bluuebunny/crossref_metadata_2025 huggingface dataset:
𝖥𝖨-hyperhomology and ordered configuration spaces
Authors: Miller Jeremy , Wilson Jennifer
Published: July 2019

Using a result of Gan–Li on

F
I

\mathsf {FI}

-hyperhomology and a semisimplicial resolution of configuration spaces due to Randal-Williams, we establish an improved representation stability stable range for configuration spaces of distinct ordered points in a manifold. Our bounds on generation degree improve the best known stability slope by a factor of 5/2 in the most general case. We adapt this result of Gan–Li to apply beyond stability arguments involving highly connected simplicial complexes, and our methods suggest that their result may be widely applicable to improving most stability ranges for

F
I

\mathsf {FI}

-modules in the current representation stability literature.
Central-spindle microtubules are strongly coupled to chromosomes during both anaphase A and anaphase B
Authors: Yu Che-Hang , Redemann Stefanie , Wu Hai-Yin , Kiewisz Robert , Yoo Tae Yeon , Conway William , Farhadifar Reza , Müller-Reichert Thomas , Needleman Daniel
Published: July 2019

Spindle microtubules, whose dynamics vary over time and at different locations, cooperatively drive chromosome segregation. Measurements of microtubule dynamics and spindle ultrastructure can provide insight into the behaviors of microtubules, helping elucidate the mechanism of chromosome segregation. Much work has focused on the dynamics and organization of kinetochore microtubules, that is, on the region between chromosomes and poles. In comparison, microtubules in the central-spindle region, between segregating chromosomes, have been less thoroughly characterized. Here, we report measurements of the movement of central-spindle microtubules during chromosome segregation in human mitotic spindles and Caenorhabditis elegans mitotic and female meiotic spindles. We found that these central-spindle microtubules slide apart at the same speed as chromosomes, even as chromosomes move toward spindle poles. In these systems, damaging central-spindle microtubules by laser ablation caused an immediate and complete cessation of chromosome motion, suggesting a strong coupling between central-spindle microtubules and chromosomes. Electron tomographic reconstruction revealed that the analyzed anaphase spindles all contain microtubules with both ends between segregating chromosomes. Our results provide new dynamical, functional, and ultrastructural characterizations of central-spindle microtubules during chromosome segregation in diverse spindles and suggest that central-spindle microtubules and chromosomes are strongly coupled in anaphase.
Laboratory Blood-Based Testing for Non-Lyme Disease Tick-Borne Infections at a National Reference Laboratory
Authors: Lee-Lewandrowski Elizabeth , Chen Zhen , Branda John , Baron Jason , Kaufman Harvey W
Published: July 2019

Objectives

We evaluated trends in non-Lyme disease tick-borne disease (NLTBI) testing at a national reference laboratory.

Methods

Testing data performed at Quest Diagnostics during 2010 to 2016 were analyzed nationally and at the state level.

Results

Testing and positivity for most NLTBIs increased dramatically from 2010 through 2016 based on testing from a large reference laboratory. The number of positive cases, though not as stringent as criteria for public health reporting, generally exceeds that reported by the Centers for Disease Control and Prevention. The frequency of NLTBI in the US is seasonal but testing activity and positive test results are observed throughout all months of the year. Positive results for NLTBI testing mostly originated from a limited number of states, indicating the geographic concentration and distribution of NLTBIs reported in this study.

Conclusions

This report provides an important complementary source of data to best understand trends in and spread of NLTBI.
Below-ground biomass of plants, with a key contribution of buried shoots, increases foredune resistance to wave swash
Authors: De Battisti Davide , Griffin John N
Published: July 2019

Background and aims

Sand dunes reduce the impact of storms on shorelines and human infrastructure. The ability of these ecosystems to provide sustained coastal protection under persistent wave attack depends on their resistance to erosion. Although flume experiments show that roots of perennial plants contribute to foredune stabilization, the role of other plant organs, and of annual species, remains poorly studied. Furthermore, it remains unknown if restored foredunes provide the same level of erosion resistance as natural foredunes. We investigated the capacity of three widespread pioneer foredune species (the perennial Ammophila arenaria and the annuals Cakile maritima and Salsola kali) to resist dune erosion, and compared the erosion resistance of Ammophila at natural and restored sites.

Methods

Cores collected in the field were tested in a flume that simulated a wave swash. A multi-model inference approach was used to disentangle the contributions of different below-ground compartments (i.e. roots, rhizomes, buried shoots) to erosion resistance.

Key Results

All three species reduced erosion, with Ammophila having the strongest effect (36 % erosion reduction versus unvegetated cores). Total below-ground biomass (roots, rhizomes and shoots), rather than any single compartment, most parsimoniously explained erosion resistance. Further analysis revealed that buried shoots had the clearest individual contribution. Despite similar levels of total below-ground biomass, coarser sediment reduced erosion resistance of Ammophila cores from the restored site relative to the natural site.

Conclusions

The total below-ground biomass of both annual and perennial plants, including roots, rhizomes and buried shoots, reduced dune erosion under a swash regime. Notably, we show that (1) annual pioneer species offer erosion protection, (2) buried shoots are an important plant component in driving sediment stabilization, and (3) management must consider both biological (plants and their traits) and physical (grain size) factors when integrating dunes into schemes for coastal protection.
Universal concept signature analysis: genome-wide quantification of new biological and pathological functions of genes and pathways
Authors: Chi Xu , Sartor Maureen A , Lee Sanghoon , Anurag Meenakshi , Patil Snehal , Hall Pelle , Wexler Matthew , Wang Xiao-Song
Published: July 2019

Identifying new gene functions and pathways underlying diseases and biological processes are major challenges in genomics research. Particularly, most methods for interpreting the pathways characteristic of an experimental gene list defined by genomic data are limited by their dependence on assessing the overlapping genes or their interactome topology, which cannot account for the variety of functional relations. This is particularly problematic for pathway discovery from single-cell genomics with low gene coverage or interpreting complex pathway changes such as during change of cell states. Here, we exploited the comprehensive sets of molecular concepts that combine ontologies, pathways, interactions and domains to help inform the functional relations. We first developed a universal concept signature (uniConSig) analysis for genome-wide quantification of new gene functions underlying biological or pathological processes based on the signature molecular concepts computed from known functional gene lists. We then further developed a novel concept signature enrichment analysis (CSEA) for deep functional assessment of the pathways enriched in an experimental gene list. This method is grounded on the framework of shared concept signatures between gene sets at multiple functional levels, thus overcoming the limitations of the current methods. Through meta-analysis of transcriptomic data sets of cancer cell line models and single hematopoietic stem cells, we demonstrate the broad applications of CSEA on pathway discovery from gene expression and single-cell transcriptomic data sets for genetic perturbations and change of cell states, which complements the current modalities. The R modules for uniConSig analysis and CSEA are available through https://github.com/wangxlab/uniConSig.
Bayesian estimation of genetic regulatory effects in high-throughput reporter assays
Authors: Majoros William H , Kim Young-Sook , Barrera Alejandro , Li Fan , Wang Xingyan , Cunningham Sarah J , Johnson Graham D , Guo Cong , Lowe William L , Scholtens Denise M , Hayes M Geoffrey , Reddy Timothy E , Allen Andrew S
Published: July 2019

Motivation

High-throughput reporter assays dramatically improve our ability to assign function to noncoding genetic variants, by measuring allelic effects on gene expression in the controlled setting of a reporter gene. Unlike genetic association tests, such assays are not confounded by linkage disequilibrium when loci are independently assayed. These methods can thus improve the identification of causal disease mutations. While work continues on improving experimental aspects of these assays, less effort has gone into developing methods for assessing the statistical significance of assay results, particularly in the case of rare variants captured from patient DNA.

Results

We describe a Bayesian hierarchical model, called Bayesian Inference of Regulatory Differences, which integrates prior information and explicitly accounts for variability between experimental replicates. The model produces substantially more accurate predictions than existing methods when allele frequencies are low, which is of clear advantage in the search for disease-causing variants in DNA captured from patient cohorts. Using the model, we demonstrate a clear tradeoff between variant sequencing coverage and numbers of biological replicates, and we show that the use of additional biological replicates decreases variance in estimates of effect size, due to the properties of the Poisson-binomial distribution. We also provide a power and sample size calculator, which facilitates decision making in experimental design parameters.

Availability and implementation

The software is freely available from www.geneprediction.org/bird. The experimental design web tool can be accessed at http://67.159.92.22:8080

Supplementary information

Supplementary data are available at Bioinformatics online.
ISoLDE: a data-driven statistical method for the inference of allelic imbalance in datasets with reciprocal crosses
Authors: Reynès Christelle , Kister Guilhem , Rohmer Marine , Bouschet Tristan , Varrault Annie , Dubois Emeric , Rialle Stéphanie , Journot Laurent , Sabatier Robert
Published: July 2019

Motivation

Allelic imbalance (AI), i.e. the unequal expression of the alleles of the same gene in a single cell, affects a subset of genes in diploid organisms. One prominent example of AI is parental genomic imprinting, which results in parent-of-origin-dependent, mono-allelic expression of a limited number of genes in metatherian and eutherian mammals and in angiosperms. Currently available methods for identifying AI rely on data modeling and come with the associated limitations.

Results

We have designed ISoLDE (Integrative Statistics of alleLe Dependent Expression), a novel nonparametric statistical method that takes into account both AI and the characteristics of RNA-seq data to infer allelic expression bias when at least two biological replicates are available for reciprocal crosses. ISoLDE learns the distribution of a specific test statistic from the data and calls genes ‘allelically imbalanced’, ‘bi-allelically expressed’ or ‘undetermined’. Depending on the number of replicates, predefined thresholds or permutations are used to make calls. We benchmarked ISoLDE against published methods, and showed that ISoLDE compared favorably with respect to sensitivity, specificity and robustness to the number of replicates. Using ISoLDE on different RNA-seq datasets generated from hybrid mouse tissues, we did not discover novel imprinted genes (IGs), confirming the most conservative estimations of IG number.

Availability and implementation

ISoLDE has been implemented as a Bioconductor package available at http://bioconductor.org/packages/ISoLDE/.

Supplementary information

Supplementary data are available at Bioinformatics online.
The nPYc-Toolbox, a Python module for the pre-processing, quality-control and analysis of metabolic profiling datasets
Authors: Sands Caroline J , Wolfer Arnaud M , Correia Gonçalo D S , Sadawi Noureddin , Ahmed Arfan , Jiménez Beatriz , Lewis Matthew R , Glen Robert C , Nicholson Jeremy K , Pearce Jake T M
Published: July 2019

As large-scale metabolic phenotyping studies become increasingly common, the need for systemic methods for pre-processing and quality control (QC) of analytical data prior to statistical analysis has become increasingly important, both within a study, and to allow meaningful inter-study comparisons. The nPYc-Toolbox provides software for the import, pre-processing, QC and visualization of metabolic phenotyping datasets, either interactively, or in automated pipelines.

Availability and implementation

The nPYc-Toolbox is implemented in Python, and is freely available from the Python package index https://pypi.org/project/nPYc/, source is available at https://github.com/phenomecentre/nPYc-Toolbox. Full documentation can be found at http://npyc-toolbox.readthedocs.io/ and exemplar datasets and tutorials at https://github.com/phenomecentre/nPYc-toolbox-tutorials.
TFEA.ChIP: a tool kit for transcription factor binding site enrichment analysis capitalizing on ChIP-seq datasets
Authors: Puente-Santamaria Laura , Wasserman Wyeth W , del Peso Luis
Published: July 2019

The computational identification of the transcription factors (TFs) [more generally, transcription regulators, (TR)] responsible for the co-regulation of a specific set of genes is a common problem found in genomic analysis. Herein, we describe TFEA.ChIP, a tool that makes use of ChIP-seq datasets to estimate and visualize TR enrichment in gene lists representing transcriptional profiles. We validated TFEA.ChIP using a wide variety of gene sets representing signatures of genetic and chemical perturbations as input and found that the relevant TR was correctly identified in 126 of a total of 174 analyzed. Comparison with other TR enrichment tools demonstrates that TFEA.ChIP is an highly customizable package with an outstanding performance.

Availability and implementation

TFEA.ChIP is implemented as an R package available at Bioconductor https://www.bioconductor.org/packages/devel/bioc/html/TFEA.ChIP.html and github https://github.com/LauraPS1/TFEA.ChIP_downloads. A web-based GUI to the package is also available at https://www.iib.uam.es/TFEA.ChIP/

Supplementary information

Supplementary data are available at Bioinformatics online.
Predicting promoters in phage genomes using PhagePromoter
Authors: Sampaio Marta , Rocha Miguel , Oliveira Hugo , Dias Oscar
Published: July 2019

The growing interest in phages as antibacterial agents has led to an increase in the number of sequenced phage genomes, increasing the need for intuitive bioinformatics tools for performing genome annotation. The identification of phage promoters is indeed the most difficult step of this process. Due to the lack of online tools for phage promoter prediction, we developed PhagePromoter, a tool for locating promoters in phage genomes, using machine learning methods. This is the first online tool for predicting promoters that uses phage promoter data and the first to identify both host and phage promoters with different motifs.

Availability and implementation

This tool was integrated in the Galaxy framework and it is available online at: https://bit.ly/2Dfebfv.

Supplementary information

Supplementary data are available at Bioinformatics online.
geneCo: a visualized comparative genomic method to analyze multiple genome structures
Authors: Jung Jaehee , Kim Jong Im , Yi Gangman
Published: July 2019

In comparative and evolutionary genomics, a detailed comparison of common features between organisms is essential to evaluate genetic distance. However, identifying differences in matched and mismatched genes among multiple genomes is difficult using current comparative genomic approaches due to complicated methodologies or the generation of meager information from obtained results. This study describes a visualized software tool, geneCo (gene Comparison), for comparing genome structure and gene arrangements between various organisms. User data are aligned, gene information is recognized, and genome structures are compared based on user-defined GenBank files. Information regarding inversion, gain, loss, duplication and gene rearrangement among multiple organisms being compared is provided by geneCo, which uses a web-based interface that users can easily access without any need to consider the computational environment.

Availability and implementation

Users can freely use the software, and the accessible URL is https://bigdata.dongguk.edu/geneCo. The main module of geneCo is implemented by Python and the web-based user interface is built by PHP, HTML and CSS to support all browsers.

Supplementary information

Supplementary data are available at Bioinformatics online.
The Changing Uses of Herbarium Data in an Era of Global Change: An Overview Using Automated Content Analysis
Authors: Heberling J Mason , Prather L Alan , Tonsor Stephen J
Published: July 2019

Widespread specimen digitization has greatly enhanced the use of herbarium data in scientific research. Publications using herbarium data have increased exponentially over the last century. Here, we review changing uses of herbaria through time with a computational text analysis of 13,702 articles from 1923 to 2017 that quantitatively complements traditional review approaches. Although maintaining its core contribution to taxonomic knowledge, herbarium use has diversified from a few dominant research topics a century ago (e.g., taxonomic notes, botanical history, local observations), with many topics only recently emerging (e.g., biodiversity informatics, global change biology, DNA analyses). Specimens are now appreciated as temporally and spatially extensive sources of genotypic, phenotypic, and biogeographic data. Specimens are increasingly used in ways that influence our ability to steward future biodiversity. As we enter the Anthropocene, herbaria have likewise entered a new era with enhanced scientific, educational, and societal relevance.
A Critical Perspective on Advance Care Planning for Older People
Authors: Duffy Francis
Published: July 2019

How older people plan ahead for ageing in relation to accommodation, care arrangements, healthcare and medical treatment, and end of life decisions has attracted particular attention in recent years and as a result there has been considerable promotion of the importance of planning ahead and executing planning instruments with the aim of making one’s wishes and preferences known in advance. Planning ahead is promoted as allowing older people to have their voices heard, to advance their autonomy, choice and self-determination and to allow them to decide what treatment they may not want to receive. This article provides a critique of advance care planning, based on a subset of findings from a qualitative intergenerational study on ageing in Australia. The findings suggest that advance care planning is a much more complex and at times problematic endeavour, compared to what is promoted about advance care planning, in particular with regard to the use of planning instruments.
Asian Territorial Disputes and the 1951 San Francisco Peace Treaty: The Case of Dokdo
Authors: Schwartz Thomas , Yoo John
Published: July 2019

This Article analyzes whether the 1951 San Francisco Peace Treaty, the only multilateral international agreement that draws borders in East Asia, resolves the longstanding dispute over Dokdo between Korea and Japan. It uses the dispute to draw larger lessons about the nature of the treaty that ended World War II in the Pacific and how it structured the peace in Asia differently from that in Europe. It uses U.S. archival material to reconstruct the history of the making of the Treaty, which continues to be the most significant international legal instrument governing post-WWII Asia.

Although the Republic of Korea demonstrated a long history of control over Dokdo, Japan annexed the island on February 22, 1905. Japan places much importance on the Treaty’s silence because the Treaty otherwise required Japan to relinquish the territories it acquired before and during World War II. After the fall of the Nationalist government in China, the United States decided to rebuild Japan into a strong regional ally, and consequently negotiated a generous peace treaty with its former WWII enemy. This Article concludes that the Treaty left Dokdo, along with other important issues, open for future resolution.
Emergence of Polymyxin Resistance in Clinical Klebsiella pneumoniae Through Diverse Genetic Adaptations: A Genomic, Retrospective Cohort Study
Authors: Macesic Nenad , Nelson Brian , Mcconville Thomas H , Giddins Marla J , Green Daniel A , Stump Stephania , Gomez-Simmonds Angela , Annavajhala Medini K , Uhlemann Anne-Catrin
Published: July 2019

Background

Polymyxins are antimicrobials of last resort for the treatment of carbapenem-resistant Enterobacteriaceae, but resistance in 5% to >40% isolates has been reported. We conducted a genomic survey of clinical polymyxin-resistant (PR) Klebsiella pneumoniae to determine the molecular mechanisms of PR and the role of polymyxin exposure versus transmission in PR emergence.

Methods

We included 88 patients with PR K. pneumoniae from 2011–2018 and collected demographic, antimicrobial exposure, and infection data. Whole-genome sequencing was performed on 388 isolates, including 164 PR isolates. Variant calling and insertion sequence detection were performed, focusing on key genes associated with PR (mgrB, crrAB, phoPQ, and pmrAB). We conducted phylogenetic analyses of key K. pneumoniae multi-locus sequence types (ST258, ST17, ST307, and ST392).

Results

Polymyxin exposure was documented in 53/88 (60%) patients prior to PR detection. Through an analysis of key PR genes, we detected 129 individual variants and 72 unique variant combinations in PR isolates. This included multiple, distinct changes in 36% of patients with serial PR isolates. Insertion sequence disruption was limited to mgrB (P < .001). Polymyxin minimum inhibitory concentrations showed stepwise increases with the number of PR genes affected (P < .001). When clusters containing PR isolates in ≥2 patients were analyzed, 10/14 had multiple genetic events leading to PR.

Conclusions

Molecular mechanisms leading to PR in clinical K. pneumoniae isolates are remarkably heterogenous, even within clusters or individual patients. Polymyxin exposure with de novo PR emergence led to PR in the majority of patients, rather than transmission. Optimizing polymyxin use should be a key strategy in stopping the spread of PR.
Prevalence of Hepatitis B Virus Infection Among US Adults Aged 20–59 Years With a History of Injection Drug Use: National Health and Nutrition Examination Survey, 2001–2016
Authors: Shing Jaimie Z , Ly Kathleen N , Xing Jian , Teshale Eyasu H , Jiles Ruth B
Published: July 2019

Background

Hepatitis B virus (HBV) can transmit through needle sharing. The national HBV infection prevalence in persons who inject drugs remains ill-defined. We estimated the prevalence of total HBV core antibody (anti-HBc) positivity, indicating a previous or ongoing HBV infection, among adults aged 20–59 years with an injection drug use (IDU) history. We compared select characteristics by anti-HBc status.

Methods

Using 2001–2016 National Health and Nutrition Examination Survey data, we calculated the anti-HBc positivity prevalence among adults with IDU histories and among the general US population. For adults with IDU histories, we compared sex, age group, birth cohort, race/ethnicity, health insurance coverage, and hepatitis A immunity by anti-HBc status. Using marginal structural models, we calculated model-adjusted prevalence rates and ratios to determine the characteristics associated with anti-HBc positivity among adults with IDU histories.

Results

From 2001–2016, the anti-HBc positivity prevalence was 19.7% (95% confidence interval [CI] 16.0–24.0%) among those with IDU histories, compared with 4.6% (95% CI 4.3–5.0%) in the general population. The HBV surface antigen positivity prevalence was 0.4% (95% CI 0.3–0.5%) in the general population. Among adults with IDU histories, 19.8% reported prior-year IDU and 28.5% had a hepatitis A immunity.

Conclusions

One-fifth of adults with IDU histories had a previous or ongoing HBV infection: a rate over 4 times higher than the prevalence in the general population. One-fifth of adults with IDU histories reported prior-year use. Programs promoting safe IDU practices, drug treatment, and hepatitis A and B vaccinations should be key components of viral hepatitis prevention.
Efficacy of Direct-acting Antivirals for Chronic Hepatitis C Virus Infection in People Who Inject Drugs or Receive Opioid Substitution Therapy: A Systematic Review and Meta-analysis
Authors: Graf Christiana , Mücke Marcus M , Dultz Georg , Peiffer Kai-Henrik , Kubesch Alica , Ingiliz Patrick , Zeuzem Stefan , Herrmann Eva , Vermehren Johannes
Published: July 2019

Background

Treatment uptake for hepatitis C virus (HCV) infection in people who inject drugs (PWID) and patients on opioid substitution therapy (OST) is still low despite treatment guidelines that advocate the use of direct-acting antivirals (DAAs) in all patients. Our aim in this review was to investigate treatment outcomes among PWID and patients on OST in comparison to control cohorts.

Methods

A search of Embase, Medline, PubMed, and Web of Science (from October 2010 to March 2018) was conducted to assess sustained virologic response (SVR), discontinuation rates, adherence, and HCV reinfection in PWID and patients on OST.

Results

We identified 11 primary articles and 12 conference abstracts comprising 1702 patients on OST, 538 PWID, and 19 723 patients who served as controls. Among patients on OST, the pooled SVR was 90% (95% confidence interval [CI], 87% to 93%) and pooled treatment discontinuation rate was 7% (95% CI, 4% to 11%). Similarly, the pooled SVR was 88% (95% CI, 80% to 93%) in PWID and the pooled treatment discontinuation rate was 9% (95% CI, 5% to 15%). There was no significant difference regarding pooled rates of SVR, adherence, and discontinuation between patients on OST and controls as well as between PWID and controls. HCV reinfection rates among patients on OST ranged from 0.0 to 12.5 per 100 person-years.

Conclusions

HCV treatment outcomes in PWID and patients on OST are similar to those in patients without a history of injecting drugs, supporting current guideline recommendations to treat HCV in these patient populations.
Hybrid Network Intrusion Detection System for Smart Environments Based on Internet of Things
Authors: Subbarayalu Venkatraman , Surendiran B , Arun Raj Kumar P
Published: July 2019

The proliferation of Internet of Things (IoT) devices has led to many applications, including smart homes, smart cities and smart industrial control systems. Attacks like Distributed Denial of Service, event control hijacking, spoofing, event replay and zero day attacks are prevalent in smart environments. Conventional Network Intrusion Detection Systems (NIDSs) are tedious to deploy in the smart environment because of numerous communication architectures, manufacturer policies, technologies, standards and application-specific services. To overcome these challenges, we modeled the operational behavior of IoT network events using timed ACs and proposed a novel hybrid NIDS in this paper. A web server is integrated with IoT devices for remote access, and Constrained Application Protocol is employed in inter- and intra-smart device communication. Experiments are conducted in real time to validate our proposal and achieve 99.17% detection accuracy and 0.01% false positives.
Heterogeneity and plasticity in healthy and atherosclerotic vasculature explored by single-cell sequencing
Authors: van Kuijk Kim , Kuppe Christoph , Betsholtz Christer , Vanlandewijck Michael , Kramann Rafael , Sluimer Judith C
Published: July 2019

Cellular characteristics and their adjustment to a state of disease have become more evident due to recent advances in imaging, fluorescent reporter mice, and whole genome RNA sequencing. The uncovered cellular heterogeneity and/or plasticity potentially complicates experimental studies and clinical applications, as markers derived from whole tissue ‘bulk’ sequencing is unable to yield a subtype transcriptome and specific markers. Here, we propose definitions on heterogeneity and plasticity, discuss current knowledge thereof in the vasculature and how this may be improved by single-cell sequencing (SCS). SCS is emerging as an emerging technique, enabling researchers to investigate different cell populations in more depth than ever before. Cell selection methods, e.g. flow assisted cell sorting, and the quantity of cells can influence the choice of SCS method. Smart-Seq2 offers sequencing of the complete mRNA molecule on a low quantity of cells, while Drop-seq is possible on large numbers of cells on a more superficial level. SCS has given more insight in heterogeneity in healthy vasculature, where it revealed that zonation is crucial in gene expression profiles among the anatomical axis. In diseased vasculature, this heterogeneity seems even more prominent with discovery of new immune subsets in atherosclerosis as proof. Vascular smooth muscle cells and mesenchymal cells also share these plastic characteristics with the ability to up-regulate markers linked to stem cells, such as Sca-1 or CD34. Current SCS studies show some limitations to the number of replicates, quantity of cells used, or the loss of spatial information. Bioinformatical tools could give some more insight in current datasets, making use of pseudo-time analysis or RNA velocity to investigate cell differentiation or polarization. In this review, we discuss the use of SCS in unravelling heterogeneity in the vasculature, its current limitations and promising future applications.
Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance
Authors: Gyöngyösi Mariann , Lukovic Dominika , Zlabinger Katrin , Spannbauer Andreas , Gugerell Alfred , Pavo Noemi , Traxler Denise , Pils Dietmar , Maurer Gerald , Jakab Andras , Riesenhuber Martin , Pircher Andreas , Winkler Johannes , Bergler-Klein Jutta
Published: July 2019

Aims

The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies.

Methods and results

We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups.

Conclusions

All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.
High-sensitivity C-reactive protein in chronic heart failure: patient characteristics, phenotypes, and mode of death
Authors: Pellicori Pierpaolo , Zhang Jufen , Cuthbert Joe , Urbinati Alessia , Shah Parin , Kazmi Syed , Clark Andrew L , Cleland John G F
Published: July 2019

Aims

Plasma concentrations of high-sensitivity C-reactive protein (hsCRP) are often raised in chronic heart failure (CHF) and might indicate inflammatory processes that could be a therapeutic target. We aimed to study the associations between hsCRP, mode and cause of death in patients with CHF.

Methods and results

We enrolled 4423 patients referred to a heart failure clinic serving a local population. CHF was defined as relevant symptoms or signs with either a reduced left ventricular ejection fraction <40% or raised plasma concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP >125 pg/mL). The median [interquartile range (IQR)] plasma hsCRP for patients diagnosed with CHF (n = 3756) was 3.9 (1.6–8.5) mg/L and 2.7 (1.3–5.1) mg/L for those who were not (n = 667; P < 0.001). Patients with hsCRP ≥10 mg/L (N = 809; 22%) were older and more congested than those with hsCRP <2 mg/L (N = 1117, 30%). During a median follow-up of 53 (IQR 28–93) months, 1784 (48%) patients with CHF died. Higher plasma hsCRP was associated with greater mortality, independent of age, symptom severity, creatinine, and NT-proBNP. Comparing a hsCRP ≥10 mg/L to <2 mg/L, the hazard ratio for all-cause mortality was 2.49 (95% confidence interval 2.19–2.84; P < 0.001), for cardiovascular (CV) mortality was 2.26 (1.91–2.68; P < 0.001), and for non-CV mortality was 2.96 (2.40–3.65; P < 0.001).

Conclusion

In patients with CHF, a raised plasma hsCRP is associated with more congestion and a worse prognosis. The proportion of deaths that are non-CV also increases with higher hsCRP.
Income contingent university loans: Policy design and an application to Spain
Authors: Cabrales Antonio , Güell Maia , Madera Rocio , Viola Analía
Published: July 2019

In Europe, the need for additional funding coming from either budget cuts and/or increased costs due to increased competition in university quality has reopened the debate on the financing of university systems. An attractive alternative to the current general-tax-financed subsidies is Income Contingent Loans (ICL), a flexible scheme that puts more weight on private resources while enhancing progressivity. One challenge of the viability of ICL systems is the functioning of the labor market for university graduates. This paper offers a general analysis of the economics of ICL, followed by an application to Spain. We set up a loan laboratory in which we can explore the distributional effects of different loan systems to finance tertiary education at current costs as well as to increase university funding to improve its quality. We use simulated lifetime earnings of graduates matching the dynamics of employment and earnings in the Spanish administrative social security data to calculate the burden of introducing ICL for individuals at different points of the earnings distribution and for the government. We find that (1) our proposed structure is highly progressive under all specifications, with the top quarter of the distribution paying close to the full amount of the tuition and the bottom 10% paying almost no tuition and (2) the share of total university education subsidized by the government is between 16 and 56 percentage points less than under the current system.
Routinely reported ejection fraction and mortality in clinical practice: where does the nadir of risk lie?
Authors: Wehner Gregory J , Jing Linyuan , Haggerty Christopher M , Suever Jonathan D , Leader Joseph B , Hartzel Dustin N , Kirchner H Lester , Manus Joseph N A , James Nick , Ayar Zina , Gladding Patrick , Good Christopher W , Cleland John G F , Fornwalt Brandon K
Published: July 2019

Aims

We investigated the relationship between clinically assessed left ventricular ejection fraction (LVEF) and survival in a large, heterogeneous clinical cohort.

Methods and results

Physician-reported LVEF on 403 977 echocardiograms from 203 135 patients were linked to all-cause mortality using electronic health records (1998–2018) from US regional healthcare system. Cox proportional hazards regression was used for analyses while adjusting for many patient characteristics including age, sex, and relevant comorbidities. A dataset including 45 531 echocardiograms and 35 976 patients from New Zealand was used to provide independent validation of analyses. During follow-up of the US cohort, 46 258 (23%) patients who had undergone 108 578 (27%) echocardiograms died. Overall, adjusted hazard ratios (HR) for mortality showed a u-shaped relationship for LVEF with a nadir of risk at an LVEF of 60–65%, a HR of 1.71 [95% confidence interval (CI) 1.64–1.77] when ≥70% and a HR of 1.73 (95% CI 1.66–1.80) at LVEF of 35–40%. Similar relationships with a nadir at 60–65% were observed in the validation dataset as well as for each age group and both sexes. The results were similar after further adjustments for conditions associated with an elevated LVEF, including mitral regurgitation, increased wall thickness, and anaemia and when restricted to patients reported to have heart failure at the time of the echocardiogram.

Conclusion

Deviation of LVEF from 60% to 65% is associated with poorer survival regardless of age, sex, or other relevant comorbidities such as heart failure. These results may herald the recognition of a new phenotype characterized by supra-normal LVEF.
2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias
Authors: Cronin Edmond M , Bogun Frank M , Maury Philippe , Peichl Petr , Chen Minglong , Namboodiri Narayanan , Aguinaga Luis , Leite Luiz Roberto , Al-Khatib Sana M , Anter Elad , Berruezo Antonio , Callans David J , Chung Mina K , Cuculich Phillip , d’Avila Andre , Deal Barbara J , Della Bella Paolo , Deneke Thomas , Dickfeld Timm-Michael , Hadid Claudio , Haqqani Haris M , Kay G Neal , Latchamsetty Rakesh , Marchlinski Francis , Miller John M , Nogami Akihiko , Patel Akash R , Pathak Rajeev Kumar , Sáenz Morales Luis C , Santangeli Pasquale , Sapp John L , Sarkozy Andrea , Soejima Kyoko , Stevenson William G , Tedrow Usha B , Tzou Wendy S , Varma Niraj , Zeppenfeld Katja ,   ESC Scientific Document Group, Asirvatham Samuel J , Sternick Eduardo Back , Chyou Janice , Ernst Sabine , Fenelon Guilherme , Gerstenfeld Edward P , Hindricks Gerhard , Inoue Koichi , Kim Jeffrey J , Krishnan Kousik , Kuck Karl-Heinz , Avalos Martin Ortiz , Paul Thomas , Scanavacca Mauricio I , Tung Roderick , Voss Jamie , Yamada Takumi , Yamane Teiichi
Published: July 2019

Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. An expert writing group, after reviewing and discussing the literature, including a systematic review and meta-analysis published in conjunction with this document, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Each recommendation is presented in knowledge byte format and is accompanied by supportive text and references. Further sections provide a practical synopsis of the various techniques and of the specific ventricular arrhythmia sites and substrates encountered in the electrophysiology lab. The purpose of this document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow-up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias.
Pulmonary vein encirclement using an Ablation Index-guided point-by-point workflow: cardiovascular magnetic resonance assessment of left atrial scar formation
Authors: O’Neill Louisa , Karim Rashed , Mukherjee Rahul K , Whitaker John , Sim Iain , Harrison James , Razeghi Orod , Niederer Steven , Ismail Tevfik , Wright Matthew , O’Neill Mark D , Williams Steven E
Published: July 2019

Aims 

A point-by-point workflow for pulmonary vein isolation (PVI) targeting pre-defined Ablation Index values (a composite of contact force, time, and power) and minimizing interlesion distance may optimize the creation of contiguous ablation lesions whilst minimizing scar formation. We aimed to compare ablation scar formation in patients undergoing PVI using this workflow to patients undergoing a continuous catheter drag workflow.

Methods and results

Post-ablation cardiovascular magnetic resonance imaging was performed in patients undergoing 1st-time PVI using a parameter-guided point-by-point workflow (n = 26). Total left atrial scar burden and the width and continuity of the pulmonary vein encirclement were determined on analysis of atrial late gadolinium enhancement sequences. Comparison was made with a cohort of patients (n = 20) undergoing PVI using continuous drag lesions. Mean post-ablation scar burden and scar width were significantly lower in the point-by-point group than in the control group (6.6 ± 6.8% vs. 9.6 ± 5.0%, P = 0.03 and 7.9 ± 3.6 mm vs. 10.7 ± 2.3 mm, P = 0.003). More complete bilateral pulmonary vein encirclements were seen in the point-by-point group (P = 0.038). All patients achieved acute PVI.

Conclusion

Pulmonary vein isolation using a point-by-point workflow is feasible and results in a lower scar burden and scar width with more complete pulmonary vein encirclements than a conventional drag lesion approach.
A comparison of European countries FBDG in the light of their contribution to tackle diet-related health inequalities
Authors: Carrillo-Álvarez Elena , Boeckx Hilde , Penne Tess , Palma Linares Imma , Storms Berénice , Goedemé Tim
Published: July 2019

Background

The purpose of this article is to report on a comparative analysis of the official food-based dietary guidelines (FBDG) that were applicable in 2015 in 25 EU Member States. We assess FBDG in relation to the main guidelines established by the FAO/WHO, the EURODIET project and the EFSA, with a particular focus on identifying strengths and limitations of current FBDG in Europe towards addressing diet-related health inequalities.

Methods

This is a review research, in which a mixed-methods sequenced procedure was utilized. In each EU country key informants, including sociologists, economists, dietitians and nutritionists were asked to provide data regarding: (i) current dietary guidelines and national health priorities, (ii) model of health promotion currently available, (iii) results of the latest food consumption survey. All documents were reviewed by the coordinating team. Full data were analysed by two nutritionists, using a tabulated sheet to organize and compare the results.

Results

While all countries have national FBDG, the level of detail and quality varies substantially with regard to: time of last update; availability of recommendations for specific target groups; specification of frequency and portion size; the graphical representation; recommended amounts and limits of foods consumed; and recommendations regarding physical activity.

Conclusions

European countries have great opportunities to improve FBDG to better serve Public Health policy through a more consistent foundation of how these guidelines are developed, the inclusion of different population subgroups as a target for recommendations and the implementation of monitoring systems.
Variation in Local and Systemic Pro-Inflammatory Immune Markers of Wild Wood Mice after Anthelmintic Treatment
Authors: Rynkiewicz Evelyn C , Clerc Melanie , Babayan Simon A , Pedersen Amy B
Published: July 2019

The immune system represents a host’s main defense against infection to parasites and pathogens. In the wild, a host’s response to immune challenges can vary due to physiological condition, demography (age, sex), and coinfection by other parasites or pathogens. These sources of variation, which are intrinsic to natural populations, can significantly impact the strength and type of immune responses elicited after parasite exposure and infection. Importantly, but often neglected, a host’s immune response can also vary within the individual, across tissues and between local and systemic scales. Consequently, how a host responds at each scale may impact its susceptibility to concurrent and subsequent infections. Here we analyzed how characteristics of hosts and their parasite infections drive variation in the pro-inflammatory immune response in wild wood mice (Apodemus sylvaticus) at both the local and systemic scale by experimentally manipulating within-host parasite communities through anthelmintic drug treatment. We measured concentrations of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) produced in vitro in response to a panel of toll-like receptor agonists at the local (mesenteric lymph nodes [MLNs]) and systemic (spleen) scales of individuals naturally infected with two gastrointestinal parasites, the nematode Heligmosomoides polygyrus and the protozoan Eimeria hungaryensis. Anthelmintic-treated mice had a 20-fold lower worm burden compared to control mice, as well as a four-fold higher intensity of the non-drug targeted parasite E. hungaryensis. Anthelmintic treatment differentially impacted levels of TNF-α expression in males and females at the systemic and local scales, with treated males producing higher, and treated females lower, levels of TNF-α, compared to control mice. Also, TNF-α was affected by host age, at the local scale, with MLN cells of young, treated mice producing higher levels of TNF-α than those of old, treated mice. Using complementary, but distinct, measures of inflammation measured across within-host scales allowed us to better assess the wood mouse immune response to changes in parasite infection dynamics after anthelmintic treatment. This same approach could be used to understand helminth infections and responses to parasite control measures in other systems in order to gain a broader view of how variation impacts the immune response.