Search Results (65,281)

Neuropeptide Y [NPY; encoded by the NPY gene] is a widely expressed 36-amino-acid neuropeptide that regulates neuronal function, vascular regulation, and immune regulation; its role in glioblastoma [GBM] remains incompletely characterized. We performed an integrative in silico multi-scale transcriptomic analysis combining bulk RNA-sequencing of IDH-wildtype GBM [n = 169] and lower-grade glioma [n = 510] surgical resections from TCGA, normal cortical tissue from GTEx [n = 207], and four independent GEO validation cohorts of surgical GBM and non-tumor brain specimens [GSE4290, GSE50161, GSE131928 scRNA-seq of ~20,426 cells from 28 patients, and GSE194329 10X Visium spatial transcriptomics from five patients], along with survival modeling, pathway enrichment, single-cell RNA sequencing, spatial transcriptomics, and cell–cell communication analysis. NPY and its principal receptor, NPY1R, were significantly downregulated in GBM, while genes associated with hypoxia, angiogenesis, invasion, and immune suppression were upregulated. Single-cell analysis showed that NPY-axis transcript expression was elevated in neural progenitor-like populations. In contrast, hypoxia and metabolic programs were concentrated in mesenchymal tumors and stromal compartments, indicating distinct cellular contexts. Spatial analysis revealed a weak and heterogeneous relationship between NPY and hypoxia signatures, with substantial inter-patient variability and no significant global spatial cross-correlation. These findings indicate that loss of NPY signaling is a consistent feature of GBM and is associated with hypoxia-driven tumor states, while the spatial relationship between NPY and hypoxia appears weak, heterogeneous, and patient-specific. Full article

Growing up without parental care may negatively affect adolescents’ behavioral and emotional development, particularly among adolescents in conflict with the law. In a selected secure care center in the Vhembe District, limited research has explored the lived experiences and behavioral impact of growing up without parents. This study aimed to explore and describe the behavioral and emotional impact of growing up without parents among adolescents in conflict with the law in a child and adolescent secure care center in Limpopo Province. A qualitative, explorative, descriptive, and contextual research design was employed. Purposive sampling was used to recruit twelve (12) adolescents aged 15–17 years admitted to a secure care center in the Vhembe District. Data was collected through individual semi-structured interviews conducted in Xitsonga or Tshivenda, depending on participants’ preferred language. Interviews were audio-recorded, transcribed, translated into English, and analyzed using Tesch’s eight steps of data analysis. Ethical considerations and measures to ensure trustworthiness were observed throughout the study. The findings revealed that adolescents experienced low self-esteem, diminished self-confidence, early initiation of substance use, poor educational engagement, survival-oriented delinquent behavior, and feelings of neglect. These findings highlight the need for an integrated intervention approach to ensure coordinated psychosocial, educational, behavioral, and socio-economic support for this population. Full article

Protein–protein interactions (PPIs) represent a vast and largely underexplored landscape of therapeutic targets, yet their structural features—including large, flat, and dynamic interfaces—have historically limited their druggability. In this context, cyclic peptides have emerged as a powerful class of PPI modulators, sitting at the interface between biologics and small molecules, and thus garnering key advantages of both classes. Their conformational constraint enhances binding affinity, proteolytic stability and, in some instances, cell permeability, thus enabling access to intracellular targets. This review provides an updated overview of cyclic peptides as modulators of PPIs, focusing on both conceptual foundations and practical strategies for their discovery and optimization. The main discovery approaches include natural sources, de novo design based on secondary structure mimetics, high-throughput screening, and computational approaches. Integration of these complementary strategies is crucial to enhance success rates in the discovery of effective and developable cyclic peptides. Accordingly, the present review aims to provide a practical guide for researchers entering this rapidly growing field, outlining current opportunities, methodological advances, and remaining challenges in the development of cyclic peptide-based PPI modulators. Full article

Post-dissection thoracoabdominal aortic aneurysm (PD-TAAA) is a late sequela of chronic aortic dissection. Complex endovascular aneurysm repair (EVAR), including fenestrated and branched techniques (F/B-EVAR), enables aneurysm exclusion while preserving visceral perfusion; however, bridging stents are not specifically designed for PD-TAAA and are frequently used off-label. Evidence on bridging stent performance is largely derived from degenerative aneurysm cohorts, and PD-TAAA-specific data remain limited. This study evaluated outcomes of the VBX Stent Graft when used as a bridging stent during F/B-EVAR for PD-TAAA. This retrospective analysis included patients with PD-TAAA from the EMBRACE registry (ClinicalTrials.gov: NCT05143138), a multicenter, single-arm registry with retrospective and prospective components, with all outcomes core-laboratory-adjudicated. Procedural, early (thirty-day), and midterm outcomes at one and three years were assessed. The primary endpoints were all-cause mortality and freedom from target vessel instability, defined as loss of durable target vessel reconstruction. Twenty-one patients (mean age 61.5 years; range, 28–77 years) underwent F/B-EVAR with at least one VBX Stent Graft. In total, 82 visceral arteries were treated, of which 51 were bridged with a VBX Stent Graft. Technical success was 100%. Two serious adverse events occurred perioperatively, one requiring reintervention, with no thirty-day mortality or major adverse events. Freedom from all-cause mortality was 95.2% at one year and 90.5% at three years, with two deaths during follow-up. Freedom from target vessel instability at the patient level was 85.7% at both one and three years (95% CI, 62.0–95.2%). VBX Stent Grafts used as bridging stents during F/B-EVAR for PD-TAAA demonstrated high technical success, low early morbidity and mortality, and acceptable mid-term survival and target vessel stability, supporting their use in this challenging anatomical setting within the limitations of a small PD-TAAA cohort. Full article

Fermented foods and beverages based on plant-derived ingredients are of growing technological interest, especially when they are designed as alternatives to conventional dairy products. This study evaluated the effects of herbal extracts from Verbascum thapsus L., Cnicus benedictus L., and Fumaria officinalis L. on lactic acid bacteria growth, acidification kinetics, and viable cell counts during the fermentation of organic milk, coconut beverage, and soy beverage. The extracts were characterized for extraction yield, total phenolic content, and antioxidant activity before use in fermentation trials. Mixtures of organic solvents and water produced extracts with higher total phenolic content and antioxidant activity than water alone. The highest values were obtained for F. officinalis extracts prepared with water and methanol or water and acetone, while for C. benedictus, the most effective solvents were water and acetone or water and ethanol. The agar well-diffusion assay showed no relevant antibacterial activity against the tested LAB strains under the applied conditions. No biologically relevant inhibition zones were observed in any of the 84 extract-strain combinations under the tested conditions. The only borderline response was observed for Lactobacillus acidophilus La-14 exposed to the 70% ethanolic extract of C. benedictus. The clear halo did not exceed 1.50 mm outside the 5 mm well and was treated as a weak, strain-specific screening result. Fermentation kinetics depended mainly on the food matrix. The coconut beverage acidified most rapidly, reaching pH 4.38 to 4.79 after 6 h, whereas the soy beverage required 24 h to reach pH 4.31 to 4.56. Organic milk showed the slowest acidification, and selected C. benedictus extracts delayed pH reduction. All analyzed fermented samples contained more than 7 log CFU/mL of viable LAB. These results indicate that selected herbal extracts can be used in fermented milk and plant-based beverages without reducing LAB survival, but their suitability should be assessed separately for each strain and matrix. Full article

Background: Traditional cardiovascular risk models often overlook “residual risk” driven by psychopathological factors. This study investigates the exploratory prognostic baseline associations of Type D personality (TDP) and specific symptomatic dimensions with long-term all-cause mortality in patients with coronary artery disease (CAD). Methods: We conducted a retrospective case study based on hospital records evaluating 221 patients with confirmed CAD. Anatomical complexity was quantified via the SYNTAX Score (SS). Psychological profiling utilized the DS14 scale for TDP and the SCL-90 for granular symptoms (depression, anxiety, and hostility). Mortality was analyzed over a mean follow-up of 1026 days using multivariate Cox proportional hazards models. Results: Over a mean follow-up of 1026 days, the overall all-cause mortality rate was 33.0% ($n=73$). TDP prevalence was 19.0% ($n=42$) and significantly correlated with higher anatomical complexity (SS: 26.21 vs. 15.49; $p<0.001$). In the adjusted psychological model, baseline anxiety symptom severity presented an exploratory, borderline relationship with survival (HR = 0.941; $p=0.049$), with the 95% confidence interval upper bound reaching the null threshold (1.000), suggesting a potential, hypothesis-generating “Anxiety Paradox”. The psychological model demonstrated variations in descriptive validation indices (C-index = 0.624) compared to a baseline model integrating trait metrics and anatomical severity (C-index = 0.527). Significant correlations were confirmed between SS and psychological distress ($r=0.493$). Conclusions: TDP components and granular psychological tracks show significant baseline associations with coronary anatomical distributions, while anxiety dimensions present an exploratory relationship with long-term survival. Given the lack of adjustment for major clinical determinants of mortality (such as age, comorbidities, or ventricular function), these findings must be interpreted strictly as hypothesis-generating and exploratory. Full article

Background/Objectives: Oral squamous cell carcinoma (OSCC) remains clinically heterogeneous, and prognosis is not always fully explained by conventional clinicopathological parameters. Systemic inflammation and tumor metabolic alterations may provide complementary information on tumor biology. This study aimed to assess associations between preoperative inflammatory markers, isotope ratio mass spectrometry (IRMS)-derived tumor signatures, clinicopathological features, and survival outcomes in OSCC. Methods: This exploratory retrospective secondary analysis included 50 consecutive patients with surgically treated, histologically confirmed OSCC. Preoperative blood-based markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), white blood cell count, lymphocyte count, and C-reactive protein, were retrieved from routine laboratory tests. Matched tumor, surgical margin, and healthy oral mucosa samples were analyzed by IRMS for δ¹³C, δ¹⁵N, carbon and nitrogen content, and [N]/[C] ratio. Associations with clinicopathological variables, nodal status, overall survival (OS), and disease-free survival (DFS) were evaluated using non-parametric tests, Spearman correlations, and Cox regression models. Results: Tumor tissue showed a consistent isotope and elemental phenotype compared with healthy mucosa, including higher nitrogen content, lower carbon content, increased [N]/[C] ratio, lower δ¹⁵N, and less negative δ¹³C values. NLR, PLR, SII, and CRP were not robustly associated with standard clinicopathological features after correction for multiple testing. Correlations between inflammatory and isotope-derived parameters were modest. Higher NLR was associated with worse OS and DFS and remained significant after adjustment for pathologic nodal status. Less negative tumor δ¹³C showed a potential adverse prognostic signal. Conclusions: Systemic inflammatory markers and IRMS-derived tumor signatures appear to reflect partly distinct biological domains in OSCC. NLR may provide accessible prognostic information, while tumor δ¹³C warrants further validation as a metabolic biomarker. Full article

Dense simultaneous localization and mapping (SLAM) via 3D Gaussian splatting (3DGS) faces memory bottlenecks due to the explosive growth of primitives during long-sequence mapping. We propose SATA-SLAM, a framework featuring spatial-aware truncation and adaptive anti-hallucination. The online front-end maintains a constant memory footprint via a spatial-aware pruning module (SAPM), which employs a survival scoring function that couples primitive opacity with view-frustum projection coverage and a temporal protection window. Subsequently, an anti-hallucination generative refinement module (AGRM) utilizes texture priors from pretrained diffusion models for offline inpainting of residual regions. In addition, an adaptive gating mechanism to verify and suppress AIGC-induced hallucinations caused by pose drift, ensuring multiview consistency. Experiments on the public Replica dataset show that SATA-SLAM improves rendering quality from 12.5 dB to 37.44 dB (averaged over the Replica room0 and office0 scenes) while using only 26% of the original memory, outperforming the unconstrained baseline. This study provides a pathway toward low-power, high-fidelity environmental perception for mobile robots. Full article

The probability of failure of a power transformer is difficult to quantify within a single utility because major failures are rare and operating histories are often incomplete. This paper uses large-scale CIGRE surveys (50 utilities, 26,533 transformers, 331,379 operating years) to estimate age-dependent component reliability by voltage class. In total, 1358 major failures and 991 retirements were reported for a reference period of up to 34 years. The data were treated as left-truncated and right-censored. Hazard rates were calculated for active parts, bushings, and on-load tap changers, retirements were assessed using the Kaplan–Meier estimator, and Weibull distribution models were fitted to 100–199 kV and 200–700 kV populations. The overall major failure rate was 0.41% per year. For the 100–199 kV transformers, the component hazard rates were close to constant with age (β ≈ 1), and the late-life pattern was influenced by increasing retirements. For the 200–700 kV transformers, bushing hazard showed a stronger age dependency and exceeded active-part hazard at around 50 years. The results highlight the value of component-focused risk management and show that fleet reliability should be interpreted alongside retirement and condition-management practices. Key limitations include data truncation, censoring, and the lack of categorisation of failures by technology type. Full article

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but are associated with immune-related adverse events (irAEs) and variable clinical outcomes. Clinical predictors of organ-specific irAEs remain indeterminate, particularly in real-world populations. Methods: We conducted a retrospective single-center cohort study including 751 adult patients with solid tumors treated with ICIs between 2018 and 2025. Clinical, demographic, and treatment-related variables were analyzed. Multivariable logistic regression identified predictors of irAEs, while associations with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were assessed using logistic and Cox regression models. Results: The most frequent irAEs were endocrine (9.9%), dermatologic (9.1%), gastrointestinal (7.6%), and pulmonary (4.7%). Female sex independently predicted endocrine (aOR 1.98, p = 0.007) and rheumatologic irAEs (aOR 4.06, p = 0.007). Combination immunotherapy was associated with increased dermatologic (aOR 2.66, p = 0.013) and gastrointestinal irAEs (aOR 2.65, p = 0.016), while concurrent radiotherapy predicted gastrointestinal toxicity (aOR 1.82, p = 0.044). Atezolizumab was associated with higher pulmonary irAE risk (aOR 2.97, p = 0.048). Endocrine, dermatologic, gastrointestinal, and pulmonary irAEs were independently associated with improved ORR (OR range: 2.53–4.30, all p < 0.01). Conclusions: Organ-specific irAEs exhibit distinct clinical predictors and differential prognostic implications in patients receiving ICIs. Select irAEs are associated with improved treatment response and disease control, yet our results should be regarded as hypothesis-generating requiring further investigation. Full article

Peritoneal metastasis (PM) is the most frequent and lethal pattern of dissemination in gastrointestinal malignancies. Despite advances in systemic chemotherapy, outcomes remain poor because the unique biology of PM, characterized by poor vascularization and the peritoneal–plasma barrier (PPB), limits drug penetration and contributes to treatment resistance. To address these challenges, several locoregional treatment strategies have been developed, including cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). However, their widespread adoption is constrained by invasiveness, strict patient selection, and inconsistent survival benefits. Normothermic intraperitoneal and systemic treatment (NIPS) has emerged as a practical and less invasive alternative, particularly in East Asia. Through an implanted intraperitoneal port, NIPS enables repeated drug administration, providing sustained regional exposure while imposing minimal procedural burden. Importantly, it can be readily integrated with systemic chemotherapy, making it suitable for long-term multimodal treatment. Among available agents, paclitaxel (PTX) is particularly well suited for intraperitoneal administration because of its prolonged retention within the peritoneal cavity and limited systemic absorption. These pharmacokinetic properties allow high local drug concentrations with relatively low systemic toxicity. Consequently, PTX-based NIPS represents a biologically rational and clinically feasible treatment strategy for PM. This review summarizes the pharmacological rationale, clinical evidence, and emerging innovations in drug formulation and delivery that may further enhance the efficacy of PTX-based intraperitoneal chemotherapy for this challenging disease. Full article

Background and Objectives: Rheumatic diseases confer excess cardiovascular risk, yet prognosis after acute coronary syndrome (ACS) in contemporary angiography-treated care remains incompletely characterized, particularly when psychiatric multimorbidity is considered. We evaluated whether documented rheumatic disease was associated with psychiatric comorbidity and post-discharge mortality after ACS. Materials and Methods: We retrospectively analyzed a predefined two-center registry extract of 2950 consecutive patients who underwent coronary angiography for ACS. Documented rheumatic disease was identified from diagnoses recorded in admission history, prior medical records, or discharge documentation and was not re-adjudicated. The primary outcome was post-discharge all-cause mortality. Results: Documented rheumatic disease was present in 106 patients (3.6%). Compared with patients without documented rheumatic disease, exposed patients were older, more often women, more often hypertensive, and more likely to have a documented psychiatric disorder (25.5% vs. 14.1%). Short-term mortality was similar, whereas crude overall long-term mortality was higher (27.4% vs. 19.3%). Among hospital survivors with usable follow-up, post-discharge survival was worse (log-rank p = 0.013). Documented rheumatic disease was associated with higher post-discharge mortality in unadjusted analysis (hazard ratio 1.66, 95% confidence interval 1.11–2.48) and in a prespecified parsimonious model (adjusted hazard ratio 1.56, 95% confidence interval 1.04–2.34); the association attenuated and was no longer statistically significant in a broader exploratory model (adjusted hazard ratio 1.35, 95% confidence interval 0.87–2.07). Documented psychiatric disorder independently predicted mortality. Conclusions: In angiography-treated ACS, documented rheumatic disease was associated with greater psychiatric comorbidity and worse post-discharge survival in a small, documentation-defined, heterogeneous subgroup. Because the signal attenuated in broader exploratory adjustment and exposure ascertainment was documentation-based, the findings should be regarded as hypothesis-generating rather than disease-specific or causal. Full article

This article introduces the Evidence Propagation Calculus (EPiC), an operational framework for first-order reasoning built on a simple but productive observation: familiar inference patterns such as Modus Ponens and Modus Tollens behave like the movement of evidential markers across a structured graph. Positive evidence at an antecedent propagates forward to the consequent; negative evidence at a consequent propagates backward. When both markers coexist at a node, the system is locally inconsistent but not operationally broken. To make this observation precise, EPiC grounds reasoning in a four-valued evidential domain $\mathbb{V}=\{N,T,F,B\}$, where N denotes absence of evidence, T positive evidence, F negative evidence, and B their coexistence. Each logical connective is assigned a local evidential table, and inference is treated uniformly as the progressive restriction of admissible configurations under an evidential order: inadmissible values are eliminated, minimal surviving values are selected as the next effective evidential states, and the resulting restrictions propagate across shared variables. Compound formulas are decomposed into families of local unary and binary constraints through auxiliary variables, making the propagation process explicit and structurally uniform. Within this setting, Modus Ponens, Modus Tollens, and polarity-switching negation are not postulated as primitive rules. They emerge as derived consequences of the same local table calculus. The framework distinguishes different operational routes of justification. In some cases, positive support reaches the target formula directly through successive local restrictions. In others, propagation first stabilizes the relevant components and the target occurrence is then fixed by the corresponding connective table. Consistency is not a second basic notion of justification but a distinguished property of certain justified outcomes. The article establishes local and global soundness, conservativity over the classical fragment, and a conditional adequacy result. It further develops a translation between decomposed formulas and informational graphs, with a reverse reconstruction theorem for well-formed graphs. The result is a unified operational account of first-order reasoning situated between model-theoretic and proof-theoretic approaches, in which semantics, propagation, and graphical structure are mutually supporting rather than independently layered. Full article

Background: Distal cholangiocarcinoma (dCCA) has a poor prognosis and the prognostic impact of ductal margin status, particularly carcinoma in situ (CIS) or high-grade dysplasia (HGD) at the margin, remains controversial. This retrospective single-center study evaluated whether ductal margin distance (DMD) is a stronger prognostic indicator than ductal margin status (DMS) after curative resection. Methods: We reviewed 416 patients who underwent pancreaticoduodenectomy for distal cholangiocarcinoma between 2003 and 2022. DMS was classified as negative, CIS/HGD, or invasive carcinoma (IC). The DMD was defined pathologically as the linear distance from the proximal ductal margin to IC and patients were divided into two groups using 10 mm as the cut-off. Survival was analyzed with Kaplan–Meier and Cox regression. Results: Overall, 349, 52, and 15 patients had negative, CIS/HGD, and IC margins, and 249 and 167 had DMD > 10 and ≤10 mm, respectively. Overall survival (OS) and disease-free survival (DFS) did not differ significantly according to DMS, whereas DMD ≤ 10 mm was associated with significantly worse 5-year OS (48.5% vs. 67.9%) and DFS (39.9% vs. 55.9%). On multivariable analysis, DMD ≤ 10 mm was an independent adverse prognostic factor for both OS (hazard ratio 1.669; p = 0.003) and DFS (hazard ratio 1.394; p = 0.026). Conclusions: DMD demonstrated a stronger association with prognosis than DMS in patients with negative or CIS/HGD at the ductal resection margin following dCCA resection. A DMD of ≤10 mm was significantly associated with decreased OS and DFS. Well-designed prospective studies are warranted to validate these results. Full article

Background and Objective: Romosozumab carries a warning for potential severe cardiovascular events, while denosumab is widely used for osteoporosis but requires safety considerations in advanced chronic kidney disease (CKD). Given the limited direct real-world evidence comparing these treatments, in this study, we aimed to compare the cardiovascular and survival outcomes associated with romosozumab versus denosumab in adults with CKD. Materials and Methods: In this retrospective propensity score-matched cohort study, we utilized de-identified electronic health records from the TriNetX Global Collaborative Network, where eligible participants were adults aged 40 to 90 years with CKD who initiated either romosozumab or denosumab. Patients with bone/bone marrow malignancies or recent acute cardiovascular events were excluded. Following 1:1 propensity score matching based on demographics, diagnoses, medications, and laboratory characteristics, patients were followed for up to 1095 days. The primary outcome was a composite cardiovascular measure (all-cause mortality, acute myocardial infarction, or cerebrovascular event), while secondary outcomes included the individual components of the composite outcome and acute heart failure. Outcomes were evaluated using fixed-window cumulative risks, risk ratios (RRs), odds ratios, and hazard-ratio estimates. Results: After 1:1 propensity score matching, 1201 patients remained in each cohort; the mean age was 74.1 years in the romosozumab cohort and 74.2 years in the denosumab cohort, and 94.9% and 93.8%, respectively, were women. Romosozumab was associated with lower 1095-day cumulative risk of the composite cardiovascular outcome than denosumab (12.6% vs. 18.8%; RR, 0.668 [95% CI, 0.553–0.808]), as well as lower cumulative risk of cerebrovascular event (5.0% vs. 7.0%; RR, 0.714 [95% CI, 0.518–0.985]), all-cause mortality (6.6% vs. 9.5%; RR, 0.693 [95% CI, 0.526–0.913]), acute myocardial infarction (3.8% vs. 6.2%; RR, 0.613 [95% CI, 0.429–0.878]), and heart failure (2.7% vs. 6.1%; RR, 0.438 [95% CI, 0.292–0.659]). Conclusions: In this propensity score-matched EHR cohort of adults with CKD, cardiovascular and survival estimates associated with romosozumab versus denosumab varied by follow-up window and analytic approach. Although 1095-day fixed-window cumulative risks were lower in the romosozumab cohort, corresponding time-to-event estimates were neutral or directionally inconsistent. These findings should not be interpreted as evidence of cardioprotection or causal superiority but rather as showing no clear and consistent excess cardiovascular risk signal for romosozumab compared with denosumab. Full article