Search Results (47,786)

Background/Objectives: Systemic lupus erythematosus (SLE) is a heterogeneous disease with substantial variability in clinical manifestations and outcomes, influenced by ethnic and geographical diversity. Remission is the optimal treatment target, while low lupus disease activity state is an accepted alternative goal. Although sustained remission has been associated with reduced organ damage, the impact of early attainment of treatment targets on subsequent damage accrual in SLE remains incompletely defined. To explore a potential window of opportunity, this study aimed to identify factors associated with achieving remission or low lupus disease activity state within the first year of SLE diagnosis and to examine their associations with organ damage. Methods: This retrospective study was conducted across 22 rheumatology centres in Malaysia and included patients with systemic lupus erythematosus (SLE) who had complete follow-up from diagnosis until attainment of treatment targets. Treatment targets were defined as achieving either early remission or a low disease activity state (LDAS). Given the retrospective nature of the study and the unavailability of complete Physician’s Global Assessment data, the definitions of early remission and LDAS were modified by excluding this component. Accordingly, treatment targets were defined as attainment of a clinical SLE Disease Activity Index (cSLEDAI) score of 0 with oral prednisolone doses of ≤5 mg/day and ≤7.5 mg/day, respectively, within 12 months of SLE onset. Multivariable Cox proportional hazards regression and logistic regression analyses were performed to determine factors associated with early remission and organ damage, respectively. Results: A total of 1599 patients were included, the majority of whom were female (92.5%). The cohort was predominantly Malay (68.7%), followed by Chinese (17.4%), Indigenous groups (10.8%) and Indian (3.0%). Early attainment of treatment targets was achieved in 45.7% of patients, while 54.3% experienced delayed attainment. In the multivariable cox regression model, the Malay and Chinese ethnic group demonstrated a significantly lower likelihood of achieving early remission compared to the Indigenous ethnic group. Patients with longer SLE duration, low C4 levels, presence of haematological and renal manifestations at the initial presentation, were identified as additional adverse factors associated with lower likelihood of early remission. Overall, 16.9% of patients accrued organ damage. Independent factors associated with organ damage included Indian ethnicity [OR 5.75, 95% CI 1.39–23.81, p = 0.02], delayed remission [OR 2.97, 95% CI 1.51–5.83) and absence of baseline hydroxychloroquine therapy [OR 4.13, 95% CI 1.21–14.07; p = 0.020]. Conclusions: Ethnic disparities were observed in the early attainment of the treatment targets, as well as in organ damage accrual within the Malaysian multi-ethnic SLE cohort. The significant association between the delay in achieving the treatment targets and organ damage underscores the importance of adopting an early treat-to-target approach in SLE management. Full article

Objectives: To investigate the predictive value of the peripheral blood neutrophil percentage and serum albumin ratio (NPAR) for overall survival after radical resection of hepatocellular carcinoma, and to construct a nomogram prediction model. Methods: A retrospective cohort study was performed, including patients who underwent radical resection of hepatocellular carcinoma at the Second Hospital of Lanzhou University from 2013 to 2023. The optimal cut-off value of the NPAR was determined by a ROC curve. Kaplan–Meier and log-rank tests were used for grouping. Cox regression was used to analyze prognostic factors and construct a nomogram. Results: A total of 207 patients were included in this study. ROC curve analysis was conducted using preoperative NPAR values, and the results showed an area under the curve (AUC) of 0.72, the optimal cut-off value of the NPAR was 14.83, and the high NPAR (≥14.83) group had better overall survival and disease-free survival. Multivariable analysis showed that an NPAR ≥ 14.83, tumor diameter > 5 cm, multiple tumors, and low tumor differentiation were independent risk factors for overall survival. The C-index of the nomogram for overall survival (OS) was 0.77, indicating a moderate but clinically acceptable discriminative ability for predicting overall survival. Conclusions: Preoperative NPAR is an effective prognostic marker, and the established nomogram can accurately predict the overall survival of patients. Full article

Background/Objectives: The itch–scratch cycle is a key driver of exacerbation in atopic dermatitis (AD) and requires objective monitoring, yet patient-reported itch scores are often unreliable in children. This study aimed to evaluate smartwatch-derived nocturnal scratching metrics as digital biomarkers of disease activity and treatment response in pediatric AD. Methods: In this prospective observational study, 50 children (median age 9 years) with physician-diagnosed AD wore an Apple Watch with the Itch Tracker application for 5–14 nights during initiation of topical therapy. Three scratch metrics—scratch count rate (SCR), scratch duration ratio (SDR), and scratch burden index (SBI, duration × intensity)—were analyzed. Associations with clinical outcomes [Eczema Area and Severity Index (EASI), Patient-Oriented Eczema Measure (POEM)], serum thymus and activation-regulated chemokine (TARC), and itch numerical rating scale (NRS) were examined. Logistic regression models were evaluated to examine whether these metrics could identify children who achieved clinically meaningful improvement, defined as EASI-50 plus ≥ 4-point POEM reduction. Results: All scratch metrics correlated with baseline EASI (r = 0.60–0.64, p < 0.001) and serum TARC (r = 0.58–0.60, p < 0.001). Reductions in scratching paralleled clinical improvement (r = 0.67–0.71, p < 0.0001). Among models, the SBI-based logistic regression demonstrated the best discriminative performance (AUC = 0.78, 95% CI: 0.64–0.92). Conclusions: Wearable-derived nocturnal scratching metrics showed moderate but consistent associations with disease severity and short-term improvement. Although predictive capability remains to be established, these metrics may serve as treatment-responsive digital measures. Given the cross-sectional nature of biomarker analyses and other study limitations, further prospective validation is required before clinical application in real-world pediatric AD monitoring. Full article

The dipeptidyl peptidase (DPP) family comprises enzymes with important metabolic and immunomodulatory properties. This narrative review summarizes recent clinical and experimental evidence on the role of DPP-1, DPP-4, DPP-9, and DPP-10 in pulmonary diseases. The strongest translational evidence currently supports DPP-1 inhibition in non-cystic fibrosis bronchiectasis, where brensocatib reduces exacerbations and prolongs time to first exacerbation, with additional DPP-1 inhibitors in development. By contrast, the roles of DPP-4, DPP-9, and DPP-10 are supported mainly by preclinical studies in pulmonary hypertension, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), pulmonary fibrosis, asthma, non-small cell lung cancer (NSCLC), and nonsteroidal anti-inflammatory drugs (NSAIDs)/aspirin-exacerbated respiratory disease. Across these models, DPP inhibition modulates inflammation, protease activation, epithelial or endothelial mesenchymal transition, extracellular matrix (ECM) remodeling, and related signaling pathways. Overall, DPP-targeted interventions are promising in pulmonary medicine, but broader clinical translation will require well-designed prospective trials. Full article

Background: Colchicine is a microtubule-targeting anti-inflammatory agent with emerging relevance in cardiovascular disease; however, its effects on injury-induced vascular remodeling remain incompletely defined. Methods: In this study, a rat iliac artery clamp injury model was used to evaluate the effects of colchicine (0.5 mg/kg/day, oral gavage) over 28 days. Histomorphometric, histopathological, and immunohistochemical analyses were performed to assess vascular remodeling. In parallel, molecular docking and STRING/Cytoscape-based protein–protein interaction (PPI) network analyses were conducted to provide structural and systems-level context. Results: Colchicine significantly reduced intimal thickness, the intima-to-media (I/M) ratio, luminal stenosis, adventitial thickness, and collagen deposition, while preserving the lumen area and improving the remodeling index. Medial thickness was not significantly affected. Proliferative activity showed a decreasing trend without statistical significance. Circulating inflammatory cytokines, including TNF-α and IL-1β, did not differ significantly between groups. Docking analyses suggested potential interactions with β-tubulin, ADAM17, NLRP3, IKKβ, and RELA, while network analysis identified an interaction architecture centered on NF-κB-related regulatory components and inflammasome-associated signaling pathways. Conclusions: Colchicine attenuates injury-induced vascular remodeling in this experimental model. These findings, together with complementary in silico analyses, suggest a multi-target, inflammation-associated framework involving NF-κB-related and inflammasome-linked pathways. The in silico analyses provide supportive mechanistic context but do not establish causal relationships. Full article

Alzheimer’s disease (AD) is increasingly recognized as a multisystem neurodegenerative disorder in which sensory dysfunction accompanies cognitive decline. As an accessible extension of the central nervous system, the retina provides a valuable window for investigating early neurodegenerative processes; however, the cellular mechanisms underlying AD-associated retinal pathology remain incompletely understood. Here, using the APP/PS1 mouse model, we systematically examined structural, functional, and glial alterations in the retina across disease stages. Despite robust age-dependent amyloid plaque accumulation in visual-related brain regions, no plaque-like β-amyloid (Aβ) deposits were detected in the retina even at advanced ages. Nevertheless, young APP/PS1 mice exhibited early thinning of inner retinal layers, impaired retinal electrophysiological responses, and reduced excitatory synaptic inputs to retinal ganglion cells (RGCs), preceding overt neuronal loss. These neuronal changes were accompanied by pronounced Müller glial activation, characterized by upregulation of gliosis markers and extensive morphological remodeling. Functional analyses further revealed dynamic alterations in glial homeostasis, including early elevation followed by age-dependent decline of glutamine synthetase activity, together with increased expression and disrupted perivascular polarity of aquaporin-4. Consistently, transcriptomic profiling of young AD retinas identified coordinated dysregulation of genes involved in amino acid metabolism, transport, and oxidative stress responses. Together, our findings identify Müller glial remodeling as an early feature of AD-associated retinal pathology that coincides with synaptic vulnerability of RGCs and occurs independently of local Aβ plaque deposition, highlighting retinal glia as potential early indicators and modulators of neurodegeneration. Full article

Crimean–Congo hemorrhagic fever virus (CCHFV) and severe fever with thrombocytopenia syndrome virus (SFTSV) are tick-borne pathogens that cause severe illness and high mortality. Early diagnosis is critical, particularly in resource-limited settings, to enable timely intervention. Host gene expression profiling offers a promising approach to identify potential biomarkers for early detection, disease staging, and logical treatment decision-making. Using a transient IFN-α/β receptor-suppressed mouse model, we performed targeted transcriptomic analysis on blood samples collected at 2, 3, and 4 days after CCHFV or SFTSV challenge. A significant increase in viral load and changes in gene expression were observed as early as two days post-challenge. CCHFV induced a progressively evolving interferon-driven response, while SFTSV triggered rapid, sustained immune activation. Affected targets included interferon-stimulated genes, chemokines, cytokines, Toll-like receptors, and genes associated with viral evasion and innate immune response. Despite shared expression patterns, unique genes were identified as potential biomarkers to distinguish between CCHFV and SFTSV infections. Differential gene expression revealed distinct immune response dynamics, with suppression of critical immune regulatory genes suggesting transcriptional signatures associated with viral evasion mechanisms contributing to disease severity. These findings provide a comparative analysis of molecular pathways and gene expression changes, offering critical insights for biomarker discovery, effective triage, and evaluation of appropriate medical intervention. Full article

Celiac disease (CD) is an autoimmune inflammatory enteropathy triggered by consuming gluten-containing cereals. A key role in its pathogenesis is played by type 2 transglutaminase, an enzyme that causes an increase in gluten immunogenicity. Celiac cells seem to present constitutive characteristics, even recognizable under a gluten-free diet, such as defects in vesicular trafficking and autophagy, protein hyperphosphorylation, and cytoskeleton rearrangement. In this work, by using an omics approach, we attempted to identify those proteins differentially expressed or differentially phosphorylated in a cell model suitable to study cell behavior in the absence of inflammation, i.e., primary cultures of dermal fibroblasts from control or CD subjects. By performing mass spectrometry analyses, we found several up- and-down expressed or phosphorylated proteins in CD samples, mainly involved in signaling, homeostatic responses, cytoskeleton organization, vesicular trafficking, and extracellular vesiculation. These proteins may represent a molecular signature of the celiac cellular phenotype and may contribute to adding new insight into the comprehension of the complex mechanisms of CD pathogenesis. Full article

Background: Pediatric liver disease is frequently associated with abnormal conventional coagulation tests; however, prothrombin time expressed as international normalized ratio (PT-INR) incompletely reflect global hemostatic balance. Thrombin generation assay (TGA) provide an integrated assessment of coagulation and may offer complementary information in children with acute liver failure (ALF) and chronic liver disease (CLD). Methods: We enrolled 61 pediatric patients with liver disease (50 CLD, 8 ALF, 3 extrahepatic portal vein obstruction EHPVO) and 51 healthy controls. Platelet-poor plasma was prepared according to international recommendations. Thrombin generation was measured using ST Genesia (STG) with normalization to reference plasma. Group comparisons were performed using non-parametric tests; correlations between PT-INR and thrombin generation parameters were assessed, and principal component analysis (PCA) was used to explore the variance structure of thrombin generation indices and conventional coagulation variables. Results: PT-INR was significantly higher in patients than controls, particularly in ALF. Bleeding events were uncommon. Compared with controls, patients showed reduced levels of fibrinogen and multiple procoagulant/anticoagulant factors (including antithrombin and protein C), with increased factor VIII. Among thrombin generation parameters, the endogenous thrombin potential (ETP) ratio differed significantly across groups (p = 0.001), while correlations between PT-INR and thrombin generation parameters were weak or absent, no significant associations were observed even at higher Pediatric/Model for End-Stage Liver Disease scores. PCA separated thrombin generation indices from PT-INR and conventional coagulation factors, suggesting complementary information. Conclusions: In pediatric liver disease, PT-INR does not reliably reflect global coagulation capacity. Thrombin generation testing provides additional, integrative information on hemostasis and may improve laboratory assessment beyond conventional tests. Full article

Aluminum chloride (AlCl₃)-induced rat models are widely used to investigate Alzheimer-like neurodegeneration, yet substantial methodological variability limits cross-study comparability. A structured synthesis focused specifically on the methodological architecture of these models, including dose, exposure duration, route of administration, and behavioral assessment, remains lacking. This review aimed to synthesize the behavioral paradigms used to assess learning and memory in rat models of aluminum chloride-induced Alzheimer’s disease, with particular emphasis on dose, duration, and route of administration. A structured narrative review incorporating systematic elements was conducted following PRISMA-informed procedures using PubMed, Web of Science, and Scopus. The reviewed literature showed a predominance of oral administration, low-to-moderate AlCl₃ doses and subchronic exposure durations, most commonly 31–60 days. Behavioral assessment was dominated by hippocampal-dependent paradigms, particularly the Morris water maze and Y-maze. Across studies, AlCl₃ exposure was associated with multidomain behavioral impairment accompanied by consistent hippocampal and cortical histopathological abnormalities and convergent biochemical and molecular changes, including cholinergic dysfunction, oxidative stress, neuroinflammation, and amyloid- and tau-related alterations. Overall, the available literature does not support a standardized experimental protocol or a clear overall dose–effect or duration–effect relationship. Greater harmonization of study design is needed to improve reproducibility and translational relevance. Full article

There has been an immense concern in the healthcare industry about the globally raising rate of cardiovascular disease (CVD). As per recent WHO reports, CVD is the leading cause of disability, hospitalization and premature death. Studies indicate that oxidative stress negatively impacts the heart and vascular system, which could potentially lead to myocardial infarction, hypertension, cardiomyopathies, atherosclerosis and diabetic heart failure, highlighting its significance as a prognostic indicator in cardiovascular conditions. Nowadays, many common experimental assays are used for in-vitro and in-vivo evaluation of oxidative stress and its negative effects on the cardiovascular system. This review aims to serve as a comprehensive guide for researchers seeking to evaluate the impact of oxidative stress on DNA damage in CVD utilizing standardized methods published by leading institutions. To achieve this, we analyzed 208 relevant articles from prominent databases such as Scopus, PubMed, ScienceDirect, etc., summarizing experimental validation of oxidative stress measurements from 1955 to the present. Oxidative stress-induced DNA damage is a key driver of cardiovascular disease progression, yet experimental approaches to study it remains highly variable. This review systematically summarizes established in-vitro and in-vivo models, oxidative stress inducers, and analytical assays used in cardiovascular research. By integrating mechanistic insights with standardized methodologies, it provides a practical framework to guide model selection, improve reproducibility, and enhance translational relevance. This work serves as a concise reference for researchers investigating redox biology, cardiovascular pathology, and antioxidant-based therapeutic strategies. Full article

Background/Objectives: Vascular calcification and arterial stiffness are common in chronic kidney disease (CKD). Gla-rich protein (GRP) is a vitamin K-dependent protein implicated in mineral biology, but clinical evidence across CKD stages is limited. We evaluated associations of serum GRP with vascular calcification (VC) burden and arterial stiffness across CKD stages, including hemodialysis, compared with controls. Methods: In this prospective observational study, 185 adults were enrolled: controls (n = 61), individuals with CKD stage IIIb–IV (n = 61), and individuals with CKD stage V on hemodialysis (HD) (n = 63). Abdominal aortic calcification was assessed by the Kauppila score, and arterial stiffness was assessed by oscillometric pulse wave velocity (PWV). Serum GRP, FGF-23, and β-Klotho (KLb) were measured by ELISA. Non-parametric group comparisons and Bonferroni-corrected Spearman correlations were used. Results: GRP differed across groups (p < 0.001), showing a non-linear pattern with the lowest values in CKD IIIb–IV. PWV and Kauppila score increased across CKD stages (both p < 0.001). After Bonferroni correction, GRP correlated with KLb (ρ = 0.720) and FGF-23 (ρ = 0.625), but not with PWV or Kauppila score. In multivariable analyses, GRP showed a statistically significant but modest association with PWV and Kauppila score. Conclusions: In this CKD spectrum cohort, serum GRP was associated with CKD-MBD biochemical markers (KLb and FGF-23) much more strongly than with vascular phenotypes; its associations with vascular calcification burden and arterial stiffness were modest in multivariable modelling, supporting GRP as a marker of the CKD-MBD biochemical profile rather than a strong surrogate of vascular phenotype. Full article

The proteolytic processing of the amyloid precursor protein (APP) is a core pathological event in Alzheimer’s disease (AD) pathogenesis, yet the global genetic regulatory networks modulating this process have not been fully characterized. To systematically identify novel regulators of APP cleavage, we performed a genome-wide CRISPR/Cas9 knockout screen utilizing an optimized UAS-GAL4-based cellular reporter, and identified genetic modulators governing amyloidogenic and non-amyloidogenic processing. The screen uncovered distinct functional gene clusters regulating the APP, prominently involving cellular metabolism, protein modification, and vesicular trafficking. Specifically, LDHB, PIAS2, CCDC53, and TRIM61 emerged as novel functional modulators. Biochemical validation confirmed that ablating these genes significantly alters the metabolic balance between sAPPα and amyloid-β (Aβ) production. Finally, integration with human AD transcriptomic datasets demonstrated that these identified modulators undergo significant dysregulation in clinics. Together, these findings establish a reporter-based functional screening framework for APP processing and identify candidate regulatory nodes linked to metabolism, protein modification, and vesicular trafficking. These candidates provide a resource for future mechanistic investigation and validation in more disease-relevant AD models. Full article

Background: Right ventricular (RV) dysfunction is a key contributor to morbidity and mortality in systemic sclerosis (SSc), emerging from the combined effects of microvascular disease, myocardial fibrosis, interstitial lung involvement, and increasing pulmonary vascular load. Conventional echocardiography frequently fails to detect early RV impairment, prompting growing interest in deformation-based parameters such as RV free-wall longitudinal strain (RV-FWS), global longitudinal strain (RV-GLS), and RV–pulmonary artery (PA) coupling indices. Although natriuretic peptides reflect myocardial stress and are widely used in cardiopulmonary diseases, their integration with advanced RV imaging has been inconsistently reported in SSc. This systematic review synthesizes available evidence on RV strain, RV–PA coupling, and their relationship with clinical outcomes and biomarkers in SSc. Methods: A systematic search was conducted to identify clinical studies evaluating RV strain (RV-FWS, RV-GLS), right atrial strain, or RV–PA coupling indices in adult patients with SSc or SSc-associated pulmonary arterial hypertension (SSc-PAH). Eligible studies included those using speckle-tracking echocardiography or cardiac magnetic resonance feature-tracking. Study selection and data extraction were performed in accordance with PRISMA guidelines. Results: Seven studies met the eligibility criteria. Across unselected SSc cohorts, early disease without pulmonary hypertension (PH), and right-heart-catheterization-confirmed SSc-PAH, RV strain consistently detected myocardial impairment even when conventional echocardiographic indices remained normal. RV-FWS and RV-GLS were commonly reduced, and longitudinal data demonstrated progressive deterioration independent of standard measures. Strain-derived RV–PA coupling, particularly RV-FWS/PASP, significantly improved prognostic stratification when added to established PAH risk models. Two studies identified impaired RV deformation as a predictor of mortality, and CMR-derived right atrial strain provided additional prognostic value. Biomarker integration was limited, with only one study reporting an association between natriuretic peptide elevation (NT-proBNP) and impaired RV–PA coupling suggesting that biomarkers may reflect the hemodynamic load, although evidence remains limited captured by strain abnormalities. Conclusions: RV strain and RV–PA coupling indices are more sensitive than conventional echocardiography for detecting early RV dysfunction, monitoring disease progression, and predicting adverse outcomes in SSc. Although biomarker evidence remains limited, available data suggest that natriuretic peptides may provide complementary information to deformation-based assessment, although current evidence remains limited by reflecting combined myocardial and pulmonary vascular load. Standardized prospective studies including both strain imaging and biomarkers are needed to clarify the integrated diagnostic and prognostic value of advanced RV assessment in SSc. Full article

Gait impairment is a common motor manifestation of Parkinson’s disease (PD), which is also frequently accompanied by other motor abnormalities such as bradykinesia, rigidity, postural instability, and movement asymmetry. These motor impairments are closely associated with reduced mobility and increased fall risk. Although wearable plantar insole sensing provides a promising basis for objective gait assessment, existing studies have mainly focused on conventional time- or frequency-domain descriptors, whereas the nonlinear complexity of gait, laterality-related imbalance, and deviation from normal gait patterns remain insufficiently characterized in an integrated manner. To address this gap, this paper proposes FID-Gait, which is a three-domain fusion framework for PD identification using instrumented insole data. The framework combines automated gait-cycle segmentation with multidomain feature modeling, including a fractal domain for nonlinear gait complexity, a plantar-loading–phase imbalance (PLPI) domain for loading asymmetry and temporal disturbance, and a covariance-adjusted deviation (CAD) domain for measuring deviation from normal gait patterns. Experiments on the PhysioNet Gait in Parkinson’s Disease dataset showed that FID-Gait achieved strong discriminative performance under multiple evaluation protocols. At the gait-cycle level, the selected MLP classifier achieved an accuracy of 99.11% and an F1-score of 99.47%. At the subject level, the selected AdaBoost classifier achieved the highest accuracy of 90.22% and the best F1-score reached 93.02%. Five-fold cross-validation further supported the robustness of the proposed representation, and leave-one-subject-out evaluation provided preliminary evidence of subject-independent generalization. Overall, FID-Gait provides an effective and interpretable framework for PD gait characterization and identification in offline experimental settings. Full article