bluuebunny/crossref_metadata_2025 huggingface dataset:
Peran Teori Motivasi Dalam Mendukung Pembelajaran PAI Bagi Siswa Berkebutuhan Khusus
Authors: Sari Nofita , Sari Dewi Purnama , Warsah Idi
Published: February 2025

Penelitian ini bertujuan untuk menganalisis pengaruh game online Mobile Legend terhadap perilaku bertutur kata siswa di MTs Baitul Makmur. Objek penelitian adalah siswa yang aktif memainkan game Mobile Legend. Tujuan utama penelitian ini adalah untuk mengetahui apakah terdapat perubahan dalam cara siswa berkomunikasi, baik secara positif maupun negatif, sebagai dampak dari interaksi dalam permainan tersebut. Metode yang digunakan adalah metode deskriptif kualitatif dengan pendekatan studi kasus. Data dikumpulkan melalui observasi, wawancara, dan kuesioner kepada siswa dan guru, serta analisis interaksi siswa di dalam dan luar lingkungan sekolah. Hasil penelitian menunjukkan bahwa terdapat perbedaan signifikan dalam perilaku bertutur kata siswa yang sering bermain Mobile Legend. Sebagian siswa menunjukkan peningkatan kreativitas dalam berbahasa dan kerja sama dalam komunikasi kelompok, namun sebagian lainnya cenderung meniru kata-kata kasar atau tidak pantas yang sering muncul dalam permainan. Kesimpulan dari penelitian ini adalah bahwa game online Mobile Legend memiliki dampak ganda terhadap perilaku bertutur kata siswa. Diperlukan peran aktif dari guru dan orang tua untuk mengarahkan siswa agar mampu menyaring dan menerapkan penggunaan bahasa yang positif serta mengurangi dampak negatif dari permainan tersebut.
Features of international trade contract
Authors: Ekram Yawar Mohammad , Amani Anwarulhaq
Published: February 2025

The electronic environment of the Internet is considered one of the most modern means of concluding contracts and fulfilling the obligations arising from them, especially in the field of commercial transactions. The nature of electronic contracts in relation to their validity, form, and conformity with the general rules and regulations of civil law regarding contracts is one of the new debates, the understanding and examination of which relations and legal effects arise from it, depend on the formal structure of the electronic environment and the concepts of communication technology recognized in this field.
The conclusion of electronic contracts and the characteristics specific to these contracts, the impact of the electronic nature on their formation, and the aspect of harmonization of general rules and regulations of electronic contracts are the main objectives of this article. Electronic contracts, in principle, do not have a different nature from traditional contracts. However, with this existence, the formal structure of the electronic environment has given new characteristics and concepts to this type of contract.
In this regard, it can be said that the formal structure and technical characteristics of the electronic environment have created a modern and extensive transformation in various dimensions of contract law, which will potentially affect the concepts of benefits in the way contracts are concluded. The present article attempts to address the characteristics of such contracts in a descriptive and analytical manner.
Nueva política económica para el desarrollo de Centroamérica
Authors: Olmos Guevara Ricardo Humberto
Published: February 2025

El artículo analiza los obstáculos al desarrollo económico de Centroamérica: el aporte residual o nulo del sector exportador al crecimiento económico de la región, la desarticulación de las economías y la limitada participación del Estado en el desarrollo. Para la verificación empírica de la tesis central utiliza el Sistema de Contabilidad Nacional, así como la matriz insumo-producto de cada país. Los resultados de la investigación indican que el crecimiento económico es posible con una nueva política económica orientada al desarrollo con la ejecución de una planificación económica conducida por el Estado, a travésde las ramas y sectores dinámicos de las economías de los países de América Central.
Conflictos familiares y la participación de las hijas e hijos en la mediación familiar
Authors: Muñoz Zepeda Emma Patricia
Published: February 2025

La mediación familiar es una alternativa a la resolución de conflictos, evitando procesos judiciales que demoran la solución de una controversia en la que madres, padres, hijas e hijos pueden alcanzar a partir de la figura del mediador. Las niñas, niños y adolescentes son sujetos de derechos y tienen un rol activo en estos procesos que permiten discutir problemas que afectan a su área de derechos. En consecuencia, debe permitirse su participación. La metodología empleada es documental, para propiciar un análisis crítico–reflexivo que permita identificar los beneficios de la participación de niñas, niños y adolescentes. Se concluye que es necesario visualizar los derechos de niñas, niños y adolescentes a partir del principio del interés superior y prioridad absoluta.
La salvación en la consejería: un caso de infidelidad y conflicto de identidad
Authors: García Rivera Eduardo Rafael
Published: February 2025

La doctrina de la salvación es fundamental en la teología cristiana, y su comprensión adecuada es crucial para abordar problemas prácticos en la vida de los creyentes. Este ensayo explora cómo aplicar el entendimiento teológico de la salvación a un caso específico de consejería: una persona que ha sido infiel en su matrimonio y ha experimentado un conflicto de identidad. La falta de arrepentimiento y las decisiones que demuestran una posible vida de doble estándar indican una comprensión deficientede la doctrina de la salvación. A través del análisis de esta situación, se evaluará cómo el entendimiento teológico puede influir en la consejería y en el proceso de restauración espiritual.
La robótica educativa en el proceso de enseñanza y aprendizaje en el fablab esfe
Authors: Aguilar Esquivel Ulises , Bolaños de Cáceres Helen Karina
Published: February 2025

En la presente investigación se han analizado diversas estrategias para mejorar el entorno de aprendizaje de los estudiantes. Se trata de fortalecer los conocimientos de los jóvenes aplicando un método de enseñanza que estimule el constructivismo y la metacognición para responder a las necesidades educativas de la sociedad de la información. La teoría describe los beneficios de integrar la robótica como herramienta de apoyo para la enseñanza de diferentes contenidos curriculares, reconoce que la disciplina promueve el constructivismo, la interdisciplinariedad y el aprendizaje significativo en un entorno controlado para la obtención de losaprendizajes de robótica básica. La robótica educativa se posiciona como un elemento nuevo y necesario a conocer por las nuevasgeneraciones. El uso de la robótica en la educación implica el diseño y la construcción de un robot. Se concluye que un robot es un ente programado para moverse, manipular o desempeñar diferentes acciones de forma autónoma o guiada por medio de controles o aplicaciones diseñadas para teléfonos móviles o laptops.
PERSPECTIVAS A RESPEITO DA ESTIMULAÇÃO ENCEFÁLICA PROFUNDA EM SINTOMAS NÃO MOTORES EM PACIENTES COM DOENÇA DE PARKINSON: TCSR, CONSTIPAÇÃO E DEPRESSÃO.
Authors: Alencar Marco Antônio Melo , Canizo Hélio Assayag , Barbosa Maria Júlia Leal , Rocha Mateus Moreira , Pinto Victor Hugo Xavier , Correia José Luiz da Silva , Ferreira Vinícius dos Santos , Shimozato Lucas Eichi Brito , Gonçalves Ana Beatriz de Oliveira , Ribeiro Fabiano Assayag
Published: February 2025

A Doença de Parkinson é neurodegenerativa, com sintomas motores (SM) e não motores (SNM). A Estimulação Encefálica Profunda (EEP) implanta eletrodos para modular circuitos cerebrais. A  A EEP no Núcleo Ventral Intermédio (EEP-VI) trata tremores, a  EEP no globo pálido interno (EEP-GPi) melhora SM, e a EEP no núcleo subtalâmico (EEP-NST) atua em SM e SNM, sendo o alvo preferencial. Objetivos: Avaliar a visão atual acerca da EEP em sintomas não motores: transtorno comportamental do sono REM (TCSR), Constipação e Depressão, para DP. Métodos: Esta revisão integrativa sintetiza resultados de pesquisas nas bases PubMed, MEDLINE e Scielo, com termos-chave específicos. Foram selecionados 17 artigos (2019-2024), mas apenas 10 embasaram o projeto. Os demais foram excluídos por não cobrirem a seção temática. Resultados: A EEP-NST bilateral alivia SNM, incluindo TCSR, mas piora sintomas olfativos e melhora parcialmente a constipação. A EEP-GPi mostrou eficácia apenas em SM. Alguns pacientes não evoluíram em SNM, e a EEP-NST pode causar deterioração cognitiva ao longo do tempo. Conclusão: A EEP é eficaz para tratar SM, mas há poucos estudos sobre seus efeitos em SNM, especialmente neuropsicológicos. Mais pesquisas são necessárias para compreender melhor sua ação nos SNM e otimizar o tratamento para pacientes com Doença de Parkinson.
QUALIDADE DO TRATAMENTO DE INIBIÇÃO DA CORROSÃO EM SISTEMA DE ÁGUA
Authors: Silva Maxwell Ray da
Published: February 2025

A qualidade do tratamento de prevenção da corrosão em sistemas de água é essencial para garantir a integridade das estruturas metálicas e a pureza da água fornecida. O objetivo geral do presente trabalho foi abordar sobre as corrosões no sistema de água. Enquanto os objetivos específicos foram abordar sobre os tipos de corrosão, discorrer sobre os inibidores de corrosão, abranger sobre o monitoramento de corrosão e salientar sobre a qualidade da água e saúde pública bem como os desafios e tendências futuras. O presente trabalho trata-se de uma revisão bibliográfica buscado em bases de dados online com tempo recorte de 10 anos. A corrosão em sistemas de água representa uma ameaça à qualidade da água potável e à saúde pública, liberando íons metálicos e produtos de manipulação que afetam o sabor e a segurança da água. O controle e monitoramento contínuo da corrosão são essenciais para a proteção dos componentes metálicos e a prevenção da contaminação da água. No futuro, os desafios incluem a demanda crescente por água, infraestruturas envelhecidas e a necessidade de abordagens mais sustentáveis, enquanto as tendências envolvem o desenvolvimento de tecnologias avançadas de monitoramento e a busca por materiais resistentes à corrosão.
Mulheres togadas: diversidade de gênero e perspectivas sociais em cortes constitucionais
Authors: Bogéa Daniel
Published: February 2025

O artigo apresenta argumento teórico pela diversidade de gênero em tribunais constitucionais. A literatura analisada enquadra-se em duas visões: argumentos simbólicos, que defendem a importância de mulheres em posições socialmente valorizadas; e argumentos empiristas, que tentam estabelecer correlações entre juízas e decisões pró-mulheres. O estudo desenvolve uma terceira tese (argumento procedimental), segundo a qual a diversidade de gênero deve ser compreendida como ferramenta para melhoria da qualidade deliberativa. Com base no conceito de perspectiva social de Iris Marion Young, desloca-se o foco da presença de interesses para a pluralidade de pontos de partida. A diversidade de gênero possibilita que perspectivas de grupos sociais que sofrem opressão e dominação influenciem o empreendimento coletivo de aplicação da Constituição. A tese responde de forma mais adequada ao problema do essencialismo de gênero e enfrenta particularidades de tribunais vis-à-vis outros poderes políticos, notadamente o ideal de imparcialidade e o suposto conflito entre igualdade e mérito
Dez anos da lei federal das cotas universitárias: avaliação de seus efeitos e propostas para sua renovação e aperfeiçoamento
Authors: Godoi Marciano Seabra de , Santos Maria Angélica dos
Published: February 2025

Como contribuição para o processo legislativo que levará à revisão pelo Congresso Nacional, em 2022, do programa de reserva de vagas em universidades e instituições federais de ensino técnico de nível médio criado pela Lei nº 12.711/2012, este artigo promove uma revisão bibliográfica sobre o histórico e os principais efeitos das cotas universitárias surgidas no País nos primeiros anos do século XXI. Em seguida, o estudo relaciona os pontos dessa lei que merecem atenção e revisão do legislador federal. Aponta-se que o Ministério da Educação não tem cumprido as obrigações legais de monitoramento e avaliação do programa; e as exigências da lei que instituiu em 2014 a cota de 20% das vagas para negros também não têm sido cumpridas pela maioria dos concursos públicos para docentes universitários. É preciso reforçar a regulamentação das comissões de heteroidentificação dos candidatos que se autodeclaram negros e avançar nas iniciativas de ação afirmativa no âmbito da pós-graduação
Participação da pessoa com deficiência intelectual ou mental curatelada no processo eleitoral brasileiro: o direito político de ser votada
Authors: Pereira Elizabete Aparecida
Published: February 2025

Analisa-se o direito político de candidatura da pessoa com deficiência intelectual ou mental curatelada, instituído pela Convenção Internacional sobre os Direitos das Pessoas com Deficiência, internalizada no Brasil como emenda constitucional. Problematiza-se como tal direito subsiste à regra de sua perda ou suspensão por incapacidade civil absoluta, prevista no art. 15, II, da Constituição da República Federativa do Brasil. Parte-se da contextualização dos direitos políticos das pessoas com deficiência e passa-se à análise da temática nas Constituições brasileiras, na Convenção e na Lei nº 13.146/2015 no que se refere às alterações promovidas no regime das incapacidades, com reflexos na curatela para as deficiências intelectual e mental. Os resultados da revisão bibliográfica, legislativa e jurisprudencial evidenciam descompassos entre a Lei Brasileira de Inclusão, a Convenção que lhe dá suporte e o texto constitucional, bem como a ausência de enfrentamento do assunto pelos tribunais
Políticas institucionais da Defensoria Pública do Estado de São Paulo: uma análise com base nos ciclos de conferências
Authors: Lemes Maurício Buosi , Severi Fabiana Cristina
Published: February 2025

O objetivo deste artigo é analisar o processo de implementação e de monitoramento das políticas institucionais da Defensoria Pública do Estado de São Paulo relacionadas ao acesso à justiça na temática de habitação, urbanismo e conflitos agrários, com base no estudo dos ciclos de conferências no período 2007-2017. Considerando a diversidade de contextos em que a instituição está inserida, buscamos identificar e descrever alguns desafios relativos ao melhoramento de políticas públicas e das capacidades estatais. Tais desafios relacionam-se ao fortalecimento das capacidades burocrático-organizacionais e de coordenação entre os distintos órgãos da Defensoria Pública do Estado de São Paulo, com o envolvimento mais ativo dos recursos humanos e organizacionais no âmbito das unidades regionais e locais. A pesquisa é sociojurídica empírica, de cunho qualitativo, no formato de estudo de caso, com a utilização de dados documentais fornecidos por registros institucionais
Os “novos homens bons”: eleição, representação e cidadania nos debates parlamentares sobre as municipalidades oitocentistas (Brasil, 1826-1828)
Authors: Souza Williams Andrade de
Published: February 2025

Este é um trabalho historiográfico que aborda alguns aspectos da representação e da cidadania no Brasil oitocentista. Tomando como objeto de estudo os debates parlamentares em torno da Lei de 1º de outubro de 1828, que deu nova forma às câmaras municipais, marcou suas atribuições e o processo para a sua eleição, discorreremos sobre como as casas legislativas no Império (re)definiram a participação popular na eleição municipal e estabeleceram os limites e possibilidades para alcançar os postos de “novos homens bons”. A temática é histórica, porém atual, pois desvela o universo legislativo e seu papel na regulação das instituições representativas, o cariz eletivo da governança local e as possibilidades de acesso e participação política da sociedade no respectivo processo eleitoral na primeira metade do século XIX
“Esse silêncio todo me atordoa”: a surdez e a cegueira seletivas para as dinâmicas raciais nas Relações Internacionais
Authors: Silva Karine de Souza
Published: February 2025

A disciplina das Relações Internacionais está intimamente relacionada com as hierarquias raciais. Entretanto, paradoxalmente, as dinâmicas da raça têm sido silenciadas nas análises do sistema internacional pelas teorias hegemônicas da área. Este artigo objetiva evidenciar os silêncios que concorrem para a perpetuação do racismo como eixo fundante da disciplina e afirmar a necessidade de introduzir a raça e a branquitude como categorias analíticas fundamentais no estudo das Relações Internacionais e das relações de poder no sistema-mundo. Este artigo tem sua base teórica nas epistemologias anticoloniais, pós-coloniais e decoloniais, porque estas permitem compreender como o padrão de dominação colonial fundado na raça e no gênero ainda segue em operação. Reconhecer as interações entre raça e poder é condição sine qua non para corrigir as deformações em leituras produzidas pela disciplina sobre o sistema-mundo e para viabilizar horizontes emancipatórios baseados em sociabilidades não hierarquizadoras
Última palavra e diálogos constitucionais: caminhos e descaminhos na jurisdição constitucional brasileira
Authors: Barreiro Guilherme Scodeler de Souza , Cruz Álvaro Ricardo de Souza
Published: February 2025

O objetivo geral do presente artigo é investigar os caminhos e descaminhos da jurisdição constitucional brasileira e refletir sobre as possibilidades e os entraves para uma jurisdição mais dialogal. Para isso, analisam-se as recentes reformas no Poder Judiciário e busca-se inserir no debate, entre a “última palavra” e os diálogos constitucionais, o papel das reclamações constitucionais e a intensificação do fenômeno da monocratização no Supremo Tribunal Federal. Por um lado, com base nos dados coletados em pesquisa bibliográfica e documental, percebeu-se um aumento na incidência das reclamações constitucionais, o que pode indicar um caminho para a implementação dos diálogos constitucionais. Por outro, diante da crescente utilização de decisões monocráticas pelos ministros, constata-se a dificuldade estrutural de inserção da jurisdição constitucional brasileira em um ambiente mais dialógico
O caso Abaporu e as restrições à livre circulação de obras de arte no Direito brasileiro
Authors: Silva Neto Francisco Antônio de Barros e
Published: February 2025

O ensaio aborda as restrições à circulação internacional de obras de arte portadoras de referência à ação, à identidade e à memória dos grupos formadores da sociedade brasileira, com ênfase no Decreto-lei nº 25/1937 e nas Leis nºs 4.845/1965 e 5.471/1968, a partir do caso Abaporu, quadro de Tarsila do Amaral
A natureza jurídica do ato de nominação de espaços públicos
Authors: Cunha Filho Francisco Humberto , Magalhães Allan Carlos Moreira
Published: February 2025

O artigo analisa a natureza jurídica do ato de nominação de espaços públicos tendo por premissa que nomear as coisas é uma atividade essencial aos seres humanos, os quais as categorizam, as classificam e delas se apropriam. Não é atividade administrativa banal: envolve aspectos sensíveis da memória coletiva. Para compreender essa natureza, este trabalho adota como recorte o Brasil e a hipótese de que, com a Constituição da República Federativa do Brasil de 1988 e o redimensionamento conferido ao patrimônio cultural, batizar um bem público e ao mesmo tempo homenagear algo ou alguém se situa na interseção dos direitos culturais com o Direito Administrativo. Adota-se uma metodologia analítica e crítica com revisão bibliográfica e análise do Direito posto e proposto. Como resultado, apresentam-se critérios temporais, axiológicos e participativos para uma regulamentação da matéria por norma geral da União, pois o ato de nominar espaços públicos é competência legislativa concorrente e, em termos materiais, comum aos entes da Federação
Presença parlamentar nas mídias sociais: a estruturação dos mandatos digitais na Câmara dos Deputados
Authors: Barros Antonio Teixeira de , Bernardes Cristiane Brum , Faria Cristiano Ferri Soares de , Busanello Elisabete
Published: February 2025

O estudo tem como objetivo analisar as estratégias que os deputados federais da 56ª Legislatura (2019-2022) adotam no uso dos sites de redes sociais. Com base em questionário aplicado aos assessores dos gabinetes parlamentares, examinam-se as práticas adotadas pelos representantes em cada rede digital e os objetivos políticos que pretendem alcançar. Incluem-se no estudo as seguintes plataformas de redes: Facebook, Instagram, YouTube, Twitter, WhatsApp, Telegram e LinkedIn. A amostragem, composta por 155 informantes, corresponde a 30,21% do total dos 513 gabinetes parlamentares brasileiros. As conclusões mostram que 65% dos gabinetes adotam estratégias específicas para cada tipo de mídia social, embora haja uma diretriz maior, que é a constituição de multirredes, de forma coordenada e complementar
Impact of motor control exercises on postural alterations in the elderly
Authors: Mera Natalya Alexandra Gordon , Prado Jorge Emilio Chávez , Carrión Sonia Alexandra Alvarez
Published: February 2025

As people age, it is common for them to experience changes in posture due to factors such as decreased muscle mass, joint degeneration, poor postural habits and/or the effects of chronic diseases. For this reason, the application of physiotherapy treatment is essential to improve their quality of life and postural condition, to avoid complications, especially in their lifestyle. For this reason, the present research is intended to analyze motor control in the rehabilitation process of postural alterations in the elderly of physiotherapy in postural alterations in older adults. For this, a qualitative research approach is used, since through this approach the intrinsic characteristics of the research topic can be analyzed, as well as through the systematic method of research to reach reliable conclusions, through the realization of a complete synthesis. As a main finding, it is found that physiotherapy is essential to address postural alterations in older adults. Through a comprehensive approach that includes exercises, education, and manual therapy, physical therapists can help improve patients’ quality of life, reduce pain, and prevent further complications.
Mechanistic mathematical model of emicizumab
Authors: Madrigal Jamie , Monroe Dougald , Sindi Suzanne , Leiderman Karin
Published: February 2025

A mechanistic mathematical model of emicizumabEmicizumab is a bispecific antibody that brings together activated Factor IX and Factor X, replacing the missing Factor VIII in hemophilia A patients. Although widely used as an FDA approved therapeutic, the lipid-surface dependence of emicizumab is not well understood. A key mechanistic difference between emicizumab and FVIII is that emicizumab does not bind directly to the lipid surface, while FVIII does. In biochemical assays, emicizumab has been shown to inhibit FX activation by TF:VIIa – a lipid-surface dependent reaction.Previously, we developed and validated a mathematical model that uniquely captured the lipid-surface dependence of TF:VIIa activation of FX. In this work, we expand the model to include emicizumab and consider all plausible biochemical mechanisms. As emicizumab does not bind TF:VIIa, this tests interaction of emicizumab and FX alone, a one arm interaction. We calibrate the model with experimental data under several conditions. We then take knowledge from the one arm interaction and apply it to a model for FIXa activation of FX, a two arm interaction.Results agree with experiments and capture the inhibitory effect of high concentrations of emicizumab on FX activation by TF:VIIa. The results imply that emicizumab inhibits the binding of FX to the lipid-surface. Through this assumption, the model is able to capture FIXa activation of FX under several experimental conditions. The results have implications for the design of second generation bifunctional antibodies. Future directions include further exploration of the off-target effects of emicizumab, specifically the effect of emicizumab on the lipid-binding of FIXa.Citations: [1] Mak, Stefanie, Agnes Marszal, Nena Matscheko, and Ulrich Rant. mAbs (2023): 2149053. https://doi.org/10.1080/19420862.2022.2149053.[2] Mertens, K, R Cupers, A Van Wijngaarden, and R M Bertina. “Biochemical Journal (1984): 599–605.[3] Rawala-Sheikh, Razia, Syed S. Ahmad, Barrie Ashby, and Peter N. Walsh. Biochemistry (1990): 2606–11. https://doi.org/10.1021/bi00462a025.[4] Van De Waart, Piet, Harry Bruls, H. Coenraad Hemker, and Theo Lindhout. Biochemistry (1983): 2427–32. https://doi.org/10.1021/bi00279a019.
Evaluating concomitant medication use in cystic fibrosis patients using real-world data (RWD) to inform drug-drug interaction risk assessment and clinical trial design of GDC-6988
Authors: Zhu Rui , Boudreau Denise , Dayal Parul , Risse-Adams Oona , Sun Veronica , She Gaohong , De Bruyn Tom , Galanter Joshua , Ma Fang , Chen Yuan
Published: February 2025

Background: Cystic fibrosis (CF) is a rare disease characterized by mutations in the Cystic Fibrosis Transmembrane Receptor (CFTR) gene resulting in the missing or malfunctioning CFTR activity and impaired lung clearance. CFTR modulators are the standard of care for CF patients; however, they are not indicated for approximately 10% of CF patients due to their CFTR mutation type. By potentiating the calcium-activated chloride channel TMEM16A, GDC-6988 is expected to compensate for CFTR and restore mucus hydration and mucociliary clearance irrespective of the CFTR mutation in CF patients. Objectives/Methods: In vitro studies showed that GDC-6988 may be a moderate inhibitor and inducer of the CYP3A4 enzyme, indicating co-administration of GDC-6988 with CYP3A4 sensitive substrate concomitant medications (conmeds) may change the conmeds concentration and affect their safety and efficacy. To inform the conmeds exclusion criteria in future GDC-6988 clinical trials in CF patients, physiologically based pharmacokinetic (PBPK) model refined with GDC-6988 Phase 1b study data was used to assess the drug-drug interaction (DDI) risk. IQVIA PharMetrics® Plus claims data between Jan 2020 and March 2021 were used to evaluate the prevalence of conmeds that are considered CYP3A substrates among CF patients with and without CFTR modulator. Detailed medication information that may further influence drug interactions including dose regimen, treatment duration (eg, acute vs. chronic), route of administration, and common diagnosis were also extracted for selected conmeds. Results: PBPK DDI simulations showed minimal to mild (geometric mean exposure change < +/- 15%) impact of GDC-6988 as a perpetrator on midazolam. RWD showed that the majority of the most frequently used sensitive CYP3A4 substrate conmeds in the CF population are considered less sensitive to CYP3A compared to midazolam and do not have a narrow therapeutic window, except for tacrolimus and sirolimus, which are indicated for lung transplant patients who would typically be excluded from clinical studies. Conclusions: Use of RWD allowed the DDI risk assessment to be conducted in a more realistic way by focusing on most frequently used CYP3A sensitive conmeds in the target population. Based on the PBPK modeling and RWD data, CF patients taking CYP3A4 substrates as conmeds will not be excluded from future clinical trials, and instead they will be monitored for adverse events for sensitive CYP3A substrates with narrow therapeutic window.Citations: None
A Physiological-Based Pharmacokinetic (PBPK) Model embedded with Pulmonary Compartmental Absorption and Transit (PCAT™️) Module to Predict Intranasal Ketamine Pharmacokinetics in Pediatric Population
Authors: Rachid Ousama , Alkilany Alaaldin , Rayan Menatallah , Amine Leena , Al Ansari Khalid
Published: February 2025

Objectives: Intravenous ketamine (IVK) is commonly utilized for emergency pediatric procedural sedation but is resource-consuming and associated with significant child distress. Conversely, intranasal ketamine (INK) is noninvasive and provides rapid absorption and onset of action, which could improve patient outcomes. The objective of the present study is to model the pharmacokinetics of INK in pediatric patients using GastroPlus® to aid in the design of a clinical trial. Methods: Compartmental and physiological-based pharmacokinetic (PBPK) models of IVK 3 mg/kg and INK 3 mg/kg in pediatric patients were constructed using existing literature data1 and a Pulmonary Compartmental and Absorption and Transit (PCAT™️) module was used to model nasal deposition. The model was calibrated through optimization of nasal systemic absorption rate constant and inclusion of lysosomal trapping in the model. The population simulator was used to simulate INK at three dose levels (4, 6, and 9 mg/kg) in 200 pediatric patients ages 3 months-17 years and weighing 10-65 kg. Results: Using preexisting data, a compartmental and PBPK models were built for IVK. The PBPK INK model was able to predict Cmax, tmax, and AUC values that closely matched observed values of INK 3 mg/kg (R2=0.923). Using population pharmacokinetics incorporating the demographics of the intended clinical trial population, the PBPK INK model predicted the Cp-time profiles, and estimated the Cmax, tmax and AUC0-inf to be 623ng/mL, 0.43h, and 1694ng.h/mL, respectively for the 4 mg/kg dose; 899ng/mL, 0.43h, and 2395ng.h/mL, respectively for the 6 mg/kg dose; and 1378ng/mL, 0.43h, and 3723ng.h/mL, respectively for the 9 mg/kg dose. Conclusion: A PBPK model was successfully developed and used to predict the pharmacokinetics of INK in the pediatric population at three different doses. This data represents a valuable strategic tool to aid in the careful planning of pediatric clinical trials.Citations: Citations: [1] Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996 Aug;77(2):203-7. doi: 10.1093/bja/77.2.203. PMID: 8881626
A Minimal QSP Model for Treg Responses of IL-2 Mutein MK-6194 – A Conceptual Model for Autoimmune Disease
Authors: Du Lihong , Duffull Stephen , Johnson Martin , Nieddu Garrett
Published: February 2025

Objectives: The balance of regulatory T cells (Tregs) and conventional T cells (Tcons) plays a crucial role in maintaining immune homeostasis and preventing autoimmune diseases. Low-dose Interleukin-2 (IL-2) therapy has emerged as a promising approach for modulating Treg activity in various immunotherapy settings. However, mechanistic understanding of how IL-2 influences Treg dynamics remains incomplete. MK-6194 is an IL-2 mutein that was designed as a specific biologic response modifier of Tregs through increasing the binding affinity for IL-2 receptor alpha chain (IL-2Rα or CD25) and reducing the binding affinity for IL-2Rβ but without effects on Tcons [1]. The objective of this study was to develop a minimal QSP model to explore the intricate mechanisms between IL-2 mutein and Treg expansion.Methods: The development of the minimal QSP model involved four steps: (1) adapting an existing literature QSP IL-2 model [2] with the addition of IL-2 mutein, (2) reducing the adapted QSP model to include only essential components, (3) conducting identifiability and global sensitivity analyses to support estimation of parameters, and (4) parameter estimation including inter-individual variabilities (IIVs) using NONMEM. Results: The final developed model consisted of 5 ordinary differential equations: (1) PK depot compartment, (2) PK central compartment, (3) compartment of Tregs, (4) compartment of sCD25 (soluble form of CD25), and (5) compartment of IL-2R on Tregs. Known mechanisms of IL-2 mediated Treg expansion and unique characteristics of MK-6194 were incorporated into the model structure. This includes MK-6194 binding to IL-2R, signaling of MK-6194/IL-2R complex for Treg proliferation, dynamic IL-2R density on Treg as well as the interaction of MK-6194 with sCD25. Furthermore, the model was used to explore tolerance of Treg response with chronic dosing via an added tolerance compartment for cumulative receptors reflecting changes in IL-2R density on Tregs. It was suspected that the tolerance might be caused by a potential imbalance of IL-2Rα and IL-2Rβγ on Tregs or down regulation of these receptors. Using the model, the effects of dose and dosing frequency on Treg changes over time were predicted, and the potential impacts of different dosing regimens on tolerance was also evaluated. Conclusions: We have developed a minimal-QSP model to assess the complex interactions between regulatory T-cells and an IL-2 mutein. The model enhances our understanding to the dynamic multi-cell system governing Treg biology in IL-2 mutein therapy. As the model is driven by underlying mechanisms, it can be applied to the same class of compounds for dose optimization or hypothesis testing with a potential to accelerate immunotherapeutic discovery and development.Citations: [1] Valentina Lykhopiy et al., Genes Immun., 2023; 24(5): 248–262. [2] Xin Gao et al., iScience, 2022 Sep 16; 25(9): 104911.
Direct and Indirect Exposure-Response Modeling for Transthyretin Amyloid Cardiomyopathy Treated with Acoramidis
Authors: Adam Brian , Chepyala Surendhar , Poland Bill , Rao Satish , Tamby Jean-Francois , Sinha Uma
Published: February 2025

Objectives: Acoramidis (AG10) is a novel investigational stabilizer of transthyretin (TTR or prealbumin) that achieves ≥ 90% TTR stabilization, in development for the treatment of TTR amyloid cardiomyopathy (ATTR-CM), a progressive, fatal disease in which the deposition of amyloid resultant of dissociation of either variant or wild-type TTR causes progressive heart failure. The Phase 3, 30-month ATTRibute-CM study showed a 25% risk reduction in all-cause mortality (ACM) with acoramidis relative to placebo. The objective was to evaluate exposure-efficacy relationships based on this study and two Phase 2 studies. Too few serious adverse events (SAE) occurred to establish an exposure-response model between acoramidis exposure and incidence of any particular SAE. Cardiovascular (CV)-related SAEs were excluded from the analysis since ATTR-CM patients are inclined to experience CV-related AEs and acoramidis exposure decreased the expected number of hospitalizations due to CV AEs. Methods: Using individual-subject steady-state exposure measures (plasma AUC, Cmax, and Cmin) estimated with a population pharmacokinetic model based on 8 clinical studies (Phase 1-3), exposure-efficacy relationships were modeled for cumulative CV-related hospitalization (CVH) counts using Poisson regression. Other efficacy measures could not be related directly to exposure but were related to change in serum TTR, an in vivo measure of TTR stabilization that increased with plasma exposure and served as an indirect exposure measure. ACM was modeled with logistic regression, and over time with Cox proportional hazards (CPH), while percent change from baseline (%CfB) in the Six Minute Walk Test (6MWT) at Month 30 was modeled as linear. Results: Change in serum TTR was predictive of ACM risk (p=0.00539) when adjusting for baseline demographic variables, diuretics, New York Heart Association (NYHA) class, baseline serum TTR, TTR variant vs wild-type and National Amyloidosis Centre (NAC) stage. For every 5 mg/dL increase in serum TTR from baseline to Day 28, the models predicted a 26.1% decrease in instantaneous mortality risk (CPH model) and a 30.9% (logistic model) decrease in the odds of mortality by Month 30, and the linear 6MWT model predicted an increase of 8.9 meters in the CfB 6MWT at Month 30. For every 1000 ng/mL increase in acoramidis steady-state Cmax, the Poisson model for CVH predicted a 2.7% decrease in the expected number of cumulative CVH events. Conclusions: Acoramidis exposure was found to directly predict cardiovascular hospitalizations, but change in serum TTR, which increases with acoramidis exposure, was needed to predict improved survival and 6MWT performance in ATTR-CM patients. The need for this indirect exposure measure could be due to limited and sparse concentration data at a single dose.Citations: .
A quantitative systems pharmacology model to explore resistance mechanisms and combination strategies in ALK+ NSCLC targeted therapies
Authors: Braniff Nathaniel , Wong Jim , Singh Anurag , Drescher Stephanie , Reddy Micaela , Shtylla Blerta
Published: February 2025

Objectives: Next generation anaplastic lymphoma kinase inhibitors (ALKi) have shown tremendous promise in circumventing on-target resistance mutations in ALK+ non-small cell lung cancer (NSCLC). However, additional on-target mutations and bypass signaling can allow for resistance to ALKi therapies to emerge (Yoda 2018, Schneider 2023). In this setting, inhibition of signaling nodes that act at the junction of multiple bypass mechanisms, such as those achieved by PF-07284892 (ARRY-558), an allosteric SHP2 inhibitor (SHP2i), offers a promising combination strategy in conjunction with ALKi (Drilon et al. 2023). In this work, we describe the development of a quantitative systems pharmacology (QSP) model to support and enhance mechanistic interpretation of clinical response to combination strategies between small molecule therapies for ALK+ NSCLC. Methods: This work makes use of several in vitro and in vivo datasets, including a set of resistant patient-derived cell lines, to calibrate a QSP signaling and tumor growth model and capture the range of resistance mechanisms and efficacy variability in response to combination ALKi & SHP2i treatments. The model incorporates pharmacokinetic simulations to drive a signaling pathway model including both drug effects and potential resistance mechanisms. The signaling pathway in turn is used to drive a simulation of tumor growth and to predict growth inhibition under treatment. Results: We use the model to contextualize mechanistic understanding from preclinical experiments and to better understand potential clinical resistance mechanisms and combination efficacy in translation to the clinic. The model is shown to capture the combination drug effect across varying levels of resistance. Simulations for ALK+ NSCLC supported the hypothesis that the SHP2i can re-sensitize resistant patients to ALKi.Citations: Drilon A, et al. Cancer Discovery (2023): 1789-1801.Schneider, J. et al. Nature Cancer 4.3 (2023): 330-343.Yoda, S, et al. Cancer Discovery 8.6 (2018): 714-729.
Effect of Convenience Sampling on Overall Drug Exposure during Pregnancy
Authors: Long Yuhan , Barry Jessica , Lyu Xintian , Sherwin Catherine , Birnbaum Angela
Published: February 2025

Objectives: Measuring drug exposure during pregnancy is important for understanding child postpartum outcomes. Researchers and clinicians often work with convenience samples collected during clinic visits with random time after dose (TAD). We characterized how different noncompartmental measures of drug exposure were affected by convenience sampling for different pharmacokinetic parameters.Methods: Predicted drug concentrations were simulated using a one-compartment model with first order absorption and 1000mg twice daily dosing with linearly increasing clearance (0.032 L/hr/wk) and volume of distribution (0.12 L/wk) for the 40 weeks of pregnancy (Julia v.1.9.2). Two preconception clearances (0.5 and 4 L/h) and two preconception volumes (8 and 128 L) were simulated. Ten mid-monthly samples were taken with uniformly distributed TAD (0-12 h). Four methods were used to calculate drug exposure during pregnancy: 1) lowest concentration, 2) average concentration, 3) highest concentration, 4) trapezoidal AUC0-40wks. To account for gestational age, the methods 1, 2, and 3 were time-weighted by 40 weeks, and for method 4, the first and last concentrations were extended to the beginning and end of pregnancy. Sensitivity analyses on rate of change for volume and clearance were performed.Results: Drug exposure by method 4 stayed within 3% of exposure calculated by method 3. At high volumes, the range of exposures was smaller (~44,000-46,000 mg/L*wk) and more uniformly distributed than exposures at low volumes (~500,000-600,000 mg/L*wk and heavily skewed right). As expected, the mean of calculated exposure values for each method were lower (~5x) in lower clearance than higher clearance due to decreased drug concentrations. Faster rate of volume increases during pregnancy resulted in a lower the range of possible exposures, which affected methods 1 and 2 more than method 3. For faster increases in clearance, the range in exposure due to TAD stayed consistent until the clearance was high enough to completely eliminate the drug between doses, at which point the range in exposure decreased.Conclusions: Range of exposures due to random TAD is closely related to volume of distribution, while mean exposure level is more closely related to clearance. For drugs with higher volumes, use of convenience sampling minimally influences exposure measures, but drugs with lower volume may need more consideration of TAD and sampling design. With the physiological volume increases experienced in pregnancy, TAD may be of less concern in data analysis. Clinical studies for postpartum outcomes should consider varying TAD to prevent biasing results due to convenience sampling for overall exposure.Citations: none
How to Make a Salad? Rethinking Pharmacometric/QSP Model Composition Using Open-Source Julia Tools
Authors: Elmokadem Ahmed , Kirouac Daniel , Knab Timothy , Swanson Ellen
Published: February 2025

Objectives: Pharmacometric and systems pharmacology models are often modular as different, independent components can be joined together to form a more complex model. The process of combining and reusing model components can be challenging with no clear framework and, as such, investigators often resort to rewriting models from scratch rather than reusing the individual components. Additionally, model components could be written in different notations such as ordinary differential equations (ODEs) or reactions, depending on the most convenient way to represent a system. This adds an additional complexity to the model composition process. A framework is presented that allows an investigator to seamlessly combine different model components represented in their respective notations and reuse these independent components to create multiple combinations of integrated models, just like mixing the components of a salad.Methods: Julia [1] open-source tools, namely ModelingToolkit.jl [2] and Catalyst.jl [3], were used to present a convenient framework for pharmacometric model composition. The symbolic-numeric model representation of ModelingToolkit.jl and the reaction notation provided by Catalyst.jl allowed for seamless composition of independent model components presented as ODEs or reactions.Results: The framework was demonstrated by composing different model components (e.g., Pharmacokinetic (PK), Pharmacodynamic (PD), physiological organs) to build larger models (e.g., PKPD, Physiologically Based PK (PBPK), Quantitative Systems Pharmacology (QSP)). Both ODEs and reaction notations were combined into integrated PKPD and QSP models with examples drawn from bispecific T cell engagers, viral dynamics, and drug-drug interactions (DDI). The framework enabled seamless transitions from in vitro to in vivo murine to clinical settings for a bispecific T cell engager application [4]. Conclusions: A framework based on Julia open-source tools was proposed in this work to allow for seamless pharmacometric and QSP model composition. This framework enables model reusability and translation using convenient and flexible model notation.Citations: 1. Bezanson J, Edelman A, Karpinski S, Shah VB. Julia: A Fresh Approach to Numerical Computing. SIAM Rev. 2017;59: 65–98.2. Ma Y, Gowda S, Anantharaman R, Laughman C, Shah V, Rackauckas C. ModelingToolkit: A Composable Graph Transformation System For Equation-Based Modeling. arXiv [cs.MS]. 2021. Available: http://arxiv.org/abs/2103.052443. Loman TE, Ma Y, Ilin V, Gowda S, Korsbo N, Yewale N, et al. Catalyst: Fast and flexible modeling of reaction networks. PLoS Comput Biol. 2023;19: e1011530.4. Betts A, Haddish-Berhane N, Shah DK, van der Graaf PH, Barletta F, King L, et al. A translational quantitative systems pharmacology model for CD3 bispecific molecules: Application to quantify T cell-mediated tumor cell killing by P-cadherin LP DART®. AAPS J. 2019 May 22;21(4):66.
Immune Correlates of Protection against Respiratory Syncytial Virus Infection and an Application to Model-Informed Vaccine Development for an internal compound: a Model-Based Meta-Analysis
Authors: Kashihara Yushi , Qin Li , Shimizu Shinji , Diderichsen Paul , Oka Takaaki , Kotsuma Masakatsu , Yoshihara Kazutaka
Published: February 2025

Objectives: Respiratory syncytial virus (RSV), a common contagious virus that causes infections of the respiratory tract and can cause more severe disease such as pneumonia in infants and young children as well as older adults. As in other vaccine areas such as COVID-19, establishment of immune correlates of protection against RSV can accelerate vaccine development [1]. The aim of this study was twofold: first, to quantify the relationship between immunomarker and vaccine efficacy by model-based meta-analysis as evidence of immune correlate of protection against RSV, and second, to apply this knowledge in model-informed vaccine development for an internal compound (Compound X).Methods: We conducted a systematic literature search of PubMed and ClinicalTrials.gov for randomized placebo-controlled registry studies that evaluated RSV vaccines in older adults (≥60 years). Two linear mixed effect meta-regression models were built to describe (1) the relationship between serum neutralizing activity (SNA) and log-transformed vaccine efficacy across three different clinical severity levels, i.e., acute respiratory infection, RSV lower respiratory tract disease (LRTD) with ≥2 clinical symptoms, and RSV LRTD with ≥3 clinical symptoms, and (2) the contribution of cell-mediated immunity (CMI) response to the relationship between SNA and transformed vaccine efficacy. The developed models were applied to predict vaccine efficacy of Compound X using immunogenicity data from a phase 2 dose-finding study.Results: Seven studies were selected for inclusion in the meta-regression analyses and evaluated to define a quantitative relationship between SNA and vaccine efficacy. SNA correlated with vaccine efficacy across three different clinical severity levels. Five studies reported SNA, CMI, and vaccine efficacy. CMI was found to only affect vaccine efficacy for RSV LRTD with ≥3 clinical symptoms, suggesting that CMI plays an important role for suppressing the severity of RSV infection. The meta-regression model predicted vaccine efficacy for Compound X based on SNA and CMI and was leveraged to support internal decision-making and development strategy.Conclusions: The meta-regression analysis established a quantitative relationship between immunomarker and vaccine efficacy and suggested immune correlates of protection against RSV infection. The developed literature search, data selection, and analysis framework can be applied to model-informed vaccine development including immuno-bridging strategy and internal decision making.Citations: [1] Khoury DS et al. Nat Med. 2021; 27:1205-1211.