bluuebunny/crossref_metadata_2025 huggingface dataset:
Automatic single cell segmentation on highly multiplexed tissue images
Authors: Schüffler Peter J. , Schapiro Denis , Giesen Charlotte , Wang Hao A. O. , Bodenmiller Bernd , Buhmann Joachim M.
Published: July 2015

The combination of mass cytometry and immunohistochemistry (IHC) enables new histopathological imaging methods in which dozens of proteins and protein modifications can be visualized simultaneously in a single tissue section. The power of multiplexing combined with spatial information and quantification was recently illustrated on breast cancer tissue and was described as next‐generation IHC. Robust, accurate, and high‐throughput cell segmentation is crucial for the analysis of this new generation of IHC data. To this end, we propose a watershed‐based cell segmentation, which uses a nuclear marker and multiple membrane markers, the latter automatically selected based on their correlation. In comparison with the state‐of‐the‐art segmentation pipelines, which are only using a single marker for object detection, we could show that the use of multiple markers can significantly increase the segmentation power, and thus, multiplexed information should be used and not ignored during the segmentation. Furthermore, we provide a novel, user‐friendly open‐source toolbox for the automatic segmentation of multiplexed histopathological images. © 2015 International Society for Advancement of Cytometry
Peritoneal cytology as prognostic factor in cervical cancer
Authors: Ditto Antonino , Martinelli Fabio , Carcangiu Marialuisa , Lorusso Domenica , Raspagliesi Francesco
Published: July 2015

Background

To investigate the prognostic role of peritoneal cytology (PC) in cervical cancer patients undergoing radical hysterectomy.

Methods

We retrospectively analyzed 120 stage IA1–IIIB patients with cervical cancer who underwent peritoneal fluid collection for cytology during radical hysterectomy. Neoadjuvant chemotherapy and/or radiotherapy was performed in 48% of the cases. All PC specimens were obtained by aspiration of free‐fluid when present or by peritoneal washing. The relationships between cytological diagnosis, histological variables, and prognosis were investigated.

Results

PC was positive in 4 out of 120 (3.3%) cases. All were advanced stage adenocarcinomas. Overall, 4 out of 26 (15.3%) cases with adenocarcinoma were positive, and all presented with free fluid in the pelvis. No positive PC was found among squamous cancers. Histological subtype (P: 0.002) and parametrial (P < 0.001) and vaginal (P: 0.002) involvement presented a statistically significant correlation with PC positivity. The prognostic analysis of histological parameters demonstrated that parametrial (P: 0.007), vaginal (P: 0.04), and lymph node involvements (P: 0.003) were significantly correlated with a shorter disease‐free survival.

Conclusions

The series indicates that PC in squamous cell cervical cancer is not a significant prognostic factor. Its routine collection in squamous cancer should be abandoned in this setting. On the other hand, the unfavorable prognostic profile of PC positive cases in our investigation suggest a possible impact of this variable on outcome. The significant link between PC and locally advanced adenocarcinomas underwent neoadjuvant therapy before surgery warrants a further investigation to assess its real prognostic value and its indication in this particular clinical setting. Diagn. Cytopathol. 2015;43:705–709. © 2015 Wiley Periodicals, Inc.
Assessement of the pharmacokinetics, tissue distribution and excretion studies of a novel antiplatelet agent S007‐867, following administration to rats
Authors: Chandasana Hardik , Chhonker Yashpal S. , Laxman Tulsankar Sachin , Prasad Yarra Durga , K. S. Anil Kumar , Dikshit Dinesh K. , Bhatta Rabi S.
Published: July 2015

S007‐867 is a promising novel antiplatelet agent with better efficacy and lesser bleeding risk than existing agents. The present study investigated the absorption, tissue distribution, and excretion of S007‐867 in rat model for further advancement of the molecule. A simple and robust ultra fast liquid chromatography‐tandem mass spectrometry (UFLC‐MS/MS) bioanalytical method was used to determine S007‐867 in various matrices. Following oral administration, the compound was quickly dispersed in the various tissues and peak concentration levels were achieved within 0.5–1 h. Overall, exposure of drug, i.e., AUC in different tissues was found in the order of small intestine > liver > heart > spleen > lungs > kidney > brain. The total recoveries of the S007‐867 within 96 h were 3.36% in urine and faeces. This might be due to a first‐pass effect by the liver and intestine as most of the drug was eliminated in metabolite form. These findings provide a crucial information about further development of S007‐867 as antithrombotic agent. Copyright © 2015 John Wiley & Sons, Ltd.
SmedGD 2.0: The Schmidtea mediterranea genome database
Authors: Robb Sofia M.C. , Gotting Kirsten , Ross Eric , Sánchez Alvarado Alejandro
Published: July 2015

Planarians have emerged as excellent models for the study of key biological processes such as stem cell function and regulation, axial polarity specification, regeneration, and tissue homeostasis among others. The most widely used organism for these studies is the free‐living flatworm Schmidtea mediterranea. In 2007, the Schmidtea mediterranea Genome Database (SmedGD) was first released to provide a much needed resource for the small, but growing planarian community. SmedGD 1.0 has been a depository for genome sequence, a draft assembly, and related experimental data (e.g., RNAi phenotypes, in situ hybridization images, and differential gene expression results). We report here a comprehensive update to SmedGD (SmedGD 2.0) that aims to expand its role as an interactive community resource. The new database includes more recent, and up‐to‐date transcription data, provides tools that enhance interconnectivity between different genome assemblies and transcriptomes, including next‐generation assemblies for both the sexual and asexual biotypes of S. mediterranea. SmedGD 2.0 (http://smedgd.stowers.org) not only provides significantly improved gene annotations, but also tools for data sharing, attributes that will help both the planarian and biomedical communities to more efficiently mine the genomics and transcriptomics of S. mediterranea. genesis 53:535–546, 2015. © 2015 Wiley Periodicals, Inc.
Cost‐effectiveness of natriuretic peptide‐based screening and collaborative care: a report from the STOP‐HF (St Vincent's Screening TO Prevent Heart Failure) study
Authors: Ledwidge Mark T. , O'Connell Eoin , Gallagher Joseph , Tilson Lesley , James Stephanie , Voon Victor , Bermingham Margaret , Tallon Elaine , Watson Chris , O'Hanlon Rory , Barry Michael , McDonald Kenneth
Published: July 2015

Aims

Prevention of cardiovascular disease and heart failure (HF) in a cost‐effective manner is a public health goal. This work aims to assess the cost‐effectiveness of the St Vincent's Screening TO Prevent Heart Failure (STOP‐HF) intervention.

Methods and results

This is a substudy of 1054 participants with cardiovascular risk factors [median age 65.8 years, interquartile range (IQR) 57.8:72.4, with 4.3 years, IQR 3.4:5.2, follow‐up]. Annual natriuretic peptide‐based screening was performed, with collaborative cardiovascular care between specialist physicians and general practitioners provided to patients with BNP levels >50 pg/mL. Analysis of cost per case prevented and cost‐effectiveness per quality‐adjusted life year (QALY) gained was performed. The primary clinical endpoint of LV dysfunction (LVD) with or without HF was reduced in intervention patients [odds ratio (OR) 0.60; 95% confidence interval (CI) 0.38–0.94; P = 0.026]. There were 157 deaths and/or emergency hospitalizations for major adverse cardiac events (MACE) in the control group vs. 102 in the intervention group (OR 0.68; 95% CI 0.49–0.93; P = 0.01). The cost per case of LVD/HF prevented was €9683 (sensitivity range –€843 to €20 210), whereas the cost per MACE prevented was €3471 (sensitivity range –€302 to €7245). Cardiovascular hospitalization savings offset increased outpatient and primary care costs. The cost per QALY gain was €1104 and the intervention has an 88% probability of being cost‐effective at a willingness to pay threshold of €30 000.

Conclusion

Among patients with cardiovascular risk factors, natriuretic peptide‐based screening and collaborative care reduced LVD, HF, and MACE, and has a high probability of being cost‐effective.

Trial registration

NCT00921960
Increasing exercise capacity and quality of life of patients with heart failure through Wii gaming: the rationale, design and methodology of the HF‐Wii study; a multicentre randomized controlled trial
Authors: Jaarsma Tiny , Klompstra Leonie , Ben Gal Tuvia , Boyne Josiane , Vellone Ercole , Bäck Maria , Dickstein Kenneth , Fridlund Bengt , Hoes Arno , Piepoli Massimo F. , Chialà Oronzo , Mårtensson Jan , Strömberg Anna
Published: July 2015

Aims

Exercise is known to be beneficial for patients with heart failure (HF), and these patients should therefore be routinely advised to exercise and to be or to become physically active. Despite the beneficial effects of exercise such as improved functional capacity and favourable clinical outcomes, the level of daily physical activity in most patients with HF is low. Exergaming may be a promising new approach to increase the physical activity of patients with HF at home. The aim of this study is to determine the effectiveness of the structured introduction and access to a Wii game computer in patients with HF to improve exercise capacity and level of daily physical activity, to decrease healthcare resource use, and to improve self‐care and health‐related quality of life.

Methods and results

A multicentre randomized controlled study with two treatment groups will include 600 patients with HF. In each centre, patients will be randomized to either motivational support only (control) or structured access to a Wii game computer (Wii). Patients in the control group will receive advice on physical activity and will be contacted by four telephone calls. Patients in the Wii group also will receive advice on physical activity along with a Wii game computer, with instructions and training. The primary endpoint will be exercise capacity at 3 months as measured by the 6 min walk test. Secondary endpoints include exercise capacity at 6 and 12 months, level of daily physical activity, muscle function, health‐related quality of life, and hospitalization or death during the 12 months follow‐up.

Conclusion

The HF‐Wii study is a randomized study that will evaluate the effect of exergaming in patients with HF. The findings can be useful to healthcare professionals and improve our understanding of the potential role of exergaming in the treatment and management of patients with HF.

Trial registration

NCT01785121
IRAK‐M regulates the inhibition of TLR‐mediated macrophage immune response during late in vitro Leishmania donovani infection
Authors: Srivastav Supriya , Saha Amrita , Barua Jayita , Ukil Anindita , Das Pijush K.
Published: July 2015

Intramacrophage protozoan parasite Leishmania donovani, causative agent of visceral leishmaniasis, escapes Toll‐like receptor (TLR) dependent early host immune response by inducing the deubiquitinating enzyme A20, which is sustained up to 6 h postinfection only. Therefore, Leishmania must apply other means to deactivate late host responses. Here, we elucidated the role of IL‐1 receptor‐associated kinase M (IRAK‐M), a negative regulator of TLR signaling, in downregulating macrophage proinflammatory response during late hours of in vitro infection. Our data reveal a sharp decline in IRAK1 and IRAK4 phosphorylation at 24 h postinfection along with markedly reduced association of IRAK1–TNF receptor associated factor 6, which is mandatory for TLR activation. In contrast, IRAK‐M was induced after A20 levels decreased and reached a maximum at 24 h postinfection. IRAK‐M induction coincided with increased stimulation of TGF‐β, a hallmark cytokine of visceral infection. TGF‐β‐dependent signaling‐mediated induction of SMAD family of proteins, 2, 3, and 4 plays important roles in transcriptional upregulation of IRAK‐M. In infected macrophages, siRNA‐mediated silencing of IRAK‐M displayed enhanced IRAK1 and IRAK4 phosphorylation with a concomitant increase in downstream NF‐κB activity and reduced parasite survival. Taken together, the results suggest that IRAK‐M may be targeted by L. donovani to inhibit TLR‐mediated proinflammatory response late during in vitro infection.
Utilization of the terrestrial weed Antigonon leptopus in the rapid and green synthesis of stable gold nanoparticles with shape/size control
Authors: Ganaie Sami U. , Abbasi Tasneem , Abbasi Shahid A.
Published: July 2015

We report for the first time the utilization of a highly invasive weed Antigonon leptopus in synthesizing gold nanoparticles. For this purpose, aqueous extracts of the weed's leaves/stem/roots served the dual purpose of reducing gold ions to uncharged metal nanoparticles and then capping the nanoparticles thus formed to stabilize them. The synthesis occurs very swiftly leading to spherical, hexagonal, or triangular nanoparticles. The influence of the key variables that control the shape/size of the gold nanoparticles (AuNPs)—concentrations of the extract relative to Au (III), temperature, interaction time, stirring, and pH‐was studied employing UV–visible spectrophotometry, scanning electron microscopy, transmission electron microscopy, energy dispersive analysis of X‐rays, dynamic light scattering (DLS), X‐ray diffraction, and Fourier transform infrared spectroscopy. Besides being simple and rapid, the present process is distinguished by its ability to gainfully utilize an otherwise harmful plant in a manner which consumes little energy and generates no waste emissions. The AuNPs were found to catalyze the degradation of organic pollutants Congo red and Remazol Brilliant Blue R. © 2015 American Institute of Chemical Engineers Environ Prog, 35: 20–33, 2016
Seismic behavior of steel buildings with out‐of‐plumb
Authors: Rad Ali A. , MacRae Gregory A. , Yeow Trevor Z. , Bull Desmond K.
Published: July 2015

A structure that has a permanent offset from a true vertical line is commonly referred to as being ‘out‐of‐plumb’. Out‐of‐plumb may result from construction tolerances or post‐earthquake permanent deformations in steel buildings. This paper quantifies the displacements of buildings with out‐of‐plumb in subsequent seismic events by means of inelastic dynamic time history analysis. Structures considered have different structural heights, force design reduction factors (R), and target inter‐story drifts. It is shown that buildings with greater out of plumb and force design reduction factor have larger normalized peak inter‐story drift ratio and ratio of residual‐to‐peak drift. Also, the ratio of residual‐to‐peak drift was not strongly dependent on structural height or design drift. A design procedure and example provided, based on the results obtained, show how peak and residual inter‐story drift ratio can be estimated. Copyright © 2015 John Wiley & Sons, Ltd.
Englacial and subglacial water flow at Skálafellsjökull, Iceland derived from ground penetrating radar,in situGlacsweb probe and borehole water level measurements
Authors: Hart Jane K. , Rose Kathryn C. , Clayton Alexander , Martinez Kirk
Published: July 2015

We reconstruct englacial and subglacial drainage at Skálafellsjökull, Iceland, using ground penetrating radar (GPR) common offset surveys, borehole studies and Glacsweb probe data. We find that englacial water is not stored within the glacier (water content ~0–0.3%). Instead, the glacier is mostly impermeable and meltwater is able to pass quickly through the main body of the glacier via crevasses and moulins. Once at the glacier bed, water is stored within a thin (1 m) layer of debris‐rich basal ice (2% water content) and the till. The hydraulic potential mapped across the survey area indicates that when water pressures are high (most of the year), water flows parallel to the margin, and emerges 3 km down glacier at an outlet tongue. GPR data indicates that these flow pathways may have formed a series of braided channels. We show that this glacier has a very low water‐storage capacity, but an efficient englacial drainage network for transferring water to the glacier bed and, therefore, it has the potential to respond rapidly to changes in melt‐water inputs. © 2015 The Authors. Earth Surface Processes and Landforms published by John Wiley & Sons Ltd.
Occurrence and distribution pattern of acidic pharmaceuticals in surface water, wastewater, and sediment of the Msunduzi River, Kwazulu-Natal, South Africa
Authors: Agunbiade Foluso O. , Moodley Brenda
Published: July 2015

The paucity of information on the occurrence of pharmaceuticals in the environment in African countries led the authors to investigate 8 acidic pharmaceuticals (4 antipyretics, 3 antibiotics, and 1 lipid regulator) in wastewater, surface water, and sediments from the Msunduzi River in the province of KwaZulu-Natal, South Africa, using solid-phase extraction (SPE) and liquid chromatography–mass spectrometry (LC/MS). The method recoveries, limits of detection (LOD), and limits of quantification were determined. The method recoveries were 58.4% to 103%, and the LODs ranged between 1.16 ng/L and 29.1 ng/L for water and between 0.58 ng/g and 14.5 ng/g for sediment. The drugs were all present in wastewater and in most of the surface water and sediment samples. Aspirin was the most abundant pharmaceutical observed, 118 ± 0.82 μg/L in wastewater influent, and the most observed antibiotic was nalidixic acid (25.2–29.9 μg/L in wastewater); bezafibrate was the least observed. The distribution pattern of the antipyretic in water indicates more impact in suburban sites. The solid–liquid partitioning of the pharmaceuticals between sediment and water, measured as the distribution coefficient (log KD) gave an average accumulation magnitude of 10× to 32× in sediments than in water. The downstream distribution patterns for both water and sediment indicate discharge contributions from wastewater, agricultural activities, domestic waste disposal, and possible sewer system leakages. Although concentrations of the pharmaceuticals were comparable with those obtained from some other countries, the contamination of the present study site with pharmaceuticals has been over time and continues at present, making effective management and control necessary. Environ Toxicol Chem 2016;35:36–46. © 2015 SETAC
Heterogeneous access class barring with QoS guarantee in machine‐type communications
Authors: Han Xiao , Lim Teng Joon , Xu Jie
Published: July 2015

In machine‐to‐machine (M2M) communications, networking a large number of devices with bursty heterogeneous traffic is one of the most critical challenges. In the medium access control layer, the access class barring (ACB) mechanism may be used to regulate the transmission of packets by machine‐type communications devices. In the current literature, the backlogged and newly arrived devices are treated with no difference and are given identical ACB factors (homogeneous ACB scheme), which means that there is a substantial probability that some devices will be backlogged for many slots and then subsequently violate their delay constraints. In this paper, a heterogeneous genie‐aided ACB scheme is first proposed, in which the backlogged and newly arrived devices are treated differently. A more practical scheme is then proposed. Simulation results show that our proposed heterogeneous genie‐aided ACB scheme and practical heterogeneous ACB algorithm always outperform the homogeneous ACB scheme in terms of delay violation probability. Copyright © 2015 John Wiley & Sons, Ltd.
Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for hepatitis C virus genotype 1b–infected Japanese patients with or without cirrhosis
Authors: Kumada Hiromitsu , Chayama Kazuaki , Rodrigues Lino , Suzuki Fumitaka , Ikeda Kenji , Toyoda Hidenori , Sato Ken , Karino Yoshiyasu , Matsuzaki Yasushi , Kioka Kiyohide , Setze Carolyn , Pilot‐Matias Tami , Patwardhan Meenal , Vilchez Regis A. , Burroughs Margaret , Redman Rebecca
Published: July 2015

GIFT‐I is a phase 3 trial evaluating the efficacy and safety of a 12‐week regimen of coformulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) for treatment of Japanese hepatitis C virus genotype 1b–infected patients. It consists of a double‐blind, placebo‐controlled substudy of patients without cirrhosis and an open‐label substudy of patients with compensated cirrhosis. Patients without cirrhosis were randomized 2:1 to once‐daily OBV/PTV/r (25 mg/150 mg/100 mg; group A) or placebo (group B). Patients with cirrhosis received open‐label OBV/PTV/r (group C). The primary efficacy endpoint was the rate of sustained virological response 12 weeks posttreatment in interferon‐eligible, treatment‐naive patients without cirrhosis and hepatitis C virus RNA ≥100,000 IU/mL in group A. A total of 321 patients without cirrhosis were randomized and dosed with double‐blind study drug (106 received double‐blind placebo and later received open‐label OBV/PTV/r), and 42 patients with cirrhosis were enrolled and dosed with open‐label OBV/PTV/r. In the primary efficacy population, the rate of sustained virological response 12 weeks posttreatment was 94.6% (106/112, 95% confidence interval 90.5‐98.8). Sustained virological response 12 weeks posttreatment rates were 94.9% (204/215) in group A, 98.1% (104/106) in group B (open‐label), and 90.5% (38/42) in group C. Overall, virological failure occurred in 3.0% (11/363) of patients who received OBV/PTV/r. The rate of discontinuation due to adverse events was 0%‐2.4% in the three patient groups receiving OBV/PTV/r. The most frequent adverse event in patients in any group was nasopharyngitis. Conclusion: In this broad hepatitis C virus genotype 1b–infected Japanese patient population with or without cirrhosis, treatment with OBV/PTV/r for 12 weeks was highly effective and demonstrated a favorable safety profile. (Hepatology 2015;62:1037‐1046)
Long‐term follow‐up of the risk for cervical intraepithelial neoplasia grade 2 or worse in HPV‐negative women after conization
Authors: Gosvig Camilla F. , Huusom Lene D. , Andersen Klaus K. , Duun‐Henriksen Anne Katrine , Frederiksen Kirsten , Iftner Angelika , Svare Edith , Iftner Thomas , Kjaer Susanne K.
Published: July 2015

Little research has been conducted on the long‐term value of human papillomavirus (HPV) testing after conization. We investigated whether cytology adds to the value of a negative HPV test for long‐term prediction of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). In addition, we compared risk of CIN2+ following a negative HPV test in women after conization with that in women from the general population. During 2002–2005, 667 women treated for CIN2+ were tested for HPV and cytology 46 months after conization. Only HPV‐negative women were included. Women participating in routine screening were age‐matched with post‐conization HPV‐negative women, leaving 13,230 and 477 women, respectively, for analysis. By linkage to the Pathology Data Bank, we identified all cases of CIN2+ by December 2013. The 3‐, 5‐, 8‐ and 10‐year risks for CIN2+ were 0.7, 0.9, 2.8 and 5.7% after a negative HPV test and 0.5, 0.8, 2.9 and 6.1% in HPV and cytology‐negative women. HPV‐negative women in the general population had similar 3‐year and 5‐year risks of 0.4 and 1.0%; thereafter, they had lower risks of 1.9% at 8 years and 2.7% at 10 years. Our results indicate that HPV testing may be used as a test of cure after conization. In the first 5 years after testing, the risk for CIN2+ of women who were HPV‐negative at 34 months after conization was similar to that of HPV‐negative women in the general population. After 67 years, however, women who have undergone conization may be at higher risk for CIN2+.
Urocortin Attenuates TGFβ1‐Induced Snail1 and Slug Expressions: Inhibitory Role of Smad7 in Smad2/3 Signaling in Breast Cancer Cells
Authors: Jin Lai , Zhu Chao , Wang Xiaofei , Li Chuanhua , Cao Chunxuan , Yuan Jie , Li Shengnan
Published: July 2015

Corticortropin‐releasing hormone (CRH) family are multifunctional endocrine‐factors that regulate proliferation, apoptosis, and migration of various types of cancer cells. Deregulation of the transforming growth factor β1(TGFβ1) signal transduction promotes aggressive metastatic properties in late‐stage breast cancers. We previously have demonstrated in breast cancer cell line that CRH suppressed TGFβ1‐induced Epithelial‐Mesenchymal Transition (EMT) via induction of E‐cadherin. Our present data in MCF‐7 and MDA‐MB‐231 cells showed that Urocortin (Ucn, a member of CRH family) inhibited TGFβ1 signaling by reducing Smad2/3 activation and subsequent nuclear translocation through increasing Smad7 expression, leading to downregulation of Snail1 and Slug, the two EMT promoters. We further found that Antalarmin (CRH receptor type 1, CRHR1 antagonist) and Antisauvagine‐30 (CRH receptor type2, CRHR2 antagonist) abrogated the effects of Ucn on TGFβ1 signaling, implying that both active CRHR1 and CRHR2 participate in Ucn‐repressed TGFβ1 signaling. Our findings, for the fist time, identify Ucn as a potential mediator that inhibits oncogenic signaling by TGFβ1 and suggest that activating CRHR1 and R2 may prove effective in diminishing breast cancer progression stimulated by TGFβ1. J. Cell. Biochem. 116: 2494–2503, 2015. © 2015 Wiley Periodicals, Inc.
Benchmark calculations of the adsorption of aromatic molecules on graphene
Authors: Wang Weizhou , Sun Tao , Zhang Yu , Wang Yi‐Bo
Published: July 2015

Selecting the saturated graphene fragment as a model of graphene, we have investigated seven popular density functionals, including ωB97X‐D, B97‐D, B‐LYP‐D3, M05‐2X, M06‐2X, M11‐L, and N12, for their performance in describing the adsorption of aromatic molecules on graphene. The best performing functionals are B97‐D, B‐LYP‐D3, and ωB97X‐D. M05‐2X, M06‐2X, and M11‐L significantly underestimate the adsorption strengths, while N12 fails completely in this respect. The effects of the basis sets and size of the saturated graphene fragments on the geometries, energies, and properties for the adsorption of aromatic molecules on graphene have also been studied. It was found that the small basis sets such as 6–31G(d) and jun‐cc‐pVDZ are not suitable for the accurate description of the adsorption of aromatic molecules on graphene. The size of selected graphene fragments has a little effect on both the ωB97X‐D and SCS‐SAPT0 interaction energies, but the effects of the size of selected graphene fragments on the energy components are significant in some cases of the adsorption of aromatic molecules on graphene. The surprising weakness of electrostatic interactions by F substitution for the adsorption of F‐substituted benzenes on graphene was explained using the energy component analysis. © 2015 Wiley Periodicals, Inc.
Meta‐analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling
Authors: Upreti Vijay V. , Wahlstrom Jan L.
Published: July 2015

The accurate prediction of pharmacokinetics (PK) is fundamental to underwriting safety and efficacy in pediatric clinical trials; age‐dependent PK may be observed with pediatrics because of the growth and maturation processes that occur during development. Understanding the ontogeny of drug‐metabolizing enzymes is a critical enabler for pediatric PK prediction, as enzyme expression or activity may change with age. Although ontogeny functions for the cytochrome P450s (CYPs) have been developed, disconnects between ontogeny functions for the same CYP may exist, depending on whether the functions were derived from in vitro or in vivo data. This report describes the development of ontogeny functions for all the major hepatic CYPs based on in vitro or in vivo data; these ontogeny functions were subsequently incorporated into a physiologically based pharmacokinetic model and evaluated. Pediatric PK predictions based on in vivo–derived ontogeny functions performed markedly better than those developed from in vitro data for intravenous (100% versus 51% within 2‐fold, respectively) and oral (98% versus 67%, respectively) dosing. The verified models were then applied to complex pediatric scenarios involving active metabolites, CYP polymorphisms and physiological changes because of critical illness; the models reasonably explained the observed age‐dependent changes in pediatric PK.
An integrative population pharmacokinetics approach to the characterization of the effect of hepatic impairment on clobazam pharmacokinetics
Authors: Tolbert Dwain , Bekersky Ihor , Chu Hui‐May , Ette Ene I.
Published: July 2015

An integrative population pharmacokinetics (PPK)–based approach was used to characterize the effect of hepatic impairment on clobazam PK and its major metabolite in systemic circulation,N‐desmethylclobazam (N‐CLB). At therapeutic clobazam dosages, N‐CLB plasma concentrations are 3–5 times greater than the parent compound. PK data from clinical trials in patients with Lennox–Gastaut syndrome (LGS; OV‐1002 and OV‐1012), healthy participants (OV‐1016), and participants with and without renal impairment (OV‐1032), as well as those from a publication describing the effects of hepatic impairment on clobazam PK, were merged to create the PPK model. Individual patient clobazam PK parameters from the publication were used to generate patient plasma‐concentration data. Clobazam PK was linear and the formation of N‐CLB was elimination‐rate limited. Hepatic impairment did not affect the total apparent clearance of clobazam but may affect the PK of N‐CLB. Because the formation of N‐CLB is elimination‐rate limited and the total apparent clearance of clobazam is unaffected by hepatic impairment, the PPK model suggests that patients with LGS and hepatic impairment may not require clobazam dosage modification.
Multimodal MRI can identify perfusion and metabolic changes in the invasive margin of glioblastomas
Authors: Price Stephen J. , Young Adam M.H. , Scotton William J. , Ching Jared , Mohsen Laila A. , Boonzaier Natalie R. , Lupson Victoria C. , Griffiths John R. , McLean Mary A. , Larkin Timothy J.
Published: July 2015

Purpose

To use perfusion and magnetic resonance (MR) spectroscopy to compare the diffusion tensor imaging (DTI)‐defined invasive and noninvasive regions. Invasion of normal brain is a cardinal feature of glioblastomas (GBM) and a major cause of treatment failure. DTI can identify invasive regions.

Materials and Methods

In all, 50 GBM patients were imaged preoperatively at 3T with anatomic sequences, DTI, dynamic susceptibility perfusion MR (DSCI), and multivoxel spectroscopy. The DTI and DSCI data were coregistered to the spectroscopy data and regions of interest (ROIs) were made in the invasive (determined by DTI), noninvasive regions, and normal brain. Values of relative cerebral blood volume (rCBV), N‐acetyl aspartate (NAA), myoinositol (mI), total choline (Cho), and glutamate + glutamine (Glx) normalized to creatine (Cr) and Cho/NAA were measured at each ROI.

Results

Invasive regions showed significant increases in rCBV, suggesting angiogenesis (invasive rCBV 1.64 [95% confidence interval, CI: 1.5–1.76] vs. noninvasive 1.14 [1.09–1.18]; P < 0.001), Cho/Cr (invasive 0.42 [0.38–0.46] vs. noninvasive 0.35 [0.31–0.38]; P = 0.02) and Cho/NAA (invasive 0.54 [0.41–0.68] vs. noninvasive 0.37 [0.29–0.45]; P = < 0.03), suggesting proliferation, and Glx/Cr (invasive 1.54 [1.27–1.82] vs. noninvasive 1.3 [1.13–1.47]; P = 0.028), suggesting glutamate release; and a significantly reduced NAA/Cr (invasive 0.95 [0.85–1.05] vs. noninvasive 1.19 [1.06–1.31]; P = 0.008). The mI/Cr was not different between the three ROIs (invasive 1.2 [0.99–1.41] vs. noninvasive 1.3 [1.14–1.46]; P = 0.68). In the noninvasive regions, the values were not different from normal brain.

Conclusion

Combining DTI to identify the invasive region with perfusion and spectroscopy, we can identify changes in invasive regions not seen in noninvasive regions. J. Magn. Reson. Imaging 2016;43:487–494.
Emission of volatile sesquiterpenes and monoterpenes in grapevine genotypes following Plasmopara viticola inoculation in vitro
Authors: Algarra Alarcon Alberto , Lazazzara Valentina , Cappellin Luca , Bianchedi Pier Luigi , Schuhmacher Rainer , Wohlfahrt Georg , Pertot Ilaria , Biasioli Franco , Perazzolli Michele
Published: July 2015

The grapevine (Vitis vinifera) is one of the most widely cultivated fruit crops globally, and one of its most important diseases in terms of economic losses is downy mildew, caused by Plasmopara viticola. Several wild Vitis species have been found to be resistant to this pathogen and have been used in breeding programs to introduce resistance traits to susceptible cultivars. Plant defense is based on different mechanisms, and volatile organic compounds (VOCs) play a major role in the response to insects and pathogens. Although grapevine resistance mechanisms and the production of secondary metabolites have been widely characterized in resistant genotypes, the emission of VOCs has not yet been investigated following P. viticola inoculation. A Proton Transfer Reaction‐Time of Flight‐Mass Spectrometer (PTR‐ToF‐MS) was used to analyze the VOCs emitted by in vitro‐grown plants of grapevine genotypes with different levels of resistance. Downy mildew inoculation significantly increased the emission of monoterpenes and sesquiterpenes by the resistant SO4 and Kober 5BB genotypes, but not by the susceptible V. vinifera Pinot noir. Volatile terpenes were implicated in plant defense responses against pathogens, suggesting that they could play a major role in the resistance against downy mildew by direct toxicity or by inducing grapevine resistance. The grapevine genotypes differed in terms of the VOC emission pattern of both inoculated and uninoculated plants, indicating that PTR‐ToF‐MS could be used to screen hybrids with different levels of downy mildew resistance. Copyright © 2015 John Wiley & Sons, Ltd.
Creative Behavior, Motivation, Environment and Culture: The Building of a Systems Model
Authors: Hennessey Beth A.
Published: July 2015

With the exception of research examining the productivity of teams, the empirical study of creativity was until recently almost exclusively focused at the level of the individual creator. Investigators and theorists typically chose to decontextualize the creative process and failed to include a consideration of anyone or anything beyond the person doing the creating. The last decade has seen a long overdue proliferation of research focused on the creative milieu and the myriad of environmental factors that impact creators and serve to boost or inhibit their creativity of performance. In particular, the increasing globalization of corporate, entrepreneurial, and educational environments has underscored the need to take into consideration the impact of cultural forces. This article chronicles the construction of a systems model of creativity designed to incorporate a consideration of creative behavior at multiple levels of analysis. Over and above an examination of individual difference variables, the argument is made that creativity must be explored at the “little‐c” cultural level (e.g., the culture of the classroom or workplace), at the societal level, and at the “Big‐C” cultural level (i.e., culture writ large). An application of this systems approach is made to classroom‐based data collected in the U.S. and Saudi Arabia.
Measurement of the lens accommodation in viewing stereoscopic displays
Authors: Hong Hyungki , Kang Seok Hyon
Published: July 2015

In observing the stereoscopic display at the viewing distance of 1 m, the amount of the perceived depth was determined by the positions of the crossing point that the viewing direction of two eyes intersect. The positions of the crossing points of stereoscopic stimuli were controlled, and the accommodation was measured by the autorefractometer for the seven participants. Accommodation was also measured when viewing the real film chart which was placed at the same position as these crossing points. The accommodation change when viewing the stereoscopic display was measured to be noticeable only when the crossing point was quite near the participant, but this change was still much smaller compared with the accommodation change when viewing the real film chart. This change in accommodation implies the possible occurrence of fatigue related to the accommodation–convergence conflict, while the constant accommodation within the range of DOF implies no conflict between the accommodation and convergence. This measurement scheme may be used to define the range of DOF where the accommodation remains little changed, and thus define the depth of the 3D object at which no accommodation–convergence conflict occurs, for a given stereoscopic display.
Hysteretic Buckling for Actuation of Magnet–Polymer Composites
Authors: Ahmed Anansa S. , Ramanujan Raju V.
Published: July 2015

The development of bioinspired, novel, high‐performance, “artificial muscle” materials is a topic of high current interest. Flexibility for folding and actuation are key parameters in the development of such artificial muscles, especially for self‐assembly and origami engineering. A current challenge is to develop a multifunctional material that combines the biological functions of actuation, sensing, and healing. In this work, for the first time experimental and modeling results of the actuation capability of a multifunctional magnet–polymer (Magpol) composite material that is already capable of damage sensing and self‐healing are reported. Actuation by constrained buckling of Magpol in an external magnetic field shows two buckling modes. The stress and strain are studied and optimized for various actuator geometries. Work density of up to 16 J kg−1 is obtained, comparable to electroactive polymers. Magpol is successfully able to lift more than four times its own weight at relatively low applied magnetic field. Good agreement is observed between the experimental and modeling results. An Ashby design chart is employed to compare its performance to other actuators. This work provides insight into the development of next generation flexible, active multifunctional materials.

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Influence of relative blood flow restriction pressure on muscle activation and muscle adaptation
Authors: Counts Brittany R. , Dankel Scott J. , Barnett Brian E. , Kim Daeyeol , Mouser J. Grant , Allen Kirsten M. , Thiebaud Robert S. , Abe Takashi , Bemben Michael G. , Loenneke Jeremy P.
Published: July 2015

Introduction: The aim of this study was to investigate the acute and chronic skeletal muscle response to differing levels of blood flow restriction (BFR) pressure. Methods: Fourteen participants completed elbow flexion exercise with pressures from 40% to 90% of arterial occlusion. Pre/post torque measurements and electromyographic (EMG) amplitude of each set were quantified for each condition. This was followed by a separate 8‐week training study of the effect of high (90% arterial occlusion) and low (40% arterial occlusion) pressure on muscle size and function. Results: For the acute study, decreases in torque were similar between pressures [–15.5 (5.9) Nm, P = 0.344]. For amplitude of the first 3 and last 3 reps there was a time effect. After training, increases in muscle size (10%), peak isotonic strength (18%), peak isokinetic torque (180°/s = 23%, 60°/s = 11%), and muscular endurance (62%) changed similarly between pressures. Conclusion: We suggest that higher relative pressures may not be necessary when exercising under BFR. Muscle Nerve 53: 438–445, 2016
Paraspinal muscle denervation and balance impairment in lumbar spinal stenosis
Authors: Ozcan‐Eksi Emel Ece , Yagci Ilker , Erkal Hatice , Demir‐Deviren Sibel
Published: July 2015

Introduction: Denervation of the paraspinal muscles may impair posture and displace the center of gravity. Therefore, we assessed balance impairment in patients with lumbar spinal stenosis (LSS) with and without paraspinal denervation. Methods: Thirty‐two women with LSS (15 symptomatic, 17 asymptomatic), aged 42–78 years, were assessed for disability, pain, and mobility, and underwent masked mini‐paraspinal mapping (mPSM). Berg Balance Scale (BBS) and device‐assisted balance (DAB) tests were used for balance assessment. Results: The symptomatic group had worse balance and higher mPSM scores than the asymptomatic group. Among DAB tests, limit of stability (LOS) had the highest correlations with BBS and mPSM in the symptomatic group. Conclusions: Paraspinal denervation correlated highly with static and dynamic balance in symptomatic patients. We recommend paraspinal mapping, balance assessment, rehabilitation, and follow‐up with the LOS test for symptomatic patients. Muscle Nerve 53: 422–430, 2016
A square‐shaped wrist as a predictor of carpal tunnel syndrome: A meta‐analysis
Authors: Shiri Rahman
Published: July 2015

Introduction: This meta‐analysis aims to assess an association between wrist ratio (wrist thickness/wrist width) and carpal tunnel syndrome (CTS). Methods: Sixteen studies qualified for a random‐effects meta‐analysis. Results: Mean wrist ratio was higher in individuals with CTS compared with those without CTS [pooled mean difference 0.036, 95% confidence interval (CI) 0.025–0.046]. Pooled odds ratio (OR) of CTS for mean wrist ratio was 4.56 (95% CI 2.97–6.99), and for wrist ratio ≥0.70 vs. <0.70 it was 2.73 (95% CI 1.49–5.01). In addition, the pooled OR for a 1‐unit (0.01) increase in wrist ratio was 1.12 (CI 1.09–1.16). The association between wrist ratio and CTS did not differ between men and women. Moreover, there was no evidence of publication bias. Conclusions: This meta‐analysis suggests that a square‐shaped wrist is a predictor for CTS in both men and women. Future studies should explore whether a square‐shaped wrist can potentiate the adverse effects of obesity and occupational workloads on CTS. Muscle Nerve 52: 709–713, 2015
Effects of Early‐Stage Group Psychoeducation Programme for Patients with Depression
Authors: Tanaka Sachie , Ishikawa Eri , Mochida Ayumi , Kawano Koujiro , Kobayashi Masayoshi
Published: July 2015

The purpose of this study was to examine the effect of a psychoeducational group programme on inpatients with depression. We compared the attributes and Inventory Scale for Mood and Sense of Fatigue (SMSF) scores of 45 people who participated in the programme (participation group) with those of 37 people who did not participate (control group). Further, we investigated the rate of readmission 6 months after discharge and the number of patients in the participation group who had consulted a psychiatric social worker. Statistically, there were no significant differences in the SMSF score between the two groups on admission and at the time of discharge. The programme had no effect on the readmission rate. However, the SMSF score of the participation group significantly improved from the start of the programme to patient discharge. Furthermore, improvement of depressive symptoms, feeling of recovery and adherence were found in the participation group. The programme seemed to provide a psychotherapeutic effect for the patients and promoted cooperation with occupational therapist and other specialists in the hospital. The efficacy of psychoeducation in preventing recurrence of depression remains to be demonstrated, and methods of investigating effective approaches for this purpose need to be considered in the future. Copyright © 2015 John Wiley & Sons, Ltd.
A comparative study on dielectric, structure, and thermal behavior of micro‐ and nano‐sized CCTO in nylon 6,9 matrix
Authors: Ramaswami Sachidanandan Ernest Ravindran , Paramanandam Thomas , Sahadevan Renganathan
Published: July 2015

Calcium copper titanium oxalate CaCu3Ti4O12 (CCTO) particles as a filler with both micro‐ and nano‐sized into nylon 6,9 polymer have been investigated under structural, thermal, and dielectric properties to find that particle satisfy all the same. Micro‐sized CCTO particles (point out as mCCTO) was synthesized using solid‐state route using ball milling and nano‐sized CCTO particles (point out as nCCTO) was synthesized using complex oxalate precursor route. Fabrication of nylon 6,9/CCTO composite for both micro‐ and nano‐sized CCTO particles were employed separately into nylon 6,9 matrix and examined comparatively. The composite containing 20 vol% of nCCTO achieve 24.5 dielectric permittivity at 100 Hz in room temperature that was significantly higher than mCCTO which was 14 at the same condition. From the structural analysis, we obtained that the nCCTO was well dispersed in the matrix medium, whereas the mCCTO were also dispersed with some agglomeration that was the reason for the interaction failure between the particles and matrix material. The dielectric permittivity results obtained from this study specify that the composite containing nano‐sized CCTO particles may be suitable for energy storage devices and in the higher temperature sensor applications. POLYM. COMPOS., 38:927–935, 2017. © 2015 Society of Plastics Engineers
Minimal Prolongation of Prothrombin Time with Extended Exposure to Argatroban
Authors: McAlister Renee K. , Ito Satoru
Published: July 2015

In the setting of acute heparin‐induced thrombocytopenia (HIT), argatroban is one of the initial anticoagulants of choice, which is eventually bridged to warfarin over a period of 5 or more days. Argatroban prolongs prothrombin time (PT) and increases international normalized ratio (INR). However, the effects of prolonged argatroban exposure on the PT and INR are not known. We describe an unusual case of prolonged argatroban treatment in a patient with heparin‐induced thrombocytopenia with thrombosis syndrome (HITTS) resulting in a minimal elevation of the INR. The patient received a total of 58 days of argatroban and was resistant to warfarin therapy, requiring a 13‐day bridge to achieve a therapeutic INR of 2.0 to 3.0. Ultimately, argatroban was successfully transitioned to warfarin therapy when the INR was 2.7 on both agents, producing the confirmatory true INR of 2.4. Argatroban and warfarin cotherapy did not increase the INR beyond 4.0 after prolonged argatroban exposure. Clinicians should consider this unusual response in other cases of prolonged argatroban use, and monitor INR carefully during warfarin and argatroban cotherapy. The use of other methods to monitor anticoagulant therapy, such as chromogenic factor X assay (CFX), may be helpful in this setting.