bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phospholipid Autoantibodies and the Antiphospholipid Antibody Syndrome: Diagnostic Accuracy of 23 Methods Studied by Variation in ROC Curves with Number of Clinical Manifestations
Authors: Wasmuth Jan-Christian , Oliver y Miñarro Desamparados , Homrighausen Angela , Leifeld Ludger , Rockstroh Jürgen K , Sauerbruch Tilman , Spengler Ulrich 
Published: January 2020

Abstract
Background: We analyzed the diagnostic accuracies for the diagnosis of antiphospholipid syndrome (APS) of 23 antiphospholipid antibody (APL-Ab) assays targeted at different antigen preparations and immunoglobulin isotypes.
Methods: In 144 patients with suspected APS, anti-cardiolipin (aCL) and anti-β2-glycoprotein I (aβ2GPI) antibodies were measured with 23 different ELISAs from three manufacturers. Data were analyzed by ROC curves. In the absence of an accepted criterion standard, the endpoint “diagnosis of APS” was varied according to the number (two through five) of signs and symptoms of APS.
Results: Although the presence of lupus anticoagulant was associated significantly with APL-Ab in 10 of 23 assays (P = 0.01–10−4) and recurrent arterial or venous occlusions were significantly associated with APL-Ab of IgM isotype in 5 of 6 assays (P = 0.02–10−4), sensitivity for detection of APS did not exceed 67%. With the exception of IgA APL-Ab, the diagnostic accuracy of the assays improved when the diagnosis of APS was based on an increasing number of simultaneous features of APS. For most methods, areas under the ROC curves were &gt;0.8 irrespective of the method’s subclass specificity and antigen preparation (aCL or aβ2GPI), if the clinical diagnosis of APS was based on four or more signs and symptoms of APS.
Conclusion: Despite considerable heterogeneity in the individual test results, a single test of IgG or IgM isotype targeted at either aCL or aβ2GPI antibodies has excellent diagnostic accuracy when the criterion for diagnosis requires four or more typical manifestations of APS.
Technical Evaluation of a New Immunoradiometric and a New Immunoluminometric Assay for Thyroglobulin
Authors: Morgenthaler Nils G , Froehlich Juergen , Rendl Johann , Willnich Marita , Alonso Christine , Bergmann Andreas , Reiners Christoph 
Published: January 2020

AbstractBackground: After removal of differentiated thyroid carcinoma (DTC), serum thyroglobulin (Tg) can indicate persistent or recurrent disease. We describe two novel two-step assays designed to measure low Tg concentrations.Methods: We evaluated prototypes of the new IRMA, DYNOtest® Tg-pluS, and the new immunoluminometric assay (ILMA), LUMItest® Tg-pluS. In the first step, a high-salt incubation buffer leads to dissociation of Tg-Tg antibody complexes in serum and is intended to reduce nonspecific interference and interference of potential Tg autoantibodies in the system. We studied recovery of human Tg (from thyroid glands) added to horse serum. We also studied 58 patients with DTC in whom Tg values under thyroid-stimulating hormone (TSH) suppression and TSH stimulation (without thyroxine) were available.Results: The detection limits were 0.04 μg/L Tg for the IRMA and 0.02 μg/L for the ILMA. Intraassay imprecision (CV) was &lt;10% over the range of the calibration curve in both assays. The day-to-day CV was &lt;20% at 0.2 μg/L for the IRMA and at 0.06 μg/L for the ILMA. No high-dose hook effect was seen with up to 200 000 μg/L added Tg or in dilutions of 12 patient sera with Tg values of 307–38 880 μg/L. Mean recovery of 50 μg Tg/L was 96% in those patients. Among 77 samples with Tg antibody values of 65.2–8150 kilounits/L, recovery by the IRMA was disturbed in 7 cases (9%) and by the ILMA in 9 cases (12%). Tg increased as measured in both assays in 50 of 58 patients after thyroxine withdrawal.Conclusions: The new assays have improved precision for Tg &lt;1 μg/L, and even low measured Tg concentrations respond physiologically to thyroxine withdrawal. The assays are free of a high-dose hook effect up to a Tg concentration of at least 38 000 μg/L and may further reduce Tg antibody interference.
Independent Risk Factor for Moderate to Severe Internal Carotid Artery Stenosis: T786C Mutation of the Endothelial Nitric Oxide Synthase Gene
Authors: Ghilardi Giorgio , Biondi Maria Luisa , DeMonti Marco , Bernini Mara , Turri Olivia , Massaro Federico , Guagnellini Emma , Scorza Roberto 
Published: January 2020

AbstractBackground: NO synthesized from l-arginine by the constitutive endothelial NO synthase (eNOS) plays a key role in the atherosclerotic process. We investigated whether common variants in the NOS3 gene (a T786C mutation in the 5′ flanking region and the polymorphism on exon 7 that produced the Glu298Arg polymorphism in the protein) are associated with an increased risk of moderate to severe internal carotid artery (ICA) stenosis.Methods: We studied 88 patients consecutively operated for ICA stenosis and 133 healthy controls. A T786C mutation in the 5′ flanking region and the polymorphism in exon 7 that produces the Glu298Asp polymorphism in the protein were explored by PCR and fluorescent probe analysis.Results: Genotype distribution was significantly different between patients and controls only for T786C, the CC genotype frequency being 26% and 13%, respectively [odds ratio (OR), 2.26; 95% confidence interval (CI), 1.14–4.46; P = 0.018]. Moreover, the CC genotype was significantly more frequent in a subgroup of patients with ulcerative plaques compared with patients with nonulcerative lesions (44% vs 17%; OR, 3.82; 95% CI, 1.79–8.14; P = 0.003). Multiple logistic regression analysis using the most frequent risk factors and the eNOS gene variant showed that the CC genotype is an independent risk factor for ICA stenosis (P = 0.023).Conclusion: C allele homozygosity in position 786 of the eNOS promoter seems to be an independent risk factor for the development of moderate to severe ICA stenosis, especially ulcerative lesions.
The Proportion of Prostate-specific Antigen (PSA) Complexed to α1-Antichymotrypsin Improves the Discrimination between Prostate Cancer and Benign Prostatic Hyperplasia in Men with a Total PSA of 10 to 30 μg/L
Authors: Martínez Manuel , España Francisco , Royo Montserrat , Alapont José M , Navarro Silvia , Estellés Amparo , Aznar Justo , Vera César D , Jiménez-Cruz Juan F 
Published: January 2020

Abstract
Background: The aim of this study was to assess the diagnostic accuracy of the proportion of prostate-specific antigen (PSA) complexed to α1-antichymotrypsin (PSA-α1ACT:PSA ratio) in the differential diagnosis of prostate cancer (CaP) and benign prostatic hyperplasia (BPH) in men with total PSA of 10–30 μg/L.
Methods: We used our immunoassays (ELISAs) for total PSA and PSA-α1ACT complex to study 146 men. In 123, total PSA was between 10 and 20 μg/L; 66 of these had CaP and 57 BPH. In 23 men, total PSA was between 20 and 30 μg/L; 14 of these had CaP and 9 BPH. We calculated the area under the ROC curves (AUC) for total PSA, PSA-α1ACT complex, and PSA-α1ACT:PSA ratio, and determined the cutoff points that gave sensitivities approaching 100%.
Results: In the total PSA range between 10 and 20 μg/L, the AUC was significantly higher for the PSA-α1ACT:PSA ratio (0.850) than for total PSA (0.507) and PSA-α1ACT complex (0.710; P &lt;0.0001). A cutoff ratio of 0.62 would have permitted diagnosis of all 66 patients with CaP (100% sensitivity) and avoided 19% of unnecessary biopsies (11 of 57 patients). In the total PSA range between 20 and 30 μg/L, the AUC for the PSA-α1ACT:PSA ratio (0.980; 95% confidence interval, 0.82–0.99) was greater than the AUC for total PSA (0.750; 95% confidence interval, 0.51–0.89; P = 0.042). In this range, a cutoff point of 0.64 would have permitted the correct diagnosis of all 14 patients with CaP and 6 of the 9 with BPH.
Conclusions: The diagnostic accuracy of the PSA-α1ACT:PSA ratio persists at high total PSA concentrations, increasing the specificity of total PSA. Prospective studies with large numbers of patients are needed to assess whether the ratio of PSA-α1ACT to total PSA is a useful tool to avoid unnecessary prostatic biopsy in patients with a total PSA &gt;10 μg/L.
Simultaneous Quantification of Prostate-specific Antigen and Human Glandular Kallikrein 2 mRNA in Blood Samples from Patients with Prostate Cancer and Benign Disease
Authors: Ylikoski Alice , Pettersson Kim , Nurmi Jussi , Irjala Kerttu , Karp Matti , Lilja Hans , Lövgren Timo , Nurmi Martti 
Published: January 2020

Abstract
Background: Detection or quantification of circulating cancer cells has been proposed as an aid in detection and monitoring of several solid tumors. We investigated the classification accuracy of prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) mRNA copy numbers in blood for the differentiation of patients with prostate cancer (PC) and benign disease.
Methods: PSA and hK2 mRNA expression was studied in blood samples from 51 men with PC and 19 men with benign disease. Among the PC patients, 10 had organ-confined disease (pT1–pT2). We used a multiplexed reverse transcription-PCR assay with two highly target-like mRNA internal standards for the simultaneous quantification of PSA and hK2 mRNA. An external calibration curve covered the range of 102–106 mRNA copies.
Results: PSA and hK2 mRNA were detected in 41 of 51 (median, 1200 copies/0.5 mL of blood) and 43 of 51 (median, 3800 copies/0.5 mL of blood) patients with PC, respectively, whereas only 1 of 19 men with benign disease was positive for both mRNAs (1500 PSA and 3100 hK2 mRNA copies/0.5 mL of blood; P &lt;0.0001, Mann–Whitney U-test). Of the 10 patients with organ-confined PC, only 3 with low Gleason scores (≤5) were negative for both PSA and hK2 (P = 0.02, Mann–Whitney U-test).
Conclusions: The presence of PC cells in the blood circulation is an early event in PC progression, and quantitative assays for PSA and hK2 mRNA discriminate benign from PC cases. Further studies are needed to determine the diagnostic accuracy and prognostic value of the assays.
Proteomics and Bioinformatics Approaches for Identification of Serum Biomarkers to Detect Breast Cancer
Authors: Li Jinong , Zhang Zhen , Rosenzweig Jason , Wang Young Y , Chan Daniel W 
Published: January 2020

Abstract
Background: Surface-enhanced laser desorption/ionization (SELDI) is an affinity-based mass spectrometric method in which proteins of interest are selectively adsorbed to a chemically modified surface on a biochip, whereas impurities are removed by washing with buffer. This technology allows sensitive and high-throughput protein profiling of complex biological specimens.
Methods: We screened for potential tumor biomarkers in 169 serum samples, including samples from a cancer group of 103 breast cancer patients at different clinical stages [stage 0 (n = 4), stage I (n = 38), stage II (n = 37), and stage III (n = 24)], from a control group of 41 healthy women, and from 25 patients with benign breast diseases. Diluted serum samples were applied to immobilized metal affinity capture Ciphergen ProteinChip® Arrays previously activated with Ni2+. Proteins bound to the chelated metal were analyzed on a ProteinChip Reader Model PBS II. Complex protein profiles of different diagnostic groups were compared and analyzed using the ProPeak software package.
Results: A panel of three biomarkers was selected based on their collective contribution to the optimal separation between stage 0–I breast cancer patients and noncancer controls. The same separation was observed using independent test data from stage II–III breast cancer patients. Bootstrap cross-validation demonstrated that a sensitivity of 93% for all cancer patients and a specificity of 91% for all controls were achieved by a composite index derived by multivariate logistic regression using the three selected biomarkers.
Conclusions: Proteomics approaches such as SELDI mass spectrometry, in conjunction with bioinformatics tools, could greatly facilitate the discovery of new and better biomarkers. The high sensitivity and specificity achieved by the combined use of the selected biomarkers show great potential for the early detection of breast cancer.
Predictive Value of Routine Circulating Soluble Endothelial Cell Adhesion Molecule Measurements during Pregnancy
Authors: Krauss Thomas , Emons Günter , Kuhn Walther , Augustin Hellmut G 
Published: January 2020

Abstract
Background: The present study was aimed at determining whether routine prenatal measurements of circulating soluble intercellular adhesion molecule (sICAM-1; CD54) and soluble vascular cell adhesion molecule (sVCAM-1; CD106) in midgestation have predictive value for the identification of pregnant women destined to develop preeclampsia or other complications of pregnancy during late gestation.
Methods: Plasma sICAM-1 and sVCAM-1 were analyzed between weeks 22 and 29 of gestation in 1543 pregnant women and related to the outcome of pregnancy in a prospective longitudinal study.
Results: Plasma sICAM-1 and sVCAM-1 in uncomplicated pregnancies were normally distributed and varied over a small range (sICAM-1, SD = 22.5%; sVCAM-1, SD = 25.5%). Of all analyzed uncomplicated pregnancies, 54 (3.95%) were identified with concentrations of sICAM-1 or sVCAM-1 above the mean + 2 SD. In contrast, of 177 pregnancies with complications (prevalence, 11.5%), 97 (55%) had sICAM-1 or sVCAM-1 concentrations above the same cutoffs weeks before the onset of disease. The sensitivities of sICAM-1 and sVCAM-1 measurements were 66% for preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome), 42% for gestational hypertension, 50% for fetal retardation, 46% for preterm labor, 50% for gestational diabetes mellitus, 67% for gestational proteinuria, and 70% for infections during pregnancy. Taken together, routine prenatal sICAM-1 and sVCAM-1 measurements had an overall predictive value of 64%.
Conclusions: Midgestation measurements of circulating sICAM-1 and sVCAM-1 have a high predictive value (area under the curve of combined sICAM-1 and sVCAM-1 measurements determined by ROC analysis, 0.85) and may identify up to 55% of pregnant women who will later develop a severe pregnancy-related complication.
Plasma and Oral Fluid Pharmacokinetics and Pharmacodynamics after Oral Codeine Administration
Authors: Kim Insook , Barnes Allan J , Oyler Jonathan M , Schepers Raf , Joseph Robert E , Cone Edward J , Lafko Diana , Moolchan Eric T , Huestis Marilyn A 
Published: January 2020

AbstractBackground: The ease, noninvasiveness, and safety of oral fluid collection have increased the use of this alternative matrix for drugs-of-abuse testing; however, few controlled drug administration data are available to aid in the interpretation of oral fluid results.Methods: Single oral codeine doses (60 and 120 mg/70 kg) were administered to 19 volunteers. Oral fluid and plasma were analyzed for free codeine, norcodeine, morphine, and normorphine by solid-phase extraction combined with gas chromatography–mass spectrometry (SPE/GC-MS). Physiologic and subjective effects were examined.Results: Mean (SE) peak codeine concentrations were 214.2 ± 27.6 and 474.3 ± 77.0 μg/L in plasma and 638.4 ± 64.4 and 1599.3 ± 241.0 μg/L in oral fluid. The oral fluid-to-plasma ratio for codeine was relatively constant (∼4) from 1 to 12 h. The mean half-life (t1/2) of codeine was 2.2 ± 0.10 h in plasma and 2.2 ± 0.16 h in oral fluid. Significant dose-related miosis and increases in sedation, psychotomimetic effect, and “high” occurred after the high dose. Mean codeine oral fluid detection time was 21 h with a 2.5 μg/L cutoff, longer than that of plasma (12–16 h). Detection times with the proposed Substance Abuse and Mental Health Services Administration cutoff (40 μg/L) were only 7 h. Norcodeine, but not morphine or normorphine, was quantified in both plasma and oral fluid.Conclusions: The disposition of codeine over time was similar in plasma and oral fluid, but because of high variability, oral fluid codeine concentrations did not reliably predict concurrent plasma concentrations. Oral fluid testing is a useful alternative matrix for monitoring codeine exposure with a detection window of 7–21 h for single doses, depending on cutoff concentrations. These controlled drug administration data should aid in the interpretation of oral fluid codeine results.
Validation of a High-Throughput Liquid Chromatography–Tandem Mass Spectrometry Method for Urinary Cortisol and Cortisone
Authors: Taylor Robert L , Machacek Dwaine , Singh Ravinder J 
Published: January 2020

Abstract
Background: Urinary free cortisol and cortisone measurements are useful in evaluation of Cushing syndrome, apparent mineralocorticoid excess, congenital adrenal hyperplasia, and adrenal insufficiency. To reduce analytical interference, improve accuracy, and shorten the analysis time, we developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for urinary cortisol and cortisone.
Methods: We added 190 pmol (70 ng) of stable isotope cortisol-9,11,12,12-d4 to 0.5 mL of urine as an internal standard before extraction. The urine was extracted with 4.5 mL of methylene chloride, washed, and dried, and 10 μL of the reconstituted extract was injected onto a reversed-phase C18 column and analyzed using a tandem mass spectrometer operating in the positive mode.
Results: Multiple calibration curves for urinary cortisol and cortisone exhibited consistent linearity and reproducibility in the range 7–828 nmol/L (0.25–30 μg/dL). Interassay CVs were 7.3–16% for mean concentrations of 6–726 nmol/L (0.2–26.3 μg/dL) for cortisol and cortisone. The detection limit was 6 nmol/L (0.2 μg/dL). Recovery of cortisol and cortisone added to urine was 97–123%. The regression equation for the LC-MS/MS (y) and HPLC (x) method for cortisol was: y = 1.11x + 0.03 μg cortisol/24 h (r2 = 0.992; n = 99). The regression equation for the LC-MS/MS (y) and immunoassay (x) methods for cortisol was: y = 0.66x − 12.1 μg cortisol/24 h (r2 = 0.67; n = 99).
Conclusion: The sensitivity and specificity of the LC-MS/MS method for urinary free cortisol and cortisone offer advantages over routine immunoassays or chromatographic methods because of elimination of drug interferences, high throughput, and short chromatographic run time.
Optimal Monetary Policy when Information is Market-Generated
Authors: Benhima Kenza , Blengini Isabella 
Published: January 2020

AbstractThe nature of the private sector’s information changes the optimal conduct of monetary policy. When firms observe their individual demand and use it as a signal of real shocks, the optimal policy consists in maximising the information content of that signal. When real shocks are deflationary (like labour supply shocks), the optimal policy is countercyclical and magnifies price movements, which contrasts with the exogenous information case, where optimal monetary policy is procyclical and stabilises prices. When the central bank communicates its information to the public, this policy is still optimal if firms pay limited attention to central bank announcements.
Application of the 2019 ESC/EAS dyslipidaemia guidelines to nationwide data of patients with a recent myocardial infarction: a simulation study
Authors: Allahyari Ali , Jernberg Tomas , Hagström Emil , Leosdottir Margrét , Lundman Pia , Ueda Peter 
Published: January 2020

Abstract

Aims
To estimate the proportion of patients with a recent myocardial infarction (MI) who would be eligible for additional lipid-lowering therapy according to the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidaemias, and to simulate the effects of expanded lipid-lowering therapy on attainment of the low-density lipoprotein cholesterol (LDL-C) target as recommended by the guidelines.

Methods and results
Using the nationwide SWEDEHEART register, we included 25 466 patients who had attended a follow-up visit 6–10 weeks after an MI event, 2013–17. While most patients (86.6%) were receiving high-intensity statins, 82.9% of the patients would be eligible for expanded lipid-lowering therapy, as they had not attained the target of an LDL-C level of &lt;1.4 mmol and a ≥50% LDL-C level reduction. When maximized use of high-intensity statins followed by add-on therapy with ezetimibe was simulated using a Monte Carlo model, the LDL-C target was reached in 19.9% using high-intensity statin monotherapy and in another 28.5% with high-intensity statins and ezetimibe, while 50.7% would still be eligible for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. When use of alirocumab or evolocumab was simulated in those who were eligible for PCSK9 inhibitors, around 90% of all patients attained the LDL-C target.

Conclusion
Our study suggests that, even with maximized use of high-intensity statins and ezetimibe, around half of patients with MI would be eligible for treatment with PCSK9 inhibitors according to the 2019 ESC/EAS guidelines. Considering the current cost of PCSK9 inhibitors, the financial implications of the new guidelines may be substantial.
Clinical application of the 4th Universal Definition of Myocardial Infarction
Authors: Hartikainen Tau S , Sörensen Nils Arne , Haller Paul Michael , Goßling Alina , Lehmacher Jonas , Zeller Tanja , Blankenberg Stefan , Westermann Dirk , Neumann Johannes Tobias 
Published: January 2020

Abstract

Aims
The recently released 4th version of the Universal Definition of Myocardial Infarction (UDMI) introduces an increased emphasis on the entities of acute and chronic myocardial injury. We applied the 4th UDMI retrospectively in patients presenting to the emergency department with symptoms potentially indicating myocardial infarction (MI) to investigate its effect on diagnosis and prognosis.

Methods and results
We included 2302 patients presenting to the emergency department with symptoms suggestive of MI. The final diagnosis was adjudicated sequentially according to the 3rd and 4th UDMI. Reclassification after readjudication was assessed. Established diagnostic algorithms for patients with suspected MI were applied to compare diagnostic accuracy. All patients were followed to assess mortality, recurrent MI, revascularization, and rehospitalization to investigate the effect of the 4th UDMI on prognosis. After readjudication, 697 patients were reclassified. Most of these patients were reclassified as having acute (n = 78) and chronic myocardial injury (n = 585). Four hundred and thirty-four (18.9%) patients were diagnosed with MI, compared with 501 (21.8%) MIs when adjudication was based on the 3rd UDMI. In the non-MI population, patients with myocardial injury (n = 663) were older, more often female and had worse renal function compared with patients without myocardial injury (n = 1205). Application of diagnostic algorithms for patients with suspected MI revealed a high accuracy after readjudication. Reclassified patients had a substantially higher rate of cardiovascular events compared with not-reclassified patients, particularly patients reclassified to the category of myocardial injury.

Conclusion
By accentuating the categories of acute and chronic myocardial injury the 4th UDMI succeeds to identify patients with higher risk for cardiovascular events and poorer outcome and thus seems to improve risk assessment in patients with suspected MI. Application of established diagnostic algorithms remains safe when using the 4th UDMI.