bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dengue Virus Evolution under a Host-Targeted Antiviral
Authors: Plummer Emily , Buck Michael D. , Sanchez Marisa , Greenbaum Jason A. , Turner Julia , Grewal Rajvir , Klose Brennan , Sampath Aruna , Warfield Kelly L. , Peters Bjoern , Ramstedt Urban , Shresta Sujan 
Published: March 2015

ABSTRACT

The host-targeted antiviral drug UV-4B reduces viral replication and promotes survival in a mouse model of experimental dengue virus (DENV) infection. UV-4B is an iminosugar that inhibits the α-glucosidase family of enzymes and subsequently the folding of glycosylated proteins, both viral and host. Here, we utilized next-generation sequencing to investigate evolution of a flavivirus under selective pressure by a host-targeted antiviral
in vivo
. In viral populations recovered from UV-4B-treated mice, there was a significant increase in the number of single-nucleotide polymorphisms (SNPs) and the ratio of nonsynonymous to synonymous SNPs compared to findings in viral populations from vehicle-treated mice. The strongest evidence of positive selection was in the glycosylated membrane protein, thereby providing
in vivo
validation of the mechanism of action of an iminosugar. In addition, mutations in glycosylated proteins were present only in drug-treated mice after a single passage. However, the bulk of the other mutations were present in both populations, indicating nonspecific selective pressure. Together with the continued control of viremia by UV-4B, these findings are consistent with the previously predicted high genetic barrier to escape mutations in host-targeted antivirals.

IMPORTANCE
Although hundreds of millions of people are infected with DENV every year, there is currently no approved vaccine or antiviral therapy. UV-4B has demonstrated antiviral activity against DENV and is expected to enter clinical trials soon. Therefore, it is important to understand the mechanisms of DENV resistance to UV-4B. Host-targeted antivirals are thought to have a higher genetic barrier to escape mutants than directly acting antivirals, yet there are very few published studies of viral evolution under host-targeted antivirals. No study to date has described flavivirus evolution
in vivo
under selective pressure by a host-based antiviral drug. We present the first
in vivo
study of the sequential progression of viral evolution under selective pressure by a host-targeted antiviral compound. This study bolsters support for the clinical development of UV-4B as an antiviral drug against DENV, and it provides a framework to compare how treatment with other host-targeted antiflaviviral drugs in humans and different animal models influence viral genetic diversity.
Efficient Interaction between Arenavirus Nucleoprotein (NP) and RNA-Dependent RNA Polymerase (L) Is Mediated by the Virus Nucleocapsid (NP-RNA) Template
Authors: Iwasaki Masaharu , Ngo Nhi , Cubitt Beatrice , de la Torre Juan C. 
Published: March 2015

ABSTRACT

In this study, we document that efficient interaction between arenavirus nucleoprotein (NP) and RNA-dependent RNA polymerase (L protein), the two
trans
-acting viral factors required for both virus RNA replication and gene transcription, requires the presence of virus-specific RNA sequences located within the untranslated 5′ and 3′ termini of the viral genome.
Latent Herpes Simplex Virus 1 Infection Does Not Induce Apoptosis in Human Trigeminal Ganglia
Authors: Himmelein Susanne , Lindemann Anja , Sinicina Inga , Strupp Michael , Brandt Thomas , Hüfner Katharina 
Published: March 2015

ABSTRACT

Herpes simplex virus 1 (HSV-1) can establish lifelong latency in human trigeminal ganglia. Latently infected ganglia contain CD8
+
T cells, which secrete granzyme B and are thus capable of inducing neuronal apoptosis. Using immunohistochemistry and single-cell reverse transcription-quantitative PCR (RT-qPCR), higher frequency and transcript levels of caspase-3 were found in HSV-1-negative compared to HSV-1-positive ganglia and neurons, respectively. No terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-positive neurons were detected. The infiltrating T cells do not induce apoptosis in latently infected neurons.
Glycaemic control efficacy of oral antidiabetic drugs in treating type 2 diabetes: a protocol for network meta-analysis
Authors: Jia Yongliang , Lao Yaoguang , Leung Siu-wai 
Published: March 2015

IntroductionPast studies of network meta-analysis focused on evaluating drug combinations in treating type 2 diabetes but not on evaluating antidiabetic drugs in monotherapy. Clinical guidelines (eg, NICE (National Institute of Health and Care Excellence) clinical guidelines 66 and 87) were based only on the findings of individual clinical trials and pairwise meta-analysis in evaluating monotherapy. This study aims to fill this gap of research by conducting a Bayesian network meta-analysis to compare major antidiabetic drugs, including metformin, glimepiride, glyburide, glipizide, repaglinide, nateglinide, sitagliptin, vildagliptin, saxagliptin and SGLT-2 (sodium-glucose transporter-2) inhibitors.Methods and analysesRandomised controlled trials (RCTs) on the drug therapy of type 2 diabetes with outcome measures including glycosylated haemoglobin or fasting blood glucose will be included. The quality of included RTCs will be evaluated according to the Cochrane Collaboration's risk of bias tool. Traditional pairwise meta-analysis and Bayesian network meta-analysis will be conducted to compare the efficacies of antidiabetic drugs. Sensitivity analysis on the sample size of RCTs, meta-regression analysis on the follow-up periods, dosages and baselines of outcome measure, contradiction analysis between pairwise and network meta-analyses, and publication bias analysis, will be performed.Ethics and disseminationEthical approval is not required because this study includes no confidential personal data and interventions on the patients. Pairwise and network meta-analyses are based on the published RCT reports of eligible drugs in treating type 2 diabetes. The results of this study will be disseminated by a peer-reviewed publication.Protocol registration numberPROSPERO CRD42014010567.
Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial
Authors: Shaw E , Miró J M , Puig-Asensio M , Pigrau C , Barcenilla F , Murillas J , Garcia-Pardo G , Espejo E , Padilla B , Garcia-Reyne A , Pasquau J , Rodriguez-Baño J , López-Contreras J , Montero M , de la Calle C , Pintado V , Calbo E , Gasch O , Montejo M , Salavert M , Garcia-Pais M J , Carratalà J , Pujol M 
Published: March 2015

IntroductionDespite the availability of new antibiotics such as daptomycin, methicillin-resistantStaphylococcus aureus(MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone.Methods and analysisA multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis.Ethics and disseminationThe protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study.Trial registration numberNCT01898338.
Effects of electroconvulsive therapy on cognitive functioning in patients with depression: protocol for a systematic review and meta-analysis
Authors: Oremus Carolina , Oremus Mark , McNeely Heather , Losier Bruno , Parlar Melissa , King Matthew , Hasey Gary , Fervaha Gagan , Graham Allyson C , Gregory Caitlin , Hanford Lindsay , Nazarov Anthony , Restivo Maria , Tatham Erica , Truong Wanda , Hall Geoffrey B C , Lanius Ruth , McKinnon Margaret 
Published: March 2015

IntroductionDepression is the leading cause of disability worldwide, affecting approximately 350 million people. Evidence indicates that only 60–70% of persons with major depressive disorder who tolerate antidepressants respond to first-line drug treatment; the remainder become treatment resistant. Electroconvulsive therapy (ECT) is considered an effective therapy in persons with treatment-resistant depression. The use of ECT is controversial due to concerns about temporary cognitive impairment in the acute post-treatment period. We will conduct a meta-analysis to examine the effects of ECT on cognition in persons with depression.MethodsThis systematic review and meta-analysis has been registered with PROSPERO (registration number: CRD42014009100). We developed our methods following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We are searching MEDLINE, PsychINFO, EMBASE, CINAHL and Cochrane from the date of database inception to the end of October 2014. We are also searching the reference lists of published reviews and evidence reports for additional citations. Comparative studies (randomised controlled trials, cohort and case–control) published in English will be included in the meta-analysis. Three clinical neuropsychologists will group the cognitive tests in each included article into a set of mutually exclusive cognitive subdomains. The risk of bias of randomised controlled trials will be assessed using the Jadad scale. We will supplement the Jadad scale with additional questions based on the Cochrane risk of bias tool. The risk of bias of cohort and case–control studies will be assessed using the Newcastle-Ottawa Scale. We will employ the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess the strength of evidence.Statistical analysisSeparate meta-analyses will be conducted for each ECT treatment modality and cognitive subdomain using Comprehensive Meta-Analysis V.2.0.
Time to initial antibiotic administration, and short-term mortality among patients admitted with community-acquired severe infections with and without the presence of systemic inflammatory response syndrome: a follow-up study
Authors: Henriksen Daniel Pilsgaard , Laursen Christian B , Hallas Jesper , Pedersen Court , Lassen Annmarie Touborg 
Published: March 2015

BackgroundThe prognosis for patients with severe infection is related to early treatment, including early administration of antibiotics. The study aim was to compare the short-term mortality among patients admitted with severe infection with and without systemic inflammatory response syndrome (SIRS) at arrival, and to ascertain whether the presence of SIRS might affect the timing of antibiotic administration.MethodsIn this retrospective follow-up study, we included all adult patients (≥15 years) presenting to a medical emergency department in the period between September 2010 and August 2011 with a first-time admission of community-acquired severe infection (infection with evidence of organ dysfunction), with and without SIRS at arrival. The presence of SIRS was defined as two or more of the criteria according to the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) definitions. Cases were identified by manual chart review using predefined criteria of infection. Data on vital signs, laboratory values and antibiotic treatment were obtained electronically.ResultsWe included 1169 patients with infection and organ dysfunction, treated with antibiotics within 24 h after arrival (median age 76.1 years (IQR 63.1–83.5), 567 (48.5%) men). In all, 886 (75.8%) presented with SIRS, and 283 (24.2%) presented without SIRS. Median time to antibiotics was 4.6 h (IQR 2.9–7.0) in patients with SIRS and 6.7 h (IQR 4.5–10.3) in patients without SIRS (p<0.0001). Thirty-day mortality in patients with and without SIRS was 18.4% (95% CI 15.9% to 21.1%) and 16.6% (95% CI 12.5% to 21.5%), respectively.ConclusionsSIRS was absent in one-quarter of patients admitted with severe infection. The ‘door-to-antibiotics’ time was significantly shorter for patients with SIRS compared with patients without SIRS, but no difference was found in 30-day mortality.
Concept for a holistic sustainability assessment of the end-of-life phase of masonry
Authors: Herbst Tristan , Meng Birgit 
Published: March 2015

Abstract
In Germany, a quantity of more than 10 million metric tons of masonry rubble is generated per year. With regard to a sustainable closed substance cycle waste management, these rest masses have to be recovered if possible. The end-of-life (EOL) phase of masonry includes the planning steps of demolition, processing and application. The choice of the most sustainable solution raises questions regarding material technology, plant engineering, economic efficiency and ecological issues. For this purpose, a methodological concept for a holistic assessment of the EOL phase of masonry is developed within the scope of a doctoral thesis. For the assessment the Cost-Effectiveness Analysis (CEA) is adapted. The assessment concept enables a holistic comparison of different EOL scenarios for masonry while integrating all planning steps. It combines Material Flow Analysis (MFA), Life Cycle Analysis (LCA), Life Cycle Working Environment (LCWE), economic evaluation methods and material testing. In future, various scenarios can be evaluated with regard to the goals of the European and German waste management industry.
TiO
2
–SiO
2
–PDMS nanocomposites with self-cleaning properties for stone protection and consolidation
Authors: Kapridaki Chrysi , Maravelaki Noni-Pagona 
Published: March 2015

Abstract

This study deals with the design of two hydrophobic hybrid SiO
2
–TiO
2
materials and their application in the field of monument conservation. The nanocomposite consolidants were based on the modification of tetraethoxysilane (TEOS) with the incorporation of both TiO
2
nanoparticles and hydroxyl-terminated polydimethylsiloxane (PDMS). The TiO
2
nanoparticles have been prepared from the hydrolysis of titanium tetraisopropoxide (TTIP) in the presence of oxalic acid as a catalyst. The physico-chemical properties of the designed hydrophobic nanocrystalline SiO
2
–TiO
2
–PDMS composites have been extensively studied before their application as consolidants on a limestone. Overall, the effectiveness of the nanocomposites was evaluated by the comparative characterization of untreated and treated stone specimens. The results of both capillary water absorption and contact angle measurements point out that the TiO
2
–SiO
2
–PDMS nanocomposites functioned as hydrophobic coatings. Furthermore, the results obtained from microdrilling resistance and Fourier Transform Infrared spectroscopy (FTIR) revealed a penetration depth of the nanocomposites within the stone of
c.
15 mm. The innovation of these syntheses pertains to the application of hydrophobic semi-transparent and transparent nanocomposites with self-cleaning and strengthening properties, without altering the colour of the stone surface and the water vapour permeability.
The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses
Authors: Christiansson Lisa , Söderlund Stina , Mangsbo Sara , Hjorth-Hansen Henrik , Höglund Martin , Markevärn Berit , Richter Johan , Stenke Leif , Mustjoki Satu , Loskog Angelica , Olsson-Strömberg Ulla 
Published: March 2015

Abstract
Immune escape mechanisms promote tumor progression and are hurdles of cancer immunotherapy. Removing immunosuppressive cells before treatment can enhance efficacy. Tyrosine kinase inhibitors (TKI) may be of interest to combine with immunotherapy, as it has been shown that the inhibitor sunitinib reduces myeloid suppressor cells in patients with renal cell carcinoma and dasatinib promotes expansion of natural killer–like lymphocytes in chronic myeloid leukemia (CML). In this study, the capacity of dasatinib and imatinib to reduce myeloid suppressor cells and to induce immunomodulation in vivo was investigated ex vivo. Samples from CML patients treated with imatinib (n = 18) or dasatinib (n = 14) within a Nordic clinical trial (clinicalTrials.gov identifier: NCT00852566) were investigated for the presence of CD11b+CD14−CD33+ myeloid cells and inhibitory molecules (arginase I, myeloperoxidase, IL10) as well as the presence of natural killer cells, T cells (naïve/memory), and stimulatory cytokines (IL12, IFNγ, MIG, IP10). Both imatinib and dasatinib decreased the presence of CD11b+CD14−CD33+ myeloid cells as well as the inhibitory molecules and the remaining myeloid suppressor cells had an increased CD40 expression. Monocytes also increased CD40 after therapy. Moreover, increased levels of CD40, IL12, natural killer cells, and experienced T cells were noted after TKI initiation. The presence of experienced T cells was correlated to a higher IFNγ and MIG plasma concentration. Taken together, the results demonstrate that both imatinib and dasatinib tilted the immunosuppressive CML tumor milieu towards promoting immune stimulation. Hence, imatinib and dasatinib may be of interest to combine with cancer immunotherapy. Mol Cancer Ther; 14(5); 1181–91. ©2015 AACR.
Accommodation of End-State Comfort Reveals Subphonemic Planning in Speech
Authors: Derrick Donald , Gick Bryan 
Published: March 2015

Abstract
Applying the ‘end-state comfort' hypothesis of Rosenbaum et al. [J Exp Psych Learn Mem Cogn 1992;18:1058; Acta Psychol (Amst) 1996;94:59] to tongue motion provides evidence of long-distance subphonemic planning in speech. Speakers' tongue postures may anticipate upcoming speech up to three segments, two syllables, and a morpheme or word boundary later. We used M-mode ultrasound imaging to measure the direction of tongue tip/blade movements for known variants of flap/tap allophones of North American English /t/ and /d/. Results show that speakers produce different flap variants early in words or word sequences so as to facilitate the kinematic needs of flap/tap or other /r/ variants that appear later in the word or word sequence. Similar results were also observed across word boundaries, indicating that this is not a lexical effect.
Paediatric arterial ischaemic stroke and cerebral sinovenous thrombosis
Authors: Suppiej Agnese , Gentilomo Chiara , Saracco Paola , Sartori Stefano , Agostini Manuela , Bagna Rossana , Bassi Bianca , Giordano Paola , Grassi Massimo , Guzzetta Andrea , Lasagni Donatella , Luciani Matteo , Molinari Angelo C. , Palmieri Antonella , Putti Maria Caterina , Ramenghi Luca Antonio , Rota Lidia Luciana , Sperlì Domenico , Laverda Anna Maria , Simioni Paolo ,   the Stroke working group of the R. I. T. I. (Registro Italiano Trombosi Infantili)
Published: March 2015

SummaryData from large case series of children with cerebral thrombotic events are pivotal to improve prevention, early recognition and treatment of these conditions. The Italian Registry of Pediatric Thrombosis (R. I. T. I.) was established in 2007 by a multidisciplinary team, aiming for a better understanding of neonatal and paediatric thrombotic events in Italy and providing a preliminary source of data for the future development of specific clinical trials and diagnostic-therapeutic protocols. We analysed data relative to the paediatric cerebral thrombotic events of the R. I. T. I. which occurred between January 2007 and June 2012. In the study period, 79 arterial ischaemic stroke (AIS) events (49 in males) and 91 cerebral sinovenous thrombosis (CSVT) events (65 in males) were enrolled in the R. I. T. I. Mean age at onset was 4.5 years in AIS, and 7.1 years in CSVT. Most common modes of presentation were hemiparesis, seizures and speech disturbances in AIS, and headache, seizures and lethargy in CSVT. Most common etiologies were underlying chronic diseases, vasculopathy and cardiopathy in AIS, and underlying chronic diseases and infection in CSVT. Time to diagnosis exceeded 24 hours in 46 % AIS and 59 % CSVT. Overall data from the Italian Registry are in substantial agreement with those from the literature, despite small differences. Among these, a longer time to diagnosis compared to other registries and case series poses the accent to the need of an earlier recognition of paediatric cerebrovascular events in Italy, in order to enable prompt and effective treatment strategies.
Mechanism of Urbanization Impact on a Summer Cold-Frontal Rainfall Process in the Greater Beijing Metropolitan Area
Authors: Zhong Shi , Yang Xiu-Qun 
Published: March 2015

AbstractThe WRF–Noah–urban canopy model (UCM) coupled modeling system is used to investigate the influence of urbanization on a typical frontal rainfall event that occurred in June 2008 over the greater Beijing metropolitan area (GBMA). The comparison between results of two experiments with and without the presence of urban areas suggests that more precipitation can be induced over and in the area downwind of Beijing because of the urbanization effects while less rainfall is found in the upwind region of central urban areas. The urbanization effects delay the onset of precipitation over Beijing but keep it sustained for a longer period with stronger rainfall intensity. The underlying urban surface not only retards the cold-frontal movement but also favors the development of a wet and unstable atmosphere. This explains why the precipitation can be sustained for a longer time with higher rainfall intensity over urban areas. From analyses of a density-current speed equation, it is found that the abrupt pressure jump during the frontal passage has a significant influence on the cold-frontal movement. A method derived from the surface pressure tendency equation is used to explore the mechanism of urban effects on the cold-frontal system. The cold advection is less intense in the experiment with urban land surface than in the experiment with urban areas replaced by cropland. Hence, the weaker-than-normal cold advection and subsequent smaller pressure jump during the frontal passage over the GBMA are the major mechanisms behind the urbanization effects, which lead to the retardation of the cold-frontal movement and late onset of precipitation over the GBMA.