Search Results (49)

Following the discovery of therapeutic molecules and the identification of specific biological targets, preparation of regulatory dossiers entails extensive product development and characterization to support their safety, efficacy, and stability. We have examined the drug development and relevant regulatory considerations related to inhaled biological proteins in the accompanying article. This review focuses on the characterization of locally acting inhaled biological proteins. Drug product characterization is a regulatory requirement, and it ensures drug product safety, efficacy, stability, and usability by the target populations. Together, these two articles provide a comprehensive discussion based on our review and analysis of the available open literature. We have attempted to fill gaps and simulate discussion of challenges following sound scientific pathways. This approach has the prospect of addressing regulatory expectations leading to rapid solutions to unmet medical needs. The robustness of characterization strategies and the development of analytical methods used in the in vitro testing for the evaluation of drug product attributes is assured through application of the Design-of-Experiment (DOE) and Quality-by-Design (QBD) approaches. Drug product characterization entails a variety of in vitro studies evaluating drug products for purity and contamination, and determination of drug delivery by the intended route of administration. Measurement of the proportion of the labeled amount per dose and the form suitable for delivery to the intended target sites is central to this assessment. For respiratory Drug–Device combination products, the testing may vary with the product designs. However, determination of the single-dose content, delivered-dose uniformity, aerodynamic particle size distribution, and device robustness when used by the target populations is common to all combination products. Characterization of aerosol plumes is limited to inhalation aerosols that produce specific aerosol clouds upon actuation. The flow rate dependency of devices is also examined. Product characterization also includes safety-related product attributes such as degradation products and leachables. For inhaled biological proteins, safety-related in vitro testing includes additional testing to assure maintenance of the three-dimensional structural integrity and the sustained biological activity of the drug substance in the formulation, during aerosolization and upon deposition. This article discusses various tests employed for regulatory-compliant product characterization. In addition, the stability testing and handling of possible changes during product development and post-approval are discussed. Full article

From the 9th century onwards, Tāmdult was one of the three major caravan ports in the Western Maghreb, alongside Sijilmāssa and Nūl Lamṭa. By the mid-20th century, the remains of dwellings, metallurgical production sites and fortifications had been located a few kilometres south of the present-day oasis of Aqqa, which is irrigated by the resurgence of the wadi of the same name. In 1999, our research, which was based on field surveys and aerial photographs, revealed exceptionally well-preserved traces of a large-scale agricultural system and an irrigation canal network adjacent to the ruins. This completed the picture of this pre-Saharan oasis. An initial study was published in 2011. However, the question of the chronological relationship between the two oases, Tāmdult and Aqqa, remained unresolved. Processing recent satellite images (Airbus © 2023) of these two oases and creating a WebGIS interface now enables us to refine and correct our observations from 1999. This new data largely confirms our initial proposals, such as the joint development of an urban settlement and an agricultural area with an irrigation network. Furthermore, these new images show the branching structure of the various water distribution channels, the regularity of the agricultural land parcels and the existence of interstitial rural settlements. They thus reveal a hierarchy in this distribution that was perhaps insufficiently explored in our initial publication. Given the limited historical sources available, we can now make more informed arguments regarding the possibility of the two oases coexisting over time. We can also propose initial hypotheses about the main reasons for the abandonment of one of the oases and discuss the identity of their founders, which could be local tribal groups and/or branches of the Idrisid dynasty. The central issue of the dossier to which our contribution is addressed—‘The Role of Urban Elites in the Construction of Rural Landscape’—is adapted here to the specific characteristics of the pre-Saharan context in terms of both climate and settlement structure. Full article

This manuscript takes the form of a social fiction doctoral application that refuses pretense. Framed as an admissions packet, it blends autoethnography, poetry, and political critique to confront the growing legislative assault on Diversity, Equity, and Inclusion (DEI) in higher education. These assaults, though cloaked in new rhetoric, extend a long-standing tradition: the erasure of marginalized epistemologies within doctoral education. Structured as a hybrid dossier, complete with reflective essays, imagined recommendations, and lyrical interludes, the manuscript examines how doctoral programs across varied contexts are either resisting or reinforcing this erasure. Positioned within a comparative framework, it explores how global and national pressures shape institutional responses to anti-DEI mandates and what these tensions reveal about the trajectory of doctoral education. Ultimately, the manuscript challenges the academy to confront its complicity in silencing dissent and to reimagine doctoral study as a crucible for epistemic justice, where knowledge is not policed but pluralized. Full article

Background: Accurate operative risk stratification is essential for treatment selection in severe aortic stenosis. We developed an automated workflow using large language models (LLMs) to replicate Heart Team risk assessment. Methods: We retrospectively analyzed 231 consecutive patients with severe aortic stenosis evaluated by multidisciplinary Heart Teams (January 2022–December 2024). An automated system using GPT-4o was developed, comprising the following: (1) structured data extraction from clinical dossiers; (2) EuroSCORE II calculation via two methods (algorithmic vs. LLM-based); (3) clinical vignette generation; and (4) risk stratification comparing EuroSCORE-based thresholds versus guideline-integrated LLM approaches with/without EuroSCORE values. The primary endpoint was the risk stratification accuracy of each method compared to Heart Team decisions. Results: Mean age was 79.5 ± 7.7 years, with 58.4% female. The automated workflow processed patients in 32.6 ± 6.4 s. The LLM-calculated EuroSCORE II showed a lower mean difference from Heart Team values (−1.42%, 95% CI −2.32 to −0.53) versus algorithmic calculation (−1.88%, 95% CI −2.38 to −1.38). For risk stratification, the guideline-integrated LLM without EuroSCORE achieved the highest accuracy (90.0%) and AUC (0.93), outperforming both the EuroSCORE-based (accuracy 50.2% for high-risk, AUC 0.63) and guideline-integrated LLM with EuroSCORE approaches (accuracy 82.4%, AUC 0.76). However, systematic hallucinations occurred for cardiovascular risk factors when data were missing. Conclusions: LLMs accurately calculated EuroSCORE II and achieved 90% concordance with multidisciplinary Heart Team decisions. However, hallucinations, reproducibility concerns, and the absence of clinical outcome validation preclude direct clinical application. Full article

Reliable quality of epicutaneous patch test (PT) preparations is a prerequisite for establishing a robust diagnosis in patients with suspected allergic contact dermatitis due to delayed-type sensitization. It is difficult to identify potential quality issues in daily practice, since confirmatory methods are lacking and assessment of PT-relevance is predominantly based on patients’ history and exposure. The quality of PT products can be affected, e.g., by the properties of the active substance, an insufficient development of the PT preparation or issues during manufacturing. Resulting quality deficiencies can cause both false-negative and false-positive test results. As PT preparations are medicinal products according to Directive 2001/83/EC, they require a marketing authorization (MA) entailing assessment of quality, safety and efficacy by the competent authorities. The corresponding product dossier is the basis for MA. It is continuously updated, e.g., upon change of a source material supplier, ensuring comparability of the respective product over time. Compliance with regulatory requirements is a crucial foundation for sustainable quality to prevent product deficiencies, ensuring reliable test results in practice. Harmonization across the EU is important to ensure the widespread availability of high-quality PT products. This review presents the MA requirements of PT preparations in the EU, as well as challenges previously reported by physicians. Full article

Biological control with beneficial bacteria offers a sustainable alternative to synthetic agrochemicals for managing plant pathogens and enhancing plant health. However, bacterial biocontrol agents (BCAs) remain underexploited due to regulatory hurdles (such as complex registration timelines and extensive dossier requirements) and limited strain characterization. Recent advances in omics technologies (genomics, transcriptomics, proteomics, and metabolomics) have strengthened the bioprospecting pipeline by uncovering key microbial traits involved in biocontrol. Genomics enables the identification of biosynthetic gene clusters, antimicrobial pathways, and accurate taxonomy, while comparative genomics reveals genes relevant to plant–microbe interactions. Metagenomics uncovers unculturable microbes and their functional roles, especially in the rhizosphere and extreme environments. Transcriptomics (e.g., RNA-Seq) sheds light on gene regulation during plant-pathogen-bacteria interactions, revealing stress-related and biocontrol pathways. Metabolomics, using tools like Liquid Chromatography–Mass Spectrometry (LC-MS) and Nuclear Magnetic Resonance spectroscopy (NMR), identifies bioactive compounds such as lipopeptides, Volatile Organic Compounds (VOCs), and polyketides. Co-culture experiments and synthetic microbial communities (SynComs) have shown enhanced biocontrol through metabolic synergy. This review highlights how integrating omics tools accelerates the discovery and functional validation of new BCAs. Such strategies support the development of effective microbial products, promoting sustainable agriculture by improving crop resilience, reducing chemical inputs, and enhancing soil health. Looking ahead, the successful application of omics-driven bioprospection of BCAs will require addressing challenges of large-scale production, regulatory harmonization, and their integration into real-world agricultural systems to ensure reliable, sustainable solutions. Full article

Background/Objectives: Fibroblast activation protein (FAP) is highly expressed in tumor stroma and selected inflammatory conditions, offering a promising target for molecular imaging. [⁶⁸Ga]Ga-FAPI-46 is a DOTA-based FAP inhibitor with excellent tumor-to-background ratio and potential advantages over [¹⁸F]FDG in low-glycolytic tumors. This article aims to highlight the quality elements that are relevant to clinical practice and to describe the development of an investigational medicinal product dossier for a bicentric clinical trial involving [⁶⁸Ga]Ga-FAPI-46. Methods: The radiolabeling was performed by the two facilities using different automated synthesizers, but with the same specifications and acceptance criteria Results: Three validation batches per site were analyzed for radiochemical/radionuclidic purity, pH, endotoxin, sterility, and bioburden according to European Pharmacopoeia standards. Stability was as sessed up to 2 h post-synthesis. All batches met predefined acceptance criteria. Conclusions: Despite differences in radiosynthesizer modules, product quality and process reproducibility were maintained across both centers. [⁶⁸Ga]Ga-FAPI-46 can be reliably produced in academic settings under GMP-like conditions, enabling multicenter clinical research and facilitating IMPD submissions for broader adoption of FAP-targeted PET imaging. Full article

Background: In light of increasing breast cancer survival rates, it is essential to address cancer-related cognitive impairment (CRCI), a common yet often underestimated symptom. Methods: A randomised controlled trial is proposed involving 50 newly diagnosed participants, divided into a control group (CG) and an intervention group (IG). Both groups will receive an educational leaflet, while the IG will also take part in an individualised cognitive training programme based on everyday cognition (80 sessions distributed across four periods, compiled in a training dossier). Cognitive, emotional, and functional variables will be assessed before and after the intervention: cognitive function (MoCA test), everyday cognition (PECC), anxiety (Hamilton), functionality (LB), sleep quality (PSQI), quality of life (ECOG), and subjective memory complaints (FACT-COG). Expected results: Findings may guide future interventions and tailored protocols to alleviate CRCI in breast cancer patients undergoing active treatment. Ethics and dissemination: This study was approved by the Ethics Committee of the University of Salamanca (PI 2023 12 1478-TD). Full article

In recent years, numerous regions worldwide have experienced devastating natural disasters, leading to significant structural damage to buildings and loss of human lives. The reconstruction process highlights the need for a reliable method to document and track the maintenance history of buildings. This paper introduces a novel approach for managing and monitoring restoring interventions using a secure and transparent digital framework. We will also present an application aimed at improving building structures with respect to earthquake resistance. The proposed system, referred as the “Building Ledger Dossier”, leverages a Digital Twin approach applied to blockchain to establish an immutable record of all structural interventions. The framework models buildings using OpenSees, while all maintenance, repair activities, and documents are registered as Non-Fungible Tokens on a blockchain network, ensuring timestamping, transparency, and accountability. A Decentralized Autonomous Organization oversees identity management and work validation, enhancing security and efficiency in building restoration efforts. This approach provides a scalable and globally applicable solution for improving both ante-disaster monitoring and post-disaster reconstruction, ensuring a comprehensive, verifiable history of structural interventions and fostering trust among stakeholders. The proposed method is also applicable to other types of processes that require the aforementioned properties for document monitoring, such as the life-cycle management of tax credits and operations in the financial or banking sectors. Full article

With the European Union (EU) Health Technology Assessment (HTA) regulation, Joint Clinical Assessments (JCA) are now required for oncological and advanced therapy medicinal products. The JCA assessment scope is determined through the PICO framework (Population, Intervention, Comparator, Outcome). Given the tight JCA timelines, Health Technology Developers (HTD) must anticipate PICO elements early to prepare dossiers effectively. This study investigates whether PICO can be predicted across EU member states using publicly available information. A systematic literature review was conducted to identify relevant peer-reviewed articles. Additionally, an extensive search of publicly available HTA documents, including reports, methodological guidelines, submission templates, and market access information was performed across 29 European countries. Relevant information for PICO anticipation was extracted. For many member states, a wealth of relevant information is publicly accessible: 66% have HTA reports publicly available, 79% have HTA methodological guidelines, 69% have dossier templates, and 100% have market access status lists. Between countries, the requirements for population and outcomes are largely aligned, making comparator the central element in PICO anticipation. PICO can be anticipated reliably based on public information. HTDs must be prepared to adjust their strategies as national procedures adapt, ensuring alignment with both current and emerging EU and national requirements. Full article

Heritage conservation projects involve diverse stakeholders, such as property owners, communities, NGOs, and governments, whose “misaligned” incentives produce high transaction costs and often pose persistent challenges. Considering heritage sites as analogous to common pool resources (CPR), this study examines whether sustainable heritage projects adhere to Elinor Ostrom’s design principles for managing CPRs. The UNESCO Asia-Pacific Awards for Cultural Heritage Conservation are used as a benchmark to identify best practices in private–public collaborations over the past two decades. Through content analysis of award application dossiers, the researchers assess whether the design principles are applied differently between successful and unsuccessful projects and evaluate the sufficiency of Ostrom’s principles in the heritage conservation context. The findings indicate that four design principles are more consistently balanced in award-winning projects: “Collective Choice Arrangements”, “Congruence with Local Conditions”, “Monitoring Mechanisms”, and “Minimum Recognition of Rights”. Additionally, successful projects tend to incorporate “people growth-oriented activities”, such as skills training and education for local workers and youth, benefiting current and future project beneficiaries. These insights suggest that adapting Ostrom’s design principles can enhance the sustainability of heritage conservation efforts by better aligning stakeholder incentives and addressing the “misalignment of incentives” challenge commonly encountered in such projects. Full article

In 2015, the 62nd session of the Regional Committee [RC] of the Eastern Mediterranean Region [EMR] endorsed the Eastern Mediterranean Vaccine Action Plan 2016–2020 (EMVAP) that included postponement of the measles elimination target to before 2020. However, the EMR does not have a regional rubella control or elimination goal. We reviewed the progress of measles and rubella surveillance in context of measles elimination in the Eastern Mediterranean Region during 2019–2022. We compiled data on coverage, reported cases, surveillance indicators, incidence, and genotypes. We conducted an age-cohort analysis to estimate the size of the susceptible population using coverage and SIAs coverage data. We reviewed the dossiers of countries that applied to the Regional Verification Commission [RVC] for the verification of measles and rubella elimination. Between 2019 and 2022, the regional coverage of the vaccine against measles and rubella was stable at 83% for the first dose [MCV1] and increased from 75% to 78% for the second dose [MCV2] after a dip during COVID-19. In the EMRO, eighteen countries are using MR (measles–rubella) and/or measles–mumps–rubella (MMR) vaccines and four are using measles vaccines. The reported regional measles incidence per 1,000,000 was 23.3 in 2019, decreased to 7.4 in 2020, and re-increased to 50 in 2022, with two main genotypes–D8 and B3–in circulation. Both genotypes are considered to be actively circulating in eighteen countries, with different circulating variants of each genotype. There were no genotyping data available from four countries. Measles and rubella surveillance indicators deteriorated in the region. The number of susceptible individuals exceeded one birth cohort in nine of the 22 countries. In 2019–2022, Bahrain, Egypt, Iran, and Oman were verified to have eliminated measles and rubella. While four countries eliminated measles and rubella and another five progressed toward measles and rubella elimination, however, immunity gaps and reported incidence increased in eleven countries. Countries approaching elimination need to prepare verification dossiers, while others need to increase their routine coverage, conduct follow-up campaigns, and improve surveillance. Submission of progress reports to the RVC will measure progress toward the goal. Full article

The vision of a unified European HTA is by no means a new endeavor. At its core are the publicly declared ambitions to harmonize assessments of clinical data within the EU and avoid the duplication of efforts. Not surprisingly, these ambitions are publicly announced to be motivating the new 2022 EU HTA regulation. However, industry experts typically see more of a risk for additional bureaucracy resulting in delays, further scrutiny, and one additional EU (clinical) dossier to submit on top of all national HTA dossiers, which could be considered a duplication of effort and therefore counterproductive. Regardless of how the details of the process will be defined and how the entire process will work in practice, we can be sure that EU officials will refer to the EU HTA and Joint Clinical Assessment (JCA) in particular as a learning system. The purpose of this article is to take a closer look at the new EU HTA regulation and analyze threats and opportunities for manufacturers and what the resulting opportunities and threats will be at the affiliate level throughout the EU. Full article

mRNA-lipid nanoparticle (LNP) medicinal products can be considered a platform technology because the development process is similar for different diseases and conditions, with similar noncoding mRNA sequences and lipid nanoparticles and essentially unchanged manufacturing and analytical methods often utilised for different products. It is critical not to lose the momentum built using the platform approach during the development, regulatory approval and rollout of vaccines for SARS-CoV-2 and its variants. This review proposes a set of modifications to existing regulatory requirements for mRNA products, based on a platform perspective for quality, manufacturing, preclinical, and clinical data. For the first time, we address development and potential regulatory requirements when the mRNA sequences and LNP composition vary in different products as well. In addition, we propose considerations for self-amplifying mRNA, individualised oncology mRNA products, and mRNA therapeutics. Providing a predictable development pathway for academic and commercial groups so that they can know in detail what product characterisation and data are required to develop a dossier for regulatory submission has many potential benefits. These include: reduced development and regulatory costs; faster consumer/patient access and more agile development of products in the face of pandemics; and for rare diseases where alternatives may not exist or to increase survival and the quality of life in cancer patients. Therefore, achieving consensus around platform approaches is both urgent and important. This approach with mRNA can be a template for similar platform frameworks for other therapeutics and vaccines to enable more efficient development and regulatory review. Full article

This review aims to analyze Mentha piperita L. as a potential raw material for the development of new health-promoting products (nutraceuticals, cosmetics, and pharmaceutical products). A lot of scientific publications were retrieved from the Scopus, PubMed, and Google Scholar databases which enable the study and generalization of the extraction procedures, key biologically active compounds of essential oil and extracts, biological properties, and therapeutic potential of M. piperita, along with perspectives on the development of its dosage forms, including combinations of synthetic active substances and herbal preparations of M. piperita. The results of this review indicate that M. piperita is a source rich in phytoconstituents of different chemical nature and can be regarded as a source of active substances to enhance health and to develop medicinal products for complementary therapy of various conditions, especially those related with oxidant stress, inflammation, and moderate infections. Essential oil has a broad spectrum of activities. Depending on the test and concentration, this essential oil has both anti- and prooxidant properties. Gram-positive bacteria are more sensitive to the essential oil of M. piperita than Gram-negative ones. This review also considered some facets of the standardization of essential oil and extracts of M. piperita. Among the identified phenolics of extracts were caffeic acid, rosmarinic acid, eriocitrin, luteolin derivates (luteolin-7-O-rutinoside, luteolin-7-O-glucoronide), and hesperidin. The concentration of these phenolics depends on the solvent used. This review also considered the relationships between the chemical component and biological activity. The results showed that the essential oil and extracts reduced inflammation in vitro by inhibiting the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and in vivo by reducing the paw edema induced using carrageenan injection in rats. Therefore, herbal preparations of M. piperita are promising medicinal and cosmetic preparations for their usage in skincare and oral cavity care products with antimicrobial, anti-inflammatory, and wound-healing properties. This plant can also be regarded as a platform for the development of antibacterial preparations and combined anti-inflammatory and cardioprotective medicinal products (synthetic active substances plus herbal preparations). This review could be considered for the justification of the composition of some medicinal products during their pharmaceutical development for writing a registration dossier in the format of Common Technical Document. Full article