Search Results (612)

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by high metabolic activity, chronic endoplasmic reticulum stress, and persistent redox imbalance. Excessive immunoglobulin synthesis and adaptation to the hypoxic bone marrow microenvironment lead to sustained production of reactive oxygen species (ROS). Their excessive accumulation promotes genomic instability, disease progression, osteolytic bone disease, and resistance to therapy. Paradoxically, MM cells adapt to oxidative stress by activating antioxidant and metabolic defense mechanisms, including Nuclear factor erythroid 2-related factor 2 (NRF2)- and Heme Oxygenase 1 (HMOX1)-dependent pathways, metabolic reprogramming, and overexpression of ROS-scavenging enzymes such as peroxiredoxin 6 (PRDX6), allowing survival at the threshold of oxidative toxicity. Evidence indicates that biomarkers of oxidative stress—such as lipid and protein oxidation products, antioxidant enzyme activity, and the Oxidative Stress Score—correlate with disease stage, prognosis, and treatment response. Redox-modulating therapeutic strategies, including pharmacological ROS induction, inhibition of antioxidant defenses, and the use of natural pro-oxidant compounds, are emerging as promising adjuncts to standard MM therapies. Recent studies also highlight the gut microbiota as an indirect regulator of oxidative balance, immune modulation, and metabolic homeostasis in MM. This review summarizes current knowledge on oxidative stress in multiple myeloma, emphasizing its role in pathogenesis, drug resistance, biomarker development, and emerging therapeutic and supportive strategies. Full article

Systematically characterizing the time series deformation evolution of open-pit mine slopes is key to revealing their potential instability development and supporting subsequent deformation-level classification. Interferometric Synthetic Aperture Radar (InSAR), by enabling measurement of ground deformation at a global scale approximately every ten days, may hold the key to those interactions. However, atmospheric propagation delays still have a significant impact on deformation calculations, and open-pit mine slopes monitored by InSAR often suffer from low coherence. This noise can obscure nonlinear and transient precursory signatures in deformation time series, reducing the identifiability of key temporal patterns required for automated interpretation. Here, we present a Coherence-conditioned Encoder–Decoder Long Short-Term Memory (CED-LSTM) denoising network for deformation time series. We generate a physics-aware synthetic dataset by modeling coherence-dependent measurement noise and temporally correlated atmospheric delays. The network jointly models deformation time series and coherence, using residual learning and adaptive gated composite loss to preserve deformation trends. It is designed to autonomously extract ground deformation signals from noise in InSAR time series without prior knowledge of where deformation occurs or how it evolves. On the synthetic validation set, the network achieved a root mean square error (RMSE) of 2.2 mm across the validation sequences. Applied to three InSAR datasets over an open-pit mine from March 2019 to March 2022, denoising suppresses noise and stabilizes deformation boundaries, enabling extraction of trend and transient indicators and a data-driven deformation-level score. Using quantile-based thresholds, these scores are then used to produce multi-year deformation-level classification maps. Full article

Background: Youth mental health services increasingly encounter adolescents and young adults with complex affective presentations and trauma histories. Dissociation has been proposed as a clinically relevant marker within bipolar vulnerability pathways but remains underrecognized in early-intervention settings. This pilot study investigated the prevalence and clinical correlates of bipolar at-risk (BAR) status in a help-seeking youth sample, with specific focus on dissociative symptoms in this vulnerable population. Methods: A pilot study with a cross-sectional design was conducted in a specialized outpatient clinic for 14–25-year-olds. Seventy-six participants without Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision bipolar disorder completed a multidimensional assessment, including dissociative (Dissociative Experiences Scale version 2 [DES-II], Adolescent-DES [A-DES], Structured Clinical Interview for DSM Dissociative Disorders [SCID-D]), affective, anxiety, impulsivity, and prodromal symptom measures. BAR status (BAR+) was determined via clinical interview according to Bechdolf criteria. Clinically significant dissociation (DES+) was defined by established cut-offs at the DES-II and A-DES scales. Group comparisons, binary logistic regression and exploratory mediation analysis were performed. Results: In our sample, 44.7% of the participants met BAR+ criteria and 42.9% displayed clinically significant dissociation. Patients with BAR+ status more frequently reported familiar history of affective disorders, previous antidepressant use, loneliness, and non-suicidal self-injury. They displayed more severe depressive symptoms and impulsivity, as well as higher scores at all the affective temperament subscale except for hyperthymic. BAR+ patients displayed higher prevalence of dissociative symptoms than BAR− (51.6% vs. 24.2%; p = 0.045). Among the BAR+ subgroup, DES+ youths showed greater traumatic burden, depressive symptoms, and anxious temperament scores. Dissociation was associated with BAR+ status (OR 3.2) after adjusting for age, gender, and loneliness, while attentional impulsivity did not mediate this relationship. Conclusions: Dissociative symptomatology is highly prevalent among help-seeking youths and is directly associated with subthreshold bipolar-spectrum vulnerability. A dissociative BAR phenotype, marked by emotional instability and trauma exposure, may delineate a clinically complex subgroup, supporting the integration of dissociation-focused assessment into youth bipolar-risk staging and early-intervention protocols. Full article

Structure-based strategies are widely used in tuberculosis drug discovery; however, their translational impact remains limited. This review examines how structure-based virtual screening (SBVS) is applied in practice to Mycobacterium tuberculosis targets and explores why docking-derived predictions frequently fail to translate into measurable biological activity. Rather than treating docking scores as quantitative predictors of potency, representative case studies are analyzed to demonstrate that SBVS is most effective when employed as a prioritization framework integrated with appropriate target preparation, physicochemical filtering, and early experimental validation. Across diverse targets, molecular dynamics simulations emerge as a critical discriminator, enabling the identification of binding instability and false-positive hits that persist after static docking. Tuberculosis-specific constraints—including cofactor-dependent catalysis, resistance-associated mutations, membrane-rich environments, and permeability barriers—are discussed as key factors decoupling in silico affinity from whole-cell efficacy. Collectively, these observations support a workflow-oriented view of computational drug discovery in tuberculosis, in which iterative integration of structural modeling and experimental validation is required for meaningful lead identification. Full article

Background: Work-related stress represents a major challenge for nursing professionals and has significant implications for well-being, job satisfaction, and workforce stability. This study aimed to assess psychosocial working conditions and workplace stress among nurses in Slovenia and to identify organisational and occupational factors associated with stress exposure across different levels of care. Methods: A cross-sectional, non-experimental study was conducted using an online self-administered questionnaire. The sample included 736 nurses employed in outpatient settings, hospital wards, and high-intensity care units. Work-related stress was assessed using the Health and Safety Executive (HSE) Work-Related Stress Indicator Tool. Group differences were examined using the Kruskal–Wallis test with Bonferroni-adjusted post hoc comparisons. Associations between HSE dimensions and sociodemographic and work-related variables were analysed using Spearman’s correlation coefficients and multiple linear regression models. Results: Statistically significant differences between job positions by level of care were observed for all HSE domains except Demands. Differences in psychosocial working conditions were observed across levels of care, with several domains showing more favourable scores in outpatient and hospital ward settings compared with high-intensity care environments. Regression analyses identified job position by level of care, education level, income, workload indicators, continuous healthcare provision, and job mobility intentions as significant predictors across multiple HSE dimensions. Correlation analyses revealed consistent associations between adverse psychosocial working conditions, increased workload, and indicators of job mobility. Conclusions: This study shows that psychosocial working conditions among nurses in Slovenia differ by level of care, with several domains showing more favourable scores in outpatient and hospital ward settings than in high-intensity care environments. Work organisation—especially workload, role clarity, and managerial and peer support—was central to stress, linking adverse conditions to workforce instability and retention risks. Full article

Background/Objectives: The aim of this study was to report first experiences with dynamic intraligamentary stabilization (DIS) technique for anterior cruciate ligament (ACL) rupture in children and adolescents. Methods: A case series of 22 children and adolescents with a mean age of 13.3 years underwent primary repair of an ACL rupture using the DIS technique as an off-label use in skeletally immature patients. Patients were evaluated for laxity, strength, range of motion (ROM), and functional tests, as well as Tegner, Lysholm, International Knee Documentation Committee (IKDC), and PedsQL scores after 3 years. A follow up after 11 years was conducted to analyze long-term results, rerupture rates and reinterventions. Results: Three years after surgery, there was no significant difference in laxity, strength, ROM, and in the functional tests comparing the injured to the contralateral knee. The Tegner Index after surgery showed a slight drop of 0.8 points, from 7.1 preoperatively to 6.3. Mean IKDC, Lysholm, and peds-QL scores were 91.17 (range 62.64–98.85, median 94.25), 88.27 (range 58–100, median 93), and 88.78 (range 58.15–100, median 91.30). Overall failure rate of the DIS-repaired knees was 55% (12 of 22 patients). In ten patients, reruptures happened at an average time of 3.2 years after initial surgery; additionally, two patients with chronic instability had to undergo revision ACL reconstruction. Conclusions: DIS repair might help ACL healing with satisfactory functional outcomes. However, given the high failure and reintervention rates, further studies need to show non-inferiority of the DIS technique in children and adolescents before being considered a valid treatment option. Full article

The Swine hepatitis E virus (SHEV) ORF3 protein is pivotal in pathogenesis, yet its regulation of host metabolic homeostasis via endogenous RNA networks remains unclear. This study aimed to elucidate how the SHEV ORF3-mediated circRNA-miRNA network modulates riboflavin metabolism and triggers the aberrant activation of the ko05212 pathway, while also evaluating their physical interactions using AlphaFold 3 structural simulations. To achieve this, high-throughput RNA sequencing, KEGG pathway analysis, and AlphaFold 3 structural simulations were employed to elucidate the circRNA-miRNA-mRNA regulatory network and potential physical interactions. Transcriptomics revealed a “dual activation” of Riboflavin metabolism and Pancreatic cancer pathways. Specifically, we identified an “ENPP Isozyme Switch,” where upregulated hsa_circ_0077855 sponges miR-181a-2-3p, relieving repression of the metabolic enzyme ENPP3 and proto-oncogene KRAS. Furthermore, AlphaFold 3 simulations yielded an extremely low interface predicted Template Modeling score (ipTM = 0.08), refuting direct physical binding, and ORF3 was found to suppress the m6A eraser FTO, suggesting host epigenetic instability. Consequently, SHEV ORF3 induces metabolic remodeling through a dual “epigenetic-post-transcriptional” mechanism: disrupting m6A homeostasis via FTO suppression and constructing a pathogenic ceRNA network via the ENPP3/miR-181a/KRAS axis. These findings highlight the critical role of non-coding RNAs in driving the virus-induced “pre-pathological state”. Full article

Despite anatomically successful fixation of distal radius and Galeazzi fractures, a subset of patients develops persistent pain and functional limitation, suggesting that factors beyond osseous alignment influence recovery. Distal radioulnar joint instability has been implicated in unfavorable outcomes, yet intraoperative assessment remains inconsistently standardized and has rarely been validated as a prognostic variable. This prospective multicenter observational cohort study included 120 consecutive patients with distal radius or Galeazzi fractures treated with plate fixation in two tertiary centers. After fracture reduction and stabilization, intraoperative distal radioulnar joint stability was systematically assessed using a previously published classification system comprising Grades I to III, with patients demonstrating no instability serving as the reference group. The primary outcome was the QuickDASH score at 12 months, while secondary outcomes included pain intensity, grip strength, radiographic distal radioulnar joint gap, and postoperative complications. Multivariable linear regression was used to evaluate the association between intraoperative instability grade and outcomes, adjusting for age, sex, fracture type, and treatment center. Increasing instability grade was independently associated with worse functional outcome, higher pain levels, reduced grip strength, and greater postoperative distal radioulnar joint widening at 12 months, with an adjusted increase of approximately 5 to 6 QuickDASH points per grade. Intraoperative distal radioulnar joint instability grading provides clinically relevant prognostic information and supports postoperative risk stratification following distal radius and Galeazzi fractures. Full article

Background: Latent tuberculosis infection (LTBI) is the principal reservoir for active tuberculosis, with >85% of cases attributable to reactivation. Bacillus Calmette-Guérin fails to block this transition, leaving a critical gap in prevention. Methods: An immunoinformatics/reverse-vaccinology pipeline was applied to seven dormancy-related antigens retrieved from Mycobrowser. T-cell epitopes were predicted with NetMHCI/IIpan-4.1 and B-cell epitopes with ABCpred; antigenicity, allergenicity, and toxicity were evaluated with VaxiJen, AllerTOP, and ToxinPred. Secondary/tertiary structures were modeled with PSIPRED and AlphaFold-3; docking to Toll-like receptors (TLR) 2/4 and 100 ns molecular dynamics simulations assessed complex stability. Immune responses were simulated with C-ImmSim, and the mRNA sequence was human-codon-optimized using ExpOptimizer. Results: The resulting construct, RP14914P, encodes 14 cytotoxic T lymphocyte, 9 helper T lymphocyte, and 14 B-cell epitopes within an 866-aa, 90.4 kDa polypeptide. Antigenicity score = 0.7797, immunogenicity score = 8.58629. and no toxicity or allergenicity was predicted. Physicochemical analysis: instability index = 28.65, and solubility = 0.513. Estimated population coverage is 82.35% and 99.67% for Human Leukocyte Antigen (HLA)-I and HLA-II globally. Docking energies: −1477.8 kcal/mol (TLR2) and −1480.1 kcal/mol (TLR4). Molecular dynamics trajectories confirm stable binding. Immune simulation predicts potent activation of Natural Killer cells, macrophages, and dendritic cells, Th1 polarization, high interferon-γ/interleukin-2 secretion, and durable memory. Conclusions: In silico analyses predict that RP14914P exhibits favorable immunogenicity, safety, and broad population coverage, suggesting its potential as a promising mRNA vaccine candidate to prevent LTBI reactivation. However, these computational predictions require thorough experimental validation to confirm the vaccine’s immunogenicity and protective efficacy. Full article

Background: Atrial fibrillation (AF) is frequently encountered in patients presenting with acute coronary syndrome (ACS); however, its clinical significance beyond being a simple rhythm disturbance remains debated. We hypothesized that AF at presentation may be associated with a high-risk clinical profile characterized by hemodynamic instability and increased inflammatory and ischemic activity. Methods: This single-center, retrospective observational study included consecutive adult patients with acute coronary syndrome admitted to a tertiary cardiology center between January 2022 and December 2024. Patients were classified into two groups according to cardiac rhythm at presentation: AF and sinus rhythm. Baseline demographic characteristics, hemodynamic parameters, laboratory biomarkers, validated risk scores, and revascularization strategies were compared between groups. Multivariable logistic regression analysis was performed to evaluate whether AF was independently associated with a high-risk presentation, primarily defined by elevated GRACE risk score, reduced left ventricular ejection fraction, and increased inflammatory markers. Results: A total of 158 patients were included, of whom 50 (31.6%) presented with atrial fibrillation (mean age 71.2 ± 11.4 years, 46% female). Compared with patients in sinus rhythm, those with AF had significantly higher GRACE risk scores, lower left ventricular ejection fraction, faster heart rate, and higher white blood cell counts and peak high-sensitivity troponin levels. These associations remained significant after multivariable adjustment. Patients with AF also showed a numerically higher prevalence of severe angina at presentation. Conclusions: In patients presenting with ACS, atrial fibrillation is associated with a high-risk hemodynamic profile accompanied by increased inflammatory and ischemic activity. Rather than being an incidental finding, AF may represent a clinically relevant marker of acute cardiovascular stress and may contribute to early risk stratification in this setting. Full article

Background: Chronic ankle instability (CAI) is a common functional disorder in older adults, affecting their balance and quality of life. Therefore, finding effective ways to enhance ankle stability and function under safe conditions remains a key issue for healthy aging. Objective: This study aims to explore the effects of the Otago Exercise Program (OEP) combined with Neuromuscular Electrical Stimulation (NMES) on ankle stability, the pain index, and balance ability in older adults aged 60 and above with CAI. Methods: This study is a single-blind pilot randomized controlled trial, including 36 eligible older adults with CAI, with 34 completing the trial. Participants were randomly assigned to the OEP group, the combined group (OEP + NMES), and the control group. The intervention period lasted 8 weeks. Evaluation measures included the Cumberland Ankle Instability Tool (CAIT), Visual Analog Scale (VAS), Eyes-closed Single-Leg Stance Test (UST), and the Modified Star Excursion Balance Test (mSEBT), with assessments conducted before the intervention, at week 4, and at week 8. Result: After the intervention, all three groups showed significant improvements in CAIT, VAS, UST, and mSEBT scores (p < 0.05), with a large group × time effect observed for the primary outcome CAIT (partial η² = 0.414). The combined group (OEP + NMES) demonstrated the most significant improvement in CAIT and UST scores (p < 0.05) and outperformed the other two groups in dynamic balance in the posteromedial and posterolateral directions. Conclusions: The combined intervention of OEP and NMES significantly improves ankle stability, both static and dynamic balance abilities, and alleviates pain in older adults with CAI. This combined approach offers a safe and effective rehabilitation strategy for the older adults, with promising clinical application prospects. Full article

Background/Objectives: The optimal transport strategy for patients with traumatic brain injury (TBI) remains debated, particularly in trauma systems where inter-hospital transfer is common. Whether secondary transfer independently influences mortality after risk adjustment is unclear. This study aimed to evaluate the association between admission route and in-hospital mortality among patients with TBI at a major trauma center (MTC). Methods: This retrospective observational study included 417 patients with TBI and an Abbreviated Injury Scale (AIS) head score ≥ 3 (direct admission: 245; inter-hospital transfer: 172). Severe TBI was defined as a total Glasgow Coma Scale (GCS) score ≤ 8 or the need for advanced airway management. Multivariable logistic regression was performed to assess whether admission route was independently associated with in-hospital mortality after adjustment for age, physiological status at MTC arrival, and injury severity. Subgroup analysis was conducted in patients with severe TBI. Results: Crude mortality was higher in the direct admission group than in the transfer group (40.8% vs. 26.7%; p = 0.003), despite significantly longer injury-to-trauma center arrival times in transferred patients (219.0 vs. 44.0 min). In multivariable analysis, admission route was not independently associated with mortality in the overall cohort (adjusted odds ratio [aOR] 0.75; 95% CI 0.44–1.28; p = 0.298) or in the severe TBI subgroup (n = 233; aOR 0.88; 95% CI 0.47–1.67; p = 0.705). Increasing age and lower GCS motor scores were consistently associated with higher mortality in both analyses. Conclusions: Inter-hospital transfer was not independently associated with increased in-hospital mortality among patients with TBI. After consideration of patient age and neurological severity, initial stabilization at a nearby hospital followed by transfer may be an acceptable transport strategy for patients who present with physiological instability requiring immediate resuscitative interventions. Full article

Epicardial adipose tissue (EAT) has previously been associated with coronary artery calcium scores, an increased burden of coronary artery disease (CAD), and features of plaque instability. These associations are likely mediated by endocrine and paracrine signaling from bioactive molecules secreted by EAT, which may contribute to coronary atherosclerosis. EAT can be non-invasively quantified on images obtained during coronary computed tomography angiography (CCTA). This study aimed to evaluate the potential association between EAT and non-calcified coronary plaques with severe stenosis using radiomic methodology. Materials and Methods: A total of 128 consecutive patients undergoing CCTA—both with and without contrast—for known or suspected CAD were retrospectively analyzed. EAT features were extracted from contrast scans. Coronary artery plaque features were evaluated using Coronary Artery Disease-Reporting and Data System (CAD-RADS). Results: EAT features showed a statistically significant positive correlation with non-calcified coronary plaques with severe grades of stenosis (CAD-RADS > 4). The Ensemble Machine Learning (EML) model combined with coronary plaque data showed a sensitivity of 1.00 and a specificity of 0.93, with a negative predictive value of 1.00 and a positive predictive value of 0.85, and an accuracy of 0.95 (95% CI: 0.9221–1) in internal validation. Conclusions: EAT may represent a novel imaging biomarker associated with the presence of actionable coronary plaques. Radiomic texture analysis of EAT could enhance the non-invasive prediction of coronary stenoses. These preliminary findings support the clinical utility of EAT evaluation via CCTA in patients with low to intermediate cardiovascular risk. Full article

Hemophilia is an X-linked inherited bleeding disorder characterized by joint hemorrhages and progressive arthropathy. While mutation type is known to influence disease severity, its impact on postural balance strategies has remained unclear. This cross-sectional study investigated the relationship between gene mutation type and postural control in hemophilia A patient using center of pressure (CoP) analysis and radiographic joint assessment with the Pettersson score. Thirty-five participants were divided into an INV group (intron 22 or intron 1 inversion of the F8 gene) and a NonINV group (other mutations). While the Pettersson scores and traditional time-domain CoP parameters (sway area, velocity) were comparable between groups, frequency domain analysis revealed a significant difference. INV group exhibited significantly higher energy content above 2 Hz in the anteroposterior direction compared to NonINV group. This genotype-specific spectral signature emerged despite comparable radiographic arthropathy and conventional CoP metrics, suggesting that frequency-domain CoP analysis can uncover subclinical postural adaptations in hemophilia A. These findings highlight the need for targeted proprioceptive training in this specific subpopulation to prevent subclinical instability and potential falls. Full article

Shoulder pain and shoulder surgery are increasingly prevalent and encompass a broad spectrum of pathologies, including rotator cuff disease, glenohumeral osteoarthritis, and shoulder instability. Growing evidence suggests that gender-related factors influence disease presentation, patient-reported outcomes, and postoperative recovery; however, these effects remain inconsistently reported across the literature. This current concepts review synthesizes available evidence on the influence of gender on pre-operative characteristics, non-operative management, and postoperative outcomes following common shoulder procedures, including rotator cuff repair, anatomic and reverse shoulder arthroplasty, and surgical stabilization for instability. A comprehensive literature search of PubMed, the Cochrane Library, and Google Scholar was performed for studies published through October 2025, with outcomes assessed using validated instruments such as the Western Ontario Rotator Cuff Index, American Shoulder and Elbow Surgeons score, Constant–Murley score, Simple Shoulder Test, Visual Analog Scale, and Shoulder Pain and Disability Index. Across shoulder pathologies, female patients consistently demonstrated worse pre-operative functional scores, higher pain levels, and greater perceived disability despite similar structural disease severity. Postoperatively, both genders experienced meaningful clinical improvement; however, females often reported higher early postoperative pain and lower absolute functional outcomes, particularly following shoulder arthroplasty for glenohumeral osteoarthritis and surgical treatment of multidirectional instability. In contrast, outcomes following rotator cuff repair and anterior instability stabilization were largely comparable between genders. Recognition of these gender-related differences is essential for individualized patient counseling, expectation setting, and optimization of management strategies, and highlights the need for future studies with robust gender-disaggregated analyses. Full article