Search Results (47,822)

(1) Background: Despite the success of combination antiretroviral therapy (cART), immune recovery in treated HIV infection remains heterogeneous, and discordant immune–virologic responses persist in a substantial proportion of people living with HIV (PLWH). These patterns may reflect ongoing immune dysregulation despite effective viral suppression. This study aimed to characterize discordant treatment classifications, evaluate immune imbalance using the CD4/CD8 ratio, identify associated clinical predictors, and assess opportunistic infection burden in a Romanian cohort of people living with HIV receiving long-term cART. (2) Methods: A retrospective cross-sectional study was conducted in 462 adults with HIV-1 infection receiving cART at the “Prof. Dr. Matei Balș” National Institute of Infectious Diseases, Bucharest (2018–2021). PLWH were classified as concordant responders (CR), immunological discordant responders (ID), or virological discordant responders (VD) based on plasma HIV-1 RNA and CD4+ T-cell count thresholds. Immune dysregulation was assessed using the CD4/CD8 ratio. Multinomial logistic, logistic, and negative binomial regression models were used to identify predictors of discordant responses, severe CD4/CD8 ratio inversion, and opportunistic infection burden. (3) Results: Discordant responses were observed in 30.7% of PLWH (14.5% ID, 16.2% VD). CD4/CD8 ratio inversion occurred in 71.2% and severe inversion in 40.0%. Significant differences across clinical classification groups were found for CD4+T-cell counts (H = 153.62, p < 0.001, ε² = 0.33) and CD4/CD8 ratio (H = 115.10, p < 0.001, ε² = 0.25), while CD8+ counts were similar (p = 0.571). Male sex was associated with both ID and VD, and severe CD4/CD8 inversion was strongly associated with ID. Opportunistic infection burden was associated with duration of HIV infection and CDC stage. (4) Conclusions: Discordant immune–virologic responses remain frequent during long-term cART and are characterized by persistent immune imbalance reflected by CD4/CD8 ratio inversion. The CD4/CD8 ratio may provide clinically relevant information on immune recovery beyond CD4+ T-cell counts. Full article

Introduction: Chronic subdural hematoma (CSDH) is a complex disease with an overall incidence of 1.7–20.6 per 100,000 persons per year and is more commonly encountered in the elderly population. It is projected to be one of the most common neurosurgical procedures. Postoperative delirium is a common complication associated with the elderly, causing increased morbidity and prolonged hospital stay. However, its risk factors in chronic subdural hematoma patients have not been well studied. Methods: A total of 202 consecutive patients with chronic subdural hematoma at different neurosurgical centers in Europe between January 2023 and June 2025 were enrolled. Various clinical indicators were analyzed to identify independent risk factors for postoperative delirium using univariate and multivariate regression analyses. Results: Out of the 202 patients (age, 71 (IQR, 18); female-to-male ratio, 1:2.7) studied, 63 (31.2%) experienced postoperative delirium. Univariate analysis identified age (p < 0.001), gender (p = 0.014), restraint belt use (p < 0.001), electrolyte imbalance (p < 0.001), visual analog scale (VAS) pain score (p < 0.001), hematoma thickness (p < 0.001), midline shift (p < 0.001), hematoma side (p = 0.013), hematoma location (p = 0.018), and urinal catheterization (p = 0.028) as significant factors. Multivariate regression analysis confirmed the significance of restraint belt use (B = 7.657, p < 0.001), electrolyte imbalance (B = −3.993, p = 0.001), VAS pain score (B = 2.331, p = 0.016), and midline shift (B = 0.335, p = 0.007). Hematoma thickness and age had no significant impact. Conclusions: Increased midline shift and VAS pain scores, alongside restraint belt use and electrolyte imbalance, elevate delirium risk in chronic subdural hematoma surgery. Our prediction models may offer a reference value in this context. Full article

Acute pancreatitis is a common inflammatory digestive disease with an unpredictable clinical course, ranging from self-limited forms to severe forms, associated with complications and increased mortality. Early identification of patients at risk of severe disease is particularly important from a surgical perspective, as it has a significant impact on subsequent management. Traditional severity scores, such as APACHE (Acute Physiology And Chronic Health Evaluation) II and BISAP (Bedside Index for Severity in Acute Pancreatitis), remain widely used, but their rigid structure and delayed applicability may limit initial risk assessment. In this review we highlight the evolving role of artificial intelligence in predicting the severity of acute pancreatitis and supporting clinical decision-making, with a focus on surgical management. Recent advances show that data-driven models could improve early risk assessment compared to traditional methods. Although their potential clinical benefits are becoming increasingly clear, real-world implementation remains limited. Initial results are encouraging, but important questions regarding reliability, safety, and integration into clinical practice still need to be addressed. Full article

Background/Objectives: Understanding the regulatory mechanisms of intramuscular fat accumulation is crucial for maintaining skeletal muscle function and treating muscle-related diseases. It is known that cold exposure can lead to fat deposition in the muscles of mice and pigs. However, so far, there is very limited knowledge about the factors influencing its formation under cold exposure conditions. This study used piglets as an animal model to investigate intramuscular fat accumulation under cold exposure. Methods: Six piglets were exposed to 10 °C, and six piglets were exposed to 25 °C. A whole transcriptome joint analysis was performed on the longissimus dorsi muscle of three piglets randomly selected from each group. Results: No fever or cough symptoms were observed in all experimental groups, and the cold exposure vs. control groups’ RNA data were compared. The study identified 705 differentially expressed messenger RNAs, 87 long non-coding RNAs, 57 microRNAs, and 236 circular RNAs. CD36 Molecule (CD36 Blood Group) (CD36) was upregulated, while adiponectin (ADIPOQ) was downregulated. Conclusion: We established a competing endogenous RNA network centered around CD36, Protein Phosphatase 1 Regulatory Subunit 3G (PPP1R3G) and ADIPOQ for intramuscular fat accumulation by using a pig model exposed to a cold temperature. This study provides important references for further understanding the regulatory mechanism of intramuscular fat. Full article

Background/Objectives: In Palliative Care (PC), the communication is an essential aspect of care becoming particularly significant at the end-of-life. In neurodegenerative diseases, communication involves additional complexity due to prolonged disease trajectories, early cognitive decline, and frequent loss of decision-making capacity. The aim of this study was to explore PC healthcare professionals’ experiences with communication process and relational dynamics involving families of patients with advanced and terminal neurogenerative disease. Methods: The study design was qualitative, using semi-structured interviews and reflexive thematic analysis. Participants were healthcare professionals directly involved in communication with the family. Results: Twenty PC professionals were interviewed, generating 792 coded excerpts. Four themes emerged: (1) Navigating PC in neurodegenerative diseases, highlighting shift from oncology-centred palliative models toward neuropalliative care, with distinctive relational challenges; (2) Navigating conversations between professionals and families, describing multidisciplinary communication, core clinical and emotional topics, and goal-oriented decision-making in contexts of impaired patient capacity; (3) Facing challenges in health care professional–family communication, including conspiracy of silence, absence of Advance Treatment Directives (ATD) or Shared Care Planning (SCP), and limited collaboration with neurologists; and (4) Envisioning methods for improvement, emphasizing the need for disease-specific competencies, advanced relational skills, interprofessional coordination, and support for professionals’ emotional wellbeing. Conclusions: Communication in neurodegenerative palliative care is an ongoing relational and interpretative process requiring professionals to mediate uncertainty, surrogate decision-making, and caregiver burden. Strengthening disease-specific communication skills, early integrated PC, and structured interprofessional collaboration may enhance shared decision-making, caregiver support, and care continuity. Full article

Astrocytes are now recognized as active and essential participants in neural circuit function, extending far beyond their traditional roles as passive support cells. Emerging evidence highlights their critical involvement in synaptic modulation, information processing, and complex behaviors, making them key targets for understanding cognitive dysfunction in psychiatric disorders. This narrative review synthesizes current findings from rodent models to elucidate the relationship between astrocytic networks and multidomain cognitive performance. We first outline the morphological and physiological features of astrocytes, followed by a comprehensive overview of the modern experimental toolkit, including observational markers and advanced interventional strategies. Next, we evaluate commonly used behavioral assays that capture distinct cognitive domains, ranging from basic spatial and recognition memory to higher-order executive functions, cognitive flexibility, and social cognition. By integrating recent experimental evidence, we detail the specific mechanistic pathways, such as intracellular calcium signaling, gliotransmission, and neuroinflammatory reactivity, through which astrocytes directly govern these cognitive processes. Finally, we highlight critical knowledge gaps stemming from methodological limitations, arguing for the integration of more ethologically relevant, high-throughput behavioral tasks alongside highly specific targeting tools to better capture the functional heterogeneity of astrocytes in cognitive health and disease. Full article

Amyloid-β (Aβ) protein, a cleavage product of the amyloid precursor protein (APP), is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer’s pathogenesis. Aβ has been a primary target for therapy since the amyloid cascade theory was put forth, with methods designed to prevent the generation of Aβ. The APP 5′-untranslated region (UTR) mRNA encodes a functional structured iron-responsive element (IRE) that represents a potential target for small molecule inhibitors as an anti-amyloid therapy for AD. Here, we offer a comprehensive strategy that uses RNA-targeted binding to inhibit APP translation. The IRE family is among the few 3-D mRNA regulatory elements with a known 3-D structure. Accordingly, we exploit these structural and functional characteristics as our strategy to target APP IRE structured mRNA to identify anti-amyloid drugs. The mRNA encoding proteins involved in iron metabolism are regulated by this family of similar nucleotide sequences. Post-transcriptional control of cytoplasmic mRNA is a rapidly developing area of biomedicine. Across animals, evolutionarily conserved IRE mRNAs serve as a model system for 3-D mRNAs. IRE mRNAs have shown great promise for chemical manipulation of mRNA and protein expression in biological systems by yielding “proof of principle” data for small molecules targeting mRNA structures. A novel approach to identifying RNA-directed therapeutics to regulate APP expression and Aβ-peptide generation for AD treatments is exemplified by APP 5′-UTR-directed small molecule inhibitors. Full article

Background/Objectives: Hospitalisations in systemic lupus erythematosus (SLE) reflect disease severity, accumulated damage, and the burden of comorbidity, remaining a major determinant of healthcare utilisation. Recent evidence suggests a shift from flare-driven admissions toward complications related to infections, comorbidities, and long-term treatment effects. We aimed to analyse the causes, characteristics, and outcomes of hospital admissions in patients with systemic lupus erythematosus (SLE) over a 30-year period in a tertiary referral centre in Catalonia (Spain) and to evaluate changes over time and prognostic factors associated with adverse outcomes. Methods: A retrospective observational study was conducted including all SLE patients admitted to the Department of Autoimmune Diseases at Hospital Clínic de Barcelona between June 1995 and December 2024. Admissions lasting less than 48 h or lacking clinical documentation were excluded. Variables analysed included demographics, disease duration, comorbidities, cause of admission, treatments, and outcomes. A composite outcome was defined as intensive care unit (ICU) admission, 30-day readmission, or prolonged hospital stay. Statistical analyses included univariate and multivariate regression models. Results: Among the 1216 hospital admissions, SLE flares and infections were the most frequent causes. Over the study period, admissions due to infections increased significantly and, in the last five years, exceeded those related to disease flares (33.7% vs. 26.1%). Patients hospitalized for flares were younger and had a shorter disease duration, whereas infection-related admissions were more common among older patients, those with overlap syndromes, and those with higher damage scores. Vascular events and SLE flares were independently associated with poorer outcomes. Although antimalarial use increased over time, it remained suboptimal, largely due to drug toxicity and newly diagnosed cases (from 45.2% to 69.7%; p < 0.001). Treatment strategies also evolved, with a shift toward lower glucocorticoid doses (from 14.5% to 38.3%; p < 0.001), and mycophenolate mofetil replacing cyclophosphamide as the preferred immunosuppressive agent. Conclusions: Hospitalisation patterns in SLE have shifted over time, with infections emerging as the leading cause of admission. This trend reflects an evolving patient profile characterized by older age, greater accumulated damage, comorbidities, and increased exposure to immunosuppressive therapies. These findings underscore the need for optimized infection prevention strategies and individualized treatment approaches to improve outcomes in contemporary SLE care. Full article

Background/Objectives: Sebaceous carcinoma (SC) is a rare and aggressive malignancy most often arising in the head and neck. The reported rate of lymph node metastasis is variable and current clinical guidelines surrounding pre-treatment imaging and management of lymph nodes are not well defined. The aim of our systematic review and meta-analysis was to determine a pooled rate of clinically apparent and occult lymph node metastases for SC of the head and neck to inform clinical guidelines. Methods: Per PRISMA guidelines, systematic search of the Pubmed/MEDLINE and EMBASE databases identified studies published before October 2023 reporting regional lymph node status in adults with SC of the head and neck. Meta analysis using the random-effects model was applied to calculate the pooled proportion of subjects with lymph node metastasis. Clinical characteristics of subjects were further analyzed using chi square tests and univariate logistic regression. Results: Thirty-eight studies met inclusion criteria with a total of 2371 patients. The pooled prevalence of regional lymph node involvement, including clinically apparent and occult disease, was 16% (95% CI 13–18%, I² 65%), with increased risk with increasing T stage. The pooled rate of occult lymph node metastases was 7% (95% CI 4–9%, I² 68%). Conclusions: There is a high rate of lymph node involvement in SC of the head and neck, much of which goes undetected during initial workup and treatment. Initial workup should reflect this risk and include appropriate physical exam, imaging, consideration for sentinel lymph node biopsy, and involvement of a multi-disciplinary team. Full article

Objectives: Educational attainment appears to be associated with non-alcoholic fatty liver disease (NAFLD). The inconsistent findings across existing studies necessitate a thorough meta-analysis to elucidate this association. Methods: A systematic search of PubMed, Web of Science, and Scopus was conducted from inception to 31 December 2024, without language restrictions. Data were analyzed using Review Manager 5.4, with pooled odds ratios (ORs) and 95% confidence intervals (CIs) estimated via appropriate models. Results: 27 studies involving 446,312 participants (93,116 NAFLD; 353,196 healthy individuals) were included. Noteworthy heterogeneity was detected, with I² = 96% for more-than-high-school and I² = 95% for high-school-education when we pooled all the studies together. Further subgroup analyses suggested that higher education was inversely associated with NAFLD risk in some developed countries, like the United States, while potential gender-specific effects were found among the Chinese population. Conclusions: The current meta-analysis suggests that the association between educational attainment and NAFLD is complex and context-dependent, and it may vary across different countries and types of sex. Full article

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition affecting over 10–20% of individuals older than 70 years, characterized by the expansion of hematopoietic stem cell clones carrying somatic mutations in leukemia-associated driver genes in the absence of overt hematologic disease. Initially recognized as a precursor to hematologic malignancies, CHIP has since been implicated in diverse non-malignant disorders, notably increasing the risk of cardiovascular events by 40%. Recent epidemiological and experimental evidence suggests a potential disease-modifying influence of CHIP in neurodegenerative diseases, particularly Alzheimer’s disease (AD), although findings remain heterogeneous and sometimes contradictory. This review synthesizes recent evidence linking CHIP to AD risk, neuropathology, and disease progression. In this study, we summarize population-based cohort studies reporting a 36 to 54% reduction in the odds of clinical AD among CHIP carriers, alongside emerging data indicating that DNMT3A and TET2 mutations may exert divergent effects on neurodegeneration. Mechanistic insights from experimental models are examined, highlighting the ability of mutated myeloid cells to infiltrate the central nervous system and modulate neuroinflammation and amyloid clearance. We discuss conflicting findings and analyze how CHIP-driven vascular disease and stroke confound neuroprotective signals. We propose that CHIP may differentially influence AD and vascular contributions to cognitive impairment and dementia, shaping mixed dementia phenotypes. Methodological challenges, including survivor bias, competing risks, variable mutation detection thresholds, and incomplete Apolipoprotein E stratification, are discussed. Ultimately, our review clarifies that CHIP is not a simple protective factor, but a complex systemic modulator that reshapes the neurodegenerative and vascular drivers of cognitive decline, necessitating cross-disciplinary neuro-hematology collaboration to establish its role as a novel risk stratificator for improving diagnostic precision and personalizing clinical outcomes in Alzheimer’s disease. Full article

Cardiometabolic diseases, encompassing obesity, insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), hypertension, and atherosclerotic cardiovascular disease (ASCVD), represent a vast continuum driven by multi-organ network dysregulation. Clinical risk assessment remains dominated by late-stage measures (e.g., fasting glucose, HbA1c, standard lipids). While these assessments predominate the literature and clinical trial endpoints, each incompletely capture early mechanistic risk, inter-individual heterogeneity, and differential response to interventions. Multiomics (genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, microbiomics, and extracellular vesicle/exosome cargo profiling) expands the biomarker landscape but introduces translational barriers: high dimensionality, cohort heterogeneity, limited causal inference, and insufficient validation pipelines. AI-driven systems biology platforms can support cardiometabolic biomarker discovery and therapeutic translation by enabling systems-level biological inference across heterogeneous datasets, prioritizing mechanism and traceability over purely correlation-based models. GATC Health’s Operon™ platform is described as a proprietary, AI-driven internal scientific computing platform designed to support therapeutic discovery and development decision-making across the pharmaceutical lifecycle, including evaluation of drug efficacy, safety, off-target effects, pharmacokinetics (PK), pharmacodynamics (PD), and overall development risk. Operon evolved from earlier generations of GATC Health’s internal multiomic modeling systems (formerly referred to as the Multiomics Advanced Technology, MAT) and incorporates expanded data types, orchestration layers, validation workflows, and productization frameworks. Operon is operated by GATC scientists and generates structured, productized outputs (e.g., formal assessments, analyses, and decision frameworks) that are reviewed by experts. Operon methodologies have undergone internal validation and independent academic evaluation under blinded conditions, with reported classification performance (true positive rate 86% and true negative rate 91%) in controlled evaluation settings; these performance metrics should not be interpreted as guarantees of clinical success. This review provides a T2D-centered cardiometabolic biomarker landscape with cardiovascular extension and outlines how Operon-enabled multiomic integration and scenario-based simulation can support early screening, endotype stratification, mechanistic interpretation, and precision intervention design, including AI-guided polypharmacology strategies. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related death, and resistance to chemotherapy and radiotherapy continues to limit durable disease control. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has therefore emerged as a potential therapeutic strategy. However, models focused solely on glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) do not fully explain why CRC cells differ in their sensitivity to ferroptosis. In this review, we examine how ferroptosis in CRC is shaped by iron trafficking and selenium-dependent antioxidant defense. We first discuss the poly(rC)-binding proteins 1 and 2 (PCBP1/2)-nuclear receptor coactivator 4 (NCOA4) axis, which regulates iron storage, trafficking, and ferritinophagy. We then review the AlkB homolog 8 (ALKBH8)-directed selenoprotein network, which supports the detoxification of lipid peroxides and maintenance of redox homeostasis. We next consider how these two systems intersect and how their interplay influences ferroptosis sensitivity. We also discuss why concurrent disruption of iron handling and selenium-dependent defense mechanisms may enhance therapeutic efficacy. Finally, we outline potential clinical applications, including combination strategies and biomarker development. Full article

Ulcerative colitis (UC) is a type of inflammatory bowel disease without curative therapeutics. Recent studies demonstrate that Akkermansia muciniphila exerts mitigating effects on UC, but the underlying mechanisms remain unclear. In this study, we isolated a strain of A. muciniphila, designated NND9, from the feces of DSS-induced ulcerative colitis model mice and investigated its effects on UC of the mouse model. NND9 significantly alleviated UC severity in the mice by restoring gut barrier integrity through improving colonic mucus layer thickness, mitigating goblet cell depletion, and halting epithelial cell death. Mechanistically, NND9 suppressed the expression of the Tnfrsf10b gene encoding death receptor 5 (DR5) on the surface of colonic epithelial cells. Additionally, NND9 inhibited the phosphorylation of kinase 3 (RIPK3) and the pseudokinase mixed-lineage kinase domain-like protein (MLKL) associated with the necrotic apoptosis pathway, thereby reducing gut epithelial cell death. NND9 also markedly ameliorated the gut microbiome of the colitis mice. Untargeted metabolomics analysis demonstrated that NND9 modulated both tryptophan and bile acid metabolism. In conclusion, NND9 exhibits curative effects on UC by resolving inflammatory reactions of the gut mucosa through the DR5-RIPK3/p-RIPK3-MLKL/p-MLKL pathway and redressing gut dysbiosis. This study provides valuable information for the development of innovative therapeutic strategies for the treatment of UC. Full article

Background/Objectives: Cervical cancer, predominantly driven by persistent infection with high-risk human papillomaviruses (HPVs), is one of the most common malignancies and an important cause of cancer-related mortality among women worldwide. Although existing licensed prophylactic HPV vaccines confer excellent protection, their global use remains suboptimal due to concentrated manufacturing capacity and high production costs. This study aimed to establish a cost-effective multivalent HPV virus-like particle (VLP) vaccine platform. Specifically, we used an enhanced baculovirus expression vector system to produce a 12-valent HPV VLP vaccine to improve antigen yield, thereby reducing manufacturing costs and ultimately improving affordability and availability in low- and middle-income countries. Methods: Optimized expression cassettes and an insect cell culture process were designed to enhance productivity across 12 HPV L1 genotypes. A scalable purification scheme integrating ion-exchange and adsorption chromatography was developed to produce high-purity VLPs with consistent structural integrity. Immunogenicity was assessed in a murine model. Elicited HPV type-specific IgG antibody responses were compared with those induced by the licensed 9-valent HPV vaccine. Results: The assembled 12-valent VLPs were comprehensively characterized using biophysical and immunochemical analyses, confirming structural stability and correct antigenicity. In vivo immunogenicity studies in mice showed strong and serotype-specific IgG responses, comparable or superior to those induced by the licensed 9-valent commercial vaccine. Conclusions: The enhanced baculovirus expression vector system is a versatile and economically sustainable platform for next-generation HPV vaccine production. This technology offers a promising approach to lowering vaccine manufacturing costs and improving global access, particularly in low- and middle-income regions heavily burdened by HPV-associated diseases. Full article