bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Philosophy of Bitcoin/Blockchain Technology: Is it a Chaotic, Complex System?
Authors: Dos Santos Renato P.
Published: October 2017

The philosophy of blockchain technology is concerned, among other things, with blockchain ontology, how it might be characterised, how it is being created, implemented, and adopted, how it operates in the world, and how it evolves over time. This paper concentrates on whether Bitcoin/blockchain can be considered a complex system and, if so, whether it is a chaotic one. Beyond mere academic curiosity, a positive response would raise concerns about the likelihood of Bitcoin/blockchain entering a 2010‐Flash‐Crash‐type of chaotic regime, with catastrophic consequences for financial systems based on it. The paper starts by highlighting the relevant details of the Bitcoin/blockchain ecosystem formed by the blockchain itself, bitcoin end users (payers and payees), capital gains seekers, miners, full nodes maintainers, and developers, and their interactions. Then the Information Theory of Complex Systems is briefly discussed for later use. Finally, the blockchain is investigated with the help of Crutchfield's Statistical Complexity measure. The low non‐null statistical complexity value obtained suggests that the blockchain may be considered algorithmically complicated but hardly a complex system and unlikely to enter a chaotic regime.
Blockchain Identities: Notational Technologies for Control and Management of Abstracted Entities
Authors: Dupont Quinn
Published: October 2017

This paper argues that many so‐called digital technologies can be construed as notational technologies, explored through the example of Monegraph, an art and digital asset management platform built on top of the blockchain system originally developed for the cryptocurrency bitcoin. As the paper characterizes it, a notational technology is the performance of syntactic notation within a field of reference, a technologized version of what Nelson Goodman called a “notational system.” Notational technologies produce abstracted entities through positive and reliable, or constitutive, tests of socially acceptable meaning. Accordingly, this account deviates from typical narratives of blockchains (usually characterized as Turing or state machines), instead demonstrating that blockchain technologies are effective at managing digital assets because they produce abstracted identities through the performance of notation. Since notational technologies rely on configurations of socially acceptable meaning, this paper also provides a philosophical account of how blockchain technologies are socially embedded.
Philosophical Criteria in Whitehead and Rorty
Authors: Duvernoy Russell J.
Published: October 2017

Rorty's aversion to metaphysics is well known, so the extent of his early work on Whitehead might come as a surprise. This article examines the young Rorty's critical assessment of Whitehead to show how it demonstrates the consequences of diverging metaphilosophical orientations. It argues that Rorty's insistence on judging Whitehead's work through an exclusively epistemological frame causes him to miss its more radical existential and epistemic implications. After examining how Rorty and Whitehead operate with different cost‐benefit analyses as to the risks and benefits of speculative philosophy, it suggests that closer attention to the fuller stakes of Whitehead's project shows that his metaphysics are not opposed to the “poeticized” culture that Rorty calls for, one where the distinction between making and finding is no longer metaphysically foundational.
Ankyloglossia as a risk factor for maxillary hypoplasia and soft palate elongation: A functional – morphological study
Authors: Yoon A. J. , Zaghi S. , Ha S. , Law C. S. , Guilleminault C. , Liu S. Y.
Published: October 2017

Structured Abstract

Objectives

To characterize associations between restricted tongue mobility and maxillofacial development.

Setting and Sample Population

Cross‐sectional cohort study of 302 consecutive subjects from an orthodontic practice.

Material and Methods

Tongue mobility (measured with tongue range of motion ratio [TRMR] and Kotlow free tongue measurement) was correlated with measurements of the maxillofacial skeleton obtained from dental casts and cephalometric radiographs.

Results

Tongue range of motion ratio and Kotlow measures of restricted tongue mobility were associated with (i) ratio of maxillary intercanine width to canine arch length, (ii) ratio of maxillary intermolar width to canine arch length and (iii) soft palate length. Restricted tongue mobility was not associated with hyoid bone position or Angle's skeletal classification.

Conclusions

Restricted tongue mobility was associated with narrowing of the maxillary arch and elongation of the soft palate in this study. These findings suggest that variations in tongue mobility may affect maxillofacial development.
The Line, the Void and the Current: Iron Age Art from a Design Theory Perspective
Authors: Romankiewicz Tanja
Published: October 2017

Objects from the European Iron Age decorated with swirls and scrolls, faces and figures, and generally referred to as Early Celtic Art, can offer deep insight into later prehistoric notions of creativity. By drawing on archaeology and social anthropology, art and architectural design, this theoretical discourse investigates the design processes involved in the creation of Early Celtic Art. Rather than attempting to decipher a meaning behind decoration, this enquiry uses architectural ‘Design Theory’ to explore the implications of certain design choices. It starts with the premise that these designs are integral to the objects in order to identify different layers of complexity, innovation and emulation, and ends with wider reflections on who was creative and how. This approach, borrowed from architectural analysis, aims to open a new line of enquiry into the fascinating world of Iron Age creativity.
Prognosis, risk stratification, and management of asymptomatic individuals with Brugada syndrome: A systematic review
Authors: Letsas Konstantinos P. , Asvestas Dimitrios , Baranchuk Adrian , Liu Tong , Georgopoulos Stamatis , Efremidis Michael , Korantzopoulos Panagiotis , Bazoukis George , Tse Gary , Sideris Antonios , Takagi Masahiko , Ehrlich Joachim R.
Published: October 2017

Brugada syndrome (BrS) is a primary electrical disease associated with increased risk of sudden cardiac death due to polymorphic ventricular arrhythmias. The prognosis, risk stratification, and management of asymptomatic individuals remain the most controversial issues in BrS. Furthermore, the decision to manage asymptomatic patients with an implantable cardioverter‐defibrillator should be made after weighing the potential individual risk of future arrhythmic events against the risk of complications associated with the implant and follow‐up of patients living with such devices, and the accompanying impairment of the quality of life. Several clinical, electrocardiographic, and electrophysiological markers have been proposed for risk stratification of subjects with BrS phenotype, but the majority have not yet been tested in a prospective manner in asymptomatic individuals. Recent data suggest that current risk factors are insufficient and cannot accurately predict sudden cardiac death events in this setting. This systematic review aims to discuss contemporary data regarding prognosis, risk stratification, and management of asymptomatic individuals with diagnosis of Brugada electrocardiogram pattern and to delineate the therapeutic approach in such cases.
Connecting governance and the front lines: How work pressure and autonomy matter for coping in different performance regimes
Authors: van Loon Nina Mari , Jakobsen Mads Leth
Published: October 2017

How frontline employees cope with perceived work pressure may be of direct influence on policy outcomes. This study contributes to the street‐level bureaucracy literature in several ways. First, we study both passive client‐oriented and active system‐oriented coping. Second, we analyse how these coping behaviours relate to work pressure and work autonomy. Finally, this article analyses whether these relationships are conditioned by the performance regime. Using a unique set‐up of hospital employees (n = 979) working in external and internal performance regimes, we find a higher level of system‐oriented active coping than client‐oriented passive coping. Moreover, we find that autonomy matters for system‐oriented coping and work pressure for client‐oriented coping, and that these relationships are context‐dependent.
Quantitative trait loci underlying soybean seed tocopherol content with main additive, epistatic and QTL × environment effects
Authors: Liu Huancheng , Cao Guanglu , Wu Depeng , Jiang Zhenfeng , Han Yingpeng , Li Wenbin
Published: October 2017

Soybean (Glycine max [L.] Merrill) seeds are a major source of tocopherols (Toc), which could significantly improve immune system health of human and prevent or treat many serious diseases. Selection for higher Toc contents of seeds could increase nutritional value of soybean‐derived food, laying on an important breeding goal for many soybean breeders. The present objectives of the work were to evaluate various genetic effects of QTL associated with individual and total Toc content based on a RIL population (“Beifeng 9” × “Freeborn”) in six environments to improve the efficiency of molecular marker‐assisted selection (MAS) for high‐Toc breeding. The results described that eighteen, thirteen, eleven and thirteen QTL were associated with α‐Toc, γ‐Toc, δ‐Toc and total Toc content, respectively, and have additive main effects (a) and/or additive × environment interaction effects (ae) in certain environments. Among them, four QTL for α‐Toc, two QTL for γ‐Toc, one QTL for δ‐Toc and four QTL for total Toc could increase α‐Toc, γ‐Toc, δ‐Toc and total Toc content via significant a effect, respectively, which have stronger stability in different years and locations. It implied a value for MAS. Additionally, twenty‐five, fifteen, eleven and twenty epistatic pairwise QTL associated with α‐Toc, γ‐Toc, δ‐Toc and total Toc contents, respectively, were detected. The genetic information of the QTL effects obtained here would be beneficial for breeding soybean variety with high‐Toc content by MAS.
Considering self‐interests and symbolism together: How instrumental and value‐expressive motives interact to influence supervisors’ justice behavior
Authors: Qin Xin , Ren Run , Zhang Zhi‐Xue , Johnson Russell E.
Published: October 2017

Drawing upon functional theories of attitudes and the organizational justice literature, the current research suggests that people's attitudes toward justice likely serve an instrumental function (grounded in self‐interest, rewards maximization, and punishment minimization) as well as a value‐expressive function (grounded in the expression of self‐concept and values). Importantly, these two functions co‐exist and interact to influence supervisors’ justice behavior and the consistency of such behavior via supervisors’ justification for unjust behavior. Findings from a set of experimental and correlational studies confirmed these predictions. The positive effects of supervisors’ value‐expressive function on justice behavior and its consistency were stronger when their instrumental function was lower (vs. higher), and justification for unjust behavior mediated these effects. Also, supplementary analyses showed that the consistency of supervisors’ justice behavior positively predicted subordinates’ overall justice perceptions beyond the effects of the overall level of justice behavior. We conclude by discussing the theoretical and practical implications of these findings.
Citizenship allocation and withdrawal: Some normative issues
Authors: Ferracioli Luara
Published: October 2017

Philosophical discussion about citizenship has traditionally focused on the questions of what citizenship is, its relationship to civic virtue and political participation, and whether or not it can be meaningfully exercised at the supra‐national level. In recent years, however, philosophers have turned their attention to the legal status attached to citizenship and have questioned existing principles of citizenship allocation and withdrawal. With regard to the question of who is morally entitled to citizenship, philosophers have argued for principles of citizenship allocation that go beyond birth and lineage and have focused instead on the value of political attachment and located life plans. These principles have several advantages over existing legal principles, but they suffer from being under‐specified, as well as being over and under‐inclusive. With regard to loss of citizenship, philosophers have primarily denounced citizenship withdrawal as a form of punishment by appealing to principles of fair and equal treatment. However, theories purporting to show that denationalization is always wrong have trouble explaining why loss of citizenship is so problematic for persons who have committed the most horrendous crimes against their fellow citizens and who, in so doing, have in effect self‐excluded from the political community.
Pollination in the Chilean Mediterranean‐type ecosystem: a review of current advances and pending tasks
Authors: Medel R. , González‐Browne C. , Fontúrbel F.E.
Published: October 2017

We conducted a systematic review of the scientific literature published on plant–pollinator interactions, from both the plant and pollinator perspective, in the Chilean Mediterranean‐type ecosystem (MTE hereafter). Our search identified 69 published papers on 235 native plant species from 62 families. Less than 7.9% of the flowering species inhabiting the Chilean Mediterranean have been studied, and most studies were restricted to only one locality and one reproductive season. The geographic location of the studies differed from a random pattern, showing two well‐defined areas where most studies were conducted. Likewise, most studies in the Andes Range were performed above 2000 m a.s.l. The number of species of flower visitor per plant species was low (4.25 ± 0.22), which probably results from the historical and biogeographic isolation of Chile. This literature survey shows that studies relating floral traits with pollinator attraction and plant reproduction are the most frequent topics of research, reaching 37.6% of studies, followed by studies that examine pollination in relation to human impact (16.1%), micro‐ and macroevolution (14.0%), relationships between pollination and other ecological interactions (10.8%), community and network assessments (11.8%), and effects of abiotic variables on pollination interactions (9.7%). Our review highlights a lack of research on the effects of pollination for anthropogenic land use especially as agricultural practice is one of the most salient features of the Chilean MTE. Future directions to increase our understanding of the role of plant–pollinator relationships for biodiversity maintenance should include: to extend the taxonomic and geographic scope of research, to increase the number of spatial and temporal replicates, to increase the number of studies on pollination networks as they provide estimates of community complexity and putative stability, to develop studies that estimate the importance of pollination for plant demographic parameters and conservation, and to conduct studies that estimate the ecological service provided by Chilean native pollinators for crop yield and sustainable agriculture.
Strength training improves double‐poling performance after prolonged submaximal exercise in cross‐country skiers
Authors: Øfsteng S. , Sandbakk Ø. , van Beekvelt M. , Hammarström D. , Kristoffersen R. , Hansen J. , Paulsen G. , Rønnestad B. R.
Published: October 2017

The purpose of this study was to investigate the effects of adding strength training with or without vibration to cross‐country (XC) skiers’ endurance training on double‐poling (DP) performance, physiological, and kinematic adaptations. Twenty‐one well‐trained male XC‐skiers combined endurance‐ and upper‐body strength training three times per week, either with (n = 11) or without (n = 10) superimposed vibrations for 8 weeks, whereas eight skiers performed endurance training only (CON). Testing included 1RM in upper‐body exercises, work economy, neural activation, oxygen saturation in muscle, and DP kinematics during a prolonged submaximal DP roller ski test which was directly followed by a time to exhaustion (TTE) test. TTE was also performed in rested state, and the difference between the two TTE tests (TTEdiff) determined the ability to maintain DP performance after prolonged exercise. Vibration induced no additional effect on strength or endurance gains. Therefore, the two strength training groups were pooled (STR, n = 21). 1RM in STR increased more than in CON (P < .05), and there were no differences in changes between STR and CON in any measurements during prolonged submaximal DP. STR improved TTE following prolonged DP (20 ± 16%, P < .001) and revealed a moderate effect size compared to CON (ES = 0.80; P = .07). Furthermore, STR improved TTEdiff more than CON (P = .049). In conclusion, STR superiorly improved 1RM strength, DP performance following prolonged submaximal DP and TTEdiff, indicating a specific effect of improved strength on the ability to maintain performance after long‐lasting exercise.
Approaches to civil society in authoritarian states: The case of China
Authors: Gleiss Marielle Stigum , Sæther Elin
Published: October 2017

Both civil society in China and research on Chinese civil society have developed profoundly over the last three decades. Research on Chinese civil society can be classified into two categories: a structure‐oriented approach and an agency‐oriented approach. Both approaches acknowledge the state's dominant position in restricting the political space for civil society engagement, but they differ in their understanding of state–civil society relations. A key concern within the structure‐oriented approach is to analyze how the autonomy of civil society organizations is shaped by their structural position vis‐à‐vis the state. Agency‐oriented scholars, on the other hand, reject the analytical focus on structural autonomy. Instead, they build on a more nuanced understanding of the authoritarian yet nonmonolithic context in China and analyze how civil society organizations develop specific strategies to be able to operate within their restricted political space. In particular, agency‐oriented scholars have analyzed two ways in which organizations exercise agency: by strategically developing formal or informal ties with state actors and by bringing their engagement into the public sphere to raise awareness and express their voice. What could be further developed in the agency‐oriented approach is, however, a deeper understanding of the political dimensions of civil society agency.
Morphology‐based modeling of aggregation effect on the patch area size for GlobeLand30 data
Authors: Tan Shiteng , Xu Zhu , Ti Peng , Li Zhilin
Published: October 2017

Currently, research on the scale effect mainly concentrates on revealing and describing the phenomenon; little work has been done to model the scaling of analysis indicators along with the scale change of the data. Such models can help explain and estimate the scale effect and are thus of great interest. As patch morphology significantly influences patch evolution over data scale transformation, this study proposes a model that applies patch morphology metrics to explain and estimate the change in the patch and category area ratio in the upscaling of raster categorical data. In the experimental evaluation, area scaling of GlobeLand30 data under majority aggregation is studied intensively. Two metrics—the ratio of the patch area after aggregation to its original area and the ratio of the category area after aggregation to its original area—are used in this evaluation. The experimental results indicate that this model can adequately describe the pattern of the patch area change and precisely estimate the category area change arising from the resolution change. It is also demonstrated that the spatial distribution of patches has much less influence on the change in the category areas compared with the patch morphology. Additionally, the modeling approach in this study may also be adopted to investigate the scaling of other landscape metrics.
Computed tomographic findings in 205 dogs with clinical signs compatible with middle ear disease: a retrospective study
Authors: Belmudes Audrey , Pressanti Charline , Barthez Paul Y. , Castilla‐Castaño Eloy , Fabries Lionel , Cadiergues Marie C.
Published: October 2017

Background

Computed tomography (CT) is considered to be the reference method to evaluate middle ear structures.

Objectives

To evaluate the presence and severity ofCTchanges in the middle ear and establish if any specific clinical presentations are associated with otitis media.

Animals

Medical records of animals referred forCTwith history and clinical signs consistent with middle ear disease.

Methods

Retrospective evaluation ofCTexaminations of tympanic bullae performed over a six year period. Medical records were reviewed for signalment, clinical signs and cytological evaluation of the external ear canal. Dogs were divided into three clinical groups: chronic otitis externa (Group 1), peripheral vestibular disorder (Group 2) and other clinical presentations (Group 3).

Results

Group 1 – Of 214 ears, 87 (40.7%) hadCTabnormalities: 38 of 87 (17.7%) had material‐filled bullae, 42 of 87 (19.6%) had thickened bullae walls and seven of 87 (3.2%) had lysis of the bulla. Abnormalities were significantly more frequent in dogs with suppurative otitis than in erythemato–ceruminous otitis (57% and 23%, respectively;P = 0.003). Proliferative otitis, particularly in French bulldogs, was associated with severe otitis media.

Group 2 – Of the 106 ears, 91 (85.8%) had normal tympanic bullae.

Group 3 – Of the 26 ears from deaf dogs, 17 had filled bullae; all nine affected dogs were Cavalier King Charles spaniels. All dogs with Claude Bernard Horner syndrome or head tilt had normal tympanic bullae.

Clinical significance

CTis useful for canine chronic otitis externa, particularly in suppurative or proliferative otitis, even in the absence of associated neurological signs.
The computed tomographic “tree‐in‐bud” pattern: Characterization and comparison with radiographic and clinical findings in 36 cats
Authors: Hahn Harriet , Specchi Swan , Masseau Isabelle , Reinero Carol , Benchekroun Ghita , Rechy Jaime , Seiler Gabriela , Pey Pascaline
Published: October 2017

In humans, a CT “tree‐in‐bud” pattern has been described as a characteristic of centrilobular bronchiolar dilation, with bronchiolar plugging by mucus, pus, or fluid. Aims of this retrospective, descriptive, multi‐center study were to characterize the CT appearance of a “tree‐in‐bud” pattern in a group of cats, and compare this pattern with radiographic and clinical findings. Databases from four hospitals were searched during the period of January 2012 to September 2015 and cats with thoracic radiographs, thoracic CT scans and CT reports describing findings consistent with a “tree‐in‐bud” pattern were included. Images were reviewed by two veterinary radiologists and characteristics were recorded based on consensus. Clinical findings were recorded by one observer from each center. Thirty‐six cats met inclusion criteria. Six cats were asymptomatic, 12 were diagnosed with bronchial disease and 23 were suspected to have bronchial disease. Right cranial and right caudal lung lobes were most commonly affected on both imaging modalities. Localization of the “tree‐in‐bud” pattern was most often peripheral. On radiographs, the CT “tree‐in‐bud” pattern often appeared as soft‐tissue opacity nodules; their number and affected pulmonary segments were often underestimated compared with CT. In conclusion, the “tree‐in‐bud” pattern should be considered as a differential diagnosis for radiographic soft tissue opaque nodules in feline lungs. Based on lesion localization and presence or suspicion of a concomitant bronchial disease for cats in this sample, authors propose that the CT “tree‐in‐bud” pattern described in humans is also a characteristic of bronchial or bronchiolar plugging and bronchial disease in cats.
New function method to the (n+1)-dimensional nonlinear problems
Authors: Aktürk Tolga , Gürefe Yusuf , Bulut Hasan
Published: October 2017

In this study, a new approach that assumes  and  is applied to construct the traveling wave solutions of the (N + 1)-dimensional double sine-Gordon and (N + 1)-dimensional double sinh-cosh-Gordon equations. Some new elliptic integral function solutions are respectively obtained by this method, and then these solutions are converted into the Jacobi elliptic function solutions. According these results, one can easily see that this method is very effective mathematical tool for the (N+1)-dimensional nonlinear physical problems.
Using self-organizing maps to classify humpback whale song units and quantify their similarity
Authors: Allen Jenny A. , Murray Anita , Noad Michael J. , Dunlop Rebecca A. , Garland Ellen C.
Published: October 2017

Classification of vocal signals can be undertaken using a wide variety of qualitative and quantitative techniques. Using east Australian humpback whale song from 2002 to 2014, a subset of vocal signals was acoustically measured and then classified using a Self-Organizing Map (SOM). The SOM created (1) an acoustic dictionary of units representing the song's repertoire, and (2) Cartesian distance measurements among all unit types (SOM nodes). Utilizing the SOM dictionary as a guide, additional song recordings from east Australia were rapidly (manually) transcribed. To assess the similarity in song sequences, the Cartesian distance output from the SOM was applied in Levenshtein distance similarity analyses as a weighting factor to better incorporate unit similarity in the calculation (previously a qualitative process). SOMs provide a more robust and repeatable means of categorizing acoustic signals along with a clear quantitative measurement of sound type similarity based on acoustic features. This method can be utilized for a wide variety of acoustic databases especially those containing very large datasets and can be applied across the vocalization research community to help address concerns surrounding inconsistency in manual classification.
Effects of exposure to sonar playback sounds (3.5 – 4.1 kHz) on harbor porpoise (Phocoena phocoena) hearing
Authors: Kastelein Ronald A. , Helder-Hoek Lean , Van de Voorde Shirley
Published: October 2017

Safety criteria for naval sonar sounds are needed to protect harbor porpoise hearing. Two porpoises were exposed to sequences of AN/SQS-53C sonar playback sounds (3.5–4.1 kHz, without significant harmonics), at a mean received sound pressure level of 142 dB re 1 μPa, with a duty cycle of 96% (almost continuous). Behavioral hearing thresholds at 4 and 5.7 kHz were determined before and after exposure to the fatiguing sound, in order to quantify temporary threshold shifts (TTSs) and hearing recovery. Control sessions were also conducted. Significant mean initial TTS1-4 of 5.2 dB at 4 kHz and 3.1 dB at 5.7 kHz occurred after 30 min exposures (mean received cumulative sound exposure level, SELcum: 175 dB re 1 μPa2s). Hearing thresholds returned to pre-exposure levels within 12 min. Significant mean initial TTS1-4 of 5.5 dB at 4 kHz occurred after 60 min exposures (SELcum: 178 dB re 1 μPa2s). Hearing recovered within 60 min. The SELcum for AN/SQS-53C sonar sounds required to induce 6 dB of TTS 4 min after exposure (the definition of TTS onset) is expected to be between 175 and 180 dB re 1 μPa2s.
Dual enhancement of T and NK cell function by pulsatile inhibition of SHIP1 improves antitumor immunity and survival
Authors: Gumbleton Matthew , Sudan Raki , Fernandes Sandra , Engelman Robert W. , Russo Christopher M. , Chisholm John D. , Kerr William G.
Published: October 2017

Intermittent inhibition of the phosphatase SHIP1 promotes antitumor immunity and memory in mouse models of lymphoma and colon cancer.
Papers of note in
Nature
550
(7674)
Authors: VanHook Annalisa M.
Published: October 2017

This week’s articles highlight retrograde semaphorin signaling at synapses; a driver of age-related decreases in lipolysis; and a mechanism by which melanoma cells become resistant to combined therapies.
New connections: Pregnancy-specific signaling
Authors: Wong Wei
Published: October 2017

Three papers highlight the cross-talk that occurs between mother and fetus during pregnancy.
Impact of Morphological Sectors on Antifungal Susceptibility Testing and Virulence Studies
Authors: Jukic Emina , Blatzer Michael , Binder Ulrike , Mayr Lisa , Lass-Flörl Cornelia , Lackner Michaela
Published: October 2017

Morphological heterogeneity of
Aspergillus terreus
cultures was observed during continued cultivation of amphotericin B (AMB)-resistant isolates on drug-free medium. Outgrowth leads to the emergence of multiple sectors that might result from increased growth rates at drug-free conditions. We evaluated the differences in AMB susceptibility and virulence between sector subcultures (ATSec), AMB-resistant (ATR) strains, and AMB-susceptible (ATS) strains. By comparing
A. terreus
AMB-resistant (ATR) strains and
A. terreus
sector (ATSec) cultures we observed a highly significant reduction of AMB MICs in ATSec (ATR MIC, 2 to 32 μg/ml; ATSec MIC, 0.12 to 5 μg/ml). Furthermore,
Galleria mellonella
survival studies revealed an enhanced virulence of ATSec, which was comparable with that of AMB-sensitive
Aspergillus terreus
strains (median survival rates for ATS isolates, 72 h; for ATSec isolate ATSec
G1
, 84 h; for ATR isolates, 144 h). Our findings clearly demonstrate that spontaneous culture degeneration occurs in
A. terreus
and, most importantly, crucially impacts drug efficacy and virulence.
Amikacin Pharmacokinetics To Optimize Dosing in Neonates with Perinatal Asphyxia Treated with Hypothermia
Authors: Cristea Sinziana , Smits Anne , Kulo Aida , Knibbe Catherijne A. J. , van Weissenbruch Mirjam , Krekels Elke H. J. , Allegaert Karel
Published: October 2017

Aminoglycoside pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed for treating neonates with (suspected) septicemia; however, none provide adjustments for cases of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations. Based on amikacin therapeutic drug monitoring data collected retrospectively from neonates with PATH, combined with a published data set, we assessed the impact of PATH on amikacin PK by using population modeling. Monte Carlo and stochastic simulations were performed to establish amikacin exposures in neonates with PATH after dosing according to the current guidelines and according to proposed model-derived dosing guidelines. Amikacin clearance was decreased 40.6% in neonates with PATH, with no changes in volume of distribution. Simulations showed that increasing the dosing interval by 12 h results in a decrease in the percentage of neonates reaching toxic trough levels (>5 mg/liter), from 40 to 76% to 14 to 25%, while still reaching efficacy targets compared to the results of current dosing regimens. Based on this study, a 12-h increase in the amikacin dosing interval in neonates with PATH is proposed to correct for the reduced clearance, yielding safe and effective exposures. As amikacin is renally excreted, further studies into other renally excreted drugs may be required, as their clearance may also be impaired.
Effects of Maraviroc versus Efavirenz in Combination with Zidovudine-Lamivudine on the CD4/CD8 Ratio in Treatment-Naive HIV-Infected Individuals
Authors: Serrano-Villar Sergio , Caruana Giorgia , Zlotnik Alexander , Pérez-Molina José A. , Moreno Santiago
Published: October 2017

A low CD4/CD8 ratio during treated HIV infection reflects heightened immune activation and predicts death. The effects of different antiretroviral therapy regimens on CD4/CD8 ratio recovery remains unclear. We performed a
post hoc
analysis of the MERIT study, a randomized, double-blind trial of maraviroc versus efavirenz in combination with zidovudine-lamivudine in treatment-naive HIV-infected individuals. We found higher rates of CD4/CD8 ratio normalization with efavirenz, which was driven by a greater CD8
+
T-cell decline.
Phosphatidylinositol 4,5-Bisphosphate-Dependent Oligomerization of the Pseudomonas aeruginosa Cytotoxin ExoU
Authors: Zhang Angelica , Veesenmeyer Jeffrey L. , Hauser Alan R.
Published: October 2017

The
Pseudomonas aeruginosa
type III secretion system delivers effector proteins directly into target cells, allowing the bacterium to modulate host cell functions. ExoU is the most cytotoxic of the known effector proteins and has been associated with more severe infections in humans. ExoU is a patatin-like A
2
phospholipase requiring the cellular host factors phosphatidylinositol 4,5-bisphosphate [PI(4,5)P
2
] and ubiquitin for its activation
in vitro
. We demonstrated that PI(4,5)P
2
also induces the oligomerization of ExoU and that this PI(4,5)P
2
-mediated oligomerization does not require ubiquitin. Single amino acid substitutions in the C-terminal membrane localization domain of ExoU reduced both its activity and its ability to form higher-order complexes in transfected cells and
in vitro
. Combining inactive truncated ExoU proteins partially restored phospholipase activity and cytotoxicity, indicating that ExoU oligomerization may have functional significance. Our results indicate that PI(4,5)P
2
induces the oligomerization of ExoU, which may be a mechanism by which this coactivator enhances the phospholipase activity of ExoU.
Dairy Heifers Naturally Exposed to Fasciola hepatica Develop a Type 2 Immune Response and Concomitant Suppression of Leukocyte Proliferation
Authors: Graham-Brown John , Hartley Catherine , Clough Helen , Kadioglu Aras , Baylis Matthew , Williams Diana J. L.
Published: October 2017

Fasciola hepaticais a parasitic trematode of global importance in livestock. Control strategies reliant on anthelmintics are unsustainable due to the emergence of drug resistance. Vaccines are under development, but efficacies are variable. Evidence from experimental infection suggests that vaccine efficacy may be affected by parasite-induced immunomodulation. Little is known about the immune response toF. hepaticafollowing natural exposure. Hence, we analyzed the immune responses over time in calves naturally exposed toF. hepaticainfection. Cohorts of replacement dairy heifer calves (n= 42) with no prior exposure toF. hepatica, on three commercial dairy farms, were sampled over the course of a grazing season. Exposure was determined through anF. hepatica-specific serum antibody enzyme-linked immunosorbent assay (ELISA) and fluke egg counts. Concurrent changes in peripheral blood leukocyte subpopulations, lymphocyte proliferation, and cytokine responses were measured. Relationships between fluke infection and immune responses were analyzed by using multivariable linear mixed-effect models. All calves from one farm showed evidence of exposure, while cohorts from the remaining two farms remained negative over the grazing season. A type 2 immune response was associated with exposure, with increased interleukin-4 (IL-4) production, IL-5 transcription, and eosinophilia. Suppression of parasite-specific peripheral blood mononuclear cell (PBMC) proliferation was evident, while decreased mitogen-stimulated gamma interferon (IFN-γ) production suggested immunomodulation, which was not restricted to parasite-specific responses. Our findings show that the global immune response is modulated toward a nonproliferative type 2 state following natural challenge withF. hepatica. This has implications in terms of the timing of the administration of vaccination programs and for host susceptibility to coinfecting pathogens.
Ehrlichia Activation of Wnt-PI3K-mTOR Signaling Inhibits Autolysosome Generation and Autophagic Destruction by the Mononuclear Phagocyte
Authors: Lina Taslima T. , Luo Tian , Velayutham Thangam-Sudha , Das Seema , McBride Jere W.
Published: October 2017

In multicellular organisms, autophagy is induced as an innate defense mechanism. Notably, the obligate intracellular bacterium
Ehrlichia chaffeensis
resides in early endosome-like vacuoles and circumvents lysosomal fusion through an unknown mechanism, thereby avoiding destruction in the autophagolysosome. In this report, we reveal that Wnt signaling plays a crucial role in inhibition of lysosomal fusion and autolysosomal destruction of ehrlichiae. During early infection, autophagosomes fuse with ehrlichial vacuoles to form an amphisome indicated by the presence of autophagy markers such as LC3 (microtubule-associated protein 1 light chain 3), Beclin-1, and p62. LC3 colocalized with ehrlichial morulae on days 1, 2, and 3 postinfection, and increased LC3II levels were detected during infection, reaching a maximal level on day 3. Ehrlichial vacuoles did not colocalize with the lysosomal marker LAMP2, and lysosomes were redistributed and dramatically reduced in level in the infected cells. An inhibitor specific for the Wnt receptor signaling component Dishevelled induced lysosomal fusion with ehrlichial inclusions corresponding to p62 degradation and promoted transcription factor EB (TFEB) nuclear localization.
E. chaffeensis
infection activated the phosphatidylinositol 3-kinase (PI3K)–Akt–mTOR (mechanistic target of rapamycin) pathway, and activation was induced by three ehrlichial tandem repeat protein (TRP) effectors, with TRP120 inducing the strongest activation. Moreover, induction of glycogen synthase kinase-3 (GSK3) performed using a Wnt inhibitor and small interfering RNA (siRNA) knockdown of critical components of PI3K-GSK3-mTOR signaling decreased ehrlichial survival. This report reveals
Ehrlichia
exploitation of the evolutionarily conserved Wnt pathway to inhibit autolysosome generation, thereby leading to evasion of this important innate immune defense mechanism.
Dysbiosis and Its Discontents
Authors: Hooks Katarzyna B. , O’Malley Maureen A.
Published: October 2017

Dysbiosis is a key term in human microbiome research, especially when microbiome patterns are associated with disease states. Although some questions have been raised about how this term is applied, its use continues undiminished in the literature. We investigate the ways in which microbiome researchers discuss dysbiosis and then assess the impact of different concepts of dysbiosis on microbiome research. After an overview of the term’s historical roots, we conduct quantitative and qualitative analyses of a large selection of contemporary dysbiosis statements. We categorize both short definitions and longer conceptual statements about dysbiosis. Further analysis allows us to identify the problematic implications of how dysbiosis is used, particularly with regard to causal hypotheses and normal-abnormal distinctions. We suggest that researchers should reflect carefully on the ways in which they discuss dysbiosis, in order for the field to continue to develop greater predictive scope and explanatory depth.
Unusual complications from amitriptyline intoxication
Authors: Nishimura Takeshi , Maruguchi Hayato , Nakao Atsunori , Nakayama Shinichi
Published: October 2017

Althoughtricyclic antidepressants(TCAs) are frequently prescribed to patients with depression, these drugs can also be misused. A 21-year-old comatose patient was referred to our hospital presenting with ventricular tachycardia. Despite initial treatment including intravascular lipid emulsion, ventricular fibrillation occurred soon after arrival. Venoarterial extracorporeal membrane oxygenation and therapeutic hypothermia were administered. Refractory arrhythmia disappeared on the next day. A high concentration of amitriptyline was identified in his blood samples on arrival. Mechanical bowel obstruction followed after abdominal compartment syndrome caused by anticholinergic effects, and refractory seizure occurred due to TCA intoxication. Although seizure was brought under control with anticonvulsant agents, his Glasgow Coma Scale did not recover to the full score. MRI presented irreversible damage to the bilateral frontal lobe and insula. Amitriptyline has the potential to cause unusual serious complications, such as abdominal compartment syndrome, irreversible central nervous system disability and lethal arrhythmia.
Impact of surgical timing of postoperative ocular motility in orbital blowout fractures
Authors: Yamanaka Yukito , Watanabe Akihide , Sotozono Chie , Kinoshita Shigeru
Published: October 2017

Purpose

To investigate the surgical timing postinjury in regard to ocular motility in patients with orbital-floor blowout fractures.

Methods

This study involved 197 eyes (92 right eyes and 105 left eyes) of 197 patients (154 males and 43 females, mean age: 29.0 years, range: 7–85 years) with pure orbital blowout fractures. All patients underwent surgical repair within 30 days postinjury and were followed up for 3 months or more postoperative (mean follow-up period: 8.4 months, range: 3–59 months). Orbital blowout fractures were classified into one of three shapes: (1) trap-door fracture with muscle entrapment, (2) trap-door fracture with incarcerated tissue and (3) depressed fragment fracture. Ocular motility was estimated by percentage of Hess area ratio (HAR%) on the Hess chart at the final follow-up examination. In addition, correlations between postinjury surgical timing and HAR% were analysed.

Results

The mean postinjury surgical timing was 10.7±7.8 days (range: 0–30 days). The mean postoperative HAR% (92.9%±10.5%) was significantly improved compared with preoperative HAR% (73.5%±21.7%) (p<0.01). The mean postoperative HAR% (98.3%±4.4%) of the orbital-floor trap-door fracture patients with incarcerated tissue who underwent surgical repair within 8 days postinjury was significantly better than that of the patients who underwent surgical repair after 8 days (94.2%±5.8%) (p<0.01).

Conclusions

Patients with orbital-floor trap-door blowout fractures with incarcerated tissue that were repaired within 8 days postinjury had better outcomes than those repaired after 8 days, and HAR% is a useful method to record orbital fracture surgical outcomes.
Characterisation of the rural indigent population in Burkina Faso: a screening tool for setting priority healthcare services in sub-Saharan Africa
Authors: Ouédraogo Samiratou , Ridde Valéry , Atchessi Nicole , Souares Aurélia , Koulidiati Jean-Louis , Stoeffler Quentin , Zunzunegui Maria-Victoria
Published: October 2017

Background

In Africa, health research on indigent people has focused on how to target them for services, but little research has been conducted to identify the social groups that compose indigence. Our aim was to identify what makes someone indigent beyond being recognised by the community as needing a card for free healthcare.

Methods

We used data from a survey conducted to evaluate a state-led intervention for performance-based financing of health services in two districts of Burkina Faso. In 2015, we analysed data of 1783 non-indigents and 829 people defined as indigents by their community in 21 villages following community-based targeting processes. Using a classification tree, we built a model to select socioeconomic and health characteristics that were likely to distinguish between non-indigents and indigents. We described the screening performance of the tree using data from specific nodes.

Results

Widow(er)s under 45 years of age, unmarried people aged 45 years and over, and married women aged 60 years and over were more likely to be identified as indigents by their community. Simple rules based on age, marital status and gender detected indigents with sensitivity of 75.6% and specificity of 55% among those 45 years and over; among those under 45, sensitivity was 85.5% and specificity 92.2%. For both tests combined, sensitivity was 78% and specificity 81%.

Conclusion

In moving towards universal health coverage, Burkina Faso should extend free access to priority healthcare services to widow(er)s under 45, unmarried people aged 45 years and over, and married women aged 60 years and over, and services should be adapted to their health needs.

Ethics considerations

The collection, storage and release of data for research purposes were authorised by a government ethics committee in Burkina Faso (Decision No. 2013-7-066). Respondent consent was obtained verbally.
Knowledge, attitudes, perceptions and habits towards antibiotics dispensed without medical prescription: a qualitative study of Spanish pharmacists
Authors: Vazquez-Lago Juan , Gonzalez-Gonzalez Cristian , Zapata-Cachafeiro Maruxa , Lopez-Vazquez Paula , Taracido Margarita , López Ana , Figueiras Adolfo
Published: October 2017

Objective

To investigate community pharmacists’ knowledge, attitudes, perceptions and habits with regard to antibiotic dispensing without medical prescription in Spain.

Methods

A qualitative research using focus group method (FG) in Galicia (north-west Spain). FG sessions were conducted in the presence of a moderator. A topic script was developed to lead the discussions, which were audiorecorded to facilitate data interpretation and transcription. Proceedings were transcribed by an independent researcher and interpreted by two researchers working independently. We used the Grounded Theory approach.

Setting

Community pharmacies in Galicia, region Norwest of Spain.

Participants

Thirty pharmacists agreed to participate in the study, and a total of five FG sessions were conducted with 2–11 pharmacists. We sought to ensure a high degree of heterogeneity in the composition of the groups to improve our study’s external validity. Pharmacists’ participation had no gender or age restrictions, and an effort was made to form FGs with pharmacists who were both owners and non-owners, provided in all cases that they were Official Colleges of Pharmacists-registered community pharmacists. For the purpose of conducting FG discussions, the basic methodological principle of allowing groups to attain their ‘own structural identity’ was applied.

Main outcome measurements

Community pharmacists’ habits and knowledge with regard to antibiotics and identification of the attitudes and/or factors that influence antibiotic dispensing without medical prescription.

Results

Pharmacists attributed the problem of antibiotics dispensed without medical prescription and its relationship to antibiotic resistance to the following attitudes: external responsibility (doctors, dentists and the National Health Service (NHS)); acquiescence; indifference and lack of continuing education.

Conclusions

Despite being a problem, antibiotic dispensing without a medical prescription is still a common practice in community pharmacies in Galicia, Spain. This practice is attributed to acquiescence, indifference and lack of continuing education. The problem of resistance was ascribed to external responsibility, including that of patients, physicians, dentists and the NHS.