bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary care randomised controlled trial of a tailored interactive website for the self-management of respiratory infections (Internet Doctor)
Authors: Little Paul , Stuart Beth , Andreou Panayiota , McDermott Lisa , Joseph Judith , Mullee Mark , Moore Mike , Broomfield Sue , Thomas Tammy , Yardley Lucy 
Published: April 2016

ObjectiveTo assess an internet-delivered intervention providing advice to manage respiratory tract infections (RTIs).DesignOpen pragmatic parallel group randomised controlled trial.SettingPrimary care in UK.ParticipantsAdults (aged ≥18) registered with general practitioners, recruited by postal invitation.InterventionPatients were randomised with computer-generated random numbers to access the intervention website (intervention) or not (control). The intervention tailored advice about the diagnosis, natural history, symptom management (particularly paracetamol/ibuprofen use) and when to seek further help.OutcomesPrimary: National Health Service (NHS) contacts for those reporting RTIs from monthly online questionnaires for 20 weeks. Secondary: hospitalisations; symptom duration/severity.Results3044 participants were recruited. 852 in the intervention group and 920 in the control group reported 1 or more RTIs, among whom there was a modest increase in NHS direct contacts in the intervention group (intervention 37/1574 (2.4%) versus control 20/1661 (1.2%); multivariate risk ratio (RR) 2.25 (95% CI 1.00 to 5.07, p=0.048)). Conversely, reduced contact with doctors occurred (239/1574 (15.2%) vs 304/1664 (18.3%); RR 0.71, 0.52 to 0.98, p=0.037). Reduction in contacts occurred despite slightly longer illness duration (11.3 days vs 10.7 days, respectively; multivariate estimate 0.60 days longer (−0.15 to 1.36, p=0.118) and more days of illness rated moderately bad or worse illness (0.52 days; 0.06 to 0.97, p=0.026). The estimate of slower symptom resolution in the intervention group was attenuated when controlling for whether individuals had used web pages which advocated ibuprofen use (length of illness 0.22 days, −0.51 to 0.95, p=0.551; moderately bad or worse symptoms 0.36 days, −0.08 to 0.80, p=0.105). There was no evidence of increased hospitalisations (risk ratio 0.25; 0.05 to 1.12; p=0.069).ConclusionsAn internet-delivered intervention for the self-management of RTIs modifies help-seeking behaviour, and does not result in more hospital admissions due to delayed help seeking. Advising the use of ibuprofen may not be helpful.Trial registration numberISRCTN91518452.
Non-invasive versus invasive management in patients with prior coronary artery bypass surgery with a non-ST segment elevation acute coronary syndrome: study design of the pilot randomised controlled trial and registry (CABG-ACS)
Authors: Lee Matthew M Y , Petrie Mark C , Rocchiccioli Paul , Simpson Joanne , Jackson Colette , Brown Ammani , Corcoran David , Mangion Kenneth , McEntegart Margaret , Shaukat Aadil , Rae Alan , Hood Stuart , Peat Eileen , Findlay Iain , Murphy Clare , Cormack Alistair , Bukov Nikolay , Balachandran Kanarath , Papworth Richard , Ford Ian , Briggs Andrew , Berry Colin 
Published: April 2016

IntroductionThere is an evidence gap about how to best treat patients with prior coronary artery bypass grafts (CABGs) presenting with non-ST segment elevation acute coronary syndromes (NSTE-ACS) because historically, these patients were excluded from pivotal randomised trials. We aim to undertake a pilot trial of routine non-invasive management versus routine invasive management in patients with NSTE-ACS with prior CABG and optimal medical therapy during routine clinical care. Our trial is a proof-of-concept study for feasibility, safety, potential efficacy and health economic modelling. We hypothesise that a routine invasive approach in patients with NSTE-ACS with prior CABG is not superior to a non-invasive approach with optimal medical therapy.Methods and analysis60 patients will be enrolled in a randomised clinical trial in 4 hospitals. A screening log will be prospectively completed. Patients not randomised due to lack of eligibility criteria and/or patient or physician preference and who give consent will be included in a registry. We will gather information about screening, enrolment, eligibility, randomisation, patient characteristics and adverse events (including post-discharge). The primary efficacy outcome is the composite of all-cause mortality, rehospitalisation for refractory ischaemia/angina, myocardial infarction and hospitalisation for heart failure. The primary safety outcome is the composite of bleeding, stroke, procedure-related myocardial infarction and worsening renal function. Health status will be assessed using EuroQol 5 Dimensions (EQ-5D) assessed at baseline and 6 monthly intervals, for at least 18 months.Trial registration numberNCT01895751 (ClinicalTrials.gov).
Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats
Authors: Kovács Árpád , Fülöp Gábor Á. , Kovács Andrea , Csípő Tamás , Bódi Beáta , Priksz Dániel , Juhász Béla , Beke Lívia , Hendrik Zoltán , Méhes Gábor , Granzier Henk L. , Édes István , Fagyas Miklós , Papp Zoltán , Barta Judit , Tóth Attila 
Published: April 2016

Hypertension (HTN) is a major risk factor for heart failure. We investigated the influence of HTN on cardiac contraction and relaxation in transgenic renin overexpressing rats (carrying mouse Ren-2 renin gene, mRen2, n = 6). Blood pressure (BP) was measured. Cardiac contractility was characterized by echocardiography, cellular force measurements, and biochemical assays were applied to reveal molecular mechanisms. Sprague-Dawley (SD) rats ( n = 6) were used as controls. Transgenic rats had higher circulating renin activity and lower cardiac angiotensin-converting enzyme two levels. Systolic BP was elevated in mRen2 rats (235.11 ± 5.32 vs. 127.03 ± 7.56 mmHg in SD, P < 0.05), resulting in increased left ventricular (LV) weight/body weight ratio (4.05 ± 0.09 vs. 2.77 ± 0.08 mg/g in SD, P < 0.05). Transgenic renin expression had no effect on the systolic parameters, such as LV ejection fraction, cardiomyocyte Ca2+-activated force, and Ca2+ sensitivity of force production. In contrast, diastolic dysfunction was observed in mRen2 compared with SD rats: early and late LV diastolic filling ratio (E/A) was lower (1.14 ± 0.04 vs. 1.87 ± 0.08, P < 0.05), LV isovolumetric relaxation time was longer (43.85 ± 0.89 vs. 28.55 ± 1.33 ms, P < 0.05), cardiomyocyte passive tension was higher (1.74 ± 0.06 vs. 1.28 ± 0.18 kN/m2, P < 0.05), and lung weight/body weight ratio was increased (6.47 ± 0.24 vs. 5.78 ± 0.19 mg/g, P < 0.05), as was left atrial weight/body weight ratio (0.21 ± 0.03 vs. 0.14 ± 0.03 mg/g, P < 0.05). Hyperphosphorylation of titin at Ser-12742 within the PEVK domain and a twofold overexpression of protein kinase C-α in mRen2 rats were detected. Our data suggest a link between the activation of renin-angiotensin-aldosterone system and increased titin-based stiffness through phosphorylation of titin's PEVK element, contributing to diastolic dysfunction. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/diastolic-dysfunction-in-the-hypertensive-mren2-rat/ .
BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
Authors: Tasdemir Nilgun , Banito Ana , Roe Jae-Seok , Alonso-Curbelo Direna , Camiolo Matthew , Tschaharganeh Darjus F. , Huang Chun-Hao , Aksoy Ozlem , Bolden Jessica E. , Chen Chi-Chao , Fennell Myles , Thapar Vishal , Chicas Agustin , Vakoc Christopher R. , Lowe Scott W. 
Published: April 2016

Abstract
Oncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes while simultaneously activating an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here, we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell–mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program.
Significance: This study reveals how cells undergoing oncogene-induced senescence acquire a distinctive enhancer landscape that includes formation of super-enhancers adjacent to immune-modulatory genes required for paracrine immune activation. This process links BRD4 and super-enhancers to a tumor-suppressive immune surveillance program that can be disrupted by small molecule inhibitors of the bromo and extra terminal domain family of proteins. Cancer Discov; 6(6); 612–29. ©2016 AACR.
See related commentary by Vizioli and Adams, p. 576.
This article is highlighted in the In This Issue feature, p. 561
Antithrombin Dublin (p.Val30Glu): a relatively common variant with moderate thrombosis risk of causing transient antithrombin deficiency
Authors: Navarro-Fernández José , Morena-Barrio María , Padilla José , Miñano Antonia , Bohdan Nataliya , Águila Sonia , Martínez-Martínez Irene , Sevivas Teresa , de Cos Carmen , Fernández-Mosteirín Nuria , Llamas Pilar , Asenjo Susana , Medina Pilar , Souto Juan , Overvad Kim , Kristensen Søren R. , Corra Javier , Vicente Vicente 
Published: April 2016

SummaryThe key haemostatic role of antithrombin and the risk of thrombosis associated with its deficiency support that the low incidence of antithrombin deficiency among patients with thrombosis might be explained by underestimation of this disorder. It was our aim to identify mutations in SERPINC1 causing transient antithrombin deficiency. SERPINC1 was sequenced in 214 cases with a positive test for antithrombin deficiency, including 67 with no deficiency in the sample delivered to our laboratory. The p.Val30Glu mutation (Antithrombin Dublin) was identified in five out of these 67 cases, as well as in three out of 127 cases with other SERPINC1 mutations. Genotyping in 1593 patients with venous thrombosis and 2592 controls from two populations, revealed a low prevalent polymorphism (0.3 %) that moderately increased the risk of venous thrombosis (OR: 2.9; 95 % CI: 1.07–8.09; p= 0.03) and identified one homozygous patient with an early thrombotic event. Carriers had normal anti-FXa activity, and plasma antithrombin was not sensitive to heat stress or proteolytic cleavage. Analysis of one sample with transient deficit revealed a type I deficiency, without aberrant or increased latent forms. The recombinant variant, which lacked the two amino-terminal residues, had reduced secretion from HEK-EBNA cells, formed hyperstable disulphidelinked polymers, and had negligible activity. In conclusion, p.Val30Glu by affecting the cleavage of antithrombin’s signal peptide, results in a mature protein lacking the N-terminal dipeptide with no functional consequences in normal conditions, but that increases the sensitivity to be folded intracellularly into polymers, facilitating transient antithrombin deficiency and the subsequent risk of thrombosis.
Antiphospholipid antibodies in a large population-based cohort: genome-wide associations and effects on monocyte gene expression
Authors: Müller-Calleja Nadine , Rossmann Heidi , Müller Christian , Wild Philipp , Blankenberg Stefan , Pfeiffer Norbert , Binder Harald , Beutel Manfred , Manukyan Davit , Zeller Tanja , Lackner Karl 
Published: April 2016

SummaryThe antiphospholipid syndrome (APS) is characterised by venous and/ or arterial thrombosis and pregnancy morbidity in women combined with the persistent presence of antiphospholipid antibodies (aPL). We aimed to identify genetic factors associated with the presence of aPL in a population based cohort. Furthermore, we wanted to clarify if the presence of aPL affects gene expression in circulating monocytes. Titres of IgG and IgM against cardiolipin, D2glycoprotein 1 (antiD2GPI), and IgG against domain 1 of D2GPI (anti-domain 1) were determined in approx. 5,000 individuals from the Gutenberg Health Study (GHS) a population based cohort of German descent. Genotyping was conducted on Affymetrix Genome-Wide Human SNP 6.0 arrays. Monocyte gene expression was determined in a subgroup of 1,279 individuals by using the Illumina HT-12 v3 BeadChip. Gene expression data were confirmed in vitro and ex vivo by qRT-PCR. Genome wide analysis revealed significant associations of anti-D2GPI IgG and APOH on chromosome 17, which had been previously identified by candidate gene approaches, and of anti-domain1 and MACROD2 on chromosome 20 which has been listed in a previous GWAS as a suggestive locus associated with the occurrence of anti-D2GPI antibodies. Expression analysis confirmed increased expression of TNFD in monocytes and identified and confirmed neuron navigator 3 (NAV3) as a novel gene induced by aPL. In conclusion, MACROD2 represents a novel genetic locus associated with aPL. Furthermore, we show that aPL induce the expression of NAV3 in monocytes and endothelial cells. This will stimulate further research into the role of these genes in the APS.
Immunisation against αIIbβ3 and αvβ3 in a type 1 variant of Glanzmann’s thrombasthenia caused by a missense mutation Gly540Asp on β3
Authors: Wihadmadyatami Hevi , Röder Lida , Berghöfer Heike , Bein Gregor , Heidinger Kathrin , Sachs Ulrich J. , Santoso Sentot 
Published: April 2016

SummaryTreatment of bleeding in patients with Glanzmann’s thrombasthenia (GT) can be hampered by iso-antibodies against the αIIbβ3 integrin, which cause rapid clearance of transfused donor platelets. Type 1 GT patients with a total absence of αIIbβ3 from the platelet surface are known to be susceptible to form such isoantibodies. In this study, we describe a type 1 GT patient with a missense mutation (Gly540Asn) located in the EGF3 domain of the β3 integrin subunit. Cotransfection analysis in CHO cells demonstrates total absence of αIIbβ3 from the surface, based on inappropriate αIIb maturation. The patient’s serum was reactive with αIIbβ3 and αvβ3 integrins in a capture assay, when platelets and endothelial cells were used. Two specificities could be isolated from the patient’s serum, anti-αIIbβ3 and anti-αvβ3 isoantibodies. Both specificities did not interfere with platelet aggregation. In contrast, isoantibodies against αvβ3, but not against αIIbβ3, were able to disturb endothelial cell adhesion onto vitronectin, triggered endothelial cell apoptosis and interfered with endothelial tube formation. This intriguing finding may explain more recently observed features of fetal/neonatal iso-immune thrombocytopenia in children from type 1 GT mothers with intracranial haemorrhage, which could be related to anti-endothelial activity of the maternal antibodies. In conclusion, we give evidence that two isoantibody entities exist in type 1 GT patients, which are unequivocally different, both in an immunological and functional sense. Further research on the clinical consequences of immunisation against αvβ3 is required, predominantly in GT patients of childbearing age.Supplementary Material to this article is available online at www.thrombosis-online.com.
The Mean Air Flow as Lagrangian Dynamics Approximation and Its Application to Moist Convection
Authors: Pauluis Olivier M. 
Published: April 2016

AbstractThis paper introduces the Mean Airflow as Lagrangian Dynamics Approximation (MAFALDA), a new method designed to extract thermodynamic cycles from numerical simulations of turbulent atmospheric flows. This approach relies on two key steps. First, mean trajectories are obtained by computing the mean circulation using height and equivalent potential temperature as coordinates. Second, thermodynamic properties along these trajectories are approximated by using their conditionally averaged values at the same height and θe. This yields a complete description of the properties of air parcels that undergo a set of idealized thermodynamic cycles.MAFALDA is applied to analyze the behavior of an atmosphere in radiative–convective equilibrium. The convective overturning is decomposed into 20 thermodynamic cycles, each accounting for 5% of the total mass transport. The work done by each cycle can be expressed as the difference between the maximum work that would have been done by an equivalent Carnot cycle and a penalty that arises from the injection and removal of water at different values of its Gibbs free energy. The analysis indicates that the Gibbs penalty reduces the work done by all thermodynamic cycles by about 55%. The cycles are also compared with those obtained for doubling the atmospheric carbon dioxide, which in the model used here leads to an increase in surface temperature of about 3.4 K. It is shown that warming greatly increases both the energy transport and work done per unit mass of air circulated. As a result, the ratio of the kinetic energy generation to the convective mass flux increases by about 20% in the simulations.
Moisture and Precipitation Evolution during Tropical Cyclone Formation as Revealed by the SSM/I–SSMIS Retrievals
Authors: Wang Zhuo , Hankes Isaac 
Published: April 2016

Abstract
The simultaneous precipitation and column water vapor retrievals from the SSM/I and SSMIS passive microwave instruments were used to examine the convective and moisture evolution during tropical cyclone formation. Using a wave-pouch-track dataset, composites of precipitation and column water vapor were constructed with more than 2000 satellite overpasses for a 3-day time period prior to genesis. It was found that high column water vapor occurs near the pouch center and starts to increase about 42 h prior to genesis while a substantial increase in precipitation occurs within 24 h prior to genesis. These features are consistent with a recently proposed two-stage conceptual model for tropical cyclone formation, in which gradual moisture preconditioning precedes an abrupt transition to sustained deep convection leading up to genesis.
The relationship between precipitation and saturation fraction (SF) is examined for the developing waves and compared with the general tropical North Atlantic. Precipitation rate is found to increase at the same exponential rate above the same critical point of SF in the two groups, but convection in the developing waves has a higher probability of occurrence near and above criticality. This can be attributed to the positive feedback between convection and the low-level moisture convergence, which counteracts the negative feedback of convection on water vapor and makes convection in a developing tropical cyclone more sustainable.
The Variability of the Indian–East Asian Summer Monsoon Interface in Relation to the Spring Seesaw Mode between the Indian Ocean and the Central-Western Pacific
Authors: Cao Jie , Gui Shu , Su Qin , Yang Yali 
Published: April 2016

Abstract
The interannual zonal movement of the interface between the Indian summer monsoon and the East Asian summer monsoon (IIE), associated with the spring sea surface temperature (SST) seesaw mode (SSTSM) over the tropical Indian Ocean (TIO) and the tropical central-western Pacific (TCWP), is studied for the period 1979–2008. The observational analysis is based on Twentieth Century Reanalysis data (version 2) of atmospheric circulations, Extended Reconstructed SST data (version 3), and the Climate Prediction Center Merged Analysis of Precipitation. The results indicate that the IIE’s zonal movement is significantly and persistently correlated with the TIO–TCWP SSTSM, from spring to summer. The results of two case studies resemble those obtained by regression analysis. Experiments using an atmospheric general circulation model (ECHAM6) substantiate the key physical processes revealed in the observational analysis. When warmer (colder) SSTs appear in the TIO and colder (warmer) SSTs occur in the TCWP, the positive (negative) SSTSM forces anomalous easterly (westerly) winds over the Bay of Bengal (BOB), South China Sea (SCS), and western North Pacific (WNP). The anomalous easterly (westerly) winds further result in a weakened (strengthened) southwest summer monsoon over the BOB and a strengthened (weakened) southeast summer monsoon over the SCS and WNP. This causes the IIE to shift farther eastward (westward) than normal.
The Seasonal and Diurnal Cycles of Refractivity and Anomalous Propagation in the Sahelian Area from Microwave Radiometric Profiling
Authors: Louf Valentin , Pujol Olivier , Sauvageot Henri 
Published: April 2016

AbstractThe Sahelian zone of West Africa is a semiarid area where strong amplitude of the seasonal and diurnal cycles of water vapor and temperature is observed. One year of continuous observation of vertical profiles of water vapor and temperature gathered from Niamey, Niger, with a profiling microwave radiometer is used to analyze the climatology of refractivity and microwave propagation regimes in the low troposphere. Seasonal and diurnal cycles of refractivity and ground-based radar anomalous propagation are emphasized. It is shown that the combined effect of water vapor and temperature vertical gradients is responsible for strong seasonal and diurnal cycles of the ducting propagation regime. Statistics of propagation regimes are given. The probability density functions of the refractivity gradient are found lognormally distributed. Three months of C-band radar data simultaneous with the profiling microwave radiometer observations have also been collected. Relations between the vertical refractivity gradient and the ground-based radar anomalous propagation echoes (APE) are illustrated and discussed. APE spatial distributions are found strongly related to the main features of the orography and topography inside the radar-observed area. Contingency tests show that the probability for APE to be linked to ducting is higher than 95%. In addition, this paper suggests that observing the refractivity vertical profiles from a microwave radiometer profiler located close to a meteorological radar provides information on whether anomalous propagation has to be considered as a potential cause of spurious signal in the measured reflectivity field.
Climatology of Polar Mesocyclones over the Sea of Japan Using a New Objective Tracking Method
Authors: Watanabe Shun-ichi I. , Niino Hiroshi , Yanase Wataru 
Published: April 2016

AbstractPolar mesocyclones (PMCs) are mesoscale cyclonic vortices that develop poleward of the main polar front. This article reports on a new algorithm for the objective tracking of PMCs, including meso-β-scale vortices, which will facilitate the study of their climatology. The algorithm is based mainly on the vorticity field and consists of three parts: the identification of vortices, the connection of vortices at consecutive time steps, and discrimination between PMCs and synoptic-scale disturbances. The objective tracking method was applied to Mesoscale Analysis (MA) data provided by the Japan Meteorological Agency, which has a horizontal resolution of 5 km. The detected tracks of PMCs were confirmed by subjective analysis of the MA data and satellite images. The method used here to discriminate between PMCs and synoptic-scale disturbances differs from that used in previous studies, which is based on the difference between the sea surface temperature and the temperature at 500 hPa, but gives a consistent result. This objective tracking method was used to obtain the climatology of PMCs over the Sea of Japan, which were classified into three groups according to the regions where they attained their maximum intensity. In each region, the PMCs have different characteristics with respect to their direction of movement, size, and intensity, which are likely to be related to their environment or development mechanism.