bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient blood management knowledge and practice among clinicians from seven European university hospitals: a multicentre survey
Authors: Manzini P. M. , Dall'Omo A. M. , D'Antico S. , Valfrè A. , Pendry K. , Wikman A. , Fischer D. , Borg‐Aquilina D. , Laspina S. , van Pampus E. C. M. , van Kraaij M. , Bruun M. T. , Georgsen J. , Grant‐Casey J. , Babra P. S. , Murphy M. F. , Folléa G. , Aranko K.
Published: October 2017

Background and Objectives

The aim of this survey was to evaluate the knowledge about Patient Blood Management (PBM) principles and practices amongst clinicians working in seven European hospitals participating in a European Blood Alliance (EBA) project.

Materials and Methods

A web‐based questionnaire was sent to 4952 clinicians working in medical, surgery and anaesthesiology disciplines. The responses were analysed, and the overall results as well as a comparison between hospitals are presented.

Results

A total of 788 responses (16%) were obtained. About 24% of respondents were not aware of a correlation between preoperative anaemia (POA) and perioperative morbidity and mortality. For 22%, treatment of POA was unlikely to favourably influence morbidity and mortality even before surgery with expected blood loss. More than half of clinicians did not routinely treat POA. 29%, when asked which is the best way to treat deficiency anaemia preoperatively, answered that they did not have sufficient knowledge and 5% chose to ‘do nothing’. Amongst those who treated POA, 38% proposed red cell transfusion prior to surgery as treatment. Restrictive haemoglobin triggers for red blood cell transfusion, single unit policy and reduction of number and volumes of blood samples for diagnostic purposes were only marginally implemented.

Conclusion

Overall, the responses indicated poor knowledge about PBM. Processes to diagnose and treat POA were not generally and homogeneously implemented. This survey should provide further impetus to implement programmes to improve knowledge and practice of PBM.
Brexit and the future of English in Europe
Authors: BOLTON KINGSLEY , DAVIS DANIEL R.
Published: October 2017

In this issue of the journal we present a forum on a current topic of key sociolinguistic interest to both linguists and the wider population in Europe and elsewhere, that is, the expected future of the English language in a reconfigured Europe after the impending British exit (or ‘Brexit’) from Europe. The key document discussed in this forum is a position paper from Marko Modiano, which has drawn a number of responses from leading linguists across the field of world Englishes. We are sincerely thankful to Modiano for initiating this forum, and grateful also to all those that have contributed their responses to his article, which has resulted, we believe, in an insightful and lively discussion of the sociolinguistics of English and multilingualism in contemporary Europe.
ICE vs GloWbE: Big data and corpus compilation
Authors: LOUREIRO‐PORTO LUCÍA
Published: October 2017

ICE and GloWbE are the two main corpora available for the study of world Englishes, and as such they share several features. However, they also differ in a number of respects owing to the different techniques adopted during compilation: while ICE is a traditional corpus with 32 text types represented, GloWbE only contains material from the Internet. This article compares the two corpora from a number of perspectives: (i) frequency and collocation of modal verbs of necessity, (ii) degree of orality and informality of the blogs included in GloWbE versus the spoken component of ICE; and (iii) the vernacular and globalised nature of both corpora. Findings show that big data cannot be considered as an alternative source to corpus compilation. Rather, the new text type(s) found in Internet material should be included in traditional corpora.
Liquidity Risk under The New Basel Global Regulatory Framework
Authors: Hlebik Sviatlana
Published: October 2017

This paper contributes to understanding  liquidity risk and its role in systemic financial crises. It focuses on the new banking regulation Basel III, in particularly on the Liquidity risk ratio that measures long-term liquidity positions of European banks. It emphasizes the importance and the issues relating to the Net Stable Funding Ratio (NSFR) which will become a minimum standard by 1 January 2018. Application at a level of 100% to credit institutions and systemic investment firms is not however expected before 2020, two years after the date of entry into force of the proposed Regulation. The paper aims to analyze the relationship between NSFR and banking stability, financial markets factors and central bank operations, in order to understand the potential impact of the key components of the new Basel global regulatory framework.
High and New Technology Enterprise Performance and Financial Constraints: Is Clustering Efficient?
Authors: Shu Qianfei , Yano Go
Published: October 2017

Using firm level panel data for non-listed high and new technology enterprises in the Yangtze River Delta of China from 2002–2009, we investigated the importance of the high and new technology industrial development zone (HNTIDZ) established by the Chinese government for improving enterprise performance. We found that high and new technology enterprises located in HNTIDZs enjoy superior productivity, growth potential, export and innovation activity; better access to trade credit and bank loan facilities plays a significant role in promoting productivity, growth and export, but it does not affect innovation activity; in national HNTIDZs, enterprises that are more in need of trade credit and bank loan have better performance in the respect of productivity, growth, export as well as innovation activity.
Reviewer Acknowledgements
Authors: Young James
Published: October 2017

Reviewer AcknowledgementsInternational Journal of Social Science Studies (IJSSS) would like to acknowledge the following reviewers for their assistance with peer review of manuscripts for this issue. Many authors, regardless of whether IJSSS publishes their work, appreciate the helpful feedback provided by the reviewers. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Each of the reviewers listed below returned at least one review for this issue.Reviewers for Volume 5, Number 11 Adrienne L. Edwards, University of Nevada, USAAhmet Yıkmış, Abant Izzet Baysal Univeersity, TurkeyAyşegül Sili Kalem, Necmettin Erbakan Universitesi, TurkeyE.Ozan Aksoz, Anadolu University, TurkeyGülsüm Depeli, Hacettepe University, TurkeyHenry Poduthas, West Texas A&M University, USAJehu Onyekwere Nnaji, University of Naples II, Italy and Globe Visions Network Italy, ItalyRasa Poceviciene, Siauliai University, LithuaniaYanzhe Zhang, Jilin University, China, China/AustraliaZlatan Begić, University of Tuzla, Bosnia and Herzegovina
Effect of 5E Learning Model on Academic Achievement, Attitude and Science Process Skills: Meta-Analysis Study
Authors: Cakır Nevin Kozcu
Published: October 2017

Today, with the development of science and technology and its rapid progress, the importance attached to science education has increased. This increase in interest has led to the development of the methods, techniques, and approaches that enable the students to be active, question and construct knowledge. The 5E learning model is one of them, and many studies have been conducted in literature related to this model. These independent studies have been carried out in different study areas, with different study groups, and different results have been achieved. In order to evaluate these results in general, it is necessary to make use of as many studies as possible. Meta-analysis was considered to work to reveal how each work has impacted the situation and make a generalization. From this point of view, a meta-analysis study was planned in this study to evaluate the effect of the 5E learning model on academic achievement, retention and scientific process skills. For this purpose, all the Master's, doctoral theses and articles in Turkish and English languages which were carried out in Turkey between 2006 and 2016 and which are suitable for the research problem have been scanned and included in the scope of the study. In order to limit studies and conduct meta-analysis in this context, studies had to be planned with semi-experimental design with experiment and control groups; there had to be quantitative data such as mean, standard deviation, and sample size and they had to be applied only in science courses. The data obtained from the articles and theses were meta-analyzed and it was determined that the 5E learning model had an effect on the students' academic achievement, attitude towards science and science process skills. In this context, studies should be conducted in order to limit the studies and to perform the meta-analysis, in which semi-experimental design with experimental and control groups is planned, t-test is applied only in science courses. By analyzing the data obtained from the articles and theses, a general evaluation was made about the effect of the 5E learning model on academic achievement, attitude toward science and science process skills. As a result of the study, the effect of the method applied for each dependent variable was found to favor the experimental group.
Effectiveness of Learning with 3D-Lab on Omani Basic Education Students' Achievement, Attitudes and Scientific Thinking
Authors: Musawi Ali Al , Ambusaidi Abdullah , Al-Balushi Sulaiman , Al-Sinani Mohamed , Al-Balushi Kholoud
Published: October 2017

This paper aims to measure the effectiveness of the 3DL on Omani students' acquisition of practical abilities and skills. It examines the effectiveness of the 3D-lab in science education and scientific thinking acquisition as part of a national project funded by The Research Council. Four research tools in a Pre-Post Test Control Group Design, findings show statistically significant differences in student achievement in favor of the experimental group. The results show students' attitudes are positive towards using 3D-lab in teaching. Improvements in logical and visual thinking are also observed. The paper then draws conclusions and recommendations.
Lock-In Detection of Directivity of Fluorescence From a Minute Particle Using TAS Chip Incorporated With Radially Arranged Light Waveguides
Authors: Ohkubo Toshifumi , Terada Nobuyuki , Yoshida Yoshikazu
Published: October 2017

It has long been thought that an optical sensor, such as a light waveguide implemented total analysis system (TAS), is one of the most functional components that will be needed to realize a “ubiquitous human healthcare system”. A transparent resin-based TAS chip incorporated with a light waveguide [1] is quite preferable in such a cost-effective and disposal use. In line with the technical demand, we have already proposed a specially fabricated structure for an epoxy resin-based monolithic light waveguide capable of illuminating a cell or particle running along a microfluidic channel [2], as well as of obtaining directivity of fluorescence with a radially arranged waveguide structure (as shown in Figure 1) and a sequential light scanning mechanism based on a forced vibrated optical fiber [3]. Utilizing this TAS system, we have successfully detected preliminary results of fluorescence directivity of a 5-μm-diameter polystyrene particle with scanning angle range of 180 degrees, at illuminating light scanning frequency of approximately 1.7 kHz [4]. However, the transmittance of the trial-manufactured light waveguides was slightly lower owing mainly to its smaller cross section size, and, as a result, signal-to-noise ratio of detected fluorescence signal waveform was not as good as we have expected. To improve the S/N ratio, it is necessary to increase illuminating power of a laser source, and, at the same time, to increase multiplication factor of a photo-electron multiplier sensor to beyond its performance limit. Unfortunately, with the capability of the current equipment, it is difficult to drastically improve the S/N ratio. In this paper, we attempted to apply AC detection method to measure extremely weak fluorescence with a high frequency modulated laser source of its wavelength of 488 nm, and with a high speed lock-in-amplifier having both higher reference frequency up to 3MHz and smaller time constant.
A New Highly Sensitive Dielectric Slip Detection Sensor for a Robotic Operation
Authors: Kim Sung Joon , Koo Ja Choon
Published: October 2017

For dexterous grasping and manipulation, tactile sensors recognizing contact object are essential. Electronic skin (E-skin) with tactile sensors plays a role as both receiving information for grasping and protecting robot frame. This paper presents a polymer tactile sensor covering large area to fulfill role of E-skin. The sensor has a thin air gap between polymer layers and it is deformed reacting slip input. When slip is occurred, there is relative displacement between surrounding layer and it incurs change of electrode separation. NBR is used to sensor substrate because of its tough and flexible characteristic. Ultrathin aluminum tape is employed for electrodes. There is a changeability of size of the sensor because of its simple but effective working principle and structure. Slip detecting algorithm doesn’t have a post process such as FFT or DWT, so there isn’t delay for processing time. It realizes real-time slip detection reducing reaction time of robot hand.
Advanced Numerical Modeling of Nonlinear Elastic Cable With Permanent Stretch Using Cable Driven Parallel Robot
Authors: Choi Sung-Hyun , Park Kyoung-Su
Published: October 2017

Since cable driven parallel robots (CDPRs) have many advantages, they have been used in many industrial fields. Fully constrained CDPRs mainly use Dyneema polyethylene because it has advantage of the lower weight than steel wire. However, the polyethylene cable has complex elastic characteristics (e.g. permanent stretch and hysteresis). In this paper, the advanced numerical modeling of nonlinear elastic cable with permanent stretch using cable driven parallel robot was derived and simulated for various cable condition. Based on the advanced numerical nonlinear cable model, the simulation was carried out under the various cable lengths and tensions. Compared to the experimental results, the simulation results are good agreement with the experimental data.
PES Simulation by Using Surrogate Drive Measurement for a HDD in a Storage Box
Authors: Eguchi Takehiko , Asai Yohei , Ichikawa Kazuhide , Takada Shigenori
Published: October 2017

In recent storage boxes, fan vibrations have become a major vibration source because of increasing processing power and storage capacity. The fan vibration causes high frequency vibration up to 10 kHz in the head positioning error (PES) of HDDs, and the FEM simulation method for them have been required from the viewpoint of the HDD developments. In this paper, we conducted PES simulation by using rigid-body accelerations as the input, which were measured by using a surrogate drive. The surrogate drive has six accelerometers inside and its rigid-body motion in a box was calculated by using the least-square method. Comparing simulation and measurement results, it was found that surrogate drive measurement was effective to understand characteristics of box vibrations. The simulations also showed a problem of under-estimation at low frequencies from 1 to 2 kHz. Improvement of the boundary condition and input of the simulation model will be necessary.
A Numerical Investigation of the Nanoscale Heat Transfer in Heat Assisted Magnetic Recording
Authors: Hu Yueqiang , Wu Haoyu , Meng Yonggang , Bogy David
Published: October 2017

The heat management problem in the heat assisted magnetic recording (HAMR) has been a long-term issue. In this paper, we investigated the temperature increase of a “lollipop” type near field transducer (NFT) in HAMR. We included the electromagnetic (EM) field analysis in the modeling and considered the back-heating from the media to the head with various heat transfer mechanisms. The results showed that the overcoat layer of the NFT plays an important role for protecting the NFT from high temperature. Degradation of the overcoat layer may result in the early failure of the NFT.
Optimum Design of a BLDC Motor for Electric Continuous Variable Valve Timing System
Authors: Baek Soo-Whang
Published: October 2017

In order to save resources and prevent global warming, it has been urgently needed to reduce CO2 emissions and decrease automobile fuel consumption in recent years. The trend in automotive applications are being studied to improve fuel efficiency and to reduce volume and weight. For these reasons, the mechanical parts of the automobile are being replaced by electric components.

This paper deals with the optimum design process for a small Brushless DC (BLDC) motor used in Electric-Continuous Variable Valve Timing (E-CVVT) system in automobiles with internal combustion engines. It is also proposed to improve the rated efficiency and the maximum torque and reduce the cogging torque to improve the characteristics of the BLDC motor. To maximize the maximum torque as well as to maintain the rated efficiency, the radial basis function based on latin hypercube sampling and genetic algorithm are utilized. The design variables, objective functions, and constraints are selected for the optimum design of the BLDC motor, which is divided into three steps. Step I and step II are calculated to improve the rated efficiency and the maximum torque respectively, while step III utilizes to reduce cogging torque. To verify the proposed optimum design process, the improvement of characteristic is suggested with FE-analysis.
Analysis on Effect of Birefringence in an Image Forming Lens of a Laser Scan Unit on Optical Characteristics
Authors: Kim Wan-Chin , Cho Won-Young
Published: October 2017

In most cases of molding process with glass or optical polymer, it is inevitable to avoid birefringence arisen due to residual internal mechanical stress in a molded material. Even though distribution of the residual stress can be annealed by slow cooling, it has a disadvantage on shape accuracy and manufacturing time. This study mainly analyzes variation in optical performance considering optical phase delay and difference in orientation angles between two principal optical axes due to birefringence. And the simulated optical characteristics are compared with experimental spot profiles from the image forming lens of a laser scan unit, which has specific degree of generation of birefringence. Through this study, we are going to clarify birefringence condition of the image forming lens for a LSU (Laser Scan Unit) to induce degradation in optical performance.
Control of Dual-Stage HDDs With Enhanced Repetitive Disturbance Rejection
Authors: Zhou Shiying , Zheng Minghui , Chen Xu , Tomizuka Masayoshi
Published: October 2017

Nowadays, despite the emerging adoption of the solid state drives, hard disk drives (HDDs) are still used extensively as cost-effective and reliable solutions for data storage. In addition to its usual application in desktops and laptops, HDDs become the primary storage medium for the data centers. The track following control task in HDD requires that the read/write head be positioned over the data track center at nano-scale accuracy, which requires an error tolerance about 7nm. Therefore, the dual-stage HDD is introduced to enhance the HDD control performance for extended bandwidth and improved disturbance rejection.
Design and Implement the Readout Circuit of an In-Cell High-Resolution Capacitive Touch Panel
Authors: Ku Tsung-Yen , Chao Paul C.-P. , Huang Chin-Hai , Liu En-Chih , Yeh Ming-Hua , Chen Han-Chang , Wang Tong-Wen
Published: October 2017

This paper proposes a high resolution capacitive touch panel readout circuit to sense the Variation by self-capacitance method. This AM display of in-cell structure includes an active architecture for improved resolution, that controlling the TFT (Thin-film transistor) to make the accuracy better. In addition, the panel has 60 sensing point per 0.88 inches and the proposed readout circuit used switched capacitor charge amplifier (SCCA) to sensing the charge change and enhances the SNR (Signal-to-noise) by eliminating the baseline. The experimental results show that the proposed readout circuit SNR achieves 38dB and the frame rate is 200Hz.
Head Disk Spacing Effect on Heat Transfer in Heat Assisted Magnetic Recording
Authors: Xiong Shaomin , Schreck Erhard , Canchi Sripathi
Published: October 2017

Heat transfer at nanometer scale attracts a lot of interest from both academia and industries. The hard disk drive (HDD) industry cares about the heat transfer between the head and disk, as several heating and thermal sensing elements are integrated into the HDD system. Understanding the heat transfer mechanism and its dependency on spacing becomes very critical for heat assisted magnetic recording (HAMR). In this paper, we propose a new method to study the head disk spacing effects on heat transfer by introducing a small perturbation to the spacing while maintaining the heating source unchanged. The dependency of heat transfer on the nanoscale spacing provides insights to the understanding of heat transfer mechanisms inside the nanoscale gap.
Theoretical Analyses of Surface Interaction Stresses Considering Two-Dimensional Periodic Material Distributions
Authors: Matsuoka Hiroshige , Miyake Ryoya , Maegawa Satoru , Fukui Shigehisa
Published: October 2017

The interaction stresses (pressure and shear stress) for (001) surface between a half-space consisting of a uniform material and a half-space with a spatially periodic material distribution have been derived based on the Lennard-Jones potential. The periodically distributed material property function is expanded as a complex Fourier series. The interaction pressures consist of non-fluctuation terms and fluctuation terms, while the shear stresses have only fluctuation terms. The interaction stresses for a distribution of two materials were then calculated as a typical example of a periodic material distribution. The basic characteristics of the interaction stresses are clarified.
Photoplethysmography Signals Processing Using Polynomial Profile Fitting for Measuring the Blood Flow Volume in Arteriovenous Fistula
Authors: Chao Paul C.-P. , Chiang Pei-Yu
Published: October 2017

In this work, a new photoplethysmography (PPG) signal processing methodology using polynomial profile fitting for measuring blood flow volume (BFV) in arteriovenous fistula (AVF) is proposed. After calibration, the experiment results using proposed method shows higher correlation (R = 0.7883) and lower error (RMSE = 109 ml/min) compared to the ones using conventional methods (R = 0.3212, RMSE = 168 ml/min).
Smear Growth of Siloxane Outgas at Laser Heating
Authors: Tani Hiroshi , Tagawa Norio , Lu Renguo , Koganezawa Shinji
Published: October 2017

Siloxane outgas is well known to cause smears on magnetic head sliders. Siloxane outgas is vaporized from certain components in hard disk drives (HDDs), that adsorbs on the magnetic disk surfaces, and SiO2 that is denatured from siloxane by flash temperature at a slider and disk contact gets accumulated on the slider surface. On the other hand, heat assisted magnetic recording (HAMR) is being developed to improve areal density. In HAMR, a laser light heats the magnetic disk surface to 400–500 K. Siloxane adsorbed on a disk surface easily gets desorbed from the disk surface owing to thermal evaporation and dissociation by laser heating. In this study, we have studied smear growth from siloxane outgas on laser heating. We observe that the siloxane adsorbed on the disk surface grew on the glass surface above the disk surface at the laser heating spot.
Sensitivity Analysis on Solder Joint Fatigue Life of Solid State Drives by Finite Element Method and Monte Carlo Simulation
Authors: Cho Y. J. , Jang J. W. , Jang G. H.
Published: October 2017

We proposed a method to estimate a distribution of fatigue life of solid state drives (SSDs) due to thermal cycling excitation by using finite element method and Monte Carlo simulation. In the developed finite element model, we utilized the Anand model to represent the viscoplastic behavior of the solder balls, and we also utilized the Prony series to represent the viscoelastic behavior of the polymer material in underfill. We determined a fatigue life of the SSD by using the Morrow’s energy-based fatigue model. Finally, we determined a distribution of fatigue life considering the manufacturing tolerance of the design variables and the variation of material properties in the Monte Carlo simulation. Finite element analysis shows that the outermost solder ball at the corner of dynamic random access memory was the most vulnerable component under the thermal cycling excitation. We also show that temperature profile and diameter of solder ball affect dominantly the fatigue life of the SSD.
Mechanical Feasibility of Airfoil Shaped Energy Harvesting Device Based on Aerodynamic Instability Phenomena
Authors: Yun Gangsik , Oh Dongho , Kim Youngjin , Kim JiHyeon , Kim TaeHyeong
Published: October 2017

Unsteady aerodynamic forces generally have been treated as subjects to avoid or control. However, more energy resources could be gained if humans could use the unsteady aerodynamic force that can destroy massive structures.

In this paper, an energy harvesting device was proposed using the flutter phenomenon, which is one of the phenomena of aerodynamic instability. Unlike existing flutter-based energy harvesting devices, the proposed device can be operated regardless of wind direction. A prototype was developed for a performance evaluation in a wind tunnel, and displacement measurements were taken over varying wind speeds.
Lubricant Evaporation and Flow due to Laser Heating With a Skewed Temperature Distribution Induced by Disk Motion
Authors: Haq M. Ashraful , Wang Shao
Published: October 2017

Due to the fast disk rotation, the temperature distribution on the disk under laser illumination in heat-assisted magnetic recording (HAMR) tends to deviate significantly from an axisymmetric distribution. A lognormal approximation scheme for the temperature distribution containing a tail based on a fast-moving heat source solution was proposed for use in an equation for the lubricant film involving evaporation, surface tension, disjoining pressure and thin-film enhanced effective viscosity. The results reveal the process of formation of a lubricant trough: an indent of the lubricant profile first forms and grows to a steady-state depth, followed by a continuous extension at the rate of the disk velocity. Both evaporation and thermal capillarity due to the surface tension gradient contribute greatly to the creation of a trough in the lubricant profile while the latter also causes boundary ridges. Unlike the Gaussian temperature-based solution, the local minimum of the lubricant thickness occurs at the trailing edge of the thermal spot.
The influence of air-filled structures on wave propagation and beam formation of a pygmy sperm whale (Kogia breviceps) in horizontal and vertical planes
Authors: Song Zhongchang , Zhang Yu , Thornton Steven W. , Li Songhai , Dong Jianchen
Published: October 2017

The wave propagation, sound field, and transmission beam pattern of a pygmy sperm whale (Kogia breviceps) were investigated in both the horizontal and vertical planes. Results suggested that the signals obtained at both planes were similarly characterized with a high peak frequency and a relatively narrow bandwidth, close to the ones recorded from live animals. The sound beam measured outside the head in the vertical plane was narrower than that of the horizontal one. Cases with different combinations of air-filled structures in both planes were used to study the respective roles in controlling wave propagation and beam formation. The wave propagations and beam patterns in the horizontal and vertical planes elucidated the important reflection effect of the spermaceti and vocal chambers on sound waves, which was highly significant in forming intensive forward sound beams. The air-filled structures, the forehead soft tissues and skull structures formed wave guides in these two planes for emitted sounds to propagate forward.
Development of a Novel Multipenicillin Assay and Assessment of the Impact of Analyte Degradation: Lessons for Scavenged Sampling in Antimicrobial Pharmacokinetic Study Design
Authors: Kipper Karin , Barker Charlotte I. S. , Standing Joseph F. , Sharland Mike , Johnston Atholl
Published: October 2017

Penicillins are widely used to treat infections in children; however, the evidence is continuing to evolve in defining the optimal dosing. Modern pediatric pharmacokinetic study protocols frequently favor opportunistic, “scavenged” sampling. This study aimed to develop a small-volume single assay for five major penicillins and to assess the influence of sample degradation on inferences made using pharmacokinetic modeling, to investigate the suitability of scavenged sampling strategies. Using a rapid ultrahigh-performance liquid chromatographic-tandem mass spectrometric method, an assay for five penicillins (amoxicillin, ampicillin, benzylpenicillin, piperacillin, and flucloxacillin) in blood plasma was developed and validated. Penicillin stabilities were evaluated under different conditions. Using these data, the impact of drug degradation on inferences made during pharmacokinetic modeling was evaluated. All evaluated penicillins indicated good stability at room temperature (23 ± 2°C) over 1 h, remaining in the range of 98 to 103% of the original concentration. More-rapid analyte degradation had already occurred after 4 h, with stability ranging from 68% to 99%. Stability over longer periods declined: degradation of up to 60% was observed with delayed sample processing of up to 24 h. Modeling showed that analyte degradation can lead to a 30% and 28% bias in clearance and volume of distribution, respectively, and falsely show nonlinearity in clearance. Five common penicillins can now be measured in a single low-volume blood sample. Beta-lactam chemical instability in plasma can cause misleading pharmacokinetic modeling results, which could impact upon model-based dosing recommendations and the forthcoming era of beta-lactam therapeutic drug monitoring.
In Vitro
Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS3/4A Protease Inhibitor Glecaprevir
Authors: Ng Teresa I. , Tripathi Rakesh , Reisch Thomas , Lu Liangjun , Middleton Timothy , Hopkins Todd A. , Pithawalla Ron , Irvin Michelle , Dekhtyar Tatyana , Krishnan Preethi , Schnell Gretja , Beyer Jill , McDaniel Keith F. , Ma Jun , Wang Guoqiang , Jiang Li-Juan , Or Yat Sun , Kempf Dale , Pilot-Matias Tami , Collins Christine
Published: October 2017

Glecaprevir (formerly ABT-493) is a novel hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) with pangenotypic activity. It inhibited the enzymatic activity of purified NS3/4A proteases from HCV genotypes 1 to 6
in vitro
(half-maximal [50%] inhibitory concentration = 3.5 to 11.3 nM) and the replication of stable HCV subgenomic replicons containing proteases from genotypes 1 to 6 (50% effective concentration [EC
50
] = 0.21 to 4.6 nM). Glecaprevir had a median EC
50
of 0.30 nM (range, 0.05 to 3.8 nM) for HCV replicons containing proteases from 40 samples from patients infected with HCV genotypes 1 to 5. Importantly, glecaprevir was active against the protease from genotype 3, the most-difficult-to-treat HCV genotype, in both enzymatic and replicon assays demonstrating comparable activity against the other HCV genotypes. In drug-resistant colony selection studies, glecaprevir generally selected substitutions at NS3 amino acid position A156 in replicons containing proteases from genotypes 1a, 1b, 2a, 2b, 3a, and 4a and substitutions at position D/Q168 in replicons containing proteases from genotypes 3a, 5a, and 6a. Although the substitutions A156T and A156V in NS3 of genotype 1 reduced susceptibility to glecaprevir, replicons with these substitutions demonstrated a low replication efficiency
in vitro
. Glecaprevir is active against HCV with most of the common NS3 amino acid substitutions that are associated with reduced susceptibility to other currently approved HCV PIs, including those at positions 155 and 168. Combination of glecaprevir with HCV inhibitors with other mechanisms of action resulted in additive or synergistic antiviral activity. In summary, glecaprevir is a next-generation HCV PI with potent pangenotypic activity and a high barrier to the development of resistance.
Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection
Authors: Xiao Peng , Gumber Sanjeev , Marzinke Mark A. , Date Abhijit A. , Hoang Thuy , Hanes Justin , Ensign Laura M. , Wang Lin , Rohan Lisa , Fuchs Edward J. , Hendrix Craig , Villinger Francois
Published: October 2017

Oral preexposure prophylaxis (PrEP) has been approved for prophylaxis of HIV-1 transmission but is associated with high costs and issues of adherence. Protection from anal transmission of HIV using topical microbicides and methods congruent with sexual behavior offers the promise of improved adherence. We compared the pharmacokinetics (PK) and
ex vivo
efficacy of iso-osmolar (IOsm) and hypo-osmolar (HOsm) rectal enema formulations of tenofovir (TFV) in rhesus macaques. Single-dose PK of IOsm or HOsm high-dose (5.28 mg/ml) and low-dose (1.76 mg/ml) formulations of TFV enemas were evaluated for systemic uptake in blood, colorectal biopsy specimens, and rectal CD4
+
T cells. Markedly higher TFV concentrations were observed in plasma and tissues after administration of the HOsm high-dose formulation than with all other formulations tested. TFV and TFV diphosphate (TFV-DP) concentrations in tissue correlated for the HOsm high-dose formulation, demonstrating rapid uptake and transformation of TFV to TFV-DP in tissues. TFV-DP amounts in tissues collected at 1 and 24 h were 7 times and 5 times higher, respectively (
P
< 0.01), than the ones collected in tissues with the IOsm formulation. The HOsm high-dose formulation prevented infection in
ex vivo
challenges of rectal tissues collected at 1, 24, and 72 h after the intrarectal dosing, whereas the same TFV dose formulated as an IOsm enema was less effective.
Use of Calgary and Microfluidic BioFlux Systems To Test the Activity of Fosfomycin and Tobramycin Alone and in Combination against Cystic Fibrosis Pseudomonas aeruginosa Biofilms
Authors: Díez-Aguilar María , Morosini María Isabel , Köksal Emin , Oliver Antonio , Ekkelenkamp Miquel , Cantón Rafael
Published: October 2017

Pseudomonas aeruginosa
is a major cause of morbidity and mortality in chronically infected cystic fibrosis patients. Novel
in vitro
biofilm models which reliably predict the therapeutic success of antimicrobial therapies against biofilm bacteria should be implemented. The activity of fosfomycin, tobramycin, and the fosfomycin-tobramycin combination against 6 susceptible
P. aeruginosa
strains isolated from respiratory samples from cystic fibrosis patients was tested by using two
in vitro
biofilm models: a closed system (Calgary device) and an open model based on microfluidics (BioFlux). All but one of the isolates formed biofilms. The fosfomycin and tobramycin minimal biofilm inhibitory concentrations (MBIC) were 1,024 to >1,024 μg/ml and 8 to 32 μg/ml, respectively. According to fractional inhibitory concentration analysis, the combination behaved synergistically against all the isolates except the
P. aeruginosa
ATCC 27853 strain. The dynamic formation of the biofilm was also studied with the BioFlux system, and the MIC and MBIC of each antibiotic were tested. For the combination, the lowest tobramycin concentration that was synergistic with fosfomycin was used. The captured images were analyzed by measuring the intensity of the colored pixels, which was proportional to the biofilm biomass. A statistically significant difference was found when the intensity of the inoculum was compared with the intensity of the microchannel in which the MBIC of tobramycin, fosfomycin, or their combination was used (
P
< 0.01) but not when the MIC was applied (
P
> 0.01). Fosfomycin-tobramycin was demonstrated to be synergistic against cystic fibrosis
P. aeruginosa
strains in the biofilm models when both the Calgary and the microfluidic BioFlux systems were tested. These results support the clinical use of this combination.
Identification of Vancomycin Exposure-Toxicity Thresholds in Hospitalized Patients Receiving Intravenous Vancomycin
Authors: Zasowski Evan J. , Murray Kyle P. , Trinh Trang D. , Finch Natalie A. , Pogue Jason M. , Mynatt Ryan P. , Rybak Michael J.
Published: October 2017

Evidence supports vancomycin therapeutic-drug monitoring by area under the concentration-time curve (AUC), but data to establish an AUC upper limit are limited and published nephrotoxicity thresholds range widely. The objective of this analysis was to examine the association between initial vancomycin AUC and nephrotoxicity. This was a multicenter, retrospective cohort study of adult patients receiving intravenous vancomycin from 2014 to 2015. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/liter and 50% from baseline on consecutive measurements. Vancomycin exposure profile during the initial 48 h of therapy was estimated using maximum
a posteriori
probability Bayesian estimation. Vancomycin AUC and minimum-concentration (
C
min
) thresholds most strongly associated with nephrotoxicity were identified via classification and regression tree (CART) analysis. Predictive performances of CART-derived and other candidate AUC thresholds was assessed through positive and negative predictive value and receiver operating characteristic curves. Poisson regression was used to quantify the association between exposure thresholds and nephrotoxicity while adjusting for confounders. Among 323 patients included, nephrotoxicity was significantly higher in patients with AUCs from 0 to 48 h (AUC
0–48
) of ≥1,218 mg · h/liter, AUC
0–24
of ≥677 mg · h/liter, AUC
24–48
of ≥683 mg · h/liter, and day 1
C
min
(
C
min24
) of ≥18.8 mg/liter. Vancomycin exposure in excess of these thresholds was associated with a 3- to 4-fold-increased risk of nephrotoxicity in Poisson regression. The predictive performance of AUC for nephrotoxicity was maximized at daily AUC values between 600 and 800 mg · h/liter. Although these data support an AUC range for vancomycin-associated nephrotoxity rather than a single threshold, available evidence suggests that a daily AUC limit of 700 mg · h/liter is reasonable.
Detection of
Mycobacterium tuberculosis pncA
Mutations by the Nipro Genoscholar PZA-TB II Assay Compared to Conventional Sequencing
Authors: Willby Melisa J. , Wijkander Maria , Havumaki Joshua , Johnson Kartee , Werngren Jim , Hoffner Sven , Denkinger Claudia M. , Posey James E.
Published: October 2017

Pyrazinamide (PZA) is a standard component of first-line treatment regimens for
Mycobacterium tuberculosis
and is included in treatment regimens for drug-resistant
M. tuberculosis
whenever possible. Therefore, it is imperative that susceptibility to PZA be assessed reliably prior to the initiation of therapy. Currently available growth-based PZA susceptibility tests are time-consuming, and results can be inconsistent. Molecular tests have been developed for most first-line antituberculosis drugs; however, a commercial molecular test is not yet available for rapid detection of PZA resistance. Recently, a line probe assay, the Nipro Genoscholar PZA-TB II assay, was developed for the detection of mutations within the
pncA
gene, including the promoter region, that are likely to lead to PZA resistance. The sensitivity and specificity of this assay were evaluated by two independent laboratories, using a combined total of 249 strains with mutations in
pncA
or its promoter and 21 strains with wild-type
pncA
. Overall, the assay showed good sensitivity (93.2% [95% confidence interval, 89.3 to 95.8%]) and moderate specificity (91.2% [95% confidence interval, 77.0 to 97.0%]) for the identification of
M. tuberculosis
strains predicted to be resistant to PZA on the basis of the presence of mutations (excluding known PZA-susceptible mutations) in the
pncA
coding region or promoter. The assay shows promise for the molecular prediction of PZA resistance.
Activation of the Innate Immune System by Treponema denticola Periplasmic Flagella through Toll-Like Receptor 2
Authors: Ruby John , Martin Michael , Passineau Michael J. , Godovikova Valentina , Fenno J. Christopher , Wu Hui
Published: October 2017

Treponema denticola
is an indigenous oral spirochete that inhabits the gingival sulcus or periodontal pocket. Increased numbers of oral treponemes within this environment are associated with localized periodontal inflammation, and they are also part of an anaerobic polymicrobial consortium responsible for endodontic infections. Previous studies have indicated that
T. denticola
stimulates the innate immune system through Toll-like receptor 2 (TLR2); however, the pathogen-associated molecular patterns (PAMPs) responsible for
T. denticola
activation of the innate immune system are currently not well defined. In this study, we investigated the role played by
T. denticola
periplasmic flagella (PF), unique motility organelles of spirochetes, in stimulating an innate immune response. Wild-type
T. denticola
stimulated the production of the cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, and IL-12 by monocytes from human peripheral blood mononuclear cells, while its isogenic nonmotile mutant lacking PF resulted in significantly diminished cytokine stimulation. In addition, highly purified PF were able to dose dependently stimulate cytokine TNF-α, IL-1β, IL-6, IL-10, and IL-12 production in human monocytes. Wild-type
T. denticola
and the purified PF triggered activation of NF-κB through TLR2, as determined using a variety of TLR-transfected human embryonic 293 cell lines, while the PF-deficient mutants lacked the ability to stimulate, and the complemented PF-positive
T. denticola
strain restored the activation. These findings suggest that
T. denticola
stimulates the innate immune system in a TLR2-dependent fashion and that PF are a key bacterial component involved in this process.
Characterization of Mutations That Affect the Nonoxidative Pentose Phosphate Pathway in Sinorhizobium meliloti
Authors: Hawkins Justin P. , Ordonez Patricia A. , Oresnik Ivan J.
Published: October 2017

Sinorhizobium meliloti
is a Gram-negative alphaproteobacterium that can enter into a symbiotic relationship with
Medicago sativa
and
Medicago truncatula
. Previous work determined that a mutation in the
tkt2
gene, which encodes a putative transketolase, could prevent medium acidification associated with a mutant strain unable to metabolize galactose. Since the pentose phosphate pathway in
S. meliloti
is not well studied, strains carrying mutations in either
tkt2
and
tal
, which encodes a putative transaldolase, were characterized. Carbon metabolism phenotypes revealed that both mutants were impaired in growth on erythritol and ribose. This phenotype was more pronounced for the
tkt2
mutant strain, which also displayed auxotrophy for aromatic amino acids. Changes in pentose phosphate pathway metabolite concentrations were also consistent with a mutation in either
tkt2
or
tal
. The concentrations of metabolites in central carbon metabolism were also found to shift dramatically in strains carrying a
tkt2
mutation. While the concentrations of proteins involved in central carbon metabolism did not change significantly under any conditions, the levels of those associated with iron acquisition increased in the wild-type strain with erythritol induction. These proteins were not detected in either mutant, resulting in less observable rhizobactin production in the
tkt2
mutant. While both mutants were impaired in succinoglycan synthesis, only the
tkt2
mutant strain was unable to establish symbiosis with alfalfa. These results suggest that
tkt2
and
tal
play central roles in regulating the carbon flow necessary for carbon metabolism and the establishment of symbiosis.

IMPORTANCE
Sinorhizobium meliloti
is a model organism for the study of plant-microbe interactions and metabolism, especially because it effects nitrogen fixation. The ability to derive the energy necessary for nitrogen fixation is dependent on an organism's ability to metabolize carbon efficiently. The pentose phosphate pathway is central in the interconversion of hexoses and pentoses. This study characterizes the key enzymes of the nonoxidative branch of the pentose phosphate pathway by using defined genetic mutations and shows the effects the mutations have on the metabolite profile and on physiological processes such as the biosynthesis of exopolysaccharide, as well as the ability to regulate iron acquisition.
Increasing admissions to paediatric intensive care units in England and Wales: more than just rising a birth rate
Authors: Davis Peter , Stutchfield Christopher , Evans T Alun , Draper Elizabeth
Published: October 2017

Objective

To determine the number of individual children admitted to Paediatric Intensive Care Units (PICUs) in England and Wales between 2004 and 2013 and to investigate potential factors for any change over time, including ethnicity.

Methods

Anonymised demographic and epidemiological data were extracted from the Paediatric Intensive Care Audit Network (PICANet) database and analysed for all children resident in England and Wales admitted to PICUs of National Health Service (NHS) hospitals in those countries between 2004 and 2013. Population data, including births, were obtained from the Office of National Statistics and analysed. Predicted numbers of children admitted to PICU were compared with actual admissions, averaged over 3-year periods.

Results

Increasing numbers of individual children were admitted to PICUs in England and Wales between 2004 and 2013. The largest increases were among younger children (0–5 years) and those with primary respiratory or cardiac diagnoses. They were also greatest in regions with the most mothers born overseas. From 2009 onwards, more children were admitted to PICUs than predicted, separate from overall population growth, South Asian ethnicity or requirement for ventilation.

Conclusions

An additional increase in the number of children from England and Wales admitted to PICU from 2009 onwards is not explained by a rising child population or an increased risk of admission among South Asian children. There was no evidence of a reduction in the admission criteria to PICUs. Given healthcare funding in England and Wales, continued increases would present a challenging prospect for both providers and commissioners of these services.