Leisure time physical activity in 9- to 11-year-old children born moderately preterm: a cohort study.

BACKGROUND: Physical activity is one of the best documented activities with impacts on health in children and adults. Children born preterm show reduced physical and psychosocial function compared to children born at term. This may influence their level of physical activity. Reports on moderately preterm children's physical activities during childhood are limited. Thus, the aim of this study was to compare the leisure time physical activity at age 9-11 years of moderately preterm children with that of children born at term. METHODS: Data from 4941 mother-child pairs from the Aarhus Birth Cohort (1989-91) were used. The cohort gathered clinical information, including gestational age at delivery. Information about parental socio-demographic and lifestyle factors was obtained from questionnaires completed during the second trimester of pregnancy. Information about children's physical activities was reported in a 9- to 11-year follow-up questionnaire completed by parents detailing how many times per week their child participated in sports activities outside of school, hours spent per week playing outside, and hours per week engaged in sedentary activities. Data were analysed using multiple logistic regression with the lowest activity group as a reference group. RESULTS: A total of 158 children (3.2%) were born moderately preterm, i.e., between 32 and 36 completed weeks. Children born moderately preterm participated in sports activities as often as their peers born at term; they also participated in frequent sports activities (≥ 4 times per week) as often as their peers. There were no differences in hours per week spent playing outside or in sedentary activities between the two groups. CONCLUSIONS: Nine- to 11-year-old moderately preterm children participated in sports activities outside school to a similar extent as their peers and engaged in outdoor activities and sedentary activities for the same duration of time per week as their peers born at term.

Impact of motion compensation and partial volume correction for 18F-NaF PET/CT imaging of coronary plaque.

Recent studies have suggested that 18F-NaF-PET enables visualization and quantification of plaque micro-calcification in the coronary tree. However, PET imaging of plaque calcification in the coronary arteries is challenging because of the respiratory and cardiac motion as well as partial volume effects. The objective of this work is to implement an image reconstruction framework, which incorporates compensation for respiratory as well as cardiac motion (MoCo) and partial volume correction (PVC), for cardiac 18F-NaF PET imaging in PET/CT. We evaluated the effect of MoCo and PVC on the quantification of vulnerable plaques in the coronary arteries. Realistic simulations (Biograph TPTV, Biograph mCT) and phantom acquisitions (Biograph mCT) were used for these evaluations. Different uptake values in the calcified plaques were evaluated in the simulations, while three 'plaque-type' lesions of 36, 31 and 18 mm3 were included in the phantom experiments. After validation, the MoCo and PVC methods were applied in four pilot NaF-PET patient studies. In all cases, the MoCo-based image reconstruction was performed using the STIR software. The PVC was obtained from a local projection (LP) method, previously evaluated in preclinical and clinical PET. The results obtained show a significant increase of the measured lesion-to-background ratios (LBR) in the MoCo + PVC images. These ratios were further enhanced when using directly the tissue-activities from the LP method, making this approach more suitable for the quantitative evaluation of coronary plaques. When using the LP method on the MoCo images, LBR increased between 200% and 1119% in the simulated data, between 212% and 614% in the phantom experiments and between 46% and 373% in the plaques with positive uptake observed in the pilot patients. In conclusion, we have built and validated a STIR framework incorporating MoCo and PVC for 18F-NaF PET imaging of coronary plaques. First results indicate an improved quantification of plaque-type lesions.

32nd International Austrian Winter Symposium : Zell am See, the Netherlands. 20-23 January 2016.

TABLE OF CONTENTS: A1 68Ga-PSMA PET/CT in staging and restaging of Prostate Cancer Patients: comparative study with 18F-Choline PET/CTW Langsteger, A Rezaee, W Loidl, HS Geinitz, F Fitz, M Steinmair, G Broinger, L Pallwien-Prettner, M BeheshtiA2 F18 Choline PET - CT: an accurate diagnostic tool for the detection of parathyroid adenoma?L Imamovic, M Beheshti, G Rendl, D Hackl, O Tsybrovsky, M Steinmair, K Emmanuel, F Moinfar, C Pirich, W LangstegerA3 [18F]Fluoro-DOPA-PET/CT in the primary diagnosis of medullary thyroid carcinomaA Bytyqi, G Karanikas, M Mayerhöfer, O Koperek, B Niederle, M HartenbachA4 Variations of clinical PET/MR operations: An international survey on the clinical utilization of PET/MRIT Beyer, K Herrmann, J CzerninA5 Standard Dixon-based attenuation correction in combined PET/MRI: Reproducibility and the possibility of Lean body mass estimationI Rausch, P Rust, MD DiFranco, M Lassen, A Stadlbauer, ME Mayerhöfer, M Hartenbach, M Hacker, T BeyerA6 High resolution digital FDG PET/MRI imaging for assessment of ACL graft viabilityK Binzel, R Magnussen, W Wei, MU Knopp, DC Flanigan, C Kaeding, MV KnoppA7 Using pre-existing hematotoxicity as predictor for severe side effects and number of treatment cycles of Xofigo therapyA Leisser, M Nejabat, M Hartenbach, G Kramer, M Krainer, M Hacker, A HaugA8 QDOSE - comprehensive software solution for internal dose assessmentWencke Lehnert, Karl Schmidt, Sharok Kimiaei, Marcus Bronzel, Andreas KlugeA9 Clinical impact of Time-of-Flight on next-generation digital PET imaging of Yttrium-90 radioactivity following liver radioembolizationCL Wright, K Binzel, J Zhang, Evan Wuthrick, Piotr Maniawski, MV KnoppA10 Snakes in patients! Lessons learned from programming active contours for automated organ segmentationM Blaickner, E Rados, A Huber, M Dulovits, H Kulkarni, S Wiessalla, C Schuchardt, RP Baum, B Knäusl, D GeorgA11 Influence of a genetic polymorphism on brain uptake of the dual ABCB1/ABCG2 substrate [11C]tariquidarM Bauer, B Wulkersdorfer, W Wadsak, C Philippe, H Haslacher, M Zeitlinger, O LangerA12 Outcome prediction of temporal lobe epilepsy surgery from P-glycoprotein activity. Pooled analysis of (R)-[11C]-verapamil PET data from two European centresM Bauer, M Feldmann, R Karch, W Wadsak, M Zeitlinger, MJ Koepp, M-C Asselin, E Pataraia, O LangerA13 In-vitro and in-vivo characterization of [18F]FE@SNAP and derivatives for the visualization of the melanin concentrating hormone receptor 1M Zeilinger, C Philippe, M Dumanic, F Pichler, J Pilz, M Hacker, W Wadsak, M MitterhauserA14 Reducing time in quality control leads to higher specific radioactivity of short-lived radiotracersL Nics, B Steiner, M Hacker, M Mitterhauser, W WadsakA15 In vitro 11C-erlotinib binding experiments in cancer cell lines with epidermal growth factor receptor mutationsA Traxl, Thomas Wanek, Kushtrim Kryeziu, Severin Mairinger, Johann Stanek, Walter Berger, Claudia Kuntner, Oliver LangerA16 7-[11C]methyl-6-bromopurine, a PET tracer to measure brain Mrp1 function: radiosynthesis and first PET evaluation in miceS Mairinger, T Wanek, A Traxl, M Krohn, J Stanek, T Filip, M Sauberer, C Kuntner, J Pahnke, O LangerA17 18F labeled azidoglucose derivatives as "click" agents for pretargeted PET imagingD Svatunek, C Denk, M Wilkovitsch, T Wanek, T Filip, C Kuntner-Hannes, J Fröhlich, H MikulaA18 Bioorthogonal tools for PET imaging: development of radiolabeled 1,2,4,5-TetrazinesC Denk, D Svatunek, T Wanek, S Mairinger, J Stanek, T Filip, J Fröhlich, H Mikula, C Kuntner-HannesA19 Preclinical evaluation of [18F]FE@SUPPY- a new PET-tracer for oncologyT Balber, J Singer, J Fazekas, C Rami-Mark, N Berroterán-Infante, E Jensen-Jarolim, W Wadsak, M Hacker, H Viernstein, M MitterhauserA20 Investigation of Small [18F]-Fluoroalkylazides for Rapid Radiolabeling and In Vivo Click ChemistryC Denk, D Svatunek, B Sohr, H Mikula, J Fröhlich, T Wanek, C Kuntner-Hannes, T FilipA21 Microfluidic 68Ga-radiolabeling of PSMA-HBED-CC using a flow-through reactorS Pfaff, C Philippe, M Mitterhauser, M Hartenbach, M Hacker, W WadsakA22 Influence of 24-nor-ursodeoxycholic acid on hepatic disposition of [18F]ciprofloxacin measured with positron emission tomographyT Wanek, E Halilbasic, M Visentin, S Mairinger, B Stieger, C Kuntner, M Trauner, O LangerA23 Automated 18F-flumazenil production using chemically resistant disposable cassettesP Lam, M Aistleitner, R Eichinger, C ArtnerA24 Similarities and differences in the synthesis and quality control of 177Lu-DOTA-TATE, 177Lu -HA-DOTA-TATE and 177Lu-DOTA-PSMA (PSMA-617)H Eidherr, C Vraka, A Haug, M Mitterhauser, L Nics, M Hartenbach, M Hacker, W WadsakA25 68Ga- and 177Lu-labelling of PSMA-617H Kvaternik, R Müller, D Hausberger, C Zink, RM AignerA26 Radiolabelling of liposomes with 67Ga and biodistribution studies after administration by an aerosol inhalation systemU Cossío, M Asensio, A Montes, S Akhtar, Y te Welscher, R van Nostrum, V Gómez-Vallejo, J LlopA27 Fully automated quantification of DaTscan SPECT: Integration of age and gender differencesF VandeVyver, T Barclay, N Lippens, M TrochA28 Lesion-to-background ratio in co-registered 18F-FET PET/MR imaging - is it a valuable tool to differentiate between low grade and high grade brain tumor?L Hehenwarter, B Egger, J Holzmannhofer, M Rodrigues-Radischat, C PirichA29 [11C]-methionine PET in gliomas - a retrospective data analysis of 166 patientsN Pötsch, I Rausch, D Wilhelm, M Weber, J Furtner, G Karanikas, A Wöhrer, M Mitterhauser, M Hacker, T Traub-WeidingerA30 18F-Fluorocholine versus 18F-Fluorodeoxyglucose for PET/CT imaging in patients with relapsed or progressive multiple myeloma: a pilot studyT Cassou-Mounat, S Balogova, V Nataf, M Calzada, V Huchet, K Kerrou, J-Y Devaux, M Mohty, L Garderet, J-N TalbotA31 Prognostic benefit of additional SPECT/CT in sentinel lymph node mapping of breast cancer patientsS Stanzel, G Pregartner, T Schwarz, V Bjelic-Radisic, B Liegl-Atzwanger, R AignerA32 Evaluation of diagnostic value of TOF-18F-FDG PET/CT in patients with suspected pancreatic cancerS Stanzel, F Quehenberger, RM AignerA33 New quantification method for diagnosis of primary hyperpatahyroidism lesions and differential diagnosis vs thyropid nodular disease in dynamic scintigraphyA Koljevic Markovic, Milica Jankovic, V Miler Jerkovic, M Paskas, G Pupic, R Dzodic, D PopovicA34 A rare case of diffuse pancreatic involvement in patient with merkel cell carcinoma detected by 18F-FDGMC Fornito, D FamiliariA35 TSH-stimulated 18F-FDG PET/CT in the diagnosis of recurrent/metastatic radioiodine-negative differentiated thyroid carcinomas in patients with various thyroglobuline levelsP Koranda, H Polzerová, I Metelková, L Henzlová, R Formánek, E Buriánková, M KamínekA36 Breast Dose from lactation following I131 treatmentWH Thomson, C LewisA37 A new concept for performing SeHCAT studies with the gamma cameraWH Thomson, J O'Brien, G James, A NotghiA38 Whole body F-18-FDG-PET and tuberculosis: sensitivity compared to x-ray-CTH Huber, I Stelzmüller, R Wunn, M Mandl, F Fellner, B Lamprecht, M GabrielA39 Emerging role 18F-FDG PET-CT in the diagnosis and follow-up of the infection in heartware ventricular assist system (HVAD)MC Fornito, G LeonardiA40 Validation of Poisson resampling softwareWH Thomson, J O'Brien, G JamesA41 Protection of PET nuclear medicine personnel: problems in satisfying dose limit requirementsJ Hudzietzová, J Sabol, M Fülöp.

Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery - the SAVE-HIP3 study.

There is currently limited information available on the benefits and risks of extended thromboprophylaxis after hip fracture surgery. SAVE-HIP3 was a randomised, double-blind study conducted to evaluate the efficacy and safety of extended thromboprophylaxis with the ultra-low molecular-weight heparin semuloparin compared with placebo in patients undergoing hip fracture surgery. After a seven- to ten-day open-label run-in phase with semuloparin (20 mg once daily subcutaneously, initiated post-operatively), patients were randomised to once-daily semuloparin (20 mg subcutaneously) or placebo for 19 to 23 additional days. The primary efficacy endpoint was a composite of any venous thromboembolism (VTE; any deep-vein thrombosis and non-fatal pulmonary embolism) or all-cause death until day 24 of the double-blind period. Safety parameters included major and clinically relevant non-major bleeding, laboratory data, and treatment-emergent adverse events (TEAEs). Extended thromboprophylaxis with semuloparin demonstrated a relative risk reduction of 79% in the rate of any VTE or all-cause death compared with placebo (3.9% vs 18.6%, respectively; odds ratio 0.18 (95% confidence interval 0.07 to 0.45), p < 0.001). Two patients in the semuloparin group and none in the placebo group experienced clinically relevant bleeding. TEAE rates were similar in both groups. In conclusion, the SAVE-HIP3 study results demonstrate that patients undergoing hip fracture surgery benefit from extended thromboprophylaxis.

Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups.

BACKGROUND: New oral anticoagulants for thromboprophylaxis after hip or knee arthroplasty have been given as fixed-dose regimens. OBJECTIVE: To evaluate the consistency of the antithrombotic efficacy and bleeding risk of apixaban 2.5 mg twice daily compared with enoxaparin 40 mg once daily after knee or hip arthroplasty across the clinical characteristics of age, gender, body weight, body mass index (BMI) and creatinine clearance. METHODS: The pooled results of the ADVANCE-2 (knee arthroplasty) and -3 (hip arthroplasty) randomized trials were used to evaluate if treatment had a statistically significantly different effect (P < 0.10) on major venous thromboembolism (VTE) and bleeding for the characteristics of age, gender, body weight, BMI and creatinine clearance. Both univariate analysis and multivariate logistic regression were used. RESULTS: Univariate analyses identified statistically significant interactions for age and major VTE (P = 0.09); for both age (P = 0.07) and body weight (P = 0.07) and the outcome of major bleeding; and for creatinine clearance (P = 0.03) and the composite outcome of major and clinically relevant non-major bleeding. Estimates of these possible differences were not precise, with wide 95% confidence intervals (CIs) that included a zero difference for several subgroups. Multivariate logistic regression analysis did not detect a statistically significant interaction for any outcomes. CONCLUSIONS: This analysis found no convincing evidence that age, weight, gender, BMI or creatinine clearance influenced the balance of benefit to risk for apixaban compared with enoxaparin. Because only 5% of patients had a creatinine clearance between 30 and 50 mL min(-1), further data are needed in such patients.

Prevention and treatment of venous thromboembolism--International Consensus Statement.

The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE).

The effects of rivaroxaban on the complications of surgery after total hip or knee replacement: results from the RECORD programme.

Post-operative complications after total hip or knee replacement can delay recovery, prolong hospitalisation, increase rates of re-admission and, in the most severe cases, lead to long-term disability or even death. In this analysis of pooled data from four large, randomised, phase III clinical trials that compared the oral, direct Factor Xa inhibitor rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement (n = 12,729), the incidence of complications, including bleeding and adverse events related to surgery (such as wound infection, wound dehiscence and haemarthrosis) are reported. Interventions and procedures relating to surgery are also compared between the groups. Bleeding events, including excessive wound haematoma and surgical-site bleeding, occurred at similar rates in the rivaroxaban and enoxaparin groups. Over the total study duration, adverse surgical events occurred at a similar rate in the rivaroxaban group compared with the enoxaparin group after total knee replacement (2.26% vs. 2.69%, respectively) and total hip replacement (1.48% vs. 1.65%, respectively). Blood loss, wound drainage and transfusion requirements were also similar between the two groups. This analysis shows that the incidence of adverse surgical events with rivaroxaban was similar to enoxaparin.

Practical use of apixaban in the prevention of venous thromboembolism after total knee or hip replacement.

Apixaban is an anticoagulant drug that acts by directly inhibiting coagulation factor Xa. Unlike low-molecular-weight heparins and fondaparinux, apixaban can be taken orally; in contrast to vitamin K antagonists, its clinical use does not require dose adjustments according to coagulation monitoring. Apixaban in a regimen of 2.5 mg twice daily has been approved in Europe for the prevention of venous thromboembolism in patients undergoing elective total hip or knee replacement. This approval was based on the results of two large phase III trials showing that, compared to the European approved regimen of enoxaparin for total hip and knee replacement (i.e., 40 mg once daily starting preoperatively), apixaban 2.5 mg twice daily initiated 12-24 hours after wound closure was more effective in preventing venous thromboembolism, without increasing the risk of bleeding. This apixaban regimen may therefore represent a convenient alternative to conventional anticoagulant drug regimens in the prevention of venous thromboembolism in this surgical setting. However, there are several precautions that prescribers should take into account before using this drug regimen. In this article, various points are considered, notably bleeding risk and the use of this novel oral anticoagulant in special populations or in the context of neuraxial anesthesia.

Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE.

BACKGROUND: Semuloparin is a novel ultra-low-molecular-weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. OBJECTIVES: Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE-KNEE), elective hip replacement (SAVE-HIP1) and hip fracture surgery (SAVE-HIP2). PATIENTS/METHODS: All studies were multinational, randomized and double-blind. Semuloparin and enoxaparin were administered for 7-10 days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non-fatal pulmonary embolism or all-cause death. Safety outcomes included major bleeding, clinically relevant non-major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). RESULTS: In total, 1150, 2326 and 1003 patients were randomized in SAVE-KNEE, SAVE-HIP1 and SAVE-HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE-HIP1. In SAVE-HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE-KNEE and SAVE-HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. CONCLUSIONS: Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles.

Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials.

In order to compare the effect of oral apixaban (a factor Xa inhibitor) with subcutaneous enoxaparin on major venous thromboembolism and major and non-major clinically relevant bleeding after total knee and hip replacement, we conducted a pooled analysis of two previously reported double-blind randomised studies involving 8464 patients. One group received apixaban 2.5 mg twice daily (plus placebo injection) starting 12 to 24 hours after operation, and the other received enoxaparin subcutaneously once daily (and placebo tablets) starting 12 hours (± 3) pre-operatively. Each regimen was continued for 12 days (± 2) after knee and 35 days (± 3) after hip arthroplasty. All outcomes were centrally adjudicated. Major venous thromboembolism occurred in 23 of 3394 (0.7%) evaluable apixaban patients and in 51 of 3394 (1.5%) evaluable enoxaparin patients (risk difference, apixaban minus enoxaparin, -0.8% (95% confidence interval (CI) -1.2 to -0.3); two-sided p = 0.001 for superiority). Major bleeding occurred in 31 of 4174 (0.7%) apixaban patients and 32 of 4167 (0.8%) enoxaparin patients (risk difference -0.02% (95% CI -0.4 to 0.4)). Combined major and clinically relevant non-major bleeding occurred in 182 (4.4%) apixaban patients and 206 (4.9%) enoxaparin patients (risk difference -0.6% (95% CI -1.5 to 0.3)). Apixaban 2.5 mg twice daily is more effective than enoxaparin 40 mg once daily without increased bleeding.

Naturally phase-matched second-harmonic generation in a whispering-gallery-mode resonator.

We demonstrate for the first time natural phase matching for optical frequency doubling in a high-Q whispering-gallery-mode resonator made of lithium niobate. A conversion efficiency of 9% is achieved at 30 microW in-coupled continuous wave pump power. The observed saturation pump power of 3.2 mW is almost 2 orders of magnitude lower than the state-of-the-art value. This suggests an application of our frequency doubler as a source of nonclassical light requiring only a low-power pump, which easily can be quantum noise limited. Our theoretical analysis of the three-wave mixing in a whispering-gallery-mode resonator provides the relative conversion efficiencies for frequency doubling in various modes.

Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthroplasty. A dose finding study (ONYX-2).

BACKGROUND: Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic surgery, with atrial fibrillation and with acute coronary syndrome, respectively. OBJECTIVES: To investigate the efficacy and safety of YM150 for the prevention of VTE following elective total hip arthroplasty. PATIENTS/METHODS: Patients were randomized to postoperative, once-daily, oral YM150 (5, 10, 30, 60 or 120 mg) (double-blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary safety outcome was major bleeding up to 9 days after surgery. RESULTS: Primary efficacy endpoint: of 1017 patients randomized, 960 patients were evaluable for safety and 729 patients for efficacy. A dose-related decrease in VTE incidence from YM150 5 to 60 mg (P = 0.0005) and from 5 to 120 mg (P = 0.0002) was found. The VTE incidence was 27.4%, 31.7%, 19.3%, 13.3% and 14.5% for 5, 10, 30, 60 and 120 mg YM150, respectively, and 18.9% for enoxaparin. Primary safety endpoint: there was one major bleed with YM150 (60 mg) and one with enoxaparin. CONCLUSIONS: The oral direct FXa inhibitor YM150 demonstrated a significant dose response regarding efficacy. Doses from 30 to 120 mg had comparable efficacy to enoxaparin, without compromising safety regarding major bleeding events.

Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients.

The definition of major bleeding varies between studies on surgical patients, particularly regarding the criteria for surgical wound-related bleeding. This diversity contributes to the difficulties in comparing data between trials. The Scientific and Standardization Committee (SSC), through its subcommittee on Control of Anticoagulation, of the International Society on Thrombosis and Haemostasis has previously published a recommendation for a harmonized definition of major bleeding in non-surgical studies. That definition has been adopted by the European Medicines Agency and is currently used in several non-surgical trials. A preliminary proposal for a parallel definition for surgical studies was presented at the 54(th) Annual Meeting of the SSC in Vienna, July 2008. Based on those discussions and further consultations with European and North American surgeons with experience from clinical trials a definition has been developed that should be applicable to all agents that interfere with hemostasis. The definition and the text that follows have been reviewed and approved by relevant co-chairs of the subcommittee and by the Executive Committee of the SSC. The intention is to seek approval of this definition from the regulatory authorities to enhance its incorporation into future clinical trial protocols.

Assessing the polarization of a quantum field from stokes fluctuations.

We propose an operational degree of polarization in terms of the variance of the Stokes vector minimized over all the directions of the Poincaré sphere. We examine the properties of this second-order definition and carry out its experimental determination. Quantum states with the same standard (first-order) degree of polarization are correctly discriminated by this new measure. We argue that a comprehensive quantum characterization of polarization properties requires a whole hierarchy of higher-order degrees.

Continuous variable entanglement and squeezing of orbital angular momentum states.

We report the first experimental characterization of the first-order continuous variable orbital angular momentum states. Using a spatially nondegenerate optical parametric oscillator (OPO) we produce quadrature entanglement between the two first-order Laguerre-Gauss modes. The family of orbital angular momentum modes is mapped on an orbital Poincaré sphere, where the mode's position on the sphere is spanned by the three orbital parameters. Using a nondegenerate OPO we produce squeezing of these parameters, and as an illustration, we reconstruct the "cigar-shaped" uncertainty volume on the orbital Poincaré sphere.

Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement.

A once-daily dose of rivaroxaban 10 mg, an oral, direct Factor Xa inhibitor, was compared with enoxaparin 40 mg subcutaneously once daily for prevention of venous thromboembolism in three studies of patients undergoing elective hip and knee replacement (RECORD programme). A pooled analysis of data from these studies (n = 9581) showed that rivaroxaban was more effective than enoxaparin in reducing the incidence of the composite of symptomatic venous thromboembolism and all-cause mortality at two weeks (0.4% vs 0.8%, respectively, odds ratio 0.44; 95% confidence interval 0.23 to 0.79; p = 0.005), and at the end of the planned medication period (0.5% vs 1.3%, respectively; odds ratio 0.38; 95% confidence interval 0.22 to 0.62; p < 0.001). The rate of major bleeding was similar at two weeks (0.2% for both) and at the end of the planned medication period (0.3% vs 0.2%). Rivaroxaban started six to eight hours after surgery was more effective than enoxaparin started the previous evening in preventing symptomatic venous thromboembolism and all-cause mortality, without increasing major bleeding.

AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery--TREK: a dose-ranging study.

BACKGROUND: AVE5026 is a new hemisynthetic ultra-low-molecular-weight heparin, with a novel anti-thrombotic profile resulting from high anti-factor (F)Xa activity and residual anti-FIIa activity. AVE5026 is in clinical development for venous thromboembolism (VTE) prevention, a frequent complication after total knee replacement (TKR) surgery. OBJECTIVES: This study evaluated the dose-response of AVE5026 for the prevention of VTE in patients undergoing TKR surgery. PATIENTS/METHODS: In this parallel-group, double-blind, double-dummy study, 690 patients were randomized, and 678 treated with once-daily doses of AVE5026 (5, 10, 20, 40, or 60 mg) or enoxaparin 40 mg in the calibrator arm. The primary efficacy end point was VTE until post-operative day 11, defined as deep vein thrombosis (DVT) detected by bilateral venography, symptomatic DVT, non-fatal pulmonary embolism (PE) and VTE-related death. The primary safety outcome was the incidence of major bleeding. RESULTS: The primary efficacy outcome was assessed in 464 patients. There was a significant dose-response across the five AVE5026 groups for VTE prevention (P<0.0001), with the incidence of VTE ranging from 5.3% to 44.1% compared with 35.8% in the enoxaparin group and for proximal DVT (P=0.0002). Also, a significant dose-response for AVE5026 was seen for major bleeding (P=0.0231) and any bleeding (P=0.0003). Six patients in the AVE5026 groups, four in the 60 mg group, experienced major bleeding; none did in the enoxaparin group. CONCLUSIONS: The safety and efficacy results of this study suggest that a AVE5026 dose of between 20 and 40 mg presents an adequate benefit-to-risk ratio.

Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran.

BACKGROUND: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.

Differences in urinary prothrombin fragment 1 + 2 levels after total hip replacement in relation to venous thromboembolism and bleeding events.

BACKGROUND: Prothrombin fragment 1 + 2 is excreted in urine (uF1 + 2) as a result of thrombin generation and, therefore, may be a useful marker of coagulation status. OBJECTIVES: To assess uF1 + 2 levels after total hip replacement (THR) in patients with venous thromboembolism (VTE) and bleeding events. PATIENTS/METHODS: This study was conducted in parallel with a prospective, dose-finding study evaluating the efficacy and safety of different doses of rivaroxaban (Xarelto, Bayer HealthCare AG, Wuppertal, Germany) for thromboprophylaxis, relative to enoxaparin. Deep vein thrombosis was diagnosed by mandatory venography performed 5-9 days after THR, or earlier if symptomatic. Symptomatic pulmonary embolism was diagnosed by objective testing. Bleeding complications were registered and stratified into major bleeding, clinically relevant, non-major bleeding, and minor bleeding, using predefined criteria. RESULTS: Eighty-four patients had a VTE and 57 patients had a bleeding event (n = 722). Significantly higher median uF1 + 2 levels were observed in the VTE group on day 3 after THR (P = 0.03), compared with control. Median uF1 + 2 levels were lower in the bleeding group on day 3 after THR (P = 0.005) and on the day of venography (P = 0.36), compared with control. Comparisons between the VTE and bleeding groups showed significantly lower median uF1 + 2 levels in the bleeding group on day 3 after THR and on the day of venography (P < 0.0001 and P = 0.006, respectively). CONCLUSIONS: Measurement of uF1 + 2 could provide a simple clinical test to evaluate non-invasively the intensity of coagulation activation after THR. However, further studies are required to confirm these encouraging preliminary results.