Search Results (36,879)

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can develop as post-vaccination syndrome (PVS) or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). In our prior retrospective study, most patients with PVS who developed ME/CFS had vitamin D insufficiency or deficiency. We evaluated the efficacy of vitamin D replacement therapy guidance for ME/CFS symptom improvement in patients with vitamin D insufficiency or deficiency. Methods: This open-label randomized controlled trial enrolled 91 participants with ME/CFS as PVS or PASC and serum 25(OH) vitamin D < 30 ng/mL across five clinical sites. Participants were randomized 1:1 to intervention (active vitamin D preparation plus vitamin D replacement therapy guidance: 25 μg daily supplementation, dietary counseling, sun exposure, and exercise) or control (active vitamin D preparation alone) for 12 weeks. The primary endpoint was the change in ME/CFS symptom count from screening to Week 12. Results: Mean symptom change was −6.7 in the intervention group versus −1.2 in the control group (between-group difference −5.6; 95% CI: −7.2, −3.9; p < 0.001). Serum 25(OH) vitamin D improved from 18.6 to 27.1 ng/mL in the intervention group, while the control group showed a decreasing trend (between-group difference 10.2 ng/mL; 95% CI: 7.9, 12.5). Achievement of <8 symptoms (i.e., no longer meeting ME/CFS diagnostic criteria) was significantly higher in the intervention group, with 16 participants achieving this threshold compared to 1 in the control group (p < 0.001). Subgroup analyses showed consistent benefit in both PVS (n = 56) and PASC (n = 29) cohorts. Conclusions: Vitamin D replacement therapy guidance significantly reduced ME/CFS symptoms along with improvement of serum 25(OH) vitamin D levels in patients with vitamin D insufficiency or deficiency who developed ME/CFS as PVS or PASC. Full article

RNA viruses pose a persistent global threat due to their high mutation rates, zoonotic potential, and rapid adaptability. Emergence events have risen steadily, as demonstrated by major outbreaks caused by Influenza A, Ebola, Zika, and Chikungunya viruses, followed by the coronavirus epidemics of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-1) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and culminating in the COVID-19 pandemic. These characteristics frequently compromise the durability of existing vaccines and antiviral therapies, highlighting the urgent need for new antiviral agents. Alkaloids, a structurally diverse class of nitrogen-containing natural compounds, have gained attention for their ability to interfere with multiple stages of the viral life cycle, including entry, replication, protein synthesis, and host immune modulation. To our knowledge, this review compiles all currently reported alkaloids with antiviral activity against RNA viruses and summarizes their proposed mechanisms of action, distinguishing evidence from in vitro, in vivo, and in silico studies. Quaternary alkaloids are discussed separately because their permanent ionic charge enables distinctive interactions with membranes and host pathways. Although many findings are promising, clinical translation remains limited by incomplete mechanistic validation, scarce in vivo data, suboptimal bioavailability, narrow therapeutic windows, and inconsistent experimental methodologies. To advance the field, future research should prioritize RT-qPCR–based antiviral evaluation to accurately quantify viral replication, incorporate mechanistic assays to clarify modes of action, apply structure–activity relationship (SAR) approaches for rational optimization, and expand in vivo pharmacokinetic and efficacy studies to assess therapeutic feasibility. Overall, alkaloids represent a promising yet underdeveloped reservoir for next-generation antiviral discovery against rapidly evolving RNA viruses. Full article

Background/Objectives: Penetrating atherosclerotic ulcer (PAU) is a type of acute aortic syndrome (AAS) characterized by an ulcer that penetrates from the inner lining into the middle layer of the aorta, often leading to serious complications such as intramural hematoma (IMH), aortic dissection, aneurysm, and rupture. PAU incidence has risen significantly in recent years. Advancements in imaging technologies like CT and MRI have improved early detection, yet the true prevalence remains unclear due to the asymptomatic nature of many cases. Thoracic endovascular aortic repair (TEVAR) is becoming the preferred treatment, but questions remain regarding its effectiveness in different clinical settings. This systematic review and meta-analysis aim to consolidate findings on PAU’s clinical presentation, imaging characteristics, and outcomes to improve diagnosis, risk assessment, and treatment strategies. Methods: PubMed, Scopus, Embase, and Web of Science (WOS) were systematically searched from 1994 until November 2023. Related data were collected and evaluated. We used a random-effect model to calculate a forest plot, a funnel plot, pooled prevalence, and publication bias by STATA 18. Results: Of 1179 studies, 56 met the inclusion criteria, and we analyzed 3023 PAU patients. The 30-day mortality rate was 4.4%, with a late mortality rate of 15.6%. According to our study, open surgery, pre-operation (pre-op) aortic rupture, post-operation (post-op) endoleak, distant year of publication, symptomatic patients, lesions in the ascending aorta, and greater diameter of the lesion were associated with mortality. TEVAR was the most common treatment (67.3%), the endoleak rate was 3.7%, and re-intervention occurred in 4.4% of cases. Significant heterogeneity and publication bias were noted across several outcomes. Conclusions: PAU primarily affects elderly males with cardiovascular comorbidities; interventions like TEVAR reduce short-term mortality; however, long-term outcomes remain challenging, which indicates further investigation is needed into early detection and treatment. Full article

Background/Objectives: Lynch syndrome (LS), is traditionally managed uniformly despite being caused by pathogenic variants in four distinct mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). This approach fails to leverage gene-specific characteristics for precision healthcare delivery. This review redefines LS as four distinct genetic syndromes and establishes a genotype-guided precision management framework to optimize risk stratification, surveillance, and therapeutic interventions. Methods: We synthesized molecular, clinical, and outcomes data from the Prospective Lynch Syndrome Database (8500+ carriers; 70,000 person-years), genomic studies characterizing gene-specific mutational patterns, and immunotherapy trials while referencing international guidelines [National Comprehensive Cancer Network (NCCN), European Hereditary Tumour Group (EHTG)/European Society of Coloproctology (ESCP), and European Society for Medical Oncology (ESMO)] to formulate genotype-stratified recommendations. Results: Fundamental molecular differences necessitate differentiated management strategies. MLH1 deficiency exhibits unique “two-in-one hit” mechanisms driving aggressive tumorigenesis with high interval cancer rates. MSH2 deficiency presents the highest tumor mutational burden (≈47 mutations per megabase; Mut/Mb) and broadest cancer spectrum. MSH6 deficiency displays distinctive high-single-nucleotide variant (SNV)/low-insertion–deletion (Indel) patterns often presenting as microsatellite instability-low (MSI-low) or microsatellite stable (MSS), complicating conventional detection. PMS2 deficiency demonstrates substantial attenuation due to redundancy. These translate into precision interventions: MLH1/MSH2 carriers require colonoscopy from age 25 at 1–2-year intervals with extended colectomy preferred, while MSH6/PMS2 carriers can defer surveillance to age 35–40 with longer intervals and undergo segmental resection. Immune checkpoint inhibitors (ICIs) are effective in deficient MMR (dMMR)/microsatellite instability-high (MSI-H) tumors across all four MMR genotypes. Conclusions: Genotype-specific precision management optimizes the benefit–burden balance, enhances early cancer detection, reduces overtreatment, and enables personalized genetic counseling, advancing precision healthcare for LS families and addressing critical gaps in hereditary cancer care. Full article

Background and Clinical Significance: Hypoglossal nerve palsy is an uncommon neurological complication of infectious mononucleosis and is only rarely reported. Putative mechanisms include virus-triggered neuritis (Epstein–Barr virus (EBV) or Cytomegalovirus (CMV)) and/or mechanical compression related to cervical lymphadenopathy. Case Presentation: We report two children with infectious mononucleosis and transient unilateral hypoglossal nerve palsy. Case 1 was a 15-year-old boy with 7 days of fever and typical mononucleosis features who developed leftward tongue deviation accompanied by sialorrhea, dysarthria, and dysphagia. Laboratory testing showed marked hepatocellular injury and EBV-specific IgM positivity. Case 2 was a 9-year-old girl with a 24 h history of bilateral lateral cervical lymphadenopathy with overlying inflammatory signs; examination revealed rightward tongue deviation with similar associated symptoms. CMV-specific IgM antibodies were detected on serological testing. Both patients received systemic corticosteroids and empiric intravenous antibiotics, with supportive care. Hypoglossal nerve function fully recovered within 2–4 weeks of treatment initiation. Conclusions: These cases underscore that isolated hypoglossal nerve palsy may complicate EBV- or CMV-associated mononucleosis in children. Although the prognosis is generally favorable, the presentation warrants careful evaluation to exclude alternative causes of lower cranial neuropathies and close follow-up until complete neurological resolution. Full article

Primary Sjogren’s Disease (SjD) is characterized by features of dryness arising from inflammation in the secretary glands, particularly the salivary and lachrymal glands. Generalized symptoms of fatigue and limb pain are very common but, in addition, about 40% of patients have one or more features of organ-specific systemic disease. This review goes through the background of SjD including diagnosis and classification, epidemiology, impact and investigations such as ultrasound and lip biopsy. It then focuses in detail on each of the systemic organ-specific features, principally using the European League against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) along with some non-ESSDAI domains, before concluding with comments on disease heterogeneity, treatment, vaccination, pregnancy and surgery along with observations on patient perspectives. The aim is to provide a general overview of these aspects of the disease to complement other chapters in this monograph. Full article

Cholestatic diseases in children represent a heterogeneous group of disorders that, with few exceptions, have no cure. For decades, off-label drugs and/or drugs with little evidence of efficacy have been used to treat pruritus or as supportive therapy. In recent years, a family of molecules known as bile acid transporter inhibitors (IBATis) has been developed, with two of these being approved for treating pruritus in progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (ALGS). Blocking the ileal reabsorption of bile acids (BAs) lowers serum levels. This contributes to reducing cholestatic pruritus. Such a mechanism of action may also have a potential benefit in other cholestatic diseases and even in the consequences of chronic cholestasis. This is a narrative review of the literature, including the most recent communications, to summarize data on the efficacy and safety of IBATis in the treatment of pruritus in PFIC and ALGS in children, including a description of the latest results from their use in a real-world setting. Reports on off-label use and experiences in adults are also discussed. This review aims to help physicians understand the potential and limitations of these new drugs in the treatment of cholestatic pruritus. Full article

Background: Severe lower urinary tract dysfunction (LUTD) in neurologically and anatomically normal children is uncommon and frequently underdiagnosed. When severe, functional voiding disorders may closely mimic obstructive or reflux pathology, leading to diagnostic errors, unnecessary invasive procedures, and potential risk to the upper urinary tract. Case presentation: We present three pediatric cases (aged 3–10 years) referred for recurrent febrile urinary tract infections, incontinence, or acute urinary retention in the absence of neurological or structural abnormalities. Urodynamic evaluation identified three distinct severe functional phenotypes: detrusor overactivity with reduced bladder capacity, poor compliance with detrusor–sphincter dyssynergia and secondary high-grade vesicoureteral reflux (Hinman syndrome), and detrusor underactivity with significant post-void residual volumes. All patients demonstrated marked bladder wall remodeling on cystoscopy, including trabeculation and pseudopolypoid mucosal changes. Case discussion: Despite similar clinical severity, the cases illustrated substantial functional heterogeneity and differing risks of upper urinary tract involvement. Urodynamic phenotyping proved central to diagnosis, differentiation from structural disease, and treatment planning. Multimodal conservative management—including urotherapy, pelvic floor biofeedback, targeted pharmacologic therapy, and, when indicated, clean intermittent catheterization or antibiotic prophylaxis—led to resolution of recurrent infections and meaningful improvement in bladder function during medium-term follow-up, although symptom recurrence occurred in one patient after treatment withdrawal. Conclusions: These cases highlight the heterogeneity and potential reversibility of severe functional LUTD in otherwise healthy children. Early functional recognition based on urodynamic assessment is essential to avoid misdiagnosis, prevent unnecessary surgical intervention, and protect renal function. Conservative, function-oriented management remains the cornerstone of effective treatment. The findings are discussed in the context of the existing literature on severe non-neurogenic LUTD and Hinman syndrome. Full article

A Group A Streptococcus (GAS, Streptococcus pyogenes) is an exclusively human pathogen whose virulence is driven by a diverse array of surface structures, secreted toxins, and immune evasion mechanisms. Central to its pathogenicity is the M protein, a surface-anchored molecule that inhibits phagocytosis by interfering with complement deposition and binding host factors such as fibrinogen. GAS also secretes a wide range of toxins and enzymes that damage tissues and disrupt host defences. Streptolysin O and streptolysin S are potent cytolysins that lyse immune cells and contribute to tissue necrosis. Pyrogenic exotoxins (such as SpeA and SpeC) act as superantigens, triggering massive, dysregulated T cell activation and cytokine release, an underlying mechanism in streptococcal toxic shock syndrome. Additional factors like DNases and streptokinase facilitate bacterial spread by breaking down host tissue and counteracting neutrophil extracellular traps (NETs). Immune evasion is further supported by the production of enzymes that interfere with complement functions, like the cleavage of chemokines and the targeting of antibodies. Together, these virulence determinants allow GAS to cause a wide spectrum of diseases, ranging from uncomplicated pharyngitis and impetigo to invasive conditions like necrotising fasciitis and sepsis. This review provides a timely overview of the important GAS virulence factors and an update on the current vaccine landscape. Full article

Because CKMS was only proposed by the American Heart Association in 2023, there has been a paucity of information about the distribution and determinants of the syndrome across population groups. We reviewed published studies of the prevalence of CKMS in the U.S. and other countries and obtained new estimates of the prevalence of this syndrome among U.S. adults by birth decade and sociodemographic attributes using 2019, 2021, and 2023 Behavioral Risk Factor Surveillance System (BRFSS) data. The results of this study indicate that CKMS is widespread in the general U.S. population, especially among older cohorts born before 1940 and during the 1940s, 1950s, and 1960s. Except for the three younger cohorts, born in the 1980s, 1990s, and 2000 or later, the prevalence of CKMS stage 4 was significantly higher among males than in females. Among those born between the 1950s and 1990s, the prevalence was significantly higher among non-Hispanic Blacks compared to their non-Hispanic white counterparts. Across all birth decades, prevalence of CKMS stage 4 was generally higher among those without a college degree, from a low-income household, and residing in rural areas. These prevalence rate estimates will further our understanding of the burden and unique needs of different population groups in improving cardiovascular–kidney–metabolic health across the life course. Full article

Background: In Parkinson’s disease (PD), a higher prevalence of polyneuropathy (PNP) is increasingly recognized, although the causal association is still under debate. In contrast, PNP in atypical parkinsonian syndromes (APS) has been insufficiently addressed, despite preliminary evidence suggesting elevated prevalence. Methods: Nerve conduction studies were performed on 13 patients with multiple system atrophy (MSA) and 9 patients with progressive supranuclear palsy (PSP) at baseline. PNP was diagnosed according to standard electrophysiological criteria after exclusion of common secondary causes. Comprehensive clinical evaluation included motor and non-motor assessments over two years of follow-up. Results: At baseline, PNP was present in 53.8% of MSA patients and 66.7% of PSP patients. MSA patients with PNP showed greater motor symptom severity (UPDRS III score; p = 0.046) and worse cognitive performance (MoCA; p = 0.044) compared to those without PNP. Over two years, a significant reduction in the tibial nerve amplitude was observed exclusively in MSA patients (p = 0.039), paralleling disease progression. Conclusions: This study provides the first longitudinal evaluation of clinical and electrophysiological PNP progression in MSA and PSP. A high comorbidity of PNP in patients with APS could contribute to motor and sensory impairments in these patients. Our findings indicate that PNP progression may reflect disease progression in MSA. Given the limited sample size, larger-scale longitudinal studies are needed to further investigate biomarker potential of PNP in APS and to clarify differences in peripheral nerve involvement between synucleinopathies and tauopathies. Full article

Background/Objectives: Energy availability (EA) is associated with Relative Energy Deficiency in Sport syndrome. This study assessed the EA, body composition, and phase angle (φ) of adolescent artistic gymnasts during a competitive season. Methods: Thirty non-elite artistic gymnasts aged 11–14 years participated in this cross-sectional study. Anthropometric data were collected and body mass index (BMI) was assessed using the World Health Organization growth charts. Bioelectrical impedance analysis was performed and diet and physical activity were recorded for three days. Dietary and physical activity records were analyzed to estimate energy intake, total energy expenditure (TEE), and exercise energy expenditure, from which energy balance (EB) and EA were calculated. The 95% confidence ellipses of the impedance (Z) vectors were compared with a reference population using the two-sample Hotelling’s T² test. Correlations between variables were examined by Pearson’s or Spearman’s correlation analysis. Statistical significance was set at α = 0.05. Results: All participants were classified within the normal BMI category, except for one who was classified as being overweight. Mean (± SD) fat mass, fat-free mass (FFM), and φ were 16.1 ± 3.4%, 83.9 ± 3.4%, and 6.0 ± 0.6°, respectively. The 95% confidence ellipses of Z vectors differed significantly from the reference population. Energy balance was 32 ± 223 kcal/day and EA was 49.2 ± 11.4 kcal/kg FFM/day. Energy availability was significantly correlated with EB, TEE, and body composition variables. Conclusions: Adolescent non-elite artistic gymnasts showed no clear indications of LEA and exhibited a normal body composition and φ during the competitive season, consistent with their EA. Full article

Objectives: Systemic low-grade inflammation is associated with steatohepatitis in adults. We aim to explore if systemic low-grade inflammation, measured by plasma high-sensitivity C-reactive protein (hs-CRP), is also linked to steatotic liver disease in adolescents. Methods: In the cross-sectional Early Vascular Ageing in the YOUth study, systemic low-grade inflammation was measured by hs-CRP and liver fat content was quantified by the controlled attenuation parameters (CAP) derived from FibroScan^® (Echosense, Paris, France) measurements in 14- to 19-year-old Austrian adolescents. Cardiovascular risk factors and anthropometric data were collected through face-to-face interviews, physical examinations, and comprehensive fasting blood analyses. Linear regression models were performed to analyze the association between hs-CRP and CAP values. Results: A total of 1300 adolescents (64.6% female) with a mean age of 17.2 ± 1.3 years were included in this analysis. hs-CRP was significantly associated with CAP values in the simple linear regression model (b = 1.35, p = 0.044) and after adjustment for sex and age (b = 1.84, p = 0.006), suggesting an increase in systemic low-grade inflammation with increasing liver fat content. However, further adjustment for major factors of the metabolic syndrome (Homeostatic Model Assessment for Insulin Resistance, non-high-density lipoprotein cholesterol, body mass index z-score, systolic blood pressure z-score) led to a loss of significance of the mentioned association (b = −0.55, p = 0.419). Conclusions: Systemic low-grade inflammation measured by hs-CRP is linked to higher liver fat content in our adolescent cohort. However, this association is largely driven by components of the metabolic syndrome and the overall metabolic milieu, rather than reflecting liver-specific inflammation. Full article

Autologous serum (AS) tears are an effective therapeutic option for advanced DED, mimicking the biochemical composition of natural tears. However, the absence of universally accepted guidelines has resulted in variability in AS tear concentration, diluents, processing of collected blood, and storage conditions, raising questions regarding the optimal parameters for AS tear use. This perspective provides a framework to inform clinical implementation and to guide future research on AS tear therapy optimization. PubMed, Scopus, and the Cochrane Library were searched for English-language articles from January 2022 through September 2025 using the terms “autologous serum,” “dry eye disease,” “dry eye syndrome,” “dry eye,” and “DED.” Evidence suggests that AS tears diluted to 20% are widely used for moderate DED, whereas higher concentrations may provide faster, more pronounced and more durable improvements, particularly in severe cases. Levofloxacin-containing eye drops, artificial tears without emphasis on a specific component, sodium hyaluronate (SH)-containing eye drops, cyclosporine A (CsA)-containing ultra-nano emulsions, and methylcellulose have been investigated as alternatives to conventional diluents. Standardization of clotting, centrifugation and storage parameters is expected to enhance efficacy of AS tears and ensure stability of growth factors. Combination with estrogen replacement therapy in perimenopausal women or with topical insulin eye drops, as well as perioperative prophylactic use in patients with graft-versus-host disease (GVHD)-associated dry eye undergoing cataract surgery, represent emerging applications of AS tears that demonstrate potential to improve therapeutic outcomes. Overall, this perspective highlights the need for consensus protocols, supports severity-based concentration tailoring, and notes that diluents and processing methods require further refinement. Full article

Background/Objectives: The gut microbiota is increasingly recognized as a key determinant of human health, playing a vital role in metabolism, immunity, and disease susceptibility. Dysbiosis, or microbial imbalance, is associated with gastrointestinal disorders such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and Clostridioides difficile infection (CDI), as well as extraintestinal conditions, including obesity, cardiovascular disease, and neuropsychiatric disorders. This review aims to provide an updated overview of emerging therapeutic strategies to modulate the gut microbiota to restore eubiosis and improve health outcomes. Methods: A narrative review of recent literature was conducted, focusing on preclinical and clinical studies investigating microbiota-targeted therapies. The review primarily covers innovative interventional approaches, including fecal microbiota transplantation (FMT), bacterial consortium transplantation (BCT), bacteriophage therapy and outer membrane vesicles (OMVs). Results: Evidence supports the role of probiotics, prebiotics, and synbiotics in remodeling microbial communities and improving host health, although their effects may be strain- and context-dependent. FMT has demonstrated high efficacy in the treatment of recurrent Clostridium difficile infections and is being studied for IBD, IBS and extraintestinal diseases, following the recent Food and Drug Administration approval of the first commercial FMT products. BCT offers a standardized alternative to donor-derived material, with early clinical successes such as FDA-approved SER-109. Phage therapy and OMVs represent promising frontiers, offering targeted microbial modulation and interactions with the immune system, although clinical data remain limited. Conclusions: Emerging gut microbiota modulation strategies offer new perspectives for precision medicine and could transform the prevention and treatment of many diseases, but further studies are needed to ensure their safety, standardization, and clinical application. Full article