bluuebunny/crossref_metadata_2025 huggingface dataset:
Public Perceptions of Misinformation: Sources, Impacts, and Societal Implications
Authors: Prajapati Ujjwal , Pandey Lekhanath
Published: February 2025

This chapter draws from a survey and focus group discussions in all seven provinces, and
key informant interviews in Madhes and Lumbini provinces to assess the spread, prevalence, and impact of misinformation at the grassroots level. They state that widespread access to social media platforms has significantly contributed to the spread of misinformation and impacted vulnerable groups such as children, youth, women, and those who primarily rely on social media for news. They also identify social media, especially Facebook, as the primary medium for misinformation, with
political groups, celebrities, and social media influencers being the primary sources.
Mapping Misinformation: An Analysis of 10 Prominent Misinformation Cases
Authors: Acharya Ujjwal
Published: February 2025

This chapter is an analysis of 10 prominent misinformation cases in Nepal. I use ABCDE Framework to analyze the cases on various topics and of varying degree of impact and importance. The cases analyzed spread from unintentional simple error to coordinated information operations in various issues including foreign relations, and health, and responsible actors ranging from media to social media users to foreign governments. The chapter not only gives a glimpse of actors involved, behavior, content, degree and effect of misinformation, but also provides an overview on types, prevalence and spread of misinformation in Nepal.
Fact Checking: How Misinformation Challenges Mass Media Authenticity
Authors: Acharya Ujjwal , Kunwar Chetana
Published: February 2025

This chapter analyses 407 fact-checks published on three fact-checking websites of Nepal from March 2020 to August 2024, and four case studies, with an objective to understand how misinformation challenges mass media’s authenticity and credibility. The decline in the public trust of mass media communication is a well-documented fact and consumption of misinformation is also associated with a decrease in media trust. The authors state that the mainstream media is also almost equally responsible for spreading misinformation making it sources of misinformation.

The authors state that mass media are largely playing a reactive role either helping the spread the misinformation or, at least, not putting on efforts to combat misinformation even in the highly debated issues. They conclude that such practice by mass media degrades the public trust on their contents creating a situation where the public were losing confidence in mass media as source of authentic information.
Legitimate Strategies for Countering Rumors: A Subjective Exploration of Quranic and Prophetic Guidance
Authors: Hakami Ikram Hassan , Shehab Ali bin Muhammad Ibrahim
Published: February 2025

This study detects the Islamic strategies derived from the Quran and the Sunnah be employed to enhance intellectual awareness and confront digital rumors. It also analyzes the role of Saudi Arabia in combating rumors. The study used eclectic methods to achieve the research aim. It attains descriptive analytical to analyze concepts related to strategies, intellectual awareness, and digital rumors. It also followed the deductive approach to spots to strategies derive from the Quran and the Sunnah to confront digital rumors. It also used applied techniques to provide practical means and tools to enhance intellectual awareness and confront digital rumors, including the optimal use of digital tools to guide individuals and communities toward responsible media behavior. The study found that the Quran and Sunnah provide strategies to safeguard society from malicious rumors. It emphasizes the need to learn and teach these principles. The Islamic religion emphasizes adhering to the Muslim community and its leadership to maintain social cohesion. Therefore, causing harm through rumors is unjustified under any circumstances or pretexts. Furthermore, the analysis revealed that the Kingdom of Saudi Arabia has undertaken significant initiatives to immunize individuals against rumors. The study recommends addressing intellectual issues to be carried out by specialists in the Quran and Sunnah.
Development of Printed Log-Periodic Planar Antenna using Fractal Kochgeometry
Authors: Salmingo Rene
Published: February 2025

Digital terrestrial television (TV) broadcasting has been adopted in the Philippines with the Digital Switch last 2017. TV viewers can now experience the digital picture and sound through free-to-air TV signals in the household. Nevertheless, the quality of TV pictures and sound studies on digital TV has not been realized because it requires the International Telecommunication Union (ITU) assessment (ITU-R BT.500-13) reference. This paper aimed to develop a printed log[1]periodic planar antenna where the antenna arrays were based on Fractal Koch geometry and determine the digital picture and sound quality received from a digital television box. The calculated Fractal Koch geometry was applied to the printed circuit board, and circuitry was assembled to evaluate TV picture and sound quality. Ten (10) random TV viewers participated in the subjective assessment using ITU-R BT.500-13 evaluation procedure for sound and picture quality laboratory set-up. Mean and standard deviation was used to measure the digital TV signal’s picture and sound quality level. Based on the results, the overall mean scores of the TV picture and sound quality were 4.59 and 4.68 with the standard deviation values of 0.58 and 0.48, interpreted as excellent respectively. TV picture and sound quality were imperceptible to the TV viewers. FractalKoch Geometry is a novel method for reducing antenna array length in the development of log-periodic printed planar antennas that receive a digital television signal, allowing TV viewers to experience smoother images and better sound quality from digital television broadcasts.
Pre-Service Teachers' Mathematics Achievement and Content Competence in the K to 6 Basic Education Program
Authors: Jalandoni Perlyn
Published: February 2025

This study ascertained the pre-service teachers’ (PTs) Mathematics content competence (MCC) of the common content knowledge (CCK) and specialized content knowledge (SCK) emphases of the K to 6 Basic Education Program (BEP) and the relationship between MCC and mathematics achievement among the seventy-eight randomly chosen Bachelor of Elementary Education (BEEd) major in General Education(GenEd) PTs. MCC data were obtained using a researcher-made instrument which was subjected to validation and reliability testing (Cronbach’s alpha =0.978). Mathematics achievement data were obtained using the PTs’ records from the Registrar’s Office. The statistical analyses employed in the study were mean, SD, and Spearman’s rho. The findings revealed that the PTs had good MCC in CCK while poor MCC in SCK emphases of the K to 6 BEP and showed very good mathematics achievements. A significant relationship was found between the PTs’ mathematics achievement and MCC in the CCK emphases of the K to 6 BEP. Therefore, the PTs showed competence in the basic concepts and procedures of elementary mathematics. However, they had inadequate competence needed in the actual effective teaching of the discipline. Moreover, the more mathematics content and procedures they had learned from their teacher education program, the better were their MCC in the CCK emphases of the K to 6 Program. The findings from this study have implications for faculty development as well as for future research.
THE EFFECT OF TREATMENT BASED ON ACCEPTANCE AND COMMITMENT ON SELF-COMPASSION OF PEOPLE WITH DIABETES
Authors: Bakhtiari Bahareh
Published: February 2025

The present study was conducted to investigate the effect of treatment based on acceptance and commitment to self-compassion of people with diabetes. The research method was quasi-experimental (control group and experimental group). The statistical population of the present study was all type 1 diabetic patients among those who were referred to the hospitals of Borujerd City in 2023. The sample size of the research was 40 people (20 people in the experimental group and 20 people in the control group), which was done using a random sampling method. The present research was conducted using the self-compassion questionnaire (Naf, 2003; quoted by Khosravi et al., 2012). One-way analysis of variance Test was used to analyze the data. The results of the data analysis showed that participating in therapy classes based on acceptance and commitment to self-compassion of people with diabetes improved their self-compassion. Therefore, it is concluded that treatment based on acceptance and commitment is effective in any self-compassion in diabetic patients.
Untitled Thesis Record
Authors: Publication Support Karolinska Institutet University Library
Published: February 2025

No description
Aprendizaje Basado en Proyectos (ABP) en las Instituciones de Educación Superior: Reseña de la Literatura
Authors: Barcia Cedeño Erika Iveth
Published: February 2025

El Aprendizaje Basado en Proyectos (ABP) ha surgido como una metodología pedagógica fundamental en la Educación Superior, orientada a fomentar competencias transversales como la resolución de problemas, el pensamiento crítico y el trabajo en equipo. Este artículo presenta una reseña de la literatura sobre la implementación y los efectos del ABP en contextos universitarios, destacando su capacidad para vincular la teoría con la práctica y preparar a los estudiantes para enfrentar escenarios laborales complejos. Se analizan estudios publicados en bases de datos académicas entre los años 2015 y 2024, que evidencian mejoras en la motivación, el compromiso estudiantil y el desarrollo de habilidades prácticas mediante el ABP. Asimismo, se examinan las principales barreras, como la resistencia al cambio pedagógico y la necesidad de formación docente en estrategias de diseño y evaluación. Finalmente, se discuten las oportunidades futuras, incluyendo la integración de tecnologías digitales para enriquecer los procesos de aprendizaje. Esta reseña concluye que el ABP no solo transforma el rol del docente y del estudiante, sino que también contribuye a la innovación educativa, especialmente en un contexto de globalización y demanda de competencias adaptativas.
La infraestructura del transporte y el desempeño logístico del distrito de aduana – Latacunga
Authors: Rubio Toledo Oswaldo Henry , Heredia Campaña Argenis Lissander , Realpe Cabrera Iván Alirio
Published: February 2025

El presente estudio analiza la infraestructura de transporte y el desempeño logístico en el Distrito de Aduana de Latacunga, con énfasis en el transporte aéreo como elemento clave para las exportaciones ecuatorianas. Utilizando un enfoque mixto, se integraron métodos cuantitativos y cualitativos para examinar datos sobre la calidad de la infraestructura, los tiempos de despacho y la capacidad operativa. Los resultados evidencian deficiencias en áreas críticas, como la falta de almacenes especializados y conexiones multimodales, lo que limita la competitividad del aeropuerto de Latacunga frente a otros de la región. El análisis propone estrategias como la modernización de la infraestructura, incentivos fiscales, implementación de conexiones ferroviarias, automatización de procesos y consolidación de carga. Estas medidas buscan optimizar la eficiencia operativa y posicionar a Latacunga como un centro logístico competitivo. Finalmente, se subraya la importancia de fortalecer la sostenibilidad logística mediante prácticas responsables, como el uso de energías renovables y certificaciones ambientales.
Pensamiento lógico y resolución de problemas: El uso de estrategias de aprendizaje colaborativo para desarrollar habilidades de razonamiento matemático en contextos cotidianos
Authors: Bernal Párraga Augusto Paolo , Alcívar Vélez Viviana Elizabeth , Pinargote Carreño Vinicio Gregorio , Pulgarín Feijoo Yeraldín Alexandra , Medina Garate Carlos Leonardo
Published: February 2025

La publicación titulada "Pensamiento lógico y resolución de problemas: "La implementación de estrategias de aprendizaje colaborativo para el desarrollo de habilidades de razonamiento matemático en contextos diarios" examina la manera en que el aprendizaje colaborativo promueve competencias matemáticas y razonamiento lógico en los estudiantes. Esta metodología, orientada hacia la resolución de problemas contextualizados, establece una conexión entre conceptos abstractos y aplicaciones prácticas, fomentando la colaboración y la toma de decisiones fundamentadas en evidencias. La investigación, de naturaleza mixta, implicó la participación de 180 alumnos de nivel secundario, divididos en un grupo experimental y otro de control. El conjunto experimental empleó tácticas colaborativas, tales como la generación de ideas colectivas, la resolución de problemas en equipo y la reflexión colectiva, mientras que el conjunto de control recurrió a métodos convencionales. Durante un semestre, se evaluó la eficacia de estas metodologías a través de evaluaciones estandarizadas, encuestas y observaciones en el entorno del aula. Los hallazgos indicaron que el grupo experimental logró una mejora del 40% en sus habilidades de razonamiento lógico y resolución de problemas, en comparación con el 18% del grupo de control. Además, se observó un aumento en la confianza y la motivación hacia la adquisición de conocimientos matemáticos. El 85% de los alumnos enfatizó la eficacia y el enriquecimiento de las actividades colaborativas. Desde una perspectiva cualitativa, las dinámicas grupales potenciaron competencias transversales tales como la comunicación, la empatía y el pensamiento crítico. No obstante, se detectaron desafíos, tales como la necesidad de formación de los educadores y las variaciones en la participación estudiantil. Para concluir, el aprendizaje colaborativo emerge como una táctica esencial para capacitar a los estudiantes para abordar eficazmente problemas del mundo real.
Mobile Phones and Multidrug Resistant Bacteria: A Growing Concern for Healthcare Workers
Authors: Nagat Elbarghathi  , Masoud Eldernawi  , Mohammed Abdulmawlay
Published: February 2025

Healthcare workers' mobile phones can potentially transmit a range of pathogenic bacteria causing Hospital acquired infections to patients and community. The study was conducted to determine the prevalence of bacterial contamination of mobile phones of healthcare workers, assessing the kinds of bacterial isolates, their antibiotic susceptibility and resistance patterns, and the factors contributing to contamination. A cross-sectional study was conducted at Elhwari Nephro Center including 125 health care workers. Demographic data, and data regarding antibiotic usage history as well as mobile cleaning behaviour were collected using a structured questionnaire. Antimicrobial susceptibility testing was performed for all the collected mobile swabs samples. Data analysis using SPSS version 28. Prevalence rates of resistant micro-organisms were revealed together with the corresponding patterns of antibiotic susceptibility. Results are presented using tables for clarity. The overall prevalence of mobile phone contamination was 84% of swabbed samples. The most common bacterial isolate was pseudomonas aeruginosa 21.6% followed by E. coli 20.8%, staphylococcus epidermidis 16.8%, Klebsiella pneumonia 14.4%, staphylococcus aureus 6.4%, and clostridium spp 4%. Most isolates were susceptible to levofloxacin (98.1%), ciprofloxacin (88.6%), and ceftriaxone (84.8%). Vancomycin showed limited effectiveness specifically against staphylococcus aureus with only 13% susceptibility. 86.7% and 71.2% of bacterial isolates were resistant to erythromycin and clindamycin respectively. No significant correlation was found between mobile phone contamination and different participant variables such as gender, age, occupation, mobile phone usage and hygiene practices. The overall prevalence of multidrug-resistant bacteria was 80%. This study points out the scary role that mobile phones play in the dissemination of multidrug-resistant organisms and the urgent need to revisit policies on the use of antibiotics, as well as the reinforcement of antibiotic stewardship.
Competencias metodológicas adquiridas en la educación superior privada ante la crisis por covid-19
Authors: López Tobar Raúl Alfredo , Orantes Henríquez Natalia Marcela , Zelaya Colón Christian Edgardo , Maribel Castillo Reina
Published: February 2025

Ante la crisis provocada por la pandemia del COVID-19, los docentes universitarios tuvieron que asumir un cambio con el objetivo de generar una reestructuración de sus actividades tradicionales empleadas en el proceso de enseñanza-aprendizaje en el aula física, a una modalidad muy diferente, pero con un mismo fin: continuar el proceso de formación de los estudiantes desde la virtualidad. Esto llevó al uso de herramientas tecnológicas y, por tanto, al dominio de nuevas competencias metodológicas. La investigación identificó las metodologías y herramientas tecnológicas utilizadas por los docentes de educación superior y cotejó estos procesos con la actitud mostrada, pero, ante todo, sirvió para dar un aporte complementario desde la filosofía educativa, para mantener de forma sistematizada lo que se empleaba en instituciones privadas ubicadas en el departamento de Santa Ana.
Cambios cíclicos en el empleo de diferentes grupos demográficos
Authors:   Profesora de Teoría Económica, Plaza Acero Raquel
Published: February 2025

El objetivo del trabajo es analizar la influencia de las variaciones cíclicas de la actividad sobre el cociente entre el empleo y la población potencialmente activa. Esto se hace para diferentes grupos demográficos. Las principales conclusiones que se obtienen son: en primer lugar, que se debe considerar la participación y el desempleo conjuntamente para analizar los cambios cíclicos del mercado de trabajo; en segundo lugar, que los jóvenes son los que experimentan mayores variaciones cíclicas en el empleo; finalmente, el nivel educativo juega un papel estabilizador en el caso de la mujer, tanto en su participación laboral como en su tasa de empleo.
Participación y modernización en las PYME europeas
Authors:   Sociólogo y economista, Laville Jean-Louis
Published: February 2025

Según la hipótesis formulada en este artículo, las dos ideas-tipo de relaciones sociales: comunidad (Gemeinschaft) y sociedad (Gesellschaft), diferenciadas por Tonnies y Weber, pueden permitir una distinción heurística en la aproximación de la economía a condición de actualizar la definición de comunidad. En efecto, la empresa considerada como el lugar de la relación societaria se ve obligada, ante los cambios en curso, a tomar en consideración la comunidad productiva. En esta nueva configuración, que rompe con los principios taylorianos, si las ocupaciones tradicionales se encuentran desestabilizadas, los comportamientos exigidos a los obreros se aproximan a los puestos en marcha en el universo profesional. Esto explica la adaptación particular de algunas PYMES al contexto productivo contemporáneo. Esto es, al menos, lo que se pone de manifiesto en el análisis comparativo de prácticas participativas en las PYME europeas (21 estudios de casos realizados en cuatro países: Alemania, España, Francia e Italia), algunas de cuyas conclusiones se presentan aquí.
ARRITMIA CARDÍACA NO BRASIL: UMA ANÁLISE DAS INTERNAÇÕES HOSPITALARES DO ANO DE 2019 A 2023
Authors: Peres Gabriella de Lima , Companhoni Maria Gabriela , Castanhel Isadora Freitas Del , Sales Dandara Virginia Guia Semedo , Bezerra Gustavo Palaro Albano , Barros Paulo Menna Barreto Pompeo de , Alves Gustavo Anzolin , Alves Ana Clara França , Vale Lucas Rosal Silveira , Manrique Maite Kasumi Sato
Published: February 2025

Introduction: Cardiac arrhythmias are rhythm disturbances that can impair the heart's pumping function, primarily caused by abnormalities in the electrical conduction system. While many patients remain asymptomatic, symptoms such as palpitations, dizziness, and dyspnea are common. The clinical significance of arrhythmias is highlighted by their impact on quality of life and the burden they impose on healthcare systems. Objectives: To analyze hospital admissions due to cardiac arrhythmia in Brazil. Methods: This is a cross-sectional, descriptive, and retrospective study, based on data extracted from the Hospital Information System (SIH/SUS), available on the DATASUS platform, regarding hospital admissions for cardiac arrhythmia from 2019 to 2023. Data analysis was categorized by year, sex, ethnicity, age group, geographic region, and type of hospital admission. Results: This study analyzed data on hospitalizations for cardiac arrhythmia in Brazil from 2019 to 2023, totaling 283,970 cases. The highest number of admissions occurred in 2023 (74,492), which also recorded the highest incidence rate (36.7 per 100,000 inhabitants) and the highest number of deaths (9,067). The Southeast region had the highest incidence, whereas the Central-West region exhibited the highest mortality rate. The prevalence was higher among males, White individuals, and older adults, particularly those aged 70–79 years. Additionally, 81% of hospitalizations occurred as emergency admissions, underscoring the severity of the condition. Conclusion: The findings suggest regional disparities in the distribution and management of arrhythmias, highlighting the need for public policies that prioritize prevention, early diagnosis, and equitable access to treatment. This study reinforces the importance of raising awareness about cardiac arrhythmias to reduce their morbidity, mortality, and overall impact on the healthcare system.
Biochar as a Sustainable Cement Replacement for Enhancing Concrete Composite Properties: A Review
Authors: Md. Saniul Haque Mahi  , Md. Abdul Mun-Im-Dinar  , Tanjun Ashravi Ridoy
Published: February 2025

Concrete, a highly adaptable and extensively utilized material, encounters difficulties stemming from the environmental repercussions of cement manufacturing and the exhaustion of natural resources such as river sand and gravel. These concerns have stimulated investigation into sustainable alternatives like biochar, a carbon-dense substance generated by the thermochemical conversion of biomass. Biochar’s distinctive characteristics, such as elevated surface area, porosity, and cation exchange capacity, render it a viable supplemental cementitious material (SCM). This study evaluates the impact of biochar inclusion on concrete’s mechanical characteristics, concentrating on compressive, tensile, and flexural strengths. Research indicates that biochar enhances early-age compressive strength, with findings documenting an increase of up to 40% at a 2% replacement rate. Nonetheless, elevated doses (>5%) diminish strength owing to heightened porosity and water requirements. Flexural strength exhibited considerable enhancements, especially with presoaked biochar and certain feedstocks, but tensile strength advantages were noted at less replacement levels (e.g., 5%). The results underscore biochar’s potential as a supplementary cementitious material for sustainable concrete, including enhancements in early-age strength and environmental advantages such as carbon sequestration. Future research should concentrate on improving biochar dose and assessing long-term performance to improve its applicability in extensive building uses.
Peran Opinion Leader Dalam Pilihan Politik Masyarakat Pesisir (Studi Di Kelurahan Ampenan Kecamatan Ampenan Kota Mataram)
Authors: Hamid Ihsan , Ramdani Ihwanul , Zuhairi Ahmad
Published: February 2025

Dalam masyarakat yang hidup berkelompok berdasarkan karakterisitk dan kesamaan latar belakang tertntu seperti kesamaan tempat tinggal, profesi atau tradisi, peran opinion leader sangat penting dan dominan dalam menentukan sikap sosial politik dari masayarakat tersebut, bahkan tidak jarang peran opinion leader tersebut juga sekaligus memiliki peran-peran penting dalam urusan menyelesaian konflik dan urusan keluarga sehingga pada batas tertentu opinion leader menjadi sangat sentral dalam sebuah komunitas masyarakat. Begitu juga halnya yang terjadi di beberapa wilayah di Lombok, seperti halnya di Kelurahan Ampenan Kota Mataram, seperti apa peran dan siapa tokoh opinion leadernya maka penting diteliti untuk mengetahui jawaban dari pertanyaan tersebut. Untuk mencari jawaban atas pertanyaan tersebut maka penelitian ini menggunakan metode kualitatif dengan dengan data primer bersumber dari observasi dan wawancara dengansejumlah informan, baik itu dari perwakilan masyarakat maupun dari unsur tokoh pemuda, sedangkan data sekunder diperoleh dari berbagai media maupun hasil penelitian pihak lain yangdapat menunjang analisa. Hasil dari penelitian ini adalah bahwa opinion leader diwilayah tersebut adalah orang yang mempunyai keunggulan dari pada masyarakat kebanyakan. Salah satu keunggulan opinion leader daibandingkan dengan masyarakat kebanyakan adalah pada umumya opinion leader itu lebih mudah menyesuaikan diri dengan masyarakatnya, lebih kompeten dan lebih mengetahui tatacara pemeliharaan norma yang ada didalam masyarakat. Dari hasil pengolahan data yang diperoleh dari jawaban setiap narasumber, dapat diketahui bahwa tokoh opinion leader yang berpengaruh pada masyarakat pesisir kelurahan Ampenan Tengah adalah Ibu Sukini S.Pd, yang menjabat sebagai Kepala Lingkungan Melayu Bangsal.Selain itu, dia juga memiliki sifat suka membantu masyarakat, juga karena memiliki profesi/jabatan cukup sentral disitu sehingga dia menjadi tokoh opinion leader diwilayah tersebut
Strategi Pelatih Tari Bali dalam Meningkatkan Minat Belajar Siswa di Pasraman Widya Santa Dharma Lingkungan Sweta Cakranegara Kota Mataram
Authors: Miantari Ni Made Dwi , Armayani Ni Made Ria Taurisia , Prajawati Yani Timor
Published: February 2025

This study explains that the strategy of Balinese dance trainers has an important role in increasing interest in learning sisya in Pasraman Widya Santa Dharma. The research method uses qualitative methods. The dance learning process at Pasraman Widya Santa Dharma is held on Monday and Thursday at 16.00-18.00. The obstacles of Balinese dance trainers in increasing their interest in learning in Pasraman Widya Santa Dharma are, first, lack of parental support; secondly, transportation; third, school activities; Fourth, different children's comprehension; fifth, interest; sixth, age; Seventh, time. The strategies of Balinese dance trainers in increasing interest in learning sisya at Pasraman Widya Santa Dharma are, first, varied Balinese Dance Training; second, involving Sisya in Dance Performance; third, the division of groups; carry out an independent dance exam.
Mental Health as a Public Health Priority: A National Strategy for Addressing the Mental Health Crisis in the Post-Pandemic Era
Authors: Kizito Uzoma Ndugbu
Published: February 2025

Mental health remains a critical yet underfunded area of public health, with significant disparities in access to care globally. Despite recent shifts in policy and increased recognition of mental health issues, over 70% of individuals with mental illness do not receive adequate treatment, primarily due to stigma, lack of awareness, and insufficient resources. This article examines the funding trends for mental health services, particularly in the context of the American Rescue Plan Act, highlighting the urgent need for systemic reforms and increased investment. It emphasizes the importance of integrating mental health into broader health initiatives and the role of community engagement in addressing these challenges. By advocating for a human rights perspective, the article calls for collaborative efforts among policymakers, healthcare providers, and communities to ensure equitable access to mental health care and improve overall well-being.
FOREIGN DIRECT INVESTMENT: A CRITICAL REVIEW FROM NIGERIA PERSPECTIVE AND THE EASE OF DOING BUSINESS IN NIGERIA
Authors: GAD BHILIPNANDI EMMANUEL
Published: February 2025

This paper will ex-ray the economic challenges currently affecting the ease of doing business in Nigeria. Also, concentrating on the assessment of some relevant issues that will give a clear understanding on the nature of starting or doing business in Nigeria. The key issues to look at are the main users of corporate reporting, the main providers of funds for business, government legal system, the role of legislation, the development and implementation of local and international accounting standards, task of the professional bodies, the influence of religion and culture on the economy, corporate social responsibility (CSR) and inflation/deflation. All these factors are essential towards providing a clear picture of the economy in Nigeria to provide potential investors making decision on expansion to Nigeria.
Population Pharmacokinetics of Enoxaparin in Neonates and Infants
Authors: Attah Michael , Quinney Sara , Heathman Michael , Centers Gabriela , Overholser Brian
Published: February 2025

Background – Enoxaparin is an anticoagulant used for preventing and treating venous thromboembolism. However, there is limited information on optimal enoxaparin dosing and an absence of evidence-based dosage regimens in neonates and infants, especially in critically ill patients. This project aims to develop a population pharmacokinetic model to describe the anti-factor Xa (anti-Xa) activity-time profile and to identify sources of variation in anti-Xa activity following enoxaparin subcutaneous administration in neonates and infants.Method – Anti-Xa activity, dosing, demographic and clinical covariates were obtained from the electronic health records of neonates and infants admitted between 2016 to 2021 for cardiac indications to the intensive care unit Riley Hospital for Children at Indiana University Health in Indianapolis, IN. Demographic data included date of birth, body weight, and laboratory measurements for serum creatinine (SCr), hemoglobin, and platelet count. PK modeling was performed using NONMEM 7.4 and Pirana 2.10 with the FOCE-I method. Goodness-of-fit plots were generated using xpose package in R 4.3. Stepwise covariate modeling was used for covariate selection based on model objective function value, relative standard error, BIC, and condition number. Results – This analysis included 499 patients with a median age of 2.2 (IQR, 0.9 – 4.9) mos, 24098 enoxaparin doses, and 2721 plasma samples analyzed for anti-Xa activity. The PK of enoxaparin was best characterized by a one-compartment model with first-order absorption and elimination. Inter- and intra-individual variability were modeled exponentially, and proportionally, respectively. The model that fit the data best integrated weight scaled allometrically with exponents of 0.75 and 1.0 on apparent clearance (CL/F) and apparent volume of distribution (Vd/F), respectively. The estimated population CL/F, Vd/F, and Ka were 1.27 L/h/70 kg (95% CI: 1.17 to 1.37), 26.9 L/70 kg (95% CI: 23.2 to 30.6), and 0.77 h-1 (95% CI: 0.36 to 1.18), respectively. The disposition of enoxaparin using anti-Xa activity as a surrogate was influenced by SCr and postnatal age (PNA). The Vd/F was notably affected by PNA, with higher exposure observed as age increased until about 1.5 mos PNA, at which point the effect plateaus. The final model incorporated SCr on CL/F using a power function with estimated effect of -0.21 (95% CI: -0.31 to -0.09). A piecewise function was used to model PNA on Vd/F with an inflection point of 1.5 mos, and an estimated effect of -0.57 (95% CI: -0.77 to -0.37).Conclusions – The estimated CL/F, and Vd/F of enoxaparin in neonates and infants in this study are higher than reported values in adults (CL/F ≈ 0.74 L/h, Vd/F ≈ 5.0 L). The inverse relationship between SCr and CL/F indicates dose adjustment may be required in this population. Additionally, pediatric patients less than 1.5 mos of age require higher body-weight adjusted doses of enoxaparin than older infants and adults.Citations: N/A
Semi-physiological population pharmacokinetic (PPK) model using dose optimization data for ASTX030, an oral fixed-dose combination (FDC) of CDA inhibitor cedazuridine and azacitidine in MDS patients
Authors: Chan Danna , Elmokadem Ahmed , Sano Yuri , Keer Harold , Oganesian Aram
Published: February 2025

Objectives: Cytidine deaminase (CDA) rapidly degrades azacitidine (AZA), an approved parenteral treatment for myelodysplastic syndromes (MDS), resulting in poor and variable bioavailability. ASTX030, an oral fixed-dose combination (FDC) of AZA with the CDA inhibitor cedazuridine (CED), produces systemic exposures similar to subcutaneous (SC) AZA with acceptable inter-patient variability. Here, a semi-physiological population pharmacokinetic (PPK) model was developed and qualified to assess the comparable bioavailability of SC AZA and ASTX030 at different AZA and CED dose level combinations.Methods: A previously developed semi-physiological PPK model [1] that characterized the PK enhancement of oral decitabine when dosed with CED (ASTX727) was utilized and the parameters were updated using data from a phase 1 first-in-human dose optimization study for ASTX030 (NCT04256317). The model included semi-physiologic elements (SC AZA depot, oral AZA and CED transit compartment absorption and portal vein, liver, central and peripheral compartments) and a competitive inhibition model describing CED effect on AZA metabolism which was assumed to occur in the gut, liver, and systemic circulation. A sequential modeling approach was adopted where CED model parameters were fixed to the previously estimated values for ASTX727, assuming similar CED PK, then a simulation was run to obtain the CED concentrations in gut, liver, and systemic circulation. These concentrations were then used to influence the inhibitory effect on AZA clearance in these respective compartments. The model used height to scale physiological parameters. Pearson correlation (r) was used for data processing, exploratory analysis, and visual predictive checks (VPCs), while parameter estimation utilized NONMEM.Results: The developed semi-physiologic model parameters were estimated using phase 1 ASTX030 data (n = 68). The model’s performance was evaluated using standard goodness-of-fit plots and visual predictive checks (VPCs) that compared model predictions to the observed data. Parameter uncertainty was quantified using bootstrapping (600 samples).Conclusions: A semi-physiologic PPK model was sequentially developed using ASTX030 phase 1 trial data to characterize the PK enhancement of oral AZA when dosed with CED. Simulations will inform future clinical development of ASTX030 and evaluate the appropriate AZA:CED doses in FDC that would achieve a comparable exposure to the SC AZA dosing.Citations: [1] Burroughs, E., Oganesian, A., Zhang, X. and Hoke, F. Development of a Semi-Mechanistic PK/PD Model of an Oral Fixed Dose Combination (FDC) of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) in Subjects withMyelodysplastic Syndromes. ASCPT AnnualMeeting. 2017. Available: https://astx.com/wp-content/uploads/2017/03/2017_ASTX727_Poster_ASCPT_Oganesian_Final-web.pdf
Model-based meta-analysis of safety for monomethyl auristatin E-conjugated antibody drug conjugates in cancer patients
Authors: Doi Yohei , Shiomi Mari , Ieiri Ichiro , Hirota Takeshi
Published: February 2025

Objectives: MMAE is one of the most-commonly used payloads for ADCs in clinical development as well as in the clinic for cancer treatment. Due to its potent cytotoxicity by preventing tubulin polymerization, which causes arrest of cell cycle and apoptosis, MMAE-conjugated ADCs often requires safety management for adverse events (AEs) during treatment, such as bone marrow toxicity, peripheral neuropathy, or skin reactions, etc. The purpose of this MBMA was to characterize the safety profiles across MMAE-conjugated ADCs in a quantitative manner and to assess the relationships between MMAE exposure and AE frequences. Methods: A comprehensive literature search was conducted in the public databases for the approved MMAE-conjugated ADCs, including brentuximab vedotin, disitamab vedotin, enfortumab vedotin, tisotumab vedotin and polatuzumab vedotin, administered alone or in combination to cancer patients. The pharmacokinetic data for unconjugated-MMAE in the blood, the frequency of AEs of interest (anemia, neutropenia, hyperglycemia, peripheral neuropathy, skin reactions and alopecia) and the study-level baseline characteristics were retrieved. A meta-regression model was applied to derive a functional form of AE rate dependence on MMAE exposure to quantitatively estimate parameters that would characterize dependence [1, 2]. The following model was used to describe the data with maximum likelihood: logit(PrAE) = β0 + β1*Cmmae, where logit(PrAE) refers to the logit-transformed probability of a given AE and Cmmae corresponds to the average concentration of MMAE normalized over the standard dosing cycle per ADC. After the base model for exposure dependence of AE rates was established, trial-level patient baseline characteristics were included to explore potential covariates. Meta-regression model development and evaluation were performed using R software version 4.3.0.Results: A total of 59 articles were identified, covering 5,842 patients in 155 dosing cohorts treated with ADC therapies. For anemia, neutropenia and peripheral neuropathy, no exposure dependence was found; the overall AE rates were, 24.6%, 23.4% and 31.5%, respectively. The developed models indicated that the all-grade AE rates for hyperglycemia, skin reactions and alopecia were driven by MMAE: the regression coefficient (β1) describing the payload exposure was 0.371 (95%CI: 0.0636-0.679), 0.493 (0.195-0.790), 0.806 (0.544-1.07), respectively. Conclusion: The MBMA results provided a quantitative overview of safety profiles across MMAE-conjugated ADCs associated with MMAE exposure. This framework also helps to better understand and manage the safety when MMAE-conjugated ADCs are administered to patients in the clinic.Citations: [1] Shulgin B et al. Oncoimmunology. 2020; 9(1): 1748982.[2] Zhang R et al. CPT Pharmacometrics Syst Pharmacol. 2022; 11(8):1135-1146.
Role of quantitative systems pharmacology (QSP) in optimizing elranatamab dosing regimen for relapsed/refractory multiple myeloma
Authors: Poels Kamrine , Elmeliegy Mohamed , Wang Diane , Hibma Jennifer , Musante Cynthia , Shtylla Blerta
Published: February 2025

Objectives: Bispecific antibodies (BsAb) are a rapidly evolving treatment modality for multiple myeloma (MM). Elranatamab, an approved BsAb, forms an immune synapse between T-cells via surface marker CD3 and B-cell maturation antigens (BCMA) on tumor cells1. Membrane-bound BCMA can undergo shedding from the cell surface, leading to circulation of soluble BCMA (sBCMA), which is associated with disease burden and reduces drug exposure and may impact efficacy. Establishing a recommended dose based on non-clinical and early clinical data can be challenging especially for drugs with complex dynamics such as BsAb and for a disease with a shed target. We use QSP to form a framework that can help inform dosing decisions for elranatamab monotherapy in relapsed/refractory multiple myeloma (RRMM) patients.Methods: Here, we develop a mathematical model that captures the mechanism of action of elranatamab and corresponding disease dynamics for MM patients using datasets from studies MagnetisMM-1 and MagnetisMM-32-3. Important properties affecting disease response and progression, such as shedding of BCMA receptors, drug-binding to sBCMA, and T-cell exhaustion are accounted for. We also form virtual populations (VPop) that represent variability in biological, pharmacological, and tumor-related parameters from clinical participants to inform clinical dose-response relationships, and to identify biological determinants of clinical response. Results: Simulations predict 76 mg weekly (QW) as the optimal dose regimen that would benefit most RRMM patients, especially those with high sBCMA. Additionally, the simulations suggest a left-shift in the bell-shaped dose-response curves among virtual responders, supporting gradual reduction of the dosing intensity after persistent response. Specifically, our model advocated a dosing transition from QW to every 2 weeks (Q2W). Conclusions: Our mechanistic model supported the dosing regimen in the phase 2 MagnetisMM-3 study. This modeling platform continues to be used to inform dosing recommendations for elranatamab studies with combination treatments or in earlier treatment lines. Additionally, this framework can be expanded and applied to the next generation of CD3 BsAbs.Citations: Shah, N., et al. Leukemia (2020)Bahlis, N.J., et al. Nature Medicine (2023)Lesokhin, A.M., et al. Nature Medicine (2023)
Population Pharmacokinetics/Pharmacodynamics Modeling of INCAGN02390 in Patients with Select Advanced Malignancies
Authors: Fang Yunlan , Barker Breann , Dong Zhiwan , Liu Xiang , Sheng Jennifer , Chen Xuejun , Yang Yan-ou
Published: February 2025

Objectives: INCAGN02390 is a fully human, immunoglobulin G1κ (IgG1κ) monoclonal antibody that selectively binds to the extracellular domain of T-cell immunoglobulin and mucin domain containing protein-3 (TIM-3), and potentially elicits an antitumor response by enhancing T-cell responsiveness. INCAGN02390 is being developed for the treatment of advanced malignancies. The objective of this study was to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model to characterize INCAGN02390 exposures, peripheral TIM-3 receptor occupancy (RO), and interpatient variability in patients with advanced malignancies. Methods: The model was developed using INCAGN02390 PK and TIM-3 RO profiles from the first-in-human study of INCAGN02390 (NCT03652077); a total of 348 serum concentration records from 37 patients enrolled in the study were used for this analysis. Patients received intravenous INCAGN02390 doses ranging from 10 to 1,600 mg given every two weeks (q2w). Flow cytometry was performed to monitor total TIM-3 and unbound TIM-3 on circulating monocytes. TIM-3 RO was subsequently calculated as the percentage of INCAGN02390 bound TIM-3 in total TIM-3. PK/PD analyses were performed using a nonlinear mixed effects model within the Monolix® software (version 2021R2). Patient demographic and baseline characteristic data, including body weight, age, sex, baseline serum albumin and alkaline phosphatase concentrations, were evaluated during a covariate search using a stepwise forward-addition process. The predictive performance of the model was assessed by goodness of fit (GOF) plots and visual predictive checks (VPCs). Results: INCAGN02390 PK and TIM-3 RO profiles were described using a two-compartment PK model with linear elimination coupled with a sigmoid Emax PD model, where Emax is the maximal drug effect. All parameters and their variabilities were estimated within an acceptable degree of precision and were physiologically plausible for an antibody. The mean (% relative standard error of estimate) estimates of linear clearance (CL) and central volume of distribution (V) were 0.011 L/h (6.4%) and 2.96 L (5.4%), respectively. Patient body weight was identified as a significant covariate for both CL and V. Baseline serum albumin concentration was also found to influence CL. The GOF plots and VPCs demonstrated that the final model provided adequate description of the observed data. Conclusions: A population PK/PD model was successfully developed to describe the INCAGN02390 PK and peripheral TIM-3 RO in patients with advanced malignancies. The model could be leveraged as a valuable prediction tool to support future dose selection for clinical development.Citations: N/A
Real world examples of PBPK impact on CYP3A4 victim DDI drug label content
Authors: Templeton Ian , Jones Hannah
Published: February 2025

PBPK modelling has been successfully applied to support all stages of drug development, from drug discovery, through drug approval, and post marketing requests. But how do we measure this success? One objective measure of meaningful impact on drug development is evidence of approved drug label claims supported by PBPK modelling and simulations. The objective of this analysis was to review new drug applications, and approved drug labels, for examples of successful application of PBPK to provide guidance on CYP450 victim DDI liability. Examples where model-based approaches were accepted in lieu of clinical DDI studies, and equally important, examples where these approaches were not accepted, have been investigated and summarized.Small molecule drug approvals, from 2021 to present, were reviewed to identify examples where PBPK modelling was applied to investigate CYP victim DDI liability. Summary Reviews were filtered for references to PBPK modelling in drug interaction sections, and classified as either having had an impact on drug label indications, or as rejected by the FDA Clinical Pharmacology reviewer. Relevant properties of each drug were collected from the review report and the literature to identify patterns, and to predict when the results of PBPK simulations are most likely to be accepted in lieu of clinical victim drug interaction studies.16 drug approvals were identified, which included a submitted PBPK model in support of CYP450 victim drug interaction guidance in the drug label. These examples included substrates of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, and 3A4. Of these 16 examples, 15 drugs included examples of victim interaction label guidance supported by PBPK modeling and simulation. For one of these drugs, no model predictions were accepted. Of the 15 drugs with some accepted predictions, there were also examples of additional PBPK supported drug interaction predictions which were not accepted by the regulatory reviewer.In conclusion, PBPK model supported CYP victim interaction guidance have been included in the labels of many drug approvals over the past three years. While many CYPs contribute to the metabolism of these drugs, CYP3A4 was most commonly the major CYP responsible for drug metabolism. In general, successful application of PBPK to support label wording relied on at least one clinical drug interaction study; typically, with a strong CYP inhibitor, and in some cases a strong CYP inducer also. In scenarios where PBPK was not accepted, the most common reasons given by the regulatory reviewer were a lack of proper model validation, or uncertainty in the relative fraction metabolized by individual CYP isoforms. This analysis represents a novel and powerful method for evaluating the relative impact of PBPK models on CYP victim drug interaction guidance. Based on these results, drug development teams will have a better understanding of when, and when not, to apply PBPK in lieu of clinical CYP victim DDI studies.Citations: no citations