Search Results (8,548)

Background: Non-suicidal self-injury (NSSI) is highly prevalent during adolescence and is associated with a range of emotional, cognitive, and interpersonal vulnerabilities. Although prior research has identified key correlates such as emotion dysregulation, hopelessness, interpersonal distress, and attachment insecurity, these factors have largely been examined in isolation, limiting understanding of how they jointly contribute to NSSI. Methods: The present study examined the network structure of NSSI and associated vulnerability processes in a community sample of 2067 Spanish adolescents (M age = 14.62, SD = 1.80). A regularized partial correlation network (EBICglasso) was estimated, including NSSI frequency and functions, emotion dysregulation, hopelessness, perceived burdensomeness, thwarted belongingness, and attachment representations. Centrality and network stability were evaluated using standard indices and bootstrapping procedures. Results: The network revealed a differentiated structure of associations. Perceived burdensomeness and intrapersonal NSSI functions emerged as the most influential nodes, whereas emotion dysregulation occupied a key bridging position connecting attachment-related experiences, interpersonal vulnerability, and NSSI processes. In contrast, NSSI frequency and interpersonal functions showed a more peripheral role. Attachment security was negatively associated with core risk variables, consistent with a protective role within the network. Conclusions: Findings suggest that NSSI in adolescence is embedded within a system of interacting emotional and interpersonal processes, structured around the functional meaning of the behavior and key interpersonal appraisals. Emotion dysregulation emerged as a highly connected node linking multiple domains, while attachment was associated with several key variables within the network. These findings suggest potential targets for early identification and intervention, particularly focusing on emotion regulation, perceived burdensomeness, and intrapersonal functions of NSSI. Full article

Background: Although routine use of episiotomy is widely discouraged in spontaneous vaginal deliveries, the use of episiotomy in operative vaginal delivery (OVD) remains highly debated. This systematic review and meta-analysis evaluated the current evidence on the safety of episiotomy in preventing obstetric anal sphincter injuries (OASIS) during OVD. Methods: A systematic literature search was conducted on PubMed/MEDLINE and CENTRAL databases with a cut-off date of November 2025. The protocol was registered in PROSPERO. We included studies which encompassed the incidence of OASIS when episiotomy (median or medio-lateral) was performed during vacuum or forceps delivery and when episiotomy was not performed. Randomized controlled trials (RCTs), prospective or retrospective cohort studies and observational studies were considered appropriate study designs. A meta-analysis using risk ratio as the outcome measure was performed to compare the presence of the event (OASIS) in patients with or without episiotomy. Results: A total of 15 studies were analyzed to evaluate the role of medio-lateral episiotomy (MLE) in OVD. The results demonstrated a statistically significant lower rate of severe perineal trauma in the experimental group (pooled RR 0.5; 95% CI: 0.30–0.84). A statistically significant difference in support of the use of MLE was found in two further subgroup analyses, comprising 14 studies focusing on the role of MLE during vacuum delivery (VD) and 9 studies considering the role of MLE during forceps delivery (FD). Conclusions: This study highlights that the use of MLE in nulliparous women undergoing OVD is associated with a significantly decreased risk of OASIS. Full article

Background: Hyperhomocysteinemia (homocysteine [Hcy] ≥15 μmol/L) is frequently observed in patients with impaired kidney function and has been associated with vascular remodeling and increased cardiovascular risk. We aimed to evaluate the relationship between Hcy, arterial stiffness, coronary artery disease (CAD), peripheral arterial disease, and biomarkers of kidney injury in patients undergoing elective coronary angiography. Methods: In this prospective observational study, 133 patients undergoing elective coronary angiography were stratified according to serum Hcy levels (Hcy <15 vs. Hcy ≥15 μmol/L). CAD severity was assessed angiographically. Arterial stiffness was evaluated using carotid–femoral pulse wave velocity (cfPWV), while peripheral arterial disease was assessed using ankle–brachial index (ABI). Kidney function was evaluated using serum creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and urinary albumin-to-creatinine ratio (UACR). Correlation, multivariable regression, logistic regression, and receiver operating characteristic (ROC) analyses were performed. Results: Patients with hyperhomocysteinemia demonstrated significantly worse kidney function, including higher serum creatinine, cystatin C, and UACR levels, and lower eGFR (all p < 0.01). Patients with elevated Hcy levels also exhibited significantly higher cfPWV values (11.4 ± 3.3 vs. 9.7 ± 2.1 m/s, p < 0.001). Hcy correlated positively with cystatin C, creatinine, UACR, and cfPWV, and inversely with eGFR. In multivariable linear regression analysis, Hcy remained independently associated with increased cfPWV after adjustment for age, sex, and eGFR (β = 0.137, 95% CI 0.047–0.226, and p = 0.003). This association remained significant in sensitivity analyses incorporating hypertension, diabetes mellitus, LDL cholesterol, and statin therapy (β = 0.124, 95% CI 0.032–0.216, and p = 0.008). No independent associations were observed between Hcy and angiographic CAD severity or ABI values. ROC analysis demonstrated modest discrimination for elevated arterial stiffness (AUC = 0.66, 95% CI 0.56–0.76) and good discrimination for impaired kidney function (AUC = 0.82, 95% CI 0.69–0.92). Conclusions: Elevated Hcy levels were independently associated with impaired kidney function and increased central arterial stiffness, but not with angiographic CAD severity or peripheral arterial disease. These findings suggest that hyperhomocysteinemia may reflect cardiorenal vascular dysfunction and diffuse vascular remodeling rather than focal obstructive atherosclerotic disease. Further studies are needed to determine its clinical utility and prognostic value. Full article

Background/Objectives: Cardiovascular disease increases with ageing and remains the leading cause of death worldwide. Cellular senescence contributes to cardiac dysfunction in the older population by secreting the senescence-associated secretory phenotype (SASP). Cardiac injury models induced by surgery have been shown to induce senescence in young adult rodents. However, surgical models are complex and associated with high mortality. Methods: We established a rat model of injury and senescence using isoproterenol (ISO). Male SD rats received ISO (100 mg/kg) for five days, then hearts were collected on days 10 and 28 after the first ISO dose. Results: ISO administration caused cardiac injury, manifested by inflammatory infiltration, fibrosis, and increased cardiomyocyte cross-sectional area. Cardiac injury was accompanied by an increase in the senescence markers SA-β-gal, p16 and p21, and DNA damage marker γH2AX. Moreover, the mRNA levels of p21 increased on day 10, along with several SASP factors, whereas the mRNA levels of p16 increased on day 28. Fibrosis, hypertrophy, and senescence persisted until day 28, indicating long-lasting cardiac remodeling and senescent cell accumulation. Conclusions: These findings suggest that ISO can provide a simple, cost-effective platform for studying senescence and cardiac injury. This model facilitates the study of timing, dosage, mechanisms and efficacy of senolytic interventions and may contribute to the development of senescence-targeted therapies. Full article

Vitamin D has long been recognized for its role in calcium homeostasis and bone metabolism; however, it is now emerging as an important regulator of central nervous system (CNS) function. Recent evidence suggests that vitamin D signaling contributes to the pathogenesis and progression of several neurodegenerative disorders. Vitamin D exerts neuroprotective effects through multiple mechanisms, including regulation of calcium homeostasis, modulation of immune responses, reduction in oxidative stress, stimulation of neurotrophic factors, and maintenance of blood–brain barrier (BBB) integrity. Vitamin D receptors and metabolizing enzymes are widely distributed across several brain regions, highlighting their direct involvement in neuronal function. This review summarizes the biosynthesis, metabolism, and signaling pathways of vitamin D. It explores its role in neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). Evidence from experimental and clinical studies indicates that vitamin D deficiency is associated with an increased risk and severity of these conditions, while supplementation may provide therapeutic benefits. Full article

Background/Objectives: Artificial intelligence (AI), machine-learning (ML), and deep-learning (DL) models are increasingly used for prognostic prediction in intensive care unit (ICU) sepsis, but their clinical readiness remains uncertain. This systematic review aimed to evaluate AI-, ML-, and DL-based models for mortality and clinically relevant outcome prediction in adult ICU patients with sepsis or septic shock. Methods: PubMed/MEDLINE, Scopus, and the Cochrane Library were searched up to April 2026. Eligible studies included adult ICU sepsis or septic shock cohorts evaluating AI/ML/DL-based prognostic models. Screening, full-text assessment, and data extraction were performed independently by two reviewers. Outcomes, model families, validation strategies, discrimination, calibration, clinical utility, explainability, comparative performance versus conventional severity scores, risk of bias, and reporting completeness were synthesized. Risk of bias was assessed using PROBAST domains supplemented by PROBAST + AI considerations, and reporting completeness was evaluated according to TRIPOD/TRIPOD + AI domains. Results: Seventy-five studies were included, comprising 50 PubMed-derived and 25 additional Scopus-derived studies. AUROC or C-statistic was extractable in 64 studies, external validation was reported in 27, prospective evaluation in three, calibration in 38, decision-curve analysis or clinical utility assessment in 37, and explainability in 64. Across 17 directly extractable within-study comparisons from nine studies, AI/ML models usually, but not uniformly, achieved higher discrimination than conventional severity scores, with a median paired ΔAUROC of +0.108 (IQR, +0.082 to +0.148; range, −0.013 to +0.203). Externally validated fixed-horizon models showed clinically relevant but heterogeneous discrimination across sepsis phenotypes, with stronger evidence in selected sepsis-induced coagulopathy cohorts and more variable transportability in respiratory and liver-injury subgroups. However, 45 studies were judged at high risk of bias, mainly because of limitations in the analysis domain. Conclusions: AI/ML models for adult ICU sepsis show a recurrent signal of prognostic discrimination and often perform comparably to or better than conventional severity scores in directly extractable within-study comparisons; however, this signal should be interpreted cautiously given clinical and methodological heterogeneity, limited prospective validation, incomplete calibration, and frequent high risk of bias. The strongest evidence comes from externally validated, phenotype-specific models, although routine clinical implementation remains limited by heterogeneous endpoints, incomplete calibration, insufficient prospective validation, and scarce workflow-level evaluation. Future studies should shift from retrospective AUROC optimization toward calibrated, externally validated, clinically actionable, and workflow-integrated decision-support tools tested in prospective ICU settings. Full article

Background/Objectives: Ischemic stroke remains a major global health challenge, yet therapeutic options are severely restricted by narrow treatment windows and the risk of hemorrhagic transformation. Natural small molecules represent a valuable reservoir for discovering novel neuroprotective leads with favorable safety profiles. Cinchonidine, a natural quinoline alkaloid, has shown anti-inflammatory and cytoprotective properties, but its potential in treating ischemic stroke is largely unexplored. This study aimed to evaluate the neurovascular protective effects and hemostatic safety of cinchonidine in preclinical stroke models. Methods: We evaluated cinchonidine using a mouse model of middle cerebral artery occlusion (MCAO) and in vitro oxygen–glucose deprivation (OGD) models in cerebral endothelial cells (CECs) and Neuro2A cells. Infarct volume, brain edema, and neurological recovery were assessed. Blood–brain barrier (BBB) integrity was measured via Evans blue extravasation. Mechanistic markers, including microglial activation, pro-inflammatory mediators (iNOS, COX-2), and apoptosis-related signaling, were examined. Additionally, cinchonidine’s effect on platelet aggregation was also tested. Results: Cinchonidine significantly reduced infarct volume and brain edema while improving neurological functional recovery. It effectively preserved BBB integrity and enhanced cell viability under OGD conditions. Furthermore, cinchonidine suppressed microglial activation and decreased the expression of pro-inflammatory mediators. These protective effects were associated with the modulation of apoptotic signaling pathways. These protective effects were accompanied by reduced p53-associated stress signaling in endothelial cells and ischemic brain tissue. Importantly, cinchonidine did not significantly interfere with platelet aggregation, suggesting a potentially favorable hemostatic profile. Conclusions: Cinchonidine attenuates ischemic brain injury and is associated with endothelial protection, preservation of BBB integrity, and modulation of inflammatory and apoptotic responses. As a natural lead compound that does not compromise hemostasis, cinchonidine represents a promising lead compound for further development as a neurovascular protective strategy in ischemic stroke. Full article

Accelerating eutrophication of aquatic ecosystems worldwide has increased concern regarding cyanotoxin exposure as an emerging environmental and public health issue, with Microcystin-LR (MC-LR) among the most extensively studied congeners due to its widespread occurrence and high toxicity. Evidence from experimental animal and cellular studies indicates that MC-LR elicits pronounced toxic impacts on both the male and female reproductive systems. In males, MC-LR induces overt testicular injury, compromises the structural and functional integrity of the blood–testis barrier, and triggers severe disorders in reproductive hormone synthesis and secretion. In females, it precipitates ovarian dysfunction, impedes normal follicular maturation and development, and induces distinct embryotoxic effects. The underlying pathogenic mechanisms involve the synergistic interplay of multiple signaling pathways, primarily including oxidative stress induction, aberrant apoptosis activation, endocrine disruption, and epigenetic modifications. Of particular significance, emerging evidence suggests that parental exposure to MC-LR may induce intergenerational or potentially transgenerational reproductive effects through epigenetic modifications in germ cells, impairing fertility and developmental outcomes in subsequent offspring and thus posing a sustained, long-term threat to population-level health. This review systematically delineates the reproductive toxicity profiles and underlying molecular mechanisms of MC-LR, evaluates its transgenerational health hazards, and aims to furnish robust scientific evidence for the formulation of targeted environmental health policies and risk management strategies. Full article

Stroke remains one of the leading causes of long-term disability and death worldwide. Growing evidence suggests that both stroke onset and severity exhibit strong circadian patterns. This blood–brain interface (BBI), which regulates bidirectional communication between the peripheral circulation and the central nervous system, plays a critical role in cerebrovascular injury. Aging further exacerbates these processes by dampening the molecular clock function and increasing inflammatory activation. In this review, we examine the circadian regulation of the BBI, aging, and its implications in stroke vulnerability. Understanding how circadian biology modulates neurovascular function may reveal novel therapeutic targets and time-of-day-dependent approaches for stroke prevention and treatment. Full article

Background/Objectives: Inflammation plays a central role in the pathophysiology of ST-elevation myocardial infarction (STEMI) and may influence myocardial injury, ventricular dysfunction and clinical outcomes. Simple inflammatory biomarkers derived from routine laboratory tests have been proposed as potential prognostic indicators in patients undergoing primary percutaneous coronary intervention (PCI). Objective: This study aimed to evaluate the association between admission inflammatory biomarkers, echocardiographic markers of ventricular dysfunction and in-hospital mortality in patients with STEMI treated with primary PCI. Methods: We conducted a retrospective observational study including 600 consecutive patients admitted with STEMI and treated with primary PCI between January 2021 and August 2025. Inflammatory biomarkers measured at admission included C-reactive protein (CRP); neutrophil-to-lymphocyte ratio (NLR); platelet-to-lymphocyte ratio (PLR); systemic immune-inflammation index (SII) and C-reactive protein-to-lymphocyte ratio (CLR). Echocardiographic parameters and clinical outcomes were recorded. Multivariable logistic regression analysis was performed to identify independent predictors of in-hospital mortality. Results: In-hospital mortality occurred in 54 patients (9.0%). Patients with reduced left ventricular ejection fraction (LVEF ≤ 40%) had significantly higher CRP and CLR levels (p < 0.01). Inflammatory biomarkers were associated with markers of ventricular dysfunction but were not independent predictors of mortality. Age, LVEF < 40% and the number of residual coronary lesions independently predicted in-hospital death. Conclusions: In STEMI patients undergoing primary PCI, early mortality is mainly determined by age; ventricular dysfunction and residual coronary disease burden, while inflammatory biomarkers primarily reflect the severity of myocardial injury rather than independently predicting short-term mortality. Full article

Background: Foot degloving injuries are associated with extensive soft-tissue disruption, compromised perfusion, and a high risk of flap necrosis. Hyperbaric oxygen therapy (HBOT) is known to enhance tissue oxygenation and support flap survival; however, its application in pediatric patients may be limited due to poor cooperation, intolerance to chamber-based treatment, and limited accessibility. Case Presentation: A 7-year-old girl presented with a crush injury to the left foot after being run over by a vehicle, resulting in severe soft-tissue damage. Evaluation revealed a dorsal foot degloving injury, a proximal phalanx fracture of the great toe, and dislocations of the fourth proximal interphalangeal and fifth distal interphalangeal joints. Emergency surgery included open reduction, K-wire fixation, debridement, and artificial dermal grafting using Pelnac. On postoperative day 1, the flap showed signs of compromised perfusion. As HBOT was not feasible, topical oxygen therapy using Natrox was applied continuously for 17 days. Serial wound assessments demonstrated gradual improvement in flap viability. Although ischemic changes developed in the toes, necrosis remained superficial and was successfully managed with local debridement and dressings. Residual skin defects with partial necrosis were treated with split-thickness skin grafting, which healed without major complications. The patient resumed ambulation after splint removal. Conclusions: In pediatric patients with compromised flaps in whom HBOT is not feasible, topical oxygen therapy may serve as a practical adjunctive treatment option. Although its independent effect cannot be established in a single case, this report suggests its potential role in flap salvage and in limiting tissue necrosis. Full article

Chronic liver disease (CLD) constitutes a major global health burden, with high morbidity and mortality, limited treatment options for several etiologies, and an urgent need for novel therapeutic targets. Fibroblast growth factor 1 (FGF1) is a unique member of the FGF family capable of binding all four FGFR subtypes, thereby regulating multiple signaling pathways including PI3K/AKT, Ras/MAPK, and PLCγ, which are involved in metabolism, cell survival, proliferation, and tissue repair. Emerging evidence highlights the multifaceted and context-dependent roles of FGF1 in CLD. In drug-induced liver injury (DILI) caused by anti-tuberculosis drugs, acetaminophen, or doxorubicin, FGF1 confers protection by restoring bile acid homeostasis, reducing oxidative stress, inflammation, and apoptosis. In Metabolic dysfunction-associated steatotic liver disease (MASLD), FGF1 ameliorates hepatic steatosis, oxidative injury, and insulin resistance through downregulation of SREBP1, upregulation of PPARα, and activation of Nrf2-mediated antioxidant responses. Conversely, in primary sclerosing cholangitis (PSC), FGF1 aggravates ductular reaction, biliary senescence, and liver fibrosis via upregulation of SASP and TGF-β1, suggesting that inhibition of the FGF1/FGFR axis may be therapeutic. For alcohol-related liver disease (ALD), although direct experimental evidence is lacking, FGF1 is hypothesized to confer protection given its known activities against oxidative stress, lipid dysregulation, and cell death. Despite its promise, the mitogenic potential of FGF1 raises safety concerns; however, N-terminally modified FGF1 analogs (e.g., FGF1Δ) retain metabolic benefits with reduced proliferative activity. Collectively, FGF1 represents a versatile and disease-dependent regulator in CLD, warranting further mechanistic studies, safety evaluations, and development of targeted analogs as a novel therapeutic strategy for difficult-to-treat liver diseases. Full article

Intestinal oxidative stress severely compromises the health and growth of weaned piglets. The fly maggot-derived antioxidant peptide FMP was previously identified, but its protective mechanisms remain unclear. Here, we explored how FMP alleviates oxidative intestinal injury. In IPEC-J2 cells, FMP pretreatment significantly attenuated H₂O₂-induced cytotoxicity, ROS accumulation, and apoptosis, while enhancing antioxidant enzyme activities and activating Nrf2 signaling (p < 0.05). Co-treatment with the Nrf2 inhibitor ML385 abolished FMP-mediated mitophagy enhancement and cytoprotection, revealing that FMP enhances PINK1/Parkin-dependent mitophagy via Nrf2 activation. In diquat-challenged weaned piglets, oral FMP administration restored serum SOD and GSH-Px activities, reduced MDA and DAO levels (p < 0.05), upregulated jejunal tight junction proteins, and enriched Lactobacillus populations. These findings demonstrate that FMP targets the Nrf2-mitophagy axis to protect against intestinal oxidative damage, supporting its application as a green feed additive. Full article

Spinal cord injury (SCI) is a major cause of long-term disability and is frequently accompanied by chronic pain, substantially reducing quality of life. Although spinal neuroinflammation is a recognized contributor to neuropathic pain, the role of supraspinal neuroinflammation remains less well defined. This systematic review critically evaluated experimental evidence linking SCI-induced supraspinal neuroinflammation with pain-related behaviors in animal models. A systematic literature search in PubMed, Web of Science Core Collection, and Scopus identified studies published over the last 20 years using rodent SCI models that assessed both supraspinal neuroinflammatory markers and pain-related behaviors. After screening, nine studies met the predefined criteria. The analyzed studies suggested that SCI is associated with supraspinal neuroinflammatory alterations, including increased microglial and astrocytic activation and upregulation of pro-inflammatory cytokines and chemokine-related pathways, in several brain regions. In intervention studies, reduced neuroinflammation was accompanied by improvement in mechanical or thermal pain-related behaviors. However, considerable methodological heterogeneity and moderate to high risk of bias were observed. Current evidence suggests an association between supraspinal neuroinflammatory alterations and chronic pain-related behaviors after SCI, but the limited number of studies and methodological variability restrict firm conclusions. Further well-designed experimental studies are needed to clarify underlying mechanisms. Full article

Background: Spinopelvic dissociation secondary to sacral fracture–dislocation is a rare but severe injury, most often resulting from high-energy trauma. Management remains challenging, particularly in adolescents, and the optimal choice between open and percutaneous fixation is still debated. Methods: We present two adolescent cases of traumatic sacral fracture–dislocation with spinopelvic dissociation, one treated with percutaneous fixation and one with open lumbopelvic stabilization both with the use of navigation. The systematic literature review included 29 published studies. Together with the present two-patient case series, the overall analysis comprised 30 studies/series and 739 patients. Data on demographics, mechanisms of injury, neurological involvement, treatment strategies, and outcomes were extracted and analyzed. Results: Case 1 (18 years) was managed with closed reduction and percutaneous fixation, achieving complete neurological and functional recovery at 6 months. Case 2 (14 years) underwent open reduction, decompression, and lumbopelvic fixation, with favorable radiological outcomes but residual sphincter dysfunction at follow-up. In the literature, the weighted mean age was 40.6 years (range 5–91), with 48.6% presenting neurological deficits, most frequently cauda equina syndrome. Surgical management was performed in nearly all cases, with mean time to fixation ranging from 3.6 to 8.6 days. Open techniques were predominantly used in patients with severe displacement or neurological compromise, whereas percutaneous fixation was associated with reduced surgical morbidity and satisfactory neurological recovery in selected patients. Permanent bladder and bowel dysfunction persisted in up to 33% of cases. Conclusions: Spinopelvic dissociation following sacral fracture–dislocation remains a rare and highly unstable injury with frequent neurological impairment. Early surgical stabilization may be beneficial when the patient’s clinical condition permits, and the choice between open and percutaneous fixation should be individualized according to fracture morphology, neurological status, and the need for direct decompression. Our adolescent cases highlight both the potential for complete recovery and the risk of residual dysfunction, reflecting the complexity of these injuries. Full article