Search Results (1,907)

Microbial resistance to antibiotics necessitates the development of alternative treatments to address the challenges posed by severe bacterial infections. Bacteriophages are regaining clinical relevance, but the effectiveness of phage therapy depends directly on the route of administration and the carrier used. This review provides a critical overview of the therapeutic potential of phages, emphasizing different strategies for delivery to the site of infection. We focus on the preclinical and clinical data on phage therapies using various routes of administration, such as oral, intravenous, inhalation, topical, and local administration to joints and bones. In view of different phage formulations, including liquid suspension, phages immobilized in polymers or liposome-based carriers, we highlight the potential challenges and obstacles that may affect phage stability and bioavailability and limit the successful outcome of therapy. This review serves to enhance the understanding of the integration of materials engineering with clinical practice and production standardization, to address these issues. Additionally, a clear knowledge of the bacteriophage and pharmacokinetics of phage preparations is necessary to implement safe and efficacious bacteriophage treatment in the era of antimicrobial resistance. Full article

Objectives: This study aimed to evaluate the radiographic characteristics of medication-related osteonecrosis of the jaw (MRONJ) by digital panoramic radiographs and to investigate the associations between radiographic findings and clinical, demographic, and treatment-related variables in patients receiving antiresorptive therapy. Methods: A retrospective analysis was performed on 55 patients receiving antiresorptive therapy, categorized into a tooth-extraction group (n = 20) and an MRONJ group (n = 35). Standardized panoramic radiographs obtained at baseline (T0) and during the 6-month follow-up (T1) were evaluated for lamina dura thickness, trabecular bone alteration, osteosclerosis, cancellous bone loss, sequestration, and periosteal response. Statistical analyses were conducted on associations involving drug type, administration route, therapy duration, smoking, diabetes, hypertension, gender, and serum C-terminal telopeptide (CTX) levels. Results: The incidence of sequestrum development and cancellous bone loss was considerably higher in the MRONJ group. Sequestration demonstrated significant associations with both the duration of antiresorptive therapy (>3 years) and intermediate-risk CTX levels. No significant correlations were found between CTX and other radiographic parameters. Lamina dura thickening, trabecular alterations, osteosclerosis, and periosteal reaction exhibited no differences across groups or in relation to smoking, diabetes, age, or gender; periosteal reaction was an uncommon and variable finding. Conclusions: Panoramic radiography provides clinically useful information in the evaluation of MRONJ, particularly for identifying sequestration and cancellous bone degradation. The formation of sequestrum appears to be the most indicative radiographic indicator, representing both the duration of treatment and biochemical risk. Full article

Campylobacter is a leading foodborne bacterial pathogen, and poultry production is a major reservoir contributing to human exposure. Reducing Campylobacter at farm level is therefore critical to limit downstream contamination. This systematic review and meta-analysis aimed to identify and quantitively summarise the current interventions and control measures applied in poultry farms to control the contamination and bird colonisation by Campylobacter. The Scopus electronic database was accessed to collect primary research articles that focused on observational studies and in vivo experiments, reporting results on Campylobacter concentrations or prevalence in both non-intervened and intervened groups. A total of 4080 studies were reviewed, from which 112 were selected and included in the meta-analysis according to predefined criteria, yielding 1467 observations. Meta-regression models were adjusted to the full data set and by intervention strategy based on the type of outcome measure (i.e., concentration and prevalence). In general terms, the results reveal that the effectiveness to reduce Campylobacter colonisation vary among interventions. A highly significant effect (p < 0.001) was observed in interventions such as organic acids, bacteriophages, plant extracts, probiotics, and organic iron complexes added to feed or drinking water; although drinking water was proven to be a more effective means of administration than feed for extracts and organic acids. In contrast, interventions such as chemical treatments, routine cleaning and disinfection, and vaccination showed both lower and more heterogeneous effects on Campylobacter loads. Vaccination effects were demonstrated to be driven by route and schedule, with intramuscular administration, longer vaccination periods and sufficient time before slaughter linked to greater reduction in Campylobacter colonisation. Probiotics, plant extracts and routine cleaning and disinfection were associated with lower Campylobacter prevalence in flocks. Meta-regression models consistently showed that the interventions were proven more effective when the sample analysed was caecal contents in comparison to faeces (p < 0.001). Overall, the findings of this meta-analysis study emphasise the application of a multi-barrier approach that combines targeted interventions with robust biosecurity and hygiene measures in order to reduce Campylobacter levels in poultry farms. Full article

Background/Objectives: Infantile epileptic spasms syndrome (IESS) is a severe epilepsy of infancy. Corticotropin (ACTH) and vigabatrin are the only FDA-approved therapies. The efficacy of ACTH together with the strong convulsant effects of corticotropin-releasing hormone (CRH) suggests that excess CRH, secondary to impaired ACTH feedback, may contribute to spasms. We therefore hypothesized that CRH receptor 1 (CRHR1) antagonists would suppress spasms in a route- and drug-dependent manner. Methods: Using our validated rat model of IESS, in which prenatal priming with betamethasone was followed by postnatal triggering of spasms with N-methyl-D-aspartic acid (NMDA), we tested two CRHR1 antagonists, CP376395 and SN003, delivered intracranially (via intracerebroventricular or intraparenchymal infusion) or systemically. Results: Intracerebroventricular infusion of both antagonists suppressed spasms, with CP376395 providing more consistent effects. Intraparenchymal administration into the hypothalamic arcuate nucleus also reduced spasms, whereas misses into the mammillary bodies were ineffective, highlighting site specificity. Systemic administration yielded divergent results: SN003 robustly suppressed spasms, whereas CP376395 unexpectedly exacerbated them. No sex differences were observed. Conclusions: These findings demonstrate that CRHR1 blockade modifies experimental spasms in a route- and drug-specific manner and implicates discrete hypothalamic circuits, particularly those including the arcuate nucleus, in spasm generation. The divergent systemic responses between CP376395 and SN003 likely reflect differences in CRHR1 engagement (competitive and non-competitive antagonism, respectively) as well as differences in binding properties that may include differential network interactions beyond local CRH signaling or duration of receptor occupancy. In conclusion, SN003 may be a better option than CP376395 for further development as a CRHR1-targeted therapy pending additional pharmacokinetic/pharmacodynamic studies. Further work should explore dosing paradigms of CP376395 to determine if a therapeutic range for CP376395 exists. Full article

This paper addresses the problem of imbalance between coastal and inland areas and recognises the reuse of abandoned buildings as an evolutionary regeneration strategy which, through specific interventions linked by a system of routes for tourism and sport, can gradually trigger sustainable development on a regional scale. It presents research conducted in recent years on behalf of local administrations and continued in national and European projects. The reference context is the Abruzzo region, where coastal, hilly and mountainous areas are a short distance apart and include both densely built-up and populated urban centres and small depopulated towns surrounded by landscapes of high environmental value. The objective is to define, through the responsible use of built resources, viable and sustainable strategies for regeneration and rebalancing oriented towards the concept of transformative resilience. The methodology adopted is divided into phases and includes both theoretical developments and case study applications according to an approach that networks building restoration and reuse interventions in the region. The key results consist of defining a reuse logic that considers the regional territory as a whole, linking different resources, functions and environments. This logic, which envisages the organisation of new functions on a regional scale, emphasises the capacity of building reuse to produce positive effects on the territory and trigger socio-economic development dynamics. This research forms part of the experience underlying a project of significant national interest (PRIN 2022 TRIALs), which will provide guidelines for activating the transformative resilience capacities of inland areas of central Italy. Full article

Pulmonary drug delivery represents a promising approach in the treatment of respiratory diseases, allowing for passive targeting and enhanced drug efficacy. Background/Objectives: The aim of the present study was to develop inhalable dry powders from lyophilized sildenafil citrate (SC)-loaded liposomes made from phosphatidylcholine and either cholesterol (CH) or resveratrol (RSV). Methods: Liposomes were prepared via a pH gradient method to increase drug entrapment efficiency and drug loading, and then the liposomes were lyophilized using different proportions of ethanol, mannitol, and lactose as excipients. The resulting dry cakes were converted into powders and evaluated for aerodynamic performance using a custom-designed air-blowing device. Notably, this is the first time that resveratrol has been used as a substitute for cholesterol in SC-loaded liposomes. Results: Our results demonstrate that RSV is a suitable liposome bilayer component and improves drug loading. Our findings prove that lyophilized cakes containing liposomes produce a dry powder that is suitable for aerosolization with potential application to pulmonary delivery of sildenafil citrate. The results suggest that RSV represents a potential alternative to traditional cholesterol-based liposomal formulations. Conclusions: This work presents a novel strategy for the pulmonary delivery of sildenafil, using biocompatible and FDA-approved mannitol and lactose for this administration route. Full article

Protein-bound uremic toxins (PBUT), particularly indoxyl sulphate (IS) and p-cresyl sulphate (pCS), are poorly removed by conventional haemodialysis because of their strong albumin binding. These toxins are associated with cardiovascular morbidity and mortality in haemodialysis patients. Displacer molecules such as ibuprofen enhance PBUT clearance by competing for albumin-binding sites, but the optimal dose and route of administration remain unclear. The aim of this study was to evaluate the effect of different ibuprofen doses, infusion durations, and routes of administration on the removal of IS and pCS during on-line hemodiafiltration (OL-HDF). In this prospective, single-centre, crossover study, 21 chronic haemodialysis patients receiving intradialytic analgesia underwent nine OL-HDF sessions. Ibuprofen was administered at two doses (400 or 800 mg) either in the arterial pre-filter line (infusion over 1 h, 2 h, or 3 h) or in the venous post-filter line (30 min). Reduction ratios (RR) of total IS and pCS were determined by LC-MS and corrected for haemoconcentration. Statistical analysis included repeated-measures ANOVA with post-hoc testing. Baseline RR for IS and pCS were 53.7 ± 9.9% and 47.1 ± 10.9%, respectively. The highest RR was achieved with 800 mg ibuprofen infused via the arterial line over 2 h (IS: 60.8 ± 8.6%; pCS: 57.8 ± 9.7%). All arterial-line 800 mg regimens and the 3-h 400 mg infusion significantly improved pCS clearance versus baseline; IS clearance improved significantly only with arterial-line 800 mg regimens and with the 400 mg 3-h infusion. Infusion rate (1–3 h) had no significant effect on RR within the same dose group. Pain scores decreased significantly after dialysis regardless of ibuprofen regimen. Arterial-line administration of ibuprofen enhances total IS and pCS removal during OL-HDF, with higher doses yielding greater clearance. Prolonged low-dose infusion appears similarly effective for pCS and may reduce systemic exposure, potentially lowering toxicity risk. These findings support the arterial line as the preferred route for displacer administration in clinical practice. Full article

Background: While intravenous administration of nanoparticles (NPs) is effective for targeting the lungs and liver, directing them to other organs and tissues remains challenging. Methods: Here, we report alternative administration routes that improve organ-specific accumulation of poly (lactic-co-glycolic acid) (PLGA) NPs (100 nm, negatively charged) loaded with the near-infrared dye Cyanine 7 (Cy7). NP cytotoxicity was evaluated in HEK293, mMSCs, C2C12, L929, and RAW264.7 cells. Hemocompatibility was assessed using WBCs and RBCs. NPs were administered via the tail vein, carotid, renal, and femoral arteries in BALB/c mice. Administration safety was evaluated by laser speckle contrast imaging and histological analysis. NP biodistribution and accumulation were assessed using in vivo and ex vivo fluorescence tomography and confocal microscopy of cryosections. Results: PLGA-Cy7 NPs demonstrate low cytotoxicity even at high doses and exhibit good hemocompatibility. Administration of NPs through the mouse carotid, renal, and femoral arteries significantly increases accumulation in the target ipsilateral brain hemisphere (31.7-fold) and salivary glands (28.3-fold), kidney (13.7-fold), and hind paw (3.6-fold), respectively, compared to intravenous administration. Injection of NPs through arteries supplying the target organs and tissues does not result in significant changes in blood flow, morphological alterations, or irreversible embolization of vessels, provided the procedure is performed correctly and the optimal dosage is used. Conclusions: These results highlight the potential of intra-arterial delivery of NPs for organ-specific drug targeting, underscoring the synergistic impact of advances in materials science, minimally invasive endovascular surgery, and nanomedicine. Full article

Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood–brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations—critical for successful clinical implementation and commercial development—remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical–clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway—or, more precisely, the “Nose-to-Neurons” pathway—offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment. Full article

Constructing reusable accident-text corpora is hindered by anonymization, heterogeneous sources, and sparse labels, which complicate cross-document event linking. We propose a spatiotemporal lattice-constrained approach that encodes administrative hierarchies and temporal granularity, defines domain-informed consistency criteria, instantiates spatial/temporal relations via a subset of RCC-8 and Allen’s interval algebra, estimates anchor weights via smoothing with monotonic projection, and fuses signals using a constrained monotonic network with explicit probability calibration. An active-learning decision rule—combining maximum probability with a probability-gap criterion—supports scalable automatic labeling, and controlled augmentation leverages instruction-tuned LLMs under lattice constraints. Experiments show competitive ranking (Hit@1 = 41.51%, Hit@5 = 77.33%) and discrimination (ROC-AUC = 87.34%), with the best F1 (62.46%). The method yields the lowest calibration errors (Brier = 0.14; ECE = 1.97%), maintains performance across sources, and exhibits the smallest F1 fluctuation across thresholds (Δ = 1.7%). In deployment-oriented analyses, it auto-labels 77.7% of cases with 97.51% accuracy among high-confidence outputs while routing 22.3% to review, where the true-positive rate is 81.46%. These findings indicate that integrating structured constraints with calibrated probabilistic fusion enables accurate, auditable, and scalable event linking for accident-corpus construction. Full article

Ischemic heart disease remains the leading cause of cardiovascular mortality worldwide. In myocardial infarction (MI), extracellular vesicles (EVs)—particularly small EVs (sEVs)—transport therapeutic cargo such as miR-21-5p, which suppresses apoptosis, and other proteins, lipids, and RNAs that can modulate cell death, inflammation, angiogenesis, and remodeling. This review synthesizes recent mechanistic and preclinical evidence on native and engineered EVs for post-MI repair, mapping therapeutic entry points across the MI timeline (acute injury, inflammation, and healing) and comparing EV sources (stem-cell and non-stem-cell), administration routes, and dosing strategies. We highlight engineering approaches—including surface ligands for cardiac homing, rational cargo loading to enhance potency, and biomaterial depots to prolong myocardial residence—that aim to improve tropism, durability, and efficacy. Manufacturing and analytical considerations are discussed in the context of contemporary guidance, with emphasis on identity, purity, and potency assays, as well as safety, immunogenicity, and pharmacology relevant to cardiac populations. Across small- and large-animal models, EV-based interventions have been associated with reduced infarct/scar burden, enhanced vascularization, and improved ventricular function, with representative preclinical studies reporting approximately 25–45% relative reductions in infarct size in rodent and porcine MI models, despite substantial heterogeneity in EV sources, formulations, and outcome reporting that limits cross-study comparability. We conclude that achieving clinical translation will require standardized cardiac-targeting strategies, validated good manufacturing practice (GMP)-compatible manufacturing platforms, and harmonized potency assays, alongside rigorous, head-to-head preclinical designs, to advance EV-based cardiorepair toward clinical testing. Full article

Background/Objectives: Extracellular vesicles (EVs) are nanosized carriers with high biocompatibility, low immunogenicity, and the ability to cross biological barriers, making them attractive for drug delivery. Despite growing interest, the clinical translation of drug-loaded EVs remains limited. This systematic review aimed to summarize current evidence on EV sources, loading strategies, therapeutic applications, and translational challenges. Methods: Following PRISMA 2020 guidelines, a systematic search was conducted in Embase, PubMed, Reaxys, and Scopus for the period 2020–2025. Eligible studies included original articles on drug-loaded EVs from human, animal, plant, or other sources. Data on EV source, drug type, particle size, loading method, administration route, and therapeutic application were extracted. Clinical trials were identified through ClinicalTrials.gov. Results: A total of 65 studies were included after screening 5316 records, along with two clinical trials. Human mesenchymal stem cell (MSC)-derived EVs were the most frequent source in oncology, while plant-derived EVs predominated in non-oncology applications. Anti-cancer drugs such as doxorubicin, gemcitabine, and docetaxel were most frequently loaded, alongside curcumin, berberine, and atorvastatin. EV sizes generally ranged from 50 to 200 nm, with larger vesicles reported for plant-derived EVs. Intravenous administration predominated, with most studies demonstrating sustained release and enhanced therapeutic efficacy. Passive loading was most common, especially for hydrophobic drugs, whereas active methods such as electroporation and sonication were preferred for hydrophilic cargo. Two clinical trials showed preliminary therapeutic benefits with favorable safety. Conclusions: Drug-loaded EVs represent a promising and versatile drug delivery platform, yet their clinical translation is hindered by variability in isolation and loading methods, production scalability, and safety evaluation. Further standardization and large-scale studies are needed to advance EV-based therapeutics toward clinical use. Full article

Vitamin B1 (thiamine) is a water-soluble B vitamin. As a cofactor of many enzymes, it is essential for the proper functioning of many body systems and organs, including metabolic and energy metabolism. In extreme cases, vitamin B1 deficiency causes neurodegenerative disorders, including beri-beri, or cognitive impairment resulting from encephalopathy. B1 avitaminosis may result from increased demand, dietary errors, malabsorption, or excessive loss. Thiamine supplementation is used in cases of vitamin B1 deficiency or for preventative measures in situations of increased demand. Vitamin B1 can be administered enterally or parenterally (intravenously, intramuscularly, subcutaneously). The route and dose depend on the individual patient’s clinical situation. Hypersensitivity to vitamin B1 is rare and appears to be primarily associated with rapid intravenous infusion of large doses of thiamine hydrochloride over a short period (intravenous bolus). Hypersensitivity to thiamine administered by routes other than intravenous or intramuscular injection appears to be an incidental phenomenon. Thiamine should also be considered as an occupational allergen. The mechanism of thiamine hypersensitivity has not been clearly elucidated. However, considering the clinical nature and dynamics of the reaction, the most likely reaction seems to be an immediate type of hypersensitivity reaction (immunoglobulin E (IgE)-dependent), in which thiamine (but not its metabolites) acts as a hapten. Diagnosing hypersensitivity to vitamin B1 is difficult due to the lack of validated tests for additional testing. In individuals requiring thiamine supplementation who have experienced hypersensitivity to intramuscular or intravenous administration of this vitamin, switching to oral administration may be considered (provided this does not reduce treatment efficacy). This form of supplementation is usually well tolerated by individuals allergic to parenteral thiamine. However, if enteral supplementation does not guarantee the maintenance of therapeutic potential, thiamine desensitization may be considered, which seems to be an effective therapeutic method in such a clinical situation. Full article

Flight delay serves as a pivotal metric for assessing service quality in the aviation industry. Accurately estimating flight delay duration is increasingly acknowledged as a cornerstone of aviation management, with significant implications for operational efficiency, passenger satisfaction, and economic outcomes. Most existing approaches often focus on single airports or airlines and overlook the complex interdependencies within the broader aviation network, limiting their applicability for system-wide planning. To address this gap, this study proposes a novel integrated framework that combines deep learning and complex network theory to predict flight arrival delay duration from a multi-airport and multi-airline perspective. Leveraging Bayesian optimization, we fine tune hyperparameters in the XGBoost algorithm to extract critical aviation network features at both node (airports) and edge (flight routes) levels. These features, which capture structural properties such as airport congestion and route criticality, are then used as inputs for a deep kernel extreme learning machine to estimate delay duration. Numerical experiment using a high-dimensional flight dataset from the U.S. Bureau of Transportation Statistics reveals that the proposed framework achieves superior accuracy, with an average delay error of 3.36 min and a 7.8% improvement over established benchmark methods. This approach fills gaps in network-level delay prediction, and the findings of this research could provide valuable insights for the aviation administration, aiding in making informed decisions on proactive measures that contribute to the sustainable development of the aviation industry. Full article

Caffeine is widely used to enhance cognitive performance, but its efficacy may vary with the administration route and circadian timing. This study compared the acute effects of caffeine capsule ingestion and caffeine mouth rinsing on cognitive performance across morning, midday, and evening sessions in well-trained, adolescent male volleyball players. Twenty-four athletes completed three randomized, double-blind, crossover trials involving a caffeine capsule (3 mg·kg⁻¹), a caffeine mouth rinse of the same dose (expectorated), and a placebo. Cognitive performance was assessed using simple and choice reaction time tests and the Stroop task, alongside a side-effects questionnaire. Both caffeine forms improved performance versus the placebo, with the greatest enhancements occurring at midday and moderate benefits evident in the morning. Capsule ingestion produced the most consistent improvements across reaction speed and executive control, whereas mouth rinsing elicited smaller, task-dependent effects, particularly at midday. No consistent or practically relevant benefits were observed for either caffeine condition in the evening, when cognitive performance was naturally highest. Side effects were mild and infrequent, with occasional headaches after capsule ingestion. These findings indicate that caffeine capsules most effectively enhance cognitive performance when baseline alertness is suboptimal, while caffeine mouth rinsing represents a practical ingestion-free alternative with moderate efficacy. Full article