bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating Potential QT Effects of JNJ‐54861911, a BACE Inhibitor in Single‐ and Multiple‐Ascending Dose Studies, and a Thorough QT Trial With Additional Retrospective Confirmation, Using Concentration‐QTc Analysis
Authors: Timmers Maarten , Sinha Vikash , Darpo Borje , Smith Brian , Brown Randy , Xue Hongqi , Ferber Georg , Streffer Johannes , Russu Alberto , Tritsmans Luc , Solanki Bhavna , Bogert Jennifer , Van Nueten Luc , Salvadore Giacomo , Nandy Partha 
Published: March 2018

AbstractNonclinical assays with JNJ‐54861911, a β‐secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4‐way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ‐54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high‐precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first‐in‐human single‐ascending dose (SAD) and multiple‐ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo‐corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9‐18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure–response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ‐54861911 peak plasma concentrations (Cmax) comparable to those in the SAD study (∼750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; Cmax, 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ‐54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation.
Disease–Drug Interactions in Inflammatory States via Effects on CYP‐Mediated Drug Clearance
Authors: Coutant David E. , Hall Stephen D. 
Published: March 2018

AbstractThe human inflammatory response can result in the alteration of drug clearance through effects on drug‐metabolizing enzymes or drug transporters. In this article, clinical examples are reviewed of how diseases with moderate to severe inflammation can decrease cytochrome P450 (CYP)–mediated drug clearance and alter plasma protein binding. Also examined is how albumin, α‐1‐acid glycoprotein, drug fraction unbound in plasma, CYP content, and oral clearance can change dynamically with time in response to inflammation.
Lack of interruption of the gene network underlying wing polyphenism in an early‐branching ant genus
Authors: Béhague Julien , Fisher Brian L. , Péronnet Romain , Rajakumar Rajendhran , Abouheif Ehab , Molet Mathieu 
Published: March 2018

AbstractAnts evolved about 140 million years ago and have diversified into more than 15,000 species with tremendous ecological and morphological diversity, yet evolution of the gene regulatory networks (GRNs) underlying this diversification remains poorly understood. Wing polyphenism, the ability of a single genome to produce either winged or wingless castes during development in response to environmental cues, is a nearly universal feature of ants. The underlying wing GRN is evolutionarily labile in worker castes of phylogenetically derived species: it is conserved in winged castes but interrupted at different points in wingless castes of different species. However, it remains unknown whether the wing GRN is interrupted in wingless castes of species from early branching lineages, and if so, whether it is interrupted at similar locations in worker castes of derived species. We therefore used in situ hybridization to assay the expression of nine genes in the wing GRN in wing imaginal discs of larvae from two species from the early branching (‘basal’) genus Mystrium. These species possess two castes each: Mystrium rogeri has winged queens and wingless workers, and M. oberthueri has wingless queens and wingless workers. In contrast to derived species, we found no evidence of interruption points in the wing GRN kernel of wingless castes. Our finding supports: (1) a “phylogenetic ladder model” of wing GRN evolution, where interruption points move further upstream in the wing GRN as ant lineages become more derived; and (2) that evolutionary lability of the GRN underlying wing polyphenism originated later during ant evolution.
Tissue characterization of uterine fibroids with an intravoxel incoherent motion model: The need for T2 correction
Authors: Qu Feifei , Hor Pei‐Herng , Fischer John , Muthupillai Raja 
Published: March 2018

BackgroundDiminished signal intensity of uterine fibroids in T2‐weighted images is routinely used as a qualitative marker of fibroid hypoperfusion. However, quantitative classification of fibroid perfusion with intravoxel incoherent motion (IVIM) model‐based metrics is not yet clinically accepted.PurposeTo investigate the influence of T2 correction on the estimation of IVIM model parameters for characterizing uterine fibroid tissue.Study TypeProspective.PopulationFourteen women with 41 fibroids (12 Type I and 29 Type II, per Funaki classification) underwent diffusion‐weighted imaging and T2 mapping.Field StrengthDiffusion‐weighted images (b values: 0, 20, 40, 60, 100, 200, 400, 600, 800, 1000 s/mm2) and T2 maps were obtained at 1.5T.AssessmentThe effect of uterine fibroid T2 variation on IVIM model parameters (diffusion coefficient, perfusion coefficient, and perfusion volume fraction) were numerically modeled and experimentally evaluated without (D, D*, f) and with (Dc,
, fc) T2 correction. The relationship of T2 with D and the T2‐corrected perfusion volume fraction (fc) was also examined.Statistical TestD‐values and f‐values estimated with and without T2 correction were compared by using a two‐tailed Student's t‐test.ResultsType II fibroids had higher D and f than Type I fibroids, but the differences were not significant (Type I vs. Type II, D: 0.83 ± 0.20 vs. 0.80 ± 0.25 mm2/s, P = 0.78; f: 23.64 ± 4.87% vs. 25.27 ± 7.46%, P = 0.49). For Type I and Type II fibroids, fc was lower than f, and fc of Type II fibroids was significantly higher than that of Type I fibroids (Type I vs. Type II, fc: 7.80 ± 1.88% vs. 11.82 ± 4.13%, P = 0.003). Both D and fc exponentially increased with the increase of fibroid T2 as functions:
and
respectively. D asymptotically approached 1.79 × 10−3 mm2/s, and fc approached 21.74%.Data ConclusionT2 correction is important when using IVIM‐based models to characterize uterine fibroid tissue.Level of Evidence: 2Technical Efficacy: Stage 1J. Magn. Reson. Imaging 2018;48:994–1001.
Evaluation of noncontrast MR enterography for pediatric inflammatory bowel disease assessment
Authors: Lanier Michael Hunter , Shetty Anup S. , Salter Amber , Khanna Geetika 
Published: March 2018

BackgroundGadolinium deposition in normal tissues is being increasingly recognized. Children with inflammatory bowel disease (IBD) undergo frequent imaging with contrast‐enhanced MR enterography (MRE).PurposeTo determine the impact of intravenous (IV) gadolinium in assessment of pediatric IBD by MRE.Study TypeRetrospective, case series.PopulationRadiology information system was searched to identify all children who underwent MRE and endoscopy within 30 days in 2016.Field Strength/Sequence1.5T and 3T.AssessmentImaging studies were evaluated for bowel inflammation interpreted by two blinded radiologists in two sessions 6 weeks apart (session 1 pre‐MRE; session 2 pre/postcontrast‐MRE). Endoscopic histology was the reference standard.Statistical TestsA logistic regression model was evaluated using receiver operating characteristics curves and expressed by c‐statistics. Agreement between readers was evaluated using Cohen's or weighted kappa statistic, as appropriate. Two‐sided P < 0.05 was considered statistically significant. Descriptive statistics were used for assessment of IBD complications.ResultsIn all, 52 children (46% female), mean age 13.2 (SD 3.42) years formed the study cohort. 77% (40/52) had inflammation on endoscopic biopsy. Pre/post‐MRE showed no significant increase in the c‐statistic compared to pre‐MRE for assessment of small bowel (Reader 1 P = 0.56, Reader 2 P = 1.00) or large bowel inflammation (Reader 1 P = 0.42, Reader 2 P = 1.00)). Intravenous contrast showed no improvement in interobserver agreement for assessment of inflammation in small (kappa 0.92 pre‐MRE, 0.88 pre/post‐MRE) or large bowel (kappa 0.83 pre‐MRE, 0.73 pre/post‐MRE). IV contrast had no meaningful impact on interobserver agreement for length of small bowel inflamed (intraclass correlation coefficient 0.90 pre‐MRE, 0.95 pre/post‐MRE). Assessment of IBD complications was improved with IV contrast, with 3/5 cases with perianal penetrating disease not recognized on pre‐MRE.Data ConclusionRoutine administration of IV gadolinium has no impact on the assessment of bowel inflammation. However, there is potential for missing perianal complications using a noncontrast MRE protocol without dedicated pelvic imaging.Level of Evidence: 3Technical Efficacy: Stage 2J. MAGN. RESON. IMAGING 2018;48:341–348.
Comparison of 3He and 129Xe MRI for evaluation of lung microstructure and ventilation at 1.5T
Authors: Stewart Neil J. , Chan Ho‐Fung , Hughes Paul J.C. , Horn Felix C. , Norquay Graham , Rao Madhwesha , Yates Denise P. , Ireland Rob H. , Hatton Matthew Q. , Tahir Bilal A. , Ford Paul , Swift Andrew J. , Lawson Rod , Marshall Helen , Collier Guilhem J. , Wild Jim M. 
Published: March 2018

BackgroundTo support translational lung MRI research with hyperpolarized 129Xe gas, comprehensive evaluation of derived quantitative lung function measures against established measures from 3He MRI is required. Few comparative studies have been performed to date, only at 3T, and multisession repeatability of 129Xe functional metrics have not been reported.Purpose/HypothesisTo compare hyperpolarized 129Xe and 3He MRI‐derived quantitative metrics of lung ventilation and microstructure, and their repeatability, at 1.5T.Study TypeRetrospective.PopulationFourteen healthy nonsmokers (HN), five exsmokers (ES), five patients with chronic obstructive pulmonary disease (COPD), and 16 patients with nonsmall‐cell lung cancer (NSCLC).Field Strength/Sequence1.5T. NSCLC, COPD patients and selected HN subjects underwent 3D balanced steady‐state free‐precession lung ventilation MRI using both 3He and 129Xe. Selected HN, all ES, and COPD patients underwent 2D multislice spoiled gradient‐echo diffusion‐weighted lung MRI using both hyperpolarized gas nuclei.AssessmentVentilated volume percentages (VV%) and mean apparent diffusion coefficients (ADC) were derived from imaging. COPD patients performed the whole MR protocol in four separate scan sessions to assess repeatability. Same‐day pulmonary function tests were performed.Statistical TestsIntermetric correlations: Spearman's coefficient. Intergroup/internuclei differences: analysis of variance / Wilcoxon's signed rank. Repeatability: coefficient of variation (CV), intraclass correlation (ICC) coefficient.ResultsA significant positive correlation between 3He and 129Xe VV% was observed (r = 0.860, P < 0.001). VV% was larger for 3He than 129Xe (P = 0.001); average bias, 8.79%. A strong correlation between mean 3He and 129Xe ADC was obtained (r = 0.922, P < 0.001). MR parameters exhibited good correlations with pulmonary function tests. In COPD patients, mean CV of 3He and 129Xe VV% was 4.08% and 13.01%, respectively, with ICC coefficients of 0.541 (P = 0.061) and 0.458 (P = 0.095). Mean 3He and 129Xe ADC values were highly repeatable (mean CV: 2.98%, 2.77%, respectively; ICC: 0.995, P < 0.001; 0.936, P < 0.001).Data Conclusion129Xe lung MRI provides near‐equivalent information to 3He for quantitative lung ventilation and microstructural MRI at 1.5T.Level of Evidence: 3Technical Efficacy Stage 2J. Magn. Reson. Imaging 2018;48:632–642.
High Signal in Bone Marrow on Diffusion‐Weighted Imaging of Female Pelvis: Correlation With Anemia and Fibroid‐Associated Symptoms
Authors: Chen Ying‐Yuan , Wu Ching‐Lan , Shen Shu‐Huei 
Published: March 2018

BackgroundThe diffusion‐weighted imaging (DWI) signals of the female pelvic bone marrow show great variability and are usually high in female patients with fibroid‐associated symptoms and anemia.PurposeTo ascertain clinical factors contributing to high signal intensity in the bone marrow of the female pelvis on DWI.Study TypeRetrospective case–control study.SubjectsA single‐institution review of 221 female patients underwent a pelvic magnetic resonance study from December 2012 to July 2014.Field Strength/Sequence1.5T/DWI (b = 0 and 1000) and apparent diffusion coefficient (ADC).AssessmentThe ADC of pelvic bone marrow and the muscle‐normalized signal intensity (SI) on DWI (mnDWI) were measured. A brightness grading scale ranging from 0 to 4 was used for pelvic bone assessment. Clinical factors, namely, age, the lowest hemoglobin level in the last 6 months, the presence of large uterine fibroids, and/or adenomyosis and fibroid‐associated symptoms were recorded.Statistical TestsThe relationships between the brightness grade and clinical factors were evaluated through multinomial logistic regression, and correlations of mnDWI and the ADC with the clinical factors were analyzed through the Kruskal–Wallis test, Jonckheere's trend test, and the Mann–Whitney U‐test with Bonferroni correction.ResultsAge and the hemoglobin level were inversely associated with the bone marrow brightness grade on DWI (both P < 0.05), whereas the presence of fibroid‐associated symptoms showed a positive association (P = 0.028). The ADC and mnDWI in women younger than 50 years were significantly higher than those in older women (both P < 0.0001). The ADC had no significant correlation with anemia (P = 0.511), whereas mnDWI increased as the severity of anemia increased (P = 0.00154).Data ConclusionOur study showed an association of high DWI SI of pelvic bone marrow with anemia in premenopausal women.Level of Evidence: 4Technical Efficacy Stage 3J. Magn. Reson. Imaging 2018;48:1024–1033.
Self‐assembling peptide matrix for treatment of dentin hypersensitivity: A randomized controlled clinical trial
Authors: Schlee Markus , Rathe Florian , Bommer Claudine , Bröseler Frank , Kind Lucy 
Published: March 2018

AbstractBackgroundPatient‐reported dentin hypersensitivity [DHS] pain is a common finding linked with periodontal disease. This pilot clinical study investigates a novel therapeutic regimen using self‐assembling peptide matrix [SAPM] gel (test) compared with use of an 8% arginine and calcium carbonate [ACC] toothpaste (control) for treatment of DHS.MethodsA total of 50 patients with history of supportive periodontal therapy were enrolled in this prospective, randomized monocentric clinical study, of which 45 (test: n = 22; control: n = 23) fulfilled all the study visits. Test group patients performed ex‐office application of SAPM gel over 1 week, while control group patients performed ex‐office application of ACC toothpaste over 90 days. DHS was assessed in office by Visual Analog Scale [VAS], and patient's perception of pain relief was evaluated by questionnaire. In support of the clinical data, scanning electron microscopy images were recorded to investigate tubule occlusion of both control and test product.ResultsBoth SAPM and ACC significantly reduced DHS in patients throughout the study, with the patient questionnaire indicating higher patient satisfaction at the earlier time points for the test group.ConclusionsBoth SAPM gel and ACC toothpaste were successful in providing relief from DHS and showed similar outcomes on VAS and verbal response scale (VRS) throughout the study period of 90 days. The new therapeutic regimen using SAPM resulted in higher patient satisfaction at day 7, as indicated by the patient questionnaire and the higher number of pain‐free patients at day 7 and day 90. This is a pilot study describing a novel therapy for DHS.
Chemical modifications of Tonda Gentile Trilobata hazelnut and derived processing products under different infrared and hot‐air roasting conditions: a combined analytical study
Authors: Binello Arianna , Giorgis Marta , Cena Clara , Cravotto Giancarlo , Rotolo Laura , Oliveri Paolo , Malegori Cristina , Cavallero Maria Chiara , Buso Stefania , Casale Monica 
Published: March 2018

AbstractBACKGROUNDFor the processing industry, it is crucial to know what effect the roasting process and conditions have on hazelnut quality. The present study investigates, for the first time, the effects of hot‐air and infrared (IR) roasting at different time–temperature combinations on Tonda Gentile Trilobata hazelnut: whole kernels and derived processing products (paste and oil).RESULTSThe nutritional and physical characteristics of hazelnuts and processing products were investigated to determine the influence of the different roasting conditions as a function of intended use. The antioxidant profile (2.2‐diphenyl‐1‐picrylhydrazyl radical, oxygen radical absorbance capacity and total phenolic content) were analyzed on roasted hazelnut and paste extracts. For a comprehensive understanding of the complex biochemical phenomena occurring during roasting, E‐nose and near‐IR spectroscopy were also applied. All analytical data were processed using univariate and multivariate data analyses. Hazelnuts derived from IR roasting at higher temperatures (195 °C) showed a richer antioxidant profile and a more intense flavour. On the other hand, the yield associated with the oil extraction under the same conditions was unsatisfactory, making this process completely inadequate for oil production. Oil obtained by hot‐air roasting and IR roasting at lower temperature (135 °C) was found to be of good quality, showing rather similar acidity grade, peroxide number and acidic composition. In particular, a slightly but significantly lower acidity was related to lower roasting temperatures (0.21–0.22% versus 0.27% for higher temperatures). All roasting conditions tested allowed the quantitative homogeneous hazelnut paste to be obtained and, from a rheological point of view, a higher roasting temperatures resulted in pastes characterized by higher density and viscosity values.CONCLUSIONThe use of IR was found to be a promising alternative method for hazelnut roasting, as a result of its capability with respect to preserving nutritional values and enhancing organoleptic quality. © 2018 Society of Chemical Industry
Controlled Polymerization of Isoprene with Chromium‐Based Metal‐Organic Framework Catalysts: Switching from Cyclic to cis‐1,4‐Selectivity Depending on Activator
Authors: Gao Fei , Zhang Li , Yu Chao , Yan Xinwen , Zhang Shaowen , Li Xiaofang 
Published: March 2018

AbstractChromium‐based metal‐organic framework (MOF) Cr‐MIL‐100/101 activated by activator and aluminum trialkyl compound serve as unique, highly efficient heterogeneous single‐site catalysts for the controlled polymerization of isoprene, which not only exhibit quasi‐living nature in isoprene polymerization but also unprecedentedly switch from cyclic to cis‐1,4‐selectivity depending on the activator used to yield low molecular weight cyclic PIPs or extremely high molecular weight cis‐1,4‐PIPs. Such heterogeneous Cr‐MOF catalysts can be recycled approximately five times. Based on nitrogen sorption isotherm tests and powder X‐ray diffraction, a cationic mechanism is suggested, in which the polymerization takes place inside the open nanochannels of MOF catalysts and the space confinement effect of narrow open nanochannels originated from the coordination of PhNMe2 from activator [PhNHMe2][B(C6F5)4] with the multiple metal centers of MOF catalysts might give a rational explanation for such controlled adjustment on the PIP's structure and properties.
Influence of nitrate and nitrite concentration on N2O production via dissimilatory nitrate/nitrite reduction to ammonium in Bacillus paralicheniformis LMG 6934
Authors: Sun Yihua , De Vos Paul , Willems Anne 
Published: March 2018

AbstractUntil now, the exact mechanisms for N2O production in dissimilatory nitrate/nitrite reduction to ammonium (DNRA) remain underexplored. Previously, we investigated this mechanism in Bacillus licheniformis and Bacillus paralicheniformis, ubiquitous gram‐positive bacteria with many industrial applications, and observed significant strain dependency and media dependency in N2O production which was thought to correlate with high residual NO2−. Here, we further studied the influence of several physicochemical factors on NO3− (or NO2−) partitioning and N2O production in DNRA to shed light on the possible mechanisms of N2O production. The effects of NO3− concentrations under variable or fixed C/N‐NO3− ratios, NO2− concentrations under variable or fixed C/N‐NO2− ratios, and NH4+ concentrations under fixed C/N‐NO3− ratios were tested during anaerobic incubation of soil bacterium B. paralicheniformis LMG 6934 (previously known as B. licheniformis), a strain with a high nitrite reduction capacity. Monitoring of growth, NO3−, NO2−, NH4+ concentration, and N2O production in physiological tests revealed that NO3− as well as NO2− concentration showed a linear correlation with N2O production. Increased NO3− concentration under fixed C/N‐NO3− ratios, NO2− concentration, and NH4+ concentration had a significant positive effect on NO3− (or NO2−) partitioning ([N–NH4+]/[N–N2O]) toward N2O, which may be a consequence of the (transient) accumulation and subsequent detoxification of NO2−. These findings extend the information on several physiological parameters affecting DNRA and provide a basis for further study on N2O production during this process.