LabMedica International October 2018 by Globetech

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WORLD’S CLINICAL LABORATORY NEWS LEADER ISSN 1068-1760

Vol. 35 No.6 • 10/2018

DAILY CLINICAL LAB NEWS

Simple Blood Test Devised for Hepatitis B

Extracellular RNA Helps Diagnose Medical Conditions

iral hepatitis is a major global health problem, and estimates suggest that hepatitis B was responsible for about half of the 1.45 million viral hepatitis-related deaths that occurred worldwide in 2013. A simple inexpensive blood test has been devised

or some diseases, biomarkers can be used to determine how far the illness has advanced, but not shed light on how quickly it will progress in the future. Circulating extracellular RNAs (exRNAs) have the potential to serve as biomarkers for a wide

range of medical conditions. However, limitations in existing exRNA isolation methods and a lack of knowledge on parameters affecting exRNA variability in human samples may hinder their successful discovery and clinical implementation. A new way has

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Microfluid Application To Enable Noninvasive Prenatal Testing

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urrently, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is estimated to affect more than one million people in the USA, and up to 24 million people worldwide. This often-debilitating condition is characterized by feelings of extreme exhaustion, muscle and joint pain, and insomnia, as well as difficulty concentrating or remembering things.

here is no accurate method for distinguishing between the hypervirulent strain from the classical strain of Klebsiella pneumoniae (cKp), which is most often seen in the Western hemisphere, and is less virulent and usually causes infections in hospital settings. Several biomarkers have been discovered that can accurately identify hypervirulent K. pneumoniae (hvKp), a pathogen

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Point-of-Care Test Diagnoses Respiratory Viruses from Saliva

INSIDE

he use of saliva as a specimen for the detection of respiratory viruses has been proposed as an alternative to nasopharyngeal aspirate or nasopharyngeal swab. Saliva may have the advantage to cause less discomfort in patients and less risk for healthcare workers.

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Genetic Connections Uncovered Between Psychiatric Disorders

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Biomarker Discovered for Hypervirulent Pathogen

Image: Dr. Marnie Winter examining fetal trophoblastic cells isolated using inertial microfluidics

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breakthrough application of inertial microfluA idics technology toward the efficient isolation of trophoblastic cells from maternal peripheral blood, could lead to noninvasive prenatal diagnosis testing, thereby replacing current invasive procedures such as amniocentesis and chorionic villus sampling.

rain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a consid-

erable challenge. Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor Cont’d on page 5

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Extracellular RNA Helps Diagnose Medical Conditions cont’d from cover

been found to probe blood samples for fragments of RNA released by tumors or diseased organs. Scientists at The Rockefeller University (New York, NY, USA; www. rockefeller.edu) and their colleagues recruited 13 healthy subjects, seven males and six females, were recruited from Bronx, New York, to participate in the study. Blood Sample collection was performed over a period of four months from November 19, 2014, to March 24, 2015. The team developed a new method, which involves multiple refinements in the preparation and processing of the plasma and serum samples tested, solves that longstanding scarcity problem, and it has other advantage as well. In developing the new technique, the scientists processed and analyzed a total of 312 blood samples collected from 13 healthy subjects, including both men and women, over a two-month period. That schedule was designed to answer another critical question about exRNA: does it remain stable over time? Silica-matrix adsorption-based RNA purification was based on the commercial RNeasy MinElute Cleanup Kit (Qiagen, Hilden Germany; www.qiagen.com) following organic extraction showed greater tracer integrities when using the TRIzol-based protocol. Stability is essential for biomarkers, which, among other things, often need to be routinely moni-

ab-on-a-chip (LOC) technology integrates laboratory functions on a chip ranging from a few millimeters to a few square centimeters. The special design of the device allows large volumes of blood to be screened, paving the way for an efficient, cheap and quick method of separating fetal cells from maternal blood cells. Currently, prenatal diagnostic tests involve an amniocentesis procedure or taking a sample of cells from the placenta (chorionic villus sampling), both of which carry a risk of inducing miscarriage. While noninvasive prenatal testing based on cell free fetal DNA has recently revolutionized the field of aneuploidy screening in pregnancy, it remains limited to aneuploidy and microdeletion screening, and is unable to reliably detect single gene disorders. Bioengineers at the University of South Australia (Adelaide, Australia; www.unisa.edu.au) and their colleagues demonstrated for the first time the utility of inertial microfluidics for efficient isolation of trophoblastic cells from maternal peripheral blood. Under optimal operating conditions, high recovery yields (79%) are obtained using a trophoblastic cell line, which is subsequently confirmed with analysis

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tored in long-term clinical studies. Results confirmed that the subjects’ circulating exRNA, which came from muscle, neuroendocrine, and epithelial cells, remained consistent in composition and concentration over the two months. Thomas Tuschl, PhD, a professor of Molecular Biology and senior author of the study, said, “We can survey thousands of pieces of RNA, with origins across all cell types. Identifying the specific tissue where the exRNA originates along with its molecular structure and its abundance in the circulation has enormous potential for detecting disease processes and discovering new abnormalities.”

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Image: The RNeasy MinElute cleanup kit (Photo courtesy of Qiagen).

Microfluidic Application to Enable Noninvasive Prenatal Testing

of maternal blood. Feasibility of obtaining a diagnosis from cells isolated from a maternal sample was demonstrated in a case of confirmed fetal trisomy 21 in which six fetal cells are found in a 7 mL blood sample using fluorescence in situ hybridization. Finally, it was demonstrated that trophoblastic cells isolated using inertial microfluidics could be picked and subjected to a clinically validated sequencing assay, paving the way for further validation of this technology and larger clinical studies. Marnie Winter, PhD, a bioengineer and first author of the study, said, “From about five weeks into the pregnancy, fetal cells originating from the placenta can be found in a mother’s bloodstream. Using modern microfluidic technology, we can now isolate these extremely rare cells (about one in a million) from the mother’s white blood cells and collect them for genetic analysis. We are hopeful that this device could result in a new, non-invasive prenatal diagnostic test able to detect a wide range of genetic abnormalities in early pregnancy from a simple blood sample.” The study was first published on June 14, 2018, in the journal Advanced Materials Technologies.

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ISSN 1068-1760 Vol.35 No.6. Published, under license, by Globetech Media LLC; Copyright © 2018. All rights reserved. Reproduction in any form is forbidden without express permission. Opinions expressed are solely those of the authors, and do not represent an endorsement, or lack thereof, by the Publisher of any products or services. Teknopress Yayıncılık ve Ticaret Ltd. Şti. adına İmtiyaz Sahibi: M. Geren • Yazı işleri Müdürü: Ersin Köklü Müşir Derviş İbrahim Sok. 5/4, Esentepe, 34394 Şişli, İstanbul P. K. 1, AVPIM, 34001 İstanbul • E-mail: Teknopress@yahoo.com Baskı: Postkom A.Ş. • İpkas Sanayi Sitesi 3. Etap C Blok • 34490 Başakşehir • İstanbul Yerel süreli yayındır. Yılda sekiz kere yayınlanır, ücretsiz dağıtılır.

LabMedica International October/2018

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LabMedica International

Genetic Connections Uncovered Between Psychiatric Disorders cont’d from cover

function, or alterations of consciousness. Psychiatric disorders share a genetic overlap with each other that neurological disorders do not. A large team of scientists led by those at Massachusetts General Hospital (Boston, MA, USA; www.massgeneral.org) quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. The team used a linkage disequilibrium score regression approach they developed to calculate heritability estimates and correlations. The scientists found that common variant risk for psychiatric disor-

Point-of-Care Test Diagnoses Respiratory Virus from Saliva cont’d from cover

Automated point-of-care molecular assays have greatly shortened the turnaround time of respiratory virus testing. One of the major bottlenecks now lies at the step of the specimen collection especially in a busy clinical setting. Saliva is a convenient specimen type, which can be provided easily from adult patients. Scientists from the University of Hong Kong (Pokfulam, Hong Kong; www.hku.hk) recruited between July and October 2017, 214 patients and carried out a prospective diagnostic validity study comparing the detection rate of respiratory viruses between saliva and nasopharyngeal aspirate (NPA) among adult hospitalized patients using Xpert Xpress Flu/RSV (Cepheid, Sunnyvale, CA, USA; www. cepheid.com). The cost and time associated with the collection of saliva and nasopharyngeal specimens were also estimated. The team found that the overall agreement between saliva and NPA were 93.3% (196/210). There was no significant difference in the detection rate of respiratory viruses between saliva and NPA; (69/210 (32.9%) versus 75/210 (35.7%). The overall sensitivity and specificity were 90.8% (81.9-96.2%) and 100% (97.3100%), respectively, for saliva, and were 96.1% (88.9-99.2%) and 98.5% (94.7-99.8%), respectively, for NPA. The time and cost associated with the collection of saliva were 2.3-fold and 2.6-fold lower, respectively, than those of NPA. The authors concluded that saliva specimen had high sensitivity and specificity in the detection of respiratory viruses by an automated multiplex Clinical Laboratory Improvement Amendments (CLIA)-waived point-ofcare molecular assay when compared with that of NPA. The use of saliva also reduces the time and cost associated with specimen collection. The study was published on June 12, 2018, in the journal Clinical Microbiology and Infection.

LabMedica International October/2018

ders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. In the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn’s disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Ben Neale, PhD, an associate professor and co-lead author of the study, said, “This work is starting to reshape how we think about disorders of the brain. If we can uncover the genetic influences and patterns of overlap between different disorders, then we might be able to better understand the root causes of these conditions, and potentially identify specific mechanisms appropriate for tailored treatments.” The study was published on June 22, 2018, in the journal Science.

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PRODUCT NEWS NETWORK ARCHITECTURE

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COAGULATION ANALYZER

CELL CULTURE ANALYZER

Diagnostica Stago

Erba Mannheim

Nova Biomedical

The Connect.One is a secure network architecture that allows labs to benefit from remote monitoring of their automated analyzers. Connect.One can track analyzer performance and send notifications while downloading software improvements.

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

The BioProfile FLEX2 combines Nova’s MicroSensor Card technology with optical measurement and freezing point osmometry. It eliminates chemistry sensor maintenance, increases analyzer speed and reduces sample volume.

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Simple Blood Test Devised for Hepatitis B cont’d from cover

that could be used widely in low-income and middle-income countries (LMICs) to help determine which patients with hepatitis B require immediate treatment. The affordable test is based on measurements of hepatitis B virus e antigen (HBeAg), and levels of the liver enzyme alanine aminotransferase (ALT), to generate a diagnostic score. An international team of scientists led by the Institute Pasteur (Paris, France; www.pasteur.fr) derived a score indicating treatment eligibility by a stepwise logistic regression using a cohort of 804 chronic HBV infections in The Gambia. They subsequently validated the score in an external cohort of 327 HBV-infected Africans from Senegal, Burkina Faso, and Europe. The team has developed and validated a diagnostic score, known as TREAT-B (treatment eligibility in Africa for the HBV), which is based on simple blood tests that are widely available in local laboratories in LMICs, and which do not rely on HBV DNA, liver tests or Fibroscan. HBsAg-positive participants underwent a standardized clinical staging, including fasting transient elastography, abdominal ultrasonography, hematology (Medonic, Boule Medical AB, Spånga, Sweden; www. boule.com), biochemistry (VITROS 350 analyzer, Ortho, Raritan, NJ. USA; www.orthoclinicaldiagnostics.com), hepatitis B e antigen (HBeAg) (ETI-EBK Plus, Diasorin, Saluggia, Italy; www.diasorin.com), and HBV

DNA using an in-house real-time polymerase chain reaction (PCR, limit of detection: 50 IU/mL). The team reported that out of several parameters, two remained in the final model, namely HBV e antigen (HBeAg) and ALT level, constituting a simple score (treatment eligibility in Africa for the hepatitis B virus: TREATB). The score demonstrated a high area under the receiver operating characteristic curve (0.85, 95% CI 0.79–0.91) in the validation set. The score of 2 and above (HBeAg-positive and ALT ≥20 U/L or HBeAg-negative and ALT ≥40 U/L) had a sensitivity and specificity for treatment eligibility of 85% and 77%, respectively. The sensitivity and specificity of the World Health Organization criteria based on the aspartate aminotransferase-toplatelet ratio index (APRI) and ALT were 90% and 40%, respectively. The authors concluded that TREAT-B represents a promising simple and low-cost diagnostic score that can assist physicians to easily identify HBV-infected individuals in need of treatment in Africa. Its use may contribute towards global HBV elimination by facilitating the scale up and decentralization of HBV treatment programs in LMICs. Both ALT and HBeAg measurements are widely available in LMICs, and their total cost of less than USD 10 is much lower than the cost of the conventional tests required indicating treatment eligibility. The study was published on July 1, 2018, in the Journal of Hepatology.

Accurate Test for Chronic Fatigue Syndrome cont’d from cover

The causes of ME/CFS remain unknown, and in the absence of a proper diagnostic test for it, healthcare professionals have to exclude other disorders and examine a patient’s history before they can tell whether a person has ME/CFS or not. Patients with ME/CFS frequently report a prodrome consistent with infection that includes a sore throat and cervical lymphadenopathy. Scientists at Columbia University Mailman School of Public Health (New York, NY, USA; www.mailman.columbia.edu) and their colleagues examined the blood samples of 50 people with ME/CFS and compared them with those of 50 age-matched healthy controls. The team reported association modeling, biomarker discovery, biochemical enrichment analysis and topological network visualization of plasma metabolomic, fecal bacterial metagenomic and clinical data. The team performed three untargeted metabolomic assays and one targeted assay for 562 metabolites from over 20 biochemical pathways with gas chromatography time-of-flight (GCTOF) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) instruments by the West Coast Metabolomics Center (University of California, Davis, CA, USA; www.metabolomics.ucdavis.edu). Irritable bowel syndrome (IBS) co-

morbidity was based on self-reported diagnosis of IBS on the medical history form. IBS was diagnosed in 24 of the 50 ME/CFS patients (48%). The team confirmed reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide. Integration of fecal metagenomic and plasma metabolomic data resulted in a stronger predictive model of ME/CFS (cross-validated AUC = 0.836) than either metagenomic (cross-validated AUC = 0.745) or metabolomic (cross-validated AUC = 0.820) analysis alone. Among the top plasma biomarkers differentiating ME/CFS patients from controls were decreased levels of betaine, complex lipids (lysophosphatidylcholine (LPC), phosphatidylcholine (PC) and sphingomyelin (SM), and increased levels of triglycerides (TG), α-N-phenylacetyl-glutamine, εcaprolactam and urobilin. The authors concluded that identification of ME/CFS subgroups characterized by specific metabolomic profiles that integrate primary metabolites, biogenic amines, complex lipidomics and oxylipins may enable delineation of subtypes and lead to specific diagnostic and therapeutic strategies. The study was published on July 3, 2018, in the journal Scientific Reports. LabMedica International October/2018

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Biomarker Discovered for Hypervirulent Pathogen cont’d from cover

that infects completely healthy people and can cause blindness in one day and flesh-eating infections, brain abscesses and death in just a few days. An international team of scientists led by those at the University at Buffalo (Buffalo, NY, USA; www.buffalo.edu) identified a biomarker to differentiate hvKp from cKp strains they chose to use clinical data to develop strain cohorts for evaluation, given that the inclusion of any bacterial genotypic or phenotypic information in the definition of strain cohorts could introduce bias. The hvKp-rich cohort consisted of 85 strains isolated from deidentified patients from Taiwan and the USA. Since most K. pneumoniae infections in the North America and the UK presumably are due to cKp strains, the 90 cKp-rich strain cohort was generated from randomly chosen, deidentified blood isolates from different countries. Study isolates were assessed for the presence of 10 genes and markers for capsule types. These included several genes located on the virulence plasmid, which have been shown experimentally to contribute to hypervirulence in in vivo infection models. Two hypothetically discriminatory phenotypic traits were evaluated. Polymerase chain reactions (PCR)based detection of various capsule types were performed using the Applied Biosystems GeneAmp PCR system 9700 instrument (Foster City, CA, USA; www.appliedbiosystems.com). The scientists found that the genes peg-344, iroB, iucA, prmpA, and prmpA2 all demonstrated >0.95 diagnostic accuracy for identifying strains in the hvKp-rich cohort. Quantitative siderophore production of ≥ 30 μg/mL also strongly predicted strains as members of the hvKprich cohort (accuracy 0.96) and exhibited a hazard ratio of 31.7 for severe illness or death. The string test, a widely used marker for hvKp strains, performed less well, achieving an accuracy of only 0.90. Thomas A. Russo, MD, a professor of medicine and senior author of the study said, “The advantage of identifying these genetic biomarkers is that they can be developed into rapid nucleic acid tests, and if approved by the US Food and Drug Administration, would then provide clinicians with an accurate method to quickly determine if a patient is suffering from an infection due to the classical or hypervirulent strain.” The study was published on June 20, 2018, in the Journal of Clinical Microbiology. Image: A human neutrophil (grey) is interacting with Klebsiella pneumoniae (pink). A hypervirulent version of this pathogen is sparking increasing concern due to recent reports describing hypervirulent strains that are antimicrobial resistant (Photo courtesy of National Institute of Allergy and Infectious Diseases).

LabMedica International October/2018

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LabMedica International

PRODUCT NEWS LAB MIXER

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AUTO IFA MICROSCOPE

URINE ANALYZER

Kabe Labortechnik

Inova Diagnostics

Erba Mannheim

The KABE-mixer BM 24 mixes blood sedimentation tubes and optional EDTA tubes for analyses. It has a sample plate with 24 clips and can be equipped with a sample plate with an additional holding ring for tubes with a 1016mm diameter.

The NOVA View is a microscope combined with a digital imaging system that reads and archives images of IFA-stained slides. It uses digital IFA technology to acquire and display digital images for analysis, helping to reduce transcription errors.

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

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Parent Age May Help Predict Alzheimer Biomarker Levels lzheimer disease (AD) develops during several decades and presymptomatic individuals might be the best candidates for clinical trials, but their identification is challenging because they have no symptoms. Asymptomatic people with a family history of sporadic AD were more likely to show abnormal cerebrospinal fluid and brain amyloid- biomarkers as they neared their parent’s onset age, indicating that proximity to parental symptom onset may help predict amyloid- biomarker changes. A team of scientists led by those at McGill University (Montreal, QC, Canada; www.mcgill.ca) analyzed amyloid-1-42 (Aβ1-42) in cerebrospinal fluid (CSF) specimens from 101 cognitively unimpaired individuals enrolled in the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) cohort from September 1, 2011, through November 30, 2016. Along with a subset of the 101 PREVENT-AD participants, analysis included 128 Adult Children Study (ACS) participants (112 of whom underwent CSF measurement and 107 of whom underwent Pittsburgh compound B carbon 11–labeled positron emission tomography (PIB-PET) and 135 Wisconsin Registry for Alzheimer Prevention (WRAP) participants (85 of whom underwent CSF measurement and all of whom underwent PIB-PET).

The scientists found that PREVENT-AD participants nearing their parent’s Alzheimer’s disease onset age had lower CSF amyloid-1-42 levels; this relationship was stronger in APOE4 carriers and women. Among ACS participants, the team observed the same association using PIB-PET data, and using CSF and PIB-PET data also replicated the female sex interaction. Although the findings were not replicated using cross-sectional data among WRAP participants, the link between parent’s Alzheimer’s disease onset age and CSF amyloid- levels and the APOE interaction were replicated using PIB-PET longitudinal data. Sylvia Villeneuve, PhD, the lead author of the study, said, “The best time window to prevent Alzheimer’s disease is likely when individuals are still asymptomatic, before extensive neuronal degeneration has occurred. Identifying asymptomatic individuals is challenging and expensive, posing significant difficulties for the current generation of clinical trials. In autosomal dominant Alzheimer’s disease, symptom onset is determinable across generations.” The authors concluded that their results suggest that proximity to parental symptom onset may help estimate Aβ biomarker changes in women or APOE4 carrier asymptomatic individuals with a parental history of sporadic AD. The study was published on February 26, 2018, in the journal JAMA Neurology.

Solvatochromic Trehalose Probe Rapidly Detects TB espite its devastating toll on health, the bacteria causing tuberculosis (TB), Mycobacterium tuberculosis, can be hard to spot. Current tests rely on chemical stains and estimates put the sensitivity of these stains anywhere from 32% to 94%. Better detection methods are sorely needed to combat TB, which killed more than 1.7 million people worldwide in 2016. A new staining technique has been developed that is quick and simple and detects the pernicious bacteria that are a major cause of deadly lung infection that is particularly common in developing countries. A team of international scientists led by those at Stanford University (Stanford, CA, USA; www.stanford.edu) designed a color-changing dye based on trehalose, a sugar that makes up the outer membrane of M. tuberculosis. The dye stained live bacteria within minutes, emitting fluorescence upon incorporation into the hydrophobic mycobacterial membrane. Heat-inactivated bacteria did not fluoresce, and drug-treated bacteria emitted reduced fluorescence. The designed 4-N,N-dimethylamino-1,8-naphthalimide–conjugated trehalose (DMN-Tre) probe undergoes >700-fold increase in fluorescence intensity when transitioned from aqueous to hydrophobic environments. This enhancement occurs upon metabolic conversion of DMNTre to trehalose monomycolate and incorporation into the mycomem-

brane of Actinobacteria. DMN-Tre labeling enabled the rapid, no-wash visualization of mycobacterial and corynebacterial species without nonspecific labeling of Gram-positive or Gram-negative bacteria. Microscopy was performed on a Nikon A1R confocal microscope equipped with a Plan Fluor 60× oil immersion 1.30–numerical aperture objective. In tests on sputum samples from 16 people with TB, DMN-Tre picked up M. tuberculosis cells in all of the samples. The new technique performed similarly to the standard, but more complex and time-consuming, labeling method based on the Auramine O stain, a dye that sticks to acids in bacterial cell walls. Human cells and other types of bacteria, both of which are plentiful in sputum samples, do not incorporate the molecule. Unlike existing TB detection methods, DMN-Tre can also distinguish cells that are metabolically active from those that are not. Because the molecule relies on bacteria to actively incorporate it into the membrane, only healthy cells are labeled, whereas cells that are compromised by drug treatment do not label as well. That property may allow clinicians to monitor how well treatments are working in people, and perhaps even test whether certain mixtures of drugs would work against specific strains of M. tuberculosis. The study was published on February 28, 2018, in the journal Science Translational Medicine. LabMedica International October/2018

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LABORATORY SOFTWARE

DIGITAL SLIDE SCANNER

Quantimetrix

Randox Laboratories

Roche Diagnostics

The Dropper is used to monitor the performance of routine and stat urine chemistry assay methods. Designed for use with most major chemistry analyzers, its easy-to-use dropper bottle provides simple dispensing and maximum use.

The Acusera 24-7 assists labs in the management of QC data and has the unique ability to provide peer group data instantly in RT. The software is able to speed up troubleshooting and aid laboratories as they strive for accreditation.

The VENTANA DP 200 offers excellent image quality to enhance pathologistsâ&#x20AC;&#x2122; review of digital slides. The scannerâ&#x20AC;&#x2122;s low-volume capacity is well-suited for first-time digital pathology users, remote site scanning, frozen section scanning and more.

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Urine Particle Analyzer Compared with Standard Methods rinary tract infections (UTIs) are characterized by the presence of microbial pathogens within the urinary tract, and they represent one of the most common infections identified in both hospitalized and clinic patients. Most UTIs are easily treated without difficulty. In certain patient populations, such as children, pregnant women, and the elderly, significant complications may arise. The symptoms observed with UTIs are diverse and can range from mild irritation with voiding to bacteremia or even sepsis. When sepsis is present, it can lead to death if it is not diagnosed and treated early. Medical scientists working at Prescient Medicine (Hummelstown, PA, USA; www. prescientmedicine.com) and their colleagues compared data from urine samples collected in sterile containers for bacterial culture and microscopic analysis during a 3-month period in a laboratory at a 572-bed, acute-care hospital. Upon receipt, one sample was used to inoculate a 5% sheep blood agar and a MacConkey agar plate with a 0.001-mL calibrated loop. The second sample was analyzed for bacteria and leukocytes with the Sysmex UF-1000i urine analyzer (Sysmex Corporation, Kobe, Japan; www.sysmex.com) which is a fully automated, fluorescent flow cytometer that categorizes red blood cells, white blood cells, epithelial cells, small round cells, sperm cells, crystals, and pathologic and hyaline casts, yeast, and bacteria. The second sample was also analyzed by urinalysis-associated microscopy for the presence of epithelial cells, leukocytes, yeast, and bacteria. Urine cultures showed no growth in 2,034 samples (50%) and growth of less than 104 colony-forming units (CFUs)/mL in 1,812 samples (45%). Of the 4.033 results, 754 sam-

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ples (19%) showed bacterial growth of 105 CFUs/mL or more, and 190 samples (5%) were considered contaminated specimens because they contained multiple species. However, if the growth of bacteria exceeded the definition of a negative result, they were considered to be positive, even though the likelihood of a UTI was low in those patients. Of the culture-positive samples, the most commonly identified microorganisms were Escherichia coli and Klebsiella spp, which is consistent with known epidemiologic data. Of the 4,033 unique urine samples obtained from adult patients, 2,736 (67.8%) specimens had positive white blood cell counts and bacteria and 1,215 (30.1%) specimens had negative white blood cell counts and bacteria as reported by the UF-1000i. The negative predictive value for any positive culture in the adult population included in the study was 95.5%, and the negative predictive value for positive cultures containing growth of 100,000 or more CFUs was 99.3% using the Sysmex UF-1000i. There were 373 unique urine specimens collected in pediatric patients and using the UF-1000i method, 269 specimens (72%) had positive white blood cell counts and bacteria, and 104 (27.9%) tested negative for an elevation in white blood cell counts and bacteria. The authors concluded that the Sysmex UF-1000i showed 98% sensitivity and 93.7% specificity with a 95.5% negative predictive value. Thus, a negative screen with the UF1000i using defined thresholds for white blood cell counts and bacteria was likely to be a true negative, decreasing the need for presumptive antibiotics. The study was published in the November 2017 issue of the journal Archives of Pathology & Laboratory Medicine. LabMedica International October/2018

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BLOOD ANALYSIS SYSTEM

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Sebia

Siemens Healthineers

B&E Scientific

The CAPILLARYS 3 MC2 provides highthroughput testing for HbA1c or protein electrophoresis. It combines two CAPILLARYS 3 instruments with a high-capacity tube loader and provides accurate results for both HbA1c and protein assays.

The epoc offers real-time, lab-quality results at the patient’s side. Its room temperature, single-use test cards simplify management of reagents, maximize efficiencies and provide results for a full panel of tests in less than one minute.

The CBS-500 uses multi-biosensor technology for maintenance-free electrode and pressure sensor technology for TCO2 measurement. It features multi-level calibrators/controls for accurate results and can store up to 1,000 sample results.

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Link Identified Between Inflammation and Depression t is well established that people with both type-1 and type-2 diabetes have an increased risk of developing depression, a debilitating mental health disorder with potentially serious consequences, but the causes remain poorly understood. Depression in type-1 diabetes patients is associated with higher levels of the inflammatory protein galectin-3, which is a key protein involved in promoting inflammatory immune system responses that are needed to repair tissue damage throughout the body, in response to injury or disease. Scientists at Lund University (Lund, Sweden; www.lunduniversity. lu.se) and their colleagues carried out a cross-sectional study that included 283 type-1 diabetes (T1D) patients (56% men, age 18-59 years, diabetes duration ≥1 year). Depression was assessed by Hospital Anxiety and Depression Scale depression subscale. Blood samples, anthropometrics and blood pressure were collected, supplemented with data from medical records and the Swedish National Diabetes Registry. Galectin-3 was analyzed using a commercial human DuoSet enzyme linked immunosorbent assay (ELISA) and supplementary ancillary kit (R&D Systems, Minneapolis, MN, USA; www.rndsystems.com). The ELISA analysis was performed and absorbance was measured at 450580 nm in a FLOUstar optima plate reader (BMG Labtech Gmbh, Ortenberg, Germany; www.bmglabtech.com). Concentrations of un-

known samples were calculated using a four parameter logistic regression curve. The intra-assay coefficient of variation for the analysis was 4.3%. Galectin-3 levels equal to or greater than. 2.562 μg/L, corresponding to the 85th percentile, was defined as high galectin-3. The scientists found that the median (quartile1, quartile3) galectin-3 was 1.3 μg/L (0.8, 2.9) for the 30 depressed patients, and 0.9 μg/L (0.5, 1.6) for the 253 non-depressed. Depression was associated with high galectin-3 in all the 283 patients (Adjusted odds ratio (AOR) 3.5), in the 161 men (AOR 3.4), and in the 122 women (AOR 3.9). HbA1c, serum-lipids, serum-creatinine, blood pressure, obesity, smoking, physical inactivity, cardiovascular complications, and drugs (antihypertensive, lipid lowering, oral anti-diabetic drugs, and antidepressants) were not associated with high galectin-3. The authors concluded that their study was the first to show an association between depression and galectin-3. Depression was the only explored parameter associated with high circulating galectin-3 levels in 283 T1D patients. High galectin-3 levels might contribute to the increased risk for Alzheimer’s disease, cardiovascular and all-cause mortality observed in persons with depression. Potentially, in the future, treatment targeting galactin-3 might improve the prognosis for patients with high galectin-3 levels. The study was published on May 14, 2018, in the journal Endocrine Connections.

Tool Predicts Deadly Form of Mycosis Fungoides ycosis fungoides (MF), the most common cutaneous T cell lymphoma (CTCL) is a malignancy of skin-tropic memory T cells. Most MF cases present as early stage (stage I A/B, limited to the skin), and these patients typically have a chronic, indolent clinical course. However, a small subset of early-stage cases develops progressive and fatal disease and because outcomes can be so different, early identification of this high-risk population is an urgent unmet clinical need. If identified early, patients with this aggressive form of MF may be eligible for a stem cell transplant to cure the disease, but once MF progresses and becomes treatment-resistant, it is nearly impossible to achieve the complete remission required for a successful stem cell transplant. Scientists from the Brigham and Women’s Hospital (Boston, MA, USA; www.brighamandwomens.org) and their colleagues evaluated the use of next-generation high-throughput DNA sequencing of the T cell receptor gene (TCRB) in lesional skin biopsies to predict progression and survival in a discovery cohort of 208 patients with CTCL (177 with MF) from a 15-year longitudinal observational clinical study. They compared these data to the results in an independent validation cohort of 101 CTCL patients (87 with MF).

The team used high-throughput DNA sequencing, a technique that allowed them to sequence massive amounts of DNA at once, producing a snapshot of the TCRB genes from a large number of cells at the site of the lesion. The team could use this to measure “tumor clone frequency (TCF)” – the percentage of T cells that are clones of the mutated MF lymphoma T cells. An elevated TCF predicted the likelihood of progression and overall survival of patients with MF with high sensitivity and specificity. Thomas S. Kupper, MD, a professor of Dermatology and senior author of the study, said, “Under the microscope, benign T cell and MF T cells are hard to distinguish. However, every T cell has a unique DNA sequence of its T cell receptor, which we can detect by high-throughput DNA sequencing. High throughput DNA sequencing and calculations of TCF allow us to make predictions that would never before have been possible. As a physician who has treated patients with this disease for decades, I am excited to be involved with work that so directly and profoundly affects the care and management of these patients.” The study was published on May 9, 2018, in the journal Science Translational Medicine. LabMedica International October/2018

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ANTIGEN MULTIKIT

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Sclavo Diagnostics

ELITech Group

The Prietest TOUCH provides access to more than 200 tests through test keys, RT graph with online reading and multi-standard calibration & memory. Other features include maintenance-free pump, long lamp life and triple cuvette system.

The Febrile Antigen Multikit diagnoses Typhoid, Brucellosis, Rickettsiosis and Listeriosis. It allows for simultaneous application of three techniques, and provides unequivocal readings in both rapid slide tests and microplate titrations.

The Aerospray Hematology Stat Series 2 has a quick stain cycle with slides ready for the microscope in four minutes. Staining is reproducible between stain cycles, resulting in textbook-quality staining with trouble-free operation.

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Leprosy Neural Impairment Diagnosis Evaluated by Tests eprosy is a chronic infectious disease caused by Mycobacterium leprae, an obligate intracellular parasite with a predilection for infecting peripheral nerves and skin. Leprosy is a current and challenging disease, because it still represents a problem for public health in developing countries. Despite the apparent progress observed in recent years in leprosy control, early identification of cases remains one of the primary objectives of control programs. The long incubation period of leprosy, its insidious symptoms and signs make the diagnosis difficult. The predominance of multibacillary (MB) cases with neural disabilities indicates late diagnosis, reinforcing the ineffective epidemiological control in many countries. Scientists at the Federal University of Uberlândia (UFU, Uberlândia, Brazil; www.ufu.br) and their colleagues recruited 175 seropositive and 35 seronegative household contacts from 2014 to 2016, who were subjected to an extensive protocol that included clinical, molecular (peripheral blood quantitative polymerase chain reaction (qPCR), slit-skin smear qPCR, skin biopsy qPCR) and electroneuromyographic evaluations. Enzyme-linked immunosorbent assay (ELISA) was performed on all household contacts. Serum anti-phenolic glycolipid I (PGL-I) IgM an-

tibodies were detected by enzyme-linked immunosorbent assay (ELISA) performed against the purified native PGL-I from the M. leprae cell wall. The quantitative real-time PCR (qPCR) assay targeting M. leprae DNA was performed by targeting the bacillus-specific genomic region (RLEP) in a real-time PCR system (ABI 7300, Applied Biosystems, Foster City, CA, USA; www.appliedbiosystems.com). The investigators found that the positivity of peripheral blood qPCR of seropositive contacts was 40.6% (71/175) whereas only 8.6% (3/35) were qPCR positive in seronegative contacts. For the slit-skin smear, only 4% (7/175) of seropositive contacts presented positive bacilloscopy, whereas the qPCR detected 47.4% (83/175) positivity in this group compared with only 17.1% (6/35) in seronegative contacts. Seropositive contacts presented a 4.04-fold higher chance of neural impairment. The peripheral blood qPCR positivity presented odds of 2.08-fold higher towards neural impairment. Contrarily, the presence of at least one BCG vaccine scar demonstrated 2.44-fold greater protection against neural impairment (OR = 0.41). The study was published on May 21, 2018, in the journal Public Library of Science Neglected Tropical Diseases.

Earlier Measurements Offer Quicker Treatment for Sepsis epsis remains a significant cause of morbidity and mortality in the USA, leading to the implementation of the Severe Sepsis and Septic Shock Early Management Bundle (SEP-1). SEP-1 identifies patients with “severe sepsis” via clinical and laboratory criteria and mandates interventions, including lactate draws and antibiotics, within a specific time window. Because of a known association between elevated lactate levels and increased mortality, sepsis guidelines mandate that lactate levels should be tested soon after the onset of sepsis. A new study found that a significant proportion of patients with suspected sepsis do not have their lactates measured within the recommended timeframe. Medical scientists at the University of Chicago (Chicago, IL, USA; www.uchicago.edu) reviewed the records of close to 150,000 patients admitted to a single tertiary care academic hospital from November 2008 to January 2016. Information regarding each patient’s characteristics, vital signs, laboratory measurements, and medical therapy was analyzed. There was a particular focus on lactate measurements and levels. The team identified 5,762 admissions that met the three SEP-1 criteria for severe sepsis within a six-hour period. Of these, only 60% had an initial lactate drawn within the SEP-1 specified timeframe. The team reported that 14% had their levels measured between three and 24 hours after the time of first suspicion of sepsis (“delayed lactates”), and more

than one quarter had no lactate measurements at all. Whether lactates were measured promptly varied with where the patient was being treated; 79% of patients treated in the emergency department had levels measured within the specified time period compared with 55% in the intensive care unit (ICU) but only 32% in hospital wards. Patients with delayed lactate measurements demonstrated the highest in-hospital mortality at 29%, with increased time to antibiotic administration (median time, 3.9 hours versus 2.0 hours). Patients with initial lactates greater than 2.0 mmol/L demonstrated an increase in the odds of death with hourly delay in lactate measurement (odds ratio = 1.02). The authors concluded that delays in lactate measurement are associated with delayed antibiotics and increased mortality in patients with initial intermediate or elevated lactate levels. Matthew M. Churpek, MD, MPH, PhD, an Assistant Professor of Medicine and lead investigator of the study, said, “Systematic early lactate measurements in patients presenting with sepsis would result in a significant increase in the number of lactates measured on patients but may be of benefit in identifying patients with elevated initial lactates who are at risk for poorer outcomes. Patients with early lactate measurements received earlier interventions such as antibiotic administration, which is known to improve mortality in sepsis.” The study was published on May 24, 2018, in the journal CHEST. LabMedica International October/2018

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LabMedica International

Vitamin D Blood Test May Speed Pediatric Bipolar Diagnosis ajor mood disorders (MMD), specifically bipolar disorder (BD) and major depressive disorder (MDD), are some of the most prevalent albeit under-diagnosed health problems in children and adolescents. Worldwide among adolescents, MDD and BD are the first and fourth most disabling conditions, respectively. A blood test may have the potential to speed accurate diagnosis and proper treatment of bipolar disorder in children. It has been reported that children with bipolar disorder had higher blood levels of a protein associated with vitamin D compared to children without mood disorders. A blood test to confirm bipolar disorder could improve care and cut the current 10-year average lag time between onset and diagnosis. Scientists from The Ohio State University (Columbus, OH, USA; www.osu.edu) collected plasma samples from 36 participants in a study that were grouped into three categories: 13 non-mood controls, 12 bipolar (BD) and 11 major mood disorders (MDD). Concentrations of inflammatory cytokine interleukin-6 (IL-6), autoantibodies to oxidized low-density lipoprotein (oxLDL), and vitamin D in serum as well as serum nuclear factor kappa-light-chain-enhancer of activated B cells (NF B) activity were measured and analyzed in conjunction with metabolic characteristics (body mass index (BMI)). Vitamin D (25-hydroxycalciferol and 25-hydroxyergocalciferol) analysis on serum was performed by highpressure liquid chromatography (HPLC) coupled with mass spectrometry (MS) detection. The cumulative NF B activation potential of plasma was measured using NF- B/green fluorescence protein biosensor assay on a Synergy H1 Hybrid Multi-Mode Microplate Reader (BioTek, Winooski, VT, USA; www.biotek.com). IL-6 serum concentrations were analyzed using Immulite 1000 IL-6 assay (Siemens Healthcare Diagnostics, Deerfield, IL, USA; www.healthcare. siemens.com). Human IgG autoantibodies to oxidized low-density lipoproteins (oxLDL) in serum were measured using an Anti-Oxidized LDL (oLAB) ELISA Kit (Biomedica, Vienna, Austria; www.bmgrp.at). To identify potential biomarkers, the team developed a screening immunoprecipitation-sequencing approach based on inflammatory brain glia maturation factor beta (GMFβ). They discovered that a homolog of

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GMFβ in human plasma is vitamin D-binding protein (DBP) and validated this finding using immunoprecipitation with anti-DBP antibodies and mass spectrometry/sequencing analysis. They quantified DBP levels in participants by western blot. DBP levels in BD participants were significantly higher than in participants without MMD. DBP measured by monoclonal ELISA also showed no correlation with vitamin D concentration in serum in non-mood control. However, in MDD participants, but not in BD participants DBP levels recognized by polyclonal ELISA were inversely associated with vitamin D levels. The authors concluded that DBP holds promise as a diagnostic biomarker changing in response to all major factors contributing to pathogenesis of BD, and may shed light on BD pathophysiologic mechanisms. Barbara L. Gracious, MD, associate professor of clinical psychiatry and nutrition and a lead study co-author, said, “Childhood bipolar disorder can be very difficult to distinguish from other disorders, especially in youth with certain types of depression. Prompt diagnosis and appropriate treatment alleviates the suffering of the child and family, and can potentially lessen the risk for suicide.” The study was published on March 13, 2018, in the journal Translational Psychiatry.

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PRODUCT NEWS COAGULATION ANALYZER

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LAB ANALYZER

MULTIPLEX READER

Rayto Life and Analytical Sciences

Diasorin

Gold Standard Diagnostics

The RT-2204C four-channel analyzer uses the scattered light principle and offers percentage analysis. It offers four different parameter analysis with three kinds of QC levels and has a large memory.

The LIAISON XL performs complete sample processing, as well as measurement and evaluation. It adopts the “Flash” chemiluminescence technology with paramagnetic microparticle solid phase and optimizes throughput.

The FIDIS Multiplex Reader allows simultaneous and specific detection of multiple analytes from the same sample in a single assay. It allows labs to perform analysis more rapidly and at lower cost than with conventional kit formats.

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New Dipstick Rapidly Detects Cholera in Acute Diarrhea holera is an acute watery diarrheal disease caused mainly by Vibrio cholerae serogroup O1 and less commonly by V. cholerae O139. Cholera can lead to severe diarrhea and death if untreated. Recognizing cholera cases early, especially in the initial phase of an outbreak and in areas where cholera has not previously circulated, is a high public health priority and laboratory capacity in such settings is often limited. Globally, 3 to 5 million cases and over 100,000 deaths occur annually due to cholera. An international team of scientists working with the International Centre for Diarrhoeal Disease Research (Dhaka, Bangladesh; www. icddrb.org) collected fresh stools from 76 hospitalized adults and children at the Dhaka Hospital who presented with acute watery diarrhea. They performed conventional stool culture by streaking stool directly on selective TTGA (taurocholate-tellurite gelatin agar) plates, and incubated these plates overnight at 37 °C. Colonies morphologically consistent with V. cholerae were analyzed by slide agglutination with monoclonal antibodies specific to V. cholerae serovar O1 (Ogawa or Inaba) and O139. The team compared their recently developed rapid diagnostic test (RDT) termed Cholkit that is

based on an immunochromatographic lateral flow assay for the diagnosis of cholera cases using stool with the commercially available RDT, Crystal VC (Span Diagnostics; Surat, India; http://spandiag.com) and a polymerase chain reaction (PCR) targeting the rfb and ctxA genes of V. cholerae. The scientists reported that stool specimens from 76 patients were tested by all four of microbial culture, Cholkit, Crystal VC and PCR assays. Nineteen samples were positive by culture and all of them were confirmed as positive for V. cholerae O1 Inaba except one sample that was V. cholerae O1 Ogawa. Out of 19 stools positive by culture, all 19 (100%) were positive by both Cholkit and Crystal VC assays, and 15 (79%) were positive by PCR. Of all of the 57 patients with a negative stool culture Cholkit, Crystal VC and PCR were positive for 11 (19%), 12 (21%), and 6 (11%), respectively. The authors concluded that the Cholkit dipstick is simple to use, requires no dedicated laboratory capacity, and has a sensitivity and specificity for V. cholerae O1 of 98% and 97%, respectively. The study was published on March 14, 2018, in the journal Public Library of Science Neglected Tropical Diseases.

Helicobacter Pylori Immunoassays Evaluated for Efficacy elicobacter pylori are curved gram negative bacilli and have been etiologically associated with several pathogenic conditions of the stomach ranging from gastritis to gastric cancer. Prevalence of H. pylori infection varies based on several factors globally and in developing countries more than 80% of the population is infected with H. pylori. Helicobacter pylori antibody titers fall very slowly even after successful treatment. Therefore, tests detecting H. pylori antibody lack specificity and sensitivity. On the other hand, H. pylori stool antigen tests are reported as an alternative assay because of their reliability and simplicity. Serology is a widely available and inexpensive test but with low diagnostic accuracy. On the other hand, the H. pylori stool antigen (HpSA) test has been put in the market as optional technique because of its reliability and simplicity. Medical scientists at the University of Gondar (Gondar, Ethiopia; www.uog.edu.et) conducted a cross sectional study on patients with dyspepsia from February to March 2015 attending the medical outpatient department of the University Hospital. Stool and blood specimens were collected from each patient for serologic tests. The blood was centrifuged until serum was separated and stored at –20 °C. The stool specimens were also stored at –20 °C until the laboratory tests were performed. A total of 201 dyspeptic patients were included in the study of which 140 (69.7%) were males and 60 (30.3%) were females. The age of the par-

ticipants ranged from 7 to 85 years with a mean age of 29.5 ±14.85 years. The team evaluated the performance of SD BIOLINE H. pylori Ag rapid test (Standard Diagnostics, Yongin, South Korea; www.alere.com) with reference to the commercially available SD BIOLINE H. pylori Ag ELISA and the EZ- STEP ELISA (DINONA, Inc, Seoul, Seoul, Korea; www.dinonainc. com) tests. The dBest H. pylori Test Disk (Ameritech Diagnostic Reagent Co Ltd, Tongxiang, China; www.ameritek.com.cn) was also evaluated. The team found that 75 (37.1%) of the participants were positive by the SD BIOLINE H. pylori Ag rapid test, while 92 (45.8%) were positive by the SD H. pylori Ag ELISA. The EZ-STEP H. pylori Ag ELISA detected 81 (40.3%) of the samples as positives for H. pylori infection. On the other hand, 68 (33.8%) were positive using both ELISA tests. The dBest H. pylori Test disk detected 143(71.1%) of the samples as positive. The sensitivity, specificity, positive and negative predictive values of the SD BIOLINE H. pylori Ag rapid test were: 95.6%, 92.5%, 86.7%, and 97.6%, respectively. The authors concluded that The SD BIOLINE H. pylori Ag rapid test has a much better sensitivity, specificity and predictive values compared to the currently available antibody test in the market, in Ethiopia. Therefore, the SD BIOLINE H. pylori Ag rapid stool test could be used to diagnose active H. pylori infection before the commencement of eradication therapy. The study was published on March 5, 2018, in the journal BMC Clinical Pathology. LabMedica International October/2018

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CHEMISTRY SYSTEM

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Siemens Healthineers

Biomerieux

The Xevo TQ-S reduces complexity and increases ease of use. It is intended to offer clinical laboratories access to the selectivity, sensitivity, and versatility of LC-MS/MS analysis not seen using traditional techniques.

The Dimension Xpand Plus combines chemistry, STAT and specialty testing in a single, compact, easy-to-use system. It offers fullrange integrated capability in a small footprint, along with improved workflow efficiency.

The NUCLISENS MINIMAG is designed for total NA amplification from various specimens. It can process 1 to 12 samples, allows for parallel processing of different sample types in one run and can undertake 12 extractions in one hour.

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Dried Blood Spot Protein Assays Evaluated for Biochemistry ried blood spots have long been used in applications like newborn testing, but they have yet to make their way into clinical proteomic testing in a significant way. This is due in part to the fact that conventional immunoassays, which are widely used for protein measurements in the clinic, are poorly suited to analyzing dried blood spots given their limited sample volume. Typically consisting of microliter volumes of blood spotted and dried on filter paper, dried blood spots offer potentially significant advantages compared to traditional blood draws. For instance, because dried blood spots use a finger prick as opposed to conventional phlebotomy, patients could conceivably draw samples themselves without needing to visit a doctor’s office. Scientists at the University of Victoria-Genome BC Proteomics Centre (Victoria, BC, Canada; www.proteincentre.com) found that dried blood spot samples might be somewhat less stable than thought. They looked at the stability of 21 amino acids under various conditions, finding that a number of amino acids were degraded due to heat and humidity with histidine and tryptophan among the most affected. A team at the University of Washington (Seattle, WA, USA; www.washington.edu) developed mass spec-based dried blood spot assays to glycated hemoglobin-β (HbA1c), apolipoprotein A-I, and apolipoprotein B and compared them to existing clinical assays (immunoassays for ApoA-1 and ApoB and HLPC-

UV for HbA1c) using conventional plasma and whole blood samples. This team analyzed samples from 36 patients, and found a large discrepancy between the values they were getting from the dried blood spots and the conventional plasma samples. They also found a discrepancy between whole blood drawn via venipuncture and then spotted to make dried blood spots and paired capillary dried blood spot samples. Scientists at SISCAPA Assay Technologies (Washington, DC, USA; www.siscapa.com) have developed a fully automated mass spec workflow for running dried blood spot samples, and the objective in the near term they will implement multiplex panels of existing clinical analytes as laboratory-developed tests offered out of a CLIA facility. N. Leigh Anderson, PhD, CEO of SISCAPA, said, “We are getting total workflow CVs with replicate dried blood spot samples on the order of 2%, and they calibrate very tightly with the clinical assays done on serum at the same time. We want more volume than [is provided by] one dried blood spot. We would like to have 100 to 150 μL of whole blood. And we really want the volume precision to be 1 or 2 percent instead of 4 or 5 or 10%, which is what it typically is now. Our assays are good to 2%, and so we don’t want to lose our precision just based on the volume of sample.” The studies were presented at Mass Spectrometry: Applications to the Clinical Lab (MSACL) meeting held January 21 - 25, 2018, Palm Springs, CA, USA.

Continuous Glucose Monitor Benefits Diabetics ontinuous glucose monitors (CGM) offer significant, daily benefits to people with type 1 diabetes, providing near-real time measurements of blood sugar levels, but they can be expensive. A continuous glucose monitor uses a tiny sensor inserted under the skin to test blood sugar levels every few minutes throughout the day and wirelessly sends those data to a monitor. The first generation of CGMs transmitted data to a stand-alone electronic device that looks like a pager, but newer models can work with apps on smartphones and smartwatches. Scientists at the University of Chicago Medicine (Chicago, IL, USA; www.uchospitals.edu) carried out a randomized trial of 158 patients with type 1 diabetes who relied on multiple, daily injections of insulin, but not an insulin pump. Two-thirds of the group used CGMs, and the remaining third used the finger prick method with test strips and a meter to check their blood sugars. Participants were surveyed at baseline and six months and had hemoglobin A1C equal to or greater than 7.5%. Within-trial and lifetime cost-effectiveness analyses were conducted. At the end of the six-month trial, the total health care costs of using a CGM was USD 11,032, compared to USD 7,236 for manual testing. The

cost differences were mostly due to the upfront cost of the CGM device (Dexcom G5, San Diego, CA, USA; www.dexcom.com) of about USD 2,500, but the CGM group saw statistical reductions in their HBA1c levels (0.60 ± 0.74% difference in difference), a common measure of blood sugar control, and experienced fewer non-severe low blood sugar events. The team also used a statistical model to simulate costs and health effects of CGM use over the average expected lifetime of patients. The model calculated a value called quality-adjusted life years (QALYs) for each patient, which represents the amount of time they live free of any complications or serious medical incidents. In the lifetime analysis, the CGM was projected to reduce the risk of complications from type 1 diabetes and increase QALYs by 0.54, basically adding six months of good health. Elbert S. Huang, MD, Associate Director of the Chicago Center for Diabetes Translation Research, and senior author of the study, said, “Based on this analysis, the CGM looks like a very valuable technology, one that doesn’t cause harm and makes people’s lives better. Hopefully, this will become an important part of the decision-making process to make the CGM available to more people.” The study was published on April 12, 2018, in the journal Diabetes Care. LabMedica International October/2018

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LabMedica International

Biological Markers in Tears May Diagnose Parkinson’s arkinson’s disease is a progressive disorder that kills brain cells that produce dopamine, which is a chemical messenger important for the control of movement. The main symptoms of Parkinson’s include slowness of movement, tremors, rigidity, and difficulty maintaining balance and coordination. Tear samples from individuals with Parkinson’s disease (PD) had different levels of a protein linked to the disease than those who did not have it. Such a marker could be very useful in helping to diagnose, and perhaps even treat Parkinson’s because the disease can begin many years before its symptoms appear. Scientists at the University of Southern California (Los Angeles, CA, USA; www.usc.edu) and their colleagues compared tear samples from 55 PD patients of varying severity and 27 age- and gendermatched non-PD controls were collected and pooled from both eyes for analysis of alpha synuclein, CC chemokine ligand 2 (CCL-2) and DJ-1 (Parkinson’s disease protein 7) using a Human magnetic Luminex assay kit (R&D systems, Minneapolis, MN, USA; www.rndsystems.com) and analysis of oligomeric alpha-synuclein using an Human alpha-synuclein oligo enzyme-linked immunosorbent assay (ELISA) kit (MyBioSource, San Diego, USA; www.mybiosource.com), respectively. The team revealed that total alphasynuclein decreased significantly in PD patients (423.12 ± 52.6 pg/mg tear protein) relative to healthy controls (703.61 ± 136.4 pg/mg tear protein) in tears from patients acquired from Schirmer’s strips taken during an anesthetized Schirmer’s test. Oligomeric alpha-synuclein increased significantly in PD patients (1.45 ± 0.31 ng/mg tear protein) relative to controls (0.27 ± 0.07 ng/mg tear protein). While detectable in tears, neither CCL-2 nor DJ-1 varied between PD patients and non-PD controls. While it is not yet clear how Parkinson’s disease kills brain cells, scientists have discovered that toxic protein deposits known as Lewy bodies are often present in many brain cells of people with the disease. These deposits contain clusters of proteins that have not folded correctly. A major component of Lewy bodies is an oligomeric form of the protein alpha-synuclein. The oligomeric form of a protein comprises several repeats of the protein’s essential amino acids, but not as many as the polymeric form. An author of a re-

LabMedica International October/2018

cently published study of alpha-synuclein in Parkinson’s has suggested that the oligomeric protein’s ability to “disrupt the integrity of the membrane” might be a key step in the process that ultimately kills the cell. Mark F. Lew, MD, a professor of Neurology and lead investigator in the study, said, “We believe our study is the first to show that tears may be a reliable, inexpensive, and noninvasive biological marker of Parkinson’s disease.” The study will be presented at the 70th annual meeting of the American Academy of Neurology, which will be held April 21-27, 2018, in Los Angeles, CA, USA. Image: The Schirmer’s test is an invasive filter paper strip folded over the lower lid to absorb

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the tear film for five minutes. The tears collected on the Schirmer’s strips can be analyzed for biomarkers (Photo courtesy of Innovative Eye Care).

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IFA ANALYZER

ELISA PROCESSOR

Inova Diagnostics

A. Menarini

Trinity Biotech

The AUTOLoader automatically transfers NOVA Lite IFA slides to and from NOVA View to minimize the need to handle individual slides. It has a capacity for 1,200 wells or 100 slides and offers continuous slide loading and interpretation.

The Zenit PRO streamlines the whole IFA protocol from slide processing to reading and interpretation of results. Its on-board reading unit provides unparalleled accuracy and allows automated whole-well digitization for better test interpretation.

The AP22 IF BLOT ELITE can run two ELISA microplates with eight tests online, 16 IFA slides or 24 western blot or LIA strips. It can also perform full automation of Western Blot and LIA strips, and assessment of each strip.

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Metabolite Biomarkers of Chronic Typhoid Carriage Detected etecting chronic carriers of typhoid is of public health relevance in areas where enteric fever is endemic, but there are no routinely used methods for prospectively identifying those carrying Salmonella in their gallbladder. Salmonella Typhi and Salmonella Paratyphi A are the agents of enteric (typhoid) fever; both can establish chronic carriage in the gallbladder. Chronic Salmonella carriers are typically asymptomatic, intermittently shedding bacteria in the feces, and contributing to disease transmission. Scientists from Umeå University (Umeå, Sweden; www.umu.se) and their international colleagues collected blood samples patients undergoing cholecystectomy at a hospital in Nepal from June 2007 to October 2010. Stool sample were collected for microbiological culture Surgeons collected bile samples and gallbladder tissue during the procedure. After recruiting 1,377 cholecystectomy patients over three years and culturing their bile they identified 24 and 22 individuals with S. Typhi and S. Paratyphi A inside their gallbladder, respectively; 35/46 (76%) were female and the median age was 34.5 years (range; 20–67). The team used two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) and supervised pattern recognition modeling. Extracted and derivatized plasma samples were analyzed, in a random order (within the analytical batches), on a Pegasus 4D

(LECO Corporation, St Joseph, MI, USA; www.leco.com) equipped with an Agilent 6890 gas chromatograph (Agilent Technologies, Palo Alto, GA, USA; www.agilent.com), a secondary gas chromatograph oven, a quad-jet thermal modulator, and a time-of-flight mass spectrometer. The scientists were able to significantly discriminate Salmonella carriage samples from non-carriage control samples. They were also able to detect differential signatures between S. Typhi and S. Paratyphi A carriers. The team additionally compared carriage metabolite profiles with profiles generated during acute infection; these data revealed substantial heterogeneity between metabolites associated with acute enteric fever and chronic carriage. Lastly, they found that Salmonella carriers could be significantly distinguished from non-carriage controls using only five metabolites, indicating the potential of these metabolites as diagnostic markers for detecting chronic Salmonella carriers. The authors concluded that their novel approach highlights the potential of using metabolomics to search for diagnostic markers of chronic Salmonella carriage. They identified metabolite patterns signifying carriage of S. Typhi and S. Paratyphi A in the gallbladder among a cohort of patients with cholelithiasis in Nepal. The study was published on January 26, 2018, in the journal Public Library of Science Neglected Tropical Diseases.

Enzymatic Assay Developed for Ether Phospholipids in Plasma thanolamine ether phospholipid (ePE) and choline ether phospholipid (ePC) are found in human plasma (serum), but the relative concentration of the ether phospholipids in the phospholipids of human serum are very low as compared to those in tissues such as leukocytes and erythrocytes. Functions or physiological roles of the ether phospholipids in serum (plasma) are not well elucidated; however, decreases in plasmalogens in serum (plasma) have been reported in several diseases such as Alzheimer’s disease, Parkinson’s disease, metabolic syndrome, schizophrenia, and uremic patients. Scientists at the Institute of Rheological Functions of Food, (Fukuoka, Japan; www.reoken.com) obtained blood samples from 12 volunteers who were aged over 70 years (76.3 ± 5.7). Plasma was separated by using a clinical centrifuge at 1000g for 5 minutes. Hemolysis was checked visually and all of the plasma with hemolysis was discarded. Lipids were extracted from the plasma after treatment with Phospholipase A1. Phospholipase A1 (PLA1) hydrolyzes diacyl phospholipids in plasma (serum) and leaves ePE and ePC intact. After lipid extraction, ePE is hydrolyzed by glycerophospholipid specific phospholipase D (GPL-PLD) to ethanolamine, and ePC is hydrolyzed by GPL-PLD to choline. Oxidation

of ethanolamine is catalyzed by amine oxidase, and oxidation of choline is catalyzed by choline oxidase. The last steps are catalyzed by peroxidase, and Amplex Red reacts with hydrogen peroxide (H2O2) to produce fluorescent resorufin. The fluorescence intensity was measured using a fluorescence microplate reader (DTX series, Beckman Coulter, Tokyo, Japan; www.beckmancoulter.com). The excitation and emission wavelengths were set to 535 and 595 nm, respectively. The team found that the amount of ePE in human plasma measured by the enzymatic method was well correlated to that by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC/ESI-MS) method, but the correlation of ePC between the two methods was slightly less good than that of ePE. The authors concluded that the method is sensitive and high-throughput for assay of plasma ether phospholipids. The method may also be performed by using a colorimetric microplate readers and/or spectrophotometers. Therefore, the enzymatic method may be performed at many ordinary clinical laboratories without use of expensive apparatus. Furthermore, the enzymatic method may be applied to assay of ether phospholipids (ePE and ePC) not only in human plasma but also to assay of ePE and ePC in the other tissues. The study was published in the March 2018 issue of the journal Practical Laboratory Medicine. LabMedica International October/2018

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LabMedica International

Microbiological Features of Chronic Rhinosinusitis Compared ifferent phenotypes of rhinitis and chronic rhinosinusitis (CRS) have been described based on symptom severity and duration, atopy status, level of control, comorbidities, and presence or absence of nasal polyps in CRS. Scientists have compared the microbiological features in middle meatus samples from chronic rhinosinusitis (CRS) patients with nasal polyps (CRSwNP) and those without nasal polyps (CRSsNP), and control subjects. Otolaryngology specialists at Beijing Tongren Hospital (Beijing, China; www.trhos.com) enrolled a total of 136 CRSwNP patients, 66 CRSsNP patients, and 49 control subjects who underwent endoscopic surgery between January 2014 and January 2016. Swab samples were obtained from the middle meatus during surgery and processed for the presence of aerobic and non-aerobic bacteria and fungi. Information on the allergic rhinitis, asthma, the percentage of eosinophils in peripheral blood, and the history of smoking and surgery was collected. The scientists reported that the overall isolation rate for bacteria was 81.3% for the three groups, with the lowest in the CRSsNP group (77.3%) and the highest in the CRSwNP group (88.4%). The three most common bacterial species were: Coagulase-negative Staphylococcus (24.3%), Corynebacterium (19.9%), and Staphylococcus epidermidis (19.1%) in the CRSwNP group; S. epidermidis (21.2%), Corynebacterium (21.2%), Coagulase-negative staphylococcus (18.2%), and Staphylococcus aureus (13.6%) in the CRSsNP group; S. epidermidis (30.6%), Coagulase-negative Staphylococcus (28.6%), and S. aureus (14.3%) in

the control group. For the bacterial species with high isolation rates, no significant difference in the microbial cultures was observed among the three groups; while in the CRSwNP group, a relatively high proportion of Citrobacter (5.9%, a bacterium with low isolation rate) was observed compared with the CRSsNP and control groups, which were negative. The study was published on March 22, 2018, in the journal European Archives of Oto-Rhino-Laryngology. Image: The habitat and morphology of Staphylococcus aureus (Photo courtesy of Sagar Aryal).

Breath and Urine Tests Detect Early Breast Cancer reast cancer is the most commonly diagnosed malignancy among females and the leading cause of death around the world. In 2016, breast cancer accounted for 29% of all new cancers identified in the USA and was responsible for 14% all cancerrelated deaths. Current diagnostic imaging detection for smaller tumors has significant drawbacks: dual-energy digital mammography, while effective, increases radiation exposure, and magnetic resonance imaging (MRI) is expensive. Biopsies and serum biomarker identification processes are invasive, equipment-intensive and require significant expertise. Scientists at the Ben-Gurion University of the Negev (Beersheba, Israel; www.bgu.ac.il) collected exhaled breath samples from 48 breast cancer (BC) patients and 45 healthy women that served as a control group. Urine samples were collected from 37 patients who were diagnosed with BC based on physical or mammography tests prior to any surgery, and from 36 healthy women. Two commercial electronic noses (ENs) were used for the exhaled breath analysis. Urine samples were analyzed using Gas-Chromatography Mass-Spectrometry (GCMS). Statistical analysis of results was based on an artificial neural network (ANN) obtained following feature extraction and feature selection processes. The model obtained allows classification of breast cancer patients with an accuracy of 95.2% ± 7.7% using data of one EN, and an accuracy of 85% for the other EN and for urine samples. The authors concluded that the developed statistical analysis method enables accurate classification of patients as healthy or with BC based on simple non-invasive exhaled breath and a urine sample analysis. This study demonstrates that available commercial ENs can be used, provided that the data analysis is carried out using an appropriate method. Yehuda Zeiri, PhD, a professor of Biomedical Engineering and senior author of the study said, “Our new approach utilizing urine and exhaled breath samples, analyzed with inexpensive, commercially available processes, is non-invasive, accessible and may be easily implemented in a variety of settings.” The study was published on May 1, 2018, in the journal Computers in Biology and Medicine.

LabMedica International October/2018

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CELL CULTUREWARE

Instrumentation Lab

Mindray

Eppendorf

The GEM Premier 3000 measures pH, blood gases, electrolytes, metabolites and more, while providing quality management. It simplifies and standardizes whole blood testing, while delivering rapid results in the lab or at the POC.

The BC-3000Plus features 19 parameters +3 histograms, color LCD display, built-in thermal printer and huge storage capacity. It offers two counting modes and has a throughput of 60 samples per hour and can store up to 35,000 sample results.

The ready-to-use surface with synthetic fibronectin-derived motifs supports cell attachment by mimicking native ECM proteins. The surface supports expansion of hiPSCs over 25 passages and is ideal for hMSCs and ECM-dependent cells.

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Aggressive Meningioma Linked to Transcription Factor Activity eningioma, a cancer of the cerebral and spinal meninges, is the most common primary CNS tumor in the USA. Meningioma is the most common primary intracranial tumor, but the molecular drivers of aggressive meningioma are incompletely understood. A new integrated analysis suggests that the transcription factor Forkhead box protein M1 (FOXM1) can act as a meningioma driver, prompting proliferation, progression, and relatively poor outcomes in individuals with the disease, which is a primary central nervous system tumor that forms in meninges tissue surrounding the brain and spinal cord. Scientists at the University of California, San Francisco (CA, USA; www.ucsf.edu) and the California State University Channel Islands (Camarillo, CA, USA; www.csuci.edu) profiled from 280 tumor samples from 261 individuals with meningioma, the fresh-frozen or formalinfixed, paraffin-embedded samples with RNA sequencing, exome sequencing, array-based DNA methylation profiling, immunohistochemistry, NanoString technology-based targeted gene expression testing, and chromatin immunoprecipitation sequencing. Matched normal samples were subjected to exome sequencing for a subset of two dozen aggressive meningioma cases. Nucleic acids were isolated for sequencing and DNA and RNA were isolated from flash-frozen meningiomas containing more than 70% tumor cells as determined by H&E staining of frozen sections. Whole ex-

ome sequencing and DNA methylation profiling, DNA was isolated using standard techniques. For RNA-seq and real-time quantitative polymerase chain reaction (RT-qPCR), RNA was isolated from meningiomas and primary meningioma cells using the RNeasy Mini Kit (QIAGEN, Valencia, CA, USA; www.qiagen.com). Fluorescent microscopy was performed using an SP5 confocal microscope (Leica, Wetzlar, Germany; www.leica-microsystems.com). The scientists found that transcriptomic analyses identified FOXM1 as a key transcription factor for meningioma proliferation and a marker of poor clinical outcomes. Consistently, they discovered genomic and epigenomic factors associated with FOXM1 activation in aggressive meningiomas. Finally, they defined a FOXM1/Wnt signaling axis in meningioma that is associated with a mitotic gene expression program, poor clinical outcomes, and proliferation of primary meningioma cells. David R. Raleigh MD, PhD, an assistant professor and senior author of the study, said, “We now need to find out what other genes FOXM1 is activating to drive meningioma growth, and block those targets with clinical therapies. For clinicians, patients, and families, these are the most heartbreaking cases because we expect to cure meningiomas, but sometimes we can’t and we don’t always do a good job of differentiating ‘good’ and ‘bad’ meningiomas ahead of time.” The study was published on March 27, 2018, in the journal Cell Reports.

Amino Acids Can Predict Cardiovascular Disease Risk in Women esults of a recent study supported the hypothesis that plasma BCAAs (branched-chain amino acids) were positively associated with cardiovascular disease (CVD) risk and were linked to an intermediate diagnosis of type II diabetes (T2D). A branched-chain amino acid (BCAA) is an amino acid having aliphatic side-chains with a branch (a central carbon atom bound to three or more carbon atoms). Among the amino acids found in proteins, there are three BCAAs: leucine, isoleucine, and valine. These three BCAAs are among the nine essential amino acids for humans, accounting for 35% of the essential amino acids in muscle proteins and 40% of the preformed amino acids required by mammals. Circulating branched-chain amino acids (isoleucine, leucine, and valine) are strong predictors of type II diabetes mellitus (T2D), but their association with cardiovascular disease (CVD) is uncertain. To determine if BCAAs have a role in CVD, investigators at Brigham and Women’s Hospital (Boston, MA, USA; www.brighamandwomens.org) measured BCAA levels in blood samples using NMR spectrometry. Of the more than 27,000 women studied, 2,207 experienced a cardiovascular event over the 18-year follow up period.

BCAAs were found to be positively associated with CVD at a degree comparable to LDL-C (low-density lipoprotein cholesterol). BCAAs were associated with coronary events (myocardial infarction, revascularization, and borderline significant association with stroke). The BCAACVD association was greater among women who developed T2D before CVD versus women without T2D. Adjusting for LDL-C, an established CVD risk factor, did not attenuate these findings; however, adjusting for HbA1c (glycosylated hemoglobin) and insulin resistance eliminated the associations of BCAAs with CVD. “We examined more than 27,000 women in the Women’s Health Study and found that a one-time measurement of branched chain amino acids in the blood stream - a test that now can be easily done - predicted future risk of cardiovascular events to the same extent and independent of LDL cholesterol and other risk factors,” said senior author Dr. Samia Mora, a researcher at the center for lipid metabolomics at Brigham and Women’s Hospital. “This was particularly so for women who developed type II diabetes prior to their cardiovascular disease.” The work was published in the March 23, 2018, online edition of the journal Circulation: Genomic and Precision Medicine. LabMedica International October/2018

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LabMedica International

Telomere Length Test Influences Treatment Decisions elomeres protect the ends of DNA and they normally shorten with aging. They are made up of repetitive sequences of DNA, and normal telomeres have enough length to withstand the erosion that occurs over the normal lifespan of a cell. Cells with very short telomeres may thrust through these endcaps more quickly and this can lead to specific diseases. In addition to pulmonary fibrosis and bone marrow failure, people with short telomeres are prone to developing emphysema, liver disease, myelodysplastic syndrome and other cancers. Scientists led by those at Johns Hopkins Medicine (Baltimore, MD, USA; www. hopkinsmedicine.org) and their colleagues measured telomere length (TL) in 100 people from 60 families who are known to carry mutations in genes linked to telomeres and their associated enzyme, telomerase. Among them, 73 had symptoms of diseases associated with short telomeres, and 27 had no symptoms. Of the 73, the 21 with bone marrow failure were, on average, three decades younger than the 41 who had pulmonary fibrosis or emphysema. In addition, among 38 children and adult patients with bone marrow failure due to an unknown cause were also seen. The team used the flow cytometry and fluorescence in situ hybridization (flow-FISH) test, which specifically measures the telomere length in each cell within a patient’s blood sample. DNA was extracted from peripheral blood using a PureGene Blood Core Kit (Qiagen, Hilden, Germany; www.qiagen. com). Mutations were detected by either polymerase chain reaction (PCR) amplification and Sanger sequencing, whole-exome sequencing, whole-genome sequencing, or custom amplicon sequencing followed by confirmation with Sanger sequencing. The investigators found the TL had a discrete and reproducible normal range with definable upper and lower boundaries. While TL above the 50th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations, the lower threshold in mutation carriers was age-dependent, and adult mutation carriers often overlapped with the lowest decile of controls. The extent of telomere shortening correlated with the age at diagnosis as well as the short telomere syndrome phenotype. Extremely short TL caused bone marrow failure and immunodeficien-

LabMedica International October/2018

cy in children and young adults, while milder defects manifested as pulmonary fibrosis-emphysema in adults. The team prospectively examined whether TL altered treatment decisions for newly diagnosed idiopathic bone marrow failure patients and found abnormally short TL enriched for patients with mutations in some inherited bone marrow failure genes, such as Runt Related Transcription Factor 1 (RUNX1), in addition to telomerase and telomere maintenance genes. The study was published on February 20, 2018 in the journal Proceedings of the National Academy of Sciences.

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Image: Chromosomes with telomeres at their tips, in green. The intensity of the green signal is one indicator of telomere length, which is a measure of cellular “aging” and determines how many times a cell can divide (Photo courtesy of Professor George Daley, MD, PhD).

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Euroimmun

Diatron

Rayto Life and Analytical Sciences

The EUROLINE DPA-Dx Pollen Southern Europe 1 detects and differentiates specific IgE antibodies against inhalation allergens. It identifies the allergy-causing proteins, distinguishing primary sensitizations from cross reactions and aids therapy.

The KleeYab offers superior assay performance and provides ease of use with cost containment. The open platform system features a unique trigger cartridge technology that allows the use of both flash and glow detection technologies.

The RT-7200 offers a single counting channel and three counting modes: whole blood, prediluted blood and peripheral blood. It delivers test results in multi-format output and features an external power supply adaptor to reduce electrical noises.

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Malaria Rapid Tests Remain Positive after Drug Treatment apid diagnostic tests (RDTs) are increasingly becoming a paradigm for both clinical diagnosis of malaria infections and for estimating community parasite prevalence in household malaria indicator surveys in malaria-endemic countries. The antigens detected by RDTs are known to persist in the blood after treatment with anti-malarial drugs, but reports on the duration of persistence and the effect this has on RDT positivity of these antigens post-treatment have been variable. Scientists at the University of Oxford (Oxford, UK; www.ox.ac.uk) reviewed systematically publications on the persistence of antigenaemia and positivity of RDTs after treatment was conducted using the search term “antigen persist RDT”. The Google Scholar search yielded more than 4,100 results, sorted by relevance. The proportion of individuals who still tested positive via RDT was extracted for each day of followup and analyzed as a time series. The team found that half of RDTs that detect the antigen histidinerich protein II (HRP2) are still positive 15 (5–32) days post-treatment, 13 days longer than RDTs that detect the antigen Plasmodium lactate dehydrogenase, and that 5% of HRP2 RDTs are still positive 36 (21–61) days after treatment. The duration of persistent positivity for combination RDTs that detect both antigens falls between that for HRP2- or pLDH-only RDTs, with half of RDTs remaining positive at 7 (2–20) days post-treatment. The study showed that children display persistent RDT positivity for longer after treatment than adults, and that persistent positivity is more common when an individual is treated with artemisinin combination therapy than when treated with other anti-malarial drugs.

The authors concluded that RDTs remain positive for a highly variable amount of time after treatment with anti-malarial drugs, and the duration of positivity is highly dependent on the type of RDT used for diagnosis. Additionally, age and treatment both impact the duration of persistence of RDT positivity. The results suggest that caution should be taken when using RDT-derived diagnostic outcomes from cross-sectional data where individuals have had a recent history of anti-malarial treatment. The study was published on June 8, 2018, in the Malaria Journal. Image: Rapid diagnostic tests for malaria (Photo courtesy of the Mashhad University of Medical Sciences).

Hormone Levels Alter CVD Risk in Older Women igher androgen and lower estrogen levels are associated with cardiovascular disease (CVD) risk factors in women; however, studies on sex hormones and incident CVD events in women have yielded conflicting results. Studies have shown that, prior to menopause, women have lower heart disease rates than men, and because estrogen levels drop sharply after menopause, physicians once thought that replacing estrogen would reduce cardiovascular disease risk. Other studies have shown replacement female hormones were not necessarily protective and could possibly raise the risk of strokes, blood clots and heart disease. A team of scientists working with Johns Hopkins Medicine (Baltimore, MD, USA; www.hopkinsmedicine.org) analyzed data from 2,834 postmenopausal women who had participated in the federally funded Multi-Ethnic Study of Atherosclerosis (MESA). Participants were a mean age of 65 at the start of the study, and 38% white, 28% African-Ameri-

can, 22% Hispanic and 12% Chinese-American. At an initial visit that took place between 2000 and 2002, scientists took blood samples and measured levels of testosterone and estradiol. Over 12 years of follow up, the women had 283 instances of cardiovascular disease, including 171 instances of coronary heart disease and heart attacks, 88 strokes and 103 instances of heart failure as determined by medical records, hospitalizations, telephone interviews and death certificates. When team compared testosterone and estradiol levels to instances of heart and cardiovascular diseases, they found, in general, that higher testosterone was associated with increased risk and higher estradiol levels with lower risk. For every standardized unit increase in the ratio of testosterone to estrogen, there was a 19% increase in cardiovascular disease risk, a 45% increase in coronary heart disease risk and a 31% increase in heart failure risk. The study was published in the June 2018 issue of the Journal of the American College of Cardiology. LabMedica International October/2018

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LabMedica International

Genetic Scores Stratify Risk of Developing Type 1 Diabetes pproximately 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. Precision medicine typically relies on the ability to identify individuals with precise genetic elements that define a disease. These elements may be used not only to select optimal treatment modalities, but also to identify individuals who may benefit from preventative interventions. An international team of scientists led by those at the Technische Universität Dresden (Dresden, Germany; https://tu-dresden.de) performed a case-control study and followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between September 1, 2004 and February 28, 2010 and monitored until May 31, 2016. A total of 421,047 newborn children were screened for high-risk Human leukocyte antigen (HLA) genotypes for type 1 diabetes. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. The study was published on April 3, 2018, in the journal PLoS Medicine.

Urine of Kidney Disease Patients Contains Diverse Bacteria acterial communities in the bladders of men and women without clinical urinary tract infections (UTI) have been discovered and emerging studies suggests that the urinary microbiome may influence bladder health. Chronic kidney disease (CKD) is a disease generally associated with advanced age and comorbidities, such as diabetes and obesity. The older age of adults with CKD along with accompanying comorbidities may influence midstream urine microbiome diversity and could influence urinary symptoms and bladder health. Scientists at Loyola University Chicago (Maywood, IL, USA; www.luc.edu) and their colleagues examined the urine of 41 women and 36 men who had Stage 3 to Stage 5 kidney disease but were not on dialysis. Patients were age 60 or older and had less than 60% of kidney function, with an average of 27% of function. Sixty-nine percent of the men and 70% of the women also had diabetes, 42% of the men and 51% of the women had urinary urgency and 78% of the men and 51% of the women had nocturia. Midstream voided urine specimens were collected using the cleancatch method. The bacterial composition was determined by sequencing the hypervariable (V4) region of the bacterial 16S ribosomal RNA gene. Genomic DNA was extracted from midstream voided urine samples using a validated mixture of lysozyme and mutanolysin. The amount of DNA in each sample was quantified using the Qubit 2.0 Flurometer (Life Technologies, Carlsbad, CA, USA; www.thermofisher. com). The processed samples were sequenced on the Illumina MiSeq bench-top sequencer rendering 250 base-pair paired-end reads (Illumina, San Diego, CA, USA; www.illumina.com). The study found 19 types of bacteria in the urine samples, and few samples were overwhelmingly dominated by a single genus. In addition to Staphylococcus and Streptococcus, bacteria found in kidney patients’ urine included Corynebacterium, Lactobacillus, Gardnerella, Prevotella, Escherichia/Shigella and Enterobacteriaceae. Even samples that contained one dominant type of bacteria also contained several other prominent types. Significant differences in diversity measures were observed for those reporting urgency urinary incontinence (UUI) versus those without UUI. The study was published on April 12, 2018, in the journal International Urology and Nephrology.

LabMedica International October/2018

Image: Islet of Langerhans from the pancreas of a patient with chronic type 1 diabetes of 19 years duration. A single lobe of the pancreas was found to contain islets rich in residual beta cells (alpha cells in red; beta cells in green) (Photo courtesy of Diapedia). S TOR Y IBU APPL R T O DIS ED T IT INV

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The Stat Profile Prime offers a 10-test menu, and has a throughput of up to 45 samples per hour. It delivers test results in 60 seconds and is so compact it can be located anywhere in the hospital or operated on a mobile cart with battery backup.

The KOS 2 for clotting, chromogenic and immunoturbidimetric assays offers five points calibration curve for each test. Other features include quantitative D-Dimer, autosense optics, double determination and magnetic stirrer for reagents.

The Hemax-530AL has a throughput of 80 tests per hour and comes with automatic sleep and wake up function. It requires a sample of whole blood, capillary blood or prediluted capillary blood and can store information on 10,000 test results.

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Metagenomic Sequencing Can Diagnose Cases of Meningitis ubacute and chronic meningitis are diagnostically challenging given the wide range of potential infectious, autoimmune, neoplastic, paraneoplastic, parameningeal, and toxic causes. Securing a final diagnosis can require weeks or months of testing or remain unsolved, necessitating empirical treatment approaches that may be ineffective or even harmful. Unlike traditional testing for specific microbes or categories of infection, metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) or brain tissue screens for nearly all potential central nervous system (CNS) infections and can identify novel or unexpected pathogens. However, mNGS data require careful analysis to determine which, if any, of the identified microbes represent a true pathogen rather than environmental contamination. A large team of scientists led by those at University of California, San Francisco (San Francisco, CA, USA; www.ucsf.edu) enrolled seven patients who were recruited between September 2013 and March 2017 as part of a larger study applying mNGS to biological samples from patients with suspected neuroinflammatory disease. The seven participants enrolled in the present study had subacute or chronic leptomeningitis with or without encephalitis. The team performed metagenomic next-generation sequencing on total RNA extracted from surplus CSF (250-500 L), and one participant also had mNGS performed on total RNA extracted from snap frozen surplus tissue (<50 mg) obtained from a lumbar meningeal biopsy. Paired-end sequences of 125 to 150 base pairs were analyzed using a previously described rapid computational pathogen detection pipeline consisting of open-source components. To distinguish putative pathogens from contaminating microbial sequences derived from skin, collection tubes, laboratory reagents, or the environment, a composite background model of metagenomic data was used. This model incorporated 24 water control samples and 94 CSF samples from patients with noninfectious diagnoses, including 21 patients with chronic meningitis with or without encephalitis. The seven participants ranged in age from 10 to 55 years, and three (43%) were female. A parasitic worm, Taenia solium in two participants, a virus (HIV-1), and four fungi: Cryptococcus neoformans, Aspergillus oryzae, Histoplasma capsulatum, and Candida dubliniensis were identified among the seven participants by using mNGS. The authors concluded that diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neuro-

cysticercosis that defied diagnosis for one year, the first reported case of CNS vasculitis caused by Aspergillus oryzae, and the fourth reported case of C. dubliniensis meningitis. The study was published on April 16, 2018, in the journal JAMA Neurology. Image: A photomicrograph of a brain tissue specimen revealed the presence of hooklets in a case of cysticercosis, an infection due to the ingestion of eggs of a pork tapeworm, Taenia solium (Photo courtesy of the University of Pennsylvania Medical Center). LabMedica International October/2018

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LabMedica International

Alzheimer Cerebrospinal Fluid Biomarker Used in Clinical Setting nalysis of cerebrospinal fluid (CSF) is one of the key tools for the state-of-the-art differential diagnosis of dementias. Dementia due to Alzheimer’s disease (AD) is characterized by elevated CSF levels of total Tau (tTau) and phospho-181-Tau (pTau) and low CSF amyloid-β42 (Aβ42). CSF plays and important role in the differential diagnosis of AD, but lack of standardization compromises use in clinical laboratories, presenting risk of over- and underdiagnoses. It has recently been shown that analysis of Aβ40 as well as Aβ42 concentrations may provide greater sensitivity and specificity. Scientists at the University Medical Center Göttingen (Germany; www.med.uni-goettingen.de ) sent parallel aliquots of CSF samples from 114 subjects to two independent laboratories for analysis of t-Tau, p-Tau, Aβ42, and Aβ40 and concentrations and Aβ42/40 concentration ratios, with measurements done in accordance with each laboratory’s specific standard operating procedures and cut-off points. Mean age of study subjects was 66.5 years, and 52% of the cohort were men. Biomarker levels and corresponding diagnostic classifications were compared, and the degree of agreement between results of the different laboratories was assessed. The Aβ42 and Aβ40 measurements performed by the two laboratoNE DES W IGN ries showed statistically significant correlations. Statistically significant correlations for p-Tau and t-Tau measurements and CSF Aβ40 was also were seen. Not surprisingly, though, substantial discrepancies in regard WORLD’S MEDICAL PRODUCT MARKETPLACE to the Aβ42 concentrations and Aβ42/40 ratios were noted, likely owing to use of different assay kits, from IBL International (Hamburg, SIGN UP Germany; www.ibl-international. FOR FREE! com) and Fujirebio (Malvern, PA, USA; www.fujirebio-us.com). Discrepancies were not seen for Aβ40 or t-Tau and p-Tau measures; however, diagnostic interpretations between laboratories were often discordant for Aβ42 as well as t-Tau and p-Tau, as cut-off points differed between laboratories. Of note, however, is that, when subjects were diagnostically classified via interpretation of Aβ42 levels (normal versus pathological range), a discordance was cited in 32% of cases whereas, when the classification was based on the Aβ42/40 ratio, discordance was reduced to 17% of cases. The authors concluded that CSF Aβ42/40 can outperform Aβ42 as a biomarker for AD neuropathology, not only under well-controlled study conditions but also in real life clinical Connecting Buyers with routine. Thus, they recommend the Suppliers Worldwide inclusion of Aβ42/40 as a CSF bioReach new sources of supply marker in the diagnostic procedure. Identify latest products and technologies The study was published online on Send inquiries directly to suppliers February 6, 2018, in the Journal of Receive latest product alerts Alzheimer’s Disease. Chat live with suppliers

Image: Human Amyloidß Oligomers enzyme-linked immunosorbent assay (ELISA) Kit (Photo courtesy of IBL International).

LabMedica International October/2018

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Biomarkers Identified for Irritable Bowel Syndrome he causes of gastrointestinal complaints in irritable bowel syndrome (IBS) remain poorly understood. Altered nerve function has emerged as an important pathogenic factor as IBS mucosal biopsy supernatants consistently activate enteric and sensory neurons. The enteric nervous system (ENS) in the gut wall coordinates and maintains normal gut functions. Its central role for normal motility, secretion and immune cell function also indicates that altered ENS function is often associated with gut pathologies. Irritable bowel syndrome (IBS) is a functional gastrointestinal disease and belongs with a population prevalence of ~11% to the most common gut disorders. An international team of scientists led by those at the Technical University of Munich (Freising, Germany; (www.wzw.tum.de) studied the effect of supernatants from seven healthy controls (HC), 20 IBS and 12 ulcerative colitis (UC) patients on human and guinea pig submucous neurons were studied with neuroimaging techniques. They identified differentially expressed proteins with proteome analysis. Macroscopically normal intestinal specimens (as determined by visual inspection by a pathologist) were taken from 105 patients (51 male, 54 female, mean age 69 years) who underwent surgery for various pathologies. Analysis of imaging studies was performed with Neuroplex 10.1.2. (RedShirtImaging, Decatur, GA, USA; www.redshirtimaging.com). Nanoflow liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed by coupling an Eksigent nanoLC-Ultra 1D+ (Eksigent, Dublin, CA, USA; www.eksigentllc.com) to an Orbitrap Elite mass spec-

trometer (Thermo Scientific, Bremen, Germany; www.thermofisher.com). The team found that for the nerve activating properties of IBS and UC supernatants were mainly due to proteases, which are not only enzymes but also important signaling molecules. However, there was an important difference. Proteome analysis revealed 204 differently expressed proteins in IBS supernatants and four proteases that were only enhanced in IBS supernatants. The study was published on March 12, 2018, in the journal Public Library of Science ONE. Image: The nanoLC-Ultra 1D+ for nanoflow liquid chromatography (Photo courtesy of Eksigent).

Portable Quadruplex PCR System Unveiled n early-access program for a portable real time quantitative polymerase chain reaction (qPCR) system has been launched. The platform weighs one kilogram and can run quadruplex qPCR on each of four samples simultaneously. The system combines low-light complementary metal–oxide–semiconductor, or CMOS, biosensors with microfluidics to miniaturize medical devices at a reduced cost. The system is initially targeting the platform toward the research and applied markets, and eventually diagnostics. The system is called Maverick (Anitoa Systems, Menlo Park, CA; www.anitoa.com) and is an ultra-portable, Bluetooth(R) 2.0 enabled qPCR system that is compatible with standard qPCR assays, with up to 4-channel multiplexing. Target applications are rapid, on-the-site nucleic acid test of infectious diseases; blood screening; food safety and environmental monitoring. Maverick features a 4-channel fluores-

cence optical system based on Anitoa ULS24 Ultra-low light Bio-imaging chip. With no internal moving parts, Maverick is rugged and requires no calibration to operate. In terms of the thermal cycler itself, the instrument uses standard Peltier cycling, but Anitoa has adapted techniques from the computing industry to miniaturize its systems. For example, it used technologies to manage heat that are commonly used in handset manufacturing, and heat sink innovations from the personal computing industry. Overall, the system can heat at 5° C per second and cool at 4° C per second, enabling a sub-30-minute test cycle. The Maverick is different from some of the other available systems in that it is real-time PCR, so it is quantitative, and it can be multiplexed with optical channels enabling detection of up to four targets per tube. The company plans for a commercial release of the Maverick in the summer, and is currently supplying beta products as part of its early-access program. LabMedica International October/2018

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

NEWS

36th Nordic Congress Held In Helsinki on June 12-15 by Annakaisa Herrala and Tuomas Mäntylä, Congress Organizing Committee he Finnish Society of Clinical Chemistry organized the 36th Nordic Congress in Clinical Chemistry in Helsinki, Finland 12-15 June 2018. This Nordic congress is organized every second year in one of the five Nordic countries at a time by the local clinical chemistry society. This time a total of 455 delegates from 35 different countries attended the congress. The four-day congress program consisted of 16 symposia under the main theme “Information Beyond Numbers” covering recent topics of both traditional clinical chemistry and hematology, general laboratory process and basics of genetic and epigenetic testing. Participants were also able to follow plenary lectures from past presidents of IFCC Prof. Maurizio Ferrari and Prof. Graham Beastall who covered the future of molecular biology in diagnostic laboratories and the future of laboratory medicine in their lectures. Keynote speakers director Ravinder Singh from Mayo Clinic spoke about recent advances in clinical mass spectrometry and Prof. Tari Haahtela the effect of nature and environment on our health. During the congress the Lorentz Eldjarn and the Astrup Prizes were also awarded. The Lorentz Eldjarn Prize for the most prominent study published in Scandinavian Journal of Clinical and Laboratory Investigation (SCJLI) during 2013-2017 was awarded to Linda Hilsted from the article dealing pediatric reference intervals. With the Astrup Prize the Nordic Society for Clinical Chemistry rewards contemporary Nordic research work related to the field of clinical chemistry. This year the winner of the Astrup Prize was Stefan Stender with his study "Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci”. In addition to the scientific program and exhibition, the 36th Nordic Congress in Clinical Chemistry offered a warm-hearted event to meet old friends and colleagues and make new acquaintances and connections. The next Nordic Congress in Clinical Chemistry will be held in Trondheim, Norway in 2020. See you there!

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LabMedica International October/2018

Photo: Past president of IFCC Prof. Maurizio Ferrari and Congress president Solveig Linko. (Photo Feng Deng)

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

Reporting of Protein Electrophoresis and Serum Free Light Chains, and Quantification of Small Monoclonal Proteins: Results of International Survey By Jill Tate, Chemical Pathology, Pathology Queensland, Health Support Queensland, Royal Brisbane & Women's Hospital AU on behalf of the IFCC WG Harmonisation of Interpretive Commenting EQA (WG-ICQA) subgroup: Jill Tate (AU), Maria Stella Graziani (IT), Maria Willrich (US), Hans Jacobs (NL), Mike Moss (CA)

Introduction: linical laboratory testing plays an important role in the diagnosis, monitoring and prognostication of monoclonal gammopathies. Analytical methods using serum and urine protein electrophoresis (SPEP, UPEP), immunofixation electrophoresis (IFE) and immunosubtraction (IS), serum free light chains (FLC), immunoglobulin (Ig) and heavy/light chain (HLC) immunoassay, and more recently mass spectrometry, identify and are used to quantify monoclonal proteins. While international clinical guidelines for myeloma, AL amyloidosis, and Waldenström macroglobulinemia advise on the required M-protein testing for these monoclonal gammopathies, they do not recommend the exact methodology that clinical laboratories should use for the quantification and reporting of M-proteins. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) subgroup of the Working Group on the Harmonisation of Interpretive Commenting in EQA (WG-ICQA) developed a survey to determine how clinical laboratories that perform routine protein testing for monoclonal gammopathy quantitate, interpret, and comment on M-proteins when reporting results. The survey was conducted between January and April 2017 and contained 30 questions that addressed specific aspects of the Pre-analytical, Analytical and Post-analytical phases, as well as laboratory demographics of each responding laboratory. Complete responses to all questions were received from 31 countries and included 245 laboratories. As it was uncertain if some laboratories participated more than once, only completed survey responses have been included in this report.

Fig. 1: Question 1 responses (number; %)

Fig. 2: Question 11 responses (number; %)

Results and conclusions: An example of adherence to clinical guidelines is shown for Question 1 which asked: “If you screen for a monoclonal gammopathy, which of the following describe best your laboratory procedure?” According to the survey the clinical guidelines are generally followed when screening for a monoclonal gammopathy with 70% of laboratories either reflexing to, or recommending follow-up tests when an M-protein is found on SPEP (Fig. 1). However, if a light chain (kappa or lambda) is identified for the first time on serum IFE or IS, without a corresponding heavy chain, 19% of labs would not have tested for IgD but would report either a monoclonal light chain or reflex to serum FLC (Question 7). In response to: “How do you currently quantitate the M-protein migrating in the gamma fraction?” the perpendicular drop (orthogonal, top to bottom) method of gating is the most popular method for quantification of M-proteins in the gamma region on SPEP (Question 11). For monoclonal proteins in the beta and alpha2 regions, 35% of labs quantitate the M-protein by perpendicular drop (28%) or tangent skimming (7%) whereas 32% report the “Total beta/alpha-2 + M-protein” (Question 16). Several questions addressed the reporting

and interpretative commenting of small bands on SPEP. For example: “How do you report a new, small abnormal band with different electrophoretic mobility from the original M-protein in a patient with a known M-protein?” (Question 24). Only 35% of responses recommended adding a comment when a small band of different electrophoretic mobility from the original Mprotein was present. In the case of the band identified as IgG kappa, this may represent the presence of a monoclonal antibody (mAb) and 31% of responses would include the comment: “A new small monoclonal IgG kappa band has been found in the gamma fraction on immunofixation. This could represent a new clone or the presence of a therapeutic monoclonal antibody. Clinical correlation is required”. Currently only 4% of labs perform routine testing to

distinguish between an endogenous M-protein and a therapeutic mAb (Question 8) and there is no clear consensus of the preferred method to detect mAb interference (Question 9). A report and accompanying slides regarding the survey results are now available on the IFCC website at: http://www.ifcc.org/ifcc-education-division/working-groups-special-projects/wg-icqa/ The survey provides a baseline of information from 31 countries doing protein electrophoresis. The quantification and reporting of M-proteins is heterogeneous across laboratories. It is recommended that Laboratory Medicine societies in individual countries work with their clinical haematologists and immunologists to achieve greater harmonisation of methodology and results. LabMedica International October/2018

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

LABAC: New IFCC/EFLM Affiliate Member from France by Dr Jean-Marc Giannoli, LABAC President; Dr Bernard Gouget, SFBC-International Committee, IFCC Chair, Committee on Mobile Health and Bioengineering in Laboratory Medicine (C-MHBLM) and past-Chair Nominations Committee he ”Réseau de Laboratoires de Biologie médicale Accrédités” called “LABAC” (Network of Accredited Medical Labs, (www.labac. eu) is one of the main French associations in the field of medical biology and laboratory medicine. LABAC brings together medical biologists, those practising privately or at the general or university hospitals; as well as in any other health institution (Reference laboratories, Atomic Energy Commission etc.), as well as the IVD industry. LABAC was established in year 2000; members are medical biologists. According to French law, they are medical doctors or pharmacists-section biologists with a specialized diploma in medical biology (Diplôme d’études spécialisées en biologie médicale (DESBM 4 years) and authorized to lead a medical laboratory; LABAC represents a large number of medical biologists (2246) working in 344 medical Labs (219 in private practice, 39 from the public sector (general or University hospital), 5 from Institutions, and 12 from IVD sector, 69 in other medical structures. The medical labs are spread all over France. LABAC Executive Board members are: Jean-Marc GIANNOLI, President, Thierry AVELLAN, Vice-President: Raymond

Zins, Vice-President, Jean-Pierre BOUILLOUX, Treasurer, Jean-Michel DREVAIT, deputyTreasurer, Fabienne PROST-DAME, Secretary, Elisabeth GUIBOURGE, deputy-Secretary, Mouloud HAMMAD, EB Member. One of the main goals of the association is to be a forum to foster the medical laboratory accreditation process with the vision to develop a national network of mutual recognition and to contribute to the continuous improvement of quality of services for the patient. LABAC accredited community values the importance of laboratory medicine and making the association a genuine tool for management, motivation and promotion of the medical biologist profession. LABAC representatives are also members of the Cofrac Healthcare section and accreditation technical committees. LABAC has established different working groups with the following objectives: To accelerate the adoption of new evidencebased diagnostic technologies and to facilitate access to well integrated lab services; To develop an extensive laboratory medicine technology watch and scientific / clinical activities to improve the knowledge, the daily practice and the efficiency/visibility of

IFCC Vitamin D Standardization Program (WG-Vit D) by Christopher T. Sempos, Ph. D. Coordinator, Vitamin D Standardization Program (VDSP) he Vitamin D Standardization Program (VDSP) has moved and given rise to a new IFCC Working Group (WG-Vit D). It is chaired by Prof. Christopher Sempos. In January 2019, this working group will become part of a new IFCC Committee on Bone Metabolism to be Chaired by Prof. Étienne Cavalier. Terms of Reference include a re-evaluation of the VDSP’s performance criteria for serum total 25hydroxyvitamin D [25(OH)D], i.e. Total CV ≤ 10% and Mean Bias ≤ 5%, and developing new performance criteria for 3-epi-25(OH)D3 and 24,25-dihydroxyvitamin D3. Given the VDSP’s history, and the importance of assay standardization in the IFCC this new working group will be an integral component of the Committee on Bone Metabolism. The VDSP was founded in 2010 by the US National Institutes of Health, Office of Dietary Supplements (ODS) with the goal to “Promote the standardized laboratory measurement of 25hydroxyvitamin D – a measure of vitamin D status – in order to improve clinical and public health practice.” It became an independent program in April 2018. The first step was to develop a reference

LabMedica International October/2018

measurement system in collaboration with many organizations and individuals around the world. It includes reference measurement procedures and standard reference materials (SRM) developed by the US National Institute for Standards and Technology (NIST), a standardization-certification program conducted by the US Centers for Disease Control and Prevention (CDC), accuracy-based PT/EQA conducted by the College of American Pathologists and the Vitamin D External Quality Assessment Scheme (DEQAS), and general guidelines for standardizing 25(OH)D measurement both prospectively and retrospectively. Recent VDSP efforts include NIST’s development of a reference measurement procedure and SRMs for serum 24,25-dihydroxyvitamin D3. NIST is currently working to develop reference measurement procedures for Vitamin D Binding Protein (DBP), 1,25-di-hydroxyvitamin D3 and parathyroid hormone (PTH). Conducting research is an important component of the VDSP. An interlaboratory comparison/commutability study was conducted in 2012. In the commutability portion, it was found that NIST SRM 972, CAP Accuracy-Based Vitamin D

NEWS the Medical biologist community; To learn about the emerging trends in diagnostics and patient monitoring for creating collaborative and innovative interactions among the medical biologist community; To strengthen the evidence on the benefits of accreditation and to demonstrate that laboratory accreditation has a positive influence on performance in other areas of health care systems by allowing laboratories to demonstrate high standards of service delivery. Accreditation is an effective mechanism for health system improvement yielding long-term benefits in the quality, cost-effectiveness, and sustainability of the public health programmes. Twice a year, in March and October, LABAC organizes national conferences to strengthen the evidence of the benefits of accreditation and to demonstrate the added value of the medical lab in delivering safe and effective patient care in the new healthcare environment. At each conference, LABAC invites internationally known scientists for the Opening Keynote lecture. As examples in 2016: the invitees were Prof Greg Miller, Past President of AACC (2012) and CLSI (2015), in 2017: Prof Sverre Sandberg, EFLM President, EFLM-IFCC regional representative. The next conference will be held on 21 November 2018, at the Maison de la Chimie, Paris 7. LABAC has been recognized as an EFLM affiliate member during the EFLM General Assembly in Mannheim on 19 June 2018 and accepted as an affiliate member of IFCC by EB approval 26 June 2018. LABAC members are ready to play an active role in laboratory medicine in both federations!

(ABVD) Survey and DEQAS serum materials were commutable. That was very good news. However, in the tandem interlaboratory comparison study a weakness in Mean Bias was discovered. That is, while many assays had a mean bias within the specified range of -5% to + 5% they also exhibited an unacceptable level of variability around that mean. A second VDSP interlaboratory comparison/ commutability study was conducted in 20162017 by ODS, NIST and Prof. Cavalier’s laboratory in order to include a greater number of commercial assay platforms. Preliminary analyses confirmed Mean Bias’s fundamental weakness and the urgent need to revise the VDSP 25(OH)D performance guidelines. The IFCC WG-Vit D is composed of many of the stakeholders in the VDSP’s effort to promote vitamin D assay standardization including representatives from assay manufacturers, NIST, CDC, CAP and DEQAS and other interested parties. As NIST completes its work on developing reference methods for DBP, 1,25(OH)D3 and PTH, it is anticipated that the WG-Vit D will expand its current Terms of Reference to include the development of performance criteria for those metabolites, as well.

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

NEWS

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VIEWPOINT

HIV / AIDS Epidemics: Between Successes and Fears by Dr. Bernard Gouget Counselor for Public Health FHF; Chair-IFCC Committee on Mobile Health and Bioengineering in Laboratory Medicine (C-MHBLM), SFBC-International Committee; General Secretary of the International Francophone Federation of Clinical Biology and Laboratory Medicine (FIFBCML), Chair-Human Health Care Committee-COFRAC

f we do not change the way we design and lead the global response to HIV/AIDS, the world will not achieve the goals set by the United Nations which foresees the eradication of the epidemic by 2030. Since the start of the epidemic 77.3 million people have become infected with HIV and 35.4 million have died from AIDS-related illnesses. Spectacular progresses have been made, but they are still insufficient. In 2017, 36.9 million people globally were living with HIV and 21.7 million (60%) have access to antiretroviral therapy. The number of new infections is only just declining;1.8 million were newly infected with HIV and 940 000 people died from AIDS-related illnesses last year. Tuberculosis accounts for around one in three AIDS-related deaths. The current rate of decline is not enough despite the impact of the antiretroviral therapy. Michel Sidibé, Executive Director ONUSIDA, recently sounded the alarm in the report: “Closing gaps; breaking barriers; righting injustices “. He noted that the pace is not matching global ambition and called for immediate action. The global response to HIV is a worrying situation. Entire regions are falling behind and the key populations at risk are still ignored. In addition, the steady stream of new infections is increasing and so is the population that needs to be treated, since it has been shown that with well-designed treatments and and monitoring, the risk of transmission is almost close to zero. The current moment has paradoxical connotations, with new suc-

cesses, the fears are more and more concrete. The proportion of HIV-positive people who have access to AIDS treatment has never been so high globally. However, the number of new infections are not decreasing and even increasing in several countries. Despite a decrease in eastern and southern Africa, of 30% since 2010, new HIV infections are rising in around 50 countries. In eastern Europe and central Asia, the annual number of infections has doubled and new HIV infections have increased by more than a quarter in the Middle East and North Africa over the past 20 years. Inequality, lack of empowerment, violence and human right violations against women are continuing to fuel new contaminations. Progress in children has slowed but gains are not being sustained. 180 000 children acquired HIV during birth or breastfeeding and 110 000 died of AIDS related diseases last year. Key populations account for 47% all new HIV infections worldwide. The right for health for all is not negotiable. Sex workers, gay people, prisoners, refugees, transgenders, drug addicts are highly affected but are still being left out from HIV programmes. There is an urgent need to have universal access to adapted health services and protection from discrimination. Discrimination is preventing young and people living with HIV from accessing prevention, treatment and other sexual and reproductive health services. In addition, overall investments in the HIV response, taking into account both domestic and international sources, has remained relatively flat in recent years. It seems that US$ 7 billions are missing and this questions the success of 90-90-90, an ambitious target to help end the AIDS epidemic. In other words, by 2020, 90% of all people living with HIV will know their HIV status (75% in 2017), by 2020, 90% of all people with diagnosed HIV infection will receive sustained antiretroviral therapy (79% in 2017) and by 2020, 90% of all people receiving antiretroviral therapy will have viral suppression (81% in 2017). This ambitious target can and must be achieved. In order to tackle this scourge, the specialists of laboratory medicine together with the international community must be mobilized on a massive scale for prevention, diagnosis and therapeutic followup. We have to assemble forces for a genuinely multidimensional global mobilization in order to halt and begin to reverse the HIV/AIDS epidemic. Multiple and innovative solutions are driving progress in tackling HIV/AIDS. When the combination of HIV prevention, including condoms and voluntary medical male circumcision, is pursued at scale, population-level declines in new HIV infections are achieved. Oral pre-exposure prophylaxis (PrEP) is having an impact, particularly among key populations. Offering HIV testing and counselling to family members and the sexual partners diagnosed with HIV have significantly improved testing access. New mobile technologies offer exciting opportunities for linking patients and professionals. The creation of more integrated services that respond to HIV, but also to other diseases affecting the same groups at risk and often coexisting in patients is becoming essential. Such an offer would include sexual and reproductive health, tuberculosis, viral hepatitis, drug addictions and mental disorders. International celebrities such as Elizabeth Taylor in the US and her foundation ETAF today or Line Renaud in France and many others such as the Bill and Melinda Gates foundation supports organizations delivering direct care and services to people living with HIV. They are also providing information for HIV prevention education programmes and supporting existing organizations that create new and innovative programs that help spread awareness of HIV prevention and treatment. These examples have to be followed and strengthened and more help is needed worldwide from the international organizations and governments. The HIV pandemic remains the epidemic of our time; it is not on track to end but remains a major global challenge for the future. The HIV response offers important lessons from which global health can learn. Without further reductions in HIV incidence, a resurgence of the epidemic is inevitable. The fall ininternational solidarity is disturbing while a strong, joint international resolution is essential in developing, implementing, sustaining a well-coordinated action against HIV/AIDS. A new worldwide reinforced solidarity would be an opportunity to construct something new towards the goal of universal health coverage. LabMedica International October/2018

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LabMedica International

Microfluidic Device Brings Single-Cell Technology to Bedside he complex architecture and associated higher-order function of human tissues relies on functionally and molecularly diverse cell populations. Defining the cellular subsets found in pathologic tissues provides insights into disease etiology and treatment options. Traditional methods such as flow cytometry, which require a priori knowledge of cell type-specific markers, have begun to define this landscape, but fall short in comprehensively identifying cellular states in a tissue, with particular difficulty detecting extremely rare subpopulations. Scientists at the New York Genome Center (New York, NY, USA; www.nygenome.org) and their colleagues have facilitated broad access to single-cell sequencing by developing a 3D-printed, portable and low-cost microfluidic controller. They adapted this device to perform massively parallel single-cell RNAseq (Drop-seq), observing metrics and performance that are indistinguishable from a study level Dropseq setup. The group used the instrument to profile joint synovial tissue from rheumatoid arthritis (RA) patients. RA is an autoimmune disease that affects 1% of the population and is associated with painful swelling in the joints. The precise cause of RA is undetermined and muddled by the diversity of cells found in the swollen joints of patients. The portability of the controller permitted patient samples to be processed on-site and immediately after surgery, minimizing handling and transport to optimize sample quality. The team collected samples from five RA patients totaling 20,387 cells and looked at the individual gene expression patterns for each cell. By analyzing the complete dataset and searching for clusters of similar cells, the scientists identified 13 groups, representing both infiltrating immune and inflamed stromal populations. Of particular interest were distinct groups of fibroblasts with strikingly different gene expression patterns. They were able to validate the presence of these multiple groups using BD FACSAria II flow cytometry sorter (BD Bioscience, San Jose, CA, USA; www.bdbiosciences. com), and discovered that they exhibited distinct localization patterns with the joint tissue as well. The instrument processes 1 mL of cells at a concentration of 150–200 cells/μL in about 30 minutes, generating over one million droplets at a generation rate of approximately 700 Hz.

LabMedica International October/2018

Instructions and assembly manuals for the instrument can be found online at the popular microfluidics repository Metafluidics (MIT Lincoln Laboratory, Lexington, MA, USA metafluidics.org/devices/minidrops). William Stephenson PhD, a Senior Research Engineer, and lead author of the study, said, “Most commercial microfluidic instruments are very costly; as a result, not every lab has access to exciting technology for single-cell analysis. We designed the instrument to perform droplet microfluidics and in particular Drop-seq, a massively parallel technology for single cell RNA-sequencing.” The study was published on February 23, 2018, in the journal Nature Communications.

Image: The microfluidic control instrument performing a Drop-seq run (Photo courtesy of the New York Genome Center).

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

International Calendar, LabMedica International P.O.Box 801932, Miami, FL 33280-2214, USA Fax: 1-954-893-0038 • E-mail: info@globetech.net

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

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