Search Results (793)

Background: The recently proposed Staging of Airflow Obstruction by Ratio (STAR) system classifies severity based on the FEV₁/FVC ratio, potentially offering improved prognostic performance. This study aimed to evaluate the prognostic performance of STAR in patients hospitalized for COPD exacerbation. Methods: A retrospective observational single-center study was conducted including COPD patients who were discharged after hospitalization for a severe exacerbation at a university hospital. The clinical and spirometric data in a stable condition, GOLD classification, STAR system, and mortality outcomes were recorded. Results: A total of 197 patients (23% female) were included. The follow-up was performed for a minimum of 38 months or until death if it occurred earlier. During the study period, 91 patients died (46%). Patients were distributed according to the STAR classification as follows: 21% in STAR 1, 32% in STAR 2, 28% in STAR 3, and 19% in STAR 4. The agreement between STAR and GOLD was fair (Cohen’s kappa = 0.28), with a moderate correlation (Tau-b = 0.49, p < 0.001). STAR grades 2 to 4 demonstrated progressively increasing mortality, while STAR grade 1 showed a mortality similar to grade 2. STAR showed a trend toward a superior discrimination for mortality than GOLD (AUC 0.63 [95%CI 0.55–0.71] vs. 0.55 [0.47–0.63]; p = 0.055), although BODEx remained the most accurate predictor (AUC = 0.70 [0.63–0.77]). Conclusions: The STAR system effectively stratified the mortality risk among hospitalized COPD patients across grades 2 to 4. However, STAR grade 1 failed to differentiate patients with a lower risk. Although STAR may underestimate severity in individual patients with relatively preserved ratios, its integration into clinical evaluation could enhance prognostic assessments. Full article

Background: Hyperphosphorylated tau accumulation and neurofibrillary tangles (NFTs) are hallmarks of tauopathies, including Alzheimer’s disease (AD), and are strongly associated with cognitive decline. The rTg4510 mouse model, which expresses mutant human tau (P301L), develops progressive tauopathy in the absence of amyloid-β pathology, providing a valuable tool for investigating tau-driven neurodegeneration. Previous studies have demonstrated spatial and object-recognition memory deficits at six months of age, which can be prevented by doxycycline (DOX)-mediated suppression of tau expression. However, it remained unclear whether non-spatial hippocampal learning, particularly temporal associative learning, would be similarly affected. Methods: We evaluated six-month-old rTg4510 mice with or without DOX treatment. To control for potential motor confounds, we first assessed spontaneous home cage activity. We then tested hippocampus-dependent non-spatial learning using two paradigms: trace eyeblink conditioning (500-ms trace interval) and contextual fear conditioning. Results: General motor function remained intact; however, rTg4510 mice without DOX treatment exhibited increased rearing behavior. These mice demonstrated significant deficits in trace eyeblink conditioning acquisition, with particularly clear impairment on the final day of training. Contextual fear conditioning showed milder deficits. Analysis of response peak latency revealed subtle temporal processing abnormalities during early learning. Two months of DOX treatment initiated at four months of age prevented these learning deficits, confirming their association with tau overexpression. Conclusions: Our findings demonstrate that rTg4510 mice exhibit deficits in non-spatial temporal associative learning alongside previously reported spatial and object-recognition impairments. Trace eyeblink conditioning serves as a sensitive behavioral assay for detecting tau-related hippocampal dysfunction, and the prevention of learning deficits by DOX treatment highlights its potential utility as a translational biomarker for evaluating tau-targeted interventions. Full article

Background: Sodium/iodide symporter (NIS) is a membrane protein involved in iodide transport into cells, making it a key component of thyroid physiology and radioiodine therapy for thyroid cancer. Although NIS is expressed in many extrathyroidal tissues, including breast tumors, its functional role and prognostic significance in these contexts remain a subject of active investigation. Understanding the mechanisms regulating NIS, its influence on cellular processes such as migration and metastasis, and its connection with transcription factors like FOXA1 could contribute to the development of new therapeutic strategies for breast cancer treatment. This study aims to investigate the correlation between sodium/iodide symporter (NIS) expression and response to neoadjuvant chemotherapy in patients with triple-negative breast cancer (TNBC). Methods: The current retrospective study included 161 TNBC patients who received neoadjuvant chemotherapy followed by mastectomy. NIS expression was assessed via immunohistochemistry, graded semi-quantitatively from 0 to 3+. The Residual Cancer Burden (RCB) scale was used to evaluate the response to chemotherapy. Statistical analysis included Lilliefors tests and Kendall’s tau correlation coefficient. Publicly available Cancer Genome Atlas datasets were analyzed to assess the relationship between NIS and FOXA1 expression. Results: NIS immunopositivity was observed in 69.5% of TNBC samples compared to 63.3% GATA-3-positive and 31.0% of Mammaglobin-positive samples. While no significant correlation was found between NIS expression and age, TNM stage, or Ki-67, a statistically significant moderate positive correlation (τ = 0.481, p < 0.01) was identified between NIS expression and RCB index, indicating that higher NIS expression was associated with a poorer response to neoadjuvant chemotherapy. TCGA data analysis revealed a statistically significant increase in NIS mRNA expression in FOXA1-mutated TNBC samples compared to FOXA1-wild-type samples (p < 0.05). Younger patients exhibited higher Ki-67 levels (τ = −0.416, p < 0.05). Conclusions: Higher NIS expression correlates with chemoresistance to neoadjuvant chemotherapy in TNBC patients. This phenomenon may be linked to FOXA1 activity, suggesting that NIS may represent a potential biomarker for chemoresistance in TNBC. The inverse correlation between patient age and Ki-67 levels may be associated with a different mutational landscape in younger patients. Full article

Background/Objectives: Alzheimer’s disease (AD) exhibits clinical and biological variability. This study aimed to identify MRI-defined subtypes reflecting distinct biological pathways of neurodegeneration and cognitive decline. Methods: We applied principal component analysis followed by k-means clustering (k = 3) on volumetric MRI data from 924 participants and validated clusters using cerebrospinal fluid (CSF) biomarkers (Aβ₄₂, total tau, p-tau, CTRED, MAPres, glucose, CTWHITE). Results: Three major phenotypes emerged: (1) a tau/vascular limbic subtype with pronounced hippocampal and amygdala atrophy and elevated tau and CTRED levels; (2) a volume-preserved, low-amyloid subtype consistent with early-stage or cognitively resilient AD; and (3) a diffuse-atrophy subtype with high amyloid and tau burden and ventriculomegaly. Comparative analysis revealed progressive biological shifts from amyloid accumulation to tau aggregation and vascular compromise across these clusters. Conclusions: MRI-based clustering validated by CSF biomarkers delineates biologically meaningful AD endophenotypes. The results suggest a gradual cognitive decline driven by amyloid–tau–vascular interactions, supporting multimodal phenotyping as a practical approach for precision staging and intervention. Full article

Alzheimer’s disease (AD), the most prevalent form of dementia, is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, ultimately leading to loss of independence and reduced quality of life. Since current treatments are most effective in early stages, the development of reliable and noninvasive biomarkers for early diagnosis and monitoring is crucial. Abnormal tau protein aggregation is a key pathological hallmark of AD, disrupting neuronal integrity, accelerating progression, and associating closely with cognitive decline and the transition to mild cognitive impairment, a prodromal stage of AD. Currently, tau pathology is evaluated mainly by cerebrospinal fluid analysis and tau positron emission tomography (tau PET), which are invasive or costly, limiting their clinical applicability. This systematic review and meta-analysis synthesized evidence on tau as a blood-based biomarker for dementia, with emphasis on its relationship to tau PET, the gold standard for in vivo tau assessment. Findings indicate that elevated plasma tau levels such as p-tau181, p-tau217 and p-tau231 consistently reflect brain tau pathology, supporting their role as surrogate markers. Large-scale longitudinal validation is warranted to establish blood-based tau as a practical, accessible tool for early detection and disease monitoring, thereby improving therapeutic outcomes in AD. Full article

Tau was initially identified as a microtubule-binding protein critical for microtubule stabilization. It is also a pathological hallmark of tauopathies, a group of neurodegenerative diseases that include Alzheimer’s disease. Under pathological conditions, Tau becomes hyperphosphorylated at numerous sites and aggregates into filamentous deposits, contributing to neuronal cell death and disease progression. While significant research has focused on Tau phosphorylation dynamics and their consequences in pathological contexts, comparatively few studies have investigated Tau phosphorylation during physiological processes, despite the potential relevance to the early onset of pathology. Previous findings have suggested similarities between mitotic Tau phosphorylation and hyperphosphorylation observed in tauopathies, particularly at sites such as AT8, PHF1, S214, and S422. In this study, we quantified the relative levels of phosphorylation at 12 Tau phospho-epitopes during interphase and mitosis in vitro to establish a preliminary mitotic phospho-Tau signature, which was subsequently validated in vivo. Our results demonstrated pronounced phosphorylation of Tau at AT8, p-T217, and p-S422 epitopes during mitosis, both in vitro and in vivo. These findings provide new insights into the physiological phosphorylation of Tau and its potential links to pathological processes. Full article

Background/Objectives: Cerebrospinal fluid erythrocyte load (CTRED) reflects occult red-blood-cell ingress into brain/CSF and consequent heme–iron exposure, a toxic pathway relevant to Alzheimer’s disease (AD). We aimed to develop explainable machine learning (ML) models that classify high vs. low CTRED from routine, largely non-invasive inputs, and to position a blood-first workflow leveraging contemporary plasma amyloid–tau biomarkers. Methods: Twenty-six ADNI participants were analyzed. Inputs were age, sex, mean arterial pressure (MAPres), amyloid (Aβ42), total tau, phosphorylated tau, and hippocampal atrophy rate (APC) derived from longitudinal MRI. APC was computed from normalized hippocampal volumes. CTRED was binarized at the median (0 vs. >0). Data were split into train (n = 20) and held-out test (n = 6). Five classifiers (linear SVM, ridge, logistic regression, random forests, and MLP) were trained in leakage-safe pipelines with stratified five-fold cross-validation. To provide a comprehensive assessment, we presented the contribution AUC, thresholded performance metrics, summarized model performance, and the permutation feature importance (PFI). Results: On the test set, SVM, ridge, logistic regression, and random forests achieved AUC = 1.00, while the MLP achieved AUC = 0.833. Across models, PFI consistently prioritized p-tau/tau, Aβ42, and MAPres; age, sex, and APC contributed secondarily. The attribution profile aligns with mechanisms linking BBB dysfunction and amyloid-related microvascular fragility with tissue vulnerability to heme–iron. Conclusions: In this proof-of-concept study, explainable ML predicted CTRED from routine variables with biologically coherent drivers. Although ADNI measurements were CSF-based and the sample was small, the framework is non-invasive by adding plasma p-tau217/Aβ1–42 for amyloid, tau inputs, and integrating demographics, hemodynamic context, and MRI. External, plasma-based validation in larger cohorts is warranted, alongside extension to MCI and multimodal correlation (QSM, DCE-MRI) to establish clinically actionable CTRED thresholds. Full article

This study focused on the abnormal phosphorylation of tau and its aggregation process, characteristic of Alzheimer’s disease, and aimed to compare the morphology and formation process of phosphorylated tau aggregates produced by four kinases: Cdk5/p25, GSK3β, MARK4, and p38α. Using quantum dots for 2D and 3D structural analysis, tau aggregates were confirmed in non-phosphorylated tau (non p-tau), as well as tau phosphorylated by GSK3β and MARK4. Aggregation initiation times were observed around 72 h for non-p-tau, and around 96 h for GSK3β and MARK4 phosphorylated tau. The thickness of non-p-tau aggregates was approximately 11 μm, while GSK3β aggregates were significantly thicker (13 μm) and exhibited increased density. TEM analysis suggested that tau forming wavy filaments was less prone to forming large aggregates. ThT assays and CD spectra showed an increased β-sheet structure for all kinases. Non-p-tau and GSK3β exhibited an increased right-twisted β-sheet structure, while Cdk5/p25, MARK4, and p38α showed an increased left-twisted β-sheet structure. The direct correlation between kinase activity and tau aggregate morphology revealed in this study provides a potential mechanistic basis for understanding disease heterogeneity and establishing novel therapeutic targets for AD specifically or for other neurodegenerative diseases as well. Full article

Background: Frailty is a multidimensional syndrome reflecting reduced physiological reserve, increasingly recognized as a relevant factor in the clinical assessment of older adults with cognitive disorders. Objective: To explore the association between frailty, as measured by the Multidimensional Prognostic Index (MPI), cognitive performance, and plasma biomarkers of Alzheimer’s disease (AD), and to examine the correlation between plasma and cerebrospinal fluid (CSF) biomarkers. Methods: This cross-sectional observational study included 40 patients (mean age 68.0 ± 9.0 years; 42.5% female) undergoing a diagnostic workup for cognitive decline. Patients were classified into AD (n = 20) and non-AD (n = 20) groups based on CSF AT[N] profiles. Frailty was assessed using the MPI. Linear and logistic regression models adjusted for age, sex, and education examined associations between MPI, cognitive scores, and plasma biomarkers (Aβ42, Aβ42/40, p-tau181, NfL). Correlations between plasma and CSF biomarkers and ROC analyses were also performed. Results: The AD group showed significantly higher plasma p-tau181 levels and MPI scores. MPI was positively associated with plasma p-tau181 levels (β = 4.26, p = 0.009). Plasma p-tau181 correlated strongly with CSF p-tau181 (R = 0.523, p < 0.001) and with CSF Aβ42/40 ratio (R = −0.541, p < 0.001) and showed high diagnostic accuracy (AUC = 0.910). Combining MPI with plasma biomarkers improved classification between AD and non-AD cases (AUC = 0.941). Conclusions: These findings support the value of incorporating frailty assessment in the diagnostic process of AD. The integration of geriatric tools and blood-based biomarkers may improve early detection and promote a more comprehensive approach in dementia evaluation. Full article

Breast cancer is one of the most common malignancies worldwide, affecting 2.3 million and causing 670,000 deaths in women annually. However, data indicate that the risk of developing breast cancer decreases with pregnancy at a young age, and each subsequent pregnancy further reduces the risk by approximately 10%. One of the characteristics inherent in both the mammary gland epithelium in pregnant women and luminal epithelial adenocarcinomas is the increased expression of NIS—the sodium/iodide symporter, whose defective cytoplasmic forms possess pro-oncogenic properties. Therefore, the analysis of the degree of influence of pregnancy on NIS expression in breast cancer cells is of medical interest. The aim of this study is to conduct a comparative morphological analysis of NIS expression in breast cancer cells according to the number of pregnancies of each patient. This study included 161 patients with triple-negative breast cancer who visited the P.A. Herzen Moscow Oncology Research Institute from 2020 to 2023. Immunohistochemical examination was performed using antibodies to NIS. The gravidity status of women was determined based on provided medical documentation. The degree of NIS expression was assessed using a modified Gainor scale. Statistical analysis was performed using mean and standard deviation (SD) depending on the normality of the distribution (Lilliefors test: p > 0.20); a p-value ≤ 0.05 was considered statistically significant. The degree of correlation between variables was assessed using Kendall’s tau rank correlation coefficient. A weak to moderate negative correlation (τ: −0.369) was found between the number of pregnancies and the degree of NIS expression in triple-negative breast cancer cells. In patients with triple-negative breast cancer, a weak to moderate negative correlation was found between the degree of NIS expression and gravidity status. The discovered phenomenon is likely due to the terminal differentiation of the mammary gland epithelium that occurs during pregnancy. This may potentially indicate the suppression of pro-oncogenic properties of atypical cells developed from the epithelium that has undergone terminal differentiation. Full article

Background: Parkinson’s disease (PD) is characterized not only by motor dysfunction but also by widespread degeneration across cortico-striatal, limbic, and cortical circuits. Mounting evidence suggests that tau and α-synuclein pathology underlie these processes, though how these proteinopathies translate into affective and cognitive outcomes remains uncertain. Depression and anxiety are highly prevalent in PD, yet the biological correlates of these affective disturbances are poorly defined. Methods: This is a retrospective analysis of existing data from the Parkinson’s Progression Markers Initiative (PPMI). Montreal Cognitive Assessment (MoCA), geriatric depression scale (GDS), and State-Trait Anxiety Inventory (STAI) were used to assess cognition, depression, and anxiety in PD, respectively. The CSF biomarkers evaluated were Aβ42, t-tau, and p-tau181, using Elecsys electro-chemiluminescence immunoassays on the cobas e601 platform (Roche Diagnostics). Results: From the 4380 patients who had GDS information, the MoCA test was collected from 438 patients, and 445 from the GDS test for depression, and the STAI screening for anxiety. There were no significant differences in biomarker levels between patients with depression (GDS ≥ 5) and those without (GDS < 5), nor between patients with anxiety (STAI > 40) and those with lower anxiety scores (STAI ≤ 40). In contrast, cognitive outcomes showed clear associations. Patients with cognitive impairment (MoCA < 26) demonstrated higher levels of pTau (p = 0.02) and tTau (p = 0.01), as well as elevated pTau/Aβ42 (p = 0.003) and tTau/Aβ42 (p = 0.002) ratios compared to those with MoCA ≥ 26. In multivariate analysis, both pTau/Aβ42 > 0.022 (OR 4.64, 95% CI 1.67–13.8) and tTau/Aβ42 > 0.26 (OR 4.18, 95% CI 1.6–11.5) remained significantly associated with cognitive decline. In a longitudinal analysis in the first 3 years of follow-up, cognition in PD remained lower than in controls, while CSF p-tau and Aβ42 remained higher in controls. Conclusions: In our cohort, no associations were found between CSF biomarkers and depression or anxiety, underscoring that mood disturbances in PD are likely mediated by alternative mechanisms such as monoaminergic dysregulation, neuroinflammation, and psychosocial factors. By contrast, cognitive performance (MoCA) was clearly linked to tau-related pathology, rather than α-synuclein or Aβ42 alone. While Aβ42 and α-synuclein remain useful for staging and assessing global disease risk, our findings highlight the specificity of tau-related pathology for cognitive outcomes in PD. Full article

Butylparaben (BP), a widely used preservative, was implicated in cognitive impairment, though its neurotoxic mechanisms remain elusive. Basal forebrain cholinergic neurons (BFCN) are selectively lost in dementias, contributing to cognitive decline. To explore different mechanisms related with BFCN loss, we employed BF SN56 cholinergic wild-type or silenced cells for Tau, amyloid-beta precursor protein (βApp), acetylcholinesterase (AChE), or glycogen synthase kinase-3 beta (GSK3β) genes, exposing them to BP (0.1–80 µM) for 1 or 14 days alongside triiodothyronine (T3; 15 nM), N-acetylcysteine (NAC; 1 mM), or recombinant heat shock protein 70 (rHSP70; 30 µM). BP disrupted cholinergic transmission by AChE inhibition and provoked cell death through thyroid hormones (THs) pathway disruption, Aβ/p-Tau protein accumulation, AChE-S overexpression, and oxidative stress (OS). Aβ/p-Tau accumulation was correlated with HSP70 downregulation, OS exacerbation, and GSK3β hyperactivation (for p-Tau). BP-induced OS was mediated by reactive oxygen species (ROS) overproduction and nuclear factor erythroid 2-related factor 2 (NRF2) pathway disruption. All observed effects were contingent upon TH signaling impairment. These findings uncover novel mechanistic links between BP exposure and BFCN neurodegeneration, providing a framework for therapeutic strategies. Full article

Background: Borderline Personality Disorder (BPD) often emerges during adolescence and young adulthood, a period marked by heightened vulnerability to impulsivity and affective dysregulation. While impulsivity is a core feature of BPD, its multidimensional expression in this age group remains insufficiently documented. This study examined impulsivity traits in young adults with BPD, their associations with depressive and anxiety symptoms, and their links to risk behaviors. Methods: A total of 160 participants aged 16–25 were recruited in Belgium between 2021 and 2023: 44 with BPD from inpatient and outpatient psychiatric services and 116 healthy controls from schools and universities. Assessments included the short UPPS-P, Beck Depression Inventory-II (BDI-II), State-Trait Anxiety Inventory (STAI-T), and the Diagnostic Interview for Borderlines–Revised (DIB-R). Logistic regressions with robust errors and Kendall’s tau-b correlations were used. Results: Compared with controls, individuals with BPD scored higher on all UPPS-p subscales except Sensation Seeking (e.g., Negative Urgency: 14 vs. 10, p < 0.001). Logistic regression identified Negative Urgency (OR = 5.31, 95% CI: 2.07–13.62, p = 0.001) and Positive Urgency (OR = 3.26, 95% CI: 1.37–7.75, p = 0.007) as independent predictors of BPD. Within the BPD group, depressive and anxiety symptoms correlated with several UPPS-P dimensions, notably Negative Urgency and Lack of Perseverance. Suicide attempts were associated with the DIB-R total score, BDI-II, and STAI-T, while substance use was linked to the DIB-R impulsivity subscale and STAI-T. Conclusions: Emotional impulsivity—particularly Negative Urgency—emerges as a central feature of BPD in emerging adulthood. Its interplay with depressive and anxiety symptoms, and its associations with suicidal and addictive behaviors, support a dual-level conceptualization of impulsivity as both a dispositional trait and a state-dependent clinical risk factor. Full article

The prediction of stock prices is challenging due to their volatility, irregular patterns, and complex time-series structure. Reliably forecasting stock market data plays a crucial role in minimizing financial risk and optimizing investment strategies. However, traditional models often struggle to capture temporal dependencies and extract relevant features from noisy inputs, which limits their predictive performance. To improve this, we developed an enhanced recursive feature elimination (RFE) method that blends the importance of impurity-based features from random forest and gradient boosting models with Kendall tau correlation analysis, and we applied SHapley Additive exPlanations (SHAP) analysis to externally validate the reliability of the selected features. This approach leads to more consistent and reliable feature selection for short-term stock prediction over 1-, 3-, and 7-day intervals. The proposed deep learning (DL) architecture integrates a temporal convolutional network (TCN) for long-term pattern recognition, a gated recurrent unit (GRU) for sequence capture, and multi-head attention (MHA) for focusing on critical information, thereby achieving superior predictive performance. We evaluate the proposed approach using daily stock price data from three leading companies—HDFC Bank, Tata Consultancy Services (TCS), and Tesla—and two major stock indices: Nifty 50 and S&P 500. The performance of our model is compared against five benchmark models: temporal convolutional network (TCN), long short-term memory (LSTM), GRU, Bidirectional GRU, and a hybrid TCN–GRU model. Our method consistently shows lower error rates and higher predictive accuracy across all datasets, as measured by four commonly used performance metrics. Full article

Hyperechoic vertical artifacts are an essential feature of lung ultrasound (LUS) arising from various pathological states. Those that meet the criteria for B-lines have the most significant diagnostic value and should be differentiated from other hyperechoic vertical artifacts of unspecified clinical importance. Although numerous studies have assessed the impacts of transducer type on the appearance of B-lines in human medicine, comparative studies in veterinary medicine are limited and conflicting. This study compares three transducer types for the assessment of hyperechoic vertical artifacts in dogs. We hypothesize that there is high-level reviewer agreement in the assessment of HVA image quality and characteristics, and that the image quality/characteristics differ between the three transducers. Dogs (n = 8) with HVAs and sonographic absence of lung consolidations, pleural effusion, and/or pneumothorax were enrolled. Twenty-four cine-loops (5 s) containing HVAs were retrospectively and independently reviewed by two reviewers, who were blinded to the case details but not transducer type. The reviewers assessed the cine-loops for the following: whether HVAs meet the B-line criteria, ease of counting HVAs, and overall image quality. Paired cine-loops from the same patient using different transducers were then presented for HVA quality comparison. Inter-rater concordance was determined using the Kappa coefficient, Kendall’s tau, and Pearson correlation coefficient, while characteristics were compared using chi-square and Kruskal–Wallis tests (level of significance, α = 0.05). The overall concordance of image quality was good (Pearson’s coefficient = 0.82). The PA transducer scored lower in image quality (p < 0.001), HVA blending (p = 0.014), graininess (p < 0.001), and clarity of edges (p < 0.001) when compared with the microconvex and linear transducers, and the identification of B-line criteria differed between transducers (p = 0.024). Furthermore, the PA scored lowest in the comparison of paired cine-loops regarding the image and HVA quality (p < 0.001). Although more HVAs failed to reach the far field with the linear transducer (10/16, 62.5%) compared with the microconvex (8/16, 50%) and PA (3/16, 18.5%) transducers, the linear transducer scored higher than the microconvex and PA transducers regarding its ability to count B-lines (p < 0.001). This study demonstrates that the type of transducer significantly impacts the characteristics of HVAs, with the PA transducer producing lower-quality images compared with the microconvex and linear transducers. Full article