bluuebunny/crossref_metadata_2025 huggingface dataset:
α-Glutathione S-Transferase: A New Biomarker for Liver Injury?
Authors: Maina Ian , Rule Jody A , Wians Frank H , Poirier Michael , Grant Lafaine , Lee William M
Published: July 2018

Background

Serum alanine and aspartate aminotransferases (ALT/AST) have been the gold standard for detection and quantification of liver injury for over 6 decades, but have relatively long half-lives (T½) (literature estimates approximately 17 and 47 h, respectively) and thus do not reflect immediate changes in liver injury or recovery. A new point-of-care immunoassay for α-glutathione S-transferase (α-GST) measures this cytosolic liver enzyme with a predicted T½ of 60–90 min based on preliminary studies and might enable earlier detection of improving or worsening liver injury than conventional enzyme testing.

Methods

Serial serum samples collected daily from 31 patients enrolled in the Acute Liver Failure Study Group, with acetaminophen (APAP) toxicity, drug-induced liver injury, ischemic hepatopathy (IH), or autoimmune hepatitis were analyzed to determine α-GST using the Qualigen FastPack® α-GST Assay (Carlsbad), a chemiluminescent immunoassay using a paramagnetic particle matrix with an upper limit of normal of 11 ng/mL. AST and ALT values were obtained from the medical record and have an upper limit of normal of 40 IU/L. The T½ values for α-GST, AST, and ALT were calculated from the peak value for APAP and IH etiologies considered as single time point injuries, using an exponential trendline equation of the serial values.

Results

Median α-GST for all etiologies were increased on day 1, returning to normal by day 3, whereas median AST and ALT values did not return to normal, even at day 7. The median T½ for α-GST, AST, and ALT were 6.4, 22.2, and 33.9 h, respectively.

Conclusions

α-GST is a more responsive marker of liver injury/recovery, allowing for more rapid real-time assessment of improvement or worsening of liver disease.
Rapid Quantification of Medroxyprogesterone Acetate (MPA) in Human Plasma by LC-MS/MS
Authors: Hummert Pamela , Manohar Madhuri , Aung Wutyi S , Marzinke Mark A
Published: July 2018

Background

Medroxyprogesterone acetate (MPA) is a common contraceptive agent taken both orally and as a subcutaneous or intramuscular injection. Current LC-MS/MS methods for MPA quantification require large sample volumes and low-throughput analytical run times. Therefore, there are opportunities to improve upon existing methods for MPA quantification.

Methods

MPA was extracted from 600 μL plasma, evaporated to dryness, and the reconstituted solution was injected onto a Waters Acquity liquid chromatography (LC) system via an Agilent Zorbax Eclipse-Plus C18 2.1 × 50 mm (5.0 μm) column. MPA and its internal standard were monitored on a QTRAP® 5500 mass analyzer operated in positive ionization mode. The method was validated according to the Food and Drug Administration Bioanalytical Method Validation guidelines.

Results

The analytical measuring range of the assay was 200–10 000 pg/mL. QC samples prepared at the lower limit of quantification (LLOQ; 200 pg/mL) and low (600 pg/mL), mid (1750 pg/mL), and high (8500 pg/mL) levels showed interassay precision and accuracy ≤15.2% and ≤±9.6%, respectively. Stability-challenged samples yielded ≤15% from freshly prepared samples. Dilutional and matrix effects studies were also acceptable. The assay was also assessed in participants prescribed depot medroxyprogesterone acetate; observed concentrations were within the dynamic range of the assay.

Conclusions

An LC-MS/MS method for the quantification of MPA in plasma has been developed and validated. The described method is sufficiently sensitive and robust to quantify MPA in plasma and meets the criteria to support clinical trials.
Inter-Laboratory Robustness of Next-Generation Bile Acid Study in Mice and Humans: International Ring Trial Involving 12 Laboratories
Authors: Pham Hai T , Arnhard Kathrin , Asad Yasmin J , Deng Lu , Felder Thomas K , St John-Williams Lisa , Kaever Volkhard , Leadley Michael , Mitro Nico , Muccio Stephane , Prehn Cornelia , Rauh Manfred , Rolle-Kampczyk Ulrike , Thompson J Will , Uhl Olaf , Ulaszewska Maria , Vogeser Michael , Wishart David S , Koal Therese
Published: July 2018

Background

The increasing relevance of individual bile acids quantification in biological samples requires analytical standardization to guarantee robustness and reliability of laboratory results. We have organized the first international ring trial, carried out in 12 laboratories, to evaluate the newly developed LC-MS/MS–based test kit for bile acid analysis.

Methods

Each laboratory received a Biocrates® Bile Acids Kit including system suitability test (SST) protocol. The kit is designed to analyze 16 individual human and 19 mouse bile acids. A set of 9 human and mouse plasma samples was measured in replicates. Laboratories were first required to pass the acceptance criteria for the SST. Within the subset of laboratories passing SST criteria, we evaluated how many laboratories met the target criteria of 80% of reported values with a relative accuracy within the 70%–130% range and analytical precisions (%CV) below 30%.

Results

A total of 12 of 16 participating laboratories passed the SST as the prerequisite to enter the ring trial. All 12 laboratories were then able to successfully run the kit and ring trial samples. Of the overall reported values, 94% were within 70%–130% relative accuracy range. Mean precision was 8.3% CV. The condition of CV <30% was fulfilled by 99% of the reported values.

Conclusions

The first publically available interlaboratory ring trial for standardized bile acids quantification in human and mouse plasma samples showed very good analytical performance, within acceptance criteria typically applied in the preclinical environment. The kit is therefore suitable for standardized quantitative bile acid analysis and the establishment of reference values.
Verification of Claimed Limit of Detection in Molecular Diagnostics
Authors: Vaks Jeffrey E , Hemyari Parichehr , Rullkoetter Matthias , Santulli Michael J , Schoenbrunner Nancy
Published: July 2018

Background

Limit of detection (LOD) is an important performance characteristic of clinical laboratory tests. Verification, as recommended by the CLSI EP17-A2 guideline, is done by testing a sample with a claimed LOD concentration. Claimed LOD is verified if the 95% CI for the population proportion, calculated from observed proportion of positive results, contains the expected detection rate of 95% (CLSI EP17-A2; Clin Chem 2004;50:732–40). Claimed LOD, verification sample concentration, and observed rate of positive results are subjects to systematic and random errors that can cause false failure or false acceptance of the LOD verification. The aim of this study was to assess the probability to pass or fail verification of claimed LOD with various numbers of tests as function of the ratio of test sample concentration and actual LOD for PCR-based molecular diagnostics tests and provide recommendations for study design.

Methods

A method of calculating the probability of passing the claimed LOD verification following CLSI EP17-A2 guideline recommendations, based on the Poisson–binomial probability model, have been developed for PCR-based assays.

Results

Calculations and graphs have shown that the probability of passing LOD verification depends on the number of tests and has local minima and maxima between 0.975 and 0.995 for the number of tests from 20 to 1000 on samples having actual LOD concentration. The probability of detecting the difference between claimed LOD and actual LOD increases with the number of tests performed. Graphs and tables with examples are included.

Conclusions

Method, tables, and graphs helping in planning LOD verification study in molecular diagnostics are provided along with the recommendations on what to do in case of failure to verify the LOD claim.
Lipoprotein Biomarkers and Risk of Cardiovascular Disease: A Laboratory Medicine Best Practices (LMBP) Systematic Review
Authors: Sandhu Paramjit K , Musaad Salma M A , Remaley Alan T , Buehler Stephanie S , Strider Sonya , Derzon James H , Vesper Hubert W , Ranne Anne , Shaw Colleen S , Christenson Robert H
Published: July 2018

Background

Controversy exists about the incremental utility of nontraditional lipid biomarkers [e.g., apolipoprotein (apo) B, apo A-I, and non-HDL-C] in improving cardiovascular disease (CVD) risk prediction when added to a conventional model of traditional risk factors (e.g., total cholesterol, LDL cholesterol, HDL cholesterol, sex, age, smoking status, and blood pressure). Here we present a systematic review that was conducted to assess the use of nontraditional lipid biomarkers including apo B, apo A-I, apo B/A-I ratio, and non-HDL-C in improving CVD risk prediction after controlling for the traditional risk factors in populations at risk for cardiovascular events.

Content

This systematic review used the Laboratory Medicine Best Practices (LMBP™) A-6 methods. A total of 9 relevant studies published before and including July 2015 comprised the evidence base for this review. Results from this systematic review indicated that after the adjustment for standard nonlipid and lipid CVD risk factors, nontraditional apolipoprotein biomarkers apo B (overall effect = relative risk: 1.31; 95% CI, 1.22–1.40; 4 studies) and apo B/apo A-I ratio (overall effect = relative risk: 1.31; 95% CI, 1.11–1.38; 7 studies) resulted in significant improvement in long-term CVD risk assessment.

Available evidence showed that nontraditional lipid biomarkers apo B and apo B/apo I ratio can improve the risk prediction for cardiovascular events after controlling for the traditional risk factors for the populations at risk. However, because of insufficient evidence, no conclusions could be made for the effectiveness of apo A-I and non-HDL-C lipid markers to predict the CVD events, indicating a need for more research in this field.
Score Using Measurements of Plasma Midregional Pro–Atrial Natriuretic Peptide to Estimate the Duration of Atrial Fibrillation
Authors: Legallois Damien , Sorbets Emmanuel , Chenevier-Gobeaux Camille , Hallouche Maya , Boubaya Marouane , Charnaux Nathalie , Lebon Alain , Levy Vincent , Beygui Farzin , Meune Christophe
Published: July 2018

Background

An accurate estimate of the duration of atrial fibrillation (AF) is critical for its safe and successful management. We examined the ability of midregional pro–atrial natriuretic peptide (MR-proANP) to identify patients presenting with AF of ≤48 vs >48 h in duration.

Methods

We prospectively studied 106 patients presenting with AF of known duration. We examined the predictive values of MR-proANP and N-terminal pro–brain natriuretic peptide (NT-proBNP) in the detection of recent-onset AF, in addition to other factors identified by multiple variable analyses.

Results

In patients presenting with AF of ≤48 vs >48 h in duration, the median MR-proANP plasma concentration was 147.7 [95.3–197.4] pmol/L vs 220.4 [154.0–303.1] pmol/L (P <0.001). MR-proANP and NT-proBNP were correlated (r = 0.5, P <10−7), but MR-proANP tended to better discriminate AF of ≤48 h in duration than NT-proBNP (P = 0.09). A score including heart rate, dyspnea, and MR-proANP concentration accurately detected AF of ≤48 h in duration (area under the curve = 0.890; 95% CI, 0.828–0.952). A score of 98 points was an optimal cutoff that excluded AF of ≤48 h in duration with a sensitivity of 95%, while a score of 132.5 points was an optimal cutoff that confirmed AF of ≤48 h in duration with a sensitivity of 95%. Overall, a score ≤98 or ≥132.5 identified AF of ≤48 h in duration in 56% of patients.

Conclusions

A score based on a model including heart rate, dyspnea, and plasma MR-proANP concentration was helpful in identifying AF of ≤48 h in duration.
Frequency that Laboratory Tests Influence Medical Decisions
Authors: Ngo Andy , Gandhi Paras , Miller W Greg
Published: July 2018

Background

Among the variables that influence medical decisions, laboratory tests are considered to be among the most important and frequently used. The influence of laboratory tests on medical decisions has been difficult to estimate. The goal of this study was to estimate the number of patient encounters that included a laboratory test.

Methods

We extracted information for 72196 patient encounters from 1-week intervals each quarter of a year from our comprehensive academic medical center electronic medical record. The patients examined represent a comprehensive range of clinical conditions and medical services. We determined for which encounters laboratory and other orders existed.

Results

Overall 35% of encounters had 1 or more laboratory tests ordered. However, the percent varied markedly with patient care areas. For inpatient, emergency department, and outpatient populations, 98%, 56%, and 29%, respectively, had 1 or more laboratory tests ordered.

Conclusions

Our observations support that it is not possible to use a single number to categorize the frequency with which laboratory tests occur in patient encounters. Utilization of laboratory tests varied with type of medical service with almost all inpatients, approximately half of emergency department patients, and nearly one-third of outpatients having laboratory tests during their healthcare visit.
Renal Function Influences Diagnostic Markers in Serum and Urine: A Study of Guanidinoacetate, Creatine, Human Epididymis Protein 4, and Neutrophil Gelatinase–Associated Lipocalin in Children
Authors: Salvador Cathrin L , Tøndel Camilla , Rowe Alexander D , Bjerre Anna , Brun Atle , Brackman Damien , Bolstad Nils , Mørkrid Lars
Published: July 2018

Background

Impaired renal function may affect the level of diagnostic disease markers. The aim of the study was to investigate the effect of measured glomerular filtration rate (GFR) on 4 diagnostic markers in blood and urine—guanidinoacetate (GAA), creatine (CRE), human epididymis protein 4 (HE4), and neutrophil gelatinase–associated lipocalin (NGAL)—and how this could affect the decision and reference limits.

Methods

We examined 96 children (median age 9.2 years, range 0.25–17.5) with different stages of chronic kidney disease (CKD). GFR [median 65.9 mL · min−1 · (1.73 m2)−1, range 6.3–153] was measured by iohexol clearance using 7 venous blood samples after iohexol injection. Fasting serum and urinary GAA, CRE, HE4, NGAL, and creatinine (crn) were analyzed. After appropriate transformation of the markers, a multiple linear regression analysis examined the influence of age, sex, and measured GFR.

Results

The level of GFR significantly affected S-GAA (P = 2 × 10−4) and U-GAA/crn (P = 5 ×10−11), leading to decreased values in renal impairment. GFR did not correlate significantly with the level of CRE and to a minor degree did the U-CRE/crn ratio (P = 0.54 and 0.01, respectively). The level of GFR significantly affected S-HE4 (P = 4 × 10−31) and U-HE4/S-HE4 ratio (P = 2 × 10−21) with increased serum values and decreased U-HE4/S-HE4 ratio in renal impairment. S-NGAL increased with decreasing kidney function (P = 2 × 10−19).

Conclusions

Diagnostic disease markers may be influenced by the renal function, and this must be taken into account when interpreting test results. Decreased renal function could change the level of the marker above or below decision limits, leading to diagnostic misinterpretation.

Clinical Trial Registration

ClinicalTrials.gov, Identifier NCT01092260, https://clinicaltrials.gov/ct2/show/NCT01092260?term=tondel&rank=2
Validation of an Automated Assay for Levetiracetam (Keppra) on Vitros 5600
Authors: Ali Mahesheema , Tam Estella , Roper Stephen M , Cao Jing , Devaraj Sridevi
Published: July 2018

Objective

Levetiracetam (also known as Keppra™) is an antiepileptic drug that has been demonstrated as an effective adjunctive therapy in the treatment of partial onset of seizures, primary generalized tonic-clonic seizures, and myoclonic seizures. The aim of our study was to validate an automated quantitative immunoassay for levetiracetam at Texas Children's Hospital.

Method

We validated the analytical performance of ARK™ Levetiracetam Assay on an Ortho Clinical Diagnostic Vitros 5600 Analyzer at Texas Children's Hospital. Analytical performance parameters included precision, linearity, sensitivity, accuracy, and effect of common interferents (free hemoglobin, bilirubin, triglycerides). We also tested common drug interferents on the ARK Levetiracetam Assay.

Results

The assay showed good precision with <4% coefficient of variation (%CV) for intraassay and <7% for interassay precision, respectively. The assay was linear across the measurement range (0.0–100.00 μg/mL). No significant effect was seen with common interferents or commonly co-used drugs.

Conclusions

The ARK Levetiracetam Assay on Ortho Clinical Diagnostic Vitros 5600 can be used for routine determination of levetiracetam for conducting therapeutic drug monitoring and optimizing individual dosage regimen.
Cyanide-Nitroprusside Colorimetric Assay: A Rapid Colorimetric Screen for Urinary Cystine
Authors: Brady Clayton T , Giesen Callen D , Voskoboev Nikolay , Chirackal Robin S , Gavrilov Dimitar K , Flanagan Ryan M , Lieske John C
Published: July 2018

Background

Cystinuria is an autosomal recessive disorder resulting in poor proximal tubule reabsorption of cystine in the nephron, increasing the risk of cystine stone formation. A fast, inexpensive assay to screen for urinary cystine is needed because cystine stones are difficult to noninvasively differentiate from more common calcium-containing ones. Tandem mass spectrometry (MS/MS) is sensitive and specific but is labor-intensive and costly. Alternatively, a colorimetric assay is fast and cost-effective; however, creatinine interference is an issue.

Methods

A published cyanide-nitroprusside colorimetric assay was modified for a high-throughput microplate format. Creatinine interference was reduced using 0.1 mol/L PBS and a standard reaction time of 60 s and was further corrected using a formula derived from the slope of multiple creatinine standard curves.

Results

The limit of blank was determined to be 2.6 mg/L, the limit of detection 11.9 mg/L, and the limit of quantitation 15.3 mg/L. The analytic measurement range was established as 15.3–100 mg/L cystine. Intraassay and interassay CV was calculated to be 9.6% and 8.0%, respectively, for a high-level cystine concentration (83.6 mg/L). Low-level cystine (36.4 mg/L) intraassay and interassay CV was determined to be 18.1% and 17.6%, respectively. Passing–Bablok regression analysis of colorimetric vs LC-MS/MS results revealed a slope of 1.10 and y intercept of −7.14 mg/L, with an overall bias of 2% by Bland–Altman plot analysis.

Conclusions

We analytically validated a rapid colorimetric assay suitable to quantify urinary cystine. The effect of thiol drugs on this assay remains to be determined.
Comparison of 13 Commercially Available Cardiac Troponin Assays in a Multicenter North American Study
Authors: Christenson Robert H , Jacobs Ellis , Uettwiller-Geiger Denise , Estey Mathew P , Lewandrowski Kent , Koshy Thomas I , Kupfer Kenneth , Li Yin , Wesenberg James C
Published: July 2018

Background

We examined the concordance of 13 commercial cardiac troponin (cTn) assays [point-of-care, high-sensitivity (hs), and conventional] using samples distributed across a continuum of results.

Methods

cTnI (11 assays) and cTnT (2 assays) were measured in 191 samples from 128 volunteers. cTn assays included Abbott (iSTAT, STAT, and hs), Alere (Cardio 3), Beckman (AccuTnI+3), Pathfast (cTnI-II), Ortho (Vitros), Siemens (LOCI, cTnI-Ultra, Xpand, Stratus CS), and Roche [4th Generation (Gen), hs]. Manufacturer-derived 99th percentile cutoffs were used to classify results as positive or negative. Alternative 99th percentile cutoffs were tested for some assays. Correlation was assessed using Passing–Bablok linear regression, bias was examined using Bland–Altman difference plots, and concordance/discordance of each method comparison was determined using the McNemar method.

Results

Regression slopes ranged from 0.63 to 1.87, y-intercepts from 0.00 to 0.03 ng/mL, and r values from 0.93 to 0.99. The cTnT methods had a slope of 0.93, y-intercept of 0.02 ng/mL, and r value of 0.99. For the cTnI assays, positive, negative, and overall concordance was 76.2%–100%, 66.0%–100%, and 82.9%–98.4%, respectively. Overall concordance between the 4th Gen cTnT and hsTnT assays was 88.9%. A total of 30 of the 78 method comparisons showed significant differences in classification of samples (P <0.001); the iSTAT showed 10, hsTnT showed 9, AccuTnI+3 showed 5, Xpand showed 5, and Stratus CS showed 1. Using alternative 99th percentile cutoffs to those listed by manufacturers lowered the method discordance by 6-fold, from 30 to 5 (all involved iSTAT).

Conclusions

These data provide insight into characteristics of cTn methods and will assist the healthcare community in setting expectations for relationships among commercial cTn assays.
Biological Variation of Donor-Derived Cell-Free DNA in Renal Transplant Recipients: Clinical Implications
Authors: Bromberg Jonathan S , Brennan Daniel C , Poggio Emilio , Bunnapradist Suphamai , Langone Anthony , Sood Puneet , Matas Arthur J , Mannon Roslyn B , Mehta Shikha , Sharfuddin Asif , Fischbach Bernard , Narayanan Mohanram , Jordan Stanley C , Cohen David J , Zaky Ziad S , Hiller David , Woodward Robert N , Grskovic Marica , Sninsky John J , Yee James P , Bloom Roy D
Published: July 2018

Background

Previous studies have demonstrated that donor-derived cell-free DNA (dd-cfDNA) found in circulating blood of transplant recipients may serve as a noninvasive biomarker of allograft rejection. To better interpret the clinical meaning of dd-cfDNA, it is essential to understand the biological variation of this biomarker in stable healthy recipients. This report establishes the biological variation and clinical reference intervals of dd-cfDNA in renal transplant recipients by using an analytically validated assay that has a CV of 6.8%.

Methods

We sampled venous blood at patient surveillance visits (typically at posttransplant months 1–4, 6, 9, and 12) in a 14-center observational study. Patients with stable renal allograft function spanning ≥3 serial visits were selected. We used AlloSure®, a targeted next-generation sequencing-based approach, to measure dd-cfDNA in the plasma and computed the intraindividual CV (CVI) and interindividual CV (CVG), the index of individuality (II), and reference change value (RCV).

Results

Of 93 patients, 61% were men, 56% were Caucasian, mean age was 49 years, and 63% were deceased donor kidney recipients. Of 380 blood samples, the dd-cfDNA median value was 0.21% (interquartile range 0.12%–0.39%) and the 97.5th percentile was 1.20%. In 18 patients with an average of 4.1 tests, the CVI was 21%, CVG was 37%, II was 0.57, and RCV was 61%.

Conclusions

In a renal transplant recipient, a dd-cfDNA level above 1.2% is out of range and potentially abnormal. A serial increase of up to 61% in level of dd-cfDNA in a patient may be attributable to biological variation.

Clinicaltrials.gov Identifier: NCT02424227
Use of Biosynthetic Controls as Performance Standards for Next-Generation Sequencing Assays of Somatic Tumors: A Multilaboratory Study
Authors: De Abreu Francine B , Peterson Jason D , Deharvengt Sophie J , Daber Robert , Sarsani Vishal K , Spotlow Vanessa , Harrington Robin D , Lih Chih-Jian , Williams P Mickey , Bouk Courtney H , Konigshofer Yves , Huang Catherine , Anekella Bharathi , Davis Lorn , Garlick Russell K , Ferreira-Gonzalez Andrea , Dumur Catherine I , Fernandes Helen , Haralampu Stephen , Tsongalis Gregory J
Published: July 2018

Background

Next-generation sequencing (NGS) assays are highly complex tests that can vary substantially in both their design and intended application. Despite their innumerous advantages, NGS assays present some unique challenges associated with the preanalytical process, library preparation, data analysis, and reporting. According to a number of professional laboratory organization, control materials should be included both during the analytical validation phase and in routine clinical use to guarantee highly accurate results. The SeraseqTM Solid Tumor Mutation Mix AF10 and AF20 control materials consist of 26 biosynthetic DNA constructs in a genomic DNA background, each containing a specific variant or mutation of interest and an internal quality marker at 2 distinct allelic frequencies of 10% and 20%, respectively. The goal of this interlaboratory study was to evaluate the Seraseq AF10 and AF20 control materials by verifying their performance as control materials and by evaluating their ability to measure quality metrics essential to a clinical test.

Methods

Performance characteristics were assessed within and between 6 CLIA-accredited laboratories and 1 research laboratory.

Results

Most laboratories detected all 26 mutations of interest; however, some discrepancies involving the internal quality markers were observed.

Conclusion

This interlaboratory study showed that the Seraseq AF10 and AF20 control materials have high quality, stability, and genomic complexity in variant types that are well suited for assisting in NGS assay analytical validation and monitoring routine clinical applications.
The Case Back on the TRAIL: Death Receptors as Markers for rhTRAIL Sensitivity
Authors: Turner Katherine A , Kalafatis Michael
Published: July 2018

Background

Personalized cancer treatments can be applied to the clinical use of recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL). rhTRAIL holds great promise because of its selectivity for cancer cells. However, rhTRAIL clinical trials were conducted without the screening of patients' tumors for rhTRAIL-binding death receptor (DR)4 and DR5, and the unselected treatment resulted in a lack of clinical benefit. Here we propose an in vitro test to analyze tumor cells isolated from patients for the membrane expression of DRs to determine patient suitability for rhTRAIL treatment.

Methods

Using a panel of malignant melanoma cell lines, the correlation between DR membrane expression and rhTRAIL sensitivity was evaluated. The membrane expression of DR4 and DR5 was examined through staining with anti-DR4 and -DR5 antibodies followed by fluorescence-activated cell sorting. rhTRAIL sensitivity was determined through Annexin-V and propidium iodide staining and Western blotting after rhTRAIL treatment.

Results

Here we show a direct correlation between the membrane expression of DRs and rhTRAIL sensitivity. rhTRAIL-sensitive melanoma lines, on average, had nearly 4-fold more DR4 and >2-fold more DR5 than rhTRAIL-resistant lines. For a cancer cell to display rhTRAIL sensitivity, the optimum expression of DRs is essential. To overcome the apoptotic threshold, cancer cells must express DRs >2-fold higher compared with their benign counterpart.

Conclusion

These data show the potential of this flow cytometry-based assay for the analysis of isolated tumor cells for DR membrane expression. By first determining a patient's susceptibility to rhTRAIL-based treatments, they can be more appropriately placed in rhTRAIL clinical trials and improve rhTRAIL as an anticancer therapeutic.
Standardization of Urine Albumin Measurements: Status and Performance Goals
Authors: Miller W Greg , Seegmiller Jesse C , Lieske John C , Narva Andrew S , Bachmann Lorin M
Published: July 2018

Background

Urine albumin is a key laboratory test used for classification, assessment of risk, and monitoring treatment of patients with chronic kidney disease. Urine albumin measurement results are not standardized among different measurement procedures. Consequently, clinical guidelines using fixed decision values for urine albumin cannot be applied consistently.

Content

Isotope dilution mass spectrometry reference measurement procedures and certified reference materials are being developed to enable standardization of immunoassay measurement procedures for urine albumin. A previous report determined calibration bias was the major error source for differences in results among different measurement procedures for urine albumin. Performance goals for between-day precision, ≤6% CV above 15 mg/L, and for specimen-specific effects, ≤6% CV, were established on the basis of the performance capability of current measurement procedures. The biological variation model was used to estimate a total allowable error of ≤24%–30% and from that the goal for bias of ≤7%–13%.

A reference system of higher-order certified reference materials and reference measurement procedures is being developed to enable standardization of urine albumin measurement results. Goals have been established for total allowable error, specimen-specific effects, imprecision, and bias to facilitate efforts to standardize urine albumin measurement results.
High-Throughput LC-MS/MS Method for Determination of the Alcohol Use Biomarker Phosphatidylethanol in Clinical Samples by Use of a Simple Automated Extraction Procedure—Preanalytical and Analytical Conditions
Authors: Isaksson Anders , Walther Lisa , Hansson Therese , Andersson Anders , Stenton Joanna , Blomgren Anders
Published: July 2018

Background

Phosphatidylethanol (PEth) is an alcohol use biomarker with higher clinical sensitivity and specificity than commonly used alcohol markers. Since its introduction as a clinical alcohol-marker in 2006, the number of samples sent to our laboratory for the determination of PEth has shown a strong annual increase. This has prompted the need to develop a cost-effective and reliable analytical procedure with high capacity.

Methods

An LC-MS/MS method for the determination of PEth 16:0/18:1 with a short turnaround time (3 min) has been evaluated with respect to accuracy, sensitivity, and precision. We compared this method with a previously used HPLC method, as well as a manual and a simplified automated method for sample workup, and investigated potential causes of analytic and preanalytic errors.

Results

The method shows limits of detection and quantification of 0.0075 μmol/L (5.2 ng/mL) and <0.05 μmol/L (<35 ng/mL), respectively. During a 2.1-year period, the method has shown a total CV < 8% for control samples (n = 2808) in the range of 0.10 (70) to 3.5 μmol/L (2461 ng/mL). The simplified automated method for sample preparation works equally well as the manual one. No specific and clinically significant causes of preanalytic errors were found.

Conclusions

This LC-MS/MS method with automated sample workup is well suited for a clinical laboratory with LC-MS/MS experience and has the capability, proven from several years of use, to produce reliable PEth results in a high-volume laboratory (>50000 clinical samples/year).
Comparison of Clinical Laboratory Assays for Measuring Serum Infliximab and Antibodies to Infliximab
Authors: Willrich Maria Alice V , Lazar-Molnar Eszter , Snyder Melissa R , Delgado Julio C
Published: July 2018

Background

Infliximab (IFX) is a chimeric monoclonal antibody targeting tumor necrosis factor-α, used for the management of autoimmune and inflammatory diseases. Immunogenicity to this protein drug may lead to therapeutic failure. Laboratory testing for serum IFX and antidrug antibodies (ADAs) is available for the evaluation of clinical nonresponsiveness. The purpose of this study was to compare the performance of testing methodologies used by 2 clinical reference laboratories for the quantification of IFX and detection of ADAs.

Methods

Deidentified serum samples submitted for clinical testing were selected (n = 120) and tested at both sites. A trypsin-based LC-MS/MS assay for IFX and a bridging electrochemiluminescent immunoassay (ECLIA) for ADAs (Mayo Clinic) and a functional cell-based reporter gene assay (RGA) to measure both bioactive drug concentrations and neutralizing ADAs (ARUP Laboratories) were compared.

Results

In all, 105 samples had measurable concentrations of IFX by both methods and yielded a correlation coefficient (r) = 0.917, slope = 1.028, and intercept = −0.377. One outlier measured <1.0 μg/mL by LC-MS/MS and 37 μg/mL by RGA, which was confirmed to be attributed to the presence of adalimumab. Regarding detection of ADAs, 81 of 120 samples were negative by ECLIA and RGA, whereas 30 of 120 were positive by both methods, resulting in an overall 92.5% agreement.

Conclusion

Although there are substantial methodological differences in the assays used for detecting IFX and ADAs, results show significant concordance between the clinically validated methodologies performed in different laboratories.
Ulises: An Agent-Based System For Timbre Classification
Authors: Teixeira Eduardo Porto , Goncalves Eder M. N. , Adamatti Diana F.
Published: July 2018

The Sound and Music Computing (SMC) field has grown over the years and every time there are more conferences and specialized researchers in this area. The sub-field of Music Information Retrieval (MIR), one of the main research fields on SMC has focused on getting information from sound data. The most critical issue with regard to the human perception of sound is: what are the qualities of musical instrument sounds to perform recognition of its sound sources. There are four main sound dimensions: pitch, loudness, duration and timbre. The fourth dimension, timbre, is the most vague and complex dimension, a complex and high-level multidimensional property. Recognition of timbres is an area of high interest within MIR, being present in several papers state of the art on SMC. About Multi-Agent Systems (MAS), the term autonomous refers to the fact that the agents have their own existence, regardless of the existence of other agents, and are able to take own decisions without outside interference. Agents technology is particularly suitable for musical applications because of the possibility of associating a computational agent with the role of a singer or instrumentalist as can be seen in works state of art in SMC area. In this context, this paper proposes a agent-based approach to timbre recognition, focusing on the parallelization of the classification model. For this, we assign a method of recognition of timbres to different agents, where each agent is a specialized entity in a particular timbre, characteristic of a specific instrument, seeking a distributed solution for solving the timbre recognition problem.
An Agent-based Environment for Dynamic Positioning of the Fogg Behavior Model Threshold Line
Authors: Guimaraes Marcus , Adamatti Diana , Emmendorfer Leonardo
Published: July 2018

In this paper, it is presented a mathematical modeling for the action line, or threshold line, of the Fogg Behavior Model (FBM) as well as an analysis of its positioning in relation to the dataset. According to the mathematical modeling formation process for both Motivation and Ability axes, the action line evaluation was performed by simulations via agents. This behavioral model is mainly used as an empirical evaluation method applied to processes based on persuasive technologies. The results showed that the threshold line should not be fixed, as originally proposed in the model, but dynamically allocated based on the Kolmogorov mean. This dynamic allocation ensures its use as a visual feature towards greater efficiency in triggers implementations. This work aims to contribute with an approach that transits between theoretical and practical when related to applications that requires the FBM, thus allowing the use of this behavioral model with higher degree of certainty and thus maximizing efficiency in the evaluation and implementation processes based on persuasive technologies.
La doble recepción del spinozismo en Alemania durante el siglo XVIII
Authors: Solé María Jimena
Published: July 2018

Este artículo reconstruye la recepción del pensamiento de Spinoza en Alemania desde 1670 hasta 1789 y propone una nueva interpretación de este proceso. Sostenemos que la recepción del spinozismo en Alemania durante este periodo es controlado por una imagen de esta doctrina, que la presenta esencialmente como ateísta. Creemos que esta caracterización del spinozismo como un ateísmo recubre dos constelaciones problemáticas diferentes. Por un lado, se refiere a la incompatibilidad de la filosofía spinoziana con el teísmo y remite a los peligros que ésta representa para el orden religioso, moral y político basado en la existencia de un Dios teísta. El problema que subyace es, por lo tanto, la cuestión de los fundamentos metafísicos necesarios para sostener un determinado orden. Por otro lado, Spinoza es denunciado como un ateísta por su intención de demostrar racionalmente la existencia de Dios, por sostener que la razón humana es capaz de acceder a la verdad sin auxilio externo, sin iluminación sobrenatural. Este segundo aspecto de la recepción del spinozismo se superpone con la discusión acerca de los alcances y límites de la razón humana y, por lo tanto, con el núcleo mismo de la Ilustración.
Vida, historia y psicología en Wilhelm Dilthey
Authors: Lorenzo Luis María
Published: July 2018

Heidegger ve en Dilthey la figura del primer filósofo que supo dar cuenta de la vida como fenómeno. En este artículo se indaga en la filosofía de la vida diltheyana con el fin de encontrar el lugar que en ella ocupa la historia, la psicología y el mundo social. Si bien el individuo es el eje del análisis diltheyano, no lo es como un ser aislado, sino como un «punto de cruce»; el hombre deviene un ser histórico como fruto de sus múltiples contactos con el mundo socio-cultural al que pertenece. La psicología hablará del hombre y la historia hará lo propio sobre el mundo socio-cultural, ambas, en conjunto, conforman el vasto campo del que tienen que dar cuenta las Geisteswissenschaften (ciencias del espíritu). La vida humana es la que articula ambos polos del análisis, vida que fue olvidada por la filosofía y que la “filosofía de la vida” (Lebensphilosophie) busca rescatar.
Peirce y lo incognoscible. Respuesta a Damiani
Authors: Kalpokas Daniel
Published: July 2018

El presente artículo responde algunas objeciones que Damiani, en su trabajo “Comunidad, realidad y pragmatismo”, efectúa a un artículo anterior mío sobre lo incognoscible en Peirce: “Lo incognoscible y los límites del sentido”. Señalo que nuestros desacuerdos conciernen principalmente a dos puntos: (1) si tiene sentido sostener que no podemos saber si hay incognoscibles, y (2) si cabe defender la tesis de Peirce (“Lo absolutamente incognoscible es absolutamente inconcebible”) sin comprometerse con el idealismo. Al argumentar por una respuesta afirmativa al primer punto y por una negativa al segundo, intento justificar una actitud agnóstica respecto de lo incognoscible: la de que no podemos saber si hay incognoscibles.
La Modernidad estética: una noción para repensar
Authors: Rancière Jacques
Published: July 2018

Repensar la modernidad estética consiste en tratar de identificar un aspecto del tiempo como una forma de compartir lo sensible, más allá de concepciones simplistas de la temporalidad. Se trata de mostrar que hay un elemento esencial que constituye una revolución estética: ya no se construyen obras sino formas de una vida sensible; que existe la idea de una comunidad sensible liberada de cálculos estratégicos. Así, la política inspirada en este regime estético, es una política de indeterminación, de libertad, que da origen a la idea de una política propiamente estética, de un comunismo estético en el que hay comunicación directa entre las formas del arte y de la vida. Esto se muestra, analizando dos afiches de la película El hombre de la cámara (1929) de Dziga Vértov. En consecuencia, la política estética ya no consiste en producir obras, con mensajes específicos que provoquen efectos precisos, sino en construir un tejido, de fondo sensible común y no determinado, que al poner distancia produce espacios de libertad.
Marina Abramović en “The Artist Is Present” (2010): cuerpo, consciencia y performance como agentes para la crítica cultural
Authors: Gómez Beltrán Iván
Published: July 2018

A lo largo de este texto me serviré de la performance The Artist Is Present (2010), realizada por Marina Abramovi , para ahondar en la vinculación entre cuerpo-espacio y artista-audiencia. Me sumergiré en la obra de la artista para evidenciar su comprensión del arte como un “agente de cambio social” que tiene la capacidad de transformar los cuerpos y las consciencias frente a la creciente aceleración del mundo globalizado. A través de The Artist Is Present analizaré, por un lado, la importancia de entender el arte como un dispositivo de critica cultural y, por el otro, exploraré la relevancia que cobra el dolor ritualizado como un mecanismo que permite alcanzar una plena conciencia del presente.
Arte y lenguaje como formas del ser. Deseo, ritmo y desaparición
Authors: Ortega Salgado Cynthia , Mojica Arias Juan
Published: July 2018

Proponemos tres aproximaciones imaginarias que expandan las difíciles relaciones entre arte y lenguaje. La intención es dar lugar a las formas en que el arte construye la realidad. El lenguaje, comúnmente asumido desde su matiz ontológico, podría pensarla en términos de inmanencia, de gramaticalidad. Sin embargo, ¿cuáles serían estas estructuras desde el arte? Este artículo plantea la imagen como desaparición, como ritmo y como deseo para explorar el lenguaje de lo menor, de la sensación y de lo no dicho.
La modernidad estética: una noción por repensar
Authors: Rancière Jacques
Published: July 2018

Repensar la modernidad estética consiste en tratar de identificar un aspecto del tiempo como una forma de compartir lo sensible, más allá de concepciones simplistas de la temporalidad. Se trata de mostrar que hay un elemento esencial que constituye una revolución estétical que consiste idea de una comunidad sensible liberada de cálculos estratégicos.Así, la política inspirada en este régimen estético, es una política de indeterminación, de libertad, que da origen a la idea de una política propiamente estética, de un comunismo estético en el que hay comunicación directa entre las formas del arte y de la vida. Esto se muestra analizando dos afiches de la publicidad de la película: The Man with the Movie Camera (1929) de Dziga Vertov. En consecuencia, la política estética ya no consiste en producir obras, con mensajes específicos que provoquen efectos precisos, sino en construir un tejido de fondo sensible, común, no determinado que al poner distancia produce espacios de libertad.
Visualidad alcidiana y las cosas que hicieron a su pintura delirar
Authors: Brandão Ludmila
Published: July 2018

La aprehensión de la iconografía del libro didáctico fue para el artista plástico Alcides Pereira dos Santos (Rui Barbosa BA 1932-São Paulo SP 2007) un medio propicio para experimentar el sentido desconcertante del lenguaje. Sin hacer uso continuo de la escritura y de la lectura, el artista va a construir sus imágenes a partir de un modelo cultural masivo que potencializa aún más los sentidos, en la medida en que, en él, la práctica oral se complementa con la sonoridad, la escritura y la visualidad. Más específicamente, se sabe que el uso de las ilustraciones en la mayoría de los libros o manuales escolares tiene la intención de repetir o explicar una historia. Sin embargo, veremos que la aprehensión de la iconografía del libro didáctico fue para el artista plástico un medio propicio para experimentar el sentido desconcertante del lenguaje. Más que consumir las ideas y narrativas del libro didáctico tal como fueron concebidas para ser replicadas, Alcides consume las imágenes y las toma como materia para su propia producción imaginaria, sometiéndolas a "su mundo" mezclado que, por eso mismo, las aleja de una imagen occidental "moderna" e iluminista.
In the Mindset for Change: Self-Reported Quit Attempts are a Product of Discontinuity-Induced Nostalgia and Incremental Beliefs
Authors: Salmon Melissa , Kim Hyoun S. , Wohl Michael J. A.
Published: July 2018

Despite the low rate of behavior change among those engaged in addictive behaviors, some people can and do initiate change. We propose that attempting to self-regulate addictive behavior is a function of motivation and the belief that behavior is malleable. Specifically, feeling self-discontinuous (i.e., feeling that addiction has fundamentally changed the self) should motivate change by inducing nostalgia for the pre-addicted self. Importantly, we expected that discontinuity- induced nostalgia would only be associated with an attempted change among those who believe that behavior is malleable (i.e., incremental theorists). To test this moderated-mediation model, we recruited a community sample of disordered gamblers (N = 243) to assess self-reported change attempts over time. During the initial session, participants completed measures of self-discontinuity, nostalgia, and implicit theories of behavior. Three months later, participants (N = 120) reported whether they attempted to change their gambling behavior, as well as the method and extent to which they sustained this change. As expected, discontinuity-induced nostalgia was positively associated with an increased likelihood of self-reporting a change attempt, but only when behavior was believed to be malleable, rather than fixed. As very few disordered gamblers take action, these findings suggest novel psychological processes to promote positive behavior change.
The Clinical Significance of Subthreshold Borderline Personality Disorder Features in Outpatient Youth
Authors: Thompson Katherine N. , Jackson Henry , Cavelti Marialuisa , Betts Jennifer , McCutcheon Louise , Jovev Martina , Chanen Andrew M.
Published: July 2018

Studies among adult patients have found that subthreshold borderline personality disorder (BPD) features are associated with elevated psychosocial morbidity compared with patients with no BPD features. However, the clinical significance of subthreshold features of BPD has not been investigated among real-world patients during the clinical emergence of the disorder, which is usually between puberty and emerging adulthood. This study aimed to replicate and extend previous research by comparing outpatient youth aged 15–25 years with subthreshold BPD features with youth with no BPD features. The sample included 499 potential participants, of whom 111 had no DSM-IV BPD features at all, and 155 had between one and four features. Results indicated that the group with subthreshold BPD features had more severe mental illness and poorer social and occupational functioning. These findings suggest that subthreshold BPD features are clinically important and should be a focus of clinical intervention to reduce continuing disability and improve outcome.
Interlimb Generalization of Learned Bayesian Visuomotor Prior Occurs in Extrinsic Coordinates
Authors: Hewitson Christopher L. , Sowman Paul F. , Kaplan David M.
Published: July 2018

Recent work suggests that the brain represents probability distributions and performs Bayesian integration during sensorimotor learning. However, our understanding of the neural representation of this learning remains limited. To begin to address this, we performed two experiments. In the first experiment, we replicated the key behavioral findings of Körding and Wolpert (2004), demonstrating that humans can perform in a Bayes-optimal manner by combining information about their own sensory uncertainty and a statistical distribution of lateral shifts encountered in a visuomotor adaptation task. In the second experiment, we extended these findings by testing whether visuomotor learning occurring during the same task generalizes from one limb to the other, and relatedly, whether this learning is represented in an extrinsic or intrinsic reference frame. We found that the learned mean of the distribution of visuomotor shifts generalizes to the opposite limb only when the perturbation is congruent in extrinsic coordinates, indicating that the underlying representation of learning acquired during training is available to the untrained limb and is coded in an extrinsic reference frame.