bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Novel Immunosuppressive Agent Mycophenolate Mofetil Markedly Potentiates the Antiherpesvirus Activities of Acyclovir, Ganciclovir, and Penciclovir In Vitro and In Vivo
Authors: Neyts Johan , Andrei Graciela , De Clercq Erik 
Published: April 2020

ABSTRACT

The immunosuppressive agent mycophenolate mofetil (MMF) has been approved for use in kidney transplant recipients and may thus be used concomitantly for the treatment of intercurrent herpesvirus infections with drugs such as acyclovir (ACV), ganciclovir (GCV), and penciclovir (PCV). We found that MMF and its parent compound mycophenolic acid (at concentrations that are attainable in plasma) strongly potentiate the antiherpesvirus (herpes simplex virus [HSV] type 1 [HSV-1], HSV-2, thymidine kinase-deficient [TK
−
] HSV-1, both wild-type and TK
−
varicella-zoster virus, and human cytomegalovirus) activities of ACV, PCV, and GCV (up to 350-fold increases in their activities). The mechanism of potentiation was found to reside in the depletion of endogenous dGTP pools, which favored the inhibitory effect of the triphosphate of ACV, GCV, or PCV on the viral DNA polymerase. The combination of topically applied 5% MMF with 0.1% ACV strongly protected against HSV-1-induced cutaneous lesions in hairless mice, whereas therapy with either compound used singly had no protective effect. Interestingly, the combination of topically applied 5% MMF with 5% ACV was also highly effective in protecting against TK
−
HSV-2-induced cutaneous lesions (that were refractory to ACV treatment) in athymic nude mice. Topical therapy with MMF was very well tolerated, and no signs of irritation were observed. When given perorally at 200 mg/kg of body weight/day, MMF potentiated to some extent the growth retardation induced by GCV in young NMRI mice. These observations may have clinical implications (i) for those transplant recipients who receive both MMF and either ACV, GCV, or PCV and (ii) for the treatment of ACV-resistant mucocutaneous HSV infections.
Amino Acid Substitutions in the Cytochrome P-450 Lanosterol 14α-Demethylase (CYP51A1) from Azole-Resistant
Candida albicans
Clinical Isolates Contribute to Resistance to Azole Antifungal Agents
Authors: Sanglard Dominique , Ischer Françoise , Koymans Luc , Bille Jacques 
Published: April 2020

ABSTRACT

The cytochrome P-450 lanosterol 14α-demethylase (CYP51A1) of yeasts is involved in an important step in the biosynthesis of ergosterol. Since CYP51A1 is the target of azole antifungal agents, this enzyme is potentially prone to alterations leading to resistance to these agents. Among them, a decrease in the affinity of CYP51A1 for these agents is possible. We showed in a group of
Candida albicans
isolates from AIDS patients that multidrug efflux transporters were playing an important role in the resistance of
C. albicans
to azole antifungal agents, but without excluding the involvement of other factors (D. Sanglard, K. Kuchler, F. Ischer, J.-L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother. 39:2378–2386, 1995). We therefore analyzed in closer detail changes in the affinity of CYP51A1 for azole antifungal agents. A strategy consisting of functional expression in
Saccharomyces cerevisiae
of the
C. albicans CYP51A1
genes of sequential clinical isolates from patients was designed. This selection, which was coupled with a test of susceptibility to the azole derivatives fluconazole, ketoconazole, and itraconazole, enabled the detection of mutations in different cloned
CYP51A1
genes, whose products are potentially affected in their affinity for azole derivatives. This selection enabled the detection of five different mutations in the cloned
CYP51A1
genes which correlated with the occurrence of azole resistance in clinical
C. albicans
isolates. These mutations were as follows: replacement of the glycine at position 129 with alanine (G129A), Y132H, S405F, G464S, and R467K. While the S405F mutation was found as a single amino acid substitution in a
CYP51A1
gene from an azole-resistant yeast, other mutations were found simultaneously in individual
CYP51A1
genes, i.e., R467K with G464S, S405F with Y132H, G129A with G464S, and R467K with G464S and Y132H. Site-directed mutagenesis of a wild-type
CYP51A1
gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives. We speculate that these specific mutations could combine with the effect of multidrug efflux transporters in the clinical isolates and contribute to different patterns and stepwise increases in resistance to azole derivatives.
A Rapid Method for Simultaneous Detection of Phenotypic Resistance to Inhibitors of Protease and Reverse Transcriptase in Recombinant Human Immunodeficiency Virus Type 1 Isolates from Patients Treated with Antiretroviral Drugs
Authors: Hertogs Kurt , de Béthune Marie-Pierre , Miller Veronica , Ivens Tania , Schel Patricia , Van Cauwenberge Anja , Van den Eynde Christel , van Gerwen Veerle , Azijn Hilde , van Houtte Margriet , Peeters Frank , Staszewski Schlomo , Conant Marcus , Bloor Stuart , Kemp Sharon , Larder Brendan , Pauwels Rudi 
Published: April 2020

ABSTRACT

Combination therapy with protease (PR) and reverse transcriptase (RT) inhibitors can efficiently suppress human immunodeficiency virus (HIV) replication, but the emergence of drug-resistant variants correlates strongly with therapeutic failure. Here we describe a new method for high-throughput analysis of clinical samples that permits the simultaneous detection of HIV type 1 (HIV-1) phenotypic resistance to both RT and PR inhibitors by means of recombinant virus assay technology. HIV-1 RNA is extracted from plasma samples, and a 2.2-kb fragment containing the entire HIV-1 PR- and RT-coding sequence is amplified by nested reverse transcription-PCR. The pool of PR-RT-coding sequences is then cotransfected into CD4
+
T lymphocytes (MT4) with the pGEMT3ΔPRT plasmid from which most of the PR (codons 10 to 99) and RT (codons 1 to 482) sequences are deleted. Homologous recombination leads to the generation of chimeric viruses containing PR- and RT-coding sequences derived from HIV-1 RNA in plasma. The susceptibilities of the chimeric viruses to all currently available RT and/or PR inhibitors is determined by an MT4 cell–3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based cell viability assay in an automated system that allows high sample throughput. The profile of resistance to all RT and PR inhibitors is displayed graphically in a single PR-RT-Antivirogram. This assay system facilitates the rapid large-scale phenotypic resistance determinations for all RT and PR inhibitors in one standardized assay.
Inhibitory Effect of 2′-Fluoro-5-Methyl-β-
l
-Arabinofuranosyl-Uracil on Duck Hepatitis B Virus Replication
Authors: Aguesse-Germon Stéphanie , Liu Shwu-Huey , Chevallier Michèle , Pichoud Christian , Jamard Catherine , Borel Christelle , Chu Chung K. , Trépo Christian , Cheng Yung-Chi , Zoulim Fabien 
Published: April 2020

ABSTRACT

The antiviral activity of 2′-fluoro-5-methyl-β-
l
-arabinofuranosyluracil (
l
-FMAU), a novel
l
-nucleoside analog of thymidine known to be an inhibitor of hepatitis B virus (HBV) replication in hepatoma cells (2.2.1.5 cell line), was evaluated in the duck HBV (DHBV) model. Short-term oral administration (5 days) of
l
-FMAU (40 mg/kg of body weight/day) to experimentally infected ducklings induced a significant decrease in the level of viremia. This antiviral effect was sustained in animals when therapy was prolonged for 8 days. The histological study showed no evidence of liver toxicity in the
l
-FMAU-treated group. By contrast, microvesicular steatosis was found in the livers of dideoxycytidine-treated animals.
l
-FMAU administration in primary duck hepatocyte cultures infected with DHBV induced a dose-dependent inhibition of both virion release in culture supernatants and intracellular viral DNA synthesis, without clearance of viral covalently closed circular DNA. By using a cell-free system for the expression of an enzymatically active DHBV reverse transcriptase, it was shown that
l
-FMAU triphosphate exhibits an inhibitory effect on the incorporation of dAMP in the viral DNA primer. Thus, our data demonstrate that
l
-FMAU inhibits DHBV replication in vitro and in vivo. Long-term administration of
l
-FMAU for the eradication of viral infection in animal models of HBV infection should be evaluated.
Alterations in the GyrA Subunit of DNA Gyrase and the ParC Subunit of DNA Topoisomerase IV Associated with Quinolone Resistance in
Enterococcus faecalis
Authors: Kanematsu Emiko , Deguchi Takashi , Yasuda Mitsuru , Kawamura Takeshi , Nishino Yoshinori , Kawada Yukimichi 
Published: April 2020

ABSTRACT

The
gyrA
and
parC
genes of 31 clinical isolates of
Enterococcus faecalis
, including fluoroquinolone-resistant isolates, were partially sequenced and analyzed for target alterations. Topoisomerase IV may be a primary target in
E. faecalis
, but high-level fluoroquinolone resistance was associated with simultaneous alterations in both GyrA and ParC.
Arc-to-craton: Devonian air-fall tephras in the eastern United States
Authors: Ver Straeten* C.A. , Over* D.J. , Baird* G.C. 
Published: April 2020

ABSTRACT
More than 100 air-fall volcanic tephra beds are currently documented from Devonian strata in the eastern United States. These beds act as key sources of various geological data. These include within-basin to basin-to-basin correlation, globally useful geochronologic age dates, and a relatively detailed, if incomplete, record of Acadian–Neoacadian silicic volcanism. The tephras occur irregularly through the vertical Devonian succession, in clusters of several beds, or scattered as a few to single beds. In this contribution, their vertical and lateral distribution and recent radiometric dates are reviewed. Current unresolved issues include correlation of the classic Eifelian-age (lower Middle Devonian) Tioga tephras and dates related to the age of the Onondaga-Marcellus contact in the Appalachian Basin. Here, we used two approaches to examine the paleovolcanic record of Acadian–Neoacadian silicic magmatism and volcanism. Reexamination of volcanic phenocryst distribution maps from the Tioga tephras indicates not one but four or more volcanic sources along the orogen, between southeastern Pennsylvania and northern North Carolina. Finally, radiometric and relative ages of the sedimentary basin tephras are compared and contrasted with current radiometric ages of igneous rocks from New England. Despite data gaps and biases in both records, their comparisons provide insights into Devonian silicic igneous activity in the eastern United States, and into various issues of recognition, deposition, and preservation of tephras in the sedimentary rock record.
BowelScope: Accuracy of Detection Using Endocuff Optimisation of Mucosal Abnormalities (the B-ADENOMA Study): a multicentre, randomised controlled flexible sigmoidoscopy trial
Authors: Rees Colin J , Brand Andrew , Ngu Wee Sing , Stokes Clive , Hoare Zoe , Totton Nicola , Bhandari Pradeep , Sharp Linda , Bastable Alexandra , Rutter Matthew D , Verma Ajay Mark , Lee Thomas J , Walls Martin 
Published: April 2020

ObjectivesAdenoma detection rate (ADR) is an important quality marker at lower GI endoscopy. Higher ADRs are associated with lower postcolonoscopy colorectal cancer rates. The English flexible sigmoidoscopy (FS) screening programme (BowelScope), offers a one-off FS to individuals aged 55 years. However, variation in ADR exists. Large studies have demonstrated improved ADR using Endocuff Vision (EV) within colonoscopy screening, but there are no studies within FS. We sought to test the effect of EV on ADR in a national FS screening population.DesignBowelScope: Accuracy of Detection Using ENdocuff Optimisation of Mucosal Abnormalities was a multicentre, randomised controlled trial involving 16 English BowelScope screening centres. Individuals were randomised to Endocuff Vision-assisted BowelScope (EAB) or Standard BowelScope (SB). ADR, polyp detection rate (PDR), mean adenomas per procedure (MAP), polyp characteristics and location, participant experience, procedural time and adverse events were measured. Comparison of ADR within the trial with national BowelScope ADR was also undertaken.Results3222 participants were randomised (53% male) to receive EAB (n=1610) or SB (n=1612). Baseline demographics were comparable between arms. ADR in the EAB arm was 13.3% and that in the SB arm was 12.2% (p=0.353). No statistically significant differences were found in PDR, MAP, polyp characteristics or location, participant experience, complications or procedural characteristics. ADR in the SB control arm was 3.1% higher than the national ADR.ConclusionEV did not improve BowelScope ADR when compared with SB. ADR in both arms was higher than the national ADR. Where detection rates are already high, EV is unable to improve detection further.Trial registration numbersNCT03072472,ISRCTN30005319and CPMS ID 33224.
Treating traumatic injuries of canine teeth in cats
Authors: Oxford Matthew 
Published: April 2020

BackgroundCats frequently suffer dental trauma to their canine teeth, as a result of road traffic accidents, falls or fights with other animals. However, there is limited veterinary literature about the incidence and treatment options for such injuries.Aim of the articleThis article outlines how to treat traumatic injuries of canine teeth in cats by using endodontic or extraction techniques.
Influence of thrombectomy volume on non-physician staff burnout and attrition in neurointerventional teams
Authors: Fargen Kyle M , Ansari Sameer A , Spiotta Alejandro , Dabus Guilherme , Mokin Maxim , Brown Patrick , Wolfe Stacey Q , Kittel Carol , Kan Peter , Baxter Blaise W , De Leacy Reade , Milburn James , Munich Stephan A , Ducruet Andrew F , Reeves Alan , Fraser Justin F , Starke Robert M , Jadhav Ashutosh P , Mack William J , Arthur Adam S , Pride Lee , Sheth Sunil A , Rai Ansaar T , Leslie-Mazwi Thabele , Hirsch Joshua A 
Published: April 2020

BackgroundBurnout takes a heavy toll on healthcare providers. We sought to assess the prevalence and risk factors for burnout among neurointerventional (NI) non-physician procedural staff (nurses and technologists) given increasing thrombectomy demands.MethodsA 41-question online survey containing questions including the Maslach Burnout Inventory-Human Services Survey for Medical Personnel was distributed to NI nurses and radiology technologists at 20 US endovascular capable stroke centers.Results244 responses were received (64% response rate). Median (IQR) composite scores for emotional exhaustion were 25 (15–35), depersonalization 6 (2–11), and personal accomplishment 39 (35–43). Fifty-one percent of respondents met established criteria for burnout. There was no significant relationship between hospital thrombectomy volume, call frequency, call cases covered, or length of commute. On multiple logistic regression analysis, feeling under-appreciated by hospital leadership (OR 4.1; P<0.001) and working with difficult/unpleasant physicians (OR 1.2; P=0.05) were strongly associated with burnout. At participating centers, nurse and technologist attrition was 25% over the previous year. Over 50% of respondents indicated they had strongly considered leaving their position over the last 2 years.ConclusionsThis survey of US NI non-physician procedural staff demonstrates a self-reported burnout prevalence of 51%. This was driven more by interaction with leadership and physician staff than by thrombectomy procedural volume and stroke call. Attrition among NI non-physician procedural staff is high.
African–American and Caucasian mortalities are the same after traumatic injury: pair matched analysis from a national data
Authors: Ahmed Nasim , Kountz David , Kuo Yenhong 
Published: April 2020

BackgroundAfrican–Americans have worse outcomes than Caucasians in many clinical conditions studied, including trauma. We sought to analyze if mortality is different in these groups through analysis of a national data set.MethodsRecent data from the national Trauma Quality Improvement Program were assessed with analysis, including all African–American or Caucasian patients who were brought to level I or level II trauma centers for care. Propensity scores were calculated for each African–American patient using age, sex, Injury Severity Score (ISS), Glasgow Coma Scale (GCS), injury type, insurance information and American College of Surgeons trauma level. The primary outcome of this study was in-hospital mortality, and the secondary outcomes were hospital length of stay and discharge disposition.ResultsA total of 82 150 (13.65%) out of 601 768 patients who qualified for the inclusion in the study were African–American. The remaining 519 618 (86.35%) were Caucasian. The median age (IQR) of the patients was 54 (33 to 72) years old, and approximately two-thirds of the patients were male. The median ISS and GCS score were 12 (9 to 17) and 15 (15 to 15), respectively. More than 90% of patients sustained blunt injuries. Overall, there was no significant difference found in overall in-hospital mortality between Caucasians and African–American patients (3% vs. 2.9%, p=0.2); however, the median (95% CI) hospital length of stay was 1 day longer in African–American patients compared with Caucasian patients (5 (5.5) vs. 4 (4.4), p<0.001). When the discharged destinations between the two groups were compared, a higher proportion of Caucasians were discharged to home without services (66% vs. 33%).ConclusionOur study showed that trauma mortalites among African–American and Caucasians are the same. Efforts to mitigate the ethnic and racial biases in the delivery of healthcare should continue, and these results (no differences in mortality) should be validated in other clinical settings.Level of evidenceLevel II.
Mapping between different cosmological eras in scale-covariant formalism
Authors: Ribas Marlos O. , Devecchi Fernando P. , Kremer Gilberto M. 
Published: April 2020

In this work we consider the scale-covariant formalism proposed by Canuto et al.,[Formula: see text] in order to map different eras of the universe. This technique considers a scale gauge function that can be adjusted by using different arguments like Dirac’s large numbers hypothesis or a restriction on the particle production rate. A Chaplygin constituent shows to be a consistent idea to establish a mapping between an old decelerated–accelerated universe ruled by Einstein equations and an early universe, where a new equation of state appears together with a modified general relativity theory and a de Sitter universe then emerges. These properties are a direct consequence of the use of the scale-covariant formalism. Besides, a new discussion and remarks are presented related to the well-known barotropic constituent case.
Multi-language programming with Ada
Authors: Ochem Quentin 
Published: April 2020

Building complex applications often requires putting together pieces of software or requirements that have not been made to work together in the first place. Thinking of a project with a high integrity kernel written in Ada, using a set of low level libraries and drivers written in C or C++, with a graphical interface done in Java and unit tests driven by python is not thinking of sciencefiction anymore. It's actual concrete and day-to-day work. Unfortunately, having all of these technologies talking to each other is not straightforward, and often requires a deep knowledge of both sides of the technology and extensive manual work.
In this tutorial, we'll first study how to interface directly Ada with native languages, such as C or C++. We'll then have a deep look at communications with languages running on virtual machines, such as Java, Python and the .NET framework. Finally, we'll see how Ada can be interfaced with an arbitrary language using a middleware solution, such as SOAP or CORBA We?ll see how the communication can be manually done using low level features and APIs, and how a substantial part of this process can be automated using high level binding generators.
Efficient soft error protection for commodity embedded microprocessors using profile information
Authors: Khudia Daya Shanker , Wright Griffin , Mahlke Scott 
Published: April 2020

Successive generations of processors use smaller transistors in the quest to make more powerful computing systems. It has been previously studied that smaller transistors make processors more susceptible to soft errors (transient faults caused by high energy particle strikes). Such errors can result in unexpected behavior and incorrect results. With smaller and cheaper transistors becoming pervasive in mainstream computing, it is necessary to protect these devices against soft errors; an increasing rate of faults necessitates the protection of applications running on commodity processors against soft errors. The existing methods of protecting against such faults generally have high area or performance overheads and thus are not directly applicable in the embedded design space. In order to protect against soft errors, the detection of these errors is a necessary first step so that a recovery can be triggered.
To solve the problem of detecting soft errors cheaply, we propose a profiling-based software-only application analysis and transformation solution. The goal is to develop a low cost solution which can be deployed for off-the-shelf embedded processors. The solution works by intelligently duplicating instructions that are likely to affect the program output, and comparing results between original and duplicated instructions. The intelligence of our solution is garnered through the use of control flow, memory dependence, and value profiling to understand and exploit the common-case behavior of applications. Our solution is able to achieve 92% fault coverage with a 20% instruction overhead. This represents a 41% lower performance overhead than the best prior approaches with approximately the same fault coverage.
Developing verified programs with Dafny
Authors: Leino K. Rustan M. 
Published: April 2020

Reasoning about programs is a fundamental skill that every software engineer needs. This tutorial provides participants an opportunity to get hands-on experience with Dafny, a tool that can help develop this skill.
Dafny is a programming language and state-of-the-art program verifier. The language is type-safe and sequential, and it includes common imperative features, dynamic object allocation, and inductive datatypes. It also includes specification constructs like pre- and postconditions, which let a programmer record the intended behavior of the program along with the executable code that is supposed to cause that behavior. Because the Dafny verifier runs continuously in the background, the consistency of a program and its specifications is always enforced.
In this tutorial, I give a taste of how to use Dafny in program development. This includes an overview of Dafny, basics of writing specifications, how to debug verification attempts, and how to formulate and prove lemmas. Dafny has been used to verify a number of challenging algorithms, including Schorr-Waite graph marking, Floyd's ``tortoise and hare'' cycle-detection algorithm, and snapshotable trees with iterators. Dafny is also being used in teaching, with over 100,000 program-verification attempts submitted to the online version of the tool. Dafny was a popular choice in the VSTTE 2012 program verification competition, where two of the Dafny teams were among the competition's 6 medalists. Its open-source implementation has also been used as a foundation for other verification tools. More information is found from the Dafny project page, http://research.microsoft.com/dafny and in the references below. Binary downloads and sources are available from http://dafny.codeplex.com. The tool can also be run on the web at http://rise4fun.com/dafny, where there is an online version of the tutorial.