bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Two-Dimensional Transient Computational Multi-Physics Model for Analyzing Magnetic and Non-Magnetic Particle (Red Blood Cells and E. Coli Bacteria) Dynamics in a Traveling Wave Ferro-Magnetic Microfluidic Device for Potential Cell Separation and Sorting
Authors: Hewlin Rodward L. , Edwards Maegan , Smith Michael S. 
Published: May 2023

Abstract
This paper presents the theory and development, validation, and results of a transient computational multiphysics model for analyzing the magnetic field, particle dynamics, and capture efficiency of magnetic and nonmagnetic (e.g., Red Blood Cells and E. Coli bacteria) microparticles in a traveling wave ferromagnetic microfluidic device. This computational model demonstrates proof-of-concept of a method for greatly enhancing magnetic bioseparation in ferromicrofluidic systems using an array of copper conductive elements arranged in quadrature to create a periodic potential energy landscape. In contrast to previous works, our approach theoretically uses a microfluidic device with an electronic chip platform consisting of integrated copper electrodes that carry currents to generate programable magnetic field gradients locally. Alternating currents are applied to the electrodes in quadrature (using a 90 deg phase change from the neighboring electrode) to create a periodic magnetic field pattern that travels along the length of the microchannel. Our previous work evaluated magnetic and nonmagnetic particles in a static magnetic field within the same channel geometry. This work is a phase 2 study that expands on the previous work and analyzes the dynamics of magnetic and nonmagnetic entities characterized by material magnetic susceptibility in a transient magnetic field. This is an improvement over our previous work. The model, which is described in more detail in the methods section, combines a Eulerian-Lagrangian and two-way particle-fluid coupling CFD analysis with closed-form magnetic field analysis that is used to predict magnetic separation considering dominant magnetic and hydrodynamic forces similar to our previous works in magnetic drug targeting. The model was also validated with an experimental low frequency stationary flow study on separating nonmagnetic latex fluorescent particles in a water based ferrofluid. The results from the experimental study and the developed model demonstrate that the proposed device may potentially be used as an effective platform for microparticle and cellular manipulation and sorting. The developed multiphysics model could potentially be used as a design optimization tool for traveling wave ferromicrofluidic devices.
Output Estimation and Failure Detection in Cantilever Bimorph Actuator Using Transmissibility Operators
Authors: Khalil Abdelrahman , Al Saaideh Mohammad , Al Janaideh Mohammad , Rakotondrabe Micky 
Published: May 2023

Abstract
In this article, we investigate how to identify faulty sensors in piezoelectric actuators used for precise positioning. Four sensors are distributed along the actuator’s cantilever structure to measure the deflection (displacement) at various points. We suggest identifying the sensor and detecting the fault in one of the sensors, which is thought to be faulty or producing a degraded signal. To address this, we suggest using transmissibility operators, which are mathematical estimators that estimate sensor measurements based on another set of sensor measurements within the same system. This estimation is highly robust against any external excitations/disturbances, as well as any unknown nonlinearities or unmodeled dynamics. The estimation robustness allows failure detection to be carried out even in significant actuator hysteresis nonlinearity and outside disturbance. Simulation results with various sensor fault conditions verified the suggested strategy.
10 Paediatric clinical trial needs and requirements within Belgium
Authors: Degraeuwe Eva , Persijn Laura , Nuytinck Lieve , Raes Ann , Turner Mark , Vande Walle Johan 
Published: May 2023

IntroductionDue to the Paediatric Regulation in 2007, the number of paediatric clinical trials within Europe has substantially increased. Consequently, potential sites for paediatric clinical trials were overrun by trial opportunities, infrastructure pressure and their limited experience. To support sites and facilitate research, the pan-European network conect4children (c4c) was established and funded by the Innovative Medicines Initiative (IMI2). In order to attain sustainable research networks, site requirements innovation needs require further investigation.MethodsA questionnaire was conducted within the c4c Belgian Clinical trial network. An inquiry was made into the role of a national hub and other topics for support. Due to multiple responses per site, answers were grouped per site.ResultsOf the 15 connected sites, we received 32 responses coming from 13 unique sites. Within the Belgian network, around 4 (30%) of sites do not have a paediatric clinical trial unit to support trials. All sites agreed or strongly agreed that a national hub is useful for the site to conduct clinical trials. The majority namely 11 (84%) of sites identified human resources as a core improvement need for sites, specifically finding dedicated clinical research nurses and finding time for principal investigators (PI) to perform study tasks aside from clinical work. A strong need for financing of infrastructure from 10 (76%) of sites is acknowledged for consultation areas, imaging, and a biobank structure.ConclusionsIn order to foster sustainable development of new medicines in paediatric diseases, site need’s must to be taken into account and prioritized. The primary need is in human resources and financing of infrastructure.
11 Clinical, methodological and patient/parent expert advice in paediatric drug development via conect4children
Authors: Mahler Fenna , Cheng Katharine , Lutsar Irja , Nafria Escalera Begonya , Turner Mark , de Wildt Saskia 
Published: May 2023

IntroductionChildren have the right to new and improved medicines.conect4children (c4c) aims to promote innovative trial design to optimise paediatric development plans while ensuring the voice of young patients and their families is heard. To address this a multidisciplinary advice service was set upMethodsA network of Experts, divided into Expert Groups, was set-up via an open call for Experts. In parallel a Patient and Public Involvement (PPI) database was formed to include the expert opinion of paediatric patients and their parents. Advice is given according to the following process: (1) Sponsors contact c4c (2) a scoping interview is held (3) formation of ad-hoc Strategic Feasibility Advice Group (5) an advice meeting is held (6) an advice report is provided. To continuously improve this process, feedback from Experts and requestors on the service was collectedResults24 clinical and innovative methodology Expert Groups, consisting of >300 Experts, diverse in gender, seniority and geographical location were established. The PPI database includes registrations in 4 subgroups. To date (Dec 2021) 30 advice requests were received from academia and industry and 23 have been completed. Clinical, methodology and PPI Experts participated in several of these requests. Sponsors appreciated the diversity of the Expert Groups as well as the quality of the advice which in many cases significantly contributed to shaping the paediatric development strategy. Experts and PPI participants were satisfied with the advice processConclusionsc4c has shown a successful proof of concept for a European, multidisciplinary, advice service for paediatric drug development, tailored to industry and academia. This service presents a new framework for innovative and feasible paediatric trials
12 Collaboration in neonatal and paediatric clinical pharmacology: creating a peer-based mentoring platform in a pan-European clinical trial network
Authors: Degraeuwe Eva , van der Geest Tessa , Persijn Laura , Montero Campos Esther , Turner Mark , Vande Walle Johan 
Published: May 2023

IntroductionIn recent years, substantial improvements in clinical trial facilitation have been made through a pan-European network conect4children (c4c), funded by the Innovative Medicines Initiative 2. Within c4c, collaboration and experience-based teaching were attainable due to live meetings and structured social interactions. Since the COVID-19 pandemic, meeting platforms were limited and strictly virtual, creating an artificial communication environment and a gap for young talent to interact and learn.MethodsIn light of c4c’s main objective to build strong collaborations and connections between different national clinical trial networks, the younger generation was in need of support. In May 2021, the young investigators community (YIC) platform was launched to facilitate an informal teaching and connecting vehicle. However, interaction with the experienced and leading generation was lacking, in order to mentor the ‘starters’ for a durable network.ResultsWithin the first year, the YIC created an open platform in which the 32 members could interact on a regular basis. Topics included involving medical students, how to build and prepare sustainable business plans and working and interacting with industry partners. Inspired by Erasmus+ funded Pathway project and McBride at al (2017) Mentorship profiling, a 4-page intake questionnaire for both mentor and mentee has been designed, that focuses on specific skills and a plan-of-action for the mentorship session, maximizing efficiency of the interaction.ConclusionWithin YIC, a questionnaire was designed to approach mentor and mentee selection, to be used to minimize the gap between young talent and the established community. The method could be beneficial to other national and international network
15 The relation between the serum trough concentration of paracetamol and pain reduction in preterm and term neonates: a retrospective observational study
Authors: van den Berg Roland B , Céleste Laarman AR , Dijkstra Jacob A , Veldkamp Agnes I , Swart Eleonora L , van Weissenbruch Mirjam M 
Published: May 2023

Measuring concentrations of paracetamol could be a strategy to optimize the treatment of pain. It is not known if the serum trough concentration of paracetamol at steady state conditions could predict a decrease in pain scores in preterm and term neonates. Low trough concentration can result in inadequate pain relief. The aim of this study was to determine the association between the serum trough concentration of paracetamol and pain reduction in preterm and term neonates.In this retrospective observational study a hospital database was used to select neonates who were treated with at least 48 hours of paracetamol intravenously or rectally. Linear regression was performed to determine if serum trough concentration of paracetamol at steady state conditions was a predictor for pain reduction. Pain reduction was defined as the difference between COMFORTneo scores before administration and after the fifth administration of paracetamol.21 neonates were included for determining the association between serum trough concentration paracetamol and pain reduction. The median (IQR) of serum trough concentration of paracetamol after the fifth dose was 4.5 mg/L (2.7–8.5 mg/L). At steady state conditions the serum trough concentration of paracetamol was not a significant predictor of pain reduction in preterm and term neonates (p = 0.79 for preterm neonates and p = 0.49 for term neonates).No association was found between the serum trough concentration of paracetamol at steady state conditions and pain reduction in preterm and term neonates. The absence of a significant association could be due to inadequate trough concentrations paracetamol. Further research is needed to investigate the association between serum trough concentrations paracetamol of ≥ 10 mg/L and pain reduction.
21 Physiologically based pharmacokinetic model to simulate midazolam pharmacokinetics in a paediatric US population
Authors: Johnson Trevor , Kondowe Fiskani , Gardner Iain 
Published: May 2023

There has been a lot of academic and regulatory interest regarding bridging clinical trials between different populations. The aims of this study were to:Develop a PBPK model for the US paediatric population (USPP) incorporating demographic and CYP3A5 phenotype frequency of different ethnic groups (White, Hispanic, Black and Asian).Apply the USPP to predict midazolam pharmacokinetics (PK) of a clinical study performed in the US.Demographic information, height for age and weight for height relationships, and CYP3A5 phenotype frequencies were established for each US ethnic group using NHANES and literature data. Four separate US paediatric PBPK populations were defined within the Simcyp Simulator (v21).Simulations of IV and oral midazolam PK were made in the USPP and a North European paediatric population (NECP) and compared with the clinical study. The reported trial design was matched as closely as possible and 400 subjects, 0.5 female, age 0.5 to 16y were run for each population.For a 0.25mg/kg oral dose, the predicted AUC0-inf was 143±109 and 225±136 ng/ml.h and Cmax was 57.4 and 79.4ng/ml for the USPP and NECP, respectively. The observed AUC0-inf and Cmax was 137±86 ng/ml.h and 55.6ng/ml, respectively. The predicted AUC was 195, 115, 150 and 135 ng/ml.h for the White, Black, Hispanic and Asian USPP and Cmax was 72, 48, 58 and 54ng/ml, respectively.Prediction of midazolam PK was improved by including the different ethnic groups for the USPP. However, significant differences can be observed between these groups for drugs where elimination changes due to phenotypic enzyme expression (e.g. CYP3A5) and it is important that clinical studies present this information.
26 Introduction of the project of the czech drug database in neonatology and pediatrics in 2022
Authors: Pavlíková Sabina , Rozsívalová Petra , Kulíšek Petr , Pokorná Pavla 
Published: May 2023

IntroductionEvidence-based (EB) data on various medicaments and safe drug dosing in pediatric population are already available across Europe. However, their systematic translation and clear processing are lacking in daily pediatric clinical practice in the Czech Republic. The purpose of our work is the development of a Czech drug database similar to some already existing internationally based formulary lists.MethodsA systematic approach to the processing of recommended dosages of drugs used in the Czech environment, all compiled in the Czech language. The active substances will be arranged according to the ATC classification system. The strategy of the initial focus on the most commonly used drugs is set (the statistical data will be obtained from SÚKL), more rarely used drugs will be approached subsequently. The server-side system will be based on PHP and MySQL technologies, enabling easy scalability and deployment to a wide range of servers, including the ability to deploy to scalable servers with a load balancer front-end server.ResultsIn 2022, the Czech team managed to obtain support for the creation of a database called Gama 2 project TP01010040, supported by The Centre for Knowledge and Technology Transfer of Charles University (EudraCT#). As expected, the database will be developed in the most appropriate data processing framework and validated throughout the year.ConclusionsThe Gama 2 database project aims to extrapolate strictly EB data systematically processed according to ATC groups into the Czech environment, where it will become a unique reference for safe prescribing, dispensing and administration of drugs in pediatric population. When processed in the Czech language, this might be beneficial for healthcare providers in Czech medical facilities.
3 The exposure to and efficacy of doravirine in pregnant women as assessed by physiologically-based pharmacokinetic modelling
Authors: van Hove Hedwig , Bukkems Vera , Roelofsen Damian , Freriksen Jolien , van Drongelen Joris , Svensson Elin , Colbers Angela , Greupink Rick 
Published: May 2023

IntroductionDoravirine is currently not recommended for pregnant women living with HIV due to the lack of efficacy and safety data. Physiological changes during pregnancy can significantly decrease drug exposure, and, thereby, lower the efficacy. Awaiting clinical data, this study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically-based pharmacokinetic (PBPK) modelling.MethodsAn existing and validated three-compartment PBPK model of doravirine for a healthy, non-pregnant population was modified to a 18-compartment PBPK model using Simcyp Simulator V20. The permeability-limited placenta model was included in the extended PBPK model to study placental transfer to the fetus. To parameterize the placenta model, ex vivo human cotyledon perfusion experiments were performed, and a mechanistic model was developed to derive placental transfer constants. The final pregnancy PBPK model was used to predict the maternal and fetal geometric mean (GM) concentration at 24h after dosing (C24h) at 26, 32 and 40 weeks of pregnancy. The GM C24h was compared to the target derived from in vivo exposure-response analysis of 0.23 mg/L.ResultsPerfusion experiments showed that doravirine extensively crosses the placenta. In comparison to non-pregnant women, the final pregnancy PBPK model estimated a maternal decrease in GM C24h of 55% for 40 weeks pregnancy. All predicted maternal GM C24h were <0.23 mg/L.ConclusionsSubstantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine, and the use should preferentially be restricted to clinical trials.
32 Rapid drop in midazolam concentration may be linked to paediatric delirium in critically ill children – an observational pilot study
Authors: Marongiu Sabrina , Bolhuis Mathieu , Touw Daan , Kneyber Martin 
Published: May 2023

IntroductionWe sought to detect a relationship between midazolam concentration and development of new delirium in critically ill children who were on continuous midazolam administration.MethodsDelirium was detected using the Sophia Observation withdrawal Symptoms - Paediatric Delirium (SOS-PD) score and 104 left-over samples were available to measure midazolam concentrations.ResultsTwenty-five percent of the included patients developed new delirium. Median cumulative midazolam dose was higher in patients who developed delirium compared to those without delirium but lower compared with the day preceding delirium detection, indicative of a rapid decline. Similar findings were made when active metabolites 1-hydroxymidazolam and 1-hydroxymidazolam glucuronide were considered.ConclusionsA sudden and significant reduction in midazolam concentration may contribute to the development of a delirium in critically ill children.
4 Risks associated with antidepressants in patients with hypertension during pregnancy: a retrospective cohort study
Authors: Ter Horst Peter , Oude Weernink Marlieke , Damer Elvera , Edens Mireille , Hemels Marieke 
Published: May 2023

IntroductionGiven the proportion of pregnant women with gestational hypertension or pre-eclampsia using an antidepressant we aimed to gain insight into the effects concerning for both mother and neonate especially on birth weight, APGAR score, and pregnancy duration.Study designRetrospective cohort study of women with hypertension disorders, whether or not using antidepressants.Main outcome measures: Birth weight, APGAR score, admittance to Obstetrical High Care unit (OHC) and or Neonatal Intensive Care Unit and pregnancy durationResultsThe use of antidepressants was associated with lower APGAR scores at 10 minutes, p= 0.008, OR = 2.298; 95% CI 1.255–4.273, compared to neonates from mothers without antidepressants. Women using antidepressants were more often admitted to the OHC (crude OR= 1.95; p=0.049; 95% CI 0.99–3.77). Multivariable logistic regression analysis revealed that thyroid disease and preterm ending of pregnancy contributed to the model, where use of antidepressants remained significant (OR=6.28; 95% CI 2.32–18.31).ConclusionsWomen with hypertension disorders during pregnancy and using antidepressants might have an increased risk for complications leading to OHC admission.
7 Collaboration in neonatal and paediatric clinical pharmacology: involving medical students within (Inter)national clinical trial networks
Authors: Pavlíková Sabina , Degraeuwe Eva , van der Geest Tessa , Persijn Laura , Skovby Pernilla , Montero Esther , Negrini Anna , Malenfant Paul , Fernandes Ricardo , van de Walle Johan , Turner Mark , Slanař Ondřej , Pokorna Pavla 
Published: May 2023

IntroductionBetween 50 and 96% of drugs prescribed to neonatal and paediatric populations are used off-label, creating a clear need for clinical pharmacology studies and subsequent labelling. Key to the successful future of paediatric drug development is creating a collaborative community of professionals focusing on neonatal/paediatric clinical pharmacology. Offering the opportunity for students to participate in a pan-European project such as conect4children (c4c) may enhance their enthusiasm for the field of neonatal/paediatric clinical pharmacology. The primary objective of the concept is to evaluate the motivations and barriers medical students encounter when volunteering in neonatal/paediatric clinical pharmacology and to evaluate the role their tutors play.MethodsA systematic approach to volunteering in this area includes the definition of learning objectives and activities. Conceptual subjects are students and tutors of undergraduate medicine, in the 4th - 6th year, with interest in the field. The c4c Young Investigators Community (YIC) will be used as a platform to interact with established investigators in order to reach the primary objective.ResultsStudent activities include taking online training courses such as Good Clinical Practice (GCP), translating documents into local languages, actively participating in national/international meetings, and communicating with other healthcare professionals and/or the general public. Investing into involving a younger generation also aids the sustainability of international and clinical trial networks.ConclusionsThe concept of medical students volunteering in neonatal and paediatric clinical pharmacology is feasible, motivating for tutors and supports clinical