bluuebunny/crossref_metadata_2025 huggingface dataset:
Pengaruh Komitmen Organisasional, Lingkungan Kerja, dan Stres Kerja Terhadap Turnover Intention Penelitian
Authors: Pago Ardianus Gordi , Prayekti Prayekti , Subiyanto Didik
Published: February 2025

Human Resources (HR) play a crucial role in an organization, impacting its performance and success. Strategic HR management is essential for optimal employee placement, development, and utilization, enabling organizations to harness human resources for achieving company goals. This study analyzes the relationship between organizational commitment, work stress, and the work environment concerning Turnover Intention. Researchers aim to understand how organizational commitment levels, job stress, and work environment quality contribute to employees' inclination to leave. Using a quantitative approach, data collection involved distributing questionnaires to 100 respondents. Analysis using the SPSS program provided deeper insights into the relationship between organizational commitment, work stress, and the work environment in the context of Turnover Intention. Findings indicate that organizational commitment (KO) lacks a significant effect on job change intention (IT). Work stress (SK) shows a positive but nonsignificant impact on intention to move, while the work environment (LK) has a positive and significant effect on changing job intentions. The study suggests that attention to organizational commitment, work stress, and work environment can potentially reduce job change desires. These insights guide management in developing strategies to enhance employee well-being and retention, contributing to organizational stability.
हिन्दु धर्म के मङ्गल कार्यों में शंख ध्वनि का महत्त्व
Authors: Sarkar Baturam
Published: February 2025

शोधसारः- देव-मन्दिर में शंखनाद करना अत्यन्त पुण्यप्रद बताया गया है। देवताओं को भी वह अत्यन्त प्रिय है। प्रस्तुत शोध पत्र में ‘हिन्दु धर्म के मङ्गल कार्यों में शंख ध्वनि का महत्त्व’ पर प्रकाश डाला गया है।

बीजशब्दः- भारतीय संस्कृति, हिन्दू धर्म, वाद्य, शंख, शंखध्वनि।

प्रस्तावनाः- हिन्दू धर्म के सभी मङ्गल कार्यों में शंख ध्वनि परम मङ्गलमय समझी जाती है। युद्ध में भी शंख ध्वनि का विशेष महत्व है। संसार भर का यह आम रिवाज है कि जब आपस में युद्ध करने की इच्छा से दो दल के सैनिक युद्ध करने के लिये आमने सामने डट जाते हैं, तो उन्हें युद्ध के लिये तैयार होने की चेतावनी देने के तौर पर सेनापति बिगुल बजाकर सूचना देता है कि लड़ने का समय होगया, तैयार हो जाओ। यह प्रथा प्राचीन समय से चली आती है और आज भी संसार के सभ्य देशों में इस प्रथा का पालन यथा सम्भव किया जाता है। इसी प्रथा के अनुसार पूर्वकाल में पितामह भीष्म ने भी अपना शंख बजाकर सैनिकों को रण सूचना दी थी।
PSYCHOLOGICAL STRATEGIES TO ENHANCE SALES PERFORMANCE
Authors: Trevisan Daniel
Published: February 2025

Psychology plays a crucial role in the sales context by offering a deep understanding of consumer behavior and the emotions that influence their purchasing decisions. By applying psychological principles, salespeople can enhance communication, build stronger relationships with customers, and adopt effective strategies to achieve exceptional results. Understanding the emotions that affect purchasing decisions, such as desire, trust, and security, is essential for shaping strategies that address the psychological needs of consumers. Rapport-building is an example of a psychological technique that strengthens relationships with customers, increasing the likelihood of closing sales. Additionally, persuasion theories, such as those by Robert Cialdini, offer valuable tools for influencing consumer decisions. Scarcity psychology and the use of social proof, such as recommendations from other consumers or the perception of a product being exclusive, are effective methods for encouraging quick purchases. Active listening is another important technique, allowing salespeople to tailor their approaches to meet customer needs, thereby enhancing satisfaction and loyalty. Positive psychology, such as psychological capital (PsyCap), also stands out as an important factor in sales performance, fostering qualities such as hope, resilience, and optimism. Furthermore, Sauers, Hunt, and Bass's (2013) study on behavioral self-management suggests that salespeople should be empowered to monitor and adjust their own sales practices, improving overall effectiveness. The successful implementation of a sales strategy is directly linked to superior performance, as evidenced by Inyang and Jaramillo's (2020) research. These psychological strategies, combined with effective management practices, can create a more productive and satisfying sales environment for all involved.
Sem sentir e sem querer: a era colonial do Brasil à luz do Direito Internacional
Authors: Ramos André de Carvalho
Published: February 2025

Este artigo visa estudar o Direito Internacional como instrumento de compreensão da formação do Brasil a partir da era colonial com foco em três elementos sobre os quais as regras jurídicas internacionais tiveram papel de relevo: o território, o povo e a soberania. O arco do tempo do presente artigo é a era colonial, na qual esses elementos formadores do futuro Estado brasileiro foram analisados sob a perspectiva dos interesses heterogêneos que resultaram nas potencialidades e limites do projeto de colonização e influenciaram a independência. A escolha do passado colonial brasileiro tem como objetivo dar visibilidade a um Direito Internacional assimétrico, pautado por uma regulação internacional desigual, como se vê na complexa relação de Portugal com as demais potências europeias e seus reflexos no Brasil
O controle de convencionalidade da Reforma Trabalhista de 2017
Authors: Amorim Érica Ribeiro Guimarães
Published: February 2025

Este artigo propõe uma reflexão sobre o controle de convencionalidade da Lei nº 13.467/2017, com especial atenção às convenções e recomendações da Organização Internacional do Trabalho. Por meio de uma pesquisa descritiva e propositiva, procurou-se discutir as alterações introduzidas na Consolidação das Leis do Trabalho pela Reforma Trabalhista que direta ou indiretamente colidem com a Constituição brasileira e as normas internacionais. O interesse no desenvolvimento desta pesquisa revelou-se pelo caráter social que o tema apresenta. Trata-se de uma investigação bibliográfica e documental, eminentemente qualitativa, sustentada em referenciais teórico-conceituais. Ao final, algumas soluções são apresentadas para as possíveis inconformidades existentes na referida lei
Dampak Era Digital terhadap Penggunaan Bahasa Jawa Halus di Kalangan Anak-anak Desa Sribasuki Batanghari Lampung Timur
Authors: Arivani Vika
Published: February 2025

This research aims to understand how the younger generation learns and uses subtle Javanese, and the influence of technology on this process. The research was conducted in Sribasuki Village, Batanghari, East Lampung, using qualitative methods with in-depth interviews. The findings show that coarse Javanese (ngoko) is more commonly used in children's daily conversations, while their proficiency in fine Javanese is declining. Technology and social media play a role in accelerating this change, encouraging children to prefer Indonesian or ngoko which is considered more modern. The research also highlights the importance of parents' role in supporting the learning of subtle Javanese by utilizing technology. The results of this study provide guidance for educators and parents in preserving Javanese language and culture amidst the influence of globalization.
Konstruksi Sosial dalam Tradisi Begawe pada Masyarakat Dusun Tibulilin Lombok Tengah
Authors: Ubaidi Muh. Izzat , Aziz Fakhrudin
Published: February 2025

This study analyzes the tradition of working in Tibulilin Hamlet as a social construction that plays a role in strengthening social solidarity, forming collective identity, and strengthening community social capital. Begawe is a tradition of mutual cooperation in organizing family events or large celebrations, where all members of the community are actively involved. Using a qualitative approach based on participatory observation, this study draws on Emile Durkheim's theory of Structural Functionalism and Pierre Bourdieu's concept of social capital. The results of the study show that begawe is not only a cultural ritual, but also a means of strengthening social relations through mechanical solidarity, reflected in cross-individual cooperation regardless of differences. Cultural elements such as traditional clothing and special foods act as symbols of collective identity that reinforce a shared awareness of local values. The practice of mutual cooperation during work strengthens social networks, creates mutual trust, and maintains social stability. These findings show that the tradition of begawe remains relevant in the midst of the challenges of modernization, playing a role as a form of social harmony that survives and develops in the era of globalization.
Investigação do alcance da capacidade de preservação cardíaca da Alicina
Authors: Sampaio Virgínia Ribeiro , Filho Paulo César Barbosa de Brito , Almeida Isabel Moura , Junior Manoel Bras , Filho Jurandir Abrantes de Oliveira , Albuquerque Julia Mylena de Lima , Rodrigues Gabrielle Modesto , Silva Wesley Souza , Urtiga Marfran José Cunha , Araújo Francisco Brayan Lima de
Published: February 2025

O alho (Allium sativum) contém compostos bioativos com propriedades terapêuticas, incluindo efeitos anti-inflamatórios e cicatrizantes, sendo os principais a alicina (AC), o dissulfeto de dialila (DADS) e a aliina (ALL). A alicina é considerada um dos componentes mais potentes, porém sua formação ocorre apenas após o dano ao tecido do alho, quando a enzima aliinase converte a aliina em alicina. Nesse contexto, abordagens in silico são ferramentas valiosas para a identificação ágil de alvos biológicos e possíveis ligantes com potencial terapêutico. Este estudo tem como finalidade investigar a gama de atividades biológicas da alicina por meio de ferramentas computacionais, abrindo caminho para futuras análises experimentais com a molécula isolada. O procedimento metodológico envolveu uma revisão da literatura, seguida pela codificação das estruturas moleculares no banco de dados PubChem. Posteriormente, essas estruturas foram submetidas a análises preditivas de atividade biológica, identificação de alvos moleculares e avaliação de propriedades farmacocinéticas, utilizando os servidores online do PASS. Os resultados indicaram que a alicina se destaca como a molécula com maior potencial de atividade cardioprotetora, cumprindo os requisitos necessários para o desenvolvimento de um fármaco administrado por via oral. Adicionalmente, a alicina demonstrou alta taxa de absorção intestinal e capacidade significativa de atravessar a barreira hematoencefálica, sugerindo uma ação sistêmica eficaz para seu possível uso como agente de proteção cardiovascular.
Efficacy and Safety of 3D-Printed Models in the Surgical Planning of Congenital Heart Defects: A Systematic Review
Authors: Lordão Daniel Batista Monte Alto do Vale , Singui Isabele Monteiro , Silveira Mariana Cardoso Camillo da , Tenório Natália dos Anjos , Valente Miguel Lucas Silva , Denardin Caíque Jason , Vallim Gustavo Brunelli , Bessa Sthefanie da Silva , Medeiros Laura Moreira de , Rodrigues Francisco Rony de Mesquita , Couto Leonardo Lima , Prampero Lívia , Leal Alexandre Pinheiro
Published: February 2025

Background: Three-dimensional (3D) printing has emerged as a valuable tool in congenital heart disease (CHD) surgical planning, offering improved anatomical visualization and preoperative simulation. However, its clinical impact remains uncertain. Methods: A systematic review following PRISMA guidelines was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library. After screening 333 studies, four met the inclusion criteria. Primary outcomes included surgical accuracy, operative time, and complication rates. Results: 3D-printed models demonstrated high anatomical accuracy, with deviations <0.4 mm compared to imaging data. They improved surgical decision-making and facilitated complex repairs in CHD, particularly in Tetralogy of Fallot and transposition of the great arteries. Surgeons reported increased confidence, and medical trainees showed enhanced anatomical understanding. However, limitations include high costs ($55–$810 per model), prolonged fabrication time (hours to days), and reliance on expert segmentation. The absence of randomized controlled trials limits definitive conclusions on clinical outcomes. Conclusion: 3D-printed models enhance spatial visualization and preoperative planning in CHD surgery, but further studies are needed to establish their impact on surgical efficiency and patient outcomes.
Zolpidemsim: A Web-Application for Simulating Pharmacokinetics of Zolpidem
Authors: Cha Hwa Jun , Kim Hyungsub , Han Sungpil
Published: February 2025

OBJECTIVES: Zolpidem, a nonbenzodiazepine known for its sedative and hypnotic effects, is widely prescribed to treat short-term insomnia [1]. However, there is a growing concern regarding the increase in cases of zolpidem overdose, which can lead to life-threatening complications including respiratory depression and coma [1,2]. Emergency physicians face considerable challenges in effectively monitoring drug concentrations while managing overdose patients. However, our comprehension of the toxicokinetics of zolpidem overdose remains limited. In this study, we have developed ‘Zolpidemsim’, a web-based application (https://pipettox.shinyapps.io/Zolpidem/) designed to predict plasma zolpidem concentration and pharmacokinetic parameters in overdose patients.METHODS: Zolpidemsim is based on population pharmacokinetic(PK) analysis using NONMEM 7.5 with digitized data obtained from twenty-three healthy subjects after a single oral administration of zolpidem. The final model is a one-compartment model with first-order absorption and elimination. PK parameters are estimated by the first-order conditional estimation with interaction method. The population estimates for the final model are absorption rate constant (Ka, 5.41h-1), clearance (CL, 16.9L/h), volume of distribution (Vd, 61.7L), and lag time(ALAG, 0.394h). Interindividual variability (IIV) are included on Ka, CL, and Vd. The open-source R software (version 4.3.2) and R packages, ‘nonmem2rx, ‘rxode’, and ‘shiny’ allow the conversion of the NONMEM output file to RxODE syntax and reactive PK simulation. RESULTS: The simulator is divided into three panels: ‘Dosage Regimen’, ‘Simulations Results’, ‘About’. The ‘Dosage Regimen’ panel allows the users to input specific dosage regimens and displays a brief simulation result, including simulation plots, current zolpidem concentration, and a summary of the simulation results. The ‘Simulation Results’ panel provides more detailed results, such as PK parameters including minimum, maximum, and median values, and individual plots. The ‘About’ panel contains the authors, user guide, and references.CONCLUSIONS: Zolpidemsim provides prompt simulations in user-defined dosing regimens with outputs including simulation plots and PK parameters. This user-friendly predictive tool will be a valuable asset for healthcare professionals, empowering them to make well-informed decisions and gain critical prognostic insights, ultimately enhancing the management of overdose patients.Citations: [1] Robert J. Morlock et. al., Patient characteristics and patterns of drug use for sleep complaints in the United States: analysis of National Ambulatory Medical Survey data, 1997-2002. Clin Ther. 2006 Jul;28(7):1044-53. doi: 10.1016/j.clinthera.2006.07.008. [2] Robert Garnier et. al., Acute zolpidem poisoning analysis of 344 cases. J Toxicol Clin Toxicol. 1994;32(4):391-404. doi: 10.3109/15563659409011040.
Streamlining Dupilumab Nasal Polyposis Clinical Development Strategy: Leveraging Modeling and Biomarker Bridging for the Phase 3 Dose Selection
Authors: Xu Christine , Meng Zhaoling , Kamal Mohamed , Davis John
Published: February 2025

Objectives: Dupilumab is a fully human monoclonal antibody, that binds to the shared receptor component for interleukin (IL)-4 and IL-13, cytokines that are key drivers of type 2 inflammatory diseases. Dupilumab is approved in multiple indications including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). During clinical development for CRSwNP, a modeling and simulation approach was used to leverage clinical data accumulated across CRSwNP and asthma indications and streamline clinical development to move directly from the proof-of-concept (POC) study to Phase 3 studies. Methods: In a randomized, double-blind, placebo-controlled, phase 2 POC study (NCT01920893), patients with CRSwNP received SC dupilumab 300 mg every week (qw) over 16 weeks of blinded treatment and 16 weeks of follow-up. In a randomized, double-blind, placebo-controlled, dose range finding phase 2b study (NCT01854047), patients with asthma were randomly assigned (1:1:1:1:1) to receive SC dupilumab 200 mg or 300 mg every 2 weeks (q2w) or every 4 weeks (q4w), or placebo, over a 24-week period. Considering the high comorbidity of the two patient populations, the clinical data from the asthma dose ranging study were used to bridge the dose-response relationships to patients with CRSwNP. Sino-nasal Outcome Test (SNOT-22) and pharmacokinetic (PK) data were pooled from the POC study in patients with CRSwNP and the dose range finding study in patients with asthma and comorbid CRSwNP. Other efficacy endpoints such as nasal polyps score (NPS) were also modelled and extrapolated to the lower doses based on the POC study in patients with CRSwNP.Results: The PK/PD model of SNOT-22 based on the pooled datasets was developed and used to predict dupilumab effects at the lower doses in patients with CRSwNP. Baseline biomarker and patient characteristics were incorporated to adjust for differences between the two studies. The modeling approach predicted similar effects of 300 mg q2w as 300 mg qw at Week 24. The improvement of efficacy endpoints between Week 24 and later time points was small or minimal. Based on the PK/PD modeling results, the 300 mg q2w dose was recommended in the Phase 3 studies with 24 weeks as the primary treatment period. The results of phase 3 clinical studies in patients with CRSwNP confirmed the efficacy of the selected dose.Conclusions: Leveraging comorbidity of CRSwNP and asthma populations, PK/PD modeling guided the phase 3 dose selection for CRSwNP based on pooled data for a wide dose range crossing two populations. The approach illustrates a way to leverage data and information across indications to enable more efficient and robust clinical development design and planning.Acknowledgments:Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. The authors thank Leda Mannent, Nikhil Amin, and Qiang Lu for insights and guidance.Citations: ClinicalTrials.gov Identifiers: NCT01920893, NCT01854047.
PK/PD Characterization of INBRX-140, a Novel anti-FcRn x anti-albumin bispecific antibody
Authors: Bhagwat Sharvari , Kern Nadja , Eckelman Brendan , Kalabus James
Published: February 2025

Introduction: IgG is the most abundant immunoglobulin and the most prevalent autoantibody isotype. In autoimmune diseases such as Myasthenia Gravis (MG), pathogenic autoantibodies, including IgG, bind endogenous self-proteins and impair functionality or cause toxicity. FcRn inhibitors efficiently and profoundly reduce serum IgG levels in clinical settings. Reduced serum IgG levels strongly correlate with reduced pathogenic autoantibodies and disease improvement1. However, IgG-based FcRn inhibitors drive accelerated clearance of self. INBRX-140 is engineered as a highly selective FcRn inhibitor that exploits albumin binding for FcRn-mediated recycling to reduce dosing frequency and improve patient outcomes.Objectives: The pharmacokinetics (PK) of INBRX-140 and the relationship between INBRX-140 dosing and serum IgG levels in cynomolgus monkeys were explored. Simulations were conducted to predict steady-state exposures in humans and determine the appropriate dosing regimens that would enable target IgG depletion over the dosing period.Methods: The PK of INBRX-140 in cynomolgus monkeys and corresponding IgG levels were characterized following single or multiple (two doses given three weeks apart) doses of 0.2, 2, 20, 40, 70, or 100 mg/kg via IV infusion or subcutaneous injection. Compartmental modeling of serum INBRX-140 PK and IgG data was performed. The PK-PD model parameters were translated appropriately to obtain human PK-PD parameter estimates. Standard allometric scaling protocols and literature-based calibrations were used to obtain a range of human PK parameters.The human parameter estimates were used to simulate steady-state IgG levels at various doses and regimens to estimate a suitable dose that would maintain adequate IgG depletion when administered monthly.Results: INBRX-140 PK increased with dose across the dose range of 0.2 to 100 mg/kg following IV infusion of INBRX-140. The concentration-time profiles indicated target-mediated drug disposition (TMDD). A 2-compartment PK model with linear and target-mediated clearance was used to describe the data. The simultaneous fitting of PK and IgG data adequately described IgG levels. Concentration-time profiles of INBRX-140 and IgG were simulated at various doses using the range of estimated human parameters.Conclusions: The prolonged systemic half-life of INBRX-140 enables dosing on a once-every-four-week schedule while reducing IgG levels. Simulated IgG profiles were used to identify doses and regimens required to achieve target IgG depletion.Citations: [1] Patel DD, Bussel JB. Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention. J Allergy Clin Immunol. 2020 Sep;146(3):467-478. doi: 10.1016/j.jaci.2020.07.015. PMID: 32896307.
Physiologically-based pharmacokinetic modeling approach to support eliglustat development for pediatric patients with Gaucher disease
Authors: Xu Christine , Xia Binfeng , Kissell Julie , Macha Sreeraj
Published: February 2025

Background: Eliglustat, an oral drug for adults with Gaucher disease type 1 (GD1), is primarily metabolized by CYP2D6. The objective of this study was to characterize eliglustat pharmacokinetics (PK) in pediatric participants (2 to < 18 years) with GD1 and Gaucher disease type 3 (GD3) across all CYP2D6 phenotypes using a physiologically-based pharmacokinetic (PBPK) model.Methods: A PBPK model was established with physicochemical parameters, in vitro, and in vivo clinical data including the enzyme kinetics metabolism, and the dynamic competitive and mechanism-based inhibition of CYP2D6 using SimCYP software [1, 2]. Clinical data used for model development included eliglustat PK from a Phase 3 (ELIKIDS; NCT03485677), open-label, two-cohort, multicenter study to evaluate the safety, PK, and efficacy of eliglustat monotherapy or in combination with imiglucerase in pediatric participants with GD1 and GD3. The pediatric PBPK model was developed and validated with the observed eliglustat pediatric PK data by adjusting the key input parameters from the adult PBPK model. Results: The PBPK model including age-dependent system parameters (ontogeny factors) aduquately characterized the observed eliglustat pediatric PK by adjusting the clearance for the pediatric population. The fraction value of drug metabolized by hepatic CYP enzymes relative to hepatic metabolism (fm) for CYP2D6 and CYP3A4 remained the same in adult and pediatric population. CYP2D6 abundance and variability values used for the CYP2D6 extensive (EM), intermediate (IM) and poor (PM) metabolizer virtual populations are assumed the same in two populations. The majority of individual observed concentrations in the pediatric patients were within the 5th to 95th percentile of the predicted concentration range within pediatric CYP2D6 EM patients. The overall prediction fold errors for the geometric mean PK parameters (i.e., Cmax and AUC0-τ) were < 1.2 to 1.5-fold. Simulated eliglustat exposure in pediatrics were comparable with the simulated or obseved exposure in adults at the corresponding approved doses across 3 CYP2D6 phenotypes (EM, IM and PM).Conclusions: The eliglustat pediatric PBPK model was optimized from the adult PBPK model and was successfully qualified using observed pediatric PK data.Citations: 1. Chen J, Turpault S, Kanamaluru V Physiologically based pharmacokinetic modeling for assessment of eliglustat interaction potential with CYP2D6 and CYP3A inhibitors. ASCPT abstract 20182. Chen J, Turpault S, Kanamaluru V Prediction of a lack of effect of eliglustat on a sensitive CYP3A substrate using physiologically-based pharmacokinetic modeling. ASCPT abstract 2018
Population Pharmacokinetics of Nivolumab in Patients with Newly Diagnosed or Relapsed/Refractory Classical Hodgkin Lymphoma
Authors: Hudson Rachel , Gauthier Kiran , Zhao Yue , Vezina Heather
Published: February 2025

Objectives: Nivolumab is a fully human IgG4 monoclonal antibody that selectively binds to the PD-1 membrane receptor and is indicated in the treatment of various solid tumors and hematologic malignancies. Nivolumab’s clearance (CL) was shown to be ~30% lower in patients with relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) compared to patients with solid tumors.[1] The objective of this population pharmacokinetic (PopPK) analysis was to characterize the PK of nivolumab in patients with newly diagnosed (ND) cHL relative to R/R cHL and solid tumors.Methods: A previously established nivolumab PopPK model was updated.[1] Data from 1,485 adults with solid tumors and 311 adults with cHL (50 ND and 261 R/R) from 4 Phase 1 studies (MDX-1106-01, ONO-4538-01, MDX-1106-03, and CA209039); 4 Phase 2 studies (ONO-4538-02, CA209010, CA209063, and CA209205); and 3 Phase 3 studies (CA209017, CA209025, and CA209057) were included. The effect of patient population (R/R cHL vs ND cHL vs NSCLC as the reference) was introduced as a new covariate on CL in the final model. Nivolumab PK was described using a 2-compartment model with zero-order IV infusion and time-varying CL (NONMEM v7.4). Model evaluation was conducted by visual predictive check (VPC) with 1,000 simulated datasets obtained from the final model. The final model was then applied to predict and compare individual exposures in patients with ND cHL, R/R cHL, and solid tumors for nivolumab 240mg every 2 weeks (Q2W). Results: Significant covariate effects were consistent with the previous analysis.[1] Covariate effects included baseline body weight, baseline glomerular filtration rate, sex, performance status, race, baseline albumin, and patient population on CL; baseline body weight and sex on volume of distribution; and performance status on EMAX for time-varying CL. VPC with prediction-corrected concentrations demonstrated final model predictions were in reasonable agreement with observed data across all patient populations. CL was determined to be ~30% lower in ND and R/R cHL relative to solid tumors at baseline and steady state, consistent with previous findings. Average steady state predictions across Cmin, Cmax, and Cavg at nivolumab 240mg Q2W were similar among ND and R/R cHL patients. Conclusions: ND and R/R cHL patients had similar baseline and steady state CL following treatment with intravenous nivolumab. Furthermore, exposures for Cmin, Cmax, and Cavg after the first dose and at steady state were similar among cHL patient populations. These results suggest that disease stage among patients with cHL does not impact nivolumab PK.Citations: [1] Wang, X., et al., Population Pharmacokinetics and Exposure - Safety Analyses of Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma. J Clin Pharmacol, 2019. 59(3): p. 364-373.
Modeling Patient Risk Factors and their Role in Dose Optimization for Oncological Trials
Authors: Zhang Sihong , Zhao Justin , Cao Yanguang
Published: February 2025

Objectives: The first objective of our study is to investigate how prevalent oncological trials are randomized based on factors with limited prognostic values. Next, we assess how treatment effect estimation is affected by using prognostic score (PS, a collective integration of prognostic factors) as a singular randomization factor in dose optimization trials. Methods: We employed modeling and simulation techniques, utilizing a well-established prognostic model (Real wOrld PROgnostic score, ROPRO) to conduct virtual clinical trials and evaluated the impact of randomization on PS on trial efficiency in dose optimization. Specifically, forty patients-virtual trials randomized on PS (psRCT) into two arms, with each received dose for comparison. Results: Regarding the first objective, we included 101 randomized clinical trials (RCTs) in our analysis. There were 55 RCTs in non-small cell lung cancer. Interestingly, we found that 2 out of the top 3 collected randomization factors in these trials are not among the top 5 most prognostic factors identified in the prognostic models. Similarly, in 23 RCTs in metastatic breast cancer, 2 out of the top 3 collected randomization factors are not among the top 5 most prognostic factors. Concerning the second objective, compared to the trials without randomization on PS, psRCT trials exhibited much higher efficiency in selecting the optimal doses and generating faithful dose-response relationships. Furthermore, we found that for trials without PS randomization, incorporating PS into the conventional Cox proportional model and dose-response analyses can significantly increase study power in dose optimization while minimizing Type 1 error. Conclusion: Overall, conducting dose optimization trials with PS-based randomization or incorporating PS into dose-response analyses can enhance trial efficiency for dose selection.Citations: [1] Colantuoni, Elizabeth, and Michael Rosenblum. "Leveraging prognostic baseline variables to gain precision in randomized trials." Statistics in medicine 34.18 (2015): 2602-2617.[2] Becker, T., et al. "An enhanced prognostic score for overall survival of patients with cancer derived from a large real-world cohort." Annals of Oncology 31.11 (2020): 1561-1568.[3] Bender, Ralf, Thomas Augustin, and Maria Blettner. "Generating survival times to simulate Cox proportional hazards models." Statistics in medicine 24.11 (2005): 1713-1723.
Quantitative Systems Pharmacology (QSP) model for combined targeting of BAFF and CD40 pathways in systemic lupus erythematosus
Authors: Ayyar Vivaswath , Carman Julie , Bassen David , Sarkar Saheli , Peng Tao , Subramanian Kalyanasundaram , Wang Weirong
Published: February 2025

Objective: Autoreactive B cells play a key role in the pathogenesis of systemic lupus erythematosus (SLE). Cellular signaling via B cell activating factor receptor (BAFF-R) and CD40 are both required for B-cell survival, maturation, and differentiation into pathogenic autoantibody-secreting plasma cells. By combining preclinical experiments and clinical measures (PK, serum biomarkers, naïve B-cell and plasma cell counts), a quantitative systems pharmacology (QSP) model was developed to capture the effect of combined targeting of BAFF and CD40 and recapitulate clinically measurable impacts (anti-dsDNA titers) in systemic lupus erythematosus (SLE) patients.Methods: The QSP model was developed based on the clinical impact of targeting BAFF & CD40 as well as diverse published datasets informing physiologic and pharmacologic parameter values including protein and cell turnover rates, drug-ligand and ligand-receptor affinities, and relevant downstream pathway effects, including B-cell survival. The model comprised three compartments reflecting plasma (site of clinical measurements), periphery (distribution space), and an “immunologic” (splenic) space (capturing disease processes and drug effects on clinical biomarkers). The model was calibrated by leveraging human plasma PK, biomarkers (anti-dsDNA autoantibodies, naive B-cell counts), and their time- and dose-dependent clinical responses to belimumab (anti-BAFF), ruplizumab (anti-CD40L mAb), and dapirolizumab pegol (DZP; anti-CD40L pegylated Fab) in SLE.Results: Upon accounting for the plasma PK and BAFF receptor occupancy (RO) profiles for belimumab and implementing an expanded autoantibody production model (arising from distinct B-cell populations), the model demonstrated that the extent and time-course of anti-BAFF response was dependent on the reduction of naive B-cells and successfully captured the multiphasic reduction of anti-dsDNA autoantibodies observed in SLE patients receiving 1 or 10 mg/kg of belimumab. The model also captured the time- and dose-dependent decrease in anti-dsDNA autoantibodies by ruplizumab and DZP across different doses tested clinically. Therapeutically relevant scenarios of BAFF and CD40 blockade were simulated alone or in combination to assess outcome on anti-dsDNA lowering over time.Conclusion: Model simulations delineated the individual and combined effects of BAFF and CD40 blockade on response in SLE patients. This QSP model will quantitatively inform rationale clinical design and development of combination treatment strategies in SLE.Citations: (1) Brightbill HD et al. Nat Commun 9, 179 (2018).(2) Khodadadi L et al. Front Immunol 10, 721 (2019).(3) Wallace D et al. Arthritis Rheum 61, 1168 (2009).(4) Furie RA et al. Rheumatology 60, 5397 (2021).
Physiologically Based Pharmacokinetic Model of Vedolizumab in Adult Patients with Inflammatory Bowel Disease
Authors: Parikh Sanjana , Tanaka Ryota , Irie Kei , Mizuno Tomoyuki
Published: February 2025

Objective: Vedolizumab (VDZ) is an anti-α4β7-integrin antibody used to treat Ulcerative colitis (UC) and Crohn's disease (CD) in pediatric and adult patients. However, the impact of physiological changes in children and young adults on the VDZ pharmacokinetic (PK) has not been well-characterized due to limited PK data. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict VDZ PK in adult patients with UC and CD, establishing a basis for constructing a pediatric PBPK model. Method: The unique PK behavior of the antibody, characterized by convective disposition via lymph, binding to FcRn to escape endosomal degradation, and target-mediated drug disposition (TMDD), was modeled using the Simcyp Simulator (version 22). Most drug-related parameters were derived from either Simcyp default parameters for endogenous IgG or were obtained from the literature. The receptor (target) degradation rate constant (Kdeg), the rate of VDZ uptake into endothelial space (Kup), and additional linear clearance were estimated using PK data from healthy volunteers. After qualifying the model with healthy volunteer data, the target abundance (Rmax) and equilibrium dissociation constant (KD) were adjusted based on sensitivity analysis to capture the PK profiles of VDZ in patient populations. VDZ concentration-time profiles after intravenous (IV) infusion were simulated using a virtual population (n=100), and PK parameters were estimated to evaluate the predictive performance. Results: For healthy volunteer populations [1], the geometric mean of predicted/observed ratios (P/O ratios) of the area under the concentration-time curve from zero to infinity (AUC0-∞), peak concentration (Cmax), and clearance (CL) were within a ±1.25-fold difference across various VDZ doses from 0.2 to 10mg/kg. After adjusting the Rmax and KD, the geometric mean of the P/O ratio of Cmax and AUC for specific time-periods across VDZ doses from 2.0 to 10mg/kg also fell within a ±1.25-fold difference in adult patients with mild to moderate active UC [2]. Additionally, the P/O mean ratio of the trough serum concentration levels of moderate to severe UC and CD adult patients at the induction and maintenance phases remained within a 2-fold difference [3,4].Conclusion:An adult PBPK model for VDZ was successfully developed and qualified using data from healthy volunteers and patients with UC and CD. This model provides a foundation for constructing a pediatric model, which will explore the impact of pediatric physiology on VDZ disposition to facilitate precision dosing of VDZ therapy in pediatric patients.Citations: [1] Rosario, et al. Clinical Drug Investigation (2016), 36(11), 913–923.[2] Parikh, et al. Inflammatory Bowel Diseases (2012),18(8), 1470–1479.[3] Feagan, et al. New England Journal of Medicine (2013), 369(8), 699–710.[4] Sandborn, et al. New England Journal of Medicine (2013), 369(8), 711–721.
Sex differences in patients with chronic kidney disease: A quantitative systems pharmacology modeling study
Authors: Stadt Melissa , Layton Anita
Published: February 2025

Objectives: Chronic kidney disease (CKD) is a global health concern, impacting about 10-15% of the world’s population. Among patients with CKD, there are sex differences in both the prevalence and pathophysiological profiles, with women being more affected than men [1]. While quantitative systems pharmacology (QSP) models have proven to be valuable tools in studying calcium-phosphate regulation and bone health in CKD patients [2,3], these models have yet to consider the impact of sex differences. Our study addresses this gap by developing the first sex-specific QSP models of calcium-phosphate regulation in patients with CKD. Using these models, we quantify how sex differences impact patients with CKD as well as predict clinical outcomes while considering sex as a biological variable. Methods: We developed sex-specific QSP models of calcium-phosphate homeostasis which describe changes in plasma phosphate, calcium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) as well as bone remodeling during CKD progression in males versus females. Our models are based on existing sex-specific data [1,4] and QSP models [2,3]. Through model simulation and analysis, we quantify how sex differences impact calcium-phosphate homeostasis through CKD progression as well as the clinical impacts of various therapies.Results: Female susceptibility to hyperphosphatemia can be explained by underlying sex differences in pathophysiological profiles of patients with CKD.Conclusions: Impacts of sex differences in pathophysiological profiles of patients with CKD are unraveled using mathematical modeling.Citations: [1] Wyld, Melanie L. R., Nicole L. De La Mata, Andrea Viecelli, et al. 2022. “Sex-Based Differences in Risk Factors and Complications of Chronic Kidney Disease.” Seminars in Nephrology, Sex and Gender in Kidney Health and Disease, 42 (2): 153–69. [2] Peterson, Mark C., and Matthew M. Riggs. 2010. “A Physiologically Based Mathematical Model of Integrated Calcium Homeostasis and Bone Remodeling.” Bone 46 (1): 49–63. [3] Gaweda, Adam E., Devin E. McBride, et al. 2021. “Development of a Quantitative Systems Pharmacology Model of Chronic Kidney Disease: Metabolic Bone Disorder.” American Journal of Physiology-Renal Physiology 320 (2): F203–11.[4] Feldman, Harold I., Lawrence J. Appel, et al. 2003. “The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and Methods.” Journal of the American Society of Nephrology 14.
拜登政府供应链重塑战略背景下国家与美政治互信对其全球供应链参与度的影响
Authors: 黄佳丽
Published: February 2025

当前全球供应链重要性愈发突出，美国拜登政府供应链重塑战略旨在通过打造美国盟伴阵营加强自身全球供应链参与度优势并打压对手国家，因此一国与美政治互信程度对全球供应链参与度影响有着密切关系。以芯片、新能源汽车与关键矿物三大重要战略产业为例，研究发现总体上一国与美政治互信程度越高，其全球供应链参与度越强。其中，在拜登政府供应链重塑战略背景下，三大产业全球供应链参与度受到政治互信的影响有所分化，芯片产业与关键矿物产业所受影响相比于新能源汽车行业更加显著，美国及其盟伴体系在关键矿物产业全球供应链参与度有显著上升，芯片产业相比于对手国家有所轻微下降。因此，中美两国应该意识到加强政治互信合作从而实现在全球供应链参与度上的务实合作，促进双赢；中国面对美国的战略竞争也要因产业制宜，继续加强新能源汽车行业优势，提升关键矿产行业的附加值出口，加强芯片行业的创新研发投入。
Pharmacogenomics Implication of Tamoxifen in Breast Cancer Treatment: Clinical Relevance and Future Directions
Authors: Elhaj Khalda E. M. , Mudawi Mahmoud M. E. , Ali Hamad A. Albagir A.
Published: February 2025

Tamoxifen is a cornerstone therapy for estrogen receptor-positive (ER+) breast cancer, improving survival and reducing recurrence. Its efficacy and toxicity, however, vary due to genetic polymorphisms influencing metabolism and transport. Key genes, such as CYP2D6, CYP3A4, and ATP-binding cassette transporters (ABCB1, ABCC2), are crucial in forming and distributing active metabolites like endoxifen. This review explores tamoxifen pharmacogenetics through an analysis of literature from PubMed, Scopus, Google Scholar, and PharmaGKB. Genetic variations like CYP2D6*10 in Asians and CYP2D6*17/29 in Africans impact therapeutic outcomes. Barriers to personalized tamoxifen therapy include inconsistent guidelines, limited access to genetic testing, and underrepresentation of ethnic groups in research.The findings highlight the need for multidisciplinary approaches integrating genetic, clinical, and environmental factors to optimize therapy. Large-scale, diverse, population-specific studies are essential to establish universal pharmacogenetic guidelines.
A comparative analysis of transformational and transactional leadership styles in maximizing productivity and reducing burnout with sustainability
Authors: Ayaz Fazal , Ali Nasir , Taimur Khan Dr. Muhammad
Published: February 2025

The intricate interaction between leadership styles and their impacts on organizational productivity and the health of employees, particularly in the health sector, has to be critically studied. In this study, the impact of transformational and transactional leadership styles on organizational productivity and sustainable workplaces will be explored. Inspirational and visionary transformational leadership is likely to boost productivity and reduce burnout among employees through a cohesive and creative organizational environment. Transactional leadership with an emphasis on effectiveness and clear exchanges for compliance is likely to enhance productivity in the short run but maybe boost burnout unless it is complemented by sustainable interventions. Through the incorporation of sustainability as a moderator, this research will explore how sustainability can boost the strengths of transformational leadership or overcome the weaknesses of transactional leadership in health organizations in Khyber Pakhtunkhwa, Pakistan. This research will apply quantitative techniques to measure the direct impact of these leadership styles and the moderating influence of sustainability programs and aim to provide actionable recommendations for enhancing the effectiveness of leadership in yielding high productivity and resilient employees.
Unseen Bodies: Sexuality and Subordination in Manto’s "Blouse"
Authors: Samiksha
Published: February 2025

Domestic servants are shadowy yet ubiquitous presences in upper and middle-class homes in the Indian subcontinent. Separated by socio-economic divisions and hierarchies, the unavoidability of proximity between bodies from different social strata inhabiting the same domestic space often creates tensions over possibilities of cross-class intimacies. This paper, through a close reading of Saadat Hasan Manto’s short story, Blouse, examines how bodies—as sites of budding sexuality—located in structures of servitude, experience and navigate the changing contours of the self and the other. The paper focuses on how conditions of invisibilisation, which characterise the servant’s position, on one hand produce effects of marginalisation and exclusion, but on the other hand also engender conditions for the servant to observe, encounter, and experience the other in such an intimate manner that it often threatens to disrupt the carefully maintained relations of social difference. The paper attempts to understand how different bodies behave and engage with each other—through relations of indifference, fascination, and deprecation—while navigating the complex terrain of gender performativity and class politics in the private space of home.
YAŞIL ENERJİ VƏ KARBON İZİNİN AZALDILMASI
Authors: Ömər İ. İSMAYILZADƏ
Published: February 2025

Yaşıl enerji və karbon izinin azaldılması mövzusu, müasir dünyanın ekolojivə iqtisadi inkişafını təmin etmək üçün əhəmiyyətli addımlardan biridir.Məqalədə bərpa olunan enerji mənbələrinin – günəş, külək, hidroenerji vəgeotermal enerji kimi texnologiyaların istifadəsi geniş şəkildə araşdırılır vəonların iqlim dəyişikliyinin təsirlərinin azaldılmasında oynadığı rolmüzakirə edilir. Eyni zamanda, bu texnologiyaların sosial-iqtisadi faydaları,karbon izlərinin minimuma endirilməsi və davamlı inkişaf üçün yeniimkanlar yaratdığı vurğulanır. Müasir texnologiyaların, nanotexnologiya vəhidrogen enerjisi kimi sahələrin yaşıl enerjiyə verdiyi dəstək də məqaləninmərkəzi mövzularından biridir. Yaşıl enerjinin dünya miqyasındaəhəmiyyəti və gələcək üçün vəd etdiyi perspektivlər geniş və elmi bir təhlillətəqdim olunur.
QEYRİ-MÜƏYYƏNLİK ŞƏRAİTİNDƏMÜƏSSİSƏLƏRİN İDARƏ EDİLMƏSİ PROSESİNİNƏSAS ASPEKTLƏRİ
Authors: Günel N. SƏFƏROVA
Published: February 2025

Məqalədə qeyri-müəyyənlik şəraitində fəaliyyət göstərən müəssisələrin
idarə edilməsi prosesinin əsas aspektləri təhlil edilmişdir. Mövcud qeyri-müəyyənliklərin qiymətləndirilməsi üçün bir çox elmi yanaşmalardan
istifadənin mümkünlüyü qeyd edilmişdir. Həmçinin, qeyri-müəyyənlikşəraitində müəssisələrin idarə edilməsi zamanı qərarların qəbuluproblemlərinə ən düzgün yanaşmanın sinergetik yanaşma olduğu müəyyənedilmişdir.
İQTİSADİ ARTIM VƏ İNFLYASIYA ARASINDA ƏLAQƏVƏ İQTİSADİ İSLAHATLARIN ONLARA TƏSİRİ
Authors: Mətanət R. RƏSULOVA  , Pərviz HEYDƏROV
Published: February 2025

Məqalədə iqtisadi artım və inflyasiya arasında əlaqəyə dair bəzi nəzəriyanaşmalar öyrənilmişdir. Bu fərqli yanaşmalar, eləcə də onların iqtisadifikrin müxtəlif istiqamətlərinin nümayəndələri tərəfindən şərhləri monetarvə fiskal siyasət sahəsində rasional qərarlar qəbul etməyə imkan verir.Həmçinin seçilmiş siyasətə iqtisadiyyatın faktiki reaksiyası gözləniləndənfərqli olduqda onlara vaxtında düzəlişlər etmək mümkün olur. Hər biriqtisadi model mütləq bir sıra fərziyyələrə və məhdudiyyətlərə əsaslananreallığın çox sadələşdirilmiş təsviridir. İqtisadiyyatın siyasətlərə necəreaksiya verdiyinin diqqətlə öyrənilməsi bu fərziyyələrdən hansının çox sərt, hansının qeyri-dəqiq və hansının müəyyən iqtisadi sistem üçün qeyri-adekvat olduğunu müəyyənləşdirməyə kömək edir. Müəlliflər bu yanaşmalar əsasında Azərbaycan Respublikası Dövlət Statistika Komitəsinin iqtisadi artım və inflyasiya arasında əlaqəni analiz etməyə, iqtisadi sahədə həmin əsas məqamları müəyyən etməyə imkan verən bəzi statistik göstəricilərin təhlilini aparmış və bir sıra nəticələr əldə etmişlər.
İQTİSADİYYATDA QİYMƏTLƏNDİRMƏ ÜSUL VƏ MODELLƏRİNİNTƏSNİFLƏŞDİRİLMƏSİ VƏ MÜQAYİSƏLİ TƏHLİLİ
Authors: Arzu Sahib oğlu SÜLEYMANOV
Published: February 2025

Təqdim olunan məqalədə iqtisadi proseslərin təhlili, qiymətləndirilməsi vəproqnozlaşdırılması istiqamətində istifadə olunan üsul və modellər müqayisəli təhlil edilərək təsnifləşdirilmişdir. İlk öncə statistik göstəricilərin qiymətləndirmə və makroiqtisadi proqnozlaşdırma üsulları verilmiş, makromodellər təsnifləşdirilmiş və əsas makroiqtisadi qiymətləndirmə modellərinin xüsusiyyətləri şərh edilmişdir. Eyni zamanda, məqalədə şərh edilmiş və təsnifləşdirilmiş üsullar və modellər müqayisəli təhlil edilərək xüsusiyyətləri, üstün və zəif cəhətləri sistemləşdirilmişdir.Üsul və modellərin müqayisəli təhlili nəticədə cari dövrdə iqtisadi proseslərin təhlil və qiymətləndirilməsi, eləcə də simulyasiya və proqnozların həyata keçirilməsi nöqteyi-nəzərindən ölkə iqtisadiyyatının xüsusiyyətlərinə uyğun qiymətləndirmə modellərinin vahid platformada əlaqələndirilməsinin zəruri olduğunu deməyə əsas vermişdir.
YERLİ NEFT MAŞINQAYIRMASI MÜƏSSİSƏLƏRİNİN MƏHSULLARINDANİSTİFADƏ KVOTALARIN TƏTBİQİ İMKANLARI
Authors: Fikrət QURBANOV  , Əhməd HÜSEYNZADƏ
Published: February 2025

Məqalədə yerli neft maşınqayırması müəssisələrinin mövcud durumu vəperspektivləri araşdırılmışdır. Bundan başqa Milli kontentin inkişafı sahəsində əsasən təbii ehtiyatlar ilə zəngin olan Qazaxstan və Anqolada Milli kontent məsələlərini tənzimləyən əsas qanunverici aktlar araşdırılmış, eyni zamanda Azərbaycanda milli kontentin mövcud durumu tədqiq edilmişdir.