bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of Tube Bundle Leak Location Using the Combination of Acoustic Emission Testing and Logic Analysis
Authors: Xu Yanting , Wang Xiaowei , Wang Yadong , Xu Jiele
Published: June 2016

A large-scale equipment of a famous refining and chemical company of China had to be temporarily shut down for repairing, because one of its fractionation bottom reboiler tubes was suspected to leak. These tube bundles are densely distributed, and the outer casing of the reboiler is the fixed structure which can not be opened to check these tubes unless it is cut. The outer casing cutting for checking is very time-consuming (about 1–2 months) and costly. Possible pipe guided wave technology or endoscope method also can not be used because of acoustic attenuation from dense fins and severe corrosion of tubes or being inaccessible, so Acoustic Emission testing became the only choice for finding out the leaking tube in that time.

Also due to the significant acoustic attenuation, the traditional Acoustic Emission linear positioning method is difficult to find out leaked tubes, so the zonal localization method of acoustic sources was predominant in this test. The hydraulic test of pipelines was used to stimulate acoustic signals from leaking sources. However, the water from leaking holes will be splashed to the adjacent pipes and then drop onto pipes below, which will cause false leaking signals. For finding out the leaked tube, logic method is adopted to infer the real leaked tube complementarily. The spatial positions of all tubes and the sequences, frequencies, amplitudes and total hits of acoustic signals from all tubes monitored are considered in the analysis. Finally, the leaked tube was successfully found out in half a day by the combination of Acoustic Emission testing and logic analysis, the leaked tube was replaced and the production was resumed in the next three days.
An Examination of Motorcycle Antilock Brake Systems (ABS) in Reducing Crash Risk
Authors: Fowler Graeme F. , Ray Rose M. , Huang Su-Wei , Zhao Ke , Frank Todd A.
Published: June 2016

To prevent wheel lock up (and possible loss of control and capsize) during hard braking motorcycle manufacturers have equipped motorcycles with Antilock Brake Systems (ABS) either as an option or as standard equipment. Several studies utilizing real-world crash data have been published which estimate the effectiveness of motorcycle ABS in reducing the risk of a crash based on varying assumptions. These investigations have reported mixed results.

The present investigation relies upon the Fatality Analysis Reporting System (FARS) and the Florida police-reported crash databases to further investigate the effectiveness of motorcycle ABS by expanding upon and refining previous approaches. Notably a case-control approach is used whereby crashes involving ABS- and non-ABS-equipped motorcycles are divided into five groups with a varying likelihood that ABS will affect the risk of crashes in that group. The group of crashes with the least likelihood of being influenced by ABS is considered the control group and used as a measure of exposure to crashes. This methodology attempts to reduce any selection biases that might exist in the two motorcycle classes.

The results support the hypothesis that ABS is effective in reducing the crash risk in some crash types. However, it was found that the case-control approach does not incorporate all factors that might influence the overall effectiveness of ABS, for example, motorcycle class and operator age. Accounting for these additional factors would likely require the use of regression analyses and would benefit significantly from additional data.
Dominant Success Factors in Product Development
Authors: Wörz Ulrich , Göhlich Dietmar
Published: June 2016

The outcome of product development projects depends on a multitude of different influencing factors. Some of these factors are dominant over others. These Dominant Success Factors not only influence the outcome of product development projects significantly, but also influence other Success Factors to change, which is why they need to be given first and foremost attention by engineering management.

This paper illustrates the framework of a comprehensive Empirical Engineering Design Research study, which allowed for the identification of Dominant Success Factors, by applying it to 44 gas turbine component development projects in the industry. The collected data was analyzed using statistical methods, which provided information about the reliability of the results. Four Dominant Success Factors were identified which distinguished successful from less successful development projects: Priority of Project; Experience and Skills of Project Lead; Ratio of new Technology and Technical Complexity of Project; Awareness of Lessons Learned and State of the Art Technology Knowledge.
Application of the TRIZ Methodology in the Innovation of the FRICTORQ Test Equipment
Authors: Carneiro Rúben , Silva Luís F. , Seabra Eurico , Alves Anabela , Lima Mário
Published: June 2016

The TRIZ – ‘Teoria Rechenia Izobretatelskih Zadatchi’ (Russian acronym for ‘Theory of Inventive Problem Solving’ - TIPS) is a methodology applied for problem solving that aims to create a systematic and algorithmic way to find new design solutions and to enhance individual creativity. This methodology was created and developed by Genrikh Altshuller in the 40’s of the twentieth century in the former Soviet Union. Throughout the study of thousands of patents Altshuller discovered that independently of its field, all technologies follow the same defined principles, and that these principles could be used for solving new problems.

This paper is intended to demonstrate how the TRIZ methodology can be used in the innovation of a testing device (named FRICTORQ) designed and developed at the Department of Mechanical Engineering at the University of Minho to measure the friction coefficient in flexible materials. Throughout the study of the patterns of technical evolution described in this methodology, the authors will search for new possible evolution phases for this device, which will stimulate new ideas and the design of innovative solutions.
Biomechanical Effects of Kaempferol Treatments on the Bone Healing Process of Murine Tibia
Authors: Kim Hanjong , Han Changwan , Maidar Otgonbayar , Lee Sang-Soo , Park Seonghun
Published: June 2016

Kaempferol is a typical flavonol-type flavonoid and has a protective effect on postmenopausal bone loss, and previous studies have reported that kaempferol treated groups show an increase in the callus size and bone mineral density as well as improvement in biomechanical behaviors in comparison with untreated control groups in the bone healing process. The present study aims at investigating the effect of kaempferol treatments on fractured murine tibia, by measuring kaempferol dose-dependent mechanical properties in the bone healing process of murine tibia fracture models.

A stabilized fracture was generated at tibia by minor modification of the Hiltunen method for 8 weeks old ICR mice weighting 29.0 ∼ 30.5 g. Experimental mice were divided into 4 groups. Kaempferol of 0.2, 1.0, 5.0 mg/kg (body weight) with 20 % ethanol was administered to 3 groups and the remaining one group was only treated with 20 % ethanol as a control group. Three-point bending fracture tests were conducted to measure the mechanical properties (fracture load, fracture energy, stiffness) of murine tibiae at non-fractured regions near fracture sites 21 days after kaempferol treatments, via a custom-made biomechanical testing system (BTS, KST Co., Korea).

The 5.0 mg/kg kaempferol treated group shows higher fracture load (20.54 ±5.04 N) than the control group (17.82 ±5.94 N). Fracture energy, total energy applied to tibia up to bone fracture, exhibited no significant differences between the control group and any of the kampferol treated groups, although both the 1.0 mg/kg kaempferol treated and control groups showed a little higher fracture energy than the 0.2 and 5.0 mg/kg kaempferol treated groups. Bone stiffness also did not show statistically significant differences between the control group and any of the kaempferol treated groups, with the highest stiffness value observed in the 1.0 mg/kg kaempferol treated group.
Computational Evaluation of Incomplete Coating Coverage
Authors: DeGiorgi Virginia G. , Qidwai Siddiq M. , Kota Nithyanand
Published: June 2016

Corrosion is a major cause of removal from service for many industries. Pitting, which involves localized corrosion of metals, can result in catastrophic failures because of resulting crack initiation and failure. The transition from pit to crack is influenced by the pit shape, which in turn is affected by the microstructure of the corroding material. In this work the authors investigate the importance of understanding the construction of a coating layer that may be present over the pit mouth. The coating layer may be by-products of another activity or a repair coating meant to prevent further damage. Stable pit growth occurs under diffusion control at rate that depends upon the extent of protective coating over the opening of the pit. The two extreme cases are: 1) no cover due to total loss of coating and 2) full cover over an existing pit. The cases in between would represent break in coating cover over an evolving pit. To investigate the effect of coating loss, a parametric study based on coating coverage percentage on the metal is investigated. The coating sample length and gap length are taken to be the same for all cases. Coverage percentages of 0% (no coating), 50%, 75% and 100% (fully coated) are analyzed for a set growth time. Severe numerical complications are discovered in the course of these analyses. The movement of the corrosion front parallel to the spatially fixed coating causes considerable mesh distortion that terminates the simulation prematurely requiring an impractically large number of re-meshing steps. The computational concepts investigated will be discussed in addition to evaluating the influence of pit coverage.
Effect of Chirality and Geometry on the Young’s Modulus of Graphene Structure Using Spring Based Finite Element Approach
Authors: Al-Kharusi Moosa S. M. , Pervez Tasneem , Alz-Zebdeh Khalid
Published: June 2016

The development of nanocomposite materials has led to vast progress in the field of composite materials as well as in finding new solutions to technological problem that have not been solved yet. Among the newly developed materials, the most attracting is the graphene based nanocomposites that has superior mechanical, thermal, optical and electrical properties. The hexagonal structure and the high strength of carbon–carbon bond in graphene yield strong material. Estimation of mechanical properties of the graphene becomes one of the important issues, which should be reasonably and accurately predicted to further promote its application development. Simulation and modeling techniques play a significant role in characterizing mechanical behavior especially for nanomaterials where the experimental measurements are very difficult to conduct.

The aim of the current study is to estimate the Young’s modulus of elasticity of single layered graphene sheet using new spring based finite element approach. The use of spring finite elements help to accurately define the interatomic bonded interactions between carbon atoms based on potential energies obtained from molecular dynamics theory. The inclusion of both linear and torsion terms simultaneously has resulted in improved values of the Young’s modulus. The nodes in the finite element model define the position of carbon atoms in the graphene which are connected with appropriate spring-type elements. These elements are used to build the finite element model based on the observation that beam or truss elements require geometrical variables such as area and inertia, which are not required in the case of springs. Each node of this element provides six degrees of freedom (3 translations and 3 rotations) at which the complex interactions presented in the atomistic level can be considered. Parametric study is performed to investigate the effect of chirality and geometric parameters on the Young’s modulus of single graphene layer. The results are in good agreement with the published numerical and experimental results. The obtained results show an isotropic behavior, in contrast to limited molecular dynamic simulations. Young’s modulus of graphene shows a high dependency of stiffness on layer thickness.
Towards a Functional Definition of Sustainable Development in the Practice of Engineering
Authors: Burgess Richard A.
Published: June 2016

Sustainable development has become an increasingly common topic of both day-day conversations and in discussions about professional responsibility. In recent years, most of the professional engineering societies have moved to incorporate language about environmental responsibility, including sustainable development, into their codes of ethics. The ASME Code, for example, states that “Engineers shall consider environmental impact and sustainable development in the performance of their professional duties” (2).

Despite this increased focus on sustainable development, it remains a nebulous concept at both a theoretical and practical level. Few engineers would deny that they have a responsibility to the environment. Ask those same engineers what this responsibility means in practice and you are likely to get a variety of answers; most of which will probably be on the vague side. Of course, variation and generality are not always negative features of a professional ethic. Nevertheless, it is important to get more precise about what sustainable development looks like in practice.

In this paper, I will analyze ASME’s prescription that mechanical engineers consider their impact on the environment. I will examine how this prescription fits into the ASME Code as a whole. I will then survey several definitions of sustainable development; exploring challenges along the way. From here, I will begin developing a functional definition of sustainable development. In doing so, I will attempt to balance the demands of the principle of conservatism when spelling out professional obligations with those of moral leadership. The goal is to provide a useful and rigorous definition of sustainable development for practicing engineers. If am successful in this, this definition will lead to an operational understanding of sustainable development.
Machine Learning Classification Models for More Effective Mine Safety Inspections
Authors: Gernand Jeremy M.
Published: June 2016

The safety of mining in the United States has improved significantly over the past few decades, although it remains one of the more dangerous occupations. Following the Sago mine disaster in January 2006, federal legislation (The Mine Improvement and New Emergency Response {MINER} Act of 2006) tightened regulations and sought to strengthen the authority and safety inspection practices of the Mine Safety and Health Administration (MSHA). While penalties and inspection frequency have increased, understanding of what types of inspection findings are most indicative of serious future incidents is limited.

The most effective safety management and oversight could be accomplished by a thorough understanding of what types of infractions or safety inspection findings are most indicative of serious future personnel injuries. However, given the large number of potentially different and unique inspection findings, varied mine characteristics, and types of specific safety incidents, this question is complex in terms of the large number of potentially relevant input parameters. New regulations rely on increasing the frequency and severity of infraction penalties to encourage mining operations to improve worker safety, but without the knowledge of which specific infractions may truly be signaling a dangerous work environment.

This paper seeks to inform the question, what types of inspection findings are most indicative of serious future incidents for specific types of mining operations? This analysis utilizes publicly available MSHA databases of cited infractions and reportable incidents. These inspection results are used to train machine learning Classification and Regression Tree (CART) and Random Forest (RF) models that divide the groups of mines into peer groups based on their recent infractions and other defining characteristics with the aim of predicting whether or not a fatal or serious disabling injury is more likely to occur in the following 12-month period.

With these characteristics available, additional scrutiny may be appropriately directed at those mining operations at greatest risk of experiencing a worker fatality or disabling injury in the near future. Increased oversight and attention on these mines where workers are at greatest risk may more effectively reduce the likelihood of worker deaths and injuries than increased penalties and inspection frequency alone.
Stand-Up Forklift Egress Times as a Function of Operator Compartment Guarding
Authors: Railsback Ben T. , Ziernicki Richard M. , Nguyen Ricky L. , Knapp Steve D. , Pierce William H.
Published: June 2016

A significant hazard related to the use of stand-up lift trucks, or stand-up forklifts, is the hazard of a lower limb crush injury or foot crush due to the opening across the rear of the operator compartment. According to one lift truck manufacturer’s statistics, there have been over 500 accidents that resulted in an injury to the lower limb of the operator in the last 30 years that involved their stand-up lift trucks. [1] Other manufacturers have had similar accidents. The injuries have occurred to the lower limb of the operator due to the close proximity of the operator’s lower limbs to the exterior of the lift truck, and the confined areas that stand-up lift trucks operate in. The operator’s lower limb can become pinned and crushed between the moving lift and another fixed object such as a rack system, a column or another lift truck. Objects, such as a fork tine, can also intrude into the operator compartment, injuring the operator’s lower extremities.

The ANSI/ITSDF B56.1, Safety Standard for Low Lift and High Lift Trucks, encourages stand-up lift trucks to be designed with an open compartment to permit easy ingress and egress. [2] According to the standard, the open design allows an operator a free and easy egress from the truck in the event of a tip-over or off-the-dock accident. However, the standard permits the use of additional guarding and enclosure of the operator compartment. Spring loaded doors (or spring assisted closing guards) have been designed, implemented and are available from many manufacturers, but no data has been published regarding the time to open and egress from the operator compartment. Latching doors have also been designed and manufactured, but are not currently available on the market except in the case of trucks equipped with freezer cabs, for operation in refrigerated environments. However, latched doors have been criticized for extending the egress time duration by approximately 1/2 second.

This study shows that a spring loaded door can be implemented on a stand-up forklift while only increasing egress time by a negligible amount, 0.05 seconds over an open compartment configuration. Furthermore, this study shows that an optimized latching door, designed by Knott Laboratory engineers, can also be implemented for a stand-up forklift while only increasing egress time by 0.09 seconds. The latching door designed by Knott Laboratory decreases the change in egress time associated with a latched door by a factor of 5. Therefore, the addition of a spring loaded door, or a latching door will not significantly increase operator egress time and provide additional protection to the operator in the event of a collision while still maintaining quick egress.
Creation of Sacrificial Bonds by Viscous Flow Instability
Authors: Passieux R. , Therriault D. , Gosselin F.
Published: June 2016

The multiscale structure of spider silk is widely studied because of its superior mechanical properties. Its high tenacity allows the absorption of the kinetic energy of fast and large preys. The mechanism of sacrificial bonds enhances the stretchability and toughness of spider capture-silk. With this in mind, we fabricate microstructured fibers with sacrificial bonds using the dragged viscous thread instability. A thread of viscous liquid flowing towards a perpendicular moving platform buckles repetitively and creates different periodical patterns. A solution of 25% polylactid acid (PLA) dissolved in the dichloromethane (DCM) is extruded from a 30μm diameter needle onto a moving platform. By decreasing the speed ratio between the thread extrusion speed and the platform moving speed, we obtain different instability patterns: catenary, meandering, alternating (loop falling on alternate sides of the main thread), and coiling (all the loops falling on the same side). The spatial frequency of the periodical patterns linearly increases with the speed ratio until overlapping occurs. When the thread loops on itself, it welds and fuses with itself to form a bond which solidifies as the solvent evaporates and the thread dries. Different fiber patterns are tested in an electromechanical tensile machine and their performance are compared to a straight fiber. Sacrificial bonds require significant energy to break (i.e., ranging between 0 to 110% of the yield value of a straight fiber). Finally by controlling the instability parameters, we are able to tailor the mechanical properties of the resulting fibers such as its breaking strain, rigidity and toughness which could lead to different protective wear applications.
Thermofluid Analysis of the Magnetocaloric Refrigeration
Authors: Momen Ayyoub Mehdizadeh , Abdelaziz Omar , Gluesenkamp Kyle , Vineyard Edward , Benedict Michael
Published: June 2016

While there have been extensive studies on thermofluid characteristics of different magnetocaloric refrigeration systems, a conclusive optimization study using non-dimensional parameters which can be applied to a generic system has not been reported yet. In this study, a numerical model has been developed for optimization of active magnetic refrigerator (AMR). This model is computationally efficient and robust, making it appropriate for running the thousands of simulations required for parametric study and optimization. The governing equations have been non-dimensionalized and numerically solved using finite difference method. A parametric study on a wide range of non-dimensional numbers has been performed. While the goal of AMR systems is to improve the performance of competitive parameters including COP, cooling capacity and temperature span, new parameters called “AMR performance index-1” have been introduced in order to perform multi objective optimization and simultaneously exploit all these parameters. The multi-objective optimization is carried out for a wide range of the non-dimensional parameters. The results of this study will provide general guidelines for designing high performance AMR systems.
BLEVE Energy and Aerosol Formation: An Exergy Analysis
Authors: Ramirez Juan C. , Smyth Suzanne A. , Ogle Russell A.
Published: June 2016

The hazards from a boiling liquid expanding vapor explosion (BLEVE) include the formation of a blast wave and the projection of missiles. To understand the maximum work that can be obtained from a BLEVE, the authors have investigated in previous publications certain aspects of BLEVE behavior using exergy analysis. One of the key limitations in relating exergy calculations to more realistic behavior is the lack of knowledge of how the exergy of the explosion is partitioned into various types of work that occur in the BLEVE process. Some of these work terms include the formation and propagation of a shock wave, the strain work of vessel deformation and rupture into missiles, the initial kinetic energy of the missiles, and the surface work of aerosol droplet formation. In this paper we explore one of these work terms, the surface work performed in transforming the bulk liquid into aerosol droplets. The advantage of using exergy analysis to evaluate the maximum work of an explosion is that exergy is a state variable: its value depends only on the initial conditions of the high pressure fluid and the specification of the dead state. The methodology is illustrated for several pure component fluids.
Utilization of Flax Fibers and Glass Fibers in a Bio-Based Resin
Authors: Hosseini Nassibeh , Ulven Chad A. , Azarmi Fardad , Webster Dean C. , Nelson Thomas J.
Published: June 2016

A novel highly functional plant oil-based polyols, Methoxylated Sucrose Soyate Polyols (MSSP), were cross-linked with isocyanate to formulate MSSP-based polyurethane (PU) thermosets. The degree of cure or conversion was studied using differential scanning calorimetry (DSC). Compression molding process was used to make composite panels out of MSSP-based polyurethane and flax fiber reinforcement of about 50 vol %. The MSSP-based PU resin reinforced with 50 vol % unidirectional E-glass fiber mats was tested as a reference. The composites were cured at 150°C for 60 minutes. Properties of the MSSP-based PU thermosets and its corresponding flax/glass-fiber reinforced thermoset composites were assessed by tensile strength and modulus, flexural strength and modulus, interlaminar shear strength (ILSS), nanoindentation test, and impact strength. Specific tensile modulus and strength of the flax fiber composites were found to compare with those of glass/MSSP-based PU. The glass/MSSP-based PU composite exhibited superior mechanical properties compared to both bio-based and petroleum-based composites used in previous studies. Compared to soybean oil based composites used in previous studies, bio-based composites based on MSSP showed 70 % and 101 % increase in flexural strength and modulus respectively, 102 % and 93 % increase in tensile strength and modulus respectively, and 56 % increase in ILSS. Compared to petroleum-based PU/glass composites used in previous studies, bio-based composites based on MSSP showed 60 % and 40 % increase in flexural strength and modulus respectively, 102 % and 78 % increase in tensile strength and modulus respectively, 50 % increase in ILSS. Higher mechanical properties in MSSP-based PU composites can be attributed to high functionality, rigid and compact chemical structures of MSSP oligomers in polyol resin.
Reliability Evaluation for Biomechanics Transient Stresses: Case Study of Biological Cell Vitality in Freezing Process
Authors: Amirpourabasi Arezoo , Pourgol-Mohammad Mohammad , Niroomand-Oscuii Hanieh
Published: June 2016

This research proposes reliability evaluation for performance of biological transient mechanical stresses scenarios. This is part of a broader research done by the authors for comprehensive analysis of the biological reliability analysis [1]. A literature review is conducted in area of biomechanics phenomenological processes in order to classify the approaches for success criteria determination and reliability metrics calculation based on their merits and limitations. A limited failure mode and effect analysis is performed as a pre-processor for identification of the corresponding figure of merits. Biological environment is complex in correlated occurrence of microscopic and macroscopic phenomena. Therefore the modeling of this complex medium, in context of mechanical stresses, requires numerical solution of conservation equation and inclusion of corresponding constitution models. Determination of success criteria (first phase for reliability calculation in this research) is a challenging object, and requires consideration of several dependent figures of merits (e.g. temperature, mass and etc.).

The developed success criteria matrix is based on the approaches of representation of the figures of merit. A multi-objective criteria is developed according to the phenomena occurrence in the intended study and the selected proper figure(s) of merit. The matrix determines the region of acceptance as well as the rejection area. The reliability index is proposed to estimate the probability of the success based on the calculated system performance in a non-deterministic (stochastic parameters) approach. By augmentation of developed success criteria and the system analysis calculation, a decision is made on the success and rejection of the system performance the methodology is applied to the case of cell cryopreservation phenomenon. The process of freezing in living cells is considerably more complicated than in a solution, primarily due to the presence of cellular structure. The process is considered a transient mechanical stress on the cell structure including the thermal and mass transport. The success criteria is determined based on two figures of merit of temperature and mass and their rate of change. Numerical calculation is completed for study of thermal and mass behavior for the transient of the cell. The uncertain parameters are considered random and Monte Carlo simulation is conducted for inclusion of their variation in the calculation. The situation are specified for the observation of the success criteria and occurrence of the failure.
Risk Assessment of Emergency Diesel Generator Subject to Design Basis Earthquake Shaking
Authors: Uriz Patxi , Morgan Troy A.
Published: June 2016

A monitoring system intended to track vibrations associated with the electric generation of an emergency diesel generator (EDG) at a nuclear power plant was originally installed to trip generators during potential out-of-balance shaking. Years after original installation, plant engineers raised questions as to whether the monitoring system would have functioned properly in the event of excessive vibrations associated with earthquake ground shaking. As part of the plant’s examination of this issue, analytical models were developed for three vibration transducers via experimental characterization. A suite of ground motion records were selected and scaled such that their mean and dispersion was representative of the design basis event (DBE) level of intensity at the plant site. The scaled suite of ground motions was used as an input for a three-dimensional analytical model representing the structure and soil-foundation interface where the EDGs were installed. The voltage signal from the analytical transducer model provided input to the physical vibration alarm monitor. This monitor filters the vibration transducer signal and generates an output to a time delay relay that will trip the EDG if the output from the vibration monitor is not reset within five seconds. The analysis and testing completed and described in this paper concluded that a DBE would not have caused the vibration monitoring circuit to spuriously trip the EDGs.
Science Signaling
Podcast for 7 June 2016: Modeling signal integration
Authors: Janes Kevin A. , VanHook Annalisa M.
Published: June 2016

A statistical modeling approach revealed a mechanism by which insulin signaling can suppress inflammatory signaling.
Physiologically Based Pharmacokinetic Model of Rifapentine and 25-Desacetyl Rifapentine Disposition in Humans
Authors: Zurlinden Todd J. , Eppers Garrett J. , Reisfeld Brad
Published: June 2016

Rifapentine (RPT) is a rifamycin antimycobacterial and, as part of a combination therapy, is indicated for the treatment of pulmonary tuberculosis (TB) caused by
Mycobacterium tuberculosis
. Although the results from a number of studies indicate that rifapentine has the potential to shorten treatment duration and enhance completion rates compared to other rifamycin agents utilized in antituberculosis drug regimens (i.e., regimens 1 to 4), its optimal dose and exposure in humans are unknown. To help inform such an optimization, a physiologically based pharmacokinetic (PBPK) model was developed to predict time course, tissue-specific concentrations of RPT and its active metabolite, 25-desacetyl rifapentine (dRPT), in humans after specified administration schedules for RPT. Starting with the development and verification of a PBPK model for rats, the model was extrapolated and then tested using human pharmacokinetic data. Testing and verification of the models included comparisons of predictions to experimental data in several rat tissues and time course RPT and dRPT plasma concentrations in humans from several single- and repeated-dosing studies. Finally, the model was used to predict RPT concentrations in the lung during the intensive and continuation phases of a current recommended TB treatment regimen. Based on these results, it is anticipated that the PBPK model developed in this study will be useful in evaluating dosing regimens for RPT and for characterizing tissue-level doses that could be predictors of problems related to efficacy or safety.
Substrate Inhibition of VanA byd-Alanine Reduces Vancomycin Resistance in a VanX-Dependent Manner
Authors: van der Aart Lizah T. , Lemmens Nicole , van Wamel Willem J. , van Wezel Gilles P.
Published: June 2016

The increasing resistance of clinical pathogens against the glycopeptide antibiotic vancomycin, a last-resort drug against infections with Gram-positive pathogens, is a major problem in the nosocomial environment. Vancomycin inhibits peptidoglycan synthesis by binding to thed-Ala–d-Ala terminal dipeptide moiety of the cell wall precursor lipid II. Plasmid-transferable resistance is conferred by modification of the terminal dipeptide into the vancomycin-insensitive variantd-Ala–d-Lac, which is produced by VanA. Here we show that exogenousd-Ala competes withd-Lac as a substrate for VanA, increasing the ratio of wild-type to mutant dipeptide, an effect that was augmented by several orders of magnitude in the absence of thed-Ala–d-Ala peptidase VanX. Liquid chromatography-mass spectrometry (LC-MS) analysis showed that high concentrations ofd-Ala led to the production of a significant amount of wild-type cell wall precursors, whilevanX-null mutants produced primarily wild-type precursors. This enhanced the efficacy of vancomycin in the vancomycin-resistant model organismStreptomyces coelicolor, and the susceptibility of vancomycin-resistant clinical isolates ofEnterococcus faecium(VRE) increased by up to 100-fold. The enhanced vancomycin sensitivity ofS. coelicolorcells correlated directly to increased binding of the antibiotic to the cell wall. Our work offers new perspectives for the treatment of diseases associated with vancomycin-resistant pathogens and for the development of drugs that target vancomycin resistance.
Development and Evaluation of a Gentamicin Pharmacokinetic Model That Facilitates Opportunistic Gentamicin Therapeutic Drug Monitoring in Neonates and Infants
Authors: Germovsek Eva , Kent Alison , Metsvaht Tuuli , Lutsar Irja , Klein Nigel , Turner Mark A. , Sharland Mike , Nielsen Elisabet I. , Heath Paul T. , Standing Joseph F.
Published: June 2016

Trough gentamicin therapeutic drug monitoring (TDM) is time-consuming, disruptive to neonatal clinical care, and a patient safety issue. Bayesian models could allow TDM to be performed opportunistically at the time of routine blood tests. This study aimed to develop and prospectively evaluate a new gentamicin model and a novel Bayesian computer tool (neoGent) for TDM use in neonatal intensive care. We also evaluated model performance for predicting peak concentrations and the area under the concentration-time curve from time 0 h to timeth (AUC0–t). A pharmacokinetic meta-analysis was performed on pooled data from three studies (1,325 concentrations from 205 patients). A 3-compartment model was used with the following covariates: allometric weight scaling, postmenstrual and postnatal age, and serum creatinine concentration. Final parameter estimates (standard errors) were as follows: clearance, 6.2 (0.3) liters/h/70 kg of body weight; central volume (V), 26.5 (0.6) liters/70 kg; intercompartmental disposition (Q), 2.2 (0.3) liters/h/70 kg; peripheral volume V2, 21.2 (1.5) liters/70 kg; intercompartmental disposition (Q2), 0.3 (0.05) liters/h/70 kg; peripheral volume V3, 148 (52.0) liters/70 kg. The model's ability to predict trough concentrations from an opportunistic sample was evaluated in a prospective observational cohort study that included data from 163 patients and 483 concentrations collected in five hospitals. Unbiased trough predictions were obtained; the median (95% confidence interval [CI]) prediction error was 0.0004 (−1.07, 0.84) mg/liter. Results also showed that peaks and AUC0–tvalues could be predicted (from one randomly selected sample) with little bias but relative imprecision, with median (95% CI) prediction errors being 0.16 (−4.76, 5.01) mg/liter and 10.8 (−24.9, 62.2) mg · h/liter, respectively. neoGent was implemented in R/NONMEM and in the freely available TDMx software.
Role of Iron Uptake Systems in Pseudomonas aeruginosa Virulence and Airway Infection
Authors: Minandri Fabrizia , Imperi Francesco , Frangipani Emanuela , Bonchi Carlo , Visaggio Daniela , Facchini Marcella , Pasquali Paolo , Bragonzi Alessandra , Visca Paolo
Published: June 2016

Pseudomonas aeruginosa
is a leading cause of hospital-acquired pneumonia and chronic lung infections in cystic fibrosis patients. Iron is essential for bacterial growth, and
P. aeruginosa
expresses multiple iron uptake systems, whose role in lung infection deserves further investigation.
P. aeruginosa
Fe
3+
uptake systems include the pyoverdine and pyochelin siderophores and two systems for heme uptake, all of which are dependent on the TonB energy transducer.
P. aeruginosa
also has the FeoB transporter for Fe
2+
acquisition. To assess the roles of individual iron uptake systems in
P. aeruginosa
lung infection, single and double deletion mutants were generated in
P. aeruginosa
PAO1 and characterized
in vitro
, using iron-poor media and human serum, and
in vivo
, using a mouse model of lung infection. The iron uptake-null mutant (
tonB1 feoB
) and the Fe
3+
transport mutant (
tonB1
) did not grow aerobically under low-iron conditions and were avirulent in the mouse model. Conversely, the wild type and the
feoB
,
hasR phuR
(heme uptake), and
pchD
(pyochelin) mutants grew
in vitro
and caused 60 to 90% mortality in mice. The pyoverdine mutant (
pvdA
) and the siderophore-null mutant (
pvdA pchD
) grew aerobically in iron-poor media but not in human serum, and they caused low mortality in mice (10 to 20%). To differentiate the roles of pyoverdine in iron uptake and virulence regulation, a
pvdA fpvR
double mutant defective in pyoverdine production but expressing wild-type levels of pyoverdine-regulated virulence factors was generated. Deletion of
fpvR
in the
pvdA
background partially restored the lethal phenotype, indicating that pyoverdine contributes to the pathogenesis of
P. aeruginosa
lung infection by combining iron transport and virulence-inducing capabilities.
Burkholderia mallei CLH001 Attenuated Vaccine Strain Is Immunogenic and Protects against Acute Respiratory Glanders
Authors: Hatcher Christopher L. , Mott Tiffany M. , Muruato Laura A. , Sbrana Elena , Torres Alfredo G.
Published: June 2016

Burkholderia mallei
is the causative agent of glanders, an incapacitating disease with high mortality rates in respiratory cases. Its endemicity and ineffective treatment options emphasize its public health threat and highlight the need for a vaccine. Live attenuated vaccines are considered the most viable vaccine strategy for
Burkholderia
, but single-gene-deletion mutants have not provided complete protection. In this study, we constructed the select-agent-excluded
B. mallei
Δ
tonB
Δ
hcp1
(CLH001) vaccine strain and investigated its ability to protect against acute respiratory glanders. Here we show that CLH001 is attenuated, safe, and effective at protecting against lethal
B. mallei
challenge. Intranasal administration of CLH001 to BALB/c and NOD SCID gamma (NSG) mice resulted in complete survival without detectable colonization or abnormal organ histopathology. Additionally, BALB/c mice intranasally immunized with CLH001 in a prime/boost regimen were fully protected against lethal challenge with the
B. mallei
lux
(CSM001) wild-type strain.
Transcription of Sialic Acid Catabolism Genes in Corynebacterium glutamicum Is Subject to Catabolite Repression and Control by the Transcriptional Repressor NanR
Authors: Uhde Andreas , Brühl Natalie , Goldbeck Oliver , Matano Christian , Gurow Oksana , Rückert Christian , Marin Kay , Wendisch Volker F. , Krämer Reinhard , Seibold Gerd M.
Published: June 2016

Corynebacterium glutamicum
metabolizes sialic acid (Neu5Ac) to fructose-6-phosphate (fructose-6P) via the consecutive activity of the sialic acid importer SiaEFGI,
N
-acetylneuraminic acid lyase (NanA),
N
-acetylmannosamine kinase (NanK),
N
-acetylmannosamine-6P epimerase (NanE),
N
-acetylglucosamine-6P deacetylase (NagA), and glucosamine-6P deaminase (NagB). Within the cluster of the three operons
nagAB
,
nanAKE
, and
siaEFGI
for Neu5Ac utilization a fourth operon is present, which comprises
cg2936
, encoding a GntR-type transcriptional regulator, here named NanR. Microarray studies and reporter gene assays showed that
nagAB
,
nanAKE
,
siaEFGI
, and
nanR
are repressed in wild-type (WT)
C. glutamicum
but highly induced in a Δ
nanR C. glutamicum
mutant. Purified NanR was found to specifically bind to the nucleotide motifs A[AC]G[CT][AC]TGATGTC[AT][TG]ATGT[AC]TA located within the
nagA-nanA
and
nanR-sialA
intergenic regions. Binding of NanR to promoter regions was abolished in the presence of the Neu5Ac metabolism intermediates GlcNAc-6P and
N
-acetylmannosamine-6-phosphate (ManNAc-6P). We observed consecutive utilization of glucose and Neu5Ac as well as fructose and Neu5Ac by WT
C. glutamicum
, whereas the deletion mutant
C. glutamicum
Δ
nanR
simultaneously consumed these sugars. Increased reporter gene activities for
nagAB
,
nanAKE
, and
nanR
were observed in cultivations of WT
C. glutamicum
with Neu5Ac as the sole substrate compared to cultivations when fructose was present. Taken together, our findings show that Neu5Ac metabolism in
C. glutamicum
is subject to catabolite repression, which involves control by the repressor NanR.

IMPORTANCE
Neu5Ac utilization is currently regarded as a common trait of both pathogenic and commensal bacteria. Interestingly, the nonpathogenic soil bacterium
C. glutamicum
efficiently utilizes Neu5Ac as a substrate for growth. Expression of genes for Neu5Ac utilization in
C. glutamicum
is here shown to depend on the transcriptional regulator NanR, which is the first GntR-type regulator of Neu5Ac metabolism not to use Neu5Ac as effector but relies instead on the inducers GlcNAc-6P and ManNAc-6P. The identification of conserved NanR-binding sites in intergenic regions within the operons for Neu5Ac utilization in pathogenic
Corynebacterium
species indicates that the mechanism for the control of Neu5Ac catabolism in
C. glutamicum
by NanR as described in this work is probably conserved within this genus.
Comparing cognitive-behavioural psychotherapy and psychoeducation for non-specific symptoms associated with indoor air: a randomised control trial protocol
Authors: Selinheimo Sanna , Vuokko Aki , Sainio Markku , Karvala Kirsi , Suojalehto Hille , Järnefelt Heli , Paunio Tiina
Published: June 2016

Introduction

Indoor air-related conditions share similarities with other conditions that are characterised by medically unexplained symptoms (MUS)-a combination of non-specific symptoms that cannot be fully explained by structural bodily pathology. In cases of indoor air-related conditions, these symptoms are not fully explained by either medical conditions or the immunological–toxicological effects of environmental factors. The condition may be disabling, including a non-adaptive health behaviour. In this multifaceted phenomenon, psychosocial factors influence the experienced symptoms. Currently, there is no evidence of clinical management of symptoms, which are associated with the indoor environment and cannot be resolved by removing the triggering environmental factors. The aim of this study is to compare the effect of treatment-as-usual (TAU) and two psychosocial interventions on the quality of life, and the work ability of employees with non-specific indoor air-related symptomatology.

Methods and analyses

The aim of this ongoing randomised controlled trial is to recruit 60 participants, in collaboration with 5 occupational health service units. The main inclusion criterion is the presence of indoor air-related recurrent symptoms in ≥2 organ systems, which have no pathophysiological explanation. After baseline clinical investigations, participants are randomised into interventions, which all include TAU: cognitive-behavioural psychotherapy, psychoeducation and TAU (control condition). Health-related quality of life, measured using the 15D-scale, is the primary outcome. Secondary outcomes include somatic and psychiatric symptoms, occupational factors, and related underlying mechanisms (ie, cognitive functioning). Questionnaires are completed at baseline, at 3, 6 and 12-month follow-ups. Data collection will continue until 2017. The study will provide new information on the individual factors related to indoor air-associated symptoms, and on ways in which to support work ability.

Ethics and dissemination

The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa, Finland, has granted approval for the study. The results will be published in peer-reviewed journals.

Trial registration number

NCT02069002; Pre-results.
Improving physical health for people taking antipsychotic medication in the Community Learning Disabilities Service
Authors: Thomson Helen , Hall Ian , Shah Amar
Published: June 2016

Adherence with antipsychotic monitoring guidelines is notoriously low nationally. Without active monitoring and measures to improve metabolic abnormalities, more patients may develop related morbidity and mortality. An audit highlighted antipsychotic monitoring in this learning disability service in London did not match guideline recommendations. People with intellectual disability also experience health inequalities. Psychiatrists are well placed to provide advice and assistance that is suitable for those with complex communication, behaviour, and social needs.

The QI team tested ideas to increase rates of antipsychotic reviews. The focus was the follow up monitoring of all universal measures recommended by NICE 2014, collected at 2-weekly intervals. We trialled interventions in four broad categories; Intervention 1: to make monitoring more structured and planned; Intervention 2: to increase staff and patient awareness of healthy eating and exercise programs; Intervention 3: to increase the collection of diet and exercise histories from patients; Intervention 4: to improve the uptake of blood tests.

The interventions created an improvement in monitoring. There are lessons in the methodology for others carrying out similar projects.