bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of Zernike polynomials towards accelerated adaptive focusing of transcranial high intensity focused ultrasound
Authors: Kaye Elena A. , Hertzberg Yoni , Marx Michael , Werner Beat , Navon Gil , Levoy Marc , Pauly Kim Butts 
Published: September 2012

Purpose:To study the phase aberrations produced by human skulls during transcranial magnetic resonance imaging guided focused ultrasound surgery (MRgFUS), to demonstrate the potential of Zernike polynomials (ZPs) to accelerate the adaptive focusing process, and to investigate the benefits of using phase corrections obtained in previous studies to provide the initial guess for correction of a new data set.Methods:The five phase aberration data sets, analyzed here, were calculated based on preoperative computerized tomography (CT) images of the head obtained during previous transcranial MRgFUS treatments performed using a clinical prototype hemispherical transducer. The noniterative adaptive focusing algorithm [Larrat et al., “MR‐guided adaptive focusing of ultrasound,” IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57(8), 1734–1747 (2010)] 10.1109/TUFFC.2010.1612 was modified by replacing Hadamard encoding with Zernike encoding. The algorithm was tested in simulations to correct the patients’ phase aberrations. MR acoustic radiation force imaging (MR‐ARFI) was used to visualize the effect of the phase aberration correction on the focusing of a hemispherical transducer. In addition, two methods for constructing initial phase correction estimate based on previous patientˈs data were investigated. The benefits of the initial estimates in the Zernike‐based algorithm were analyzed by measuring their effect on the ultrasound intensity at the focus and on the number of ZP modes necessary to achieve 90% of the intensity of the nonaberrated case.Results:Covariance of the pairs of the phase aberrations data sets showed high correlation between aberration data of several patients and suggested that subgroups can be based on level of correlation. Simulation of the Zernike‐based algorithm demonstrated the overall greater correction effectiveness of the low modes of ZPs. The focal intensity achieves 90% of nonaberrated intensity using fewer than 170 modes of ZPs. The initial estimates based on using the average of the phase aberration data from the individual subgroups of subjects was shown to increase the intensity at the focal spot for the five subjects.Conclusions:The application of ZPs to phase aberration correction was shown to be beneficial for adaptive focusing of transcranial ultrasound. The skull‐based phase aberrations were found to be well approximated by the number of ZP modes representing only a fraction of the number of elements in the hemispherical transducer. Implementing the initial phase aberration estimate together with Zernike‐based algorithm can be used to improve the robustness and can potentially greatly increase the viability of MR‐ARFI‐based focusing for a clinical transcranial MRgFUS therapy.
Mapping of distributions of a local b‐matrix cross‐term strength using diffusion tensor MRI in patients with Alzheimerˈs disease
Authors: Jahng Geon‐Ho , Xu Songfan , Kim Min‐Ji 
Published: September 2012

Purpose:Mapping of the distribution of local susceptibility strength could be very important in understanding the mechanisms of progression in neurodegenerative diseases, due to depositions of iron and iron‐containing plaques. The goal of this study is to map the voxelwise distribution of local cross‐termb‐value (bc) effect caused by interactions between the external and internal gradients, in subjects with Alzheimerˈs disease (AD), mild cognitive impairment (MCI), and cognitively normal (CN) elderly, using a diffusion tensor (DT) MRI.Methods:Two DT‐MRI experiments were conducted with opposite polarities of the external diffusion‐sensitizing gradients, and the authors modeled the 3 × 3 tensor matrix ofbc maps and drove a rotationally independent mean bc (i.e., MBc) maps. To test whether AD has higher cross‐term gradients than MCI and/or CN, 15 AD patients, 18 MCI patients, and 16 CN controls were acquired from DT‐MRI data, with six diffusion encoding directions, five b‐values (0, 160, 360, 640, and 1000 s/mm2), and positively and negatively alternating polarities of the external diffusion‐sensitizing gradients. The bc and MBc maps were calculated and were spatially normalized into a study specific template for all subjects. The differences of MBc maps across the three subject groups were investigated with voxelwise one‐way ANOVA tests for each b‐value. The differences of MBc maps, among the four b‐values, were also investigated with a voxelwise one‐way within‐subject ANOVA test for each group.Results:The authors successfully mapped the local cross‐term strength, using a DT‐MRI data in the three groups. The MBc differences between the groups were increased with increasing b‐values. Compared with the CN group and the MCI group, MBc values in the AD group were significantly increased. However, compared with the CN group, MBc values in the MCI group were not significantly different for all the b‐values.Conclusions:In order to map theb‐matrix cross‐term effect, the authors developed a rotationally invariant index of MBc, and the index was applied in AD, MCI, and CN subjects. In the AD group, compared with the MCI and CN groups, MBc values were increased. AD patients may have much more local intrinsic gradients in the brain than those MCI or CN subjects. MBc maps may be used to detect the intrinsically susceptible materials in the human brain, such as iron‐containing plaques in the brain with AD.
Characterisation of exposure versus response of edoxaban in patients undergoing total hip replacement surgery
Authors: Rohatagi Shashank , Kastrissios Helen , Green Michelle , Green Michelle , Shi Minggao , Patel Indravadan , Salazar Daniel , Mendell Jeanne 
Published: September 2012

SummaryEdoxaban is an oral direct factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE) in Japan. The objectives of this analysis were to characterise the population pharmacokinetics (PK) of edoxaban and the relationships between edoxaban exposure and clinical outcomes in a phase IIb study of surgical patients following total hip replacement (THR). A total of 1,795 subjects from a phase IIb study, 10 phase I studies, and three phase IIa studies were included in the PK analysis. The exposure-response analysis included data from surgical patients assigned to edoxaban in the phase IIb study. Edoxaban disposition in healthy and post-surgical patients was well-described with a linear, two-compartment model. Creatinine clearance was significantly correlated with edoxaban clearance and the rate of oral absorption was affected by surgery. The probability of a post-operative VTE was significantly correlated with steady-state metrics of edoxaban exposure estimated for each subject by Bayesian post-hoc methods with age and gender being the significant and expected covariates. The incidence of bleeding was low in these studies and hence no exposure-response relationship could be identified. These analyses suggest that edoxaban has a predictable anticoagulant effect in this patient population leading to dose-proportional reduction in incidence of VTE with low incidence of bleeding.
Fractalkine is an independent predictor of mortality in patients with advanced heart failure
Authors: Koller Lorenz , Hohensinner Philipp , Rychli Kathrin , Zorn Gerlinde , Goliasch Georg , Berger Rudolf , Mörtl Deddo , Maurer Gerald , Huber Kurt , Pacher Richard , Wojta Johann , Hülsmann Martin , Niessner Alexander , Richter Bernhard 
Published: September 2012

SummaryImmunological processes are implicated in the multifactorial pathophysiology of heart failure (HF). The multifunctional chemokine fractalkine (CX3CL1) promotes the extravasation of cytotoxic lymphocytes into tissues. We aimed to assess the prognostic value of fractalkine in HF. Fractalkine plasma levels were determined in 349 patients with advanced systolic HF (median 75 years, 66% male). During a median follow-up of 4.9 years (interquartile range: 4.6–5.2), 55.9% of patients died. Fractalkine was a significant predictor of all-cause mortality (p <0.001) with a hazard ratio of 2.78 (95% confidence interval: 1.95–3.95) for the third compared to the first tertile. This association remained significant after multivariable adjustment for demographics, clinical predictive variables and N-terminal pro-B-type natriuretic peptide (NT-proBNP, p=0.008). The predictive value of fractalkine did not significantly differ between patients with ischaemic and non-ischaemic HF aetiology (p=0.79). The predictive value of fractalkine tertiles was not significantly modified by tertiles of NT-proBNP (p=0.18) but was more pronounced in the first and third tertile of NT-proBNP. Fractalkine was also an independent predictor of cardiovascular mortality (p=0.015). Fractalkine levels were significantly lower in patients on angiotensin-converting enzyme inhibitor therapy (p <0.001). In conclusion, circulating fractalkine with its pro-inflammatory and immunomodulatory effects is an independent predictor of mortality in advanced HF patients. Fractalkine improves risk prediction beyond NTproBNP and might therefore help to identify high risk patients who need special care. Our data indicate the implication of immune modulation in HF pathology.
Inhibition of endothelial nitric oxyde synthase increases capillary formation via Rac1-dependent induction of hypoxia-inducible factor-1α and plasminogen activator inhibitor-1
Authors: Weitnauer Michael , Petry Andreas , BelAiba Rachida , Görlach Agnes 
Published: September 2012

SummaryDisruption of endothelial homeostasis results in endothelial dysfunction, characterised by a dysbalance between nitric oxide (NO) and reactive oxygen species (ROS) levels often accompanied by a prothrombotic and proproliferative state. The serine protease thrombin not only is instrumental in formation of the fibrin clot, but also exerts direct effects on the vessel wall by activating proliferative and angiogenic responses. In endothelial cells, thrombin can induce NO as well as ROS levels. However, the relative contribution of these reactive species to the angiogenic response towards thrombin is not completely clear. Since plasminogen activator inhibitor-1 (PAI-1), a direct target of the proangiogenic transcription factors hypoxia-inducible factors (HIFs), exerts prothrombotic and proangiogenic activities we investigated the role of ROS and NO in the regulation of HIF-1α, PAI-1 and capillary formation in response to thrombin. Thrombin enhanced the formation of NO as well as ROS generation involving the GTPase Rac1 in endothelial cells. Rac1-dependent ROS formation promoted induction of HIF-1α, PAI-1 and capillary formation by thrombin, while NO reduced ROS bioavailability and subsequently limited induction of HIF-1α, PAI-1 and the angiogenic response. Importantly, thrombin activation of Rac1 was diminished by NO, but enhanced by ROS. Thus, our findings show that capillary formation induced by thrombin via Rac1-dependent activation of HIF-1 and PAI-1 is limited by the concomitant release of NO which reduced ROS bioavailability. Rac1 activity is sensitive to ROS and NO, thereby playing an essential role in fine tuning the endothelial response to thrombin.
A novel flow cytometry single tube bead assay for quantitation of von Willebrand factor antigen and collagen-binding
Authors: Favaloro Emmanuel , Koutts Jerry , Mina Ashraf 
Published: September 2012

SummaryDeficiency of or defects in the plasma protein von Willebrand factor (VWF) lead to bleeding and von Willebrand disease (VWD), which may be congenital or acquired. VWD is considered the most common inherited bleeding disorder and laboratory testing for VWF level and activity is critical for appropriate diagnosis and management. We have designed and established a novel Flow Cytometry (FC) based method for measuring VWF antigen (VWF:Ag) and collagen binding (VWF:CB), together in the same tube and at the same time. The results of the novel FC method have been compared against existing reference methods using a range of normal and pathological material. Methods correlated well (VWF:Ag, r=0.866; VWF:CB, r=0.888) and generally permitted similar discrimination of quantitative versus qualitative VWD types (e.g. type 1 vs type 2A or 2B VWD). The novel procedure is expected to permit future streamlined performance of VWD screening, either using stand-alone FC systems or potentially incorporated into FC-capable automated blood cell and particle counters to allow for improved, automated and faster identification or exclusion of VWD.
Differential haemostatic risk factors for pregnancy-related deep-vein thrombosis and pulmonary embolism
Authors: Dahm Anders , Jacobsen Anne Flem , Sandvik Leiv , Sandset Per Morten , Bergrem Astrid 
Published: September 2012

SummaryLimited data exist on thrombophilia and the risk of venous thrombosis (VT) during pregnancy and postpartum. The objectives of the present study were to investigate the role of haemostatic risk factors for pregnancy-related VT and their phenotypic expression in deep-vein thrombosis (DVT) and pulmonary embolism (PE). Total 313 cases with objectively verified first time VT and 353 controls were selected from a source population of 377,155 women with 613,232 pregnancies. The adjusted odds ratio (aOR) for pregnancy-related VT was 1.7 (95% confidence interval [CI] 1.1–2.8) for women with factor VIII >90th percentile. The aOR for VT for endogenous thrombin potential and D-dimer values >90thpercentiles were 1.8 (95% CI 1.1–3.0) and 2.1 (95% CI 1.3–3.3), respectively. Factor IX >90thpercentile or free protein S ≤the 5th percentile increased the risk for PE, and the aORs were 2.4 (95% CI 1.1–5.0) and 3.1 (95% CI 1.3–7.2), respectively. Women carrying the factor V Leiden (F5 rs6025) polymorphism, or who had reduced sensitivity to activated protein C (aPC) in the absence of F5 rs6025, had increased risk for DVT, with unadjusted ORs 7.7 (95% CI 4.7–12.7) and 3.5 (95% CI 2.2–5.4), respectively. Women with a history of pregnancy-related VT showed activation of coagulation and had elevated factor VIII. Furthermore, high levels of factor IX and low levels of free protein S were associated with increased risk for PE, whereas aPC resistance and F5 rs6025 were risk factors for DVT and not PE.
Randomised comparison of a simple warfarin dosing algorithm versus a computerised anticoagulation management system for control of warfarin maintenance therapy
Authors: Hubers Lowiek , Spyropoulos Alex , Eikelboom John , Connolly Benjamin , Van Spall Harriette , Schulze Karleen , Cuddy Spencer , Stehouwer Alexander , Schulman Sam , Connolly Stuart , Nieuwlaat Robby 
Published: September 2012

SummaryExcellent control of the international normalised ratio (INR) is associated with improved clinical outcomes in patients receiving warfarin, and can be achieved by anticoagulation clinics but is difficult in general practice. Anticoagulation clinics have often used validated commercial computer systems to manage the INR, but these are not usually available to general practitioners. It was the objective of this study to perform a randomised trial of a simple one-step warfarin dosing algorithm against a widely used computerised dosing system. During the period of introduction of a commercial computerised warfarin dosing system (DAWN AC) to an anticoagulation clinic, patients were randomised to have warfarin dose adjustment done according to recommendations of the existing warfarin dosing algorithm or to those of the computerised system. The study tested if the computerised system was non-inferior to the existing algorithm for the primary outcome of time in therapeutic INR range of 2.0–3.0 (TTR), with a one-sided non-inferiority margin of 4.5%. There were 541 patients randomised to commercial computerised system and 527 to the algorithm. Median follow-up was 159 days. A dose recommendation was provided and followed in 91% of occasions for the computerised system and in 90% for the algorithm (p=0.03). The mean TTR was 71.0% (standard deviation [SD] 23.2) for the computerised system and 71.9% (SD 22.9) for the algorithm (difference 0.9% [95% confidence interval: –1.4% to 4.1%];p-value for noninferiority=0.002;p-value for superiority=0.34). In conclusion, similar maintenance control of the INR was achieved with a simple one-step dosing algorithm and a commercial computerised management system.
The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition
Authors: Vinnikov Ilya , Shahzad Khurrum , Bock Fabian , Ranjan Satish , Wolter Juliane , Kashif Muhammed , Oh Jun , Bierhaus Angelika , Nawroth Peter , Kirschfink Michael , Conway Edward , Madhusudhan Thati , Isermann Berend , Wang Hongjie 
Published: September 2012

SummaryCoagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM’s lectin like domain dampens complement activation, while its EGF-like domains independently enhance activation of the anticoagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating complement. Diabetic nephropathy was analysed in mice lacking TM’s lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 μg/mg vs. 166 μg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeDmice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeDmice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeDmice (e.g. albuminuria 85 μg/mg vs. 290 μg/mg, p <0.001). In vitroTM’s lectin-like domain cell-autonomously prevented glucose-induced complement activation on endothelial cells and –notably –on podocytes. Podocyte injury, which was enhanced in diabetic TMLeD/LeDmice, was reduced following complement inhibition with enoxaparin. The current study identifies a novel mechanism regulating complement activation in diabetic nephropathy. TM’s lectin-like domain constrains glucose-induced complement activation on endothelial cells and podocytes and ameliorates albuminuria and glomerular damage in mice.
Interpretation of endpoints in a network meta-analysis of new oral anticoagulants following total hip or total knee replacement surgery
Authors: Marx Svetlana , Dahl Ola , Marder Victor , Schulze Astrid , Wehling Martin , Weiss Christel , Harenberg Job 
Published: September 2012

SummaryNew oral anticoagulant (NOAC) regimens [dabigatran 150 mg (D150) and 220 mg (D220), rivaroxaban 10 mg (R20), and apixaban 2.5 mg bid (A5)] were effective and safe compared to enoxaparin for the prevention of venous thromboembolism (VTE) following elective total knee (TKR) or hip replacement (THR) surgery. First a cluster analysis was used to identify homogeneous studies for the trial programs of each NOAC. Second, only studies reporting VTE and VTE-related death, major bleeding, and mortality were included. The odds ratio (OR) and 95% confidence interval (CI) were calculated for each NOAC regimen versus the comparator. Third, these data were used for the indirect comparison between NOACs. Cluster analysis identified duration of treatment (10 ± 5 and 34 ± 5 days) as the only homogeneous parameter across all NOAC programs (p>0.05) except for A5 and VTE over 10 ± 5 days (analysis not performed). The results of the calculated OR and 95% CI of the four NOAC regimens over 10 ± 5 and 34 ± 5 days showed inferiority of D150 and D220 compared to R10 for VTE (p<0.01, p<0.001). Comparisons of major bleeding and mortality were not different for all indirect comparisons. Despite the lack of standard definitions for VTE and bleeding outcomes, cluster analysis seems to be an appropriate tool to identify homogeneity across trial programs and to perform an indirect comparison for NOACs for prevention of VTE following TKR and THR surgery.
The effect of hyperthyroidism on procoagulant, anticoagulant and fibrinolytic factors
Authors: Zaane Bregje van , Romualdi Erica , Brandjes Dees , Gerdes Victor , Squizzato Alessandro , Stuijver Danka 
Published: September 2012

SummarySeveral coagulation and fibrinolytic parameters appear to be affected by thyroid hormone excess;however, the net effect on the haemostatic system remains unclear. We aimed to update our previous review and systematically summarise and meta-analyse the data by assessing the effects of thyrotoxicosis on the coagulation and fibrinolytic system in vivo. Data sources included MEDLINE (2006–2012), EMBASE (2006–2012), and reference lists. The sources were combined with our previous search containing studies from 1980–2006. Eligible studies were all observational or experimental studies. Two investigators independently extracted data and rated study quality. Weighted mean proportion and 95% confidence intervals were calculated and pooled using a fixed and a random-effects model. A total of 29 articles consisting of 51 studies were included, as in several articles more than one study was described. We included four intervention (before and after treatment in hyperthyroid patients), five cross-sectional (hyperthyroid subjects and euthyroid controls), and four experimental (before and after use of thyroid hormone in euthyroid subjects) medium/high quality studies for meta-analysis. We found that thyrotoxicosis shifts the haemostatic balance towards a hypercoagulable and hypofibrinolytic state with a rise in factors VIII and IX, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1. This was observed in endogenous and exogenous thyrotoxicosis, and in subclinical as well as overt hyperthyroidism. We conclude that both subclinical and overt hyperthyroidism induce a prothrombotic state, which is therefore likely to be a risk factor for venous thrombosis.
Biomarkers of platelet activation in acute coronary syndromes
Authors: Ferroni Patrizia , Riondino Silvia , Vazzana Natale , Santoro Nicole , Guadagni Fiorella , Davì Giovanni 
Published: September 2012

SummaryThe most convincing evidence for the participation of platelets in arterial thrombosis in humans comes from studies of platelet activation in patients with acute coronary syndromes (ACS) and from trials of antiplatelet drugs. Both strongly support the concept that repeated episodes of platelet activation over the thrombogenic surface of a vulnerable plaque may contribute to the risk of death from coronary causes. However, the relation of <i>in vivo</i>platelet activation and adverse clinical events to results of platelet function tests remains largely unknown. A valuable marker of <i>in vivo</i>platelet activation should be specific, unaltered by pre-analytical artefacts and reproducibly measured by easily performed methods. This article describes current biomarkers of platelet activation in ACS, reviews their advantages and disadvantages, discusses their potential pitfalls, and demonstrates emerging data supporting the positive clinical implications of monitoring in vivo platelet ac- tivation in the setting of ACS.