Description of a clinical decision support tool with integrated dose calculator for paediatrics

Medication errors, especially dosing errors are a leading cause of preventable harm in paediatric patients. The paediatric patient population is particularly vulnerable to dosing errors due to immaturity of metabolising organs and developmental changes. Moreover, the lack of clinical trial data or suitable drug forms, and the need for weight-based dosing, does not simplify drug dosing in paediatric or neonatal patients. Consequently, paediatric pharmacotherapy often requires unlicensed and off-label use including manipulation of adult dosage forms. In practice, this results in the need to calculate individual dosages which in turn increases the likelihood of dosing errors. In the age of digitalisation, clinical decision support (CDS) tools can support healthcare professionals in their daily work. CDS tools are currently amongst the gold standards in reducing preventable errors. In this publication, we describe the development and core functionalities of the CDS tool PEDeDose, a Class IIa medical device software certified according to the European Medical Device Regulation. The CDS tool provides a drug dosing formulary with an integrated calculator to determine individual dosages for paediatric, neonatal, and preterm patients. Even a technical interface is part of the CDS tool to facilitate integration into primary systems. This enables the support of the paediatrician directly during the prescribing process without changing the user interface. Conclusion: PEDeDose is a state-of-the-art CDS tool for individualised paediatric drug dosing that includes a certified calculator

Impact of a clinical decision support system on paediatric drug dose prescribing: a randomised within-subject simulation trial

BACKGROUND Drug dosing errors are among the most frequent causes of preventable harm in paediatrics. Due to the complexity of paediatric pharmacotherapy and the working conditions in healthcare, it is not surprising that human factor is a well-described source of error. Thus, a clinical decision support system (CDSS) that supports healthcare professionals (HCP) during the dose prescribing step provides a promising strategy for error prevention. METHODS The aim of the trial was to simulate the dose derivation step during the prescribing process. HCPs were asked to derive dosages for 18 hypothetical patient cases. We compared the CDSS PEDeDose, which provides a built-in dose calculator to the Summary of Product Characteristics (SmPC) used together with a pocket calculator in a randomised within-subject trial. We assessed the number of dose calculation errors and the time needed for calculation. Additionally, the effect of PEDeDose without using the built-in calculator but with a pocket calculator instead was assessed. RESULTS A total of 52 HCPs participated in the trial. The OR for an erroneous dosage using the CDSS as compared with the SmPC with pocket calculator was 0.08 (95% CI 0.02 to 0.36, p<0.001). Thus, the odds of an error were 12 times higher while using the SmPC. Furthermore, there was a 45% (95% CI 39% to 51%, p<0.001) time reduction when the dosage was derived using the CDSS. The exploratory analysis revealed that using only PEDeDose but without the built-in calculator did not substantially reduce errors. CONCLUSION Our results provide robust evidence that the use of the CDSS is safer and more efficient than manual dose derivation in paediatrics. Interestingly, only consulting a dosing database was not sufficient to substantially reduce errors. We are confident the CDSS PEDeDose ensures a higher safety and speeds up the prescribing process in practice

Erythropoietin regulates developmental myelination in the brain stimulating postnatal oligodendrocyte maturation

Myelination is a process tightly regulated by a variety of neurotrophic factors. Here, we show—by analyzing two transgenic mouse lines, one overexpressing EPO selectively in the brain Tg21(PDGFB-rhEPO) and another with targeted removal of EPO receptors (EPORs) from oligodendrocyte progenitor cells (OPC)s (Sox10-cre;EpoRfx/fx mice)—a key function for EPO in regulating developmental brain myelination. Overexpression of EPO resulted in faster postnatal brain growth and myelination, an increased number of myelinating oligodendrocytes, faster axonal myelin ensheathment, and improved motor coordination. Conversely, targeted ablation of EPORs from OPCs reduced the number of mature oligodendrocytes and impaired motor coordination during the second postnatal week. Furthermore, we found that EPORs are transiently expressed in the subventricular zone (SVZ) during the second postnatal week and EPO increases the postnatal expression of essential oligodendrocyte pro-differentiation and pro-maturation (Nkx6.2 and Myrf) transcripts, and the Nfatc2/calcineurin pathway. In contrast, ablation of EPORs from OPCs inactivated the Erk1/2 pathway and reduced the postnatal expression of the transcripts. Our results reveal developmental time windows in which EPO therapies could be highly effective for stimulating oligodendrocyte maturation and myelination

Keeping up with dynamics of next generation missiles

ABSTRACT In an effort to comply with the increasing quest for higher dynamics and increased inertia of test units modern HWILsystems are employing increasingly larger hydraulic actuators. A new 3-axis flight motion simulator with increased performance is reviewed. Also future trends of the HWIL-systems are discussed both for hydraulic and electric actuators. Some drawbacks of hydraulic systems, including increased acoustic noise levels and extensive service and maintenance requirements from the hydraulic power unit, limited stroke of the actuators for large systems and poor small signal performance are discussed and compared to the performance of electric actuators. Can the electric actuators advantages make up for the power density performance gap

Keeping up with dynamics of next generation missiles

ABSTRACT In an effort to comply with the increasing quest for higher dynamics and increased inertia of test units modern HWILsystems are employing increasingly larger hydraulic actuators. A new 3-axis flight motion simulator with increased performance is reviewed. Also future trends of the HWIL-systems are discussed both for hydraulic and electric actuators. Some drawbacks of hydraulic systems, including increased acoustic noise levels and extensive service and maintenance requirements from the hydraulic power unit, limited stroke of the actuators for large systems and poor small signal performance are discussed and compared to the performance of electric actuators. Can the electric actuators advantages make up for the power density performance gap

Competition between market-making Intermediaries

Abstract We introduce capacity constrained competition between market-making intermediaries in a model in which agents can choose between trading with intermediaries, joining a search market or remaining inactive. Recently, market-making by a monopolistic intermediary has been analyzed by Keywords: Market-making, capacity constrained competition, market microstructure. JEL-Classification: C72, D41, D43, L13. * Economics Department, University of Bern, Vereinsweg 23, CH-3012 Bern Email: [email protected] This is a preliminary version of chapter 2 of my PhDthesis. I want to thank Ernst Baltensperger, Esther Brügger, Alain Egli, Thomas Gehrig, Christian Ghiligno, Armin Hartmann, Roland Hodler, Michael Manz, Gerd Mühlheusser JeanCharles Rochet, Yves Schneider and Manuel Wälti for valuable comments and discussions. Any remaining errors are mine

Plasticity of the β-Trefoil Protein Fold in the Recognition and Control of Invertebrate Predators and Parasites by a Fungal Defence System

Discrimination between self and non-self is a prerequisite for any defence mechanism; in innate defence, this discrimination is often mediated by lectins recognizing non-self carbohydrate structures and so relies on an arsenal of host lectins with different specificities towards target organism carbohydrate structures. Recently, cytoplasmic lectins isolated from fungal fruiting bodies have been shown to play a role in the defence of multicellular fungi against predators and parasites. Here, we present a novel fruiting body lectin, CCL2, from the ink cap mushroom Coprinopsis cinerea. We demonstrate the toxicity of the lectin towards Caenorhabditis elegans and Drosophila melanogaster and present its NMR solution structure in complex with the trisaccharide, GlcNAcβ1,4[Fucα1,3]GlcNAc, to which it binds with high specificity and affinity in vitro. The structure reveals that the monomeric CCL2 adopts a β-trefoil fold and recognizes the trisaccharide by a single, topologically novel carbohydrate-binding site. Site-directed mutagenesis of CCL2 and identification of C. elegans mutants resistant to this lectin show that its nematotoxicity is mediated by binding to α1,3-fucosylated N-glycan core structures of nematode glycoproteins; feeding with fluorescently labeled CCL2 demonstrates that these target glycoproteins localize to the C. elegans intestine. Since the identified glycoepitope is characteristic for invertebrates but absent from fungi, our data show that the defence function of fruiting body lectins is based on the specific recognition of non-self carbohydrate structures. The trisaccharide specifically recognized by CCL2 is a key carbohydrate determinant of pollen and insect venom allergens implying this particular glycoepitope is targeted by both fungal defence and mammalian immune systems. In summary, our results demonstrate how the plasticity of a common protein fold can contribute to the recognition and control of antagonists by an innate defence mechanism, whereby the monovalency of the lectin for its ligand implies a novel mechanism of lectin-mediated toxicity

Caenorhabditis elegans N-glycan Core β-galactoside Confers Sensitivity towards Nematotoxic Fungal Galectin CGL2

The physiological role of fungal galectins has remained elusive. Here, we show that feeding of a mushroom galectin, Coprinopsis cinerea CGL2, to Caenorhabditis elegans inhibited development and reproduction and ultimately resulted in killing of this nematode. The lack of toxicity of a carbohydrate-binding defective CGL2 variant and the resistance of a C. elegans mutant defective in GDP-fucose biosynthesis suggested that CGL2-mediated nematotoxicity depends on the interaction between the galectin and a fucose-containing glycoconjugate. A screen for CGL2-resistant worm mutants identified this glycoconjugate as a Galβ1,4Fucα1,6 modification of C. elegans N-glycan cores. Analysis of N-glycan structures in wild type and CGL2-resistant nematodes confirmed this finding and allowed the identification of a novel putative glycosyltransferase required for the biosynthesis of this glycoepitope. The X-ray crystal structure of a complex between CGL2 and the Galβ1,4Fucα1,6GlcNAc trisaccharide at 1.5 Å resolution revealed the biophysical basis for this interaction. Our results suggest that fungal galectins play a role in the defense of fungi against predators by binding to specific glycoconjugates of these organisms