pitfalls of HbA1c POCT (Prof. Sverre Sandberg (NO)), pharmacogenetics and personalized treatment of diabetes (Prof. Ron van Schaik (NL), Dr Sanja Stankovic (RS)). Also, valuable insight was gained on standardization of HbA1c assays (Dr Erna Lenters-Westra (NL)) and clinical outcomes of HbA1c standardization (Prof. Eric Kilpatrick (QA)), NGSP experience of HbA1c (Prof. Randie Little (US)) and interferences on HbA1c assays (Prof. Andrea Mosca (IT)). The last section of 2nd SERBIS included lectures linking diabetes and cardiovascular disease (Serbian Academicians Vladimir Kanjuh, Dragan Micic, Petar Seferovic and professors Katarina Lalic and Goran Stankovic, and Dr Paivi Latinen (FI)). With the idea to support education and expanding the horizons of colleagues who work in the field, in the closing ceremony one clinical chemistlucky winner of 2nd SERBIS, was

awarded with registration fee/accommodation/travel expenses for the EuroMedLab 2019. We open the door to SERBIS and we are convinced that SERBIS will be a top level educational and scientific event in our region, giving to the participants an excellent opportunity for education, improvement of personal achievements and collaboration with colleagues from different countries. It is also an opportunity to keep up to date with industry partners who showcase the latest advances in bio-technology innovations, novel assays and therapies in diabetes field in their booths. “I have found the most beautiful place since antiquity” wrote Prince Stefan Lazarevic when he established Belgrade as the Serbian capital over 600 years ago. Belgrade has since been a gate to the East, Door to the West, and a lighthouse in the sea of time. The Belgrade’s wealth of historical, cultural and social attractions enriched SERBIS experience! See you on the 3rdSERBIS, eye-opening and mind-expanding experience for everyone involved!

IFCC Welcomes Three New Members Kosova Association of Clinical Chemistry (KACC) – Full Member KACC headquarter office is located in Pristina. Amongst the aims of KACC are: the union of Clinical Biochemists and their commitment to advance the profession and science of Clinical Biochemistry in the country, the promotion of scientific activities of the members of the society; the encouragement of professional work in the Clinical Biochemistry area and in other areas of laboratory diagnostic; the representation of the membership in all important occasions, promoting the medical laboratory profession in all areas for better diligence of health; support to the profession and educational advice; cooperation with local, national and international organizations and support to every aspect of the professional activities of society members.

Association for Quality Assurance of Laboratory Medicine - AQALM, Ukraine – Affiliate Member Since its foundation, AQALM main purpose is the realization and protection of legitimate social, scientific, economic, creative, age and other common inter-

ests of its members and activities aimed at promoting the development of laboratory medicine and improve the quality of medical laboratory services in Ukraine. Amongst its objectives is the creation of quality assurance system for clinical laboratory tests; promotion of development and implementation of regulations concerning the quality of clinical laboratory tests and other regulations; promotion of the development and introduction of modern methods of quality management of medical laboratory services to medical laboratories work; participation in the establishment and maintenance of public and private external quality assessment of clinical laboratory tests, including on the basis of international cooperation; on behalf of the Ministry of Health of Ukraine performing of professional certification, certification and licensing specialists / experts on laboratory medicine; organization of symposia, scientific conferences, seminars, workshops, lectures, courses and other scientific and educational activities and duties, without the intention of making a profit; provision of high quality patient care.

industry chain of IVD and focusing on laboratory medicine, consisting of incubator department, media department, CRO department and exhibition department, committed to the domestic and foreign IVD companies to provide the whole industry chain services. Web: www.ivdchina.com

Reduced Registration Deadline Extended Don’t miss the deadline to enjoy a reduced registration fee for the 14th International Congress of Paediatric Medicine, October 20-22, 2017, Durban, South Africa: August 7, 2017.

Beijing Dream Diagnostics Medicine Technology Co. Ltd. Beijing Dream Diagnostics Medicine (DDM) Technology Co., Ltd. is one of the mainstream IVD consultation groups in China providing services for the whole LabMedica International June-July/2017

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VIEWPOINT

Healthcare Systems Evolve Worldwide, Facing Increased Challenges by Dr. Bernard Gouget Counselor for Public Health FHF; Chair-Human Health Care Committee-COFRAC; IFCC Chair-Nominations Committee; General Secretary of the International Francophone Federation Of Clinical Biology and Laboratory Medicine (FIFBCML)

e are facing a rapidly changing society affected by underlying trends such as globalization, spread of newly-emerging and rapidlychanging infectious diseases, bioterrorism, and changes in disease patterns, all around the world. Significant climate change patterns anticipated in the decades ahead can be expected to modify disease patterns, while fear of the future in a post-modern world could lead to new mental-health challenges. Furthermore, a changed demography skewed toward an aging population would result in an increased demand for healthcare. An aging population is not just a concern for high-income countries. The majority of older people already live in low-and middle-income countries, and this is where some of the fastest rates of population aging are occurring. This demographic transition in the elderly population constitutes a significant challenge for health authorities worldwide, including a rise in the occurrence of multiple chronic diseases associated with emerging high-cost treatments. To cope with such challenges, every country needs robust and affordable healthcare systems for the well-being of its population. This means that every patient needs to have easy access to a wide network of hospitals, medical doctors, care facilities and services, including medical laboratories. A good healthcare system should also ensure that every patient can afford efficient common treatments and medications. Simultaneously, new technological advances, whether in the volume of health data generated, or in our ability to process and analyze the same data, are increasingly impacted by advances in robotics or a meteoric rise in mobile and wearable technologies and remote monitoring systems. Such advances are breaking down the information walls of the hospitals and doctors' clinics, thereby empowering people to better assess and monitor their own health in real time. It has become something of a cliche that organizations are having to change like never before. We can project that advances in healthcare are de facto driven by original, inno-

LabMedica International June-July/2017

vative, high-quality biomedical research and its rapid applications to diagnostics, therapy, healthcare, and public health. However, a first ever global study, organized by the Institute for Health Metrics and Evaluation, finds massive inequity of access to and quality of healthcare among, indicating that an extensive number of people are dying from problems whose treatments already exist. The study, published recently in The Lancet, set out to assess the availability and quality of healthcare services worldwide from 1990 to 2015 in 195 countries. Researchers created a Healthcare Access and Quality (HAQ) index based on numbers of deaths from 32 causes, including tuberculosis, breast and other cancers, leukaemia, cardiovascular and respiratory diseases, haemopathies, diarrhea-related diseases, diabetes, kidney and maternal-neonatal disorders, adverse effect of medical treatment, etc, that could be avoided by timely and effective medical care. The study aimed to use these results to better understand gaps and opportunities for improving healthcare access throughout the world. The paper does offer some favorable signs of improvement in healthcare access and quality. Since 1990, several countries have achieved progress that met or surpassed levels reached by other nations in similar level of development. These countries included Turkey, Peru, South Korea, the Maldives, Niger, Jordan, and several Western European nations such as Iceland (2nd), Switzerland (3th), Norway (5th), Spain (8th), Netherlands (9th) and France (15th). 13 of the top 15 countries are from Europe, the two others are Australia (6th) and Japan (11th). The UKâ&#x20AC;&#x2122;s health performance (30th) is better than the US ranked in 35th place, but has a low score in cancer care and lags behind many of its European neighbours including Finland (7th), Sweden (4th), Italy (12th) which have similar health systems. The top ranking is the tiny principality of Andorra. Nonetheless, nations in much of sub-Saharan Africa, as well as in South Asia and several countries in

Latin America and the Caribbean, experienced the lowest rankings. India has to improve its targets in neonatal disorders, maternal health, and tuberculosis. At the bottom of the table are Somalia, Afghanistan, and Central African Republic. China and Ethiopia, have seen sizeable gains since 1990. The results found about healthcare access and quality are somewhat disturbing. Virtually all countries improved over 25 years but many especially in Africa and Pacific regions fell behind the others in providing basic care for their citizens as well as in equality between the best and worst performing countries has grown. The warning sign is that having a strong economy does not guarantee good healthcare and having

great medical technology does not either! The interesting outcome of these data is to provide a necessary baseline for the governments to move ahead and track progress. In this context and through its regions, the IFCC has a key role to play in promoting an integrative approach based on multidisciplinary expertise to advance healthcare-related research and management, as well as in implementing Predictive, Preventive and Personalized Medicine. We need to be most effective in delivering not only high-quality results, but also to be more involved in applying early detection efforts, such as screening at-risk populations, as well as strategies for appropriate management of existing diseases and related complications. The objective of Lab Medicine is to identify knowledge gaps, to advance research with innovative biomarkers, and ultimately to promote best practices and solutions for achieving more inclusive and sustainable services toward delivering relevant and optimal patient-centred health systems accessible by each citizen.

Industry News

International Calendar

PerkinElmer to Acquire EUROIMMUN erkinElmer, Inc. (Waltham, MA, USA; www.perkinelmer. com), a provider of products, services and solutions for the diagnostics, research, environmental, industrial and laboratory services markets, has entered into a definitive agreement to acquire EUROIMMUN Medical Laboratory Diagnostics AG (Lübeck, Germany; www.euroimmun. com), which produces test systems and automation solutions for medical laboratory diagnostics. PerkinElmer’s detection, imaging, informatics and service capabilities

help customers solve critical issues, especially impacting the diagnostics, discovery and analytical solutions markets. EUROIMMUN specializes in autoimmune testing, and infectious disease and allergy testing, with extensive expertise and capabilities across immunology, cell biology, histology, biochemistry and molecular biology. The acquisition of EUROIMMUN will expand PerkinElmer's reach into autoimmune and allergy diagnostic markets, while offering new infectious disease capabilities to customers in China.

Blood Testing Market Surpasses USD 2 Billion in 2016 he global market for blood testing and typing products used in blood banking/donations of pooled blood reached USD 2.6 billion in 2016, although blood banking is not a fast-growing market and tends to grow only when new diseases are added to testing menu. These are the latest findings of Kalorama Information, (New York, NY, USA; www. kaloramainformation.com), an independent medical market research firm. In its study of the testing markets amidst increased vigilance by U.S.

health authorities and cases of Zika and other diseases, Kalorama found three common types of tests related to blood banking. Immunoassays for HIV, hepatitis B, hepatitis C and syphilis are routinely used to test blood units for blood borne infectious agents. In Latin America, all blood banks also screen donated units for Chagas disease while in some developing countries, blood banks undertake additional screening for Dengue fever and malaria, which are common and deadly in several tropical nations.

Brazilian IVD Market Fueled by Growing Demand razil's in vitro diagnostic (IVD) market is one of the largest, driven by increasing interest in molecular testing technologies, prenatal screening, and point-of-care (POC) glucose testing. Brazil, which has a growing middle class, stabilizing economy, increasing urban population, and a supportive government, is witnessing a major shift toward the private health industry, which supports the growth of IVD technologies that are expensive or not typically covered at the public level. These are the latest findings of Kalorama Information, (New York, NY, USA; www.kaloramainformation.com), an

independent medical market research firm. Brazil is the world’s sixth most populated country with 205.8 million people residing in the country in 2016 and has a market worth over USD 900 million. Brazil’s population distribution is expected to shift toward the 65 years and above age group, which will account for 21% of its total population by 2050, up from 7% in 2010. This shift in the country’s aging population is expected to lead to an increase in the incidence of diseases, as an aging population is more vulnerable to illness.

Alliance to Digitalize Medicine and Healthcare he Universitätsklinikum Erlangen, Siemens Healthineers (Erlangen, Germany; www.healthcare.siemens.com), the Friedrich-Alexander-Universität-Erlangen-Nürnberg (FAU), the Fraunhofer Institute for Integrated Circuits (IIS), and Medical Valley EMN have entered into an alliance to establish the Digital Health Innovation Platform (d.hip) with the aim of driving digitalization in medicine and healthcare. Founded in 1815, the Universitätsklinikum Erlangen covers all the ar-

eas of modern medicine with its 24 departments, 19 independent departments, and 7 institutes, and uses the latest knowledge from medical research and state-of-the-art equipment. The FAU, founded in 1743, is one of the largest universities in Germany, with around 40,000 students, 263 degree programs, 4,000 academic staff in the sciences (including 576 professors), about 180 million euros (2016) in third-party funding, and 500 partnerships with universities around the world.

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

International Calendar, LabMedica International P.O.Box 802214, Miami, FL 33280-2214, USA Fax: 1-954-893-0038 • E-mail: info@globetech.net

JULY 2017 ESHRE 2017 - European Society for Human Reproduction and Embryology Annual Meeting. Jul 2-5; Geneva, Switzerland; Web: www.eshre.eu FEMS 2017- 7th Cong. of European Microbiologists. July 9-13; Valencia, Spain; Web: www.fems-microbiology2017.kenes. com AACC 2017 – 68th Annual Meeting of American Association for Clinical Chemistry. July 30-Aug 3; San Diego, CA, USA; www.aacc.org

AUGUST 2017 FIME 2017 - Florida International Medical Exhibition. Aug 8-10; Orlando, FL, USA; Web: www.fimeshow.com

SEPTEMBER 2017 ESP 2017 - 29th European Congress of Pathology. Sep 2-6; Amsterdam, Netherlands; www.esp-congress.org ASCP 2017 – American Society for Clinical Pathology. Sep 6-8; Chicago, IL, USA; Web: www.ascp.org Eurotox 2017 – 53rd Congress of the European Societies of Toxicology. Sep 10-13; Bratislava, Slovakia; Web: www. eurotox2017.com 43rd Annual Meeting of the American Society for Histocompatibility and Immunogenetics (ASHI). Sep 11-13; San Francisco, CA, USA; Web: www.ashi-hla. org 20th Annual Meeting of the ESCV, European Congress of Virology. Sep 1316; Lago Maggiore, Italy; Web: www. escv.org 10th International Meeting of Pediatric Endocrinology. Sep 14-17; Paris, France; Web: http://internationalmeeting2017.org COLABLIOCLI 2017. Sep 17-20; Punta del Este, Uruguay; Web: www.colabiocli 2017uy.com 13th EFLM Symposium for Balkan Region. Sep 21-22; Belgrade, Serbia; Web: www.dmbj.org.rs 9th International Conference and Exhibition on Analytical & Bioanalytical Techniques. Sep 27-29; Atlanta, GA, USA; Web: http://analytical-bioanalytical. pharmaceuticalconferences.com

OCTOBER 2017 BSACI – British Society of Allergy & Clinical Immunology Annual Meeting. Oct 1-3; Telford, UK; Web: www.bsaci.org 41st European Congress of Cytology. Oct 1-4; Graz, Austria; Web: www.efcs.eu 8th International Conference and Exhibition on Analytical & Bioanalytical Techniques. Oct 16-18; Milan, Italy; Web: http://analytical-bioanalytical. pharmaceuticalconferences.com ASHG 2017 - The American Society of Human Genetics. Oct 17-21; Orlando, FL, USA; Web: www.ashg.org

14th International Congress of Paediatric Laboratory Medicine (ICPLM). Oct 20-22; Durban, South Africa; www.ifcc.org IFCC PoCT Satellite Meeting. Oct 21; Durban, South Africa; www.ifcc.org IFCC WorldLab 2017. Oct 22-25; Durban, South Africa; www.ifcc.org FEBS3 – 40th SEBBM Congress. Oct 23-26; Barcelone, Spain

NOVEMBER 2017 MEDICA 2017. Nov 13-16; Dusseldorf, Germany; Web: www.medica.de 2017 AAPS Annual Meeting and Exposition – American Association of Pharmaceutical Scientist. Nov 13-17; Denver, CO, USA; Web: www.aaps.org AMP 2017 - Annual Meeting for Association for Molecular Pathology. Nov 1618; Salt Lake City, UT; USA; Web: www.amp.org

JANUARY 2018 CBRD 2018 - 5th Caribbean Biomedical Research Days. Jan 16-18; Rodney Bay, Saint Lucia; Web: www.stress-andbehavior.com

FEBRUARY 2018 SLAS 2018 - Society of Laboratory Automation and Screening. Feb 3-7; San Diego, CA, USA; Web: www.slas.org Labquality Days 2018. Feb 8-9; Helsinki, Finland; Web: www.labquality.fi 13th Annual Biomarkers Congress. Manchester, UK; Web: www.biomarkerscongress.com Pittcon 2018. Feb 26-Mar 1; Orlando, FL, USA; Web: http://pittcon.org

MARCH 2018 ExpoMedica 2018. Mar 22-25; Istanbul, Turkey; Web: http://expomedistanbul.com AIUM Annual Convention 2018 – American Institute of Ultrasound in Medicine. Mar 24-28; New York, NY, USA; Web: www.aium.org ENDO 2018 – Endocrine Society. Mar 17-20; Chicago, IL, USA; Web: www. endocrine.org

APRIL 2018 ECCMID 2018 — 28th European Congress of Clinical Microbiology and Infectious Diseases. Apr 21-24; Madrid, Spain; Web: www.eccmid.org

MAY 2018 20th European Congress of Endocrinology. May 19-22; Barcelona, Spain; Web: www.ese-hormones.org AAI Immunology 2018 - American Association of Immunologists. May 4-8; Austin, TX, USA; Web: www.aai.org

JUNE 2018 ESHG 2018 - European Human Genetics Conference. Jun 16-18; Milan, Italy; Web: www.eshg.org LabMedica International June-July/2017

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Diagnostica Stago . . . . . . . . . . .41

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Maccura . . . . . . . . . . . . . . . . . .49

106

77 Elektronika . . . . . . . . . . . . . . .6

143

Diagnostica Stago . . . . . . . . . . .43

132

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110

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114

Medix Biochemica . . . . . . . . . . .14

133

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108

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122

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139

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158

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153

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134

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102

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115

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159

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109

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151

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129

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160

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105

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121

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112

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107

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138

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145

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103

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135

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–

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137

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157

Boule Diagnostics . . . . . . . . . . .57

–

IFCC WorldLab 2017 . . . . . . . .63

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120

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119

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147

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126

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127

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154

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168

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161

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155

Lifotronic . . . . . . . . . . . . . . . . . .55

131

Zivak . . . . . . . . . . . . . . . . . . . . .31

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