Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment

Background and Objective Ceftaroline fosamil is a β-lactam antibiotic approved as a 600 mg twice daily dose (≤1 h infusion, ‘standard dosing’) or a 600 mg thrice daily dose (2 h infusion) to treat complicated skin and soft tissue infections caused by Staphylococcus aureus (minimum inhibitory concentration [MIC] 2–4 mg/L). We sought to systematically evaluate the relative impact of the three key components of the intensified dosing regimen (i.e. shortened dosing interval, prolonged infusion duration and increased total daily dose [TDD]) on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment given different grades of bacterial susceptibility. Methods A population PK model was developed using data from 12 healthy volunteers (EudraCT-2012-005134-11) receiving standard or intensified dosing. PK/PD target attainment (ƒT>MIC = 35% and 100%) after 24 h was compared following systematically varied combinations of the (1) dosing interval (every 12 h [q12h]→ every 8 h [q8h]); (2) infusion duration (1 h→2 h); and (3) individual and total daily dose (400→900 mg, i.e. TDD 1200→1800 mg), as well as for varying susceptibility of S. aureus (MIC 0.032–8 mg/L). Results A two-compartment model with linear elimination adequately described ceftaroline concentrations (n = 274). The relevance of the dosing components dosing interval/infusion duration/TDD for ƒT>MIC systematically changed with pathogen susceptibility. For susceptible pathogens with MIC ≤1 mg/L, shortened dosing intervals appeared as the main driver of the improved target attainment associated with the intensified dosing regimen, followed by increased TDD and infusion duration. For less susceptible pathogens, the advantage of q8h dosing and 2 h infusions declined, and increased TDD improved ƒT>MIC the most. Conclusion The analysis calls to mind consideration of dose increases when prolonging the infusion duration in the case of low bacterial susceptibility

Process Control for Additive Manufacturing of Concrete Components

Additive manufacturing (AM) processes offer new possibilities in the design of concrete components. The process chain for AM processes generally consists of component design, print path generation, and manufacturing. Within the step of print path generation, the component is commonly divided into layers and filled with waypoints based on the assumption of a constant cross-section of the applied material strands. In contrast to metal or plastic, however, the material properties of fresh concrete are more sensitive to environmental influences such as temperature and humidity. This leads to cross-section variations during the process. Therefore, exclusively relying on an apriori print path planning for large-scale components leads to significant deviations between as-planed and as-printed geometries. The presented research aims to increase the manufacturing accuracy of concrete components by compensating layer inconsistencies through a controlled material application. For this purpose, varying the printing speed and nozzle distance allows for correction of the deviations of subjacent layers. Deviation detection is performed by a 2D laser sensor mounted on the printing nozzle to generate information about the underlying cross-section. Comparing the measured values to precalculated setpoints generates the error values. The control algorithm maps the error data into an adaption of the printing speed and nozzle distance to fulfill the pre-planned geometry. Applying the controller to a medium-sized component and comparing the result to the uncontrolled process shows a considerable accuracy improvement. This is the accepted Version of an article published by RILEM. Readers must contact RILEM for permission to reprint or use the material in any form

Model-Informed Target Morning 17α-Hydroxyprogesterone Concentrations in Dried Blood Spots for Pediatric Congenital Adrenal Hyperplasia Patients

Monitoring cortisol replacement therapy in congenital adrenal hyperplasia (CAH) patients is vital to avoid serious adverse events such as adrenal crises due to cortisol underexposure or metabolic consequences due to cortisol overexposure. The less invasive dried blood spot (DBS) sampling is an advantageous alternative to traditional plasma sampling, especially in pediatric patients. However, target concentrations for important disease biomarkers such as 17α-hydroxyprogesterone (17-OHP) are unknown using DBS. Therefore, a modeling and simulation framework, including a pharmacokinetic/pharmacodynamic model linking plasma cortisol concentrations to DBS 17-OHP concentrations, was used to derive a target morning DBS 17-OHP concentration range of 2–8 nmol/L in pediatric CAH patients. Since either capillary or venous DBS sampling is becoming more common in the clinics, the clinical applicability of this work was shown by demonstrating the comparability of capillary and venous cortisol and 17-OHP concentrations collected by DBS sampling, using a Bland-Altman and Passing-Bablok analysis. The derived target morning DBS 17-OHP concentration range is a first step towards providing improved therapy monitoring using DBS sampling and adjusting hydrocortisone (synthetic cortisol) dosing in children with CAH. In the future, this framework can be used to assess further research questions, e.g., target replacement ranges for the entire day

Wirtschaftsbauten in der antiken Stadt

Über die Wirtschaft der Antike sind wir gut informiert. Für den Waren- und Geldverkehr standen in den Städten eigene Gebäude zur Verfügung, die im römischen Reich von Speicherbauten in bedeutenden Wirtschaftszentren und Hafenorten bis zu Bank- und Börsengebäuden an den zentralen Plätzen der Städte reichten. Diese Bauten wurden von Archäologen und Bauhistorikern vielfach untersucht, wobei Bauweise und Gestaltung im Vordergrund standen. Wirtschaftshistoriker befassten sich intensiv mit Handels- und Geldgeschäften, ohne Zusammenhänge mit Baulichkeiten in den Blick zu nehmen. Interdisziplinäre Zusammenarbeit eröffnet neue Perspektiven. Mit dem Wissen über wirtschaftliche Vorgänge lassen sich Bauten besser verstehen, und Bauwerke können ökonomische Vorgänge sichtbar machen. Das wurde beim erstmaligen Gedankenaustausch zwischen den verschiedenen Forschungsdisziplinen rasch deutlich. Der vorliegende Tagungsband enthält Beiträge über Handelsformen und Handelsbeziehungen, er stellt Speichergebäude und Kaufmannshäuser vor und beleuchtet mit dem Magdalensberg bei Kärnten ein bedeutendes Zentrum der Erzgewinnung und der Metallverarbeitung. Einen besonderen Platz nimmt die römische Basilika als großartiges Bank- und Börsengebäude ein, dessen Entwicklung um 200 v. Chr. quasi schlagartig am Forum Romanum begann und die neue Vormacht Rom als Zentrum der antiken Wirtschaft und zentrale Instanz des Wirtschafts- und Steuerrechts mit neuen Maßstäben auch städtebaulich prägte. Die beiden letzten Beiträge befassen sich mit der weiteren Entwicklung des Begriffes Basilika und seinen Nachwirkungen im Kirchenbau und in der Architekturtheorie bis heute

Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells

Background: Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations. Methods: Genome-wide forward genetic CRISPR-Cas9 based screens were performed to identify genes associated with ALK inhibitor resistance in neuroblastoma cell lines. Furthermore, the neuroblastoma cell line NBLW-R was rendered resistant by continuous exposure to ALK inhibitors. Genes identified to be associated with ALK inhibitor resistance were further investigated by generating suitable cell line models. In addition, tumor and liquid biopsy samples of four patients with ALK-mutated neuroblastomas before ALK inhibitor treatment and during tumor progression under treatment were genomically profiled. Results: Both genome-wide CRISPR-Cas9-based screens and preclinical spontaneous ALKi resistance models identified NF1 loss and activating NRASQ61K mutations to confer resistance to chemically diverse ALKi. Moreover, human neuroblastomas recurrently developed de novo loss of NF1 and activating RAS mutations after ALKi treatment, leading to therapy resistance. Pathway-specific perturbations confirmed that NF1 loss and activating RAS mutations lead to RAS-MAPK signaling even in the presence of ALKi. Intriguingly, NF1 loss rendered neuroblastoma cells hypersensitive to MEK inhibition. Conclusions: Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells

A unifying view of multiple kernel learning

*This report is free to read on the publisher's website* Recent research on multiple kernel learning has lead to a number of approaches for combining kernels in regularized risk minimization. The proposed approaches include different formulations of objectives and varying regularization strategies. In this paper we present a unifying general optimization criterion for multiple kernel learning and show how existing formulations are subsumed as special cases. We also derive the criterion's dual representation, which is suitable for general smooth optimization algorithms. Finally, we evaluate multiple kernel learning in this framework analytically using a Rademacher complexity bound on the generalization error and empirically in a set of experiments

Foam accumulators: packaging and weight reduction for mobile applications

Standardized parts like hydraulic accumulators are used in nearly every hydraulic system, in many cases even several. Therefore, even small changes in size and weight of accumulators can save considerable material costs. In mobile applications, hydraulic accumulators are used among others in hydro-pneumatic suspension systems. There is a strong focus on miniaturization and weight reduction, as the components always have to be transported with the vehicle. Energy density and energy content of conventional hydraulic accumulators cannot be maximized at the same time. This limitation can be overcome by adding a heat capacity with large surface into the gas volume of the accumulator. The heat capacity enlarges the isothermal frequency range and therefore enlarges the energy density of the accumulator at the given frequency and the given size. In this paper an experimental comparison of conventional hydraulic accumulators and accumulators with foam inserts shows, that at a specific frequency band, the stiffness of foam filled accumulators is significantly lower than of conventional accumulators. The energy density is about 11 % higher than in conventional accumulators. Consequently, a space reduction of about 18 % is possible

One dimensional unsteady model of a hydropneumatic piston accumulator based on finite volume method

Hydraulic piston accumulators play a major role especially within the field of stationary hydraulics. The calculation of the amount of hydraulic energy which can be stored in such an accumulator is crucial when it comes to a precise system design. The knowledge of the temperature and pressure within the accumulator is required in order to calculate the amount of energy to be stored. The state of the art solution to estimate the state of change of such an accumulator is the implementation of a costly measurement system within the accumulator which tracks the position of the piston. The goal of this paper is to develop and to analyse a time efficient simulation approach for the gaseous phase within a piston accumulator depending on the accumulator’s load cycle. Temperature, pressure, density and velocity profiles inside of the gaseous phase are calculated transiently in order to achieve that goal. The simulation model is derived in one dimensional environment to save computational effort. Having derived a valid model of the gaseous phase it will be possible in future works to replace the expensive position measurement system by pressure and temperature transducers and then use the model to calculate the position of the piston and therefore estimate the state of change