Development of PET tracers for in vivo imaging of active tissue transglutaminase

Windhorst, A.D. [Promotor]Lammertsma, A.A. [Promotor

Opening up towards children’s languages : enhancing teachers’ tolerant practices towards multilingualism

Mainstream teachers struggle with linguistic diversity, often leading to restricting multilingualism. Scientific research, however, recommends including pupils' home languages in school. Various qualitative studies have evaluated implementations in schools and indicated possibilities for improving teachers' attitudes towards multilingualism. This paper evaluates an experimental implementation targeting an increase in tolerance towards multilingualism. The implementation was facilitated by external school coaches and consisted of 3 experimental tools affecting the school. Data originated from 62 Flemish primary schools (of which half were experimental schools) that participated in 3 survey waves (2012 and 2014; 763 teachers completed both waves). We used multilevel regression. We concluded that the implementation leads to higher rates of tolerance. The fulfilment of the basic conditions needed for a successful change was important, and the linguistic diversity of the pupil population and the investment by external school coaches did not affect the tolerant practices of teachers towards multilingualism

Oral lorazepam can be substituted for intravenous midazolam when weaning paediatric intensive care patients off sedation

Aim: Intravenous sedatives used in the paediatric intensive care unit (PICU) need to be tapered after prolonged use to prevent ia

Does a Dose Calculator as an Add-On to a Web-Based Paediatric Formulary Reduce Calculation Errors in Paediatric Dosing? A Non-Randomized Controlled Study

OBJECTIVES: The structured digital dosing guidelines of the web-based Dutch Paediatric Formulary provided the opportunity to develop an integrated paediatric dose calculator. In a simulated setting, we tested the ability of this calculator to reduce calculation errors. METHODS: Volunteer healthcare professionals were allocated to one of two groups, manual calculation versus the use of the dose calculator. Professionals in both groups were given access to a web-based questionnaire with 14 patient cases for which doses had to be calculated. The effect of group allocation on the probability of making a calculation error was determined using generalized estimated equations (GEE) logistic regression analysis. The causes of all the erroneous calculations were evaluated. RESULTS: Seventy-seven healthcare professionals completed the web-based questionnaire: thirty-seven were allocated to the manual group and 40 to the calculator group. Use of the dose calculator resulted in an estimated mean probability of a calculation error of 24.4% (95% CI 16.3-34.8) versus 39.0% (95% CI 32.4-46.1) with use of manual calculation. The mean difference of probability of calculation error between groups was 14.6% (95% CI 3.1-26.2; p =

Ontogeny of midazolam glucuronidation in preterm infants

Purpose: In preterm infants, the biotransformation of midazolam (M) to 1-OH-midazolam (OHM) by cytochrome P450 3A4 (CYP3A4) is developmentally immature, but it is currently unknown whether the glucuronidation of OHM to 1-OH-midazolam glucuronide (OHMG) is also decreased. The aim of our study was to investigate the urinary excretion of midazolam and its metabolites OHM and OHMG in preterm neonates following the intravenous (IV) or oral (PO) administration of a single M dose. Methods: Preterm infants (post-natal age 3-13 days, gestational age 26-34 4/7 weeks) scheduled to undergo a stressful procedure received a 30-min IV infusion (n=15) or a PO bolus dose (n=7) of 0.1 mg/kg midazolam. The percentage of midazolam dose excreted in the urine as M, OHM and OHMG up to 6 h post-dose was determined. Results: The median percentage of the midazolam dose excreted as M, OHM and OHMG in the urine during the 6-h interval after the IV infusion was 0.44% (range 0.02-1.39%), 0.04% (0.01-0.13%) and 1.57% (0.36-7.7%), respectively. After administration of the PO bolus dose, the median percentage of M, OHM and OHMG excreted in the urine was 0.11% (0.02-0.59%), 0.02% (0.00-0.10%) and 1.69% (0.58-7.31%), respectively. The proportion of the IV midazolam dose excreted as OHMG increased significantly with postconceptional age (r=0.73, p <0.05). Conclusion: The glucuronidation of OHM appears immature in preterm infants less than 2 weeks of age. The observed increase in urinary excretion of OHMG with postconceptional age likely reflects the combined maturation of glucuronidation and renal function

Effects of a clinical decision support system and patient portal for preventing medication-related falls in older fallers:Protocol of a cluster randomized controlled trial with embedded process and economic evaluations (ADFICE_IT)

BackgroundFalls are the leading cause of injury-related mortality and hospitalization among adults aged ≥ 65 years. An important modifiable fall-risk factor is use of fall-risk increasing drugs (FRIDs). However, deprescribing is not always attempted or performed successfully. The ADFICE_IT trial evaluates the combined use of a clinical decision support system (CDSS) and a patient portal for optimizing the deprescribing of FRIDs in older fallers. The intervention aims to optimize and enhance shared decision making (SDM) and consequently prevent injurious falls and reduce healthcare-related costs.MethodsA multicenter, cluster-randomized controlled trial with process evaluation will be conducted among hospitals in the Netherlands. We aim to include 856 individuals aged ≥ 65 years that visit the falls clinic due to a fall. The intervention comprises the combined use of a CDSS and a patient portal. The CDSS provides guideline-based advice with regard to deprescribing and an individual fall-risk estimation, as calculated by an embedded prediction model. The patient portal provides educational information and a summary of the patient’s consultation. Hospitals in the control arm will provide care-as-usual. Fall-calendars will be used for measuring the time to first injurious fall (primary outcome) and secondary fall outcomes during one year. Other measurements will be conducted at baseline, 3, 6, and 12 months and include quality of life, cost-effectiveness, feasibility, and shared decision-making measures. Data will be analyzed according to the intention-to-treat principle. Difference in time to injurious fall between the intervention and control group will be analyzed using multilevel Cox regression.DiscussionThe findings of this study will add valuable insights about how digital health informatics tools that target physicians and older adults can optimize deprescribing and support SDM. We expect the CDSS and patient portal to aid in deprescribing of FRIDs, resulting in a reduction in falls and related injuries

Pragmatic physiologically-based pharmacokinetic modeling to support clinical implementation of optimized gentamicin dosing in term neonates and infants: proof-of-concept

IntroductionModeling and simulation can support dosing recommendations for clinical practice, but a simple framework is missing. In this proof-of-concept study, we aimed to develop neonatal and infant gentamicin dosing guidelines, supported by a pragmatic physiologically-based pharmacokinetic (PBPK) modeling approach and a decision framework for implementation.MethodsAn already existing PBPK model was verified with data of 87 adults, 485 children and 912 neonates, based on visual predictive checks and predicted-to-observed pharmacokinetic (PK) parameter ratios. After acceptance of the model, dosages now recommended by the Dutch Pediatric Formulary (DPF) were simulated, along with several alternative dosing scenarios, aiming for recommended peak (i.e., 8–12 mg/L for neonates and 15–20 mg/L for infants) and trough (i.e., &lt;1 mg/L) levels. We then used a decision framework to weigh benefits and risks for implementation.ResultsThe PBPK model adequately described gentamicin PK. Simulations of current DPF dosages showed that the dosing interval for term neonates up to 6 weeks of age should be extended to 36–48 h to reach trough levels &lt;1 mg/L. For infants, a 7.5 mg/kg/24 h dose will reach adequate peak levels. The benefits of these dose adaptations outweigh remaining uncertainties which can be minimized by routine drug monitoring.ConclusionWe used a PBPK model to show that current DPF dosages for gentamicin in term neonates and infants needed to be optimized. In the context of potential uncertainties, the risk-benefit analysis proved positive; the model-informed dose is ready for clinical implementation