Search Results (593)

Background: Post-acute sequelae of COVID-19 (PASC), commonly known as long COVID, affects an estimated 10–30% of SARS-CoV-2 non-hospitalised and 50–70% of hospitalised survivors. This condition remains clinically heterogeneous, and the specific mechanisms driving the transition from acute infection to chronic sequelae remain poorly understood. We assessed independent risk factors, tracked the evolution of clinical features, defined distinct symptom-based phenotypes, and assessed the impact of different pandemic waves on the likelihood of developing long COVID in hospitalised survivors. Methods: We conducted a single-centre, retrospective cohort study at a university hospital in London. The population comprised 627 adults hospitalised with acute COVID-19 between February 2020 and December 2022. Baseline characteristics and outcomes were compared between long COVID and resolved cases using appropriate statistical tests for continuous and categorical variables. Multivariable logistic regression identified risk factors. McNemar’s test quantified the phenotypic shift from admission to follow-up. Latent Class Analysis (LCA) identified clinical subtypes based on symptom clusters. Results: Of 627 patients, 252 (40.2%) met long COVID criteria. Comorbidity burden was the strongest predictor; patients with a single condition had a 4-fold increase in odds (aOR 4.62, 95% CI 2.36–9.04). The ORs were also significantly elevated among patients with 2 (aOR 3.26), 3 (aOR 2.68), or 4 or more (aOR 3.24) comorbidities. Older age (aOR 1.04), acute disease severity (measured by length of hospital stay) (aOR 1.27 per log-day) and elevated admission fibrinogen (aOR 1.21 per g/L) were significant predictors. Temporal analysis revealed a precipitous decline in risk from Wild-type/Alpha (>50%) to Delta/Omicron (<21%). We observed a distinct phenotypic shift: while acute respiratory inflammation resolved, systemic fatigue increased fourfold (7.0% to 32.4%), and memory difficulties emerged in the post-acute phase. LCA identified two phenotypes: fatigue-dominant and multisystem phenotypes. Conclusions: Long COVID is a multifactorial syndrome driven by host susceptibility, acute severity, and persistent coagulopathy. Clinical management should move beyond a monolithic approach and favour phenotype-specific strategies. Full article

Background: Functional somatic disorder (FSD) is prevalent, but pathological pathways have not yet been identified. Cross-sectional studies suggest an association between FSD and lipid and glucose metabolism. The aim of the present prospective study was to assess whether metabolic factors represent possible risk factors for development of FSD. Methods: A population-based cohort of 9656 men and women aged 18–76 years was established in 2011–2015, and 5738 participated in a re-examination after a median of 65 months. At both baseline and follow-up, participants answered questionnaires on lifestyle and various delimitations of FSD including bodily distress syndrome (BDS), chronic fatigue (CF), chronic widespread pain (CWP), irritable bowel (IB), and multiple chemical sensitivity (MCS). Fasting values of cholesterol, triglycerides, glucose, HbA1c, insulin, and insulin resistance were assessed at baseline and analyzed in relation to incidence of FSD using logistic regression models, adjusted for age, sex, lipid- and glucose-lowering medications, obesity, social status, lifestyle, and sleep quality. Results: Several small, although significant, effects were observed. Lower levels of cholesterol were associated with development of BDS (OR: 0.982 (95% CI: 0.971–0.993)), CF (OR: 0.980 (95% CI: 0.964–0.996)), and CWP without co-morbid FSS among men. Higher levels of triglycerides were associated with development of CF (OR: 1.022 (95% CI: 1.003–1.041)). Glucose and HbA1c levels were not associated with development of FSD. Insulin and HOMA-IR levels were associated with development of CF in a non-linear relation, being negative at lower levels and changing to a positive relation at higher levels. Conclusions: More large-scale cohort studies are necessary to explore whether metabolism could play a role in the pathological pathway of FSD as indicated in the present study. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an idiopathic, multisystem disorder marked by debilitating fatigue, post-exertional malaise, cognitive dysfunction and neuroinflammation. Its etiology remains unclear, yet emerging evidence implicates a complex interplay between immune dysregulation, metabolic impairment, mitochondrial bioenergetics, and environmental stressors such as viral infection or low-dose ionizing radiation (LDIR). To develop treatments for ME/CFS, it is essential to identify suitable targets for therapy. In this narrative review, we discuss recent findings on the overlap of ME/CFS with LDIR effects and examine potential mechanistic links that may arise from LDIR-induced bystander effects (RIBEs). We highlight potential candidate biomarkers that bridge these domains: mitochondrial respiratory dysfunction, altered ornithine transport via SLC25A15 (ORNT1), possible roles of CD38 in the context of immunity and NAD+ depletion, cyclin D1–dependent metabolic reprogramming and modulation of gene expression, and α-synuclein as a potential neuroinflammatory damage-associated molecular pattern (DAMP). While the involvement of these biomarkers in ME/CFS is yet to be confirmed experimentally, evidence from in vitro studies of irradiated cells, exosome profiling, and patient samples suggests that RIBEs can, in theory, produce prominent cellular ME/CFS phenotypes through associated mechanisms, including those exhibiting oxidative stress, impaired ATP production, and immune modulation. We propose a hypothetical, exploratory model wherein LDIR initiates or contributes to adaptive metabolic shifts (including CD38 upregulation and cyclin D1 stabilization) that, coupled with persistent bystander signaling, could potentially culminate in chronic fatigue and neurocognitive symptoms in some reported ME/CFS cases. Finally, we outline a research agenda encompassing the establishment of standardized diagnostic criteria, multi-omics profiling of patient cohorts, exosome analysis, functional mitochondrial assays, and targeted therapeutic trials focusing on possible anti-CD38 antibodies and NAD+ precursor therapy. By integrating recent findings in low-dose radiation biology with ME/CFS pathophysiology, this review aims to promote interdisciplinary investigations that may uncover mechanistic insights and novel biomarkers for diagnosis and treatment of ME/CFS. We further review steps in a proposed model taking us from low-dose radiation exposure to a number of possible targets. Full article

Breast implant illness (BII) describes a constellation of systemic symptoms reported by some patients after breast implantation, including fatigue, cognitive dysfunction, arthralgia, myalgia, sicca symptoms, skin manifestations, and mood disturbance. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) provides a broader conceptual framework in which silicone and other biomaterials may contribute to immune dysregulation in susceptible individuals, although causality remains controversial and no validated diagnostic biomarker exists. This narrative review summarizes current evidence on BII and implant-related ASIA, focusing on epidemiology, clinical presentation, biological plausibility, diagnostic evaluation, explantation outcomes, and implant-associated complications. Proposed mechanisms include chronic foreign-body inflammation, silicone gel bleed and particulate migration, macrophage activation, inflammasome signaling, cytokine dysregulation, bacterial biofilms and biofilm-derived metabolites, adaptive immune activation, autoantibody formation, and host genetic susceptibility. The review also distinguishes BII/ASIA-like presentations from breast implant-associated anaplastic large cell lymphoma and other rare implant-associated malignancies. A practical multidisciplinary diagnostic and management algorithm is proposed to support structured assessment, red-flag triage, exclusion of alternative diagnoses, patient-centered counseling, and individualized decision-making regarding medical management and explantation. Full article

Vitamin C (L-ascorbic acid) is an essential micronutrient involved in collagen biosynthesis, redox regulation, immune function, endothelial biology, carnitine synthesis, neurotransmitter metabolism, and non-heme iron absorption. Dietary reference values are designed primarily to prevent deficiency in general populations, but vulnerability to low-vitamin C status may increase during trauma, surgery, chronic inflammation, malignancy, metabolic disease, smoking, poor intake, environmental exposure, and tissue repair. This narrative review synthesizes mechanistic, pharmacokinetic, clinical, and safety evidence on vitamin C as a stress-responsive micronutrient. Evidence is reviewed across tissue repair and wound healing, orthopedic recovery and selected complex regional pain syndrome risk contexts, fatigue, neuropsychiatric vulnerability, cancer-supportive care, vascular homeostasis, dermatologic biology, and preliminary microbiota–gut–brain axis hypotheses. The strength of evidence differs substantially across domains: biochemical functions and deficiency correction are well established, whereas benefits of supraphysiologic oral supplementation in vitamin C-replete patients remain uncertain. Oral nutritional supplementation is distinguished from intravenous pharmacologic ascorbate, with attention to route, formulation, dose division, gastrointestinal tolerance-limited adjustment, and safety monitoring. Because evidence for high-dose oral supplementation remains limited and condition-specific, such use should be individualized, time-limited, and clinician-monitored rather than presented as a population-level recommendation or evidence-defined therapeutic target. Taken together, the clinical value of vitamin C depends on baseline status, patient vulnerability, route, formulation, dosing interval, clinical endpoint, and safety review. Full article

This study aimed to investigate the therapeutic effects of camel milk (CM) on chronic fatigue syndrome (CFS) and elucidate the mechanisms underlying the microbiota–gut–brain axis. Using a murine model of CFS induced by chronic restraint and forced swimming stress, we administered lyophilized CM (1500 mg/kg/day, equivalent to approximately 121.5 mg/kg/day in humans based on body surface area conversion using the standard allometric scaling formula) orally. CM supplementation was significantly associated with ameliorated fatigue-like behaviors, as evidenced by prolonged swimming endurance and reduced immobility time. Metagenomic analysis revealed that CM was associated with reshaping of the small intestinal microbiota, including enrichment of beneficial Lactococcus lactis and suppression of pathobionts (H. hepaticus and H. typhlonius). These microbial shifts correlated with increased luminal lactic acid, improved intestinal barrier integrity (increased villus height, reduced crypt depth), and attenuated local inflammation (reduced TNF-α and IL-6, elevated IL-10). Consequently, CM was associated with reduced bacterial translocation and systemic inflammation, and normalization of hypothalamic–pituitary–adrenal (HPA) axis hyperactivity. We conclude that CM is associated with prevention of CFS-like symptoms through modulation of the gut ecosystem and strengthening of the intestinal barrier, potentially breaking the vicious cycle of gut inflammation and HPA axis dysfunction, although causality remains to be established through fecal microbiota transplantation or similar mechanistic studies. Full article

Background and Objectives: Fibromyalgia (FM) is a chronic primary pain syndrome. Its hallmark symptom is widespread pain, often accompanied by fatigue, sleep disturbances, and cognitive symptoms. Online surveys efficiently collect patient-reported data, but individuals recruited through this approach remain poorly characterized. This study aimed to describe a large online cohort of individuals with FM, providing data for comparison with the Italian Fibromyalgia Registry (IFR). Materials and Methods: Participants who self-reported a physician diagnosis of FM completed an online survey assessing socio-demographic and clinical characteristics, treatments and their perceived effectiveness, lifestyle, and impact variables. Disease severity and symptom burden were assessed using the Fibromyalgia Impact Questionnaire—Revised (FIQR), Widespread Pain Index (WPI), and Symptom Severity Scale (SSS). Participants were classified according to the 2016 American College of Rheumatology (ACR) criteria. Descriptive statistics were computed, and exploratory analyses assessed sex differences and differences according to ACR status using independent-samples t-tests with Bonferroni correction. Results: A total of 6022 participants were included (mean age 52.3 ± 10.3 years, 96.7% female). Nearly half (49.6%) reported pain duration > 10 years, and 50.4% had received conflicting diagnoses. Disease burden was high, with >70% classified as moderate-to-severe according to the FIQR. Overall, 79.4% fulfilled the 2016 ACR criteria. Participants not fulfilling the criteria showed lower symptom severity, although considerable clinical overlap was observed between groups. Pharmacological treatments were used by 81.1% of participants and non-pharmacological approaches by 55.1%, both with moderate perceived effectiveness. FM substantially affected daily life, particularly work and social functioning. After correction for multiple comparisons, sex differences were limited to FIQR functioning and symptom domains, with small effect sizes. Conclusions: Compared with published registry-based data, participants recruited through this online survey reported a higher symptom burden and longer pain duration, while showing a broadly similar symptom profile. Although the descriptive nature of the comparison precludes causal inferences, the findings suggest that online surveys and clinical registries may provide complementary perspectives on the FM population. Full article

Background/Objectives: Primary Sjögren’s syndrome (pSS) is a chronic autoimmune rheumatic disease that clinically presents with symptoms of xerostomia and xerophthalmia, as well as a wide range of other symptoms that may affect patients’ daily functioning and life satisfaction. The main purpose of this study was to assess their health-related quality of life (HRQoL) using both general and disease-specific questionnaires. Methods: This cross-sectional observational research with prospective data collection was conducted at the Rheumatology Clinic of the University Clinical Centre of Kragujevac. Participants were divided into two groups: patients with oral manifestations (oral manifestations group) and those presenting with xerostomia only, without other oral lesions or symptoms (xerostomia-only group). A complete clinical examination of the patient’s oral cavity was performed by one doctor of dental medicine. HRQoL was evaluated using various generic and disease-specific instruments. Results: A total of 80 participants were included in the study, of whom 40 were in the oral manifestations group and 40 in the xerostomia-only group. Patients with oral manifestations had significantly higher scores across all PSS-QoL domains compared with the xerostomia-only group (p < 0.001). A statistically significant difference in the total EQ-5D result was detected between groups (0.7 (0.3) vs. 0.8 (0.1), p < 0.001). In multivariable regression analysis (R² = 0.921), the ESSPRI score (β = 0.418, p < 0.001) and the presence of oral manifestations (β = −1.155, p < 0.001) were significant independent predictors of impaired HRQoL, while disease activity showed no significant association (p = 0.895). Conclusions: Patients with primary Sjögren’s syndrome presenting with oral manifestations have poorer HRQoL compared with participants with xerostomia only. Symptom burden, including dryness, pain, fatigue, and oral manifestations, may be associated with decreased HRQoL, in contrast to disease activity. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness characterised by post-exertional malaise, non-restorative sleep, and cognitive impairment, yet no objective diagnostic biomarkers have been established. Untargeted plasma metabolomics provides a broad view of the biochemical disturbances underlying ME/CFS; however, the high dimensionality of omics datasets and the limited interpretability of conventional classifiers nevertheless hinder translation into clinical practice. This study evaluates three ensemble classifiers—Explainable Boosting Machine (EBM), XGBoost, and LightGBM—for binary ME/CFS classification using plasma metabolomic and lipidomic profiles from 197 participants (106 ME/CFS; 91 healthy controls; 888 features). Feature dimensionality was reduced using a Pareto-Guided Recursive Neural Network (PRNN) pipeline. Model performance was assessed via 50-repeat stratified hold-out validation. EBM achieved the highest accuracy (0.909; 95% CI: 0.868–0.949) and area under the receiver operating characteristic curve (AUC: 0.940; 95% CI: 0.909–0.983), with XGBoost and LightGBM performing comparably. Interpretability analyses revealed that pairwise metabolite interaction terms—particularly proline & indole-3-lactate, tyrosine & N-acetylornithine, and maleic acid & arachidic acid—contributed the greatest discriminative signal. An ablation analysis comparing the full interaction-augmented EBM (AUC = 0.940) with a main-effects-only EBM (AUC = 0.882) confirmed that pairwise metabolite co-variation contributes additional discriminative value beyond individual metabolite levels, implicating amino acid catabolism, tryptophan–kynurenine pathway dysregulation, mitochondrial energy impairment, and lipid remodelling as central pathophysiological features. Global and instance-level explanations jointly demonstrated population-level metabolic signatures alongside individual heterogeneity, highlighting the added clinical value of explainable artificial intelligence (XAI) in metabolomics. These findings support EBM-based metabolomic profiling as an internally validated approach for ME/CFS classification, subject to external validation, calibration assessment, and prospective testing. Full article

Chronic overlapping pain conditions (COPCs) refer to a set of chronic pain disorders that frequently co-occur and may involve partially overlapping mechanisms. The U.S. National Institutes of Health currently recognizes ten COPCs: fibromyalgia, painful temporomandibular disorders, chronic low back pain, chronic migraine headache, chronic tension-type headache, irritable bowel syndrome, endometriosis, interstitial cystitis/bladder pain syndrome, vulvodynia, and myalgic encephalomyelitis/chronic fatigue syndrome. When multiple COPCs coexist, they are associated with a disproportionate multimorbidity burden, including greater pain, poorer psychological well-being, functional limitations, disability, fatigue, sleep disturbances, diminished quality of life, and increased healthcare utilization. Despite their impact, COPCs remain under-recognized, underdiagnosed, and undertreated. Combining structured literature searches and citation tracking with narrative syntheses, this review examines comorbid relationships, the burden of multimorbidity, and potentially overlapping nociplastic mechanisms. By adopting a multimorbidity-based perspective rather than a one-disease, one-treatment approach, it highlights barriers to care—including limited clinical awareness, under-recognition of additional COPCs, limited mechanistic understanding, and fragmented care—and proposes integrated strategies emphasizing prevention, systematic screening, mechanism-informed assessment, and coordinated, patient-centered multimodal management. Full article

Human herpesvirus-6 consists of a pair of viral species, HHV-6A and HHV-6B, which are neurotropic with the ability to invade, persist, and reactivate within the nervous system. Accumulating evidence links HHV-6 to epilepsy and other neuropathologies, including: multiple sclerosis, chronic fatigue syndrome, and neurodegeneration. Yet, mechanisms by which these viruses induce neurological disorders, including their role in epileptogenesis, remain unknown. It has been demonstrated that HHV-6 exhibits tropism for astrocytes, oligodendrocytes, and neurons. Thus, HHV-6 can perturb cellular homeostasis, neuronal signaling, and immune regulation, astrocytic glutamate clearance, GABAergic inhibition, and cholinergic or monoaminergic neurotransmission yielding network hyperexcitability. It is also reported that HHV-6 can activate neuroinflammation through Toll-Like Receptor (TLR), cytokine, and/or NF-$\kappa$B activation, which facilitates neuronal injury and network instability. Indeed, a suite of converging processes suggest a multifactorial nature for HHV-6 related neuropathology. Despite robust experimental and clinical data, definitive causal relationships between HHV-6 and epilepsy (or induction of neurodegeneration) remain elusive. This review discusses evidence for roseolovirus-induced neurological dysfunction and disorders commonly associated with HHV-6A and HHV-6B infections. A preponderance of clinical and experimental evidence suggests that differential tropism for distinct neuronal neurotransmitter chemotypes and glia as well as systemic effects are involved in roseolovirus-mediated neurological disease. Full article

Children with developmental disabilities are less physically active and at increased risk for chronic conditions that physical activity might ameliorate. This study examined the relationships between the impact of physical activity (e.g., muscles burning, body tiredness), physical activity time and fatigue in children with Cerebral Palsy (CP) and Down Syndrome (DS) in comparison to typically developing (TD) children. A convenience sample of children and parents was enrolled. All children were between 4 and 10 years, ambulatory, medically stable, not taking sleep-aid medications and were either TD (n = 20) or diagnosed with CP (n = 14) or DS (n = 5). Children and parents separately answered questionnaires about participation in physical activity and fatigue during the past week, yielding retrospective data. Additionally, they completed prospective questionnaires for 3 consecutive days. Repeated measures multivariate and univariate analyses (post hoc) of variance, along with correlations between variables were completed. Analyses of retrospective data yielded no specific findings. Prospectively, all groups of parents reported that as the impact of physical activity increased, perceptions of fatigue decreased (r = −0.349; p < 0.001). Parents of children with Cerebral Palsy noted a negative relationship between the time spent doing physical activity and perceptions of fatigue (r = −0.553; p < 0.001). Between-group differences in perceptions of fatigue occurred for children with CP compared to TD (F = 8.248; p < 0.001). Parent-reported findings suggest potential associations between physical activity participation and perceptions of fatigue across diagnostic groups. Full article

Background and Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by persistent or relapsing fatigue lasting at least six months, not alleviated by rest and not previously present. It is accompanied by post-exertional symptom exacerbation and non-restorative sleep. Fatigue is often disabling and reduces daily activity by more than 50%. This study aimed to evaluate the long-term frequency of somatic and psychiatric disorders in women previously diagnosed with ME/CFS and to describe the long-term clinical course, laboratory findings, and fatigue-related changes during a 16-year follow-up period. Materials and Methods: Sixteen years ago, 40 women diagnosed with ME/CFS according to then-current CDC criteria were enrolled at the Clinic for Infectious Diseases and the Center for Laboratory Medicine, University Clinical Center of Vojvodina. All participants provided informed consent. After 16 years, 20 women agreed to follow-up evaluation. At both time points, participants underwent structured questionnaires, clinical examination, psychological assessment, and comprehensive laboratory testing, including hematological, biochemical, endocrinological, and virological analyses. Fatigue severity was assessed using the FibroFatigue Scale (FFS) and the Multidimensional Assessment of Fatigue (MAF) scale. Results: During follow-up, 15% of participants were diagnosed with rheumatoid arthritis, 10% with cervical or breast cancer, 5% experienced premature myocardial infarction, 5% developed bronchial asthma, and 20% were diagnosed with clinical depression. Progression of ME/CFS was observed in 15%, while 5% reported infertility. Additionally, 15% developed arterial hypertension. Only 15% of participants did not report symptom worsening or new diagnoses. Conclusions: Over the 16-year follow-up, 85% of women with ME/CFS developed significant somatic or psychiatric conditions. These findings suggest that women diagnosed with ME/CFS may experience substantial long-term somatic and psychiatric disease burden, supporting the need for continued clinical monitoring and individualized follow-up. Full article

Fibromyalgia represents a complex chronic pain condition in which patients experience widespread pain accompanied by fatigue and a broad range of physical and psychological symptoms. Diagnosis relies on symptom-based diagnostic criteria that lack objectivity, making it difficult to properly diagnose and treat. The etiology of fibromyalgia is thought to be multifactorial, including neurobiological, psychological, environmental, and genetic factors. In addition to pain, many patients experience central nervous system-related symptoms, such as fatigue, sleep disturbances, cognitive impairment, anxiety, and depression. Fibromyalgia has recently been recognized as a nociplastic pain disorder. Alterations in sensory processing and pain thresholds in the central nervous system may result in the perception of widespread pain throughout the body. In a recent study, we divided fibromyalgia patients who reported widespread pain into two subgroups based on their pain threshold: a low pain threshold group and a normal pain threshold group. We comparably analyzed these subgroups by using resting-state functional magnetic resonance imaging. This hypothesis article provides an overview of the pathogenesis of fibromyalgia and discusses these two subgroups of nociplastic pain. Recognizing the various pathophysiologies of fibromyalgia will allow us to better understand patients’ conditions and select appropriate treatment options for each patient. Full article

Fibromyalgia is a chronic syndrome associated with pain, fatigue, and cognitive symptoms, often linked to gut microbiota alterations. The Mediterranean Diet (MD), particularly extra-virgin olive oil (EVOO), has antioxidant and anti-inflammatory properties that may beneficially modulate the microbiota. We conducted a prospective, randomized, double-blind, placebo-controlled clinical trial that included 250 women (206 with fibromyalgia, 44 controls). Participants followed a MD supplemented with EVOO or refined olive oil (placebo) for six months. Microbiota composition was analyzed at four time points (T0–T3) by 16S rRNA sequencing (V3–V4). At baseline, fibromyalgia patients exhibited reduced microbial diversity compared to controls. While global diversity did not change after intervention, specific taxa increased significantly with EVOO, including Bacteroides fragilis, Anaerotruncus colihominis, Adlercreutzia equolifaciens, and butyrate producers such as Faecalibacterium prausnitzii, Roseburia intestinalis, and Agathobacter. These shifts suggest EVOO supplementation might promote anti-inflammatory and metabolic bacteria, suggesting diet as a complementary strategy to modulate gut microbiota in fibromyalgia. Full article