bluuebunny/crossref_metadata_2025 huggingface dataset:
Validity of physical activity and cardiorespiratory fitness in the Danish cohort “Diet, Cancer and Health‐Next Generations”
Authors: Lerche L. , Olsen A. , Petersen K. E. N. , Rostgaard‐Hansen A. L. , Dragsted L. O. , Nordsborg N. B. , Tjønneland A. , Halkjær J.
Published: March 2017

Valid assessments of physical activity (PA) and cardiorespiratory fitness (CRF) are essential in epidemiological studies to define dose‐response relationship for formulating thorough recommendations of an appropriate pattern of PA to maintain good health. The aim of this study was to validate the Danish step test, the physical activity questionnaire Active‐Q, and self‐rated fitness against directly measured maximal oxygen uptake (VO2max). A population‐based subsample (n=125) was included from the “Diet, Cancer and Health‐Next Generations” (DCH‐NG) cohort which is under establishment. Validity coefficients, which express the correlation between measured and “true” exposure, were calculated, and misclassification across categories was evaluated. The validity of the Danish step test was moderate (women: r=.66, and men: r=.56); however, men were systematically underestimated (43% misclassification). When validating the questionnaire‐derived measures of PA, leisure‐time physical activity was not correlated with VO2max. Positive correlations were found for sports overall, but these were only significant for men: total hours per week of sports (r=.26), MET‐hours per week of sports (r=.28) and vigorous sports (0.28) alone were positively correlated with VO2max. Finally, the percentage of misclassification was low for self‐rated fitness (women: 9% and men: 13%). Thus, self‐rated fitness was found to be a superior method to the Danish step test, as well as being less cost prohibitive and more practical than the VO2max method. Finally, even if correlations were low, they support the potential for questionnaire outcomes, particularly sports, vigorous sports, and self‐rated fitness to be used to estimate CRF.
Shadow analysis via the C+K Visioline: A technical note
Authors: Houser T. , Zerweck C. , Grove G. , Wickett R.
Published: March 2017

Background/purpose

This research investigated the ability of shadow analysis (via the Courage + Khazaka Visioline and Image Pro Premiere 9.0 software) to accurately assess the differences in skin topography associated with photo aging.

Methods

Analyses were performed on impressions collected from a microfinish comparator scale (GAR Electroforming) as well a series of impressions collected from the crow's feet region of 9 women who represent each point on the Zerweck Crow's Feet classification scale. Analyses were performed using a Courage + Khazaka Visioline VL 650 as well as Image Pro Premiere 9.0 software.

Results

Shadow analysis showed an ability to accurately measure the groove depth when measuring impressions collected from grooves of known depth. Several shadow analysis parameters showed a correlation with the expert grader ratings of crow's feet when averaging measurements taken from the North and South directions. The Max Depth parameter in particular showed a strong correlation with the expert grader's ratings which improved when a more sophisticated analysis was performed using Image Pro Premiere.

Conclusion

When used properly, shadow analysis is effective at accurately measuring skin surface impressions for differences in skin topography. Shadow analysis is shown to accurately assess the differences across a range of crow's feet severity correlating to a 0‐8 grader scale. The Visioline VL 650 is a good tool for this measurement, with room for improvement in analysis which can be achieved through third party image analysis software.
C9orf72: At the intersection of lysosome cell biology and neurodegenerative disease
Authors: Amick Joseph , Ferguson Shawn M.
Published: March 2017

The discovery that expansion of a hexanucleotide repeat within a noncoding region of the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia raised questions about C9orf72 protein function and potential disease relevance. The major predicted structural feature of the C9orf72 protein is a DENN (differentially expressed in normal and neoplastic cells) domain. As DENN domains are best characterized for regulation of specific Rab GTPases, it has been proposed that C9orf72 may also act through regulation of a GTPase target. Recent genetic and cell biological studies furthermore indicate that the C9orf72 protein functions at lysosomes as part of a larger complex that also contains the Smith‐Magenis chromosome region 8 (SMCR8) and WD repeat‐containing protein 41 (WDR41) proteins. An important role for C9orf72 at lysosomes is supported by defects in lysosome morphology and mTOR complex 1 (mTORC1) signaling arising from C9orf72 KO in diverse model systems. Collectively, these new findings define a C9orf72‐containing protein complex and a lysosomal site of action as central to C9orf72 function and provide a foundation for the elucidation of direct physiological targets for C9orf72. Further elucidation of mechanisms whereby C9orf72 regulates lysosome function will help to determine how the reductions in C9orf72 expression levels that accompany hexanucleotide repeat expansions contribute to disease pathology.
Treatment of supraventricular tachycardia in a horse
Authors: Whelchel Dorothy D. , Tennent‐Brown Brett S. , Coleman Amanda E. , Rapoport Gregg S. , Blas‐Machado Uriel , Maisenbacher Herbert W. , Credille Brenton C. , Giguère Steeve
Published: March 2017

Objective

To describe the treatment of persistent supraventricular tachycardia (SVT) in a young horse in endurance training.

Case Summary

A 6‐year‐old Arab gelding in endurance training presented for a dysrhythmia and decreased performance. SVT was diagnosed and conversion to a normal sinus rhythm was achieved following administration of a constant rate infusion of amiodarone. However, reversion to SVT occurred shortly after initiation of ridden exercise. A second attempt to convert the dysrhythmia with amiodarone failed, but normal sinus rhythm was achieved with transvenous electrical cardioversion (TVEC). Postmortem examination of the heart revealed extensive fibrous replacement of most of the left atrial myocardium; these changes likely provided the structural substrate for the dysrhythmia. The underlying cause of the fibrosis was not identified.

New or Unique Information Provided

SVT is a form of supraventricular tachyarrhythmia rarely diagnosed in the horse. A recent report has described sudden death of a horse following attempted conversion of SVT with oral flecainide acetate. In the present report, we describe short‐term conversion of SVT in a horse using intravenous amiodarone with no significant adverse effects. When the dysrhythmia recurred, the animal was donated for teaching purposes and conversion was achieved with TVEC. Normal sinus rhythm persisted for 2 weeks until the horse was euthanized for postmortem evaluation of the heart. Intravenous amiodarone or TVEC could be considered as treatments for supraventricular tachyarrhyhmias other than atrial fibrillation in the horse.
Effectiveness of an Online Educational Module in Improving Evidence‐Based Practice Skills of Practicing Registered Nurses
Authors: Moore Lora
Published: March 2017

Background

Implementation of evidence‐based practice (EBP) at the bedside has been difficult to achieve. Significant gaps between current research and actual practice have been identified and must be addressed in effort to increase utilization of EBP.

Aims

The purpose of this study was to evaluate the efficacy of an online EBP educational intervention and to examine the relationship between educational preparation and years of nursing experience on nurses’ practice, attitudes, and knowledge and skills of EBP.

Methods

An experimental pretest‐posttest design study with three randomized groups utilizing the EBPQ instrument was conducted.

Results

No significant differences were noted in EBPQ subscale scores of practice, attitude, or knowledge and skills from pre‐ to posttest. In addition, no statistical difference in EBPQ subscale scores regarding educational preparation or years of experience were noted.

Linking Evidence to Practice

While nurses report positive attitudes toward EBP, their perceptions of practice and knowledge and skills score much lower. Educational interventions are needed for practicing nurses to overcome this knowledge deficit to successfully implement EBP. However, the use of online, independent, computer‐based learning modules, while cost‐efficient and offer several benefits when educating nurses, may not necessarily be the most effective method for teaching EBP knowledge and skills to practicing nurses.
Role of Tuition Centers in the Performance and Achievement of Students: A Case of Hyderabad District, Sindh, Pakistan
Authors: Sahito Zafarullah , Khawaja Mumtaz , Siddiqui Abida , Shaheen Anjum , Saeed Humera
Published: March 2017

This research is designed to explore the importance of tuition centers in the perception of students. It tries to find out the role, supporting methods, environment and good characteristics of tuition centers, their owners and management to support the student to learn effectively and bring good grades in their board examinations. A qualitative research method employed to collect data from the 30 participating students who receive tuition at different centers of Hyderabad district. Semi-structured interview protocol was design; discussed with five experts of field; improved as per suggestions of field experts; piloted on three students; and then implemented and conducted on the recruited sample of students of class Higher Secondary Certificate -II (XII) in order to collect data. The results revealed that the students who receive tuition at different centers bring good grades in their examination and have suitable knowledge about their subjects taught at centers. Their previous grades were found good and attractive such as A-1 and A with more than 80% and 70% marks respectively, due to coaching received at tuition centers that time, reveled from experiences shared by students.
Steering a Chaplygin Sleigh Using Periodic Impulses
Authors: Tallapragada Phanindra , Fedonyuk Vitaliy
Published: March 2017

The control of the motion of nonholonomic systems is of practical importance from the perspective of robotics. In this paper, we consider the dynamics of a cartlike system that is both propelled forward by motion of an internal momentum wheel. This is a modification of the Chaplygin sleigh, a canonical nonholonomic system. For the system considered, the momentum wheel is the sole means of locomotive thrust as well the only control input. We first derive an analytical expression for the change in the heading angle of the sleigh as a function of its initial velocity and angular velocity. We use this solution to design an open-loop control strategy that changes the orientation of sleigh to any desired angle. The algorithm utilizes periodic impulsive torque inputs via the motion of the momentum wheel.
A Modified Two-Timescale Incremental Harmonic Balance Method for Steady-State Quasi-Periodic Responses of Nonlinear Systems
Authors: Ju R. , Fan W. , Zhu W. D. , Huang J. L.
Published: March 2017

A modified two-timescale incremental harmonic balance (IHB) method is introduced to obtain quasi-periodic responses of nonlinear dynamic systems with combinations of two incommensurate base frequencies. Truncated Fourier coefficients of residual vectors of nonlinear algebraic equations are obtained by a frequency mapping-fast Fourier transform procedure, and complex two-dimensional (2D) integration is avoided. Jacobian matrices are approximated by Broyden's method and resulting nonlinear algebraic equations are solved. These two modifications lead to a significant reduction of calculation time. To automatically calculate amplitude–frequency response surfaces of quasi-periodic responses and avoid nonconvergent points at peaks, an incremental arc-length method for one timescale is extended for quasi-periodic responses with two timescales. Two examples, Duffing equation and van der Pol equation with quadratic and cubic nonlinear terms, both with two external excitations, are simulated. Results from the modified two-timescale IHB method are in excellent agreement with those from Runge–Kutta method. The total calculation time of the modified two-timescale IHB method can be more than two orders of magnitude less than that of the original quasi-periodic IHB method when complex nonlinearities exist and high-order harmonic terms are considered.
A Thermal Model to Predict Tool Temperature in Machining of Ti–6Al–4V Alloy With an Atomization-Based Cutting Fluid Spray System
Authors: Tanveer Asif , Marla Deepak , Kapoor Shiv G.
Published: March 2017

In this study, a heat transfer model of machining of Ti–6Al–4V under the application of atomization-based cutting fluid (ACF) spray coolant is developed to predict the temperature of the cutting tool. Owing to high tool temperature involved in machining of Ti–6Al–4V, the model considers film boiling as the major heat transfer phenomenon. In addition, the design parameters of the spray for effective cooling during machining are derived based on droplet–surface interaction model. Machining experiments are conducted and the temperatures are recorded using the inserted thermocouple technique. The experimental data are compared with the model predictions. The temperature field obtained is comparable to the experimental results, confirming that the model predicts tool temperature during machining with ACF spray cooling satisfactorily.
Frequency Domain Updating of Thin-Walled Workpiece Dynamics Using Reduced Order Substructuring Method in Machining
Authors: Tuysuz Oguzhan , Altintas Yusuf
Published: March 2017

The structural dynamics of thin-walled parts vary as the material is removed during machining. This paper presents a new, computationally efficient reduced order dynamic substructuring method to predict the frequency response function (FRF) of the workpiece as the material is removed along the toolpath. The contribution of the removed mass to the dynamics of the workpiece is canceled by adding a fictitious substructure having the opposite dynamics of the removed material. The equations of motion of the workpiece are updated, and workpiece FRFs are evaluated by solving the hybrid set of assembled equations of motion in frequency domain as the tool removes the material between two consecutive dynamics update steps. The orders of the initial workpiece structure and the removed substructures are reduced using a model order reduction method with a newly introduced automatic master set selection criterion. The reduced order FRF update model is validated with peripheral milling tests and FRF measurements on a plate-shaped workpiece. It is shown that the proposed model provides ∼20 times faster FRF predictions than the full order finite element (FE) model.
Mapping Software Augments Engineering Design Thinking
Authors: Eng Nathan , Aurisicchio Marco , Bracewell Rob
Published: March 2017

Maps are visual design representations used by engineers to model the information behind a design. This paper evaluates the application of mapping methods supported by the Decision Rationale editor (DRed) in aerospace engineering industry. Specifically, the research investigates what DRed mapping methods are used, where engineers find them useful and why. DRed was selected because it has been formally embedded in the design processes of the partner company and all engineering staff have access to it. The tool was investigated using semistructured interviews with 14 engineers, each already trained with DRed through their work and representing diverse departments and experience levels. Nineteen use cases were collected, ranging from high-profile, multistakeholder projects to everyday individual work. Collected cases were analyzed for the methods applied, common contexts of use, and reasons for use. The results validate baseline DRed mapping methods to capture design rationale and analyze the root causes of engineering problems. Further, it provides empirical evidence for new DRed mapping methods to manage requirements, analyze functional interactions in complex systems and manage personal information. The contexts where mapping methods are most used involve: system-level information that cuts across subsystem boundaries; irregular intervals between map applications; dealing with loosely structured information; individual use or small team collaborations; and addressing on-going problems. The reasons stated by engineers for using maps focus on engineering design thinking, communication, and planning support. Using empirical evidence of its recurrent use, this research establishes that DRed is a powerful and versatile tool for engineers in industry and its mapping methods aid important and otherwise unsupported work. The range and impact of the use cases found in practice suggest that engineers need better support for work with loosely structured information. Organizations involved in the design of complex systems should make greater use of semiformal, graph-based visual tools like DRed. The understanding of mapping software gained through this research demonstrates a shift in emphasis from the enrichment of the engineering record to the provision of immediate cognitive benefits for engineers. The results also support an incremental, adaptive approach for deploying this emerging class of tools in other organizations.
Searching Multibranch Propagation Paths of Assembly Variation Based on Geometric Tolerances and Assembly Constraints
Authors: Zhang Zhiqiang , Liu Jianhua , Ding Xiaoyu , Jiang Ke , Bao Qiangwei
Published: March 2017

Assembly variation should be predicted accurately in the design process of a product to ensure the performance of the assembled parts. One important issue in predicting assembly variation is to search propagation paths along which variation accumulates. In this paper, a new searching algorithm of multibranch propagation paths of assembly variation for rigid body assemblies is proposed. First, the concepts of feature set and relation set are proposed to express the information of geometric tolerances and assembly constraints among features. Second, the actual constraint directions of a reference relation considering the precedence level are obtained. Third, the search of multibranch propagation paths is conducted by intersecting the actual constraint directions of different reference relations. Finally, the accuracy and efficiency of the proposed method are validated by comparing with the commercial computer-aided tolerancing (CAT) software package, 3DCS, for predicting assembly variation of the body structure of an aircraft. The outcomes of the paper can treat geometric tolerances, which overcome the drawback of traditional dimension-chain-based methods in predicting assembly variation. It is expected that a synthetic use of the proposed method and the dimension-chain-based methods can provide a computationally efficient substitute for the classical Monte Carlo simulation in predicting assembly variation.
Robust Topology Design of Complex Infrastructure
Systems
Authors: Piacenza Joseph R. , Proper Scott , Bozorgirad Mir Abbas , Hoyle Christopher , Tumer Irem Y.
Published: March 2017

Optimizing the topology of complex infrastructure systems can minimize the impact of cascading failures due to an initiating failure event. This paper presents a model-based design approach for the concept-stage robust design of complex infrastructure systems, as an alternative to modern network analysis methods. This approach focuses on system performance after cascading has occurred and examines design tradeoffs of the resultant (or degraded) system state. In this research, robustness is classically defined as the invariability of system performance due to uncertain failure events, implying that a robust network has the ability to meet minimum performance requirements despite the impact of cascading failures. This research is motivated by catastrophic complex infrastructure system failures such as the August 13th Blackout of 2003, highlighting the vulnerability of systems such as the North American power grid (NAPG). A mathematical model was developed using an adjacency matrix, where removing network connections simulates uncertain failure events. Performance degradation is iteratively calculated as failures cascade throughout the system, and robustness is measured by the lack of performance variability over multiple cascading failure scenarios. Two case studies are provided: an extrapolated IEEE 14 test bus and the Oregon State University (OSU) campus power network. The overarching goal of this research is to understand key system design tradeoffs between robustness, performance objectives, and cost, and explore the benefits of optimizing network topologies during the concept-stage design of these systems (e.g., microgrids).
Ultrasonic attenuation and phase velocity of high-density polyethylene pipe material
Authors: Egerton J. S. , Lowe M. J. S. , Huthwaite P. , Halai H. V.
Published: March 2017

Knowledge of acoustic properties is crucial for ultrasonic or sonic imaging and signal detection in nondestructive evaluation (NDE), medical imaging, and seismology. Accurately and reliably obtaining these is particularly challenging for the NDE of high-density polyethylene (HDPE), such as is used in many water or gas pipes, because the properties vary greatly with frequency, temperature, direction and spatial location. Therefore the work reported here was undertaken in order to establish a basis for such a multiparameter description. The approach is general but the study specifically addresses HDPE and includes measured data values. Applicable to any such multiparameter acoustic properties dataset is a devised regression method that uses a neural network algorithm. This algorithm includes constraints to respect the Kramers-Kronig causality relationship between speed and attenuation of waves in a viscoelastic medium. These constrained acoustic properties are fully described in a multidimensional parameter space to vary with frequency, depth, temperature, and direction. The resulting uncertainties in acoustic properties dependence on the above variables are better than 4% and 2%, respectively, for attenuation and phase velocity and therefore can prevent major defect imaging errors.
Decision-directed speech power spectral density matrix estimation for multichannel speech enhancement
Authors: Jin Yu Gwang , Shin Jong Won , Kim Nam Soo
Published: March 2017

In this letter, a multichannel decision-directed approach to estimate the speech power spectral density (PSD) matrix for multichannel speech enhancement is proposed. There have been attempts to build multichannel speech enhancement filters which depend only on the speech and noise PSD matrices, for which the accurate estimate of the clean speech PSD matrix is crucial for a successful noise reduction. In contrast to the maximum likelihood estimator which has been applied conventionally, the proposed decision-directed method is capable of tracking the time-varying speech characteristics more robustly and improves the noise reduction performance under various noise environments.
Perceptual significance of seat-dip effect related direct sound coloration in concert halls
Authors: Tahvanainen Henna , Haapaniemi Aki , Lokki Tapio
Published: March 2017

In concert halls, the spectrum of direct sound (here 0 to 15 ms) is influenced by the seat-dip effect that causes selective low frequency attenuation. The seat-dip effect has been considered to be detrimental to the acoustic quality of halls, yet there is little evidence about the perceptual significance of the effect. This paper studies the discrimination and preference of seat-dip effect related changes in the direct sound, with realistic auralization of multichannel anechoic orchestra recordings in halls measured with the loudspeaker orchestra. Comparisons are made with a free-field direct sound and direct sound magnitude changes typically associated with the seat-dip effect. Overall, the differences were not significantly audible, except with a subgroup of participants in one out of four halls, and two out of three comparisons. Furthermore, participants' preference for the uncolored direct sound was significant in the halls with less reflected energy, but non-significant in the halls with more reflected energy. The results imply that for most seats in adequately reverberant halls, typical seat-dip effect related coloration in the direct sound can be perceptually negligible.
Listeners' attitudes toward accented talkers uniquely predicts accented speech perception
Authors: Ingvalson Erin M. , Lansford Kaitlin L. , Federova Valeriya , Fernandez Gabriel
Published: March 2017

Listeners' sensitivity to indexical information influences their ability to perceive and remember speech, but it is less clear if listeners' subjective ratings of talker characteristics also impact speech perception ability. The present experiment tested the increase in variance accounted for by listeners' ratings of foreign accented talkers' manner of speaking and of the talkers themselves beyond the variance already accounted for by listeners' age, executive function, and hearing thresholds. Adding listeners' ratings significantly improved model fit, indicating that listeners' subjective experience of talker impacts speech perception accuracy along with objective listener characteristics such as hearing thresholds or executive function.
Grad students, postdocs with U.S. visas face uncertainty
Authors: Wadman Meredith , Stone Richard
Published: March 2017

New worries over draft order on skilled worker visas.
World's most endangered marine mammal down to 30
Authors: Morell Virginia
Published: March 2017

Acoustic survey speeds last-ditch plans to round up the vaquita—for its own good.
A prominent glycyl radical enzyme in human gut microbiomes metabolizes
trans
-4-hydroxy-
l
-proline
Authors: Levin B. J. , Huang Y. Y. , Peck S. C. , Wei Y. , Martínez-del Campo A. , Marks J. A. , Franzosa E. A. , Huttenhower C. , Balskus E. P.
Published: March 2017

Chemically guided functional profiling

The big challenge posed by the microbiota living in or on humans is working out what they do for us. Microorganisms generate large quantities of peptides and proteins that may have profound systemic effects on the host. Levin
et al.
took microbial metagenome data and used a combination of bioinformatic tools to generate a network that clusters sequences of enzymes sharing similar biological functions (see the Perspective by Glasner). Experiments verified these homology and structural-chemical inferences. The analysis identified enzymes involved in anaerobic short-chain fatty acid production and L-proline biosynthesis, both of which are key mediators of healthy microbiota-host symbioses.

Science
, this issue p.
eaai8386
; see also p.
577
Revealing Rorschach
The Inkblots Hermann Rorschach, His Iconic Test, and the Power of Seeing
Damion Searls
Crown, 2017. 416 pp.
Authors: McKay Erin
Published: March 2017

A new biography challenges common misconceptions about the famous psychological tool and the man behind it
Measurement error and the replication crisis
Authors: Loken Eric , Gelman Andrew
Published: March 2017

The assumption that measurement error always reduces effect sizes is false
Finding enzymes in the gut metagenome
Authors: Glasner Margaret E.
Published: March 2017

Metagenomic data help to elucidate enzymatic pathways in the human gut microbiome
Identifying protein kinase–specific effectors of the osmostress response in yeast
Authors: Romanov Natalie , Hollenstein David Maria , Janschitz Marion , Ammerer Gustav , Anrather Dorothea , Reiter Wolfgang
Published: March 2017

Phosphoproteomics identifies direct and indirect targets of the kinase Hog1 during the yeast osmostress response.
Cytoskeletal adaptivity regulates T cell receptor signaling
Authors: Thauland Timothy J. , Hu Kenneth H. , Bruce Marc A. , Butte Manish J.
Published: March 2017

A stiffer cytoskeleton limits the responsiveness of naïve T cells; a flexible cytoskeleton enables easy activation of effector T cells.
Of nerves and stomach cancer
Authors: Ferrarelli Leslie K.
Published: March 2017

Blocking a feed-forward cholinergic loop between gastric neurons and the mucosal epithelium may inhibit proliferation in tumor-associated stem cells.
A Risk Score for Fluconazole Failure among Patients with Candidemia
Authors: Ostrosky-Zeichner Luis , Harrington Rachel , Azie Nkechi , Yang Hongbo , Li Nanxin , Zhao Jing , Koo Valerie , Wu Eric Q.
Published: March 2017

This study aimed to develop a prediction model to identify patients with candidemia who were at high risk of failing fluconazole treatment. Adult patients in the United States with candidemia who received fluconazole during hospitalization were selected from the Cerner Health Facts Hospital Database (04/2004 to 03/2013). Fluconazole failure was defined as switching/adding another antifungal, positive
Candida
culture ≥10 days after fluconazole initiation, or death during hospitalization. Patients were randomized into modeling and validation samples. Using the modeling sample, a regression analysis of least absolute shrinkage and selection operator was used to select risk predictors of fluconazole failure (demographics,
Candida
species, initiation of fluconazole before positive culture and after admission, and comorbidities, procedures, and treatments during the 6 months before admission and fluconazole initiation). The prediction model was evaluated using the validation sample. We found that of 987 identified patients (average age of 61 years, 51% male, 72% Caucasian), 49% failed and 51% did not fail fluconazole treatment. Of those who failed, 70% switched or added another antifungal, 21% had a second positive
Candida
test, and 42% died during hospitalization. Nine risk factors were included in the prediction model: days to start fluconazole after admission,
Candida glabrata
or
Candida krusei
infection, hematological malignancy, venous thromboembolism (VTE), enteral nutrition, use of nonoperative intubation/irrigation, and other antifungal use. All but VTE were associated with a higher risk of failure. The model's c-statistic was 0.65, with a Hosmer-Lemeshow test
P
value of 0.23. In summary, this prediction model identified patients with a high risk of fluconazole failure, illustrating the potential value and feasibility of personalizing candidemia treatment.
MCR-1.6, a New MCR Variant Carried by an IncP Plasmid in a Colistin-Resistant Salmonella enterica Serovar Typhimurium Isolate from a Healthy Individual
Authors: Lu Xin , Hu Yongfei , Luo Ming , Zhou Haijian , Wang Xiaoxun , Du Yu , Li Zhenpeng , Xu Jialiang , Zhu Baoli , Xu Xuebin , Kan Biao
Published: March 2017

In this study, we report a novel
mcr-1
gene variant, named
mcr-1.6
, carried by an IncP plasmid in a colistin-resistant
Salmonella enterica
serovar Typhimurium isolate from a healthy person. Compared with
mcr-1
, the
mcr-1.6
gene contains two single-nucleotide polymorphisms, one of which results in an arginine to histidine variation (Arg536→His). The plasmid carrying the
mcr-1.6
gene was designated pMCR1.6_P053 and is similar to a recently discovered
mcr-1
-bearing plasmid found in
Klebsiella pneumoniae
.
Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model
Authors: Bergen Phillip J. , Bulitta Jürgen B. , Kirkpatrick Carl M. J. , Rogers Kate E. , McGregor Megan J. , Wallis Steven C. , Paterson David L. , Nation Roger L. , Lipman Jeffrey , Roberts Jason A. , Landersdorfer Cornelia B.
Published: March 2017

Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A
Pseudomonas aeruginosa
isolate (MIC
meropenem
0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼10
7.5
CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ∼10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log
10
). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5- and 1-g regimens with normal renal function (
fT
>5×MIC
= 56 and 69%,
fC
min
/MIC < 2); the emergence of less-susceptible populations (≥32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (
fT
>5×MIC
≥ 82%,
fC
min
/MIC ≥ 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.
In Vivo
Pharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model
Authors: Zhou Yu-Feng , Tao Meng-Ting , Huo Wei , Liao Xiao-Ping , Sun Jian , Liu Ya-Hong
Published: March 2017

Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against seven
Klebsiella pneumoniae
isolates by using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic (PK) studies were conducted at single subcutaneous doses of 2.5, 10, 40, and 160 mg/kg of body weight. Mice were infected intratracheally with
K. pneumoniae
and treated using 2-fold-increasing total doses of antofloxacin ranging from 2.5 to 160 mg/kg/24 h administered in 1, 2, 3, or 4 doses. The
E
max
Hill equation was used to model the dose-response data. Antofloxacin could penetrate the lung epithelial lining fluid (ELF) with pharmacokinetics similar to those in plasma with linear elimination half-lives over the dose range. All study strains showed a 3-log
10
or greater reduction in bacterial burden and prolonged postantibiotic effects (PAEs) ranging from 3.2 to 5.3 h. Dose fractionation response curves were steep, and the free-drug area under the concentration-time curve over 24 h (AUC
0–24
)/MIC ratio was the PD index most closely linked to efficacy (
R
2
= 0.96). The mean free-drug AUC
0–24
/MIC ratios required to achieve net bacterial stasis, a 1-log
10
kill, and a 2-log
10
kill for each isolate were 52.6, 89.9, and 164.9, respectively. When integrated with human PK data, these PD targets could provide a framework for further optimization of dosing regimens. This could make antofloxacin an attractive option for the treatment of respiratory tract infections involving
K. pneumoniae
.
Expanding Role of Type II Secretion in Bacterial Pathogenesis and Beyond
Authors: Cianciotto Nicholas P. , White Richard C.
Published: March 2017

Type II secretion (T2S) is one means by which Gram-negative pathogens secrete proteins into the extracellular milieu and/or host organisms. Based upon recent genome sequencing, it is clear that T2S is largely restricted to theProteobacteria, occurring in many, but not all, genera in theAlphaproteobacteria,Betaproteobacteria,Gammaproteobacteria, andDeltaproteobacteriaclasses. Prominent human and/or animal pathogens that express a T2S system(s) includeAcinetobacter baumannii,Burkholderia pseudomallei,Chlamydia trachomatis,Escherichia coli,Klebsiella pneumoniae,Legionella pneumophila,Pseudomonas aeruginosa,Stenotrophomonas maltophilia,Vibrio cholerae, andYersinia enterocolitica. T2S-expressing plant pathogens includeDickeya dadantii,Erwinia amylovora,Pectobacterium carotovorum,Ralstonia solanacearum,Xanthomonas campestris,Xanthomonas oryzae, andXylella fastidiosa. T2S also occurs in nonpathogenic bacteria, facilitating symbioses, among other things. The output of a T2S system can range from only one to dozens of secreted proteins, encompassing a diverse array of toxins, degradative enzymes, and other effectors, including novel proteins. Pathogenic processes mediated by T2S include the death of host cells, degradation of tissue, suppression of innate immunity, adherence to host surfaces, biofilm formation, invasion into and growth within host cells, nutrient assimilation, and alterations in host ion flux. The reach of T2S is perhaps best illustrated by those bacteria that clearly use it for both environmental survival and virulence; e.g.,L. pneumophilaemploys T2S for infection of amoebae, growth within lung cells, dampening of cytokines, and tissue destruction. This minireview provides an update on the types of bacteria that have T2S, the kinds of proteins that are secreted via T2S, and how T2S substrates promote infection.
Optogenetic Manipulation of Cyclic Di-GMP (c-di-GMP) Levels Reveals the Role of c-di-GMP in Regulating Aerotaxis Receptor Activity in Azospirillum brasilense
Authors: O'Neal Lindsey , Ryu Min-Hyung , Gomelsky Mark , Alexandre Gladys
Published: March 2017

Bacterial chemotaxis receptors provide the sensory inputs that inform the direction of navigation in changing environments. Recently, we described the bacterial second messenger cyclic di-GMP (c-di-GMP) as a novel regulator of a subclass of chemotaxis receptors. In
Azospirillum brasilense
, c-di-GMP binds to a chemotaxis receptor, Tlp1, and modulates its signaling function during aerotaxis. Here, we further characterize the role of c-di-GMP in aerotaxis using a novel dichromatic optogenetic system engineered for manipulating intracellular c-di-GMP levels in real time. This system comprises a red/near-infrared-light-regulated diguanylate cyclase and a blue-light-regulated c-di-GMP phosphodiesterase. It allows the generation of transient changes in intracellular c-di-GMP concentrations within seconds of irradiation with appropriate light, which is compatible with the time scale of chemotaxis signaling. We provide experimental evidence that binding of c-di-GMP to the Tlp1 receptor activates its signaling function during aerotaxis, which supports the role of transient changes in c-di-GMP levels as a means of adjusting the response of
A. brasilense
to oxygen gradients. We also show that intracellular c-di-GMP levels in
A. brasilense
change with carbon metabolism. Our data support a model whereby c-di-GMP functions to imprint chemotaxis receptors with a record of recent metabolic experience, to adjust their contribution to the signaling output, thus allowing the cells to continually fine-tune chemotaxis sensory perception to their metabolic state.

IMPORTANCE
Motile bacteria use chemotaxis to change swimming direction in response to changes in environmental conditions. Chemotaxis receptors sense environmental signals and relay sensory information to the chemotaxis machinery, which ultimately controls the swimming pattern of cells. In bacteria studied to date, differential methylation has been known as a mechanism to control the activity of chemotaxis receptors and modulates their contribution to the overall chemotaxis response. Here, we used an optogenetic system to perturb intracellular concentrations of the bacterial second messenger c-di-GMP to show that in some chemotaxis receptors, c-di-GMP functions in a similar feedback loop to connect the metabolic status of the cells to the sensory activity of chemotaxis receptors.
GigA and GigB are Master Regulators of Antibiotic Resistance, Stress Responses, and Virulence in Acinetobacter baumannii
Authors: Gebhardt Michael J. , Shuman Howard A.
Published: March 2017

A critical component of bacterial pathogenesis is the ability of an invading organism to sense and adapt to the harsh environment imposed by the host's immune system. This is especially important for opportunistic pathogens, such as
Acinetobacter baumannii
, a nutritionally versatile environmental organism that has recently gained attention as a life-threatening human pathogen. The emergence of
A. baumannii
is closely linked to antibiotic resistance, and many contemporary isolates are multidrug resistant (MDR). Unlike many other MDR pathogens, the molecular mechanisms underlying
A. baumannii
pathogenesis remain largely unknown. We report here the characterization of two recently identified virulence determinants, GigA and GigB, which comprise a signal transduction pathway required for surviving environmental stresses, causing infection and antibiotic resistance. Through transcriptome analysis, we show that GigA and GigB coordinately regulate the expression of many genes and are required for generating an appropriate transcriptional response during antibiotic exposure. Genetic and biochemical data demonstrate a direct link between GigA and GigB and the nitrogen phosphotransferase system (PTS
Ntr
), establishing a novel connection between a novel stress response module and a well-conserved metabolic-sensing pathway. Based on the results presented here, we propose that GigA and GigB are master regulators of a global stress response in
A. baumannii
, and coupling this pathway with the PTS
Ntr
allows
A. baumannii
to integrate cellular metabolic status with external environmental cues.

IMPORTANCE
Opportunistic pathogens, including
Acinetobacter baumannii
, encounter many harsh environments during the infection cycle, including antibiotic exposure and the hostile environment within a host. While the development of antibiotic resistance in
A. baumannii
has been well studied, how this organism senses and responds to environmental cues remain largely unknown. Herein, we investigate two previously identified virulence determinants, GigA and GigB, and report that they are required for
in vitro
stress resistance, likely comprising upstream elements of a global stress response pathway. Additional experiments identify a connection between GigA/GigB and a widely conserved metabolic-sensing pathway, the nitrogen phosphotransferase system. We propose that coordination of these two pathways allows
A. baumannii
to respond appropriately to changing environmental conditions, including those encountered during infection.
Cost-effectiveness analysis of an 18-week exercise programme for patients with breast and colon cancer undergoing adjuvant chemotherapy: the randomised PACT study
Authors: May Anne M , Bosch Marcel J C , Velthuis Miranda J , van der Wall Elsken , Steins Bisschop Charlotte N , Los Maartje , Erdkamp Frans , Bloemendal Haiko J , de Roos Marnix A J , Verhaar Marlies , ten Bokkel Huinink Daan , Peeters Petra H M , de Wit G Ardine
Published: March 2017

Objective

Meta-analyses show that exercise interventions during cancer treatment reduce cancer-related fatigue. However, little is known about the cost-effectiveness of such interventions. Here we aim to assess the cost-effectiveness of the 18-week physical activity during cancer treatment (PACT) intervention for patients with breast and colon cancer. The PACT trial showed beneficial effects for fatigue and physical fitness.

Design

Cost-effectiveness analyses with a 9-month time horizon (18 weeks of intervention and 18 weeks of follow-up) within the randomised controlled multicentre PACT study.

Setting

Outpatient clinics of 7 hospitals in the Netherlands (1 academic and 6 general hospitals)

Participants

204 patients with breast cancer and 33 with colon cancer undergoing adjuvant treatment including chemotherapy.

Intervention

Supervised 1-hour aerobic and resistance exercise (twice per week for 18 weeks) or usual care.

Main outcome measures

Costs, quality-adjusted life years (QALY) and the incremental cost-effectiveness ratio.

Results

For colon cancer, the cost-effectiveness analysis showed beneficial effects of the exercise intervention with incremental costs savings of €4321 and QALY improvements of 0.03. 100% of bootstrap simulations indicated that the intervention is dominant (ie, cheaper and more effective). For breast cancer, the results did not indicate that the exercise intervention was cost-effective. Incremental costs were €2912, and the incremental effect was 0.01 QALY. At a Dutch threshold value of €20 000 per QALY, the probability that the intervention is cost-effective was 2%.

Conclusions

Our results suggest that the 18-week exercise programme was cost-effective for colon cancer, but not for breast cancer.

Trial registration number

ISRCTN43801571.
Effects of school breaks on influenza-like illness incidence in a temperate Chinese region: an ecological study from 2008 to 2015
Authors: Chu Yanhui , Wu Zhenyu , Ji Jiayi , Sun Jingyi , Sun Xiaoyu , Qin Guoyou , Qin Jingning , Xiao Zheng , Ren Jian , Qin Di , Zheng Xueying , Wang Xi-Ling
Published: March 2017

Objective

To assess the effects of winter/summer school breaks on occurrences of influenza-like illness (ILI).

Methods

We jointly analysed ILI surveillance data with the timing of school breaks in a temperate district in Beijing, China from 2008 to 2015. ILI incidence rate ratios (IRRs) of schoolchildren (5–14 and 15–24 years of age) to adults (25–59 and >60 years of age) were used to measure the age shift of ILI incidence before, during and after the 4-week winter/7-week summer breaks. Serfling-based Poisson regression model with adjustment for unmeasured confounders was built to further assess the effect of winter school breaks.

Results

ILI incidences were consistently lower during winter breaks than before winter breaks for all age groups. IRRs of younger schoolchildren aged 5–14 to adults were higher during winter school breaks than before breaks, while the opposite was true for the IRRs of older schoolchildren aged 15–24 to adults. Schoolchildren-to-adults IRRs during summer breaks were significantly lower than before or after school breaks (p<0.001).

Conclusions

Both winter and summer breaks were associated with reductions of ILI incidences among schoolchildren and adults. Our study contributes additional evidence on the effects of school breaks on ILI incidence, suggesting school closure could be effective in controlling influenza transmission in developing countries.