bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro Activity of a New Oral Triazole, BMS-207147 (ER-30346)
Authors: Fung-Tomc Joan C. , Huczko Elizabeth , Minassian Beatrice , Bonner Daniel P. 
Published: April 2020

ABSTRACT

The antifungal activity of BMS-207147 (also known as ER-30346) was compared to those of itraconazole and fluconazole against 250 strains of fungi representing 44 fungal species. MICs were determined by using the National Committee for Clinical Laboratory Standards (NCCLS)-recommended broth macrodilution method for yeasts, which was modified for filamentous fungi. BMS-207147 was about two- to fourfold more potent than itraconazole and about 40-fold more active than fluconazole against yeasts. With the NCCLS-recommended resistant MIC breakpoints of ≥1 μg/ml for itraconazole and of ≥64 μg/ml for fluconazole against
Candida
spp., itraconazole and fluconazole were inactive against strains of
Candida krusei
and
Candida tropicalis
. In contrast, all but 9 (all
C. tropicalis
) of the 116
Candida
strains tested had BMS-207147 MICs of <1 μg/ml. The three triazoles were active against about half of the
Candida glabrata
strains and against all of the
Cryptococcus neoformans
strains tested. The three triazoles were fungistatic to most yeast species, except for BMS-207147 and itraconazole, which were fungicidal to cryptococci. BMS-207147 and itraconazole were inhibitory to most aspergilli, and against half of the isolates, the activity was cidal. BMS-207147 and itraconazole were active, though not cidal, against most hyaline
Hyphomycetes
(with the exception of
Fusarium
spp. and
Pseudallescheria boydii
), dermatophytes, and the dematiaceous fungi and inactive against
Sporothrix schenckii
and zygomycetes. Fluconazole, on the other hand, was inactive against most filamentous fungi with the exception of dermatophytes other than
Microsporum gypseum
. Thus, the spectrum and potency of BMS-207147 indicate that it should be a candidate for clinical development.
Single-Dose Pharmacokinetics of Indinavir and the Effect of Food
Authors: Yeh Kuang C. , Deutsch Paul J. , Haddix Heidi , Hesney Michael , Hoagland Vicki , Ju William D. , Justice Steven J. , Osborne Barbara , Sterrett Andrew T. , Stone Julie A. , Woolf Eric , Waldman Scott 
Published: April 2020

ABSTRACT

Indinavir sulfate is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor indicated for treatment of HIV infection and AIDS in adults. The purpose of this report is to summarize single-dose studies which characterized the pharmacokinetics of the drug and the effect of food in healthy volunteers. Indinavir concentrations in plasma and urine were obtained by high-pressure liquid chromatography and UV detection assay methods. The results indicate that indinavir was rapidly absorbed in the fasting state, with the time to the maximum concentration in plasma occurring at ∼0.8 h for all doses studied. Over the 40- to 1,000-mg dose range studied, concentrations in plasma and urinary excretion of unchanged drug increased greater than dose proportionally. The nonlinear pharmacokinetics were attributed to the dose-dependent oxidative metabolism of first-pass metabolism as well as to metabolism in the systemic circulation. Renal clearance slightly exceeded the glomerular filtration rate, suggesting a net tubular secretion component. At high concentrations in plasma, tubular secretion appeared to be lowered because there was a trend for a decreased renal clearance. Administration of 400 mg of indinavir sulfate following a high-fat breakfast resulted in a blunted and decreased absorption (areas under the concentration-time curves [AUCs], 6.86 μM·h in the fasted state versus 1.54 μM·h in the fed state;
n
= 10). However, two types of low-fat meals were found to have no significant effect on the absorption of 800 mg of indinavir sulfate (AUCs, 23.15 μM·h in the fasted state versus 22.71 and 21.36 μM·h, respectively, in the fed state;
n
= 11). Immediately following dosing, the concentrations of indinavir in urine often exceeded its intrinsic solubility. To reduce the risk of nephrolithiasis, it is recommended that indinavir sulfate be administered with water.
Cellular Accumulation, Localization, and Activity of a Synthetic Cyclopeptamine in Fungi
Authors: Capobianco John O. , Zakula Dorothy , Frost David J. , Goldman Robert C. , Li Leping , Klein Larry L. , Lartey Paul A. 
Published: April 2020

ABSTRACT

A novel synthetic cyclopeptamine, A172013, rapidly accumulated by passive diffusion into
Candida albicans
CCH442. Drug influx could not be totally facilitated by the membrane-bound target, β-(1,3)-glucan synthase, since accumulation was unsaturable at drug concentrations up to 10 μg/ml (about 1.6 × 10
−7
molecules/cell), or 25× MIC. About 55 and 23% of the cell-incorporated drug was associated with the cell wall and protoplasts, respectively. Isolated microsomes contained 95% of the protoplast-associated drug, which was fully active against glucan synthesis in vitro. Drug (0.1 μg/ml) accumulation was rapid and complete after 5 min in several fungi tested, including a lipopeptide/cyclopeptamine-resistant strain of
C. albicans
(LP3-1). The compound penetrated to comparable levels in both yeast and hyphal forms of
C. albicans
, and accumulation in
Aspergillus niger
was 20% that in
C. albicans
. These data indicated that drug-cell interactions were driven by the amphiphilic nature of the compound and that the cell wall served as a major drug reservoir.
The Cys607→Tyr Change in the UL97 Phosphotransferase Confers Ganciclovir Resistance to Two Human Cytomegalovirus Strains Recovered from Two Immunocompromised Patients
Authors: Baldanti Fausto , Underwood Mark R. , Talarico Christine L. , Simoncini Lavinia , Sarasini Antonella , Biron Karen K. , Gerna Giuseppe 
Published: April 2020

ABSTRACT
Two ganciclovir (GCV)-resistant human cytomegalovirus (HCMV) strains recovered from an AIDS patient (strain VR4990) and a heart transplant recipient (strain VR5474) showed a Cys607→Tyr change in the UL97-encoded phosphotransferase. No amino acid substitutions were observed in the viral DNA polymerase. Marker transfer experiments showed marked reduction in GCV phosphorylation and drug susceptibility of the recombinant HCMV strain VR4990rec2-1-1. These results further extend the region of the carboxy-terminal domain of the UL97 phosphotransferase involved in GCV substrate recognition.
A Mutation at Position 190 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Interacts with Mutations at Positions 74 and 75 via the Template Primer
Authors: Boyer Paul L. , Gao Hong-Qiang , Hughes Stephen H. 
Published: April 2020

ABSTRACT
We have analyzed amino acid substitutions at position G190 in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1). The mutation G190E, which is responsible for resistance to certain nonnucleoside inhibitors, results in RT that has significantly less polymerase activity and that is less processive than wild-type RT. Its kinetic profile with respect to dGTP and poly(rC) · oligo(dG) is significantly altered compared to that of wild-type RT. The combination of either of the mutations L74V or V75I with the G190E mutation appears to be compensatory and mitigates many of the deleterious effects of the G190E mutation.
QacA Multidrug Efflux Pump from
Staphylococcus aureus
: Comparative Analysis of Resistance to Diamidines, Biguanidines, and Guanylhydrazones
Authors: Mitchell Bernadette A. , Brown Melissa H. , Skurray Ronald A. 
Published: April 2020

ABSTRACT
The staphylococcal multidrug efflux pump QacA mediates resistance to a broad spectrum of monovalent and divalent antimicrobial cations. Resistance toward various classes of these compounds identified features of the substrate that may be important for interaction with QacA. Analysis of combinations of two substrates suggested that the same mechanism is used for the extrusion of different classes of compounds.
Use of prehospital emergency medical services according to income of residential area
Authors: Aitavaara-Anttila Mia , Liisanantti Janne , Ehrola Ari , Spalding Michael , Ala-Kokko Tero , Raatiniemi Lasse 
Published: April 2020

BackgroundThe increasing usage of emergency medical services (EMS) missions is a challenge in modern practice. This study was designed to examine the association of the income level of residential areas on the rate of EMS missions and the frequency of EMS use in these areas.MethodsAll EMS missions for adult patients (>18 years) encountered by one rescue department in Northern Finland between June 2015 and May 2017 were analysed. The area served was categorised into four categories, according to the median annual income of the postal code areas. EMS missions per 1000 person-years, rate of non-transport missions and the number of dispatches to frequent (>4 EMS calls/year and highly frequent (>10 calls/year)EMS users per area were investigated.ResultsThere were 62 759 EMS missions, 34.8% of which resulted in non-transport. The crude rate of EMS dispatches was higher in the low-income area compared with other income areas (133.3 vs 108.9 vs 111.3 vs 73.6/1000 person-years) as well as the rate of high-frequency user dispatches (21.5 vs 11.5 vs 7.2 vs 4.3/1000-person years). The rate of non-transports missions was higher also (69.4 vs 43.4 vs 42.5. vs 30.6/1000 person-years). The highest crude rate of EMS use was found in people older than 65 years living in the lowest income areas (294.8/1000 person-years). After age adjustment, the highest rate of EMS use was found in rural areas with the lowest income (146.3/1000 person-years).ConclusionsThe rate of the EMS missions and non-transport missions differs significantly among different income areas. Resource usage was significantly higher in the low income areas. This information can be used in planning allocation of EMS and preventive healthcare resources.
Consensus practice guidelines on interventions for lumbar facet joint pain from a multispecialty, international working group
Authors: Cohen Steven P , Bhaskar Arun , Bhatia Anuj , Buvanendran Asokumar , Deer Tim , Garg Shuchita , Hooten W Michael , Hurley Robert W , Kennedy David J , McLean Brian C , Moon Jee Youn , Narouze Samer , Pangarkar Sanjog , Provenzano David Anthony , Rauck Richard , Sitzman B Todd , Smuck Matthew , van Zundert Jan , Vorenkamp Kevin , Wallace Mark S , Zhao Zirong 
Published: April 2020

BackgroundThe past two decades have witnessed a surge in the use of lumbar facet blocks and radiofrequency ablation (RFA) to treat low back pain (LBP), yet nearly all aspects of the procedures remain controversial.MethodsAfter approval by the Board of Directors of the American Society of Regional Anesthesia and Pain Medicine, letters were sent to a dozen pain societies, as well as representatives from the US Departments of Veterans Affairs and Defense. A steering committee was convened to select preliminary questions, which were revised by the full committee. Questions were assigned to 4–5 person modules, who worked with the Subcommittee Lead and Committee Chair on preliminary versions, which were sent to the full committee. We used a modified Delphi method, whereby the questions were sent to the committee en bloc and comments were returned in a non-blinded fashion to the Chair, who incorporated the comments and sent out revised versions until consensus was reached.Results17 questions were selected for guideline development, with 100% consensus achieved by committee members on all topics. All societies except for one approved every recommendation, with one society dissenting on two questions (number of blocks and cut-off for a positive block before RFA), but approving the document. Specific questions that were addressed included the value of history and physical examination in selecting patients for blocks, the value of imaging in patient selection, whether conservative treatment should be used before injections, whether imaging is necessary for block performance, the diagnostic and prognostic value of medial branch blocks (MBB) and intra-articular (IA) injections, the effects of sedation and injectate volume on validity, whether facet blocks have therapeutic value, what the ideal cut-off value is for a prognostic block, how many blocks should be performed before RFA, how electrodes should be oriented, the evidence for larger lesions, whether stimulation should be used before RFA, ways to mitigate complications, if different standards should be applied to clinical practice and clinical trials and the evidence for repeating RFA (see table 12 for summary).ConclusionsLumbar medial branch RFA may provide benefit to well-selected individuals, with MBB being more predictive than IA injections. More stringent selection criteria are likely to improve denervation outcomes, but at the expense of more false-negatives. Clinical trials should be tailored based on objectives, and selection criteria for some may be more stringent than what is ideal in clinical practice.
Optimizing crash dump in virtualized environments
Authors: Huang Yijian , Chen Haibo , Zang Binyu 
Published: April 2020

Crash dump, or core dump is the typical way to save memory image on system crash for future offline debugging and analysis. However, for typical server machines with likely abundant memory, the time of core dump can significantly increase the mean time to repair (MTTR) by delaying the reboot-based recovery, while not dumping the failure context for analysis would risk recurring crashes on the same problems.
In this paper, we propose several optimization techniques for core dump in virtualized environments, in order to shorten the MTTR of consolidated virtual machines during crashes. First, we parallelize the process of crash dump and the process of rebooting the crashed VM, by dynamically reclaiming and allocating memory between the crashed VM and the newly spawned VM. Second, we use the virtual machine management layer to introspect the critical data structures of the crashed VM to filter out the dump of unused memory. Finally, we implement disk I/O rate control between core dump and the newly spawned VM according to user-tuned rate control policy to balance the time of crash dump and quality of services in the recovery VM.
We have implemented a working prototype, Vicover, that optimizes core dump on system crash of a virtual machine in Xen, to minimize the MTTR of core dump and recovery as a whole. In our experiment on a virtualized TPC-W server, Vicover shortens the downtime caused by crash dump by around 5X.
Efficiently parallelizing instruction set simulation of embedded multi-core processors using region-based just-in-time dynamic binary translation
Authors: Kyle Stephen , Böhm Igor , Franke Björn , Leather Hugh , Topham Nigel 
Published: April 2020

Embedded systems, as typified by modern mobile phones, are already seeing a drive toward using multi-core processors. The number of cores will likely increase rapidly in the future. Engineers and researchers need to be able to simulate systems, as they are expected to be in a few generations time, running simulations of many-core devices on today's multi-core machines. These requirements place heavy demands on the scalability of simulation engines, the fastest of which have typically evolved from just-in-time (Jit) dynamic binary translators (Dbt).
Existing work aimed at parallelizing Dbt simulators has focused exclusively on trace-based Dbt, wherein linear execution traces or perhaps trees thereof are the units of translation. Region-based Dbt simulators have not received the same attention and require different techniques than their trace-based cousins.

In this paper we develop an innovative approach to scaling multi-core, embedded simulation through region-based Dbt. We initially modify the Jit code generator of such a simulator to emit code that does not depend on a particular thread with its thread-specific context and is, therefore,
thread-agnostic
. We then demonstrate that this thread-agnostic code generation is comparable to thread-specific code with respect to performance, but also enables the
sharing
of JIT-compiled regions between different threads. This sharing optimisation, in turn, leads to significant performance improvements for multi-threaded applications. In fact, our results confirm that an average of 76% of all JIT-compiled regions can be shared between 128 threads in representative, parallel workloads. We demonstrate that this translates into an overall performance improvement by 1.44x on average and up to 2.40x across 12 multi-threaded benchmarks taken from the Splash-2 benchmark suite, targeting our high-performance multi-core Dbt simulator for embedded Arc processors running on a 4-core Intel host machine.
Safety of embedded software
Authors: Leveson Nancy , Fleming Cody Harrison , Thomas John 
Published: April 2020

Traditional safety techniques were created 40-50 years ago for electro-mechanical systems. The underlying assumptions of these techniques about the cause of accidents (e.g., component failure) do not match software nor do they match the types of accidents we are having that are related to software. As a result, a large number of accidents are now related to software, although usually the pilot (for aircraft) or other human operators are blamed. Often, the software design leads to the operator errors. We will describe the problems with software that are leading to accidents (primarily in the requirements) and how to deal with them. Most of the current approaches rely on reducing "failures" although software does not fail. Something else is needed.
In the tutorial we will present a new accident causality model (STAMP) and teach how to use a new hazard analysis technique (STPA) based on it that can be used on complex, software-intensive systems. The topics will include how to generate software safety requirements from an STPA hazard analysis and how to design software that does not induce human error. The tutorial will be based on a new book, Engineering a Safer World by Nancy Leveson and published in January 2012 by MIT Press.
Program proving using intermediate verification languages (IVLs) like boogie and why3
Authors: Leino K. Rustan M. 
Published: April 2020

A program verifier is a complex piece of software. To deal with this complexity, a standard architecture of a modern program verifier consists of two basic parts: a front end and a back end, separated by an intermediate verification language (IVL). The separation of concerns obtained by this architecture is analogous to that in compilers: the front end is concerned with breaking down the semantics of given source-language programs into the more primitive operations of the intermediate language, and the back end is concerned with encoding the meaning of the intermediate program as efficient theorem-prover input.
Two prevalent IVLs today are Boogie~2 and Why3. In this invited talk, I will give a tour of the Boogie language. Through a set of examples, I will illustrate how a verifier may translate common source-program features into an IVL. A verification engine for the IVL is then applied to perform the actual verification. In this way, you can obtain a program verifier for your own language by building a new front end and reusing an existing verification engine.
Real-time Java in modernization of the aegis weapon system
Authors: Nilsen Kelvin 
Published: April 2020

The U.S. Navy's Aegis system, considered to be the "shield of the fleet", provides area air defense for a carrier battle group in addition to providing long-range ballistic missile defense. A typical Aegis deployment consists of about 100 computers, many of which have multiple cores. The application is distributed, with typical real-time threads spanning 4 or 5 different computers. End-to-end distributed thread timing constraints measured from stimulus to response are typically under 100 ms. The target jitter constraints on the individual contributions of processors to the end-to-end deadline constraint are well below 1 ms. The system is fully redundant to support fault tolerance. The software is considered to be safety critical because it aims and fires weapons.
The Aegis Weapons System software was recently rewritten into real-time Java as part of the Aegis Modernization activity. This project involved replacement of about 200,000 lines of CMS-2 and Ada code with roughly 500,000 lines of Java. The effort began in 2003 and the new Java implementation of Aegis Weapons System is now being deployed on warships. This paper describes the motivation for the modernization effort and provides a summary of Lockheed Martin's experiences with this project.
Polymorphic functions with set-theoretic types
Authors: Castagna Giuseppe , Nguyen Kim , Xu Zhiwu , Im Hyeonseung , Lenglet Sergueï , Padovani Luca 
Published: April 2020

This article is the first part of a two articles series about a calculus with higher-order polymorphic functions, recursive types with arrow and product type constructors and set-theoretic type connectives (union, intersection, and negation).
In this first part we define and study the explicitly-typed version of the calculus in which type instantiation is driven by explicit instantiation annotations. In particular, we define an explicitly-typed lambda-calculus with intersection types and an efficient evaluation model for it. In the second part, presented in a companion paper, we define a local type inference system that allows the programmer to omit explicit instantiation annotations, and a type reconstruction system that allows the programmer to omit explicit type annotations.
The work presented in the two articles provides the theoretical foundations and technical machinery needed to design and implement higher-order polymorphic functional languages for semi-structured data.
Replicated data types
Authors: Burckhardt Sebastian , Gotsman Alexey , Yang Hongseok , Zawirski Marek 
Published: April 2020

Geographically distributed systems often rely on replicated eventually consistent data stores to achieve availability and performance. To resolve conflicting updates at different replicas, researchers and practitioners have proposed specialized consistency protocols, called replicated data types, that implement objects such as registers, counters, sets or lists. Reasoning about replicated data types has however not been on par with comparable work on abstract data types and concurrent data types, lacking specifications, correctness proofs, and optimality results.
To fill in this gap, we propose a framework for specifying replicated data types using relations over events and verifying their implementations using replication-aware simulations. We apply it to 7 existing implementations of 4 data types with nontrivial conflict-resolution strategies and optimizations (last-writer-wins register, counter, multi-value register and observed-remove set). We also present a novel technique for obtaining lower bounds on the worst-case space overhead of data type implementations and use it to prove optimality of 4 implementations. Finally, we show how to specify consistency of replicated stores with multiple objects axiomatically, in analogy to prior work on weak memory models. Overall, our work provides foundational reasoning tools to support research on replicated eventually consistent stores.