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Cell-Free DNA Test Screens for Trisomies renatal screening for trisomies 21, 18, and 13 is currently performed using multiple maternal serum and ultrasound markers. Clinical implementation studies of maternal plasma cell free (cf)-DNA testing have demonstrated a much higher sensitivity and specificity

Expert Panel Releases Guideline On Diagnosis of Fungal Infections n official clinical guideline on laboratory diagnosis of fungal infections in pulmonary and critical care medicine was released in a recent publication. Timely diagnosis of fungal infections, which are of increasing incidence and importance in im-

munocompromised and immunocompetent patients, relies on appropriate use of laboratory testing in susceptible patients. In this regard, a panel of 11 experts in pulmonary and critical care, infectious disease, and invasive procedures appointed by the

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

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Artificial Intelligence Set to Transform Clinical Microbiology

Blood Test Detects Brain Injury in Minutes fter traumatic brain injury (TBI), plasma concentration of glial fibrillary acidic protein (GFAP) correlates with intracranial injury visible on computerized axial tomography (CT) scan. Some patients with suspected TBI with normal CT findings show pathology on magnetic resonance imaging (MRI). Recently scientists have found that a handheld blood analyzer

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Protein Panel for Early Lung Cancer Detection ung cancer is the most common cause of cancer-related mortality worldwide, characterized by late clinical presentation as 49%–53% of patients are diagnosed at stage IV, and consequently have poor outcomes. Screening with low-dose computed tomography (LDCT) has proven effective at reducing lung cancer mortality in high-risk populations, but there is still considerable uncertainty

pplying deep machine learning to image analysis, researchers have developed the world's first AI-augmented parasite detection system. By quickly screening out negative results and allowing laboratorians to focus on positive slides, the new technology could revolutionize clinical microbiology.

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Next-Generation Electrolyte Analyzer Eliminates Need for Individual Electrodes

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he EC 90 electrolyte analyzer replaces traditional electrodes that need to be changed periodically, with a novel all-in-one cartridge, which incorporates thick film technology to deliver accurate, reliable and fast results at lower cost.

Clinical News . . . . 4-60 IFCC News . . . . . . . . 61 Product News . . 20-60 Industry News . . . . .65 Events Calendar . . . 66

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Brain Biomarkers Predict Alzheimer's Risk and Progression

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cluster of genes has been identified that modulates the activity of TREM2 (Triggering receptor expressed on myeloid cells 2), a protein biomarker for risk and progression of Alzheimer’s disease (AD). Soluble TREM2 (sTREM2) has

been detected in human cerebrospinal fluid (CSF), where it was found to be elevated in CSF of patients with multiple sclerosis and other inflammatory neurological conditions in comparison to patients without inflammatory neurologic disorders. Moreover, Cont’d on page 6

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LabMedica International

Artificial Intelligence Set to Transform Clinical Microbiology

labmedica.com EDITORIAL BOARD Graham Beastall United Kingdom Claus Christiansen Denmark Hernán Fares Taie Argentina Bernard Gouget France Maurizio Ferrari Italy Jocelyn M. Hicks United States Anders Kallner Sweden Tahir S. Pillay South Africa Andreas Rothstein Colombia Dmitry B. Saprygin Russia Praveen Sharma India Rosa I. Sierra-Amor Mexico Peter Wilding United States Andrew Wootton United Kingdom A GLOBETECH PUBLICATION

joint undertaking between two University of Utah research affilates has unveiled the world’s first AI-augmented ova and parasite detection tool. For laboratorians, the digitally-enabled workflow is expected to decrease the physical demands of looking through a microscope for extended periods of time, including eye fatigue and neuromuscular tension. The technology can thus quickly screen out negative results, allowing laboratorians to spend more time analyzing positive slides. The ova and parasite tool is first among several projects being co-developed by ARUP Laboratories (Salt Lake City, UT, USA; www. aruplab.com) and Techcyte (Lindon, UT, USA; www.techcyte.com). ARUP’s medical expertise and access to samples, combined with Techcyte’s technical ability and digital evaluation platform, are envisioned to produce high quality algorithms that can be developed and applied to future unmet laboratory needs. Techcyte’s digital diagnostics platform applies the latest in convolutional neural networks to pre-classify the fecal sample images captured by a 3DHISTECH Pannoramic 250Flash III scanner. Pre-classifying the images using the Techcyte tool allows ARUP’s technolo-

gists to efficiently read stained glass slides manually and improves the accuracy of parasite detection. “The collaboration with Techcyte has produced an AI-augmented detection tool that significantly advances our diagnostic capabilities in our parasitology lab,” said Adam Barker, PhD, director of Research and Development at ARUP. “This will allow for faster turnaround times, decreased costs, employee satisfaction and improved patient care.” “Microscopy-based diagnostic parasitology has remained woefully static for decades. We have successfully developed a pioneering breakthrough with this tool, the likes of which had previously been unimaginable by classically trained microbiologists,” said Dr. Marc Couturier, medical director of ARUP’s Parasitology labs. “This revolutionary partnership will combine ARUP’s vast expertise and reputation in the market with Techcyte’s AI-based image analysis capabilities to change the way lab diagnostics are performed,” said Ralph Yarro, CEO of Techcyte. Image: A screenshot of E. coli fecal samples (Photo courtesy of Techcyte / Dr. Keith Kaplan).

Protein Panel for Early Lung Cancer Detection cont’d from cover

and debate about how to best define these populations. Currently, this is primarily done based on age and smoking history, but protein and other biomarkers could play a role as well. Scientists at the University of Manchester (Manchester, UK; www.manchester.ac.uk) analyzed 50 serum samples from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) biobank, 25 from healthy controls and 25 from patients who were diagnosed with lung cancer within 50 months of the blood draw. The team used blood collected during surgical resection of lung tumors in an iTRAQ isobaric tagging experiment to identify proteins effluxing from tumors into pulmonary veins. The team used sequential window acquisition of all theoretical fragment ion spectra (SWATH) on a Sciex TripleTOF 6600 mass spectrometer (Framingham, MA, USA; https:// sciex.com) to analyze the serum samples. The

samples were run using a two-hour liquid chromatograph (LC) gradient, and they identified 65 proteins that were differentially expressed between the two groups. Using hierarchical clustering and principal component analysis, they identified a panel of 11 proteins that distinguished between cases and controls one year prior to diagnosis with sensitivity of 88% and specificity of 89%. A 12-protein panel that included a marker identified by earlier research was able to distinguish between cases and controls at three years to diagnosis with sensitivity of 79% and specificity of 78%. Anthony D. Whetton, PhD, a Professor and lead author of the study, said, “I think the ideal is that we have a blood-borne biomarker test for risk and stratification, so that one can look at the results of this test and determine whether further follow-up is required. I think that’s the space that is awfully important with respect to lung cancer.” The study was published on August 13, 2019, in the Journal of Proteome Research.

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ISSN 1068-1760 Vol.36 No.7. Published, under license, by Globetech Media LLC; Copyright © 2019. All rights reserved. Reproduction in any form is forbidden without express permission. Opinions expressed are solely those of the authors, and do not represent an endorsement, or lack thereof, by the Publisher of any products or services. Teknopress Yayıncılık ve Ticaret Ltd. Şti. adına İmtiyaz Sahibi: M. Geren • Yazı işleri Müdürü: Ersin Köklü Müşir Derviş İbrahim Sok. 5/4, Esentepe, 34394 Şişli, İstanbul P. K. 1, AVPIM, 34001 İstanbul • E-mail: Teknopress@yahoo.com Baskı: Postkom A.Ş. • İpkas Sanayi Sitesi 3. Etap C Blok • 34490 Başakşehir • İstanbul Yerel süreli yayındır. Yılda sekiz kere yayınlanır, ücretsiz dağıtılır.

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Blood Test Detects Brain Injury in Minutes cont’d from cover

could help detect brain injury within 15 minutes using a commercial system that measures GFAP and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) proteins from the brain that are released into the blood after a brain injury, They assessed the discriminative ability of GFAP to identify MRI abnormalities in patients with normal CT findings. Neurologists at the University of California at San Francisco (San Francisco, CA, USA; www.ucsf.edu) and their associates enrolled patients with TBI who had a clinically indicated head CT scan within 24 hours of injury at 18 level 1 trauma centers in the USA. For this analysis, they included patients with normal CT findings (Glasgow Coma Scale score 13–15) who consented to venipuncture within 24 hours post injury and who had a MRI scan 7–18 days post injury. They compared MRI findings in these patients with those of orthopedic trauma controls and healthy controls recruited from the study sites. Plasma GFAP concentrations (pg/mL) were measured using a prototype assay on a point-of-care platform, the hand-held blood analyzer, the iSTAT Alinity system (Abbott Point of Care Inc, Princeton, NJ, USA; www.pointofcare.abbott). The scientists used receiver operating characteristic (ROC) analysis to evaluate the discriminative ability of GFAP for positive MRI scans in patients with negative CT scans over 24 hours (time between injury and venipuncture). The primary outcome was the area under the ROC curve (AUC) for GFAP in patients with CT-negative and MRI-positive findings versus patients with CTnegative and MRI-negative findings within 24 hours of injury. The team recruited between February 26, 2014, and June 15, 2018, 450 patients with normal head CT scans (of whom 330 had negative MRI scans and 120 had positive MRI scans), 122 orthopedic trauma controls, and 209 healthy controls. AUC for GFAP in patients with CT-negative and MRI-positive findings versus patients with CT-negative and MRI-negative findings was 0·777 over 24 hours. Median plasma GFAP concentration was highest in patients with CT-negative and MRI-positive findings (414.4 pg/mL), followed by patients with CT-negative and MRI-negative findings (74.0 pg/mL), orthopedic trauma controls (13.1 pg/mL), and healthy controls (8.0 pg/mL, all comparisons between patients with CTnegative MRI-positive findings and other groups. The authors concluded that analysis of blood GFAP concentrations using prototype assays on a point-of-care platform within 24 hours of injury might improve detection of TBI and identify patients who might need subsequent MRI and follow-up. The study was published on August 23, 2019, in the journal The Lancet Neurology.

LabMedica International November/2018

Image: The i-STAT Alinity system integrates with-patient testing directly into the patient-care pathway, accelerating time to treatment, improving quality and increasing access to care (Photo courtesy of Abbott).

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Brain Biomarkers Predict Alzheimer's Risk and Progression cont’d from cover

while genetic variants in TREM2 are associated with AD risk and change with AD progression, genetic modifiers of CSF sTREM2 remain unknown. In order to better understand the role of sTREM2 in AD, investigators at Washington University School of Medicine (St. Louis, MO, USA; www.wustl.edu) performed a genome-wide association study (GWAS) to identify genetic modifiers of sTREM2 in samples of CSF provided by the Alzheimer’s Disease Neuroimaging Initiative (https:// adni.loni.usc.edu). For this study, the investigators measured sTREM2 levels in the cerebrospinal fluid of 813 older adults, most of whom were ages 55 to 90. Of those subjects, 172 had Alzheimer’s disease, 169 were cognitively normal, and 183 had early mild cognitive impairment. Results revealed that common variants in the membrane-spanning 4domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. A single-nucleotide polymorphism (SNP) modified expression of the MS4A4A and MS4A6A genes in multiple tis-

sues, suggesting that one or both of these genes were important for modulating sTREM2 production. The investigators used human macrophages as a proxy for brain microglia to show that MS4A4A and TREM2 co-localized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggested that MS4A4A was a modulator of sTREM2. “We observed TREM2 risk variants more often in people who had Alzheimer’s or were mildly cognitively impaired, compared with those who were cognitively normal,” said contributing author Dr. Celeste Karch, assistant professor of psychiatry at Washington University School of Medicine. “It turns out that about 30% of the population in the study had variations in the MS4A4A gene that appear to affect their risk for developing Alzheimer’s disease. Some variants protected people from Alzheimer’s or made them more resilient while others increased their risk.” The study was published in the August 14, 2019, online edition of the journal Science Translational Medicine.

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Next-Generation Electrolyte Analyzer Eliminates Need for Individual Electrodes any laboratories are experiencing difficulties when using ion-selective electrode (ISE) analyzers with traditional electrodes, as the electrodes must be replaced periodically. Failing electrodes can give erroneous results, interrupt workflows and are expensive to replace. To solve this problem, Erba Mannheim (London, UK; www.erbamannheim.com) has developed the EC 90 electrolyte analyzer. The instrument is an automated, microprocessor-controlled analytic analyzer that uses ISE technology for the measurement of ions – potassium (K), sodium (Na), chloride (Cl), and calcium (Ca) – in human body fluids. The analyzer eliminates the need for individual electrodes by using a novel, all-in-one cartridge, which incorporates thick film technology to deliver accurate, reliable and fast results at low cost. The cartridges have an on-board stability of three months, and no additional reagents or electrode maintenance are required. The entire cartridge can simply be replaced as needed. The EC 90 combines cutting-edge technology with production efficiency. It is capable of measuring Na, K, Cl and Ca ions in 35-microliter samples of whole blood, plasma, serum or diluted urine in only 35 seconds. An ISE is a transducer (or sensor) that converts the activity of a specific ion dissolved in a solution into an electrical potential. The voltage is theoretically dependent on the logarithm of the ionic activity, according to the Nernst equation. Ion-selective electrodes are used in analytical chemistry and biochemical/biophysical research, where measurements of ionic concentration in an aqueous solution are required. Erba Mannheim plans to unveil the EC 90 at the Medica Trade Fair in Dusseldorf, Germany, to be held on November 18-21, 2019 (Hall 1, Stand D11). The instrument will be available for purchase in early 2020.

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LabMedica International

Cell-Free DNA Test Screens for Trisomies cont’d from cover

and specificity for these trisomies. However, where cfDNA screening has been adopted in public health programs, it is mostly as a second tier test. Health economic analyses have identified the necessity of more cost effective cfDNA tests to enable a wide adoption of first line screening. Targeted tests are based on high complexity genetic analysis platforms that require a relatively advanced laboratory setup. An international collaboration of scientists led by those at Vanadis Diagnostics (PerkinElmer, Sollentuna, Sweden; www.vanadisdx.com) analyzed maternal plasma samples from 1,200 singleton pregnancies, which included 158 fetal aneuploidies. Reference outcomes were determined by amniocentesis or chorionic villi sampling (CVS), followed by cytogenetic testing, such as karyotyping, fluorescence in situ hybridization (FISH) or quantitative fluorescence-polymerase chain reaction (QF PCR) or clinical examination of neonates. Processing and analysis of plasma samples was performed using the Vanadis noninvasive prenatal testing (NIPT) was performed blinded to the reference outcomes. The automated Vanadis NIPT assay targets specific chromosomes based on digital molecular quantification in a 96 well microplate format. The assay enables automated high precision cfDNA analysis from primary blood tubes. The Vanadis NIPT assay relies on a series of enzymatic steps that specifically generate labeled rolling circle replication products (RCPs) from chromosomal cfDNA targets. The scientists reported that the assay sensitivity was 100% (112/112) for trisomy 21 (Down syndrome), 89% (32/36) for trisomy 18 (Edwards syndrome), and 100% (10/10) for trisomy 13 (Patau syndrome). The respective specificities were 100%, 99.5%, and 99.9%. There were five first pass failures (0.4%), all in unaffected pregnancies. Sex classification was performed on 979 of the samples and 99.6% (975/979) provided a concordant result. Masoud Toloue, PhD, vice president and general manager of Diagnostics at PerkinElmer, the parent company of Vanadis, said, “We continue to be encouraged by clinical studies that further validate our Vanadis platform as a reliable, cost-effective solution for laboratories and obstetricians to offer aneuploidy screening. Our Vanadis platform eliminates the technical complexity of NIPT, giving more women access to cfDNA screening for common trisomies and further improving prenatal care on a global scale.” The authors concluded that the study demonstrated that cfDNA testing with the highly automated Vanadis NIPT system does not require specialized personnel for screening. The Vanadis system is also designed to help reduce cost and allow wider population-based screening. The study was published on August 19, 2019, in the journal Prenatal Diagnosis.

LabMedica International November/2018

Image: The Vanadis Core Cell-Free DNA analysis unit (Photo courtesy of PerkinElmer).

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Novel Diagnostic Device Profiles Population of Gut Microbiome esearchers used a three-dimensional (3D) printer to manufacture a novel pill-like diagnostic tool capable of profiling the bacterial species comprising the gut microbiome in the critical area between the stomach and the colon. Investigators at Tufts University (Medford/Somerville, MA, USA; www.tufts.edu) recently described a novel non-invasive diagnostic tool capable of providing a profile of microbiome populations throughout the entire GI tract. The device was manufactured in a three-dimensional printer. The surface of the pill was covered with a pH-sensitive coating, so that it did not absorb any substances until it passed through the stomach and entered the small intestine, where the coating dissolved. A semi-permeable membrane separated two chambers in

the pill - one containing helical channels that captured bacteria and the other containing a calcium salt-filled chamber, which created an osmotic flow across the membrane that forced the bacteria into the helical channels. A small magnet in the pill enabled controlled movement and targeting via a magnet outside the body. Finally, a fluorescent dye in the salt chamber marked the pill for easy identification after it left the body. The pill’s sampling performance was characterized using realistic in vitro models and validated in vivo in pigs and primates. So far, results have indicated that the bacterial populations recovered from the pills’ microfluidic channels closely resembled the bacterial population demographics of the microenvironment to which the pill was exposed. Despite these promising results, clinical trials will be needed to determine if the pill can be adapted for routine use in humans. “We are learning quite a lot about the role of gut microbiome in health and disease. However, we know very little about its biogeography,” said senior author Dr. Sameer Sonkusale,

professor of electrical and computer engineering at Tufts University. “The pill will improve our understanding of the role of spatial distribution in the microbiome profile to advance novel treatments and therapies for a number of diseases and conditions.” The microbiome profiler was described in the July 19, 2019, online edition of the journal Advanced Intelligent Systems. Image: Bacteria in the gut are pulled into the helical channels by an osmotic pump generated by a calcium salt-filled chamber within the pill (Photo courtesy of Nano Lab, Tufts University).

Amyloid Beta Blood Test Detects Asymptomatic Alzheimer’s n assay has been developed that determines the ratio of amyloid beta peptides in the blood and correlates with the accumulation of these Alzheimer’s disease risk factors in the brain. Amyloid beta (Abeta) denotes peptides of 36–43 amino acids that are crucially involved in Alzheimer’s disease as the main component of the amyloid plaques found in the brains of Alzheimer patients. The peptides derive from the amyloid precursor protein (APP), which is cleaved by the enzymes beta secretase and gamma secretase to yield Abeta. Researchers have been trying to develop a blood test to measure the level of Abeta peptides in order to identify individuals at risk for Alzheimer’s disease before symptoms arise. Toward this end, investigators at Washington University School of Medicine (St. Louis, MO, USA; www.wustl.edu) examined whether the ratio of plasma Abeta 42/Abeta40, as measured by a recently developed high-precision assay, accurately diagnosed brain amyloidosis using amyloid PET or CSF ptau181/Abeta42 as reference standards. For this study, the investigators used an immunoprecipitation and liquid chromatography–mass spectrometry assay, which had been under development for the past couple of years. They measured Abeta42/Abeta40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within 18 months of an amyloid PET scan. Results revealed that plasma Abeta42/Abeta40 had a high correspondence with amyloid

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PET status and CSF p-tau181/Abeta42. Combining the plasma Abeta42/Abeta40 ratio with age and APOE4 status yielded very high correspondence with amyloid PET. Individuals with a negative amyloid PET scan at baseline and a positive plasma Abeta42/Abeta40 had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Abeta42/Abeta40. Therefore, plasma Abeta42/Abeta40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia. “Right now we screen people for clinical trials with brain scans, which is time-consuming and expensive, and enrolling participants takes years,” said senior author Dr. Randall J. Bateman, professor of neurology at Washington University School of Medicine. “But with a blood test, we could potentially screen thousands of people a month. That means we can more efficiently enroll participants in clinical trials, which will help us find treatments faster, and could have an enormous impact on the cost of the disease as well as the human suffering that goes with it. Reducing the number of PET scans could enable us to conduct twice as many clinical trials for the same amount of time and money. It is not the $4,000 per PET scan that we are worried about. It is the millions of patients that are suffering while we do not have a treatment. If we can run these trials faster, that will get us closer to ending this disease.” The paper was published in the August 1, 2019, online edition of the journal Neurology. LabMedica International November/2018

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Expert Panel Releases Guideline on Diagnosis Of Fungal Infections cont’d from cover

American Thoracic Society (New York, NY, USA; www.thoracic.org) conducted a systematic review of medical studies on diagnosing fungal infections that had been published from 1980 to April 2016. The resulting official guideline covered the diagnosis of invasive pulmonary aspergillosis, invasive candidiasis, and the three most common endemic mycoses: blastomycosis, coccidioidomycosis, and histoplasmosis. In particular, the panel addressed four clinical questions that clinicians face when they care for patients with suspected fungal infections: 1) Is serum and/or bronchoalveolar lavage (BAL) galactomannan (GM) testing sufficiently accurate to guide therapeutic decisions in place of histopathology and/or fungal culture in patients with impaired immunity suspected of having invasive pulmonary aspergillosis (IPA)2) Should diagnosis of suspected aspergillus infections in severely immunocompromised patients be based on the application of polymerase chain reaction (PCR)3) In critically ill patients with suspected invasive candidiasis, is the (1→3)-β-D-glucan (BDG) assay alone sufficient for diagnostic decision-making? 4) Should diagnosis of the common endemic mycoses (i.e., histoplasmosis, blastomycosis, coccidioidomycosis) be based on serology and antigen testing? The guideline included specific recommendations for dealing with these situations, stressing that rapid, accurate diagnosis of fungal infections relied on appropriate application of laboratory testing, including antigen testing, serological testing, and PCRbased assays. “Our goal was to produce a concise evidence-based clinical practice guideline that will help clinicians use newer laboratory methods in diagnosis of these important infections,” said guideline co-chair Dr. Andrew H. Limper, professor of pulmonary medicine at the Mayo Clinic (Rochester, MN, USA; www.mayoclinic.org). “This guideline summarizes the best available evidence on the use of common laboratory tests to diagnose invasive pulmonary aspergillosis, invasive candidiasis, as well as histoplasmosis, blastomycosis, and coccidioidomycosis.” “As always, application of any guideline information must be integrated into the overall clinical context for an individual patient when confirming the diagnosis of invasive fungal infection,” said Dr. Limper. The guideline was published in the September 1, 2019, issue of the Journal of Respiratory and Critical Care Medicine. Image: A micrograph showing a mycosis (aspergillosis). The Aspergillus (which is spaghetti-like) is seen in the center and surrounded by inflammatory cells and necrotic debris (Photo courtesy of Wikimedia Commons).

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Immune Molecules Expressed Inside Mycetoma Lesions ycetoma is a persistent, progressive granulomatous inflammatory disease caused either by fungi or by bacteria. Characteristic of this disease is that the causative agents organize themselves in macroscopic structures called grains. These grains are surrounded by a massive inflammatory reaction. Mycetoma is caused by any of 56 different microorganisms and is endemic to many tropical and subtropical areas. It usually affects young adults and children and is most common in farmers and other workers who deal directly with soil. Mycetoma appears as a slow-growing tumor-like mass that gradually increases in size. A team of international scientists working with the University of Khartoum (Khartoum, Sudan; www.uofk.edu) studied surgical biopsies from 100 patients with con-

firmed mycetoma. Surgical biopsies from these patients were fixed in 10% formalin for 24 hours, and paraffin blocks were prepared and all sections were stained with haematoxylin and eosin (H&E). Collagen fibers were detected in tissue sections by staining them in Weigert’s iron hematoxylin working solution for 10 minutes. Immunohistochemical staining was used to determine the matrix metalloprotease-9 (MMP-9) and Interleukin-17 (IL-17) expression around the grains of different mycetoma causatives agents. In Sudan, the most commonly encountered micro-organisms are the fungus Madurella mycetomatis and the bacteria Streptomyces somaliensis, Actinomadura madurae and Actinomadura pelletierii. The scientists reported that while IL-17 was mostly found in Zones I and II of the grains, MMP-9 was present primarily in the more outer Zones II and III. Levels of the two immune molecules corresponded with

each other, and were associated with the disease duration and lesion size. Moreover, levels of MMP-9 also varied by the causative agent of mycetoma and MMP-9 expression was detected as brown cytoplasmic stain within the cells. IL-17A expression was noticed within the cytoplasm of neutrophils, macrophages and lymphocyte cells. MMP-9 was more highly expressed in A. pelletierii and S. somaliensis biopsies compared to M. mycetomatis biopsies. The authors concluded that their results obtained in the present study demonstrated that IL-17A and MMP-9 were expressed in the granuloma of different mycetoma causative agents and that the expression of IL-17A was more extensively in larger lesions and lesions with a longer disease duration. They also demonstrated a positive correlation between IL-17A expression levels and MMP-9 expression levels. The study was published on July 11, 2019, in the journal PLOS Neglected Tropical Diseases.

Gene Panel Detects Early Signs of Kidney Transplant Rejection team of European kidney transplantation researchers has developed and validated an mRNA-based gene set found in peripheral blood that can identify patients with symptoms of antibody-based kidney transplant rejection. Antibody-mediated rejection, a leading cause of kidney transplantation failure, is currently diagnosed by histological assessment of invasive allograft biopsies. Accurate non-invasive biomarkers are not available, and from 10 to 20% of rejections remain undetected, which leads to graft failure, reinitiation of dialysis, and the need for a repeat transplant. To identify potential rejection biomarkers, investigators at KU Leuven (Belgium; www. kuleuven.be) and their collaborators performed a genome-wide study (GWAS) to identify differences in RNA molecules among 117 patients with and without kidney rejection symptoms following transplant. In the second phase of the study, the different molecules of an independent group of 183 patients were processed into a mathematical model. The final biomarker consists of eight RNA molecules that were measured with an RT-PCR technique. In the third phase, the biomarker was validated in 387 patients in four European academic hospitals. Blood samples for the investigation were prospectively collected from participants in the BIOMARGIN study at time of renal allograft biopsies between June 2011 and August 2016. BIOMARGIN (Limoges, France; www. biomargin.eu) was a four-year European collaborative research project that began in March 2013. The consortium brought together 13 complementary partners, including three small and medium enterprises, one technology transfer / management company, five

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academic laboratories, and four university hospitals from four European Member States (France, Belgium, Germany, and Sweden). Results obtained during the initial phase of the study served to identify an eight-gene assay (CXCL10, FCGR1A, FCGR1B, GBP1, GBP4, IL15, KLRC1, TIMP1) in blood samples from 49 cases with and 134 cases without antibody-mediated rejection. In the validation cohort, this eight-gene assay discriminated between 41 cases with and 346 cases without antibody-mediated rejection with good diagnostic accuracy. The diagnostic accuracy of the eight-gene assay was retained both at time of stable graft function and of graft dysfunction, within the first year and also later after transplantation. “Rejection by HLA antibodies often has serious consequences,” said senior author Dr. Maarten Naesens, professor of nephrology at KU Leuven. “Traditional tests for assessing the function of transplanted kidneys can often only identify rejection when it is already chronic and irreversible. Thanks to our biomarker, we can detect rejection much earlier and with a simple blood test. Because the test is less invasive, we will be able to test more often than with the current biopsies.” “In principle, our antibody rejection test has been sufficiently validated for commercialization,” said Dr. Naesens. “This is the next and necessary step to be able to offer the test to patients. With the test, patients who have no rejection of antibodies will no longer have to undergo a biopsy. The biomarker will also help to detect rejection sooner and will support the search for better medicines against rejection by antibodies.” The eight-gene panel was described in the August 1, 2019, online edition of the journal EbioMedicine. LabMedica International November/2018

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Circulating T Cell-Monocyte Complexes Indicate Immune Perturbations ommunication between immune cells is a major component of immune responses, either directly through cell-cell contacts or indirectly through the secretion of messenger molecules such as cytokines. Scientists around the world have used a technique called flow cytometry to separate different types of immune cells, such as T cells, B cells and monocytes, but occasionally they’d see two cells stuck together as a “doublet.” Many regarded doublets as an artifact of the flow cytometry process, and it was commonplace to ignore those conjoined cells before gathering data. A team of international scientists led by the La Jolla Institute for Immunology (La Jolla, CA, USA; www.lji.org) obtained blood samples from various sources including from patients with and without tuberculosis (TB). For some latent TB and TB negative subjects, leukapheresis was performed instead of a whole blood donation in order to increase the number of peripheral blood mononuclear cells (PBMC) obtained. Laboratory parameters such as platelet and leukocyte counts, hematocrit, hemoglobin, AST, ALT and if applicable an ultrasound examination of the chest and abdomen or an X-ray were used to further diagnose patients with either dengue fever (DF) or dengue hemorrhagic fever (DHF). Latent TBI status was confirmed in subjects by a positive IFN-γ release assay (IGRA), QuantiFERON-TB Gold In-Tube, Qiagen, Hilden, Germany; www.quantiferon.com), or T-SPOT.TB (Oxford Immunotec, Abingdon, UK; www.oxfordimmunotec.com) and the absence of clinical and radiographic signs of active TB. TB uninfected control subjects

Image: A 3D-reconstructed image of a doublet of a T cell (CD3, green) and a monocyte (CD14) (Photo courtesy of La Jolla Institute for Immunology).

were confirmed as IGRA negative. Magnetic red blood cell (RBC) depletion was performed using the EasySep RBC depletion kit (STEMCELL technologies, Vancouver, BC, Canada; www.stemcell.com). PBMC were processed and acquisition was performed on a BD LSR-II cell analyzer (BD Biosciences, San Jose, CA, USA; www.bdbiosciences.com) or on their BD FACSAria III cell sorter. The team showed that cell:cell doublets pairing a T cell and a monocyte can be directly isolated from human blood, and high resolution microscopy shows polarized distribution of LFA1/ICAM1 in many doublets, suggesting in vivo formation. Intriguingly, T cell-monocyte complex frequency and phenotype fluctuate with the onset of immune perturbations such as infection or immunization, reflecting expected polarization of immune responses. Bjoern Peters, PhD, a professor in the Vaccine Discovery Division at LJI and senior author of the study, said, “It’s an important lesson learned by studying these cells and how they communicate, we might learn more about the immune system.” The study was published on June 25, 2019, in the journal eLife.

Thromboembolic Risk Increases after Hematological Cancers ematological cancer includes leukemia, bone marrow cancer and cancers of the lymph nodes. Therapeutic advances have improved survival after hematological cancers. In turn, patients may be at increased risk of thromboembolic and bleeding events. In most blood cancers, the normal blood cell development process is interrupted by uncontrolled growth of an abnormal type of blood cell. These abnormal blood cells, or cancerous cells, prevent the blood from performing many of its functions, like fighting off infections or

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preventing serious bleeding. A team of Danish scientists led by those at Aarhus University Hospital (Aarhus, Denmark; www.auh.dk) conducted a Danish population based cohort study from 2000 to 2013. They identified all adult hematological cancer patients and sampled a general population comparison cohort in a 1:5 ratio matched by age, sex, previous thromboembolic events, bleeding, and solid cancer. Ten year absolute risks of thromboembolism and bleeding were calculated and hazard ratios (HRs) were com-

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puted, controlling for matching factors. They examined the risks of myocardial infarction (MI), ischemic stroke, venous thromboembolism (VTE), and bleeding requiring hospital contact in patients with hematological cancers. They reported that among 32,141 hematological cancer patients, the 10 year absolute risk of any thromboembolic or bleeding complication following hematological cancer was 19%: 3.3% for MI, 3.5% for ischemic stroke, 5.2% for VTE, and 8.5% for bleeding. They noted that except among patients with myeloid leukemia, acute lymphoid leukemia, or myelodysplastic syndrome, the risk of thromboembolic events surpassed that of bleeding. The hematological cancer cohort overall was at increased risk for MI was HR = 1.36; for ischemic stroke HR = 1.22; for VTE the HR = 3.37; and for bleeding the HR = 2.39, compared with the general population. The study showed the heightened risk for hematological cancer patients: blood clot in the heart: 40% higher; blood clot in the brain: 20% higher; blood clot in the legs and lungs: over 300% higher; and bleeding was 200% higher. Kasper Adelborg, MD, PhD, and the lead author of the study, said, “If a person has a high risk of suffering a blood clot, treatment with anticoagulant medicine can benefit some patients. But anticoagulant medicine is not desirable if the risk of suffering bleeding is higher. This is a difficult clinical problem, but our study can set goals for what carries most weight for each individual type of cancer.” The study was first published on May 4, 2019, in the Journal of Thrombosis and Haemostasis. LabMedica International November/2018

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Random Plasma Glucose Tests Could Predict Diabetes iabetes is a major health problem in the USA, yet over seven million Americans with diabetes go undiagnosed. Diabetes is the major cause of kidney failure, blindness, and non-traumatic leg amputations in adults in the USA and a leading cause of stroke and heart disease. Early diagnosis allows the use of lifestyle changes or medications that could help prevent or delay the progression from prediabetes to diabetes and help keep diabetes from worsening. When diagnosis is delayed, diabetes-related complications could develop before treatment starts. A team of scientists working with the Emory University School of Medicine (Atlanta, GA, USA; www.emory.edu) conducted a retrospective analysis of the association of outpatient random plasma glucose (RPG) levels with the subsequent clinical diagnosis of diabetes. Study subjects were veterans with data in the Veterans Administration (VA) Informatics and Computing Infrastructure (VINCI) Corporate Data Warehouse (CDW). The team selected veterans who (a) did not have a diabetes diagnosis during a baseline year (365 days) in 2002–2007; (b) had three or more measurements of random plasma/serum glucose (RPG) during the baseline year, along with assessments of other demographic variables and cardiovascular disease (CVD) risk factors; and (c) had subsequent continuity of primary care [≥1 primary care provider (PCP) visit per year for five years immediately following the baseline year]. The scientists reported that over a five-year follow-up, about 10% of the total study group developed diabetes. Elevated random plasma glucose levels, though not meeting the diagnostic threshold for diabetes, accurately predicted the development of diabetes within the following

five years. Patients with at least two random plasma glucose measurements of 115 mg/dL or higher within a 12-month period were highly likely to be diagnosed with diabetes within a few years. Glucose levels of 130 mg/dL or higher were even more predictive of diabetes. Development of diabetes was infrequent in subjects whose highest random plasma glucose levels were below 110 mg/dL. The authors recommended that patients receive follow-up diagnostic testing for diabetes, such as a fasting glucose or HbA1c test, if they have two random glucose tests showing levels of 115 mg/dL or higher. This approach would very likely be cost-effective, they say, because clinicians can use testing that is already being done during routine outpatient visits. Using random glucose levels for screening could identify patients at higher risk for diabetes, leading to earlier intervention to prevent or control the disease. The study was published on July 19, 2019, in the journal PLOS ONE. Image: New research suggests random plasma blood glucose tests can identify diabetes patients (Photo courtesy of Chris Hannemann).

Submicroscopic Malaria Prevalence Reported in Immigrants alaria remains the most important parasitic infection for humans, causing about 2,000 deaths per day, especially in African children younger than five years old. The importance of submicroscopic malaria infections in high-transmission areas could contribute to maintain the parasite cycle. Regarding non-endemic areas, its importance remains barely understood because parasitaemia in these afebrile patients is usually below the detection limits for microscopy, hence molecular techniques are often needed for its diagnosis. The prevalence of submicro-

scopic malaria among immigrants is unknown, and it is not clear if systematic screening or systematic treatment of immigrants from endemic areas would be necessary. Scientists collaborating with the Hospital Universitario 12 de Octubre (Madrid, Spain) conducted a prospective, observational, multicenter study of 224 afebrile immigrants. Microscopic observation of Giemsa-stained thin and thick blood smears, and two different molecular techniques detecting Plasmodium spp. were performed. The commercial real-time polymerase chain reaction (PCR; FTD-Malaria,

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Fast-Track Diagnostics, Sliema, Malta; www. fast-trackdiagnostics.com) detecting Plasmodium spp. was performed. When this PCR was positive, a differential real-time PCR detecting Plasmodium malariae, P. falciparum, P. vivax and P. ovale was performed (FTD Malaria Differentiation, Fast-Track Diagnostics). In addition to this, blood samples were sent to the National Centre of Microbiology where a multiplex nested PCR detecting the four Plasmodium species was performed to validate the commercial PCR. The scientists reported that 14 patients were defined as submicroscopic malaria cases by PCR, yielding a prevalence of 5.7% (95% confidence interval 3.45–9.40). In 230 patients (94.3%) all microbiological tests for malaria were negative. In 71.4% of the positive PCR/negative microscopy cases, Plasmodium falciparum alone was the main detected species (10 out of the 14 patients) and in four cases (28.6%) Plasmodium vivax or Plasmodium ovale were detected. One patient had a mixed infection including three different species. The authors concluded that the prevalence of submicroscopic imported malaria found in this study was similar to that previously described by other authors in non-endemic areas in afebrile immigrants, namely P. vivax and P. ovale were involved in an important percentage of these infections. Screening protocols for afebrile immigrants with molecular techniques could be useful not only for a proper management and treatment of submicroscopic infections but also to prevent the potential reintroduction of malaria in areas where the vector is present. The study was published on July 17, 2019, in the Malaria Journal. LabMedica International November/2018

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High HbA1c Levels Do Not Always Lead to Diabetes rediabetes is an asymptomatic condition preceding type 2 diabetes. It is characterized by hyperglycemia, which is defined as a blood glucose level that is higher than normal but below the level for a clinical diagnosis of diabetes. Glycated hemoglobin (HbA1c) values increase with age amongst diabetes free subjects, and low glucose level may increase mortality in old age. Questions remain on which factors are related to the reversion from prediabetes to normoglycemia, independently of mortality amongst the older population. Scientists at the Karolinska Institute (Stockholm, Sweden; www. ki.se) followed 2,575 men and women aged 60 and older without diabetes for up to 12 years. At the start of the study, 918 people, or 36% of the group, did have higher-than-normal blood sugar levels that were still below the threshold for diabetes. HbA1c was collected at regular interval and until December 2010, HbA1c was assessed with Swedish Mono S filament High Performance Liquid Chromatography, and 1.1% was added to the individual’s values to render them equal to international values in accordance with National Glycohemoglobin Standardization Program (NGSP; HbA1c in %). Since 1 January 2011, HbA1c has been assessed with the International Federation of Clinical Chemistry (IFCC) reference method. A standard equation (NGSP = [0.9148 * IFCC] + 2.152; (available at: National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA; www.ngsp.org/ifccngsp.asp) was applied to convert IFCC HbA1c (in mmol mol−1) to NGSP value (in %), to render HbA1c results from all waves comparable. The scientists reported that only 119 people, 13% of those who start-

ed out with elevated blood sugar, went on to develop diabetes. Another 204, or 22%, had blood sugar levels drop enough to no longer be considered prediabetic. Obese adults with prediabetes were more likely to progress to full-blown diabetes. Ying Shang, MMSc, of the Aging Research Center at the Karolinska Institute and first author of the study, said, “Progressing to diabetes is not the only destination. In fact, the chance to stay prediabetic or even revert back to (normal blood sugar) is actually pretty high (64%), without taking medication. Lifestyle changes such as weight management or blood pressure control may help stop prediabetes from progressing.” The study was published on June 4, 2019, in the Journal of Internal Medicine. Image: The glycated hemoglobin (HbA1c) blood test gives an average level of blood sugar over the past two to three months (Photo courtesy of HealthEngine).

Genetic Loci Significantly Associated with Anorexia Nervosa ata accumulated by a large-scale genome-wide association study suggested that anorexia nervosa should be redefined as a “metabo-psychiatric disorder”, since at least eight genetic loci were identified as being significantly associated with the syndrome. Anorexia nervosa is a life-impairing mental illness, affecting 0.9–4% of women and 0.3% of men, which is characterized by dangerously low body weight, an intense fear of gaining weight, and a lack of recognition of the seri-

ousness of the low body weight. To better understand the role of genetics in anorexia, investigators at the University of North Carolina (Chapel Hill, USA; www. unc.edu) and collaborators from over 100 institutions worldwide conducted a genomewide association study of 16,992 cases of anorexia nervosa and 55,525 controls. The investigators combined data collected by the Anorexia Nervosa Genetics Initiative (ANGI) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-

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ED) from individuals of European ancestry from 17 countries across North America, Europe, and Australasia. Results pointed to eight significant genetic loci linked to anorexia nervosa. The genetic architecture of anorexia nervosa reflected its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. The eight loci overlapped other psychiatric disorders such as obsessive-compulsive disorder, depression, anxiety and schizophrenia. The loci associated with anorexia nervosa also influenced physical activity, which might explain the hyperactivity often associated with the disorder. “Until now, our focus has been on the psychological aspects of anorexia nervosa such as the patients’ drive for thinness. Our findings strongly encourage us to also shine the torch on the role of metabolism to help understand why individuals with anorexia frequently drop back to dangerously low weights, even after therapeutic renourishment. A failure to consider the role of metabolism may have contributed to the poor track record among health professionals in treating this illness,” said senior author Dr. Cynthia M. Bulik, professor of psychiatry in the University of North Carolina. The study was published in the July 15, 2019, online edition of the journal Nature Genetics. LabMedica International November/2018

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Nuclear Hormone Expression Predicts Cancer Aggressiveness large-scale retrospective analysis in patients revealed that expression of the nuclear hormone receptor “retinoic-acid-receptor-related orphan receptor gamma” (RORgamma) could predict pancreatic cancer aggressiveness, since it correlated positively with advanced disease and metastasis. Drug resistance and relapse remain key challenges in pancreatic cancer, with current multidrug chemotherapy regimens failing to eradicate all cancer cells. The remaining drug-resistant cancer stem cells can drive tumor regrowth and metastasis. Investigators at the University of California, San Diego (USA; www. ucsd.edu) used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, RORgamma, known to drive inflammation and T-cell differentiation, was upregulated during pancreatic cancer progression. In contrast, genetic or pharmacologic inhibition of RORgamma led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Furthermore, a large-scale retrospective analysis in patients revealed that RORgamma expression could predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. “These studies revealed an unexpected role for immuno-regulatory genes in the maintenance of the most aggressive, drug-resistant cells in pancreatic cancer,” said senior author Dr. Tannishtha Reya, professor of pharmacology and medicine at the University of California, San Diego. “Our work shows that immune system signals are hijacked by pancreatic cancer, and suggests that therapies currently being tested for autoimmune indications should be considered for testing in pancreatic cancer. “Using genome scale approaches to map stem cell dependencies in pancreatic cancer will be invaluable for understanding the basis of therapy resistance and recurrence and for discovering new vulnerabilities in pancreatic cancer. Beyond providing new scientific insight, this work can help identify pathways for which clinical grade inhibitors may already exist and can thus be rapidly tested in pancreatic cancer,” said Dr. Reya. The RORgamma paper was published in the April 4, 2019, online edition of the journal Cell.

Image: Pancreatic cancer cells (blue) growing as a sphere encased in membranes (red) (Photo courtesy of the U.S. National Cancer Institute).

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Blood Biomarkers Help Predict Recovery Time After Concussion study of high school and college football players suggests that biomarkers in the blood may have potential use in identifying which players are more likely to need a longer recovery time after concussion. A concussion is a mild traumatic brain injury (TBI). It can occur after an impact to the head or after a whiplash-type injury that causes the head and brain to shake quickly back and forth. A concussion results in an altered mental state that may include becoming unconscious. A team of scientists associated with the Medical College of Wisconsin (Milwaukee, WI, USA; www.mcw.edu) prospectively enrolled 857 high school and collegiate football players of whom 41 concussed athletes and 43 matched control athletes met inclusion criteria. None of the players lost consciousness with their concussions. All of the participants had blood tests at the beginning of the season. Those who had concussions had blood tests within six hours after the injury, then again 24 to 48 hours later and also eight, 15 and 45 days later. Those who did not have concussions had tests at similar times for comparison. The blood tests looked at levels of seven biomarkers for inflammation that have been related to more severe brain injury that included serum levels of interleukin (IL)–6, IL-1β, IL-10, tumor necrosis factor, C-reactive protein, interferon-γ, and IL-1 receptor antagonist. Of the seven biomarkers, two were elevated for those with concussion at six hours after the injury compared to the athletes with no concussion. The biomarkers Il-6 and interleukin 1 receptor antagonist (IL-1RA) were both elevated at six hours after concussion. For Il-6 levels at the beginning of the study were 0.44 pg/mL for those who later had concussions and 0.40 pg/mL for those who did not have concussions. At six hours after the injury, those with concussions had levels of 1.01 pg/mL, compared to levels of 0.39 pg/mL at a similar time for those without concussions. Athletes with higher levels IL-6 six hours after the injury were also more likely to take longer to recover from their symptoms. Overall, the athletes with concussions had symptoms for an average of 8.9 days. Eight of the 17 athletes with concussion and high IL-6 levels at six hours after injury, compared to their levels at the beginning of the season, still had concussion symptoms eight days after the injury. Timothy B. Meier, PhD, an Assistant Professor in Neurosurgery and a senior author of the study, said, “With so many people sustaining concussions and a sizeable number of them having prolonged symptoms and recovery, any tools we can develop to help determine who would

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be at greater risk of problems would be very beneficial, so these results are a crucial first step.” The study was published on July 3, 2019, in the journal Neurology. Image: An example of an ELISA test kit designed for quantitative determination of the concentration of human interleukin 6 (IL-6) in serum and plasma (Photo courtesy of Thermo Fisher Scientific).

Micronutrient Deficiencies Common in Celiac Disease eliac disease is an immune reaction to consuming gluten, a protein found in wheat, barley and rye. Eating gluten triggers an immune response in the small intestine that over time damages the intestine’s lining and prevents it from absorbing some nutrients, leading to diarrhea, fatigue, anemia, weight loss and other complications. Recent guidelines on the diagnosis and management of Celiac disease (CD) recommend testing for nutrient deficiencies at the time of new diagnosis, and this assessment should include vitamin D, iron, folic acid, and vitamin B12. Micronutrient deficiencies, including vitamins B12 and D, as well as folate, iron, zinc and copper, are common in adults at the time of diagnosis with celiac disease. Gastroenterologists at the Mayo Clinic (Rochester, MN, USA; www. mayoclinic.org) and their colleagues carried out a retrospective analysis of 309 adult patients with a new diagnosis of CD from January 1, 2000, and October 31, 2014. Patients included in this study were diagnosed with CD, with a combination of serological, genetic, and histological parameters yielding a confident diagnosis of CD when patients met one of two clinical scenarios. First, if the patient had positive serology for celiac disease and confirmatory duodenal biopsy, CD was diagnosed. Second, patients without positive serology for celiac disease must have biopsy findings consistent with CD, human leukocyte antigen DQ-2 or DQ-8, and positive response to a gluten-free diet for a diagnosis of CD. Laboratory parameters were included if they were collected one month before diagnosis to three months after celiac diagnosis. Tissue transglutaminase IgA data were collected to determine whether a positive result was associated with deficiency. Micronutrient data were collected for serum zinc, 25-hydroxy vitamin D, ferritin, albumin, serum copper, serum folate, and vitamin B12. Albumin was assessed, as this can influence serum zinc values and is a predictor of outcome in refractory CD studies. The investigators found that zinc was deficient in 59.4% (126/212) of patients with CD compared with 33.2% (205/618) of controls. Albumin was low in 19.7% (24/122) compared with 1.1% of controls. Copper was low in 6.4% (13/204) compared with 2.1% (13/618) of controls. Vitamin B12 was low in 5.3% (13/244) compared with 1.8% (11/618) of controls. Folate was low in 3.6% (6/159) compared with 0.3% (2/618) of controls. 25-Hydroxy vitamin D was low in 19.0% (44/213) compared with 18% (111/618) of controls. Ferritin was low in 30.8% (66/214) of patients. The study was published on June 25, 2019, in the journal Mayo Clinic Proceedings.

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PRODUCT NEWS URINE ANALYZER

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RAPID TEST

CHEMISTRY ANALYZER

Erba Mannheim

Veda Lab

Jeol

The LAURA XL offers automatic evaluation of 10 chemistry parameters and 16 sediment categories. In addition, users can select from 16 manual and four customizable sediment categories, as well as three operation modes.

The Gluten-Check-1 rapid test is designed for the detection of anti-tissue transglutaminase IgA antibodies associated with gluten intolerance (celiac disease). The test provides accurate results from serum, plasma or whole blood samples.

The JCA-ZS050 features 1,800 tests/hour with extramicro-volume measurement with a 40ÎźL reaction volume. It offers innovative operation and simple maintenance while assuring high-precision data by the wash mechanism.

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Different Clinical Hematology Lab Configurations Compared utomated hematology analyzers are key clinical laboratory instruments that measure blood counts, identify subsets of nucleated blood cells, and ďŹ&#x201A;ag specimens for further manual analysis. These analyzers range in price and functionality. Examination of stained blood smears may be performed with a microscope or may be semi-automated with digital image analysis systems. The performance and costs of currently available analysis configurations

with special focus on a proposed alternative using a minimal hematology analyzer plus a digital imaging device, allowing for remote oversight and interpretation has been compared. Medical Laboratory scientists at the University of California, San Diego (La Jolla, CA, USA; www.ucsd.edu) and their colleagues used patient samples with orders for complete blood counts (CBCs) with white blood cell (WBC) differentials. During a 6-week period, a total of 206 blood samples were selected to represent a variety of clinical conditions, including samples with no abnormalities. The team wanted to determine whether lowvolume laboratories might realize savings while gaining function by substituting commonly used configurations with a proposed alternative. The investigators evaluated the performance of the proposed alternative configuration, blood counts with automated differentials produced by a Sysmex XE5000 (complete blood count reference method) (Sysmex, Kobe, Japan; www.sysmex.com) were compared with cell counts from the Sysmex pocH-100i, CellaVision DM96 (CellaVision AB, Lund, Sweden; www.cellavision.com) preclassified differentials, and DM96 reclassified differentials (differential reference method) by using standard regression analyses, 95% CIs, and truth tables. Financial cost modeling used staffing practices, test volumes, and smear production rates observed at remote clinics performing on-site hematology analysis. The team reported that differential blood count parameters showed excellent correlation between the XE5000 and preclassification DM96. For blasts/abnormal cells, immature granulocytes, and nucleated red blood cells, the DM96 showed higher sensitivity and similar specificity to the XE5000. Cost modeling revealed that decreased personnel costs through remote monitoring of results facilitated by the DM96 would lead to lower operational costs relative to more conventional analysis configurations. The study was published on April 10, 2019, in the journal Archives of Pathology & Laboratory Medicine. Image: The CellaVision DM96 digital cell morphology system is designed to automate the time-consuming, manual effort associated with traditional microscopy (Photo courtesy of CellaVision). LabMedica International November/2018 LINKXPRESS COM

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PRODUCT NEWS CLINICAL ANALYZER

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HEMATOLOGY ANALYZER

ION ANALYZER

Erba Mannheim

Diatron

SFRI

The XL-200 random access analyzer offers ease of operation, and automated pipetting for samples and reagents. Other key benefits include auto dilution and rerun, on-board laundry and cooling, a compact size, and wide test menu.

The Diatron Aquila 5Dretics offers a throughput of 80 tests/hour and requires only a small sample volume (40ul). It has a continuous loading autoloader, making the analyzer a walk away system convenient for all customers.

The IONIX is the newest addition to SFRI’s range of ion analyzers with selective electrodes. Developed and manufactured with the latest technologies, the IONIX offers 8 parameters and a multitude of possibilities.

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Human Microbiome Features Stratify Children with IBS rritable bowel syndrome (IBS) is a disruptive gastrointestinal condition characterized by bloating, changes in bowel habits, and pain that affects up to 20% of the world’s population (children and adults). Increasing evidence indicates that the onset and symptoms of IBS are related to the gut microbiome. To improve the treatment of children with IBS, investigators have developed a sophisticated way to analyze the microbial and metabolic contents of the gut. A report describes how a new battery of tests enables scientists to distinguish patients with IBS from healthy children and identifies correlations between certain microbes and metabolites with abdominal pain. Scientists at Baylor College of Medicine (Houston, TX, USA; www.bcm.edu) and their colleagues obtained samples from 23 preadolescent children with IBS (age 7 to 12 years) and 22 healthy controls. Participants were asked to maintain daily pain and stool diaries for two weeks and to provide stool (fecal) samples. Stool DNA was extracted using the Power-

Soil DNA Isolation kit (MO BIO Laboratories, Carlsbad, CA, USA; http://mobio.com). DNA quality and yield were evaluated via agarose gels NanoDrop 1000 (NanoDrop, Wilmington, DE, USA; www.thermofisher.com) and Qubit Flurometer (Life Technologies, Carlsbad, CA, USA; www.thermofisher.com).WGS libraries were generated using 100 bp paired libraries and the HiSeq 2000 platform (Illumina, San Diego, CA, USA; www.illumina.com). The investigators found that there were differences in bacterial composition, bacterial genes, and fecal metabolites in children with IBS compared to healthy controls. In addition to identifying correlations of these factors with abdominal pain, they generated a highly accurate classifier using metagenomic and metabolic markers that distinguishes children with IBS from healthy controls with 80% or greater accuracy. This classifier assesses specific metabolites, types of bacteria, functional pathways, and other factors. This microbiome-based classifier can potentially help identify subpopulations of children with IBS that are more likely to benefit from

microbiome-related therapies including diet modification, while guiding others to alternative appropriate treatment plans. The investigators also provide insights into how specific microbiome-related findings may be related to abdominal pain, thus opening up potential novel treatment approaches. The study was published on April 17, 2019, in the Journal of Molecular Diagnostics. Image: The Qubit 4 Flurometer is designed to accurately measure DNA, RNA, and protein quantity, and now also RNA integrity and quality, using the highly sensitive Qubit assays (Photo courtesy of Thermo Fisher Scientific).

Suite of Risk Variants Revealed in Hirschsprung’s Disease irschsprung’s disease, or congenital aganglionosis, is a developmental disorder of the enteric nervous system and is the most common cause of intestinal obstruction in neonates and infants, often appearing in combination with other symptoms in a manner that may reflect specific syndromes. The disease has more than 80% heritability, including significant associations with rare and common sequence variants in genes related to the enteric nervous system, as well as with monogenic and chromosomal syndromes. Genetic factors that contribute to a highly heritable developmental condition of Hirschsprung’s disease include a complex suite of risk variants, ranging from common polymorphisms in non-coding elements to rarer coding variants and copy number variants (CNVs). Scientists at several institutions collaborated with those at Johns Hopkins University (Baltimore, MD, USA; www.jhu.edu) and genotyped and

exome-sequenced samples from 190 patients with Hirschsprung’s disease to quantify the genetic burden in patients with this condition. DNA sequence variants, large CNVs, and karyotype variants in probands were considered to be pathogenic when they were significantly associated with Hirschsprung’s disease or another neurodevelopmental disorder. These were compared with 627 unaffected controls, including 404 participants in the 1000 Genomes Project 223 so-called “pseudo-controls,” parental chromosomes that were not transmitted to the affected children. The authors concluded that among the patients in their study, Hirschsprung’s disease arose from common noncoding variants, rare coding variants, and copy-number variants affecting genes involved in enteric neural-crest cell fate that exacerbate the widespread genetic susceptibility associated with RET. The study was published on April 11, 2019, in the New England Journal of Medicine. LabMedica International November/2018

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LabMedica International

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Urine Test Directly Delivers Antibiotic Susceptibility Results ntibiotic susceptibility testing, or AST, is a widely used method of evaluating antibiotic resistance and determining patient treatment plans in clinical settings. There are a number of different methods of AST such as agar dilution, broth dilution and disc diffusion assays. Empiric treatment is often started before laboratory microbiological reports are available when treatment should not be delayed due to the seriousness of the disease. The effectiveness of individual antibiotics varies with the location of the infection, the ability of the antibiotic to reach the site of infection, and the ability of the bacteria to resist or inactivate the antibiotic. Microbiologists at the Groupe Hospitalier Paris-Saint-Joseph (Paris, France; www.hpsj.fr) collected urine samples were collected from 107 patients aged 52 to 80 years with urinary tract infections (UTIs) (ratio of females to males 2:1). The median C-reactive protein was 104 mg/L (range, 39-145). The urine specimens displayed a median leukocyturia of 380/mm3 (range, 192-1,497) and median bacteriuria of 106 colony forming units/mL (range, 105-107). Only gram-negative bacilli were evident on direct examination using microscopy. A novel rapid method was performed by direct inoculation of urine on Mueller-Hinton Rapid-SIR (MHR-SIR) agar using a swab according to a standard protocol. The resulting inhibition zones were read from digital images after eight-hours of incubation and were interpreted using standard methods. Of 70 patients who were currently receiving antibiotic therapy, the results prompted a shift in therapy for 29 patients, with no modification for the remaining 41. The most commonly used antibiotics were third generation cephalosporins, followed by fluoroquinolones, beta-lactamase inhibitors, fosfomycin, and nitrofurantoin. The rapid results lead to treatment escalation in 7% of the patients and de-escalation in 30%. The average time to obtain results was 7.2 ± 1.6 hours, representing a time saving of 42.6 hours compared with the standard technique. The team noted that the method was affordable, with an average cost of USD 6 per sample for 16 antibiotics chosen by a microbiologist. Benoît Pilmis, MD, an infectious disease specialist and a co-author of the study, said, “The diagnosis of urinary tract infection generally requires a 48-hour microbiological delay to obtain the antibiotic susceptibility test. In the context of multidrug resistance, reducing the time to obtain antibiotic susceptibility test results is an essential issue to avoid treatment failure. The rapidity of the results impact the therapeutic management of patients as it enables not only the prescription

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of the most relevant antibiotic, but also the reduction of the spectrum of antibiotic therapy.” The study was presented at Annual meeting of the American Society of Microbiology, held June 7-11, 2019, in Atlanta, GA, USA. Image: The SIRscan 2000 Automatic Agar Reader-Incubator for susceptibility testing (Photo courtesy of i2a Diagnostics).

Microfluidic Device Isolates Circulating Tumor Cell Clusters he three main challenges of cancer treatment are metastases, recurrence, and acquired therapy resistance. These challenges have been closely linked to circulating cancer cell clusters. About 90% of cancer deaths are due to metastases, when tumors spread to other vital organs, and it has recently been realized that it’s not individual cells but rather distinct clusters of cancer cells that circulate and metastasize to other organs. A team of scientists led by San Diego State University (San Diego, CA, USA; www.sdsu.edu) has shown how a well-known passive micromixer design (staggered herringbone mixer - SHM) can be optimized to induce maximum chaotic advection within antibody-coated channels of dimensions appropriate for the capture of cancer cell clusters. The design of the device makes use of 32 channels, each of 200 μm width and 100 μm spacing, which will increase the available chip surface to cross-sectional area by approximately 1.4-fold. Numerous simulations were performed by varying different properties of the HB pattern, such as channel configuration, and flow velocities to optimize for our deterministic factor cell-to-surface interactions. The Cy5-labeled streptavidin was utilized to visualize the cross-linked and functionalized alginate hydrogel coating within the micro channels. Images were captured using a fluorescence Zeiss 200M microscope (Carl Zeiss Microscopy GmbH, Jena, Germany; www.micro-shop.zeiss.com). Peter Teriete, PhD, an assistant professor and co-author of the study, said, “Our device’s channel design had to generate microfluidic flow characteristics suitable to facilitate cell capture via antibodies within the coated channels. So we introduced microfeatures, herringbone recesses, to produce the desired functionality. We also developed a unique alginate hydrogel coating that can be readily arrayed with antibodies or other biomolecules. By connecting bioengineering with materials science and basic cancer biology, we were able to develop a device and prove that it performs as desired.” The study was published on June 18, 2019, in the journal AIP Advances.

LabMedica International November/2018

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PRODUCT NEWS MDX SYSTEM

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CRP TEST KIT

HEMATOLOGY ANALYZER

Abbott Diagnostics

DxGenCo

Agappe

The ID NOW is designed for the qualitative detection of infectious diseases using isothermal NA amplification technology. The system features a large visual touch screen, while its small footprint saves bench space.

The Epithod 616 CRP test kit is intended to determine C-reactive protein quantitatively in serum/plasma or whole blood. It provides information for the diagnosis, treatment and monitoring of inflammatory diseases.

The MISPA Count features three histograms and scatter plot for WBC and a throughput of 60 samples per hour. It uses triple counting technology for accurate results and has onboard memory for storing 35,000 results with scatter plot.

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Assay Offers Rapid Measurement of LDL Cholesterol kit for the automated measurement of small dense low-density lipoprotein cholesterol (sdLDL-C) complete with controls and calibrators is now available with applications for use with a wide range of biochemistry analyzers. The lipid panel often used to assess cardiovascular disease risk comprises LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. Results of these assays only detect about 20% of all atherosclerotic cardiovascular disease patients. However, studies have shown that sdLDL-C could predict risk of coronary heart disease in individuals considered being at low cardiovascular risk based on their LDL-C levels. These studies found that patients with a predominance of sdLDL-C had a three-fold increased risk of myocardial infarction (MI), while the relative risk was 4.5 for coronary artery disease and 7.0 for MI when sdLDL-C levels were greater than 100 milligrams per deciliter. Until recently, the primary methods for determining a patientâ&#x20AC;&#x2122;s sdLDL-C levels were based on laborious and time-consuming ultracentrifugation and electrophoresis. Then, in November 2017, the [U.S.] Food and Drug Administration granted 510(k) marketing clearance to Denka Seiken (Tokyo, Japan; https://denka-seiken.com) for a small dense low-density lipoprotein cholesterol (sdLDL-C) assay designed for use on any standard clinical chemistry analyzer. The assay quantified sdLDL-C in serum and plasma samples in 10 minutes using a two-step process. The first step removed chylomicrons, very low LDL, intermediate-density lipoprotein, large LDL, and high-density lipoprotein using a surfactant and sphingomyelinase. In the second step, a specific surfactant released cholesterol only from the sdLDL-C particles for measurement by standard methods.

The Randox (Crumlin, United Kingdom; www.randox.com) sdLDLC assay utilizes the Denka Seiken method, providing accurate patient results. It was designed for use on automated biochemistry analyzers for efficiency and convenience. Applications are available detailing instrument-specific settings for the convenient use of the Randox sdLDL-C assay on a wide range of biochemistry analyzers. Dedicated sdLDL-C controls and calibrator are available providing a complete testing package. The Randox sdLDL-C assay is a niche product, and Randox is one of the only manufacturers of this test in an automated format. Image: Small particle LDL has been associated with the progression of atherosclerosis and blockage the artery lumen, because it can carry cholesterol into smaller vessels (Photo courtesy of Wikipedia).

Immune Cell Profiling Assay Boosts Use of Mass Cytometry new, multiplexed, antibody-based assay for immune cell profiling on its mass cytometry platform has been launched. The assay is comprised of a single-tube assay pre-loaded with 30 metal-labeled antibodies that target common immune cell protein markers and a custom-developed software analyzer that can identify 37 immune cell types. The assay is produced by Fluidigm (South San Francisco, CA, USA: www.fluidigm.com) is designed to run on its Helios CyTOF platform and said it expects the product to drive instrument placements and appeal to laboratories with existing Helios instruments, especially academic core facilities. The firm added that the assay offers great consistency, demonstrated in an early-access program that involved six sites.

The highly multiplexed 30-marker antibody panel was developed with input from expert immunologists in academia and biopharma and builds on the panels designed by the Human ImmunoPhenotyping Consortium. The panel was designed using industry-proven antibody clones, this assay provides the broadest single-tube view of the immune system from each precious sample. While the Maxpar Direct Immune Profiling Assay provides excellent immune cell coverage, one can easily add up to seven new antibodies to support the study goals. Because mass cytometry has limited channel crosstalk and a broad detection range, the expansion of high-parameter panels is simplified, a significant advantage over fluorescence cytometry. LabMedica International November/2018

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PRODUCT NEWS ELISA/CLIA ANALYZER

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CELIAC TEST

ELECTROLYTE ANALYZER

Awareness Technology

BIOHIT Healthcare

Caretium Medical Instruments

The ChemWell FUSION 4800 features a dual-function reader which automatically switches between readings. CLIA/ELISA assays occur on the same device and plate with reactions taking place in standard microwells/strips.

The Celiac Disease Quick Test is designed for the qualitative detection of antibodies against human tissue. It confirms diagnosis of celiac disease from fingertip blood sample within 10 minutes and is ideal for use.

The XI-931 features high performance electrodes with wide linearity range and long shelf life. It offers two sampling modes, automatic liquid level detection and alarms, and onboard memory for storage of over 100,000 test results.

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Breast Cancer Test Determines Most Effective Treatment or the clinical management of patients with estrogen receptor (ER)-positive breast cancer, several clinico-pathological and molecular characteristics of the tumor have to be considered for prognosis and treatment decisions. Over the last two decades several multigene tests have been developed to aid the selection of patients for whom adjuvant chemotherapy might be appropriate based on prognosis. All of these tests predict the likelihood of disease recurrence or progression, and some have shown to predict relative benefit from chemotherapy. An international team of scientists working with the Queen Mary University of London (London UK; www.qmul.ac.uk) performed a combined analysis of three large clinical trials, including a total of 3,746 women, who received treatments including hormone therapy and chemotherapy. The investigators found that a multigene test called EndoPredict (Myriad Genetics, Cologne, Germany; https://myriad.com) is able to predict whether chemotherapy will

work for an individual patient. The study results showed that patients with a high EndoPredict test result, indicating a high risk of metastasis, who received chemotherapy in addition to hormonal therapy, had statistically better 10-year outcomes than those who only received hormonal therapy. The study was therefore able to show that EndoPredict is not only a prognostic test, but for the first time was able to demonstrate that EndoPredict also has predictive abilities with regards to chemotherapy. With the added predictive benefit of EndoPredict demonstrated by this study, use of this test might become more commonly used to determine whether chemotherapy will effectively treat a patient, bringing enormous benefit to women diagnosed with breast cancer. Ivana Sestak, PhD, a senior lecturer and lead author of the study, said, “Our new results give clinicians good quality data to inform specific treatment recommendations for women. Our data shows that using the EndoPredict test to

assess the risk of metastasis can spare women unnecessary chemotherapy if the test results show that a woman is at low risk of recurrence by the test. The study published on April 30, 2019, in the journal Breast Cancer Research and Treatment. Image: EndoPredict is a second-generation breast cancer recurrence test for highly accurate assessment of 10-year risk of distant recurrence (Photo courtesy of Myriad Genetics).

Large GWAS Pinpoints Ovarian Cancer Risk Genes esults of a large genome-wide association study identified 34 genes that are associated with an increased risk for developing the earliest stages of ovarian cancer. The current study, which was carried out by investigators at the University of California, Los Angeles (USA; www.ucla.edu) and the DanaFarber Cancer Institute (Boston, MA, USA; www.dana-farber.org), continued the assessment of large-scale genetic data that had been gathered over a period of more than 10 years by the Ovarian Cancer Association Consortium. Those investigators had found more than 30 regions in the genome associated with ovarian cancer after having compared the genetic profiles of about 25,000 women with ovarian cancer and 45,000 control subjects. Applying advanced analytical tools, the current team of investigators identified 34 genes that were associated with an increased risk for developing ovarian cancer. Furthermore, this study implicated at least one

target gene for six out of 13 distinct genome-wide association study regions and pinpointed 23 new candidate susceptibility genes for highgrade serous ovarian cancer. “Whenever you inherit a piece of DNA from your parents, you do not inherit just every base pair of the genome, you inherit big chunks,” said Dr. Pasanuic. “That means that if you inherit a gene mutation in a given region, you inherit the entire region, which can carry 10 to 20 genes at a time. This makes it very hard to pinpoint specific genes from specific regions. With the identification of these genes, we now have a narrow list of genes that can help us better predict ovarian cancer risks in women who may have never known that they were at a higher risk for developing the disease. While we are not there yet, we are hoping this study will lead to better outcomes because we will be able to monitor women earlier, when the cancer is easier to treat.” The ovarian cancer study was published in the May 1, 2019, online edition of the journal Nature Genetics. LabMedica International November/2018

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LabMedica International

Loop-Mediated Isothermal Amplification Test Rapidly Detects Sexually Transmitted Chlamydia hlamydia trachomatis is the leading cause of sexually transmitted diseases (STDs) in females and males in both developed and developing countries, with more than 110 million cases annually. C. trachomatis resists antibiotic treatment and is a cofactor in HIV transmission and human cervical cancer. For nucleic acid amplification tests, recently loop-mediated isothermal amplification (LAMP) has presented an attractive alternative to standard methods like polymerase chain reaction (PCR) due to its low price, ease of use, rapid results, and lack of requirement for an expensive thermal cycler and specialized kits for DNA extraction and purification. Scientists at the Chulalongkorn University (Bangkok, Thailand; www.chula.ac.th) and their associates have developed a rapid, inexpensive, easy-to-interpret, sensitive and specific point-of-care (POC) C. trachomatis detection system, using a LAMP assay for target C. trachomatis DNA amplification, followed by gold nanoparticle probe (AuNP) for colorimetric C. trachomatis specific readout. The team collected endocervical swab samples were randomly selected from a prospective study cohort of sexually transmitted disease (STD) prevalence in symptomatic and healthy (which may include non-symptomatic patients) Thai women aged 15 to 54 years in Bangkok and nearby areas. The samples were collected by clinicians during 2011 and 2012 from qualified volunteers. The sample size of 130 (96 symptomatic and 34 healthy) was computed based on a standard statistical formula. A set of six primers was designed for LAMP to target eight distinct regions on the C. trachomatis ompA gene. To determine the optimal LAMP assay condition (incubation temperature and incubation time), the LAMP reaction was incubated at 59 °C to 65 °C for 30 to 60 minutes (without loop primers) and 10 to 35 minutes (with loop primers). A 25 L LAMP reaction comprised DNA template, High Pure PCR Template Preparation Kit (Roche Diagnostics, Risch-Rotkreuz, Switzerland; www.roche.com). Nanogold particles of 10 nm were appended

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to the probe to create the complementary AuNP-DNA probe specific for the C. trachomatis LAMP product. Of the 130 clinical samples, the LAMP-AuNP sensitivity was 96% (23/24) and specificity 99% (105/106). This result is higher than the LAMP-GE. The percentages of assay accuracy for PCR-GE and LAMPAuNP were equal (98%), whereas for LAMP-GE it was 96%. The AuNPs allow simple visualization of results and improve the LAMP specificity and sensitivity. The percentages of assay accuracy for the independent replicate detection were 100% for PCR-GE, 99% for LAMP-AuNP, and 98% for LAMP-GE. Verification from the UV-vis spectra supported the convenient colorimetric reading of the LAMPAuNP assay. The authors concluded that the C. trachomatis LAMP-AuNP detection is appropriate for local and resource-constrained settings. The assay directly uses clinical samples, obtains results in 32 to 47 minutes and the result is readable by the naked eye. The study was published on December 20, 2018, in the journal Public Library of Science Neglected Tropical Diseases.

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MICRO-OSMOMETER

NA EXTRACTION SYSTEM

Rayto Life and Analytical Sciences

Advanced Instruments

ACON Laboratories

The Chemray-800 offers a throughput of 800 tests per hour and a grating system with 12 wavelengths. It comes with an eight-step washing system, four independent mixing stirrers, two reagent probes and one sample probe.

The OsmoTECH PRO provides concentration measurements while delivering data management capabilities. Benefits include operational efficiency, and options that support GMP, 21 CFR Part 11 and EU Annex 11 compliance.

The NES-32 can process a variety of specimens such as blood, tissues and body fluids. It can extract the product within 40 minutes using various types of magnetic beads extraction reagents and c extraction plate.

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Blood Donations Screened for Familial Hypercholesterolemia amilial hypercholesterolemia is an autosomal-dominant disorder that often causes premature coronary artery disease. Unfortunately, familial hypercholesterolemia remains largely undiagnosed. Cardiologists know that familial hypercholesterolemia (FH), a condition that causes extremely high levels of cholesterol at an early age, is genetic. When one person is diagnosed, other family members can be identified. However, only an estimated 10% of those with FH are diagnosed, leaving many others at risk. Medical scientists at the University of Texas Southwestern Medical Center (Dallas, TX, USA; www.swmed.edu) and their colleagues estimated the prevalence of FH in a population of blood donors. Familial hypercholesterolemia was defined using the total nonfasting serum cholesterol thresholds of 270, 290, 340, and 360 mg/dL for donors younger than 20 years, 20 to 29 years, 30 to 39 years, and 40 years or older, respectively. For repeated donors, the maximum observed total cho-

lesterol level was used for analyses. The study included 1,178,102 individual donors with a total of 3,038,420 blood donations. Of all individual donors (median total cholesterol level, 183 [interquartile range (IQR), 157-212] mg/dL; median age, 32 [IQR, 19-47] years; 619, 583 [52.6%] women), a total of 3,473 individuals (or 1 in every 339) met criteria for FH. This group had a median (IQR) total cholesterol of 332 (297-377) mg/dL. Estimated prevalence was higher at younger ages (<30 years: 1:257) compared with older ages (≥30 years: 1:469) and in men (1:327) compared with women (1:351). Among 2,219 repeated donors who met FH criteria at least once, 3,116 of 10,833 total donations (28.8%) met FH criteria. Anyone with a cholesterol level higher than 200 mg/dL should see a physician for review of their family history, a full cholesterol panel (blood test), and a physical exam. The exam can identify the disease through visible signs such as cholesterol deposits in tendons,

called xanthomas. Amit Khera, MD, a Professor of Internal Medicine and principal investigator of the study, said, “The blood donor screening program could be a novel strategy to detect and notify people with potential FH, particularly younger people in whom early detection and treatment is especially impactful, as well as to guide screening of family members.” The study was published on May 22, 2019, in the journal JAMA Cardiology. Image: Tendinous xanthomas on the hand of a patient with familial hypercholesterolemia (Photo courtesy of ScreenPro FH).

Unexpected Prevalence of High-Risk HPV Types Demonstrated ow- and middle-income countries have high incidences of cervical cancer linked to human papillomavirus (HPV), and without resources for cancer screenings these countries bear 85% of all cervical cancer cases. In many of these countries, cervical cancer is the leading cause of cancer-related mortality and attributable to limited screening programs. A lack of funding, trained cytopathologists to review Papanicolaou test slides, and other health care providers for follow-up care that comprise the needed infrastructure does not allow for routine cervical cancer screening. Scientists from Dartmouth College (Lebanon, NH, USA; www. dartmouth.edu) and their Honduran colleagues collected cervical samples using cervical brushes on 1,732 participants who were employees at a manufacturing site in San Pedro Sula, Honduras, for Papanicolaou test and hrHPV testing. All cervical brushes and corresponding Papanicolaou test slides were assigned a unique study identification number.

After processing the dried cervical brushed were rehydrated in the assay tubes that contained lyophilized reagents for the MeltPro High Risk HPV Genotyping Assay (QuanDx/Zeesan Biotech, San Jose, CA, USA; www.quandx.com). Rehydrated reagents with cell lysate were then mixed and loaded directly onto the QuanDx/Zeesan Biotech SLAN-96 real-time polymerase chain reaction (PCR) instrument and run using the SLAN 8.2.2 software and HPV typing results were available within 2.5 hours. The QuanDx assay detects and distinguishes all 14 high-risk HPV types, as well as an internal human DNA sequence control. The scientists found that 480 of the 1,732 samples from the factory worker screening effort were positive for high-risk HPV, or approximately 28%, while 1,199 samples had no detectable HPV, and 53 samples failed to amplify either the internal control or an HPV target and were deemed to be invalid. The study was published on May 3, 2019, in the Journal of Global Oncology. LabMedica International November/2018

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LabMedica International

Immune-Related Gene Implicated In Chronic Candida Infection Risk andida vaginitis is a frequent clinical diagnosis with up to 8% of women experiencing recurrent vulvovaginal candidiasis (RVVC) globally. RVVC is characterized by at least three episodes per year. Although Candida often turns up as a harmless, commensal organism in healthy individuals, the fungus can prompt serious, systemic infections in immunocompromised individuals and contributes to even more common non-invasive mucosal infections. In particular a significant proportion of women go through several vulvovaginal Candida yeast infections annually, including many who lack non-genetic risk factors such as prolonged antibiotic or oral contraceptive use. A large team of international scientists led by the Radboud University Medical Center (Nijmegen, Netherlands; www.radboudumc.nl) carried out exome sequencing on women from two European cohorts: 80 cases and 77 controls from southern Europe and, from northern Europe, 75 affected women and 95 unaffected controls. The investigators used Agilent SureSelect enrichment kits (Agilent Technologies Santa Clara, CA, USA; www.agilent.com), and Illumina instruments (Illumina, San Diego, CA, USA; www.illumina.com). The team also used in vitro methods such as flow cytometry, enzymelinked immunosorbent assays, or gene silencing to track cytokine responses to Candida in 73 of the control individuals, uncovering fungusrelated shifts that were subsequently verified in 50 more participants. They fed those findings into a Candida-related cytokine quantitative trait locus (QTL) analysis, which was considered alongside exome sequences to identify SNPs, genes, and pathways contributing to frequent Candida infections. The scientists identified genes and cellular processes that contribute to the pathogenesis of RVVC, including cellular morphogenesis and metabolism, and cellular adhesion. They further identified SIGLEC15, a lectin expressed by various immune cells that binds sialic acidâ&#x20AC;&#x201C;containing structures, as a candidate gene involved in RVVC susceptibility. Candida stimulation induced SIGLEC15 expression in human peripheral blood mononuclear cells (PBMCs) and a polymorphism in the SIGLEC15 gene that was associated with RVVC in the patient cohorts led to an altered cytokine profile after PBMC stimulation. The same polymorphism led to an increase in IL1B and NLRP3 expression after Candida stimulation in HeLa cells in vitro. Last, SIGLEC15 expression was induced by Candida at the vaginal surface of mice, where in vivo silencing of SIGLEC15 led to an increase in the fungal burden. SIGLEC15 silencing was additionally accompanied by an increase in polymorphonuclear leukocytes during the course of infection. Identification of these pathways and cellular

LabMedica International November/2018

processes contributes to a better understanding of RVVC and may open new therapeutic avenues. The study was published on June 12, 2019, in the journal Science Translational Medicine. Image: A scanning electron photomicrograph of Candida albicans yeast cells (Photo courtesy of Science Photo Library).

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Lifotronic Technology

Drucker Diagnostics

Diagnostic Automation

The PA-600 features a throughput of 30 tests per hour and a RFID card with built-in QC curve. It allows for automatic loading of sample, mixing, reagent addition and testing with no pretreatment request for all sample types.

The DASH Apex 12 offers simple controls and powerful performance to minimize lab error, reduce turnaround time, and streamline training. It features a user-friendly interface to select a preset or program custom STAT cycles.

The Stat Fax 3300 features a flip-up screen with a large graphical display. With a 40-column on-board thermal printer, external printer or PC, it allows the user to create a work list, run tests, print patient reports and store patient data.

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Reagent Strips Test Analyzed for CSF in Neurological Disorders erebrospinal fluid (CSF) examination is often performed in emergency to obtain diagnostic information of various life threatening conditions such as meningitis, subarachnoid hemorrhage, demyelinating diseases or carcinomas. Initial evaluation of CSF includes protein, glucose and microscopic analysis including total and differential cell count, which requires well-equipped laboratory and trained staff. Sometimes, these facilities are not available in the small health care facilities with limited resources. Medical laboratory scientists at the Institute of Human Behavior and Allied Sciences (Delhi, India; www.ihbas.delhigovt.nic.in) conducted a study of 360 samples of CSF that were received in emergency laboratory of a tertiary care hospital in a period of six months. This study included samples of patients with age ranged from 11 to 78 years, median being 25 years. Almost equal numbers of male and female cases were found with 174 male cases and 186 female cases. Most of the cases in the study were of meningitis [tuberculous: 240 cases (66 %), bacterial: 80 cases (22%), asep-

tic: 30 cases (8%)]. There were six cases (1%) of Guillain–Barré syndrome (GBS), three cases (0.8%) of sub-acute sclerosing panencephalitis (SSPE) and one case (0.2%) of CNS tumor. All CSF samples were subjected to two types of tests-the definitive test and the index test. CSF microscopy for leucocyte and erythrocyte as well as biochemistry tests for protein and glucose on automated biochemistry analyzer were considered as definitive test. Other reference standard tests like CSF protein and glucose were performed on the biochemistry analyzer by pyrogallol red method and glucose oxidase-peroxidase (GOD-POD) method. The Combur 10 (Roche Diagnostics, Basel, Switzerland; https://diagnostics.roche.com) urinary reagent strip was used as index test to detect CSF leucocytes by leukocyte esterase estimation, glucose-by-glucose oxidase-peroxidase method, protein levels by pyrogallol red method and erythrocytes by peroxidase method. The technicians, who performed the index test, were blinded to the results of definitive tests. Undiluted CSF was mixed with the micropipette and 2–3 drops of CSF was then

added to patches of leucocytes, proteins, sugar and erythrocytes and reaction was noted after 60 to 120 seconds. Then, reaction colors of the test area were compared with the color chart on the label. The study was published on May 21, 2019, in the journal Practical Laboratory Medicine. Image: The Combur-10 brand of reagent strips for urinalysis can be used for cerebrospinal fluid analysis (Photo courtesy of Roche Diagnostics).

Technology Developed to Capture Tumor Cells he roles and clinical values circulating tumor cells (CTCs) are under intensive investigation, yet most studies are limited by technical challenges in the comprehensive enrichment of intact and viable CTCs with minimal white blood cell (WBC) contamination. CTCs break away from cancerous tumors and flow through the bloodstream, potentially leading to new metastatic tumors. The isolation of CTCs from the blood provides a minimally invasive alternative for basic understanding, diagnosis and prognosis of metastatic cancer. Chemists at The University of Georgia (Athens, GA, USA; www.uga.edu) and their collaborators developed a device, about the size of a USB drive, works by funneling blood through channels smaller in diameter than a human hair. To prepare blood for analysis, the team

adds micron-sized magnetic beads to the samples. The white blood cells in the sample attach themselves to these beads. As blood flows through the device, magnets on the top and bottom of the chip draw the white blood cells and their magnetic beads down a specific channel while the circulating tumor cells continue into another channel. Melissa B. Davis, PhD, an assistant professor and co-author of the study, said, “Physicians can only treat what they can detect. We often can’t detect certain subtypes of CTCs, but with the iFCS device we will capture all the subtypes of CTCs and even determine which subtypes are the most informative concerning relapse and disease progression.” The study was published on April 27, 2019, in the journal Lab on a Chip. LabMedica International November/2018

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LabMedica International

Pathogenic Variant Carriers Missed by Current Genetic Testing urrent guidelines recommend genetic testing for people who have a personal or family history of cancer that indicates they might be at an increased risk of harboring a pathogenic familial variant, but this approach could miss people who lack any personal or family history. Recent advancements in next-generation sequencing have greatly expanded the use of multi-gene testing panels in clinical diagnosis and management. Multi-gene panels are more sensitive and efficient than traditional testing paradigms and are increasingly more affordable. Furthermore, multi-gene panels increase the likelihood of detecting an underlying germline genetic component in diseases with genetic heterogeneity, such as cancer. A team of scientists working under the auspices of Color Genomics, Inc (Burlingame, CA, USA; www.color.com) retrospective studied included 23,179 individuals who had Color Hereditary Cancer Test results reported between May 2016 and September 2017. The Color Hereditary Cancer Test was used to analyze 30 genes in which pathogenic variants have been associated with an elevated risk of hereditary cancer, including breast, ovarian, uterine/endometrial, colorectal, melanoma, pancreatic, prostate, and stomach. DNA was extracted from blood or saliva samples and purified using the Chemagic DNA Extraction Kit (Perkin Elmer, Waltham, MA, USA; www. perkinelmer.com) automated on the Hamilton STAR (Hamilton, Reno, NV, USA; www.hamiltoncompany.com) and the Perkin Elmer Chemagic Liquid Handler instruments. The genes analyzed encompass BRCA1, BRCA2, CDKN2A, PTEN, TP53, and more. Target enrichment was performed with an automated Hamilton STAR hybrid capture procedure using SureSelect XT probes (Agilent, Santa Clara, CA, USA; www.agilent. com) before being loaded onto the NextSeq 500/550 instrument (Illumina, San Diego, CA, USA; www. illumina.com) for 150-bp paired-end sequencing. The team identified 2,811 pathogenic variants in 2,698 individuals, an overall pathogenic variant frequency of 11.6%. Pathogenic variants in BRCA1 and BRCA2 accounted for nearly a third of all positive results, while pathogenic variants linked to Lynch syndrome accounted for another 7.0% of results. They noted that pathogenic variants in BRCA1 or BRCA2 could be found across ethnic groups. While most individuals with a positive result harbored only a single pathogenic variant, a small number had two or more pathogenic variants, such as in BRCA1 or BRCA2 and in another cancer-linked gene. Of the 18,176 individuals in their cohort with sufficient health histories, 61.3% met criteria for genetic testing for breast, ovarian, colorectal, or gastric cancer and 38.7% did not. The study was published on June 11, 2019, in the Journal of Molecular Diagnostics.

LabMedica International November/2018

Image: A color hereditary cancer risk screening kit (Photo courtesy of Color Genomics).

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HEMATOLOGY ANALYZER

PLATELET TEST SYSTEM

Erba Mannheim

Contec Medical Systems

Instrumentation Lab

The Erba ITA is a range of liquid stable, ready to use reagents, offering a wide measuring range with a 1-ml calibrator in each kit. The reagents have a long shelf and can be used for semi-automatic and fully automatic analyzers.

The HA3100 is used for the quantitative analysis of blood cells in medical labs. It is ideal for the detection of WBCs, RBCs, platelets, hemoglobin and other parameters, and counting of white blood cells into three classifications.

The VerifyNow provides an easy solution to assess platelet reactivity to antiplatelet medications. It measures the effect of antiplatelet therapy prior to discharge, and identify patients at risk for bleeding or an adverse cardiac event.

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Biomarkers Predict Total Joint Replacement in Osteoarthritis Patients steoarthritis (OA) in major joints ultimately leads to joint failure for which the only curative treatment is total joint replacement. This procedure is associated with risk of complications and approximately 20% continue to experience pain. Biomarkers may act as tools in investigating the association between biochemical and pathological processes and risk of joint failure. C-telopeptide of cross-linked collagen type I (CTX-I) and C-telopeptide of cross-linked collagen type II (CTX-II) are both considered biomarkers that may reflect disease progression in OA. Scientists from the Krembil Research Institute (Toronto, ON, Canada; www.uhn.ca) performed a post-hoc analysis, looking at data from two clinical trials that involved the use of oral supplements. They included subjects with available baseline serum CTX-I and urine CTX-II for biomarker analyses. There were a total of 27 total joint replacements (TJR), 19 knee replacements, and eight hip replacements. Investigators compared the risk of TJR of the knee or hip in patients with high versus low biomarker values using statistical analysis that controlled for age, sex, and body mass index. The team showed that high baseline urine CTX-II was significantly associated with an elevated (3.08 times) risk of undergoing a TJR of the knee or hip during the period of study. For risk of knee replacement alone, patients with elevated CTX-I had an 8.94 times elevated risk. Elevated baseline serum CTX-I was associated with a 3.4 times higher risk of undergoing knee or hip replacement. However, this biomarker did

not attain statistical significance for risk of knee arthroplasty alone. Jonathan J. Bjerre-Bastos, MD, from Nordic Bioscience (Copenhagen, Denmark; www.nordicbioscience.com), and the lead author of the study, said, “Osteoarthritis is the most common indication for total joint replacement. Total joint replacement is an expensive procedure associated with complications and a portion of patients continue to have pain after surgery.” The study was published in the April 2019 issue of the journal Osteoarthritis and Cartilage. Image: Knee osteoarthritis, also known as degenerative joint disease, is typically the result of wear and tear and progressive loss of articular cartilage (Photo courtesy of Bruce Blaus).

Blood Test Measures Effectiveness of Aggressive Cancer Treatments lood tests that track the amount of tumor DNA can, after only one month of drug therapy, detect how well treatment is working in patients with skin cancer. In the USA, more than 7,200 individuals are expected to die from metastatic melanoma in 2019, with BRAF mutations playing a role in nearly half of such diagnoses. A recent study takes advantage of the nature of cancer cells, which die and are replaced by new cells continuously as part of aggressive cancer growth. Tumor cells burst as they die, spilling their DNA into the bloodstream, where it can be measured by tests, enabling improved diagnosis and better targeting of treatment based on each individual tumor’s DNA. A team of scientists led by NYU School of Medicine (New York, NY, USA; https://med.nyu.edu) analyzed blood samples from 345 male and female patients with stage III or IV melanoma, which had already spread from the skin to other organs, and who had BRAF mutations. These pa-

tients could not be treated surgically and were part of a larger group of patients participating in a clinical trial of the drugs dabrafenib and trametinib, designed to target BRAF-mutated cancers. The circulating tumor DNA (ctDNA) test was developed by Bio-Rad Laboratories (Hercules, CA, USA; www.bio-rad.com). Among the study’s key findings was that the tumor’s BRAF mutation could be detected by the new blood test in 93% of the patients before treatment started. In addition, the team found that BRAF ctDNA levels were no longer detectable after one month of therapy in the 40% of patients who had a positive clinical outcome after targeted therapy, as measured by an average survival time of 28 months. By contrast, the 60% of patients who did not respond as well still had detectable ctDNA levels, and survived for an average of just 14 months. The study was presented at the American Society of Clinical Oncology annual meeting, which was held May 31-June 4, 2019, in Chicago, IL, USA. LabMedica International November/2018

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LabMedica International

Fetal Genetic Variants Implicated in Spontaneous Preterm Birth Risk reterm live births that take place before 37 completed weeks of gestation and even as early as 22–24 weeks are a global problem. Up to 11.1% (15 million babies) of all births worldwide occur prematurely, and approximately 45% to 50% of them are idiopathic or spontaneous. Many pathways and cellular processes are reported to be associated with Spontaneous Preterm Birth (SPTB), including response to infection, regulation of inflammation, stress, and other immunologically mediated processes. A gene has been identified involved in axon guidance, neuronal migration, and inflammation, that appear to coincide with spontaneous preterm birth. An international team of Finnish and American scientists led by the Oulu University Hospital (Oulu, Finland; www.oulu.fi) studied a population that included 260 SPTB cases (139 male and 121 female infants) and 9,630 controls (4,055 males and 5,575 females). The cases were very preterm infants born between 25 and 30 weeks of gestation and were clinically defined as SPTB in 2005–2008. In the Finnish cohorts, SPTB was defined as birth occurring after spontaneous onset of labor at <36 completed weeks + 1 day of gestation. Visit us at Umbilical cord blood, umbilical cord tissue, or saliva was obtained MEDICA from the study subjects. Commercial 2019 kits were used to extract genomic Hall 3-F72 DNA from blood (UltraClean Blood DNA Isolation Kit; MO BIO Laboratories, Inc, Carlsbad, CA, USA; https://mobio.com), or Puregene Blood Core Kit (Qiagen, Hilden, Germany; www.qiagen.com) and cord tissue using Qiagen’s Gentra Puregene Tissue Kit. Genome-wide SNP genotyping was performed with the Infinium HumanCoreExome BeadChip (Illumina, San Diego, CA, USA; www.illumina.com). In total, 18 placental samples were analyzed by immunohistochemistry. The team reported that after replication testing in hundreds more babies born particularly prematurely and thousands of control infants, they were left with a single nucleotide polymorphism (SNP) in the SLIT2 gene that was significantly associated with spontaneous preterm birth, as well as suggestive associations for SNPs in other axon guidance genes. The team’s follow-up gene expression, localization, and functional experiments indicated that SLIT2 and ROBO1, which encodes SLIT2’s receptor protein, are expressed at higher-than-usual levels in certain parts of the placenta for infants experiencing spontaneous preterm birth. The most significant association with spontaneous birth involved a SNP called rs116461311 in SLIT2, prompting a series of immunohisto-

chemistry, qRT-PCR, and gene silencing experiments on placental samples or cells that the scientists used to decode SLIT2-ROBO1 interactions and their consequences for birth timing. The study was published on June 13, 2019, in the journal PLOS Genetics. Image: The UltraClean BloodSpin DNA Isolation Kit is designed to isolate genomic and mitochondrial DNA from whole blood (fresh, frozen or stored at 4°C), buffy coat or cultured cells (Photo courtesy of MO BIO Laboratories).

LabMedica International November/2018

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COAGULOMETER

MICROPLATE READER

Singuway Biotech

Axiom Laboratories

Kehua Laboratory System

The DNA extractor, when compared with other similar product, offers advantages such as being user-friendly, rapid and accurate. High pure nucleic acid can be extracted within five minutes.

The CoaRead 2a features optical clot detection, three positions for reagents and two test positions with 12 cuvettes for sample preparation. It features a graphical LCD display and an RS-232 serial port to support an external printer.

The ST-960 features a large screen-based display, enabling convenient user dialog. Its comprehensive function of qualitative and quantitative processing provides calculation formulas and equations, which can be customized.

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Stem Cell Transplantation Increases Risk of Infection-Related Mortality llogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic modality for various malignant and nonmalignant hematological conditions. The best results of allogeneic HSCT were obtained when the stem cells from a human leukocyte antigen (HLA)matched sibling were used, such a donor can only be found for approximately 30% of patients. Alternative sources of stem cells include HLA-matched unrelated donors and, in more recent times, HLA-haploidentical donors. The use of HLA-haploidentical donors has led to the near-universal availability of donors with an average of 2.7 potential donors among firstdegree relatives. A frequently encountered complication of haploidentical transplants is an increased rate of infectious complications thought to be due to a delay in immune reconstitution. Scientists at the University of Southern California (Los Angeles, CA, USA; www.usc.edu) and their colleagues conducted a retrospective

cohort study in adults with various malignant and benign hematological conditions who underwent allogeneic hematopoietic stem cell transplantation from 2011 to 2018. One hundred-day and one-year overall survival was defined as survival from the time of transplant until 100 days or one year later. Routine monitoring for cytomegalovirus (CMV) viremia was conducted three times per week by qRT-PCR for the first six months after transplant in all patients, with CMV infection defined as detectable DNA by this assay. The frequency of CMV monitoring was subsequently decreased for the remainder of the 1year post-transplant period. Patients otherwise underwent evaluation for specific bacterial, fungal, and viral infections as needed per clinical presentation as well as laboratory and imaging findings. Testing for BK viruria and viremia was performed by DNA urine RT-PCR and DNA plasma RT-PCR, respectively, in all patients who reported new-onset urinary symptoms such as dysuria and hematuria after transplant. BK virus infection was defined as

detectable DNA by these assays. The study was published on May 15, 2019, in the Journal of Blood Medicine. Image: The BK virus (BKV) is a ubiquitous human polyomavirus that causes hemorrhagic cystitis in hematopoietic stem cell transplantation patients and nephropathy in kidney transplantation recipients. Poorly cohesive urothelial cells possess amorphous and smudgy nuclei, indicative of BK viral infection (Photo courtesy of Pathos223).

Novel Stress Biomarker Measurement Method Uses UV Range recent paper described a novel label-free method for quantitative detection of human performance â&#x20AC;&#x153;stressâ&#x20AC;? biomarkers in different body fluids that is based on optical absorbance of biomarkers in the ultraviolet (UV) range of the spectrum. The concentrations of stress biomarkers (hormones and neurotransmitters) in bodily fluids (blood, sweat, urine, and saliva) predict the physical and mental state of the individual. In the current study, investigators at the University of Cincinnati (OH, USA; www.uc.edu) focused on the stress biomarkers cortisol, serotonin, dopamine, norepinephrine, and neuropeptide Y. The investigators characterized the UV properties of individual and multiple biomarkers in various biological fluids using a microfluidic/optoelectronic platform for biomarker detection in the 190-400 nm range. For this study the prime focus was cortisol evaluation. The current limit of detection of cortisol in sweat is approximately 200 nanograms per milliliter, which is in the normal range. UV measurement revealed

that plasma samples containing both serotonin and cortisol resulted in readily detectable absorption peaks at 203 (serotonin) and 247 (cortisol) nanometers, confirming the feasibility of simultaneous detection of multiple biomarkers in biological fluid samples. UV spectroscopy performed on various stress biomarkers showed a similar increasing absorption trend with concentration. The investigators reported that the detection mechanism was label free, applicable to a variety of biomarker types, and able to detect multiple biomarkers simultaneously in various biofluids. A microfluidic flow cell was fabricated on a polymer substrate to enable point-of-care UV measurement of target biomarkers. The overall sensor combined sample dispensing and fluid transport to the detection location with optical absorption measurements with a UV light emitting diode (LED) and photodiode. The UV test for stress biomarkers was described in the May 24, 2019, issue of the journal American Chemical Society Sensors. LabMedica International November/2018

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LabMedica International

Metastases May Form Early in Development Of Colorectal Cancer olorectal cancer (CRC), also known as bowel cancer and colon cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel movements, weight loss, and feeling tired all the time. Most colorectal cancers are due to old age and lifestyle factors, with only a small number of cases due to underlying genetic disorders. A new study suggests that many colorectal cancer metastases may have arisen and spread even before the primary tumor was large enough to be detected. Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts. Scientists at Stanford University School of Medicine (Stanford, CA, USA; www.med.stanford.edu) characterized the evolutionary dynamics of this lethal metastasis process by analyzing exome-sequencing data from 118 biopsies from 23 patients with colorectal cancer with metastases to the liver or brain. Through a phylogenetic analysis, the team traced the origins of these metastatic tumors. For all but one of the cases analyzed, they found the distant metastases corresponded to a monophyletic clade. Within this cohort, the scientists noted high concordance among putative driver genes. Mutations in KRAS, TP53, SMAD4, and others were similar in primary and metastatic tumor pairs. In addition, primary and metastatic tumor pairs were also likely to share somatic single nucleotide variants (SNVs) and small indels. They noted most of these metastases actually diverged early in the emergence of the primary tumor. Most of the liver and all of the brain metastases harbored many private clonal somatic SNVs, but no subclonal ones. This indicated to the team that a single cell or a small group of genetically similar cells seed most metastases. They found that in their dataset 83%of the primary metastatic tumor pairs from 17 of the 21 patients likely underwent metastatic dissemination when the primary tumor was below the limits of clinical detection, which is smaller than 0.01 cm3 in size. The scientists found in a separate cohort of 2,751 patients with colorectal cancer, including 938 patients with metastatic cancer, that most metastases harbored a set of core colorectal cancer driver genes, but also an additional candidate metastasis driver gene. In particular, they noted that the gene PTRT, a part of the STAT3 signaling pathway, appears to be a highly specific driver of metastasis. This suggested to them that early dissemination can occur in many colorectal cancer patients, underscoring the need for early detec-

LabMedica International November/2018

tion, possibly through detecting cell-free tumor DNA as these small tumors fall at the limits of detection for imaging approaches. The study was published on June 17, 2019, in the journal Nature Genetics. Image: A histopathology of lymph node with metastatic adenocarcinoma of the colon (Photo courtesy of Dr. Ed Uthman M.D).

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INFLUENZA A+B TEST

CLINICAL ANALYZER

Erba Mannheim

Nano-Ditech

RAL Tecnica

The ECL 105 measures all clotting assays, as well as D-Dimer and features a touch screen along with builtin printer. It offers five reaction cups and reagent positions, with three positions for incubated reagents.

The Fluoro-Check Influenza A+B is intended as an aid in the rapid differential diagnosis of influenza A and influenza B viral infections. The test has a turnaround time of 10 minutes and requires two drops of viral extract buffer samples.

The CLIMA PLUS solves measuring problems and avoids non-functional items, allowing working methods to be programmed and stored. User dialogues and final results can be printed, along with data to control reactions/alarm.

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FDA Clears CT/NG Assays For Extragenital Testing hlamydia trachomatis commonly known as chlamydia is a bacterium that can replicate only in human cells. It can manifest in various ways, including: trachoma, lymphogranuloma venereum, non-gonococcal urethritis, cervicitis, salpingitis, pelvic inflammatory disease. Gonorrhea is a sexually transmitted infection (STI) caused by the bacterium Neisseria gonorrhoeae. Infection may involve the genitals, mouth, or rectum. It has been estimated that there were 1.7 million cases of chlamydia and more than 500,000 cases of gonorrhea in the USA in 2017, and the number of cases is rising, as is drug-resistance. The US Food and Drug Administration (FDA, Silver Springs, MD, USA; www.fda.gov) have announced that it has cleared assays for extragenital indications for chlamydia and gonorrhea testing. The FDA reviewed clinical data collected through a multi-site study of more than 2,500 patients in its evaluation of the devices. The study, which was coordinated by the Antibacterial Resistance Leadership Group, looked at the diagnostic accuracy of multiple commercially available nucleic acid amplification tests for detection of Neisseria gonorrhoeae and Chlamydia trachomatis from throat and rectal sites. The results of this study and other information reviewed by the FDA demonstrated that the Aptima

Combo 2 Assay and the Xpert CT/NG for extragenital specimens are safe and effective for extragenital testing for chlamydia and gonorrhea. Timothy Stenzel, MD, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, said, “These two tests will fill an unmet public health need by allowing for more screening.” Image: The Aptima Combo 2 detects and differentiates ribosomal RNA from Neisseria gonorrhoeae and Chlamydia trachomatis (Photo courtesy of Hologic).

Biomarker Predicts Appropriate Immunotherapy for Cancer Patients icrosatellite instability (MSI) is a hypermutable phenotype caused by the loss of DNA mismatch repair activity. MSI is detected in about 15% of all colorectal cancers; 3% are of these are associated with Lynch syndrome. MSI is a biomarker for response to immune checkpoint inhibitors (ICPIs). Programmed death-ligand 1 (PD-1) inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often less than 50%, suggesting that additional predictive biomarkers are needed. A team of scientists working with the City of Hope Comprehensive Cancer Center (Duarte, CA, USA; www.cityofhope.org) retrospectively analyzed the data of 22 patients, all of whom had high MSI, a biomarker that indicates they are good candidates to receive immune checkpoint inhibitor treatment. The patients received either pembrolizumab or nivolumab, both of which are approved by the US Food and Drug Administration (FDA, Silver Springs, MD, USA; www.fda.gov) for metastatic colorectal cancer patients. The scientists looked at tumor character-

istics, tumor genomics and outcome data and compared those analyses to a database containing 18,140 metastatic colorectal cancer patients. Clinico-pathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and reported as mutations/Mb. The team reported that the patients whose tumor cells had a mutation score less than a cut-off point of 37 were less likely to respond to immunotherapy and more likely to have their disease quickly worsen. Alexa B, Schrock, PhD, an Associate Director, Clinical Development at Foundation Medicine (Cambridge, MA, USA; www.foundationmedicine.com) and the lead author of the study, said, “Comprehensive genomic profiling is critical to assess the underlying genomic drivers of a tumor, as well as important biomarkers that require broad DNA interrogation like tumor mutational burden (TMB) and microsatellite instability (MSI). In this study, we’ve seen the importance of evaluating both TMB and MSI when making treatment decisions for metastatic colorectal cancer patients.” The study was published on April 30, 2019, in the journal Annals of Oncology. LabMedica International November/2018

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LabMedica International

Bacteriophage-Based Blood Test Rapidly Detects TB Bacteria blood test based on bacteriophage that infect living Mycobacterium tuberculosis (Mtb) bacteria has been shown to diagnose human tuberculosis (TB) and may be able to predict which patients with latent tuberculosis will progress to the active form of the disease. It is difficult to diagnosis tuberculosis through traditional culture of the slow growing Mtb. Molecular tests to detect Mtb DNA are of limited value due to the organisms’ cell wall, which complicates DNA extraction. The new PBD Biotech (Suffolk, United Kingdom; www.pbdbio.com) Actiphage test uses a specific bacteriophage that infects live Mtb and ruptures the cells to release DNA. The DNA is then analyzed by PCR. The whole testing process can be completed in as little six hours. Investigators at Leicester Biomedical Research Centre (United Kingdom; www.leicesterbrc.nihr.ac.uk) and the University of Nottingham (United Kingdom; www.nottingham.ac.uk) used the Actiphage test to study 66 subjects who were separated into four groups: those with active pulmonary TB, those with latent TB, a control group of patients referred for suspected TB but found not to have the disease, and a control group of healthy individuals. The subjects were tested for Mtb twice, 12 months apart. Results of Actiphage testing revealed positive findings for 73% of subjects who were subsequently diagnosed with TB. None of the participants in the control groups tested positive with Actiphage, and none of the patients with latent TB who tested negative with Actiphage went on to develop active TB. The finding that two of the three subjects with latent TB infection who tested positive with Actiphage went on to develop the active form of the disease more than six months later, suggested that the test may have a predictive role in identifying people with the infection at risk of developing the disease. “TB is the leading cause of death from an infectious disease. It most commonly affects the lungs and from this site is transmitted to others by coughing and sneezing. As there is a lack of diagnostic tools for people unable to bring up sputum, diagnosis is delayed, increasing the likelihood that the disease is spread,” said senior author Dr. Pranabashis Haldar, clinical senior lecturer at the University of Leicester. “Our observations provide new insights into how human TB develops and support recent evidence of the existence of a transitional state of TB infection called incipient TB that does not produce symptoms but carries a high risk of progressing to active TB. There is potential for Actiphage to be developed, both as a mainstream blood test to diagnose TB and as a test used in screening programs to help us identify and treat people with latent infection.” The study was published in the June 22, 2019, online edition of the journal Clinical Infectious Diseases.

LabMedica International November/2018

Image: A researcher preparing blood samples for Actiphage testing (Photo courtesy of the University of Nottingham, School of Bioscience).

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HUMAN C-PEPTIDE ELISA

CENTRIFUGE

Sekisui Diagnostics

Alpco Diagnostics

Drucker Diagnostics

The Acucy Influenza A&B test offers fast and accurate results that aid in the treatment of patients. It offers Read Now or Walk Away modes, and provides results within 15 minutes using a CLIA-waived procedure.

The STELLUX is for the quantification of human Cpeptide in serum/plasma samples in both clinical/research labs. A single kit can measure up to 36 samples in duplicate by utilizing a dual-monoclonal antibody sandwich ELISA format.

The HORIZON 6 FA features simple set and lock controls for blood and urine tubes up to 15 mL/125 mm. It allows the user to set and lock to preferred settings with a simple, two-button interface, or choose from three preset cycles.

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Masspec Pen Evaluated for Rapid Diagnosis of Cancer varian cancer is a highly lethal disease and the fifth leading cause of all cancer-related deaths in women. Accurate diagnosis and stratification of ovarian cancer is important to develop personalized treatment approaches. Current methods for intraoperative tissue evaluation can be time intensive and subjective. A handheld and biocompatible device coupled to a mass spectrometer, has been developed, which uses a discrete water droplet for molecular extraction and rapid tissue diagnosis. Scientists at The University of Texas at Austin (Austin, TX, USA; www.utexas.edu) used the devise called the MasSpec Pen to analyze its performance on 192 ovarian, fallopian tube, and peritoneum tissue samples. The analyzed area of the tissue was demarcated and registered through optical images. Demarcated tissue or a parallel piece was frozen and sectioned at 10–16 m using a CryoStar NX50 cryostat (Thermo Fisher Scientific, Waltham MA, USA; www.thermofisher.com), stained by standard hematoxylin and eosin procedure, and evaluated by expert pathologists to confirm diagnosis of the analyzed area. Performance using an Orbitrap and a linear ion trap mass spectrometer was tested. Of note, the final diagnoses were performed after MasSpec Pen analyses. Only 164 samples with clear diagnosis were used for statistical analysis. The team reported that a high performance for 131 high-grade serous carcinoma (clinical sensitivity, 96.7%; specificity, 95.7%) and 138 overall cancer (clinical sensitivity, 94.0%; specificity, 94.4%) diagnoses was achieved using Orbitrap data. Discrimination between cancer and fallopian tube or peritoneum tissues was also achieved with accuracies of 92.6% and 87.9%, respectively, and 100% clinical specificity for both.

Using ion trap data, excellent results for high-grade serous cancer versus normal ovarian differentiation were achieved. The authors concluded that the MasSpec Pen, together with machine learning, provides robust molecular models for ovarian serous cancer prediction and thus has potential for clinical use for rapid and accurate ovarian cancer diagnosis. The study was published in the May 2019 issue of the journal Clinical Chemistry. Image: The handheld MasSpec Pen device which can be connected to a Mass Spectrometer for diagnosing ovarian and other cancers (Photo courtesy of the University of Texas at Austin).

Study Explains Link Between Genetic Variation and Vaccine Persistence o better explain how genetic variation affects antibody production and specificity following immunization, researchers conducted a GWAS (genome-wide association study) to examine the persistence of immunity following administration of three childhood vaccines. The efficacy of vaccine-induced immunity depends on the considerable variability in magnitude and persistence of specific antibodies. Maintenance of these specific antibodies is essential for continuity of vaccine-induced serological protection. Investigators at the University of Oxford (United Kingdom; www.ox.ac.uk) conducted a genome-wide association study into the persistence of immunity to three childhood vaccines: capsular group C meningococcal (MenC), Haemophilus influenzae type b, and tetanus toxoid (TT) vaccines. Working with genetic data collected from 3,602

children in the United Kingdom and The Netherlands, the investigators analyzed approximately 6.7 million genetic variants affecting single nucleotide polymorphisms (SNPs) associated with vaccine-induced antibody levels. Following analysis of the results, the investigators published detailed associations between variants in a locus containing a family of signal-regulatory proteins and the persistence of MenC immunity. “Evoking robust and sustained vaccine-induced immunity from early life is a crucial component of global health initiatives to combat the burden of infectious disease,” said first author Dr. Daniel O’Connor, postdoctoral researcher in pediatrics at the University of Oxford. The vaccine study was published in the June 11, 2019, online edition of the journal Cell Reports. LabMedica International November/2018

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LabMedica International

Genomic Data Affects Prognosis Of Advanced Prostate Cancer eterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Various genomic and histologic features of prostate cancer have been described as conferring a worse prognosis. Among these is the presence of neuroendocrine or small-cell characteristics in tumors, sometimes referred to as aggressive variant prostate cancer or neuroendocrine prostate cancer. A large international team of scientists led by the Memorial Sloan Kettering Cancer Center (New York, NY, USA; www.mskcc.org) used exome sequencing and RNA sequencing to assess coding mutations and transcriptomic features in samples from more than 400 individuals with metastatic, castration-resistant prostate cancer (mCRPC) who also had clinical data available. They focused on a matched tumor-normal dataset for 429 mCRPC patients treated at seven centers around the world, using exome sequencing to profile coding alterations in 444 prostate, lymph node, bone, liver, lung, or other biopsy samples from these cases. They also performed RNA sequencing on 332 tumor samples from a subset of 323 mCRPC patients. Reviews were conducted on H&Estained frozen sections, allowing for review of the exact material that was used for nucleic acid extraction. Flashfrozen needle biopsies and matched normal samples underwent nucleic acid extraction and extracted DNA underwent whole-exome library construction and somatic mutation analysis. Amplifications and homozygous deletions for a set of 20 genes previously implicated in prostate cancer underwent further confirmatory review of segmentation files. Transcriptome libraries were prepared using polyA+ RNA isolation, or captured using Agilent SureSelect Human All Exon V4 reagents (Agilent Technologies, Santa Clara, CA, USA; www.agilent.com) or in some cases using both polyA and capture methods. The team used these genomic and transcriptomic data, and looked at the frequency and interactions between new and known genomic alterations in the advanced prostate cases, identifying frequent mutations in genes such as the androgen receptor gene AR, ETS, TP53, or PTEN, as well as co-occurring alterations affecting genes such as CDK12, CDK4, and CCND1 that fall in cell cycle pathways previously linked to potential immune activity against tumors. When they focused on 18 recurrently mutated genes in 128 patients who received androgen receptor signaling inhibitor drugs, they saw ties between relapse, or shorter time on treatment, and shifts in genes such as AR, TP53, or RB1. The RB1 gene alterations alone showed significant interactions with patient survival following andro-

LabMedica International November/2018

gen receptor signaling inhibitor treatment, the scientists reported, though chromosomal aneuploidy in general also tended to correspond with shorter survival times and relapse. The study was published on May 6, 2019, in the journal Proceedings of the National Academy of Sciences. Image: A histopathology of castration-resistant prostate cancer (Photo courtesy of Andrew J. Armstrong, MD, ScM).

Visit us at MEDICAÂŽ 2019

Hall 1A-64

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SAMPLE TRANSPORTATION

EXTRACTION SYSTEM

EKF Diagnostics

POREX

Taigen Bioscience

The HemoPoint H2 provides a precise hemoglobin and hematocrit measurement in just 30 seconds. Its cuvette holder prevents optics contamination, while its intuitive backlit touch screen allows simple and easy operation.

The Matrix Sampling Technology allows the porous matrix to collect, transport, store and release a sample upon demand. With the ability to be customized, it reduces costs, protects sample integrity and decreases workflow time.

The LabTurbo 48 Compact System automates DNA/RNA extraction of up to 48 samples in 90 minutes from raw sample to NA elution. It can effectively purify cellular, viral, bacterial, tissue and circulation DNA/ RNA from samples.

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Study Validates Use of Tumor Markers in Treatment Of Metastatic Cancer romising results obtained in a recently conducted pilot study demonstrated the feasibility of using molecular tumor markers as the basis for selecting the chemotherapeutic agents to use in patients with metastatic pancreatic cancer. Investigators at Georgetown University (Washington, DC, USA; www.georgetown.edu) and collaborators at several other institutions carried out a study designed to assess the feasibility of following a treatment algorithm based on the expression of three published predictive markers of response to chemotherapy: ribonucleotide reductase catalytic subunit M1 (for gemcitabine); excision repair cross-complementation group 1 (for platinum agents); and thymidylate synthase (for 5-fluorouracil) in patients with untreated, metastatic pancreatic cancer. Initially, 30 patients were enrolled in the study. However, 10 patients failed screening primarily due to inadequate tumor tissue availability. Of the remaining 20 patients, tumor biopsy analysis was used to assign them to one of seven doublet treatment regimens. Key secondary objectives included response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results revealed promising indications for progression-free survival and overall survival, with a partial response seen in 28% of patients and stable disease in 50% by completion of the study.

Based on the results from this pilot study, a larger phase II randomized trial of molecularly targeted therapy versus physiciansâ&#x20AC;&#x2122; choice of standard of care has been initiated. Results of the pilot study were discussed in the May 2, 2019, online edition of the Journal of Pancreatic Cancer. Image: A new study validated the use of tumor markers to select chemotherapy drugs for patients with metastatic pancreatic cancer (Photo courtesy of SPL).

Biomarker Found for Celiac Patients on Gluten-Free Diet eliac disease is a complex condition, routinely treated by means of a strict gluten-free diet (GFD). One of the diagnostic challenges of this disease is that patients need to be consuming gluten so that a correct diagnosis by means of endoscopy can be made. Celiac disease (CeD) is an immune-mediated enteropathy with a strong genetic component, where alleles encoding Human Leukocyte Antigen (HLA)-DQ2 and -DQ8 molecules account for 40% of disease heritability. A genetic, constitutive biomarker present also when the disease-triggering insult is absent would be extremely useful for the diagnosis this conditions. Scientists associated with the University of the Basque Country (Leioa, Spain; www.ehu.eus) hypothesized that merging different levels of genomic information through Mendelian Randomization (MR) could help discover genetic biomarkers useful for CeD diagnosis. MR was performed using public databases (9,451 cases and 16,434 controls) of expression quantitative trait loci (eQTL) and methylation QTL (mQTL) as exposures,

and the largest CeD genome-wide association study (GWAS) conducted to date as the outcome, in order to identify potential causal genes. The scientists identified UBE2L3, an ubiquitin ligase located in a CeD-associated region. They interrogated the expression of UBE2L3 in an independent dataset of peripheral blood mononuclear cells (PBMCs) and found that its expression is altered in CeD patients on GFD when compared to non-celiac controls. The relative expression of UBE2L3 isoforms predicts CeD with 100% specificity and sensitivity and could be used as a diagnostic marker, especially in the absence of gluten consumption. The authors concluded that the relative expression of the isoforms of the UBE2L3 gene in the blood makes it possible to distinguish with 100% sensitivity and specificity celiac patients on a gluten-free diet. The approach used could be applicable to other diseases where diagnosis of asymptomatic patients can be complicated. The study was published on May 29, 2019, in the journal Human Molecular Genetics. LabMedica International November/2018

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Urinary Biomarkers Diagnose Serious Kidney Allergic Reaction cute interstitial nephritis is a condition marked by inflammation and swelling of the renal tubules, the tiny portals in the kidneys where blood is filtered. As a result, the tubules cannot properly reabsorb water and useful organic substances, such as glucose and amino acids, or secrete waste products such as urea and creatinine into urine. Acute interstitial nephritis (AIN) is commonly the result of autoimmune diseases or allergic reactions to more than 100 medications, including antibiotics, pain relievers and antacids. The disease is estimated to cause 15% to 20% of all hospitalizations for acute kidney injury. Currently, the only method of diagnosing AIN is by examining renal tissue obtained with a biopsy, putting patients at some risk from complications. A large team of scientists collaborating with Johns Hopkins Medicine (Baltimore, MD, USA; www.hopkinsmedicine.org) prospectively enrolled participants who were scheduled to undergo a clinically indicated kidney biopsy at two Yale Universityâ&#x20AC;&#x201C;affiliated hospitals from January 2015 to June 2018. Three renal pathologists independently evaluated biopsy slides to establish AIN diagnosis. The investigators measured the amounts of 12 urine and 10 blood plasma proteins in samples from 79 adult, biopsy-confirmed AIN patients, and compared them to the amounts in 186 adult kidney biopsy patients without an AIN diagnosis. The scientists measured biomarkers from plasma and urine samples stored at -80 ÂşC after a single controlled thaw. The team used the manufacturer-validated 10-plex Proinflammatory Panel 1 (Meso Scale Discovery, Rockville, MD, USA; www. mesoscale.com) to test plasma cytokines and validated the above 10plex panel in the urine. They also created and validated a custom 2-plex urine assay for IL-5 and IL-9. The team also performed urine albumin and creatinine measurements using Randox RX Daytona machine (Crumlin, UK; www.randox.com) and urine dipstick analysis using Clinitek Status analyzer (Siemens Healthcare Diagnostics Inc., Erlangen Germany; www.siemens-healthineers.com). They also performed urine sediment microscopy using a Laxco LMC4BF, (Fisher Scientific, Hampton, NH, USA; www.fishersci.com). The results, reviewed independently by three pathologists, showed that none of the plasma biomarkers were associated with AIN, but that two proteins, tumor necrosis factoralpha (TNF- ) and interluken-9 (IL9), were consistently seen in the urine of AIN patients. Neither cytokine was present in the control samples, either in plasma or urine. To test the sensitivity of using IL-9 in this manner, the scientists compared its AIN-detecting ability in patients whose disease was confirmed by pathologists who evaluated biopsied material or was symptomatically diagnosed by clinicians prior to the

LabMedica International November/2018

biopsies. The study was published on May 16, 2019, in the Journal of Clinical Investigation Insight. Image: The RX Daytona chemistry analyzer is a compact fully automated benchtop clinical chemistry analyzer perfect for small- to mediumthroughput laboratories (Photo courtesy of Randox Laboratories).

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Regulatory T-Cell Responsiveness Predicts Risk of Cancer Relapse he risk of future breast cancer relapse can be predicted by analyzing the signaling responsiveness of peripheral blood Treg II cells (CD45RA−FOXP3hi Treg cells) to immunosuppressive T helper type 1 (TH1) and T helper type 2 (TH2) cytokines. Th1 helper cells lead to an increased cell-mediated response, typically against intracellular bacteria and protozoa. Th2 helper cells lead to a humoral immune response, typically against extracellular parasites including helminths. The regulatory T-cells (Tregs) are a subpopulation of T-cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T-cells. Tregs express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4 cells. Because effector T-cells also express CD4 and CD25, Tregs are very hard to effectively discern from effector CD4+, making

them difficult to study. Investigators at City of Hope (Duarte, CA, USA; www.cityofhope.org) studied the origin of breast cancer- related intratumoral Treg cells and their relationship with peripheral blood Treg cells. In this study, the investigators evaluated data on 40 breast cancer patients who had been monitored for a median of four years. Results were validated in a separate cohort of 38 additional breast cancer patients to create a benchmark that could be used to predict whether a breast cancer patient would be likely to relapse within a short span of years. “This is the first success linking a solid tumor with blood biomarkers - an indicator of whether a patient will remain in remission,” said senior author Dr. Peter P. Lee, professor of cancer immunotherapeutics at City of Hope. “When patients are first diagnosed with cancer, it is important to identify those at higher risk for relapse for more aggressive treatments and monitoring. Staging and new tests based on genomics analysis of the tumor are current-

ly available for risk stratification. However, a predictive blood test would be even more attractive but is not yet available. We are trying to change the status quo. Knowing the chance of cancer relapse will inform doctors how aggressive a particular patient’s cancer treatment should be.” The breast cancer relapse study was published in the July 8, 2019, online edition of the journal Nature Immunology. Image: A scanning electron micrograph (SEM) of a human T-cell from the immune system of a healthy donor (Photo courtesy of [U.S.] NIAID).

Nasal Microbiome Influences Pneumonia and Related Diseases recent study examined the influence of the natural microbial flora in the nose and viral co-infection on the acquisition of Streptococcus pneumoniae bacteria and the development of pneumococcal diseases. S. pneumoniae is the main bacterial pathogen involved in pneumonia. It has been speculated that acquisition of the bacteria and colonization density was probably affected by viral co-infections, the local microbiome composition, and mucosal immunity. To examine the relationship between the nasal microbiome and acquisition of S. pneumoniae bacteria, investigators at Liverpool School of Tropical Medicine (United Kingdom; www.liv.ac.uk/lstm) and the University of Edinburgh (United Kingdom; www.ed.ac.uk) used an experimental human challenge model (the Experimental Human Pneumococcal Challenge) and inoculated live bacteria in combination with a live virus in the form of the readily available nasal vaccine for influenza. Working with this model, the investigators examined the interactions

between live-attenuated influenza vaccine (LAIV), successive pneumococcal challenge, and the healthy adult nasal microbiota and mucosal immunity. Results indicated that the equilibrium between the nasal microbiome and the host immune system had an impact on pneumococcal acquisition and density, in particular when combined with a viral co-infection. The microbial flora in the nose also appeared to have an effect on replication of the pathogenic virus itself. Contributing author Dr. Daniela Ferreira, professor of respiratory vaccines and infection immunology at Liverpool School of Tropical Medicine, said, “We knew relatively little about the relationship between viral infections and the microbiota. Our model helped us to establish a link between baseline microbiota and colonization with the bacteria which causes pneumonia and shows the way that it is apparently altered with the introduction of a viral pathogen.” The work was published in the July 5, 2019, online edition of the journal Nature Communications. LabMedica International November/2018

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CtDNA Forecasts Non-Metastatic Colorectal Cancer Recurrence olorectal cancer (CRC), also known as bowel cancer and colon cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Most colorectal cancers are due to old age and lifestyle factors, with only a small number of cases due to underlying genetic disorders. Colorectal cancer diagnosis is performed by sampling of areas of the colon suspicious for possible tumor development, typically during colonoscopy or sigmoidoscopy, depending on the location of the lesion. It is confirmed by microscopical examination of a tissue sample. In Europe the five-year survival rate for colorectal cancer is less than 60% and in the developed world about a third of people who get the disease die from it. An international team of scientists led by those at the Johns Hopkins University School of Medicine (Baltimore, MD, USA; www.hopkinsmedicine. org) included in a study 58 patients with stage I, II, or III CRC who underwent radical surgical resection at four Swedish hospitals from February 2, 2007, to May 8, 2013. Blood samples were collected at one month after the surgical procedure and every 3 to 6 months thereafter for circulating tumor DNA (ctDNA) analysis. Patients were followed up until metachronous metastases were detected, or for a median of 49 months. Data analysis was performed from March 1, 2009, to June 23, 2018. While most of the patients did not have detectable levels of ctDNA in their blood after surgery, their search for known patient tumor mutations, using the Safe-SeqS assay, identified more than a dozen patients who were positive for ctDNA. The team found that disease recurrence and relapse occurred in all but three of the 13 early-stage CRC patients with post-surgical ctDNA, pointing to the potential benefit of ongoing testing for ctDNA after surgical tumor resection. On average, the ctDNA turned up in relapsing patients some three months before clinicians could see the recurrent disease by radiologic screening or clinical symptoms. The team did not see disease recurrence over an average of more than four years of follow up in the 45 remaining, ctDNA-free CRC patients.

Louise Olsson, MD, PhD, a corresponding author of the study, said, “Serial circulating tumor DNA levels during post-operative surveillance can be used as a triage test to stratify patients with resected colorectal cancer on the basis of their risk of recurrence.” The study was published on May 9, 2019, in the journal JAMA Oncology. Image: A histopathology of colorectal carcinoma: an example of moderately differentiated adenocarcinoma showing complicated glandular structures in a desmoplastic stroma (Photo courtesy of the David Geffen School of Medicine at the University of California).

Neurofilament Light Considered As NIV Biomarker for Alzheimer’s esults presented in a recently published paper suggested that plasma neurofilament light protein may serve as a noninvasive biomarker to monitor neurodegeneration in Alzheimer disease (AD). Neurofilament light polypeptide (NfL), also known as neurofilament light chain, is a neurofilament protein that in humans is encoded by the NEFL gene. Neurofilament light chain is a biomarker that can be measured with immunoassays in cerebrospinal fluid and plasma and reflects axonal damage in a wide variety of neurological disorders. It is a useful marker for disease monitoring in amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s disease, and more recently Huntington’s disease. An international team of investigators examined whether longitudinal plasma NfL levels were associated with other hallmarks of AD such as amyloid plaques and tau phosphorylation. To accomplish this task, they used data from 1583 individuals in the multicenter Alzheimer’s Disease Neuroimaging Initiative study had been conducted from September 2005 through June 2016. Patients were eligible for inclusion if they had NfL measurements. Annual plasma NfL samples were collected for up to 11 years and were analyzed in 2018. Results revealed that of the included 1583 participants, 716 (45.2%) were women, and the mean age was 73 years; 401 had cognitive impairment, 855 had mild cognitive impairment, and 327 had AD dementia. The NfL level was increased at baseline in patients with mild cognitive impairment and AD dementia and increased in all diagnostic groups, with the greatest increase in patients with AD dementia. The findings suggested that plasma NfL could be used as a noninvasive biomarker associated with neurodegeneration in patients with AD and could be useful to monitor effects in trials of disease-modifying drugs. The study was published in the April 22, 2019, online addition of the journal JAMA Neurology.

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Genetic Changes Linked to Leukemia in Down’s Syndrome f the 30% of children with Down’s syndrome who are found to have ‘myeloid preleukemia’, only 10% of those will go on to develop myeloid leukemia (3% of all children with Down’s syndrome). Until now, it was not understood why only some children with the GATA1 mutation were progressing to full leukemia, while others were not. The specific gene mutations required for the development of leukemia in children with Down’s syndrome have been discovered. Children with Down’s syndrome have a 150-fold increased risk of myeloid leukemia, and while some of the genetic causes of this have been previously established, and a new study has identified a wide range of mutations and how they functionally interact to lead to leukemia. An international team of scientists collaborating with those at the University of Oxford (Oxford, UK; www.ox.ac.uk) combined exome and targeted resequencing of 111 transient ab-

normal myelopoiesis (TAM) and 141 myeloid leukemia-Downs’s syndrome (ML-DS) samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. The scientists identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, they tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS. Paresh Vyas, MRCP FRCP FRCPath, a Professor of Hematology and a study author, said, “90% of babies with Down’s syndrome do not go on to develop preleukemia. But until now, we did not fully understand why some babies did develop leukemia. ‘To answer this ques-

tion, we carefully characterized the mutations in genes required for leukemia to develop. We found that additional genetic changes are required in the altered GATA1 blood cells, and these additional changes transform the preleukemic blood cells into leukemic blood cells.” In total, 43 different altered genes were found. The study was published on July 11, 2019, in the journal Cancer Cell. Image: Bone marrow aspirate of a patient with myeloid leukemia associated with Down’s syndrome. The smear includes frequent atypical megakaryocytes. Blasts are increased (11%). As in the peripheral blood, a subset of the blasts has cytoplasmic blebs (Photo courtesy of Elizabeth L. Courville, MD).

Electronic Device May Help Diagnose Early Bladder Cancer t is estimated that bladder cancer will affect 80,470 people in the USA this year, and about 17,670 deaths are likely to result from these cases. Doctors diagnose approximately half of all bladder cancers while the cancer is still in situ, while in about one-third the disease has already spread to other parts of the bladder. Currently, the most common ways of detecting bladder cancer are cystoscopies and urine cytology tests. The former are costly, invasive, and heavily reliant on how the operator performs them, while the latter are not very effective at detecting cancer in its early stages. Additionally, cytology tests are prone to error, as they are not the best tool for telling the difference between inflammation and malignancy. Bioengineers at the Polytechnic University of València (València, Spain; www.upv.es) and their colleagues have developed a complex electronic device as a possible new, efficient, simple, and cost-effective way of detecting bladder cancer in its early stages and monitoring people living with bladder cancer. The devices are called electronic tongues, which are a voltammetric device that can “mimic” the mechanism of

human taste by using pattern-information software and sensors that can detect soluble compounds. The scientists built on previous studies that revealed metabolic differences in the urine of people who had bladder cancer. These previous studies used established metabolomic techniques, such as liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy, to look at the metabolic profiles both before and after surgery. Bladder cancer has a high relapse rate, which is why monitoring patients is particularly important. In 2012, bladder cancer “was the ninth most common malignancy worldwide, with 430,000 newly diagnosed cases. M. Carmen Martínez Bisbal, PhD, a biochemist and co-author of the study, said, “The preliminary results of this study, with a 75% accuracy rate, indicate that the shapes of current waveforms induced in urine through pulse voltammetry could allow, with an appropriate processing of the data, for a noninvasive diagnosis in the monitoring of patients with bladder cancer.” The study was presented at the XIII International Workshop on Sensors and Molecular Recognition held July 4-5, 2019, in Valencia, Spain. LabMedica International November/2018

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Flow Cytometry Leukemia / Lymphoma Antibody Panel Receives Approval panel of immune-phenotyping flow cytometer reagents that identifies both lymphoid and myeloid cell lines has been granted diagnostic marketing clearance by the [U.S.] Food and Drug Administration to complement its European IVD classification. The Beckman Coulter (Brea, CA, USA; www.beckmancoulter.com) ClearLLab 10C System offers all components needed: from quality controls, sample preparation and antibody panels to analysis software and training materials. The ClearLLab 10C dry pre-mixed antibody panels rely on DURA Innovations technology, eliminating the need to pipette antibodies, thereby improving efficiency while reducing potential for human error. The DURA (Dry Unitized Reagent Assays) drying process creates a uniform reagent layer at the bottom of the tubes. The reagents do not require refrigeration, which allows the technician to produce a single batch and store it at room temperature for the duration of the study. The ClearLLab 10C kit contains four premixed, dry 10-color panels: Lymphoid (B-cells, T-cells), Myeloid (M1, M2). In addition, there are normal and abnormal control cells as a liquid preparation of stabilized human erythrocytes and leukocytes. The kit, which was validated for the use on

the Beckman Coulter Navios/Navios EX flow cytometers, uses Kaluza C analysis software for data analysis and reporting. ClearLLab 10C is supported by a unique resource, the ClearLLab 10C case book. The case book provides 24 diagnostic vignettes giving characteristic findings after flow cytometric analysis, with expert assessment by hematopathologists. Image: Normal and abnormal control cells from the ClearLLab 10C kit (Photo courtesy of Beckman Coulter).

Lipid Levels from Non-Fasting Patients Deemed Suitable for Assessing CVD Risk esults published in a recent paper suggested strongly that lipid levels measured in blood samples from non-fasting patients were accurate and predicative of future cardiovascular risk. A team of investigators from Brigham and Women’s Hospital (Boston, MA, USA; www.brighamandwomens.org), Harvard Medical School (Boston, MA, USA; www.harvard.edu), and Imperial College London (United Kingdom; www.icl.ac.uk) sought to determine how non-fasting lipid levels compared with fasting lipid levels measured in the same individuals for assessing cardiovascular risk, and what was their association with incident cardiovascular events. To this end they performed a secondary analysis of the results of a randomized clinical trial that included 8270 of 10,305 participants from the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA) with non-fasting and fasting lipid levels measured four weeks apart (including 6855 participants with no prior vascular disease). Data were collected from February 1, 1998, to December 31, 2002, and analyzed from February 1, 2016, to November 30, 2018. Analysis of the results revealed that among the 8270 participants (82.1% male; mean age, 63.4 years), non-fasting samples had modestly higher triglyceride levels and similar cholesterol levels compared to fasting samples. Associations of non-fasting lipid levels with coronary events were similar to those for fasting lipid levels. “We hope this study will be the final nail in the coffin, providing strong evidence that, within the same person, fasting or not before a lipid level test does not matter for predicting cardiovascular risk,” said senior author Dr. Samia Mora, director of the center for lipid metabolomics at Brigham and Women’s Hospital. “This should reassure health care providers and patients that it does not make a difference if you fast or do not fast if the goal is to predict your cardiovascular risk.” “We spend most of our lives in a non-fasting state. And for some patients, especially those who are elderly or have diabetes, it can be risky to fast before lipid testing,” said Dr. Mora. “Health care providers held back because of concerns of variability within individuals, but the data here is so convincing. It should allow people to feel more comfortable with non-fasting lipid testing for cardiovascular risk assessment, including when taking a statin.” The paper was published in the May 28, 2019, online edition of the journal JAMA Internal Medicine.

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Microfluidic Device Rapidly Diagnoses Sepsis epsis is a life-threatening condition and early diagnosis is crucial to ensure that treatment is not delayed. However, as current diagnostic methods are imprecise, the condition is misdiagnosed in 30% of patients. It is estimated that, each year, sepsis affects over 30 million people around the world. Sepsis may also lead to around six million deaths each year. To prevent sepsis from evolving into septic shock, a complication that makes premature death more likely, doctors have to diagnose it early and act on it quickly. Yet current diagnostic methods are often symptomatic, combined with tests checking for general markers of infection or organ damage. Bioengineers and their colleagues at Massachusetts Institute of Technology (Cambridge, MA, USA; www.mit.edu) have developed a microfluidics-based system that automatically detects clinically significant levels of interleukin-6 (IL-6) for sepsis diagnosis in about 25 minutes, using less than a finger prick of blood. In one microfluidic channel, microbeads laced with antibodies mix with a blood sample to capture the IL-6 biomarker. In another channel, only beads containing the biomarker attach to an electrode. Running voltage through the electrode pro-

duces an electrical signal for each biomarker-laced bead, which is then converted into the biomarker concentration level. The device uses about 5 μL of blood, which is about a quarter the volume of blood drawn from a fingerprick and a fraction of the 100 μL required to detect protein biomarkers in laboratory-based assays. The device captures IL-6 concentrations as low as 16 pg/mL, which is below the concentrations that signal sepsis, meaning the device is sensitive enough to provide clinically relevant detection. This suggests that the device is very sensitive to the presence of key biomarkers. More importantly, the scientists argue that the innovative tool is highly adaptable and could be set to detect other sepsis biomarkers, such as interleukin8, C-reactive protein, and procalcitonin, among others. Dan Wu, a PhD student in the Department of Mechanical Engineering, and first author of the study said, “For an acute disease, such as sepsis, which progresses very rapidly and can be life-threatening, it’s helpful to have a system that rapidly measures these non-abundant biomarkers. You can also frequently monitor the disease as it progresses.” The study was presented at the Engineering in Medicine and Biology Conference held July 23-27, 2019, in Berlin, Germany.

Abnormal Metabolite Observed in Early CKD Patients hronic kidney disease (CKD) has been a growing health burden worldwide, and the patients with CKD continue to suffer from a wide range of complication including electrolyte imbalance, fluid overload, bone and mineral metabolism disorder to anemia. CKD has been recognized as risk factors for 25-hydroxyvitamin D (25(OH) D) deficiency and low levels of 25 (OH) D have been suggested to be a trigger factor of decreased level of hemoglobin. However, there is lack of information about the magnitude of 25(OH) D deficiency and hemoglobin level in Nepalese CKD patients. Two Nepalese scientists associated with Purbanchal University (Kathmandu, Nepal; www.puexam.edu.np) carried out a cross-sectional study was carried out between June 2016 to May 2017 in the patients visiting outpatient nephrology unit at Kathmandu medical and teaching hospital and a total 172 patients who met the inclusion criteria were included in the study. All the patients had had measurement of serum creatinine, 25(OH) D and urine albumin creatinine. Clinically stable and with a diagnosis of CKD stage 2–5 who were not on dialysis were recruited for the study. The core variables of interest in this study were 25(OH) D level and hemoglobin concentration. The following covariates included in statistical analysis: age, sex, co-morbidities (hypertension, and diabetes),

biochemical laboratory test including estimated glomerular filtration rate (eGFR), hemoglobin (Hb), intact parathyroid hormone (iPTH), serum phosphate, albumin, calcium, and phosphate. Electrochemiluminescence immunoassay (ECLIA) test was used to measure the level of 25(OH) D and cyanmethemoglobin method for the estimation of Hb level. The scientists reported that the estimated prevalence of abnormal 25(OH) D metabolite of less than 30 ng/mL in the predialysis patients were (87.8%), with 32% and 55.8% deficiency and insufficiency 25(OH) D metabolite, respectively. On regression analysis, serum 25(OH) D was positively associated with male subjects, serum albumin, and eGFR, while inversely associated with age, iPTH. Hb concentration was found to be positively correlated with 25(OH) D in both univariate as well as in multivariate analysis. The authors concluded that Hb concentration significantly, positively correlated with 25(OH) D age, eGFR and calcium level. Conversely, there was inverse relationship between Hb and iPTH. The study shows that lower level of 25(OH) D level are associated with lower level of Hb and higher level of iPTH, and could play a role in the development of anemia and hyperparathyroidism. The study was published on July 17, 2019, in the journal BMC Nephrology. LabMedica International November/2018

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Reaction to Vancomycin Linked to Immune System Human Leukocyte Antigen Variant simple and inexpensive assay for the HLA-A*32:01 genetic variant was developed for routine use in diagnostic laboratories to identify patients likely to suffer from vancomycin-associated drug rash with eosinophilia and systemic symptoms (DRESS). DRESS is a severe reaction to antibiotic treatment caused by an aberrant T-cell mediated immune response that is characterized by fever, widespread skin rash, and internal organ damage. Vancomycin is a prevalent cause of DRESS, which commonly occurs in the setting of combination antibiotic therapy. Variations in human leukocyte antigen (HLA) class I in particular have been associated with serious T-cell mediated adverse drug reactions, which has led to preventive screening strategies for some drugs. Investigators at Vanderbilt University Medical Center (Nashville, TN, USA; www.vander bilthealth.com) sought to determine if variation in the HLA region was associated with vancomycin-induced DRESS and whether a diagnostic test could detect this association. For this study, the investigators analyzed data from Vanderbilt University Medical Centerâ&#x20AC;&#x2122;s biobank, BioVU, which contains approximately 250,000 unique DNA samples linked to deidentified patient records. Results of this survey revealed that 86% of patients who developed probable vancomycin-associated DRESS carried the genetic variation HLA-A*32:01, compared to none of the matched control patients, who received vancomycin treatment and did not

develop DRESS. HLA-A is one particular group within the human Class I major histocompatibility complex (MHC). It consists of several hundred different genes and several thousand variant alleles. HLA-A is critical to the cytotoxic T-cell controlled immune response to viruses and other intracellular pathogens. Because each HLA-A gene has a high affinity for slightly different peptides, certain HLA-As are associated with increased risk, more rapid progression, and/or increased severity of many diseases. The work was published in the February 15, 2019, online edition of the Journal of Allergy and Clinical Immunology. Image: An illustration of HLA-A complexed with HIV TAX peptide (Photo courtesy of Wikimedia Commons).

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Protein Atlas Accelerates Personalized Medicine in Leukemia Patients cute myelogenous leukemia is associated with risk factors that are largely unknown and with a heterogeneous response to treatment. Only about one in four people diagnosed with acute myelogenous leukemia (AML) survive five years after the initial diagnosis. To improve that survival rate, scientists have created an online atlas to identify and classify protein signatures present at AML diagnosis. The new protein classifications will help clinicians recommend better treatment and personalized medicine for patients suffering from this aggressive cancer, which occurs in the blood and bone marrow. A team of scientists at The University of Texas at San Antonio (UTSA, San Antonio, TX, USA; www.utsa.edu) and the University of Texas MD Anderson Cancer Center (Houston, TX, USA; www.mdanderson.org) examined the genetic, epigenetic and environmental diversity that occurs in cancerous cells due to AML. They analyzed proteomic screens of 205 patient biopsies and developed a new computa-

LabMedica International November/2018

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tional method called MetaGalaxy (www. leukemiaatlas.org) to categorize the protein signatures into 154 different patterns based on their cellular functions and pathways. By approaching this challenge through the unique lens of developing a quantitative map for each leukemia patient from protein expression in their blood and bone marrow, rather than the standard lens of qualitative metrics and genetic risks alone, the collaborators will be able to more precisely categorize patients into risk groups and better predict their treatment outcomes. The team found 11 constellations of correlated functional patterns and 13 signatures that stratify the outcomes of patients. The scientists found limited overlap between proteomics data and both cytogenetics and genetic mutations. Moreover, leukemia cell lines show limited proteomic similarities with cells from patients with AML, suggesting that a deeper focus on patient-derived samples is needed to gain disease-relevant insights. The study was published on April 15, 2019, in the journal Nature Biomedical Engineering.

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PRODUCT NEWS CHEMISTRY ANALYZER

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ELISA/CLIA ANALYZER

ELECTROLYTE ANALYZER

Agappe

Awareness Technology

Woodley Equipment Company

The MISPA NANO Plus offers a throughput of 360 tests per hour, and its reagent tray provides 24-hour onboard refrigeration at 2°C-12°C. Sample positions can accommodate primary sample tubes, aliquot tubes and micro cups.

The ChemWell 2 features two probes with a disposable tip option and offers in-plate mixing with incubation up to 37°C. It features an integrated eight-manifold wash head with adjustable wash volumes and a sensor-enabled sample rack.

The i-Smart 30 PRO is for the diagnosis, monitoring and treatment of diseases involving electrolyte imbalance. It provides fast, accurate analysis with results displayed on a touch screen, and has storage capacity for 300,000 tests.

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Clostridioides difficile Contamination Uncovered in Clinical Lab lostridioides (formerly Clostridium) difficile infection is one of the most common hospital-acquired (nosocomial) infections and is an increasingly frequent cause of morbidity and mortality among older adult hospitalized patients. C. difficile is a spore-forming, Gram-positive anaerobic bacillus that produces two exotoxins: toxin A and toxin B. C. difficile colonizes the human intestinal tract after the normal gut flora has been disrupted (frequently in association with antibiotic therapy) and is the causative organism of antibiotic-associated diarrhea and pseudomembranous colitis. C. difficile infection has traditionally considered to be transmitted predominantly within healthcare settings. C. difficile is not recognized as a pathogen that presents a risk of laboratory acquisition. A team of scientists collaborating with the staff at the Hospital General Universitario Gregorio Marañón (Madrid, Spain; www.ucm.es) screened laboratory surfaces for C. difficile.

Samples were taken in areas that handle C. difficile isolates (high-exposure areas), areas adjacent to high-exposure HE areas or those processing fecal samples (medium exposure areas), and areas that do not process fecal samples or C. difficile isolates (low exposure areas). They also examined C. difficile carriage (hands/rectal samples) of laboratory workers. The team collected a total of 140 environmental samples from two high-exposure areas (n = 56), two medium exposure areas (n=56), and two low exposure areas (n = 28). Overall, 37.8% (37/98) of surfaces were contaminated with C. difficile, and 17.3% (17/98) with toxigenic C. difficile. High-exposure areas were significantly more contaminated with toxigenic C. difficile than low exposure areas (38.1% [16/42] versus 0.0% [0/14]) and medium exposure areas (38.1% [16/42] versus 2.4% [1/42]). Hands were colonized with toxigenic C. difficile in 11.8% (4/34) of cases. They found no rectal carriage of C. difficile.

The authors concluded that they had found a significant proportion of laboratory surfaces to be contaminated with toxigenic C. difficile, as well as hand colonization of laboratory personnel. They recommend specific control measures for high-risk areas and laboratory personnel working in these areas. The study was published on July 5, 2019, in the journal Clinical Microbiology and Infection. Image: A photomicrograph of Gram stain of toxigenic Clostridioides difficile from a stool sample (Photo courtesy of the University of Washington).

Study Shows Heritability of Amyotrophic Lateral Sclerosis myotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) or Lou Gehrig’s disease, is a specific disease that causes the death of neurons controlling voluntary muscles. ALS is characterized by stiff muscles, muscle twitching and gradually worsening weakness due to muscles decreasing in size. It may begin with weakness in the arms or legs, or with difficulty speaking or swallowing and about 50% of the people affected develop at least mild difficulties with thinking and behavior and most people experience pain. Neurologists at Trinity College Dublin (Dublin, Ireland; www.tcd.ie) conducted a prospective population-based parent-offspring heritability study from January 1, 2008, to December 31, 2017, to assess ALS heritability. This was the first study to assess heritability in the context of known gene mutations of large effect. A total of 1,123 incident cases of ALS, diagnosed according to the El Escorial criteria and recorded on the Irish ALS register, were identified. Annual age-specific and sex-specific standardized ALS incidence and mortality-adjusted lifetime risk were determined. Sex-specific heritability estimates were calculated for the

overall study cohort, for those known to carry the C9orf72 variant, and for those with no known genetic risk. The team identified a total of 32 parent-child ALS dyads were identified during the study period. Affected offspring were younger at the onset of disease (mean age, 52.0 years) compared with their parents (mean age, 69.6 years). Lifetime risk of developing ALS in first-degree relatives of individuals with ALS was increased compared with the general population (1.4% [32/2,234] versus 0.3% [2.6/1,000]. Marie Ryan, MRCPI, MD, the first author of the study, said, “While difference inheritance patterns based on who transmits the gene have been reported in other neurological disorders, this is the first time this kind of inheritance pattern has been discovered among those with motor neuron disease.” The authors concluded that this population-based study confirms that up to 50% of variance in ALS has a genetic basis, and that the presence of the C9orf72 variant is an important determinant of heritability. The study was published on July 22, 2019, in the journal JAMA Neurology. LabMedica International November/2018

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LabMedica International

Immunodiagnostic Test Predicts Progression of Pancreatic Cyst to Cancer y using an immunodiagnostic test to detect the Das-1 antibody biomarker in fluid from pancreatic cysts, researchers were able to identify those cysts that were likely to become cancerous with 95% accuracy. Although pancreatic cystic lesions (PCLs) are frequently and incidentally detected, it has been difficult to determine their risk of malignancy. Previous studies had indicated that in immunohistochemical and ELISA analyses of tissue and cyst fluid from pancreatic intraductal papillary mucinous neoplasms (IPMNs), the monoclonal antibody Das-1 identified those at risk for malignancy with high levels of specificity and sensitivity. Therefore, investigators at Washington University (St. Louis, MO, USA; www.wustle.edu) used pancreatic cyst samples from a multicenter cohort to validate the ability of Das-1 to identify high-risk PCLs, in comparison to clinical guidelines and clinical features. For this study, the investigators obtained cyst fluid samples of 169 PCLs (90 IPMNs, 43 mucinous cystic neoplasms, and 36 non-mucinous cysts) from patients undergoing surgery at four tertiary referral centers. Histology findings from surgical samples, analyzed independently and centrally re-reviewed in a blinded manner, were used as the reference standard. An ELISA with Das-1 was performed in parallel using banked cyst fluid samples. The results of the analyses revealed that the ELISA for Das-1 identified high-risk PCLs with 88% sensitivity and 99% specificity, and 95% accuracy, at a cut-off optical density value of 0.104. In 10-fold cross validation analysis with 100 replications, Das-1 identified high-risk PCLs with 88% sensitivity and 98% specificity. “Some cysts have the potential to become pancreatic cancer, so there is the thought that we should err on the side of caution and remove the cysts,” said first author Dr. Koushik K. Das, assistant professor of medicine at Washington University. “But pancreas surgery is complicated. It often requires removal of the spleen, portions of the stomach, small intestine, and bile duct. In an ideal world, we only would do surgery on people whose pancreatic cysts are likely to develop into cancer. As it is, we probably do not operate on some people who need surgery and sometimes do operate when cancer is not present because we are working with imprecise information. Many cysts, if not most, probably should be left alone. But we do that at our peril because we may miss individuals harboring cancer. If we had a better biomarker, we would not have to rely on imperfect clinical and radiographic information.” The Das-1 ELISA study was published in the June 5, 2019, online edition of the journal Gastroenterology.

brown areas were stained for a biomarker in tissue from a patient who developed pancreatic cancer from a cyst (Photo courtesy of Dr. Koushik Das, Washington University).

Image: In this photomicrograph, the

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PRODUCT NEWS SLIDE DRYING BENCH

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COAGULATION ANALYZER

TRAB RIA KIT

Karl Hecht

RAL Tecnica

KRONUS

The microscope slide drying bench with heating speeds enhance the preparation of up to 48 slides of standard size (76 x 26 mm). The slides can be placed on the bars, against the bars or flat on the heating foil.

The AutoClot 2 is an automatic benchtop 2-channel coagulation analyzer for the determination of essential tests of the plasma phase of hemostasis. Its exclusive basic operating principle allows the use of any type of reagent.

The TSH Receptor Antibody (TRAb) RIA Kit is intended for the determination of autoantibodies to the TSH receptor in serum. As part of a thyroid autoimmune diagnostic profile, it can assist the diagnosis/management of thyroid disease.

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Diagnostic Process Detects Alzheimer’s Years before Symptoms Appear lzheimer’s disease (AD) pathology is accompanied by misfolding of amyloid-b (Ab) and tau from monomeric into b-sheet–enriched pathogenic species. This process is suggested to precede about 10 to 15 years before clinical onset of the disease. A new two-step diagnostic process could detect Alzheimer’s disease nearly a decade before clinical symptoms appear. It’s hoped that the method, which involves the measurement of both amyloid and tau

proteins in blood and cerebrospinal fluid, will improve the results of clinical trials by helping better identify patients at the earliest stages of the disease. A team of scientists working with the Ruhr-University Bochum (Bochum, Germany; www.ruhr-uni-bochum.de) carried out a prospective study of 61 disease control (DC) subjects and 39 AD cases were acquired from a prospective study designed and initiated by a gerontopsychiatric unit of the department of psychiatry and psychotherapy between 2009 and 2013. For all subjects, CSF levels of Ab40, Ab42, ttau, ptau, the Ab42/40 ratio, and demographic data were available. All CSF samples were assessed with the Meso Scale Discovery VPLEX Ab peptide panel multiplex kit using monoclonal antibody 6E10 for detection (MSD, Rockville, MD, USA; www.mesoscale.com). The Ab peptides Ab38, 40, and 42 were determined after 16-fold dilution of the CSF samples with “Diluent 35” (MSD). CSF concentrations of ttau and ptau were measured in duplicate by commercially available ELISA in an accredited expert laboratory for CSF-guided neurochemical dementia diagnostics. An immuno-infrared sensor was functionalized with a monoclonal antibody for Ab detection in blood plasma and CSF and monoclonal antibody TAU-5 for tau detection in CSF, respectively. The recorded amide I absorbance band represented the biomarker secondary structure distribution in the respective body fluid by its maximum frequency. The scientists said that through the combination of both analyses, 87 of 100 Alzheimer’s patients were correctly identified in their study and they reduced the number of false positive diagnoses in healthy subjects to 3 of 100. The second analysis is carried out in cerebrospinal fluid that is extracted from the spinal cord. At this stage the second diagnostic test for tau proteins can only be measured using cerebrospinal fluid. Due to the invasive nature of collecting cerebrospinal fluid the team admitted this is not ideal, and work is underway to find effective ways to detect tau in blood samples. However, the two-step process can be rolled out relatively soon in its current form, with the suggestion the second cerebrospinal fluid test be only carried on subjects testing positive in the first blood test. Klaus Gerwert, PhD, a professor and senior author of the study, said, “Now, new clinical studies with test participants in very early stages of the disease can be launched. Recently, two major promising studies have failed, especially Crenezumab and Aducanumab – not least because it had probably already been too late by the time therapy was taken up. The new test opens up a new therapy window.” The study was published online on March 12, 2019, in the journal Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. LabMedica International November/2018

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LabMedica International

Transcriptome Analysis Can Detect Asymptomatic Alzheimer’s Disease ranscriptome analysis was used as a method for detecting individuals with Alzheimer’s disease (AD) who were not yet displaying symptoms of the disorder. Currently there are no good methods for detecting asymptomatic AD patients despite the fact that they may share similar neuropathological burdens as symptomatic individuals while experiencing significantly different rates of cognitive decline. To develop a method for diagnosing asymptomatic AD patients, investigators at the University of California, San Diego (USA; www.ucsd.edu) used the transcriptome as a proxy for functional state, and selected 414 expression profiles of symptomatic AD subjects and age-matched non-demented controls from a community-based neuropathological study. Because it includes all mRNA transcripts in the cell, the transcriptome reflects the genes that are being actively expressed at any given time. Unlike the genome, which is roughly fixed for a given cell line (excluding mutations), the transcriptome can vary with external environmental conditions. Results of the transcriptome survey revealed that by combining brain tissue-specific protein interactomes (an interactome is the whole set of molecular interactions in a particular cell) with gene networks, the investigators were able to identify functionally distinct composite clusters of genes that revealed extensive changes in expression levels in AD. Global expression for clusters broadly corresponding to synaptic transmission, metabolism, cell cycle, survival, and immune response were downregulated, while the upregulated cluster included largely uncharacterized processes. These results highlighted the utility of integrating protein interac-

tions with gene perturbations to generate a comprehensive framework for characterizing alterations in the molecular network as applied to AD. “One of the big problems in AD research is identifying patients at risk at the right time,” said senior author Dr. Robert Rissman, professor of neurosciences at the University of California, San Diego. “Understanding the gene networks that may change in specific patient groups can help streamline clinical trials recruitment efforts and reduce costs and time to enroll trials. With the field shifting more and more toward presymptomatic disease, we need to expand our understanding of the molecular mechanisms that underlie the entire disease spectrum.” The transcriptome analysis study was published in the July 23, 2019, issue of the journal Cell Reports. Image: In brains affected by Alzheimer‚Äôs disease, abnormal levels of the beta-amyloid protein clump together to form plaques (seen in brown) that collect between neurons and disrupt cell function. Abnormal collections of the tau protein accumulate and form tangles (seen in blue) within neurons, harming synaptic communication between nerve cells (Photo courtesy of the [U.S.] National Institute on Aging).

White Blood Cell Population May Serve as MS Biomarker discrete population of white blood cells was found to be present in samples taken from patients with multiple sclerosis (MS) and this group of cells may serve both diagnostic and therapeutic roles. MS is among the class of chronic inflammatory diseases that is modulated by cytokine dysregulation. To better understand the link between cytokines and MS, investigators at the University of Zurich (Switzerland; www.uzh.ch) sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing–remitting multiple sclerosis (RRMS) by using advanced high-dimensional single-cell mass cytometry (CyTOF). CyTOF is a mass spectrometry technique based on inductively coupled plasma mass spectrometry and time of flight mass spectrometry used for the determination of the properties of cells (cytometry). In this approach, antibodies are conjugated with isotopically pure elements, and these antibodies are used to label cellular proteins. Cells are nebulized and sent in the form of a mist through an argon plasma, which ionizes the metal-conjugated antibodies. The metal signals are then analyzed by a time-of-flight mass spectrometer. The approach overcomes limitations of spectral overlap in flow cytometry by utilizing discrete isotopes as a reporter system instead of traditional fluorophores, which have broad emission spectra. The use of CyTOF technology allowed the investigators to identify an expanded T helper cell subset in patients with MS, characterized by the expression of granulocyte–macrophage colony-stimulating factor and the C-X-C chemokine receptor type 4. This cellular signature, which included expression of very late antigen 4 in peripheral blood, was also enriched in the central nervous system of patients with relapsing–remitting multiple sclerosis. In independent validation cohorts, the investigators confirmed that this cell population was increased in patients with MS compared with other inflammatory and non-inflammatory conditions. The report was published in the July 22, 2019, online edition of the journal Nature Medicine.

LabMedica International November/2018

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PRODUCT NEWS URINALYSIS CONTROL

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HEMATOLOGY ANALYZER

PRE-ANALYTICAL SYSTEMS

Quantimetrix

Edan Instruments

Roche Diagnostics

The Dip&Spin comes with the rod-shaped E. coli and Calcium Oxalate Dihydrate crystals that are easily recognized by microscopy methodologies. It is an ideal urinalysis dipstick and sediment combination QC for the clinical lab.

The H30 is a fully automated 3-part differential hematology analyzer with a throughput of 60 samples per hour. It adopts a new user-centered design and offers higher stability and reduced maintenance costs.

The cobas p 512/612 can be used for automating and simplifying processes in clinical labs and blood banks. Both systems perform a comprehensive inspection of samples at an early stage, optimizing the lab workflow.

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Glycated Hemoglobin Levels Associated with Fibromyalgia

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ibromyalgia (FM) is one of the most frequent generalized pain disorders with poorly understood neurobiological mechanisms. In the general population, the estimated global prevalence of FM is 2.7% with a 3 to 1 female to male ratio. Patients afflicted with FM have chronic widespread pain and protean somatic symptoms including fatigue, non-restorative sleep, gastrointestinal complaints and problems of cognition and mood. Due to lower pain thresholds, patients with FM also have a higher incidence of symptomatic musculoskeletal and spinal disorders, which in themselves contribute to the financial burden of managing this disorder. Scientists from the University of Texas Medical Branch (Galveston, TX, USA; www.utsystem.edu) recruited 23 people with fibromyalgia whose doctors had referred them to a specialist clinic for the treatment of muscular or connective tissue pain. Since there is a known association between small fiber neuropathy and FM, many of these patients had undergone laboratory investigations in commercial CLIA (United States Clinical Laboratory Improvement Act) accredited laboratories. This comprised diagnostic panels for peripheral neuropathy, which included HbA1c values. The HbA1c values from 23 patients with FM (eight Hispanic; 11 White; four African-American; 21 females, two males) were compared with the HbA1c means of two independent control populations. One was a non-diabetic population with normal glucose tolerance and the second population used for confirmation was extracted from the National Health and Nutrition Examination Survey dataset (NHANES non-diabetic). When the investigators compared the HbA1c test results of the people with fibromyalgia with those of age-matched controls, they found that the former group had significantly higher levels of HbA1c than the latter, indicating a measure of insulin resistance. The regression estimates that HbA1c values in patients with FM mean 0.59 ± 0.1 units higher than Framingham Offspring Study (FOS NGT) and 0.39 units higher than the NHANES non-diabetic values. A subgroup of patients meeting criteria for pre-diabetes or diabetes (patients with HbA1c values of 5.7% or greater) who had undergone treatment with metformin showed dramatic improvements of their widespread myofascial pain, as shown by their scores using a pre- and post-treatment numerical pain rating scale (NPRS) for evaluation. These findings suggest a pathogenetic relationship between FM and IR, which may lead to a radical paradigm shift in the management of this disorder. The study was published on May 6, 2019, in the journal PLOS ONE.

LabMedica International November/2018

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LabMedica International

High HbA1c Levels Linked To Pregnancy Risks or pregnant women with diabetes mellitus some particular challenges exist for both mother and child. If the woman has diabetes as an intercurrent disease in pregnancy, it can cause early labor, birth defects, and larger than average infants. High blood sugar levels are harmful to the mother and her fetus. Experts advise diabetics to maintain blood sugar level close to normal range for two to three months before planning for pregnancy. Managing blood sugar close to normal before and during pregnancy helps to protect the health of mother and the baby. Maternal type 1 diabetes (T1D) has been linked to preterm birth and other adverse pregnancy outcomes. Scientists at the Karolinska Institute (Solna, Sweden; https://ki.se) and their associates examined how these risks vary with glycated hemoglobin (or HbA1c) levels. They examined preterm birth risk according to periconceptional HbA1c levels in women with T1D. In a population-based cohort study carried out from 2003 to 2014 and they followed 2,474 singletons born to women with T1D and 1,165,216 reference infants born to women without diabetes. Measurement for the study included risk for preterm birth (<37 gestational weeks), secondary outcomes were neonatal death, large for gestational age, macrosomia, infant birth injury, hypoglycemia, respiratory distress, 5-minute Apgar score less than 7, and stillbirth. The investigators reported that preterm birth occurred in 552 (22.3%) of 2,474 infants born to mothers with T1D versus 54,287 (4.7%) in the infants born to mothers without diabetes. The incidence of preterm birth was 13.2% in women with a periconceptional HbA1c level below 6.5% (adjusted

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risk ratio [aRR] versus women without T1D, 2.83), 20.6% in those with a level from 6.5% to less than 7.8% (aRR, 4.22), 28.3% in those with a level from 7.8% to less than 9.1% (aRR, 5.56) and 37.5% in those with a level of 9.1% or higher (aRR, 6.91). The corresponding aRRs for 320 medically indicated preterm birth were 5.26, 7.42, 11.75, and 17.51, respectively. The corresponding aRRs for 223 spontaneous preterm birth were 1.81, 2.86, 2.88, and 2.80, respectively. Increasing HbA1c levels were associated with the study’s secondary outcomes: large for gestational age, hypoglycemia, respiratory distress, low Apgar score, neonatal death, and stillbirth. Jonas F. Ludvigsson, MD, PhD, a professor of pediatrics and lead author of the study, said, “This is the first study large enough to demonstrate a clear relationship between different hemoglobin A1C (Hb A1C) levels and preterm birth. Our study has been conducted nationally and thus provides a result that can be applied to the average woman with type 1 diabetes.” The study was published on April 23, 2019, in the journal Annals of Internal Medicine.

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LabMedica International

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Methods Evaluated to Detect Asymptomatic Visceral Leishmaniasis isceral leishmaniasis (VL) is caused by Leishmania infantum [synonymous L. chagasi] in the New World or L. donovani in the Old World, VL can be classified as an anthroponotic or zoonotic disease because it is transmitted between humans and others mammals, such as dogs. Visceral leishmaniasis in humans presents with fever, anemia, and splenomegaly and can be lethal if not treated. Nevertheless, the majority of L. infantum-infected individuals don’t manifest symptoms, and remain so provided they are not immunosuppressed. Direct and indirect methods are used for diagnosis of VL. A team of scientists working with the Ribeirão Preto School of Medicine (Ribeirão Preto, Brazil; www.fmrp.usp.br) included in a study of patients with VL before and after treatment, who were hospitalized in the city of Teresina, and volunteers without any symptom of the disease residing in the same city. Sample collections were carried out between August and November 2017. Samples obtained from healthy volunteers residing in the city of Ribeirão Preto, were used as control of non-endemic area. The diagnosis of VL was confirmed by the positivity of amastigote forms in samples of bone marrow aspirate stained by Giemsa, and confirmed by cell culture in NNN medium. Immunochromatographic tests (IC) were performed using Kalazar Detect Rapid (InBIOS International, Seattle, WA; https://inbios.com), and the OnSite Leishmania IgG/IgM Combo test (CTK Biotech, Poway, CA, USA; https://ctkbiotech.com). An in-house enzyme-linked immunosorbent assay (ELISA) was performed and read on a Multiskan GO microplate spectrophotometer (Fisher Scientific, Waltham, MA, USA;

www.fishersci.com). DNA extraction was performed using 200 L of total peripheral blood. IFN-γ-induced protein 10 (IP-10) and monokine induced by IFN-γ (MIG) were quantified in the study in 50 L of plasma from whole blood soluble Leishmania antigen (SLA)-stimulated or non-SLA-stimulated using the BD Cytometric Bead Array Human Flex Set (BD Biosciences, San Jose, CA, USA; www.bdbiosciences.com). The authors concluded that the association of different techniques can detect asymptomatic infections, however, more investigation is necessary to develop ideal biomarkers that are simple to use in the clinic and in field studies in areas endemic for visceral leishmaniasis. The study was published on July 1, 2019, in the journal PLOS Neglected Tropical Diseases. Image: The Multiskan GO microplate spectrophotometer (Photo courtesy of Thermo Fisher Scientific).

Rare Neurodegenerative Disorders Share DNA Repeat Mutation enomics researchers have found that at least four rare neurodegenerative diseases result from CGG (cytosine-guanine-guanine) repeat mutations the DNA located in distant, seemingly unrelated areas of the genome. Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis, and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in the FMR1 (fragile X mental retardation 1) gene, investigators at the University of Tokyo (Japan; www.u-tokyo.ac.jp) used advanced nextgeneration genome sequencing and data analysis techniques to search directly for repeat expansion mutations. Results of the DNA sequencing study identified noncoding CGG repeat expansions in the NBPF19 (Neuroblastoma breakpoint family member 19) gene as the causative mutations for NIID. NIID is a slowly progressive, neurodegenerative disease that may affect any part of the nervous system (central, peripheral, and/or autonomic), as well as various organs. The features of NIID result from the presence of eosinophilic intranuclear inclusions inside neurons and glial cells. Both sporadic and familial cases have been reported. However, specific genes known to cause NIID had not previously been found. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, the investigators identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy. “Because the mutations causing the diseases are so similar, in the future, all these patients might benefit from the same treatment,” said first author Dr. Hiroyuki Ishiura, an assistant professor at the University of Tokyo Hospital. The study was published in the July 22, 2019, online edition of the journal Nature Genetics.

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LabMedica International

Gastric Cancer Analysis Identifies Four Subtypes n previous studies of gastric cancers (GCs), genomic and transcriptomic analyses have identified molecular signatures associated with phenotypes of the disease, such as patient subtypes and survival. New proteogenomic analysis of diffuse gastric cancers (GCs) in young populations identified four subtypes of the disease. The Cancer Genome Atlas (TCGA) identified four GC subtypes and associated molecular signatures: Epstein-Barr virus (EBV)-positive tumors with recurrent PIK3CA mutations, DNA hypermethylation, and amplification of JAK2, CD274, and PDCD1LG2; tumors with microsatellite instability with high mutation rates; genomically stable tumors enriched for diffuse histological variants and mutations in RHOA; and tumors with chromosomal instability showing aneuploidy and amplifications of genes encoding receptor tyrosine kinases. A large team of scientists collaborating with the Korea University, Seoul, Republic of Korea; www.korea.edu) collected paired tumor and adjacent normal tissues, as well as blood samples, from 80 patients with early-onset GCs (EOGCs) under 45 years of age. These 80 tumors included 74 diffuse, three intestinal, two mixed types, and one inflammatory myoblastic tumor. For each patient, the team performed exome sequencing of the tumors and peripheral blood mononuclear cells, as well as mRNA sequencing of the paired tumor and adjacent normal tissues. The team used exome sequencing data, and identified 56,502 nonsynonymous single-nucleotide variants and 3,598 frameshift indels. Further, they found 11,938 genes were expressed in the tumor and adjacent normal samples, on average, in the mRNA data. They then used

these variants and expressed transcripts from each patient to build a sample-specific database and identified 156,135 peptides, 28,944 phosphopeptides, and 4,376 N-glycopeptides from the global proteomes, phosphoproteomes, and N-glycoproteomes, respectively. These peptides were mapped to 10,295 protein-coding genes, on average. The scientists compared their own GC subtypes to GC subgroups in TCGA data, and found that subtype 2- and 4-like TCGA subgroups showed the best and worst survivals, respectively. MSI- and EBV-positive GCs were significantly enriched in the subtype 2-like subgroup, while genomically stable GCs were enriched in the subtype 4-like subgroup. They defined subtype 2 as representing immune response-related processes (antigen presentation, BCR/TNF/Toll-like receptor signaling, TCR signaling, and phagosome). Subtype 3 uniquely represented metabolism-related processes (oxidative phosphorylation, fatty acid boxidation, and citrate cycle). Subtype 4 mainly represented invasion-related processes (actin cytoskeleton and MAPK, PI3K-AKT, WNT, RHOA, and cadherin signaling). The authors concluded that based on their data, subtypes 2 and 4 can be characterized as immunogenic and invasive tumors with possibly good and poor survival rates, respectively, similar to subtypes 2- and 4-like subgroups in TCGA cohort. They noted that the tumors in subtype 2 show strong immune activity that may contribute to a good prognosis and that the tumors in subtype 4 show strong invasion potential that may contribute to a poor prognosis. The study was published on January 14, 2019, on the journal Cancer Cell.

Microbiome Helps Identify Patients with Early-Stage Cancer early 10,000 people are diagnosed with pancreatic cancer in the UK each year, with less than 1% surviving beyond ten years. An early diagnosis can greatly improve the chances of successful treatment, but this poses challenges for this disease as it grows deep inside the body and often shows few symptoms before it has already spread. Scientists are searching for biological changes that can accurately detect early signs of pancreatic cancer, which could be developed into new screening tests. A current hot topic is the potential role of the microbiome in the development of cancer, with previous studies identifying dramatic disruptions to bacteria in saliva, intestinal and fecal samples collected from pancreatic cancer patients compared to healthy individuals. Scientists at Zhejiang University (Hangzhou, P.R. China; www.zju.edu.cn) and their associates recruited a group of 30 patients with early-stage disease (diagnosed with a tumor positioned in the ‘head’ area of the pancreas) and a similar group of 25 healthy people. Participants were all between 45 and 65 years in age, had no other diseases or oral health problems and had not taken any antibiotics or other drugs for the three months before the study. The team used sophisticated gene sequencing technologies to examine the microbiome diversity of tongue coat samples, finding that pancreatic cancer patients were colonized by remarkably different tongue coating microbiomes compared to healthy individuals. Microbial DNA was extracted using the Qiagen Mini Kit (Hilden, Germany;

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www.qiagen.com), was quantified using a Qubit 2.0 Fluorometer (Invitrogen, Carlsbad, CA, USA; www.thermofisher.com), and diluted to 10 ng/ L for PCR amplification in an Eppendorf Mastercycler thermocycler (Hamburg, Germany; www.eppendorf.com). The team reported that there was a striking difference of the abundance of four types of bacteria: low levels of Haemophilus and Porphyromonas and high levels of Leptotrichia and Fusobacterium, could distinguish pancreatic cancer patients from healthy individuals. The team hypothesized that the immune system is the most likely link between any confirmed shifts in the mi-

crobiome with pancreatic cancer. For example, disease development in the pancreas may influence the immune response in ways that favor the growth of certain bacteria or vice versa. The authors concluded that complete characterization of the gastrointestinal, saliva and tongue coating microbiomes, and alterations in the microbiotic communities in pancreatic head carcinoma (PHC) patients compared with healthy controls could potentially lead to the development of early diagnostic or preventive tools for PHC. The study was published on January 28, 2019, in the Journal of Oral Microbiology.

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Whole-Exome Sequencing Evaluates Fetal Structural Anomalies n about 3% of pregnancies, ultrasound imaging will reveal a significant fetal physical anomaly and knowing the cause of the anomaly can help doctors and parents be better prepared, both during the pregnancy and after delivery. The current standard of care is to obtain a sample of amniotic fluid and perform karyotyping to determine if the fetus has the right number of chromosomes and if small regions are missing, but this test can only pinpoint the underlying cause for about 40% of anomalies found on ultrasound, leaving the majority of families in the dark. A team of scientists collaborating with the Columbia University Medical Center (New York, NY, USA; www.cumc.columbia.edu) enrolled 234 pregnant women with abnormal ultrasound findings but whose standard genetic tests were negative. The team used whole-exome sequencing to identify genetic variants that indicated an underlying cause (diagnostic genetic variants) and genetic variants that met the criteria of bioinformatic signatures that had previously been described to be significantly enriched among diagnostic genetic variants. DNA samples from 234 (45%) eligible trios were used for analysis of the primary outcome. By use of trio sequence data, the scientists identified diagnostic genetic variants in 24 (10%) families. Mutations

with bioinformatic signatures that were indicative of pathogenicity but with insufficient evidence to be considered diagnostic were also evaluated; 46 (20%) of the 234 fetuses assessed were found to have such signatures. Since the science surrounding genomic analysis is still developing, some of the gene sequence patterns had been associated, but not definitively linked, to the specific developmental abnormality. Clinicians need to balance their desire to give patients definitive answers against the sometimes murky state of genomic science. A team of multidisciplinary experts such as clinical and molecular geneticists, genetic counselors, developmental biologists, and maternal fetal medicine specialists, are needed to ensure an accurate interpretation of the new test results. Ronald Wapner, MD, director of reproductive genetics, a professor of obstetrics and gynecology, and co-author of the study, said, “Based on our findings, whole exome sequencing could serve as a valuable addition to standard prenatal genetic tests, with the potential to improve perinatal care for infants with genetic conditions and ease parents’ fears by offering a clear diagnosis.” The study was published on January 31, 2019, in the journal The Lancet.

Genetic Causes of Salivary Gland Carcinoma Discovered cinic cell carcinoma is the third most common malignant form of salivary gland cancer. These tumors are similar to normal salivary gland tissue and occur most frequently in the parotid gland. Until now, the molecular causes for the illness were unknown. Acinic cell carcinoma (AciCC) shows serous differentiation closely resembling normal acini of salivary glands, which produce major components of saliva. Regulatory rearrangements driving oncogene overexpression through enhancer hijacking or insulator dysfunction are increasingly recognized in other cancer types. A large team of scientists led by those at the University of Erlangen-Nuremberg (Erlangen, Germany; www.fau.de) and their colleagues enrolled 10 patients with diagnosis of AciCC of the salivary glands in the initial study co-

hort, and their tumor material underwent extensive comprehensive genetic and epigenetic profiling. After formalin-fixation and paraffinembedding of tumor material, a tissue microarray was conducted with two 2 mm cores per tumor using the TMA Grandmaster automated tissue microarrayer (3DHistech, Budapest, Hungary; www.3dhistech.com). Immunohistochemistry was performed on 3 μm sections freshly cut from the TMA block using a fully automated staining system, the Benchmark XT System (Ventana Medical Systems Inc, Tucson, AZ, USA; www.roche.com). Representative images of tumor and normal parotid gland areas were obtained using an Axio Imager A2 microscope and AxioCam MRc at ×400 magnification (Carl Zeiss Microscopy GmbH, Jena, Germany; www.zeiss.com). Fluorescence in situ hybridization (FISH) was performed on freshly cut sections from tumor tis-

sue blocks. DNA from AciCC tumors and from normal salivary glands was isolated from freshfrozen tissues using DNeasy Tissue kits, and from blood of the same patients using the DNeasy Blood Kit (all Qiagen, Hilden, Germany; www.qiagen.com). Whole genome bisulfite sequencing and RNA sequencing were also performed. The team used genome sequencing on tumor tissue, and identified a translocation of genetic material between chromosomes 4 and 9, which was present in all acinic cell carcinomas examined. Typically, such translocations in tumors lead to a new combination of genes, which then acquire new oncogenic properties. In the case of acinic cell carcinomas, the translocation that has been discovered causes regulatory elements of DNA to be transferred from an active chromosome region to a normally inactive oncogene. When the chromosomes are rearranged, these highly active regulatory elements come into the vicinity of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) gene, which is usually switched off once embryonic development has been completed. The activation signals of the regulatory elements in the acinic cell carcinoma cause the gene to be switched on again. NR4A3 acts as a transcriptional factor to regulate the activity of a number of other genes, which then trigger cell division and growth, leading ultimately to the tumor starting to grow. The study was published on January 21, 2019, in the journal Nature Communications. V

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Novel 3D-Printed Technology Lowers Cost of ELISA Tests raditional enzyme-linked immunosorfor three biomarker proteins with results well bent assay (ELISA) tests are percorrelated to conventional ELISA and an esformed on plates featuring 96 microtablished microfluidic electrochemical imwells; each well works as a separate testing munoassay. chamber where samples can be combined Mohamed Sharafeldin, MSc, a research aswith various agents that will then react with sistant and first author of the study, said, “We the sample, typically by changing color. didn’t want to make a big change in the tradiWhile effective and accurate, the equiptional ELISA; we just made engineered, conment used to run ELISA is expensive, often trolled changes. So, the basics are the same. costing thousands of dollars to install in a labWe use the same antibodies at the same conoratory, and requires specialized training to centrations that they use with conventional or conduct testing, as improper techniques can traditional ELISA, so we are using the same lead to incorrect results. The agents used in protocols. Anything that can be run by normal the actual tests, usually various forms of antiELISA can be run by this, with the advantage Image: The unique pipette tip was created bodies, can also be expensive. of being less expensive, much faster and acceswith a 3D printer to perform enzyme-linked imScientists at the University of Connecticut sible.” The study was published on May 3, munosorbent assays (Photo courtesy of Sean Flynn/ University of Connecticut). (Storrs, CT, USA; www.uconn.edu) created a 2019, in the journal Analytical Chemistry. novel pipette-based “ELISA in a tip” as a new versatile diagnostic tool featuring better sensitivity, shorter incuNE DES W bation time, accessibility, and low IGN sample and reagent volumes compared to traditional ELISA. Capture and analysis of data by a cell phone facilitates electronic delivery of results to health care providers. WORLD’S MEDICAL PRODUCT MARKETPLACE Pipette tips were designed and 3D printed as adapters to fit most commercial 50–200 L pipettes. Capture antibodies (Ab1) are immobilized on SIGN UP the inner walls of the pipette tip, FOR FREE! which serves as the assay compartment where samples and reagents are moved in and out by pipetting. Signals Visit us at are generated using colorimetric or chemiluminescent (CL) reagents and MEDICA can be quantified using a cell phone, 2019 CCD camera, or plate reader. Hall 1-H61 Traditional ELISA plate microwells hold 400 μL of fluids each, but the reactions needed to measure test results only occur on the plastic walls of the well. While the 3D-printed ELISA tips hold only 50 μL, the design of the reservoir inside the tip dramatically increases the surface area where reactions occur, allowing the scientists to use much less of the costly antibodies used to conduct the test, and significantly reducing the time needed to process the test and read the results. The team utilized pipet-tip ELISA Connecting Buyers with to detect four cancer biomarker proSuppliers Worldwide teins with detection limits similar to Reach new sources of supply or lower than microplate ELISAs at Identify latest products and technologies 25% assay cost and time. Recoveries Send inquiries directly to suppliers of these proteins from spiked human Receive latest product alerts serum were 85% to 115% or better, Chat live with suppliers depending slightly on detection mode. Using CCD camera quantification of CL with femto-luminol TradeMed provides a sophisticated yet easy-to-use global B2B platform for sourcing medical reagent gave limits of detection equipment. TradeMed connects buyers and sellers worldwide through a safe, secure and dy(LOD) as low as 0.5 pg/mL. Thirnamic network. Solely dedicated to medical products, TradeMed is the premier choice for medteen patient samples were assayed ical suppliers, hospital decisionmakers and buyers worldwide, regardless of size or budget.

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Molecular Test Accurately Distinguishes Breast Tumors new laboratory test has been developed to identify chemical changes to a group of cancer-related genes that can accurately detect which breast tumors are cancerous or benign, and do it in far less time than gold-standard tests on biopsied breast tissue. In developing countries, women present with late-stage breast lesions due to lack of breast cancer screening/pathology programs. Even after the biopsy of palpable lumps, diagnosis is delayed since most countries in Sub-Saharan Africa average less than one pathologist per million population. Pathology and treatment services are available only at regional hospitals. A team led by investigators from the Johns Hopkins Kimmel Cancer Center (Baltimore, MD, USA; www.hopkinsmedicine.org) obtained gathered 226 samples of breast tissue. These samples came from women in the USA, China, and South Africa. Their ages ranged from 25 years old to 85 years old and represented all subtypes of breast cancer: estrogen receptor positive, HER2 positive, triple negative breast cancer, ductal and lobular cancers, and ductal carcinoma in situ (DCIS). Four different kinds of benign lesions and normal breast were also sampled. A genetically diverse collection helped assure that results would be widely applicable. Sampling both malignant and benign lesions allowed the scientists to distinguish methylation differences between the two groups. The team used these samples, and evaluated the utility of 25 genes that previous studies have shown are often, although not always, methylated differently in breast cancer and benign lesions. A patient’s biopsy sample is loaded into cartridges and inserted in a machine that tests levels of gene methylation, a chemical addition to genes that results in changes in gene activity. Collaborators from Cepheid (Sunnyvale, CA, USA; www.cepheid.com) developed this novel technology platform.

This platform returns methylation marker results within five hours. Eventually, they narrowed their candidate genes to a panel of 10 with methylation characteristics that were more likely able to distinguish between a majority of the malignant and benign training samples. The team evaluated a 10-gene panel using 246 more breast tissue samples, showing similar success in the panel’s ability to distinguish cancer from non-cancer. They then ran a pilot study using 73 samples from Portugal and Hong Kong of fine needle aspirates obtained from breast lesions first deemed suspicious through mammography. The test differentiated the 49 benign lesions from the 24 cancerous ones with 96% accuracy. With the five-hour-long return on results, low skill required running the test, and relatively low expense, it could offer hope of speeding diagnosis for thousands of women worldwide. The study was published in the July 2019 issue of the journal Clinical Cancer Research. Image: A scientist assembling the cartridge assay that distinguishes cancer from benign aspirates from mammographically suspicious breast lesions (Photo courtesy of Wanjun Ding).

Abnormal Hemoglobin Levels Predict Risk of Developing Dementia oth elevated and diminished levels of serum hemoglobin have been linked to an increased risk of developing various types of dementia including Alzheimer’s disease. Investigators at Erasmus Medical Center (Rotterdam, The Netherlands; www.erasmusmc.nl) recently published results of a study to determine the long-term association of hemoglobin levels and anemia with risk of dementia. During the study, serum hemoglobin was measured in 12,305 participants without dementia of the population-based Rotterdam Study (mean age 64.6 years, 57.7% women). Overall, 745 (6%) of the participants were classified as being anemic at the beginning of the study. Participants’ hemoglobin levels were measured at the start of the study, and their health was monitored for an average of 12 years. Results revealed that during the period of monitoring 1,520 individuals developed dementia, of who 1,194 had Alzheimer’s disease. Individuals with anemia were found to be 41% more likely to develop Alzheimer’s disease and 34% more likely to develop any type of dementia than those who did not have anemia. Of the 745 people with anemia at the start of the study, 128 (17.2%) developed dementia, compared to 1392 (12%) of the 11,560 people who were not anemic. Compared to individuals with normal levels of hemoglobin, those with the highest levels were 20% more likely to develop dementia, while those with the lowest hemoglobin levels were 29% more likely to develop dementia than those in the normal group. “With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia, especially as the prevalence of dementia is expected to increase threefold over the next decades, with the largest increases predicted in the countries where the anemia rate is the highest,” said senior author Dr. M. Arfan Ikram, assistant professor of neuroepidemiology at Erasmus Medical Center. The study was published in the July 31, 2019, online issue of the journal Neurology.

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Edited by Katherina Psarra MSc, PhD IFCC members may send news to: Katherina Psarra, MSc, PhD, Dept of Immunology – Histocompatibility, Evangelismos Hospital, Ipsilantou 45-47, Athens 10676, Greece; Email: enews@ifcc.org

NEWS

IFCC Task Force on History: Chronicling the Real and Virtual World of IFCC in the 21st Century! By Prof Mathias M Muller and Dr Bernard Gouget rof. Mathias M. Müller and Dr. Bernard Gouget have been appointed as co-chairs of the IFCC Task Force on History (TF-H). They will share the responsibility to prepare a new edition of “IFCC Milestones” covering the years 2002 to 2020. The publication is meant to be available in Seoul, at the IFCC WorldLab Congress in 2020. It will be shaped in the same spirit of the “IFCC Celebrating 50 Years (1952-2002)” edited by John Lines and Jacques Heeren. Also, a new Anniversary Book (2002-2022) to celebrate the 70th IFCC anniversary is planned. The IFCC Executive Board decided to continue with a publication on the history of the federation. Under the Chairmanship of Prof. Peter Wilding, the Task Force on History (TF-H) had successfully published the “History of IFCC Member Societies” on the IFCC website (www.ifcc.org/about/history-of-ifcc-members-societies/). The first meeting of the TF-H has been held last June at the IFCC office in Milano (IT) to look at the archives that might have material appropriate for the research needs. The IFCC archives constitute an invaluable resource for contemporary history of Lab Medicine in general, allowing a better understanding of the growth as well as leadership evolution and sustainability of the Federation. The structure and scope of the two publications had been discussed extensively together with the three IFCC secretaries. Only their support and collaboration will allow us to work in an effective and concrete manner and to meet deadlines. Laboratory Medicine has witnessed a remarkable wave of innovations that transformed the specialist in Lab Medicine from a peripheral to a central player in healthcare delivery. The value of advanced diagnostics is a key factor for the future of quality and efficiency in healthcare. The two publications will deal with all the relevant points that have been the subject of studies within IFCC: all the scientific, research, educational and training aspects and the evolution of the profession. This will allow readers to better understand how IFCC's organization has evolved since 2002, while Laboratory Medicine was facing ongoing innovations and technological upheavals as well as major environmental challenges, and society changes. In Laboratory Medicine meaningful, accurate and precise routine measurements are essential for diagnosis, risk assessment, treatment and follow-up of patients. To achieve these goals and to improve the quality of their test results IFCC as the global professional and leading organization for laboratory diagnostics plays an important role by publishing diagnostic and educational guidelines, reference systems that are important for the pre-analytical, the analytical and the post-analytical steps in the overall diagnostic process. These accomplishments are fulfilled through the IFCC strategic plan, and the activities of IFCC’s Divisions and their Committees and Working Groups. The rich and nearly countable and continuously expanding knowledge in science and research has been fascinating since many years. The last 2 decades need special attention, since in this period genomics, proteomics,

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Photo: Prof. Mathias M. Müller, TF-H Chair; Dr. Bernard Gouget, TF-H coChair; and IFCC Staff (from left to right), Paola Bramati, Silvia Cardinale, Silvia Colli-Lanzi.

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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Editorial by Katherina Psarra MSc, PhD t is with great pleasure that in this IFCC Corner we are announcing the election of the president elect Dr. Khosrow Adeli. It is even more important for us, because Dr. Khosrow Adeli offered a lot to CPD, in fact he has been CPD chair. We, the CPD

The IFCC is Pleased to Announce President-Elect Prof. Khosrow Adeli he election of the next IFCC Presidentelect was concluded on September 30th, 2019. IFCC is pleased to announce Prof. Khosrow Adeli (CA) as the successful candidate, commencing his term in office on January 1st, 2020. Prof Adeli brings considerable expertise and experience to the role, having recently completed terms as Vice-Chair and Chair of the IFCC Communications and Publications Division (CPD). Prof Adeli believes that future holds considerable promise for the IFCC organization and its family of national societies and corporate members. He looks forward to being part of the IFCC’s continued journey towards global leadership in Lab Medicine, contributing to its most valuable mission of improving clinical decision making and better healthcare worldwide. The IFCC congratulates the President Elect and wishes him a fruitful and successful term of work for the promotion of Clinical Chemistry and Laboratory Medicine world-wide. For a short profile of Prof Adeli visit: www.ifcc.org/executive-board-and-council/ executive-board/prof-khosrow-adeli-ifcc-president-elect/

people, can really appreciate his election and give him our sincere congratulations and best wishes for success. Be inspired by the outstanding achievements of the teams awarded by prestigious honor of UNIVANTS of Healthcare Excellence Award - working together for the benefit of patients. IFCC history Task Force next steps, and a new IFCC Corporate member are featured, along with an interesting report on an IFCC VLP in Panama.

Linking the Value of Laboratory Medicine to Key Performance Indicators Across Healthcare Stakeholders linical laboratories have long been overlooked as a strategic asset to health systems. Often considered as “cost centers”, their essential role in healthcare has been underappreciated and underrecognized. Efforts to elevate the visibility of the Clinical Laboratory have been vast, but complex. A byproduct of that complexity is that experts even within the Clinical Laboratory have begun to undervalue their potential contributions, which extend beyond lean and efficient operations of high quality diagnostic testing to maximizing the predictive and interpretative impact of diagnostic testing to patient prognosis, treatment and outcomes. The UNIVANTS of Healthcare Excellence Award Program was designed to inspire and amplify best practice examples of integrated care projects who have achieved measurable outcomes in healthcare performance through partnerships directly associated with and/or led by the Clinical Laboratory. Outcome metrics required for this annual award involve proven success measures via key performance indicators (KPIs) associated with patients, payors, clinicians and health systems. Twelve care projects received various levels of recognition in the program’s inaugural year, including 3 teams receiving the prestigious honor of 2019 UNIVANTS of Healthcare Excellence WINNER. Collective metrics across all 2019 teams with recognition indicate a relatively balanced distribution across stakeholders, ranging from 18.1% (payor KPIs) to 29.1% (patient KPIs). Off note, the most frequently quantified KPIs across all recognized care projects in 2019 were increased clinical confidence, decreased overall healthcare costs, and increased clinician satisfaction. Standout KPIs for patients included increased safety and earlier diagnosis whereas standout health system KPIs included decreased hospital admissions and increased documentation accuracy. Importantly, all care projects had at least one KPI metric associated with each stakeholder, highlighting the powerful cascade of outcomes following new processes and avant-garde thinking/strategies involving insights and data from the Clinical Laboratory. Such connections have long been appreciated, but rarely measured; in large part due to the complexity and investment required to do so. Never the less, measurements of this nature are essential for value creation, highlighting the power of new thinking and opportunities for new funding/business models, while also advancing patient care. If you and your team have achieved measurably better healthcare performance for an integrated clinical care project at your institution and/or network, the application deadline for the 2020 nominations is February 28, 2020. For more details about the award or the care projects associated with the measurable KPIs discussed above, visit www.UnivantsHCE.com.

IFCC TF-H: Chronicling the Real and Virtual World of IFCC in the 21st Century! Cont’d from page 61 metabolomics, cellular signalling patterns entered medicine, changing the basis of several diseases and physiological conditions and minimizing side effects. New forms of treatment, especially for inherited diseases, will emerge based on genome editing and cellular replacement. We need also to prepare the Lab Medicine professionals to deliver the digital future. New analytical and communication techniques entered the diagnostic laboratory. Outstanding scientists in basic and applied research changed the overall concepts. More than 30 years ago there was a specific European, American, Japanese way to laboratory diagnostics. With economic globalisation and the movement of people as well as because of international or regional regulations, our discipline has become more global. The concepts put forward by IFCC intend to create a uniform and harmonised approach. What might be valid in one country is now checked for its global usefulness. Thanks to the Internet it is possible for individuals to obtain this new knowledge by on-line electronic self-education. Therefore, much effort is put forward to push e-learning nowadays. The main advantage of this kind of accumulating knowledge is the fact that one has not to move away from his office or PC. The disadvantage is the fact that individuals are left alone, they are lacking a critical appraisal and might be disturbed by daily obligations. In addition to the electronic gaining of new knowledge, IFCC is supporting personal, individualised update by its working parties in a kind of criti-

cal review of experiences gained in research and diagnostic business. The fast changing pace of digital medicine is already having a positive impact on the Lab Medicine. There is also great potential for all to improve Lab Medicine. The remarkable promise is particularly centered on machine learning, including deep learning. Carefully designed algorithms will also enhance productivity, through large-scale process optimisation, clinical pathway streamlining and public health applications. The digital medicine and genomics will have an enormous impact on improving efficiency and precision in Lab Medicine. The IFCC’s extraordinary accomplishments during the last 20 years will be, of course, highlighted by the TF on History in the 2 publications, to power a sustainable and vibrant IFCC in the 21st century!

IFCC OFFICE Via Carlo Farini 81, 20159 Milan, ITALY Tel: (39) 02-6680-9912 • E-mail: ifcc@ifcc.org • Web: www.ifcc.org Office Hours: 8:30-12:30 and 13:00-17:00 Staff Members: Paola Bramati, Silvia Cardinale, Silvia Colli-Lanzi The views and positions expressed in the IFCC News section are those of the IFCC or the individual authors, and do not necessarily represent the views or positions of LabMedica magazine or its publishers.

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NEWS

IFCC Visiting Lecturer Program: Report from COLABIOCLI 2019 by Tomris Ozben, IFCC Treasurer would like to express my sincere gratitude to the VLP Committee and Abbott company for supporting my attendance to the COLABIOCLI 2019 Congress. The joint 24th Latin American Congress of Biochemistry and 14th National Congress of Clinical Laboratory of Panama took place from September 10 to September 13, 2019, at the Megapolis Convention Center, in Panama, Republic of Panama. The Pan-American Society for Clinical Virology (PASCV), in conjunction with the National Association of Clinical Laboratory Technologists of Panama (CONALAC), organized, within the setting of the 24th Latin American Congress of Clinical Biochemistry (COLABIOCLI), a prior scientific activity on September 10 (8:00-17:30) – September 11, 2019 (9:00-12:30) with the goal of reinforcing the technical and practical aspects of the diagnostic virology laboratory. This event was aimed at directors of clinical laboratories, laboratory technologists, physician trainees, and specialists in infectious diseases. A day and a half of lectures by experts from the USA and Latin American countries included general discussions related to organization and function of clinical virology laboratories, and specific talks on the diagnosis of blood-borne viruses, papilloma virus, and arbo-viruses. Clinical case presentations provided an opportunity for inter-active discussion regarding diagnostic challenges routinely encountered when caring of patients with viral infections. The aim of the meeting was to provide the participants knowledge of fundamentals in clinical virology, and a unique opportunity to interact and collaborate with colleagues in similar diagnostic settings throughout Latin America. During the main congress, five parallel sessions were organized at the MEGAPOLIS Congress Center from September 11, 2019 till the end of September 13, 2019. Simultaneous translation from English/Spanish was provided. The participants of the congress were students, residents of Clinical Chemistry and Pathology, Medical Laboratory Technicians licensed in Laboratory Sciences, Clinical Biochemists, Clinical Pathologists, Biochemists, Biologists, Pharmacists, Chemists, and Physicians. In addition to the lectures, several workshops were held during the congress. The Posters’ Exhibition and Commercial Exhibition were held every congress day between 9:00-10:00 and 17:30. Visits to Posters and Commercial Exhibitions were performed during coffee and lunch breaks. On Wednesday, September 11, 2019, in the Gatun Hall, the IFCC sponsored a symposium on HbA1c, which was held between 09:00-12:30. Prof. Garry John from UK, Dr Emma English from UK, Dr Cas Weykamp from NL and Dr David Sacks-EUA delivered talks on the following topics. Haemoglobin A1c Measurement: an overview: Can HbA1c POCT be used for diagnosis of Diabetes; HbA1c in Clinical Practice; current thinking and future prospective. Quality Targets for HbA1c; Lessons learn from External Quality Assessment. Parallel sessions were held between 09:00-12:30 in the other four Halls namely, SALÓN AGUA CLARA, SALÓN COCOLÍ, SALÓN PEDRO MIGUEL, and SALÓN MIRAFLORES on different topics such as Tuberculosis, Coagulation, Virology, D-dimer, Vitamin D, etc. Between 12:30 and 13:30, Prof. Ferrari delivered a plenary lecture titled: The Future of Molecular Biology in the Diagnostic Laboratory. Between 13:30 till 14:30, open buffet lunch was served to the participants sitting together at the round tables. At 14:30, afternoon sessions started at the five halls. I delivered my lecture titled “Diagnostic Proteomic Markers to Detect Kidney Diseases” between 14:30 and 15:15 in the Hall named SALÓN MIRAFLORES. Following my presentation, Prof. Tomas Zima talked on the topic “Alcohol related health problems – alcohol and carcinogenesis, biological marker for abuse and addiction” from 15:15 till 16:00. Dr Montserrat Blanes from the IFCC C-CC gave a talk on “Metabolic syndrome, approach in adolescents, adults, elderly and children”. Between 16:15 and 17:00, Prof. Ferrari presented a talk on “Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer”. The parallel sessions ended at 17:00, but the exhibition lasted till 17:30. The day ended with a dinner for all participants at the congress venue starting from 20:00. On Thursday, September 12, 2019, there were five parallel sessions on the following topics between 9:00-11:00: Symposium on neonatal screening; SEQC-ML Symposium on POCT; AEFA Symposium on sterility and fertility; IFCC CPD Symposium on Distance Learning; IFCC Symposium on Quality consideration for molecular diagnostic, Pre and Post-examina-

LabMedica International November/2018

Photo: COLABIOCLI colleagues along with scholarship recipients. In the center Prof. Ferrari, IFCC President, and Prof. Ozben, IFCC Treasurer.

tion factors for Molecular Diagnostics, EQA and Alternate Assesment Strategies in Molecular Diagnostic; How to imagine the future of Laboratory Medicine and Symposium on “Quality consideration for Molecular diagnostics in Central and South America. 11.00-11:30 were reserved for visits for the exhibition/posters. Between 11:30-12:30, five parallel symposia were held in the halls on the following topics including Symposium on Education; Curricula of Laboratory Medicine in Medical School. Dr. Aristides Quintero–Panamá delivered the plenary lecture titled “Investigation of new therapeutic strategies against breast cancer and T cell leukemia” between 12:30-13:30. Between 13:30 till 14:30, open buffet lunch was served to the participants sitting together at the round tables. At 14:30, afternoon sessions started at the five halls. I delivered my lecture titled “In vitro diagnostic and evolving regulatory challenges in laboratory medicine” between 14:30 and 15:15. The afternoon sessions in five parallel halls lasted from 14:30 till 17:00. Thursday night, a dinner was organized for the speakers in a restaurant in the city. On Friday, September 13, 2019, there were five parallel sessions. A symposium on accreditation of the laboratories was held from 9:00 till 12:30. Dr Juan Miguel Pascale gave a Plenary Lecture on HIV in Latin America between 12:30 and 13:30. Other symposia on standardization of creatinine” and on “Pre-analytical errors” were held in addition to the interesting lectures such as “Review of the WHO Classification of Hematological Neoplasms and its Application in the Clinical Laboratory”; “Risk Management in the Clinical Laboratory and Blood Bank”; New guidelines for the management of dyslipidemias; new biomarkers of cardiovascular disease, and International Certification of the professionals of the Clinical Laboratory. The Congress ended by the closing cocktail held at 20:00 on Friday, September 13, 2019.

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NEWS

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

VIEWPOINT

Laboratory Accreditation and Healthcare: A Matter of Trust by Dr. Bernard Gouget Chair, Committee on Mobile Health and Bioengineering in Laboratory Medicine (C-MHBLM), Past-Chair, IFCC Nominations Committee (NC), SFBC-International Committee; General Secretary of the International Francophone Federation of Clinical Biology and Laboratory Medicine (FIFBCML); President Healthcare Division Committee - Comité Français d’accréditation (Cofrac) edical laboratory services are essential to patient care and therefore have to be available to meet the needs of both patients and clinicians. Such services include arrangements for examination requests, patient preparation, patient identification, collection of samples, transportation, storage, processing and examination of clinical samples, together with subsequent interpretation, reporting and advice, in addition to the considerations of safety and ethics. Accreditation is emerging as a preferred framework for building quality medical laboratory systems. By contributing to the continuous improvement of controls, to the quality of products and services, and to the accuracy of their declared compliance or performance, accreditation increases confidence while being a differentiating asset for bodies that have recourse to it. Accreditation has the potential to improve the quality of health care for patients through the reduction of testing errors and attendant decreases in inappropriate treatment. Accreditation is most effective when it is rooted in a policy framework for evaluating laboratory quality and patient safety. As a voluntary or regulatory initiative, accreditation consists in assessing and recognizing the technical competence as well as the impartiality of conformity assessment bodies verifying that products, services, systems, installations and persons comply with specific requirements. In some countries, accreditation is a mandatory requirement for testing operations, while in other countries, accreditation is voluntary and driven by market incentives. International and/or national quality standards are the backbone of accreditation. Standards provide the guiding framework within which laboratory performance is evaluated. ISO 15189, a laboratory standard from the International Standards Organization (ISO), specifies quality management system and competency requirements for medical testing. Adherence to such quality standards and participation in accreditation programs that certify this adherence can improve operational efficiency and customer service and reduce rates of laboratory errors. A recent survey in 2019 organized by EA under the coordination of Hélène Mehay, Director Cofrac Healthcare Division, demonstrated that ISO 15189 is widely used in Europe. Accreditation goes further than recognition of the conformity of the quality management system with a reference document or standard. It includes peer assessment and recognition according to international regulations of the competence, in particular technical competence of the body’s personnel and the suitability of the resources used. Operating in

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accordance with standard ISO/IEC 17011, the national body for accreditation as Cofrac is France, is regularly assessed by its European peers to ensure its accreditation practices are consistent and in harmony with the accreditation bodies signatory multilateral agreements. Cofrac remains present in all of EA’s technical committees, the International Laboratory Accreditation Cooperation (ILAC), and the International Accreditation Forum (IAF). The Cofrac Healthcare section’s main mission is to accredit medical labs, pathological anatomy and cytology entities. Accreditation is not a fixed system and accreditation schemes are regularly developed to meet the needs and demands as for example in imagery. In the light of our public interest mission and international standing, the specialists in Lab Medicine and the national body of accreditation are playing a crucial role in supporting innovation and public policies. Also, following the first regulatory deadline of 31 December 2017, 2018 was marked in France by the progressive resumption by the medical labs of moves to extend their accreditation scope with a view to cover by 1 November 2020 their entire activity. The Cofrac Healthcare Division is continuing its improvement of the performance of its actions by optimizing the accreditation process, developing its IT management tools and planning assessments better, in order to optimize the assessors’ activities towards their set priorities. As a part of this, exchanges with the professionals were intensified ro promote a progressive and optimized approach. As the accreditation is internationally recognized, in collaboration with the Labac team ( Jean-Marc Giannoli, President ; JeanPierre Bouilloux, Irene Revenko) , myself and with the permission of Cofrac, we decided to translate in English The “French technical guide to medical laboratory accreditation ”SH-GTA version 01” Cofrac (https://tools.cofrac.fr/ documentation/SH-GTA-01 ) to help in a practical way the specialists in Lab Medicine in the implementation of the accreditation. This technical guide to accreditation presents a review of good practices and establishes certain recommendations resulting from the application of these standards, NF EN ISO 15189 and NF EN ISO 22870, in medical laboratories, as part of accreditation. This guide does not replace the requirements and/or standards applicable within the medical laboratory. The recommendations it contains are those recognized by the French National body of accreditation “Cofrac” ( Comité Français d’accréditation) as appropriate to satisfy the requirements of NF EN ISO 15189, and NF EN ISO 22870.This guide deals specifically with technical aspects covering, for example, the qualification of personnel and the pre-examination, examination and post-examination phases. This technical guide to accreditation is applicable in France from 1 November 2018. In the field concerned, Laboratory Medicine, and on the day of its approval, this technical guide to accreditation reflects the state of knowledge in terms of recommendations for accreditation in this field. The document contains both requirements and recommendations. Accreditation is a mark of quality and is objective proof that a laboratory is not only competent, but safe, patient-focused, efficient and reliable. Efforts made to achieve accreditation may also lead to improvements in the management of Medical Labs by focusing attention on areas of greatest need and accelerating improvement in areas such as supply chain, training, and instrument maintenance. Laboratory accreditation may also have a positive influence on performance in other areas of health care systems by allowing laboratories to demonstrate high standards of service delivery. Accreditation may, thus, provide an effective mechanism for health system improvement yielding long-term benefits in the quality, cost-effectiveness, and sustainability of public health programs.

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ERBA Mannheim Opens New Subsidiary in Brazil RBA Mannheim has expanded its global footprint by opening a new subsidiary in Brazil. The new organization, Erba Mannheim Brazil, will be headquartered in Nova Lima, north of the nation’s capital, will sell a full range of blood and urine test automation solutions in clinical chemistry, hematology, hemostasis, immunoassay, urinalysis, diabetes, critical care and microbiology. “This new operation significantly enhances our footprint in LATAM,” said Nikhil Vazirani, MD of Erba Mannheim. “We have an excellent team who are looking forward to helping improve workflow and quality whilst reducing cost and turnaround time of Brazilian labs.” “We are very excited to be able to serve our customers and support our channel partners from within Brazil,” said Tarcisio Vilhena, Brazil country manager. “We have a dedicated team ready to support our customers with application and service expertise as well as sales and marketing support. From the simplest semi-automatic system to the impressive sophistication of our future NEXUS range, we are committed to help improve the lives of millions in Brazil through high quality, affordable automation.” Erba Mannheim Brazil also showcased key products, including XL200 and XL640 clinical chemistry instruments, LAURA XL automatic urinalysis system, Elite 580 and H560 automatic hematology analyzers and the ECL760 automatic coagulation analyzer, at the 53rd Brazilian Congress of Clinical Pathology in Rio Janeiro, held September 24-27, 2019.

Baxter Acquisition Expands Hemodynamic Monitoring Offerings axter International Inc. (Deerfield, IL, USA; www.baxter.com), a global medical products company, has acquired Cheetah Medical (Boston, MA, USA; www.cheetah-medical.com), a provider of non-invasive hemodynamic monitoring technologies. Baxter offers a wide portfolio of critical care, nutrition, renal, hospital and surgical products across more than 100 countries. Cheetah Medical is a global provider of 100% non-invasive fluid management monitoring technologies, designed for use in critical care, operating room and emergency department settings. The acquisition of Cheetah Medical is in line with Baxter’s commitment towards improving clinical outcomes with an established patient monitoring technology to better inform and guide clinicians’ treatment decisions. Cheetah Medical is a natural adjacency for Baxter, given Baxter’s presence in infusion systems and intravenous (IV) solutions, fluid management, and critical care and IV therapy.

Global POC Testing Market to Reach USD 30 Billion by 2022 he global Point-of-Care (POC) testing market is projected to reach USD 30 billion by 2022, driven by the immense potential of POC tests to improve global health and eventually reduce public and national spending on health. These are the latest findings of Research and Markets, (Dublin, Ireland; www.researchand markets.com), a global market research company. POC testing devices have now found applications in a large number of medical conditions and their increased usage in the field of critical care settings for delivering decentralized, patient-centric healthcare to patients is expected to drive a rapid growth in the POC testing market. Increasing awareness about POCT, technological advancements and increasing FDA approvals are the major drivers of the global POC testing market. However, some challenges, such as product recalls and lack of regulatory standards, are hindering market growth. On the basis of type of product, glucose monitoring kits accounted for the largest market share in 2017 due to the rising prevalence of diabetes & technological advancements in self-monitoring of blood glucose. Based on geography, North America accounted for the largest share of the global POC testing market in 2017.

LabMedica International November/2018

Industry News

AI-Enabled Technology to Help Global Molecular Imaging Market Exceed USD 11 Billion by 2028 he global molecular imaging market was estimated at USD 6.84 billion in 2018 and is projected to grow at a CAGR of 5.03% during the forecast period 2019-2028 to reach USD 11.13 billion by 2028. The market growth will be driven by significant developments in the field of multimodality and optical imaging, particularly the emergence of AI-enabled imaging technology. These are the latest findings of Research and Markets, Inc. (Fremont CA, USA; www. researchandmarkets.com), a global B2B market intelligence and advisory firm. Within the past few decades, the medical imaging industry has been witnessing significant technological advancements. Currently, the demand for preventive care and early diagnosis is rising due to the increasing incidence of chronic disorders. Since the past few years, the market has been witnessing an increased demand for molecular imaging technologies such as PET, SPECT, and multimodality imaging due to rising awareness as well as increasing number of government initiatives to promote the early detection of diseases using molecular imaging. However, ongoing technological advancements such as the launch of next generation of SPECT cameras containing cadmium zinc telluride (CZT) detectors and the emergence of AI-enabled imaging technology is expected to further aid the market growth during the forecast period. The advent of multimodality imaging technology has led to increased adoption of PET-CT, PET-MRI, SPECT-CT, and related procedures in routine practice. Currently, the oncology application-specific molecular imaging segment is expected to be the major contributor to the molecular imaging market. The launch of novel contrast agents is expanding the scope of application of molecular imaging while small molecule-based imaging agents hold a major share of the molecular imaging market.

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

International Calendar, LabMedica International E-mail: info@globetech.net JANUARY 2020 Fertility 2020 – 13th Joint Conference of the UK Fertility Societies. Jan 9-11; Edinburgh, UK; Web: fertilityconference.org SLAS 2020 – Society of Laboratory Automation and Screening. Jan 25-29; San Diego, CA, USA; Web: www.slas.org

FEBRUARY 2020 MEDLAB Middle East 2020. Feb 3-6; Dubai, UAE; Web: www.medlabme.com CHINALAB 2020. Mar 11-13; Guangzhou, China; Web: www.chinalabexpo.com

MARCH 2020 Pittcon 2020. Mar 1-5; Chicago, IL, USA; Web: pittcon.org Medical Fair India 2020. Mar 5-7; Mumbai, India; Web: www.medicalfair-india. com CHINALAB 2020. Mar 11-13; Guangzhou, China; Web: www.chinalabexpo.com ARABLAB 2020. Mar 16-18. Dubai, UAE; Web: www.arablab.com ExpoMED Eurasia 2020. Mar 19-21; Istanbul, Turkey; Web: expomedistanbul.com KIMES 2020. Mar 19-22; Seoul, Korea; Web: www.kimes.kr MEDLAB Asia Pacific 2020. Mar 24-26; Singapore; Web: www.medlabasia.com ENDO 2020 – Annual Meeting of the Endocrine Society. Mar 28-31; San Francisco, CA, USA; Web: www.endocrine.org/ endo2020 Analytica 2020. Mar 31-Apr 3; Munich, Germany; Web: www.analytica.de

APRIL 2020 World Vaccine Congress 2020. Apr 7-9; Washington, DC, USA; Web: www.terrapinn. com/conference CMEF Spring 2020 – China International Medical Equipment Fair. Apr 9-12; Shanghai, China; Web: www.cmef.com.cn KoreaLab 2020. Apr 14-17; Seoul, Korea; Web: www.korealab.org India Lab Expo & analytica Anacon India. Apr 16-17; Mumbai, India; Web: www.indialabexpo.com ECCMID 2020 – 30th European Congress of Clinical Microbiology and Infectious Diseases. Apr 18-21; Paris, France; Web: www.eccmid.org AACR Annual Meeting 2020 – American Association for Cancer Research. Apr 24-29; San Diego, CA, USA; Web: www. aacr.org

MAY 2020 29th Annual Scientific and Clinical Congress of the American Association of Clinical Endocrinologists (AACE). May 6-10; Washington, DC, USA; Web: www. aace.com Immunology 2020 – 104th Annual Meeting of the American Association of Immunologists (AAI). May 8-12; Honolulu, Hawaii, USA; Web: www.immunology2020.org FOCUS 2020 – National Meeting (UK) of the Association for Clinical Biochemistry & Laboratory Medicine (ACB). May 13-15; Belfast, UK; Web: www.acb.org.uk ASRI 2020 – 40th Annual Meeting of the American Society for Reproductive Immunology. May 17-21; Santa Fe, NM, USA; Web: www.theasri.org/2020-santa-fe Hospitalar 2020. May 19-22; Sao Paulo, Brazil; Web: www.hospitalar.com ISLH 2020 – International Society of Laboratory Hematology. May 21-23; Melbourne, Australia; Web: www.islh.org ECE 2020 – 22nd European Congress of Endocrinology. May 23-26; Prague, Czech Republic; Web: www.ese-hormones. org IFCC WorldLab Seoul 2020 – 24th International Congress of Clinical Chemistry and Laboratory Medicine. May 24-28; Seoul, Korea; Web: www.seoul2020.org ASCO 2020 – Annual Meeting of the American Society of Clinical Oncology. May 29-Jun 2; Chicago, IL, USA; Web: am.asco.org

JUNE 2020 ESGH 2020 – European Human Genetics Conference. Jun 6-9; Berlin, Germany;

Web: www.eshg.org 36th Congress of the International Society of Blood Transfusion (ISBT). Jun 6-10; Barcelona, Spain; Web: www. isbtweb.org EAACI Congress 2020 – European Academy of Allergy & Clinical Immunology. Jun 6-10; London, UK; Web: www. eaaci.org BIO International Convention 2020. Jun 8-11; San Diego, CA, USA; Web: www. convention.bio.org 37th Nordic Congress in Medical Biochemistry. Jun 9-12; Trondheim, Norway; Web: www.nfkk2020.no 25th Annual Congress of the European Hematology Association (EHA). Jun 11-14; Frankfurt, Germany; Web: www. ehaweb.org/congress American Diabetes Association (ADA) 80th Scientific Sessions. Jun 12-16; Chicago, IL, USA; Web: www.professional. diabetes.org/scientific-sessions ASM Microbe 2020 – American Society for Microbiology. Jun 18-22; Chicago, IL, USA; Web: www.asm.org LABWorld China 2020 (CPhI & P-MEC China). Jun 22-24; Shanghai, China; Web: www.cphi.com/china/visit/labworld FOCIS 2020 – Annual Meeting of the Federation of Clinical Immunology Societies. Jun 22-26; San Francisco, CA, USA; Web: www.focisnet.org

JULY 2020 ESHRE 2020 – 36th Annual Meeting of the European Society of Human Reproduction and Embryology. Jul 5-8; Copenhagen, Denmark; Web: www.eshre.eu AIDS 2020 – 23rd International AIDS Conference. Jul 6-10; San Francisco, CA, USA; Web: www.aids2020.org ISTH 2020 – 28th Congress of International Society on Thrombosis and Haemostasis. Jul 11-15; Milan, Italy; Web: www.isth.org 72nd AACC Annual Scientific Meeting & Clinical Lab Expo – American Association for Clinical Chemistry. Jul 26-30; Chicago, IL, USA; Web: www.aacc.org

AUGUST 2020 32nd Congress of the European Society of Pathology (ESP). Aug 29-Sep 2; Glasgow, UK; Web: www.esp-congress. org

SEPTEMBER 2020 EUROTOX 2020 – 56th Congress of the European Societies of Toxicology. Sep 6-9; Copenhagen, Denmark; Web: eurotox-congress.com/2020 16th International Thyroid Congress. Sep 8-13; Xi’an, China; Web: itc2020.medmeeting.org ASCP 2020 – Annual Meeting of the American Society for Clinical Pathology. Sep 9-11; Austin, TX, USA; Web: www.ascp.org ESPE 2020 – 59th Annual Meeting of the European Society of Paediatric Endocrinology. Sep 10-12; Liverpool, UK; Web: www.eurospe.org ISH 2020 – 38th World Congress of the International Society of Hematology. Sep 13-16; Bangkok, Thailand; Web: www.ishworld.org EASD 2020 – 56th Annual Meeting of the European Association for the Study of Diabetes. Sep 22-25; Vienna, Austria; Web: www.easd.org

OCTOBER 2020 ECC 2020 – 43rd European Congress of Cytology. Oct 4-7; Wroclaw, Poland; Web: cytology2020.eu ICE 2020 – 19th International Congress of Endocrinology. Oct 4-7; Buenos Aires, Argentina; Web: ice-2020.com ASHI 2020 – 46th Annual Meeting of the American Society for Histocompatibility & Immunogenetics. Oct 19-23; Anaheim, CA, USA; Web: www.ashi-hla.org ASHG 2020 – American Society of Human Genetics. Oct 27-31; San Diego, CA, USA; Web: www.ashg.org

NOVEMBER 2020 MEDICA 2020. Nov 16-19; Dusseldorf, Germany; Web: www.medica-tradefair.com LabMedica International November/2018

Advertising Index

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Vol. 36 No.7 • 11/ 2019 Advertiser

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

111 ELITechGroup . . . . . . . . . .11

113 Nova Biomedical . . . . . . . .13

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

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

108 Alcor . . . . . . . . . . . . . . . . . . .8

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

168 Randox . . . . . . . . . . . . . . .68

145 Awareness Technology . . .45

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121 Sekisui . . . . . . . . . . . . . . . .21

151 Biokit . . . . . . . . . . . . . . . . .51

120 GeneReach . . . . . . . . . . . .20

114 Buhlmann . . . . . . . . . . . . . .14

135 Greiner Bio-One . . . . . . . .35

157 Caretium . . . . . . . . . . . . . .57

116 Huisong . . . . . . . . . . . . . . .16

156 CDG Biotech . . . . . . . . . . .56

– IFCC WorldLab 2020 . . . . .65

103 Chemclin . . . . . . . . . . . . . . .3

119 Instrumentation Laboratory 19

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125 Instrumentation Laboratory 25

137 Diagnostica Stago . . . . . . .37

109 JEOL . . . . . . . . . . . . . . . . . .9

139 Diagnostica Stago . . . . . . .39

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154 Vicotex . . . . . . . . . . . . . . . .54

131 Diasys . . . . . . . . . . . . . . . .31

164 Labex . . . . . . . . . . . . . . . . .64

127 Vircell . . . . . . . . . . . . . . . . .27

117 Diatron . . . . . . . . . . . . . . . .17

163 Mast Group . . . . . . . . . . . .63

155 Wiener . . . . . . . . . . . . . . . .55

147 DxGen . . . . . . . . . . . . . . . .47

153 Monlab . . . . . . . . . . . . . . . .53

149 Xunda . . . . . . . . . . . . . . . .49

124 Dymind . . . . . . . . . . . . . . . .24

133 NG Biotech . . . . . . . . . . . .33

143 YHLO . . . . . . . . . . . . . . . . .43

160 SFRI . . . . . . . . . . . . . . . . . .60 112 Singuway . . . . . . . . . . . . . .12 102 SNIBE . . . . . . . . . . . . . . . . .2 122 SNIBE . . . . . . . . . . . . . . . .23 – TradeMed.com . . . . . . . . . .59 141 VEDA.LAB . . . . . . . . . . . . .41

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