bluuebunny/crossref_metadata_2025 huggingface dataset:
Interferon stimulated exonuclease gene 20 kDa links psychiatric events to distinct hepatitis C virus responses in human immunodeficiency virus positive patients
Authors: Katsounas Antonios , Rasimas Joseph J. , Schlaak Joerg F. , Lempicki Richard A. , Rosenstein Donald L. , Kottilil Shyam
Published: April 2014

Hepatitis C Virus (HCV) infection occurs frequently in patients with preexisting mental illness. Treatment for chronic hepatitis C using interferon formulations often increases risk for neuro‐psychiatric symptoms. Pegylated‐Interferon‐α (PegIFN‐α) remains crucial for attaining sustained virologic response (SVR); however, PegIFN‐α based treatment is associated with psychiatric adverse effects, which require dose reduction and/or interruption. This study's main objective was to identify genes induced by PegIFN‐α and expressed in the central nervous system and immune system, which could mediate the development of psychiatric toxicity in association with antiviral outcome. Using peripheral blood mononuclear cells from Human Immunodeficiency Virus (HIV)/HCV co‐infected donors (N = 28), DNA microarray analysis was performed and 21 differentially regulated genes were identified in patients with psychiatric toxicity versus those without. Using these 21 expression profiles a two‐way‐ANOVA was performed to select genes based on antiviral outcome and occurrence of neuro‐psychiatric adverse events. Microarray analysis demonstrated that Interferon‐stimulated‐exonuclease‐gene 20 kDa (ISG20) and Interferon‐alpha‐inducible‐protein 27 (IFI27) were the most regulated genes (P < 0.05) between three groups that were built by combining antiviral outcome and neuro‐psychiatric toxicity. Validation by bDNA assay confirmed that ISG20 expression levels were significantly associated with these outcomes (P < 0.035). Baseline levels and induction of ISG20 correlated independently with no occurrence of psychiatric adverse events and non‐response to therapy (P < 0.001). Among the 21 genes that were associated with psychiatric adverse events and 20 Interferon‐inducible genes (IFIGs) used as controls, only ISG20 expression was able to link PegIFN‐α related neuro‐psychiatric toxicity to distinct HCV‐responses in patients co‐infected with HIV and HCV in vivo. J. Med. Virol. 86:1323–1331, 2014. © 2014 Wiley Periodicals, Inc.
Projected changes in characteristics of precipitation spatial structures over North America
Authors: Guinard Karine , Mailhot Alain , Caya Daniel
Published: April 2014

Spatial structures of hourly precipitation fields were studied from three simulations of the Canadian Regional Climate Model (CRCM) and observations of the National Centers for Environmental Prediction (NCEP) Stage IV analysis. Each precipitation structure, defined as a contiguous area of precipitation above a given threshold, was analysed through geometric characteristics (position, area, major and minor axes, eccentricity, orientation) and intensity characteristics (volume, mean and maximum intensities, precipitation distribution within the structure) for 16 climatic regions covering North America. While providing new insights on the spatial facet of precipitation, this study aimed to: (1) assess the performance of the CRCM to reproduce observed precipitation structures and (2) analyse the changes in precipitation structures between historical (1961–1990) and future (2071–2100) periods. In addition, the effect of internal variability was investigated using two CGCM‐driven CRCM simulations. In order to assess the CRCM performance, a reanalysis‐driven CRCM simulation was first compared with observations and then with CGCM‐driven CRCM simulations. Results suggest that reanalysis‐driven CRCM precipitation structures displayed intensities spatially more homogeneous than observed ones for the central and eastern United States and showed significantly lower precipitation volumes, intensities and areas. However, annual cycles of characteristic values were well reproduced. In addition, CGCM‐driven CRCM showed significantly lower precipitation volumes and intensities during summer months for southeastern regions when compared to reanalysis‐driven CRCM. Precipitation structures were also larger and shifted further north. Boundary conditions seemed to influence mainly central and eastern regions of North America. In future climate, results suggest more convective summer precipitations for central and eastern regions (increases in volumes, intensities and heterogeneity of structures), drier spring and summer conditions for southwestern regions (decreases in numbers of structures), wetter winter and spring conditions for northern regions (increases in numbers of structures) and wetter autumn conditions for southeastern regions (increases in volumes and intensities).
Phonon confinement effects in Raman spectra of porous silicon at non‐resonant excitation condition
Authors: Kosović Marin , Gamulin Ozren , Balarin Maja , Ivanda Mile , Đerek Vedran , Ristić Davor , Marciuš Marijan , Ristić Mira
Published: April 2014

Light emitting porous silicon samples with different porosities, i.e. crystalline sizes, were produced from the low level doped p‐type silicon wafers by the anodization process. The effects of strong phonon confinement, redshift and broadening, were found on the O(Γ) phonon mode of the Raman spectra recorded at non‐resonant excitation condition using a near infrared 1064 nm laser excitation wavelength. Similarly, the blueshift of the photoluminescence peak was observed by reducing the crystalline sizes. Vibrational and optical findings were analysed within the existing models of confinement on the vibrational and electronic states of silicon nanocrystals. Since the energy of the photoluminescence peak of small nanocrystals also depends on the oxygen content on the surface of nanocrystals, the surface oxidation states were examined using infrared and energy dispersive spectroscopy. The partial coverage of the surface of nanocrystals was found due to the sample exposure to air. As a consequence, the photoluminescence energy did not increase as would be expected from the quantum confinement model. These results further indicate that the oxygen passivation along with the quantum confinement determines the electronic states of the silicon nanocrystals in porous silicon. Copyright © 2014 John Wiley & Sons, Ltd.
Recycling slaughterhouse waste into fertilizer: how do pyrolysis temperature and biomass additions affect phosphorus availability and chemistry?
Authors: Zwetsloot Marie J , Lehmann Johannes , Solomon Dawit
Published: April 2014

BACKGROUND

Pyrolysis of slaughterhouse waste could promote more sustainable phosphorus (P) usage through the development of alternative P fertilizers. This study investigated how pyrolysis temperature (220, 350, 550 and 750 °C), rendering before pyrolysis, and wood or corn biomass additions affect P chemistry in bone char, plant availability, and its potential as P fertilizer.

RESULTS

Linear combination fitting of synchrotron‐based X‐ray absorption near edge structure spectra demonstrated that higher pyrolysis temperatures decreased the fit with organic P references, but increased the fit with a hydroxyapatite (HA) reference, used as an indicator of high calcium phosphate (CaP) crystallinity. The fit to the HA reference increased from 0% to 69% in bone with meat residue and from 20% to 95% in rendered bone. Biomass additions to the bone with meat residue reduced the fit to the HA reference by 83% for wood and 95% for corn, and additions to rendered bone by 37% for wood. No detectable aromatic P forms were generated by pyrolysis. High CaP crystallinity was correlated with low water‐extractable P, but high formic acid‐extractable P indicative of high plant availability. Bone char supplied available P which was only 24% lower than Triple Superphosphate fertilizer and two‐ to five‐fold higher than rock phosphate.

CONCLUSION

Pyrolysis temperature and biomass additions can be used to design P fertilizer characteristics of bone char through changing CaP crystallinity that optimize P availability to plants. © 2014 Society of Chemical Industry
Protein gels and emulsions from mixtures of Cape hake and pea proteins
Authors: Tomé Ana Sofia , Pires Carla , Batista Irineu , Sousa Isabel , Raymundo Anabela
Published: April 2014

BACKGROUND

Portioning of frozen fish generates by‐products such as fish ‘sawdust’ and cut‐offs which can be further processed into protein concentrates and isolates. The objective of the present work was to produce gels and emulsions using recovered Cape hake protein powder (HPP). In previous works, the structures of the gels produced by HPP were found to be strong, with a high rubbery character. In this work, the addition of commercial pea proteins (PPC) to HPP gels and emulsions was studied.

RESULTS

Physical properties of gels and emulsions prepared with different proportions of mixtures of PPC and HPP were evaluated. In general, gels and emulsions showed high values for whiteness and, as expected, the higher content of HPP in the protein mixtures led to higher firmness values of the gels. The gel network was rapidly formed upon heating due to the fish protein macromolecules and further reinforced by the pea protein macromolecules when cooled to 5 °C. Both visco‐elastic parameters, storage and loss moduli, of the produced gels increased with the HPP proportion in the protein mixtures, corresponding to more structured systems. For the emulsions, two different pH environments were studied: 3.8 and 7.0. At neutral pH a synergy was found between the vegetable and fish protein, which is not so strong when pH is lowered to 3.8, near the isoelectric point of pea proteins (pI = 4.5). This evidence was supported by the results from the texture measurements, viscosity and visco‐elastic parameters.

CONCLUSIONS

Gels made from Cape hake proteins showed a softer texture and were less rubbery with the addition of pea proteins. Emulsions stabilised by these mixtures showed slightly different behaviour when produced at pH 7.0 or pH 3.8. © 2014 Society of Chemical Industry
The influence of processing on the microbial risk associated with Rooibos (Aspalathus linearis) tea
Authors: Gouws Pieter , Hartel Toni , van Wyk Rudean
Published: April 2014

This review discusses the influence of processing on the microbial risk associated with Salmonella in Rooibos tea, the identification of Salmonella and preventative and control measures to control microbial contamination. Rooibos tea, like other plant products, naturally contains a high microbial load. Downstream processing steps of these products usually help in reducing any contaminants present. Due to the delicate flavour properties and nature of Rooibos, gentle processing techniques are necessary for the production of good quality tea. However, this has a major influence on the microbiological status of the product. The presence of Salmonella in Rooibos is poorly understood. The ubiquitous distribution of Salmonella in the natural environment and its prevalence in the global food chain, the physiological adaptability, virulence of the bacterial pathogen and its serious economic impact on the food industry, emphasises the need for continued awareness and stringent controls at all levels of food production. With the advances of technology and information at hand, the processing of Rooibos needs to be re‐evaluated. Since the delicate nature of Rooibos prohibits the use of harsh methods to control Salmonella, alternative methods for the steam pasteurisation of Rooibos show great potential to control Salmonella in a fast, efficient and cost‐effective manner. These alternative methods will significantly improve the microbiological quality of Rooibos and provide a product that is safe to consumers. © 2014 Society of Chemical Industry
Intraoperative electrochemotherapy of colorectal liver metastases
Authors: Edhemovic Ibrahim , Brecelj Erik , Gasljevic Gorana , Marolt Music Maja , Gorjup Vojka , Mali Barbara , Jarm Tomaz , Kos Bor , Pavliha Denis , Grcar Kuzmanov Biljana , Cemazar Maja , Snoj Marko , Miklavcic Damijan , Gadzijev Eldar M. , Sersa Gregor
Published: April 2014

Background and Objectives

Electrochemotherapy is effective in treatment of various cutaneous tumors and could be translated into treatment of deep‐seated tumors. With this aim a prospective pilot study was conducted to evaluate feasibility, safety, and efficacy of intraoperative electrochemotherapy in the treatment of colorectal liver metastases.

Methods

Electrochemotherapy with bleomycin was performed during open surgery, by insertion of long needle electrodes into and around the tumor according to the individualized pretreatment plan.

Results

A 29 metastases in 16 patients were treated in 16 electrochemotherapy sessions. No immediate (intraoperative) and/or postoperative serious adverse events related to electrochemotherapy were observed. Radiological evaluation of all the treated metastases showed 85% complete responses and 15% partial responses. In a group of seven patients that underwent a second operation at 6–12 weeks after the first one, during which electrochemotherapy was performed, the histology of resected metastases treated by electrochemotherapy showed less viable tissue (P = 0.001) compared to non‐treated ones.

Conclusions

Electrochemotherapy of colorectal liver metastases proved to be feasible, safe, and efficient treatment modality, providing its specific place in difficult to treat metastases, located in the vicinity of major hepatic vessels, not amenable to surgery or radiofrequency ablation. J. Surg. Oncol. 2014 110:320–327. © 2014 The Authors. Journal of Surgical Oncology published by Wiley Periodicals, Inc.
Correlation between Reflux and multichannel intraluminal impedance pH monitoring in untreated volunteers
Authors: Jetté Marie E. , Gaumnitz Eric A. , Birchall Martin A. , Welham Nathan V. , Thibeault Susan L.
Published: April 2014

Objectives/Hypothesis

Although probable causative agents have been identified (e.g., refluxate components, tobacco smoke), the definitive mechanism for inflammation‐related laryngeal mucosal damage remains elusive. Multichannel intraluminal impedance combined with pH monitoring (MII/pH) has emerged as a sensitive tool for diagnosis and characterization of gastroesophageal reflux disease with laryngopharyngeal manifestations. To determine the relationship between laryngeal signs and MII/pH, we examined correlations between Reflux Finding Score (RFS) ratings of videostroboscopic laryngeal examinations and findings from MII/pH.

Study Design

Correlational study.

Methods

Healthy, untreated volunteers (n = 142) underwent reflux diagnosis using data acquired from MII/pH testing. Eight trained clinicians performed RFS ratings of corresponding laryngeal examinations. Averaged RFS ratings were compared to MII/pH data using Pearson correlation coefficients. The relationship between RFS and MII/pH findings and demographic/clinical information (age, sex, smoking status, reflux) was assessed using general linear modeling. Rater reliability was evaluated.

Results

Posterior commissure hypertrophy was negatively correlated with minutes of nonacid refluxate (R = −0.21, P = .0115). General linear modeling revealed that 28% to 40% of the variance in ratings of ventricular obliteration, erythema/hyperemia, vocal fold edema, diffuse laryngeal edema, posterior commissure hypertrophy, and granulation/granuloma could be explained by main and interaction effects of age, sex, smoking status, and reflux. Intra‐ and inter‐rater reliability for RFS were poor–fair.

Conclusions

These results support the theory that the RFS is not specific for reflux in healthy, untreated volunteers, suggesting there may be alternate explanations for inflammatory clinical signs commonly ascribed to reflux in this population.

Level of Evidence

1b Laryngoscope 124:2345–2351, 2014
Prokinetic agents and laryngopharyngeal reflux disease: Prokinetic agents and laryngopharyngeal reflux disease: A systematic review
Authors: Glicksman Jordan T. , Mick Paul T. , Fung Kevin , Carroll Thomas L.
Published: April 2014

Objectives

Our objective was to systematically identify and evaluate prospective studies providing evidence for and against the use of prokinetic agents in the treatment of laryngopharyngeal reflux (LPR) disease.

Data Sources

Our data sources were PubMed, Embase, BIOSIS, and Web of Science databases.

Review Methods

A systematic literature review was conducted to identify studies prospectively evaluating the effectiveness of prokinetic agents in the treatment of LPR. Data from eligible studies were independently extracted from each study by two authors. The primary outcome of interest was the improvement of LPR symptoms among study participants. Secondary outcomes included resolution of LPR physical signs and the development of side effects from therapy.

Results

Among 724 unique articles identified, four studies met inclusion criteria. These four investigations provided mixed evidence about the effectiveness of prokinetic agents in the treatment of LPR. The studies included in the review were deemed to be at high risk of bias. Three of the four investigations demonstrated a statistically significant difference in patient symptoms that favored the use of prokinetics in the management of LPR. The investigations were mixed in their report of improvement in physical examination findings among patients receiving and those not receiving prokinetic medical therapy. No significant adverse effects were described in any of these trials.

Conclusions

Prokinetic agents may be a viable treatment option for LPR. The current body of literature is inadequate to make a recommendation for their use in this disease process. Further research should be conducted to assess the use of prokinetic medications in the management of LPR.

Level of Evidence

NA Laryngoscope 124:2375–2379, 2014
A case‐control study on proinflammatory genetic Polymorphisms on sudden sensorineural hearing loss
Authors: Cadoni Gabriella , Gaetani Eleonora , Picciotti Pasqualina M. , Arzani Dario , Quarta Miriam , Giannantonio Sara , Paludetti Gaetano , Boccia Stefania
Published: April 2014

Objectives/Hypothesis

Sudden sensorineural hearing loss (SSNHL) is strictly related to inner ear vascular injuries and recently to some atherosclerotic risk factors. The pathogenic role of inflammatory molecules in atherosclerosis is well established. However, there is little knowledge about the potential role of inflammatory cytokines and adhesion molecules on SSNHL etiology.

Study Design

The aim of this study was to evaluate the role of proinflammatory genetic polymorphisms of the MCP‐1 (CCL2), E‐selectin, and interleukin (IL)−6 gene in SSNHL patients.

Methods

We evaluated the frequency and distribution of selected single nucleotide polymorphisms of the MCP‐1 (CCL2), E‐selectin, and IL‐6 gene in 87 SSNHL patients and 107 healthy controls.

Results

Our results did not show significant difference between the compared groups for MCP‐1 and E‐selectin genes, whereas a significant difference was reported for the IL‐6 gene (P < .0001).

Conclusions

The main finding of our study is that the 174G/G polymorphism (with a wider distribution of wt/wt genotype in SSNHL patients than in the healthy controls) of the IL‐6 gene is significantly associated with the risk of SSNHL, which is consistent with a previous finding on serum levels of IL‐6 in SSNHL. It is possible that the variant acts as a triggering agent of different lipidemia‐related phenotypes. Both the −174G/G polymorphism and elevated IL‐6 levels in SSNHL patients could suggest that IL‐6 plays a role in the inner ear involvement by atherosclerotic inflammatory events.

Level of Evidence

3b Laryngoscope, 125:E28–E32, 2015
Tuberculosis in liver transplant recipients: Experience of a South Indian liver transplant center
Authors: Olithselvan Arikichenin , Rajagopala Srinivas , Vij Mukul , Shanmugam Vivekanandan , Shanmugam Naresh , Rela Mohammed
Published: April 2014

Tuberculosis (TB) is a serious disease for liver transplant recipients (LTRs). Data on post–liver transplant TB from high-burden countries are scant. The aims of this study were to describe the prevalence of TB in LTRs from a high-prevalence area and to analyze the risk factors for the development of post–liver transplant TB. We performed a retrospective review of our database and a case-control study of identified cases with TB and age-matched LTRs without TB. The overall prevalence of TB in LTRs was comparable to the prevalence of TB in LTRs from low-prevalence countries (5/214 or 2.3%). A low rate of interferon-γ release assay (IGRA) testing before liver transplantation was observed (68/214 or 31%). Most patients were screened clinically and with chest radiography alone before transplantation. TB developed variably after transplantation [median = 72 days, interquartile range (IQR) = 534 days]. The presentation was mostly extrapulmonary and/or disseminated (4/5 or 80%). When cases with posttransplant TB were compared with matched healthy LTRs, the presence of unexplained granulomas in explants (2/5 or 40%, P = 0.01) was the only factor associated with the development of TB. When all explants showing granulomas were reviewed, TB (52.9%) remained the most common cause; however, in almost half (47.1%), other attributable causes were found. Patients were treated with a standard daily regimen for a median of 12 months (IQR = 7.5 months). Posttransplant TB was associated with a high mortality rate (2/5 or 40%). In conclusion, we observed a low prevalence of TB in LTRs from a high-prevalence region. The presence of granulomas suggestive of TB in liver explants warrants isoniazid prophylaxis in the absence of disease. Post–liver transplant TB is associated with a high mortality rate. The roles of routine IGRA testing and isoniazid prophylaxis in a high-prevalence setting urgently need to be studied. Liver Transpl 20:960–966, 2014. © 2014 AASLD.
Non‐isothermal and isothermal oxidation behaviors of AlON translucent ceramic in air
Authors: Qi J. Q. , Xie X. M. , Wang Y. , Wang J. , Xiao L. , Wei N. , Wu D. , Lu T. C.
Published: April 2014

The oxidation behavior of AlON translucent ceramic was investigated both in non‐isothermal (from room temperature to 1573 K) and isothermal (at 1373 and 1473 K) conditions. The mass gains, phase compositions and micromorphology of oxidized samples were examined by thermogravimetric analysis (TGA), X‐ray diffraction (XRD), and scanning electron microscopy (SEM), respectively. The results suggest that in non‐isothermal environment the oxidation reaction starts at about 1173 K for both AlON bulk sample and powder. In isothermal condition, the mass gain indicates the two‐stage reaction mechanism which starts with chemical reaction, followed by diffusion controlled stage. XRD patterns suggest that AlON is thermodynamically unstable and it partly decomposes into corundum phase Al2O3 and AlN during the oxidation process. SEM results indicate that different micromorphology is obtained at different temperatures in the oxidation process. The estimated apparent activation energy for the diffusion rate controlled stage from isothermal experiment is about 245.2 kJ/mol.
Genetic variations in SLC3A2/CD98 gene as prognosis predictors in non‐small cell lung cancer
Authors: Guo Xu , Li Hongwei , Fei Fei , Liu Boya , Li Xiaofei , Yang Hushan , Chen Zhinan , Xing Jinliang
Published: April 2014

Non‐small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict the risk of progression. This study aims to assess the effects of single nucleotide polymorphisms (SNPs) in the CD98 gene on prognosis of NSCLC patients. We genotyped three potential functional SNPs in CD98 gene using Sequenom iPLEX genotyping system in a cohort of 482 NSCLC patients. Multivariate cox proportional hazards model and Kaplan–Meier curve were used for the survival analysis. The variant‐containing genotypes of rs1059292 in 5′‐flanking region of CD98 gene were significantly associated with an increased risk of death in the multivariate analysis (Hazard ratio [HR], 1.49; 95% confidence interval [95% CI]: 1.04–2.14 in a dominant model). In stratified analysis, the association remained significant in patients with poor differentiation (HR = 1.81, 95% CI = 1.01–3.25). In addition, rs1059292 also showed a borderline significant association with T stage (OR = 1.49; 95% CI: 0.96–2.35) and N stage (OR = 1.53; 95% CI: 0.98–2.39). Functional analysis demonstrated that variant genotype of SNP rs1059292 significantly enhanced the transcription activity of CD98 gene promoter. Our data suggest that genetic variation of rs1059292 in CD98 gene may affect clinical outcome of NSCLC in Chinese population. © 2014 Wiley Periodicals, Inc.
Photoreceptor layer thinning in idiopathic Parkinson's disease
Authors: Roth Nicolas M. , Saidha Shiv , Zimmermann Hanna , Brandt Alexander U. , Isensee Justine , Benkhellouf‐Rutkowska Agnieszka , Dornauer Matthias , Kühn Andrea A. , Müller Thomas , Calabresi Peter A. , Paul Friedemann
Published: April 2014

This study was undertaken to quantify retinal and intra‐retinal layer thicknesses in Parkinson's disease (PD), and to evaluate whether retinal structural changes may be related to altered discrimination of color vision and to severity and duration of PD disease. We examined 97 PD patients and 32 healthy controls (HC) with spectral‐domain optical coherence tomography (OCT), including intra‐retinal layer segmentation. In total, we compared 111 retinal nerve fiber layer (RNFL)‐scans and 114 macula scans from 68 PD patients with 62 RNFL and 63 macula scans from 32 HC. For clinical evaluation of disease severity, we used the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. To determine color discrimination, we performed the Farnsworth Munsell 100 Hue Test (FMT) in a subgroup of PD patients. We found significant combined outer nuclear and photoreceptor layer thinning in PD versus HC (118.6 vs. 123.5 µm, P = 0.001). Differences in RNFL, total macular volume, or the other retinal layer thicknesses were not detected. The OCT measures were not associated with disease severity, duration, or color vision. By showing photoreceptor cell layer thinning, our findings support previous in vivo and autopsy studies demonstrating retinal alterations in PD. Optical coherence tomography may help to assess morphological retinal changes in PD patients; however, the utility of OCT in routine clinical practice may be limited because many PD patients have difficulties complying with OCT investigation because of disease‐related symptoms such as tremor, axial rigidity, or cognitive impairment. © 2014 International Parkinson and Movement Disorder Society
Nonlinear radial consolidation of vertical drains under a general time‐variable loading
Authors: Lu Mengmeng , Wang Shanyong , Sloan Scott W. , Indraratna Buddhima , Xie Kanghe
Published: April 2014

By incorporating the nonlinear variation of a soil's compressibility and permeability during the process of consolidation, an analytical solution for the radial consolidation of vertical drains has been developed for a general time‐variable loading. The general solution was verified for the cases of instantaneous loading and ramp loading. Detailed solutions were further derived for two special loading schemes: multistage loading and preloading–unloading–reloading. The nonlinear consolidation behavior of a vertical drain subjected to these two types of loading schemes was then investigated by a parametric study. The results show that the loading rate, the ratio of the compressibility index to the permeability index (Cc/Ck), and the initial stress state have a significant influence on the consolidation rate. A smaller value of Cc/Ck, a larger initial stress, or a fast loading rate always leads to a rapid consolidation rate. During the unloading period, a negative excess pore water pressure may occur, and a slower unloading rate may reduce this negative value. Copyright © 2014 John Wiley & Sons, Ltd.
Coarse‐graining molecular dynamics models using an extended Galerkin projection method
Authors: Li Xiantao
Published: April 2014

We present a new framework for coarse‐graining molecular dynamics models for crystalline solids. The reduction method is based on a Galerkin projection to a subspace, whose dimension is much smaller than that of the full atomistic model. To effectively reduce artificial reflections of phonons at the interface, we construct extended subspaces with increasing accuracy by adding more coarse‐grained variables near the interface between lattice defects and the surrounding region. This approach is equivalent to the generalized Langevin model. But it eliminates the need to precompute the memory function, a well‐known practical difficulty. Further, the variational formulation preserves the stability of the molecular models. Copyright © 2014 John Wiley & Sons, Ltd.
Efficient uncertainty propagation for network multiphysics systems
Authors: Constantine P.G. , Phipps E.T. , Wildey T.M.
Published: April 2014

We consider a multiphysics system with multiple component PDE models coupled together through network coupling interfaces, that is, a handful of scalars. If each component model contains uncertainties represented by a set of parameters, a straightforward uncertainty quantification study would collect all uncertainties into a single set and treat the multiphysics model as a black box. Such an approach ignores the rich structure of the multiphysics system, and the combined space of uncertainties can have a large dimension that prohibits the use of polynomial surrogate models. We propose an intrusive methodology that exploits the structure of the network coupled multiphysics system to efficiently construct a polynomial surrogate of the model output as a function of uncertain inputs. Using a nonlinear elimination strategy, we treat the solution as a composite function: the model outputs are functions of the coupling terms, which are functions of the uncertain parameters. The composite structure allows us to construct and employ a reduced polynomial basis that depends on the coupling terms. The basis can be constructed with many fewer PDE solves than the naive approach, which results in substantial computational savings. We demonstrate the method on an idealized model of a nuclear reactor. Copyright © 2014 John Wiley & Sons, Ltd.
Tissue‐specific and age‐dependent effects of global Mdm2 loss
Authors: Zhang Yun , Xiong Shunbin , Li Qin , Hu Sophia , Tashakori Mehrnoosh , Van Pelt Carolyn , You Mingjian James , Pageon Laura , Lozano Guillermina
Published: April 2014

Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. In this study we utilized a conditional Mdm2 allele, Mdm2FM, and a CAG–CreER tamoxifen‐inducible recombination system to examine the effects of global Mdm2 loss in adult mice. Two different tamoxifen injection regimens caused 100% lethality of Mdm2FM/−;CAG–CreER mice; both radio‐sensitive and radio‐insensitive tissues were impaired. Strikingly, a large number of radio‐insensitive tissues, including the kidney, liver, heart, retina and hippocampus, exhibited various pathological defects. Similar tamoxifen injections in older (16–18 month‐old) Mdm2FM/−;CAG–CreER mice yielded abnormalities only in the kidney. In addition, transcriptional activation of Cdkn1a (p21), Bbc3 (Puma) and multiple senescence markers in young (2–4 month‐old) mice following loss of Mdm2 was dampened in older mice. All phenotypes were p53‐dependent, as Mdm2FM/−;Trp53−/−;CAG–CreER mice subjected to the same tamoxifen regimens were normal. Our findings implicate numerous possible toxicities in many normal tissues upon use of cancer therapies that aim to inhibit Mdm2 in tumours with wild‐type p53. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
A modular, prospective, semi‐automated drug safety monitoring system for use in a distributed data environment
Authors: Gagne Joshua J. , Wang Shirley V. , Rassen Jeremy A. , Schneeweiss Sebastian
Published: April 2014

Purpose

The aim of this study was to develop and test a semi‐automated process for conducting routine active safety monitoring for new drugs in a network of electronic healthcare databases.

Methods

We built a modular program that semi‐automatically performs cohort identification, confounding adjustment, diagnostic checks, aggregation and effect estimation across multiple databases, and application of a sequential alerting algorithm. During beta‐testing, we applied the system to five databases to evaluate nine examples emulating prospective monitoring with retrospective data (five pairs for which we expected signals, two negative controls, and two examples for which it was uncertain whether a signal would be expected): cerivastatin versus atorvastatin and rhabdomyolysis; paroxetine versus tricyclic antidepressants and gastrointestinal bleed; lisinopril versus angiotensin receptor blockers and angioedema; ciprofloxacin versus macrolide antibiotics and Achilles tendon rupture; rofecoxib versus non‐selective non‐steroidal anti‐inflammatory drugs (ns‐NSAIDs) and myocardial infarction; telithromycin versus azithromycin and hepatotoxicity; rosuvastatin versus atorvastatin and diabetes and rhabdomyolysis; and celecoxib versus ns‐NSAIDs and myocardial infarction.

Results

We describe the program, the necessary inputs, and the assumed data environment. In beta‐testing, the system generated four alerts, all among positive control examples (i.e., lisinopril and angioedema; rofecoxib and myocardial infarction; ciprofloxacin and tendon rupture; and cerivastatin and rhabdomyolysis). Sequential effect estimates for each example were consistent in direction and magnitude with existing literature.

Conclusions

Beta‐testing across nine drug‐outcome examples demonstrated the feasibility of the proposed semi‐automated prospective monitoring approach. In retrospective assessments, the system identified an increased risk of myocardial infarction with rofecoxib and an increased risk of rhabdomyolysis with cerivastatin years before these drugs were withdrawn from the market. Copyright © 2014 John Wiley & Sons, Ltd.
Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti‐TNF alpha antibodies
Authors: Beigel Florian , Steinborn Anni , Schnitzler Fabian , Tillack Cornelia , Breiteneicher Simone , John Jestinah Mahachie , Van Steen Kristel , Laubender Rüdiger P. , Göke Burkhard , Seiderer Julia , Brand Stephan , Ochsenkühn Thomas
Published: April 2014

Purpose

We aimed to analyse malignancy rates and predictors for the development of malignancies in a large German inflammatory bowel disease (IBD) cohort treated with thiopurines and/or anti‐tumour necrosis factor (TNF) antibodies.

Methods

De novo malignancies in 666 thiopurine‐treated and/or anti‐TNF‐treated IBD patients were analysed. Patients (n = 262) were treated with thiopurines alone and never exposed to anti‐TNF antibodies (TP group). In addition, patients (n = 404) were exposed to anti‐TNF antibodies (TNF+ group) with no (7.4%), discontinued (80.4%) or continued (12.1%) thiopurine therapy.

Results

In the TP group, 20 malignancies were observed in 18 patients compared with 8 malignancies in 7 patients in the TNF+ group (hazard ratio 4.15; 95% CI 1.82–9.44; p = 0.0007; univariate Cox regression). Moreover, 18.2% of all patients in the TP group ≥50 years of age developed a malignancy, compared with 3.8% of all patients <50 years of age (p = 0.0008). In the TNF+ group, 6.5% of all patients ≥50 years of age developed malignancies compared with 0.3% of all patients <50 years of age (p = 0.0007). In both groups combined, thiopurine treatment duration ≥4 years was associated with the risk for skin cancer (p = 0.0024) and lymphoma (p = 0.0005).

Conclusions

Our data demonstrate an increased risk for the development of malignancies in IBD patients treated with thiopurines in comparison with patients treated with anti‐TNF antibodies with or without thiopurines. Copyright © 2014 John Wiley & Sons, Ltd.
Pharmacologic Management of Human Immunodeficiency Virus Wasting Syndrome
Authors: Badowski Melissa , Pandit Neha Sheth
Published: April 2014

Pharmacologic interventions for human immunodeficiency virus (HIV) wasting have been studied since the 1990s, but the results of these interventions have been difficult to compare because the studies used different HIV wasting definitions and assessed various patient outcomes. Thus, we performed a systematic review of the current literature to identify studies that evaluated pharmacologic management of HIV wasting and to compare and contrast treatment options. Further, we provide a comprehensive review of these treatment options and describe the definition of HIV wasting used in each study, the outcomes assessed, and whether antiretroviral therapy was used during the HIV wasting treatment. Literature searches of the PubMed/Medline (1946–2014) and Google Scholar databases were performed, and a review of the bibliographies of retrieved articles was performed to identify additional references. Only English‐language articles pertaining to humans and HIV‐infected individuals were evaluated. Thirty‐six studies were identified that assessed pharmacologic interventions to treat HIV wasting. Appetite stimulants, such as megestrol acetate, have been shown to increase total body weight (TBW) and body mass index in HIV‐infected patients with wasting. Studies evaluating dronabinol showed conflicting data on TBW increases, but the drug may have minimal benefit on body composition compared with other appetite stimulants. Testosterone has been shown to be effective in HIV wasting for those who suffer from hypogonadism. Recombinant human growth hormone has been evaluated for HIV wasting and has shown promising results for TBW and lean body mass increases. Thalidomide has been studied; however, its use is limited due to its toxicities. Although megestrol acetate and dronabinol are approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV wasting, it is important to recognize other comorbidities such as depression or hypogonadism that may contribute to the patient's appetite and weight loss. If a patient is diagnosed with hypogonadism and HIV wasting, testosterone would be a good therapeutic option. Although mirtazapine is not FDA approved for the management of HIV wasting, it has been shown to promote weight gain while treating depression symptoms. Mirtazapine may be a promising pharmacologic option in the management of HIV wasting and depression, but further research is needed.
Antifungal Catheter Lock Therapy for the Management of a Persistent Candida albicans Bloodstream Infection in an Adult Receiving Hemodialysis
Authors: Paul DiMondi V. , Townsend Mary L. , Johnson Melissa , Durkin Michael
Published: April 2014

Antifungal catheter lock therapy (AfLT) with liposomal amphotericin B has been used in the treatment of pediatric central line infections caused by Candida species; however, reports describing the use of liposomal amphotericin B lock therapy in the adult hemodialysis patient population are lacking. Management of central line–associated candidemia with systemic therapy alone is often challenging due to the propensity of Candida species to form biofilms on foreign bodies. We describe a 64‐year‐old woman who was receiving hemodialysis 3 times/week and was hospitalized with persistent fungemia. Despite receiving intravenous micafungin, she had multiple positive blood cultures for Candida albicans, which finally cleared after 7 days. Her double‐lumen catheter was considered the most likely nidus of infection. Although catheter removal would have been preferred, this was not possible given her vasculopathy, history of multiple bloodstream infections, and lack of other available sites for vascular access. Catheter exchange was performed, and liposomal amphotericin B AfLT was administered in combination with intravenous micafungin for a total of 6 days. During this time, the patient experienced no discernible adverse effects secondary to AfLT. At discharge, AfLT was discontinued, and intravenous micafungin was changed to oral fluconazole. After 6 months of treatment, the patient remained culture negative and maintained her dialysis access. To our knowledge, this is the first case report of liposomal amphotericin B catheter lock therapy used to manage a persistent C. albicans bloodstream infection in an adult receiving hemodialysis. AfLT is a novel concept for treating catheter‐associated fungal infections. Liposomal amphotericin B was chosen based on its favorable in vitro activity against Candida species biofilms in catheter lock environments. We identified several barriers to implementing AfLT, and these issues may prohibit the use of AfLT. This case report illustrates the benefits and challenges of managing catheter‐associated fungal infections with AfLT. Further study is required to examine the efficacy, safety, and feasibility of this approach.
Pyrrolidone‐functional smart polymers via nitroxide‐mediated polymerization
Authors: Savelyeva Xeniya , Marić Milan
Published: April 2014

Nitroxide‐mediated polymerization (NMP) of N‐(2‐methacryloyloxyethyl) pyrrolidone (MAEPYR) with 2‐([tert‐butyl[1‐(diethoxyphosphoryl)‐2,2‐dimethylpropyl]amino]oxy)‐2‐methylpropanoic acid (BlocBuilder) initiator and N‐tert‐butyl‐N‐[1‐diethylphosphono‐(2,2‐dimethylpropyl)] (SG1) nitroxide permitted controlled synthesis of poly(N‐(2‐methacryloyloxyethyl)‐pyrrolidone‐stat‐9‐(4‐vinylbenzyl)‐9H‐carbazole) (poly(MAEPYR‐stat‐VBK)) statistical copolymers. With at least 5 mol % VBK, the dispersity Đ of the copolymers was below 1.4 at conversions less than 50%. At conversions higher than 50%, and at lower VBK feed content, there was a significant amount of termination reactions, which broadened the molecular weight distribution of the final polymers (Đ = 1.4–2.3). The MAEPYR‐rich statistical copolymers were subsequently tested for thermoresponsive behavior in aqueous media. The cloud point temperatures (CPTs) in aqueous solution were tuned by changing the VBK composition, solution concentration, and heating rate, and the transitions were thermally reversible with partial loss of reversibility at higher heating rates. The CPT decreased from 59.0 to 49.7 °C with addition of only 1 mol % of VBK in the copolymer, and at more than 6 mol % VBK, the copolymer was water insoluble. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 2011–2024
Efficient one‐pot synthesis of water‐compatible and photoresponsive molecularly imprinted polymer nanoparticles by facile RAFT precipitation polymerization
Authors: Ma Yue , Li Haiyang , He Shangjin , Zhang Hongtao , Zhang Huiqi
Published: April 2014

A facile, general, and highly efficient one‐pot approach to obtain azobenzene (azo)‐containing molecularly imprinted polymer (MIP) nanoparticles with photoresponsive template binding and release properties in aqueous media is described, which involves the combined use of hydrophilic macromolecular chain transfer agent‐mediated reversible addition‐fragmentation chain transfer precipitation polymerization and easily available water‐insoluble azo functional monomers. The resulting azo‐containing MIPs were characterized with dynamic laser scattering (DLS), SEM, FTIR, static contact angle and water dispersion studies, and equilibrium binding experiments. They have proven to be nanoparticles (their diameters being around 104–397 nm, as determined by DLS in methanol) with surface‐grafted hydrophilic polymer brushes and exhibit excellent pure water‐compatible template binding properties. Moreover, obvious photoregulated template binding behaviors were observed for such azo‐containing MIP nanoparticles, which led to their largely accelerated template release in the aqueous media under the UV light irradiation. Furthermore, the general applicability of the strategy was also demonstrated. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 1941–1952
Experimental and Numerical Investigations on the Dynamic Fracture of a Cylindrical Shell with Grooves Subjected to Internal Explosive Loading
Authors: Li Xiang Yu , Liang Min Zhu , Wang Ma Fa , Lu Guo Xing , Lu Fang Yun
Published: April 2014

A detailed experimental investigation on the dynamic fracture of a cylindrical shell with internal and external grooves subjected to internal explosive loading was carried out. Distributions of fragment velocities and fragment masses were measured and analyzed for specimens with different depths of the external grooves and different explosive materials, with the internal grooves of a fixed rectangular shape. Based on the experimental results, corresponding numerical simulations using the commercial software LS‐DYNA were undertaken. By inspecting the fragments recovered from the experiments and the numerical results, the dynamic fracture of the casing led to fragments of approximately three shapes: a large cuboid fragment, a small cuboid fragment, and two irregular fragments formed by three classical fracture trajectories. The formation mechanism of fragment shapes was analyzed using the fracture trajectories. A good agreement has been obtained between the numerical and experimental results. Finally, a parametric study for the casing thickness, grid patterns of the grooves and explosive materials was carried out in order to investigate the effects of fracture. The results showed that grid patterns of grooves and explosive materials had significant effects on the fracture mechanism of the casing. The numerical technique was used to predict the dynamic fracture of casing with internal and external grooves under internal explosive loading and for structural design in order to achieve desirable fragments with controlled shapes.
A new proportion measure of the treatment effect captured by candidate surrogate endpoints
Authors: Kobayashi Fumiaki , Kuroki Manabu
Published: April 2014

The use of surrogate endpoints is expected to play an important role in the development of new drugs, as they can be used to reduce the sample size and/or duration of randomized clinical trials. Biostatistical researchers and practitioners have proposed various surrogacy measures; however, (i) most of these surrogacy measures often fall outside the range [0,1] without any assumptions, (ii) these surrogacy measures do not provide a cut‐off value for judging a surrogacy level of candidate surrogate endpoints, and (iii) most surrogacy measures are highly variable; thus, the confidence intervals are often unacceptably wide. In order to solve problems (i) and (ii), we propose a new surrogacy measure, a proportion of the treatment effect captured by candidate surrogate endpoints (PCS), on the basis of the decomposition of the treatment effect into parts captured and non‐captured by the candidate surrogate endpoints. In order to solve problem (iii), we propose an estimation method based on the half‐range mode method with the bootstrap distribution of the estimated surrogacy measures. Finally, through numerical experiments and two empirical examples, we show that the PCS with the proposed estimation method overcomes these difficulties. The results of this paper contribute to the reliable evaluation of how much of the treatment effect is captured by candidate surrogate endpoints. Copyright © 2014 John Wiley & Sons, Ltd.