A mutated factor X activatable by thrombin corrects bleedings in vivo in a rabbit model of antibody-induced hemophilia A

Rendering coagulation factor X sensitive to thrombin was proposed as a strategy that can bypass the need for factor VIII. In this paper, this non-replacement strategy was evaluated in vitro and in vivo in its ability to correct factor VIII but also factor IX, X and XI deficiencies. A novel modified factor X, named Actiten, was generated and produced in the HEK293F cell line. The molecule possesses the required post-translational modifications, partially keeps its ability to be activated by RVV-X, factor VIIa/tissue factor, factor VIIIa/factor IXa and acquires the ability to be activated by thrombin. The potency of the molecule was evaluated in respective deficient plasmas or hemophilia A plasmas, for some with inhibitors. Actiten corrects dose dependently all the assayed deficient plasmas. It is able to normalize the thrombin generation at 20 μg/mL showing however an increased lagtime. It was then assayed in a rabbit antibody-induced model of hemophilia A where, in contrast to recombinant factor X wild-type, it normalized the bleeding time and the loss of hemoglobin. No sign of thrombogenicity was observed and the generation of activated factor X was controlled by the anticoagulation pathway in all performed coagulation assays. This data indicates that Actiten may be considered as a possible non replacement factor to treat hemophilia's with the advantage of being a zymogen correcting bleedings only when needed

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Speed of Sound of 2-Methylpentane, 2,3-Dimethylpentane, and 2,2,4-Trimethylpentane from (293.15 to 373.15) K and up to 150 MPa

International audienceIn this work, ultrasonic velocity measurements in the compressed liquid phase of three branched alkanes (2-methylpentane, 2,3-dimethylpentane, and 2,2,4-trimethylpentane) from (293.15 to 373.15) K and for pressures ranging up to 150 MPa are presented. These results were used to estimate various thermophysical properties such as density and isentropic or isothermal compressibilities in the same range of pressure and temperature

Nonlinear parameter (B/A) measurements in methanol, 1-butanol and 1-octanol for different pressures and temperatures

International audienceExperimental determinations versus pressure of the nonlinear acoustic parameter B/A have been conducted for methanol, 1-butanol and 1-octanol in the pressure range 0-50 MPa and temperature range 303.15-373.15 K. These measurements proceed from an experimental technique based on a phase comparison method allowing to measure the change in sound speed with the pressure for an isentropic process. The value of B/A is found to decrease with increasing pressure and seems to be an increasing function of temperature. A comparison with the data determined numerically by the classical thermodynamic method has also been performed

Measurement of the B/A nonlinearity parameter under high pressure: Application to water

International audienceAn experimental apparatus was developed to measure, over a wide range of pressure, the acoustical nonlinear parameter B/A with an uncertainty of 2.2% in order to study the influence of pressure on the value of this parameter in liquids. The experimental technique rests on an improved thermodynamic method which uses a highly sensitive phase comparison technique to measure the change in speed of sound with pressure. The apparatus was then used to measure B/A in water within the pressure range from 0.1 to 50 MPa and at temperatures of between 303.15 and 373.15 K. The data obtained were compared with those in the literature which come from numerical derivation of speed of sound measurements

Evaluation of glycerol intermolecular free lengths at different temperatures by a thermo-acoustic approach

International audienceThe mean intermolecular free length in glycerol is estimated over a wide range of temperatures by making use of thermo-acoustical parameters followed by measurements of glycerol surface tension. To achieve this objective, the glycerol surface tension is measured by using video digital image processing techniques to extract the entire experimental drop profile with subsequent numerical procedures based upon the Laplace equation of capillarity. Glycerol surface tension measurements are extended from 10°C - 90°C with a step of 10°C. The developed model for the evaluation of the glycerol intermolecular free length requires the estimate of the glycerol internal pressure which is derived, in this study, from the Tait equation by exploiting the glycerol nonlinearity parameter and further glycerol properties already measured in a previous study. The experimental results show that the mean intermolecular free length increases, with rise in temperature, from a small value. Inversely, the internal pressure decreases by increasing temperature which describes perfectly the dispersion part of cohesion and reflects the molecular ordering of glycerol versus temperature

Speed of Sound and Some Thermodynamic Properties of Liquid Methylcyclopentane and Butylcyclohexane in a Wide Range of Pressure

International audienceUltrasonic velocity measurements were performed on liquid methylcyclopentane and butylcyclohexane at pressures from atmospheric up to 150 MPa in the temperature range from 293 to 373 K using a pulse echo technique operating at 3 MHz. The data were used to evaluate various thermophysical properties such as density, and isentropic and isothermal compressibilities up to 150 MPa with the help of additional density measurements

Measurement of the acoustic nonlinearity parameter in liquid alkanes under pressure and comparison with the Lee - Kesler correlation

International audienceMeasurements of the nonlinear acoustic parameter B/A as a function of pressure and temperature have been conducted for three linear alkanes (n-pentane, n-hexane, and n-heptane) in the pressure range 0.1 to 50 MPa and temperature range 303.15 to 373.15 K. The experimental technique used is based on a phase-comparison method involving measurement of the change of the speed of sound with pressure in an isentropic process. Predictions of the nonlinear acoustic parameter based on the Lee - Kesler correlation are also presented and compared with the experimental values

Evaluation of the third order nonlinear parameter C/A for glycerol from measurements of ultrasonic velocity versus temperature and pressure

International audienceOur purpose in the present study is to evaluate the C/A values for glycerol by using a thermodynamic method. It is assumed in the developed model that the thermal conductivity of the analyzed fluid is low and the Taylor development of the state equation is extended up to the third order. The theoretical expression of the C/A parameter is developed on the basis of some thermodynamic considerations. C/A parameter is not only function of ultrasonic velocity, density, B/A parameter but also on a second partial derivation term which is obtained from the equation of ultrasonic velocity versus pressure for a given temperature. The temperature and pressure dependence of the third order nonlinear parameter for glycerol has been estimated from 10 to 100°C and from 0.1 to 100 MPa, respectively. C/A parameter is essentially determined from measurements of glycerol ultrasonic velocity versus temperature and pressure by using a high pressure measurement cell equipped with temperature and pressure monitoring and control instrumentation. A time of flight method is exploited to measure, under high pressure, the glycerol ultrasonic velocity at different temperatures. The experimental data of glycerol ultrasonic velocity combined with measurements of density and those of B/A parameter at each considered temperature and pressure are used to evaluate, under high pressure, the third order nonlinear parameter versus temperature. The present investigation shows that the third order nonlinear parameter C/A is a decreasing function of pressure. C/A values vary from positive values at low pressures to negative values above 60 MPa. The third order nonlinear parameter C/A is found to be highly dependent upon hydrostatic pressure. The accuracy of the measured C/A values is estimated at about 10%

A phase comparison technique for sound velocity measurement in strongly dissipative liquids under pressure

International audienceAn accurate technique for the sound velocity measurement in strongly dissipative liquids is elaborated. This technique is based upon high sensitive phase detection. Each medium, at a given temperature and pressure, is characterized by a specific phase shift due to the propagation of the ultrasonic wave within the analyzed medium. By tuning the insonation frequency of the ultrasonic signal, a succession of consecutive nulls of the output dc voltage generated by the phase detector is observed. Thus from the obtained series of frequency values, the sound velocity is computed. Numerous organic liquids, such as alcohols and alkanes, have been used to validate this experimental procedure. As the developed method is well suited for the sound velocity measurement in strongly dissipative liquids, measurements of compressional wave velocity in heavy oil are also carried out over the temperature range 10 °C to 50 °C. The experimental results agree well with those found in the literature. The accuracy of the developed method is estimated at about ±0.3%