bluuebunny/crossref_metadata_2025_split huggingface dataset:
C1-esterase inhibitor treatment: preclinical safety aspects on the potential prothrombotic risk
Authors: Raquet Elmar , Nolte Marc , May Frauke , Müller-Cohrs Jochen , Björkqvist Jenny , Dickneite Gerhard , Schürmann Daniel , Herzog Eva , Pragst Ingo 
Published: August 2014

SummaryHuman plasma-derived C1-esterase inhibitor (C1–INH) is an efficacious and safe treatment for hereditary angioedema. However, thrombotic events in subjects treated with C1–INH at recommended or offlabel, high doses have been reported. In this study, we addressed the potential prothrombotic risk of C1–INH treatment in high doses using a non-clinical rabbit model. Following intravenous infusion of C1–INH to rabbits at doses up to 800 IU/kg, the exposure and the pharmacodynamic efficacy of C1–INH in rabbits were confirmed by activity measurements of C1-esterase, and coagulation factors XIa and XIIa, respectively. Potential prothrombotic effects were assessed following induction of venous and arterial thrombosis using in vivo models of venous and arterial stasis, complemented by various in vitro assays of coagulation markers. Administration of C1–INH at doses up to 800 IU/ kg did not potentiate thrombus formation during venous stasis. In contrast, inhibition of arterial occlusion was observed upon C1–INH administration when compared with isotonic saline treatment, indicating antithrombotic rather than prothrombotic activity of high dose C1–INH treatment in vivo. This was further confirmed in vitro by decreased thrombin generation, increased activated partial thromboplastin time, clotting time and clot formation time, and inhibition of platelet aggregation. No relevant changes in fibrinolysis or in the levels of thrombin-antithrombin complexes, and prothrombin fragment 1+2 were observed upon high dose C1–INH treatment. The data suggest that treatment of healthy rabbits with high doses of C1–INH could potentially inhibit coagulation and thrombus formation rather than induce a prothrombotic risk.
Genetic deletion of platelet glycoprotein Ib alpha but not its extracellular domain protects from atherosclerosis
Authors: Koltsova Ekaterina , Sundd Prithu , Zarpellon Alessandro , Ouyang Hui , Mikulski Zbigniew , Zampolli Antonella , Ruggeri Zaverio , Ley Klaus 
Published: August 2014

SummaryThe pathogenesis of atherosclerosis involves the interplay of haematopoietic, stromal and endothelial cells. Platelet interactions with endothelium and leukocytes are pivotal for atherosclerosis promotion. Glycoprotein (GP) Ibα is the ligand-binding subunit of the platelet GPIb-IX-V receptor complex; its deficiency causes the Bernard-Soulier syndrome (BSS), characterised by absent platelet GPIb-IX-V, macrothrombocytopenia and bleeding. We designed this study to determine the role of platelet GPIbα in the pathogenesis of atherosclerosis using two unique knockout models. Ldlr-/- mice were reconstituted with wild-type (wt), GPIbα-/- (lacks GPIbα) or chimeric IL-4R/GPIbα-Tg (lacks GPIbα extracellular domain) bone marrow and assayed for atherosclerosis development after feeding with pro-atherogenic “western diet”. Here, we report that Ldlr-/- mice reconstituted with GPIbα-/- bone marrow developed less atherosclerosis compared to wt controls; accompanied by augmented accumulation of pro-inflammatory CD11b+ and CD11c+ myeloid cells, reduced oxLDL uptake and decreased TNF and IL 12p35 gene expression in the aortas. Flow cytometry and live cell imaging in whole blood-perfused microfluidic chambers revealed reduced platelet-monocyte aggregates in GPIbα-/- mice, which resulted in decreased monocyte activation. Interestingly, Ldlr -/- mice reconstituted with IL-4R/GPIbα-Tg bone marrow, producing less abnormal platelets, showed atherosclerotic lesions similar to wt mice. Platelet interaction with blood monocytes and accumulation of myeloid cells in the aortas were also essentially unaltered. Moreover, only complete GPIbα ablation altered platelet microparticles and CCL5 chemokine production. Thus, atherosclerosis reduction in mice lacking GPIbα may not result from the defective GPIbα-ligand binding, but more likely is a consequence of functional defects of GPIbα-/- platelets and reduced blood platelet counts.
Coagulation factor VII variants resistant to inhibitory antibodies
Authors: Pfeiffer Caroline , Batorova Angelika , Giansily-Blaizot Muriel , Schved Jean , Mariani Guglielmo , Pinotti Mirko , Branchini Alessio , Baroni Marcello , Bernardi Francesco 
Published: August 2014

SummaryReplacement therapy is currently used to prevent and treat bleeding episodes in coagulation factor deficiencies. However, structural differences between the endogenous and therapeutic proteins might increase the risk for immune complications. This study was aimed at identifying factor (F)VII variants resistant to inhibitory antibodies developed after treatment with recombinant activated factor VII (rFVIIa) in a FVII-deficient patient homozygous for the p.A354V-p.P464Hfs mutation, which predicts trace levels of an elongated FVII variant in plasma. We performed fluorescent bead-based binding, ELISA-based competition as well as fluorogenic functional (activated FX and thrombin generation) assays in plasma and with recombinant proteins. We found that antibodies displayed higher affinity for the active than for the zymogen FVII (half-maximal binding at 0.54 ± 0.04 and 0.78 ± 0.07 BU/ml, respectively), and inhibited the coagulation initiation phase with a second-order kinetics. Isotypic analysis showed a polyclonal response with a large predominance of IgG1. We hypothesised that structural differences in the carboxyl-terminus between the inherited FVII and the therapeutic molecules contributed to the immune response. Intriguingly, a naturally-occurring, poorly secreted and 5-residue truncated FVII (FVII-462X) escaped inhibition. Among a series of truncated rFVII molecules, we identified a well-secreted and catalytically competent variant (rFVII-464X) with reduced binding to antibodies (half-maximal binding at 0.198 ± 0.003 BU/ml) as compared to the rFVII-wt (0.032 ± 0.002 BU/ml), which led to a 40-time reduced inhibition in activated FX generation assays. Taken together our results provide a paradigmatic example of mutation-related inhibitory antibodies, strongly support the FVII carboxyl-terminus as their main target and identify inhibitor-resistant FVII variants.
Cost-Effectiveness of Routine Surveillance Endomyocardial Biopsy After 12 Months Post–Heart Transplantation
Authors: Lampert Brent C. , Teuteberg Jeffrey J. , Shullo Michael A. , Holtz Jonathan , Smith Kenneth J. 
Published: August 2014

Background—
Despite low risk of late rejection after heart transplant (HT), surveillance endomyocardial biopsies (EMBs) are often continued for years. We assessed the cost-effectiveness of routine EMB after 12 months post-HT.

Methods and Results—
Markov model compared the following surveillance EMB strategies to baseline strategy of stopping EMB 12 months post-HT: (1) every 4 months during year 2 post-HT, (2) every 6 months during year 2, (3) every 4 months for years 2 to 3, and (4) every 6 months for years 2 to 3. Patients entered the model 12 months post-HT and were followed until 36 months. In all strategies, patients had EMB with symptoms; in biopsy strategies after 12 months, EMB was also performed as scheduled regardless of symptoms. One-way and Monte Carlo sensitivity analyses were performed. Stopping EMB at 12 months was dominant (more effective, less costly), saving $2884 per patient compared with the next best strategy (every 6 months for year 2) and gaining 0.0011 quality-adjusted life-years. Increasing the annual risk of asymptomatic rejection in years 2 to 3 from previously reported 2.5% to 8.5% resulted in the biopsy every 6 months for year 2 strategy gaining 0.0006 quality-adjusted life-years, but cost $4 913 599 per quality-adjusted life-year gained. EMB for 12 months was also no longer dominant when mortality risk from untreated asymptomatic rejection approached 11%; competing strategies still cost >$200 000 per quality-adjusted life-year as that risk approached 99%.

Conclusions—
Surveillance EMB for 12 months post-HT is more effective and less costly than EMB performed after 12 months, unless risks of asymptomatic cellular rejection and its mortality are strikingly higher than previously observed.
Measures to Reduce Radiation in a Modern Cardiac Catheterization Laboratory
Authors: Agarwal Shikhar , Parashar Akhil , Ellis Stephen G. , Heupler Frederick A. , Lau Evan , Tuzcu E. Murat , Kapadia Samir R. 
Published: August 2014

Background—

X-ray use in the catheterization laboratory is guided by the principle of
as low as reasonably achievable
. In accordance with this principle, we reduced the default fluoroscopic frame rate from 10 to 7.5 frames/s and increased the emphasis on the use of low-dose acquisition starting January 1, 2013. We aimed to study the impact of these measures on the total air kerma during diagnostic catheterization (DC) and percutaneous interventions (PCI).

Methods and Results—

Propensity matching based on age, sex, body surface area, total fluoroscopy time, and total acquisition time was used to select matched patients for 2012 and 2013, further stratified by DC or PCI. The total air kerma was subsequently compared between 2012 and 2013, separately for DC and PCI. Median total air kerma during DC in 2013 was 625 mGy, which was significantly lower than the corresponding values in 2012 (median, 798 mGy;
P
<0.001). Similarly, median total air kerma during PCI in 2013 was 1675 mGy, which was significantly less than corresponding values in 2012 (median 2463 mGy,
P
<0.001). On comparison of air kerma rates between corresponding projections in 2 years, we observed a significant reduction in fluoroscopy- and acquisition-based air kerma rates in 2013, after institution of radiation reduction measures in all projections.

Conclusions—
With reduction in the default fluoroscopic frame rate and a greater use of low-dose acquisition, there has been a marked reduction in the total air kerma and air kerma rates for DC and PCI.
Defining Clinically Relevant Cerebral Hemorrhage After Thrombolytic Therapy for Stroke
Authors: Rao Neal M. , Levine Steven R. , Gornbein Jeffrey A. , Saver Jeffrey L. 
Published: August 2014

Background and Purpose—
Several definitions have been proposed to distinguish clinically relevant from incidental cerebral hemorrhagic transformation after thrombolytic therapy for acute ischemic stroke. We investigated which definition best identifies cerebral hemorrhages that alter long-term functional outcome in the National Institute of Neurological Disorders and Stroke (NINDS) tissue-type plasminogen activator (tPA) trials.

Methods—
We analyzed 4 candidate hemorrhage definitions for which the NINDS tPA trials public data set had relevant data. For each, we identified tPA-treated patients having that hemorrhage type and compared their actual functional outcomes at 90 days with their predicted outcomes had they not received tPA and not had the hemorrhage. Projected outcomes without tPA were based on a 17-variable prognostic model derived from the NINDS tPA trials placebo group.

Results—

Among the 312 patients treated with intravenous tPA, 33 (10.6%) experienced any radiological intracerebral hemorrhage <36 hours of treatment, 16 (5.1%) a radiological parenchymal hematoma, 20 (6.4%) a NINDS tPA trials–defined symptomatic intracerebral hemorrhage, 12 (3.8%) an European-Australian Cooperative Acute Stroke Study 2 (ECASS2)–defined symptomatic intracerebral hemorrhage, and 6 (1.9%) a modified version of the Safe Implementation of Thrombolysis in Stroke Monitoring Study (mSITS-MOST)–defined symptomatic intracerebral hemorrhage. The ECASS2 and mSITS-MOST definitions identified the largest hemorrhage-related change in 90-day modified Rankin Scale scores (2.26−0.32=1.94,
P
=0.0001; 2.81−0.63=2.18,
P
=0.0002, respectively). These definitions also distinguished the largest hemorrhage-related change in 90-day mortality (64.7%–7.6%=57.1%;
P
=0.0004 for ECASS2; 68.4%–19.5%=48.9%;
P
=0.0152 for mSITS-MOST).

Conclusions—
The ECASS2 and mSITS-MOST symptomatic intracerebral hemorrhage definitions, which combine radiological features and occurrence of substantial early neurological deterioration, best identify tPA hemorrhages that alter final patient outcome.
Computed Tomographic Angiography and Cerebral Blood Volume Can Predict Final Infarct Volume and Outcome After Recanalization
Authors: Lum Cheemun , Ahmed Muhammad Ejaz , Patro Satya , Thornhill Rebecca , Hogan Matthew , Iancu Daniela , Lesiuk Howard , dos Santos Marlise , Dowlatshahi Dar 
Published: August 2014

Background and Purpose—
Recanalization rates are higher in acute anterior stroke treated with stent-retrievers when compared with older techniques. However, some still have sizeable infarcts and poor outcome. This may be related to underestimation of core infarct on nonenhanced computed tomography (NECT). CT angiography (CTA) source images (CTASI) and CT perfusion may be more informative. We hypothesize that core infarct estimation with NECT, CTA, and CT perfusion predicts infarct at 24 hours and outcome after fast recanalization.

Methods—
Consecutive good recanalization patients with proximal anterior circulation stroke were evaluated. We assessed Alberta Stroke Program Early CT Score (ASPECTs) on NECT for subtle early infarct, hypodensity, loss of gray–white (CTASI), and low cerebral blood volume (CBV; CT perfusion). Sensitivity and specificity for predicting infarct by region were calculated.

Results—

Of 46 patients, 36 (78%) had successful thrombectomy. Median ASPECTS was 10 for NECT early infarct and frank hypodensity; for CBV, CTASI-ASPECTS was 8. CTASI had the highest sensitivity of 71% and specificity of 82% for 24 hours NECT infarct. There was moderate correlation and concordance between CBV/24-hour NECT (
R
p
=0.51;
R
c
=0.50) and CTASI/24-hour NECT (
R
p
=0.54 and
R
c
=0.53). Thirty-four patients (74%) had good outcomes. Median ASPECTS was higher on CTASI (8 versus 5;
P
=0.04) and CBV (9 versus 5;
P
=0.03) for patients with good versus bad outcome. There were better outcomes with increasing CTASI-ASPECTS (
P
=0.004) and CBV-ASPECTS (
P
=0.02).

Conclusions—
CTASI and CBV were better at predicting 24-hour infarct and outcome than NECT. Appropriate advanced imaged guided selection may improve outcomes in large-vessel stroke treated with the newest techniques.
Dynamical Simulations of North Atlantic Tropical Cyclone Activity Using Observed Low-Frequency SST Oscillation Imposed on CMIP5 Model RCP4.5 SST Projections
Authors: LaRow Timothy E. , Stefanova Lydia , Seitz Chana 
Published: August 2014

Abstract
The effects on early and late twenty-first-century North Atlantic tropical cyclone statistics resulting from imposing the patterns of maximum/minimum phases of the observed Atlantic multidecadal oscillation (AMO) onto projected sea surface temperatures (SSTs) from two climate models from phase 5 of the Coupled Model Intercomparison Project (CMIP5) are examined using a 100-km resolution global atmospheric model. By imposing the observed maximum positive and negative phases of the AMO onto two CMIP5 SST projections from the representative concentration pathway (RCP) 4.5 scenario, this study places bounds on future North Atlantic tropical cyclone activity during the early (2020–39) and late (2080–99) twenty-first century. Averaging over both time periods and both AMO phases, the mean named tropical cyclones (NTCs) count increases by 35% when compared to simulations using observed SSTs from 1982 to 2009. The positive AMO simulations produce approximately a 68% increase in mean NTC count, while the negative AMO simulations are statistically indistinguishable from the mean NTC count determined from the 1995–2009 simulations—a period of observed positive AMO phase. Examination of the tropical cyclone track densities shows a statistically significant increase in the tracks along the East Coast of the United States in the future simulations compared to the models’ 1982–2009 climate simulations. The increase occurs regardless of AMO phase, although the negative phase produces higher track densities. The maximum wind speeds increase by 6%, in agreement with other climate change studies. Finally, the NTC-related precipitation is found to increase (approximately by 13%) compared to the 1982–2009 simulations.
Dynamical and Thermodynamical Causes of Large-Scale Changes in the Hydrological Cycle over North America in Response to Global Warming*
Authors: Seager Richard , Neelin David , Simpson Isla , Liu Haibo , Henderson Naomi , Shaw Tiffany , Kushnir Yochanan , Ting Mingfang , Cook Benjamin 
Published: August 2014

Abstract
The mechanisms of model-projected atmospheric moisture budget change across North America are examined in simulations conducted with 22 models from phase 5 of the Coupled Model Intercomparison Project. Modern-day model budgets are validated against the European Centre for Medium-Range Weather Forecasts Interim Re-Analysis. In the winter half year transient eddies converge moisture across the continent while the mean flow wets the west from central California northward and dries the southwest. In the summer half year there is widespread mean flow moisture divergence across the west and convergence over the Great Plains that is offset by transient eddy divergence. In the winter half year the models project drying for the southwest and wetting to the north. Changes in the mean flow moisture convergence are largely responsible across the west but intensified transient eddy moisture convergence wets the northeast. In the summer half year widespread declines in precipitation minus evaporation (P − E) are supported by mean flow moisture divergence across the west and transient eddy divergence in the Great Plains. The changes in mean flow convergence are related to increases in specific humidity but also depend on changes in the mean flow including increased low-level divergence in the U.S. Southwest and a zonally varying wave that wets the North American west and east coasts in winter and dries the U.S. Southwest. Increased transient eddy fluxes occur even as low-level eddy activity weakens and arise from strengthened humidity gradients. A full explanation of North American hydroclimate changes will require explanation of mean and transient circulation changes and the coupling between the moisture and circulation fields.
Reading Text While Driving
Authors: Liang Yulan , Horrey William J. , Hoffman Joshua D. 
Published: August 2014

Objective In this study, we investigated how drivers adapt secondary-task initiation and time-sharing behavior when faced with fluctuating driving demands. Background Reading text while driving is particularly detrimental; however, in real-world driving, drivers actively decide when to perform the task. Method In a test track experiment, participants were free to decide when to read messages while driving along a straight road consisting of an area with increased driving demands (demand zone) followed by an area with low demands. A message was made available shortly before the vehicle entered the demand zone. We manipulated the type of driving demands (baseline, narrow lane, pace clock, combined), message format (no message, paragraph, parsed), and the distance from the demand zone when the message was available (near, far). Results In all conditions, drivers started reading messages (drivers’ first glance to the display) before entering or before leaving the demand zone but tended to wait longer when faced with increased driving demands. While reading messages, drivers looked more or less off road, depending on types of driving demands. Conclusions For task initiation, drivers avoid transitions from low to high demands; however, they are not discouraged when driving demands are already elevated. Drivers adjust time-sharing behavior according to driving demands while performing secondary tasks. Nonetheless, such adjustment may be less effective when total demands are high. Application This study helps us to understand a driver’s role as an active controller in the context of distracted driving and provides insights for developing distraction interventions.
Comments on ‘Current emerging situation of dengue in India’: with regard to the clinical and laboratory characteristics of paediatric dengue in India
Authors: Chakravarti Anita , Roy Priyamvada 
Published: August 2014

Dengue is a major public health problem in India. We evaluated clinical and laboratory characteristics of 700 suspected dengue patients below the age of 12 years. Serum samples of the patients were analysed for dengue NS1 antigen and IgM antibody by ELISA, and were correlated with clinical and haematological parameters. The positivity percentage of the serological tests showed an inverse relationship with age. Positive NS1 antigen and IgM antibody results were significantly associated with patients aged less than 3 years and more than 3 years, respectively. Maximum association with features of haemodynamic instability was seen in infants. The haemorrhagic manifestations of thrombocytopaenia, leucopaenia and anaemia were associated more with older age groups. This study provides evidence for age-related differences in clinical and laboratory features of paediatric dengue in an Indian setting.
Clinical Assessment of Scapula and Hip Joint Function in Preadolescent and Adolescent Baseball Players
Authors: Beckett Michael , Hannon Michael , Ropiak Christopher , Gerona Christopher , Mohr Karen , Limpisvasti Orr 
Published: August 2014

Background: Proper scapulothoracic and hip mechanics are essential aspects of the throwing kinetic chain. Little is known regarding these entities in preadolescent and adolescent baseball players. Hypothesis: Scapular malposition and dyskinesis as well as hip dysfunction are highly prevalent in preadolescent and adolescent baseball players and may be identified by simple clinical testing. Study Design: Descriptive laboratory study. Methods: A total of 112 baseball players aged 7 to 18 years were recruited from local Little Leagues, traveling teams, and high schools. Participants were divided into 2 groups: preadolescents (players aged 7-12 years) and adolescents (players aged 13-18 years). Scapular symmetry was tested with the yes/no method of Kibler and by measuring forward shoulder posture via the “coracoid distance.” Hip abductor strength was measured by use of a handheld digital dynamometer. Functional gluteal and core strength was assessed by video analysis of the subjects performing the single-legged squat test. Hip range of motion was measured in the prone position by use of a handheld goniometer. Results: Compared with the preadolescent group, the adolescent group had a significantly higher prevalence of scapular dyskinesis in the throwing shoulder (50% vs 25.9%, P = .011). The adolescents had significantly higher normalized hip abduction strength in both the stride (17.41 vs 12.62 N/kg, P < .001) and stance (17.82 vs 12.61 N/kg, P < .001) legs. The preadolescent group was unable to perform the single-legged squat test correctly in either the stance (0% preadolescent vs 13% adolescent, P = .0127) or stride (0% preadolescent vs 9.3% adolescent, P = .0567) leg. The mean coracoid distance was elevated in the dominant (throwing) shoulder after controlling for scapular dyskinesis ( P < .0001). Presence of scapular dyskinesis was associated with a higher mean coracoid distance ( P = .0067). Conclusion: There was a high prevalence of dominant shoulder scapular dyskinesis in the adolescent compared with the preadolescent group, as well as universally poor single-legged squat test performance. The mean coracoid distance was higher in the dominant or throwing side compared with the nondominant side independent of scapular dyskinesis. Presence of scapular dyskinesis was associated with higher mean coracoid distance. Clinical Relevance: Identification of players thought to be at increased risk for throwing injuries and initiation of targeted rehabilitation programs may decrease injury rates in preadolescent and adolescent baseball players.