Pieter Van Laer

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Distribution and Excretion of TEGDMA in Guinea Pigs and Mice

The monomer triethyleneglycoldimethacrylate (TEGDMA) is used as a diluent in many resin-based dental materials. It was previously shown in vitro that TEGDMA was released into the adjacent biophase from such materials during the first days after placement. In this study, the uptake, distribution, and excretion of 14C-TEGDMA applied via gastric, intradermal, and intravenous administration at dose levels well above those encountered in dental care were examined in vivo in guinea pigs and mice as a test of the hypothesis that TEGDMA reaches cytotoxic levels in mammalian tissues. 14C-TEGDMA was taken up rapidly from the stomach and small intestine after gastric administration in both species and was widely distributed in the body following administration by each route. Most 14C was excreted within one day as 14 CO2. The peak equivalent TEGDMA levels in all mouse and guinea pig tissues examined were at least 1000-fold less than known toxic levels. The study therefore did not support the hypothesis

Predictors of Time to Discontinuation of Levodopa-Carbidopa Intestinal Gel Infusion:A Retrospective Cohort Study

Background: Continuous intra-duodenal infusion of levodopa-carbidopa intestinal gel (LCIG) is a well-established therapy for patients with advanced Parkinson's disease (PD) suffering from motor complications despite optimized treatment with oral dopaminomimetics. However, time to discontinuation of treatment with LCIG varies considerably between patients, ranging from a few months to more than ten years. To improve the selection of candidates for LCIG, knowledge of prognostic factors is of paramount importance. Objective: To explore baseline predictors of time to discontinuation of LCIG. Methods: In this two-center retrospective cohort study, we reviewed the medical files of 98 PD patients treated with LCIG between April 2006 and December 2015 (53% male; mean age: 66.2 years; mean disease duration: 12.3 years). Baseline patient characteristics were used as covariates in Cox regression models. Results: During follow-up (mean observation time: 2.6 years; range: 0.1-9.3) eighteen patients discontinued treatment (18.4%), while seven patients died (7.1%). Median duration of treatment with LCIG, estimated with Kaplan-Meier analysis, was 7.8 years (95% CI: 6.7-9.0). Disease duration (in years) at baseline was a statistically significant predictor of time to discontinuation of LCIG (HR: 0.85; 95% CI: 0.75-0.96, p = 0.006). All other characteristics studied, e.g. age >70 years, did not show statistically significant associations with the total duration of treatment with LCIG. Conclusion: Our findings show a low overall rate of discontinuation of LCIG infusion, with a median duration of treatment of 7.8 years. Shorter disease duration at baseline appeared to be a predictor of earlier discontinuation of LCIG

A levodopa dry powder inhaler for the treatment of Parkinson's disease patients in off periods

Adequate treatment of Parkinson's patients in off periods with orally administered levodopa is hindered by a poor bioavailability and a slow onset of action. Hence, there is a need for a fast and reliable alternative as for instance via pulmonary administration of the drug. We developed a levodopa containing powder formulation for pulmonary delivery by a recently presented high dose dry powder inhaler (Cyclops). The objective was to produce the drug formulation by means of simple techniques such as micronization, either as pure active substance or with a minimum amount of excipients. After an initial screening on dispersion behaviour, the most promising formulation in the Cyclops was characterized in vitro over a range of pressure drops (2-6 kPa) and doses (20, 30 and 40 mg), representative of those to be expected in practice. A co-micronized levodopa formulation with 2% l-leucine appeared to yield the best aerosol properties for inhalation and highest delivered dose reproducibility. The combination of this particular formulation and the Cyclops inhaler seems to meet the basic requirements for satisfactory deposition in the airways. This formulation is therefore expected to be a promising candidate for the treatment of Parkinson's patients in an off period

Flight Stability and Control and Performance Results from the Linear Aerospike SR-71 Experiment (LASRE)

The Linear Aerospike SR-71 Experiment (LASRE) is presently being conducted to test a 20-percent-scale version of the Linear Aerospike rocket engine. This rocket engine has been chosen to power the X-33 Single Stage to Orbit Technology Demonstrator Vehicle. The rocket engine was integrated into a lifting body configuration and mounted to the upper surface of an SR-71 aircraft. This paper presents stability and control results and performance results from the envelope expansion flight tests of the LASRE configuration up to Mach 1.8 and compares the results with wind tunnel predictions. Longitudinal stability and elevator control effectiveness were well-predicted from wind tunnel tests. Zero-lift pitching moment was mispredicted transonically. Directional stability, dihedral stability, and rudder effectiveness were overpredicted. The SR-71 handling qualities were never significantly impacted as a result of the missed predictions. Performance results confirmed the large amount of wind-tunnel-predicted transonic drag for the LASRE configuration. This drag increase made the performance of the vehicle so poor that acceleration through transonic Mach numbers could not be achieved on a hot day without depleting the available fuel

Loslaten, maar niet overlaten. Succesvol regionaal water governance en de rol van rijkspartijen

SAMENVATTENDE CONCLUSIE: Aan de RMNO is gevraagd om een advies uit te brengen aan het Ministerie van Verkeer & Waterstaat, dat ingaat op het bestuurlijk vermogen rond watervraagstukken als onderdeel van gebiedsontwikkeling. In welke mate zijn de betrokken actoren in staat oplossingen voor watervraagstukken te realiseren? Hoe kan dit vermogen vergroot worden? Onze conclusie, aan de hand van een steekproef van zeven gebieden die we hebben onderzocht, is dat het bestuurlijk vermogen lijkt toe te nemen, maar de complexiteit van de vraagstukken ook. Er is een cumulatie van maatschappelijke wensen in gebieden, en het proces van integratie of synchronisatie van de doelen van verschillende gebiedspartijen wordt lastiger. De watergovernance is aangeland in een fase waar met name expliciet aandacht nodig is voor de manier waarop de communicatie en interactie tussen het nationaal waterbeleid en regionaal ruimtelijk beleid is vormgegeven...

IguideME: Supporting Self-Regulated Learning and Academic Achievement with Personalized Peer-Comparison Feedback in Higher Education

Personalized feedback is important for the learning process, but it is time consuming and particularly problematic in large-scale courses. While automatic feedback may help for self-regulated learning, not all forms of feedback are effective. Social comparison offers powerful feedback but is often loosely designed. We propose that intertwining meaningful feedback with well-designed peer comparison using a learning analytics dashboard provides a solution. Third-year bachelor students were randomly assigned to have access to the learning analytics dashboard IguideME (treatment, n=31) or no access (control, n=31). Dashboard users were asked to indicate their desired grade, which was used to construct peer-comparison groups. Personalized peer-comparison feedback was provided via the dashboard. The effects were studied using quantitative and qualitative data, including the Motivated Strategies for Learning Questionnaire (MSLQ) and the Achievement Goal Questionnaire (AGQ). Compared to the control group, the treatment group achieved higher scores for the MSLQ components “metacognitive self-regulation” and “peer learning,” and for the AGQ component “other-approach” (do better than others). The treatment group performed better on reading assignments and achieved higher grades for high-level Bloom exam questions. These data support the hypothesis that personalized peer-comparison feedback can be used to improve self-regulated learning and academic achievement

A population pharmacokinetic model to predict the individual starting dose of tacrolimus in adult renal transplant recipients

Aims: The aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clinical tool for selecting the best starting dose for each patient. Methods: Data on tacrolimus exposure were collected for the first 3 months following renal transplantation. A population pharmacokinetic analysis was conducted using nonlinear mixed-effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. Results: A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two-compartment model. The mean absorption rate was 3.6 h-1 , clearance was 23.0 l h-1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose: [Formula: see text] Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added value of the starting dose model. Conclusions: For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation

A Method to Exchange Recombinant Differentially Phosphorylated Rhodamine-Labeled Cardiac RLC into Permeabilized Cardiac Trabeculae

Cyclosporine, everolimus, and tacrolimus are the cornerstone of immunosuppressive therapy in renal transplantation. These drugs are characterized by narrow therapeutic windows, highly variable pharmacokinetics (PK), and metabolism by CYP3A enzymes. Recently, the decreased activity allele, CYP3A4*22, was described as a potential predictive marker for CYP3A4 activity. This study investigated the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on cyclosporine, everolimus, and tacrolimus PK in renal transplant patients. CYP3A4*22 carriers showed a significant lower clearance for cyclosporine (−15%), and a trend was observed for everolimus (−7%) and tacrolimus (−16%). Patients carrying at least one CYP3A5*1 allele had 1.5-fold higher tacrolimus clearance compared with noncarriers; however, CYP3A5*3 appeared to be nonpredictive for everolimus and cyclosporine. CYP3A combined genotype did not significantly improve prediction of clearance compared with CYP3A5*3 or CYP3A4*22 alone. These data suggest that dose individualization of cyclosporine, everolimus, or tacrolimus therapy based on CYP3A4*22 is not indicated