bluuebunny/crossref_metadata_2025 huggingface dataset:
A Pharmacokinetic Analysis of Drug Concentration Using a Novel Deep Learning Model
Authors: Khusial Richard , Roberts Mary Scott , Rao Satish , Akil Ayman
Published: February 2025

Objectives: Pharmacometrics and the use of population pharmacokinetics (PPK) plays a critical role in model informed drug discovery and development (MIDD). Recently, there has been an interest in the application of deep learning to support various activities within MIDD. In this study, a novel deep learning model, LSTM-ANN, was implemented to predict drug concentrations using a real-world case study. We hypothesized this unique deep learning approach would be able to capture the relationships within the pharmacokinetic (PK) data and provide accurate predictions. Methods: A time series deep learning LSTM-ANN model with multiple inputs was constructed. A total of 5,176 drug concentrations from 224 subjects along with 10 patient-specific covariates were used in the LSTM-ANN model development. The PK data was divided into time dependent and independent variables. The time dependent variables were fed to the LSTM layer to learn the time dependent patterns. These patterns were then combined with their respective time independent variables and fed into an ANN layer. Additionally, to determine the optimal data splitting strategy, different splitting strategies were tested: splitting based on time, random shuffling, and splitting based on unique subject identifier. The splitting percentage was kept consistent between all three strategies, with 70 percent of the data as training and 30 percent of the data as validation. Each of the LSTM-ANN model hyperparameters were optimized through Bayesian optimization with a tree-structured Parzen estimator surrogate model along with a hyperband pruner. The performance evaluation criteria included visual goodness-of-fit (GOF) plots and validation root mean square error (RMSE). Additionally, a permutation analysis was conducted to evaluate the impact of subject specific covariates on the LSTM-ANN model performance. Results: A preliminary LSTM-ANN model was generated and optimized for each of the splitting strategies. An LSTM-ANN model optimized with the randomly splitted strategy achieved the lowest validation RMSE of 252.833. Permutation analysis revealed age, sex, baseline body weight and fed status were the covariates with the highest level of impact on the LSTM-ANN model performance. Splitting based on time had the highest RMSE in the validation set with 1092.003. A separate PPK modeling using NONMEM was executed, and the covariates identified to have a significant impact on model parameters were baseline body weight, sex, age, fed status and dose. Conclusions: A novel LSTM-ANN framework was used to analyze and predict PK data from a real-world case study. The splitting strategy showed a significant impact on the learning and performance of the model. Permutation analysis for covariate influence applied on the best performing LSTM-ANN model identified the most impactful covariates to be similar to those selected by stepwise covariate modeling using NONMEM.Citations: None
A Novel Approach to Capturing the Dynamics of Nontarget and New Tumors in Mechanistic Models of Progression-Free Survival
Authors: Pourzanjani Arya , Connarn Jamie , Mehta Khamir , Modi Saurabh , Upreti Vijay
Published: February 2025

Objectives: Progression-free survival (PFS) is an important endpoint in oncology trials that is determined by applying the RECIST criteria to longitudinal measurements of tumor size and appearance of new tumors. While traditionally modeled as a whole, practitioners have recently begun directly modeling the underlying longitudinal components of PFS via mechanistic models (Yu, 2020) (Baaz, 2023). Specifically, they use tumor growth inhibition (TGI) models to model the size of target lesions over time, and they jointly use a hazard function to model progression of new and nontarget tumors.This presents several advantages. First, the model is fit using the entire longitudinal history of data instead of a single progression time, providing more statistical power and allowing for earlier prediction of PFS. Second, a more detailed, mechanistic approach is more generalizable and allows for the modeling of PFS under novel conditions such as combination therapies or new complex dosing regimens.We explore whether these existing models can be further improved by using data on nontarget and new tumors to directly model their size longitudinally, rather than treating them as a time-to-event data.Methods: We introduce a way to directly model the size of nontarget and new tumors using existing longitudinal data. Our approach directly estimates the continuous size of nontarget and new lesions, as well as their measured size at scan times by utilizing their entire available longitudinal history. We illustrate the method and its advantages on publicly available data from a trial in colorectal cancer.Results: Our approach provides an even further mechanistic approach closer to the true data-generating process of longitudinal nontarget and new lesion data. This has several practical advantages to the hazard approach such as the ability to account for the different types of progression and handle non-measurable patients. Conclusions: The size of nontarget and new lesions can be modeled longitudinally in a TGI model using existing data on nontarget and new lesions. This approach presents several advantages over current time-to-event based methods.Citations: [1] Baaz, M. T. (2023). Model‐based prediction of progression‐free survival for combination therapies in oncology. CPT: Pharmacometrics & Systems Pharmacology, 1227-1237.[2] Yu, J. N. (2020). A new method to model and predict progression free survival based on tumor growth dynamics. CPT: Pharmacometrics & Systems Pharmacology, 177-184.
Beyond Subcutaneous Dosing: Efficiency of liver-targeting siRNAs dosed via alternates routes and formulations.
Authors: Rao Satyajit , Dharmarajan Lekshmi , Kearns Jeffrey , Phung Thien-Khoi
Published: February 2025

Objectives & MethodsThe discovery of trimeric N-galactosamine (GalNAc) conjugation revolutionized the delivery of siRNAs to the human liver because of the high specificity of GalNAc for the asialoglycoprotein receptor (ASGPR) abundantly expressed on hepatocytes [1]. At present, several GalNAc-conjugated oligonucleotides (siRNA or ASO) are approved or in clinical development with a subcutaneous bolus (SC) dosing regimen, each with a mechanism of action to down-regulate target gene expression in the liver. Modeling platforms for the development of GalNAc-siRNAs have matured recently [2], however, assessing optimal dosing routes and regimens to maximize pharmacodynamic effect for patients remains unexplored. Here, we present a model-driven analysis of the pharmacokinetic (PK) and pharmacodynamic (PD) effects of different dosing routes and formulations. Results & ConclusionsThere is increasing understanding that the relative biodistribution of GalNAc-siRNAs to the liver and other organs (mainly kidney) is dependent on both dose and route of administration. It has been reported that bolus intravenous (IV) dosing, for example, biases the biodistribution away from the liver and presumably towards renal clearance. Subcutaneous (SC) administration of the drug allows for slower absorption in the blood, and a lower maximal plasma concentration (Cmax) compared to IV bolus, increasing efficiency of ASGPR-mediated endocytosis that transports drug to the cells [3]. Here, we report a mechanistic PBPK/PD modeling approach to characterize traditional IV bolus and IV infusion routes and explore potential continuous infusion or slow-release formulations. Using a reference dataset for vutrisiran [4], we predict pharmacodynamics for alternative dosing regimens and compare to the current standard of SC administration. Leveraging the wealth of data available for this modality, we propose model-informed dosing routes and regimens that can maximize pharmacodynamic effect in patients.Citations: [1] Nair, J. K. et al. Multivalent N -acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc 136, 16958–16961 (2014).[2] Ayyar, V. S. & Song, D. Mechanistic Pharmacokinetics and Pharmacodynamics of GalNAc-siRNA: Translational Model Involving Competitive Receptor-Mediated Disposition and RISC-Dependent Gene Silencing Applied to Givosiran. J Pharm Sci 113, 176–190 (2024).[3] McDougall, R. et al. The Nonclinical Disposition and Pharmacokinetic/Pharmacodynamic Properties of N-Acetylgalactosamine-Conjugated Small Interfering RNA Are Highly Predictable and Build Confidence in Translation to Human. Drug Metabolism and Disposition vol. 50 781–797[4] Habtemariam, B. A. et al. Single-Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N-acetylgalactosamine–Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects. Clin Pharmacol Ther 109, 372–382 (2021).
Cellular and Humoral Semi-mechanistic Immune Response Models of a Vaccine Candidate for Respiratory Syncytial Virus Infection
Authors: Oka Takaaki , Rhodes Sophie , Shimizu Shinji , Hennig Stefanie , Lin YuWei , Kotsuma Masakatsu , Yoshihara Kazutaka
Published: February 2025

Objectives: Respiratory syncytial virus (RSV) is a widespread contagious virus that causes respiratory infections. RSV causes infections at all ages and repeated RSV infection is common throughout life. The aim of this analysis was to develop semi-mechanistic models to describe i) cellular and ii) humoral immunity dynamics after two times of vaccinations of compound X, a vaccine candidate for RSV infection, to eventually support dose selection. Methods: The immunogenicity data for this analysis, IFN-γ response for cellular immunity and anti-RSV/A neutralization activity for humoral immunity, were obtained from a Phase 2 dose-finding study of compound X. The cellular immunity model was a two-compartmental model of active or memory IFN-γ secreting CD4+ T cells and included an antigen compartment. It assumes that memory T cells exist at baseline due to previous infection. The humoral immunity model was a four-compartmental model of active or memory B cells, long-lived plasma cells and neutralizing antibody titer and included an antigen compartment. It also assumes the existence of memory B cells, long-lived plasma cells and neutralizing antibody at baseline, attributable to previous infection. Given the complexity of the structural models and the sparsity of available data, the Cluster Gauss-Newton method (CGNM) [1] was used to determine fixed parameter values for structurally and/or practically unidentifiable parameters and initial values of parameters to be estimated. Model evaluation was based on the parameter precision, objective function value, biological plausibility of parameter estimates, goodness-of-fit (GOF) plots, and visual predictive checks (VPC). Results: Key parameters related to the dynamics of active and memory T cells for the cellular immunity model as well as the dynamics of memory B cells and neutralizing antibodies for the humoral immunity model were well estimated with high precision ( < 20% relative standard error). Final models described the data adequately with predicted immune responses consistent with observed immune responses in GOF and VPC across all antigen doses. Additionally, the models accurately captured limited immune responses observed after revaccination compared to immune response observed after the initial vaccination which is in line with other RSV vaccines in older adults [2, 3]. Conclusions: Cellular and humoral semi-mechanistic immune response models for an RSV vaccine candidate were developed. These models will be utilized as a platform to support and accelerate future model-informed vaccine dose selection and development.Citations: [1] Aoki, Y., et al. Optimization and Engineering, 2022; 23:169-199.[2] Kotb, S, et al. Respiratory Investigation, 2023, 61.2: 261-269.[3] Baber, J, et al. The Journal of Infectious Diseases, 2022, 226.12: 2054-2063.
Creating Cell-specific Computational Models of Stem Cell-derived Cardiomyocytes Using Optical Experiments
Authors: Yang Janice , Daily Neil , Pullinger Taylor , Sobie Eric , Wakatsuki Tetsuro
Published: February 2025

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have gained traction as a powerful model in cardiac disease and therapeutics research, since iPSCs are self-renewing and can be derived from healthy and diseased patients without invasive surgery. However, current iPSC-CM differentiation methods produce cardiomyocytes with immature, fetal-like electrophysiological phenotypes, and the variety of maturation protocols in the literature results in phenotypic differences between labs. Heterogeneity of iPSC donor genetic backgrounds contributes to additional phenotypic variability. Several mathematical models of iPSC-CM electrophysiology have been developed to help understand the ionic underpinnings of, and to simulate, various cell responses, but these models individually do not capture the phenotypic variability observed in iPSC-CMs. Here, we tackle these limitations by developing a computational pipeline to calibrate cell preparation-specific iPSC-CM electrophysiological parameters. We used the genetic algorithm (GA), a heuristic parameter calibration method, to tune ion channel parameters in a mathematical model of iPSC-CM physiology. To systematically optimize an experimental protocol that generates sufficient data for parameter calibration, we created simulated datasets by applying various protocols to a population of in silico cells with known conductance variations, and we fitted to those datasets. We found that calibrating models to voltage and calcium transient data under 3 varied experimental conditions, including electrical pacing combined with ion channel blockade and changing buffer ion concentrations, improved model parameter estimates and model predictions of unseen channel block responses. This observation held regardless of whether the fitted data were normalized, suggesting that normalized fluorescence recordings, which are more accessible and higher throughput than patch clamp recordings, could sufficiently inform conductance parameters. Therefore, this computational pipeline can be applied to different iPSC-CM preparations to determine cell line-specific ion channel properties and understand the mechanisms behind variability in perturbation responses.Citations: N/A
Dual Target-Mediated Drug Disposition Model to Guide the Selection of Starting Dose and Escalation in FTIH Trials for Volrustomig (MEDI5752), a Monovalent Bispecific Antibody Targeting PD-1 and CTLA-4
Authors: Tang Zoey , Song Xuyang , Zhou Diansong , Ayyoub Amal , Eck Steven , Mazor Yariv , Dovedi Simon , Achour Ikbel , Subramaniam Deepa S. , Freeman Dan , Khan Anis , Ren Song , Gibbs Megan , Phipps Alex
Published: February 2025

Objectives: Volrustomig (MEDI5752) is a monovalent bispecific antibody (DuetMab) with an Fc-domain engineered to reduce effector function, targeting two clinically validated negative T cell regulators, Programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). The bispecific antibody has been designed to suppress the PD-1 pathway and provide enhanced CTLA4 inhibition in the context of PD1 expression, such as PD1+/CTLA4+ activated T cells. Our goal was to develop and validate a dual TMDD model by incorporating the cell binding data to predict a safe starting dose and clinical efficacious exposure in humans for the First-Time-In-Human (FTIH) study. Methods: The dual TMDD model included human monoclonal antibody (mAb) PK, PD-1 and CTLA-4 receptor occupancy (RO) on different T cell populations including PD-1- (non-activated) and PD-1+ (activated T cells / Tumour infiltrating Lymphocytes (TIL)). The in vitro cell binding data, including antibody affinity and antigen density, were incorporated into the model to predict human exposure and extent of volrustomig for PD-1 and CTLA-4 RO on both resting and activated T cell populations in the periphery and TILs. By integrating the comprehensive data into the model, a safe starting dose and escalation scheme for FTIH trial were determined based on toxicology and pharmacology considerations. The model predictions were later confirmed with clinical PK and RO data from the Phase 1 study (NCT03530397). Results: The dual TMDD model adequately predicted the observed in vitro cell based binding data and human PKPD. Model-predicted EC50 values (6.5 and 30 nM respectively) were consistent with the observed EC50 values for CTLA-4 and PD-1 (4.07 nM and 84.9 nM, respectively) in functional cell-based assay for volrustomig. Based on the predicted human PK and RO, the MABEL-based starting human dose of 2.25 mg Q3W was proposed by identifying the dose needed to keep Cmax concentration below the EC20 values for CTLA-4 occupancy on PD-1-/CTLA-4 + single positive cells. The starting dose was predicted to show a safety margin of 1025-fold compared to the cynomolgus monkey AUC at the highest non-severely toxic dose (HNSTD) level. Predicted human PK profiles were in good agreement with clinical PK data. Conclusions: This model predicts that a flat dose of 2.25 Q3W volrustomig is a safe starting dose in FTIH study. The model can be used generally for design, optimization and human dose prediction of similar class of bispecific antibodies.Citations: No citations
IMPACT OF SOCIAL MEDIA ON MENTAL HEALTH OF YOUNG ADULTS IN PAKISTAN
Authors: Karim Shazia , Bibi Asima , Nazik Asia , Karim Rabia
Published: February 2025

Background: Social media has become an integral part of modern life, influencing individual perceptions, behaviors, and mental well-being. Digital platforms allow users to interact, express themselves, and shape their self-identity, but excessive usage has been linked to adverse psychological effects. Young adults, being highly engaged with social media, are particularly vulnerable to its impact on emotional and mental health. Understanding these effects within the Pakistani context is essential for developing effective interventions and awareness programs.
Objective: This study aimed to assess the impact of social media usage on the mental health of young adults in Pakistan.
Methods: A quantitative descriptive cross-sectional study was conducted over four months. A total of 150 young adults were recruited using a convenience sampling technique. Participants aged above 20 years and willing to participate were included, while those under 20 or unwilling to cooperate were excluded. Data were collected using a structured questionnaire assessing demographic characteristics, social media usage patterns, and mental health indicators. The responses were analyzed using the Statistical Package for Social Sciences (SPSS) version 25.0, applying descriptive and inferential statistical methods to examine the association between social media usage and mental health outcomes.
Results: Among the participants, 46.6% were aged 20–25 years, 33.3% were 26–30 years, and 20% were 31–40 years. Males comprised 53.3% of the sample, while females accounted for 46.6%. The majority (66.6%) reported spending more than 11 hours daily on social media, while 26.6% spent 6–10 hours and 6.6% used it for 1–5 hours. The most frequently used platform was TikTok (53.3%), followed by Facebook (26.6%) and Twitter (20%). Over 70% of participants reported experiencing negative mental health effects, including anxiety (72%), sleep disturbances (88%), fatigue (75%), body dissatisfaction (82%), and difficulty concentrating (85%).
Conclusion: The findings indicate that excessive social media usage negatively affects the mental health of young adults in Pakistan, contributing to anxiety, sleep disturbances, and self-perception issues. Targeted mental health awareness programs and digital well-being initiatives are essential to mitigate these effects. Future research should explore qualitative perspectives for a more comprehensive understanding of social media’s psychological impact.
Exploring types and functions slang words in television series season 4
Authors: Yulia Erin , Ningsih Tri Wahyu Retno
Published: February 2025

Slang is an ever-evolving form of language that includes new vocabulary in phrases with extended meanings, often associated with younger generations. This study aims to discover the types and functions of slang words applied in On My Block TV Series Season 4 based on Allan and Burridge’s theory, the characters in On My Block TV Series Season 4 use slang in their daily or informal contexts. In this study, the writer used descriptive qualitative methods and utilized Allan and Burridge’s (2006) theory of types and functions of slang words to analyse the data. The research results showed 105 slang words used in On My Block TV Series Season 4 and identified 5 types of slang  words applied. There were 53 fresh and creative types, 23 flippant types, 6 imitative types, 14 acronym types, and 9 clipping types. The writer also collected 6 functions of slang words applied, which are 7 to addresses, 7 to humiliates, 7 to initiate relax conversations, 6 to form an intimate atmosphere, 4 to express impressions, and 7 to reveal angers. The function of slang words to show intimacy does not apply in this series. Fresh and creative slang types and to initiate relax conversation slang functions are used more often in On My Block TV Series Season 4.
Academic motivation and learner empowerment of Indonesian EFL students
Authors: Rini Happy Cruzia , Triastuti Anita
Published: February 2025

Learning is a process in which students experience change. During the learning process, teachers need to empower students to lead them to be independent in learning. Therefore, the present study focused on learner empowerment and academic motivation from the students' perspectives and the probable relationship. The participants were high school students who took English as a compulsory subject and were selected randomly. The researchers conducted mix method in this study. Two kinds of instruments were used as the quantitative data, namely the Academic Motivation Scale and the Learner Empowerment Scale. Meanwhile, open-ended questions were used as the instrument for the qualitative one. The result revealed that students' academic motivation and learner empowerment levels were at the moderate level. Moreover, the findings implied a statistically significant relationship between academic motivation and learner empowerment. Thus, higher motivation and empowerment in learning English are associated with each other. This expected study could explain the relationship between two crucial things in the classroom: motivation and empowerment.
Decomposition of N2O on different iron-containing catalysts
Authors: Makova Anna S , Chesnokova Alena V , Kustov Aleksandr Leonidovich , Leonov Alexander Vasilyvich , Pribytkov Petr Vadimovich , Plenkin Danil Sergeyevich , Ter-Akopyan Marina N , Kustov Leonid Modestovich
Published: February 2025

In this work, Fe-containing catalysts (2.5 wt
Mechanisms of action of the antibiotic ciprofloxacin on the DNA-binding protein Dps detected by molecular modeling techniques
Authors: Tereshkina K B , Tereshkin Eduard V , Kovalenko Vladislav V , Krupyanskii Yurii Fedorovich , Loiko Nataliya G
Published: February 2025

A comprehensive analysis of the effect of the antibiotic ciprofloxacin on the DNA-binding protein Dps of the bacterium Escherichia coli was carried out using three molecular modeling methods: docking, umbrella sampling for calculating mean force potential profiles and classical molecular dynamics. It was shown that ciprofloxacin can penetrate into the internal cavity of the protein, as well as adsorb to the surface, reducing the ability of the N-termini to bind DNA.
Fluorescent conjugates of PSMA-targeting ligand with cyanine dyes: synthetic approaches and photochemical properties
Authors: Uspenskaia Anastasiia Alekseevna , Doroshenko Irina Andreevna , Popovicheva Kseniia A. , Shmychkov Nazar Vasilyvich , Levina Irina I , Beklemishev Mikhail Konstantinovich , Tashlitsky Vadim Neronovich , Podrugina Tatyana Aleksandrovna , Machulkin Aleksei Eduardovich , Beloglazkina Elena Kimovna
Published: February 2025

Fluorescent conjugates of carbocyanine dyes with a ligand selective to prostate-specific membrane antigen were accessed by either peptide synthesis or CuAAC methodology, with the latter being more promising. The introduction of a propargylamino moiety at the meso-position of the polymethine chain of the fluorophores afforded the alkyne counterparts for the CuAAC reaction toward the ligand bearing azido group. The photochemical studies showed that the quantum yields of the obtained conjugates exceeded those for the unmodified fluorophores by more than 20 times.
Protection mechanism of Dps protein of bacterial DNA during sublethal heat shock
Authors: Tereshkina Ksenia Borisovna , Potokina Victoriya V , Tereshkin Eduard V , Kovalenko Vladislav V , Krupyanskii Yurii Fedorovich , Loiko Nataliya G
Published: February 2025

The mechanism of protective action of the DNA-binding protein Dps from Escherichia coli  during sublethal exposure to thermal shock has been deciphered using in vivo experimental methods and in silico molecular modelling methods. The strength of the DNA-Dps complex was shown to increase when the temperature was raised to 55 °C, and to maintain this state after cooling down to 28 °C. It is proved that this favors the survival of bacteria and their acquisition of additional stress resistance.
CsPbBr3 and Cs4PbBr6 perovskite nanoparticles: hidden potential of Cs4PbBr6 or ineffective fluorescence?
Authors: Son Alexandra Grigorievna , Gushchina Valeria A , Egorova Anastasia A , Sadovnikov Alexey A , Bert Nikolay A , Tameev Alexey Raisovich , Kozyukhin Sergei Aleksandrovich
Published: February 2025

All-inorganic perovskite CsPbBr3 and Cs4PbBr6 nanoparticles are intensively studied for their unique optical properties, though synthesizing single-phase nanoparticles has posed challenges. Detailed synthesis method of CsPbBr3 and Cs4PbBr6 single-phase nanoparticles and their chemical and phase analysis are described. Distinctive optical characteristics, such as photoluminescence, optical band gap and the Urbach tail region, are revealed and explained within the current conception of perovskite band structures.
Site-specific sortase-catalyzed lipidation of proteins
Authors: Melikhova Tatiana D , Bovin Nicolai Vladimirovich , Shoshina Natalia S , Bobik Tatiana V , Gavrilov Leonid A , Sablina Marina Aleksandrovna , Rapoport Eugenia M , Stepanenko Vasily N , Tuzikov Alexander Borisovich
Published: February 2025

A methodology for the enzymatic ligation of proteins with a lipid is proposed, a feature of which is the use of a hydrophilized [thanks to a CMG(2) spacer] and therefore highly water-soluble lipid. Its H2N-Gly5 terminus and the recombinant protein amino acid sequence LPETG are substrates of the enzyme sortase A. Two lipid-ligated proteins, red fluorescent mCherry and Protein A, are shown to be inserted into the cell membrane.
New tricyclic cage compound as allosteric modulator of the glutamatergic system: synthesis and biological activity
Authors: Golubeva Elena Andreevna , Lavrov Mstislav Igorevich , Veremeeva Polina Nikolaevna , Matthews James , Radchenko Eugene V , Zamoyski Vladimir L , Grigoriev Vladimir Viktorovich , Palyulin Vladimir Alexandrovich
Published: February 2025

A new tricyclic derivative of 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane was synthesized in three steps using 2-aminoindane-5-carbonitrile. A positive modulatory activity of this compound towards the glutamatergic system in a wide range of nanomolar and subnanomolar concentrations has been demonstrated in electrophysiological studies in vitro using patch clamp technique. A putative binding mode of this compound has been revealed by means of molecular docking and molecular dynamics simulations.
European soft law instruments for sustainability agreements – presentation of procedural issues, critical analysis and recommendations for the President of the OCCP
Authors:   King’s College London, Zawłocka-Turno Agata
Published: February 2025

The article focuses on the procedural aspects of soft law tools employed by competition authorities in Europe, in order to help businesses advance sustainable development. In response to global challenges, such as the climate crisis, some authorities have introduced guidelines and informal guidance to enable companies to undertake pro-environmental collaboration, without breaching competition laws. Examples include guidelines from the European Commission, as well as those from the UK, Dutch, and French competition authorities. The article examines how effective these tools are, their impact on legal certainty for businesses, and explores how a similar approach could be implemented by the Polish Competition Authority (the President of UOKiK).
Search Browse Latest additions Theses Statistics Policies and Help Contact us Uncertainty quantification and personalisation of lumped parameter models of the cardiovascular system
Authors:   , Saxton Harry
Published: February 2025

Abstract
Personalised medicine, facilitated by the growing capacity to collect comprehensive patient data, aims to provide personalised therapies for each individual. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. These models, which are based on physiology and physics rather than on population statistics, enable computational simulations to reveal diagnostic information that would have otherwise remained concealed and to predict treatment outcomes for individual patients. The inherent need for patient-specific models in cardiology is clear and is driving the rapid development of tools and techniques for creating personalised methods to guide pharmaceutical therapy, deployment of devices and surgical interventions. For computational models to have clinical utility, we must be able to provide a quantification of the risk associated with any predictions or interpretations which are made from the model. Lumped parameter models (LPM) represent the cardiovascular system as a series of electrical segments, each characterised by parameter values that offer insights into the associated health status. Given one can constrain the model with patient specific data such that the parameter values are updated, one obtains a digital representation of a patient’s cardiovascular system. This research investigates the crucial offline stage of uncertainty quantification for models, primarily employing sensitivity analysis, with the goal of achieving personalisation. As such, this work first examines the process of performing a global sensitivity analysis of a cardiovascular LPM, establishing some best practices to ensure accurate model interpretations. Then we assess the impact of the chosen outputs of a model when looking to quantify uncertainty. We demonstrate how variation in the chosen outputs can significantly impact one’s interpretation of a model. Following the enhanced understanding of the best practices around sensitivity analysis, we extend a method for obtaining a personalised subset of input parameters, acknowledging the inherent variability among individuals in medicine. Alongside this, a novel examination of the sensitivity indices is proposed within the context of personalised medicine to provide insight associated with the calibration of model parameters. Finally, we investigate a data assimilation technique and explore the method’s effectiveness for model personalisation. The primary outcome of this research is the development of an offline model personalisation workflow, designed to reduce the uncertainty associated with calibrating models to patient data to the greatest extent possible.
Una revisión historiográfica sobre el legado pictórico de José Quero González
Authors: Martínez Fernández Javier
Published: February 2025

La figura de José Quero González merece una revisión historiográfica. Su legado artístico se traduce en más de medio millar de obras pictóricas debido a su incesante producción creativa durante el último tercio del siglo XX y la primera década del presente siglo. El objetivo del presente artículo académico pretende reconocer su aportación al arte español contemporáneo, actualizar información referente a su amplio repertorio artístico gracias a la labor de inventariado realizada recientemente y poner en valor su trayectoria dentro del contexto internacional en el cual participó de manera activa.
Sagas de plateros compostelanos inéditos: Emilio Bacariza, Manuel Bacariza y María Varela
Authors: Pérez Varela Ana
Published: February 2025

La platería compostelana sigue siendo una asignatura pendiente de la historiografía gallega. Para contribuir a esta línea de investigación, decidimos abordar al gremio de plateros desde un punto de vista documental, vaciando los archivos disponibles para hallar todas las noticias posibles relativas a estos artistas. El resultado ha sido el conocimiento de algunos plateros completamente olvidados, cuya importancia para el desarrollo artístico de la ciudad queda patente gracias a las numerosas referencias en prensa histórica. En este artículo presentamos a la familia Bacariza, una de las más interesantes e importantes en la Compostela del tránsito del siglo XIX al XX. Hasta ahora el hijo, Manuel, era completamente desconocido y todo punzón «BACARIZA» se atribuía a su padre. Gracias a los archivos hemos podido hallar una cantidad de documentos y piezas que nos permiten reconstruir parte de sus biografías, periodizar su producción y constatar su importancia en la sociedad de su época, además de hallar mencionada a María Varela, como la única «platera» compostelana de la que tenemos noticia.
MARTÍ BONAFÉ, María Ángeles (coord.) Marías. Entre la adoración y el estigma. Valencia: Tirant Humanidades, 2022, 103 págs., ISBN: 978-84-19071-69-9.
Authors: Ríos Moyano Sonia
Published: February 2025

Reseña de libro
Síndrome cólica causada por ingestão de Panicum maximum cultivar Massai: relato de cinco casos
Authors: Silva Jorgy Luiz Campos de Magela , Lima Ellian Marinho , Ferreira Filho José Daniel Alves , Maia Marcelo Augusto Emerenciano , De Melo Ubiratan Pereira , Ferreira Cintia
Published: February 2025

A síndrome cólica equina é uma condição clínica comum e grave, frequentemente associada a diversas patologias no trato gastrointestinal. Este estudo relata cinco casos de cólica equina em éguas alimentadas com capim Panicum maximum cultivar Massai, caracterizados por distensão abdominal e sinais clínicos típicos de cólica. O diagnóstico foi confirmado por palpação retal e ultrassonografia, que indicaram compactação colônica em todos os casos. Os animais re-ceberam tratamento com analgésicos, fluidoterapia e terapia pró-cinética, além de gluconato de cálcio e sorbitol para manejo da distensão abdominal. O caso 1, 2 e 3 apresentaram resolução clínica, com melhora observada entre 24 e 96 horas após a intervenção. O caso 4 necessitou de intervenção cirúrgica após a falha da terapia conservadora, sendo realizada enterotomia da flexura pélvica para remoção da compactação. O caso 5 evoluiu para óbito, apesar da tentativa de tratamento conservador e diagnóstico cirúrgico. Este estudo destaca a importância do diagnóstico rápido e tratamento adequado na síndrome cólica equina, além de evidenciar a eficácia da enterotomia em casos de complicações graves. Embora a maioria dos casos tenha mostrado recuperação, o prognóstico pode ser influenciado pela gravidade do quadro clínico e pela resposta ao tratamento.
IMPLEMENTATION OF CONTROL POLICY OF DIPHTHERIA OUTBREAK AND OUTBREAK RESPONSE IMMUNIZATION (ORI) IN KOTA DEPOK, 2017
Authors:   Health Policy and Administration, Faculty of Public Health, Universitas Indonesia, Depok, Indonesia, Sari Dian Novita , Achadi Anhari ,   Health Policy and Administration, Faculty of Public Health, Universitas Indonesia, Depok, Indonesia
Published: February 2025

Diphtheria is a contributor to an outbreak (KLB) for some regions in Indonesia, included West Java Province. Diphtheria cases had increased through 2015 - 2016, the cases increased from 59 cases to 153 cases. Depok City became one of the contributors of diphtheria cases that have fluctuating incidents. Disease trends have decreased in 2013-2015 but then increased in 2016 to 8 cases. This study discusses policy implementation, viewed from policy sources, resource arrangements, the characteristics of implementing agencies, bureaucratic structures, communications, the influence of dispositions and socio-economic and political circumstances in control of Diphtheria Outbreak and Outbreak Response Immunization (ORI) in Depok City in 2017. This type of research is qualitative research with descriptive design, through in-depth interviews and document review. The results showed that the limited resources, especially human resources, the lack of cross-sectoral concern and social environment factors, including the rejection of some community for vaccination, became a challenge in controlling the Diphtheria Outbreak and Outbreak Response Immunization (ORI) in Depok City. It is expected that policy implementers can commit to working together, and taking into the influential factors in policy implementation, as well as government support in providing halal and safe vaccines and research on bioterrorism can also be done as solving cases of diphtheria fluctuating annually.
THE DETERMINANT OF OUTPATIENT HEALTH SERVICES UTILIZATION FOR ELDERLY PATIENT IN INDONESIA (SUSENAS 2017 DATA ANALYSIS)
Authors:   Health Policy and Administration, Faculty of Public Health, Universitas Indonesia, Depok, Indonesia, Putri Rizki Asriani , Ilyas Yaslis ,   Health Policy and Administration, Faculty of Public Health, Universitas Indonesia, Depok, Indonesia
Published: February 2025

Indonesia has entered an aging population as showed by the number of elderly population which has reached more than 7% of the population. Basically, the increase in the elderly population will also increase the number of illnesses, because the more a person ages, the physical condition will decrease and be more susceptible to disease. This research is a quantitative study that aims to determine the determinants of outpatient health service use for Indonesian elderly in 2017. This research used secondary data from the 2017 National Socio-Economic Survey (Susenas) results with the unit of analysis is people aged ≥ 60 years who had health complaints. The analytical method used is logit regression analysis. The results showed that gender, education, employment status, residential area, health insurance ownership, economic status, and disruption of activity due to illness had a p-value of 0,000 < 0,05 which meansthat it was significantly associated with the utilization of outpatient health services. The most dominant variable is the disruption of activity due to illness. The government can issue policies related to efforts to register each elderly person into health insurance through optimizing a healthy Indonesian program with a family approach. The government is expected to be more assertive in monitoring and evaluating elderly health services by considering factors that support the elderly in utilizing health services to achieve healthy aging and active aging.
Mechanisms of PP2A-Ankle2 dependent nuclear reassembly after mitosis
Authors: Li Jingjing , Wang Xinyue , Jordana Laia , Bonneil Éric , Ginestet Victoria , Ahmed Momina , Bourouh Mohammed , Pascariu Cristina Mirela , Schmeing T Martin , Thibault Pierre , Archambault Vincent
Published: February 2025

In animals, mitosis involves the breakdown of the nucleus. The reassembly of a nucleus after mitosis requires the reformation of the nuclear envelope around a single mass of chromosomes. This process requires Ankle2 (also known as LEM4 in humans) which interacts with PP2A and promotes the function of the Barrier-to-Autointegration Factor (BAF). Upon dephosphorylation, BAF dimers cross-bridge chromosomes and bind lamins and transmembrane proteins of the reassembling nuclear envelope. How Ankle2 functions in mitosis is incompletely understood. Using a combination of approaches in Drosophila, along with structural modeling, we provide several lines of evidence that suggest that Ankle2 is a regulatory subunit of PP2A, explaining how it promotes BAF dephosphorylation. In addition, we discovered that Ankle2 interacts with the endoplasmic reticulum protein Vap33, which is required for Ankle2 localization at the reassembling nuclear envelope during telophase. We identified the interaction sites of PP2A and Vap33 on Ankle2. Through genetic rescue experiments, we show that the Ankle2/PP2A interaction is essential for the function of Ankle2 in nuclear reassembly and that the Ankle2/Vap33 interaction also promotes this process. Our study sheds light on the molecular mechanisms of post-mitotic nuclear reassembly and suggests that the endoplasmic reticulum is not merely a source of membranes in the process, but also provides localized enzymatic activity.
The relationship between gut and nasopharyngeal microbiome composition can predict the severity of COVID-19
Authors: Martin-Castaño Benita , Diez-Echave Patricia , García-García Jorge , Hidalgo-García Laura , Ruiz-Malagon Antonio Jesús , Molina-Tijeras José Alberto , Rodríguez-Sojo María Jesús , Redruello-Romero Anaïs , Martínez-Zaldívar Margarita , Mota Emilio , Cobo Fernando , Díaz-Villamarin Xando , Alvarez-Estevez Marta , García Federico , Morales-García Concepción , Merlos Silvia , Garcia-Flores Paula , Colmenero-Ruiz Manuel , Hernández-Quero José , Nuñez Maria , Rodriguez-Cabezas Maria Elena , Carazo Angel , Martin Javier , Moron Rocio , Rodríguez Nogales Alba , Galvez Julio
Published: February 2025

Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that displays great variability in clinical phenotype. Many factors have been described to be correlated with its severity, and microbiota could play a key role in the infection, progression, and outcome of the disease. SARS-CoV-2 infection has been associated with nasopharyngeal and gut dysbiosis and higher abundance of opportunistic pathogens. To identify new prognostic markers for the disease, a multicentre prospective observational cohort study was carried out in COVID-19 patients divided into three cohorts based on symptomatology: mild (n = 24), moderate (n = 51), and severe/critical (n = 31). Faecal and nasopharyngeal samples were taken, and the microbiota was analysed. Linear discriminant analysis identified Mycoplasma salivarium, Prevotella dentalis, and Haemophilus parainfluenzae as biomarkers of severe COVID-19 in nasopharyngeal microbiota, while Prevotella bivia and Prevotella timonensis were defined in faecal microbiota. Additionally, a connection between faecal and nasopharyngeal microbiota was identified, with a significant ratio between P. timonensis (faeces) and P. dentalis and M. salivarium (nasopharyngeal) abundances found in critically ill patients. This ratio could serve as a novel prognostic tool for identifying severe COVID-19 cases.
Modelo multicritério para avaliação de competitividade no setor energia renováveis
Authors: Paiva Antonia Claudenice Pinheiro de Almeida , Figueiredo Ciro José Jardim de , Pedrosa Camila Karen Alves
Published: February 2025

As organizações têm buscado constantemente a excelência na gestão dos seus negócios, devido à competição acentuada e às crescentes demandas do mercado, precisam ser cada vez mais ágeis e adaptáveis. No setor solar, essa competitividade torna-se ainda mais intensa, devido a grande quantidade de empresas no país, a natureza do serviço, e a falta de barreiras para novos entrantes. Assim, é importante que estudos aprofundem estratégias que potencializem a competitividade dessas empresas e sua consolidação no mercado. O presente estudo tem como objetivo criar um modelo de avaliação da competitividade para empresas instaladoras de sistemas fotovoltaicos, utilizando a metodologia de apoio multicritério à decisão (AMD). Para isso, foi realizada uma revisão de literatura com intuito de elencar os principais critérios que impactam a competitividade das empresas integradoras, adotando o método Delphi para validar os critérios encontrados na literatura. Para a construção do modelo, utilizou-se a metodologia de Apoio Multicritério à Decisão e para a modelagem das preferências, o método PROMETHEE II, além da análise de sensibilidade para avaliação da eficácia do modelo. Como principais resultados, o modelo criado para avaliar a competitividade das empresas integradoras foi composto por 27 critérios e foi aplicado com 21 empresas. O modelo desenvolvido demonstrou pertinência e aplicabilidade à realidade das empresas estudadas, apoiando o processo de tomada de decisão.  Dessa forma, essa pesquisa contribuiu com a criação de um modelo que possibilita avaliar as empresas integradoras.
Manejo de la flora arvense en forestaciones en terrenos agrícolas abandonados en la península ibérica
Authors: Monreal Montoya José Antonio , Copete Carreño Miguel Ángel , Botella Miralle Olga , Copete Carreño Elena , Espín Montoro Yolanda , Herranz Sanz José María
Published: February 2025

Las forestaciones en terrenos agrícolas abandonados proliferan en muchas regiones del mundo. Bajo clima mediterráneo, su arraigo puede verse comprometido por la competencia con la abundante flora arvense característica de estos ecosistemas. Nuestros objetivos fueron evaluar el potencial colonizador de la comunidad arvense en un antiguo cultivo tras 25 años de abandono, y estudiar el efecto de diferentes técnicas de control en la supervivencia y desarrollo de plantas forestales. Se muestreó el banco edáfico de semillas (métodos directo e indirecto) antes de forestar la parcela con Pinus halepensis, Quercus ilex subsp. ballota y Retama sphaerocarpa. Tras la plantación se aplicaron diferentes técnicas de control: laboreo, siega y tratamiento químico. Durante tres años se midió supervivencia, diámetro y altura. Los resultados mostraron una comunidad arvense abundante (67 taxones) con banco edáfico de semillas persistente (casi 20 000 semillas/m2), causante de elevada mortalidad principalmente en el pino. El laboreo resultó la mejor técnica el primer año para el arraigo del pino, mientras que la encina y la retama no mostraron diferencias entre tratamientos. A partir del segundo año, el tratamiento químico fue el óptimo al favorecer el crecimiento, recomendándose con las precauciones que conlleva el uso de herbicidas. Independientemente de que la respuesta de cada especie forestal a la competencia arvense pueda ser distinta, es fundamental analizar la necesidad de control de esta vegetación para incrementar el éxito de las forestaciones en ambientes tan exigentes como los mediterráneos.