bluuebunny/crossref_metadata_2025 huggingface dataset:
Divine Relations as a Basis of Subjective Social Status During Later‐Life: Direct and Moderating Effects
Authors: Upenieks Laura , Bierman Alex , Lee Yeonjung
Published: May 2023

Early social theorists, including W.E.B Du Bois, recognized the importance of religion and its links to inequality, particularly in how religious vocabularies are attuned to frictions with inimical concrete social and political realities. We apply these ideas to research on the intersection of religious beliefs and economic deprivation, examining how beliefs in divine relations not only structure subjective social status (SSS), but also the association between financial stress and SSS. Analyses of data from the Caregiving, Aging, and Financial Experiences Study—a national study of Canadian older adults (N = 4010)—show that financial strain is associated with lower SSS, but better divine relations (higher support from a divine power and lower troubled relationships with a higher power) benefit SSS. Divine support also attenuates the association between financial strain and SSS. This research suggests a Du Bosian “double consciousness,” in which relations with a divine power serve as a basis for individual conceptualizations of social status that run counter to predominant narratives based on economic standing. We suggest directions for future research to explore the nuances of SSS within the religious context informed by a Du Boisian mode of inquiry.
Reconstruction of sub‐mm 3D pavement images using recursive generative adversarial network for faster texture measurement
Authors: Wang Guolong , Wang Kelvin C. P. , Yang Guangwei
Published: May 2023

It is challenging to collect 3D pavement images with desired resolution for accurate texture measurement at driving speeds with current devices, particularly in the longitudinal direction. This paper presents a novel superresolution technique with recursive generative adversarial network, called Pavement Texture Super Resolution Generative Adversarial Network (PT‐SRGAN), to reconstruct 0.1‐mm pavement 3D image from low‐resolution data for faster texture measurement. With the proposed pseudo‐Laplacian pyramid and an array of learning strategies, the developed PT‐SRGAN reconstructs 0.1‐mm 3D texture images with multiple upscaling factors in longitudinal direction. Combined with the evaluation mask, the proposed method is substantially superior to other methods in terms of three metrics when comparing the image quality of reconstructed 0.1‐mm 3D images against ground truth. The preliminary results indicate that the proposed method enables data collection at driving speeds up to 24 mph to collect 3D pavement images at sub‐mm resolution for faster texture measurement.
The impact of COVID‐19 on mental health and well‐being in critical care nurses – a longitudinal, qualitative study
Authors: Credland Nicola , Griffin Martyn , Hamilton Peter , Harness Oonagh , McMurray Robert
Published: May 2023

Background

The COVID‐19 pandemic has had both a psychological and physiological effect on the human race. For those working in health care, particularly in critical care, the pandemic has put unprecedented strain on staff. Witnessing suffering during crisis in an organizational setting can be a traumatic experience and critical care nurses often risked, not only their own lives, but their psychological well‐being, so that those infected with the virus might have a better chance at survival.

Aim

The aim of this study was to explore the challenges to mental health and psychological well‐being experienced by Critical Care Nurses during the COVID‐19 pandemic.

Study Design

A longitudinal, qualitative study involving semi‐structured interviews with 54 critical care nurses across 38 hospitals in the United Kingdom and Ireland. Interviews were transcribed verbatim and analysed using thematic analysis.

Results

Four key themes were identified which represent the challenges faces by critical care nurses during the COVID‐19 pandemic: Lack of control, Psychological trauma, Unexpected leadership, Public‐political betrayal.

Conclusions

While public‐political praise may lead to a short‐term lift in morale for front line workers; where it is not accompanied by practical support in terms of appropriate equipment, leadership, emotional support and renumeration it is likely to be damaging in the longer term.

Relevance to Clinical Practice

This study has provided a greater understanding of the factors which affected the well‐being and mental health of critical care nurses during a global pandemic.
Emerging roles of brain tanycytes in regulating blood–hypothalamus barrier plasticity and energy homeostasis
Authors: Kannangara Hasni , Cullen Liam , Miyashita Sari , Korkmaz Funda , Macdonald Anne , Gumerova Anisa , Witztum Ronit , Moldavski Ofer , Sims Steven , Burgess Jocoll , Frolinger Tal , Latif Rauf , Ginzburg Yelena , Lizneva Daria , Goosens Ki , Davies Terry F. , Yuen Tony , Zaidi Mone , Ryu Vitaly
Published: May 2023

Seasonal changes in food intake and adiposity in many animal species are triggered by changes in the photoperiod. These latter changes are faithfully transduced into a biochemical signal by melatonin secreted by the pineal gland. Seasonal variations, encoded by melatonin, are integrated by third ventricular tanycytes of the mediobasal hypothalamus through the detection of the thyroid‐stimulating hormone (TSH) released from the pars tuberalis. The mediobasal hypothalamus is a critical brain region that maintains energy homeostasis by acting as an interface between the neural networks of the central nervous system and the periphery to control metabolic functions, including ingestive behavior, energy homeostasis, and reproduction. Among the cells involved in the regulation of energy balance and the blood–hypothalamus barrier (BHB) plasticity are tanycytes. Increasing evidence suggests that anterior pituitary hormones, specifically TSH, traditionally considered to have unitary functions in targeting single endocrine sites, display actions on multiple somatic tissues and central neurons. Notably, modulation of tanycytic TSH receptors seems critical for BHB plasticity in relation to energy homeostasis, but this needs to be proven.
Tomato leaf disease recognition based on improved convolutional neural network with attention mechanism
Authors: Ni Jiangong , Zhou Zhigang , Zhao Yifan , Han Zhongzhi , Zhao Longgang
Published: May 2023

Plant diseases are common factors restricting crop yield and quality. For individuals without training, it is still difficult to identify various diseases accurately because many leaf diseases are similar in colour, shape and other aspects. Requiring an expert diagnosis can cause delays and lead to increasing costs. Therefore, this paper proposes an improved convolutional neural network for recognition of tomato leaf diseases. The experimental dataset was from the publicly available dataset PlantVillage. Based on the original ResNet18 model, a new convolutional neural network, TomatoNet, was constructed by adding a squeeze‐and‐excitation module and modifying the classifier structure. The results show that the average recognition accuracy of the TomatoNet network is 99.63%, which is 0.53% higher than the ResNet18 network. In addition, the recognition accuracy improved from 88.97% to 98.35% after the improvement of the AlexNet network. Finally, the superiority of TomatoNet was verified by comparison with other advanced models. This experiment verifies the feasibility of a deep learning algorithm for plant leaf disease recognition, which can provide a more efficient and convenient solution for detecting plant leaf disease.
Gender variation across the Oromo dialects: A corpus‐based study*
Authors: Feleke Tekabe Legesse , Lohndal Terje
Published: May 2023

This study aims to (1) demonstrate the position of the Oromo gender system in Corbett's (1991) typology of gender; (2) illustrate major syntactic gender variation across the Oromo dialects; (3) identify factors that contributed to the gender variation, and (4) illustrate the morphosyntax of the Oromo gender system. The data obtained from the Oromo Speech Corpus shows a high degree of lexical and syntactic variation between the Western‐Northern dialects on the one hand, and the Eastern‐Southern dialects on the other hand. The Western and Northern dialects have shifted from the historically Cushitic phonology‐based gender assignment pattern to the semantic‐based assignment pattern. This shift has resulted in a widespread neutralization of feminine gender markers. The contact between Oromo and the neighboring non‐Cushitic languages contributed to these changes. The study also argues that Kramer's (2015) morphosyntactic approach can be extended to the analysis of Oromo gender system.
The use of sub‐Tenon's anesthesia versus a low‐dose neuromuscular blockade for canine cataract surgery: A comparative study of 224 eyes
Authors: Bayley Kellam D. , Gates M. Carolyn , Anastassiadis Zoe , Read R. A.
Published: May 2023

Objective

Assess the utility of a Sub‐Tenon's anesthesia (STA) protocol to provide suitable operating conditions for canine cataract surgery and compare it to an alternative low‐dose neuromuscular blockade (LD‐NMB) protocol used for canine cataract surgery.

Procedures

Clinical study of dog eyes undergoing cataract surgery with either an STA or LD‐NMB protocol. While intraoperative vitreal expansion scores and intraoperative complications were collected prospectively, globe position, intraocular pressure, return of vision, and postoperative complications were collected retrospectively. Statistical testing was used to compare results between the STA and the LD‐NMB groups for the data available.

Results

A total of 224 eyes from 126 dogs were assessed, with 133/224 (59.4%) eyes from 99/126 (78.6%) dogs receiving STA and 91/124 (40.6%) eyes from 72/126 (57.1%) dogs receiving LD‐NMB. Forty‐five of these dogs (45/126; 37.7%) received STA for one eye and LD‐NMB for the other eye. There was no significant change in intraocular pressure measurements following STA administration. This was not measured for the LD‐NMB group. The globe achieved a central position in 110/133 (82.7%) of eyes that received STA. This was not measured for the LD‐NMB group. Intraoperative vitreal expansion scores were slightly higher in STA‐treated eyes compared to LD‐NMB‐treated eyes. The intraoperative complication rate for STA‐treated eyes was higher (73/133; 54.8%) compared to NMB‐treated eyes (12/91; 13.2%). The most common intraoperative complication for STA was chemosis (64/133; 48.1%), the risk of which increased with an increase in the volume of local anesthetic injected. The post‐operative complication rate was higher in STA‐treated eyes (28/133; 21.1%) compared to NMB‐treated eyes (16/91; 17.6%). Post‐operative corneal ulceration was the most common postoperative complication in STA‐treated eyes (6/133; 4.5%).

Conclusion

The STA protocol described resulted in suitable operating conditions, but more intraoperative and postoperative complications compared to the LD‐NMB protocol. Despite these complications, the STA protocol did not cause a significant deleterious impact on post‐operative outcomes as defined in the present study.
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

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

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.
Releasing global forests from human management: How much more carbon could be stored?
Authors: Roebroek Caspar T. J. , Duveiller Gregory , Seneviratne Sonia I. , Davin Edouard L. , Cescatti Alessandro
Published: May 2023

Carbon storage in forests is a cornerstone of policy-making to prevent global warming from exceeding 1.5°C. However, the global impact of management (for example, harvesting) on the carbon budget of forests remains poorly quantified. We integrated global maps of forest biomass and management with machine learning to show that by removing human intervention, under current climatic conditions and carbon dioxide (CO
2
) concentration, existing global forests could increase their aboveground biomass by up to 44.1 (error range: 21.0 to 63.0) petagrams of carbon. This is an increase of 15 to 16% over current levels, equating to about 4 years of current anthropogenic CO
2
emissions. Therefore, without strong reductions in emissions, this strategy holds low mitigation potential, and the forest sink should be preserved to offset residual carbon emissions rather than to compensate for present emissions levels.
Manganese Acts as an Environmental Inhibitor of Pseudomonas aeruginosa Biofilm Development by Inducing Dispersion and Modulating c-di-GMP and Exopolysaccharide Production via RbdA
Authors: Park Soyoung , Dingemans Jozef , Sauer Karin
Published: May 2023

While diverse environmental conditions such as the availability of metal ions have been shown to affect biofilm development, little is known about the mechanism. Here, we demonstrate that Mn
2+
affects
Pseudomonas aeruginosa
biofilm development by stimulating phosphodiesterase RbdA activity to reduce the signaling molecule c-di-GMP levels, thereby hindering polysaccharide production and biofilm formation but enhancing dispersion.
Hepatitis E Virus Protease Inhibits the Activity of Eukaryotic Initiation Factor 2-Alpha Kinase 4 and Promotes Virus Survival
Authors: Kumar Amit , Subramani Chandru , Raj Shivani , Ranjith-Kumar C. T. , Surjit Milan
Published: May 2023

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis in humans. It causes chronic infection in organ transplant patients.
Microbiological Epidemiology of Invasive Infections Due to Non-Beta-Hemolytic Streptococci, France, 2021
Authors: Plainvert Céline , Matuschek Erika , Dmytruk Nicolas , Gaillard Marine , Frigo Amandine , Ballaa Yassine , Biesaga Eddy , Kahlmeter Gunnar , Poyart Claire , Tazi Asmaa
Published: May 2023

NBHS are recognized as opportunistic pathogens particularly involved in infections of the elderly and immunocompromised patients. This study underlines their importance as common causes of severe and difficult-to-treat infections such as endocarditis.
Comparative Genomics and Physiological Investigations Supported Multifaceted Plant Growth-Promoting Activities in Two Hypericum perforatum L.-Associated Plant Growth-Promoting Rhizobacteria for Microbe-Assisted Cultivation
Authors: Raj Yog , Kumar Anil , Kumari Sareeka , Kumar Rakshak , Kumar Rakesh
Published: May 2023

Hypericum perforatum
L. (St. John’s wort) herbal preparations are among the top-selling products to treat depression worldwide.
Gut Microbiome and Metabonomic Profile Predict Early Remission to Anti-Integrin Therapy in Patients with Moderate to Severe Ulcerative Colitis
Authors: Liu Jie , Fang Huaying , Hong Na , Lv Chaolan , Zhu Qihua , Feng Yinping , Wang Bo , Tian Jiashuang , Yu Yue
Published: May 2023

It is reported that patients with ulcerative colitis (UC) have low response rates to anti-integrin medications in the latest VARSITY study. Therefore, our primary goals were to discover differences in the gut microbiome and metabonomics patterns between early remission and nonremission patients and to explore the diagnostic value in predicting clinical remission to anti-integrin therapy accurately.
Biological Characteristics and Pathogenicity Analysis of a Low Virulence G2a Porcine Epidemic Diarrhea Virus
Authors: Yu Kechen , Liu Xueting , Lu Ying , Long Meijing , Bai Jiaguo , Qin Qiuying , Su Xueli , He Guifu , Mi Xue , Yang Chunjie , Wang Ruomu , Wang Hejie , Chen Ying , Wei Zuzhang , Huang Weijian , Ouyang Kang
Published: May 2023

The current epidemic of porcine epidemic diarrhea virus (PEDV) G2 has caused huge economic losses to the pig industry. Evaluation for low virulence of the PEDV strains of subgroup G2a would be useful for the future development of effective vaccines.
Bacterioplankton Communities in Dissolved Organic Carbon-Rich Amazonian Black Water
Authors: Sylvain François-Étienne , Bouslama Sidki , Holland Aleicia , Leroux Nicolas , Mercier Pierre-Luc , Val Adalberto Luis , Derome Nicolas
Published: May 2023

The Amazon basin discharge carries an important load of terrestrially derived dissolved organic matter (DOM) to the ocean. The bacterioplankton from this basin potentially plays important roles in transforming this allochthonous carbon, which has consequences on marine primary productivity and global carbon sequestration.
Liver-Humanized NSG-PiZ Mice Support the Study of Chronic Hepatitis B Virus Infection and Antiviral Therapies
Authors: Colón-Thillet Rossana , Stone Daniel , Loprieno Michelle A. , Klouser Lindsay , Roychoudhury Pavitra , Santo Tracy K. , Xie Hong , Stensland Laurence , Upham Sarah L. , Pepper Gregory , Huang Meei-Li , Aubert Martine , Jerome Keith R.
Published: May 2023

Liver-humanized mouse models have become the gold standard for the
in vivo
study of hepatitis B virus (HBV), yet their complexity and cost have prohibited widespread use of existing models in research. Here, we show that the NSG-PiZ liver-humanized mouse model, which is relatively inexpensive and simple to establish, can support chronic HBV infection.
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

Introduction

Due 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.

Methods

A 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.

Results

Of 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.

Conclusions

In 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

Introduction

Children 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 up

Methods

A 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 collected

Results

24 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 process

Conclusions

c4c 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

Introduction

In 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.

Methods

In 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.

Results

Within 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.

Conclusion

Within 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

Introduction

Evidence-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.

Methods

A 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.

Results

In 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.

Conclusions

The 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

Introduction

Doravirine 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.

Methods

An 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.

Results

Perfusion 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.

Conclusions

Substantially 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

Introduction

We sought to detect a relationship between midazolam concentration and development of new delirium in critically ill children who were on continuous midazolam administration.

Methods

Delirium was detected using the Sophia Observation withdrawal Symptoms - Paediatric Delirium (SOS-PD) score and 104 left-over samples were available to measure midazolam concentrations.

Results

Twenty-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.

Conclusions

A 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

Introduction

Given 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 design

Retrospective 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 duration

Results

The 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).

Conclusions

Women 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

Introduction

Between 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.

Methods

A 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.

Results

Student 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.

Conclusions

The concept of medical students volunteering in neonatal and paediatric clinical pharmacology is feasible, motivating for tutors and supports clinical
8 The influence of sepsis on the tissue penetration of piperacillin-tazobactam in children: a microdialysis study in the juvenile pig
Authors: Hermans Eline , Meganck Freya , de Paepe Peter , Vande Walle Johan , de Cock Pieter , Devreese Mathias
Published: May 2023

Introduction

Antibiotics are the cornerstone in the treatment of sepsis. Microdialysis (MD) data from adults suggest an impaired antibiotic tissue penetration in the case of sepsis. Tissue pharmacokinetics (PK) remain largely understudied in children. Juvenile pig models have proven to provide an accurate prediction of PK behavior in pediatric patients. This study aimed to investigate the influence of sepsis on antibiotic tissue penetration in a piglet model.

Methods

In 17 piglets, piperacillin (PIP) - tazobactam (TAZ) was administered (75 mg/kg IV over 30 minutes, 6h dosing interval) over 4 days. Blood and MD samples (muscle) were collected in first-dose (FD) and steady-state (SS) conditions. In 11 piglets a continuous LPS infusion (36h) was administered to induce a septic state. In the 6 control animals (no LPS) time effects during the study period were evaluated. Non-compartmental PK analysis was used to determine the tissue penetration (AUC-ratio tissue/plasma). The AUC ratios were pairwise compared between the healthy and septic states in each piglet, data are reported as mean ± SD.

Results

For PIP, the AUC ratio in FD conditions was significantly lower in the septic state (0.84 ± 0.22) compared to the healthy baseline measurement (1.06 ± 0.46) (P = 0.042). In SS conditions, comparable results were found with an AUC ratio of 1.09 ± 0.27 during baseline and 0.80 ± 0.22 in the septic state (p=0.009). The results for TAZ were similar to PIP. There were no time effects found in the control group.

Conclusion

In this juvenile piglet model, sepsis impaired the PIP-TAZ tissue penetration. The results of this study warrant further research into the tissue PK of septic children to optimize the antibiotic dosing in this population.
Acute carbon monoxide poisoning as a cause of rhabdomyolysis in a case of flame burn
Authors: Al Khaldi Turki , Gulreez Rasheeqa , Abdelhamid Mokhtar Mahmoud , Louri Nayef
Published: May 2023

Carbon monoxide (CO) poisoning typically occurs from inhalation of CO at excessive levels. Rhabdomyolsis is not an uncommon complication following acute CO poisoning, yet there are very few reported cases in the literature. It is characterised by rapid breakdown of skeletal muscles and release of its contents into the circulation, leading to acute kidney injury (AKI). Early diagnosis and treatment are crucial to avoid anticipated morbidity and mortality. We are presenting a case of a woman in her 40s with 28% flame burn in a closed space. The patient developed CO poisoning, which led to rhabdomyolysis as evidenced by clinical manifestations and laboratory findings (creatine kinase had reached an unmeasurable level). The patient developed AKI and was successfully managed in our ICU. Here, we are highlighting the importance of considering CO poisoning as one of the potential causes of rhabdomyolysis in burn victim.
A cross-sectional study factors associated with resilience among medical staff in radiology departments during COVID-19, Riyadh, Kingdom of Saudi Arabia
Authors: Asiri Fatimah Khalid , Al Harbi Nouf Sahal , Alanazi Manal Abdullah , Aljuaid Mohammed M , Fahlevi Mochammad , Heidler Petra
Published: May 2023

Objectives

This study aims to assess the level of resilience of medical workers in radiology departments in Riyadh, Kingdom of Saudi Arabia, during the COVID-19 outbreak and to explore associated factors.

Setting

Medical staff, including nurses, technicians, radiology specialists and physicians, working in radiology departments at government hospitals in Riyadh, Saudi Arabia during the COVID-19 outbreak.

Design

A cross-sectional study.

Participants

The study was conducted among 375 medical workers in radiology departments in Riyadh, Kingdom of Saudi Arabia. The data collection took place from 15 February 2022 to 31 March 2022.

Results

The total resilience score was 29.37±6.760 and the scores of each dimension showed that the higher mean score was observed in the domain of ‘flexibility’, while the lowest was observed in ‘maintaining attention under stress’. Pearson’s correlation analysis showed that there was a significant negative correlation between resilience and perceived stress (r=–0.498, p<0.001). Finally, based on multiple linear regression analysis, factors affecting resilience among participants are the availability of psychological hotline (available, B=2.604, p<0.050), knowledge of COVID-19 protective measures (part of understanding, B=−5.283, p<0.001), availability of adequate protective materials (partial shortage, B=−2.237, p<0.050), stress (B=−0.837, p<0.001) and education (postgraduate, B=−1.812, p<0.050).

Conclusions

This study sheds light on the level of resilience and the factors that contribute to resilience in radiology medical staff. Moderate levels of resilience call for health administrators to focus on developing strategies that can effectively help cope with workplace adversities.
Adolescent, caregiver and provider perspectives on tuberculosis treatment adherence: a qualitative study from Lima, Peru
Authors: Chiang Silvia S , Senador Liz , Altamirano Elmer , Wong Milagros , Beckhorn Catherine B , Roche Stephanie , Coit Julia , Oliva Rapoport Victoria Elena , Lecca Leonid , Galea Jerome T
Published: May 2023

Objectives

To understand the perspectives of adolescents (10–19 years old), their caregivers and healthcare providers regarding factors that impact adherence to tuberculosis (TB) treatment among adolescents.

Design

We conducted in-depth interviews using semistructured interview guides based on the World Health Organization (WHO)’s Five Dimensions of Adherence framework, which conceptualises adherence as being related to the health system, socioeconomic factors, patient, treatment and condition. We applied framework thematic analysis.

Setting

Between August 2018 and May 2019, at 32 public health centres operated by the Ministry of Health in Lima, Peru.

Participants

We interviewed 34 adolescents who completed or were lost to follow-up from treatment for drug-susceptible pulmonary TB disease in the preceding 12 months; their primary caregiver during treatment; and 15 nurses or nurse technicians who had ≥6 months’ experience supervising TB treatment.

Results

Participants reported numerous treatment barriers, the most common of which were the inconvenience of health facility-based directly observed therapy (DOT), long treatment duration, adverse treatment events and symptom resolution. The support of adult caregivers was critical for helping adolescents overcome these barriers and carry out the behavioural skills (eg, coping with the large pill burden, managing adverse treatment events and incorporating treatment into daily routines) needed to adhere to treatment.

Conclusion

Our findings support a three-pronged approach to improve TB treatment adherence among adolescents: (1) reduce barriers to adherence (eg, home-based or community-based DOT in lieu of facility-based DOT, reducing pill burden and treatment duration when appropriate), (2) teach adolescents the behavioural skills required for treatment adherence and (3) strengthen caregivers’ ability to support adolescents.