bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metastabile Epiallele – beeinflussen epigenetische Varianten das individuelle Adipositasrisiko?
Authors: Krude H. , Kühnen P. 
Published: December 2018

ZusammenfassungEpigenetische Modifikationen der DNA stellen einen sehr konservierten Regulationsmechanismus bei Pflanzen, Tieren und Menschen dar. Veränderungen beispielsweise der DNA Methylierung können zu der Entwicklung von Tumoren führen und spielen bei der Entstehung von sogenannten Imprinting Erkrankungen eine Rolle. Unklar ist jedoch die Bedeutung dieser Modifikationen für die Entstehung von chronischen Erkrankungen wie beispielsweise Adipositas. Gewebespezifität, genetischer Einfluss und Variabilität der DNA Methylierung stellen eine große Herausforderung für die Untersuchung dieser Zusammenhänge dar. Ergebisse aus epigenom-weiten Assoziationsstudien (EWAS) sowie die Identifikation von sogenannten metastabilen Epiallelen weisen jedoch darauf hin, dass es Unterschiede in der DNA Methylierung gibt, die das individuelle Risiko für die Entwicklung von Adipositas beeinflussen. Es werden zukünftige Studien zeigen, inwieweit Epigenetik im einzelnen von Bedeutung für die Adipositasentwicklung ist und ob dieses Wissen auch therapeutisch von Nutzen sein könnte.
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.
Unbiased Hamiltonian Monte Carlo with couplings
Authors: Heng J , Jacob P E 
Published: December 2018

SummaryWe 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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract
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

Abstract
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

Abstract
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

AbstractObjectivesTo 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.MethodsRASFs 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.ResultsIn 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.ConclusionAPC 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.
Technologies for Young Femoral Neck Fracture Fixation
Authors: Duffin Matthew , Pilson Holly T. 
Published: December 2018

Summary:
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

Summary:
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.