bluuebunny/crossref_metadata_2025 huggingface dataset:
SUITABILITY STUDY OF ANO ALIAKMONAS RIVER BEDS FOR THE DEVELOPMENT OF RAFTING
Authors: Παυλίδης Τ. , Δημητριάδης Ι. , Γκαϊτατζής Δ. , Τσιώρας Π.
Published: July 2018

The river and torrents sports (rafting, canoe kayak) have spread in Greece during the last years. These sports, with an increasing number of friends, are centered at Evinos and Aoos rivers, due to their hydrologie and géomorphologie suitability. The impressive routes, the fascination of these sports as well as their organization at different seasons (winter-spring season) create an increasing demand of new impressive routes, which will also fulfill the appropriate géomorphologie and hydrologic prerequisites. The very exciting sport of rafting can act as an important factor for the development of alternative forms of inner tourism, in the context of supporting the less developed mountain areas in Greece. This paper is investigating the suitability of the proposed routes in terms of geometry and morphology (width, length and inclinations of the river bed etc) as well as hydrology (sufficient water load movement for a long time which will reinsure the desired river bed, rainfall intensity etc). All of the above are investigated in the context of achieving the high levels of satisfaction from the rafting experience and the connection of the suggested routes with their starting and finishing points.
Tourette syndrome research highlights from 2017
Authors: Hartmann Andreas , Worbe Yulia , Black Kevin J.
Published: July 2018

This is the fourth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2017 relevant to Tourette syndrome and other tic disorders. The authors briefly summarize reports they consider most important or interesting. The highlights from 2018 article is being drafted on the Authorea online authoring platform, and readers are encouraged to add references or give feedback on our selections using the comments feature on that page. After the calendar year ends, the article is submitted as the annual update for the Tics collection on F1000Research.
Longitudinal serological measures of common infection in the Avon Longitudinal Study of Parents and Children cohort
Authors: Mitchell Ruth E. , Jones Hannah J. , Yolken Robert H. , Ford Glen , Jones-Brando Lorraine , Ring Susan M. , Groom Alix , FitzGibbon Sophie , Smith George Davey , Timpson Nicholas John
Published: July 2018

Antibodies against pathogens provide information on exposure to infectious agents and are meaningful measures of past and present infection. Antibodies were measured in the plasma of children that are the offspring in a population-based birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Plasma was collected during clinics at age 5, 7, 11 and 15 years. The antigens examined include: fungal (Saccharomyces cerevisiae); protozoan (Toxoplasma gondii and surface antigen 1 of T. gondii); herpes viruses (cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1); common colds (influenza virus subtypes H1N1 and H3N2); other antigens (measles); animal (feline herpes virus, Theiler’s virus); bacteria (Helicobacter pylori); dietary antigens (bovine casein alpha protein, bovine casein beta protein). Alongside the depth of data available within the ALSPAC cohort, this longitudinal resource will enable the investigation of the association between infections and a wide variety of outcomes.
On Application of Transformations at Descriptive Geometry’s Problems Solution
Authors: Боровиков И. , Borovikov Ivan , Иванов Геннадий , Ivanov Gennadiy , Суркова Н. , Surkova N.
Published: July 2018

This publication is devoted to the application of transformations at descriptive geometry’s problems solution. Using parametric calculus lets rationally select the number of transformations in the drawing. In Cartesian coordinates, on condition that an identical coordinate plane exists, the difference between parameters of linear forms, given and converted ones, is equal to the number of transformations in the composition. In affine space under these conditions, this difference is equal to two. Based on parameters calculation the conclusion is confirmed that the method of rotation around the level line, as providing the transformation of the plane of general position to the level plane, is a composition of two transformations: replacement of projections planes and rotation around the projection line. In various geometries (affine, projective, algebraic ones, and topology) the types of corresponding transformations are studied. As a result of these transformations are obtained affine, projective, bi-rational and topologically equivalent figures respectively. Such transformations are widely used in solving of applied problems, for example, in the design of technical surfaces of dependent sections. At the same time, along with transformation invariants, the simplicity of the algorithm for constructing of corresponding figures should be taken into account, with the result that so-called stratified transformations are preferred. A sign of transformation’s stratification is a value of dimension for a set of corresponding points’ carriers. This fact explains the relative simplicity of the algorithm for constructing the corresponding points in such transformations. In this paper the use of stratified transformations when finding the points of intersection of a curve with a surface, as well as in the construction of surfaces with variable cross-section shape are considered. The given examples show stratification idea possibilities for solving the problems of descriptive geometry.
Modeling of Surface’s Micro- And Nanostructures for Solving of Gas Dynamics, Heat And Mass Transfer Problems
Authors: Брылкин Ю. , Brylkin Yuriy
Published: July 2018

This paper is devoted to the problem of modeling a rough surface to ensure calculations for a flow around aircraft by high-enthalpy gas. The surface layer’s geometric characteristics along with the material’s chemical composition affect the surface’s optical indices and catalytic properties, and, consequently, on the measured heat flux. The problem of construction a geometric model for micro-surface has both fundamental and applied aspects. The fundamental nature stems from the fact that considered processes arising from the interaction of gas atoms and molecules with the surface are very complex ones. In such a case the correct interpretation for results of aircraft fragments’ ground experimental method is required. The work’s applied significance is determined by the need to optimize tools for flows diagnostic in high-enthalpy installations, in which simulation of thermal load affecting the aircraft in flight is taking place, as well as simulation of technological processes for heat-shielding materials and coatings development. Effective way for modeling of undifferentiated surfaces for gas dynamics problems solving is the use of fractal methods accounting the roughness at the micro- and nano-scale. They are based on the assertion that the natural surface’s structure has the same fractality at all levels. The development of this hypothesis has led to the emergence of a whole direction – material engineering – allowing most adequately describe self-organizing structures. Also, with the development of nanotechnologies, fractal geometry has found its own place in solving problems related to obtaining certain materials properties. As has been shown in the paper, fractal theory is a good mathematical tool for study of rigid bodies’ surface geometry and mechanisms influencing on the obtaining surface structure.
Multisourcing and Miscoordination in Supply Chain Networks
Authors: Bimpikis Kostas , Fearing Douglas , Tahbaz-Salehi Alireza
Published: July 2018

This paper studies sourcing decisions of firms in a multitier supply chain when procurement is subject to disruption risk. We argue that features of the production process that are commonly encountered in practice (including differential production technologies and financial constraints) may result in the formation of inefficient supply chains, owing to the misalignment of the sourcing incentives of firms at different tiers. We provide a characterization of the conditions under which upstream suppliers adopt sourcing strategies that are suboptimal from the perspective of firms further downstream. Our analysis highlights that a focus on optimizing procurement decisions in each tier of the supply chain in isolation may not be sufficient for mitigating risks at an aggregate level. Rather, we argue that a holistic view of the entire supply network is necessary to properly assess and secure against disruptive events. Importantly, the misalignment we identify does not originate from cost or reliability asymmetries. Rather, firms’ sourcing decisions are driven by the interplay of the firms’ risk considerations with nonconvexities in the production process. This implies that bilateral contracts that could involve under-delivery penalties may be insufficient to align incentives.

The e-companion is available at https://doi.org/10.1287/opre.2017.1708 .
Approximating the First-Come, First-Served Stochastic Matching Model with Ohm’s Law
Authors: Fazel-Zarandi Mohammad M. , Kaplan Edward H.
Published: July 2018

The first-come, first-served (FCFS) stochastic matching model, where each server in an infinite sequence is matched to the first eligible customer from a second infinite sequence, developed from queueing problems addressed by Kaplan (1984) in the context of public housing assignments. The goal of this model is to determine the matching rates between eligible customer types and server types, that is, the fraction of all matches that occur between type-i customers and type-j servers. This model was solved in a beautiful paper by Adan and Weiss, but the resulting equation for the matching rates is quite complicated, involving the sum of permutation-specific terms over all permutations of the server types. Here, we develop an approximation for the matching rates based on Ohm’s Law that in some cases reduces to exact results, and via analytical, numerical, and simulation examples is shown to be highly accurate. As our approximation only requires solving a system of linear equations, it provides an accurate and tractable alternative to the exact solution.
Disputas pela história contemporânea de Portugal: a polêmica político-historiográfica entre José Agostinho de Macedo e Hipólito da Costa
Authors: Ramos André Da Silva , Araújo Valdei Lopes de
Published: July 2018

Este artigo analisa as disputas pela história contemporânea de Portugal entre José Agostinho de Macedo e Hipólito da Costa, que escreveram capítulos alternativos sobre o reinado de D. Maria I em suas reedições da História de Portugal composta em inglês por uma sociedade de literatos, publicadas respectivamente em 1802 e 1809. Para tanto, será tematizado primeiramente as dinâmicas de compilação e tradução que possibilitaram a emergência da História de Portugal..., publicada pela primeira vez em 1788. Por fim, analisa-se como as polêmicas político-historiográficas desencadeadas evidenciam a aceleração do tempo histórico e a impossibilidade da redução da experiência da história de Portugal a narrativas homogeneizadoras em um contexto de crise.
O espaço da nobreza: hierarquia do poder em Minas Gerais no século XIX
Authors: Saraiva Luiz Fernando
Published: July 2018

Resumo: A presente pesquisa aborda as relações de poder construídas na província de Minas Gerais ao longo do século XIX tendo como objeto central de análise a nobilitação dos principais grupos políticos mineiros. Partindo de uma revisão sobre os estudos da nobiliarquia brasileira, optamos por destacar algumas das principais correntes interpretativas para aprofundar posteriormente as titulações dos nobres em Minas Gerais como um poderoso indicativo da construção das relações de poder em uma das províncias mais importantes do Brasil no Oitocentos. A análise da nobreza mineira pode se revelar como um indicativo dos processos de povoamento e da construção das relações de poder no Estado Brasileiro.Abstract: This research addresses to power relations built in the province of Minas Gerais throughout the 19th century, with the central object of analysis the nobleness of the major political groups from Minas Gerais. Starting from a review on Brazilian nobiliary studies, we opted to highlight some of the main theories and intepretive analysis, with the intent to posteriorly deepen the titrations of nobles from Minas Gerais as a powerful indicatory of the construction of power relations in one of the major Brazilian provinces in the 19th century. The analysis on the nobility from Minas Gerais can be revealed as an indicative of settlement processes and construction of power relations on the Brazilian State.
Expediente
Authors: Correa Claudio Miranda
Published: July 2018

Expediente. Revista Maracanan, Rio de Janeiro, Programa de Pós-graduação em História da Universidade do Estado do Rio de Janeiro, n. 18 - dossiê "Nobrezas e hierarquias sociais, séculos XV-XIX", jul.-dez. 2018.
Using ustekinumab to treat Crohn's disease
Authors: Stansfield Cath
Published: July 2018

Ustekinumab is an IV induced, SC maintained biological therapy that has been shown to induce and maintain remission in Crohn's disease, as well as promoting deep mucosal healing. Ustekinumab has been licensed for use in patients who have not responded to a traditional medical therapy, such as an aminosalicylate, corticosteroid or immunosupressant, or another biologic, such as infliximab. There is debate as to whether biologics should be commenced at the end of a step-up approach or the beginning of a step-down approach.
Teacher-Students´ Interaction in Comparison of Teacher´s Self-perception and Students´ Point of View
Authors: Balagova Lucia , Halakova Zuzana
Published: July 2018

Building a teacher-student relationship is important for creating trust, mutual understanding and respect. The interaction of teacher and students can be found using the 48-item Questionnaire on Teacher Interaction. The result is the Model for Interpersonal Teacher Behavior, consisting of four dimensions, which are further divided into eight sectors to evaluate the teacher. The main goal of our study was to show how the teacher and students perceive the environment of the class, whether their views match, and whether it is a statistical significant dependence among different sectors of the model teacher-students interaction. The sample size consisted of 63 Slovak students of 12th grade and their teacher of biology. Our results have shown that the teacher has evaluated herself similarly to the students, but without a statistical significant difference. In monitoring of the relationship of scales in the whole group of respondents, in the group of male and female respondents we showed statistically significant differences between the sectors. Using of Questionnaire on Teacher Interaction can help mutual knowing of students and teachers and the creation of positive relationships.
Cascade Screening for Familial Hypercholesterolemia: PCR Methods with Melting-Curve Genotyping for the Targeted Molecular Detection of Apolipoprotein B and LDL Receptor Gene Mutations to Identify Affected Relatives
Authors: Pandey Sarojini , Leider Michaela , Khan Mike , Grammatopoulos Dimitris K
Published: July 2018

Background

A key objective of the UK National Institute for Health and Care Excellence (NICE) pathway for diagnosis of familial hypercholesterolemia (FH) is the identification of affected relatives of index cases through cascade screening. At present, there is no systematic appraisal of available methodological options to identify the appropriate diagnostic testing protocol that would allow cost-effective cascade genetic screening. The majority of FH-causing mutations identified in the LDL receptor (LDLR) or apolipoprotein B (APOB) genes are single-nucleotide changes. This pattern of mutations suggests that PCR methods using melting curve–based genotyping might offer a convenient methodological approach for screening relatives.

Methods

We developed and validated one-tube PCR methods for the mutations APOB c.10580G>A (p.Arg3527Gln), LDLR c.1474G>A (p.Asp492Asn), and c.2054C>T (p.Pro685Leu) and 3 novel LDLR mutations identified in the Coventry and Warwickshire population: LDLR c.1567G>C (p.Val523Leu), c.487dupC (p.Gln163Profs17), and c.647G>C (p.Cys216Ser).

Results

These methods successfully amplified target sequence from genomic DNA extracted from either peripheral blood or saliva. They also demonstrated acceptable analytical performance characteristics (specificity of amplification, repeatability, and reproducibility) over a wide range of DNA concentrations and purity. This approach was used for cascade testing of relatives of index FH cases with confirmed mutations and identified family members with high plasma LDL cholesterol as heterozygous for disruptive alleles.

Conclusions

Our study generates proof-of-concept evidence of methods suitable for detecting single nucleotide substitutions and insertions that can deliver reliable, easy, low-cost, and rapid family screening of FH patients and can be adopted by nonspecialist molecular diagnostic laboratories.
Assessment of FUS-200 Performance: Comparison with Quantitative Urine Culture Shows that Identifying the Right Cutoff for Optimizing Analyzer Performance Is Challenging
Authors: Gras Jérémie M , Henry Nathalie , Othmane Myriam , Vranken Guido R
Published: July 2018

Background

Urine sediment analysis is a frequently ordered test, since it permits screening for many clinical conditions. Here, the technical and bacteriuria diagnostic performance of FUS-200, a new sediment analyzer, was assessed.

Methods

Carry-over, imprecision, and linearity were measured according to CLSI protocols. FUS-200 was compared to sediMAX™, our current laboratory analyzer, in terms of particle recognition/counting in 382 fresh urine samples, and bacteriuria diagnosis was based on white blood cell (WBC) and bacteria counts in a subgroup of the same samples. In the diagnostic study, quantitative bacterial cultures served to classify the samples as bacteria-positive or bacteria-negative.

Results

FUS-200 did not show carryover for the particles tested. Total imprecision for red blood cells (RBCs) and WBCs in positive controls was 3.6%–10.5% and complied with European guidelines. RBC and WBC recovery was linear. When FUS-200 particle counts were edited by a reviewer, concordance with sediMAX improved for epithelial cells, yeast, and crystals, and recognition of casts and crystals improved. FUS-200 concordance with sediMAX varied between 97% for yeast and 58% for bacteria and was satisfactory. FUS-200 detected bacteriuria better than sediMAX (P = 0.004). FUS-200 WBC and bacteria cutoff values based on the Youden index detected bacteriuria better than manufacturer cutoffs. The best sensitivity with which FUS-200 detected bacteriuria was 79%.

Conclusions

Although casts and crystal recognition should be improved, the overall technical performance of FUS-200 was acceptable to good. FUS-200 exhibited good screening accuracy for bacteria and WBC. Editing only mildly influenced FUS-200 outcomes.
Stability of Biochemical Components in Blood Samples Transported by Tempus600/Sysmex GLP Robot Reception System
Authors: Andersen Ida Boegh , Mogensen Nina , Brandslund Ivan
Published: July 2018

Background

The Department of Clinical Immunology and Biochemistry, Lillebaelt Hospital, Denmark, and TIMEDICO invented and developed the Tempus600®, a pneumatic tube system (PTS). This system is only 2.5 cm in diameter and sends blood tubes directly, without packing before transport. Request forms need not be enclosed, since samples are labeled with patient and barcode ID. At the end of the pipes, a robot receives and places the tubes onto a GLP transport system after the principle of “first in, first out” (FIFO), whereafter the tubes are delivered to centrifuges and analytical equipment. The whole system has decreased the total turnaround time (ToTAT) from 2 to 3 h to <60 min. The aim of the study was to validate the Tempus600/GLP robot system for the 89 most frequent or critical components.

Methods

Two sets of blood samples were drawn from 100 patients. One set was sent by the Tempus600/GLP robot system, and the other was couriered directly to the laboratory for analysis. Results were compared using difference plots.

Results

The results for 85 of the components did not deviate from the optimized fast courier reference transport more than could be expected by the analytical variation. O2 saturation, oxyhemoglobin, and partial pressure of oxygen (P  o  2) deviated considerably from a clinical point of view. Partial pressure of carbon dioxide (P  co  2) results were clinically acceptable for assessing patients with obstructive lung disease for hypercapnia.

Conclusions

The Tempus600/GLP robot system can be used for transport of the majority of routinely used analytical tests.
Quality Monitoring Approach for Optimizing Antinuclear Antibody Screening Cutoffs and Testing Work Flow
Authors: Tacker Danyel H , Perrotta Peter L
Published: July 2018

Background

An antinuclear antibody (ANA) testing strategy involving enzyme immunoassay (EIA) screening that reflexed to immunofluorescence assay (IFA) was implemented, monitored, and optimized for clinical utility.

Methods

The clinical utility, test performance, and workload implications of various ANA testing strategies were compared during the following study phases: (a) Preimplementation (n = 469) when IFA was used for all ANA screening, (b) Verification (n = 58) when EIA performance was confirmed, (c) Implementation (n = 433) when a reflexive strategy (EIA screen/IFA confirmation) was implemented, and (d) Postimplementation (n = 528) after the reflexive strategy was optimized. Sequential samples were captured in the Preimplementation, Implementation, and Postimplementation phases for clinical performance evaluation.

Results

Clinical performance of the EIA screen, per ROC analysis yielded area under the curve (AUC) of 0.846 in the Implementation phase and increased to 0.934 Postimplementation (P < 0.01); AUC for IFA similarly increased, from 0.678 to 0.808 (P = 0.05). The reflexive testing strategy increased screening sensitivity from 61% Preimplementation (IFA) to 98% (EIA) at Implementation and was maintained after optimization (98%, Postimplementation). Optimization decreased the false-positive rates for both EIA (from 40% to 18%) and IFA (18% to 8%) and was associated with reductions in daily full-time equivalent (by 33%) and IFA slide use (by 50%).

Conclusions

Continuous quality monitoring approaches that incorporate sequential data sets can be used to evaluate, deploy, and optimize sensitive EIA-based ANA screening methods that can reduce manual IFA work without sacrificing clinically utility.
Interassay Comparison of the Tumor Markers CA125, CA15.3, and CA27.29
Authors: Winston-McPherson Gabrielle N , Merrill Anna E , Lo Sheng-Ying , Hoofnagle Andrew N , Greene Dina N
Published: July 2018

Background

Cancer antigens 125, 27.29, and 15-3 (CA125, CA27.29, and CA15-3) are markers of ovarian and breast cancer. Comparing tumor marker results across methods is challenging because of the lack of harmonization. Documenting comparability of results is important.

Methods

Siemens Advia Centaur CA125 and CA27.29 assays were compared to their corresponding Beckman Coulter DxI CA125 and CA15-3 assays. The interassay bias was determined and the manufacturer-recommended reference intervals were evaluated.

Results

The DxI CA125 assay demonstrated an overall positive 29% bias relative to the Centaur CA125 assay. The DxI CA15-3 assay demonstrated an overall negative 65% bias relative to the Centaur CA27.29 assay. For patients with multiple comparisons during the study period, the trend of results over time was similar across both sets of assays. Implementing the manufacturer-recommended reference interval for the DxI CA125 assay increased the abnormal flagging rate by 4.5%. In contrast, implementing the manufacturer-recommended reference interval for the DxI CA15-3 assay decreased the abnormal flagging rate by 13.0%.

Conclusions

The overall trends for the majority of patients were similar. Therefore, despite the overall biases, transitioning tumor marker assays should not affect clinical interpretation of results.
Analytical Validation of Relative Average Telomere Length Measurement in a Clinical Laboratory Environment
Authors: Blauwkamp Marsha N , Fasching Clare L , Lin Jue , Guegler Karl , Hytopoulos Evangelos , Watson Drew , Harley Calvin B
Published: July 2018

Background

Average telomere length in whole blood has become a biomarker of aging, disease, and mortality risk across a broad range of clinical conditions. The most common method of telomere length measurement for large patient sample sets is based on quantitative PCR (qPCR). For laboratory-developed tests to be performed on clinical samples, they must undergo a rigorous analytical validation, currently regulated under CLIA.

Methods

Whole blood samples from 40 donors were used in the analytical validation of methods for relative average telomere length (rATL) measurement. Three technical replicate DNA samples were extracted from each whole blood sample and placed in three independent wells on a sample plate. Each of these sample plates was assayed 12 times during the validation process. The study was conducted over a 20-day period, once in the morning and once in the evening, using 3 different operators.

Results

Our process of rATL measurement beginning with DNA extraction followed by qPCR-based assay resulted in repeatability and reproducibility CV of <5% and amplification efficiencies near 100%. The validated assay was used to establish a reference interval derived from 2 cohorts of individuals: (a) San Francisco Bay area (n = 504) and (b) a US cross-sectional, demographic population (n = 357).

Conclusions

We present advances in the establishment of a highly reproducible analytically validated process for determining rATLs in a CLIA laboratory environment.
Effect of Preanalytical Factors on the Stability of Maternal Serum Biomarkers and Calculated Risk for Trisomy 21, Trisomy 18, and Open Neural Tube Defect
Authors: Walker Brandon S , Barakauskas Vilte E , Grenache David G , Schmidt Robert L
Published: July 2018

Background

Biochemical prenatal screening tests are used to determine the risk of fetal aneuploidy based on the concentration of several biomarkers. The concentration of these biomarkers could be affected by preanalytical factors (PAFs) such as sample type (whole blood vs serum), storage time, and storage temperature. The impact of these factors on posttest risk is unknown.

Methods

Blood samples were collected from 25 pregnant patients. Each sample was divided into 24 aliquots, and each aliquot was subjected to 1 of 24 different treatments (2 sample types × 2 temperatures × 6 storage times). The impact of each PAF on calculated risk was estimated using mixed-effects regression and simulation analysis.

Results

PAFs were associated with statistically significant changes in concentration for some analytes. Simulation studies showed that PAFs accounted for 6% of the variation in posttest risk, and analytical imprecision accounted for 94% of the variation. We estimated that the background misclassification rate due to analytical imprecision is approximately 1.37% for trisomy 21 and 0.12% for trisomy 18. Preanalytical factors increased the probability of misclassification by 0.46% and 0.06% for trisomies 21 and 18, respectively.

Conclusions

Relaxing sample specifications for biochemical prenatal serum screening tests to permit analysis of serum samples stored for up to 72 h at room temperature or 4 °C as well as serum obtained from whole blood stored similarly has a small impact in calculated posttest aneuploidy risk.
Heart Fatty Acid Binding Protein for the Diagnosis of Myocardial Ischemia and Infarction
Authors: Collinson Paul O , Hersey Jennifer , Bray Rosalind , Gaze David , Lim Pitt , Firoozi Sami , Ntalianis Argyrios , Boa Frances , Prasad Abhiram
Published: July 2018

Objective

To establish the analytical performance of a heart fatty acid binding protein (HFABP) method suitable for routine clinical use and examine its role for the diagnosis of myocardial ischemia and myocardial infarction.

Methods

Analyses of HFABP were performed on an Advia 2400 (Siemens Healthcare Diagnostics). Imprecision, limit of detection (LOD), limit of blank (LOB), and linearity were assessed using standard methods. Stability was assessed at 4 °C, −20 °C, and with 3 repeated freeze-thaw cycles. Clinical diagnostic performance was assessed using chest pain in patients, with a final diagnosis according to the universal definition of myocardial infarction with cardiac troponin I (cTnI) measured on the Siemens Advia Centaur (cTnI Ultra method, 99th percentile 50 ng/L, 10% CV 30 ng/L). Ischemia was detected using sampling pre- and postangioplasty.

Results

LOD and analytical imprecision exceeded the manufacturer's specification (LOD 1.128 μg/L, 20% CV 1.3 μg/L, 10% CV 2.75 μg/L). Clinical diagnostic efficiency was less than cTnI. Addition of HFABP to cTnI produced a modest increase in diagnostic sensitivity at a cost of significant loss of specificity.

Conclusions

Although the test had excellent analytical performance, it did not contribute to the clinical diagnosis of patients with chest pain. HFABP appears to be a marker of myocardial infarction not myocardial ischemia.
Stability of Fibroblast Growth Factor 23 in Human Plasma
Authors: Cui Salena , Vaingankar Sucheta M , Stenger Anneke , Waikar Sushrut S , Leaf David E
Published: July 2018

Background

Given the important emerging field of fibroblast growth factor 23 (FGF23) biology, there is a growing need for reliable data on FGF23 assay characteristics. We therefore evaluated the effects of different processing and storage conditions on FGF23 stability, as well as the assay precision of FGF23 measurements using 2 commercially available FGF23 ELISA kits.

Methods

We measured plasma concentrations of intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) in duplicate in 12 patients with a wide range of kidney function. We used blinded replicate samples to calculate the interassay CV for both assays. We processed the samples immediately after collection, after 6 h at 22 °C, or after 24 h at 4 °C. We also exposed samples to 0, 1, 2, or 3 freeze-thaw cycles.

Results

The interassay CVs for iFGF23 and cFGF23 were 5.2% and 7.2%, respectively. Delayed processing for either 6 h at 22 °C or 24 h at 4 °C had no significant effect on either iFGF23 or cFGF23, although a nonsignificant trend toward decreased iFGF23 concentrations was observed compared with immediate processing (23% relative decline in concentrations under both delayed processing conditions). Three freeze-thaw cycles had no effect on either iFGF23 or cFGF23 concentrations.

Conclusions

FGF23 measurements in human plasma are stable with delayed processing or after undergoing multiple freeze-thaw cycles.
Use of Dual-Force Aggregation as a Multiplexed, Rapid Point-of-Care Screening Method for White Blood Cell Counting from Whole Blood Samples
Authors: Nelson Daniel A , Hughes Jacob D , Engel Casey E , Haverstick Doris M , Landers James P
Published: July 2018

Background

Enumeration of blood cells is an integral metric for evaluating patient health and can be used to screen for a wide range of diseases and conditions. Conventional methods rely on large, expensive, and complicated instrumentation that requires trained technicians and is not amenable to point-of-care analysis. This work demonstrates the use of a multiplexed, bead-based assay for both rapid white blood cell (WBC) count screening and accurate, multiplexed WBC counts for point-of-care analysis.

Methods

Blood samples were lysed and diluted before being incubated with silica-coated magnetic particles under chaotropic conditions, a rotating magnetic field, and a source of agitation. The resulting bead aggregation was imaged and correlated to a known WBC count. After establishing standard curves, the WBC count for 18 whole blood samples were determined by this method and compared to values obtained conventionally.

Results

When the optimal dilution factor for lysis of whole blood samples was established, 17 of 18 samples (94.4%) were correctly screened and categorized as having high, typical, or low WBC count, while 14 of 18 samples were within 16% of the reported clinical values. The developed system provides analysis of 13 samples in <3 min with a total analysis time of approximately 10 min (including incubation and dilution) and represents comparable throughput to conventional instrumentation, while providing point-of-care capability with reduced size (14 × 21 × 14 cm) and simplicity.

Conclusions

This work demonstrates the potential for a multiplexed, bead-based assay to be used as a rapid, point-of-care screening method for WBC counting from whole blood samples.
Serum Fibrosis Marker Panels FIB-4 Index and Aspartate Aminotransferase (AST)-to-Platelet Ratio Index (APRI) Are Equivalent to AST Alone at Predicting Liver Fibrosis in a Cohort of 1731 Patients Infected with Hepatitis C Virus
Authors: Drees Julia C , Wi Soora , Ready Joanna B , Dlott Richard S , Fetterman Barbara J , Seo Suk I , Pat Pauly Mary , Petrie Matthew S , Lorey Thomas S
Published: July 2018

Background

Efficient tools are needed to stage liver disease before treatment of patients infected with hepatitis C virus (HCV). Compared to biopsy, several studies demonstrated favorable performance of noninvasive multianalyte serum fibrosis marker panels [fibrosis-4 (FIB-4) index] and aspartate aminotransferase (AST)-to-platelet ratio index (APRI), but suggested cutoffs vary widely. Our objective was to evaluate FIB-4 index and APRI and their component tests for staging fibrosis in our HCV-infected population and to determine practical cutoffs to help triage an influx of patients requiring treatment.

Methods

Transient elastography (TE) results from 1731 HCV-infected patients were mapped to an F0–F4 equivalent scale. Each patient's APRI and FIB-4 index were calculated. Areas under the receiver operator curve (AUROCs) and false-positive and false-negative rates were calculated to retrospectively compare the performance of the indices and their component tests.

Results

The highest AUROCs for distinguishing severe (F3–F4) from mild-to-moderate (F0–F2) fibrosis had overlapping 95% CIs: APRI (0.77; 0.74–0.79), FIB-4 index (0.76; 0.73–0.78), and AST (0.74; 0.72–0.77). Cutoffs had false-negative rates of 2.7%–2.8% and false-positive rates of 6.4%–7.4% for all 3 markers.

Conclusions

AST was as effective as FIB-4 index and APRI at predicting fibrosis. Published cutoffs for APRI and FIB-4 index would have been inappropriate in our population, with false-negative rates as high as 11%. For our purposes, no serum fibrosis marker was sufficiently sensitive to rule-out significant fibrosis, but cutoffs developed for AST, FIB-4 index, and APRI all had specificities of 79.2%–80.3% for ruling-in severe fibrosis and could be used to triage 1/3 of our population for treatment without waiting for TE or liver biopsy.
Laboratory Utilization and Analytical Validation of Fecal Electrolyte Tests
Authors: Parakh Rugvedita , Greene Dina N , Mathias Patrick C , Block Darci R , Ranjitkar Pratistha
Published: July 2018

Background

Chronic diarrhea can be categorized as fatty, watery, or inflammatory. Watery diarrhea is further divided into secretory or osmotic types and can be differentiated by measuring fecal electrolytes and osmotic gap. However, with widespread use of endoscopy, it is unclear if these measurements are being used clinically. Furthermore, because stool is not a validated specimen type for Food and Drug Administration–approved electrolyte assays, utilization is a practical concern for laboratories before analytical validation. Here, we determined the clinical utility and validated the performance characteristics of stool electrolytes on the Beckman Coulter AU680.

Methods

Historical results and literature review were used to determine the clinically relevant ranges for stool electrolytes (Na+, Cl−, K+, phosphate, and Mg2+). Additionally, medical chart review was performed (n = 44 patients) on results to evaluate their clinical utility in chronic diarrhea work-up. Linearity, precision, and stability studies were performed on the AU680. Accuracy was evaluated by comparing results to the Roche Cobas 6000 c501.

Results

For all cases, stool electrolytes and osmotic gap proved valuable in chronic diarrhea work-up. The imprecision of the assays ranged from 0% to 5.9%. All assays were found to be linear within the instrument's analytical measurement range with appropriate slopes and intercepts. The bias between the AU680 and the Roche c501 ranged from −0.48 to 2.39 (mmol/L or mg/dL). Na+, Cl−, and K+ were stable refrigerated for 5 days and up to 1 freeze-thaw cycle. Phosphate and Mg2+ were stable refrigerated for 48 h, but unstable to freeze-thaw cycles.

Conclusions

Stool osmotic gap is valuable for evaluating chronic diarrhea and can be calculated using electrolyte concentrations measured on the AU680.
Application of a Simulation Model to Estimate Treatment Error and Clinical Risk Derived from Point-of-Care International Normalized Ratio Device Analytic Performance
Authors: Lyon Martha E , Sinha Roona , Lyon Oliver A S , Lyon Andrew W
Published: July 2018

Background

In 2016, the Food and Drug Administration (FDA) proposed to enhance performance expectations for point-of-care testing (POCT) international normalized ratio (INR) devices relative to International Organization for Standardization (ISO) 17593:2007. The objective of the study was to estimate the frequency of warfarin dosing errors associated with a central laboratory INR method, a POCT INR method, and the proposed FDA performance goals.

Methods

A data set of INR results (n = 51912) from adult patients with INR ≤4 was used to assess the influence of adding assay imprecision and bias on warfarin dose decisions. The frequency of error in warfarin dose and size of error (≥1 or ≥2 dose categories) was compared using published assay specifications for the Instrumentation Laboratory ACL TOP® and the Roche Diagnostics CoaguChek® XS relative to the proposed FDA guidelines.

Results

The frequency of warfarin dose misclassification was largely influenced by bias and was not sensitive to assay imprecision. The central laboratory and POCT INR methods met the FDA performance specifications, had equal rates of ≥2 warfarin dose category error, and had statistically different rates of ≥1 warfarin dose category error in large samples (n >250).

Conclusions

Simulation models are useful tools for evaluating POCT INR assay performance criteria required to achieve the proposed FDA guidelines. This simulation depicted how the Roche Diagnostics CoaguChek XS instrument meets the guideline.
Use of Automation and Process Improvement to Achieve a Six Sigma Level of Nonanalytic Quality
Authors: Messinger Bonnie L , Rogers David N , Hawker Charles D
Published: July 2018

Background

Clinical laboratories have focused on quality for more than 60 years. While analytic quality is considered excellent in most laboratories, nonanalytic quality is an area for focused improvement. One of our quality metrics, lost samples, has been tracked continuously for 25 years and has demonstrated steady improvement. Nonanalytic processes have become highly automated within our organization, which, we believe, was a major factor in reducing lost samples. We have also implemented numerous behavioral controls and completed many process reengineering projects that have had a demonstrable effect on lost sample rates. Our objective in this study was to determine the overall contributions of our error-proofing methods to reducing lost samples.

Methods

Using data spanning 25 years, we plotted the correlation between lost samples and the implementation dates for 8 major phases of automation along with 16 process improvements and engineering controls.

Results

The lost sample rate decreased nearly 100-fold. In Six Sigma terms, the 12-month moving average for lost samples currently hovers around 5.85-sigma, with several months at or better than 6-sigma. While implementation of process improvements, engineering controls, and automation all contributed to the reduction, automation was the most significant contributor.

Conclusions

The custom automation in use by our laboratory has led to improved nonanalytic quality. Although this level of automation might not be possible for all laboratories, our description of 16 behavior and engineering controls may be useful to other laboratories seeking to design high-quality nonanalytic processes.
Effects of Plasma Exchange and Heparin Concentration on the Serotonin Release Assay in Heparin-Induced Thrombocytopenia
Authors: Tillman Benjamin F , Matafonov Anton , Kingeter Adam J , Shah Ashish S , Gailani David
Published: July 2018

Background

Heparin-induced thrombocytopenia (HIT) is a hypercoagulable state caused by a transient antibody to heparin-bound platelet factor 4 (PF4). Treatment involves discontinuing heparin and administering a nonheparin anticoagulant. Procedures requiring heparin, such as cardiopulmonary bypass, are preferably delayed until the offending antibody is no longer detectable. For patients with a high-titer anti-PF4-heparin antibody and who require exposure to heparin, therapeutic plasma exchange (TPE) has been used to remove the antibody. Recent work indicates that a functional assay for detecting platelet-activating antibodies in HIT patients, the serotonin release assay (SRA), is preferable to ELISAs for anti-PF4-heparin antibodies for following the effectiveness of plasma exchange.

Methods

Two cases of acute heparin-induced thrombocytopenia managed with plasma exchange before emergent cardiac surgery were evaluated with SRAs using a range of heparin concentrations that included those used in cardiopulmonary bypass.

Results

We observed that a single round of plasma exchange led to greater reduction in platelet reactivity at heparin concentrations between 1 and 3 U/mL than at lower concentrations, consistent with the impression that heparin-PF4-antibody complexes form optimally within a limited heparin concentration range.

Conclusions

The findings suggest there may be a range of heparin concentration in which cardiac surgery may be safely performed in HIT patients, and that a single TPE in an emergent setting may lower antibody concentration sufficiently to lower platelet reactivity in the presence of heparin.
Pervasive Gabapentin Interference in the LC-MS/MS Analysis of Amphetamine
Authors: Shugarts Sarah B
Published: July 2018

Background

An LC-MS/MS urine confirmation assay was developed using a “dilute and shoot” sample preparation method that was subject to interference arising from gabapentin column overload in approximately 4% of patient samples, leading to interference in amphetamine analysis.

Methods

The initial analysis method used dilute and shoot sample preparation followed by LC-MS/MS analysis. The improved assay used solid-phase extraction sample preparation followed by LC-MS/MS analysis.

Results

The improved assay using solid-phase extraction and alternative chromatographic conditions resolved the gabapentin interference in amphetamine analysis.

Conclusions

This experience illustrates the importance of thorough knowledge of likely comedications in a patient population and these drugs' elimination mechanisms. Laboratorians should be aware of the phenomenon of mass effect LC-MS/MS interference, in addition to the more common LC-MS/MS interferences caused by matrix effects and isobaric compounds.
Analytical Considerations When Developing an LC-MS/MS Method for More than 30 Analytes
Authors: Enders Jeffrey R , Smith Jeremy P , Feng Sheng , Strickland Erin C , McIntire Gregory L
Published: July 2018

Background

While validation of analytical (LC-MS/MS) methods has been documented in any number of articles and reference texts, the optimal design and subsequent validation of a method for over 30 analytes presents special challenges. Conventional approaches to calibration curves, controls, and run time are not tenable in such methods. This report details the practical aspects of designing and implementing such a method in accordance with College of American Pathologists validation criteria.

Methods

Conventional criteria were followed in the design and validation of a method for 34 analytes and 15 internal standards by LC-MS/MS. These criteria are laid out in a standard operating procedure, which is followed without exception and is consistent with College of American Pathologists criteria.

Results

The method presented herein provides quality results and accurate medication monitoring. The method was optimized to negate interferences (both from within the method and from potential concomitant compounds), increase throughput, and provide reproducible quality quantification over relevant analyte concentrations ranges.

Conclusions

The method was designed primarily with quality and accurate medication monitoring in mind. The method achieves these goals by use of novel approaches to calibration curves and controls that both improve performance and minimize risk (financial and operational). As automation and LC-MS/MS equipment continue to improve, it is expected that more methods like this one will be developed.
Selective, Accurate, and Precise Quantitation of Glutarylcarnitine in Human Urine from a Patient with Glutaric Acidemia Type I
Authors: Minkler Paul E , Stoll Maria S K , Ingalls Stephen T , Hoppel Charles L
Published: July 2018

Background

Although correctly used in expanded newborn screening programs to identify patients with possible diseases, flow-injection tandem mass spectrometry (MS/MS) acylcarnitine “profiles” are inadequate for standard clinical uses owing to their limited quantitative accuracy and lack of selectivity. We report the application of our selective, accurate, and precise method for quantification of acylcarnitines, applied to urine glutarylcarnitine from a patient with glutaric acidemia type I (GAI).

Methods

A previously validated acylcarnitine ultra-HPLC-MS/MS method was used, with a focus on analysis of glutarylcarnitine. Calibrants and samples were isolated by solid-phase extraction and derivatized with pentafluorophenacyl trifluoromethanesulfonate. Acylcarnitine pentafluorophenacyl esters were eluted in 14-min chromatograms. Standardized calibrants and a 13-point, 200-fold concentration range calibration curve were used for accurate quantification of glutarylcarnitine. Quality control samples validated method accuracy and long-term analytic stability.

Results

Quantification of glutarylcarnitine in urine from a patient with GAI is reported. Long-term analytical stability of the method over a 5-year period is shown.

Conclusions

Our method for acylcarnitine quantification is shown to be selective, accurate, and precise; thus, we recommend it for confirmatory testing and monitoring of plasma and urine samples from patients with GAI.