Search Results (15,881)

Background and aim: Advanced Therapy Medicinal Products (ATMPs) are innovative drugs based on genes, tissues, or cells that target rare and severe diseases. ATMPs have shown promising clinical outcomes but are associated with high costs, raising questions about cost-effectiveness. Hence, this systematic review aims to analyze the cost-effectiveness and cost-utility profiles of the European Medicines Agency-authorized ATMPs for treating rare diseases. Methods: A systematic review was conducted following PRISMA guidelines. Studies were identified by searching PubMed, Embase, Web of Science, and ProQuest scientific databases. Economic evaluations reporting incremental cost-effectiveness/utility ratios (ICERs/ICURs) for ATMPs were included. Costs were standardized to 2023 Euros, and a cost-effectiveness plane was constructed to evaluate the results against willingness-to-pay (WTP) thresholds of EUR 50,000, EUR 100,000, and EUR 150,000 per QALY, as part of a sensitivity analysis. Results: A total of 61 studies met the inclusion criteria. ATMPs for rare blood diseases, such as tisagenlecleucel and axicabtagene ciloleucel, were found to be cost-effective in a majority of studies, with incremental QALYs ranging from 1.5 to 10 per patient over lifetime horizon. Tisagenlecleucel demonstrated a positive cost-effectiveness profile in the treatment of acute lymphoblastic leukemia (58%), while axicabtagene ciloleucel showed a positive profile in the treatment of diffuse large B-cell lymphoma (85%). Onasemnogene abeparvovec for spinal muscular atrophy (SMA) showed uncertain cost-effectiveness results, and voretigene neparvovec for retinal diseases was not cost-effective in 40% of studies, with incremental QALYs around 1.3 and high costs exceeding the WTP threshold set. Conclusions: ATMPs in treating rare diseases show promising economic potential, but cost-effectiveness varies across indications. Policymakers must balance innovation with system sustainability, using refined models and the long-term impact on patient outcomes. Full article

Carassius auratus exhibits significant physiological and behavioral alterations under the combined stress of temperature and dissolved oxygen (DO) fluctuations, which are common challenges in aquaculture. In this investigation, we employed controlled thermal and DO gradients to characterize the multidimensional response profile of this species. The key findings revealed that thermal elevation profoundly influenced blood glucose and cortisol concentrations. Notably, exposure to hyperoxic conditions markedly attenuated stress responses relative to hypoxia at equivalent temperatures: cortisol levels were significantly suppressed (reductions of 60.11%, 118.06%, and 34.72%), while blood glucose levels exhibited concurrent increases (16.42%, 26.43%, and 26.34%). Distinctive behavioral patterns, including floating head behavior, surface swimming behavior, and rollover behavior, were identified as indicative behaviors of thermal–oxygen stress. Molecular analysis demonstrated the upregulated expression of stress-associated genes (HSP70, HSP90, HIF-1α, and Prdx3), which correlated temporally with elevated cortisol and glucose concentrations and the manifestation of stress behaviors. Furthermore, a muscle texture assessment indicated that increased DO availability mitigated the textural deterioration induced by heat stress. Collectively, this work establishes an authentic biomarker framework, providing crucial threshold parameters essential for the development of intelligent, real-time environmental monitoring and dynamic regulation systems to enhance climate-resilient aquaculture management. Full article

Schistosoma mansoni infection is associated with hepatic inflammation and fibrosis, but its systemic metabolic effects remain poorly understood. This study aimed to investigate changes in the serum lipidomic profile associated with S. mansoni infection and parasite load in individuals from an endemic area. This cross-sectional analysis was nested within a longitudinal cohort study conducted in northeastern Brazil. Parasitological diagnosis and quantification were performed using the Kato–Katz technique. A total of 45 individuals were selected and divided into three groups: high parasite load (HL), low parasite load (LL), and uninfected controls (NegE). Serum samples were analyzed using mass-spectrometry-based lipidomics. The most abundant lipid subclasses across all groups were phosphatidylcholines (PC), triacylglycerols (TAG), and phosphatidylethanolamines (PE). However, individuals in the HL group exhibited distinct lipidomic profiles, with increased levels of specific phosphatidylinositols (PI) and reduced levels of certain TAG species compared to the NegE group. These changes may reflect host–parasite interactions and immune–metabolic alterations driven by intense infection. Our findings suggest that S. mansoni infection, particularly at higher parasite burdens, can influence the host’s serum lipid profile and may contribute to metabolic disturbances in endemic populations. Full article

Demand Side Management (DSM) plays a crucial role in modern energy systems, enabling more efficient use of energy resources and contributing to the sustainability of the power grid. This study examines DSM strategies within a multi-environment context encompassing residential, commercial, and industrial sectors, with a focus on diverse appliance types that exhibit distinct operational characteristics and user preferences. Initially, a single-objective optimization approach using Genetic Algorithms (GAs) is employed to minimize the total energy cost under a real Time-of-Use (ToU) pricing scheme. This heuristic method allows for the effective scheduling of appliance operations while factoring in their unique characteristics such as power consumption, usage duration, and user-defined operational flexibility. This study extends the optimization problem to a multi-objective framework that incorporates the minimization of CO₂ emissions under a real annual energy mix while also accounting for user discomfort. The Non-dominated Sorting Genetic Algorithm II (NSGA-II) is utilized for this purpose, providing a Pareto-optimal set of solutions that balances these competing objectives. The inclusion of multiple objectives ensures a comprehensive assessment of DSM strategies, aiming to reduce environmental impact and enhance user satisfaction. Additionally, this study monitors the Peak-to-Average Ratio (PAR) to evaluate the impact of DSM strategies on load balancing and grid stability. It also analyzes the impact of considering different periods of the year with the associated ToU hourly schedule and CO₂ emissions hourly profile. A key innovation of this research is the integration of detailed, category-specific metrics that enable the disaggregation of costs, emissions, and user discomfort across residential, commercial, and industrial appliances. This granularity enables stakeholders to implement tailored strategies that align with specific operational goals and regulatory compliance. Also, the emphasis on a user discomfort indicator allows us to explore the flexibility available in such DSM mechanisms. The results demonstrate the effectiveness of the proposed multi-objective optimization approach in achieving significant cost savings that may reach 20% for industrial applications, while the order of magnitude of the trade-offs involved in terms of emissions reduction, improvement in discomfort, and PAR reduction is quantified for different frameworks. The outcomes not only underscore the efficacy of applying advanced optimization frameworks to real-world problems but also point to pathways for future research in smart energy management. This comprehensive analysis highlights the potential of advanced DSM techniques to enhance the sustainability and resilience of energy systems while also offering valuable policy implications. Full article

Poly(organo)phosphazenes (PPZs) are increasingly recognized as versatile biomaterials for drug delivery applications in nanomedicine. Their unique hybrid structure—featuring an inorganic backbone and highly tunable organic side chains—confers exceptional biocompatibility and adaptability. Through precise synthetic methodologies, PPZs can be engineered to exhibit a wide spectrum of functional properties, including the formation of multifunctional nanostructures tailored for specific therapeutic needs. These attributes enable PPZs to address several critical challenges associated with conventional drug delivery systems, such as poor pharmacokinetics and pharmacodynamics. By modulating solubility profiles, enhancing drug stability, enabling targeted delivery, and supporting controlled release, PPZs offer a robust platform for improving therapeutic efficacy and patient outcomes. This review explores the fundamental chemistry, biopharmaceutical characteristics, and biomedical applications of PPZs, particularly emphasizing their role in zero-dimensional nanotherapeutic systems, including various nanoparticle formulations. PPZ-based nanotherapeutics are further examined based on their drug-loading mechanisms, which include electrostatic complexation in polyelectrolytic systems, self-assembly in amphiphilic constructs, and covalent conjugation with active pharmaceutical agents. Together, these strategies underscore the potential of PPZs as a next-generation material for advanced drug delivery platforms. Full article

Fistulina hepatica (Schaeff.) With. and Clitocybe nuda (Bull.) H.E. Bigelow & A.H. Sm. are wild edible mushrooms with nutritional and functional potential that remain insufficiently characterized. This study provides the first comparative assessment of their nutritional profiles, phenolic composition, and antioxidant activity, using specimens collected from Montesinho Natural Park (Portugal). Proximate composition, organic and phenolic acids, free sugars, and fatty acids were analyzed by chromatographic methods, and antioxidant capacity was assessed through OxHLIA and TBARS assays. F. hepatica showed higher carbohydrates (9.3 ± 0.2 g/100 g fw) and estimated energy values (43 ± 1 kcal/100 g fw), increased phenolic acids content (2.7 ± 0.1 mg/g extract), and the exclusive presence of p-coumaric and cinnamic acids, along with OxHLIA activity (IC₅₀ = 126 ± 5 µg/mL at Δt = 60 min). C. nuda displayed higher protein (2.5 ± 0.1 g/100 g dw) and quinic acid contents (4.13 ± 0.02 mg/g extract), a PUFA-rich profile, and greater TBARS inhibition (EC₅₀ = 303 ± 17 µg/mL). These findings highlight distinct and complementary bioactive traits, supporting their valorization as natural functional ingredients. Their compositional features offer promising applications in sustainable food systems and nutraceutical development, encouraging further investigations into safety, bioaccessibility, and formulation strategies. Notably, F. hepatica is best consumed at a young developmental stage, as its sensory properties tend to decline with maturity. Full article

To enable the practical application of passive back-support exoskeletons employing pneumatic artificial muscles (PAMs) in tasks such as agricultural work, we evaluated their assistive effectiveness in a half-squatting posture with a staggered stance. In this context, assistive force profiles were adjusted according to body posture to achieve more effective support. The targeted assistive force profile was designed to be continuously active from the standing to the half-squatting position, with minimal variation across this range. The assistive force profile was developed based on a PAM contractile force model and implemented using a cam mechanism. The effectiveness of assistance was assessed by measuring body flexion angles and erector spinae muscle activity during lifting and carrying tasks. The results showed that the assistive effect was greater on the side with the forward leg. Compared to the condition without exoskeleton assistance, the conventional pulley-based system reduced muscle activity by approximately 20% whereas the cam-based system achieved a reduction of approximately 30%. Full article

This research considers a preliminary comparative technical evaluation of two micro-gas turbine (MGT) systems in combined heat and power (CHP) mode (100 kWe), aimed at supplying heat to a residential community of 15 average-sized buildings located in Central Europe over a year. Two systems were modelled in Ebsilon 15 software: a natural gas case (benchmark) and an ammonia-fueled case, both based on the same on-design parameters. Off-design simulations evaluated performance over variable ambient temperatures and loads. Idealized, unrecuperated cycles were adopted to isolate the thermodynamic impact of the fuel switch under complete combustion assumption. Under these assumptions, the study shows that the ammonia system produces more electrical energy and less excess heat, yielding marginally higher electrical efficiency and EUF (26.05% and 77.63%) than the natural gas system (24.59% and 77.55%), highlighting ammonia’s utilization potential in such a context. Future research should target validating ammonia combustion and emission profiles across the turbine load range, and updating the thermodynamic model with a recuperator and SCR accounting for realistic pressure losses. Full article

The historical use of toxic chemicals to cause intentional harm has evolved from blister agents in World War I to highly lethal organophosphates and emerging families of chemicals, such as Novichok. In turn, medical or recreational substances like fentanyl, lysergamides, and phencyclidine pose a growing risk of hostile use, particularly related to the rapid proliferation of new psychoactive substances (NPSs). A narrative literature review was conducted covering specialized databases (PubMed, ScienceDirect, SciELO, Google Scholar) and sources from international organizations (OPCW, UNODC, ONU), analyzing historical and recent cases of the use of nerve agents in conflicts and the use of NPSs for hostile purposes. The main families of conventional agents (G, V, A series, and Novichok) and NPSs (lysergamides, PCP, fentanyl derivatives) were identified, highlighting their ease of synthesis, high toxicity profiles, and the regulatory gaps that facilitate their illicit production. In this scenario, it is essential to strengthen regulatory frameworks, surveillance systems, and ethical protocols in chemical research, as well as to promote international cooperation to prevent these substances from becoming chemical threats. Full article

Background/objectives: Polycystic ovary syndrome (PCOS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are common co-morbidities in women of reproductive age. PCOS is highly heterogeneous and is, therefore, divided into four phenotypes. MASLD leads to numerous systemic complications. Studies to date have shown an association between PCOS and MASLD. This study was designed to compare the FIB-4 score (based on age, alanine aminotransferase, aspartate aminotransferase and platelet count) and the results of shear wave elastography in assessing the risk of developing MASLD by patients with PCOS divided by phenotypes. Methods: The study enrolled 242 women age 18–35 years with PCOS diagnosed according to Rotterdam criteria, hospitalized at the Department of Gynaecological Endocrinology of the University Clinical Centre in Katowice. The study subjects were assigned to phenotypes A to D. Clinical and biochemical assessments were performed (including androgens and metabolic parameters), and the FIB-4 index was calculated. Liver fibrosis was evaluated by shear wave elastography. To balance the group sizes of phenotypes, oversampling with replacement was applied (PROC SURVEYSELECT, SAS), increasing the number of observations for phenotypes B, C, and D fivefold. Statistical analyses were performed based on data distribution (Shapiro–Wilk test), using ANOVA or the Kruskal–Wallis test with Dunn’s correction. Statistical significance was set at p < 0.05. Results: The FIB-4 score was the highest in phenotype B patients (0.50 ± 0.15), and the lowest in phenotypes A and C (0.42 ± 0.14). The highest rate of positive elastography findings was recorded in phenotype A patients (34.7%) and the lowest in phenotype C group (13.5%). Significant differences between the phenotypes were also found in terms of androgen levels, insulin, HOMA-IR, and the lipid profile. Among patients with positive elastography, the highest FIB-4 scores were recorded in phenotype C group (0.44 ± 0.06), but the differences between the phenotypes were not statistically significant. Conclusions: The FIB-4 score was the highest in phenotype B patients and differed significantly from phenotypes A, C and D. In the elastography exam, the fibrosis index was statistically significantly higher in phenotype A compared to other phenotypes. No correlation was detected between the FIB-4 index and positive elastography. The findings suggest that the FIB-4 index may be used for MASLD screening, but its usefulness as a predictor of eligibility for elastography requires more research. Full article

Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of tumors with a complex molecular profile. Despite therapeutic advances, patient prognosis remains poor, emphasizing the need for more effective treatment strategies. Traditional chemotherapy, with cisplatin and 5-fluorouracil (5-FU), remains the gold standard but is limited by toxicity and tumor resistance. Immunotherapy, particularly immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand (PD-L1), has improved overall survival, especially in patients with high PD-L1 expression. In parallel, targeted therapies such as poly (ADP-ribose) polymerase 1 (PARP1) inhibitors—which impair DNA repair and increase replication stress—have shown promising activity in HNSCC. Cyclin-dependent kinase (CDK) inhibitors are also under investigation due to their potential to correct dysregulated cell cycle control, a hallmark of HNSCC. This review aims to summarize current and emerging pharmacotherapies for HNSCC, focusing on chemotherapy, immunotherapy, and PARP and CDK inhibitors. It also discusses the evolving role of targeted therapies in improving clinical outcomes. Future research directions include combination therapies, nanotechnology-based delivery systems to enhance treatment specificity, and the development of diagnostic tools such as PARP1-targeted imaging to better guide personalized treatment approaches. Full article

Efficient and accurate panel assignment is critical in expert and peer review processes. Traditional methods—based on manual preferences or Heuristic rules—often introduce bias, inconsistency, and scalability challenges. We present an automated framework that combines transformer-based document similarity modeling with optimization-based reviewer assignment. Using the all-mpnet-base-v2 from model (version 3.4.1), our system computes semantic similarity between proposal texts and reviewer documents, including CVs and Google Scholar profiles, without requiring manual input from reviewers. These similarity scores are then converted into rankings and integrated into an Integer Linear Programming (ILP) formulation that accounts for workload balance, conflicts of interest, and role-specific reviewer assignments (lead, scribe, reviewer). The method was tested across 40 researchers in two distinct disciplines (Chemical Engineering and Philosophy), each with 10 proposal documents. Results showed high self-similarity scores (0.65–0.89), strong differentiation between unrelated fields (−0.21 to 0.08), and comparable performance between reviewer document types. The optimization consistently prioritized top matches while maintaining feasibility under assignment constraints. By eliminating the need for subjective preferences and leveraging deep semantic analysis, our framework offers a scalable, fair, and efficient alternative to manual or Heuristic assignment processes. This approach can support large-scale review workflows while enhancing transparency and alignment with reviewer expertise. Full article

Background/Objectives: Myelodysplastic syndrome (MDS) is a heterogeneous clonal hematopoietic disorder characterized by ineffective hematopoiesis and leukemic transformation risk. Current therapies show limited efficacy, with ~50% of patients failing hypomethylating agents. This review aims to synthesize recent discoveries through an integrated network model and examine translation into precision therapeutic approaches. Methods: We reviewed breakthrough discoveries from the past three years, analyzing single-cell multi-omics technologies, epitranscriptomics, stem cell architecture analysis, and precision medicine approaches. We examined cell-type-specific splicing aberrations, distinct stem cell architectures, epitranscriptomic modifications, and microenvironmental alterations in MDS pathogenesis. Results: Four interconnected mechanisms drive MDS: genetic alterations (splicing factor mutations), aberrant stem cell architecture (CMP-pattern vs. GMP-pattern), epitranscriptomic dysregulation involving pseudouridine-modified tRNA-derived fragments, and microenvironmental changes. Splicing aberrations show cell-type specificity, with SF3B1 mutations preferentially affecting erythroid lineages. Stem cell architectures predict therapeutic responses, with CMP-pattern MDS achieving superior venetoclax response rates (>70%) versus GMP-pattern MDS (<30%). Epitranscriptomic alterations provide independent prognostic information, while microenvironmental changes mediate treatment resistance. Conclusions: These advances represent a paradigm shift toward personalized MDS medicine, moving from single-biomarker to comprehensive molecular profiling guiding multi-target strategies. While challenges remain in standardizing molecular profiling and developing clinical decision algorithms, this systems-level understanding provides a foundation for precision oncology implementation and overcoming current therapeutic limitations. Full article

Background/objectives: This was a post hoc analysis of safety data across the bivalent respiratory syncytial virus prefusion F (RSVpreF) vaccine clinical trial development program. Methods: Data from eight clinical trials in 46,913 immunocompetent adults who received RSVpreF or placebo were analyzed. Local reactions and systemic events were assessed among non-pregnant ≥18-year-olds (n = 9517); adverse events (AEs) among pregnant and non-pregnant 18–59-year-olds (n = 9238); and vaccine-related AEs among non-pregnant ≥18-year-olds (n = 39,314). Post-marketing data in non-pregnant adults were considered. Results: Local reactions and systemic events were reported more frequently in RSVpreF versus placebo recipients; injection site pain was the most common local reaction (RSVpreF, 18.9%; placebo, 7.4%), and fatigue (23.5%; 18.4%) and headache (19.5%; 15.0%) were the most common systemic events. Percentages of AEs within 1 month after vaccination were similar across groups (RSVpreF, 12.8%; placebo, 13.1%); severe AEs were reported in ≤1.5% of participants. Differences in percentages of individuals reporting vaccine-related AEs between the RSVpreF and placebo groups were <0.2% for all related AEs. Serious AEs throughout the study were reported in ≤14.0% (RSVpreF, 12.6%; placebo, 14.0%). No atrial fibrillation, Guillain-Barré syndrome, or acute polyneuropathy cases were reported. The AE data from post-marketing data sources were consistent with the safety profile from the clinical trial program, with no new safety concerns. Conclusions: Integrated data demonstrated that RSVpreF was well tolerated with a favorable safety profile in non-pregnant and pregnant adults. Ongoing surveillance through real-world use and clinical trial experience continue to support the safety profile of RSVpreF. ClinicalTrials.gov: CT03529773/NCT04071158/NCT04785612/NCT05035212/NCT05096208/NCT05842967/NCT04032093/NCT04424316. Full article

Urochloa brizantha (Brizantha) is cultivated under varying altitudinal and management conditions. Twelve full-sun (monoculture) plots and twelve shaded (silvopastoral) plots were established, proportionally distributed at 170, 503, 661, and 1110 masl. Evaluations were conducted 15, 30, 45, 60, and 75 days after establishment. The conservation and integration of trees in silvopastoral systems reflected a clear anthropogenic influence, evidenced by the preference for species of the Fabaceae family, likely due to their multipurpose nature. Although the altitudinal gradient did not show direct effects on soil properties, intermediate altitudes revealed a significant role of CaCO₃ in enhancing soil fertility. These edaphic conditions at mid-altitudes favored the leaf area development of Brizantha, particularly during the early growth stages, as indicated by significantly larger values (p < 0.05). However, at the harvest stage, no significant differences were observed in physiological or productive traits, nor in foliar chemical components, underscoring the species’ high hardiness and broad adaptation to both soil and altitude conditions. In Brizantha, a significant reduction (p < 0.05) in stomatal size and density was observed under shade in silvopastoral areas, where solar radiation and air temperature decreased, while relative humidity increased. Nonetheless, these microclimatic variations did not lead to significant changes in foliar chemistry, growth variables, or biomass production, suggesting a high degree of adaptive plasticity to microclimatic fluctuations. Foliar ash content exhibited an increasing trend with altitude, indicating greater efficiency of Brizantha in absorbing calcium, phosphorus, and potassium at higher altitudes, possibly linked to more favorable edaphoclimatic conditions for nutrient uptake. Finally, forage quality declined with plant age, as evidenced by reductions in protein, ash, and In Vitro Dry Matter Digestibility (IVDMD), alongside increases in fiber, Neutral Detergent Fiber (NDF), and Acid Detergent Fiber (ADF). These findings support the recommendation of cutting intervals between 30 and 45 days, during which Brizantha displays a more favorable nutritional profile, higher digestibility, and consequently, greater value for animal feeding. Full article