Search Results (994)

Background: Bipolar disorder (BD) is a chronic and disabling psychiatric condition characterized by recurring episodes of mania, hypomania, and depression. Despite the availability of mood stabilizers, antipsychotics, and antidepressants, long-term management remains challenging due to incomplete symptom control, adverse effects, and high relapse rates. Methods: This paper is a narrative review aimed at synthesizing emerging trends and future directions in the pharmacological treatment of BD. Results: Future pharmacotherapy for BD is likely to shift toward precision medicine, leveraging advances in genetics, biomarkers, and neuroimaging to guide personalized treatment strategies. Novel drug development will also target previously underexplored mechanisms, such as inflammation, mitochondrial dysfunction, circadian rhythm disturbances, and glutamatergic dysregulation. Physiological endophenotypes, such as immune-metabolic profiles, circadian rhythms, and stress reactivity, are emerging as promising translational tools for tailoring treatment and reducing associated somatic comorbidity and mortality. Recognition of the heterogeneous longitudinal trajectories of BD, including chronic mixed states, long depressive episodes, or intermittent manic phases, has underscored the value of clinical staging models to inform both pharmacological strategies and biomarker research. Disrupted circadian rhythms and associated chronotypes further support the development of individualized chronotherapeutic interventions. Emerging chronotherapeutic approaches based on individual biological rhythms, along with innovative monitoring strategies such as saliva-based lithium sensors, are reshaping the future landscape. Anti-inflammatory agents, neurosteroids, and compounds modulating oxidative stress are emerging as promising candidates. Additionally, medications targeting specific biological pathways implicated in bipolar pathophysiology, such as N-methyl-D-aspartate (NMDA) receptor modulators, phosphodiesterase inhibitors, and neuropeptides, are under investigation. Conclusions: Advances in pharmacogenomics will enable clinicians to predict individual responses and tolerability, minimizing trial-and-error prescribing. The future landscape may also incorporate digital therapeutics, combining pharmacotherapy with remote monitoring and data-driven adjustments. Ultimately, integrating innovative drug therapies with personalized approaches has the potential to enhance efficacy, reduce adverse effects, and improve long-term outcomes for individuals with bipolar disorder, ushering in a new era of precision psychiatry. Full article

Background and Aim: Type 2 diabetes (T2D) continues to pose a significant public health challenge worldwide. Among therapeutic options, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have proven effective in optimizing glycemic control and improving cardiometabolic profiles. Semaglutide, now available in an oral formulation, represents a modern strategy to improve patient adherence while supporting glucose and weight regulation. This study primarily investigated the effects of oral semaglutide on key metabolic indicators and secondary endpoints included cardiovascular risk markers (blood pressure and lipid profile) and patient-reported quality of life (QoL). Study Design and Methods: A longitudinal, prospective observational study was conducted involving patients with T2D across two Italian healthcare facilities. Participants were assessed at baseline (T0) and at three subsequent intervals—6 months (T1), 12 months (T2), and 18 months (T3)—following the initiation of oral semaglutide use. Key Findings: Out of 116 participants enrolled, 97 had complete and analyzable data. Across the 18-month follow-up, significant improvements were observed in glycemic parameters, with a notable reduction in HbA1c levels (T0 vs. T3, p = 0.0028; p ≤ 0.05, statistically significant). Self-reported outcomes showed enhanced quality of life, especially in treatment satisfaction and perceived flexibility (T0 vs. T3, p < 0.001). Conclusions: Daily administration of 14 mg oral semaglutide in individuals with T2D resulted in substantial benefits in glycemic regulation, weight reduction, cardiovascular risk management, and overall patient satisfaction. These findings reinforce its potential role as a sustainable and effective option in long-term diabetes care from both a clinical and public health perspective. Full article

Periodontal diseases in pediatric subjects represent a challenging and relatively underexplored area compared to the extensive data available about periodontal diseases in adults. The present narrative review aims to explore the periodontal status and the related subgingival and/or salivary microbial profiles in pediatric subjects (≤18 years), focusing also on the state of health or systemic diseases. In healthy periodontium, early colonizers, such as Streptococcus and Actinomyces spp., dominate the subgingival microbiota, supporting an eubiosis state. Low levels of Candida albicans and latent Herpesviridae may be detected. In gingivitis, the microbial profile shifts towards more pathogenic species, including Prevotella intermedia and Fusobacterium nucleatum. In necrotizing gingivitis, typically affecting systemically compromised children, the microbial profile is characterized by spirochetes, Fusobacterium, and Prevotella intermedia. Viral coinfections—especially with HSV, CMV, and EBV—are more frequently detected. In periodontitis, the microbiota was dominated by red complex pathogens along with Aggregatibacter actinomycetemcomitans in the aggressive forms, especially in systemically compromised children, as Herpesviridae reactivation and co-infections. Fungal involvement is less well characterized; Candida albicans may be present, particularly in cases of severe immune suppression. Nevertheless, the lack of pediatric longitudinal studies investigating periodontal disease progression after periodontal treatment and related changes in microbiological composition limited the understanding and exploration of the oral microbiota over time. Full article

Schistosoma mansoni infection is associated with hepatic inflammation and fibrosis, but its systemic metabolic effects remain poorly understood. This study aimed to investigate changes in the serum lipidomic profile associated with S. mansoni infection and parasite load in individuals from an endemic area. This cross-sectional analysis was nested within a longitudinal cohort study conducted in northeastern Brazil. Parasitological diagnosis and quantification were performed using the Kato–Katz technique. A total of 45 individuals were selected and divided into three groups: high parasite load (HL), low parasite load (LL), and uninfected controls (NegE). Serum samples were analyzed using mass-spectrometry-based lipidomics. The most abundant lipid subclasses across all groups were phosphatidylcholines (PC), triacylglycerols (TAG), and phosphatidylethanolamines (PE). However, individuals in the HL group exhibited distinct lipidomic profiles, with increased levels of specific phosphatidylinositols (PI) and reduced levels of certain TAG species compared to the NegE group. These changes may reflect host–parasite interactions and immune–metabolic alterations driven by intense infection. Our findings suggest that S. mansoni infection, particularly at higher parasite burdens, can influence the host’s serum lipid profile and may contribute to metabolic disturbances in endemic populations. Full article

Tennis is a demanding sport that requires physical abilities and optimal body composition. The aim of this study was to investigate the anthropometric characteristics, body composition, and somatotype development of young Slovenian tennis players (754 boys and 514 girls aged 12 to 18 years) over the last two decades. Using standardised anthropometric measurements and the Heath-Carter method, somatotypes were calculated and analysed by age and gender. The results showed clear age- and gender-specific trends and differences in both somatotype profiles and detailed anthropometric characteristics. Significant differences were found in height, body mass, BMI, skinfolds, girths, and limb lengths, with gender differences becoming more pronounced in the older age groups. In boys, mesomorphy increased with age, reflecting an increase in musculature, while in girls, a shift from ectomorphic to endomorphic profiles was observed during adolescence, probably influenced by pubertal and hormonal changes. Significant sex-specific differences were observed in all three somatotype components in most age groups, especially in fat mass and muscle. The longitudinal design provides valuable data and insights into the evolving physical profiles of adolescent tennis players that support more effective talent identification and training. Despite the changes that have taken place in tennis over time, standardised measurement protocols ensured comparability, making the results relevant for practitioners working with adolescents in tennis development. Full article

Lotus (Nelumbo nucifera Gaertn.) is a quintessential medicinal and edible plant, exhibiting marked differences in therapeutic effects among its various parts. The lotus seed constitutes a key component of this plant. Notably, the entire seed and the plumule display distinct medicinal properties. To investigate the “homologous plants with different effects” phenomenon in traditional Chinese medicine, this study established a Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) method. This study employed immature lotus seeds as the experimental material, diverging from the mature seeds conventionally used. Conductive double-sided tape was employed for sample preparation, and complete longitudinal sections of the seeds were obtained, followed by MALDI-MSI analysis to identify and visualize the spatial distribution of characteristic secondary metabolites within the entire seeds. The results unveiled the diversity of metabolites in lotus seeds and their differential distribution across tissues, with pronounced distinctions in the plumule. A total of 152 metabolites spanning 13 categories were identified in lotus seeds, with 134, 89, 51, and 98 metabolites discerned in the pericarp, seed coat, cotyledon, and plumule, respectively. Strikingly, young lotus seeds were devoid of liensinine/isoliensinine and neferine, the dominant alkaloids of mature lotus seed plumule, revealing an early-stage alkaloid profile that sharply contrasts with the well-documented abundance found in mature seeds and has rarely been reported. We further propose a biosynthetic pathway to explain the presence of the detected benzylisoquinoline and the absence of the undetected bisbenzylisoquinoline alkaloids in this study. These findings present the first comprehensive metabolic atlas of immature lotus seeds, systematically exposing the pronounced chemical divergence from their mature counterparts, and thus lays a metabolomic foundation for dissecting the spatiotemporal mechanisms underlying the nutritional and medicinal value of lotus seeds. Full article

This study introduces a novel methodology for assessing ice-jam flood hazards along river channels. It employs empirical equations that relate non-dimensional ice-jam stage to discharge, enabling the generation of an ensemble of longitudinal profiles of ice-jam backwater levels through Monte-Carlo simulations. These simulations produce non-exceedance probability profiles, which indicate the likelihood of various flood levels occurring due to ice jams. The flood levels associated with specific return periods were validated using historical gauge records. The empirical equations require input parameters such as channel width, slope, and thalweg elevation, which were obtained from bathymetric surveys. This approach is applied to assess ice-jam flood hazards by extrapolating data from a gauged reach at Fort Simpson to an ungauged reach at Jean Marie River along the Mackenzie River in Canada’s Northwest Territories. The analysis further suggests that climate change is likely to increase the severity of ice-jam flood hazards in both reaches by the end of the century. This methodology is applicable to other cold-region rivers in Canada and northern Europe, provided similar fluvial geomorphological and hydro-meteorological data are available, making it a valuable tool for ice-jam flood risk assessment in other ungauged areas. Full article

Prognostic markers such as overall survival (OS) and tertiary lymphoid structure (TLS) ratios, alongside diagnostic signatures like primary cancer-type classification, provide critical information for treatment selection, risk stratification, and longitudinal care planning across the oncology continuum. However, extracting these signals solely from sparse, high-dimensional multi-omics data remains a major challenge due to heterogeneity and frequent missingness in patient profiles. To address this challenge, we present SeNMo, a self-normalizing deep neural network trained on five heterogeneous omics layers—gene expression, DNA methylation, miRNA abundance, somatic mutations, and protein expression—along with the clinical variables, that learns a unified representation robust to missing modalities. Trained on more than 10,000 patient profiles across 32 tumor types from The Cancer Genome Atlas (TCGA), SeNMo provides a baseline that can be readily fine-tuned for diverse downstream tasks. On a held-out TCGA test set, the model achieved a concordance index of 0.758 for OS prediction, while external evaluation yielded 0.73 on the CPTAC lung squamous cell carcinoma cohort and 0.66 on an independent 108-patient Moffitt Cancer Center cohort. Furthermore, on Moffitt’s cohort, baseline SeNMo fine-tuned for TLS ratio prediction aligned with expert annotations (p < 0.05) and sharply separated high- versus low-TLS groups, reflecting distinct survival outcomes. Without altering the backbone, a single linear head classified primary cancer type with 99.8% accuracy across the 33 classes. By unifying diagnostic and prognostic predictions in a modality-robust architecture, SeNMo demonstrated strong performance across multiple clinically relevant tasks, including survival estimation, cancer classification, and TLS ratio prediction, highlighting its translational potential for multi-omics oncology applications. Full article

Introduction: Burnout syndrome, long described as an “occupational phenomenon”, now affects 15–20% of the general workforce and more than 50% of clinicians, teachers, social-care staff and first responders. Its precise nosological standing remains disputed. We conducted a mechanistic review of electroencephalography (EEG) studies to determine whether burnout is accompanied by reproducible brain-function alterations that justify disease-level classification. Methods: Following PRISMA-adapted guidelines, two independent reviewers searched PubMed/MEDLINE, Scopus, Google Scholar, Cochrane Library and reference lists (January 1980–May 2025) using combinations of “burnout,” “EEG”, “electroencephalography” and “event-related potential.” Only English-language clinical investigations were eligible. Eighteen studies (n = 2194 participants) met the inclusion criteria. Data were synthesised across three domains: resting-state spectra/connectivity, event-related potentials (ERPs) and longitudinal change. Results: Resting EEG consistently showed (i) a 0.4–0.6 Hz slowing of individual-alpha frequency, (ii) 20–35% global alpha-power reduction and (iii) fragmentation of high-alpha (11–13 Hz) fronto-parietal coherence, with stage- and sex-dependent modulation. ERP paradigms revealed a distinctive “alarm-heavy/evaluation-poor” profile; enlarged N2 and ERN components signalled hyper-reactive conflict and error detection, whereas P3b, Pe, reward-P3 and late CNV amplitudes were attenuated by 25–50%, indicating depleted evaluative and preparatory resources. Feedback processing showed intact or heightened FRN but blunted FRP, and affective tasks demonstrated threat-biassed P3a latency shifts alongside dampened VPP/EPN to positive cues. These alterations persisted in longitudinal cohorts yet normalised after recovery, supporting trait-plus-state dynamics. The electrophysiological fingerprint differed from major depression (no frontal-alpha asymmetry, opposite connectivity pattern). Conclusions: Across paradigms, burnout exhibits a coherent neurophysiological signature comparable in magnitude to established psychiatric disorders, refuting its current classification as a non-disease. Objective EEG markers can complement symptom scales for earlier diagnosis, treatment monitoring and public-health surveillance. Recognising burnout as a clinical disorder—and funding prevention and care accordingly—is medically justified and economically imperative. Full article

Obesity and metabolic dysfunction are established risk factors for luminal breast cancer, yet current preclinical models inadequately recapitulate the complex metabolic and immune interactions driving tumorigenesis. To develop and characterize an immunocompetent rat model of luminal breast cancer induced by chronic exposure to a cafeteria diet mimicking Western obesogenic nutrition, female rats were fed a cafeteria diet or standard chow from weaning. Metabolic parameters, plasma biomarkers (including leptin, insulin, IGF-1, adiponectin, and estrone), mammary gland histology, tumor incidence, and gene expression profiles were longitudinally evaluated. Gene expression was assessed by PCR arrays and qPCR. A subgroup underwent dietary reversal to assess the reversibility of molecular alterations. Cafeteria diet induced significant obesity (mean weight 426.76 g vs. 263.09 g controls, p < 0.001) and increased leptin levels without altering insulin, IGF-1, or inflammatory markers. Histological analysis showed increased ductal ectasia and benign lesions, with earlier fibroadenoma and luminal carcinoma development in diet-fed rats. Tumors exhibited luminal phenotype, low Ki67, and elevated PAI-1 expression. Gene expression alterations were time point specific and revealed early downregulation of ID1 and COX2, followed by upregulation of MMP2, THBS1, TWIST1, and PAI-1. Short-term dietary reversal normalized several gene expression changes. Overall tumor incidence was modest (~12%), reflecting early tumor-promoting microenvironmental changes rather than aggressive carcinogenesis. This immunocompetent cafeteria diet rat model recapitulates key metabolic, histological, and molecular features of obesity-associated luminal breast cancer and offers a valuable platform for studying early tumorigenic mechanisms and prevention strategies without carcinogen-induced confounders. Full article

Periodontitis is a prevalent chronic inflammatory disease with complex etiopathogenesis involving microbial dysbiosis, host immune response, environmental factors, and genetic susceptibility. Among the cytokines implicated in periodontal immunoregulation, interleukin-35 (IL-35) has emerged as a novel anti-inflammatory mediator with potential diagnostic and therapeutic relevance. This narrative review evaluates the role of IL-35 in periodontal disease by exploring its local and systemic expression, response to non-surgical periodontal therapy (NSPT), and association with clinical disease severity. Additionally, current evidence regarding IL-35 gene polymorphisms and their potential contribution to individual susceptibility and disease progression, as well as their relevance in related systemic conditions, is assessed. A comprehensive review and synthesis of recent clinical and experimental studies were conducted, focusing on IL-35 levels in saliva, serum, and gingival crevicular fluid (GCF) among patients with healthy periodontium, gingivitis, and various stages of periodontitis, both before and after NSPT. Emphasis was placed on longitudinal studies evaluating IL-35 dynamics in correlation with periodontal parameters, as well as genetic association studies investigating IL-12A and EBI3 gene polymorphisms. IL-35 levels were generally found to be higher in healthy individuals and reduced in periodontitis patients, indicating a possible protective role in maintaining periodontal homeostasis. Following NSPT, IL-35 levels significantly increased, corresponding with clinical improvement and reduced inflammatory burden. Genetic studies revealed variable associations between IL-35 polymorphisms and susceptibility to periodontitis and related systemic conditions, although further research is needed for validation. IL-35 appears to function as a modulator of immune resolution in periodontal disease, with potential utility as a non-invasive biomarker for disease activity and therapeutic response. Its upregulation during periodontal healing supports its role in promoting tissue stabilization. The integration of cytokine profiling and genetic screening may enhance personalized risk assessment and targeted interventions in periodontal care. Full article

Due to their clinical heterogeneity, nonspecific symptoms, and the limitations of existing biomarkers and imaging modalities, metabolic brain diseases (MBDs), such as mitochondrial encephalopathies, lysosomal storage disorders, and glucose metabolism syndromes, pose significant diagnostic challenges. This review examines the growing potential of cell-free DNA (cfDNA) derived from cerebrospinal fluid (CSF) epigenetic profiling as a dynamic, cell-type-specific, minimally invasive biomarker approach for MBD diagnosis and monitoring. We review important technological platforms and their use in identifying CNS-specific DNA methylation patterns indicative of neuronal injury, neuroinflammation, and metabolic reprogramming, including cfMeDIP-seq, enzymatic methyl sequencing (EM-seq), and targeted bisulfite sequencing. By synthesizing current findings across disorders such as MELAS, Niemann–Pick disease, Gaucher disease, GLUT1 deficiency syndrome, and diabetes-associated cognitive decline, we highlight the superior diagnostic and prognostic resolution offered by CSF cfDNA methylation signatures relative to conventional CSF markers or neuroimaging. We also address technical limitations, interpretive challenges, and translational barriers to clinical implementation. Ultimately, this review explores CSF cfDNA epigenetic analysis as a liquid biopsy modality. The central objective is to assess whether epigenetic profiling of CSF-derived cfDNA can serve as a reliable and clinically actionable biomarker for improving the diagnosis and longitudinal monitoring of metabolic brain diseases. Full article

The tumor microenvironment (TME) in advanced solid tumors is determined by immune checkpoints (PD-1, CTLA-4, and CD95) and cytokine networks (IL-2, IL-10, and TNF-α) that drive CD8+ T cell exhaustion, metabolic reprogramming, and apoptosis resistance, enabling immune evasion. Some studies revealed PD-1/CD95 co-expression is a marker of T cell dysfunction, while CTLA-4 upregulation correlates with suppressed early T cell activation. IL-10 has emerged as a potential biomarker for chemoresistance and tumor aggressivity, consistent with its role in promoting anti-apoptotic signaling in cancer stem cells (CSCs). Engineered IL-2 variants and TNF-α modulation are highlighted as promising strategies to revitalize exhausted CD8+ T cells and disrupt CSC niches. This prospective single-center study investigated the dynamic TME alterations in 16 patients with immunotherapy-naïve stage IV non-small-cell lung cancer (NSCLC) and metastatic melanoma treated with anti-PD-1 nivolumab. The longitudinal immunophenotyping of peripheral blood lymphocytes (via flow cytometry) and serum cytokine analysis (via ELISA) were performed at the baseline, >3, and >6 months post-treatment to evaluate immune checkpoint co-expression (PD-1/CD95 and CTLA-4/CD8+) and the cytokine profiles (IL-2, IL-10, and TNF-α). Full article

Borderline personality disorder (BPD) is a complex and heterogeneous condition characterized by emotional instability, impulsivity, and impaired regulation of interpersonal relationships. This narrative review integrates findings from recent neuroimaging, neurochemical, and treatment studies to identify core neurobiological mechanisms and highlight translational potential. Evidence from 112 studies published up to 2025 is synthesized, encompassing structural MRI, resting-state and task-based functional MRI, EEG, PET, and emerging machine learning applications. Consistent disruptions are observed across the prefrontal–amygdala circuitry, the default mode network (DMN), and mentalization-related regions. BPD shows a dominant and stable pattern of hyperconnectivity in the precuneus. Transdiagnostic comparisons with PTSD and cocaine use disorder (CUD) suggest partial overlap in DMN dysregulation, though BPD-specific traits emerge in network topology. Machine learning models achieve a classification accuracy of 70–88% and may support the tracking of early treatment responses. Longitudinal fMRI studies indicate that psychodynamic therapy facilitates the progressive normalization of dorsal anterior cingulate cortex (dACC) activity and reductions in alexithymia. We discuss the role of phenotypic heterogeneity (internalizing versus externalizing profiles), the potential of neuromodulation guided by biomarkers, and the need for standardized imaging protocols. Limitations include small sample sizes, a lack of effective connectivity analyses, and minimal multicenter cohort representation. Future research should focus on constructing multimodal biomarker panels that integrate functional connectivity, epigenetics, and computational phenotyping. This review supports the use of a precision psychiatry approach for BPD by aligning neuroscience with scalable clinical tools. Full article

Background: Medullary thyroid carcinoma (MTC) has a high rate of local and distant metastases. In particular, the RET protooncogene appears to be the predominant driver mutation for oncogenesis. The German S3 thyroid carcinoma guidelines recommend molecular genetic analysis of the tumour without specifying the site of the tissue sampling. Whether there is difference in RET protooncogene between the primary tumour, lymph node, and distant metastasis has not yet been investigated. However, differences could be important with regard to biopsy localization, and also, thus, the choice of single- or multi-tyrosine-kinase-inhibitor therapy. Methods: In a case of sporadic MTC, Cancer Hotspot panel diagnostics were performed on the primary tumour, lymph node metastasis, and distant metastasis. Mutations were classified using different gene databases, and the different stages of metastasis were compared. Results: RET protooncogene (chr10:43609933, c.1886_1891delTGTGCG, p.Leu629_Asp631delinsHis) was found to be present in the MTC tissue of the primary tumour, lymph node, and distant metastasis in the Cancer Hotspot Panel diagnostic, while the other investigated therapy-relevant mutational profiles were not consistently found. Conclusions: Further longitudinal studies in larger patient cohorts are required to elucidate the role of the RET protooncogene in the metastatic progression of MTC and to determine its impact on the selection of biopsy sites and the subsequent decision-making regarding single- versus multi-tyrosine kinase inhibitor therapy. Full article