bluuebunny/crossref_metadata_2025 huggingface dataset:
Herramientas digitales para la gamificación aplicada a la enseñanza de ciencia y tecnología
Authors: Ramos Martínez José Antonio
Published: February 2025

Las herramientas digitales para la didáctica educativa en temas de ciencia y tecnología han revolucionado la forma en que se desarrollan los procesos pedagógicos. Estas herramientas incluyen programas de simulación, plataformas de aprendizaje en línea, inteligencia artificial, aplicaciones móviles, realidad aumentada y juegos educativos, entre otros. El anglicismo gamificación nace por la necesidad de llevar el juego a ámbitos donde no es común. Esta técnica pretende fomentar el interés y la participación en el ámbito educativo. En este estudio se presentan las perspectivas o apreciaciones de los profesionales en educación en diferentes niveles.
Universidad digital. proceso de digitalización de las universidades de el salvador
Authors: Paniagua Martínez Marta Guadalupe
Published: February 2025

Con los avances tecnológicos en las empresas, incluyendo las instituciones de enseñanza, los procesos administrativos, de enseñanza-aprendizaje y la relación con el cliente, no están exentos a los procesos de digitalización. Por tal motivo, el presente trabajo trata de reunir la información básica para generar ese cambio o facilitar el proceso de digitalización de las Instituciones de Educación Superior.
El problema del paro en Europa: causas y remedios
Authors:   Universidad Autónoma de Barcelona, Fina Lluis
Published: February 2025

Este artículo está en gran medida basado en el análisis y propuestas contenidas en el Libro Blanco de la Comisión Europea sobre Crecimiento, Competitividad, Empleo. En primer lugar se describen los rasgos específicos que caracterizan el problema del paro en Europa y su evolución. A continuación se presentan los principales factores explicativos de la situación descrita, con especial énfasis en los denominados factores estructurales. Finalmente el trabajo esboza las soluciones propuestas para resolver el problema, donde se incluyen tanto las acciones a desarrollar a nivel de la Unión Europea como las que recaen bajo la responsabilidad de las autoridades nacionales.
Nuevas tendencias en el mercado laboral europeo: la reorganización del tiempo de trabajo
Authors:   Universidad del País Vasco, Sánchez María Isabel , Rasines Luis Alberto ,   Universidad del País Vasco
Published: February 2025

El aumento del paro en la Comunidad a partir del año 1990 ha llevado, por un lado a muchos gobiernos europeos a fomentar las reducciones de las jornadas laborales en las empresas y, por otra parte, a numerosos sindicatos y patronos a firmar de forma descentralizada convenios colectivos con importantes reducciones de los tiempos de trabajo. El debate sobre la reducción de la jornada laboral sigue abierto y se vislumbra como un importante elemento de ajuste en el mercado laboral que permita hacer compatibles la eficiencia productiva con ciertos niveles de equidad social.
Indicadores ocupacionales y sectoriales del mercado de trabajo en la C.A. de Euskadi
Authors:   IKEI, Garayalde Maiztegui Iñigo , Salvador Arrillaga Lide ,   IKEI
Published: February 2025

El artículo compara brevemente la información estadística disponible sobre el mercado de trabajo de la C.A. de Euskadi, incidiendo en las limitaciones que existen para analizar la estructura ocupacional con la desagregación deseable. Se presentan a continuación diversos indicadores para 64 grupos ocupacionales, utilizando la evolución del empleo y diversas características demográficas, sectoriales y educativas. El artículo finaliza presentando una clasificación de los 64 grupos ocupacionales en seis tipos homogéneos en base al valor de estos indicadores en el Censo de Población de 1991 y a su evolución en 1981-91.
Las ocupaciones en el año 2000: un ejercicio de proyección
Authors:   Gobierno Vasco, Sasigain Saenz de Buruaga Francisco Javier
Published: February 2025

El análisis de los cambios y de la estructura ocupacional de una economía nos permite inferir interesantes conclusiones sobre su grado de desarrollo cualitativo como reflejo desde el punto de vista de la fuerza de trabajo de la tecnología de los diferentes sectores de actividad. La previsión de su evolución nos permite adelantar los probables desajustes futuros que se podrían dar entre la oferta y la demanda de trabajo para cada una de sus cualificaciones, entre la formación y las necesidades de las empresas. Este es el objetivo del presente estudio, realizar un pequeño ejercicio de proyección de las ocupaciones del País Vasco en el año 2000 cuantificando sus respectivos crecimientos esperados. De su conocimiento se destilan amplias aplicaciones en los campos de la planificación y de las políticas de información, orientación e inserción laboral y educativa.
La contratación temporal en España: mercado de trabajo y prácticas empresariales
Authors:   Universidad Complutense de Madrid, Cachón Rodríguez Lorenzo
Published: February 2025

En España se ha ido produciendo una descomposición del principio de estabilidad en el empleo, descomposición producida tanto en el mercado como en la construcción jurídica. El resultado ha sido una explosión de la contratación temporal. El artículo examina, a partir de los datos de la Encuesta de Población Activa (1987-1994) la evolución y características de los contratos temporales y los flujos de entrada y salida de la contratación temporal. Entre las entradas aparecen tres tercios diferenciados y entre las salidas aparecen flujos significativos hacia el paro y hacia empleos estables, lo que apunta la existencia de tipos diferentes de prácticas empresariales respecto a la contratación temporal.
Desempleo juvenil en España: ¿Qué determina su duración?
Authors:   Universidad del País Vasco, Ahn Namke , Ugidos Olazabal Arantza ,   Universidad del País Vasco
Published: February 2025

En este artículo se analiza la duración del desempleo juvenil en España. Los resultados empíricos, usando datos de la ECVT (1985), indican que es importante distinguir entre hombres y mujeres y entre dos posibles transiciones: desempleo-empleo y desempleo-no participación. Primero, el seguro de desempleo aumenta la duración principalmente por retrasar la salida del mercado de trabajo para mujeres y por retrasar el tener un empleo para hombres. Segundo, la situación familiar es un importante factor de la duración del desempleo de un individuo. Los hombres cabeza de familia son más rápidos en encontrar empleo que los que no lo son, mientras que las mujeres solteras encuentran empleo más rápidamente que las casadas. Tener una educación universitaria aumenta de forma sustancial la probabilidad de encontrar empleo de las mujeres jóvenes, pero la variable educación no tiene un efecto significativo en la probabilidad de encontrar empleo entre los hombres jóvenes. Tanto para hombres como para mujeres, aquellos que están desempleados por haber finalizado su contrato laboral son mas rápidos en abandonar el mercado laboral que los que son despedidos.
A IMPORTÂNCIA DA UTILIZAÇÃO DO CHECKLIST NA UNIDADE PRODUTORA DE REFEIÇÃO EM RELAÇÃO AS BOAS PRÁTICAS E PROTOCOLO COVID-19
Authors: Ferreira Mirian dos Santos , Melo Fabio Lima de , Flor Adanny Aparecida Lemos Queiroz , Dalfolo Alice de Carvalho , Alexandre Antônia Stéfane Silva , Nascimento Bruna Pereira do , Freitas Ivanila de Sousa , Ferreira Nailyne Costa , Oliveira Náquia Franco , Silva Paula Vieira Nascimento Oliveira
Published: February 2025

RESUMO

Unidade Produtora de Refeição (UPR) é todo ambiente de caráter fora do lar, onde se fornece alimento nutricionalmente equilibrado e com garantia higiênico-sanitário, devido a um aumento no número de refeições fora dos lares os níveis de doenças transmitida por alimentos vem crescendo conforme os aumentos das empresas que fornecem alimentos. Em fevereiro de 2020 surgiu no Brasil a covid-19 com isso os números de desempregos, principalmente nos setores de serviços foram os mais atingidos. O presente trabalho teve como objetivo relacionar o novo protocolo da covid-19 com a legislação pré-existente na prevenção de doenças transmitida por alimentos (DTA). Trata-se de um estudo observacional do tipo transversal com abordagem qualitativa onde foram utilizados dois checklist como ferramenta de identificação das inconformidades de duas unidades avaliadas, localizada na região metropolitana do Recife, um para comensais criado pela Secretaria de Saúde do Estado de Pernambuco, composto por 10 itens e o outro pela Resolução de Diretoria Colegiada ( RDC) de 2002, onde foram analisados os blocos: Edificações e Instalações, Equipamentos, Móveis e Utensílios, Manipuladores, Produção e Transporte de Alimentos. Os Resultados após análise dos dados através da aplicação dos checklist observamos que as empresas atingiram o grau de conformidade estabelecido pela Resolução de Diretoria Colegiada (RDC) de 2002 os valores entre 76 a 100% são considerados ótimos para a produção de alimentos, de acordo com a média dos dias que foram aplicados o checklist a unidade A o percentual encontrado de conformidade foram 84,51%, já a unidade B foram 80,29%. o papel do nutricionista trouxe resultados positivos nessas empresas deixando-os conforme a legislação, trazendo qualidade e segurança para os que frequentam.

Palavras-chave: RDC em UPR, checklist em UAN, boas práticas de manipulação, DTA.
A sistemática de conteúdo local e a cooperação entre TCU e ANP: um passo importante rumo à coerência regulatória
Authors: Dantas Bruno , Caldas Evandro , Martins Fernanda
Published: February 2025

O Tribunal de Contas da União realizou auditoria operacional para avaliar a Política de Conteúdo Local nas licitações do mercado de petróleo e gás, bem como as implicações e os impactos da ausência de regulamentação adequada sobre o tema dentro da Agência Nacional de Petróleo, Gás Natural e Biocombustíveis. Esse Tribunal fez recomendações e determinações à Agência e ao Ministério de Minas e Energia, e acabou por contribuir de forma efetiva para o aprimoramento regulatório da matéria. Investiga-se, no presente artigo, se é possível haver uma atuação coordenada de um agente regulador e seu controlador ou se, invariavelmente, pode-se pressupor certa dose de conflito entre eles
Suspeição do juiz por relacionamento pessoal ou relação de parentesco com advogado no Direito alemão
Authors: Trivisonno Alexandre Travessoni Gomes , Oliveira Júlio Aguiar de
Published: February 2025

O artigo objetiva analisar o princípio da imparcialidade do juiz no Direito brasileiro e no alemão, bem como sua concretização, no segundo, em casos de relacionamento pessoal ou relação de parentesco entre juiz e advogado. Trata-se, portanto, metodologicamente, de um estudo de Direito Comparado. A análise abrange o conteúdo, a validade nos sistemas jurídicos brasileiro e alemão, a correção prática geral e a classificação normativa do princípio da imparcialidade do juiz. Demonstra-se que, do ponto de vista da moderna teoria dos princípios, o “princípio” da imparcialidade do juiz deve ser classificado como uma regra, não como princípio. Em seguida, são estudadas as medidas adotadas pelo Direito alemão vigente para a efetivação do princípio da imparcialidade do juiz nos casos em que existe relacionamento entre juiz e advogado. A análise mostra que na Alemanha os meios processuais são suficientes para implementar o princípio da imparcialidade do juiz
Prevalence of Fatty Liver in Duhok Governorate; a cross-sectional study
Authors: Ahmed Jeen Shahab , Ghazi Dezhwar Yahya , Salih Hawar M. , Salih Zaynab M.
Published: February 2025

Background and objectives: fatty liver disease has an estimated prevalence of around 30% worldwide. The gold-standard method for the diagnosis is by liver biopsy. Ultrasound imaging can be used as a screening tool for the disease since it is less invasive, more widely available, and acceptable. The method uses B-mood for the detection of the features of the disease. Methodology: This cross-sectional study was conducted in a duration of 3 months; Jan-10th, 2024 to March 10th, 2024. A total of 413 samples were collected. Sampling started with filling out a questionnaire followed by the performance of ultrasound using the B-mood. All the data were analyzed using SPSS. A P value of < 0.05 was regarded as statistically significant. Results: The prevalence of fatty liver was found to be 22% in the total sample. The prevalence was higher among males (32.8%) compared to females (20.1%). We found that 45.1% of patients with a history of diabetes had fatty liver on ultrasound (P < 0.0001). The prevalence of fatty liver was higher among males than females and among overweight and obese compared to other groups; P = 0.028 and 0.008, respectively. Conclusion: Fatty liver is a burden on the population. The prevalence of the disease keeps rising over time leading to an increase in morbidity and mortality. Ultrasound should be used widely as a screening tool for detection of fatty liver.
Resveratrol como terapia adjuvante para manejo da endometriose: Evidências clínicas
Authors: De Fatima da Conceição Veríssimo Lopes Juliana , Nascimento da Silveira Gomes Rebecca , Carvalho Reinoso Rayane , Momente Martins Saturnino Caroline , Gomes da Silva Daniel , Guida Chagas Esther , De Matos Silva Daiane , Martins de Oliveira Nunes Raissa , Da Silva Almeida Lilian , Wilson Cosme de Mesquita Júnior José , Maria Gonçalves de Caldas Almeida Marina , Daiane Oliveira dos Santos Mayla
Published: February 2025

A  endometriose é uma doença ginecológica e inflamatória caracterizada pelo desenvolvimento do endométrio e de glândulas endometriais fora da cavidade uterina. Tal patologia pode manifestar-se de forma assintomática em algumas mulheres, no entanto, a maioria apresenta sintomas clínicos em diferentes intensidades, sendo os principais: dismenorreia, dispareunia, dor abdominal baixa e/ou nas costas, disquezia, disúria e hábitos intestinais alterados. Dessa forma, a endometriose tornou-se uma das principais causas de incapacidade e comprometimento significativo da qualidade de vida em adolescentes e mulheres adultas. Nesse contexto, em virtude do seu potencial biológico como antioxidante, anti-inflamatório e imunoprotetor, o resveratrol, emerge como uma potencial terapia complementar ao tratamento da endometriose e melhora da qualidade de vida dos indivíduos acometidos por essa patologia. Trata-se de uma revisão integrativa, elaborada a partir de uma pesquisa realizada na base de dados da Biblioteca Virtual em Saúde (BVS) e Google Scholar através do cruzamento dos descritores selecionados com o auxílio dos operadores booleanos “AND”, “OR” e “PARÊNTESES”. A análise dos resultados revelam que a suplementação de resveratrol pode contribuir para a melhora do quadro clínico das mulheres afetadas por essa condição, reduzindo a intensidade dos sintomas e, consequentemente, melhorando a qualidade de vida. Portanto, torna-se evidente o potencial do resveratrol como uma terapia adjuvante no manejo da endometriose, destacando suas propriedades antioxidantes, anti-inflamatórias e imunoprotetoras.
Four Attributes of Great Leadership: Confidence, Connection, Commitment, and Courage
Authors: Westover Jonathan
Published: February 2025

This paper explores four key attributes that define great organizational leaders: confidence, connection, commitment, and courage. Academic research and practical examples demonstrate how these qualities of character are equally significant for leadership effectiveness as technical skills and strategic abilities. Confident leaders believe in their vision and inspire optimism, while connected leaders build trust and motivation through strong relationships. Committed leaders prioritize organizational and individual development over self-interest, while courageous leaders persevere through challenges with integrity. Cultivating these four attributes provides a critical foundation for maximizing positive influence and impact as a leader, regardless of industry or context. The research and application show that developing confidence, connection, commitment, and courage is vital for any aspiring or current leader aiming to drive success.
Impacto do tempo de exposição às telas no comportamento alimentar de crianças e adolescentes com excesso de peso
Authors: Targino Mayra Bezerra , Bezerra Alane Nogueira , Souza Luana Matos de , Lourenço Eric Wenda Ribeiro , Carvalho Annelise Barreto de , Montenegro Júnior Renan Magalhães , Maia Carla Soraya Costa , Lopes Synara Cavalcante
Published: February 2025

O objetivo deste trabalho é avaliar a relação entre o tempo de exposição à tela e o comportamento alimentar de crianças e adolescentes com excesso de peso. Trata-se de um estudo transversal realizado com crianças e adolescentes com excesso de peso de Fortaleza. Foram investigados dados sociodemográficos, clínicos, prática de atividade física, hábitos de exposição às telas e estado nutricional. O Questionário Children’s Eating Behaviour Questionnaire (CEBQ) avaliou o comportamento alimentar.  Participaram 82 crianças e adolescentes, sendo 69,5% do sexo feminino. O estado nutricional apresentou associação apenas com a subescala de “sobreingestão emocional” (p = 0,006). O tempo diário de exposição às telas apresentou associação significativa com o comportamento alimentar nas subescalas que refletem interesse pela comida (“resposta à comida”: p = 0,039; “prazer em comer”: p = 0,002; “desejo de beber”: p = 0,01) com maiores médias no grupo que tinha exposição diária excessiva às telas. Além disso, também obtiveram uma pior resposta à saciedade, referido pela subescala “resposta à saciedade” (p = 0,037). O hábito de comer em frente à tela apresentou associação significativa com as subescalas “sobreingestão emocional” (p = 0,019) e “subingestão emocional” (p = 0,014). O comportamento alimentar de crianças e adolescentes com excesso de peso, expostos excessivamente às telas, mostra aumento do interesse pela comida, maior sensibilidade a estímulos alimentares externos, desejo por bebidas açucaradas e menor capacidade de regular o consumo alimentar. Comer em frente às telas e o estado nutricional foram associados ao comportamento alimentar influenciado por fatores de estresse emocional.
Impacts of dose titration on logistic exposure-response in simulated flexible-dose clinical trials
Authors: Xu Shuang , Poland Bill
Published: February 2025

Objectives: Dose titration based on response seeks to optimize individual responses while minimizing the risk of side effects. However, this technique is not widely adopted in drug development due to the selection bias it creates, where responders tend to receive lower doses and non-responders tend to receive higher doses. This bias can sometimes obscure or even reverse the expected dose-response exposure-response (E-R) relationship, a phenomenon known as the "titration paradox” [1]. The objective of this work was to illustrate the effects of dose titration on E-R analysis for a binary endpoint and to examine factors that could help resolve the paradox. Methods: A simple dose titration study was simulated: 200 patients treated for 24 weeks for a liver disease resulting in elevated alkaline phosphatase (ALP) levels at baseline, with no dropouts. Participants were randomly assigned to either the 50 mg or the 100 mg dose arm in a 1:1 ratio, and a 2-fold increase in dose was permitted at 12 weeks if a participant had an ALP > 1.67×upper limit of normal (ULN). At 24 weeks, the relationship between drug exposure and a binary efficacy endpoint of ALP (BALP) was evaluated: whether a patient achieved ALP ≤ 1.67×ULN or not. Baseline ALP, steady-state drug exposure, and the intrinsic half-maximal effective exposure (EC50) for percent change in ALP were simulated to follow a lognormal distribution across subjects, while maximal percent decrease in ALP (Emax) was assumed to follow a normal distribution. Responses in terms of absolute ALP, change from baseline ALP, and the BALP endpoint were derived from the simulated percent change in ALP values, modeled as: E0 + Emax * exposure / (EC50 + exposure) + random error Results: The simulations demonstrated the titration paradox, where the E-R relationship for BALP in a logistic model unexpectedly reversed at week 24. Adding a titration flag as an interaction term to drug exposure in the logistic model allowed for dynamic E-R relationships in subgroups of patients with and without up-titration. Results showed that the titration flag helped resolve the paradox in patients without up-titration, as higher drug exposure increased the probability of achieving BALP. The positive E-R relationship became less significant with increasing random dropouts. The titration paradox was also observed in the E-R relationship of continuous absolute ALP but not continuous change from baseline ALP. Conclusions: The simulations suggest that continuous response measured as change from baseline is a better endpoint than the absolute response or the binary form because it is less susceptible to the titration paradox, and that a titration flag could help unveil the true E-R relationship in the subgroup of patients without dose titration.Citations: [1] Schnider T W et al. (2021). The drug titration paradox: correlation of more drug with less effect in clinical data. Clinical Pharmacol. Ther. 110(2), 401-408.
Hybrid Population PK-Machine Learning Model Approach to Predict Infliximab Concentrations in Pediatric Patients with Crohn's Disease
Authors: Irie Kei , Minar Phillip , Reifenberg Jack , Mizuno Tomoyuki
Published: February 2025

Objectives: Bayesian estimation using a population pharmacokinetic (PK) model is a valuable tool for individualizing dosages, particularly when faced with limited sample availability. However, the accuracy of such predictions can be compromised by various factors, including misspecification in prior information and uncertainties in PK changes. In this study, we developed a hybrid machine learning (ML) and population PK-based Bayesian approach to enhance the predictive performance of infliximab (IFX) concentrations using the Bayesian estimation in pediatric patients with Crohn's Disease.Methods: Residuals between predicted IFX trough concentrations by Bayesian estimation using a pediatric IFX population PK model [1] and observed concentrations were computed using real-world data from pediatric patients with Crohn’s disease (292 concentrations from 93 patients). To predict the degree of residuals, we employed various ML algorithms, including linear regression, random forest, support vector regression, neural networks, and XGBoost, and evaluated their performance. Features for the ML models were identified based on the Pearson correlation coefficient (r) between the residuals and patient-related data, such as laboratory results, PK parameters, and dosing history. The predictive performance of the ML model-corrected Bayesian estimation was assessed using root mean square error (RMSE) and mean prediction error (MPE) with 5-fold cross-validation.Results: For Bayesian estimation alone, the RMSE and MPE were 4.8 µg/mL and -0.7 µg/mL, respectively. We observed associations between the residuals and the observed IFX concentrations used for Bayesian estimation (i.e. prior trough) (r=-0.47, p < 0.001), the deviation to typical clearance (ETA for CL) (r = -0.140, p = 0.0168), erythrocyte sedimentation rate (ESR) (r = -0.15, p = 0.015), anti-IFX antibodies (r = -0.19, p=0.001), change in weight (r = -0.16, p = 0.005), and change in ESR (r = 0.23, p < 0.001) during the last dosing interval. Among the evaluated algorithms with selected features, the XGBoost model demonstrated the best predictive performance. The RMSE and MPE of the XGBoost model-corrected Bayesian estimation were 3.72 ± 0.88 µg/mL and -0.01 ± 0.54 µg/mL, respectively, with 5-fold cross-validation.Conclusions: The ML model-corrected Bayesian estimation significantly improved predictive performance in predicting IFX trough concentrations in real-world data, surpassing the performance of Bayesian estimation alone. This hybrid population PK-ML approach may offer a framework for continually enhancing the predictive performance of Bayesian estimation through adaptive learning from new clinical data for dose individualization.Citations: [1] Xiong et al., Real-World Infliximab Pharmacokinetic Study Informs an Electronic Health Record-Embedded Dashboard to Guide Precision Dosing in Children with Crohn's Disease. Clin Pharmacol Ther. 109(6):1639-1647, 2021
Identifying Determinants of Vaccine Efficacy: A Mechanistic Modeling Approach
Authors: Schiavone Carmine , Cave Joseph , Wang Zhihui , Cristini Vittorio , Dogra Prashant
Published: February 2025

Objectives: Vaccines are pivotal in combating infectious diseases, saving millions of lives worldwide and vastly improving public health. Despite their success, the effectiveness of vaccines varies across individuals, posing a significant challenge in achieving optimal community-wide protection. Several host factors such as virus pre-exposure, age, sex, genetics, and co-morbidities can influence the strength of the vaccine-induced immune response[1,2]. This variability thus affects the population-scale efficacy of vaccines and underlines the need for an approach to optimize the use of vaccines to improve outcomes. In this study we developed a mechanistic model to analyze how these factors influence the immune response to vaccination, aiming to enhance vaccine efficacy across populations.Methods: Based on our previous work[3], we developed a model based on a system of ordinary differential equations to define the temporal evolution of the key immunological variables, including CD4+ T-cells, antibody-secreting plasma cells, neutralizing antibodies, and cytokines (IL-2 and IFN-gamma). A closed form solution of the kinetics of the injected antigen governs the activation of CD4+ T-cells, which initiate the downstream immunological processes leading to antibody-induced immunity. Analyzing immune responses to COVID-19 vaccines in approximately 3700 healthy adults, we fitted our model to population-scale data and performed a global sensitivity analysis to identify critical parameters affecting antibody production.Results: The model fits were in good agreement with the data (Pearson correlation R > 0.9) Global Sensitivity Analysis (GSA) revealed that the duplication rate of plasma cells (P_PB), antigen potency (K_Ant), death rate of plasma blasts (D_PB), and the production rate of antibodies per cell (P_Ab) were the four key parameters driving antibody responses. Subsequently, we characterized the distribution of these 4 parameters for various cohorts representing a demographically diverse population. Significant differences were observed between the parameter distributions of cohorts, thereby quantifying the effect of demographic covariates on vaccine-induced immunity. This allowed us to simulate vaccine clinical trials and identify strategies, such as injection timing optimization, to enhance the immune response of weakly responsive cohorts. Conclusion: Our findings provide insights into the variability of vaccine-induced immune response and propose a framework for optimizing vaccine efficacy tailored to demographic characteristics. This approach can improve vaccine distribution strategies and aid in the design of clinical trials, particularly crucial during pandemics.Citations: [1] S. L. Klein and K. L. Flanagan, Nature Reviews Immunology 16, 626 (2016).[2] M. M. A. R. van Dorst et al., Nature Reviews Immunology (2023).[3] P. Dogra et al., JCI Insight (2023).
A Scalable Cloud-Based QSP Modeling System for Virtual Patient Generation
Authors: Matteson Andrew , Hagen David , Swat Maciej , Matthews Richard , Kierzek Andrzej , Apgar Joshua
Published: February 2025

Objectives: This study focuses on enhancing the efficiency of generating virtual patient populations, a critical component in various Quantitative Systems Pharmacology (QSP) modeling workflows such as virtual clinical trial simulation, digital twin generation, characterizing biological variability, and biomarker generation. The primary objectives are to streamline the generation process, reduce computational costs, and improve the quality of the generated population. Methods: We developed a comprehensive cloud-based QSP modeling system that supports the entire virtual patient population workflow. This includes population parameter estimation, virtual population generation, and virtual population simulation. Our system integrates multiple algorithms for creating virtual patients, notably the Allen et. al. algorithm and the No-U-Turn (NUTS) algorithm, a Monte-Carlo-like sampling algorithm (1,2,3). In this work, we compare the populations generated, and computational performance of different algorithms across a representative sample of QSP and minimal-PBPK style models. We explore several changes to the proposal distribution produced in the Allen et. al. algorithm. Results: The implementation of the system demonstrated significant performance improvements. Specifically, the simulation times on a single thread and single worker were 30-40% faster than those of compiled SimBiology models for a selection of QSP and minimal-PBPK models. The cloud-based system can scale up to over 1000s of worker CPUs, leveraging cost-effective computational resources to rapidly generate virtual populations. Our approach achieved substantial enhancements in the speed and efficiency of generating virtual patient populations. Conclusions: The newly developed QSP modeling system markedly improves the generation and simulation of virtual patient populations, affirming the feasibility of scaling the process while managing computational costs effectively. Further exploration of modifications to the Allen et. al. algorithm showed potential for incremental improvements in population quality, computational resource utilization, and overall performance. We compare algorithmic approaches for their impact on the quality of population generated, efficient use of compute resources, and wall-clock performance.Citations: [1] Abril-Pla, Oriol, et al. "PyMC: a modern, and comprehensive probabilistic programming framework in Python." PeerJ Computer Science 9 (2023): e1516. [2] Allen, R. J., Theodore R. Rieger, and Cynthia J. Musante. "Efficient generation and selection of virtual populations in quantitative systems pharmacology models." CPT: pharmacometrics & systems pharmacology 5.3 (2016): 140-146. [3] Rieger, Theodore R., et al. "Improving the generation and selection of virtual populations in quantitative systems pharmacology models." Progress in biophysics and molecular biology 139 (2018): 15-22.
Leveraging AI for improved reproducibility of mathematical disease models: insights from a retinitis pigmentosa case study
Authors: GREUGNY Elea THIBAULT , Ratto Nicolas , Etheve Loïc , Gourlet Jean-Baptiste , Cogny Frederic , Monteiro Claudio
Published: February 2025

Objectives: This study aims to demonstrate the utility of Artificial Intelligence in enhancing the reproducibility of mathematical disease models. Through a case study of a disease progression mechanistic model of Retinitis Pigmentosa [1], the potential of AI in streamlining the model re-implementation process is showcased.Methods: Chat GPT 4, a sophisticated large language model developed by OpenAI, customized by Mathpix with additional functionalities, was employed. This customized model enabled the extraction of equations from PDF documents and their conversion into Antimony, a human-readable, text-based language. Subsequently, the model was translated into Systems Biology Markup Language (SBML) using the Python package tellurium. The converted model was then uploaded onto the jinkō platform for simulations.Results: The efficient and accurate implementation of the RP model using AI techniques was demonstrated in this study. The disease progression biological phenomena such as the evolutions of rods, cones and the nutrient pool (representative of the total number of retinal-pigment epithelium neuroprotective factors, growth factors and nutrients) as reported in the literature was successfully reproduced. Conclusion: The findings of this study underscore the value of AI in enhancing the reproducibility of mathematical disease models. By automating the re-implementation process and facilitating swift verification, AI offers a promising avenue for decision-makers to independently validate model results. This encourages the broader adoption of AI in mathematical model re-implementations to ensure reliability and reproducibility of the results.Citations: [1] Camacho, E. T., Punzo, C. & Wirkus, S. A. Quantifying the metabolic contribution to photoreceptor death in retinitis pigmentosa via a mathematical model. Journal of Theoretical Biology vol. 408 75–87 (2016).
A Minimal Physiology-based Pharmacokinetics Model of Blood-Brain Barrier Transport for Monoclonal Antibodies Targeting the Transferrin Receptor
Authors: Zhang Xianwei , Wang Haiqing
Published: February 2025

Objective: The limited efficiency of systemic drug delivery to central nervous system (CNS) has led to the use of invasive intrathecal dosing in clinical studies. Recent advances have identified the transferrin receptor (TfR) as a potential target for antibody-mediated blood-brain barrier (BBB) transport, offering a promising avenue for delivering large-molecule therapeutics to CNS. Despite some clinical successes of TfR-conjugated drugs, achieving the desired drug profile for efficient TfR-mediated delivery to specific brain compartments remains challenging. Our objective was to develop a quantitative model integrating antibody binding affinity and corresponding drug exposure in plasma and CNS compartments to understand how various factors of anti-TfR antibodies affect the efficiency of CNS drug delivery and whether high-affinity TfR-antibody accumulation in BBB endothelial cells affects delivery efficiency.Methods: We developed a physiology-based pharmacokinetics (PBPK) model to explore how brain and cerebrospinal fluid (CSF) exposures are affected by varying antibody binding affinities at different dosing levels and routes of administration. Our model is calibrated against published preclinical pharmacokinetics (PK) data and simplifies the mathematical description of TfR-mediated trans- and intracellular disposition of anti-TfR antibodies via BBB. Subsequently, we conducted a sensitivity analysis to examine the effects of multiple factors, including dosing levels, binding affinities, etc.Results: Our model replicates PK profiles of both non-specific and TfR antibodies in plasma, CSF, and brain ISF. Notably, over an extended duration, CSF and brain ISF exhibit parallel trends, suggesting that CSF PK measurements may serve as predictive tools for brain ISF PK for both non-specific and TfR antibodies in long term. The model quantified the contributions to brain drug uptake by BBB-crossing and CSF-crossing pathways, depending on the route of administration. Specifically, brain ISF predominantly acquires drugs via the BBB during both intravenous and intracerebroventricular administration, with minimal contribution from CSF to brain ISF uptake. Moreover, reducing systemic clearance significantly enhances plasma PK, resulting in prolonged exposure in CSF and brain ISF. Additionally, diminishing lymphatic clearance modestly increases brain ISF exposure. As binding affinity increases, the area under the curve (AUC) for brain ISF, CSF, and the brain ISF-to-plasma AUC ratio initially rises, then declines, exhibiting a bell-shaped curve in relation to the logarithm of binding affinity.Conclusions: Our model provides insights into the biodistribution and the influence of binding affinity in the CNS, informing the development of monoclonal antibodies for CNS diseases.Citations: no
Exposure-Response Efficacy and Safety Analysis of Repotrectinib to Support the Dose Recommendation for Patients with ROS1-positive NSCLC
Authors: du Shengnan , Hamuro Lora , Hu Zheyi , Kondic Anna , Lu Ming , Roy Amit , Shen Jun , Zhu Li
Published: February 2025

Objectives: Repotrectinib is a tyrosine kinase inhibitor approved in the US for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC and currently being developed for the treatment of adult and pediatric patients with NTRK-positive solid tumors. Exposure - response (E-R) models were developed with selected key efficacy endpoints (OR: objective response rate and PFS: progression-free survival) and clinical safety endpoints (Gr2+ dizziness : ≥ Grade 2 dizziness, DRDI: dose reduction or interruption due to AEs) to support the benefit-risk assessment of repotrectinib and dose justification for the treatment of patients with ROS1-positive NSCLC.Methods: Data from TRIDENT-1 (NCT03093116) were used to evaluate E-R relationships. A logistic regression model was used to understand E R of objective response with respect to time-averaged repotrectinib concentration over the first 56 days of dosing (Cavg56). Cox Proportional-Hazards (CPH) models were used to characterize the relationship of PFS as well as safety endpoints (Gr2+ dizziness, DRDI) with respect to time-varying cumulative repotrectinib concentration (Cavgc) averaged over every 12-hours . The logistic regression model and CPH model were used to predict and compare the efficacy and safety for dosing regimens 160 mg QD/BID (160 mg QD for 14 days, if tolerated, followed by 160 mg BID) and 160 mg QD under different food status.Results: The probability of OR or PFS for ROS1-positive NSCLC increased with exposure. As compared with 160 mg QD, the recommended dose regimen of 160 mg QD/BID was predicted to show improved efficacy (eg, ORR 85.0% vs 76.1% and 46.6% vs 33.1% for TKI-naive and TKI-pretreated respectively) but with only a small increase in AEs (eg, Gr2+ dizziness 15% vs 13%). The model-predicted probabilities of all evaluated efficacy endpoints and AEs are similar among the different food conditions and supports repotrectinib dosing without regard to food status. This work emphasizes the importance of selecting an appropriate exposure for the E-R analyses when dose or dose frequencies change throughout treatment.Citations: NA
FIVEDB as a tool for analysis of in vitro experimental data: cytokine production by primary cells and cell lines
Authors: Goryacheva Ekaterina , Kopeikina Anna , Polinova Almina , Gizzatkulov Nail , Stepanov Alexander , Demin Oleg
Published: February 2025

Objectives: Mathematical biomodels include a lot of processes and regulatory interactions. Use of in vitro data for parameters estimation is important but time-consuming work for modelers. To facilitate searching and analysis of experimental data for model calibration we developed fIVEDB [1], which collects experimental data from literature, automatically converts them to unified units and calculates kinetic parameters describing cell death, proliferation, migration, differentiation, and secretion. Quantitative in vitro results are often obtained using immortalized cell lines because they are considered as good biological models and have some advantages: easy to use, last longer and provide a homogenous population of cells. But cell lines are genetically modified and that can alter physiological properties in case of extensive passaging. In our study we compared production of cytokines secreted by primary cells and immortalized cell lines to find out if cell lines data are suitable for model parameters estimation. Our results can help modelers choose appropriate experimental data for model calibration. Methods: In vitro experimental data for fIVEDB are manually extracted from literature sources and translated into kinetic parameters (kbase, Emax, Imax, EC50, IC50 etc.) The parameter calculation based on equations for standard in vitro experiments developed by InSysBio [2]. For comparing of kinetic parameters for cell lines and primary cells cytokine production, we downloaded data for primary monocytes and monocytic cell lines: THP-1 and Mono-Mac-6. For each group of data for primary cells and cell lines, we performed statistical data processing using a one-sided Mann-Whitney test.Results: A comparative analysis of pro-inflammatory cytokine production (TNFα, IL-6, IL-1β), anti-inflammatory (IL-8, IL-10), and chemokines CCL2, CCL3 was carried out between THP-1 cell line and primary monocytes obtained from healthy donors. No statistically significant differences were found in any comparison group, suggesting that THP-1 is a good alternative for modelers when the main data pool is lacking. The same analysis was performed for Mono-Mac-6, no significant differences were observed for this cell line compared to primary cells.Conclusions: Using in vitro experimental data collected in fIVEDB we compared cytokine production by monocytic cell lines (THP-1, Mono-Mac-6) and corresponding primary cells. Performed analysis showed that there are no significant differences between calculated parameters for these cultures, so quantitative results obtained for studied cell lines (THP-1, Mono-Mac-6) can be used for estimation of biological model parameters in case of lack of primary cells data.Citations: [1] fIVE Database. InSysBio. https://5db.insysbio.com/[2] InSysBio Blog. InSysBio. https://insysbio.com/blog
Concentration-QTc Analysis of PF-07220060 in Patients with Advanced Solid Tumors
Authors: Gao Xizhe
Published: February 2025

Objectives: PF-07220060 is a next-generation highly selective CDK4 inhibitor with significant sparing of CDK6 currently being investigated in participants with metastatic or advanced solid tumors with focus on HR+/HER2- metastatic breast cancer. The purpose of this work was to assess the impact of PF-07220060 plasma level on cardiovascular parameters, including RR-interval and heart rate-corrected QT interval (QTc), in patients from the ongoing first-in-human Phase 1/2a study (NCT04557449).Methods: A preliminary PK/PD analysis (data-cut date: November 1, 2023) was conducted to explore the relationship between electrocardiogram (ECG) endpoints and plasma PF-07220060 concentration based on time-matched PK and triplicate mean ECG data. A graphical summary and linear mixed-effects modeling approach was applied. The ECG endpoints were RR interval and the change-from-baseline QTc corrected for heart rate. To obtain QTc values that are independent of the heart rate, three correction methods were evaluated: Fredericia’s formula (site reported QTcF), Bazett’s formula (QTcB), and study-specific estimated correction (QTcS). A 90% confidence interval (CI) of the slope which includes “zero” was interpreted as PF-07220060 having no statistically significant concentration-dependent effect on the ECG parameter. Results: The dataset consisted of 3848 paired PK-ECG measurements collected from 164 patients in the dose escalation and dose expansion cohorts. The upper bound of 90% CI for the concentration-RR slopes was below 0, indicating that RR-intervals decrease with increasing drug concentrations. The predicted heart rate change at the observed steady state geometric mean Cmax at 300 mg BID was 0.97 bpm (90% CI: 0.01, 1.95) and the drug effect on heart rate is considered minimal. Using only baseline data, the confounding relationship between QT and RR was adequately eliminated by the Fridericia correction or study-specific correction. By visual inspection, QTcF was as effective as QTcS in correcting the effect of heart rate on the QT interval, therefore QTcF was chosen for the concentration-ΔQTc analysis. The 90% CI for the concentration-ΔQTcF slope included 0, indicating PF-07220060 did not have a statistically significant concentration-dependent effect on QTcF. The predicted ΔQTcF at the observed steady state geometric mean Cmax at 300 mg BID was 3.9 msec (90% CI: 1.9, 5.9). Even at a 2-fold greater concentration, the predicted ΔQTcF is 5.5 msec (90% CI: 1.9, 9.1), and the upper bound of the 90% CI of the predicted QTcF increase is beneath the ICH E14 threshold for regulatory concern (10 msec). Conclusions: Initial concentration-QT analysis indicates that the effect of PF-07220060 on heart rate is minimal and PF-07220060 does not exhibit a concentration-dependent impact on QTcF, suggesting a low potential for QT prolongation at clinical doses to be evaluated in the future studies.Citations: NA
Decoding Mean Viral Load in RSV Human Challenge Studies
Authors: Liao Laura , Maas Brian
Published: February 2025

Objectives: Human challenge studies (HCS) are used to evaluate new antiviral treatments and establish clinical proof of concept. Typically, a mean viral load (VL) profile is presented as a key figure in antiviral therapy publications. In contrast to fixed dosing times relative to the viral challenge (inoculation), the study design for RSV (respiratory syncytial virus) challenge models includes triggered dosing times (i.e., variable dosing time based on qualitative PCR positivity post-challenge) which adds a layer of complexity to the information encoded. We sought to illustrate common errors in interpreting the typical VL profile and propose an alternate figure that might reduce biases in interpretation. Methods: We used viral dynamics modelling to fit clinical data from a published RSV HCS [1, 2]. Placebo and treatment arms were simulated in a triggered dosing scheme. We used simulations to illustrate differences in individual VL dynamics and summary VL in terms of features (VL peak, time), and explored the impact of imputation rules for values below the lower limit of quantification (LLOQ).Results: An alternate key mean VL figure is proposed which includes stratification by dosing time relative to time of challenge, number of individuals in each stratification, and clear indication of the LLOQ. Simulated examples are used to demonstrate that the antiviral treatment effect observed via reduction in VL may be confounded by variable dosing times. Specifically, later dosing times (relative to viral challenge) may lessen the observed reduction in VL. Conclusions: An alternative presentation of the mean VL figure should be considered to provide a more unbiased illustration of antiviral effect in the setting of challenge studies with a triggered dosing design.Citations: [1] DeVincenzo, J.P., et al., Oral GS-5806 activity in a respiratory syncytial virus challenge study. N Engl J Med, 2014. 371(8): p. 711-22.[2] Kelly, G., et al., Use of qualitative integrative cycler PCR (qicPCR) to identify optimal therapeutic dosing time-points in a Respiratory Syncytial Virus Human Viral Challenge Model (hVCM). J Virol Methods, 2015. 224: p. 83-90.