bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study
Authors: Fleischmann Roy , Winkle Peter , Miner Jeffrey N , Yan Xiaohong , Hicks Liz , Valdez Shakti , Hall Jesse , Liu Sha , Shen Zancong , Gillen Michael , Hernandez-Illas Martha 
Published: February 2018

ObjectivesVerinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout.MethodsForty-one subjects were randomised into two cohorts of verinurad (2.5–20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone. Each treatment period was 7 days. Serial plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol and uric acid.ResultsSerum pharmacodynamic data pooled across cohorts demonstrated maximum per cent decreases in serum urate (sUA) from baseline (Emax) at 7–12 hours after verinurad plus allopurinol treatment. Combination treatment decreased sUA in dose-dependent manner: least-squares means Emaxwas 47%, 59%, 60%, 67%, 68% and 74% for verinurad doses 2.5, 5, 7.5, 10, 15 and 20 mg plus allopurinol 300 mg once daily, versus 40%, 54% and 54% for allopurinol 300 mg once daily, 600 mg once daily and 300 mg twice daily. Verinurad had no effect on allopurinol plasma pharmacokinetics, but decreased oxypurinol Cmaxby 19.0%–32.4% and area under the plasma concentration–time curve from time zero to the last measurable time point by 20.8%–39.2%. Verinurad plus allopurinol was well tolerated with no serious adverse events (AEs), AE-related withdrawals or renal-related events. Laboratory values showed no clinically meaningful changes.ConclusionVerinurad coadministered with allopurinol produced dose-dependent decreases in sUA. All dose combinations of verinurad and allopurinol were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout.Trial registration numberNCT02498652.
Evidence for a second ankylosing spondylitis-associatedRUNX3regulatory polymorphism
Authors: Vecellio Matteo , Cortes Adrian , Roberts Amity R , Ellis Jonathan , Cohen Carla Jayne , Knight Julian C , Brown Matthew A , Bowness Paul , Wordsworth Bryan Paul 
Published: February 2018

ObjectivesTo explore the functions ofRUNX3single nucleotide polymorphisms (SNPs) associated with ankylosing spondylitis (AS).MethodsIndividual SNP associations were evaluated in 4230 UK cases. Their effects on transcription factor (TF) binding, transcription regulation, chromatin modifications, gene expression and gene interactions were tested by database interrogation, luciferase reporter assays, electrophoretic mobility gel shifts, chromatin immunoprecipitation and real-time PCR.ResultsWe confirmed the independent association of AS withrs4265380, which was robust (P=4.7×10−6) to conditioning on another nearby AS-associatedRUNX3SNP (rs4648889). ARUNX3haplotype incorporating both SNPs was strongly associated with AS (OR 6.2; 95% CI 3.1 to 13.2, P=1.4×10−8). In a large UK cohort,rs4265380is associated with leucocyte counts (including monocytes).RUNX3expression is lower in AS peripheral blood mononuclear cells than healthy controls (P<0.002), independent ofrs4265380genotype. Enhancer function for thisRUNX3region was suggested by increased luciferase activity (approximately tenfold; P=0.005) for reporter constructs containingrs4265380. In monocytes, there was differential allelic binding of nuclear protein extracts to a 50 bp DNA probe containingrs4265380that was strongly augmented by lipopolysaccharide activation. TF binding also included the histone modifier p300. There was enrichment for histone modifications associated with active enhancer elements (H3K27Ac and H3K79Me2) that may be allele dependent. Hi-C database interrogation showed chromosome interactions of RUNX3 bait with the nearby RP4-799D16.1 lincRNA.ConclusionsThe association of AS with thisRUNX3regulatory region involves at least two SNPs apparently operating in different cell types. Monocytes may be potential therapeutic targets in AS.
Cardiovascular complications during anaesthesia for surgical correction of an aberrant right subclavian artery in a dog
Authors: Ida Keila Kazue , Sandersen Charlotte , Noël Stéphanie , Marolf Vincent 
Published: February 2018

A six‐month‐old neutered male German shepherd dog with aberrant right subclavian artery (ARSA) was premedicated with methadone, medetomidine and then fentanyl; anaesthesia was induced with propofol and maintained with infusions of medetomidine and fentanyl and isoflurane in oxygen. Hartmann’s solution and noradrenaline were administered for cardiovascular support. Arterial pressure was measured using Doppler technique in both metacarpal arteries and invasive technique in both dorsal pedal arteries. During ARSA occlusion test, severe hypotension (30 mmHg) in the right forelimb, bradycardia (45 bpm) and advanced atrioventricular blocks (AVB) were observed. The occlusion test was interrupted; atropine was administered; cardiovascular parameters, except AVB, were normalised; medetomidine and noradrenaline were interrupted. Other two attempts of ARSA occlusion generated similar cardiovascular side effects. The surgical correction was precluded and the animal was recovered from anaesthesia. This case indicates that ARSA occlusion can be followed by severe arrhythmias and focus on the management of these alterations.
Intraobserver and interobserver agreement on the radiographical diagnosis of canine cranial cruciate ligament rupture
Authors: Bogaerts Evelien , Van der Vekens Elke , Verhoeven Geert , de Rooster Hilde , Van Ryssen Bernadette , Samoy Yves , Putcuyps Ingrid , Van Tilburg Johan , Devriendt Nausikaa , Weekers Frederik , Bertal Mileva , Houdellier Blandine , Scheemaeker Stephanie , Versteken Jeroen , Lamerand Maryline , Feenstra Laurien , Peelman Luc , Van Nieuwerburgh Filip , Saunders Jimmy H , Broeckx Bart J G 
Published: February 2018

Even though radiography is one of the most frequently used imaging techniques for orthopaedic disorders, it has been demonstrated that the interpretation can vary between assessors. As such, the purpose of this study was to examine the intraobserver and interobserver agreement and the influence of level of expertise on the interpretation of radiographs of the stifle in dogs with and without cranial cruciate ligament rupture (CCLR). Sixteen observers, divided in four groups according to their level of experience, evaluated 30 radiographs (15 cases with CCLR and 15 control stifles) twice. Each observer was asked to evaluate joint effusion, presence and location of degenerative joint disease, joint instability and whether CCLR was present or absent. Overall, intraobserver and interobserver agreement ranged from fair to almost perfect with a trend towards increased agreement for more experienced observers. Additionally, it was found that stifles that were classified with high agreement have either overt disease characteristics or no disease characteristics at all, in comparison to the ones that are classified with a low agreement. Overall, the agreement on radiographic interpretation of CCLR was high, which is important, as it is the basis of a correct diagnosis and treatment.
A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma
Authors: Msaouel Pavlos , Tannir Nizar M. , Walker Cheryl Lyn 
Published: February 2018

Abstract
Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor SMARCB1. Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in SMARCB1, which is localized in a fragile region of chromosome 22. This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age dependence and predilection of RMC toward the right kidney.
Significance: This perspective proposes an integrated and testable model of renal medullary carcinoma pathogenesis. Insights provided by this model can additionally inform other malignancies arising from the renal medulla and/or associated with loss of the SMARCB1 tumor suppressor gene. Clin Cancer Res; 24(9); 2044–9. ©2018 AACR.
A Human Genome-Wide RNAi Screen Reveals Diverse Modulators that Mediate IRE1α–XBP1 Activation
Authors: Yang Zhifen , Zhang Jing , Jiang Dadi , Khatri Purvesh , Solow-Cordero David E. , Toesca Diego A.S. , Koumenis Constantinos , Denko Nicholas C. , Giaccia Amato J. , Le Quynh-Thu , Koong Albert C. 
Published: February 2018

Abstract
Activation of the unfolded protein response (UPR) signaling pathways is linked to multiple human diseases, including cancer. The inositol-requiring kinase 1α (IRE1α)–X-box binding protein 1 (XBP1) pathway is the most evolutionarily conserved of the three major signaling branches of the UPR. Here, we performed a genome-wide siRNA screen to obtain a systematic assessment of genes integrated in the IRE1α–XBP1 axis. We monitored the expression of an XBP1-luciferase chimeric protein in which luciferase was fused in-frame with the spliced (active) form of XBP1. Using cells expressing this reporter construct, we identified 162 genes for which siRNA inhibition resulted in alteration in XBP1 splicing. These genes express diverse types of proteins modulating a wide range of cellular processes. Pathway analysis identified a set of genes implicated in the pathogenesis of breast cancer. Several genes, including BCL10, GCLM, and IGF1R, correlated with worse relapse-free survival (RFS) in an analysis of patients with triple-negative breast cancer (TNBC). However, in this cohort of 1,908 patients, only high GCLM expression correlated with worse RFS in both TNBC and non-TNBC patients. Altogether, our study revealed unidentified roles of novel pathways regulating the UPR, and these findings may serve as a paradigm for exploring novel therapeutic opportunities based on modulating the UPR.
Implications: Genome-wide RNAi screen identifies novel genes/pathways that modulate IRE1α–XBP1 signaling in human tumor cells and leads to the development of improved therapeutic approaches targeting the UPR.
Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/5/745/F1.large.jpg. Mol Cancer Res; 16(5); 745–53. ©2018 AACR.
Tongue-Palate Contact Timing during /s/ and /z/ in English
Authors: Liker Marko , Gibbon Fiona E. 
Published: February 2018

AbstractAlthough numerous studies have investigated supraglottal strategies for signalling voicing in fricatives, there is still no agreement about the precise characteristics of tongue-to-palate contact timing during voiced as opposed to voiceless fricatives. In this study we use electropalatography (EPG) to investigate articulatory and coarticulatory characteristics of tongue-to-palate contact timing during /s/ and /z/ in English. Five typically speaking participants, speakers of Southern British English, produced 500 trochaic words containing the intervocalic alveolar fricatives /s/ or /z/. The time between the start of the frication and the maximum contact at the place of articulation was expressed as a percentage of each fricative's total duration (time to target, TT).This measure was used to analyse articulatory and coarticulatory timing during /s/ and /z/. Data for absolute timing were also presented. The results showed that the time between the start of the frication and the maximum contact point was longer for /s/ than for /z/. This difference was consistent across speakers but was not significant for all of them. The results of the coarticulatory effects showed that the influence of vowel context on TT values for /s/ and /z/ did not differ significantly, but there was a tendency for /z/ to be more resistant to coarticulation effects than /s/.
Transvenous Lead Extraction in Adults With Congenital Heart Disease
Authors: Gourraud Jean-Baptiste , Chaix Marie-A , Shohoudi Azadeh , Pagé Pierre , Dubuc Marc , Thibault Bernard , Poirier Nancy C. , Dore Annie , Marcotte François , Mongeon François-Pierre , Asgar Anita W. , Ibrahim Réda , Khairy Paul , Mondésert Blandine 
Published: February 2018

Background:
Safety and feasibility data on transvenous lead extraction (TLE) in the challenging population of adults with congenital heart disease (A-CHD) are limited. Herein, we report the results of TLE in A-CHD during a 20-year period.

Methods and Results:

All consecutive TLE procedures in A-CHD were included in a monocentric prospective registry from 1996. A total of 121 leads were extracted in 49 A-CHD (median age, 38 years; 51% men) during 71 TLE procedures. Twenty-four (49%) patients had transposition of the great arteries. Main indications for extraction were infection in 34 (48%) and lead failure in 22 (31%). A laser sheath was required for 56 (46%) leads and a femoral approach for 10 (8%). Complete TLE was achieved for 111 leads (92%). In multivariable analysis, lead duration (odds ratio, 1.02; 95% confidence interval, 1.00–1.04;
P
<0.01) and number of previous cardiac surgeries (odds ratio, 2.65; 95% confidence interval, 1.52–4.67;
P
<0.01) were predictive of TLE failure. No perioperative death or pericardial effusion was observed. Subpulmonary atrioventricular valve regurgitation increased in 8 patients (5 with transposition of the great arteries) and was independently associated with an implantable cardioverter defibrillator lead (odds ratio, 9.69; 95% confidence interval, 1.31–71.64;
P
=0.03) and valvular vegetation (odds ratio, 7.29; 95% confidence interval, 1.32–40.51;
P
=0.02). After a median of 54 (19–134) months of follow-up after the first TLE, 3 deaths occurred independently from lead management.

Conclusions:
Despite complex anatomic issues, TLE can be achieved successfully in most A-CHD using advanced extraction techniques. Subpulmonary atrioventricular valve regurgitation is a prevalent complication, particularly in patients with transposition of the great arteries.
Characteristics of Single-Loop Macroreentrant Biatrial Tachycardia Diagnosed by Ultrahigh-Resolution Mapping System
Authors: Kitamura Takeshi , Martin Ruairidh , Denis Arnaud , Takigawa Masateru , Duparc Alexandre , Rollin Anne , Frontera Antonio , Thompson Nathaniel , Massoullié Gregoire , Cheniti Ghassen , Wolf Michael , Vlachos Konstantinos , Martin Claire A. , Al Jefairi Nora , Duchateau Josselin , Klotz Nicolas , Pambrun Thomas , Sacher Frédéric , Cochet Hubert , Hocini Meleze , Haïssaguerre Michel , Maury Philippe , Jaïs Pierre , Derval Nicolas 
Published: February 2018

Background:
Biatrial tachycardia (BiAT) is a rare form of atrial macroreentrant tachycardia, in which both atria form a critical part of the circuit. We aimed to identify the characteristics and precise circuits of single-loop macroreentrant BiATs.

Methods and Results:
We identified 8 patients (median age, 59.5 years old) with 9 BiATs in a cohort of 336 consecutive patients from 2 institutions who had undergone AT catheter ablation using an automatic ultrahigh-resolution mapping system. Seven of the 8 patients had a history of persistent AF ablation, including septal or anterior left atrium ablation before developing BiAT. One of the 8 patients had a history of an atrial septal patch closure with a massively enlarged right atrium. Nine ATs (median cycle length, 334 ms; median 12 561 points in the left atrium; 8814 points in the right atrium) were diagnosed as single-loop macroreentrant BiATs. We observed 3 types of BiAT (1) BiAT with a perimitral and peritricuspid reentrant circuit (n=3), (2) BiAT using the right atrium septum and a perimitral circuit (n=3), and (3) BiAT using only the left atrium and right atrium septum (n=3). Catheter ablation successfully terminated 8 of the 9 BiATs.

Conclusions:
All patients who developed BiAT had an electric obstacle on the anteroseptal left atrium, primarily from prior ablation lesions. In this situation, mapping of both atria should be considered during AT. Because 3 types of single-loop BiAT were observed, ablation strategies should be adjusted to the type of BiAT circuit.
MicroRNAs Associated With Reverse Left Ventricular Remodeling in Humans Identify Pathways of Heart Failure Progression
Authors: Shah Ravi , Ziegler Olivia , Yeri Ashish , Liu Xiaojun , Murthy Venkatesh , Rabideau Dustin , Xiao Chun Yang , Hanspers Kristina , Belcher Arianna , Tackett Michael , Rosenzweig Anthony , Pico Alexander R. , Januzzi James L. , Das Saumya 
Published: February 2018

Background:
Plasma extracellular RNAs have recently garnered interest as biomarkers in heart failure (HF). Most studies in HF focus on single extracellular RNAs related to phenotypes and outcomes, and few describe their functional roles. We hypothesized that clusters of plasma microRNAs (miRNAs) associated with left ventricular (LV) remodeling in human HF would identify novel subsets of genes involved in HF in animal models.

Methods and Results:

We prospectively measured circulating miRNAs in 64 patients with systolic HF (mean age, 64.8 years; 91% men; median LV ejection fraction, 26%) with serial echocardiography (10 months apart) during medical therapy. We defined LV reverse remodeling as a 15% reduction in LV end-systolic volume index. Using principal components analysis, we identified a component associated with LV reverse remodeling (odds ratio=3.99;
P
=0.01) that provided risk discrimination for LV reverse remodeling superior to a clinical model (C statistic, 0.58 for a clinical model versus 0.71 for RNA-based model). Using network bioinformatics, we uncovered genes not previously widely described in HF regulated simultaneously by >2 miRNAs. We observed increased myocardial expression of these miRNAs during HF development in animals, with downregulation of target gene expression, suggesting coordinate miRNA–mRNA regulation. Target mRNAs were involved in autophagy, metabolism, and inflammation.

Conclusions:
Plasma miRNAs associated with LV reverse remodeling in humans are dysregulated in animal HF and target clusters of genes involved in mechanisms implicated in HF. A translational approach integrating human HF, bioinformatics, and model systems may uncover novel pathways involved in HF.

CLINICAL TRIAL REGISTRATION:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00351390
Risk of Dementia in Adults With Congenital Heart Disease
Authors: Bagge Carina N. , Henderson Victor W. , Laursen Henning B. , Adelborg Kasper , Olsen Morten , Madsen Nicolas L. 
Published: February 2018

Background:
More children with congenital heart disease (CHD) are surviving to adulthood, and CHD is associated with risk factors for dementia. We compared the risk of dementia in CHD adults to that of the general population.

Methods:
In this cohort study, we used medical registries and a medical record review covering all Danish hospitals to identify adults with CHD diagnosed between 1963 and 2012. These individuals with CHD were followed from January 1, 1981, 30 years of age, or date of first CHD registration (index date for matched members of the general population cohort) until hospital diagnosis of dementia, death, emigration, or end of study (December 31, 2012). For each individual with CHD, we identified 10 members of the general population utilizing the Danish Civil Registration System matched on sex and birth year. We computed cumulative incidences and hazard ratios (HRs) of dementia, adjusting for sex and birth year.

Results:
The cumulative incidence of dementia was 4% by 80 years of age in 10 632 adults with CHD (46% male). The overall HR comparing adults with CHD with the general population cohort was 1.6 (95% confidence interval [CI], 1.3−2.0). The HR among individuals with CHD without extracardiac defects was 1.4 (95% CI, 1.1−1.8). Adults with mild-to-moderate CHD had an HR of 1.5 (95% CI, 1.1−2.0), whereas the HR was 2.0 (95% CI, 1.2−3.3) for severe CHD, including univentricular hearts. The HR for early onset dementia (<65 years of age) was 2.6 (95% CI, 1.8−3.8), whereas the late-onset HR was 1.3 (95% CI, 1.0−1.8).

Conclusions:
CHD was associated with an increased risk of dementia compared with the general population, in particular for early onset dementia. Further understanding of dementia risk in the population with CHD is a potential target for future investigation.
Effect and Safety of Morphine Use in Acute Anterior ST‐Segment Elevation Myocardial Infarction
Authors: Bonin Mickael , Mewton Nathan , Roubille Francois , Morel Olivier , Cayla Guillaume , Angoulvant Denis , Elbaz Meyer , Claeys Marc J. , Garcia‐Dorado David , Giraud Céline , Rioufol Gilles , Jossan Claire , Ovize Michel , Guerin Patrice , Bonnefoy‐Cudraz Eric , Delarche Nicolas , Coste Pierre , Vanzetto Gerald , Metge Marc , Aupetit Jean‐François , Jouve Bernard , Motreff Pascal , Tron Christophe , Labeque Jean‐Noel , Steg Philippe Gabriel , Cottin Yves , Range Grégoire , Clerc Jérome , Coussement Patrick , Prunier Fabrice , Moulin Frédéric , Roth Olivier , Belle Loïc , Dubois Philippe , Barragan Paul , Gilard Martine , Piot Christophe , Colin Patrice , De Poli Fabien , Morice Marie‐Claude , Ider Omar , Dubois‐Randé Jean‐Luc , Unterseeh Thierry , Le Breton Hervé , Béard Thierry , Blanchard Didier , Grollier Gilles , Malquarti Vincent , Staat Patrick , Sudre Arnaud , Elmer Eskil , Hansson Magnus J. , Bergerot Cyrille , Boussaha Inesse , Derumeaux Geneviève 
Published: February 2018

Background

Morphine is commonly used to treat chest pain during myocardial infarction, but its effect on cardiovascular outcome has never been directly evaluated. The aim of this study was to examine the effect and safety of morphine in patients with acute anterior
ST
‐segment elevation myocardial infarction followed up for 1 year.

Methods and Results

We used the database of the CIRCUS (Does Cyclosporine Improve Outcome in ST Elevation Myocardial Infarction Patients) trial, which included 969 patients with anterior
ST
‐segment elevation myocardial infarction, admitted for primary percutaneous coronary intervention. Two groups were defined according to use of morphine preceding coronary angiography. The composite primary outcome was the combined incidence of major adverse cardiovascular events, including cardiovascular death, heart failure, cardiogenic shock, myocardial infarction, unstable angina, and stroke during 1 year. A total of 554 (57.1%) patients received morphine at first medical contact. Both groups, with and without morphine treatment, were comparable with respect to demographic and periprocedural characteristics. There was no significant difference in major adverse cardiovascular events between patients who received morphine compared with those who did not (26.2% versus 22.0%, respectively;
P
=0.15). The all‐cause mortality was 5.3% in the morphine group versus 5.8% in the no‐morphine group (
P
=0.89). There was no difference between groups in infarct size as assessed by the creatine kinase peak after primary percutaneous coronary intervention (4023±118 versus 3903±149 IU/L;
P
=0.52).

Conclusions

In anterior
ST
‐segment elevation myocardial infarction patients treated by primary percutaneous coronary intervention, morphine was used in half of patients during initial management and was not associated with a significant increase in major adverse cardiovascular events at 1 year.