bluuebunny/crossref_metadata_2025 huggingface dataset:
Usability Testing of Ultra High-Strength Steels
Authors: Heikkala Jouko A. , Väisänen Anu J.
Published: August 2013

New ultra high strength (UHS) steels have been developed in order to get advantages in machine design and construction. Following benefits can be obtained for example:

- less material usage due to lighter constructions;

- better payload and less fuel consumption in vehicle industry;

- energy saving in material production.

A rough distinction of structural steels can be defined to ductile steels, with tensile strength less than 300 MPa, and high strength steels, up to 700 Mpa. A steel material can be defined as UHS steel when the tensile strength exceeds 700 MPa. Steels with yield strength of 1500 Mpa have been developed so far. UHS steels can also be divided into structural steels and wear resistant steels. With the tensile strength also the hardness increases and the tensile strain decreases. That causes several difficulties when the material is processed into products. Especially mechanical processing like bending, machining and shearing gets difficult as the material strength increases. That causes problems for the construction material users to find the proper manufacturing methods in production.

In Oulu University Production Technology Laboratory material processing tests have been performed during several years in co-operation with the local steel manufacturer. The usability tests comprise mainly of bending and machining tests. Shearing and welding tests have been made to a smaller extent. Also laser treatment has been used for local heat conditioning in order to improve the bending and shearing properties, but these techniques are not yet widely used in production.

The bending tests are carried out with standard bending tools and test steel plates with standard dimensions. The plate thickness varies depending on the test material. The target is to determine the reliable minimum bending radiuses whereby the plate can be bent without failure, from both sides and along the rolling direction and orthogonally to that. Also the springback angle is measured and the bent surfaces are evaluated according to several criteria. When necessary, also the mechanical testing of the formed material is carried out.

The machining tests are made mainly by drilling. Also some milling tests have been performed. Drilling is a convenient way of machining testing because a substantial amount of holes can be drilled in one test plate. The drilling power can be observed precisely by monitoring the spindle power. Also a variety of different tool types can be used, from uncoated HSS drills to boring tools with indexable inserts. The optimal machining parameters (feed and speed) will be defined according to maximum tool life and minimum machining costs.
An Innovation System for Building Manufacturing
Authors: Craveiro Flávio , Matos João Meneses de , Bártolo Helena , Bártolo Paulo
Published: August 2013

Traditionally the construction sector is very conservative, risk averse and reluctant to adopt new technologies and ideas. The construction industry faces great challenges to develop more innovative and efficient solutions. In recent years, significant advances in technology and more sustainable urban environments has been creating numerous opportunities for innovation in automation. This paper proposes a new system based on extrusion-based technologies aiming at solving some limitations of current technologies to allow a more efficient building construction with organic forms and geometries, based on sustainable eco principles. This novel approach is described through a control deposition software.

Current modeling techniques focus only on capturing the geometric information and cannot satisfy the requirements from modeling the components made of multi-heterogeneous materials. There is a great deal of interest in tailoring structures so the functional requirements can vary with location.

The proposed functionally graded material deposition (FGM) system will allow a smooth variation of material properties to build up more efficient buildings regarding thermal, acoustic and structural conditions.
Coupling Engineering Knowledge With Product Design Knowledge by the Means of Multiple View Product Model
Authors: Rasoulifar Golnoosh , Prudhomme Guy , Brissaud Daniel
Published: August 2013

Product design involves a multitude of actors who have complementary knowledge and responsibility about the product under development.

Coupling together their views-points, particularly these of product designers and engineering designers in the upstream phases of the design, has the objectives to make the collaboration easier and to improve the product from both of their expertises.

The Product/Process multi-view model is a collaborative tool which supports engineering designers during product development processes. It allows the structuring and tracing of relative knowledge of engineering designers on the product. We make the assumption that Product/Process multi-view model could also be used to create relationships with the product designer’s representation.

The paper deals with this product model and illustrates the possible connection between engineering knowledge and product design knowledge.
Aluminum Honeycomb Energy Absorber for High-Speed Train Nose
Authors: Amraei Mohsen , Shahravi Majid
Published: August 2013

Due to the tendency to increase the velocity of high-speed trains, concerns about their probable events have increased. Since train’s frontal nose is the first part of the train which is damaged at the frontal impact, specific attention should be paid to the design of this part. In this study an effort has been conducted to design a nose with light weight which can absorb maximum amount of energy that is possible when a frontal collision occurs. To this aim and with attention to aerodynamic considerations, application of aluminum honeycomb (HC) sandwich panel as an internal layer of train nose has been studied. This paper includes two main parts. The first part is dedicated to the simulation of aluminum HC sandwich panel with both shell and solid elements under dynamic crush loads. While the frontal collision of nose with different internal layer thicknesses of HC has been simulated in the second part and an optimum thickness has been proposed based on the generated results. It has been demonstrated that for all thicknesses amount of energy absorption has been increased at least 35%. Finite element method using LS-DYNA commercial package has been used for the numerical simulation. The results have been validated with available experimental results and acceptable agreement has been observed.
A Mass-Conserving Complementarity Formulation to Study Fluid Film Lubrication in the Presence of Cavitation for Non-Newtonian and Compressible Fluids
Authors: Bertocchi Luca , Giacopini Matteo , Strozzi Antonio , Fowell Mark T. , Dini Daniele
Published: August 2013

A mass-conserving formulation of the Reynolds equation has been recently developed using the concept of complementarity [1]. The mathematical derivation of the Linear Complementarity Problem (LCP) implemented in the solver favoured in [1] overcomes the drawbacks previously associated with the use of such complementarity formulations for the solution of cavitation problems in which reformation of the liquid film occurs. In the present paper, the proposed methodology, already successfully applied to solve textured bearing and squeeze problems in the presence of cavitation in a one dimensional domain and for incompressible fluids [1], has been extend to a two dimensional domain and the fluid compressibility has been included in the formulation. The evolution of the cavitated region and the contact pressure distribution are studied for a number of different configurations.

Some of the results obtained with the proposed scheme are critically analysed and compared with the predictions obtained using alternative formulations (including full CFD calculations). The stability of the proposed algorithm and its flexibility in terms of the implementation of different compressibility laws is highlighted.
A Fast Deterministic Model to Study Adhesion in Rough Contacts
Authors: Medina Simon , Dini Daniele
Published: August 2013

As two bodies come into contact, attractive forces occur wherever a gap exists between the two surfaces. The forces are significant at distances of atomic order but become negligible at much larger separations. Their effect is insignificant in most situations for which engineers wish to understand the state of the contact since the adhesive forces are usually much smaller than the net load applied and/or surface roughness results in non-contacting areas being far enough apart that the attractive force is negligible. There are, however, certain cases in which adhesion forces do contribute to the contact mechanics and must be accounted for in any valid analysis. Materials with low elastic modulus, such as rubber, may deform sufficiently around surface asperities such that the surface separation is small and adhesion is apparent.

A model for arbitrary geometry (with surface roughness) that includes adhesive forces is reported here. It is based upon the multi-level method of contact analysis developed by Venner and Lubrecht [1]. Adhesion has been implemented using the Lennard-Jones potential as applied to two parallel surfaces, adding the requirement of specific negative pressures for the separated surface nodes [2]. The model is then compared to theoretical and numerical analysis of smooth spherical contacts and to rough contacts of different scales and material properties.
Modeling of Diffuse Damage Near Micro Cracks in Human Cortical Bone
Authors: Budyn E. , Hoc T.
Published: August 2013

Haversian cortical bone is a mineralised tissue that undergoes micro damage under daily exercise. Micro damage can either be identiable by light microscopy as microcracks or be more diffuse and difficult to visualise. Bone is maintained by mechano-sensitive cells called osteocytes located throughout the tissue. However the local mechanical stimulations on the cells are not precisely quantied. A dual experimental and numerical approach is presented to measure the in situ stress field produced by microcracks in human bone. Using the strain energy balance, the stress eld is reconstructed in the vicinity of quasi-static microcracks that are advancing in the explicit bone morphology captured by digital image correlation. The stress eld reveals the presence of diffuse damage near microcracks in agreement with experimental observations in the literature.
A Methodology for the Connecting Rod Lubrication Optimization
Authors: Francisco Arthur , Lavie Thomas , Villechaise Bernard
Published: August 2013

The numerical optimization of the connecting rod big-end lubrication involves several main steps.

The first, which can be considered as the most important one, is the identification of the main input factors and their varying range. In the same time, the meaningful resulting values have to be identified because the optimization will be performed on the basis of this choice.

The computing time for a TEHD solution prevents from performing a huge amount of calculi to draw the Pareto-Front of the solutions. Thus, the next step is the creation of a metamodel, based on polynomials, with a good predictability property and a low computing cost.

In the third step, a fast Multi Objective Optimization is performed on the metamodel. The Pareto-Front, which represents the best trade-offs of solutions, is identified: one can now easily choose the input parameters which will give a particular desired solution.

In the last step, the robustness of the solutions has to be checked: if a given solution is chosen, the corresponding input parameters have to enclose a minimal uncertainty gap to be realistic. Otherwise, this wanted solution will never be reached, because in a real-life problem, the parameter values are not deterministic.
Model Configuration for the Validation of Thermal-Mechanical Fluid-Structure-Interactions
Authors: Haupt Matthias C. , Kowollik Daniel , Horst Peter , Niesner Reinhold , Esser Burkard , Gülhan Ali
Published: August 2013

A simple configuration is described and used for computational and experimental investigations including thermal and mechanical fluid structure interactions for hypersonic flow conditions. The numerical modelling includes all relevant heat transfer mechanisms, takes into account the changes due to the heated and deformed structure and shows a good agreement with experiments.
Quality Improvement of Product Data Exchanged Between Engineering and Production Through the Integration of Dedicated Information Systems
Authors: Ben Kheder Anis , Henry Sébastien , Bouras Abdelaziz
Published: August 2013

Today, within the global Product Lifecycle Management (PLM) approach, success of design, industrialization and production activities depends on the ability to improve interaction between information systems that handle such activities. Enterprises deploy mainly PLM system, Enterprise Resource Planning system (ERP) and Manufacturing Execution System (MES) in order to manage sufficient product-related information and provide better customer-products. This paper proposes a methodological approach to improve the quality of data exchanged between engineering and production. This involves the integration among information systems especially the PLM-MES integration. Thus, the proposed approach aims to overcome the problem of data heterogeneity by proposing a mediation system resolving syntactic and semantic conflicts of data managed by these systems.
A Sustainability and Mass Customization Assessment Framework
Authors: Medini Khaled , Da Cunha Catherine , Bernard Alain
Published: August 2013

The paper presents a framework for the assessment of mass customization and sustainability performance of enterprises and supply chains. The assessment includes the product, process, enterprise and supply chain levels while considering the product life cycle phases. This two perspectives approach ensures a quite complete assessment and provides guidance to designers and managers during the decision making process. The framework construction and use methods are depicted in the current paper.
Journal Vibration: Influence of Compliant Bearing Design
Authors: Cha Matthew , Glavatskih Sergei
Published: August 2013

In this paper, the nonlinear dynamic behaviour of vertical and horizontal rotors in compliant tilting pad journal bearings has been investigated. White metal and compliant bearings with line pivot pads are compared. The dynamic response of four pad bearings with different preload factors is studied. The effect of viscoelasticity is also considered in comparison with purely elastic compliant and white metal liners. The influence of radial clearance and pad offset is analysed. It is shown how pad design parameters such as preload factor, pivot offset, viscoelasticity of the liner, and radial clearance can be selected to control the size of the journal orbit in compliant bearings.
3D Information Management Enabling Manufacture Engineering
Authors: Ali Salam , Durupt Alexandre , Adragna Pierre Antoine , Troussier Nadège
Published: August 2013

Industrial companies are confronted to reverse engineering on mechanical components. They have to define a new process planning from 3D information (points cloud, drawings, etc.). The component has to be re-engineered in order to improve and optimize new manufacturing processes. According to surveys, reverse engineering approaches begin to be supported by Knowledge Base engineering Systems (KBS). These systems are efficient to quickly obtain CAD models based on functional features. These models are successful for redesigning activities and then for defining a process planning. Industrial companies often need to re-engineered components in order to define directly a new process planning. In this case CAD models, based on functional features, are not useful. This paper suggests an approach called Reverse Engineering For Manufacturing (REFM) which allows to directly obtain a CAPP (Computer Aided Process Planning) model from 3D information. The system management is based on Design For Manufacturing (DFM) approach and enables to manage manufacturing information (such as the number of fixtures, the kind of milling operations, etc.). In addition, this system management allows to define process planning alternatives. The aim of the paper is to show the concept of REFM approach according to a use case.
Topology-Oriented Deformation of FE-Meshes in Iterative Reverse Engineering Processes
Authors: Klaus Matthias , Holtzhausen Stefan , Schöne Christine , Stelzer Ralph
Published: August 2013

Reverse Engineering methods are becoming more and more important in product development processes in cases without CAD models or modified physical objects. For numerical calculations of scanned components, using, for instance, the Finite Element Method (FEM) to look at strength or vibration characteristics, we need the previously scanned data, obtained via Geometric Reverse Engineering, to be converted into CAD surface data, a Finite Element-meshing and a determination of material parameters and constraints. Tremendous effort must be expended in the course of performing repeated Geometric Reverse Engineering and FE-meshing, which must be done when there are iterative, largely local changes in real geometry (such as when incorporating forming dies) or in the case of topologically similar objects, which must be scanned again and again.

This project is aimed at the generation of new calculation models using an appropriate adaption of existing FE meshes (made using a CAD model, for example) or FE meshes previously created with the help of scan data through the retention of intelligent meshing (constraints, material, element type etc.). In terms of their topology, these new meshes should adapt themselves to changes in geometry. Time-consuming Geometric Reverse Engineering, as well as re-meshing, can thus be bypassed. Product development cycles frequently proceed in an iterative manner. Repetition of process steps is intended to improve the product in order to achieve an optimum result in design and dimensioning. The goal of these research activities is to reduce the process steps from 3D scan data to FE-meshing, in particular in development cycles. The paper introduces the project’s concept, its initial results, and further steps.
Automated Sailing Robot Control: Global Performance Model for Local Performance Prediction
Authors: Briere Yves
Published: August 2013

The Automated Sailing Robots (ASR) concept is receiving an increasing interest among robotic researchers. Most oceanographic in situ surface measurements are currently performed via fixed buoys or passive drifting buoys. By taking advantage of the wind power an ASR will be able to conduct very long term offshore data gathering missions in virtually any place of the oceans. In this paper we describe an original prototype developed at ISAE: design, embedded systems, simulation model, performance are detailed. We eventually address the challenging problem of middle level closed loop control: rudder and sail control for course keeping. An original sail control strategy is proposed that both combine high performance and low energy consumption. The paper concludes with simulation and experimental results.
Integrated Modeling and Analysis to Support Model-Based Systems Engineering
Authors: Kim Hongman , Fried David , Menegay Peter , Soremekun Grant
Published: August 2013

Model-based systems engineering (MBSE) is an approach to improve traditional document-based systems engineering approach through the use of a system model. In the current practice of system developments, there exists a large gap between systems engineering activities and engineering analyses, because systems engineers and engineering analysts are using different models, tools and terminology. The gap results in inefficiencies and quality issues that can be very expensive. This work presents an integrated modeling and analysis capability that bridges the gap. The technical approach is based on integrating SysML modeling tools with process integration and design optimization framework. This approach connects SysML models with various engineering analysis tools through a common interface. A capability was developed to automatically generate analysis models from a system model and then execute the analytical models. Requirements conformance analysis was performed using results of engineering analysis. A technique was developed to define optimization problems in SysML, where requirements were used as design constraints. The integrated system modeling and analysis capability was demonstrated using an automobile brake pad design example. The integrated toolset was used to understand impacts of requirements changes in the SysML model and to find a new design that meets the new requirements through engineering design optimization.
Determination of lung segments in computed tomography images using the Euclidean distance to the pulmonary artery
Authors: Stoecker Christina , Welter Stefan , Moltz Jan H. , Lassen Bianca , Kuhnigk Jan‐Martin , Krass Stefan , Peitgen Heinz‐Otto
Published: August 2013

Purpose:

Computed tomography (CT) imaging is the modality of choice for lung cancer diagnostics. With the increasing number of lung interventions on sublobar level in recent years, determining and visualizing pulmonary segments in CT images and, in oncological cases, reliable segment‐related information about the location of tumors has become increasingly desirable. Computer‐assisted identification of lung segments in CT images is subject of this work.

Methods:

The authors present a new interactive approach for the segmentation of lung segments that uses the Euclidean distance of each point in the lung to the segmental branches of the pulmonary artery. The aim is to analyze the potential of the method. Detailed manual pulmonary artery segmentations are used to achieve the best possible segment approximation results. A detailed description of the method and its evaluation on 11 CT scans from clinical routine are given.

Results:

An accuracy of 2–3 mm is measured for the segment boundaries computed by the pulmonary artery‐based method. On average, maximum deviations of 8 mm are observed. 135 intersegmental pulmonary veins detected in the 11 test CT scans serve as reference data. Furthermore, a comparison of the presented pulmonary artery‐based approach to a similar approach that uses the Euclidean distance to the segmental branches of the bronchial tree is presented. It shows a significantly higher accuracy for the pulmonary artery‐based approach in lung regions at least 30 mm distal to the lung hilum.

Conclusions:

A pulmonary artery‐based determination of lung segments in CT images is promising. In the tests, the pulmonary artery‐based determination has been shown to be superior to the bronchial tree‐based determination. The suitability of the segment approximation method for application in the planning of segment resections in clinical practice has already been verified in experimental cases. However, automation of the method accompanied by an evaluation on a larger number of test cases is required before application in the daily clinical routine.
A Computational Model Predicts That Gβγ Acts at a Cleft Between Channel Subunits to Activate GIRK1 Channels
Authors: Mahajan Rahul , Ha Junghoon , Zhang Miao , Kawano Takeharu , Kozasa Tohru , Logothetis Diomedes E.
Published: August 2013

Multistage computational docking reveals how a potassium channel is activated by Gβγ.
Resolving Molecular Events in the Regulation of Meiosis in Male and Female Germ Cells
Authors: Kumar Sandeep , Cunningham Thomas J. , Duester Gregg
Published: August 2013

Genetic and pharmacological studies produce conflicting results regarding a role for retinoic acid in meiosis of the female germ cells.
Science Signaling
Podcast: 13 August 2013
Authors: Logothetis Diomedes E. , Mahajan Rahul , VanHook Annalisa M.
Published: August 2013

Structural modeling reveals how G proteins activate a potassium channel to slow heart rate.
Fatty Acids as Environmental Cues?
Authors: VanHook Annalisa M.
Published: August 2013

Long-chain unsaturated free fatty acids inhibit the expression of
Salmonella
virulence genes through the PhoP/PhoQ system.
Protecting the Endothelium
Authors: Ferrarelli Leslie K.
Published: August 2013

Two membrane receptors interact to maintain endothelial monolayer integrity in the vasculature.
Preclinical Characterization of the Novel Hepatitis C Virus NS3 Protease Inhibitor GS-9451
Authors: Yang Huiling , Robinson Margaret , Corsa Amoreena C. , Peng Betty , Cheng Guofeng , Tian Yang , Wang Yujin , Pakdaman Rowchanak , Shen Marian , Qi Xiaoping , Mo Hongmei , Tay Chin , Krawczyk Steve , Sheng X. Christopher , Kim Choung U. , Yang Chris , Delaney William E.
Published: August 2013

GS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, including
in vitro
antiviral activity, selectivity, cross-resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC
50
s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC
50
= 316 nM). Additive to synergistic
in vitro
antiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS-9451 levels were ∼40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results of
in vitro
cross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection.
Spread of Carbapenem-Resistant Acinetobacter baumannii Global Clone 2 in Asia and AbaR-Type Resistance Islands
Authors: Kim Dae Hun , Choi Ji-Young , Kim Hae Won , Kim So Hyun , Chung Doo Ryeon , Peck Kyong Ran , Thamlikitkul Visanu , So Thomas Man-Kit , Yasin Rohani M. D. , Hsueh Po-Ren , Carlos Celia C. , Hsu Li Yang , Buntaran Latre , Lalitha M. K. , Song Jae-Hoon , Ko Kwan Soo
Published: August 2013

In this surveillance study, we identified the genotypes, carbapenem resistance determinants, and structural variations of AbaR-type resistance islands among carbapenem-resistant
Acinetobacter baumannii
(CRAB) isolates from nine Asian locales. Clonal complex 92 (CC92), corresponding to global clone 2 (GC2), was the most prevalent in most Asian locales (83/108 isolates; 76.9%). CC108, or GC1, was a predominant clone in India. OXA-23 oxacillinase was detected in CRAB isolates from most Asian locales except Taiwan.
bla
OXA-24
was found in CRAB isolates from Taiwan. AbaR4-type resistance islands, which were divided into six subtypes, were identified in most CRAB isolates investigated. Five isolates from India, Malaysia, Singapore, and Hong Kong contained AbaR3-type resistance islands. Of these, three isolates harbored both AbaR3- and AbaR4-type resistance islands simultaneously. In this study, GC2 was revealed as a prevalent clone in most Asian locales, with the AbaR4-type resistance island predominant, with diverse variants. The significance of this study lies in identifying the spread of global clones of carbapenem-resistant
A. baumannii
in Asia.
Ex Vivo
Susceptibility of Plasmodium falciparum to Antimalarial Drugs in Western, Northern, and Eastern Cambodia, 2011-2012: Association with Molecular Markers
Authors: Lim Pharath , Dek Dalin , Try Vorleak , Eastman Richard T. , Chy Sophy , Sreng Sokunthea , Suon Seila , Mao Sivanna , Sopha Chantha , Sam Baramey , Ashley Elizabeth A. , Miotto Olivo , Dondorp Arjen M. , White Nicholas J. , Su Xin-zhuan , Char Meng Chuor , Anderson Jennifer M. , Amaratunga Chanaki , Menard Didier , Fairhurst Rick M.
Published: August 2013

In 2008, dihydroartemisinin (DHA)-piperaquine (PPQ) became the first-line treatment for uncomplicated
Plasmodium falciparum
malaria in western Cambodia. Recent reports of increased treatment failure rates after DHA-PPQ therapy in this region suggest that parasite resistance to DHA, PPQ, or both is now adversely affecting treatment. While artemisinin (ART) resistance is established in western Cambodia, there is no evidence of PPQ resistance. To monitor for resistance to PPQ and other antimalarials, we measured drug susceptibilities for parasites collected in 2011 and 2012 from Pursat, Preah Vihear, and Ratanakiri, in western, northern, and eastern Cambodia, respectively. Using a SYBR green I fluorescence assay, we calculated the
ex vivo
50% inhibitory concentrations (IC
50
s) of 310 parasites to six antimalarials: chloroquine (CQ), mefloquine (MQ), quinine (QN), PPQ, artesunate (ATS), and DHA. Geometric mean IC
50
s (GMIC
50
s) for all drugs (except PPQ) were significantly higher in Pursat and Preah Vihear than in Ratanakiri (
P
≤ 0.001). An increased copy number of
P. falciparum
mdr1
(
pfmdr1
), an MQ resistance marker, was more prevalent in Pursat and Preah Vihear than in Ratanakiri and was associated with higher GMIC
50
s for MQ, QN, ATS, and DHA. An increased copy number of a chromosome 5 region (X5r), a candidate PPQ resistance marker, was detected in Pursat but was not associated with reduced susceptibility to PPQ. The
ex vivo
IC
50
and
pfmdr1
copy number are important tools in the surveillance of multidrug-resistant (MDR) parasites in Cambodia. While MDR
P. falciparum
is prevalent in western and northern Cambodia, there is no evidence for PPQ resistance, suggesting that DHA-PPQ treatment failures result mainly from ART resistance.
In Vitro
Characterization of GSK2485852, a Novel Hepatitis C Virus Polymerase Inhibitor
Authors: Voitenleitner Christian , Crosby Renae , Walker Jill , Remlinger Katja , Vamathevan Jessica , Wang Amy , You Shihyun , Johnson John , Woldu Ermias , Van Horn Stephanie , Horton Joseph , Creech Katrina , Shotwell J. Brad , Hong Zhi , Hamatake Robert
Published: August 2013

GSK2485852 (referred to here as GSK5852) is a hepatitis C virus (HCV) NS5B polymerase inhibitor with 50% effective concentrations (EC
50
s) in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell culture system. We have characterized the antiviral activity of GSK5852 using chimeric replicon systems with NS5B genes from additional genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotypes 1a and 1b. The inhibitory activity of GSK5852 remained unchanged in these intergenotypic and intragenotypic replicon systems. GSK5852 furthermore displays an excellent resistance profile and shows a <5-fold potency loss across the clinically important NS5B resistance mutations P495L, M423T, C316Y, and Y448H. Testing of a diverse mutant panel also revealed a lack of cross-resistance against known resistance mutations in other viral proteins. Data from both the newer 454 sequencing method and traditional population sequencing showed a pattern of mutations arising in the NS5B RNA-dependent RNA polymerase in replicon cells exposed to GSK5852. GSK5852 was more potent than HCV-796, an earlier inhibitor in this class, and showed greater reductions in HCV RNA during long-term treatment of replicons. GSK5852 is similar to HCV-796 in its activity against multiple genotypes, but its superior resistance profile suggests that it could be an attractive component of an all-oral regimen for treating HCV.
Multilocus Sequence Typing Reveals Genetic Diversity of Carbapenem- or Ceftazidime-Nonsusceptible Pseudomonas aeruginosa in China
Authors: Ji Jingshu , Wang Jie , Zhou Zhihui , Wang Haiping , Jiang Yan , Yu Yunsong
Published: August 2013

It is unclear whether the genetic background of drug-resistant
Pseudomonas aeruginosa
was disseminated from a certain clone. Thus, we performed MLST (multilocus sequence typing) of 896
P. aeruginosa
isolates that were nonsusceptible to imipenem, meropenem, or ceftazidime. This revealed 254 sequence types (STs), including 104 new STs and 34 STs with novel alleles. Thirty-three clonal complexes and 404 singletons were found. In conclusion, drug-resistant
P. aeruginosa
clones can be developed from diverse genetic backgrounds.
Nucleic Acid Polymers Inhibit Duck Hepatitis B Virus InfectionIn Vitro
Authors: Noordeen Faseeha , Vaillant Andrew , Jilbert Allison R.
Published: August 2013

Nucleic acid polymers (NAPs) utilize the sequence-independent properties of phosphorothioate oligonucleotides (PS-ONs) to target protein interactions involved in viral replication. NAPs are broadly active against a diverse range of enveloped viruses that use type I entry mechanisms. The antiviral activity of NAPs against hepatitis B virus (HBV) infection was assessedin vitroin duck hepatitis B virus (DHBV)-infected primary duck hepatocytes (PDH). NAPs efficiently entered PDH in the absence of any transfection agent and displayed antiviral activity at concentrations of 0.01 to 10 μM, measured by their ability to prevent the intracellular accumulation of DHBV surface antigen, which was independent of their nucleotide sequence and was specifically dependent on phosphorothioation. Higher levels of antiviral activity were observed with NAPs 40 nucleotides in length or longer. The fully degenerate NAP (REP 2006) was active during DHBV infection or when added 12 h after infection. In contrast, an acidic-pH-sensitive NAP (REP 2031) that was broadly active against other viruses displayed antiviral activity when present during DHBV infection but no activity when added 12 h after infection, suggesting that NAPs exert their postentry effect in an acidic environment unique to DHBV infection. Both REP 2006 and REP 2031 displayed negligible cytotoxicity in PDH at concentrations of up to 10 μM, as assessed using an XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] cytotoxicity assay. The antiviral activity of NAPs against DHBVin vitrowas strictly dependent on their amphipathic character, suggesting that NAPs interact with amphipathic target(s) that are important for DHBV entry and postentry mechanisms required for infection.
Nucleic Acid Polymers Prevent the Establishment of Duck Hepatitis B Virus Infection
In Vivo
Authors: Noordeen Faseeha , Vaillant Andrew , Jilbert Allison R.
Published: August 2013

Nucleic acid polymers (NAPs) are novel, broad-spectrum antiviral compounds that use the sequence-independent properties of phosphorothioate oligonucleotides (PS-ONs) as amphipathic polymers to block amphipathic interactions involved in viral entry. Using the duck hepatitis B virus (DHBV) model of human hepatitis B virus infection, NAPs have been shown to have both entry and postentry antiviral activity against DHBV infection
in vitro
in primary duck hepatocytes (PDH). In the current study, various NAPs were assessed for their prophylactic activity
in vivo
against DHBV infection in ducks. The degenerate NAP REP 2006 prevented the development of widespread and persistent DHBV infection in 14-day-old ducks, while the acidic-pH-sensitive NAP REP 2031 had little or no prophylactic effect. REP 2006 displayed significant toxicity in ducks, which was attributed to CpG-mediated proinflammation, while REP 2031 (which has no CpG motifs) displayed no toxicity. A third NAP, REP 2055, which was designed to retain amphipathic activity at acidic pH and contained no CpG motifs, was well tolerated and displayed prophylactic activity against DHBV infection at doses as low as 1 mg/kg of body weight/day. These studies suggest that NAPs can be easily and predictably tailored to retain anti-DHBV activity and to have minimal toxic effects
in vivo
. Future studies are planned to establish the therapeutic efficacy of NAPs against persistent DHBV infection.
Transduction of Staphylococcal Cassette Chromosome
mec
Elements between Strains of Staphylococcus aureus
Authors: Scharn Caitlyn R. , Tenover Fred C. , Goering Richard V.
Published: August 2013

Methicillin-resistant
Staphylococcus aureus
(MRSA) is a well-known public health concern. However, the means by which methicillin resistance genes are transferred among staphylococci in nature remains unknown. Older scientific literature suggests transduction as a means of
mecA
transfer, but the optimal conditions are reported to require plasmids and potentially a lysogenic phage. These reports preceded discovery of the staphylococcal cassette chromosome
mec
(SCC
mec
) elements. We undertook studies to confirm and clarify the conditions promoting transduction of SCC
mec
in
S. aureus
populations using well-characterized donor and recipient strains primarily of the USA300 lineage. Both bacteriophages 80α and 29 were capable of transducing SCC
mec
type IV and SCC
mec
type I to recipient strains of
S. aureus
. Pulsed-field gel electrophoresis and
mec
-associated
dru
typing were used to confirm the identity of the transductants. Transfer of
mecA
via transduction occurred at low frequency and required extended selection times for
mecA
gene expression and the presence of a penicillinase plasmid in the recipient. However, interference with the process by clavulanic acid and the necessity of lysogeny with ϕ11 in the recipient or the presence of a small (4-kb) tetracycline resistance plasmid, as previously reported, were not confirmed. SCC
mec
transduction was occasionally associated with substantial deletions or truncation of SCC
mec
and the arginine catabolic metabolic element in USA300 recipients. Overall, these data clarify the conditions required for SCC
mec
transduction and document that rearrangements may occur during the process.
In Vitro
and
In Vivo
Activities of Antibiotic PM181104
Authors: Mahajan Girish , Thomas Becky , Parab Rajashri , Patel Zarine E. , Kuldharan Sandip , Yemparala Vijayaphanikumar , Mishra Prabhu Dutt , Ranadive Prafull , D'Souza Lisette , Pari Koteppa , Sivaramkrishnan H.
Published: August 2013

Drug resistance has become a global threat that, if not addressed, may return us to the preantibiotic era. A way to overcome the problem of growing incidence of global antibiotic resistance is to introduce compounds belonging to classes that are new to the clinic. During a screening of the marine microbial extract library for new antibiotics, one of the extracts showed promising antibacterial activity against Gram-positive organisms. Bioactivity-guided isolation and characterization of active metabolites led to the discovery of a novel thiazolyl cyclic-peptide antibiotic, PM181104. It was isolated and characterized from a marine sponge-associated actinobacterium strain of the genus
Kocuria
(MTCC 5269). The compound exhibited a potent
in vitro
antibacterial activity against a broad range of Gram-positive bacteria, including methicillin-resistant
Staphylococcus aureus
(MRSA) and vancomycin-resistant enterococci (VRE). The MIC values evaluated for the compound were found to be in the single-digit nanomolar range. In
in vivo
studies of PM181104 in a BALB/c murine septicemia model, the compound displayed 100% effective dose (ED
100
) values of 2.5 and 5.0 mg/kg of body weight against MRSA and 10.0 mg/kg against VRE. In this report,
in vitro
and
in vivo
studies of PM181104 are described.
Mutations of the
ompK36
Porin Gene and Promoter Impact Responses of Sequence Type 258, KPC-2-Producing Klebsiella pneumoniae Strains to Doripenem and Doripenem-Colistin
Authors: Clancy Cornelius J. , Chen Liang , Hong Jae H. , Cheng Shaoji , Hao Binghua , Shields Ryan K. , Farrell Annie N. , Doi Yohei , Zhao Yanan , Perlin David S. , Kreiswirth Barry N. , Nguyen M. Hong
Published: August 2013

Doripenem-colistin exerts synergy against some, but not all,
Klebsiella pneumoniae
carbapenemase (KPC)-producing
K. pneumoniae
strains
in vitro
. We determined if doripenem MICs and/or
ompK36
porin gene mutations impacted the responses of 23 sequence type 258 (ST258), KPC-2-producing strains to the combination of doripenem (8 μg/ml) and colistin (2 μg/ml) during time-kill assays. The median doripenem and colistin MICs were 32 and 4 μg/ml. Doripenem MICs did not correlate with KPC-2 expression levels. Five and 18 strains had wild-type and mutant
ompK36
, respectively. The most common mutations were IS
5
promoter insertions (
n
= 7) and insertions encoding glycine and aspartic acid at amino acid (aa) positions 134 and 135 (ins aa134-135 GD;
n
= 8), which were associated with higher doripenem MICs than other mutations or wild-type
ompK36
(all
P
values ≤ 0.04). Bactericidal activity (24 h) was achieved by doripenem-colistin against 12%, 43%, and 75% of ins aa134-135 GD, IS
5
, and wild-type/other mutants, respectively (
P
= 0.04). Doripenem-colistin was more active in time-kill studies than colistin at 12 and 24 h if the doripenem MIC was ≤8 μg/ml (
P
= 0.0007 and 0.09, respectively), but not if the MIC was >8 μg/ml (
P
= 0.10 and 0.16). Likewise, doripenem-colistin was more active at 12 and 24 h against the wild type/other mutants than ins aa134-135 GD or IS
5
mutants (
P
= 0.007 and 0.0007). By multivariate analysis, the absence of ins aa134-135 GD or IS
5
mutations was the only independent predictor of doripenem-colistin responses at 24 h (
P
= 0.002). In conclusion,
ompK36
genotypes identified ST258 KPC-
K. pneumoniae
strains that were most likely to respond to doripenem-colistin.
Systematic Review and Meta-Analysis of Antimicrobial Treatment Effect Estimation in Complicated Urinary Tract Infection
Authors: Singh Krishan P. , Li Gang , Mitrani-Gold Fanny S. , Kurtinecz Milena , Wetherington Jeffrey , Tomayko John F. , Mundy Linda M.
Published: August 2013

Noninferiority trial design and analyses are commonly used to establish the effectiveness of a new antimicrobial drug for treatment of serious infections such as complicated urinary tract infection (cUTI). A systematic review and meta-analysis were conducted to estimate the treatment effects of three potential active comparator drugs for the design of a noninferiority trial. The systematic review identified no placebo trials of cUTI, four clinical trials of cUTI with uncomplicated urinary tract infection as a proxy for placebo, and nine trials with reports of treatment effect estimates for doripenem, levofloxacin, or imipenem-cilastatin. In the meta-analysis, the primary efficacy endpoint of interest was the microbiological eradication rate at the test-of-cure visit in the microbiological intent-to-treat population. The estimated eradication rates and corresponding 95% confidence intervals (CI) were 31.8% (26.5% to 37.2%) for placebo, 81% (77.7% to 84.2%) for doripenem, 79% (75.9% to 82.2%) for levofloxacin, and 80.5% (71.9% to 89.1%) for imipenem-cilastatin. The treatment effect estimates were 40.5% for doripenem, 38.7% for levofloxacin, 34.7% for imipenem-cilastatin, and 40.8% overall. These treatment effect estimates can be used to inform the design and analysis of future noninferiority trials in cUTI study populations.
In Vitro
Activity of Ceftolozane-Tazobactam against Pseudomonas aeruginosa Isolates Obtained from Patients in Canadian Hospitals in the CANWARD Study, 2007 to 2012
Authors: Walkty A. , Karlowsky J. A. , Adam H. , Baxter M. , Lagacé-Wiens P. , Hoban D. J. , Zhanel G. G.
Published: August 2013

The
in vitro
activity of ceftolozane in combination with tazobactam (fixed concentration of 4 μg/ml) was evaluated against 2,435
Pseudomonas aeruginosa
clinical isolates obtained from across Canada using Clinical and Laboratory Standards Institute broth microdilution methods. The MIC
50
and MIC
90
values for ceftolozane-tazobactam were 0.5 μg/ml and 1 μg/ml, respectively (a 32-fold-lower MIC
90
than that for ceftazidime). Eighty-nine percent (141/158) of multidrug-resistant isolates were inhibited by ≤8 μg/ml of ceftolozane-tazobactam.
Identification of a Human Monoclonal Antibody To Replace Equine Diphtheria Antitoxin for Treatment of Diphtheria Intoxication
Authors: Sevigny Leila M. , Booth Brian J. , Rowley Kirk J. , Leav Brett A. , Cheslock Peter S. , Garrity Kerry A. , Sloan Susan E. , Thomas William , Babcock Gregory J. , Wang Yang
Published: August 2013

Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of
Corynebacterium diphtheriae
infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in
in vitro
cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 μg of 315C4 completely protected guinea pigs from intoxication in an
in vivo
lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic.
The first case report of McLeod syndrome in a Chinese patient
Authors: Man B L , Yuen Y P , Yip S F , Ng S H
Published: August 2013

We report the first case of McLeod syndrome (MLS) in a 47-year-old Chinese man who presented with progressive limb weakness, chorea of feet, red blood cell acanthocytosis, absence of Kx red blood cell antigen and weak expression of Kell antigens. The diagnosis of MLS was confirmed by genetic testing showing a hemizygous mutation of XK gene. We review literature on neuroacanthocytosis in the Chinese population.
The FIFA medical emergency bag and FIFA 11 steps to prevent sudden cardiac death: setting a global standard and promoting consistent football field emergency care
Authors: Dvorak Jiri , Kramer Efraim B , Schmied Christian M , Drezner Jonathan A , Zideman David , Patricios Jon , Correia Luis , Pedrinelli André , Mandelbaum Bert
Published: August 2013

Life-threatening medical emergencies are an infrequent but regular occurrence on the football field. Proper prevention strategies, emergency medical planning and timely access to emergency equipment are required to prevent catastrophic outcomes. In a continuing commitment to player safety during football, this paper presents the FIFA Medical Emergency Bag and FIFA 11 Steps to prevent sudden cardiac death. These recommendations are intended to create a global standard for emergency preparedness and the medical response to serious or catastrophic on-field injuries in football.