Uterine cancer (UC) is the most common malignancy of the female reproductive system worldwide, with a continuously rising incidence, posing a significant public health challenge. This study systematically evaluated the burden of UC using the Global Burden of Disease (GBD) database. Combined with data from the National Health and Nutrition Examination Survey (NHANES), machine learning (ML) methods - including the Boruta algorithm and 11 predictive models - were employed to identify key risk factors associated with UC. Furthermore, a bibliometric analysis of 2041 relevant publications from 2005 to 2025 in the Web of Science Core Collection was conducted to reveal research hotspots and developmental trends in the field. In 2023, the cumulative incidence and prevalence of UC were highest in the United States, Russia, Italy, and Portugal. The age group 65 to 69 years exhibited the highest incidence and disability-adjusted life years. LightGBM (AUC train set: 1, AUC test set: 0.929), XGBoost (AUC train set: 1, AUC test set: 0.952), and random forest (AUC train set: 1, AUC test set: 0.964) performed well, which identified critical risk factors including molybdenum, triglycerides, cadmium, age, lead, total cholesterol, cobalt, hypertension, uric acid, and mean arterial pressure. Bibliometric analysis indicated that the United States leads in research output, with keywords such as "multicenter," "endometrial neoplasms," "disparity," "race," and "guideline" representing current research frontiers. This study provides a comprehensive assessment of the disease burden of UC, reveals multi‑factor risk profiles through ML, and outlines evolving research trends, offering evidence‑based insights for targeted prevention strategies, clinical intervention optimization, and resource allocation.
Chronic obstructive pulmonary disease (COPD) represents a major global health burden, largely attributable to tobacco exposure, including emerging patterns such as early initiation and dual use with electronic cigarettes. Early detection through spirometry in primary care remains suboptimal, potentially limiting timely identification of early disease stages, including Pre-COPD and Preserved Ratio Impaired Spirometry (PRISm). This study aimed to assess whether the implementation of a structured, spirometry-based COPD clinic within primary care networks (Aggregazioni Funzionali Territoriali, AFTs) may be associated with improved diagnostic appropriateness, more consistent therapeutic management, and more efficient use of healthcare resources. We conducted a retrospective observational analysis of routinely collected clinical data from approximately 30,000 patients across three AFTs in the Campania Region (Italy), each including about 10,000 individuals. One AFT was equipped with a dedicated respiratory clinic providing in-house spirometry performed by trained personnel, while the other two followed standard care pathways without structured respiratory services. Key variables included spirometry utilization, diagnostic confirmation of COPD, patterns of care, and selected indicators of healthcare use. In the two standard AFTs, COPD diagnoses were not supported by spirometric confirmation in approximately 65% and 70% of cases, respectively. In contrast, the AFT with a dedicated clinic showed a substantially higher use of spirometry (approximately 80% vs. 30-35%), predominantly performed within the primary care setting. This organizational model was associated with improved alignment between diagnosis and objective testing, and with indicators suggestive of better therapeutic adherence and more appropriate use of secondary care services. The integration of structured, spirometry-enabled respiratory services within primary care networks may contribute to more appropriate COPD diagnosis and management. While the availability of spirometry alone is insufficient, organizational models that incorporate trained personnel, standardized procedures, and coordinated care pathways could represent a potentially effective approach to addressing under- and misdiagnosis in COPD.
Active surveillance of cervical intraepithelial neoplasia grade 2 (CIN2) is increasingly adopted to reduce the risk of overtreatment, particularly in young women. However, the appropriateness of this approach remains debated, especially in light of evidence suggesting an increased long-term risk of cervical cancer in certain subpopulations. A retrospective cohort study was conducted on HPV-positive women with histologically confirmed p16-positive CIN2 managed with active surveillance. Medium-term clinical outcomes included regression, persistence, and progression to CIN3 or higher during follow-up. Survival analyses (Kaplan-Meier), Cox regression models, and Modified Poisson regression models with robust standard errors were performed to identify independent factors associated with progression. The mean follow-up was 27 months, with a maximum follow-up of 48 months. During the observation period, spontaneous regression was observed in 61% of cases, while 25.5% of patients showed progression and 13.8% persistence of the lesion. Regression occurred predominantly within the first 24-36 months, followed by a plateau in the curves. Progression was significantly associated with high-grade cytology (ASC-H/HSIL) and HPV16/18 positivity. In multivariable models, both factors remained independent factors associated with progression, whereas non-16/18 HPV genotypes and low-grade cytology were associated with a higher likelihood of regression. Although this study does not allow for a direct assessment of long-term cancer risk, the identification of early factors associated with persistence and progression provides clinically relevant insights into CIN2 profiles associated with an increased risk of progression within the observed follow-up period. These findings suggest that active surveillance of CIN2 may not be equally appropriate across all patient subgroups and requires careful risk stratification based on virological and cytological factors to support selective and clinically sound management.
Heritage is a living process-our legacy from the past, including social and ecological systems, within which we live today and pass on to future generations. Assessing climate change risks is essential for understanding how hazards, exposure, vulnerability, and responses interact to produce impacts for heritage. These interactions operate across diverse spatial and temporal scales. Current approaches to risk assessment evaluate the scales of climate data, heritage processes, and governance decisions implicitly, leading to misalignments that limit how effectively risks are identified, interpreted, and managed. Here we show that these misalignments arise when observational, measurement, and operational scales diverge. The observational scale defines the boundary and timeframe of a risk assessment. The measurement scale concerns the resolutions of data used, from global climate models to site-level monitoring. The operational scale represents those of underlying processes, from short-term flooding to multi-decadal maintenance and knowledge transmission. When these scales diverge, mismatches obscure how climate change risks are understood and managed. These mismatches reveal not only technical challenges but also deeper divides between knowledge systems, institutional actions, and governance structures. A scale-aware approach can help translate risk assessments into effective actions, aligning data, processes, and responsibilities.
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Body schema is shaped by sensorimotor interactions with the environment and supports coordinated movement. Measures for quantifying body schema are limited, and little is known about how lifestyle factors influence body schema organization. We propose Shannon Entropy of digital drawing strokes as a quantitative data-driven measure of body schema complexity. Forty-four adults drew themselves (body drawing) then a flower (control drawing), and completed the International Physical Activity (PA) Questionnaire. Local Shannon Entropy was computed using a block-based, data-driven algorithm and residualized for stroke length. Body drawings showed lower entropy than control drawings, offering preliminary evidence that stroke entropy may capture body-specific differences in representational complexity, meriting further investigation with counterbalanced designs. Residual entropy decreased with age, suggesting stabilization of body schema in older adults. PA was evaluated via standard Physical Activity Levels (PAL) and data-driven tertiles. PALs showed no significant effects, likely due to sample disproportion. Tertile analysis revealed a significant interaction between PA and age: more physically active participants maintained stable drawing entropy with age, suggesting PA may be associated with age-related reductions in body representation. Findings suggest stroke entropy as an interesting method for future validation studies examining the role of PA in maintaining body representations across adulthood.
Extracorporeal membrane oxygenation (ECMO) has become a vital life-support tool in critical care, particularly during the COVID-19 pandemic. The rapid growth of ECMO research necessitates bibliometric analysis to identify trends, key contributors, and obstacles, including concerns regarding scientific integrity, such as retractions. A bibliometric analysis was conducted using the Scopus database (search date: August 25, 2025), with the phrase "extracorporeal membrane oxygenation" searched in the title, abstract, or keywords. All English-language publications from 1958 and 2025 were covered. Data on publication trends, prominent countries, institutions, journals, authors, keywords, and citation/Altmetric Attention Scores were obtained. Retractions were detected using standardized queries on PubMed, and data on publication year, retraction year, country, and reasons were obtained. A total of 26,786 ECMO-related publications were examined. The number of publications showed a significant upward trend (P < 0.001), peaking in 2022 with 240 articles. The United States was the leading country (n = 11,261), followed by Germany (n = 2,349), Italy (n = 1,756), China (n = 1,660), and the United Kingdom (n = 1,642). The ASAIO Journal was the most prolific source (n = 1,204). Harvard Medical School (n = 585) ranked first among institutions. Coronavirus disease 2019 (COVID-19)-related papers dominated citation and altmetric impact, with the 2020 JAMA Wuhan cohort publication receiving the most citations (n = 17,423). Between 2012 and 2024, nine ECMO-related articles were retracted. This analysis highlights the significant global growth of ECMO research, demonstrating considerable academic and social impact, particularly during the COVID-19 pandemic. The results offer valuable insights into publication trends, major contributors, and research visibility, potentially informing future research and partnerships in this field.
Fanconi anemia is a rare genomic instability syndrome associated with congenital abnormalities and cancer predisposition. These alterations are mainly due to deficiencies in DNA repair mechanisms. The Fanconi anemia pathway is evolutionarily conserved, allowing functional studies in model organisms like Caenorhabditis elegans, where it promotes and executes error-free homologous-recombination over the mutagenic non-homologous-end-joining pathway; fcd-2 (FANCD2 ortholog) plays a key role in this regulation to preserve genome stability. In this study, we report that the choice of DNA repair pathway for resolving double-strand breaks is influenced by absence of the RAD-51 long isoform, a key component of the Fanconi anemia pathway that plays a central role in homologous strand exchange during recombination. In C. elegans, which is predicted to encode three RAD-51 isoforms, we find that loss of RAD-51 isoform A enhances homologous recombination efficiency. Additionally, RAD-51 isoform A depletion decreases developmental and meiotic defects in fcd-2 mutants as well as reduces chromosome aggregation in fcd-2-deficient germ cells. Together, these findings reveal a novel role for RAD-51 C. elegans, suggesting that the pattern of RAD-51 isoform expression modulates the balance between homologous recombination and non-homologous-end-joining, thereby preserving genome stability.
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Deep Brain Stimulation (DBS) is an established treatment for advanced Parkinson's disease (PD), yet registry-based data from developing countries remain limited. This study reports the establishment and feasibility of the Iranian Deep Brain Stimulation Registry for Parkinson's Disease (IDBSR-PD). We conducted a single-center feasibility study at the Research Center for Neuromodulation and Pain, including all PD patients undergoing DBS implantation since 2014. Primary feasibility outcomes included patient enrollment coverage, follow-up adherence, data completeness, multidisciplinary implementation, and the sustainability of technical infrastructure. Secondary outcomes included descriptive patient characteristics. Only descriptive statistics were performed; no hypothesis testing or longitudinal outcome analyses were conducted. A total of 208 patients were enrolled (65.4% male; mean age 58.4 ± 10.2 years). Enrollment increased progressively over time, peaking in 2024 (n = 41). Patients were referred from multiple provinces across Iran. Data validation mechanisms and regular surveillance ensured acceptable data completeness. The IDBSR-PD demonstrates the feasibility and sustainability of a web-based DBS registry in a developing country. These findings confirm the viability of structured data collection and provide a foundation for future multicenter and longitudinal outcome research.
Miroslav Papiz is remembered.
Cancer continues to be the primary cause of death despite significant progress in medicine, and finding effective therapies remains a challenge. New treatments are needed to minimize the harmful effects on the body and increase the selectivity of drugs. These therapies must also overcome cancer cell resistance and prevent metastasis. Metal-based drugs are becoming increasingly crucial for treating tumors, and copper ion-based systems and nanoparticles have been identified as having unique properties and anticancer potential. Given the key role exerted by Cu in the etiology, severity, and progression of cancer diseases, it could be a vulnerable point to target for hindering cancer development. After thoroughly analyzing what is known about the mechanism of cancer cell death through a Cu-dependent mechanism, known as cuproptosis, and its potential links with ferroptosis, we report some systems that, when coadministered with copper ions, can trigger this type of cell death. This study investigates the effectiveness of cuproptosis inducers against various types of cancers. Are these cuproptosis inducers effective in combating cancer? What limitations or disadvantages might be associated with their use? This article aims to answer these questions based on the current knowledge in this evolving area of cancer research.
Atrial fibrillation and atrial flutter (AF/AFL) are major contributors to ischemic stroke, heart failure, disability, and mortality worldwide. To provide a descriptive global analysis of AF/AFL burden using GBD 2023 estimates, with emphasis on incidence, prevalence, deaths, disability-adjusted life years (DALYs), and their distribution by sex, age, and socio-demographic index (SDI). We performed a descriptive epidemiological analysis using direct extractions from the Institute for Health Metrics and Evaluation Global Burden of Disease 2023 Results Tool for the cause category "atrial fibrillation and atrial flutter." We assessed incidence, prevalence, deaths, DALYs, and selected rates globally and according to sex, quinquennial age group, and SDI. Temporal trends were examined using available historical series, and the 2023 burden was summarized across major demographic and SDI strata. In 2023, AF/AFL accounted globally for 5,021,980 incident cases, 59,045,058 prevalent cases, 9,265,726 DALYs, and 377,258 deaths. Compared with 1990, the global burden increased substantially in absolute terms. It was substantially higher in older adults, with the highest observed counts of incident and prevalent cases in the 70-74-year age group, the highest DALY counts in the 80-84-year age group, and the highest death counts in the 85-89-year age group. Men accounted for more incident and prevalent cases in absolute terms, whereas women accounted for more deaths and DALYs; age-standardized rates indicated higher male incidence, prevalence, and DALYs, but essentially equivalent mortality between sexes. High-SDI settings carried the largest absolute burden and the highest rates across all major metrics. Overall, the findings indicate a marked expansion in the global AF/AFL burden, with important heterogeneity by age, sex, and socio-demographic development. AF/AFL remains a major and growing global public health challenge. The burden is increasingly concentrated in older populations, shows persistent sex differences, and remains greater in high-SDI settings. These findings reinforce the relevance of AF/AFL to stroke prevention, health system planning, and long-term cardiovascular care worldwide.
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The hormone vasopressin (AVP) controls renal water reabsorption by modulating the expression and trafficking of the water channel aquaporin-2 (AQP2) through the activation of the cAMP/PKA signal transduction pathway. Previous studies revealed that Olive Leaf Extract (OLE) counteracts the vasopressin-dependent AQP2 functions by stimulating the calcium-sensing receptor (CaSR). Here, the biological activities of p-Coumaric acid, a selective polyphenol in OLE, were investigated. Stimulation of renal collecting duct MCD4 cells with p-Coumaric acid at a concentration of 1 nM caused a significant intracellular calcium release. NPS-2143, a selective CaSR antagonist, abolished this increase. Molecular docking analysis revealed that p-Coumaric acid can form binding interactions with the binding pocket of Tecalcet, a known CaSR activator, likely suggesting that p-Coumaric acid may stimulate the CaSR. Confocal analysis and immunoblotting experiments showed that p-Coumaric acid impaired the DDAVP-dependent membrane expression of AQP2 and the consequent increase of the osmotic water permeability (Pf). Additionally, Fluorescence Resonance Energy Transfer (FRET) experiments demonstrated that p-Coumaric acid prevented the DDAVP-induced cAMP generation, consequently attenuating the AQP2 phosphorylation at serine 256. Together, these findings suggest that p-Coumaric acid may antagonize the effects of vasopressin, possibly by binding to and stimulating the CaSR.
The differentiation status of thyroid cancer (THCA) is closely associated with prognosis; however, the underlying molecular regulatory mechanisms remain incompletely understood. This study aimed to identify hub genes associated with THCA differentiation based on progression-free interval (PFI)-related genes and to explore the underlying mechanisms. The common database datasets were integrated to identify differentially expressed genes, and univariate Cox regression analysis was performed to determine PFI-related genes. Molecular subtypes were constructed using consensus clustering based on PFI-related genes, and the differentiation status of different subtypes was evaluated. Hub genes were subsequently identified using least absolute shrinkage and selection operator (Lasso) regression and multivariate Cox regression analyses. In vitro experiments were conducted to validate the role of the hub gene in regulating dedifferentiation. Two PFI-related molecular subtypes were identified in this study. Cluster 2 exhibited a higher thyroid differentiation score (TDS), more favorable PFI outcomes, and metabolic features predominantly characterized by oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). ITM2A was identified as a hub gene. High expression of ITM2A promoted differentiation of THCA cells, suppressed malignant characteristics, and drove a metabolic shift from glycolysis toward FAO. In addition, ITM2A counteracted TGF-β-induced dedifferentiation and epithelial-mesenchymal transition, and enhanced antigen presentation as well as PD-L1-dependent T-cell responses. ITM2A maintained the differentiated state of THCA through metabolic reprogramming and shaped an immunologically favorable microenvironment, suggesting that it may serve as a potential biomarker for prognosis prediction and a therapeutic target for optimizing immunotherapy strategies.
To evaluate whether recent commercial evolutions of universal adhesives improve dentin bond strength after aging and interfacial characteristics compared with predecessor formulations and a multistep reference. Three updated universal adhesives (AFB-00, Scotchbond Universal Plus, and Clearfil Universal Quick 2) and their respective predecessors (G-Premio Bond, Scotchbond Universal, and Clearfil Universal Quick) were evaluated. OptiBond FL served as a multistep etch-and-rinse reference. One hundred eighty human molars were prepared to expose mid-coronal dentin surfaces and assigned to 15 groups (n = 12 per group). Adhesives were applied in self-etch (SE1) or etch-and-rinse (ER2) modes according to the applicable manufacturers' instructions. The macroshear bond strength (SBS) was measured after 6 months of storage in water. Failure modes were recorded, and representative samples were analyzed using scanning electron microscopy (SEM) to assess the interfacial morphology and adhesive layer thickness. The data were analyzed using one-way ANOVA and Tukey's post hoc test (α = 0.05). After aging, SBS differed among protocols. AFB-00 and Clearfil Universal Quick 2 performed comparably to their predecessors, whereas Scotchbond Universal Plus showed a significantly lower SBS than Scotchbond Universal. Most universal adhesive protocols showed SBS values comparable or superior to the multistep reference, except Clearfil Universal Quick and Clearfil Universal Quick 2 in self-etch mode. SEM revealed strategy-dependent interfacial patterns and marked differences in adhesive film thickness, particularly for AFB-00 without air drying. Recent commercial evolutions of universal adhesives did not systematically improve dentin bond strength after aging. The observed modifications primarily affected the interfacial morphology and adhesive thickness rather than demonstrating consistently higher SBS values after aging. For clinicians, these findings suggest that commercial evolutions of universal adhesives may reflect distinct formulation strategies rather than incremental improvements, and that the performance of updated materials cannot be assumed from that of their predecessors.
Klebsiella spp. are pathobionts associated with acute infections, including pneumonia and infections in the urinary tract and bloodstream, often acquired in health-care settings. They represent a global threat owing to the prevalence of multidrug-resistant strains. Moreover, Klebsiella spp., similarly to other members of the human gut microbiota, can contribute to the pathogenesis of non-communicable disorders. In this Review, we describe the taxonomical and molecular characteristics of the Klebsiella genus, as well as its epidemiology and impact as an infectious agent. We also review current evidence that associates Klebsiella spp. with different non-communicable disorders, including chronic inflammatory and metabolic disorders and cancer. We discuss different approaches to target Klebsiella spp., including tailored antibiotics, faecal microbiota transplantation, live biotherapeutic products and bacteriophages. Finally, we discuss the importance of preventative measures, such as epidemiological surveillance, infection control practices and lifestyle interventions, to reduce the spread of Klebsiella spp. in health-care settings and the broader community.