Experimental study of the flow field in patient specific lower airways

In this study Particle Image Velocimetry (PIV) is used to visualize and measure airflow in the lower airways. Using Rapid Prototyping Manufacturing (RPM) technology, a hydraulic in vitro model was developed and constructed. Preliminary 2D PIV measurements compared successfully to Computational Fluid Dynamics (CFD) results

In Vitro Flow Modelling for Mitral Valve Leakage Quantification

In this study particle image velocimetry (PIV) is used to measure and visualise the blood flow through a leaking mitral heart valve. The results are compared with the results from Doppler echocardiography and computational fluid dynamics (CFD). Using CAD, five-axis milling and Rapid Prototyping Machining (RPM) technology, a hydraulic in vitro flow model was developed and constructed which is compatible with flow investigation with 2D normal speed PIV and 2D Doppler echocardiography. The same CAD model was used to conduct the CFD analysis. PIV results compared successfully with Doppler echo and CFD results, both in the upstream converging region and downstream the turbulent regurgitated jet zone. These results are expected to improve the assessment of mitral valve regurgitation severity with Doppler echocardiography in clinical practice

Functional imaging on patient-specific lower airways using Computational Fluid Dynamics

Adding functional information to anatomical CT-data by means of Computational Fluid Dynamics (CFD) is a non-invasive method for analyzing patient-specific respiratory dynamics. As CFD is based on numerical models, validation is required to obtain reliable results. For this purpose, 2D PIV measurements are performed and compared to the CFD data

МОДЕЛІ ЕКОНОМІЧНОЇ ДІЯЛЬНОСТІ ЛЮДИНИ В СУЧАСНИХ ЕКОНОМІЧНИХ ТЕОРІЯХ

We consider human's economical activity models in neoclassical, institutional, and evolutional theories. Development of the interdisciplinary synthesis of ideas of human's activity in economics is analyzed. В статье рассматриваются модели экономической деятельности человека в неоклассической, институциональной и эволюционной теориях. Раскрываются поиски междисциплинарного синтеза представлений о деятельности человека в экономике. У статті розглядаються моделі економічної діяльності людини в неокласичній, інституціональній та еволюційній теоріях. Розкриваються пошуки міждисциплінарного синтезу уявлень про діяльність людини в економіці

Ends and means: experts debate the democratic oversight of the UK’s intelligence services

Revelations from Edward Snowden about the scope of intelligence activities in the UK have led to renewed attempts to enhance democratic oversight of the UK’s security services. The heads of MI5, MI6 and GCHQ appeared before the Intelligence and Security Committee for the first time, while Lord Macdonald called for strengthened parliamentary accountability. In this post, we ask democracy and security experts to consider the need for further reform

Pediatric pharmacology of desmopressin in children with enuresis : a comprehensive review

Desmopressin is a synthetic analogue of the natural antidiuretic hormone arginine vasopressin. Over the years, it has been clinically used to manage nocturnal polyuria in children with enuresis. Various pharmaceutical formulations of desmopressin have been commercialized for this indication-nasal spray, nasal drops, oral tablet and oral lyophilizate. Despite the fact that desmopressin is a frequently prescribed drug in children, its use and posology is based on limited pediatric data. This review provides an overview of the current pediatric pharmacological data related to the different desmopressin formulations, including their pharmacokinetics, pharmacodynamics and adverse events. Regarding the pharmacokinetics, a profound food effect on the oral bioavailability was demonstrated as well as different plasma concentration-time profiles (double absorption peak) of the desmopressin lyophilizate between adults and children. Literature about maturational differences in distribution, metabolism and excretion of desmopressin is rather limited. Regarding the pharmacodynamics, formulation/dose/food effect and predictors of response were evaluated. The lyophilizate is the preferred formulation, but the claimed bioequivalence in adults (200 mu g tablet and 120 mu g lyophilizate), could not be readily extrapolated to children. Prescribing the standard flat-dose regimen to the entire pediatric population might be insufficient to attain response to desmopressin treatment, whereby dosing schemes based on age and weight were proposed. Moreover, response to desmopressin is variable, whereby complete-, partial- and non-responders are reported. Different reasons were enumerated that might explain the difference in response rate to desmopressin observed: different pathophysiological mechanisms, bladder capacity and other predictive factors (i.e. breast feeding, familial history, compliance, sex, etc.). Also, the relapse rate of desmopressin treatment was high, rendering it necessary to use a pragmatic approach for the treatment of enuresis, whereby careful consideration of the position of desmopressin within this treatment is required. Regarding the safety of the different desmopressin formulations, the use of desmopressin was generally considered safe, but additional measures should be taken to prevent severe hyponatremia. To conclude the review, to date, major knowledge gaps in pediatric pharmacological aspects of the different desmopressin formulations still remain. Additional information should be collected about the clinical relevance of the double absorption peak, the food effect, the bioequivalence/therapeutic equivalence, the pediatric adapted dosing regimens, the study endpoints and the difference between performing studies at daytime or at nighttime. To fill in these gaps, additional well designed pharmacokinetic and pharmacodynamic studies in children should be performed

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase study

Background: Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. Methods: This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). Findings: Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0.0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0.43 [95% CI 0.32-0.58]; median progression-free survival 14.6 months [95% CI 10.4-not estimable] vs 6.2 months [4.2-7.9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). Interpretation: Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma

In vivo contribution of deoxynivalenol-3-β-D-glucoside to deoxynivalenol exposure in broiler chickens and pigs: oral bioavailability, hydrolysis and toxicokinetics

Crossover animal trials were performed with intravenous and oral administration of deoxynivalenol-3-β-D-glucoside (DON3G) and deoxynivalenol (DON) to broiler chickens and pigs. Systemic plasma concentrations of DON, DON3G and de-epoxy-DON were quantified using liquid chromatography-tandem mass spectrometry. Liquid chromatography coupled to high-resolution mass spectrometry was used to unravel phase II metabolism of DON. Additionally for pigs, portal plasma was analysed to study presystemic hydrolysis and metabolism. Data were processed via tailor-made compartmental toxicokinetic models. The results in broiler chickens indicate that DON3G is not hydrolysed to DON in vivo. Furthermore, the absolute oral bioavailability of DON3G in broiler chickens was low (3.79 ± 2.68 %) and comparable to that of DON (5.56 ± 2.05 %). After PO DON3G administration to pigs, only DON was detected in plasma, indicating a complete presystemic hydrolysis of the absorbed fraction of DON3G. However, the absorbed fraction of DON3G, recovered as DON, was approximately 5 times lower than after PO DON administration, 16.1 ± 5.4 compared with 81.3 ± 17.4 %. Analysis of phase II metabolites revealed that biotransformation of DON and DON3G in pigs mainly consists of glucuronidation, whereas in chickens predominantly conjugation with sulphate occurred. The extent of phase II metabolism is notably higher for chickens than for pigs, which might explain the differences in sensitivity of these species to DON. Although in vitro studies demonstrate a decreased toxicity of DON3G compared with DON, the species-dependent toxicokinetic data and in vivo hydrolysis to DON illustrate the toxicological relevance and consequently the need for further research to establish a tolerable daily intake