Open Access in Nederland: de volgende stap

Ten gevolge van de invloed van ICT-ontwikkelingen op onderzoek en wetenschappelijke communicatie zien we een fundamentele verandering ten opzichte van het ‘papieren tijdperk’. Toegang tot wetenschappelijke kennis, informatie en data, essentieel voor hoger onderwijs en onderzoek, kan door deze technische ontwikkeling drastisch verbeterd worden. Het is binnen de instellingen de basis voor de kennisoverdracht (onderwijs) en kennisontwikkeling (onderzoek). Maar ook in de relatie met de samenleving (kennisvalorisatie) is toegang tot kennis en informatie van groot belang. Uitgangspunt is dat resultaten van met publieke middelen gefinancierd onderzoek ook publiekelijk toegankelijk dienen te zijn. De afgelopen jaren heeft Open Access een relatief hoge vlucht genomen. Vele instellingen wereldwijd (waaronder alle Nederlandse universiteiten) hebben de zgn. Berlin Declaration ondertekend, daarmee aangevend dat men Open Access van wetenschappelijke informatie actief wil bevorderen. Er is sprake van Open Access wanneer: 1. een publicatie online wordt gepubliceerd en in minimaal een online repository (een vrij toegankelijk digitaal archief) wordt opgenomen; 2. de publicatie voor iedereen met een internetverbinding kosteloos toegankelijk is en blijft; 3. de auteur de gebruiker toestemming geeft om de content te mogen (her)gebruiken voor onderzoek en onderwijs; 4. die toestemming voor (her)gebruik twee voorwaarden heeft: een correcte bronvermelding en geen plagiaat; 5. de auteur deze toestemming vooraf geeft voor het vrije, wereldwijde en onherroepelijke gebruik. Er zijn twee scenario’s m.b.t. Open Access: 1. The Green Road / Repositories: vrijwel alle universiteiten in Europa en de VS en hebben een begin gemaakt met een “institutional repository” waarin publicaties van de instelling voor iedereen toegankelijk kunnen worden ontsloten. Via harvesting kunnen vervolgens disciplinegewijs aanvullende diensten worden geleverd met het in repositories aanwezige materiaal. De universiteit van Nottingham houdt een lijst bij van alle repositories (OpenDoar). Nederland, waar alle universiteiten, dank zij het DARE project inmiddels een redelijk gevuld repository hebben, is koploper. 2. The Golden Road / Open Access Tijdschriften: dit zijn tijdschriften waar niet de lezer betaalt (in de vorm van een abonnementsprijs) maar de kosten op een andere wijze worden gedekt. Een veel voorkomende variant is dat dit geschiedt in de vorm van article processing charges (publicatiekosten, ook wel publication fees genoemd), wat betekent dat de financier/opdrachtgever voor het onderzoek betaalt

From pediatric covariate model to semiphysiological function for maturation: part I-extrapolation of a covariate model from morphine to Zidovudine

Pharmacolog

Disorder-Driven Pretransitional Tweed in Martensitic Transformations

Defying the conventional wisdom regarding first--order transitions, {\it solid--solid displacive transformations} are often accompanied by pronounced pretransitional phenomena. Generally, these phenomena are indicative of some mesoscopic lattice deformation that ``anticipates'' the upcoming phase transition. Among these precursive effects is the observation of the so-called ``tweed'' pattern in transmission electron microscopy in a wide variety of materials. We have investigated the tweed deformation in a two dimensional model system, and found that it arises because the compositional disorder intrinsic to any alloy conspires with the natural geometric constraints of the lattice to produce a frustrated, glassy phase. The predicted phase diagram and glassy behavior have been verified by numerical simulations, and diffraction patterns of simulated systems are found to compare well with experimental data. Analytically comparing to alternative models of strain-disorder coupling, we show that the present model best accounts for experimental observations.Comment: 43 pages in TeX, plus figures. Most figures supplied separately in uuencoded format. Three other figures available via anonymous ftp

Dose-linearity of the pharmacokinetics of an intravenous [C-14]midazolam microdose in children

Aims Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [C-14]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose. Methods Preterm to 2-year-old infants admitted to the intensive care unit received [C-14]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [C-14]midazolam and [C-14]1-hydroxy-midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed. Results Of 15 infants (median gestational age 39.4 [range 23.9-41.4] weeks, postnatal age 11.4 [0.6-49.1] weeks), 6 received a microtracer and 9 a microdose of [C-14]midazolam (111 Bq kg(-1); 37.6 ng kg(-1)). In a 2-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [C-14]1-OH-midazolam/[C-14]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses. Conclusion Our data support the dose linearity of the PK of an IV [C-14]midazolam microdose in children. Hence, a [C-14]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children

Dose-linearity of the pharmacokinetics of an intravenous [C-14]midazolam microdose in children

Aims Drug disposition in children may vary from adults due to age-related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [C-14]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose. Methods Preterm to 2-year-old infants admitted to the intensive care unit received [C-14]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [C-14]midazolam and [C-14]1-hydroxy-midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed. Results Of 15 infants (median gestational age 39.4 [range 23.9-41.4] weeks, postnatal age 11.4 [0.6-49.1] weeks), 6 received a microtracer and 9 a microdose of [C-14]midazolam (111 Bq kg(-1); 37.6 ng kg(-1)). In a 2-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [C-14]1-OH-midazolam/[C-14]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses. Conclusion Our data support the dose linearity of the PK of an IV [C-14]midazolam microdose in children. Hence, a [C-14]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children

D4.6 Report on the results of cycle 3 demonstrators:Aggregates internal deliverables ID4.12, ID4.13, ID4.14, ID4.15, ID4.16

Hernández-Leo, D., Sligte, H., Glahn, C., Krekels, B., Keuls, C., Louys, A., Stefanov, K., Perez, M., Chacón, J., Santos, P., Mazzetti, A., Herder, E., Maxwell, K., Kiercheben, J., Griffiths, D., & Kluijfhout, E. (2009). D4.6 - Report on the results of cycle 3 demonstrators. Aggregates internal deliverables ID4.12, ID4.13, ID4.14, ID4.15, ID4.16. TENCompetence.This document includes the evaluation results of the Cycle 3 real-life evaluation activities. A cross-analysis of the results is compiled in order to present the impact indicators of the project in terms of outreach, learning benefits, organizational implications, and business opportunities identified in these experiences. The implementations and eight business/market-relevant demonstrators conducted in collaboration with external "adopter organizations" from different countries in Europe. These external organizations are Associated Partners or different units within the partners'organization. The revised pilots and the demonstrators test the tooling achieved along DIP-3. Both pilots and business demonstrators show to provide benefits to socially- and industrially-relevant scenarios. Areas of proven special impact include adult competence developmentfor social inclusion, provision of learning paths to support competence development of distributed professionals, informal competence development, human resources personal competence development, and sharing of competence profiles between organizations to support the mobility of their professionals.The work on this publication has been sponsored by the TENCompetence Integrated Project that is funded by the European Commission's 6th Framework Programme, priority IST/Technology Enhanced Learning. Contract 027087 [http://www.tencompetence.org

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure

Aims: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. Methods: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l-1 and 0-4 failing organs) using graphical and numerical diagnostics. Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) 180%). Conclusion: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates

From pediatric covariate model to semiphysiological function for maturation: Part I-extrapolation of a covariate model from morphine to zidovudine

New approaches to expedite the development of safe and effective pediatric dosing regimens and first-in-child doses are urgently needed. Model-based approaches require quantitative functions on the maturation of different metabolic pathways. In this study, we directly incorporated a pediatric covariate model for the glucuronidation of morphine into a pediatric population model for zidovudine glucuronidation. This model was compared with a reference model that gave the statistically best description of the data. Both models had adequate goodness-of-fit plots and normalized prediction distribution errors (NPDE), similar population clearance values for each individual, and a Δobjective function value of 13 points (Δ2df). This supports our hypothesis that pediatric pharmacokinetic covariate models contain system-specific information that can be used as semiphysiological functions in pediatric population models. Further research should explore the validity of the semiphysiological function for other UDP-glucuronosyltransferase 2B7 substrates and patient populations and reveal how this function can be used for pediatric physiologically based pharmacokinetic models

Dose-linearity of the pharmacokinetics of an intravenous C-14 midazolam microdose in children

Aims: Drug disposition in children may vary from adults due to age‐related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [14C]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose. Methods: Preterm to 2‐year‐old infants admitted to the intensive care unit received [ 14C]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36 hours. Plasma concentrations of [14C]midazolam and [14C]1‐hydroxy‐midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed. Results: Of 15 infants (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), 6 received a microtracer and 9 a microdose of [14C] midazolam (111 Bq kg−1 ; 37.6 ng kg−1 ). In a 2‐compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [14C]1‐OH‐midazolam/[14C]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses. Conclusion: Our data support the dose linearity of the PK of an IV [14C]midazolam microdose in children. Hence, a [14C]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children