In the literature: May 2024 highlights

Click here to read some interesting recently published papers from our community. If you have published an article in the field of in silico medicine, send it to us: we will include it in this section of the newsletter!

Nature - Scientific Reports: The role of the pulmonary veins on left atrial flow patterns and thrombus formation.

Jordi Mill et al

Abstract

Atrial fibrillation (AF) is the most common human arrhythmia, forming thrombi mostly in the left atrial appendage (LAA). However, the relation between LAA morphology, blood patterns and clot formation is not yet fully understood. Furthermore, the impact of anatomical structures like the pulmonary veins (PVs) have not been thoroughly studied due to data acquisition difficulties. In-silico studies with flow simulations provide a detailed analysis of blood flow patterns under different boundary conditions, but a limited number of cases have been reported in the literature. To address these gaps, we investigated the influence of PVs on LA blood flow patterns and thrombus formation risk through computational fluid dynamics simulations conducted on a sizeable cohort of 130 patients, establishing the largest cohort of patient-specific LA fluid simulations reported to date. The investigation encompassed an in-depth analysis of several parameters, including pulmonary vein orientation (e.g., angles) and configuration (e.g., number), LAA and LA volumes as well as their ratio, flow, and mass-less particles. Our findings highlight the total number of particles within the LAA as a key parameter for distinguishing between the thrombus and non-thrombus groups. Moreover, the angles between the different PVs play an important role to determine the flow going inside the LAA and consequently the risk of thrombus formation. The alignment between the LAA and the main direction of the left superior pulmonary vein, or the position of the right pulmonary vein when it exhibits greater inclination, had an impact to distinguish the control group vs. the thrombus group. These insights shed light on the intricate relationship between PV configuration, LAA morphology, and thrombus formation, underscoring the importance of comprehensive blood flow pattern analyses.

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Frontiers in Bioengineering and Biotechnology: Towards a comprehensive biomechanical assessment of the elderly combining in vivo data and in silico methods.

Giorgio Davico et al

Abstract

The aging process is commonly accompanied by a general or specific loss of muscle mass, force and/or function that inevitably impact on a person’s quality of life. To date, various clinical tests and assessments are routinely performed to evaluate the biomechanical status of an individual, to support and inform the clinical management and decision-making process (e.g., to design a tailored rehabilitation program). However, these assessments (e.g., gait analysis or strength measures on a dynamometer) are typically conducted independently from one another or at different time points, providing clinicians with valuable yet fragmented information. We hereby describe a comprehensive protocol that combines both in vivo measurements (maximal voluntary isometric contraction test, superimposed neuromuscular electrical stimulation, electromyography, gait analysis, magnetic resonance imaging, and clinical measures) and in silico methods (musculoskeletal modeling and simulations) to enable the full characterization of an individual from the biomechanical standpoint. The protocol, which requires approximately 4 h and 30 min to be completed in all its parts, was tested on twenty healthy young participants and five elderlies, as a proof of concept. The implemented data processing and elaboration procedures allowing for the extraction of several biomechanical parameters (including muscle volumes and cross-sectional areas, muscle activation and co-contraction levels) are thoroughly described to enable replication. The main parameters extracted are reported as mean and standard deviation across the two populations, to highlight the potential of the proposed approach and show some preliminary findings (which were in agreement with previous literature).

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Journal of Medical Internet Research: Envisioning the Future of Personalized Medicine: Role and Realities of Digital Twins.

Alexandre Vallée et al

Abstract

Digital twins have emerged as a groundbreaking concept in personalized medicine, offering immense potential to transform health care delivery and improve patient outcomes. It is important to highlight the impact of digital twins on personalized medicine across the understanding of patient health, risk assessment, clinical trials and drug development, and patient monitoring. By mirroring individual health profiles, digital twins offer unparalleled insights into patient-specific conditions, enabling more accurate risk assessments and tailored interventions. However, their application extends beyond clinical benefits, prompting significant ethical debates over data privacy, consent, and potential biases in health care. The rapid evolution of this technology necessitates a careful balancing act between innovation and ethical responsibility. As the field of personalized medicine continues to evolve, digital twins hold tremendous promise in transforming health care delivery and revolutionizing patient care. While challenges exist, the continued development and integration of digital twins hold the potential to revolutionize personalized medicine, ushering in an era of tailored treatments and improved patient well-being. Digital twins can assist in recognizing trends and indicators that might signal the presence of diseases or forecast the likelihood of developing specific medical conditions, along with the progression of such diseases. Nevertheless, the use of human digital twins gives rise to ethical dilemmas related to informed consent, data ownership, and the potential for discrimination based on health profiles. There is a critical need for robust guidelines and regulations to navigate these challenges, ensuring that the pursuit of advanced health care solutions does not compromise patient rights and well-being. This viewpoint aims to ignite a comprehensive dialogue on the responsible integration of digital twins in medicine, advocating for a future where technology serves as a cornerstone for personalized, ethical, and effective patient care.

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Molecular Pharmaceutics: Physiologically Based Biopharmaceutics Modeling (PBBM): Best Practices for Drug Product Quality, Regulatory and Industry Perspectives: 2023 Workshop Summary Report.

Claire Mackie et al

Abstract

Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are based on the integration of physiological, pharmacological, and pharmaceutical data to simulate and predict drug behavior in vivo. Effective utilization of PBBM requires a consistent approach to model development, verification, validation, and application. Currently, only one country has a draft guidance document for PBBM, whereas other major regulatory authorities have had limited experience with the review of PBBM. To address this gap, industry submitted confidential PBBM case studies to be reviewed by the regulatory agencies; software companies committed to training. PBBM cases were independently and collaboratively discussed by regulators, and academic colleagues participated in some of the discussions. Successful bioequivalence “safe space” industry case examples are also presented. Overall, six regulatory agencies were involved in the case study exercises, including ANVISA, FDA, Health Canada, MHRA, PMDA, and EMA (experts from Belgium, Germany, Norway, Portugal, Spain, and Sweden), and we believe this is the first time such a collaboration has taken place. The outcomes were presented at this workshop, together with a participant survey on the utility and experience with PBBM submissions, to discuss the best scientific practices for developing, validating, and applying PBBMs. The PBBM case studies enabled industry to receive constructive feedback from global regulators and highlighted clear direction for future PBBM submissions for regulatory consideration.

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The AAPS Journal - American Association of Pharmaceutical Scientists:
The Role of Model Master Files for Sharing, Acceptance, and Communication with FDA.

Lanyan Fang et al

Abstract

With the evolving role of Model Integrated Evidence (MIE) in generic drug development and regulatory applications, the need for improving Model Sharing, Acceptance, and Communication with the FDA is warranted. Model Master File (MMF) refers to a quantitative model or a modeling platform that has undergone sufficient model Verification & Validation to be recognized as sharable intellectual property that is acceptable for regulatory purposes. MMF provides a framework for regulatorily acceptable modeling practice, which can be used with confidence to support MIE by both the industry and the U.S. Food and Drug Administration (FDA). In 2022, the FDA and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop to discuss the best practices for utilizing modeling approaches to support generic product development. This report summarizes the presentations and panel discussions of the workshop symposium entitled “Model Sharing, Acceptance, and Communication with the FDA”. The symposium and this report serve as a kick-off discussion for further utilities of MMF and best practices of utilizing MMF in drug development and regulatory submissions. The potential advantages of MMFs have garnered acknowledgment from model developers, industries, and the FDA throughout the workshop. To foster a unified comprehension of MMFs and establish best practices for their application, further dialogue and cooperation among stakeholders are imperative. To this end, a subsequent workshop is scheduled for May 2-3, 2024, in Rockville, Maryland, aiming to delve into the practical facets and best practices of MMFs pertinent to regulatory submissions involving modeling and simulation methodologies.

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Date: 30/04/2024 | Tag: | News: 1576 of 1588
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