Prothrombin complex concentrate for emergency surgery in patients on oral Xa-inhibitors.

BACKGROUND: It is uncertain whether prothrombin complex concentrate (PCC) improves hemostasis in patients on treatment with oral factor Xa-inhibitors (XaI) who require emergency surgery. OBJECTIVES: To evaluate whether, in patients with therapeutic levels of oral XaI, preoperative PCC prevents excessive bleeding during and after emergency surgery and is not associated with thrombotic complications. METHODS: We conducted a prospective cohort study wherein a fixed 2000 IU dose of 4-factor PCC was given to patients taking oral XaI with plasma XaI levels of at least 75 ng/mL before the emergency surgery with an expected blood loss of at least 50 mL. Patients were followed for 30 days. The primary efficacy outcome was the incidence of normal or mildly abnormal surgical hemostasis, as assessed by the surgeon; primary safety outcome was the incidence of thromboembolic events within 7 days. RESULTS: We included 20 patients, 50% were female, on apixaban (75%) or rivaroxaban (25%) with median XaI level of 128 ng/mL (range 77-497). The median duration of surgery was 2h 42 min (15 min to 8h 17 min). Normal or mildly abnormal hemostasis was observed in 16 patients (80%), 2 patients had moderately abnormal and 2 had severely abnormal hemostasis, 1 each of those was considered due to local or technical factors. There were 4 deaths (20%) secondary to underlying disease and 1 incidental pulmonary embolism in a patient with cancer. CONCLUSION: A fixed dose PCC appears to control hemostasis in patients with therapeutic plasma levels of apixaban or rivaroxaban requiring emergency surgery.

A scalable scanning transfer cavity laser stabilization scheme based on the Red Pitaya STEMlab platform.

Many experiments in atomic and molecular physics require simultaneous frequency stabilization of multiple lasers. We present a stabilization scheme based on a scanning transfer cavity lock that is simple, stable, and easily scalable to many lasers at minimal cost. The scheme is based on the Red Pitaya STEMlab platform, with custom software developed and implemented to achieve up to 100 Hz bandwidth. As an example demonstration, we realize simultaneous stabilization of up to four lasers and a reduction of long-term drifts to well below 1 MHz/h. This meets typical requirements, e.g., for experiments on laser cooling of molecules.

Extended thromboprophylaxis following colorectal surgery in patients with inflammatory bowel disease: a comprehensive systematic clinical review.

AIM: Patients with inflammatory bowel disease (IBD) are at increased risk of postoperative venous thromboembolism (VTE) following major abdominal surgery. The pathogenesis is multifactorial and not fully understood. A combination of pathophysiology, patient and surgical risk factors increase the risk of postoperative VTE in these patients. Despite being at increased risk, IBD patients are not regularly prescribed extended pharmacological thromboprophylaxis following colorectal surgery. Currently, there is a paucity of evidence-based guidelines. Thus, the aim of this review is to evaluate the role of extended pharmacological thromboprophylaxis in IBD patients undergoing colorectal surgery. METHOD: A search of Ovid Medline, EMBASE and PubMed databases was performed. A qualitative analysis was performed using 10 clinical questions developed by colorectal surgeons and a thrombosis haematologist. The Newcastle-Ottawa Scale was utilized to assess the quality of evidence. RESULTS: A total of 1229 studies were identified, 38 of which met the final inclusion criteria (37 retrospective, one case-control). Rates of postoperative VTE ranged between 0.6% and 8.9%. Patient-specific risk factors for postoperative VTE included ulcerative colitis, increased age and obesity. Surgery-specific risk factors for postoperative VTE included open surgery, emergent surgery and ileostomy creation. Patients with IBD were more frequently at increased risk in the included studies for postoperative VTE than patients with colorectal cancer. The risk of bias assessment demonstrated low risk of bias in patient selection and comparability, with variable risk of bias in reported outcomes. CONCLUSION: There is a lack of evidence regarding the use of extended pharmacological thromboprophylaxis in patients with IBD following colorectal surgery. As these patients are at heightened risk of postoperative VTE, future study and consideration of the use of extended pharmacological thromboprophylaxis is warranted.

Thrombus stability explains the factor V Leiden paradox: a mouse model.

Humans carrying the factor V Leiden (FVL) variant have a fivefold increased risk for venous thrombosis. However, incidence of deep vein thrombosis (DVT) is proportionally greater than that of pulmonary embolism (PE) in these individuals. This is known as the FVL paradox. We hypothesized that the rate of initial DVT development is similar in FVL and noncarriers, but thrombi in FVL carriers are more stable and develop into a clinically significant DVT more often than in noncarriers. To test this, we induced thrombi in the femoral vein of wild-type (WT), heterozygous (F5L/+), and FVL homozygous (F5L/L) mice. Using intravital microscopy, thrombus size and embolization were visualized and emboli in the lungs were quantified. Compared with WT, femoral vein thrombi in F5L/+ and F5L/L mice were larger and embolized less. Total and large embolic events, the percentage of thrombus that embolized, and PE burden were significantly decreased in F5L/L mice. This suggests that in noncarriers (reflected by WT), a minor injury initially resulting in a small DVT tends to remain small and asymptomatic because of the embolization of the otherwise growing thrombus. Alternatively, the same insult in people with FVL (reflected by F5L/L) leads to thrombus growth as a result of less embolization, and thus symptomatic DVT development.

Low-level laboratory measurement of xenon radionuclides: Electron-photon versus photon measurements.

Radioactive xenon (mainly 131mXe, 133Xe, 133mXe and 135Xe) are tracked as markers of nuclear weapons testing. The CEA has developed the PIPSBox, a measurement cell able to detect electrons emitted by xenon nuclides. Combined with an ultra-low background γ spectrometer, electron detection capacities allow reaching minimum detectable activities (MDA) for a 3-day long measurement of about 0.5mBq for the four xenon radionuclides. Compared to a classical measurement cell, MDAs are improved by a factor of 2-4.

SPALAX NG: A breakthrough in radioxenon field measurement.

Lessons-learned from 10 years of noble gas stations operation and dedicated R&D allowed the design of a New Generation of station. In order to produce 60m3 air equivalent Xenon samples every 8h, it implements: (i) larger sampler unit for Xenon extraction (2 compressors and 8 nitrogen membranes), (ii) new noble gas adsorbent (Ag@ZSM5), (iii) hardened components and (iv) new high resolution coincidence low background spectrometer (HPGe/PIPSBox). Station expected radioxenon sensitivity is lower than 0.3mBq/m3.

Reversal of dabigatran-associated major bleeding with activated prothrombin concentrate: A prospective cohort study.

The reversal of dabigatran-associated major bleeding can now be achieved with the antidote idarucizumab. We evaluated activated prothrombin complex concentrate (aPCC) as an alternative for this purpose. Patients treated with dabigatran and suffering a major bleed were treated as per existing hospital protocol with aPCC. They were subsequently recruited for a 30-day follow-up. Effectiveness was evaluated by the treating physician, using an Assessment Guide. Safety outcomes were arterial or venous thromboembolism or death. A comparison was also made with historic cases with dabigatran-associated major bleeds treated with supportive care, by matching 1:2 for type of bleed, age and sex. We aimed at 32 evaluable cases but the study was prematurely discontinued after 14 cases due to the availability of the approved antidote. The effectiveness of aPCC was assessed as Good in 9 (64%), moderate in 5 (36%) and poor in none. There were no thromboembolic events and one death. In the secondary adjudication of effectiveness, using the same criteria and by the same adjudicators as previously done for the historic cases, the outcome was graded for the current cases versus the historic cases as Good, Moderate, or Poor in 10 (71%) versus 16 (57%), 3 (21%) versus 4 (14%), and 1 (7%) versus 8 (29%), respectively. Although supportive care is sufficient to manage many patients with dabigatran-associated bleeding, aPCC might provide an additional benefit to control life-threatening bleeding in selected cases and does not appear to cause an excess of thromboembolic events.

Ground surface ultralow background spectrometer: Active shielding improvements and coincidence measurements for the Gamma3 spectrometer.

The ultralow background versatile spectrometer GAMMA3 has been optimized with the following shielding improvements: (i) optimized nitrogen injection flux of 300Lh-1, and (ii) cosmic veto configuration with 9 scintillating plates. These improvements allow a reduction of 39% of the normalized integral background count rate down to 2.7±0.2min-1kgGe-1 (40-2500keV energy range). Minimum Detectable Activities when performing direct γ-ray spectrometry or γ-γ coincidence spectrometry are compared.

Comparison of the effect of dabigatran and dalteparin on thrombus stability in a murine model of venous thromboembolism.

UNLABELLED: ESSENTIALS: Does thrombus stability alter the presentation of venous thromboembolism and do anticoagulants alter this? In a murine model, we imaged a femoral vein thrombus and quantified emboli in the pulmonary arteries. Dabigatran decreases thrombus stability via factor XIII increasing embolization and pulmonary emboli. This cautions against the unapproved use of dabigatran for acute initial treatment of deep vein thrombosis. BACKGROUND: Venous thromboembolism (VTE) is a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE). Thrombus instability possibly contributes to progression of DVT to PE, and direct thrombin inhibitors (DTIs) may alter this. AIM: To develop a model to assess thrombus stability and its link to PE burden, and identify whether DTIs, in contrast to low-molecular-weight heparin (LMWH), alter this correlation. METHODS: Twelve minutes after ferric chloride-induced thrombus formation in the femoral vein of female mice, saline, dalteparin (LMWH) or dabigatran (DTI) was administered. Thrombus size and embolic events breaking off from the thrombus were quantified before treatment and at 10-min intervals after treatment for 2 h using intravital videomicroscopy. Lungs were stained for the presence of PE. RESULTS: Thrombus size was similar over time and between treatment groups. Total and large embolic events and pulmonary emboli were highest after treatment with dabigatran. Variations in amounts of pulmonary embolic events were not attributed to variations in thrombus size. Large embolic events correlated with the number of emboli per lung slice independent of treatment. Embolization in factor XIII deficient (FXIII(-/-) ) saline-treated mice was greater than that in wild-type (WT) saline-treated mice, but was similar to WT dabigatran-treated mice. CONCLUSION: We have developed a mouse model of VTE that can quantify emboli and correlate this with PE burden. Consistent with clinical data, dabigatran, a DTI, acutely decreases thrombus stability and increases PE burden compared with LMWH or saline, which is a FXIII-dependent effect.

Rapid quantitative D-dimer to exclude pulmonary embolism: a prospective cohort management study.

UNLABELLED: ESSENTIALS: It is not known if D-dimer testing alone can safely exclude pulmonary embolism (PE). We studied the safety of using a quantitative latex agglutination D-dimer to exclude PE in 808 patients. 52% of patients with suspected PE had a negative D-dimer test and were followed for 3 months. The negative predictive value of D-dimer testing alone was 99.8%, suggesting it may safely exclude PE. BACKGROUND: Strategies are needed to exclude pulmonary embolism (PE) efficiently without the need for imaging tests. Although validated rules for clinical probability assessment can be combined with D-dimer testing to safely exclude PE, the rules can be complicated or partially subjective, which limits their use. OBJECTIVES: To determine if PE can be safely excluded in patients with a negative D-dimer without incorporating clinical probability assessment. PATIENTS/METHODS: We enrolled consecutive outpatients and inpatients with suspected PE from four tertiary care hospitals. All patients underwent D-dimer testing using the MDA D-dimer test, a quantitative latex agglutination assay. PE was excluded in patients with a D-dimer less than 750 µg FEU L(-1) without further testing. PATIENTS: with D-dimer levels of 750 µg FEU L(-1) or higher underwent standardized imaging tests for PE. All patients in whom PE was excluded had anticoagulant therapy withheld and were followed for 3 months for venous thromboembolism (VTE). Suspected events during follow-up were adjudicated centrally. RESULTS: Eight hundred and eight patients were enrolled, of whom 99 (12%) were diagnosed with VTE at presentation. Four hundred and twenty (52%) patients had a negative D-dimer level at presentation and were not treated with anticoagulants; of these, one had VTE during follow-up. The negative predictive value of D-dimer testing for PE was 99.8% (95% confidence interval, 98.7-99.9%). CONCLUSIONS: A negative latex agglutination D-dimer assay is seen in about one-half of patients with suspected PE and reliably excludes PE as a stand-alone test.

Spalax™ new generation: A sensitive and selective noble gas system for nuclear explosion monitoring.

In the context of the verification regime of the Comprehensive nuclear Test ban Treaty (CTBT), CEA is developing a new generation (NG) of SPALAX™ system for atmospheric radioxenon monitoring. These systems are able to extract more than 6cm(3) of pure xenon from air samples each 12h and to measure the four relevant xenon radioactive isotopes using a high resolution detection system operating in electron-photon coincidence mode. This paper presents the performances of the SPALAX™ NG prototype in operation at Bruyères-le-Châtel CEA centre, integrating the most recent CEA developments. It especially focuses on an innovative detection system made up of a gas cell equipped with two face-to-face silicon detectors associated to one or two germanium detectors. Minimum Detectable activity Concentrations (MDCs) of environmental samples were calculated to be approximately 0.1 mBq/m(3) for the isotopes (131m)Xe, (133m)Xe, (133)Xe and 0.4 mBq/m(3) for (135)Xe (single germanium configuration). The detection system might be used to simultaneously measure particulate and noble gas samples from the CTBT International Monitoring System (IMS). That possibility could lead to new capacities for particulate measurements by allowing electron-photon coincidence detection of certain fission products.

An introduction to γ(3) a new versatile ultralow background gamma spectrometer. Background description and analysis.

The γ(3) setup has been designed as a versatile, high sensitivity spectrometry platform. State-of-the art techniques have been implemented to reduce its background to minimum level even though the system is installed at ground level. The shield design and background performance of the setup are presented. The spectrometer is composed of three identical HPGe detectors for high detection efficiency or coincidence measurement and can accommodate several sample geometries. Its shield includes three layers of increasing purity lead, a cosmic veto, an inner borated polyethylene layer, and a radon-free gas injection system. The spectrometer normalized background count rate is 4.4 counts per minutekgGe(-1) (in the 40-2500keV energy range). Its background characteristics, cosmic veto efficiency, and radon-free gas injection performances are discussed.

Clinical challenges in patients with cancer-associated thrombosis: Canadian expert consensus recommendations.

Venous thromboembolism is a common complication in cancer patients, and thromboembolism is the second most common cause of death after cancer progression. A number of clinical practice guidelines provide recommendations for the management of cancer-associated thrombosis. However, the guidelines lack recommendations covering commonly encountered clinical challenges (for example, thrombocytopenia, recurrent venous thromboembolism, etc.) for which little or no evidence exists. Accordingly, recommendations were developed to provide expert guidance to medical oncologists and other health care professionals caring for patients with cancer-associated thrombosis. The current expert consensus was developed by a team of 21 clinical experts. For each identified clinical challenge, the literature in medline, embase, and Evidence Based Medicine Reviews was systematically reviewed. The quality of the evidence was assessed, summarized, and graded. Consensus statements were generated, and the experts voted anonymously using a modified Delphi process on their level of agreement with the various statements. Statements were progressively revised through separate voting iterations and were then finalized. Clinicians using these recommendations and suggestions should tailor patient management according to the risks and benefits of the treatment options, patient values and preferences, and local cost and resource allocations.

Comparison of the effect of coagulation and platelet function impairments on various mouse bleeding models.

Haemostatic impairments are studied in vivo using one of several murine bleeding models. However it is not known whether these models are equally appropriate for assessing coagulation or platelet function defects. It was our study objective to assess the performance of arterial, venous and combined arterial and venous murine bleeding models towards impaired coagulation or platelet function. Unfractionated heparin (UFH) or αIIbß3inhibitory antibody (Leo.H4) were administered to mice, and their effects on bleeding in saphenous vein, artery, and tail tip transection models were quantified and correlated with their effects on plasma clotting and ADP-induced platelet aggregation, respectively. All models exhibited similar sensitivity with UFH (EC50 dose = 0.19, 0.13 and 0.07 U/g, respectively) (95% CI = 0.14 - 0.27, 0.08 - 0.20, and 0.03 - 0.16 U/g, respectively). Maximal inhibition of ex vivo plasma clotting could be achieved with UFH doses as low as 0.03 U/g. In contrast, the saphenous vein bleeding model was less sensitive to αIIbß3 inhibition (EC50 = 6.9 µg/ml) than tail transection or saphenous artery bleeding models (EC50 = 0.12 and 0.37 µg/ml, respectively) (95% CI = 2.4 - 20, 0.05 - 0.33, and 0.06 - 2.2 µg/ml, respectively). The EC50 of Leo.H4 for ADP-induced platelet aggregation in vitro (8.0 µg/ml) was at least 20-fold higher than that of the tail and arterial, but not the venous bleeding model. In conclusion, venous, arterial and tail bleeding models are similarly affected by impaired coagulation, while platelet function defects have a greater influence in models incorporating arterial injury.

On the use of (127)Xe standards for the quality control of CTBTO noble gas stations and support laboratories.

(127)Xe has a longer half-life than (131m)Xe, it can be easily purely produced and it is present in the environment at very low level. For these reasons, (127)Xe is supposed to be a convenient quality control radionuclide for remote noble gas stations of the International Monitoring System (IMS) network. As CEA/DAM has recently developed two new photon/electron setups for low-level detection of (131m)Xe, (133m)Xe, (133)Xe and (135)Xe, we took the opportunity to test these setups for the measurement of a (127)Xe standard. The results and a detailed description of these measurements are presented in this paper. They illustrate the complexity of (127)Xe decay, emitting simultaneously several γ, X-rays, conversion electrons and Auger electrons; this results in highly summated coincidence spectra. The measurements performed provide precise electron energy calibration of the setups. The count rate of electrons in coincidence with iodine Kα X-rays was found to be surprisingly low, leading to the study of electron-gated photon spectrum. Finally, a comparison of three photon/electron coincidence spectra obtained with three different setups is given. The use of (127)Xe as a standard for energy calibration of IMS noble gas station is possible, but it appears to be quite complicated for efficiency check of noble gas station equipped with ß/γ detectors.

Long-term performances of the 95ZR/95Nb chronometer for nuclear events dating.

The present work reports on a long-term analysis of the performances of the (95)Zr/(95)Nb chronometer for dating a nuclear event. Taking benefit of a recent Profiency Test Exercise, a sample containing a standardized mixture of fission products has been measured repeatedly with a low background HPGe spectrometer during a period extending up to one year with the aim of assessing the accuracy of the various zero-time determinations. Evaluation of the uncertainties associated to these evaluations was performed using a Monte Carlo approach. Input parameters sensitivity has been investigated, especially the influence of the (95m)Nb decay branch. The (95)Zr/(95)Nb chronometer was found to be accurate for zero-time determination within one day and one week for a decay of 3 months and 10 months respectively. Sub-day uncertainties are achievable for a two months old sample whereas sub-week uncertainties are reached after a decay of six months. Limitations of the technique for dating a real event are investigated.

Improvements of low-level radioxenon detection sensitivity by a state-of-the art coincidence setup.

The ability to quantify isotopic ratios of 135, 133 m, 133 and 131 m radioxenon is essential for the verification of the Comprehensive Nuclear-Test Ban Treaty (CTBT). In order to improve detection limits, CEA has developed a new on-site setup using photon/electron coincidence (Le Petit et al., 2013. J. Radioanal. Nucl. Chem., DOI : 10.1007/s 10697-013-2525-8.). Alternatively, the electron detection cell equipped with large silicon chips (PIPS) can be used with HPGe detector for laboratory analysis purpose. This setup allows the measurement of ß/γ coincidences for the detection of (133)Xe and (135)Xe; and K-shell Conversion Electrons (K-CE)/X-ray coincidences for the detection of (131m)Xe, (133m)Xe and (133)Xe as well. Good energy resolution of 11 keV at 130 keV and low energy threshold of 29 keV for the electron detection were obtained. This provides direct discrimination between K-CE from (133)Xe, (133m)Xe and (131m)Xe. Estimation of Minimum Detectable Activity (MDA) for (131m)Xe is in the order of 1mBq over a 4 day measurement. An analysis of an environmental radioxenon sample using this method is shown.

[Hyponatremia]. / Hyponatriämie.

Hyponatremia is the most common electrolyte disorder in the hospital setting and is defined as a serum sodium concentration less than 135 mmol/l. Most patients have mild hyponatremia (plasma sodium concentration 130-134 mmol/l) and few if any symptoms. Serum sodium concentrations between 120 and 129 mmol/l can be associated with lack of concentration, nausea, forgetfulness, apathy and loss of balance. Severe hyponatremia (<120 mmol/l) can cause coma or grand mal seizure. If hyponatremia occurs acutely (duration <48 h) it will cause more severe symptoms than are observed in chronic hyponatremia (>48 h). It is important to distinguish between different types of hyponatremia: euvolemic hyponatremia causing syndrome of inappropriate antidiuretic hormone secretion(SIADH) also known as Schwartz-Bartter syndrome, hypervolemic hyponatremia (cardiac failure and liver cirrhosis) and hypovolemic hyponatremia (diarrhoea, vomiting or other gastrointestinal fluid losses). Increased levels of ADH and continued fluid intake are the pathogenetic causes of all three types of hyponatremia; nonetheless, infusion of isotonic fluid is the therapy of choice for hypovolemic hyponatremia. In contrast, fluid restriction, lithium carbonate, urea, loop diuretics or demeclocycline have been used as therapeutic options to correct hyponatremia in euvolemic or hypervolemic hyponatremia but most of these therapies have proven to be cumbersome and inefficient. Recently a new class of pharmacological agents has become available, the vaptans, orally taken vasopressin antagonists. Clinical trials showed them to provide effective, specific and safe therapy of hyponatremia. In Europe tolvaptan, the only such agent on the market is now approved for the treatment of euvolemic hyponatremia.

Innovative concept for a major breakthrough in atmospheric radioactive xenon detection for nuclear explosion monitoring.

The verification regime of the comprehensive test ban treaty (CTBT) is based on a network of three different waveform technologies together with global monitoring of aerosols and noble gas in order to detect, locate and identify a nuclear weapon explosion down to 1 kt TNT equivalent. In case of a low intensity underground or underwater nuclear explosion, it appears that only radioactive gases, especially the noble gas which are difficult to contain, will allow identification of weak yield nuclear tests. Four radioactive xenon isotopes, 131mXe, 133mXe, 133Xe and 135Xe, are sufficiently produced in fission reactions and exhibit suitable half-lives and radiation emissions to be detected in atmosphere at low level far away from the release site. Four different monitoring CTBT systems, ARIX, ARSA, SAUNA, and SPALAX™ have been developed in order to sample and to measure them with high sensitivity. The latest developed by the French Atomic Energy Commission (CEA) is likely to be drastically improved in detection sensitivity (especially for the metastable isotopes) through a higher sampling rate, when equipped with a new conversion electron (CE)/X-ray coincidence spectrometer. This new spectrometer is based on two combined detectors, both exhibiting very low radioactive background: a well-type NaI(Tl) detector for photon detection surrounding a gas cell equipped with two large passivated implanted planar silicon chips for electron detection. It is characterized by a low electron energy threshold and a much better energy resolution for the CE than those usually measured with the existing CTBT equipments. Furthermore, the compact geometry of the spectrometer provides high efficiency for X-ray and for CE associated to the decay modes of the four relevant radioxenons. The paper focus on the design of this new spectrometer and presents spectroscopic performances of a prototype based on recent results achieved from both radioactive xenon standards and air sample measurements. Major improvements in detection sensitivity have been reached and quantified, especially for metastable radioactive isotopes 131mXe and 133mXe with a gain in minimum detectable activity (about 2 × 10-3 Bq) relative to current CTBT SPALAX™ system (air sampling frequency normalized to 8 h) of about 70 and 30 respectively.