bluuebunny/crossref_metadata_2025_split huggingface dataset:
Automated external defibrillator use and outcomes after out-of-hospital cardiac arrest: an Israeli cohort study
Authors: Merdler Ilan , Sadeh Ben , Hochstadt Aviram , Kofman Natalia , Szekely Yishay , Steinvil Arie , Shacham Yacov 
Published: October 2019

Background
Out-of-hospital cardiac arrests (OHCA) are a serious healthcare situation with low survival rates. Application of an automated external defibrillator (AED) by bystanders shortens time to defibrillation and increases survival. In Israel, a regulation ensuring the presence of AED in public places was issued and implemented since 2014. We investigated whether this regulation had an impact on the outcomes of OHCA patients.

Methods
We performed a retrospective, single-center observational study. Included in the cohort were patients who were admitted to the department of intensive care cardiac unit with OHCA. Patients were stratified into two groups according to the year the regulation was introduced: group 1 (2009–2013) and group 2 (2014–2018).

Results
A total of 77 patients were included in group 1 and 61 in group 2. The utilization of AED was significantly higher in group 2 compared to group 1 (42% vs. 27%; P = 0.04). Compared to group 1 patients, group 2 had lower 48 h (0% vs. 8%; P = 0.02) and 30-day mortality (28% vs. 42%; P = 0.02). Cognitive damage following recovery was less frequent in group 2 (55% vs. 81%; P = 0.01).

Conclusion
Deployment of AEDs in public places by mandatory regulations increased utilization for OHCA and may improve outcomes.
CHA2DS2-Vasc score and saphenous vein graft disease in patients with coronary artery bypass graft surgery
Authors: Yarlioglues Mikail , Oksuz Fatih , Yalcinkaya Damla , Duran Mustafa , Murat Sani Namik 
Published: October 2019

Background
Saphenous vein grafts (SVGs) are still frequently used in coronary artery bypass graft surgery (CABG). However, the patency rate of SVGs is lower than arterial grafts. CHA2DS2-VASc score gives important information about the prognosis of various cardiovascular diseases. In this study, we aimed to investigate the association between CHA2DS2-VASc score and saphenous vein graft disease (SVGD) in patients with history of CABG surgery.

Methods
A total of 241 patients who had undergone CABG surgery and who underwent coronary angiography due to stable angina pectoris symptoms were reviewed retrospectively. SVGD was defined as ≥50% stenosis in at least one SVG. Patients were divided into two groups according to the presence or absence of SVGD.

Results
It was found that CHA2DS2-VASc scores were significantly higher in SVGD group. In multivariate logistic regression analysis, time interval after CABG [odds ratio (OR) = 1.077, 95% confidence interval (CI) 1.004–1.155; P = 0.037], and CHA2DS2-VASc score ≥ 4 (OR = 10.10, 95% CI 4.739–21.276; P < 0.001) were found to be independent predictors of SVGD.

Conclusion
For the first time, our results have suggested that CHA2DS2-VASc score, which is commonly used in daily clinical practice and easy to calculate, can provide useful information for the risk assessment of patients with SVGs.
Diabetes mellitus is not independently associated with mortality in elderly patients with ST-segment elevation myocardial infarction. Insights from the Codi Infart registry
Authors: Gual Miquel , Ariza-Solé Albert , Formiga Francesc , Carrillo Xavier , Bañeras Jordi , Tizón Helena , Garcia-Picart Joan , Cárdenas Mérida , Regueiro Ander , Tomás Carlos , Rojas Sergio , Muñoz-Camacho Juan F. , Rosas Alba , Sánchez-Salado José C. , Lorente Victòria , Roura Gerard , Alegre Oriol , Gómez-Hospital Joan A. , Lidón Rosa M , Cequier Angel 
Published: October 2019

Background
Diabetes mellitus predicts poorer outcomes in patients with acute coronary syndrome (ACS), but the magnitude of this association in patients at older ages remains controversial.

Methods
Data were extracted from the Codi Infart database. All consecutive patients with diagnosis of ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) between 2010 and 2015 were included. We assessed the impact of diabetes mellitus on 30-day and one-year mortality in patients aged less than and at least 75 years.

Results
A total of 12 792 cases were registered, of whom 3023 (23.6%) were aged at least 75 years. About 20% patients had previous diabetes mellitus diagnosis. Patients aged at least 75 years had higher prevalence of comorbidities, higher proportion of heart failure at admission, a more extensive coronary artery disease and significant delay to reperfusion (P < 0.001). Diabetes mellitus was associated with higher 30-day mortality both in young [odds ratio (OR) 1.97, 95% confidence interval (CI): 1.43–2.70] and in elderly patients (OR 1.43, 95% CI: 1.07–1.91). After adjusting for potential confounders, this association remained significant in young patients (OR 1.47, 95% CI: 1.00–2.16, P = 0.047), but not in the elderly (OR 1.14, P = 0.43). Likewise, a crude association between diabetes mellitus and one-year mortality was observed in both groups (young patients: HR = 1.93; 95% CI: 1.51–2.46; older patients: HR = 1.33; 95% CI: 1.08–1.64). However, after adjusting for potential confounders, this association remained significant in younger patients (HR = 1.46; 95% CI: 1.13–1.89; P < 0.001), but not in the elderly (HR = 1.16; P = 0.17).

Conclusion
A significant proportion of these nonselected patients with STEMI had previous diabetes mellitus. The association between diabetes mellitus and outcomes is different according to age.
177Lu-DOTATATE peptide receptor radionuclide therapy versus Everolimus in advanced pancreatic neuroendocrine tumors: a systematic review and meta-analysis
Authors: Satapathy Swayamjeet , Mittal Bhagwant Rai 
Published: October 2019

Objective
Advanced pancreatic neuroendocrine tumors (pNETs) present a therapeutic challenge with targeted therapies like Everolimus and 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) showing beneficial effects in various cohort studies and randomized trials. Currently there is a paucity of trials with head-to-head comparison between PRRT and Everolimus in advanced pNETs. This systematic review was conducted to compare the therapeutic efficacy and safety profile of 177Lu-DOTATATE and Everolimus in advanced pNETs.

Methods
The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Searches in Pubmed, Scopus and Embase using relevant keywords selected articles up to June 2019. Data on efficacy and safety were extracted from the individual articles. Random effects model was used for meta-analysis.

Results
Fifteen articles consisting of 697 patients reported on 177Lu-DOTATATE and 12 articles consisting of 946 patients reported on Everolimus. Overall, treatment with 177Lu-DOTATATE had better objective response rate (47% vs. 12%, P < 0.001) and disease control rate (81% vs. 73%, P < 0.001) and longer progression-free survival (25.7 months vs. 14.7 months, P < 0.001) than with Everolimus. 177Lu-DOTATATE also had a better safety profile than Everolimus with fewer patients showing grade 3/4 hematological toxicity (5% vs. 11%, P = 0.02) and nephrotoxicity (1% vs. 2.5%, P = 0.34). Treatment-related adverse events caused discontinuation of therapy more frequently for Everolimus than for 177Lu-DOTATATE (59 out of 371 patients vs. 0 out of 128 patients).

Conclusion
From this meta-analysis, 177Lu-DOTATATE showed better therapeutic efficacy and safety profile compared to Everolimus in advanced pNETs.
Targeting ABL1 or ARG Tyrosine Kinases to Restrict HIV-1 Infection in Primary CD4+ T‐Cells or in Humanized NSG Mice
Authors: McCarthy Stephen D.S. , Leontyev Danila , Nicoletti Pauline , Binnington Beth , Kozlowski Hannah N. , Ostrowski Mario , Cochrane Alan , Branch Donald R. , Wong Raymond W. 
Published: October 2019

Background:
Previous studies support dasatinib as a potent inhibitor of HIV-1 replication. However, a functional distinction between 2 kinase targets of the drug, ABL1 and ARG, has not been assessed.

Setting:
We used primary CD4+ T‐cells, CD8-depleted peripheral blood mononuclear cells (PBMCs) from a treatment naïve HIV-1+ patient, and a humanized mouse model of HIV-1 infection. We assessed the roles of ABL1 and ARG during HIV-1 infection and use of dasatinib as a potential antiviral against HIV-1 in humanized mice.

Methods:
Primary CD4+ T‐cells were administered siRNA targeting ABL1 or ARG, then infected with HIV-1 containing luciferase reporter viruses. Quantitative polymerase chain reaction of viral integration of 4 HIV-1 strains was also assessed. CD8-depleted PBMCs were treated for 3 weeks with dasatinib. NSG mice were engrafted with CD34+ pluripotent stem cells from human fetal cord blood, and infected with Ba-L virus after 19 weeks. Mice were treated daily with dasatinib starting 5 weeks after infection.

Results:
siRNA knockdown of ABL1 or ARG had no effect on viral reverse transcripts, but increased 2-LTR circles 2- to 4-fold and reduced viral integration 2- to 12-fold. siRNA knockdown of ARG increased SAMHD1 activation, whereas knockdown of either kinase reduced RNA polymerase II activation. Treating CD8-depleted PBMCs from a treatment-naïve patient with 50 nM of dasatinib for 3 weeks reduced p24 levels by 99.8%. Ba-L (R5)-infected mice injected daily with dasatinib showed a 95.1% reduction in plasma viral load after 2 weeks of treatment.

Conclusions:
We demonstrate a novel nuclear role for ABL1 and ARG in ex vivo infection experiments, and proof-of-principle use of dasatinib in a humanized mouse model of HIV-1 infection.
Use of Modeling and Simulations to Determine Raltegravir Dosing in Neonates: A Model for Safely and Efficiently Determining Appropriate Neonatal Dosing Regimens: IMPAACT P1110
Authors: Clarke Diana F. , Mirochnick Mark , Acosta Edward P. , Capparelli Edmund , Chain Anne , Teppler Hedy , Smith Betsy , Lommerse Jos ,   for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1110 Study Team
Published: October 2019

Background:
Population modeling and simulations can be used to facilitate the conduct of phase I studies to develop safe and effective dosing regimens in neonates.

Setting:
P1110 is an international, multicenter trial to determine safe and effective raltegravir doses in neonates at risk for HIV infection.

Methods:
P1110 used a 2-cohort adaptive design incorporating population pharmacokinetic modeling and simulations. An initial cohort of neonates received 2 single oral doses of raltegravir with standard-of-care therapy for prevention of perinatal transmission—one within 48 hours of birth and a second at 7–10 days of life. Raltegravir concentration data after administration of these doses were combined with data from a previous study of infants aged 4 weeks to 2 years. The combined database was used for population pharmacokinetic modeling and simulations to select a daily dosing regimen for investigation in a second cohort of neonates.

Results:
Raltegravir concentration data from 6 neonates were combined with data from infants aged 4 weeks to 2 years receiving raltegravir twice daily. The combined data set allowed for successful development of a population pharmacokinetic model with reasonable precision of parameter estimates. Monte Carlo simulations were run to evaluate potential daily dosing regimens from birth to 6 weeks of age, allowing for selection of a regimen to be evaluated in a subsequent cohort of neonates receiving chronic raltegravir dosing.

Conclusions:
An adaptive design incorporating population pharmacokinetic modeling and simulations was used to select a developmentally appropriate neonatal raltegravir dosing regimen in the first 6 weeks of life.
“Namaste Flap”
Authors: Karki Durga , Muthukumar Vamseedharan , Dash Suvashis 
Published: October 2019

Introduction
The reconstruction of the postburn contracture area is always a challenge in the field of plastic surgery. Moreover, the joints are very sensitive to trauma and immobilization, showing a susceptibility to stiffness. The aim of this article is to emphasize the use of “Namaste flap”—modification of subcutaneous pedicle propeller flaps in the reconstruction of postburn axillary and elbow contractures.

Methodology
This is a prospective case study of axillary and elbow contractures managed at a tertiary care hospital using Namaste flap—modification of subcutaneous pedicle propeller flaps from 2010 to 2016. The surgical technique involved raising 2-limbed subcutaneous pedicle-based propellar flap over the contracture using the unburnt skin at the axillary and cubital fossa. The flap with both the limb thus raised was rotated by 90 degrees in the same direction and inserted into the defect.

Results
Nine patients including 6 patients with elbow and 3 patients with axillary contractures were included in this study. The mean degree of contracture in axilla and elbow was 78.3 degrees and 59.1 degrees, respectively. The functional results postoperatively were satisfactory. The mean postoperative degree of joint movements in axilla and elbow was 176.3 degrees and 173.6 degrees, respectively. No major complications were encountered. There was a mean period of 12 months of follow-up.

Conclusions
In cases where normal skin is still present on the axillary and cubital fossa with scar contracture caused by extensive burns, the subcutaneous propeller flap methods and their modifications should be considered one of the most useful versatile reconstruction methods. Namaste flap in addition to the advantages of subcutaneous pedicle propeller flap also negates the disadvantages caused by the use of split skin grafting of the donor area.
A practical method for estimating coupling functions in complex dynamical systems
Authors: Tokuda Isao T. , Levnajic Zoran , Ishimura Kazuyoshi 
Published: October 2019

A foremost challenge in modern network science is the inverse problem of reconstruction (inference) of coupling equations and network topology from the measurements of the network dynamics. Of particular interest are the methods that can operate on real (empirical) data without interfering with the system. One such earlier attempt (Tokudaet al.2007Phys. Rev. Lett.99, 064101. (doi:10.1103/PhysRevLett.99.064101)) was a method suited for general limit-cycle oscillators, yielding both oscillators' natural frequencies and coupling functions between them (phase equations) from empirically measured time series. The present paper reviews the above method in a way comprehensive to domain-scientists other than physics. It also presents applications of the method to (i) detection of the network connectivity, (ii) inference of the phase sensitivity function, (iii) approximation of the interaction among phase-coherent chaotic oscillators, and (iv) experimental data from a forced Van der Pol electric circuit. This reaffirms the range of applicability of the method for reconstructing coupling functions and makes it accessible to a much wider scientific community.This article is part of the theme issue ‘Coupling functions: dynamical interaction mechanisms in the physical, biological and social sciences’.
Nonlinear phase coupling functions: a numerical study
Authors: Rosenblum Michael , Pikovsky Arkady 
Published: October 2019

Phase reduction is a general tool widely used to describe forced and interacting self-sustained oscillators. Here, we explore the phase coupling functions beyond the usual first-order approximation in the strength of the force. Taking the periodically forced Stuart–Landau oscillator as the paradigmatic model, we determine and numerically analyse the coupling functions up to the fourth order in the force strength. We show that the found nonlinear phase coupling functions can be used for predicting synchronization regions of the forced oscillator.
This article is part of the theme issue ‘Coupling functions: dynamical interaction mechanisms in the physical, biological and social sciences’.
Synchronization transitions caused by time-varying coupling functions
Authors: Hagos Zeray , Stankovski Tomislav , Newman Julian , Pereira Tiago , McClintock Peter V. E. , Stefanovska Aneta 
Published: October 2019

Interacting dynamical systems are widespread in nature. The influence that one such system exerts on another is described by a coupling function; and the coupling functions extracted from the time-series of interacting dynamical systems are often found to be time-varying. Although much effort has been devoted to the analysis of coupling functions, the influence of time-variability on the associated dynamics remains largely unexplored. Motivated especially by coupling functions in biology, including the cardiorespiratory and neural delta-alpha coupling functions, this paper offers a contribution to the understanding of effects due to time-varying interactions. Through both numerics and mathematically rigorous theoretical consideration, we show that for time-variable coupling functions with time-independent net coupling strength, transitions into and out of phase- synchronization can occur, even though the frozen coupling functions determine phase-synchronization solely by virtue of their net coupling strength. Thus the information about interactions provided by the shape of coupling functions plays a greater role in determining behaviour when these coupling functions are time-variable.
This article is part of the theme issue ‘Coupling functions: dynamical interaction mechanisms in the physical, biological and social sciences’.
Adaptive zinc tolerance is supported by extensive gene multiplication and differences in cis-regulation of a CDF transporter in an ectomycorrhizal fungus
Authors: Ruytinx Joske , Coninx Laura , Op De Beeck Michiel , Arnauts Natascha , Rineau François , Colpaert Jan V. 
Published: October 2019

SummaryAbiotic changes due to anthropogenic activities affect selection regimes for organisms. How trees and their mycorrhizal symbionts adapt to altered environments in heterogeneous landscapes is of great interest. With a global distribution and multiple adaptive phenotypes available,Suillus luteusis an excellent ectomycorrhizal model to study evolutionary dynamics of local adaptation. We assessed pathways of homeostasis and detoxification inS. luteusisolates, displaying contrasting Zn tolerance phenotypes to identify mechanisms underlying adaptive Zn tolerance. Using 30 randomly selected isolates sampled at metal contaminated and control sites, we documented Zn tolerance phenotypes, assessed the link with identified candidate genes and explored its genetic basis via targeted amplicon sequencing and qPCR. Zn tolerance phenotypes covering a continuum from Zn sensitive to hypertolerant were identified and inversely correlate with cellular Zn accumulation. Gene expression ofSlZnT2, encoding a putative Zn transporter explains 72% of the observed phenotypic variation.SlZnT2copy number varies among isolates and different promotor genotypes were identified. Rapid adaptation in this species is supported by the cumulative effect of gene copy number variation and differences in cis-regulation and might be triggered by environmental stress rather than being the result of standing variation.Originality - significance statementTo the best of our knowledge, this is the first study linking genotypes to adaptive phenotypes in mycorrhizal fungi. It is unique in the way it combines evolutionary and functional genetics to allow a significant advance in the understanding of responses to environmental stress factors in general and, to soil metal pollution in particular. A better understanding of adaptive tolerance mechanisms in keystone symbiotic fungi is paramount for developing impactful phyto and mycoremediation strategies for metal polluted waste land and to predict the impact of future environmental change on mycorrhizal diversity and ecosystem functioning.
Computational Assessment of the Regulation-Modulating Potential for Noncoding Variants
Authors: Shi Fang-Yuan , Wang Yu , Huang Dong , Liang Yu , Liang Nan , Chen Xiao-Wei , Gao Ge 
Published: October 2019

AbstractLarge-scale genome-wide association and expression quantitative trait loci studies have identified multiple noncoding variants associated with genetic diseases via affecting gene expression. However, effectively and efficiently pinpointing causal variants remains a serious challenge. Here, we developed CARMEN, a novel algorithm to identify functional noncoding expression-modulating variants. Multiple evaluations demonstrated CARMEN’s superior performance over state-of-the-art tools. Its higher sensitivity and low false discovery rate enable CARMEN to identify multiple causal expression-modulating variants that other tools simply missed. Meanwhile, benefitting from extensive annotations generated, CARMEN provides mechanism hints on predicted expression-modulating variants, enabling effectively characterizing functional variants involved in gene expression and disease-related phenotypes. CARMEN scales well with the massive datasets and is available online as a Web server at http://carmen.gao-lab.org.
Conformational Plasticity of the ClpAP AAA+ Protease Couples Protein Unfolding and Proteolysis
Authors: Lopez Kyle E. , Rizo Alexandrea N. , Tse Eric , Lin JiaBei , Scull Nathaniel W. , Thwin Aye C. , Lucius Aaron L. , Shorter James , Southworth Daniel R. 
Published: October 2019

AbstractThe ClpAP complex functions as a “bacterial proteasome” that simultaneously unfolds and degrades proteins targeted for destruction. ClpA utilizes two AAA+ domains per protomer to power substrate unfolding and translocation into the ClpP proteolytic chamber. To understand this mechanism, we determined high-resolution structures of wildtype E. coli ClpAP in distinct substrate-bound states. ClpA forms a spiral with substrate contacts across both AAA+ domains, while protomers at the seam undergo nucleotide-specific rearrangements indicating a conserved rotary mechanism. ClpA IGL loops extend flexibly to bind the planar, heptameric ClpP surface and support a large ClpA-P rotation that re-orients the translocation channel. The symmetry mismatch is maintained at the spiral seam through bind and release states of the IGL loops, which appear precisely coupled to substrate translocation. Thus, ClpA rotates around the apical surface of ClpP to processively translocate substrate into the protease.
ModiBodies: A computational method for modifying nanobodies to improve their antigen binding affinity and specificity
Authors: Hacisuleyman Aysima , Erman Burak 
Published: October 2019

AbstractNanobodies are special derivatives of antibodies, which consist of only a single chain. Their hydrophilic side prevents them from having the solubility and aggregation problems of conventional antibodies, and they retain the similar size and affinity of the binding area to the antigen. Nanobodies have become of considerable interest for next-generation biotechnological tools for antigen recognition. They can be easily engineered due to their high stability and compact size. They have three complementarity determining regions, CDRs, which are enlarged to provide a similar binding surface to that of regular antibodies. The binding residues are more exposed to the environment. One common strategy to improve protein solubility is to replace hydrophobic residues with hydrophilic ones on the binding surface which contributes to both stability and solubility of nanobodies.[1] Here, we propose an algorithm that uses the 3D structures of protein-nanobody complexes as the initial structures and by successive mutations in the CDR domains to find optimum binding amino acids for hypervariable residues of CDRs to increase the binding affinity and nanobody selectivity. We used the MDM4-VH9 complex, (PDB id 2VYR), fructose-bisphosphate aldolase from Trypanosoma congolense, (PDB id 5O0W), and human lysozyme, (PDB id 4I0C). as benchmark studies and identified similar amino acid patterns in hypervariable residues of CDRs with experimentally optimized ones. According to this method, better binding nanobodies can be generated by using this algorithm in a short time. We suggest that this method can complement existing immune and synthetic library-based methods, without the need of experiments or large libraries.