Search Results (776)

Long COVID, characterized by persistent symptoms following acute SARS-CoV-2 infection, has emerged as a significant public health challenge with wide-ranging clinical and socioeconomic implications. Developing an effective risk assessment strategy is essential for the early identification and management of individuals susceptible to prolonged symptoms. This study uses a quantitative approach to characterize the dose–response relationships between spike protein concentrations and effects, including Long COVID symptom numbers and the release of proinflammatory mediators. A mathematical model is also developed to describe the time-dependent change in spike protein concentrations post diagnosis in twelve Long COVID patients with a cluster analysis. Based on the spike protein concentration–Long COVID symptom numbers relationship, we estimated a maximum symptom number (~20) that can be used to reflect a persistent predictor. We found that among the crucial biomarkers associated with Long COVID proinflammatory mediator, CXCL8 has the lowest 50% effective dose (0.01 μg mL⁻¹), followed by IL-6 (0.39), IL-1β (0.46), and TNF-α (0.56). This work provides a comprehensive risk assessment strategy with dose–response tools and mathematical modeling developed to estimate potential spike protein concentration. Our study suggests persistent Long COVID guidelines for personalized care strategies and could inform public health policies to support early interventions that reduce long-term disability and healthcare burdens with possible other post-infection syndromes. Full article

Background/Objectives: Students’ psychological health problems have been widely studied for a long time. However, with the COVID-19 pandemic and due to the additional challenges related to the need for individual and contextual adjustment, a more comprehensive approach to psychological health and well-being is needed. The main goal of the present study was to identify the individual and contextual factors that could discriminate middle school and high school students based on well-being and psychological symptoms. Methods: In this study, carried out within the scope of the second wave of the study “Psychological Health and Wellbeing | School Observatory”, promoted by the Ministry of Education, 3037 students from different regions and levels of public education in Portugal, 49.5% female, aged between 9 and 18 years, participated by completing a research protocol after informed consent was given. Results: Cluster analysis allowed the identification of four groups based on the scores of well-being and psychological symptoms: complete psychological health, incomplete psychological distress, incomplete psychological health and complete psychological distress. The analysis of discriminant variables additionally showed relevant differences between the two extreme groups: complete psychological health students reported higher socio-emotional skills, whereas complete psychological distress students reported higher stress and anxiety scores and low life satisfaction. Conclusions: The obtained results highlight the need for early identification of psychological distress using effective measures to prevent psychological symptoms and to promote socio-emotional skills in the school context. Full article

Cerebral cavernous malformation (CCM) is a cluster of abnormal blood vessels in the brain that leads to severe neurological deficits, seizures, and fatal hemorrhagic stroke. Currently, there is no available drug treatment for CCM. Most CCMs are conservatively managed by observing change in appearance (MRI), recent hemorrhage, or any clinical symptoms. Neurosurgery is the only current treatment option, but it is only effective in a few cases. Since most CCM lesions are surgically inaccessible, when left untreated they lead to severe neurological deficits, seizures, and fatal hemorrhagic stroke. Hence, new non-invasive, safe, and effective treatment strategies are urgently needed. Recent research has identified gut microbiome dysbiosis and its innate immune response as the critical stimulus in experimental CCM pathogenesis, demonstrating the importance of the gut–brain axis in CCM. Importantly, CCM patients also manifest gut microbiome dysbiosis and gut barrier health can impact CCM disease course. This review highlights the emerging involvement of the gut microbiome in CCM pathogenesis and its potential as a therapeutic target. While preclinical data suggest mechanistic links, the lack of clinical intervention studies limits current applicability and underscores the need for translational research. Full article

Osteoarthritis (OA) is a multifactorial chronic musculoskeletal disorder characterised by cartilage degradation, synovial inflammation, and subchondral bone remodelling. Conventional diagnostic modalities, including radiographic imaging and symptom-based assessments, primarily detect disease in its later stages, limiting the potential for timely intervention. Inflammatory biomarkers, particularly Interleukin-6 (IL-6), Tumour Necrosis Factor-alpha (TNF-α), and Myeloperoxidase (MPO), have emerged as biologically relevant indicators of disease activity, with potential applications as companion diagnostics in precision medicine. This review examines the diagnostic and prognostic relevance of IL-6, TNF-α, and MPO in OA, focusing on their mechanistic roles in inflammation and joint degeneration, particularly through the activity of fibroblast-like synoviocytes (FLSs). The influence of sample type (serum, plasma, synovial fluid) and analytical performance, including enzyme-linked immunosorbent assay (ELISA), is discussed in the context of biomarker detectability. Advanced statistical and computational methodologies, including rank-based analysis of covariance (ANCOVA), discriminant function analysis (DFA), and Cox proportional hazards modelling, are explored for their capacity to validate biomarker associations, adjust for demographic variability, and stratify patient risk. Further, the utility of synthetic data generation, hierarchical clustering, and dimensionality reduction techniques (e.g., t-distributed stochastic neighbour embedding) in addressing inter-individual variability and enhancing model generalisability is also examined. Collectively, this synthesis supports the integration of biomarker profiling with advanced analytical modelling to improve early OA detection, enable patient-specific classification, and inform the development of targeted therapeutic strategies. Full article

Grapefruit (Citrus × paradisi Macfad.) is susceptible to Huanglongbing (HLB) disease, which prominently affects tree health and leads to a substantial loss of productivity. HLB-affected trees exhibit a nutritional imbalance expressed in either deficiencies or toxicities of the essential minerals required for plant growth, as well as changes in the production of plant metabolites. Hence, understanding foliar nutritional and metabolite fluctuations as HLB-elicited symptoms progress can assist growers in improving tree health management strategies. This study evaluated changes in foliar nutrient and phloem sap amino acid concentrations of HLB-affected grapefruit trees showing a mixed canopy of HLB-induced blotchy mottle and asymptomatic mature leaves. The trees used in our experiment were fruit-bearing seven-year-old grapefruit trees (cv ‘Rio Red’ on sour orange rootstock) grown in South Texas. Two types of foliage from HLB-affected trees were studied, (a) HLB-symptomatic and confirmed Candidatus Liberibacter asiaticus (CLas)-positive (IS) and (b) CLas-negative and HLB-asymptomatic (IA) mature leaves, which were compared to asymptomatic and CLas-free mature foliage from healthy trees (HY) in terms of their leaf nutrient and phloem sap amino acid contents. Hierarchical clustering based on leaf nutrient contents showed that 70% of IA samples clustered with HY samples, thus indicating that the levels of some nutrients were statistically similar in these two types of samples. The concentrations of the macronutrients N, Ca, Mg, and S and the micronutrients Mn and B were significantly reduced in HLB-symptomatic (IS) leaves, as compared to their IA and HY counterparts, which did not show statistically significant differences. Conversely, leaf Na concentration was approximately two-fold higher in leaves from HLB-affected trees (IA and IS) independent of symptom expression as compared to leaves from healthy trees. Significantly higher concentrations of glutamine and the S-containing amino acids taurine and cystathionine were observed in the IS leaves relative to the phloem sap of IA leaves from HLB-affected trees. In contrast, the phloem sap of IA (14%) and IS (41%) leaves from HLB-affected trees exhibited lower levels of γ-amino butyric acid (GABA) as compared to HY leaves. The results of this study highlight the changes in leaf nutrient and phloem sap amino acid profiles following CLas infection and HLB symptom development in grapefruit, and we discuss these results considering the strategies that growers can implement to correct the nutritional deficiencies and/or toxicities induced by this disease. Full article

Post-exertional malaise (PEM) is a defining symptom of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its molecular underpinnings remain elusive. This study investigated the temporal–longitudinal DNA methylation changes associated with PEM using a structured two-day maximum repeated effort cardiopulmonary exercise testing (CPET) protocol involving pre- and two post-exercise blood samplings from five ME/CFS patients. Cardiopulmonary measurements revealed complex heterogeneous profiles among the patients compared to typical healthy controls, and VO₂ peak indicated all patients had poor normative fitness. The switch to anaerobic metabolism occurred at a lower workload in some patients on Day Two of the test. Reduced Representation Bisulphite Sequencing followed by analysis with Differential Methylation Analysis Package-version 2 (DMAP2) identified differentially methylated fragments (DMFs) present in the DNA genomes of all five ME/CFS patients through the exercise test compared with ‘before exercise’. With further filtering for >10% methylation differences, there were early DMFs (0–24 h after first exercise test) and late DMFs between (24–48 h after the second exercise test), as well as DMFs that changed gradually (between 0 and 48 h). Of these, 98% were ME/CFS-specific, compared with the two healthy controls accompanying the longitudinal study. Principal component analysis illustrated the three distinct clusters at the 0 h, 24 h, and 48 h timepoints, but with heterogeneity among the patients within the clusters, highlighting dynamic methylation responses to exertion in individual patients. There were 24 ME/CFS-specific DMFs at gene promoter fragments that revealed distinct patterns of temporal methylation across the timepoints. Functional enrichment of ME-specific DMFs revealed pathways involved in endothelial function, morphogenesis, inflammation, and immune regulation. These findings uncovered temporally dynamic epigenetic changes in stress/immune functions in ME/CFS during PEM and suggest molecular signatures with potential for diagnosis and of mechanistic significance. Full article

Background/Objectives: Post-discharge interventions addressing psychological, informational, and practical needs of brain tumor surgery patients are limited. This study aimed to develop and examine the effects of a post-discharge care program for patients with benign brain tumors who underwent surgery. Methods: A quasi-experimental study with a nonequivalent control group pretest–post-test non-synchronized design was employed. The post-discharge care program was developed using the ADDIE model and delivered as an 8-week, 8-session program to 65 discharged patients (Intervention: n = 33, Control: n = 32). Outcomes were measured using the Memorial Symptom Assessment Scale (MSAS) for symptom clusters, Post-Discharge Coping Difficulty Scale (PDCDS) for post-discharge adaptation, and Functional Assessment of Chronic Illness Therapy (FACIT) for quality of life. Results: Significant group × time interactions were found between intervention and control groups for symptom clusters (F = 74.878, p < 0.001), post-discharge adaptation (F = 144.687, p < 0.001), and all quality of life domains: physical (F = 38.996, p < 0.001), social/family (F = 50.865, p < 0.001), emotional (F = 39.110, p < 0.001), and functional (F = 38.917, p < 0.001). The intervention group showed clinically meaningful improvements across all outcomes. Conclusions: This study demonstrates that the post-discharge care program was effective in improving symptom clusters, post-discharge adaptation, and quality of life in patients with benign brain tumors who underwent surgery. The program can contribute to achieving better health outcomes for this population in clinical practice. Full article

Background: The SARS-CoV-2 Omicron variant became the dominant driver during the COVID-19 pandemic due to its high transmissibility and immune escape potential. Although clinical outcomes are generally mild to moderate, the inflammatory mechanisms triggered by Omicron subvariants remain poorly defined. The goal of this study was to consider both viral evolution and the host immune response by assessing plasma cytokine levels in patients infected with SARS-CoV-2 Omicron subvariants. Methods: A total of 115 individuals were recruited, including 40 with laboratory-confirmed SARS-CoV-2 infection by RT-qPCR. Demographic, clinical, and comorbidity data were collected. Plasma levels of IL-6, TNF, IFN-γ, IL-4, IL-2, IL-10, and IL-17A were quantified using Cytometric Bead Array. Subvariant data were obtained from GISAID records and grouped into early (BA.1-lineage) and late (BA.4/BA.5-lineage) Omicron clusters. Statistical analysis included non-parametric and parametric tests, correlation matrices, and multivariate comparisons. Results: Pharyngitis, nasal discharge, cough, and headache were the most common symptoms among infected individuals. Despite no significant variation in symptom distribution across subvariants, infected patients showed higher levels of IFN-γ, TNF, IL-10, IL-4, and IL-2 compared to non-SARS-CoV-2 infected controls (p < 0.05). IL-4 and IL-10 levels were significantly higher in early Omicron infections. No associations were observed between cytokine levels and comorbidities. A significant correlation was found between reporting fewer symptoms and having received three vaccine doses. Conclusions: Infection with Omicron subvariants elicits a strong yet balanced cytokine response. Despite genetic divergence between lineages, immune and clinical patterns remain conserved, with vaccination appearing to mitigate the symptom burden. Full article

Background: Delayed diagnosis of Chronic Obstructive Pulmonary Disease (COPD) in primary care is common and contributes to preventable morbidity. A deeper understanding of pre-diagnostic patterns is needed to develop targeted detection strategies. We aimed to characterize diagnostic delay and missed diagnostic opportunities (MDOs) and identify high-risk clinical profiles. Methods: We conducted a retrospective cohort study of 167 patients newly diagnosed with COPD in primary care centers in Madrid, Spain. Healthcare utilization in the 12 months preceding diagnosis was analyzed. Multivariable logistic regression was used to identify predictors of MDOs, and K-means clustering was used to identify patient phenotypes. Results: Diagnostic delay (>30 days) was present in 45.5% of patients, and MDOs in 47.3%. MDO-positive patients had significantly worse lung function (mean FEV₁: 1577 vs. 1898 mL, p = 0.008), greater symptom burden (CAT score ≥ 10: 79.7% vs. 59.1%, p = 0.003), and more frequent pre-diagnostic exacerbations (mean: 1.24 vs. 0.71, p = 0.032). After multivariable adjustment, diagnostic delay remained a powerful independent predictor of MDOs (OR 10.25, 95% CI 4.39–24.88; p < 0.001). Cluster analysis identified three distinct clinical phenotypes: ‘Paucisymptomatic–Preserved’, ‘Frequent Attenders/High-Risk’, and ‘Silent Decliners’. Conclusions: The pre-diagnostic period in COPD is a dynamic window of detectable, and potentially preventable, clinical deterioration driven by diagnostic inertia. The identification of distinct patient phenotypes suggests that a proactive, stratified, and personalized approach, rather than a one-size-fits-all strategy, is required to improve early diagnosis in primary care. Full article

Background/Objectives: Food selectivity is a prevalent and challenging issue in childhood, particularly in children with autism spectrum disorder (ASD), which may result in restricted dietary patterns and nutrient deficiencies. This study aimed to identify high-risk subgroups of children by combining food selectivity, diet, BMI, gastrointestinal symptoms, sensory processing, and parental feeding practices in children with ASD and in typically developing children (TDC). Methods: To achieve this aim, we ran a cross-sectional, survey-based study, including 408 children (aged 3 to 12.11 years), with gender-matched groups. Both parents completed a survey on children’s diet, anthropometric curves, gastrointestinal symptoms, and the Brief Autism Mealtime Behavior Inventory (BAMBI), Short Sensory Profile (SSP), and Caregiver’s Feeding Style Questionnaire (CFSQ). Data analysis included comparative tests, correlations, and k-means cluster analysis. Results: Children with ASD exhibited significantly greater sensory processing difficulties, higher food refusal, limited food variety in the diet, and autism-related mealtime characteristics compared with TDC across all age groups. Caregivers of children with ASD reported higher controlling and contingency management feeding practices compared to the parents of the TDC. We found a strong correlation between sensory sensitivities and feeding issues. Notably, Body Mass Index (BMI) was not significantly associated with dietary restriction or gastrointestinal symptoms. Cluster analysis revealed a high-risk sub-phenotype in both groups of children with some differences, characterized by high food selectivity, taste, tactile, and smell sensitivity, gastrointestinal symptoms, and overactive parental practices. Conclusions: The early identification of this subgroup might foster more tailored, multidisciplinary, and effective assessment and clinical intervention. Full article

A new negative-strand RNA virus was identified in grapevines from a 38-year-old ‘Chardonnay’ block in Idaho through high-throughput sequencing (HTS) of total RNA. This virus was tentatively named grapevine-associated cogu-like Idaho virus (GaCLIdV). GaCLIdV has three negative-sense, single-stranded RNA genome segments of ca. 7 kb, 1.9 kb, and 1.3 kb, encoding L protein (RNA-dependent RNA polymerase, RdRP), a movement protein (MP), and a nucleocapsid protein (NC), respectively, identified based on pair-wise comparisons with other cogu- and cogu-like viruses. In phylogenetic analysis based on the RdRP, GaCLIdV grouped within the family Phenuiviridae and was placed in a lineage of plant-infecting phenuiviruses as a sister clade of the genus Laulavirus, clustering most closely with switchgrass phenui-like virus 1 (SgPLV-1) and more distantly related to grapevine-associated cogu-like viruses from the Laulavirus and Coguvirus clades. Both GaCLIdV and SgPhLV-1 are proposed to form a new genus, Switvirus, within the family Phenuiviridae. The presence of GaCLIdV in the original ‘Chardonnay’ samples was confirmed by RT-PCR amplification and Sanger sequencing. This new virus was found in five wine grape cultivars and in six vineyards sampled in Idaho and in Oregon during the 2020–2024 seasons. GaCLIdV may have contributed to the decline observed in the old ‘Chardonnay’ block, although the role of the virus in symptom development awaits further investigation. Full article

Purpose: To investigate genotype–phenotype correlations in PRPH2-retinopathies in a cohort of 36 patients from the Oxford Eye Hospital and report on novel pathogenic variants. Methods: Clinical data, including best corrected visual acuities (BCVA), fundus autofluorescence (FAF), and optical coherence tomography (OCT) imaging, were analysed. Genetic testing was performed using next-generation sequencing (NGS). Results: In this cohort, 26 different PRPH2 variants, including 8 novel variants, were identified. Variants were clustered in the D2 loop of the protein. A diverse range of phenotypes were observed: pseudo-Stargardt pattern dystrophy (PSPD) (47.2%), adult-onset vitelliform macular dystrophy (AVMD) (22.2%), pattern dystrophy (PD) (25.0%), atypical macular dystrophy (2.8%), and retinitis pigmentosa (RP) (2.8%). The mean age of symptom onset was 44.0 ± 14.4 years. Mean BCVA was 0.20 ± 0.54 logMAR OD and 0.14 ± 0.29 logMAR OS at baseline and 0.33 ± 0.40 logMAR OD and 0.32 ± 0.40 logMAR OS after a mean follow up duration of 6.0 ± 3.2 years (range 1–11 years). A thickened ellipsoid zone (EZ) was noted in 34/36 patients with a mean EZ thickness of 44.3 ± 11.3 µm OD and 42.7 ± 11.6 µm OS. No clear genotype–phenotype correlations were observed. Conclusions: The significant phenotypic range described in this study is consistent with the previously reported phenotypic variability in PRPH2 retinopathy and emphasises the complexity of establishing genotype–phenotype correlations in this disease. The thickness of the EZ on OCT may serve as a useful biomarker in distinguishing PRPH2 retinopathy from other phenocopies. These findings contribute to improved understanding of PRPH2 retinopathy and help inform diagnosis and genetic counselling. Full article

Background: Ovarian cancer ranks as the fifth leading cause of cancer-related mortality among women worldwide. Owing to its insidious onset and lack of early symptoms, over 70% of patients are diagnosed at advanced stages. Methods: This study provides a comprehensive transcriptomic analysis of tumor-infiltrating CD4⁺ T cells in ovarian cancer, highlighting regulatory T cells (Tregs) as the dominant subset. By integrating seven multicenter ovarian cancer single-cell RNA-seq datasets, a robust metadata resource was created for detailed Treg investigation. Using the BayesPrism algorithm, Treg scores from TCGA bulk RNA-seq data enabled patient stratification into high and low Treg groups. These findings were further validated through survival analyses across five independent bulk RNA-seq cohorts. We experimentally validated the inhibitory role of Tregs in modulating CD8⁺ T-cell activity in ovarian cancer. Results: We conducted an in-depth investigation into the clustering patterns, differentiation trajectories, intercellular interactions, and enrichment profiles of tumor-infiltrating T cells in ovarian cancer. Among the seven functionally defined subclusters (C1–C7), we delineated two distinct “terminal states” of CD4⁺ T-cell differentiation: FOXP3⁺ regulatory T cells and STMN1⁺ proliferative T cells. The OCSCDs dataset comprises seven datasets totaling 137,648 single cells. Using the TCGA dataset, we quantified the proportion of tumor-infiltrating regulatory T cells (Tregs) in OCSCDs through the BayesPrism algorithm and performed survival analyses across five independent bulk RNA-seq datasets from different platforms. Conclusions: Our results establish a framework for studying Treg biology in ovarian cancer and these cells may be become an important point in the field of immunotherapy. Full article

The bidirectional relationship between epilepsy and depression illustrates shared neurobiological mechanisms of neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and glutamatergic dysfunction. Depression is present in 20–55% of people with epilepsy, far greater than in the general population, while depression doubles epilepsy risk 2.5-fold, indicating shared pathophysiology. Neuroinflammatory mediators (interleukin-6, tumor necrosis factor alpha, high-mobility group box 1) establish a vicious cycle: seizures exacerbate inflammation and mood disruption, and stress lowers seizure thresholds. Hippocampal damage and cortisol toxicity also link these disorders, with early life stress imprinting lifelong risk via epigenetic alteration. Genetic studies identify pleiotropic genes (brain-derived neurotrophic factor) that regulate synaptic plasticity, serotonin activity, and immune responses. New treatments target shared pathways: ketamine and AMPAkines normalize glutamate tone; mGluR5 antagonists attenuate hyperexcitability and inflammation; DNA methyltransferase inhibitors reverse aberrant DNA methylation; and probiotics manipulate the gut–brain axis by boosting neuroprotective metabolites like butyrate. Despite challenges—transient effects, precision dosing, and blood–brain barrier penetration—these advances constitute a paradigm shift toward mechanistic repair rather than symptom management. The way forward includes clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing, biomarker-led therapies, and combination approaches (e.g., ketamine and probiotics). Such comorbidity needs to be managed holistically through integrated neuropsychiatry care, offering hope to patients with treatment-refractory symptoms. Full article

Background/Objectives: Borderline Personality Disorder (BPD) frequently overlaps with trauma-related conditions, particularly PTSD and Complex PTSD (cPTSD). Adverse Childhood Experiences (ACEs)—especially emotional and sexual abuse—are considered key factors in the development of emotion dysregulation and dissociation. This study investigates the impact of different ACE dimensions on borderline symptomatology, emotion dysregulation, and dissociative symptoms. Methods: Eighty-three BPD patients were assessed using standardized self-report questionnaires: CTQ-SF (ACEs), DERS (emotion dysregulation), DES (dissociation), BSL-23 (borderline symptoms), and PDS-3 (post-traumatic symptoms). Analyses included bivariate correlations, Structural Equation Modeling (SEM), and Exploratory Graph Analysis (EGA). Results: Emotional abuse significantly predicted borderline symptoms, while sexual abuse predicted dissociation. Emotion dysregulation was strongly associated with both borderline and dissociative symptoms, emerging as a central node in the symptom network. EGA confirmed the clustering of dissociative symptoms with sexual abuse and the centrality of emotion dysregulation across domains. Conclusions: Findings support the role of specific ACEs in shaping the clinical expression of BPD. Emotion dysregulation acts as a key transdiagnostic factor linking trauma history to borderline and dissociative features. These results underscore the importance of trauma-informed assessments and interventions, such as DBT and DBT-PTSD, tailored to individual ACE profiles. Full article