Search Results (6,716)

Background: Inflammation of unknown origin (IUO) represents a persistent clinical challenge, often requiring extensive diagnostic efforts despite nonspecific inflammatory findings such as elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The complexity and heterogeneity of its etiologies—including infections, malignancies, and rheumatologic diseases—make timely and accurate diagnosis essential to avoid unnecessary interventions or treatment delays. Objective: This study aimed to evaluate the potential of machine learning (ML)-based models in distinguishing the major etiologic subgroups of IUO and to explore their value as clinical decision support tools. Methods: We retrospectively analyzed 300 IUO patients hospitalized between January 2023 and December 2024. Four binary one-vs-rest Linear Discriminant Analysis (LDA) models were first developed to independently classify infection, malignancy, rheumatologic disease, and undiagnosed cases using clinical and laboratory parameters. In addition, a multiclass LDA framework was constructed to simultaneously differentiate all four diagnostic groups. Each model was evaluated across 10 independent runs using standard performance metrics, including accuracy, sensitivity, specificity, precision, F1 score, and negative predictive value (NPV). Results: The malignancy model achieved the highest performance, with an accuracy of 91.7% and specificity of 0.96. The infection model demonstrated high specificity (0.88) and NPV (0.86), supporting its role in ruling out infection despite lower sensitivity (0.71). The rheumatologic model showed high sensitivity (0.81) but lower specificity (0.73), reflecting the clinical heterogeneity of autoimmune conditions. The undiagnosed model achieved very high accuracy (96.7%) and specificity (0.98) but limited precision and recall (0.50 each). The multiclass LDA framework reached an overall accuracy of 73.3% (mean 66%) with robust specificity (0.90) and NPV (0.89). Conclusions: ML-based LDA models demonstrated strong potential to support the diagnostic evaluation of IUO. While malignancy and infection could be predicted with high accuracy, rheumatologic diseases required integration of additional serological and clinical data. These models should be viewed not as stand-alone diagnostic tools but as complementary decision-support systems. Prospective multicenter studies are warranted to externally validate and refine these approaches for broader clinical application. Full article

Background/Objectives: Appendiceal cancer (AC) is a rare and understudied malignancy with limited genomic data available to guide clinical interventions. Historically treated as a subtype of colorectal cancer, AC is now recognized as a distinct disease with unique histologic subtypes and molecular features. This review aims to consolidate current genomic data across AC subtypes and explore the clinical relevance of recurrent mutations. Methods: A systematic literature review was performed in accordance with general Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines. Using search engines such as PubMed and Web of Science, we selected studies based on relevance to AC genomics using search terms such as “appendix cancer”, “appendiceal cancer”, “pseudomyxoma peritonei”, “sequencing”, “mutation”, and “genotype”. Results: AC comprises five major histologic subtypes—appendiceal neuroendocrine neoplasms (ANENs), mucinous appendiceal neoplasms (MANs), goblet cell adenocarcinomas (GCAs), colonic-type adenocarcinomas (CTAs) and signet ring cell adenocarcinomas (SRCs)—each with unique clinical behaviors and mutational profiles. Low-grade tumors, such as ANENs and MANs, frequently harbor KRAS and GNAS mutations, while high-grade subtypes, such as CTAs and SRCs, are enriched for TP53, APC, and SMAD gene alterations. GCA tumors exhibit a distinct mutational spectrum involving chromatin remodeling genes such as ARID1A and KMT2D. Compared to colorectal cancer, AC demonstrates lower frequencies of APC and TP53 mutations and a higher prevalence of GNAS mutations, consistent with a pathological divergence from CRC. Conclusions: The genomic heterogeneity of AC is commensurate with its histological complexity and has important implications for diagnosis, prognosis and treatment. While certain actionable mutations are present in a subset of tumors, large-scale genomic characterization efforts and development of subtype-specific models will be essential for advancing precision medicine in AC. Full article

The brain–bone axis has garnered increasing attention over the years, leading to numerous studies that have unraveled the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This review explores this profound relationship, examining the complex mechanisms that regulate it, the key players involved, and the clinical implications of its dysfunction in various pathological situations affecting the CNS and skeletal system. Ultimately, it emphasizes the potential of ongoing research to develop diagnostic tools, therapeutic interventions, and preventive strategies aimed at enhancing skeletal and neurological health. Full article

Background/Objectives: Understanding prescribing patterns for type 2 diabetes mellitus, a complex condition affecting over 10% of the global adult population, can optimise prescribing practices, guide policymakers in promoting evidence-based medicine, and help tailor first-line treatments to individual characteristics or specific subgroups, improving patient outcomes. This study aimed to identify factors influencing the prescription and non-prescription of metformin, the recommended first-line therapy in Western guidelines, and to evaluate whether these prescribing patterns align with evidence-based recommendations. It also explores factors associated with initial combination therapy, a more recent and controversial approach compared to stepwise therapy. Methods: We conducted a systematic search in PubMed, Scopus, and Web of Science on 25 August 2023, without language or time restrictions, to identify observational analytical studies assessing factors associated with the initiation of metformin or combination therapy in adults with type 2 diabetes mellitus who were naïve to antidiabetic medications. Studies involving pregnant or breastfeeding women were excluded. A narrative synthesis was conducted. Study quality was assessed using the Joanna Briggs Institute critical appraisal checklists (PROSPERO registration number CRD42023438313). Results: Thirty studies were included, evaluating 105 variables, most of which (62%) were assessed in one study. The 25 variables using combination therapy as the outcome were mostly (72%) evaluated also in one study. Initial metformin prescription was strongly and positively associated with younger age, lower glycated haemoglobin levels, higher body mass index, and absence of renal impairment. Initial combination therapy was associated with higher HbA1c levels and a lower burden of comorbidities. Findings also highlighted a discrepancy between clinical practice and evidence-based recommendations. However, concerns were raised regarding both the internal and external validity of the included studies. Conclusions: Our systematic review, which offers insights into real-world clinical practices, indicated that there is a misalignment between clinical practices and evidence-based recommendations, supporting the need for interventions in this field. Full article

Alzheimer’s disease (AD) requires early and accurate identification of affected brain regions, which can be achieved through the detection of specific biomarkers to enable timely intervention. Carbon nanomaterials (CNMs), including graphene derivatives, carbon nanotubes, graphitic carbon nitride, carbon black, fullerenes, and carbon dots, offer high conductivity, large electroactive surface area, and versatile surface chemistry that enhance biosensor performance. While such properties benefit a wide range of transduction principles (e.g., electrochemical, optical, and plasmonic), this review focuses on their role in electrochemical biosensors. This review summarizes CNM-based electrochemical platforms reported from 2020 to mid-2025, employing aptamers, antibodies, and molecularly imprinted polymers for AD biomarker detection. Covered topics include fabrication strategies, transduction formats, analytical performance in complex matrices, and validation. Reported devices achieve limits of detection from the femtomolar to picogram per milliliter range, with linear ranges typically spanning 2–3 orders of magnitude (e.g., from femtomolar to picomolar, or from picogram to nanogram per milliliter levels). They exhibit high selectivity against common interferents such as BSA, glucose, uric acid, ascorbic acid, dopamine, and non-target peptides, along with growing capabilities for multiplexing and portable operation. Remaining challenges include complex fabrication, limited long-term stability and reproducibility data, scarce clinical cohort testing, and sustainability issues. Opportunities for scalable production and integration into point-of-care workflows are outlined. Full article

The introduction of the European Union (EU) Joint Clinical Assessment (JCA) under Regulation (EU) 2021/2282 marks a transformative step in harmonizing health technology assessments (HTAs) across EU member states. This article explores the implications of JCA, particularly in oncology, for member states who utilize cost-effectiveness (CE) analysis and health technology developers (HTDs) who produce this evidence. The JCA framework attempts to standardise the assessment of relative clinical effectiveness and safety across the EU to input into national appraisals. Importantly, it excludes economic evaluations that may be required nationally, necessitating HTDs to align their CE models with the JCA PICO (Population/Intervention/Comparator/Outcome) parameters outlined by member states. This article discusses the challenges and opportunities for aligning JCA and CE modelling outcomes, contrasting evidence requirements between JCA and CE frameworks. It highlights the potential increase in complexity due to the diverse comparators in PICO surveys, necessitating the use of indirect comparison methodologies. It further underscores the importance of early communication between HTDs and HTA bodies to ensure timely, relevant, and pragmatic decision-making. By sharing national PICOs upfront to support national evidence generation, the JCA framework’s potential to aid high-quality decision-making and improve patient access to innovative medicines can be maximised. Full article

Scene Text Recognition (STR) faces significant challenges under complex degradation conditions, such as distortion, occlusion, and semantic ambiguity. Most existing methods rely heavily on language priors for correction, but effectively constructing language rules remains a complex problem. This paper addresses two key challenges: (1) The over-correction behavior of language models, particularly on semantically deficient input, can result in both recognition errors and loss of critical information. (2) Character misalignment in visual features, which affects recognition accuracy. To address these problems, we propose a Deformable-Alignment-based Dual Correction Mechanism (DADCM) for STR. Our method includes the following key components: (1) We propose a visually guided and language-assisted correction strategy. A dynamic confidence threshold is used to control the degree of language model intervention. (2) We designed a visual backbone network called SCRTNet. The net enhances key text regions through a channel attention module (SENet) and applies deformable convolution (DCNv4) in deep layers to better model distorted or curved text. (3) We propose a deformable alignment module (DAM). The module combines Gumbel-Softmax-based anchor sampling and geometry-aware self-attention to improve character alignment. Experiments on multiple benchmark datasets demonstrate the superiority of our approach. Especially on the Union14M-Benchmark, where the recognition accuracy surpasses previous methods by 1.1%, 1.6%, 3.0%, and 1.3% on the Curved, Multi-Oriented, Contextless, and General subsets, respectively. Full article

Background: Intracranial aneurysm (IA) rupture is a life-threatening cerebrovascular event with a mortality rate of up to 40%, affecting approximately 500,000 people globally each year. Although environmental pollutants such as 2,2′,4,4′-tetrabromodiphenyl ether (PBDE-47) have been implicated in the pathogenesis of IA, the causal relationship and underlying mechanisms remain unclear. This study aims to systematically explore the potential causal role of PBDE-47 in the development of IA by integrating multi-omics approaches. Methods: We utilized the UK Biobank Drug Proteomics Project (UKB-PPP) genome-wide association study (GWAS) data, including 2940 plasma proteins and 1400 metabolites, along with IA genetic data from 456,348 individuals, to perform a two-sample Mendelian randomization (MR) analysis. Instrumental variables were selected based on genome-wide significance (p < 5 × 10⁻⁸) or suggestive thresholds (p < 5 × 10⁻⁵). Analytical methods included inverse variance weighting (IVW), MR-Egger, weighted median, MR-PRESSO, and Steiger filtering for sensitivity analysis. Molecular docking and 100-nanosecond molecular dynamics simulations were used to evaluate interactions between PBDE-47 and proteins. Mediation analysis assessed the roles of plasma metabolites and miRNAs, and SMR-HEIDI tests were used to verify causal relationships. Results: MR analysis identified 93 plasma proteins potentially causally associated with IA, including 53 protective factors and 40 risk factors. By integrating PBDE-47 targets, IA-related genes, and metabolite-related genes, we identified 15 hub genes. Molecular docking revealed potential binding between PBDE-47 and F2R (binding energy: −5.516 kcal/mol), and SMR-HEIDI testing supported F2R as a potential causal risk factor for IA. Molecular dynamics simulations indicated the stability of the complex structure. Mediation analysis suggested that F2R may influence IA risk through eight plasma metabolites, and miR-130b-3p may indirectly promote IA development by upregulating F2R. Conclusions: Our findings suggest that exposure to PBDE-47 may have a potential causal relationship with IA risk, potentially mediated through the “PBDE–47–F2R–metabolite–miRNA” regulatory axis. These results provide preliminary evidence for early diagnostic biomarkers and targeted interventions for IA. The multi-omics analytical framework established in this study offers new insights into environmental determinants of neurovascular diseases, although further validation is needed to address potential limitations. Full article

Xylella fastidiosa was first detected in Portugal in 2019 in Lavandula dentata. In response, the national plant health authorities promptly established a Demarcated Zone in the affected area and implemented a series of eradication and control measures, including the systematic removal and destruction of infected and host plants. This study analyzes the economic and operational impacts of these eradication efforts in the northern region of Portugal, with a focus on Demarcated Zones such as the Porto Metropolitan Area, Sabrosa, Alijó, Baião, Mirandela, Mirandela II, and Bougado between 2019 and June 2023. During this period, about 412,500 plants were uprooted. The majority were Pteridium aquilinum (bracken fern), with 360,324 individuals (87.3%), reflecting its wide distribution and the large area affected. Olea europaea (olive tree) was the second most common species removed, with 7024 plants (1.7%), highlighting its economic relevance. Other notable species included Quercus robur (3511; 0.85%), Pelargonium graveolens (3509; 0.85%), and Rosa spp. (1106; 0.27%). Overall, destruction costs were estimated at about EUR 1.04 million, with replanting costs of roughly EUR 6.81 million. In parallel, prospection activities—conducted to detect early signs of infection and monitor disease spread—generated expenses of roughly EUR 5.94 million. While prospecting represents a significant financial investment, the results show that it is considerably more cost-effective than large-scale eradication. Prospection enables early detection and containment, preventing the widespread destruction of vegetation and minimizing disruption to agricultural production, biodiversity, and local communities. Importantly, our findings reveal a sharp decline in confirmed cases in the initial outbreak area—the Porto Demarcated Zone—from 124 cases in 2019 to just 5 in 2023, indicating the effectiveness of the eradication and monitoring measures implemented. However, the presence of 20 active Demarcated Zones across the country as of 2023 highlights the continued risk of spread and the need for sustained vigilance. The complexity of managing Xylella fastidiosa across ecologically and logistically diverse territories justifies the high costs associated with surveillance and targeted interventions. This study reinforces the strategic value of prospection as a proactive and sustainable tool for plant health management. Effective surveillance requires the integration of advanced methodologies aligned with the phenological stages of host plants and the biological cycle of vectors. Targeting high-risk locations, optimizing sample numbers, ensuring diagnostic accuracy, and maintaining continuous training for field teams are critical for improving efficiency and reducing costs. Ultimately, the findings underscore the need to refine and adapt monitoring and eradication strategies to contain the pathogen, safeguard agricultural systems, and prevent Xylella fastidiosa from becoming endemic in Portugal. Full article

The NewEcoSmart project addresses the need to foster inclusive green and digital transitions in rural habitat sectors by systematically assessing local socio-technical readiness and tailoring capacity-building interventions. We adapted the validated SCIROCCO Exchange Maturity Self-Assessment Tool—selecting eight dimensions relevant to environmental, technological and social innovation—and conducted a two-phase evaluation across three pilot sites in Italy, Portugal and Spain. Phase 1 mapped stakeholder evidence against predefined criteria; Phase 2 engaged local actors (45+ adults, SMEs and micro-firms) in a self-assessment to determine digital, green and entrepreneurial skill gaps. For each domain of the SCIROCCO Tool, local actors can assign a minimum of 0 to a maximum of 5. The final score of the SCIROCCO tool can be a minimum of 0 to a maximum of 40. Quantitative maturity scores revealed heterogeneous profiles (Pacentro and Majella Madre = 5; Yecla = 10; Adelo Area = 23), underscoring diverse ecosystem strengths and limitations. A qualitative analysis, framed by Smart Healthy Age-Friendly Environments (SHAFE) domains, identified emergent training needs that are clustered at three levels: MACRO (community-wide awareness and engagement), MESO (decision-maker capacity for strategic planning and governance) and MICRO (industry-specific practical skills). The adapted SCIROCCO tool effectively proposes the assessment of socio-technical maturity in rural contexts and guides the design of a modular, multi-layered training framework. These findings support the need for scalable deployment of interventions that are targeted to the maturity of the local ecosystems to accelerate innovations through equitable green and digital transformations in complex socio-cultural settings. Full article

Cardiovascular diseases (CVDs) are increasingly being defined not only in terms of metabolic or purely vascular disorders, but also as complex immunometabolic disorders. One of the most groundbreaking discoveries in recent years is the role of neutrophil extracellular networks (NETs/NENs) as a key link between chronic vascular wall inflammation and thrombotic processes. In this article, we present a synthetic overview of the latest data on the biology of NETs/NENs and their impact on the development of atherosclerosis, endothelial dysfunction, and the mechanisms of immunothrombosis. We highlight how these structures contribute to the weakening of atherosclerotic plaque stability, impaired endothelial barrier integrity, platelet activation, and the initiation of the coagulation cascade. We also discuss the modulating role of classic risk factors such as hypertension, dyslipidemia, and exposure to tobacco smoke, which may increase the formation or hinder the elimination of NETs/NENs. We also focus on the practical application of this knowledge: we present biomarkers associated with the presence of NETs/NENs (cfDNA, MPO–DNA complexes, CitH3, NE), which may be useful in diagnostics and risk stratification, and we discuss innovative therapeutic strategies. In addition to classic methods for indirectly inhibiting NET/NEN formation (antiplatelet, anti-inflammatory, and immunometabolic agents), we present experimental approaches aimed at their neutralization and removal (e.g., DNase I, elastase, and myeloperoxidase inhibitors). We pay particular attention to the context of cardiac and cardiac surgical procedures (Percutaneous Coronary Intervention-PCI, coronary artery bypass grafting-CABG), where rapid NET/NEN bursts can increase the risk of acute thrombotic complications. The overall evidence indicates that NETs/NENs represent an innovative and promising research and therapeutic target, allowing us to view cardiovascular diseases in a new light—as a dynamic interaction of inflammatory, atherosclerotic, and thrombotic processes. This opens up new possibilities in diagnostics, combination treatment and personalisation of therapy, although further research and standardization of detection methods remain necessary. Full article

Understanding public service performance remains a persistent challenge, particularly when services are delivered through complex interorganizational networks. This difficulty is amplified in contexts addressing wicked problems such as homelessness, where needs are multifaceted, solutions are interdependent, and outcomes are hard to measure. In the United States, the Continuum of Care (CoC) system represents a federally mandated and HUD-funded network model designed to coordinate local responses to homelessness through collaborative governance. Despite its standardized structure and federal oversight, CoC’s performance varies significantly across regions. This study investigates the conditions that influence the CoC network’s performance, focusing on the delivery of Permanent Supportive Housing (PSH) services, a critical intervention for addressing chronic homelessness. It applies to a theoretical framework that combines Ansell and Gash’s collaborative governance model with Emerson et al.’s integrative framework. This approach allows for a comprehensive assessment of internal network factors such as board size, nonprofit leadership, and federal funding, as well as external system contexts including political orientation, income levels, and rent affordability. Drawing on regression analysis of data from 343 CoCs across the United States, the study shows that federal funding, favorable political climates, and larger board size are significant predictors of PSH availability, while nonprofit leadership and income levels are not. Findings highlight the importance of aligning internal governance and external context to improve network outcomes. Full article

Obesity is a significant public health crisis with increasing rates worldwide. Chronic kidney disease (CKD) has also emerged as a leading cause of death worldwide. This review explores the intricate connection between obesity and CKD, discussing the underlying biological mechanisms, clinical consequences of their coexistence, and strategies for evidence-based management. We conducted an extensive literature review of peer-reviewed studies examining obesity–CKD relationships, including epidemiological studies, mechanistic research, clinical trials, and meta-analyses from major medical databases. Obesity serves as both a risk factor for de novo CKD development and a paradoxical protective factor observed in some studies of advanced CKD, particularly in dialysis populations. This review synthesizes current evidence on obesity-related glomerulopathy, the impact of obesity on CKD progression to end-stage renal disease, and the phenomenon known as the “obesity paradox”. Management approaches, including lifestyle interventions, pharmacological treatments, and bariatric surgery, show varying efficacy across different CKD stages. The multifaceted relationship between obesity and CKD necessitates individualized, multidisciplinary approaches to optimize patient outcomes while addressing the unique challenges presented by this complex comorbidity. Early intervention in obese patients may prevent CKD development, while careful management is required in advanced CKD stages where the obesity paradox may confer survival benefits. Full article

Background/Objectives: End-of-life (EoL) experiences are critically important for everyone involved, giving rise to a set of needs that extend far beyond bio-physiological aspects, to encompass the spiritual dimension as the core of human beings. Understanding the processes of spiritual awakening (SA) assists palliative care professionals in enhancing the quality of care provided to individuals with life-threatening illnesses, as well as to their families. SA is a fundamental occurrence linked to the fulfilment of our spiritual needs when facing an existential crisis, such as the proximity of death. However, its conceptual boundaries need to be clarified to provide qualified and humanized palliative care. Therefore, this study aims to identify the key attributes, antecedents, consequents, and empirical referents of SA at EoL, as well as to clarify the concept’s existing ambiguities. Methods: Walker and Avant’s eight-step concept analysis was used. A literature search was conducted in May 2025 across three databases (PubMed, CINAHL and Scopus). Results: Following the review, 21 articles were included for analysis. The concept analysis revealed four main attribute domains: (1) sensory–perceptual domain; (2) affective/cognitive domain; (3) relational domain; and (4) transcendental domain. Moreover, spiritual consciousness and the existential matrix were antecedents to this concept; revaluation of beliefs, finding spiritual serenity and inner freedom, fostering spiritual growth, and the desire to leave a legacy were its consequences. Conclusions: The concept of SA at the EoL reveals itself to be a complex and multifactorial phenomenon, with a profound impact on a person’s confrontation with finitude. Recognizing and integrating SA into palliative care allows for a more comprehensive understanding of human consciousness. To deal with SA experiences in healthcare settings, a multifaceted approach is needed. This encompasses acknowledging spirituality as a determinant of health, including spiritual care in standard practice, and offering education and training on spiritual care competence for healthcare practitioners. Further transdisciplinary research should be undertaken to explore SA phenomenological variations, guide clinical interventions, and evaluate SA impacts on spiritual well-being and spiritual growth. Full article

Background: The majority of parotid gland tumors are benign, while malignant forms are uncommon, affecting fewer than 1 in 100,000 individuals. The main challenge resides in the histopathological complexity and the clinical overlap between benign and malignant parotid tumors, which frequently results in misdiagnosis. Aim: The objective of this research was to evaluate the clinical and histopathological characteristics of parotid gland tumors at a Romanian healthcare center. Materials and methods: A five-year retrospective study was conducted, with the inclusion criterion being the presence of complete clinical, pathological, and surgical records. Results: Of 156 patients included in the study, 67.3% were found to have benign lesions (male/female ratio 1.14:1), and there was a slight male predominance (53.3%). Partial parotidectomy was the most common surgical intervention for benign parotid tumors (59.6%), whereas total parotidectomy was predominantly indicated for malignant tumors, with facial nerve sacrifice occurring in 20% of cases to ensure complete tumor excision. Patients with benign tumors were found to be younger. Malignant tumors were commonly diagnosed at stage III (36.4%), indicative of more advanced disease at the time of diagnosis. Clinical diagnosis showed a high specificity of 96.9%, indicating high accuracy in malignancy suspicion, yet the sensitivity of 56% indicates that a significant number of malignancies were not detected during the initial evaluation. Tumor size was found to be influenced by gender and correlated with surgical methods, suggesting that patient characteristics and tumor biology may impact surgical strategy. Conclusions: This retrospective study highlights differences in gender, tumor size, and surgical approach between benign and malignant parotid gland tumors, offering valuable contributions in terms of diagnostic accuracy and treatment patterns despite a limited number of malignant cases. Full article