Violence against children (VAC) is a major public health concern, yet persistent measurement challenges limit understanding of its epidemiology. Routinely collected administrative data, such as children entering care, represent an underused resource for measuring a subset of VAC serious enough to trigger state intervention. However, national analyses using these data have not been comprehensively updated since 2016, leaving evidence gaps. We integrated historical data from the iCoverT database (1971-2016) with recent Department for Education releases (2011-2024) to construct and analyse a 50-year national time series of children entering care in England. From 2011 to 2024, generalised estimating equations compared trends by reason for care entry, legal pathway, sex, and age. Geographic variation was examined across nine regions and 146 local authorities, and associations between child poverty and care entry for child protection reasons were assessed. Abuse and neglect were consistently the dominant reason (56-64%) for care entry. Between 1971 and 2005, care entry rates declined by 1.34% annually (95%CI:-1.53, -1.14), before reversing in 2005. From 2005 to 2024, rates increased by 1.20% per year (95% CI:0.68, 1.73), reaching 33100 new care entries in 2024 (250.0 per 100000 children). Recent increases were driven by entries for child protection reasons and emergency legal pathways, with disproportionate increases among males and adolescents. Marked geographic inequalities were observed, with higher rates concentrated in deprived local authorities; however, short-term changes in child poverty did not explain year-to-year variation in care entry for child protection reasons. This study identifies a sustained reversal in long-term declines in children entering care in England since the mid-2000s. Considerable inequalities were observed across age, sex, and place. These findings underscore the need for long-term preventive policies addressing structural disadvantage alongside national responsive measures protecting children during periods of economic and societal disruption.
Adolescents with substance use disorders (SUDs) are at higher risk for negative outcomes including suicidal ideation (SI). This is due in part to high rates of comorbid psychiatric disorders among adolescents diagnosed with a SUD. Among adolescents, SI is a sign of psychological distress that may interfere with substance use treatment engagement and completion. Identification of factors that are significant predictors of SI among adolescents engaged in risky substance use can provide valuable information for customized treatment planning. The present study is a secondary analysis of data from a racially and ethnically diverse sample of 396 adolescents receiving outpatient substance use treatment services to identify predictors of SI. Hierarchical multiple regression analyses were conducted by entering variables sequentially in four blocks: (a) gender, (b) internalizing psychiatric symptoms, externalizing psychiatric symptoms, (c) drug abuse and dependence symptoms, alcohol abuse and dependence symptoms, and (d) negative parent relations, positive parent relations to determine the unique contribution of each block. This analysis revealed that internalizing psychiatric disorder symptoms, gender, and alcohol abuse and dependence symptoms were each significant predictors of mean SI scores. Overall, the results suggested that female clients entering substance abuse treatment may have higher levels of distress than male clients and require more careful screening. Additionally, tailored integrated treatment planning for clients with complex patterns of comorbid internalizing disorder symptoms and alcohol use disorder symptoms may lead to better overall treatment outcomes.
Pseudomonas aeruginosa is a high-priority pathogen and significant burden to health care worldwide. Although often regarded as an extracellular pathogen, P. aeruginosa is also capable of existing intracellularly in multiple cell types, including epithelial cells, goblet cells, and macrophages. This designation is attributed to two of its type three secretion system (T3SS)-dependent exotoxins, ExoS and ExoT, which inactivate host proteins that facilitate phagocytosis. However, studies investigating intracellular bacteria show that ExoS can paradoxically facilitate survival and replication, seemingly overriding the anti-internalization properties of itself and ExoT through its ADP-ribosylation activity. Here, we set out to define the individual and combined contributions of ExoS and ExoT by examining how each of their two functional domain activities affects epithelial cell invasion. Through in vitro biochemical assays, we found that ExoS is capable of ADP-ribosylating ExoT and their shared human cofactor, 14-3-3. We also found that ExoT ADP-ribosylates itself, unexpectedly enhancing its GTPase-activating protein (GAP) activity. Using fluorescence microscopy, we found that GAP activity of either exotoxin does not block internalization events, but is instead associated with fewer internalized bacteria entering a phase of rapid cytoplasmic replication. We demonstrate that ExoS ADP-ribosyltransferase activity is positively associated with vacuolar exit and cytoplasmic replication, and delivery of ExoS from extracellular bacteria triggers the intracellular T3SS⁻ subpopulation to become T3SS+ and exit the vacuole. Overall, this study highlights the underappreciated ability of P. aeruginosa to become intracellular and delineates how the enzymatic domains of ExoS and ExoT dictate the intracellular localization of the pathogen.
In recent years, the concept of neuro-skeletal crosstalk, highlighting the reciprocal interactions between the nervous and skeletal systems, has opened new avenues for understanding the pathogenesis and intervention strategies of complex diseases. This review summarizes the roles of molecular networks such as neurotransmitters, endocrine factors, immune mediators, and extracellular vesicles in bone metabolism, repair, and neurodegenerative diseases, with an emphasis on recent advances regarding bone-derived signals-including the Piezo1 channel and osteocalcin-in neural regulation. Building on this foundation, we focus on advances in frontier materials such as nanomaterials and hydrogels for modulating the brain-bone microenvironment and facilitating coordinated tissue regeneration, as well as new strategies for targeted drug delivery and immune microenvironment modulation. Empowered by next-generation technologies-including multi-omics, artificial intelligence, and organ-on-a-chip systems-the investigation of the fundamental mechanisms and personalized interventions of the brain-bone axis is entering a new era of opportunity. We hope that this review will provide a theoretical basis and valuable reference for future mechanistic studies and innovation in this interdisciplinary field. By elucidating bidirectional regulatory networks, this review underscores the significant translational potential of targeting the brain-bone axis (BBA) for the treatment of skeletal disorders and neurodegenerative comorbidities. Therapeutic strategies harnessing neurotransmitters (e.g., norepinephrine, serotonin) and neuropeptides (e.g., CGRP) can directly modulate osteoblastic/osteoclastic activity and immune responses, thereby orchestrating fracture repair and metabolic homeostasis. The integration of functional materials-such as stimuli-responsive hydrogels, nanomaterials, and bioelectronic devices-enhances the spatiotemporal precision of signal modulation and facilitates drug delivery across biological barriers, including the blood-brain barrier (BBB). However, challenges regarding low cross-organ targeting efficiency, the complexity of dynamic pathological microenvironments, and physiological discrepancies between animal models and humans necessitate further optimization. Advances in multi-omics analysis, AI-driven network modeling, and intelligent biomimetic delivery systems hold promise for bridging these gaps, offering scalable solutions for clinical translation. This work highlights neuro-skeletal modulation as a transformative dual-targeting strategy for complex diseases, yet its implementation remains contingent upon the refinement of precise intervention technologies and rigorous clinical validation.
Consanguineous marriage (CM) is associated with increased risk of inherited disorders and represents an important focus for genetic counseling in many regions. Prevention strategies often assume that increased awareness of genetic risk leads to behavior change; however, evidence from collectivist contexts remains limited. This study examined whether genetic risk awareness influences CM practices in Kabul, Afghanistan, and explored social and familial factors shaping marital decision-making. A cross-sectional study was conducted in Kabul between March and June 2025 among 610 adults recruited through nonprobability sampling across five urban zones. A structured questionnaire assessed marital consanguinity, awareness of genetic risks, sociodemographic characteristics, and social influences on marriage decisions. Descriptive statistics, chi-square analyses and independent t-test were performed. Among married participants, 34.5% reported CM, and 39.5% reported parental consanguinity. Awareness of CM (63.4%) and its genetic risks (74.7%) was relatively high; however, awareness was not associated with avoidance of CM (p > 0.05), with over one-third of informed individuals still entering consanguineous unions. Higher education was strongly associated with awareness but was also associated with a greater prevalence of CM. Key determinants included emotional attachment, family-arranged marriage, trust within kinship networks, familial pressure, and fatalistic beliefs regarding destiny. Knowledge alone may be insufficient to influence CM decisions. Genetic counseling approaches in collectivist settings may benefit from family-centered and culturally responsive strategies that address social norms and shared decision-making processes beyond individual risk awareness.
Observational studies report a protective association between herpes zoster (HZ) vaccination and dementia, but they have methodological limitations or examined a live attenuated vaccine no longer available in the United States. Among older adults recently admitted to a skilled-nursing facility for postacute or long-term care, to estimate the association between dementia and receipt of the recombinant HZ vaccine (RZV) within 12 months of entering the facility or after discharge. The researchers conducted a cohort study using target trial emulation and the clone-censor-weight approach. Participants were followed for up to 4 years until the outcome of dementia, Medicare disenrollment, or death. Inverse probability of clone-censoring weights were applied to pooled logistic regression models to estimate effects. Medicare claims linked to nursing home electronic health record (EHR) data. Medicare fee-for-service beneficiaries aged 66 years or older who were admitted to a skilled-nursing facility between 1 January 2017 and 31 December 2022, had linked EHR data, had no diagnosed dementia, and were eligible for RZV. Receipt of at least 1 RZV in the facility or, if discharged, by 12 months after admission versus no receipt of RZV. Validated dementia diagnosis and 57 baseline and time-varying covariates. The study cohort included 509 926 participants (mean age, 79 years); 8843 (1.73%) received at least 1 RZV dose within 12 months after admission, and of these, 87.0% received RZV after discharge. Receipt of RZV was associated with risk for dementia being 5.8 percentage points lower (95% CI, 3.9 to 7.5 percentage points lower; risk ratio, 0.76 [CI, 0.69 to 0.84]; 4-year risk, 18.8% with ≥1 RZV vs. 24.6% with no RZV). Associations were attenuated in men and those with prior live HZ vaccination. Negative control analyses suggest some residual confounding. Receipt of RZV during admission to a skilled-nursing facility or within 12 months was associated with lower dementia risk. GlaxoSmithKline.
Significant progress has been made in embedding strong antimicrobial stewardship (AMS) practices within community pharmacy teams as their roles expand to meet growing primary care appointment demand. To maintain this momentum, it is essential that registered community pharmacy professionals, whether newly entering the workforce or refreshing their skills, have access to high quality online learning resources that support the development, renewal and expansion of their AMS knowledge. To identify and assess the available online antimicrobial stewardship training resources suitable for community pharmacy teams in England. A search was conducted to identify easily accessible online antimicrobial educational resources specifically designed for, or suitable for, community pharmacy professionals. Twenty online resources were identified, of which 12 were selected for evaluation. The resources ranged from being suitable for novices to advanced learners with specific learning needs. Although there are few education resources created specifically for community pharmacy professionals, a wide range of online materials are suitable and can provide a strong foundation in antimicrobial knowledge and support further learning at the learner's own pace. Targeted resources can help address individual learners' questions, while many of the available materials offer practical applications relevant to both community pharmacy and broader primary care settings. Since many of these resources are open to all healthcare professionals, they standardize knowledge across the workforce and support better integration of community pharmacy within the wider NHS system.
Bioplastics incorporate different renewable sources via direct biosynthesis or biotechnological intermediates, contributing to the eventual production of a biobased system. Sustainable polymers and materials represent an essential substitute for petrochemical intermediates and the synthesis of applied compounds. We listed, described, and discussed three main groups of commercially applied and produced bioplastics: polyhydroxyalkanoates (PHAs), polylactic acid/polylactide (PLA), and polybutylene succinate (PBS). Although all the mentioned biobased polymers possess biodegradability at specific conditions, their waste or spoiled primary products have significant potential for new and diverse applications. The thermally degraded, hydrolyzed, or physically aged biopolyesters lack sufficient performance in their initial applications; upcycling is an alternative and promising strategy that produces valorized, added-value products or complex multistep-derived functional systems. This comprehensive review describes the major challenges that the discussed biobased polymers face, identifies fundamental chemical approaches for bioplastics as entering substances, and outlines the potential and outlook for the waste-based molecules and precursors produced. The eventual alternative applications include the pharmaceutical industry, the cosmetics segment, the production of chemical intermediates and reactants for organic synthesis, and various functional and circular materials, such as recyclable thermoplastics and thermoset vitrimers.
Coronary artery fistulae (CAF) represent uncommon anomalous connections linking the coronary arterial tree directly to cardiac chambers or great thoracic vessels. Termination into the left atrium is extraordinarily rare, especially when presenting as multiple fistulous tracts. We describe the case of a 60-year-old woman with permanent atrial fibrillation, previous mechanical mitral valve replacement, recurrent systemic thromboembolism, and prosthetic valve thrombosis. Coronary angiography incidentally revealed two coronary-cameral fistulae arising from the proximal left circumflex artery and a third fistula originating from the right coronary artery's distal conus branch, with all channels draining exclusively into the left atrial cavity. Transesophageal echocardiography confirmed continuous turbulent flow entering the left atrium, accompanied by dense spontaneous echocardiographic contrast (SEC) and an organized mural left atrial thrombus. The combination of permanent atrial fibrillation, chronic left atrial volume overload driven by the fistulous shunt, prior mitral valve pathology, and inadequate anticoagulation likely generated a highly prothrombotic environment. This case emphasizes the critical role of multimodality cardiac imaging in characterizing intricate coronary-cameral architecture. Furthermore, it demonstrates that left atrial drainage fistulae may have contributed to atrial flow disturbance and thrombotic propensity in the context of multiple established thromboembolic risk factors, even without achieving conventional thresholds for a hemodynamically significant shunt.
With Generation Z entering the nursing workforce in growing numbers, strengthening social and emotional learning is critical for academic success, professional adaptation, and safe practice. However, the existing evidence remains fragmented because of varied interventions and inconsistent approaches. This systematic review examined (1) the social and emotional learning essential for nursing students and nurses within the Collaborative for Academic, Social, and Emotional Learning framework, (2) their impact on educational and clinical outcomes, and (3) implications for advancing nursing education and practice. Following Joanna Briggs Institute methodology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, five international (PubMed, EMBASE, CINAHL, PsycINFO, Cochrane) and three Korean (RISS, KoreaMed, KMBASE) databases were searched up to June 2025. Eighteen studies involving 2,952 participants met the inclusion criteria, including quasi-experimental quantitative studies, descriptive quantitative studies, qualitative studies, and mixed-methods studies. The methodological quality of the included studies was appraised using the Mixed Methods Appraisal Tool. Within the Collaborative for Academic, Social, and Emotional Learning framework, relationship skills and self-management were the most frequently studied competencies, emphasizing teamwork, communication, and stress regulation. Self-awareness and social awareness were underexplored, despite their importance in empathy, resilience, and reflective practice. Responsible decision-making was the least studied competency, despite its importance in ethical reasoning. Social and emotional learning was consistently associated with enhanced adaptation, communication, leadership, relationships, and clinical performance. Effective strategies included blended learning, simulation, reflective activities, and mentorship, which are aligned with Generation Z's learning preferences. Although social and emotional learning integration is associated with improvements in educational and clinical outcomes in nursing, current research has largely centered on relational and stress-related competencies while underrepresenting responsible decision-making. To cultivate reflective, empathetic, and ethically grounded nurses, curricula should integrate social and emotional learning through a balanced and structured approach. This study was registered on PROSPERO (ID: CRD420251005683).
Artificial intelligence (AI) is rapidly entering family life, reshaping how young children learn, play, and interact with technology. Yet little is known about how parents interpret these changes or organize AI use at home. This qualitative study generates a process framework of family AI use in early education and care, capturing Chinese parents' perspectives through inductive thematic analysis. Sixteen parents whose children attended nurseries and kindergartens across nine Chinese cities were purposefully selected for in-depth interviews. Through inductive analysis, we constructed a process framework suggesting that parents first articulate beliefs about AI, which inform the functions they intend AI to serve, and these functions in turn shape their mediation strategies. Parents emphasized both the significance of AI and the irreplaceability of human roles, while envisioning AI as a tool for relieving workload, offering parenting advice, entertaining, and supporting playful learning. Mediation strategies reflected ongoing negotiation, including managing AI's presence, interface, exposure, screen use, and content. This process framework illustrates how families balance opportunity with caution by shaping children's encounters with AI in ways consistent with parental values. It offers a conceptual tool for researchers, practitioners, and policymakers concerned with supporting healthy family engagement with AI in the digital age.
Totally implantable venous access ports (PORTs) are indispensable for oncology patients and others requiring prolonged intravenous therapy, eliminating repeated venipuncture and offering durable, low-maintenance vascular access. However, device-related infection remains the most frequent complication. Pantoea agglomerans (P. agglomerans), an environmental, plant-associated bacterium, rarely causes human disease, and reports of P. agglomerans colonization specifically within the PORT reservoir are scarce. We report the case of a 72-year-old Asian female who was undergoing postoperative chemotherapy for breast cancer, developed acute high fever with elevated inflammatory markers following an invasive procedure involving a PORT during chemotherapy. Blood cultures confirmed infection with P. agglomerans. Based on clinical examinations, we confirmed that the pathogen colonized the PORT reservoir itself, a phenomenon that has rarely been reported and discussed to date in P. agglomerans infections. The patient achieved complete recovery following antimicrobial therapy. In conclusion, P. agglomerans is a rare pathogen that causes a range of clinical infections. Besides entering the bloodstream to cause bacteremia, P. agglomerans, it can also lurk in the indwelling devices and trigger high fever in susceptible patients. Therefore, aseptic technique, prompt antibiotic therapy and removal of the infected source are crucial to control P. agglomerans infection.
Atherothrombosis is a complex vascular disorder in which a thrombus forms on a vascular lesion, typically following the disruption and/or erosion of an atherosclerotic plaque. Atherothrombosis is the main pathological mechanism underlying atherosclerotic cardiovascular diseases (ASCVDs) [i.e., myocardial infarction (MI), ischemic stroke, and peripheral artery disease (PAD)]. In recent years, substantial advances have reshaped our understanding of ASCVD, spanning its pathophysiology, risk stratification, and therapeutic management. Emerging insights into the mechanisms of atherosclerosis progression, including the interplay between cardiovascular risk factors and the vascular wall, endothelial dysfunction, lipid deposition, local niches of innate and adaptive immunity responses and systemic inflammation have refined our understanding of the disease. These advances have, in turn, driven the development of improved pharmacological therapies and a better clinical management of ASCVD. Emerging evidence and novel therapeutic agents have deepened our understanding of the thrombotic complications of atherosclerotic plaques, particularly the mechanisms underlying the transition from subclinical vascular lesions into overt clinical events. Despite remaining the leading cause of death and disability worldwide, ASCVD has evolved in many treated patients from a progressively worsening, rupture-prone condition to a more chronic and controlled disease. The natural history of atherothrombosis, from early lesion development to overt clinical manifestation, has been modified by these improvements in management. Continued progress is expected through the development of novel therapeutic strategies targeting the multiple pathogenic pathways affecting atherothrombosis, as well as through advances in non-invasive imaging and diagnostic tools aimed at earlier detection and personalized intervention. We are entering a new era in the care of patients with atherothrombotic disease.
Shengxian Quyu decoction (SXQY) has been suggested as a potential therapeutic strategy for heart failure (HF), but its therapeutic mechanisms remain unclear. This study investigated the therapeutic effects and underlying mechanisms of SXQY in HF. A rat model of HF was induced by transverse aortic constriction (TAC) and treated with SXQY. Cardiac function was assessed by transthoracic echocardiography, and myocardial structure and fibrosis were evaluated using hematoxylin and eosin and Masson's trichrome staining. Serum samples were analyzed by untargeted metabolomics using ultra-performance liquid chromatography-tandem mass spectrometry. Blood-entering components were mapped to targets, and intersecting HF-related targets were analyzed using protein-protein interaction (PPI) network analysis, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. SXQY significantly improved cardiac function in TAC rats, as evidenced by decreased left ventricular internal diameter in diastole and left ventricular posterior wall thickness in diastole and increased left ventricular ejection fraction, and alleviated myocardial hypertrophy, inflammation, and fibrosis. A total of 563 blood-entry compounds were identified (367 prototypes and 196 metabolites), with 5 key active compounds identified in the Traditional Chinese Medicine Systems Pharmacology database corresponding to 63 targets. Network analysis revealed 44 overlapping genes, with Formononetin, Timosaponin BII, and Sinensetin as core components, and PTGS2, PPARG, and HSP90AA1 as hub targets. PPI analysis further identified key genes including ESR1, PTGS2, PPARG, HSP90AA1, JUN, and 15 additional genes. KEGG analysis indicated that SXQY mainly acts via Ca2+, phosphatidylinositol 3-kinase-protein kinase B, cyclic adenosine monophosphate, and inflammation- and hormone-related pathways. In conclusion, SXQY exerts protective effects against HF by improving cardiac function and attenuating myocardial remodeling through multicomponent, multitarget, and multipathway mechanisms.
The Matagorda Bay system has suffered a long-term decline in benthic abundance, biomass, and diversity since the 1980's. This study examined sediment contamination to determine if legacy pollutants are degrading sediment quality and are a possible cause for ecosystem degradation. Degradation can be indicated by a decline in benthic integrity (i.e., diversity), decreased survival rates of organisms exposed to sediment, and sediment chemical contaminant concentrations over threshold limits. These methods form the Sediment Quality Triad to assess environmental effects. There were no contaminant concentrations above threshold limits for PCBs or DDTs, but 46% of 24 stations had concentrations over threshold limits, established by sediment quality guidelines, for seven trace elements and one PAH: arsenic (As), cadmium (Cd), mercury (Hg), copper (Cu), lead (Pb), nickel (Ni), and silver (Ag); and dibenzo (a,h) anthracene. Mostly near river mouths, 16 of the 24 stations had moderate to high toxicity, and 17 out of the 24 stations had fair to low diversity. Toxicity was inversely correlated with diversity, but there were no correlations between sediment chemistry and toxicity or benthic metrics. These findings indicate that legacy chemical contamination is not driving estuary-wide degradation of benthic communities The only station where high contamination was linked to high toxicity and low diversity was in the uppermost region of Lavaca Bay close to creek mouths. Low diversity and/or high toxicity was common near river and creek mouths. Because unmeasured pollution could be entering from rivers and creeks, management plans for the watershed and non-point sources could help to protect this ecosystem.
To address the critical technical bottleneck of severe matrix interference in the analysis of trace anions within electronic-grade hydrofluoric acid (HF), a novel online two-dimensional ion-exclusion/ion-exchange chromatography (2D-IC) method was developed. Highly efficient online matrix elimination was achieved by systematically optimizing the first-dimension flow rate and the valve-switching enrichment window. The primary technical breakthrough of this work is the strategic integration of a controlled delay volume that breaks conventional flow path configurations. Specifically, a 3.0 m FEP delay tubing was introduced between the conductivity cell waste outlet (CELL OUT) and the suppressor regeneration liquid inlet (REGEN IN). This configuration targets a previously overlooked interference mechanism: electrolytic fluctuation feedback. The residual ultra-high concentration HF matrix entering the suppressor's regeneration chamber can trigger violent fluctuations in the electrolytic balance, leading to anomalous baseline elevation that severely masks trace chloride (Cl-) signals. By rationally leveraging the Taylor-Aris dispersion effect and controlled time delay within the tubing, the sharp matrix pulses are physically smoothed into a steady, low-concentration flow before reaching the regeneration chamber. This strategy completely blocks the suppressor feedback interference, eliminating the matrix masking effect on chloride quantification without compromising analytical sensitivity or altering thermodynamic separation conditions. Method validation demonstrated excellent linearity for five target anions (Cl-, Br-, NO3-, SO42-, and PO43-) within the 0.1-20 µg kg-1 range (r > 0.999), with ultra-low limits of detection (0.005-0.015 µg kg-1). Requiring a single-run time of only 30 min, this highly sensitive and robust method provides a reliable chromatographic strategy for the stringent quality control of ultra-high-purity wet chemicals in the semiconductor and microelectronics industries.
On 24-25 February 2026, Alzheimer's Research UK held its annual research conference at Manchester Central Convention Complex and online. The meeting brought together over 700 researchers spanning molecular biology, data science, clinical trials, prevention, and patient engagement. Over 2 days of plenaries, parallel sessions, and discussions, a clear message emerged: the field of dementia research is entering a new, more hopeful era. This report summarises a meeting that highlighted how dementia research is moving beyond the search for a single solution and instead embracing a multidimensional, collaborative framework for precision care.
To evaluate the long-term effects of anifrolumab on hematologic and serologic parameters over four years. This analysis included 536 patients with moderate-to-severe systemic lupus erythematosus (SLE) who received intravenous anifrolumab 300 mg (n = 358) or placebo (n = 178) in the 52-week, phase 3 TULIP-1/2 trials (NCT02446912 and NCT02446899) and continued the same treatment in the 3-year, long-term extension (LTE, NCT02794285), or would have done if not discontinued early; 369 patients entered the LTE. Changes from baseline to week 208 in lymphocytes, hemoglobin, platelets, neutrophils, complement C3, C4, anti-double-stranded DNA (dsDNA), and Igs were analyzed descriptively. British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 52 was analyzed by treatment and lymphocyte, hemoglobin, and platelet normalization in responders versus nonresponders, regardless of treatment. Numerically greater improvements from baseline in lymphocyte, hemoglobin, platelet, and neutrophil levels were observed with anifrolumab over placebo. Comparing anifrolumab versus placebo, lymphocyte and hemoglobin normalization rates were higher and platelet normalization was comparable. BICLA response was associated with lymphocyte, hemoglobin, and platelet normalization over four years, regardless of treatment. Conversely, BICLA responses were higher with anifrolumab versus placebo, irrespective of baseline lymphocyte, hemoglobin, and platelet levels. Improvements in anti-dsDNA, C3, C4, and Igs from baseline were greater with anifrolumab versus placebo. The normalization of hematologic parameters and sustained improvements in serologic markers support the long-term efficacy of anifrolumab in patients with moderate-to-severe SLE. Clinical response to anifrolumab was associated with improvements in biomarkers, suggesting restoration of overall immune health.
Rho GTPases promote GTP hydrolysis aided by specific GTPase-activating proteins (GAPs). By alternating between an active GTP-bound and an inactive GDP-bound state, Rho GTPases function as molecular switches regulating cytoskeletal dynamics and cell motility. Despite their biological relevance, the detailed molecular mechanism underlying Rho GTPases catalysis remains contentious. Here, using classical and hybrid quantum-classical molecular dynamics, we resolve the mechanism of GTP hydrolysis in the RhoGAP-RhoA complex. We reveal that GTP hydrolysis proceeds through a dissociative nucleophilic substitution mechanism, driven by an amide → imide tautomerization of Gln63, which aids in delivering a proton from the nucleophilic water to the leaving phosphate group. The Gln63 imide tautomer also loosens RhoGAP-RhoA interfacial contacts, allowing solvent molecules to enter and drive a water-mediated reverse tautomerization of Gln63 that restores the catalytically competent configuration of the RhoA active site. Conservation of key interface residues across Rho/Rho GAP family members suggests that this mechanism may be shared by most Rho GTPases.
To identify risk factors for hemorrhagic transformation (HT) after mechanical thrombectomy (MT) in patients with acute anterior circulation large vessel occlusion (LVO) and to develop a predictive nomogram. This retrospective study enrolled 193 patients with acute anterior circulation LVO who underwent MT at a single center between January 2023 and December 2025. Patients were categorized into HT (n = 45, 23.32%) and non-HT (n = 148, 76.68%) groups based on postoperative imaging at 24-72 h. Univariate analysis was performed to compare baseline characteristics, biochemical indicators, and clinical variables between the two groups. Variables with p < 0.05 were subjected to Elastic Net regression with 10-fold cross-validation (StratifiedKFold) for variable selection and dimensionality reduction, with the optimal hyperparameters determined as C = 1 and l1_ratio = 0.9 (cross-validation AUC = 0.8615). Eight variables were retained and subsequently entered into binary logistic regression with forward stepwise selection to identify independent risk factors and construct a prediction model. A nomogram was developed and evaluated using receiver operating characteristic (ROC) curve, calibration curve with bootstrap validation (1,000 resamples), and decision curve analysis (DCA). Six independent risk factors for HT were identified: history of alcohol consumption (OR = 6.423, 95% CI 2.224-18.552, p = 0.001), history of leukoencephalopathy (OR = 4.555, 95% CI 1.664-12.469, p = 0.003), elevated blood glucose-to-lymphocyte ratio (GLR) (OR = 1.105, 95% CI 1.034-1.181, p = 0.003), elevated D-dimer (OR = 1.102, 95% CI 1.029-1.180, p = 0.005), elevated venous blood glucose (OR = 1.201, 95% CI 1.037-1.390, p = 0.014), and reduced mean platelet volume (MPV) (OR = 0.704, 95% CI 0.537-0.925, p = 0.012). The nomogram demonstrated favorable discriminative ability with an AUC of 0.880 (95% CI 0.820-0.939), sensitivity of 0.933, and specificity of 0.696. Calibration curve analysis indicated good model fit (χ2 = 9.059, p = 0.337). Decision curve analysis revealed a net benefit rate > 0 when the threshold probability ranged from 0.01 to 0.97. History of alcohol consumption, leukoencephalopathy, elevated GLR, D-dimer, and venous blood glucose, and reduced MPV are independent risk factors for HT after MT in acute anterior circulation LVO stroke. The constructed nomogram exhibits good discrimination, calibration, and clinical utility, providing a reliable tool for individualized risk prediction.