Assessing Dose-Exposure-Response Relationships of Miltefosine in Adults and Children using Physiologically-Based Pharmacokinetic Modeling Approach.

Miltefosine is the first and only oral medication to be successfully utilized as an antileishmanial agent. However, the drug is associated with differences in exposure patterns and cure rates among different population groups e.g. ethnicity and age (i.e., children v adults) in clinical trials. In this work, mechanistic population physiologically-based pharmacokinetic (PBPK) models have been developed to study the dose-exposure-response relationship of miltefosine in in silico clinical trials and evaluate the differences in population groups, particularly children and adults. The Simcyp population pharmacokinetics platform was employed to predict miltefosine exposure in plasma and peripheral blood mononuclear cells (PBMCs) in a virtual population under different dosing regimens. The cure rate of a simulation was based on the percentage of number of the individual virtual subjects with AUC  > 535 µg⋅day/mL in the virtual population. It is shown that both adult and paediatric PBPK models of miltefosine can be developed to predict the PK data of the clinical trials accurately. There was no significant difference in the predicted dose-exposure-response of the miltefosine treatment for different simulated ethnicities under the same dose regime and the dose-selection strategies determined the clinical outcome of the miltefosine treatment. A lower cure rate of the miltefosine treatment in paediatrics was predicted because a lower exposure of miltefosine was simulated in virtual paediatric in comparison with adult virtual populations when they received the same dose of the treatment. The mechanistic PBPK model suggested that the higher fraction of unbound miltefosine in plasma was responsible for a higher probability of failure in paediatrics because of the difference in the distribution of plasma proteins between adults and paediatrics. The developed PBPK models could be used to determine an optimal miltefosine dose regime in future clinical trials. [Abstract copyright: © 2023. The Author(s).

Identifying rail asset maintenance processes: a human-centric and sensemaking approach

Efficient asset maintenance is key for delivering services such as transport. Current rail maintenance processes have been mostly reactive with a recent shift towards exploring proactive modes. The introduction of new ubiquitous technologies and advanced data analytics facilitates the embedding of a ‘predict-and-prevent’ approach to managing assets. Successful, user-centred integration of such technology is still, however, a sparsely understood area. This study reports results from a set of interviews, based on Critical Decision Method, with rail asset maintenance and management experts regarding current procedural aspects of asset management and maintenance. We analyse and present the results from a human-centric sensemaking timeline perspective. We found that within a complex sociotechnical environment such as rail transport, asset maintenance processes apply not just at local levels, but also to broader, strategic levels that involve different stakeholders and necessitate different levels of expertise. This is a particularly interesting aspect within maintenance that has not been discussed as of yet within a process-based and timeline-based models of asset maintenance. We argue that it is important to consider asset maintenance activities within both micro (local) and macro (broader) levels to ensure reliability and stability in transport services. We also propose that the traditionally distinct notions of individual, collaborative and artefact-based sensemaking are in fact all in evidence in this sensemaking context, and argue that a more holistic view of sensemaking is therefore appropriate by placing these results within an amended Recogntion Primed Decsion making model

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

Mediators of the relation between war experiences and suicidal ideation among former child soldiers in Northern Uganda: the WAYS study

Background Globally, suicide is a public health burden especially in the aftermath of war. Understanding the processes that define the path from previous war experiences (WE) to current suicidal ideation (SI) is crucial for defining opportunities for interventions. We assessed the extent to which different types of previous WE predict current SI and whether post-war hardships and depression mediate the relations between WE and SI among former child soldiers (FCS) in Northern Uganda. Methods We performed cross-sectional analyses with a sample of 539 FCS (61% male) participating in an on-going longitudinal study. The influence of various types of previous WE on current SI and mediation by post-war hardships and depression were assessed by regression analyses. Results The following types of war experiences: “witnessing violence”, “direct personal harm”, “deaths”, “Involvement in hostilities”, “sexual abuse” and “general war experiences” significantly predicted current SI in a univariable analyses whereas “direct personal harm”, “involvement in hostilities”, and “sexual abuse” independently predicted current SI in a multivariable analyses. General WE were linked to SI (β = 0.18 (95% CI 0.10 to 0.25)) through post-war hardships (accounting for 69% of the variance in their relationship) and through depression/anxiety (β = 0.17 (95% CI 0.12 to 0.22)) accounting for 65% of the variance in their relationship. The direct relationship between previous WE and current SI reduced but remained marginally significant (β = .08, CI: (.01, .17) for depression/anxiety but not for post-war hardships (β = .09, CI: (-.03, .20). Conclusion Types of WE should be examined when assessing risks for SI. Interventions to reduce SI should aim to alleviate post-war hardships and treat depression/anxiety