Search Results (48)

Background/Objectives: This study investigates the effects of multi-sensory stimulation on brain functional connectivity in patients with disorders of consciousness (DOC). DOC patients experience prolonged loss of consciousness due to brain injury, posing significant challenges for rehabilitation. Methods: In the study, visual, olfactory, and visual–olfactory (V-O) combined stimulation were applied to DOC patients while their EEG signals were recorded. A brain functional network was constructed based on the conditional Granger causality (CGC) method to analyze its topological characteristics. Results: The results revealed that the strength of brain functional connectivity in Minimally Conscious State (MCS) patients was significantly higher than that in Vegetative State (VS) patients, indicating a strong correlation between the intensity of synergistic activity in brain functional connectivity and the level of consciousness. Furthermore, V-O combined stimulation significantly enhanced brain functional connectivity compared to single-modality stimulation. The selection of different stimulation also differentially affected brain functional connectivity, with olfactory stimulation exhibiting high pleasure, arousal, and dominance (Self-Assessment Manikin) values demonstrating unique advantages in reducing individual variability and improving global efficiency. Conclusions: The study provides a theoretical foundation for the application of multi-sensory stimulation in the rehabilitation of DOC patients. V-O stimulation not only enhances information transmission in brain regions corresponding to visual and olfactory processing under single-modality stimulation but also increases the intensity of information transfer to other brain regions; this may serve as a reference for understanding the effects of multi-sensory stimulation on brain networks. Full article

Autoimmune thyroiditis (AIT) is characterized by dysregulated endocrine–immune interactions, and vitamin D has been proposed as a potential immunomodulatory factor influencing vaccine-induced immune responses. This study investigated the association between serum vitamin D status and humoral responses to SARS-CoV-2 vaccination in patients with AIT, while exploring potential molecular mechanisms using network pharmacology, molecular docking and Molecular Dynamics (MD) simulations. Patients were stratified according to serum 25-hydroxyvitamin D levels as deficient, insufficient, or sufficient. Anti–spike receptor-binding domain (RBD) IgG titers, thyroid autoantibodies, and thyroid-stimulating hormone levels were measured. In parallel, vitamin D₃ related molecular targets were integrated with AIT-associated genes, followed by protein–protein interaction analysis, molecular docking and MD simulations were performed to assess the interactions between vitamin D₃ (cholecalciferol) and selected key proteins. An inverse correlation was observed between serum vitamin D levels and anti-RBD IgG titers (p = 0.0013), with higher antibody responses detected in vitamin D-deficient patients. Network pharmacology analysis highlighted CYP19A1, CYP17A1, and ESR1 as prioritized targets associated with steroid hormone biosynthesis and endocrine signaling pathways. Molecular docking showed compatible binding of vitamin D₃ to these proteins, while MD simulations supported the structural stability of the complexes over time. Collectively, these findings suggest that vitamin D status may influence post-vaccination humoral immune responses in AIT, potentially through modulation of endocrine–immune crosstalk. Further longitudinal and mechanistic studies are required to clarify causality and clinical relevance. Full article

This paper investigates the syntax and diachrony of Italian causal clauses introduced by perché, siccome, and poiché. Although often treated as near-synonyms in Contemporary Italian, these subordinators differ systematically in their syntactic distribution, interpretive properties, and diachronic development. We show that perché introduces central adverbial clauses, merged within the vP/TP domain, whereas siccome and poiché introduce peripheral adverbial clauses, merged in the left periphery. This structural split correlates with a cluster of diagnostics: only perché-clauses can occur within the scope of matrix focus, negation, or epistemic operators, and only they can function as fragment answers. Conversely, siccome- and poiché-clauses consistently outscope matrix operators and encode non-at-issue content. A diachronic study reveals that the internal and external syntax of causal clauses introduced by each subordinator has remained stable from Old Italian to the present. However, siccome- and poiché-clauses display different semantics, as they derive from non-causal constructions (they originate from comparative and temporal clauses, respectively). We argue that the contrasting behaviors follow from the structural composition of the subordinators. Full article

Background and Objectives: Chronic kidney disease (CKD) and maintenance hemodialysis (HD) are frequently associated with psychological distress and impaired health-related quality of life (HRQoL). However, the relationships between depressive, anxiety, and stress symptoms, clinical factors, and HRQoL remain insufficiently understood in routine care. This study aimed to assess the prevalence of psychological distress and to explore cross-sectional correlates of kidney disease-specific and generic HRQoL in Romanian patients receiving long-term HD, providing one of the first detailed characterizations of these relationships in an Eastern European maintenance HD cohort. Materials and Methods: This single-center cross-sectional study included 125 adult patients undergoing maintenance HD for at least one year. Baseline assessment comprised socioeconomic, demographic and clinical and paraclinical data, including Charlson Comorbidity Index (CCI), dialysis adequacy (spKt/V), cognitive function, psychological distress assessed with the Depression, Anxiety and Stress Scale (DASS-21R), and HRQoL evaluated using the Kidney Disease Quality of Life Short Form (KDQOL-SF™ 1.3). HRQoL domains and physical and mental component summary scores (PCS, MCS) were analyzed using descriptive statistics, correlation analyses, and multivariable linear regression. Follow-up assessments at approximately one year were summarized descriptively. Results: Disease-specific HRQoL revealed marked impairment in perceived disease burden and work status, while physical HRQoL was substantially reduced (PCS 36.5 ± 9.6). Mental HRQoL was relatively preserved (MCS 48.8 ± 8.8). At baseline, 48.0% of patients reported at least mild depressive symptoms, 34.4% anxiety symptoms, and 44.0% stress symptoms. spKt/V showed a modest association with PCS. Psychological distress demonstrated weak associations with HRQoL; stress was independently associated with lower MCS, with limited explained variance (R² ≤ 0.15). Conclusions: Psychological distress is common among Romanian HD patients and is cross-sectionally associated with markedly impaired physical HRQoL. While the present design does not allow causal inferences, these findings support the implementation of routine psychological screening and the consideration of targeted psychosocial interventions in HD care. Full article

Complete or partial loss of smell (anosmia), sometimes in association with distorted olfactory perceptions (parosmia), is a common neurological symptom affecting nearly 60% of patients suffering from post-acute neurological sequelae of COronaVIrus Disease of 2019 (COVID-19) syndrome, called long COVID. Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) may gain access from the nasal cavity to the brain (neurotropism), and the olfactory route has been proposed as a peripheral site of virus entry. COVID-19 is a risk factor for developing Alzheimer’s Disease (AD), an age-dependent and progressive neurodegenerative disorder characterized in affected patients by early olfaction dysfunction that precedes signs of cognitive decline associated with neurodegeneration in vulnerable brain regions of their limbic system. Here, we summarize the recent literature data supporting the causal correlation between the persistent olfactory deterioration following SARS-CoV-2 infection and the long-delayed manifestation of AD-like memory impairment. SARS-CoV-2 infection of the olfactory neuroepithelium is likely to trigger a pattern of detrimental events that, directly and/or indirectly, affect the anatomically interconnected hippocampal and cortical areas, thus resulting in tardive clinical dementia. We also delineate future advancement on pharmacological and rehabilitative treatments to improve the olfactory dysfunction in patients recovering even from the acute/mild phase of COVID-19. Collectively, the present review aims at highlighting the physiopathological nexus between COVID-19 anosmia and post-pandemic mental health to favor the development of best-targeted and more effective therapeutic strategies in the fight against the long-term neurological complications associated with SARS-CoV-2 infection. Full article

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the expansion of hematopoietic stem cells harboring leukemogenic mutations in the absence of overt malignancy. Strongly associated with advancing age, CHIP is detected by next-generation sequencing of peripheral blood in more than 20% of individuals over 80, most commonly through mutations in DNMT3A, TET2, ASXL1, and PPM1D. While CHIP confers over a four-fold increased risk of hematologic malignancy, it has recently emerged as a key determinant of cardiometabolic health. Epidemiological data indicated a 40% higher cardiovascular disease (CVD) risk events and a 34% increase in all-cause mortality among CHIP carriers, with specific mutations and larger clone sizes conferring greater cardiovascular burden. Preclinical studies have shown that macrophages deficient in TET2 or DNMT3A drive interleukin (IL)-1β/IL-6 inflammasome activation, thereby promoting atherosclerosis and metabolic dysfunction, whereas the JAK2V617F mutation accelerates thrombosis. CHIP integrates into a broader network of dysregulation encompassing adiposity and inflammaging, which underlies its association with diverse comorbidities, including type 2 diabetes (T2D), chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD). Multi-omics approaches have identified epigenetic and proteomic signatures correlated with CHIP expansion, providing potential biomarkers for risk stratification. Despite growing evidence of its systemic impact, CHIP screening remains limited to research settings. Emerging therapeutic strategies, including inflammasome inhibition, STING modulation, and epigenetic restoration, highlight its potential as a modifiable risk factor. This narrative review synthesizes current epidemiological, mechanistic, and translational insights, framing CHIP as an emerging causal factor in cardiometabolic disease and as a promising target for precision medicine in aging populations. Full article

Background: Repetitive transcranial magnetic stimulation (rTMS) is an established neuromodulatory method, yet its multiscale neurophysiological effects in autism spectrum disorder (ASD) remain insufficiently characterized. Recent EEG analytic advances—such as spectral parameterization, long-range temporal correlation (LRTC) assessment, and connectivity modeling—enable quantitative evaluation of excitation–inhibition (E/I) balance and network organization. Objective: This study aimed to examine whether an eight-session, EEG-guided mixed-frequency rTMS protocol—combining inhibitory 1 Hz and excitatory 10 Hz trains individualized to quantitative EEG (qEEG) abnormalities—produces measurable changes in spectral dynamics, temporal correlations, and functional connectivity in a pediatric ASD case. Methods: An 11-year-old right-handed female with ASD (DSM-5-TR, ADOS-2) underwent resting-state EEG one week before and four months after intervention. Preprocessing used a validated automated pipeline, followed by spectral parameterization (FOOOF), detrended fluctuation analysis (DFA), and connectivity analyses (phase-lag index and Granger causality) in MATLAB (2023b). No inferential statistics were applied due to the single-case design. The study was conducted at Cosmos Healthcare (London, UK) with in-kind institutional support and approved by the Atlantic International University IRB (AIU-IRB-22-101). Results: Post-rTMS EEG showed (i) increased delta and reduced theta/alpha/beta power over central regions; (ii) steeper aperiodic slope and higher offset, maximal at Cz, suggesting increased inhibitory tone; (iii) reduced Hurst exponents (1–10 Hz) at Fz, Cz, and Pz, indicating decreased long-range temporal correlations; (iv) reorganization of hubs away from midline with marked Cz decoupling; and (v) strengthened parietal-to-central directional connectivity (Pz→Cz) with reduced Cz→Pz influence. Conclusions: Mixed-frequency, EEG-guided rTMS produced convergent changes across spectral, aperiodic, temporal, and connectivity measures consistent with modulation of cortical E/I balance and network organization. Findings are preliminary and hypothesis-generating. The study was supported by in-kind resources from Cosmos Healthcare, whose authors participated as investigators but had no influence on analysis or interpretation. Controlled trials are warranted to validate these exploratory results. Full article

Background: The 2023 Delphi consensus defined metabolic and alcohol-associated liver disease (MetALD), distinguishing between alcohol abuse and moderate consumption. Although alcohol abuse is known to accelerate fatty liver disease progression, the health effects of chronic moderate alcohol intake under different dietary conditions remain unclear. This study aimed to evaluate the impact of moderate alcohol consumption on metabolic phenotypes and gut microbiota/metabolites in lean and obese mice and to propose a model approximating MetALD features. Methods: C57BL/6J mice were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 12 weeks, with access to 10% (v/v) alcohol in drinking water. Systemic metabolic parameters, liver histopathology, inflammatory and fibrotic markers, gut microbiota composition, and the fecal metabolome were assessed. Results: In LFD-fed mice, 10% alcohol intake induced multiple metabolic alterations, including elevated serum triglycerides, reduced fasting blood glucose, and changes in hepatic lipid metabolism along with steatosis and inflammation—though further studies are required to confirm causality. When combined with HFD, alcohol did not significantly exacerbate most glucose/lipid metabolic disorders but markedly increased hepatic inflammatory cell infiltration and fibrosis progression. Alcohol consistently increased gut microbial α-diversity in both dietary groups, while downregulating beneficial metabolites such as amino acids (e.g., glutamine, histidine), their derivatives, and short-chain fatty acids. Correlation analyses associated these microbial and metabolic changes with altered amino acid/cholesterol metabolism and inflammatory/fibrotic phenotypes, particularly under HFD conditions. Conclusions: These findings suggest that chronic moderate alcohol intake presents distinct risks in lean and obese individuals with different dietary structures. Full article

Background/Objectives: Physical activity and sports participation are widely recognized as effective strategies for enhancing quality of life (QoL) in individuals with disabilities. This study aimed to examine the relationship between QoL and athletic performance among male and female athletes with physical disabilities who participate in individual sports. Methods: This descriptive–correlational study involved 338 Iranian athletes with physical disabilities competing at various levels of competition. QoL was measured using the SF-36 questionnaire, and sports performance was assessed based on official competition records. Data were analyzed using SPSS v21, applying descriptive statistics and Pearson correlations. Results: Both male and female athletes reported high levels of overall QoL. No statistically significant differences were found between genders in terms of physical health, psychological well-being, or total QoL scores (p > 0.05). Furthermore, there were no significant correlations between QoL and sports performance at the provincial, national, or international levels (p > 0.05). Conclusions: The findings indicate that athletes with physical disabilities report relatively high levels of QoL, irrespective of their competitive achievements or medal standings. Although no statistically significant correlations were observed, participation in individual sports may be linked to better physical functioning and psychological resilience. These associations should be interpreted with caution and do not imply causality. Nonetheless, encouraging such participation could be beneficial in supporting various dimensions of health and promoting social inclusion among individuals with disabilities. Full article

Background: Chronic pelvic toxicity induced by radiotherapy and/or chemotherapy (R/CIPT) is a debilitating sequela in gynecological cancer survivors, often refractory to conventional treatments and potentially linked to gut microbiota dysbiosis. Ozone therapy (OT), particularly rectal insufflation, demonstrates anti-inflammatory and redox-modulating effects through hormetic mechanisms (Nrf2 activation/NF-κB inhibition). We hypothesize that its clinical benefit is mediated, in part, by restoring gut microbial homeostasis. Objective: This manuscript proposes a clinical study to evaluate the impact of rectal OT on the gut microbiota of patients with gynecological cancers and chronic R/CIPT. Proposed Methods: A prospective, observational study of 38 patients is outlined: 19 with CTCAE v5.0 Grade ≥2 chronic R/CIPT receiving compassionate rectal OT (~40 sessions over 4 months), and 19 matched controls without toxicity. Stool samples for 16S rRNA sequencing will be collected from the OT group pre- and post-intervention and once from controls. Primary endpoints are changes in microbiota composition/diversity and pelvic toxicity scores (CTCAE v5.0, EORTC QLQ-CX24). Secondary endpoints include quality of life (EORTC QLQ-C30, EQ-5D-5L), anxiety/depression (HADS), and serum inflammatory/oxidative stress biomarker analysis. Anticipated Results and Conclusion: This will be the first study to prospectively investigate whether rectal OT’s effect correlates with a beneficial shift in the gut microbiota, specifically an increase in commensals (e.g., short-chain fatty acids producers) and a decrease in pathobionts. If successful, OT could be assessed as a novel, microbiota-targeting intervention for R/CIPT. The findings from this pilot study will provide the necessary groundwork for a future randomized controlled trial to definitively establish causality and efficacy. Full article

Wastewater-based epidemiology is a robust, scalable, cost-effective, and high-performing tool to monitor and predict SARS-CoV-2 trends. We aimed to investigate whether this approach could be applied to influenza A/B viruses and respiratory syncytial virus (RSV) in Marseille, southern France. Wastewater concentrations of SARS-CoV-2, influenza A/B viruses, and RSV in Marseille were monitored by qPCR between January 2021 and October 2024. These concentrations were compared with the diagnosis numbers for the three viruses collected at public hospitals in Marseille, using cross-correlation analyses. The Granger causality test was used to determine whether wastewater concentrations can predict the number of clinical cases. SARS-CoV-2 and influenza virus concentrations in wastewater preceded the rise in the incidence of patient diagnoses by a lag of five days and nine/ten days, respectively. In contrast, for RSV, the rise in incidence of clinical cases preceded that of wastewater concentrations. We conclude that wastewater-based epidemiology is a powerful tool to monitor the level of circulation of these viruses independently of tests carried out on people. It enables earlier alerts than monitoring patients for SARS-CoV-2 and influenza symptoms. However, for RSV, it does not provide an early warning, and clinical data-based surveillance appears to be more suitable. Full article

Despite widespread adoption, traditional Agile project management practices often fail to ensure successful delivery of enterprise-scale software projects. One key limitation lies in the absence of a conceptually defined structure for the various types of Agile activities and their interactions. As a result, Agile methodologies typically lack formal indicators for evaluating the semantic content and progress status of project activities. Although widely used tools for Agile project management, such as Atlassian Jira, capture operational data, project status assessment interpretation remains largely subjective—relying on the experience and judgment of managers and team members rather than on a formal knowledge model or well-defined semantic attributes. As Agile project activities continue to grow in complexity, there is a pressing need for a modeling approach that captures their causal structure in order to describe the essential characteristics of the processes and ensure systematic monitoring and evaluation of the project. The complexity of the corresponding model must correlate with the causality of processes to avoid losing essential properties and to reveal the content of causal interactions. To address these gaps, this paper introduces a causal Agile process model that formalizes the internal structure and transformation pathways of Agile activity types. To our knowledge, it is the first framework to integrate a recursive, causally grounded structure into Agile management, enabling both semantic clarity and quantitative evaluation of project complexity and progress. The aim of the article is, first, to describe conceptually different Agile activity types from a causal modeling perspective, its internal structure and information transformations, and, second, to formally define the causal Agile management model and its characteristics. Each Agile activity type (e.g., theme, initiative, epic, user story) is modeled using the management transaction (MT) framework—an internal model of activity that comprises a closed-loop causal relationship among management function (F), process (P), state attribute (A), and control (V) informational flows. Using this framework, the internal structure of Agile activity types is normalized and the different roles of activities in internal MT interactions are defined. An important feature of this model is its recursive structure, formed through a hierarchy of MTs. Additionally, the paper presents classifications of vertical and horizontal causal interactions, uncovering theoretically grounded patterns of information exchange among Agile activities. These classifications support the derivation of quantitative indicators for assessing project complexity and progress at a given point in time, offering insights into activity specification completeness at hierarchical levels and overall project content completeness. Examples of complexity indicator calculations applied to real-world enterprise application system (EAS) projects are included. Finally, the paper describes enhancements to the Jira tool, including a causal Agile management repository and a prototype user interface. An experimental case study involving four Nordic EAS projects (using Scrum at the team level and SAFe at the program level) demonstrates that the Jira tool, when supplemented with causal analysis, can reveal missing links between themes and initiatives and align interdependencies between teams in real time. The causal Agile approach reduced the total number of requirements by an average of 13% and the number of change requests by 14%, indicating a significant improvement in project coordination and quality. Full article

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells, resulting in lifelong insulin dependence. While genetic susceptibility—particularly human leukocyte antigen (HLA) class II alleles—is a major risk factor, accumulating evidence implicates viral infections as potential environmental triggers in disease onset and progression. This narrative review synthesizes current findings on the role of viral pathogens in T1DM pathogenesis. Enteroviruses, especially Coxsackie B strains, are the most extensively studied and show strong epidemiological and mechanistic associations with beta-cell autoimmunity. Large prospective studies—including Diabetes Virus Detection (DiViD), The environmental determinans of diabetes in the young (TEDDY), Miljøfaktorer i utvikling av type 1 diabetes (MIDIA), and Diabetes Autoimmunity Study in the Young (DAISY)—consistently demonstrate correlations between enteroviral presence and the initiation or acceleration of islet autoimmunity. Other viruses—such as mumps, rubella, rotavirus, influenza A (H1N1), and SARS-CoV-2—have been investigated for their potential involvement through direct cytotoxic effects, immune activation, or molecular mimicry. Interestingly, certain viruses like varicella-zoster virus (VZV) and cytomegalovirus (CMV) may exert modulatory or even protective influences on disease progression. Proposed mechanisms include direct beta-cell infection, molecular mimicry, bystander immune activation, and dysregulation of innate and adaptive immunity. Although definitive causality remains unconfirmed, the complex interplay between genetic predisposition, immune responses, and viral exposure underscores the need for further mechanistic research. Elucidating these pathways may inform future strategies for targeted prevention, early detection, and vaccine or antiviral development in at-risk populations. Full article

This article aims to assess the conditions and prospects for biomass utilization in the Visegrad Group (V4) countries. Additionally, the relationship between biomass energy production and greenhouse gas emissions was examined. A key component of the analysis involved identifying potential directions for the development of biomass utilization in the pursuit of the sustainable development of agricultural enterprises. In relation to these research objectives, a hypothesis was formulated regarding the causal relationship between biomass energy consumption and economic growth, the abundance of natural resources, and income in reference to the European Union economies. Both static and dynamic panel studies were applied. The conducted research revealed the complex nature of the conditions influencing biomass utilization. The study period covered the years 2004–2022. A negative correlation was found between the use of biomass and greenhouse gas emissions. At the same time, factors favoring biomass utilization included economic growth, the level of natural resource consumption per capita, and government policies aimed at increasing the share of renewable resources in the economy. Full article

Background/Objectives: Diabetic kidney disease (DKD) is a common diabetic complication, driven by a multifactorial pathogenesis that includes various genetic components. However, the precise causative genes and their underlying biological pathways remain poorly understood. Methods: We performed a cross-tissue transcriptome-wide association study (TWAS) of DKD using expression quantitative trait loci (eQTL) data from 49 tissues in the Genotype—Tissue Expression (GTEx) version 8 (v8) resource. Five complementary analytical frameworks—sparse canonical correlation analysis (sCCA), functional summary-based imputation (FUSION), fine-mapping of causal gene sets (FOCUS), summary-data-based Mendelian randomization (SMR), and multi-marker analysis of genomic annotation (MAGMA)—were integrated to nominate candidate genes. Causal inference was refined using Mendelian randomization (MR), and biological significance was evaluated through pathway enrichment, protein interaction networks, and druggability profiling. Results: We identified 23 candidate genes associated with DKD risk, of which 13 were supported by MR analysis. Among these, 10 represent previously unreported susceptibility genes. Notably, four genes—HLA-DRB1, HLA-DRB5, NOTCH4, and CYP21A2—encode potentially druggable proteins, with HLA-DRB5 and CYP21A2 both qualifying as novel susceptibility genes and therapeutic targets. These genes converge on immune modulation, steroid biosynthesis, DNA repair, and transcriptional regulation—processes central to DKD pathogenesis. Conclusions: Our study represents the first systematic cross-tissue TWAS of DKD, revealing a prioritized set of genetically and functionally supported susceptibility genes. The identification of druggable targets among these genes provides critical insight into the mechanistic underpinnings of DKD and highlights their potential for future therapeutic development. These findings enhance our understanding of DKD pathophysiology and offer a foundation for precision medicine strategies in nephrology. Full article