bluuebunny/crossref_metadata_2025 huggingface dataset:
The 2017 Xe run at CERN Linac3: Measurements and beam dynamics simulations
Authors: Benedetti S. , Bellodi G. , Küchler D. , Toivanen V.
Published: December 2018

At CERN, large hadron collider heavy ion and super proton synchrotron fixed target experiments are performed thanks to the Heavy-ion Facility, composed of different accelerators. The starting point is Linac3, which delivers 4.2 MeV/u ion beams to the low energy ion ring. In 2017, Linac3 accelerated Xe instead of the most usual Pb. This article summarizes the measurements performed during the machine development time allocated to characterize the line from the source to the filtering section. A parallel effort was devoted to matching those measurements to the beam dynamics simulations, and the second part of the article highlights the results achieved in this regard. Thanks to the improved understanding of the machine critical areas, a list of possible improvements is proposed at the end.
Rigorous derivation of a Boltzmann relation from isothermal Euler-Poisson systems
Authors: Li Yachun , Peng Yue-Jun , Xi Shuai
Published: December 2018

The Boltzmann relation for electrons is well-known in plasma physics. It can be formally derived from fluid equations when the electron mass is neglected. By means of asymptotic expansions and energy estimates, we justify this relation as the zero-electron-mass limit of an isothermal Euler-Poisson system with variable ion density. The result is obtained for periodic smooth solutions of the system on a uniform time interval with respect to the electron-mass.
Fruit developmental biology and endosperm rumination in Elaeocarpus ruminatus (Elaeocarpaceae), and its taxonomic significance
Authors: Gagul Janet N. , Tng David Y. P. , Crayn Darren M.
Published: December 2018

The genus Elaeocarpus is the largest genus in the family Elaeocarpaceae, comprising more than 350 species of trees and shrubs with a mainly Indo-Pacific distribution. Approximately 28 species in the genus, including nine species from Australia, are known to possess ruminate endosperm. To provide a basis for understanding fruit development and endosperm rumination in the genus and, therefore, its taxonomic and evolutionary significance, we studied the fruit anatomy of Elaeocarpus ruminatus F.Muell. at different developmental phases (petal-fall to maturity). We found lignin in pericarp and ovary wall tissues in the earliest stages of development. In contrast, endosperm rumination occurs only after fruits have fully expanded, and becomes more pronounced as fruits ripen. Its phylogenetic distribution suggests that ruminate endosperm is a derived, albeit homoplasious character in Elaeocarpus. Comparative studies on related species will be instructive in determining the utility of ruminate endosperm for informing infra-generic taxonomy of the genus, and gaining insight into its adaptive significance.
One new endemic plant species on average per month in New Caledonia, including eight more new species from Île Art (Belep Islands), a major micro-hotspot in need of protection
Authors: Gâteblé Gildas , Barrabé Laure , McPherson Gordon , Munzinger Jérôme , Snow Neil , Swenson Ulf
Published: December 2018

The New Caledonian biodiversity hotspot contains many micro-hotspots that exhibit high plant micro-endemism, and that are facing different types and intensities of threats. The Belep archipelago, and especially Île Art, with 24 and 21 respective narrowly endemic species (1 Extinct, 21 Critically Endangered and 2 Endangered), should be considered as the most sensitive micro-hotspot of plant diversity in New Caledonia because of the high anthropogenic threat of fire. Nano-hotspots could also be defined for the low forest remnants of the southern and northern plateaus of Île Art. With an average rate of more than one new species described for New Caledonia each month since January 2000 and five new endemics for the Belep archipelago since 2009, the state of knowledge of the flora is steadily improving. The present account of eight new species from Île Art (Bocquillonia montrouzieri Gâteblé & McPherson, Cleidion artense Gâteblé & McPherson, Endiandra artensis Munzinger & McPherson, Eugenia belepiana J.W.Dawson ex N.Snow, Eugenia insulartensis J.W.Dawson ex N.Snow, Macaranga latebrosa Gâteblé & McPherson, Planchonella serpentinicola Swenson & Munzinger and Psychotria neodouarrei Barrabé & A.Martini) further demonstrates the need both to recognise the Belep Islands as a major New Caledonian micro-hotspot and to formulate concrete conservation programs for the archipelago.
Antipredator behaviour of a native marsupial is relaxed when mammalian predators are excluded
Authors: Bannister H. , Brandle R. , Moseby K.
Published: December 2018

Context
Predator-controlled environments can lead to prey species losing costly antipredator behaviours as they exploit their low-risk environment, creating a ‘predator-naïve’ population. If individuals lacking suitable antipredator behaviours are used as source populations for reintroductions to environments where predators are present, their behaviour could result in high post-release predation. In contrast, animals sourced from environments with predators (‘predator-exposed’) may show effective antipredator behaviours and thus higher survival post-release.

Aims
The aim was to compare the antipredator behaviour of brushtail possums (Trichosurus vulpecula) at predator-exposed and predator-naïve source populations, and then compare post-release survival after their reintroduction to a low predator environment.

Methods
Data were collected from possums at two sites, one with and one without mammalian predators. The behavioural responses of possums to a spotlighter, their willingness to use supplementary feeders at ‘safe’ and ‘risky’ heights, whether they avoided predator odour at traps and their general willingness to enter traps were recorded.

Key results
Predator-naïve possums showed weaker antipredator responses, were often found at ground level, engaged with novel objects, did not avoid predator scents and utilised different habitats regardless of associated predation risk. In contrast, predator-exposed possums had higher antipredator responses, chose connected trees, were rarely found at ground level and were generally difficult to capture. Post-translocation survival was high for both source populations. Predator-naïve-sourced female possums began to avoid predator urine (feral cat; Felis catus) 12 months after translocation.

Conclusions
Our research demonstrates that environmental predation risk can predict prey naïvety in brushtail possums. Some aspects of prey naïvety behaviour appear to be able to change in response to altered predation risk.

Implications
With many threatened species now existing only in feral predator-free areas, these results have implications for future reintroductions into unbounded areas where feral predators are present, and for the management of fenced reserves. The addition of a small number of predators to fenced reserves may aid in retaining antipredator behaviours in fenced prey populations.
Rapid evolution of a skin-lightening allele in southern African KhoeSan
Authors: Lin Meng , Siford Rebecca L. , Martin Alicia R. , Nakagome Shigeki , Möller Marlo , Hoal Eileen G. , Bustamante Carlos D. , Gignoux Christopher R. , Henn Brenna M.
Published: December 2018

Skin pigmentation is under strong directional selection in northern European and Asian populations. The indigenous KhoeSan populations of far southern Africa have lighter skin than other sub-Saharan African populations, potentially reflecting local adaptation to a region of Africa with reduced UV radiation. Here, we demonstrate that a canonical Eurasian skin pigmentation gene,
SLC24A5
, was introduced to southern Africa via recent migration and experienced strong adaptive evolution in the KhoeSan. To reconstruct the evolution of skin pigmentation, we collected phenotypes from over 400 ≠Khomani San and Nama individuals and high-throughput sequenced candidate pigmentation genes. The derived causal allele in
SLC24A5
, p.Ala111Thr, significantly lightens basal skin pigmentation in the KhoeSan and explains 8 to 15% of phenotypic variance in these populations. The frequency of this allele (33 to 53%) is far greater than expected from colonial period European gene flow; however, the most common derived haplotype is identical among European, eastern African, and KhoeSan individuals. Using four-population demographic simulations with selection, we show that the allele was introduced into the KhoeSan only 2,000 y ago via a back-to-Africa migration and then experienced a selective sweep (s = 0.04 to 0.05 in ≠Khomani and Nama). The
SLC24A5
locus is both a rare example of intense, ongoing adaptation in very recent human history, as well as an adaptive gene flow at a pigmentation locus in humans.
Twin-Win Model: A human-centered approach to research success
Authors: Shneiderman Ben
Published: December 2018

A 70-year-old simmering debate has erupted into vigorous battles over the most effective ways to conduct research. Well-established beliefs are being forcefully challenged by advocates of new research models. While there can be no final resolution to this battle, this paper offers the Twin-Win Model to guide teams of researchers, academic leaders, business managers, and government funding policymakers. The Twin-Win Model favors a problem-oriented approach to research, which encourages formation of teams to pursue the dual goals of breakthrough theories in published papers and validated solutions that are ready for widespread dissemination. The raised expectations of simultaneously pursuing foundational discoveries and powerful innovations are a step beyond traditional approaches that advocate basic research first. Evidence from citation analysis and researcher interviews suggests that simultaneous pursuit of both goals raises the chance of twin-win success.
Integral feedback control is at the core of task allocation and resilience of insect societies
Authors: Schmickl Thomas , Karsai Istvan
Published: December 2018

Homeostatic self-regulation is a fundamental aspect of open dissipative systems. Integral feedback has been found to be important for homeostatic control on both the cellular and molecular levels of biological organization and in engineered systems. Analyzing the task allocation mechanisms of three insect societies, we identified a model of integral control residing at colony level. We characterized a general functional core mechanism, called the “common stomach,” where a crucial shared substance for colony function self-regulates its own quantity via reallocating the colony’s workforce, which collects and uses this substance. The central component in a redundant feedback network is the saturation level of this substance in the colony. An interaction network of positive and negative feedback loops ensures the homeostatic state of this substance and the workforce involved in processing this substance. Extensive sensitivity and stability analyses of the core model revealed that the system is very resilient against perturbations and compensates for specific types of stress that real colonies face in their ecosystems. The core regulation system is highly scalable, and due to its buffer function, it can filter noise and find a new equilibrium quickly after environmental (supply) or colony-state (demand) changes. The common stomach regulation system is an example of convergent evolution among the three different societies, and we predict that similar integral control regulation mechanisms have evolved frequently within natural complex systems.
Experimental accuracy in protein structure refinement via molecular dynamics simulations
Authors: Heo Lim , Feig Michael
Published: December 2018

Significance

Protein structures in atomistic detail are essential for a full understanding of biological mechanisms, yet high-resolution structural information remains unavailable for many proteins. Computational structure prediction aims to fill the gap but does not routinely provide models that reach experimental resolution. This study explores the conformational landscape between imperfect structure predictions and correct native experimental structures via molecular dynamics computer simulations. The results presented here demonstrate that structure refinement to experimental accuracy via simulation is indeed possible, but significant challenges are revealed that have to be overcome in practical refinement protocols.
Robust forecast aggregation
Authors: Arieli Itai , Babichenko Yakov , Smorodinsky Rann
Published: December 2018

Significance

The problem of conflicting advice from multiple experts is common to policy makers, corporate governors, patients facing medical prognosis, individuals requiring financial advice, and more. We ask, How should an ignorant advisee (one that observes experts’ forecasts only) aggregate information when this is provided in probabilistic terms (such as forecasts over events)? We propose a robustness criterion based on the classical notions of scoring rule and regret. Under reasonable assumptions on the underlying information structure of the experts, we provide formulas that allow an ignorant aggregator to perform almost as well as an omniscient expert (one that aggregates perfectly all of the information) whenever there are two experts. We also show that this is hopeless when facing many experts.
Single-molecule dynamics of the P granule scaffold MEG-3 in theCaenorhabditis eleganszygote
Authors: Wu Youjun , Han Bingjie , Gauvin Timothy J. , Smith Jarrett , Singh Abhyudai , Griffin Erik E.
Published: December 2018

During the asymmetric division of the Caenorhabditis elegans zygote, germ (P) granules are disassembled in the anterior cytoplasm and stabilized/assembled in the posterior cytoplasm, leading to their inheritance by the germline daughter cell. P granule segregation depends on MEG (maternal-effect germline defective)-3 and MEG-4, which are enriched in P granules and in the posterior cytoplasm surrounding P granules. Here we use single-molecule imaging and tracking to characterize the reaction/diffusion mechanisms that result in MEG-3::Halo segregation. We find that the anteriorly enriched RNA-binding proteins MEX (muscle excess)-5 and MEX-6 suppress the retention of MEG-3 in the anterior cytoplasm, leading to MEG-3 enrichment in the posterior. We provide evidence that MEX-5/6 may work in conjunction with PLK-1 kinase to suppress MEG-3 retention in the anterior. Surprisingly, we find that the retention of MEG-3::Halo in the posterior cytoplasm surrounding P granules does not appear to contribute significantly to the maintenance of P granule asymmetry. Rather, our findings suggest that the formation of the MEG-3 concentration gradient and the segregation of P granules are two parallel manifestations of MEG-3′s response to upstream polarity cues.
Unbiased Hamiltonian Monte Carlo with couplings
Authors: Heng J , Jacob P E
Published: December 2018

We propose a method for parallelization of Hamiltonian Monte Carlo estimators. Our approach involves constructing a pair of Hamiltonian Monte Carlo chains that are coupled in such a way that they meet exactly after some random number of iterations. These chains can then be combined so that the resulting estimators are unbiased. This allows us to produce independent replicates in parallel and average them to obtain estimators that are consistent in the limit of the number of replicates, rather than in the usual limit of the number of Markov chain iterations. We investigate the scalability of our coupling in high dimensions on a toy example. The choice of algorithmic parameters and the efficiency of our proposed approach are then illustrated on a logistic regression with 300 covariates and a log-Gaussian Cox point processes model with low- to fine-grained discretizations.
IGNITE4: Results of a Phase 3, Randomized, Multicenter, Prospective Trial of Eravacycline vs Meropenem in the Treatment of Complicated Intraabdominal Infections
Authors: Solomkin Joseph S , Gardovskis Janis , Lawrence Kenneth , Montravers Philippe , Sway Angie , Evans David , Tsai Larry
Published: December 2018

Background

Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae.

Methods

IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4–14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25–31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated.

Results

Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, –0.5%; 95% confidence interval [CI], –6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, –4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI –2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively.

Conclusions

Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens.

Clinical Trials Registration

NCT01844856.
Community-acquired Respiratory Viruses Are a Risk Factor for Chronic Lung Allograft Dysfunction
Authors: Peghin Maddalena , Los-Arcos Ibai , Hirsch Hans H , Codina Gemma , Monforte Víctor , Bravo Carles , Berastegui Cristina , Jauregui Alberto , Romero Laura , Cabral Evelyn , Ferrer Ricard , Sacanell Judith , Román Antonio , Len Oscar , Gavaldà Joan
Published: December 2018

Background

The relationship between community-acquired respiratory viruses (CARVs) and chronic lung allograft dysfunction (CLAD) in lung transplant recipients is still controversial.

Methods

We performed a prospective cohort study (2009–2014) in all consecutive adult patients (≥18 years) undergoing lung transplantation in the Hospital Universitari Vall d’Hebron (Barcelona, Spain). We systematically collected nasopharyngeal swabs from asymptomatic patients during seasonal changes, from patients with upper respiratory tract infectious disease, lower respiratory tract infectious disease (LRTID), or acute rejection. Nasopharyngeal swabs were analyzed by multiplex polymerase chain reaction. Primary outcome was to evaluate the potential association of CARVs and development of CLAD. Time-dependent Cox regression models were performed to identify the independent risk factors for CLAD.

Results

Overall, 98 patients (67 bilateral lung transplant recipients; 63.3% male; mean age, 49.9 years) were included. Mean postoperative follow-up was 3.4 years (interquartile range [IQR], 2.5–4.0 years). Thirty-eight lung transplant recipients (38.8%) developed CLAD, in a median time of 20.4 months (IQR, 12–30.4 months). In time-controlled multivariate analysis, CARV-LRTID (hazard ratio [HR], 3.00 [95% confidence interval {CI}, 1.52–5.91]; P = .002), acute rejection (HR, 2.97 [95% CI, 1.51–5.83]; P = .002), and cytomegalovirus pneumonitis (HR, 3.76 [95% CI, 1.23–11.49]; P = .02) were independent risk factors associated with developing CLAD.

Conclusions

Lung transplant recipients with CARVs in the lower respiratory tract are at increased risk to develop CLAD.
Seminal Tenofovir Concentrations, Viral Suppression, and Semen Quality With Tenofovir Alafenamide, Compared With Tenofovir Disoproxil Fumarate (Spanish HIV/AIDS Research Network, PreEC/RIS 40)
Authors: Imaz Arkaitz , Niubó Jordi , Cottrell Mackenzie L , Perez Emilia , Kashuba Angela D M , Tiraboschi Juan M , Morenilla Sandra , Garcia Benito , Podzamczer Daniel
Published: December 2018

Background

This study assessed the penetration and efficacy of tenofovir alafenamide (TAF) in the male genital tract (MGT) and the semen quality of individuals infected with human immunodeficiency virus (HIV)-1 who were treated with a TAF-containing regimen.

Methods

This was a prospective, open-label, single-arm study of 14 virologically-suppressed, HIV-1–infected men on stable antiretroviral therapy with elvitegravir, cobicistat, emtricitabine (E/C/F) and tenofovir disoproxil fumarate (TDF) who switched to E/C/F and TAF. At baseline (pre-switch) and at 12 weeks post-switch, we measured HIV-1 RNA in seminal plasma (SP) and blood plasma (BP), tenofovir (TFV) in SP and BP, and TFV-diphosphate (dp) in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells (SMCs) at the end of the dosing interval (C24h). Semen quality was assessed before switching and after 12 weeks on TAF.

Results

With TAF, TFV C24 was 11.9-fold higher in SP than in BP. This concentration was significantly lower than TFV C24 in SP with TDF, but 9.6-fold higher than the 50% inhibitory concentration (IC50) (11.5 ng/mL). By contrast, the median TFV-dp concentration achieved with TAF in SMCs was 6% that of TFV-dp in PBMCs. The TFV-dp SMC:PBMC ratio was also significantly lower with TAF. Nonetheless, TFV-dp C24 in SMC was comparable with TAF and TDF. All the patients had HIV-1 RNA <40 copies/mL in BP and SP at baseline and at 12 weeks post-switch. No significant differences were observed in semen quality between TAF and TDF.

Conclusions

Extracellular and intracellular seminal TFV distribution differs between TAF and TDF. Nevertheless, both formulations, combined with elvitegravir/cobicistat/emtricitabine, maintained HIV-1 RNA suppression in semen. Differences in MGT distribution were not associated with differences in semen quality.

Clinical Trials Registration

EudraCT: 2016-001371-69
What Is the Role for Metronidazole in the Treatment of Clostridium difficile Infection? Results From a National Cohort Study of Veterans With Initial Mild Disease
Authors: Appaneal Haley J , Caffrey Aisling R , LaPlante Kerry L
Published: December 2018

Background

Metronidazole may still be an appropriate therapeutic option for mild Clostridium difficile infection (CDI) in select patients, but data are limited to guide clinicians in identifying these patients.

Methods

Our 2-stage study included a national cohort of Veterans with a first episode of mild CDI (2010–2014). First, among those treated with metronidazole, we identified predictors of success, defined as absence of all-cause mortality or recurrence 30 days posttreatment, using multivariable unconditional logistic regression. Second, among a subgroup of patients with characteristics predictive of success identified in the first stage, we compared clinical outcomes among those treated with metronidazole compared with vancomycin, using Cox proportional hazards models for time to 30-day all-cause mortality, CDI recurrence, and failure.

Results

Among 3656 patients treated with metronidazole, we identified 3282 patients with success and 374 patients without success (failure). Younger age was the only independent predictor of success. Age ≤65 years was associated with an odds of success 1.63 times higher (95% confidence interval [CI], 1.29–2.06) than age >65 years. Among 115 propensity score–matched pairs ≤65 years of age, no significant differences were observed between metronidazole and vancomycin (reference) for all-cause mortality (hazard ratio [HR], 0.29 [95% CI, .06–1.38]), CDI recurrence (HR, 0.62 [95% CI, .26–1.49]), or failure (HR, 0.50 [95% CI, .23–1.07]).

Conclusions

Among patients ≤65 years of age with initial mild CDI, clinical outcomes were similar with metronidazole and vancomycin. These data suggest that metronidazole may be considered for the treatment of initial mild CDI among patients 65 years of age or younger.
Motivations and willingness of general practitioners in France to participate in primary care research as investigators
Authors: Ferrand Devouge Eglantine , Biard Morgane , Beuzeboc Jean , Tavolacci Marie-Pierre , Schuers Matthieu
Published: December 2018

Background

Clinical research is mostly conducted among hospitalized patients, which restricts the generalizability of research results. The involvement of GPs in research has been consistently highlighted as a factor associated with successful study recruitment.

Objectives

To assess GPs’ motivations and willingness to participate in primary care research as investigators and to identify factors associated with their willingness.

Methods

We conducted an observational, cross-sectional study in Normandy, France, with a self-questionnaire sent to 3002 GPs. We collected data on GPs’ socio-demographic characteristics, their experiences and their expectations regarding research, and their reasons for non-participation.

Results

Overall, 489 questionnaires were collected. Two hundred and forty-six GPs (50.3%) were interested in participating in clinical research as investigators. The two main conditions for participation as investigators were the relevance of the study topic for clinical practice (80.5%) and the feedback of study results (80.1%). The two main reasons for non-participation were lack of time (79.4%) and administrative burden (43.6%). Age between 27 and 34 years (adjusted odds ratio [AOR] = 2.86, P = 0.004) and GP trainer status (AOR = 2.41, P < 0.001) were associated with willingness to participate in primary care research. Age between 60 and 70 years (AOR = 0.53, P = 0.03) and locum status (AOR = 0.40, P = 0.04) were associated with non-participation in research.

Conclusions

Based on our results, we were able to establish a profile of GPs willing to participate in primary care research as investigators. GPs’ involvement should be based on their preferred areas of research. Different incentives such as a dedicated clinical research nurse or financial support could also be considered.
Deciphering Latin sentences using traditional linguistic resources
Authors: Teixeira Cláudia , Rodrigues Irene
Published: December 2018

This article describes methods that can be used to construct a Latin morphological and syntactic parser, including resources that enable reordering the sentence according to the SVO (subject + verb + object) standard order, aiming to facilitate the translation of Latin phrases by users. The article also addresses the solutions that can be implemented to overcome some of the problems found in this context, namely, the difficulties in accessing different forms of dictionarization, the lack of lexicographic resources, and a methodology for processing the ‘special constructions’ required by adverbs and adjectives.
Development of the R263K Mutation to Dolutegravir in an HIV-1 Subtype D Virus Harboring 3 Class-Drug Resistance
Authors: Ahmed N , Flavell S , Ferns B , Frampton D , Edwards S G , Miller R F , Grant P , Nastouli E , Gupta R K
Published: December 2018

Dolutegravir (DTG), a second-generation integrase strand-transfer inhibitor (INSTI), is equivalent or superior to current non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and first-generation INSTI-based antiretroviral regimens (ARVs). It has the potential to make big improvements in HIV control globally and within patients. This is perhaps the most “precious” HIV drug available. The integrase mutation R263K has been observed in tissue culture experiments and in patients treated with dolutegravir monotherapy in clinical trials. Globally, adherence and monitoring may be less than optimal and therefore DTG resistance more common. This is particularly important in low–middle-income countries, where patients may remain on failing regimens for longer periods of time and accumulate drug resistance. Data on this mutation in non–subtype B infections do not exist. We describe the first report of the R263K integrase mutation in a dolutegravir-exposed subtype D–infected individual with vertically acquired HIV. We have used deep sequencing of longitudinal samples to highlight the change in resistance over time while on a failing regimen. The case highlights that poorly adherent patients should not be offered dolutegravir even as part of a combination regimen and that protease inhibitors should be used preferentially.
Measuring Tail Risks at High Frequency
Authors: Weller Brian M
Published: December 2018

I exploit information in the cross-section of bid-ask spreads to develop a new measure of extreme event risk. Spreads embed tail risk information because liquidity providers require compensation for the possibility of sharp changes in asset values. I show that simple regressions relating spreads and trading volume to factor betas recover this information and deliver high-frequency tail risk estimates for common factors in stock returns. My methodology disentangles financial and aggregate market risks during the 2007–2008 financial crisis; quantifies jump risks associated with Federal Open Market Committee announcements; and anticipates an extreme liquidity shock before the 2010 Flash Crash.

Received April 27, 2016; editorial decision August 10, 2018 by Editor Andrew Karolyi. Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online
Activated protein C targets immune cells and rheumatoid synovial fibroblasts to prevent inflammatory arthritis in mice
Authors: Xue Meilang , Dervish Suat , McKelvey Kelly J , March Lyn , Wang Fang , Little Chris B , Jackson Christopher J
Published: December 2018

Objectives

To investigate whether activated protein C (APC), a physiological anticoagulant can inhibit the inflammatory/invasive properties of immune cells and rheumatoid arthritis synovial fibroblasts (RASFs) in vitro and prevent inflammatory arthritis in murine antigen-induced arthritis (AIA) and CIA models.

Methods

RASFs isolated from synovial tissues of patients with RA, human peripheral blood mononuclear cells (PBMCs) and mouse thymus cells were treated with APC or TNF-α/IL-17 and the following assays were performed: RASF proliferation and invasion by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell invasion assays, respectively; cytokines and signalling molecules using ELISA or western blot; Th1 and Th17 phenotypes in human PBMCs or mouse thymus cells by flow cytometry. The in vivo effect of APC was evaluated in AIA and CIA models.

Results

In vitro, APC inhibited IL-1β, IL-17 and TNF-α production, IL-17-stimulated cell proliferation and invasion and p21 and nuclear factor κB activation in RASFs. In mouse thymus cells and human PBMCs, APC suppressed Th1 and Th17 phenotypes. In vivo, APC inhibited pannus formation, cartilage destruction and arthritis incidence/severity in both CIA and AIA models. In CIA, serum levels of IL-1β, IL-6, IL-17, TNF-α and soluble endothelial protein C receptor were significantly reduced by APC treatment. Blocking endothelial protein C receptor, the specific receptor for APC, abolished the early or preventative effect of APC in AIA.

Conclusion

APC prevents the onset and development of arthritis in CIA and AIA models via suppressing inflammation, Th1/Th17 phenotypes and RASF invasion, which is likely mediated via endothelial protein C receptor.
The RSc0454-Encoded FAD-Linked Oxidase Is Indispensable for Pathogenicity in Ralstonia solanacearum GMI1000
Authors: Hu Xun , Zhao Zhiwen , Zhuo Tao , Fan Xiaojing , Zou Huasong
Published: December 2018

Ralstonia solanacearum is the causal agent of bacterial wilt disease. Here, we report that a large FAD-linked oxidase encoded by RSc0454 in GMI1000 is required for pathogenicity. The FAD-linked oxidase encoded by RSc0454 is composed of 1,345 amino acids, including DUF3683, lactate dehydrogenase (LDH), and succinate dehydrogenase (SDH) domains. The RSc0454 protein showed both LDH and SDH activities. To investigate its role in pathogenicity, a deletion mutant of the RSc0454 gene was constructed in GMI1000, which was impaired in its ability to cause bacterial wilt disease in tomato. A single DUF3683, LDH, or SDH domain was insufficient to restore bacterial pathogenicity. Mutagenesis of the RSc0454 gene did not affect growth rate but caused cell aggregation at the bottom of the liquid nutrient medium, which was reversed by exogenous applications of lactate, fumarate, pyruvate, and succinate. qRT-PCR and promoter LacZ fusion experiments demonstrated that RSc0454 gene transcription was induced by lactate and fumarate (both substrates of LDH). Compared with the downregulation of the succinate dehydrogenase gene sdhBADC and the lactate dehydrogenase gene ldh, RSc0454 gene transcription was enhanced in planta. This suggests that the oxidase encoded by RSc0454 was involved in a redox balance, which is in line with the different living conditions of R. solanacearum.
Occurrence and Molecular Variability of Kiwifruit Viruses in Actinidia deliciosa ‘Xuxiang’ in the Shaanxi Province of China
Authors: Zhao Lei , Yang Wen , Zhang Yuanle , Wu Zhanmin , Wang Qiao-Chun , Wu Yunfeng
Published: December 2018

Kiwifruit (Actinidia spp.) is an economically substantial fruit crop with China the main producer. China is the primary source of wild kiwifruit and the largest producer of kiwifruit in terms of both production and planting area, and Shaanxi province is the largest kiwifruit producer in China. Previous studies reported presence of kiwifruit viruses in Actinidia chinensis. In this study, six viruses were identified in kiwifruit ‘Xuxiang’ (A. deliciosa) in Shaanxi, China. The incidence, distribution, and genetic diversity of these viruses were studied. The results showed that Actinidia virus A (AcVA), Actinidia virus B (AcVB), Actinidia chlorotic ringspot-associated virus (AcCRaV), cucumber mosaic virus (CMV), apple stem grooving virus (ASGV), and potato virus X (PVX) were the main viruses infecting Xuxiang kiwifruit in Shaanxi, China. Incidence of the various viruses with both single and multiple infection varied with different kiwifruit-growing counties. For single virus infection, the highest and the lowest numbers of samples infected were about 22 for AcCRaV and 0 for AcVB in Meixian out of 170 samples, 12 for AcVA and 0 for CMV in Zhouzhi out of 120 samples, 10 for AcVA and 0 for AcVB, AcCRaV, ASGV, PVX, and CMV in Yangling out of 70 samples, and 8 for AcCRaV and CMV and 0 for AcVA, AcVB, ASGV, and PVX in Hanzhong out of 80 samples, respectively. Samples which were multiply infected with two or more viruses were also detected. Analysis of the phylogenetic tree of these viruses showed some genetic variability in the AcVA, AcVB, and AcCRaV isolates of Shaanxi kiwifruit. There was no obvious molecular variation in the coat protein genes of ASGV, CMV, and PVX virus isolates from Shaanxi kiwifruit. The present study is the first large-scale survey of kiwifruit viruses in Shaanxi, China. To our knowledge, this is the first report of PVX infecting kiwifruit and the first report of molecular variability of AcVA, AcVB, and AcCRaV. These results provide important data for studying the genetic evolution of AcVA, AcVB, AcCRaV, ASGV, CMV, and PVX.
Get to know common sexually transmitted infections
Authors: Scott Loni J. , Shannon Mary
Published: December 2018

Nurses can have a positive influence on patients impacted by STIs through education about prevention methods.
Technologies for Young Femoral Neck Fracture Fixation
Authors: Duffin Matthew , Pilson Holly T.
Published: December 2018

Fixation of young femoral neck fractures represents a challenge in the field of orthopaedic trauma surgery. Conventional methods, including cannulated screw and sliding hip screw constructs, have been studied and found to have similar results with regards to patient outcomes, which has made choosing an optimum fixation strategy difficult. In all of these cases, quality of reduction has been shown to be the most important factor when it comes to creating a favorable environment for fracture healing. Some of these patients, however, continue to have negative sequelae including nonunion, avascular necrosis, femoral head collapse, and poor hip function as a result. In this article, we review the 2 most commonly used constructs and present 2 novel fixation constructs for the fixation of femoral neck fractures in physiologically young patients, including the Smith & Nephew Conquest system and the Aesculap Targon system. We outline techniques for usage of these systems and proposed advantages to these systems compared with conventional fixation methods. We also discuss the results of previously published studies regarding conventional fixation methods and compare with some limited studies that have been published on these newer technologies.
Treatment of Young Femoral Neck Fractures
Authors: Medda Suman , Snoap Tyler , Carroll Eben A.
Published: December 2018

Femoral neck fractures in the physiologically young patient are challenging injuries to manage. A tenuous blood supply and the intrasynovial nature of the fracture create a challenging biological environment. To make matters worse, the biomechanics are equally problematic. Frequently, these fractures in younger populations are high Pauwel angle fractures that see considerable force, especially shear. These factors combine to make nonunion and avascular necrosis all too common. In the current study, we will highlight the challenges inherent to managing these injuries and will discuss techniques and implants that may help mitigate some of these challenges.
Novel Application of the Pfirrmann Disc Degeneration Grading System to 9.4T MRI
Authors: Sher Idrees , Daly Chris , Oehme David , Chandra Ronil V. , Sher Mustafa , Ghosh Peter , Smith Julian , Goldschlager Tony
Published: December 2018

Study Design.

Reliability study.

Objective.

To evaluate the applicability and reliability of 9.4T magnetic resonance imaging (MRI) in the assessment of degenerative disc disease compared with 3T MRI.

Summary of Background Data.

MRI is a reliable indicator of biochemical changes in the intervertebral disc (IVD) including hydration status, proteoglycan content, and disc degeneration compared with anatomical and histological studies. High-field 9.4T MRI has been shown to provide superior resolution and anatomical detail. However, it has not been tested against current standard MRI techniques.

Methods.

Disc degeneration was initiated in 36 skeletally mature ewes 6 months prior to necropsy via validated surgical IVD injury models using either scalpel injury or drill-bit injury techniques at lumbar spine levels L2/3 and L3/4 with L1/2, L4/5, and L5/6 serving as control discs. All ex vivo IVDs were examined with 9.4T MRI and 3T MRI. All scans were analyzed using the Pfirrmann grading system by four independent observers. Intra- and interobserver reliability was assessed using kappa statistics and Spearman correlation.

Results.

Inter- and intraobserver agreement for 9.4T MRI was excellent, both at κ 0.91 (P < 0.001). Comparatively, 3T interobserver reliability demonstrated substantial agreement at κ 0.61 (P < 0.001). Complete agreement was obtained in 92.7% to 100% of discs at 9.4T compared with 69.7% to 83.1% at 3T. A difference of one grade or more occurred in 6.7% at 9.4T and 39.3% at 3T. 9.4T MRI scored 97.3% of discs as grade 1 to 2 compared with 71.3% at 3T. 3T MRI tended to over-score the extent of disc degeneration with 28.6% of discs scored as grade 3 or higher compared with 2.7% at 9.4T MRI.

Conclusion.

9.4T MRI study of IVD degeneration using the Pfirrmann grading system demonstrated excellent inter- and intraobserver reliability. Comparatively, 3T MRI demonstrated a tendency to over score the extent of disc degeneration. This improved reliability of 9.4T MRI holds great potential for its clinical applications.

Level of Evidence: 3
OPTIC DISK ASTROCYTOMA UNASSOCIATED WITH TUBEROUS SCLEROSIS COMPLEX MANAGED WITH SURGICAL EXCISION AND A 7-YEAR FOLLOW-UP
Authors: Lu Yao , Xu Yimin
Published: December 2018

Purpose:

Optic disk astrocytoma is a rare variant of congenital hamartoma, which is usually associated with tuberous sclerosis complex. Generally, it is stationary but in rare cases, it can show progressive growth and cause severe local complications.

Methods:

Clinical–pathologic correlation.

Results:

A 10-year-old boy presented a unilateral optic disk mass with vitreous hemorrhage that eventually necessitated vitrectomy of the affected eye. Visual acuity was hand movements at presentation. Pars plana vitrectomy was performed because of sudden loss of vision. At the time of vitrectomy, a yellow tumor that measured 1.5 mm in basal diameter and 6 mm in thickness was surgically removed. Cytological analysis revealed benign giant cells. The cells were negative for HMB-45 but stained positively for glial fibrillary acidic protein and neuron-specific enolase compatible with an astrocytic lesion. At the follow-up of 7 years, his vision was 20/80 and there has been no recurrence of the tumor.

Conclusion:

Optic disk astrocytoma can be managed with local surgical excision and vision can be preserved if treated timely. Histopathologic features can help evaluate the degree of nuclear pleomorphism and cell morphology. Special immunohistochemical studies of the tumor's coexpressed neuronal markers will help differentiate astrocytoma from other neoplasms.
Antiemetic Drug Use in Children
Authors: Romano Claudio , Dipasquale Valeria , Scarpignato Carmelo
Published: December 2018

Vomiting is not only unpleasant for both children and families, but can lead to frequent hospital admission. The persistent vomiting hampers oral intake and increases the risk of dehydration, so the proper use of antiemetic drugs can be useful. The pharmacological treatment of vomiting in children remains a challenge for the pediatrician because several antiemetics are prescribed as “off‐label,” outside their authorized drug label. Domperidone and ondansetron are the most commonly known antiemetic drugs. A single oral dose of ondansetron has been shown to reduce the risk of recurrent vomiting, the need for intravenous fluids, and hospital admissions in children with acute gastroenteritis. There is enough evidence to support ondansetron administration in children, so the clinical use can be defined as “off‐label/on evidence.” This review aims to provide an overview of therapeutic use, safety, and main pharmacological properties of antiemetic drugs in children. A comprehensive search of published literature using the PubMed MEDLINE database was carried out to identify all articles published in English from 1998 to February 2018. At present time, the “off‐label/on‐evidence” use of some antiemetics could improve the success rate of oral rehydration therapy in pediatric emergency settings and to change the management of vomiting with the prevention of the complications.
Gold nanoparticle-based colorimetric platform technology as rapid and efficient bacterial pathogens detection method from various sources
Authors: Shafiei Morvarid , Ghasemian Abdolmajid , Mostafavi Seyyed K.S. , Teimouri Maryam , Vardanjani Hossein Rajabi , Mirforughi Seyede A.
Published: December 2018

Rapid, sensitive, and reliable bacterial pathogens detection is a chief requirement. The gold nanoparticles (AuNPs) have numerous applications such as in the detection of biomolecules for their high surface to volume ratio and unique optical property facilitating development of highly efficient AuNPs-based bio-sensing tools. Although various molecular detection methods, such as PCR, real-time PCR, and loop-mediated isothermal amplification are sensitive and convenient, these techniques need elaborate work and require special skills to increase their specificity. Smartly fabricated gold nanoparticle (GNPs) play a role as probes for selective detection of pathogens. The AuNPs-based colorimetric methods have become applicable for rapid, simple, reliable and high-efficient, sensitive, inexpensive, and easy detection of the DNA, RNA, and protein biomolecules. Colorimetric detection using AuNPs has been used for rapid and high precision and multiplex detection of a large number and of bacterial pathogens. AuNPs act in functionalized and unfunctionalized ways. AuNPs-based colorimetric methods have incredible advantages compared with many other bacterial detection methods. In spite of many molecular techniques, AuNPs-based colorimetric methods do not require additional devices, fabrication cost, signal processing and interpretation complexities, and costly and complex instruments. This simple and rapid method is suitable, especially in low-income areas and for large number of samples analysis. In this review, applications of AuNPs and AuNPs-based colorimetric methods for bacterial pathogens detection have been overviewed.
Postural control skills, proprioception, and risk of fall in long-term survivor patients treated with knee rotationplasty
Authors: Benedetti Maria Grazia , Coli Michael , Campanacci Laura , Manfrini Marco
Published: December 2018

Knee A1 rotationplasty is a particular type of limb salvage surgery alternative to hip disarticulation and high transfemoral amputation for skeletally immature children with bone cancers in the distal femur. Notwithstanding optimal functional outcomes, long-term survivor patients often report frequent falls, and a sense of instability during gait, particularly on uneven terrain. This study aimed to assess the postural control, the proprioception, and the risk of fall in these patients, which have not been explored before. Eighteen long-term survivor patients participated in the study. The mean follow-up from surgery was 23 years, mean age 32 years. Patients were assessed using a specific instrumental device (Delos Postural Proprioceptive System) both for the static double-stance and the single-stance test in the open eyes and closed eyes conditions. The double-stance test showed postural instability values within the normal range for healthy individuals, whereas in the single-stance test stability index, when assessed in the average of both lower limbs, values were lower than the literature findings for older individuals. However, when separating the operated from the nonoperated limb performance, standing on the operated limb was very unstable, with a low stability index and a low degree of autonomy, indicating a certain risk of falling, whereas standing on the nonoperated limb had a performance close to normal or even superior. In conclusion, knee rotationplasty patients had very good postural control when standing on both limbs, whereas single stance on the operated limb was compromised, with particular involvement of the proprioceptive component. This may determine a higher risk of falling than their normal-age counterparts and rehabilitation intervention for prevention is indicated.