Search Results (4,057)

Neurodegenerative diseases arise when normally functional aggregation-prone proteins transition into stable cross-β amyloid fibrils. Although these fibrils share a conserved architecture, the pathways that lead to fibrillation vary across proteins and cellular environments. Liquid–liquid phase separation is now recognized as a central organizer of intracellular biochemistry that modulates protein aggregation. Physiological condensation can buffer aggregation by maintaining macromolecular solubility and providing partner interactions that compete against pathological protein–protein interactions. However, condensates can transform and age into gel-like states that can favor the emergence of β-rich oligomers and solid-state fibrils. Across six disease-linked proteins that include Tau, ⍺-synuclein, amyloid-β, TDP-43, FUS, and hnRNPA1, we compare how sequence-encoded interaction motifs, cellular cofactors, and interfacial microenvironments shape the balance between physiological condensates and pathological amyloids. Here, we highlight the unifying drivers of aggregation and intervention points that preserve native function while limiting toxic amyloid formation. Full article

Background: The metamorphopsia questionnaire (MeMoQ) is an established patient-reported outcome measure (PROM) in the context of macular disease. However, its performance has not been proved in those being treated for various macular conditions with intravitreal anti-vascular endothelial growth factor (Anti-VEGF). The objective was to eliminate misfitting items, enhance measurement precision, and ensure optimal response categorisation. Methods: Rasch analysis was performed iteratively on 2286 responses from patients with macular diseases being treated with Anti-VEGF to optimise the MeMoQ. Fit statistics, reliability indices, person and item separation measures, and principal component analysis (PCA) of residuals were assessed to determine the optimal model. This study was conducted in an outpatient clinic specialising in retinal diseases in Hywel Dda University Health Board. Results: Misfitting items were removed in successive iterations, leading to optimised category probability curves and stable fit statistics for the MeMoQ. The resulting model for all responses included two final items, with person separation remaining inadequate reducing from 1.23 to 1.12 and reliability from 0.60 to 0.56. Category probability curves demonstrated good ordering of response variables with Andrich thresholds separated by >1.2 logits. In the subgroups of neovascular age-related macular degeneration and diabetic macular oedema person separation remained below two and reliability remained low. Conclusions: Rasch analysis demonstrated that the MeMoQ was not a valid or reliable PROM in this patient population. Therefore, the MeMoQ may not provide a reliable index of patient’s perception and visual experience when undergoing Anti-VEGF treatment. Full article

Automated pig-welfare monitoring needs scalable, non-invasive signals that work across ages and individuals. A key methodological contribution of this study is the use of subject-wise validation, which ensures generalization to unseen animals and prevents inflated accuracy caused by growth-related and individual ‘voice’ differences. Vocalizations can help, but growth and individual “voice” differences can confound distress patterns and overstate accuracy without subject-wise validation. In our study, we explicitly accounted for individual variability by including animal identity as a random effect in mixed models and by using grouped cross-validation, where models were tested only on pigs not seen during training. This approach ensures that the reported accuracy reflects generalization across different individuals rather than memorization of specific vocal signatures. We analyzed 2221 vocal samples from 40 pigs (20 males, 20 females) recorded across four growth phases (farrowing, nursery, growing, finishing) under six conditions (pain, hunger, thirst, cold stress, heat stress, normal). Acoustic features extracted in Praat included energy, duration, intensity, pitch, and formants (F1–F4). Using blockwise variance decomposition, we quantified contributions of distress exposure, growth phase, and sex, and estimated the additional variance explained by animal identity. Distress exposure dominated intensity and spectral traits, particularly Formant 2, whereas the growth phase produced systematic shifts in duration and pitch. Animal identity added a modest but consistent increment in explained variance (~+0.02–0.03 R² beyond sex, phase, and distress). For prediction, we used 5-fold cross-validation grouped by animal. A Random Forest achieved a modest balanced accuracy of 0.609 and macro-F1 of 0.597; pain was most separable (recall 0.825), while other states showed moderate recall, indicating overlap. These results support hierarchical acoustic encoding of distress and establish a benchmark for precision welfare monitoring. Furthermore, they highlight that resolving complex physiological overlaps, such as heat stress and resource competition, requires a shift from unimodal acoustic models to multimodal Precision Livestock Farming (PLF) systems that integrate bioacoustics with continuous environmental and behavioral data streams. Full article

Arsenic is among the most important environmental toxicants contributing to the global prevalence of hypertension. Multiple studies have reported a greater burden of hypertension among people of African ancestry, yet the contribution of environmental factors to this burden is unclear. Therefore, we investigated the association of arsenic exposure with increased risk of hypertension and high blood pressure in 965 Afro-Caribbean adults in the Tobago Health Study. Linear and logistic regression analyses were conducted for the total cohort and stratified by sex and age separately. We also examined potential effect modification by sex. Each unit (μg/L) increase in ΣAs was associated with 2% higher odds of hypertension in the total cohort and 4% higher odds among women. Higher ΣAs was associated with higher diastolic blood pressure and mean arterial pressure (MAP) among men. The associations of higher ΣAs with hypertension among women and with higher MAP among men were significant only in mid-life but not in older age. The data suggest effect modification by sex for the relationship between ΣAs and MAP in men. The findings suggest that exposure to inorganic arsenic contributes to age- and sex-specific patterns for greater risks of hypertension and high blood pressure among Afro-Caribbean adults. Full article

Background/Objective: Cognitive frailty, the coexistence of physical frailty and cognitive impairment, is a potentially reversible and high-risk state for dementia. This study examined the association between Color Kanji Pick-out Test (CKPT) app performance and cognitive frailty independent of Mini-Mental State Examination (MMSE) scores in community-dwelling older women. Methods: In this cross-sectional study, the participants were 102 community-dwelling older women without dementia and with MMSE scores ≥ 27 (73.6 ± 6.0 years). Reversible cognitive frailty was defined as subjective cognitive decline (≥1 point in the cognitive domain of the Kihon Checklist) plus physical frailty or prefrailty, according to the Japanese Cardiovascular Health Study (J-CHS) criteria. Firth’s penalized logistic regression using three prespecified models, adjusted for age and education, was used to examine the independent associations between CKPT app performance and MMSE scores with reversible cognitive frailty. Results: Fourteen participants (13.7%) met the criteria for cognitive frailty. In separate models, higher CKPT app and MMSE scores were significantly associated with lower odds of cognitive frailty (CKPT: odds ratio [OR] 0.470, p = 0.019; MMSE: OR 0.548, p = 0.020). In a multivariable model including both measures, the CKPT app (OR 0.499, p = 0.031) and MMSE scores (OR 0.553, p = 0.031) remained independently associated with cognitive frailty, and this model had the lowest Akaike information criterion. Conclusions: The CKPT app performance was independently associated with cognitive frailty beyond global cognition. The CKPT app may detect subtle executive and attentional vulnerabilities not captured by the MMSE, supporting practical, objective, early screening and risk stratification of cognitive frailty. Full article

The development of reliable electrochemical interfaces for biosensor applications requires materials that combine high conductivity, large effective surface area, and suitable platforms for biomolecule immobilization. In this work, a hybrid electrochemical platform based on screen-printed carbon electrodes (SPCEs) modified with electropolymerized polypyrrole (PPy) and electrodeposited silver particles (AgPs) is presented for the subsequent immobilization of Ki-67 antibodies. PPy films were synthesized under optimized electrochemical conditions, producing homogeneous, porous, and electrochemically stable coatings that significantly enhanced the doping/undoping processes from 0.3280 C/0.3284 C to 0.3281 C/0.3284 C for SPCE and SPCE-PPy, respectively. Subsequently, silver particles were deposited onto the PPy matrix, resulting in a well-dispersed and uniform distribution of AgPs, promoted by the interaction between Ag⁰ and the nitrogen groups in the polymer backbone. The synergistic combination of PPy and AgPs resulted in improved charge-transfer properties and enhanced electrochemical reversibility, thereby decreasing the peak-to-peak separation of the ferricyanide/ferrocyanide redox couple used as a probe by 40%. Immobilization of Ki-67 antibodies was achieved via direct interaction with AgPs, resulting in a marked passivation effect, as evidenced by the suppression of redox probe signals, confirming successful biofunctionalization. The proposed SPCE-PPy-AgP architecture provides a robust, reproducible, and versatile platform for antibody immobilization, as demonstrated by oxidation and reduction peaks with relative standard deviations (RSDs) of 3.18% and 4.43%, respectively, highlighting its potential for developing label-free electrochemical immunosensors for clinically relevant proliferation biomarkers. Full article

Introduction: Evidence on the use of dopamine agonists (DAs) for managing residual or recurrent non-functioning pituitary adenomas (NFPAs) is limited. We aim to evaluate the use of cabergoline (CAB) for NFPAs. Methods: A retrospective cohort study was conducted at a single UK centre, between November 2011 and December 2025. Twenty-six patients were identified. Ten patients were excluded due to CAB intolerance or discontinuation (n = 5), insufficient data (n = 4), or invalid scan due to patient movement (n = 1). The remaining 16 patients (mean age 68.9 ± 4 years (range 42–89 years old), 7/16 females) were included. CAB was initiated in cases where surgery or radiotherapy were not appropriate (e.g., due to age and/or comorbidities, or patient choice). Radiological response was assessed using at least two scans separated by a minimum interval of six months. Tumour shrinkage was defined as a reduction in volume of 20% or more, growth as an increase of 20% or more, and stabilisation as interval change of less than 20%. Results: Overall, tumour shrinkage was observed in 7/16 (43.8%) patients, stabilisation in the remaining 9/16 (56.3%) patients, over 503 ± 51 days (range of 117–934 days) (from the date of CAB initiation to latest MRI scan). There was a statistically significant reduction in tumour volume (p = 0.0335). In five patients with documented tumour growth prior to CAB initiation, growth rates retarded or reversed post-CAB initiation. Conclusions: Our findings in this small cohort potentially suggests that cabergoline can retard, arrest, or even reverse tumour growth in selected patients with NFPAs. Our review also highlights ongoing uncertainty regarding optimal dosing, approaches to dose up-titration, follow-up imaging intervals, and objective criteria for defining radiological response. Our results may provide a proof of concept for future, larger-scale prospective studies and controlled trials to validate the conclusions drawn. Full article

Isotopic disequilibrium during the formation of high-temperature (HT) metamorphic complexes by anatexis during continental collision is a process that deserves intense discussion since it is fundamental to understand the evolution of continental crust. The axial sector of the Iberian Variscan Belt (IVB) is known by the profusion of synorogenic granites that are sometimes clearly associated with the migmatites composing the HT metamorphic complexes. The Pedregal Migmatitic Complex is located in the autochthonous domain of the IVB and is composed of metatexites and diatexites associated to syntectonic two-mica granites. The anatectic process occurred by dehydration melting of muscovite and biotite with the growth of peritectic minerals such as garnet, K-feldspar, and sillimanite in metatexites; and K-feldspar, sillimanite, and hercynite in diatexites reaching the metamorphic peak at 313.5 ± 0.5 Ma. A process of residuum-melt separation during crustal melting is attested by the Pedregal migmatites, giving origin to metatexites and residual diatexites as indicated by field evidence and their geochemical signature. Zircon oxygen isotopes and inherited zircon ages point to the Douro-Beiras Supergroup metasedimentary sequence (Beiras group) as a possible protolith of the Pedregal diatexites. Conversely, the isotopic composition of the diatexites suggests isotopic disequilibrium caused by residual mineral phases (biotite, monazite and garnet). Full article

Background: Indoleamine 2,3-dioxygenase (IDO) is an immune checkpoint that has been shown to play a key immunomodulatory role in various solid tumors, including breast cancer (BC). Although increased IDO expression has been previously observed in some BC subtypes, mainly triple-negative BC (TNBC), the clinical relevance of this protein across the entire range of BC and its exact correlations with other immune checkpoints remain to be elucidated. We herein aimed to further investigate the differential expression patterns of IDO and programmed death-ligand 1 (PD-L1) in variable BC subtypes and in distinct compartments of breast cancer tissue, and to explore their potential associations with standard patient- and tumor-related clinicopathological parameters as well as prognosis. Methods: This was a retrospective multi-center cohort study of 150 female patients with BC. The clinicopathological parameters analyzed were retrieved from the medical records of patients while sections from archival formalin-fixed, paraffin-embedded (FFPE) tissue blocks were also obtained for the performance of immunohistochemistry. The expression of IDO and PD-L1 was evaluated separately on tumor cells (IDO/CA, PD-L1/CA), lymphocytes (IDO/L, PD-L1/L) and stromal cells (IDO/S, PD-L1/S) and the results were correlated with the remaining clinical and pathological features of patients, as well as with local recurrence, metastasis and survival. Results: The mean age of patients was 59.5 years (SD = 13.4 years). Positive expression of IDO/CA, IDO/L and IDO/S was found in 6%, 93.3% and 90.7% of tissue samples, respectively, while 4%, 11.2% and 6.7% of tumors were positive for PD-L1/CA, PD-L1/L and PD-L1/S, respectively. A significantly higher rate of positive IDO/CA expression was observed in triple-negative BC (TNBC) patients (p = 0.037). Positive expression of IDO-CA was also significantly associated with positivity for PD-L1/L and PD-L1/S (p = 0.001 and p = 0.015, respectively). Multivariable logistic regression analysis showed independent correlations between IDO/CA and IDO/L and the presence of invasive ductal carcinoma (IDC) (OR = 1.10; p = 0.026) and N1 status (OR = 10.93; p = 0.039), respectively, IDO/S and both N1 (OR = 14.64; p = 0.018) and positive HER2 status (OR = 6.11; p = 0.019), PD-L1/L and high Ki67 (OR = 7.96; p = 0.001) as well as negative ER (OR = 0.08; 0.003) and PR status (OR = 0.09; p = 0.002), PD-L1/S and both NST (no special type) histology (OR = 4.68; p = 0.032) and negative ER status (OR = 0.21; p = 0.044). No statistically significant associations were observed between the expression patterns of the examined biomarkers and recurrence, metastasis or survival. Conclusions: In our study, IDO expression on tumor cells was predominantly observed in TNBC and was found to correlate with PD-L1 expression in the lymphocytic and stromal compartments. Furthermore, expression of PD-L1 among lymphocytes was found to independently correlate with unfavorable clinicopathological parameters, including high proliferation rate and negative hormone receptor status. Full article

Applications of Parametrized Relativistic Quantum Theory (PRQT) in curved spacetime are considered here. PRQT in curved spacetime is applied to the motion of free scalar particles in expanding universe metrics, including a generalized expanding universe (EU) metric and the Friedmann–Lemaître–Robertson–Walker (FLRW) metric. Governing equations are derived and solved through separation of variables. In addition, modern observational parameters and a rescaled Friedmann equation are used to estimate the age of the universe. Implications for cosmological models are discussed. Full article

High-density cities face dual challenges of aging populations and climate change, driving widespread renewal of aging residential communities. Current practices, however, often treat sustainability goals (e.g., energy efficiency, carbon reduction) and age-friendly design objectives (e.g., accessibility, social inclusion), often guided by frameworks like the World Health Organization’s (WHO) age-friendly cities initiative, as separate or conflicting agendas, leading to fragmented policies and suboptimal outcomes. This study addresses this gap by proposing and testing a framework for “Sustainable-Age-friendly Coordinated Renewal” (SACR). Through a mixed-methods case study of a typical old community in the humid subtropical city of Guangzhou, China, we investigate how green infrastructure and low-carbon interventions can be synergistically designed to enhance both environmental performance and the well-being of elderly residents. A “Coordinated Renewal Strategy Package” was developed, incorporating ecological shading, sponge city facilities, energy retrofits, and accessible slow-traffic systems. Post-intervention simulation and evaluation indicated significant improvements in microclimate (e.g., reduced mean radiant temperature and Physiological Equivalent Temperature (PET)) and marked increases in outdoor activity duration and social interaction frequency among elderly residents. This study concludes that a human-centric, needs-based design approach is key to unlocking synergistic benefits. The proposed SACR framework and evaluation matrix offer a practical tool for urban planners, architects, and policymakers to holistically assess and implement community renewal projects, contributing to more resilient, inclusive, and sustainable urban futures by addressing localized challenges like the Urban Heat Island (UHI) effect. Full article

Background and Objectives: Postoperative pain after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) shows substantial interindividual variability, particularly during early mobilization. Although preoperative psychological vulnerability has been associated with less favorable pain trajectories in prior AIS research, evidence focused on the acute postoperative phase remains limited. This preliminary study evaluated whether preoperative psychological factors are associated with acute postoperative pain intensity, with separate assessment of resting and standing pain. Materials and Methods: A single-center retrospective cohort study included consecutive adolescents with AIS (<18 years) who underwent primary elective posterior instrumented spinal fusion between 1 January 2024 and 31 December 2025. Preoperative psychological variables were collected using validated instruments (STAIC-State, STAIC-Trait, Pain Catastrophizing Scale, HAQ/FDI, and inverted SRS-22). Pain intensity (VAS 0–10) was recorded at postoperative day (POD) 1, POD2, POD3, discharge, and 2-week follow-up in supine and standing positions. Derived endpoints included peak in-hospital standing pain, in-hospital standing pain burden (AUC), and standing–rest pain gaps. The prespecified inferential analysis used a linear mixed-effects model with fixed effects for time, position, preoperative STAIC-State, and position × STAIC-State interaction, with a patient-level random intercept. Results: Thirty-five patients were analyzed (mean age 15.2 ± 3.4 years; 62.9% female), with complete pain data at all timepoints. During hospitalization, standing pain was descriptively higher than resting pain (largest mean difference at POD2: 0.73 VAS points), with convergence at week 2 (both 1.52). In mixed-model analysis, pain significantly decreased at week 2 versus POD1 (β = −1.261, 95% CI −1.853 to −0.669; p < 0.001). Preoperative STAIC-State was not independently associated with postoperative pain (β = 0.030, 95% CI −0.065 to 0.124; p = 0.545), and no significant position × STAIC-State interaction was found (β = −0.008, 95% CI −0.079 to 0.064; p = 0.836). Conclusions: In this retrospective preliminary AIS cohort, postoperative pain improved significantly over time, while movement-evoked pain remained relevant during early recovery. In this preliminary cohort, no clear association was detected between preoperative state anxiety and acute postoperative pain intensity, supporting the need for broader multidimensional prognostic models in future prospective multicenter studies. Full article

Background: Transient ischemic attack (TIA) and minor stroke often result in excellent functional recovery but are frequently followed by substantial psychological morbidity. It remains unclear whether mood disturbances or cognitive impairment are the primary contributors to reduced health-related quality of life (HRQoL) in this population. Methods: We conducted a prospective observational case–control study including 90 patients with acute TIA or minor stroke confirmed by diffusion-weighted imaging and 92 age-matched healthy controls. At 90 days, participants completed the Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Montreal Cognitive Assessment, and the EQ-5D-5L. Hierarchical multiple regression using standardized z-scores identified independent predictors of HRQoL. Bias-corrected bootstrapped mediation analyses (5000 iterations) assessed whether cognitive impairment mediated the relationship between mood symptoms and HRQoL. Results: Compared with controls, patients exhibited markedly higher rates of depressive symptoms (82.2% vs. 18.5%), anxiety symptoms (81.1% vs. 21.7%), and cognitive impairment (66.7% vs. 13.0%) (all p < 0.001). Psychopathological variables explained an additional 36.6% of HRQoL variance, whereas cognitive and neuroimaging variables contributed only 1.7% (ΔR² = 0.017; p = 0.523). In the fully adjusted regression model, HAM-A showed the numerically largest standardized coefficient (β = −0.055; p = 0.064), representing a trend toward significance, while HDRS-17 did not individually reach statistical significance (β = −0.043; p = 0.147); cognitive impairment had negligible independent effects (β = −0.001; p = 0.947). Both mood variables collectively accounted for the substantial majority of explained HRQoL variance, far exceeding the contribution of cognitive and neuroimaging predictors. Mediation analyses revealed no significant indirect effects, indicating that mood and cognitive complications are statistically consistent with a model in which mood and cognitive symptoms exert independent effects on HRQoL; temporal ordering cannot be established from these cross-sectional measures. Conclusions: Following TIA or minor stroke, depressive and anxiety symptoms are highly prevalent, persist despite good neurological recovery, and exert a disproportionately negative impact on HRQoL. Anxiety appears particularly influential in determining patient-reported outcomes. The statistical consistency of the mediation models with parallel rather than sequential mood–cognition pathways suggests that these represent independent neurobiological sequelae requiring separate clinical attention, underscoring the need for routine and concurrent assessment of both mood and cognitive function after TIA and minor stroke. Full article

Background: Signet-ring cell colorectal cancer (SRCC) and colorectal cancer with a signet-ring cell component (SRC) are rare histological subtypes associated with poor prognosis. Although these entities are classified separately based on pathological criteria, it remains unclear whether they differ in clinical behavior and survival outcomes. This study aimed to compare the clinicopathological characteristics and survival of patients with SRCC and SRC. Methods: Patients who underwent surgery for colorectal cancer (CRC) between January 2012 and December 2019 and were diagnosed with SRCC or SRC on histopathological examination were retrospectively included. Demographic, clinical, and survival data were analyzed and compared between the two groups. Results: A total of 32 patients (22 males, 10 females) with SRCC or SRC were included, representing 2.6% (32/1253) of all CRC cases operated at our center. Seven patients (five with SRCC and two with SRC) had synchronous distant metastases, including liver-only metastases (9%), diffuse intra-abdominal seeding (9%), and ovarian metastasis (3%). The mean disease-free survival was 19.2 ± 3.3 months overall, and 17.18 ± 3.61 months for SRCC and 19.3 ± 9 months for SRC. The mean overall survival was 70.9 ± 10.18 months overall, and 65.95 ± 13.77 months for SRCC and 79.20 ± 15.03 months for SRC. No statistically significant difference in overall survival was observed between the groups (p = 0.534). Conclusions: SRCC and SRC demonstrate broadly similar clinicopathological features, with younger age at diagnosis observed in SRCC patients. However, given the limited sample size, the absence of statistically significant differences in survival outcomes should be interpreted with caution and does not imply equivalence. Distant metastasis remains the most important prognostic factor in both groups. Full article