Search Results (85)

This study was designed to systematically identify novel umami peptides in lager beer, clarify their molecular interactions with the T1R1/T1R3 receptor, and determine their specific effects on multidimensional sensory attributes. The peptides were characterized by LC-MS/MS combined with de novo sequencing, and 906 valid sequences were obtained. Machine-learning models (UMPred-FRL, Tastepeptides-Meta, and Umami-MRNN) predicted 76 potential umami peptides. These candidates were docked to T1R1/T1R3 with the CDOCKER protocol, producing 57 successful complexes. Six representative peptides—KSTEL, DELIK, DIGISSK, IEKYSGA, DEVR, and PVPL—were selected for 100 ns molecular-dynamics simulations and MM/GBSA binding-energy calculations. All six peptides stably occupied the narrow cleft at the T1R1/T1R3 interface. Their binding free energies ranked as DEVR (−44.09 ± 5.47 kcal mol⁻¹) < KSTEL (−43.21 ± 3.45) < IEKYSGA (−39.60 ± 4.37) ≈ PVPL (−39.53 ± 2.52) < DELIK (−36.14 ± 3.11) < DIGISSK (−26.45 ± 4.52). Corresponding taste thresholds were 0.121, 0.217, 0.326, 0.406, 0.589, and 0.696 mmol L⁻¹ (DEVR < KSTEL < IEKYSGA < DELIK < PVPL < DIGISSK). TDA-based sensory validation with single-factor additions showed that KSTEL, DELIK, DEVR, and PVPL increased umami scores by ≈21%, ≈22%, ≈17%, and ≈11%, respectively, while DIGISSK and IEKYSGA produced marginal changes (≤2%). The short-chain peptides thus bound with high affinity to T1R1/T1R3 and improved core taste and mouthfeel but tended to amplify certain off-flavors, and the long-chain peptides caused detrimental impacts. Future formulation optimization should balance flavor enhancement and off-flavor suppression, providing a theoretical basis for targeted brewing of umami-oriented lager beer. Full article

Ceftazidime–avibactam (CAZ-AVI) is a second-generation intravenous β-lactam/β-lactamase inhibitor combination. In recent years, substantial evidence has emerged regarding the efficacy and safety of CAZ-AVI. However, data on its use in critically ill patients remain limited. Background/Objectives: This multicenter, retrospective, observational cohort study was conducted across four Intensive Care Units (ICUs) in three hospitals in the Marche region of Italy. The primary objective was to evaluate the 30-day clinical outcomes and identify risk factors associated with 30-day clinical failure—defined as death, microbiological recurrence, or persistence within 30 days after discontinuation of therapy—in critically ill patients treated with CAZ-AVI. Methods: The study included all adult critically ill patients admitted to the participating ICUs between January 2020 and September 2023 who received CAZ-AVI for at least 72 h for the treatment of a confirmed or suspected Gram-negative bacterial (GNB) infection. Results: Among the 161 patients included in the study, CAZ-AVI treatment resulted in a positive clinical outcome (i.e., clinical improvement and 30-day survival) in 58% of cases (n = 93/161), while the overall mortality rate was 24% (n = 38/161). Relapse or persistent infection occurred in a substantial proportion of patients (25%, n = 41/161). Notably, acquired resistance to CAZ-AVI was observed in 26% of these cases, likely due to suboptimal use of the drug in relation to its pharmacokinetic/pharmacodynamic (PK/PD) properties in critically ill patients. Furthermore, treatment failure was more frequent among immunosuppressed individuals, particularly liver transplant recipients. Conclusions: This study demonstrates that the mortality rate among ICU patients treated with this novel antimicrobial combination is consistent with findings from other studies involving heterogeneous populations. However, the rapid emergence of resistance underscores the need for vigilant surveillance and the implementation of robust antimicrobial stewardship strategies. Full article

Adverse drug events (ADEs) significantly impact patient safety and health outcomes. Manual ADE detection from clinical narratives is time-consuming, labor-intensive, and costly. Recent advancements in large language models (LLMs), including transformer-based architectures such as Bidirectional Encoder Representations from Transformers (BERT) and Generative Pretrained Transformer (GPT) series, offer promising methods for automating ADE extraction from clinical data. These models have been applied to various aspects of pharmacovigilance and clinical decision support, demonstrating potential in extracting ADE-related information from real-world clinical data. Additionally, chatbot-assisted systems have been explored as tools in clinical management, aiding in medication adherence, patient engagement, and symptom monitoring. This narrative review synthesizes the current state of LLMs in ADE detection from a clinical perspective, organizing studies into categories such as human-facing decision support tools, immune-related ADE detection, cancer-related and non-cancer-related ADE surveillance, and personalized decision support systems. In total, 39 articles were included in this review. Across domains, LLM-driven methods have demonstrated promising performances, often outperforming traditional approaches. However, critical limitations persist, such as domain-specific variability in model performance, interpretability challenges, data quality and privacy concerns, and infrastructure requirements. By addressing these challenges, LLM-based ADE detection could enhance pharmacovigilance practices, improve patient safety outcomes, and optimize clinical workflows. Full article

Invasive fungal infections (IFIs) represent a growing global health threat, particularly for immunocompromised populations, with mortality exceeding 1.5 million deaths annually. Despite their clinical and economic burden—costing billions in healthcare expenditures—fungal infections remain underprioritized in public health agendas. This review examines the current landscape of antifungal therapy, focusing on advances, challenges, and future directions. Key drug classes (polyenes, azoles, echinocandins, and novel agents) are analyzed for their mechanisms of action, pharmacokinetics, and clinical applications, alongside emerging resistance patterns in pathogens like Candida auris and azole-resistant Aspergillus fumigatus. The rise of resistance, driven by agricultural fungicide use and nosocomial transmission, underscores the need for innovative antifungals, rapid diagnostics, and stewardship programs. Promising developments include next-generation echinocandins (e.g., rezafungin), triterpenoids (ibrexafungerp), and orotomides (olorofim), which target resistant strains and offer improved safety profiles. The review also highlights the critical role of “One Health” strategies to mitigate environmental and clinical resistance. Future success hinges on multidisciplinary collaboration, enhanced surveillance, and accelerated drug development to address unmet needs in antifungal therapy. Full article

The regulation of clinical trials for medicinal products and medical devices has undergone numerous changes in recent years in the European Union, challenging manufacturers and national regulatory agencies as well. With the introduction of combined drug–device products, the regulatory landscape has been drastically changed to adapt to novel technological advancements and innovations. A comparative analysis has not yet been published highlighting the main differences and common elements of these two medicinal products, which took up almost all of the market in the pharmaceutical sector. Due to stricter regulations in the field of medical devices, the process from application up until post-market surveillance became more difficult, but a correlation between the regulation of drug trials can also be found. The main differences lie in the risk management systems, where, regardless of the background knowledge of a drug, it is always strict and mandatory structured progress, while in the case of medical devices, it is more flexible based on the risk category of the product. Generally, the utilization of e-health opportunities, transparency, and data accessibility have been improved in both fields. Via the adaptation of the mentioned regulation in the EU, the safety of patients and the efficacy of trials have been greatly increased. This manuscript aims to compare the specific regulations of these two types of medicinal products with a brief outlook on the non-EU sector as well. Full article

Background: Respiratory syncytial virus (RSV) poses a significant health burden in children, being the major cause of lower respiratory tract infection (LRTI), including bronchiolitis. During the 2023–2024 RSV season, Spain introduced nirsevimab, a monoclonal antibody for universal RSV prophylaxis in infants. This study reviews the safety of nirsevimab through post-marketing surveillance. Material and Methods: A descriptive pharmacovigilance study was made based on spontaneous reporting data of suspected adverse events (SAEs) from the Spanish Pharmacovigilance System for Medicinal Products for Human Use (SEFV-H) and industry reports. SAEs reported between September 2023 and May 2024 were extracted from the Spanish Pharmacovigilance Adverse Reactions Data (FEDRA) database. Cases were analysed by sex, age, severity, and SAEs classification using the Preferred Terms (PT) level of the Medical Dictionary for Regulatory Activities (MedDRA). Reporting rates were estimated based on immunization coverage and birth data. Results: Sixty-seven cases reported 141 SAEs, yielding an overall rate of 23.1 cases per 100,000 doses. Common events included rash (8.51%), drug ineffectiveness (7.09%), and pyrexia (7.09%). Serious events constituted 53.70% of reports, including two fatalities (3.00%). No new safety signals or unexpected risks, such as antibody-dependent enhancement (ADE), were identified. Discussion: SAEs reported peaked early in the campaign, reflecting heightened reporting in new immunization programs. The safety profile aligns with clinical trial findings and regulatory expectations, confirming nirsevimab’s benefit–risk balance. Continued pharmacovigilance is critical for maintaining public trust in RSV prophylaxis. Nirsevimab demonstrated a favorable safety profile during Spain’s initial universal RSV immunization campaign in infants, supporting its continued use in reducing RSV-related morbidity. Full article

Background: Antimicrobial resistance (AMR) poses an increasing threat to animal health and food safety. In the poultry sector, particularly in waterfowl farming, the widespread use of antibiotics may contribute to the dissemination of resistant Escherichia coli strains. This study aims to map the antibiotic resistance profiles of E. coli isolates from geese in Hungary, determine the prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, and analyze resistance patterns and co-resistance relationships. Methods: E. coli isolates from clinical cases between 2022 and 2023 were examined using minimum inhibitory concentration (MIC) determination. Susceptibility results were evaluated based on the Clinical Laboratory Standard Institute (CLSI) breakpoints. Cluster analysis and principal component analysis (PCA) were applied to identify resistance patterns. Co-resistance relationships were examined through network analysis, while Monte Carlo simulations were used to estimate the expected prevalence of MDR strains. Results: Among the examined isolates, neomycin resistance was particularly high (86.8%), while florfenicol (73.6%) and amoxicillin (65.9%) resistance levels were also significant. The prevalence of MDR strains was 86.8%, and XDR strains accounted for 38.5%. Co-resistance analysis revealed a strong correlation between neomycin and spectinomycin resistance, as well as amoxicillin and doxycycline resistance. Monte Carlo simulations estimated that the expected range of MDR strain prevalence could vary between 80.2% and 92.3%. Conclusions: The high prevalence of MDR and XDR strains highlights the urgent need to reassess antibiotic usage strategies in goose farming. These findings underscore the importance of targeted antibiotic use, continuous microbiological surveillance, and the exploration of alternative therapeutic approaches to mitigate AMR. Full article

Background/Objectives: Post-market surveillance of COVID-19 vaccines is vital. This study analyzed EudraVigilance data (Jan 2021–Dec 2023) to detect potential safety signals linking COVID-19 vaccines and specific neurological adverse events (aseptic meningitis, Guillain–Barré syndrome, polyradiculoneuropathies, multiple sclerosis, transverse myelitis, neuromyelitis optica). It also explored the impact of non-healthcare professional reports on disproportionality analysis. Methods: EudraVigilance reports were analyzed to quantify neurological events for 5 COVID-19 vaccines and 47 comparators. Disproportionality was assessed using the Proportional Reporting Ratio (PRR). Spearman’s correlation (SCC) was used to examine the impact of non-healthcare professional reports on PRR. Results: An analysis of 4,159,820 COVID-19 vaccine and 114,025 comparator reports showed a reporting decline over time. A higher proportion of adverse drug event reports were submitted by non-healthcare professionals for COVID-19 vaccines compared to control vaccines, a trend observed consistently across 2021 (57.3% vs. 33%, p < 0.001), 2022 (59.4% vs. 36.5%, p = 0.001), and 2023 (42% vs. 24.36%, p = 0.006). In 2023, significant signals (PRR ≥ 2) were found between Jcovden© and polyradiculoneuropathy (PRR 5.4, IC 95% 3.98–7.32), multiple sclerosis (PRR 2.72, IC 95% (1.08–6.87), transverse myelitis (PRR 4.68, IC 95% 1.02–21.35) and neuromyelitis optica (PRR 7.79, IC 95% 3.5–17.37). In addition, both Spikevax© and Comirnaty© showed significant signals with multiple sclerosis (PRR 2.50, IC 95% 1.70–3.68, and PRR 2.33, IC 95% 1.68–3.24) and transverse myelitis (PRR 3.50, IC 95% 1.66–7.50 and PRR 3.58, IC 95% 1.85–6.93). A significant negative correlation between the proportion of reports from non-healthcare professionals and the case/no-case ratio was found (SCC = −0.4683, p = 0.009). Conclusions: While some significant signals emerged in 2023, the combined three-year data showed no vaccine exceeding the PRR threshold of 2. High-quality data and bias mitigation strategies are crucial for accurate PRR estimation in pharmacovigilance and public health. Full article

Belatacept is a chimeric protein that acts as a selective blocker of T-lymphocyte co-stimulation. It has been proposed for the prevention of kidney transplant rejection. This paper reports a literature review on pharmacological characteristics of belatacept and genetic factors influencing its efficacy and safety profile. A severe case of neurotoxoplasmosis observed in a kidney transplant recipient (KTR) treated with belatacept is also described. It appears that the interference of belatacept on guanylate binding proteins (GBPs) expression in antigen-presenting cells (APC) cytoplasm could be involved in Toxoplasma gondii (Toxo-g) reactivation in seropositive KTRs. Additionally, genetic variations in immune regulatory genes encoding CTLA-4 and Blimp-1 may influence individual susceptibility to infection and immune modulation under belatacept therapy. In conclusion, we highlight the importance of drug avoidance and/or increased surveillance in Toxo-g IgG-positive KTR. We also retain that further studies on the host defense pathways involved in the surveillance of opportunistic pathogens in KTR are strongly desirable. Full article

This study presents a novel high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) method for simultaneous determination of oxyclozanide (OXY) and levamisole hydrochloride (LEV) residues in ovine tissues, addressing the critical gap in cross-class antiparasitic drug monitoring. Leveraging dual solid-phase extraction strategies—MAX anion-exchange for lipophilic OXY and MCX cation-exchange for hydrophilic LEV—we achieved efficient purification of these pharmacokinetically divergent compounds from complex matrices (muscle, liver, kidney, and perirenal adipose). The method demonstrated superior sensitivity with limits of detection (1.5 μg/kg) and quantification (2.5 μg/kg) below international maximum residue limits (MRLs), validated through Codex Alimentarius guidelines (CAC/GL 71-2009). Linear responses (2.5–1000 μg/kg, R² > 0.9900) and robust precision (intra-day RSD: 1.44–12.51%; inter-day RSD: 0.29–17.70%) were maintained across spiked concentrations (LOQ, 0.5×, 1×, and 2 × MRLs), with recoveries of 80.94–115.36% confirming matrix-agnostic accuracy. Stability assessments under diverse storage conditions further validated method reliability. Applied to pharmacokinetic profiling in medicated sheep, this protocol established a 28-day withdrawal period for edible tissues, reconciling regulatory compliance with food safety requirements. As the first reported simultaneous quantification platform for OXY and LEV antiparasitics, our methodology advances veterinary residue analytics by enabling efficient multi-class surveillance and evidence-based withdrawal period optimization. Full article

Background/Objectives: Controversy exists over the use of passive reporting systems, especially the Vaccine Adverse Event Reporting System, in risk assessment. One limitation of these systems is that adverse event (AE) reporting rates cannot be calculated without knowing the number of shots administered or prescriptions in the case of pharmaceuticals. Adverse event reporting rates can be a factor in a risk assessment, though they should not be solely relied on; they can be used to compare the relative safety profiles of different vaccine products or pharmaceuticals. This study introduces the Denominator-Adjusted Rate Estimates of Substance Adverse Events Frequency Evaluation (DARE-SAFE) method to analyze pharmacovigilance reporting rates for vaccines and common pharmaceuticals. Methods: We calculated reporting rates for the top 250 most prescribed drugs in the US Food and Drug Association (FDA) Adverse Event Reporting System and common vaccines in the Vaccine Adverse Events Reporting System. For vaccines, we used USA Centers for Disease Control (CDC) dose data and OpenVAERS reports. For pharmaceuticals, we utilized prescription data from ClinCalc and FAERS reports for 2022. Results: VAERS reporting rates varied significantly across vaccine types. COVID-19 vaccines showed a 63.0 ± 0.6 times higher rate of VAERS deaths per dose and an 18.95 ± 0.02 times higher rate of total adverse event reports per dose compared to influenza vaccines. The ratio of total VAERS reports to deaths for vaccines was 73 ± 4 to 1 (R² = 0.94). For pharmaceuticals, the ratio of total adverse event reports to deaths was 26 ± 2 (R² = 0.46), with a strong correlation between serious adverse events and deaths (ratio 9.1 ± 0.3, R² = 0.79). Conclusions: DARE-SAFE provides a standardized method for comparing reporting rates across different medical products. The observed differences between vaccines and pharmaceuticals, as well as among different vaccine types, warrant further investigation into reporting practices, actual safety profiles, and potential biases in surveillance systems. Full article

Background: Janus kinase (JAK) inhibitors are a new class of targeted therapies that block cytokines and the signal transduction and activators of transcription (STAT) pathway. However, post-marketing surveillance studies have led to revised recommendations, highlighting potential serious heart-related events and cancer risk of JAK inhibitors. Here, we aimed to determine the neurological adverse events (AEs) of JAK inhibitors (tofacitinib, ruxolitinib, and baricitinib) based on a global real-world database. Methods: We analyzed individual case safety reports from the Uppsala Monitoring Center from January 1968 to 4 April 2022. A disproportionality analysis was performed using the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) to detect signals. Signals were classified according to the hierarchy of the Medical Dictionary for Regulatory Activities (MedDRA). Additionally, a stratified disproportionality analysis by age group and sex was performed for major AEs. Results: A total of 30,051,159 reports for all drugs were analyzed in this study. Among 105,798 reports of tofacitinib, 14.1% (14,863 reports) were neurological AEs. For ruxolitinib and baricitinib, 14.5% (6317 reports) and 10.2% (1216 reports) were neurological AEs, respectively. Various neurological AE signals were detected for tofacitinib and ruxolitinib, with memory impairment exhibiting the highest number of reports and a positive signal in the stratified disproportionality analysis by age group. Baricitinib did not reach the signal detection threshold. Conclusions: This study suggests the potential for neurological AEs, including memory impairment, associated with tofacitinib and ruxolitinib use based on a real-world database. Full article

Background: China’s pharmaceutical regulatory framework is undergoing a pivotal shift from a traditional “command-control” model to a “lifecycle regulation” approach, aiming to balance drug safety, innovation, and accessibility. This study systematically examines the evolution, achievements, and challenges of China’s regulatory reforms, offering insights for global pharmaceutical governance. Methods: Using a mixed-methods approach integrating historical analysis, policy text mining, and case studies, we reviewed the pharmaceutical laws and regulations enacted since 1949, supplemented by case studies (e.g., COVID-19 vaccine emergency approvals) and a comparative analysis with international models (e.g., U.S. FDA and EU EMA frameworks). The data were sourced from authoritative platforms such as the PKULAW database, criminal law amendments, and international regulatory texts. Results: China’s regulatory evolution is categorized into four phases: Emergence (1949–1984), Foundational (1985–2000), Deepening Reform (2001–2018), and Lifecycle Regulation (2019–present). The revised Drug Administration Law (2019) institutionalized risk management, dynamic GMP inspections, and post-market surveillance, marking a transition to holistic lifecycle oversight. Key milestones include the introduction of the Vaccine Management Law (2019) and stricter penalties under the Criminal Law Amendment (XI) (2020). Conclusions: China’s lifecycle regulation model demonstrates potential to harmonize safety and innovation, evidenced by improved API export compliance (e.g., 15% increase in international certifications by 2023) and accelerated approvals for breakthrough therapies (e.g., domestically developed PD-1 inhibitors). However, challenges persist, including uneven enforcement capacities, tensions between conditional approvals and risk mitigation, and reliance on global supply chains. These findings provide critical lessons for developing countries navigating similar regulatory dilemmas. Full article

The healthcare sector in India has experienced significant transformations owing to the advancement in technology and infrastructure. Despite these transformations, there are major challenges to address critical issues like insufficient healthcare infrastructure for the country’s huge population, limited accessibility, shortage of skilled professionals, and high-quality care. Artificial intelligence (AI)-driven solutions have the potential to lessen the stress on India’s healthcare system; however, integrating trustworthy AI in the sector remains challenging due to ethical and regulatory constraints. This study aims to critically review the current status of the development of AI systems in Indian healthcare and how well it satisfies the ethical and legal aspects of AI, as well as to identify the challenges and opportunities in adoption of trustworthy AI in the Indian healthcare sector. This study reviewed 15 articles selected from a total of 1136 articles gathered from two electronic databases, PubMed and Google Scholar, as well as project websites. This study makes use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). It finds that the existing studies mostly used conventional machine learning (ML) algorithms and artificial neural networks (ANNs) for a variety of tasks, such as drug discovery, disease surveillance systems, early disease detection and diagnostic accuracy, and management of healthcare resources in India. This study identifies a gap in the adoption of trustworthy AI in Indian healthcare and various challenges associated with it. It explores opportunities for developing trustworthy AI in Indian healthcare settings, prioritizing patient safety, data privacy, and compliance with ethical and legal standards. Full article

A comprehensive pharmacovigilance surveillance on antibacterials is lacking. This study aims to investigate safety signals of antibacterial-related adverse drug events (ADEs) with seriousness and to identify predictors of serious ADEs. This study investigated 52,503 antibacterial-induced ADEs reported to the Korea Adverse Event Reporting System Database from January 2013 to December 2022. Disproportionality analysis was conducted, and the effect sizes were estimated by reporting odds ratios (ROR), proportional reporting ratio (PRR), and information component (IC). Multivariate logistic regression was performed to investigate the predictors of serious ADEs by estimating the odds ratio (OR). Serious events were more likely to be cardiovascular disorders (ROR 6.77, PRR 6.6, IC 2.37), urinary system disorders (ROR 5.56, PRR 5.22, IC 2.12), and platelet, bleeding, and clotting disorders (ROR 5.41, PRR 5.17, IC 2.06). The predictors may include age (OR 1.05), the number of concomitant medications (OR 1.44), concomitant proton pump inhibitors (OR 1.46) and non-steroidal anti-inflammatory drugs (OR 1.38) use, and specific antibacterial classes, while multiple antibacterial therapy was associated with lower serious ADE risks. The sensitivity analysis also suggests the male sex (OR 1.18) as a potential predictor of serious ADEs. However, further studies are imperative to determine the causality of antibacterial-induced ADEs in critically ill patients. Full article