bluuebunny/crossref_metadata_2025 huggingface dataset:
Temperature dependence of spin-orbit torques in W/CoFeB bilayers
Authors: Skowroński Witold , Cecot Monika , Kanak Jarosław , Ziętek Sławomir , Stobiecki Tomasz , Yao Lide , van Dijken Sebastiaan , Nozaki Takayuki , Yakushiji Kay , Yuasa Shinji
Published: August 2016

We report on the temperature variation of spin-orbit torques in perpendicularly magnetized W/CoFeB bilayers. Harmonic Hall voltage measurements in perpendicularly magnetized CoFeB reveal increased longitudinal and transverse effective magnetic field components at low temperatures. The damping-like spin-orbit torque reaches an efficiency of 0.55 at 19 K. Scanning transmission electron microscopy and X-ray reflectivity measurements indicate that considerable interface mixing between W and CoFeB may be responsible for strong spin-orbit interactions.
Status of neutron diagnostics on the experimental advanced superconducting tokamak
Authors: Zhong G. Q. , Hu L. Q. , Pu N. , Zhou R. J. , Xiao M. , Cao H. R. , Zhu Y. B. , Li K. , Fan T. S. , Peng X. Y. , Du T. F. , Ge L. J. , Huang J. , Xu G. S. , Wan B. N. ,   EAST Team
Published: August 2016

Neutron diagnostics have become a significant means to study energetic particles in high power auxiliary heating plasmas on the Experimental Advanced Superconducting Tokamak (EAST). Several kinds of neutron diagnostic systems have been implemented for time-resolved measurements of D-D neutron flux, fluctuation, emission profile, and spectrum. All detectors have been calibrated in laboratory, and in situ calibration using 252Cf neutron source in EAST is in preparation. A new technology of digitized pulse signal processing is adopted in a wide dynamic range neutron flux monitor, compact recoil proton spectrometer, and time of flight spectrometer. Improvements will be made continuously to the system to achieve better adaptation to the EAST’s harsh γ-ray and electro-magnetic radiation environment.
Regularity properties of fiber derivatives associated with higher-order mechanical systems
Authors: Colombo Leonardo , Prieto-Martínez Pedro Daniel
Published: August 2016

The aim of this work is to study fiber derivatives associated to Lagrangian and Hamiltonian functions describing the dynamics of a higher-order autonomous dynamical system. More precisely, given a function in T∗T(k−1)Q, we find necessary and sufficient conditions for such a function to describe the dynamics of a kth-order autonomous dynamical system, thus being a kth-order Hamiltonian function. Then, we give a suitable definition of (hyper)regularity for these higher-order Hamiltonian functions in terms of their fiber derivative. In addition, we also study an alternative characterization of the dynamics in Lagrangian submanifolds in terms of the solutions of the higher-order Euler-Lagrange equations.
Hydrogen ionic plasma generated using Al plasma grid
Authors: Oohara W. , Anegawa N. , Egawa M. , Kawata K. , Kamikawa T.
Published: August 2016

Negative hydrogen ions are produced in the apertures of a plasma grid made of aluminum under the irradiation of positive ions, generating an ionic plasma consisting of positive and negative ions. The saturation current ratio obtained using a Langmuir probe reflects the existence ratio of electrons and is found to increase in connection with the diffusion of the ionic plasma. The local increment of the current ratio suggests the collapse of negative ions and the replacement of detached electrons.
Relativistic electron beam driven longitudinal wake-wave breaking in a cold plasma
Authors: Bera Ratan Kumar , Mukherjee Arghya , Sengupta Sudip , Das Amita
Published: August 2016

Space-time evolution of a relativistic electron beam driven wake-field in a cold, homogeneous plasma is studied using 1D-fluid simulation techniques. It is observed that the wake wave gradually evolves and eventually breaks, exhibiting sharp spikes in the density profile and sawtooth like features in the electric field profile [Bera et al., Phys. Plasmas 22, 073109 (2015)]. It is shown here that the excited wakefield is a longitudinal Akhiezer-Polovin mode [A. I. Akhiezer and R. V. Polovin, Sov. Phys. JETP 3, 696 (1956)] and its steepening (breaking) can be understood in terms of phase mixing of this mode, which arises because of relativistic mass variation effects. Further, the phase mixing time (breaking time) is studied as a function of beam density and beam velocity and is found to follow the well known scaling presented by Mukherjee and Sengupta [Phys. Plasmas 21, 112104 (2014)].
S-shape spring sensor: Sensing specific low-frequency vibration by energy harvesting
Authors: Zhang Lan , Lu Jian , Takei Ryohei , Makimoto Natsumi , Itoh Toshihiro , Kobayashi Takeshi
Published: August 2016

We have developed a Si-based microelectromechanical systems sensor with high sensitivity for specific low-frequency vibration-sensing and energy-harvesting applications. The low-frequency vibration sensor contains a disk proof mass attached to two or three lead zirconate titanate (PZT) S-shape spring flexures. To obtain a faster and less expensive prototype, the design and optimization of the sensor structure are studied via finite-element method analysis. To validate the sensor structure to detect low-frequency vibration, the effects of geometrical dimensions, including the width and diameter of the S-shape spring of the proof mass, were analyzed and measured. The functional features, including the mechanical property and electrical performance of the vibration sensor, were evaluated. The results demonstrated that a very low resonant frequency of <11 Hz and a reasonably high voltage output of 7.5 mV at acceleration of >0.2g can be typically achieved. Given a low-frequency vibration sensor with ideal performance and mass fabrication, many advanced civilian and industrial applications can be possibly realized.
Al2O3 Microspheres Prepared by Cathode Plasma Electrolysis
Authors: Liu Chenxu , Zhang Jin , He Yedong , Wang Peng , Deng Shunjie , Zhang Shuguang
Published: August 2016

Al2O3 microspheres were prepared by cathode plasma electrolysis (CPE) in an aqueous solution of Al(NO)3·9H2O. Compared with high-temperature calcination methods, the CPE method afforded the preparation of microspheres directly at room temperature. The results showed that regular microspheres formed under relatively high concentrations of Al(NO)3·9H2O. The microspheres, with diameters mostly in the range of 5–30 μm, consisted of γ-Al2O3 and α-Al2O3. The possible formation mechanism included the following processes: (1) Al(OH)3 intermediate was formed during the cathodic reactions; (2) plasma energized the intermediate to Al2O3; and (3) microspheres formed under the effect of the surface tension.
Antibiotic resistance associated with aquaculture in Vietnam
Authors: Nguyen Hoang Nam Kha , Van Thi Thu Hao , Coloe Peter J
Published: August 2016

The fishery sector is an important source of income, employment and food supply in Vietnam. In 2014, Vietnam was ranked the world's fourth largest exporter and the third largest producer of farmed food fish. Vietnam seafood export has attained the value of over US$6.0 billion since 2011 and reached a peak of US$7.9 billion in 2014. However, many problems and diseases confront sustainable development of the fishery sector and overuse of antibiotics is considered a major challenge. Antibiotics are used in aquaculture for both therapeutic and prophylactic reasons. Various antimicrobials used in human medicine are also used for food animals even for non-therapeutic use. The use of antibiotics in health management of aquaculture farming is of great concern due to possible residues in aquatic products and in the development of antibiotic resistance. In 2005 the Vietnamese government first promulgated a list of medicines, chemicals and antibiotics that are banned or limited for use in aquaculture and this is regularly updated and amended to tackle the growing problem of antibiotic resistance.
Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain
Authors: Harley Carol A. , Starek Greg , Jones David K. , Fernandes Andreia S. , Robertson Gail A. , Morais-Cabral João H.
Published: August 2016

Significance

The human ether-à-go-go–related gene (hERG) potassium channel has an important role in controlling heartbeat. Genetic alterations or drug side effects can reduce the amount of current passing through hERG, prolonging action potential duration and causing irregular heartbeat and sudden death. We uncovered a family of hERG modulators, antibody fragments that bind to a cytoplasmic region [Per-Arnt-Sim (PAS) domain], increasing the magnitude of the repolarizing current I
Kr
and reducing duration of the ventricular action potential. Using the antibodies as tools, we established that it is possible to modulate hERG channel function through the PAS domain and showed a way to increase hERG channel function with the potential to treat not only perturbations of the channel itself but also arrhythmias arising from heart failure.
Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells
Authors: Moreno Alberto , Carrington Jamie T. , Albergante Luca , Al Mamun Mohammed , Haagensen Emma J. , Komseli Eirini-Stavroula , Gorgoulis Vassilis G. , Newman Timothy J. , Blow J. Julian
Published: August 2016

Significance

We provide evidence that in organisms with gigabase-sized genomes, such as humans, one or more stretches of DNA typically remain unreplicated when cells enter mitosis and are segregated to daughter cells via structures called ultrafine anaphase bridges. p53-binding protein 1 (53BP1) accumulates at the subsequent DNA structures inherited by each daughter cell in the following G1 phase to facilitate resolution in S phase. We show that the abundance of these structures match theoretical predictions for the number of unreplicated DNA segments when the number of replication origins is artificially increased or decreased. We show that 53BP1 preferentially binds to chromosomal regions with low numbers of replication origins. This work challenges the prevailing view of how genome stability is maintained in proliferating cells.
Network pharmacology of JAK inhibitors
Authors: Moodley Devapregasan , Yoshida Hideyuki , Mostafavi Sara , Asinovski Natasha , Ortiz-Lopez Adriana , Symanowicz Peter , Telliez Jean-Baptiste , Hegen Martin , Clark James D. , Mathis Diane , Benoist Christophe
Published: August 2016

Significance

JAK kinase inhibitors (JAKis) have advanced options for treatment of autoimmune diseases. Because JAKs are signaling hubs for several cytokine receptors, JAKis’ overall impact on the immune system and how they actually improve diseases like rheumatoid arthritis remain poorly understood. Combined immunophenotyping and genomic profiling revealed broad JAKi effects on the immunogenomic network, irrespective of inhibitor fine specificity, with effects on population homeostasis and coregulated gene-expression networks, particularly in innate immunocytes. Persistent repression by JAKis of IFN signature genes lasted beyond drug clearance and correlated with changes in the structure of the underlying chromatin, with direct implications for practical use of the drugs. Further JAKi development may need to take into account their broad network and epigenomic effects.
Learners and reformulative discourse markers
Authors: Corino Elisa
Published: August 2016

Building on the results of a previous study on reformulative discourse markers (Corino 2012), this paper examines the different functions and semantic features of the Italian discourse marker cioè in the hope of elaborating a clear framework for its many functions and uses. The outcomes will enable us to answer three main research questions: 1) Is there a relevant relationship between the learner’s mother tongue and the use of cioè? 2) What points in Italian as a second language (ISL) need to be taught to learners in order to improve the use of DMs? 3) What functions of cioè are used more or less by learners of ISL with respect to native speakers? To this end, the distribution of this DM will be analyzed in texts written by ISL learners, collected in the learner corpora VALICO and ADIL2, in search of regularities in acquisition vs. evidence of influence of the learners’ mother tongues.
The use of discourse markers in L2 Italian
Authors: De Marco Anna
Published: August 2016

This exploratory study intends to investigate the use of discourse markers (DM) in Italian L2 by learners with different L1s and different levels of competence (three at A2/B1 level and two at B2/C1 level). The analysis aims to describe the functions, the distribution, and some acoustic features of three DMs (però‘but’, allora‘then’, quindi ‘therefore’) in semi-spontaneous conversations between the learners and two native speakers. The purpose is to determine the possible uses and the relationship between the forms and functions of the DMs in native and non-native speakers distinguishing three main macro-functions (interactional, cognitive and metadiscursive) activated by speakers on the basis of the characteristics of the cotext (acoustic profiles), the context and the communicative situation. Such an analysis suggests a possible sequence in the emergence of DMs in the speech of L2 learners with different levels of competence in the target language. This exploratory study adopts a functional approach (Bazzanella 1995a, b; 2006; Fisher 2006). The outcomes of the analysis show that learners use a variety of DM forms and functions, and that some functions only emerge in more proficient speakers. The structural context and, to a lesser degree, the acoustic profile prove to be reliable indicators of the spectrum of functions performed by DMs in verbal interaction.
Pointing backward and forward
Authors: Pauletto Franco , Bardel Camilla
Published: August 2016

In this study, we analyze the kind of actions L1 and L2 speakers of Italian perform by prefacing their responsive turns with the discourse marker be’. As a baseline, the article begins with an analysis of how native speakers of Italian use be’. We then carry out quantitative and qualitative analyses of the use of be’ in a number of L2 learners at different proficiency levels from three data sets of different types of interactions between students and native speakers of Italian. In the qualitative analysis, we adopt a conversation analytic perspective. The results suggest that both native speakers and L2 speakers, from intermediate to advanced level, perform a variety of social actions by be’-prefacing their responsive turns.
Análisis de la familiaridad y del interés en la comprensión lectora de estudiantes españoles de inglés como lengua extranjera
Authors: Isusi Alberto , Martínez Ana Cristina Lahuerta
Published: August 2016

Este artículo es un estudio cuantitativo que compara el grado de influencia de la familiaridad con el contenido del texto y el interés en el tema del pasaje sobre la comprensión lectora de 245 estudiantes españoles de inglés como lengua extranjera de 2º y 4º ESO. La comparación se establece de forma general y en función del género del lector, del nivel de competencia en L2 y del método de evaluación (written recall y multiple choice). La recogida de datos se llevó a cabo durante la 2ª y 3ª semana del 2º trimestre del curso 2013–2014 en sendos colegios concertados de una ciudad del norte de España. Las muestras se analizaron empleando pruebas t de Student y ANOVA mediante el programa R. Los resultados muestran que (a) la familiaridad influye significativamente más que el interés; (b) según aumenta el nivel de competencia, la influencia de ambas variables decrece; (c) el género no parece influir a la comprensión lectora de textos que carecen de sesgo de género; y (d) el método de evaluación multiple choice parece facilitar en gran medida la comprensión.
Hacia una revisión del concepto de neologismo aplicado a los verbos denominales aparecidos en la prensa española
Authors: Lavale-Ortiz Ruth-María
Published: August 2016

La formación de verbos procedentes de sustantivos en español es una herramienta muy rentable y así lo demuestran las nuevas unidades aparecidas en la prensa. El análisis de los verbos denominales neológicos, recogidos de dos corpus, nos ha conducido a repensar el concepto de neologismo y a considerarlo, bajo la perspectiva de la Lingüística Cognitiva, como una categoría definida por un conjunto de criterios cuyo cumplimiento permite establecer un grupo de lexemas más prototípico y un continuo de elementos que se acercan o se alejan de ese centro. Asimismo, se estudian estas unidades neológicas desde tres puntos de vista: morfológico, con la finalidad de demostrar que los afijos empleados en su formación son los que se reconocen como más productivos; semántico, para mostrar la rentabilidad de las clasificaciones semánticas de estas unidades; y pragmático, en aras de dilucidar algunas cuestiones sobre su temática y procedencia.
Funciones comunicativas y lexicografía
Authors: Maya Rico Lina María
Published: August 2016

Este artículo tiene como objetivo desarrollar un repertorio expandido de funciones ilocutivas que pueden expresarse directamente por elementos léxicos. Un repertorio de este tipo es una herramienta importante para la creación de diccionarios que procuran proporcionar información sobre el uso contextualmente correcto de los elementos léxicos. El repertorio se desarrolla en dos pasos. Primero se combinan tres teorías diferentes sobre los actos ilocutivos para llegar a una clasificación nueva. Segundo se refina esta clasificación confrontándola con un corpus amplio de expresiones léxicas del Español hablado en Medellín y Área Metropolitana, Colombia. El resultado de este enfoque combinado es una nueva clasificación de funciones ilocutivas.
ChemTreeMap: an interactive map of biochemical similarity in molecular datasets
Authors: Lu Jing , Carlson Heather A.
Published: August 2016

Motivation: What if you could explain complex chemistry in a simple tree and share that data online with your collaborators? Computational biology often incorporates diverse chemical data to probe a biological question, but the existing tools for chemical data are ill-suited for the very large datasets inherent to bioinformatics. Furthermore, existing visualization methods often require an expert chemist to interpret the patterns. Biologists need an interactive tool for visualizing chemical information in an intuitive, accessible way that facilitates its integration into today’s team-based biological research.

Results: ChemTreeMap is an interactive, bioinformatics tool designed to explore chemical space and mine the relationships between chemical structure, molecular properties, and biological activity. ChemTreeMap synergistically combines extended connectivity fingerprints and a neighbor-joining algorithm to produce a hierarchical tree with branch lengths proportional to molecular similarity. Compound properties are shown by leaf color, size and outline to yield a user-defined visualization of the tree. Two representative analyses are included to demonstrate ChemTreeMap’s capabilities and utility: assessing dataset overlap and mining structure–activity relationships.

Availability and Implementation: The examples from this paper may be accessed at http://ajing.github.io/ChemTreeMap/. Code for the server and client are available in the Supplementary Information, at the aforementioned github site, and on Docker Hub (https://hub.docker.com) with the nametag ajing/chemtreemap.

Contact:  carlsonh@umich.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Multivariate Welch t-test on distances
Authors: Alekseyenko Alexander V.
Published: August 2016

Motivation: Permutational non-Euclidean analysis of variance, PERMANOVA, is routinely used in exploratory analysis of multivariate datasets to draw conclusions about the significance of patterns visualized through dimension reduction. This method recognizes that pairwise distance matrix between observations is sufficient to compute within and between group sums of squares necessary to form the (pseudo) F statistic. Moreover, not only Euclidean, but arbitrary distances can be used. This method, however, suffers from loss of power and type I error inflation in the presence of heteroscedasticity and sample size imbalances.

Results: We develop a solution in the form of a distance-based Welch t-test, TW2, for two sample potentially unbalanced and heteroscedastic data. We demonstrate empirically the desirable type I error and power characteristics of the new test. We compare the performance of PERMANOVA and TW2 in reanalysis of two existing microbiome datasets, where the methodology has originated.

Availability and Implementation: The source code for methods and analysis of this article is available at https://github.com/alekseyenko/Tw2. Further guidance on application of these methods can be obtained from the author.

Contact:  alekseye@musc.edu
Official American Thoracic Society/Centers for Disease Control and
Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment
of Drug-Susceptible Tuberculosis
Authors: Nahid Payam , Dorman Susan E. , Alipanah Narges , Barry Pennan M. , Brozek Jan L. , Cattamanchi Adithya , Chaisson Lelia H. , Chaisson Richard E. , Daley Charles L. , Grzemska Malgosia , Higashi Julie M. , Ho Christine S. , Hopewell Philip C. , Keshavjee Salmaan A. , Lienhardt Christian , Menzies Richard , Merrifield Cynthia , Narita Masahiro , O'Brien Rick , Peloquin Charles A. , Raftery Ann , Saukkonen Jussi , Schaaf H. Simon , Sotgiu Giovanni , Starke Jeffrey R. , Migliori Giovanni Battista , Vernon Andrew
Published: August 2016

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.
The Trade Union Act 2016 and the Failure of Human Rights
Authors: Ewing K.D. , Hendy QC John
Published: August 2016

The Trade Union Bill raised major concerns about freedom of association in particular and its compatibility with a number of treaty obligations, including notably, the European Convention on Human Rights, Article 11. Complaints were made to the International Labour Organisation, and the Parliamentary Joint Committee on Human Rights considered the Bill. This paper seeks to assess the extent to which such human rights considerations influenced the final text which became the Act. Our view is that, although the government made a number of notable concessions, these were informed more by political than by legal considerations. Despite the concessions, human rights concerns still remain. Our secondary aim in this paper is to consider some factors relevant to the possibility of a successful legal challenge based on those concerns. We think such a challenge unlikely for two reasons. Firstly, the concessions removed many of the substantive provisions most susceptible to a human rights challenge. Secondly, whilst the domestic courts have been reluctant to embrace Convention rights in trade union cases, the Strasbourg Court has recently been notably sympathetic to the British Government in Article 11 cases, carving out for this country an apparently protected position on freedom of association issues.
Pediatric Kawasaki Disease and Adult Human Immunodeficiency Virus Kawasaki-Like Syndrome Are Likely the Same Malady
Authors: Johnson Raymond M. , Bergmann Kelly R. , Manaloor John J. , Yu Xiaoqing , Slaven James E. , Kharbanda Anupam B.
Published: August 2016

Background.  Pediatric Kawasaki disease (KD) and human immunodeficiency virus (HIV)+ adult Kawasaki-like syndrome (KLS) are dramatic vasculitides with similar physical findings. Both syndromes include unusual arterial histopathology with immunoglobulin (Ig)A+ plasma cells, and both impressively respond to pooled Ig therapy. Their distinctive presentations, histopathology, and therapeutic response suggest a common etiology. Because blood is in immediate contact with inflamed arteries, we investigated whether KD and KLS share an inflammatory signature in serum.

Methods.  A custom multiplex enzyme-linked immunosorbent assay (ELISA) defined the serum cytokine milieu in 2 adults with KLS during acute and convalescent phases, with asymptomatic HIV+ subjects not taking antiretroviral therapy serving as controls. We then prospectively collected serum and plasma samples from children hospitalized with KD, unrelated febrile illnesses, and noninfectious conditions, analyzing them with a custom multiplex ELISA based on the KLS data.

Results.  Patients with KLS and KD subjects shared an inflammatory signature including acute-phase reactants reflecting tumor necrosis factor (TNF)-α biologic activity (soluble TNF receptor I/II) and endothelial/smooth muscle chemokines Ccl1 (Th2), Ccl2 (vascular inflammation), and Cxcl11 (plasma cell recruitment). Ccl1 was specifically elevated in KD versus febrile controls, suggesting a unique relationship between Ccl1 and KD/KLS pathogenesis.

Conclusions.  This study defines a KD/KLS inflammatory signature mirroring a dysfunctional response likely to a common etiologic agent. The KD/KLS inflammatory signature based on elevated acute-phase reactants and specific endothelial/smooth muscle chemokines was able to identify KD subjects versus febrile controls, and it may serve as a practicable diagnostic test for KD.
Allergy prevention by breastfeeding: possible mechanisms and evidence from human cohorts
Authors: Munblit Daniel , Verhasselt Valérie
Published: August 2016

Purpose of review

Allergy is a modern disease which does not seem to benefit from breast milk preventive effects. We propose that maternal milk composition has not adapted to the needs of allergy prevention because of the recent and rapid increase of allergy. Modulation of breast milk composition may be the best strategy to counteract allergy development. We will review recent advances in understanding of allergy physiopathology and how breast milk factors may be specifically appropriate to interfere with allergy development in early life.

Recent findings

There is strong evidence both from rodent and human studies that breast milk factors may impact on parameters which are now recognized to be essential for allergy physiopathology: infant gut barrier function, microbiota metabolites production, and oral tolerance induction. Data from human cohorts support the possibility to modify breast milk composition by selected interventions and to impact health outcomes in offspring.

Nutritional intervention in lactating mothers should endow breast milk with the capacity to combat allergy epidemics in addition to infectious disease.
Opioid Overdose: Risk Assessment and Mitigation in Outpatient Treatment
Authors: Lin Lewei Allison , Hosanagar Avinash , Park Tae Woo , Bohnert Amy S.B.
Published: August 2016

The present clinical case discussion focuses on a patient with comorbid substance use disorder (SUD) and chronic pain, who experienced an overdose of heroin. The case illustrates the complex array of risk factors that contribute to overdose risk, discusses the use of naloxone, and highlights the need for further risk mitigation interventions in patients at risk for overdose.
Understanding Risk Factors for Opioid Overdose in Clinical Populations to Inform Treatment and Policy
Authors: Park Tae Woo , Lin Lewei Allison , Hosanagar Avinash , Kogowski Amanda , Paige Katie , Bohnert Amy S.B.
Published: August 2016

Overdoses involving opioid analgesics represent a significant public health problem in the United States. We reviewed the literature on risk factors for overdose, with a focus on studies that examine clinical populations of patients receiving opioids for pain and potential risk factors for overdose in these populations. A structured review resulted in 15 articles published between 2007 and 2015 that examined risk factors for fatal and nonfatal overdose in patients receiving opioid analgesics. Opioid dosage was the factor most consistently analyzed and also associated with increased risk of overdose. Other risk factors include concurrent use of sedative-hypnotics, use of extended-release/long-acting opioids, and the presence of substance use and other mental health disorder comorbidities. Future research is needed to better characterize populations taking opioids for pain to help clarify discrepancies between existing studies and identify previously unexplored risk factors for overdose. Given that policy and clinical practice have shifted as a result of prior studies reviewed here, further efforts in understanding patient groups and opioid-related prescribing practices associated with overdose risk have great potential to impact policy and practice in the treatment of pain while improving the safety around opioid prescribing.
Preoperative Hypoalgesia After Cold Pressor Test and Aerobic Exercise is Associated With Pain Relief 6 Months After Total Knee Replacement
Authors: Vaegter Henrik B. , Handberg Gitte , Emmeluth Claus , Graven-Nielsen Thomas
Published: August 2016

Objectives:

Chronic pain after total knee replacement (TKR) is not uncommon. Preoperative impaired conditioning pain modulation (CPM) has been used to predict chronic postoperative pain. Interestingly, exercises reduce pain sensitivity in patients with knee osteoarthritis (KOA). This pilot study investigated the association between exercise-induced hypoalgesia (EIH) and CPM on post-TKR pain relief.

Methods:

Before and 6 months post-TKR, 14 patients with chronic KOA performed the cold pressor test on the nonaffected leg and 2 exercise conditions (bicycling and isometric knee extension), randomized and counterbalanced. Before and during the cold pressor test and after exercises test stimuli were applied to extract the pain sensitivity difference: computer-controlled cuff inflation on the affected lower leg until the participants detected the cuff pain threshold (cPPT) and subsequently the cuff pain tolerance (cPTT) and manual pressure pain thresholds (PPTs) at the legs, arm, and shoulder. Clinical pain intensity (numerical rating scale [NRS]) and psychological distress (questionnaires) were assessed.

Results:

Clinical pain intensity, psychological distress, cPPT, and PPT at the affected leg improved post-TKR compared with pre-TKR (P<0.05). Preoperatively, the CPM and bicycling EIH assessed by the increase in cPTT correlated with reduction in NRS pain scores post-TKR (P<0.05). Improved CPM and EIH responses after TKR were significantly correlated with reduction in NRS pain scores post-TKR (P<0.05).

Discussion:

In KOA patients, hypoalgesia after cold pressor stimulation and aerobic exercise assessed preoperatively by cuff algometry was associated with pain relief 6 months after TKR. EIH as a novel preoperative screening tool should be further investigated in larger studies.
Decision Making Among Older Adults at the End of Life
Authors: Romo Rafael D. , Dawson-Rose Carol S. , Mayo Ann M. , Wallhagen Margaret I.
Published: August 2016

Understanding changes in decision making among older adults across time is important for health care providers. We examined how older adults with a limited prognosis used their perception of prognosis and health in their decision-making processes and related these findings to prospect theory. The theme of decision making in the context of ambiguity emerged, reflecting how participants used both prognosis and health to value choices, a behavior not fully captured by prospect theory. We propose an extension of the theory that can be used to better visualize decision making at this unique time of life among older adults.
Discourse Strategies and the Production of Prosody by Prelingually Deaf Adolescent Cochlear Implant Users
Authors: Holt Colleen M. , Yuen Ivan , Demuth Katherine
Published: August 2016

Objectives:

The purpose of this study is to assess the use of discourse strategies and the production of prosody by prelingually deaf adolescent users of cochlear implants (CIs) when participating in a referential communication task. We predict that CI users will issue more directives (DIRs) and make less use of information requests (IRs) in completing the task than their normally hearing (NH) peers. We also predict that in signaling these IRs and DIRs, the CI users will produce F0 rises of lesser magnitude than the NH speakers.

Design:

Eight prelingually deaf adolescent CI users and 8 NH adolescents completed a referential communication task, where participants were required to direct their interlocutor around a map. Participants were aged from 12.0 to 14.2 years. The mean age at implantation for the CI group was 2.1 years (SD 0.9). The use of IRs, DIRs, acknowledgments, and comments was compared between the two groups. The use and magnitude of fundamental frequency (F0) rises on IRs and DIRs was also compared.

Results:

The CI users differed from the NH speakers in how they resolved communication breakdown. The CI users showed a preference for repeating DIRs, rather than seeking information as did the NH speakers. A nonparametric Mann–Whitney U test indicated that the CI users issued more DIRs (U = 8, p = 0.01), produced fewer IRs (U = 13, p = 0.05) and fewer acknowledgments (U = 5, p = 0.003) than their NH counterparts. The CI users also differed in how they used F0 rises as a prosodic cue to signal IRs and DIRs. The CI users produced larger F0 rises on DIRs than on IRs, a pattern opposite to that displayed by the NH speakers. An independent samples t-test revealed that the CI users produced smaller rises on IRs compared with those produced by the NH speakers [t(12) = −2.762, p = 0.02].

Conclusions:

The CI users differed from the NH speakers in how they resolved communication breakdown. The CI users showed a preference for repeating DIRs, rather than seeking information to understand their interlocutor’s point of view. Their use of prosody to signal discourse function also differed from their NH peers. These differences may indicate a lack of understanding of how prosody is used to signal discourse modality by the CI users. This study highlights the need for further research focused on the interaction of prosody, discourse, and language comprehension.
Cost Associated With Pediatric Delirium in the ICU
Authors: Traube Chani , Mauer Elizabeth A. , Gerber Linda M. , Kaur Savneet , Joyce Christine , Kerson Abigail , Carlo Charlene , Notterman Daniel , Worgall Stefan , Silver Gabrielle , Greenwald Bruce M.
Published: August 2016

Objective:

To determine the costs associated with delirium in critically ill children.

Design:

Prospective observational study.

Setting:

An urban, academic, tertiary-care PICU in New York city.

Patients:

Four-hundred and sixty-four consecutive PICU admissions between September 2, 2014, and December 12, 2014.

Interventions:

None.

Measurements and Main Results:

All children were assessed for delirium daily throughout their PICU stay. Hospital costs were analyzed using cost-to-charge ratios, in 2014 dollars. Median total PICU costs were higher in patients with delirium than in patients who were never delirious ($18,832 vs $4,803; p < 0.0001). Costs increased incrementally with number of days spent delirious (median cost of $9,173 for 1 d with delirium, $19,682 for 2–3 d with delirium, and $75,833 for > 3 d with delirium; p < 0.0001); this remained highly significant even after adjusting for PICU length of stay (p < 0.0001). After controlling for age, gender, severity of illness, and PICU length of stay, delirium was associated with an 85% increase in PICU costs (p < 0.0001).

Conclusions:

Pediatric delirium is associated with a major increase in PICU costs. Further research directed at prevention and treatment of pediatric delirium is essential to improve outcomes in this population and could lead to substantial healthcare savings.
Safety of Immediate-Release Nifedipine
Authors: Means Laura , Benken Scott T. , Tesoro Eljim P.
Published: August 2016

Nifedipine immediate release (IR) is a short-acting dihydropyridine calcium channel blocker historically used for hypertensive crisis, but its use has decreased because of reports of adverse reactions such as myocardial infarction (MI), arrhythmias, and stroke. This was a retrospective evaluation of the safety of nifedipine IR in 122 patients at an academic medical center from January 1, 2009, to December 31, 2014. Patients were separated into high- and low-risk groups. High risk was defined as a medical history significant for arrhythmia, MI, or stroke. The primary outcome was a comparison of the composite incidence of nifedipine-associated adverse events including the following: new cardiology consultation, sentinel arrhythmia, stroke, MI, need for blood pressure support, transition to higher levels of care, or death. A per-dose incidence of 2.4% and per-patient incidence of 7.3% in this composite endpoint were found, with no differences between the groups. Patients received median doses of 10 mg and follow-up within 2.8 hours. There were no cases of death in either group. Although nifedipine IR may cause major adverse events, the incidence seems lower than previously believed. Future research is warranted to evaluate whether nifedipine IR may be an option to treat elevated blood pressure in hospitalized patients.
Enhanced Platelet Response to Clopidogrel in Abcc3-deficient Mice Due to Its Increased Bioactivation
Authors: Tai Ting , Mi Qiong-Yu , Ji Jin-Zi , Yin Qian , Pan Yu-Qin , Zhang Meng-Ran , Huang Bei-Bei , Xie Hong-Guang
Published: August 2016

Resistance of the patient to clopidogrel (an inactive prodrug) has been recently reported to be associated with increased messenger RNA expression of ABCC3 that encodes MRP3 (multidrug resistance–associated protein 3). However, there is no evidence showing the effects of MRP3 on altered platelet responses to clopidogrel and their underlying mechanisms. To further clarify whether the presence or absence of Mrp3 could affect the formation of and response to clopidogrel active metabolite (CAM) in Abcc3 knockout (KO) versus wild-type (WT) mice, we determined pharmacokinetic profiles of clopidogrel and CAM and measured inhibition of adenosine diphosphate–induced platelet aggregation by clopidogrel after administration of a single oral dose of clopidogrel to KO and WT mice, respectively. Results indicated that Abcc3 KO mice exhibited increased formation of CAM and greater systemic exposure to clopidogrel and enhanced inhibition of adenosine diphosphate–induced platelet aggregation ex vivo by clopidogrel when compared with well-matched WT mice. We conclude that Abcc3 KO mice have enhanced platelet response to clopidogrel due to increased formation of CAM.
Common prepubertal vulvar conditions
Authors: Vilano Samantha E. , Robbins Cynthia L.
Published: August 2016

Purpose of review

The purpose of this article is to provide an update for the GP on selected common vulvar concerns in prepubertal girls. Presentation, diagnostic criteria, and management of common vulvar conditions will be described. The following conditions are frequently encountered and may pose diagnostic or management challenges if unrecognized.

Recent findings

The article is a review of current literature on pediatric vulvar conditions and was conducted through searching PubMed and published books on this topic. Areas of interest frequently encountered by providers are presented, including vulvovaginitis, genital ulcers, lichen sclerosus, and labial adhesions along with the most recent North American Society for Pediatric and Adolescent Gynecology recommendations for diagnosis and management.

Vulvar complaints in prepubertal girls are common. Many present with nonspecific symptoms and consequently, the diagnosis may be missed or delayed. Prompt recognition improves long-term outcomes and importantly, provides a positive introduction to longitudinal women's health for young girls.
Evaluation of an Amino Acid−Based Formula in Infants Not Responding to Extensively Hydrolyzed Protein Formula
Authors: Vanderhoof Jon , Moore Nancy , de Boissieu Delphine
Published: August 2016

Nearly 2% to 3% of infants and children younger than 3 years have confirmed cow's milk protein allergy with multiple clinical presentations including atopic dermatitis (AD), diarrhea, and vomiting/spitting up. Although most infants with cow's milk protein allergy experience clinical improvement with the use of an extensively hydrolyzed (EH) formula, highly sensitive infants may require an amino acid−based formula. In this observational, prospective study, 30 infants (1–12 months of age) with a history of weight loss and persistent allergic manifestations while on an EH formula were provided an amino acid−based formula for 12 weeks. Mean weight gain (z score change) improved +0.43 ± 0.28 (mean ± standard deviation) after the 12‐week feeding period. Improvement was observed for many allergic symptoms including significant decreases in AD severity (P = 0.02). These results indicate the new amino acid–based infant formula supported healthy weight gain and improvement in allergic manifestations in infants not responding to EH formulas.
Lymphocytic Esophagitis in Nonachalasia Primary Esophageal Motility Disorders
Authors: Putra Juan , Muller Kristen E. , Hussain Zilla H. , Parker Siddhartha , Gabbard Scott , Brickley Elizabeth B. , Lacy Brian E. , Rothstein Richard , Lisovsky Mikhail
Published: August 2016

Lymphocytic esophagitis (LE) is a histologic pattern with no established clinical correlates in the majority of patients. The goal of this study was to evaluate the association between nonachalasia primary esophageal motility disorders (PEMD) and LE. Sixty-nine patients with PEMD and esophageal biopsies, including 22 with nutcracker esophagus, 33 with ineffective motility, and 14 with diffuse spasm, constituted the study group. The control group consisted of 70 patients with severe dysmotility-negative gastroesophageal reflux disease requiring referral for Nissen fundoplication. To improve the criteria for LE, a lymphocyte reference range at different esophageal levels was first established in 17 healthy volunteers. The cutoffs for normal intraepithelial lymphocytes, defined as lymphocyte levels not exceeding mean level±2 SDs, were set at 62, 46, and 41 lymphocytes per high-power field at 0 to 2, 5, and 10 cm above the gastroesophageal junction, respectively. Predominantly focal peripapillary LE was observed in approximately 40% of patients with nutcracker esophagus or diffuse spasm and in 20% of patients with ineffective motility, in comparison with 4% of patients with dysmotility-negative gastroesophageal reflux disease (P<0.035 vs. any subtype of PEMD). Overall, LE was strongly associated with PEMD in multivariate analysis (adjusted odds ratio, 7.93; 95% confidence interval, 2.26-27.9; P=0.001). LE had a chronic course in 56% of the patients with follow-up biopsies. In conclusion, LE has a strong association with PEMD, suggesting the utility of LE in raising the possibility of PEMD.
Lingering representations of stimulus history at encoding influence recall organization
Authors: Chan Stephanie C.Y. , Applegate Marissa C. , Morton Neal W , Polyn Sean M. , Norman Kenneth A.
Published: August 2016

Several prominent theories posit that information about recent experiences lingers in the brain and organizes memories for current experiences, by forming a temporal context that is linked to those memories at encoding. According to these theories, if the thoughts preceding an experience X resemble the thoughts preceding an experience Y, then X and Y should show an elevated probability of being recalled together. We tested this prediction by using multi-voxel pattern analysis (MVPA) of fMRI data to measure neural evidence for lingering processing of preceding stimuli. As predicted, memories encoded with similar lingering thoughts (about the category of preceding stimuli) were more likely to be recalled together, thereby showing that the “fading embers” of previous stimuli help to organize recall.
Gene expression markers of Tumor Infiltrating Leukocytes
Authors: Danaher Patrick , Warren Sarah , Dennis Lucas , D’Amico Leonard , White Andrew , Disis Mary L. , Geller Melissa A. , Odunsi Kunle , Beechem Joseph , Fling Steven P.
Published: August 2016

Background

Assays of the abundance of immune cell populations in the tumor microenvironment promise to inform immune oncology research and the choice of immunotherapy for individual patients. We propose to measure the intratumoral abundance of various immune cells populations with gene expression. In contrast to IHC and flow cytometry, gene expression assays yield high information content from a clinically practical workflow. Previous studies of gene expression in purified immune cells have reported hundreds of genes showing enrichment in a single cell type, but the utility of these genes in tumor samples is unknown. We describe a novel statistical method for using co-expression patterns in large tumor gene expression datasets to validate previously reported candidate cell type marker genes, and we use this method to winnow previously published gene lists down to a subset of high confidence marker genes.

Methods

We use co-expression patterns in 9986 samples from The Cancer Genome Atlas (TCGA) to validate previously reported cell type marker genes. We compare immune cell scores derived from these genes to measurements from flow cytometry and immunohistochemistry. We characterize the reproducibility of our cell scores in replicate runs of RNA extracted from FFPE tumor tissue.

Results

We identify a list of 60 marker genes whose expression levels quantify 14 immune cell populations. Cell type scores calculated from these genes are concordant with flow cytometry and IHC readings, show high reproducibility in replicate RNA samples from FFPE tissue, and reveal an intricate picture of the immune infiltrate in TCGA. Most genes previously reported to be enriched in a single cell type have co-expression patterns inconsistent with cell type specificity.

Conclusions

Due to their concise gene set, computational simplicity and utility in tumor samples, these cell type gene signatures may be useful in future discovery research and clinical trials to understand how tumors and therapeutic intervention shape the immune response.