bluuebunny/crossref_metadata_2025 huggingface dataset:
Estandarización de los procesos productivos para mejorar la eficiencia en la empresa CAPOLIVERY [Standardization of production processes to improve efficiency in the CAPOLIVERY company]
Authors: Sánchez-Rosero José Israel , Lalaleo-Quispe Germania Vanessa
Published: February 2025

El presente trabajo de investigación se enfoca en el análisis y mejora de los procesos productivos de la empresa Capolivery, dedicada a la manufactura textil en el cantón Ambato, provincia de Tungurahua. Se tiene por objetivo de investigación estudiar la estandarización de los procesos productivos para mejorar la eficiencia en la empresa CAPOLIVERY ubicada en el cantón Ambato, provincia de Tungurahua de Ecuador. El estudio se desarrolló bajo un enfoque cuantitativo. El desarrollo del proyecto permitió a la empresa obtener un conocimiento claro del organigrama estructural y los procesos de confección de camisetas tipo polo para hombre y mujer. Herramientas como el Layout y el diagrama causa-efecto facilitaron la visualización y análisis de cada etapa, mientras que los diagramas de procesos detallaron las actividades y subprocesos, proporcionando una base sólida para el entendimiento y la mejora continua.
Risk factors and mechanisms of injuries among college athletes in physical education classes
Authors: Chen Guo
Published: February 2025

Injuries among college athletes in physical education (PE) classes are a significant concern, impacting both their academic performance and athletic progression. Understanding the risk factors and mechanisms behind these injuries is crucial for developing effective prevention strategies. This research aims to identify and analyze the key risk factors contributing to injuries among college athletes participating in PE classes. Data were collected through questionnaires with PE instructors. The PE instructors were trained with wearable biomechanics sensors, which were used to record joint angles, ground reaction forces, acceleration, and muscle activation during various physical activities such as running, high jumping, and basketball. Risk factors like inadequate warmup, improper techniques, and overuse. Statistical tests were conducted using SPSS to analyze the relationship between biomechanical factors and injury occurrence among college athletes, including Chi-square, Descriptive statistics, Regression, and ANOVA showed that they were strong predictors of future injuries. Descriptive statistics revealed that a significant portion of athletes reported injuries, with sprains being the most common injury type. Chi-square analysis indicated a significant relationship between sport type and injury occurrence. Results indicate that PA lessons can help prevent injuries. Regression analysis offers insights into the relationships between variables and their impact on injury occurrence. The results highlight the need for preventive strategies, such as tailored warm-up routines and monitoring injury history, to minimize injury rates.
The existence of sentencing for perpetrators of narcotics abuse crimes
Authors: Laia Fariaman
Published: February 2025

In recent developments, narcotics crimes constitute a violation of both legal and moral norms. This issue is not new but remains a significant public concern, particularly regarding its impact on the future of the nation's youth. This study employs a normative legal research method with a conceptual and legislative approach. The findings indicate that law enforcement in sentencing drug addicts or users includes not only rehabilitation but also criminal sanctions such as imprisonment. These sanctions aim to deter drug use and mitigate its negative effects on offenders. Furthermore, it is crucial to identify the sources of narcotics distribution, as only through such measures can the circulation of drugs in Indonesia be minimized. The author suggests that in enforcing existing regulations, law enforcement efforts should place greater emphasis on targeting drug dealers. Focusing solely on users will make it challenging to achieve sustainable narcotics eradication in Indonesia.
The Artistic and Intellectual Analysis of Zamir Masloob in Modern Urdu Poetry
Authors: Muhammad Nazir  , Zulfiqar Ali  , Zulfiqar Ali  , Muhammad Hasssan  , Syed Sadaqat Ali
Published: February 2025

Urdu poetry's second most celebrated genre, after ghazal, is nazm. This eloquent genre expresses various themes, with poets conveying their thoughts under a title, without adhering to traditional weight or rhyme.Nazm originated in Deccan and later flourished in North India. Initial poets included Khwaja Bande Nawaz Gisudaraz, Amir Khusrow, and Nazir Akbarabadi. The 1857 Indian Rebellion sparked modern nazm's growth, influenced by Western ideas and new emotional currents. Maulana Muhammad Hussein Azad and Altaf Hussain Hali introduced natural poetry through the Punjab Association movement in 1867. This article explores nazm's definition, origin, and evolution, focusing on Shahid Hussain Naqvi's poetry collection "Zamir Makhloob".Naqvi's poems convey beautiful messages in simple language, reflecting human compassion, sincerity, and love. His poetry expresses anguish over human suffering, solidarity with oppressed people, and commitment to social and political issues.Naqvi's nazms demonstrate national and religious loyalty, celebrating Pakistan's grandeur and honoring national and religious figures. His poetry connects internal emotions with external expressions, transforming everyday experiences into profound reflections. Studying Naqvi's poetry reveals his ability to embody the essence of political and social poetry. His work reflects human sensitivity and love, expressing deep sorrow for human oppression and solidarity with victims of injustice.Naqvi's poetry celebrates Pakistan's national heritage, honoring national and religious icons. His poems connect inner feelings with external expressions, providing a profound reflection of life.
Keywords: Natural Poetry, Punjab Association, Modern Nazm, Shahid Hussain Naqvi, Zamir Makhloob, Urdu Poetry, Ghazal, Deccan, North India, Indian Rebellion.
A Psycholinguistic Analysis of TV Play 24 Ghantay written by Usama Siddiq: A Nietzschean Model
Authors: Saiyida Shahbano Jabeen  , Sadaf Fatima  , Dr. Riaz Ahmad Mangrio
Published: February 2025

This investigation delves into the psycholinguistic examination of the Pakistani TV drama "24 Ghantay" utilizing a Nietzschean framework. The main goals are to reveal the protagonist's struggle with the concepts of good and evil, analyze the representation of human duality, outline the moral standards and ambiguities presented in the drama, and investigate psychological tensions and identity crises. Utilizing a Nietzschean framework facilitates a more profound exploration of existential themes, including the will to power, eternal recurrence, and the Übermensch, in relation to the narrative of the drama. This analysis of linguistic patterns, character interactions, and narrative elements seeks to uncover the psychological dynamics and philosophical implications that underpin the protagonist's journey. This investigation enhances our understanding of psycholinguistics and Nietzschean studies, providing valuable perspectives on the intricacies of human nature and morality as reflected in Pakistani cultural outputs.
Keywords: Narratology, Stylistics, Psycholinguistics, Pakistani drama, Thematic analysis, Nietzschean Model
Before They Vanish: Saving Nature’s Populations—and Ourselves, edited by Paul R. Ehrlich, Gerardo Ceballos, and Rodolfo Dirzo
Authors: Boutaleb Nadia
Published: February 2025

It has always been easier to condemn tragedies once they belong to the past—always after the fact, when the damage has already been done. In this work, Ehrlich, Ceballos and Dirzo boldly sound the alarm in time. The question is whether people will act to preserve endangered species before it is too late and before the consequences weigh heavily on ecosystems. The authors emphasise that the issue extends beyond mere environmental concerns; it is a fundamental challenge for humanity itself. Saving biodiversity also means protecting the conditions of our existence, often without realising it. The urgency is real, and the book urges action before disaster becomes irreversible, while populations can still be saved (p. 128).
Views and Experiences of Public Intermediate Grade Teachers as Implementers of Modular Distance Learning
Authors: Baoc Crislin Joy , Butalid Nylene , Diacono Patrice Marie , Ferraris Andria Kristi , Herbolario Christine Joy , Losbañes Frances Danica , Aguirre Jessica
Published: February 2025

Teachers as main implementers of modular instruction are raising myriad issues with the modular learning preparations. The study explored the experiences of intermediate teachers of an elementary school in Bacolod City who adopted and implemented modular distance learning during the school year 2020-2021. It is intended to provide a detailed description of the experiences of the six public school teachers concerning the quality, instructional effectiveness, challenges, and coping with challenges of modularized instruction. This paper adopted a qualitative-descriptive type of research using a narrative inquiry approach. The information describing the participants' perspectives was obtained through guided interviews and follow-up questions. The rigors of findings were established using member checking, code-recode strategy, thick description, data checking, and audit trail. Using the six-phase analysis proposed by Braun and Clarke, seven essential themes emerged from the collected data. The teacher- implementers of MDL perceived that the SLM's contents are aligned to the preset learning outcomes, logical, cohesive, and well-integrated. The MDL allowed for independent learning and parent involvement. It had an organized system of deployment of materials that ensured accessibility and less expense. Conversely, the parents’ poor academic background and unavailability and learners' low comprehension showed its essential setbacks. The lack of technology devices and inadequate resources exacerbated its disadvantage. Its assessment lacked integrity. The reproduction of voluminous modules, pressure to comply with the modular requirements, and overloaded activities posed a major challenge among the teacher-implementers. They tried to adapt, communicate with parents and use radio-based instruction to overcome the difficulties. There is a need to look into the system support and provision of the needed logistics to minimize these impediments in carrying out MDL.
Risk auditing for Digital Twins in cyber physical systems: A systematic review
Authors:   University of Jordan, Otoom Shahed
Published: February 2025

Digital Twins are emerging as a transformative technology within Cyber-Physical Systems (CPS), offering enhanced optimization, predictive maintenance, and real-time monitoring. However, their integration also introduces significant security challenges. These include vulnerabilities such as data breaches, unauthorized access, and cyber-attacks that disrupt real-time data flow between their physical and digital components. The involvement of IoT devices, sensors, and complex networked environments expands the attack surface, making Digital Twins susceptible to threats like Distributed Denial-of-Service (DDoS) attacks, malware infiltration, and insider sabotage. Effective risk management and assessment are crucial in identifying vulnerabilities, evaluating risks, and implementing mitigation strategies. Securing Digital Twins ensures data integrity, system reliability, and the continued functionality of the physical assets they represent. This paper aims to classify the various security threats associated with Digital Twins and propose structured risk management approaches to enhance their security within CPS. By addressing these challenges, organizations can ensure the dependability and trustworthiness of Digital Twin implementations across industries such as manufacturing, healthcare, smart cities, and IoT ecosystems.
ASSAYING THE IMPACT OF BLOCKCHAIN TECHNOLOGIES ON TRACKING AND VERIFYING GREEN INVESTMENTS AND FINANCING IN EMERGING MARKETS
Authors: Ahmadzadeh Seyed Ali
Published: February 2025

This article assays the impact of blockchain technology on tracking and verifying green investments in emerging markets. Green investments are increasingly emerging as a key solution to address climate change in the conditions of environmental challenges and the need for sustainable development. Blockchain technology, with its unique features such as transparency, immutability, and traceability, can serve as an effective tool for building trust and credibility in green projects. This research analyzes the challenges in emerging markets, such as corruption and lack of transparency, and shows the contribution of blockchain in solving these issues. Moreover, it reviews successful examples of blockchain implementation in financing sustainable projects in different countries. The results show that using blockchain can improve financial transparency, facilitate the financing process, and increase investor participation in green projects. The article ends by providing suggestions for policymakers and investors to benefit from blockchain technology in green finance and emphasizes that this technology can serve as a key tool in achieving sustainable development goals in emerging markets.
THE RELATIONSHIP BETWEEN LIFE SATISFACTION AND MENTAL HEALTH OF ADOLESCENTS
Authors: Dezhapoun Mahya
Published: February 2025

Introduction Adolescence and early adulthood is a time of many changes, such as changing schools, leaving home, starting college, or starting a new job. For many, these events, in addition to being exciting, can bring a lot of stress and anxiety. These feelings in some cases and if not recognized can lead to mental illnesses. The mental health of teenagers is essential because they are in a sensitive period that determines their personality and mental health. Satisfaction with life is among the things that play a significant role in the mental health of teenagers. For this reason, in this article, we are trying to examine the role of life satisfaction on the mental health of adolescents.
Method: The descriptive research method is of correlation type. The selection of samples is done using a multi-stage sampling method, and 200 adolescent girls and boys (100 people in each group) will be selected as samples. The students filled out the TSLWS life satisfaction questionnaire. To analyze the research data, in addition to using statistical description methods, the Pearson correlation method is used to test the hypothesis. The data collection method is in the field. In this research, firstly, in the first stage, districts one and three were selected among the districts of the Karaj education region; in the second stage, ten schools were randomly selected from each district. Finally, in the third stage, students who were in the teenage age stage and were culturally, socially, and economically somewhat similar were identified and selected with the cooperation of school principals and teachers.
Results: The results of the data analysis confirmed a positive and significant relationship between life satisfaction and mental health.
Humanización de la Evaluación Matemática. Influencia en la Motivación
Authors: García Flores De Válgaz Galo Roberto , Mendoza Navarrete Martha Lorena , Pín López María Mercedes , Flores De Válgaz Lilian García
Published: February 2025

El estudio se propuso evaluar el impacto de la humanización de la evaluación matemática en la percepción de los estudiantes de nuevo ingreso de la Universidad Técnica de Manabí, con respecto al nivel de motivación que esta genera. Se aplicó un diseño no experimental y transversal con enfoque interpretativo, que indagó las percepciones de 122 alumnos de diversas carreras. Los resultados revelaron una conexión positiva entre la humanización de la evaluación y la motivación académica, destacando la importancia de un enfoque integral, que fomente la conexión con el mundo, el desarrollo personal y ético. Se concluye que es necesario plantear metodologías que no solo transmitan conocimientos, sino que, promuevan el pensamiento crítico, la participación activa y el compromiso social.
Pelayanan Holistik Rumah Cerdas Di Desa Tamanrejo, Kecamatan Limbangan, Kabupaten Kendal
Authors: Sri Wijayanto Wahyudi , Franpebri Panggabean Yoel
Published: February 2025

Evangelism through holistic smart home services is very effective. Because in the process children are blessed and parents are also blessed. The Smart House in Tamanrejo Village in December 2023-February 2024 involves more than 10 members from STT Christ Alfa Omega Semarang. Coordinated by one person to organize the teaching planning. Before the implementation began, one of the representatives met with the head of the local RT to coordinate with the residents regarding the implementation of the smart home. Then after it is agreed. The coordinator divides tasks for the teaching team in teaching. In teaching in a smart home, the place used is one of the homes of residents who are willing to use it. It was agreed that the study house would be held once a week on Fridays at 16.00-17.00 WIB. In implementing the learning house, the teaching team provides teaching in accordance with the curriculum that has been created. Then after carrying out these activities, the teaching team also visited the children's parents. In this case, pre-evangelism can be carried out through curriculum studies in the home learning about character building. Apart from that, through visits to the families of the children being taught.
Desafíos, oportunidades y experiencias de la evaluación del aprendizaje en clases en línea, según docentes y estudiantes de universidades salvadoreñas. período 2020-2022
Authors: Briñis Zambrano Armando , Quintana Pérez David Alberto , Sánchez Nodoa Ramón
Published: February 2025

Antecedentes. En el ámbito educativo, la pandemia de Covid-19 no sólo develó carencias y limitaciones de la educación pública y privada salvadoreña, sino también de la resiliencia, esfuerzo e iniciativa de docentes y estudiantes por garantizar la continuidad del derecho a la educación.
SEKSUALNO NASILJE U ORUŽANOM SUKOBU: IZMEĐU MEĐUNARODNE I BOSANSKOHERCEGOVAČKE TEORIJE I PRAKSE
Authors: Omerović Enis , Zatagić Senada , Grande Andrea , Jurić-Vatrenjak Leontina
Published: February 2025

S obzirom na značajni utjecaj Rimskog statuta iz 1998. na način na koji
Krivični zakon Bosne i Hercegovine definira krivična djela protiv čovječnosti,
ratne zločine i zločin genocida, u ovom radu će se razmatrati pravni pojmovi
seksualnog nasilja u svojim različitim vrstama pojava, među kojima silovanje,
prisilna trudnoća, seksualno ropstvo, prisilna prostitucija i prisilna sterilizacija.
Vremenskim i prostornim fokusom na međunarodni oružani sukob u Bosni i
Hercegovini, navedeni će oblici seksualnog nasilja biti kontekstualizirani kako
bi se istovremeno identificirale i dodatne implikacije na pravnoj ravni, no i na
posebne kategorije žrtava koje su nepotpuno ili samo djelomično priznate. Ispitati
će se poveznica između statuta međunarodnih sudova i tribunala, na jednoj strani,
i posljedičnog bosanskohercegovačkog tumačenja u teoriji i praksi navedenih
međunarodnih zločina. Teoretski prostor ogleda se u hronološkome identificiranju
razvojnih etapa u izgrađivanju današnjih pravnih koncepcija, odnosno jedna
analiza bit će načinjena na više nivoa: ispitat će se lokalne koncepcije naspram
međunarodnih, te naknadno na zasebnim nivoima Suda Bosne i Hercegovine,
Međunarodnoga krivičnoga tribunala za bivšu Jugoslaviju i ostalih sudova i
tribunala. Korištenjem komparativnih i kategorizacijskih zaključaka iz prije
navedene sekcije, problematizirat će se i pitanja poput sudskoga tumačenja
spolnoga aspekta u pogledu analiziranih slučajeva, kao i svakodnevnih posljedica
žrtava pojedinih kategorija. Iako se rad dominantno fokusira na pravnu dimenziju
seksualnog nasilja u oružanom sukobu, istovremeno se nudi i analiza s aspekta
tranzicijske pravde u Bosni i Hercegovini, odnosno, problematizira se primjena
reparacija žrtava kao mehanizma tranzicijske pravde.
'Derechos de participación, formación y eficiencia de los trabajadores: hipótesis y evidencia empírica para Alemania
Authors:   Universidad George Washington, Smith Stephen C.
Published: February 2025

Este artículo desarrolla en primer lugar una razón de eficiencia para los derechos de participación de los trabajadores (DPTs) en la toma de decisiones a nivel de planta, incluyendo el diseño y puesta en marcha de la formación, basada en la corrección de los fallos organizativos y del mercado de trabajo. Estos derechos proporcionan a los trabajadores "controles" sobre algunos de los incentivos estructurales que empujan a la dirección al oportunismo y a una inversión menor en formación, a través de la protección de las inversiones específicas en capital humano y ayudando en los problemas de información y riesgo moral. Este análisis hace hincapié en las habilidades específicas de la empresa, pero concluye que las inversiones en capital humano general y específico generalmente no se pueden separar en su totalidad y que, por tanto, los argumentos utilizados para el capital humano específico se extienden al caso de la formación de capital humano general y específico "ligados". La implicación es que los DPTs en la formación pueden incrementar la eficiencia productiva y la efectividad de las operaciones de formación hacia sus niveles óptimos. Estas hipótesis se analizan mediante unos estudios de casos comparativos y un conjunto de datos de empresas de la región alemana North Rhine-Wesphalen.
Competencia y regulación en el comercio interior
Authors:   Universidad de Alicante, Sevilla Martín
Published: February 2025

En este artículo se analiza en primer lugar, el marco teórico de la discusión sobre la re-gulación económica del comercio minorista, para pasar posteriormente a un análisis más detallado de la evolución del sector en España y en algunas Comunidades Autónomas, comparándolo con lo sucedido en otros países europeos. El análisis de las políticas públicas puestas en marcha en los últimos años y las valoraciones de los distintos agentes económicos ocupa un tercer apartado, concluyendo con las cuestiones no resueltas en la actualidad, así como con los elementos que habría que tener en cuenta para la discusión sobre la regulación del comercio interior en el futuro.
Regulación, agencias reguladoras y defensa de la competencia
Authors:   Tribunal de Defensa de la Competencia, Sánchez Núñez Pilar , Berenguer Fuster Luis ,   Tribunal de Defensa de la Competencia
Published: February 2025

El presente trabajo está dividido en dos partes. La primera de ellas analiza el origen de la regulación y la forma de regular, las distintas funciones y modelos de agencias reguladoras y la situación en España, con la existencia y atribuciones de distintas agencias reguladoras. Por otra parte, en el segundo de los capítulos se plantea el problema derivado de decidir quién tiene las competencias para resolver las situaciones restrictivas de la competencia en los supuestos en los que existen, como ocurre en España, Agencias reguladoras y órganos dedicados a la defensa de la competencia. Se analizan los supuestos de la Comisión del Sistema Eléctrico Nacional y la Comisión del Mercado de las Telecomunicaciones y se realizan propuestas "de lege ferenda" para integrar, en ese campo, las funciones de las Agencias reguladoras y del Tribunal de Defensa de la Competencia.
PROCEDIMENTOS E ÓBITOS DA REVASCULARIZAÇÃO MIOCÁRDICA NO ESTADO DE SÃO PAULO 2004 – 2024
Authors: Juviniano Patrícia Borges de Moraes , Ito Paulo Fernando Katsuo Ogatha , Goulart Emanuela Ferreira , Pavan Amanda Ribeiro , Oliveira Gabriela Luiza Correa , Tabata ⁠Rafael Shigueru , Inohira Marjorie Albergoni , Gazel Welleson Feitosa , Barbosa Ana luiza , Arruda Éric Edmur Camargo
Published: February 2025

Introdução: O choque cardiogênico complica até 10% dos infartos agudos do miocárdio, com mortalidade de 40-50% em 30 dias. O suporte mecânico, especialmente a oxigenação por membrana extracorpórea venoarterial (ECLS), cresceu na última década, mas carece de evidências robustas. Apesar de potencial benefício hemodinâmico, há riscos significativos. Objetivos: Avaliar os óbitos nos procedimentos de revascularização miocárdica no Estado de São Paulo. Métodos: Os dados foram obtidos por meio de consulta ao Departamento de Informática do Sistema Único de Saúde (DATASUS), no endereço eletrônico (http://www.data-sus.gov.br) na base de dados da Produção Hospitalar (SIH/SUS) em todo o estado de São Paulo dos anos de 2004 a novembro de 2024. Resultados: Todos os procedimentos estudados ocorreram no estado de São Paulo entre 2004 a novembro de 2024. Revascularização miocárdica com uso de extracorpórea com um total de 24164 procedimentos, com uma média anual de 1098,36 procedimentos e 1310 óbitos durante o procedimento com uma taxa de 5,42% de óbitos, a revascularização miocárdica com uso de extracorpórea e com dois ou mais enxertos totalizaram 111865 procedimentos, com uma média anual de 5084,77 procedimentos e 4117 óbitos durante o procedimento com uma taxa de 3,68% de óbitos, a revascularização miocárdica sem uso de extracorpórea apresentou um total de 11162 procedimentos, com uma média anual de 507,36 procedimentos e 323 óbitos durante o procedimento com uma taxa de 2,89% de óbitos e a revascularização miocárdica sem uso de extracorpórea e com dois ou mais enxertos totalizaram 4908 procedimentos, com uma média anual de 223,09 procedimentos e 175 óbitos durante o procedimento com uma taxa de 3,56% de óbitos, os dados foram analisados pelo software IBM SPSS STATISTICS 20, para testar a normalidade dos dados foi aplicado os testes de Shapiro Wilk e Kolmogorv Smirnof que apresentaram distribuição não normal, foi aplicado o teste de Kruskal-Wallis o qual demonstrou haver diferença entre os grupos  e entre o número de óbitos com p< 0,001. Conclusão: O uso de circulação extracorpórea na revascularização miocárdica demonstrou uma maior taxa de morte entre os pacientes submetidos a revascularização miocárdica.
Formação de agenda legislativa para os Contratos de Impacto Social: análise de um projeto de lei em tramitação
Authors: Trombka Ilana , Rodrigues Juliana
Published: February 2025

Tramita no Congresso Nacional o Projeto de Lei do Senado nº 338/2018, que dispõe sobre o Contrato de Impacto Social como alternativa para a prestação de serviços públicos por meio de um acordo de vontades no qual uma entidade pública ou privada, com ou sem fins lucrativos, se compromete a atingir determinadas metas de interesse social. O presente artigo estuda os aspectos que determinaram o ingresso do tema na pauta pública e estatal. Por ser um processo em andamento a envolver diversos atores internos e externos à estrutura governamental, o caso configura-se como uma rica oportunidade para compreender os aspectos visíveis e ocultos relativos ao projeto de lei, com base na análise da confluência entre os fluxos do problema, da política e da política pública, a fim de contribuir para o conhecimento da formação de agenda no atual contexto brasileiro
Atos notariais por meios eletrônicos: a quarentena trouxe o futuro aos cartórios e tabelionatos
Authors: Valério Marco Aurélio Gumieri
Published: February 2025

Há anos a legislação brasileira prevê a possibilidade de se realizarem atos notariais por meios eletrônicos com videoconferência. Contudo, somente em 26/5/2020, devido à busca por instrumentos tecnológicos que superassem a necessidade de distanciamento social provocada pela pandemia da Covid-19, a Corregedoria Nacional de Justiça, órgão vinculado ao Conselho Nacional de Justiça, editou o Provimento nº 100, que dispõe sobre atos notariais eletrônicos em todo o território nacional. Em face da importante função social dos cartórios e tabelionatos, este artigo analisa a evolução legislativa que levou à atual regulamentação e destaca suas inovações. Trata-se de uma pesquisa qualitativa, que utiliza o método dedutivo e a análise de conteúdo como metodologia, com revisão bibliográfica, coleta de dados e estudo dos diplomas legais
Kolonialisme Inggris di Australia
Authors: Sari Puspita , Nugroho Alfan , Irwanto Dedi , Pamulaan Alif Bahtiar
Published: February 2025

In this article we will discuss British Colonialism in Australia. Colonialism is a time when a country is controlled by another, stronger country. Most countries in the world have experienced the practice of colonialism by other nations, one of which is Australia. Using a qualitative descriptive method through a literature study approach. This research was conducted to practice knowing British colonialism in Australia. The results of this research show that British colonialism in Australia has had many impacts felt by Australia’s indigenous population, namely the Aborigines.
Pharmacometric-Pharmacoeconomic Modeling and Simulation in Atopic Dermatitis: Informing Early Drug Development Decisions for a Hypothetical New Therapeutic
Authors: Gastonguay Marc , Polhamus Daniel , Johnson Michelle , Anderson Eric , Barrett Kyle
Published: February 2025

Objectives: This study assessed the expected impact of selected target product profile (TPP) characteristics on the cost effectiveness (CE) of a hypothetical novel therapeutic in atopic dermatitis (AD) relative to a reference therapeutic, dupilumab (DU).Methods: A pharmacometric (PM) - pharmacoeconomic (PE) model was developed to describe the PM-PE relationship for DU. The PM-PE model for hypothetical Drug X (DX) was based on the same structure, with select modifications of PM model parameters, relative to the DU reference. PM model data sources included digitized longitudinal meta-data from published studies. The PM model described longitudinal eczema area and severity index (EASI) score as a fractional decrease from baseline EASI score, including effects for placebo response, topical corticosteroids (TCS), and drug effects. The PE model was derived from a published PE analysis of dupilumab in AD and was characterized as a Markov model with transition probabilities between health states: non-responder, responder (EASI 50, EASI 75, EASI 99), and death, with each state associated with quality adjusted life years (QALYs). Simulation scenarios included variations of DX properties relative to dupilumab: increased maximum fractional decrease (Emax), shorter onset time (T50), and improved persistence of therapy (POT) for a population of mixed moderate/severe disease phenotypes. Replicate simulations were implemented in an interactive tool developed in R and Shiny, running on the Metworx platform. Results were summarized for each scenario as the difference in (DX-DU) QALYs and the probability of CE vs. willingness to pay (WTP).Results: Improvements in Emax and T50 for DX relative to DU did improve the population mean response profile, but did not impact QALYs or probability of CE at any WTP level. Improvements in POT did result in an increase of approximately 1 QALY and improved probability of CE for DX relative to DU (30% vs 15%, respectively, at a WTP of $100,000). In order to achieve a similar probability of cost effectiveness without the effect on POT, a decrease in DX pricing of approximately 10% relative to DU would be necessary.Conclusions: TPP factors that differentiate DX from DU on efficacy do not necessarily translate to increased QALYs or probability of CE. It may be important to consider the impact of new drug characteristics on CE when setting the TPP and in early development decision making.Citations: [1] Blauvelt, A et al. The Lancet, 2017, 389: 10086, 2287-2303.[2] Simpson, E et al. The New England Journal of Medicine, 2016, 375 (24): 2335-48.[3] Silverberg et al. Annals of Allergy, Asthma, & Immunology, 2021,126:1, 40-45.[4] Deng C et al. Journal of investigative dermatology, 2019, 139(9).
Population pharmacokinetic modeling of Binimetinib in Healthy Volunteers and Participants with BRAF V600-mutant or NRAS-mutant Solid Tumors
Authors: Piscitelli Joseph , Hahn Erik , Pithavala Yazdi , Hibma Jennifer
Published: February 2025

Objectives: Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity approved in combination with encorafenib for the treatment of patients with unresectable or metastatic melanoma and metastatic non-small cell lung cancer with select BRAF V600 mutations [1]. The primary metabolic pathway accounting for binimetinib metabolism is glucuronidation via UGT1A1 [1]. The objectives of this analysis were to describe the population pharmacokinetics (popPK) of binimetinib and evaluate potential covariates that may be important predictors of binimetinib pharmacokinetics (PK). Methods: Data from fifteen Phase 1, 2, and 3 clinical studies involving healthy volunteers, and cancer patients (melanoma, colorectal cancer, and lung cancer) were included in the analysis. Upon selection of a base model, covariate screening was employed to identify potentially influential covariates on binimetinib PK. The first-order conditional estimation with interaction method was used in NONMEM v 7.5.0 for binimetinib popPK model development. Perl-speaks-NONMEM version 5.6.0 was used for covariate testing. Results: A 2-compartment model with parallel but linked zero- and first-order absorption described the pooled clinical PK data well, including 10,455 concentrations from 1,457 subjects. Apparent clearance and apparent volume of distribution of central compartment for binimetinib were estimated to be 21 L/hr and 24.3 L, respectively. All model parameters were estimated with good precision (relative standard error < 25%) and were within 95% confidence intervals. Both baseline total bilirubin and age were found to be statistically significant predictors of binimetinib apparent clearance. The effect of age on binimetinib clearance was not considered clinically significant, however increases in total bilirubin, as when seen with hepatically impaired patients could lead to increases in binimetinib exposure (as observed in a study conducted in hepatically impaired participants) [1]. Conclusion: This popPK model adequately described the plasma PK of binimetinib. The results of this analysis, is in agreement with the hepatic impairment study findings and suggested adjustments in the approved product labeling [1].Citations: 1. US Food and Drug Administration. Mektovi: Highlights of prescribing information (2018).
Simulation of Trial Predictions with Model Uncertainty using NMsim
Authors: Shroff Sanaya , Zhang Weiyan , Delff Philip
Published: February 2025

Objectives: Clinical Trial Simulation (CTS) is the application of pharmacokinetics (PK) or pharmacokinetics/pharmacodynamics (PK/PD) modeling to assist in the design of clinical trials. Simulation with NMsim allows users to incorporate uncertainties from either a covariance step or bootstrap results. NMsim can moreover run simulations on multiple NONMEM models simultaneously. The user only needs to provide paths to control stream(s) and a simulation data set. We aim to show these features through some examples that are highly relevant in pharmacometrics.Methods: Two different PopPK models estimated on two separate groups of patients will be simulated. Simple modifications using the NMsim R package will be shown to address questions like:• How to create models capable of simulating data representing two groups of patients selected from a population?• How to incorporate uncertainties from a covariance step?• How to incorporate uncertainties from bootstrap results?• How to summarize simulation results during post-processing?The seamless workflow of NMsim allows the codes to be readily applicable to most NONMEM PopPK models, the user interface entirely within R.Results: NMsim provides a well-designed interface to rapidly simulate a large number of clinical trials. Model-agnostic code allows simulation of multiple NONMEM models with parameter uncertainty. The results illustrate how easily a model-based approach to some questions commonly asked in drug discovery and drug development can be performed.Conclusions: The examples provided in this work address selected questions related to parameter uncertainty of two PopPK models. NMsim's features provide a powerful tool to easily explore clinical trial simulations to support study design during the drug development process.Citations: [1] 2024. NMsim: An R package that can simulate Nonmem models. https://philipdelff.github.io/NMsim[2] 2024. NMsim: Seamless ‘Nonmem’ Simulation Platform. https://cran.r-project.org/web/packages/NMsim
Monte-Carlo simulations to assess the probability of target attainment for cefepime and enmetazobactam in patients with complicated urinary tract infections
Authors: Vollmer Jannik , Quevedo Juan , Dunkel Nathalie , Henriksen Anne Santerre , Machacek Matthias
Published: February 2025

Objectives: Cefepime (FEP)-enmetazobactam (META) is a new fixed dose combination treatment approved by the FDA for the treatment of complicated urinary tract infections (cUTI) in adults. The pharmacokinetics (PK) of META and FEP have been characterized using a compartmental population PK modelling approach using the combined phase I, II and III data. The objective of this study was to assess the clinical relevance of the PK covariates to support the dose selection and to assess whether dose adjustments are required. Methods: Clinical relevance of the PK covariates was assessed by testing their effect on exposure (Cmax and AUC0-24h) and on the probability of target attainment (PTA). For each covariate group, 4’000 subjects were generated for Monte-Carlo simulations (MCS). Random sampling was done from the joint individual FEP and META PK parameter distributions. This method considered that in the same subject the distribution and elimination of FEP and META were correlated and was therefore more likely to provide realistic MCS results. The joint FEP-META PTA, which is the fraction of subjects who simultaneously attained the PK/PD target for both FEP and META was computed from the MCS. The PK/PD targets were 60 or 68% fT >MIC for FEP and 45% fT >CT=2mg/L for META. Results: Renal clearance, as quantified by estimated glomerular filtration rate (eGFR), was the only covariate with a clinically significant effect on PTA. The proposed dosing for patients with cUTI with an eGFR of 60 to 149 mL/min in the EU and 60 to 129 mL/min in the US is 2 grams of FEP and 0.5 grams of META given every 8 hours as a 2-hour IV infusion. For patients with augmented renal clearance (ARC, eGFR ≥130 mL/min in the US, ≥150 mL/min in the EU), the infusion time is increased to 4 hours. For patients with an eGFR of < 60 mL/min, the dose is reduced. Additionally, for patients with severe renal impairment (eGFR 15 – 29 mL/min) and end stage renal disease (eGFR < 15 mL/min), the dosing interval is reduced. Simulations confirmed that this dosage achieved adequate PTAs while maintaining the exposure within the range confirmed to be safe in the phase 3 trial. Conclusions: Renal clearance was found to be the only covariate requiring dose adjustments. The proposed dosing for FEP/META based on renal function ensures an adequate exposure that is safe as well as effective in patients with normal renal function, as well as in patients with increased or decreased renal function. Using a population PK model that simultaneously described the META and FEP PK and included the intra-patient correlation of PK parameters allowed to robustly estimate the PTAs without the need for approximate methods.Citations: -
Dose determination of Lutathera in adolescents via popPK and dosimetry modeling and simulation
Authors: Silva Larissa Lachi , Sood Meemansa , Khanshan Fariba , McComarck Peter , Blumenstein Lars , Ho Yu-Yun
Published: February 2025

Lutathera® is an approved drug for the treatment of somatostatin receptor-positive advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults. There is an unmet need for treatment options in adolescent patients with advanced GEP-NETs and Pheochromocytomas and Paragangliomas (PPGL). To accelerate the access of Lutathera as a potential treatment for adolescent patients, Novartis proposed full efficacy extrapolation approach from adults to adolescents based on expected similar efficacy in both populations, under the condition that the total Lutathera dose remains the same. This extrapolation was made by comparing the blood exposure and the cumulative radioactive dose in main organs at risk, kidney, and bone marrow (BM), using already established popPK and exposure-dosimetry models in adults. The full efficacy extrapolation follows the hypothesis that adolescents can be treated with the same dose as adults without significant risk of exceeding external beam radiation therapy (EBRT) thresholds. The aims included dose determination and justification of full adult dose of Lutathera in the adolescent population (12 to < 18 y) with GEP-NET or PPGL to confirm comparable blood exposure, exposure-dosimetry relationship, and applicability of flat dosing.PopPK model development was performed based on radioactivity-blood PK for Cycle 1, including components of the structural, random effect, and residual error models. Covariates, such as age, creatinine clearance (CrCl), weight (WT), and body surface area (BSA), were tested for popPK and exposure-dosimetry models. Empirical models based on dose (exposure) and CrCl as predictors were used to predict kidney and BM dosimetry for adults. Scenario simulations based on the dosimetry models were performed to predict the probability of the median dosimetry values exceeding the EBRT thresholds for kidney and BM. Subsequently, the adult exposure-dosimetry models were updated to include the adolescent data, and the exposure-dosimetry relationship was compared between the two populations.A two-compartment model with linear elimination without any covariates adequately described the Lutathera PK in adult and adolescents. The predicted exposure metrics from this popPK model was further used to confirm the similarity of exposure between two populations. A comparable exposure-dosimetry relationship for kidney and BM dosimetry in adults and adolescents was observed, with similar probabilities of median kidney and BM dosimetry remaining below defined EBRT thresholds (≤29 Gy and ≤2 Gy respectively). Neither exposure nor kidney and BM dosimetry were clinically relevantly impacted by patients' age and WT. Both popPK and exposure-dosimetry modeling and simulations in kidney and BM confirm the appropriateness of using of full adult dose 7.4 GBq Q8W over 4 cycles of Lutathera in the adolescent population (12 to < 18 y).Citations: .
Preclinical tumor growth inhibition modeling and simulation to support dosing regimen selection of a novel EWS-FLI1 inhibitor for Ewing sarcoma treatment
Authors: Niloy Kumar Kulldeep , Leggas Markos
Published: February 2025

A novel EWS-FLI1 inhibitor, an analog of mithramycin, for Ewing sarcoma (ES) treatment was studied in a murine xenograft model of ES to evaluate its anti-tumor efficacy. The objective of this analysis was to develop a tumor growth inhibition (TGI) model to characterize the pharmacokinetic-pharmacodynamic (PK/PD) relationship of this analogue and apply the TGI model to simulate tumor regression at different doses, schedules, and cycles to propose an appropriate dosing regimen for future efficacy studies.Tumor growth data were collected from anti-tumor efficacy studies conducted in TC-32 ES tumor-bearing athymic nude mice. Mice were treated with vehicle or 0.3, 0.6, and 0.9 mg/kg of the mithramycin analog on a daily IV bolus schedule for five days (QDx5). PK was studied separately at three doses (0.3, 1, and 3 mg/kg), and parameters were estimated using population PK modeling. A sequential modeling approach was adopted, starting with PK modeling followed by TGI modeling with fixed PK parameters. The Simeoni tumor growth model was used to describe natural tumor growth1. The drug effect causing tumor growth inhibition was integrated into the model as a linear effect dependent on concentration (Equation 1). The predictive capability of the model was assessed by comparing simulated tumor growth inhibition of a 2.4 mg/kg Q3Dx6 dosing schedule with experimental data, which was not included in model development. To propose an optimal dosing regimen for future efficacy studies, various tolerated dosing regimens were explored through TGI model-based simulation, followed by survival analysis of the simulated data, to identify dosing regimen(s) that yield prolonged tumor regression and improved survival. dTV/dt=(kge×TV(t))/〖(1+〖(kge/kgl×TV(t))〗20)〗1/20 -kkill×C(t) ×TV(t) (Equation 1)A two compartment PK model adequately described the PK of this analogue with clearance (CL) 40.9 ml.h-1kg-1 (RSE=7.48%), central volume of distribution (V1) 25.36 ml.kg-1 (RSE=8.55%), intercompartmental clearance (Q) 0.76 ml.h-1kg-1 (RSE=23.3%) and peripheral volume of distribution (V2) 6.26 ml.kg-1 (RSE=18.6%). The TGI model adequately characterized the natural tumor growth over time with an exponential growth rate (kge) 0.008 h-1 (RSE=6.64%) and a linear growth rate (kgl) 6.18 mm3.h-1 (RSE=13.3%) as well as the drug effect (kkill) 0.000028 ml.ng-1.h-1 (RSE=9.31%). The observed tumor growth inhibition in mice treated with 2.4 mg/kg Q3DX6 was well predicted by the TGI model, suggesting the predictive utility of this model. TGI model-based simulations for different dosing regimens showed 2.4 mg/kg at Q3Dx5 schedule with two 21 day cycles would lead to the longest tumor regression and highest median survival ( >100 days) suggesting that this analogue has a good therapeutic window.This TGI model based prediction will be tested experimentally.Citations: [1] Simeoni M, et al. Cancer Research, 2004; 64(3):1094-1101
Weight Loss and Nausea from Subcutaneous and Oral Semaglutide Accurately Simulated with a QSP Model
Authors: Kenz Zackary , Vallejo Celeste , Siler Scott
Published: February 2025

Objectives: The recent availability of effective GLP-1R agonist (GLP-1RA) based treatments of obesity has provided great benefit to patients. Understanding the balance between body weight (BW) loss and nausea is paramount in predicting the effectiveness of GLP-1RA based medications, as is potential impact of delivery method. Quantitative systems pharmacology (QSP) modeling can aid in predicting both efficacy and adverse events of compounds, in particular assessing sources of similarities and differences between treatment protocols.Methods: OBESITYsym, a QSP model, was developed to enable simultaneous prediction of BW and nausea due to pharmacologic treatments. This mechanistic mathematical model includes components of energy balance: caloric intake, energy expenditure, body composition, adaptation, as described by Hall 2010 [1]. It also includes a novel submodel of nausea sensitivity and tolerance, a pharmacology submodel linking compound exposure, energy balance, and nausea with pharmacokinetic (PK) models and compound potency. Calibration and validation are described in Siler 2024 [2], including development for the subcutaneous (sc) semaglutide (sema) response. Here, a representation of oral sema was built through incorporation of a literature oral PK model [3] and pharmacodynamics (PD) based on the calibrated sc response. Simulated dosing included uptitration in accordance with protocols.Results: The simulated clinical responses in the SimPops aligned with reported clinical data. There was excellent correspondence between simulated and measured BW loss and nausea incidence for all time points in response to both sc and oral sema in obese populations at 2.4mg and 50mg, respectively, and good correspondence for type-2 diabetes populations used in calibration/validation at lower doses.Conclusions: OBESITYsym can be used to evaluate the efficacy and nausea potential for novel treatments, including oral GLP-1RA and compounds that utilize additional mechanisms to adjust energy balance. The PD/mechanism of action for sc and oral sema was the same in all simulations, indicating that regardless of delivery route similar efficacy results can be achieved if similar levels of compound can be reached in the systemic circulation.Citations: 1. Hall. Am J Phys End Metab. 2010; 298(3): E449-66.2. Siler. Obesity Week. 20243. Overgaard. Clin Pharm. 2021; 60: 1335-48.