BACKGROUND: The association of systemic inflammatory response index (SIRI) with prognosis of coronary artery disease (CAD) patients has never been investigated in a large sample with long-term follow-up. This study aimed to explore the association of SIRI with all-cause and cause-specific mortality in a nationally representative sample of CAD patients from United States. METHODS: A total of 3386 participants with CAD from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 were included in this study. Cox proportional hazards model, restricted cubic spline (RCS), and receiver operating characteristic curve (ROC) were performed to investigate the association of SIRI with all-cause and cause-specific mortality. Piece-wise linear regression and sensitivity analyses were also performed. RESULTS: During a median follow-up of 7.7 years, 1454 all-cause mortality occurred. After adjusting for confounding factors, higher lnSIRI was significantly associated with higher risk of all-cause (HR = 1.16, 95% CI: 1.09-1.23) and CVD mortality (HR = 1.17, 95% CI: 1.05-1.30) but not cancer mortality (HR = 1.17, 95% CI: 0.99-1.38). The associations of SIRI with all-cause and CVD mortality were detected as J-shaped with threshold values of 1.05935 and 1.122946 for SIRI, respectively. ROC curves showed that lnSIRI had robust predictive effect both in short and long terms. CONCLUSIONS SIRI was independently associated with all-cause and CVD mortality, and the dose-response relationship was J-shaped. SIRI might serve as a valid predictor for all-cause and CVD mortality both in the short and long terms.

Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure-activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC₅₀ = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC₅₀ = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy-lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.

Numerous studies on the formation and consolidation of memory have shown that memory processes are characterized by phase-dependent and dynamic regulation. Memory retrieval, as the only representation of memory content and an active form of memory processing that induces memory reconsolidation, has attracted increasing attention in recent years. Although the molecular mechanisms specific to memory retrieval-induced reconsolidation have been gradually revealed, an understanding of the time-dependent regulatory mechanisms of this process is still lacking. In this study, we applied a transcriptome analysis of memory retrieval at different time points in the recent memory stage. Differential expression analysis and Short Time-series Expression Miner (STEM) depicting temporal gene expression patterns indicated that most differential gene expression occurred at 48 h, and the STEM cluster showing the greatest transcriptional upregulation at 48 h demonstrated the most significant difference. We then screened the differentially-expressed genes associated with that met the expression patterns of those cluster-identified genes that have been reported to be involved in learning and memory processes in addition to dipeptidyl peptidase 9 (DPP9). Further quantitative polymerase chain reaction verification and pharmacological intervention suggested that DPP9 is involved in 48-h fear memory retrieval and viral vector-mediated overexpression of DPP9 countered the 48-h retrieval-induced attenuation of fear memory. Taken together, our findings suggest that temporal gene expression patterns are induced by recent memory retrieval and provide hitherto undocumented evidence of the role of DPP9 in the retrieval-induced reconsolidation of fear memory.
Animals ; Fear/physiology* ; Male ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics* ; Memory Consolidation/physiology* ; Time Factors ; Mental Recall/drug effects* ; Mice ; Gene Expression Profiling

The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson's disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K⁺ channels, or Ca²⁺-activated K⁺ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
Animals ; Histamine/metabolism* ; Male ; Oxidopamine/toxicity* ; Rats ; Ventral Thalamic Nuclei/physiopathology* ; Rats, Sprague-Dawley ; Disease Models, Animal ; Parkinson Disease/metabolism* ; Neurons/physiology* ; Humans ; Optogenetics

OBJECTIVE: To compare clinical efficacy of transaxillary posterior margin approach and translateral margin approach for the treatment of Miller typeⅡand Ⅳ scapular fractures. METHODS: From June 2020 to June 2024, 28 patients with fresh scapular fractures (Miller typeⅡand Ⅳ) who were treated with open reduction and locked plate internal fixation were retrospectively analyzed and divided into two groups. There were 13 patients in posterior axillary margin group, including 8 males and 5 females, aged from 26 to 71 years old with an average of (39.2±6.5) years old;5 patients with typeⅡand 8 patients with type Ⅳ according to Miller classification;9 patients caused by falling down, 4 patients caused by car accident;7 patients on the right side, 6 patients on the left side;the time from injury to operation ranged from 3 to 5 days with an average of (4.07±0.86) days. There were 15 patients in lateral scapula margin group, including 10 males and 5 females, aged from 27 to 63 years old with an average of (43.6±8.5) years old;7 patients with typeⅡand 8 patients with type Ⅳ according to Miller classification;10 patients caused by falling down, 5 patients caused by car accident;6 patients on the right side, 9 patients on the left side;the time from injury to operation ranged from 3 to 5 days with an average of (4.20±0.67) days. Operative time, intraoperative blood loss, fracture healing time, glenopolar angle (GPA) immediately after operation were compared between two groups. Visual analogue scale (VAS) and Constant-Murley shoulder joint function score were used to evaluate clinical effect at 3 and 6 months after operation, respectively, and the joint motions were evaluated at 6 months after operation. RESULTS: None of patients occurred wound infection, vascular and nerve damage, loosening or rupture of internal fixation. Both groups were followed up for 8 to 12 months with an average of (9.6±1.5) months. Operative time and intraoperative blood loss of posterior axillary margin group were (76.92±5.60) min and (84.86±10.08) ml, respectively, which were better than those of lateral scapula margin group(84.67±6.93) min and(115.00±12.39) ml(P<0.05). Immediate GPA in posterior axillary margin group (36.62±0.87) °and lateral scapula margin group (36.20±0.82)°were significantly improved compared with preoperative (16.10±1.14) °, (16.20±1.20) °(P<0.05), while there was no statistical significance between two groups (P>0.05). There were no significant difference in fracture healing time and postoperative VAS at 3 and 6 months between two groups (P>0.05). Postoperative Constant-Murley score of posterior axillary margin group (75.00±4.02) was higher than that of lateral scapular margin group (70.86±4.24) at 3 months (P<0.05), while there was no significant difference between two groups at 6 months after operation (P>0.05). At 6 months after operation, joint motion of posterior axillary margin group in flexion (160.38±13.61)°, abduction (154.61±13.91)°, rotation (83.08±2.53)°, rotation (62.69±2.59) ° and extension (51.54±3.15) °, respectively, which were higher than that of lateral scapular margin group in (148.00±15.44)°, (144.00±11.05)°, (79.67±3.99)°, (57.33±4.95)°, (47.33±4.16)°(P<0.05). CONCLUSION Compared with lateral margin of scapula intermuscular space approach, Buttress approach through the posterior axillary margin for the treatment of Miller typeⅡand Ⅳ scapular fractures provides extensive intraoperative visual field exposure, stable fracture support and less surgical trauma, which could shorten operative time and reduce intraoperative blood loss, providing a new reference for the treatment of complex scapular fractures.
Humans ; Male ; Female ; Middle Aged ; Scapula/surgery* ; Adult ; Aged ; Fractures, Bone/physiopathology* ; Fracture Fixation, Internal/methods* ; Retrospective Studies ; Axilla/surgery*

OBJECTIVES: To investigate the application value of thromboelastography (TEG) in assessing coagulation function in children with severe hemophilia A (HA) after emicizumab (EMI) therapy. METHODS: A retrospective analysis was performed on the activated partial thromboplastin time (APTT) and TEG testing results of 17 children with severe HA before and after EMI treatment at Shenzhen Children's Hospital from January 2023 to July 2024. Correlation analysis was conducted between coagulation factor VIII (FVIII) equivalent activity and reaction time (R value) measured by TEG. RESULTS: After EMI treatment, the mean bleeding rate for children with severe HA was 1.6 events per year, with 15 children (88%) without spontaneous bleeding or joint bleeding. The children with severe HA showed a significant reduction in APTT after EMI treatment (P<0.05), with a significantly shorter APTT than the normal control group (P<0.05). There was no correlation between APTT and FVIII equivalent activity after treatment (P>0.05). After EMI treatment, TEG parameters, including R value, kinetic time, alpha angle (α), maximum amplitude, clot strength, and coagulation index, shifted from a hypocoagulable state before treatment to a nearly normal state after treatment (P<0.05). The R value demonstrated a strong negative correlation with FVIII equivalent activity (r=-0.758, P<0.05). CONCLUSIONS The bleeding condition of children with severe HA can be effectively controlled after EMI treatment. Routine APTT testing cannot reflect true coagulation function, whereas TEG testing is clinically valuable in assessing the coagulation function of children with severe HA undergoing EMI treatment.
Humans ; Thrombelastography ; Hemophilia A/physiopathology* ; Male ; Child ; Antibodies, Bispecific/therapeutic use* ; Antibodies, Monoclonal, Humanized/therapeutic use* ; Blood Coagulation/drug effects* ; Child, Preschool ; Retrospective Studies ; Female ; Partial Thromboplastin Time ; Adolescent ; Infant

OBJECTIVES: To investigate the chain mediating role of family care and emotional management in the relationship between social support and anxiety among rural primary school students. METHODS: A questionnaire survey was conducted among students in grades 4 to 6 from four counties in Hunan Province. Data were collected using the Social Support Rating Scale, Family Care Index Scale, Emotional Intelligence Scale, and Generalized Anxiety Disorder -7. Logistic regression analysis was used to explore the influencing factors of anxiety symptoms. Mediation analysis was conducted to assess the chain mediating effects of family care and emotional management between social support and anxiety. RESULTS: A total of 4 141 questionnaires were distributed, with 3 874 valid responses (effective response rate: 93.55%). The prevalence rate of anxiety symptoms among these students was 9.32% (95%CI: 8.40%-10.23%). Significant differences were observed in the prevalence rates of anxiety symptoms among groups with different levels of social support, family functioning, and emotional management ability (P<0.05). The total indirect effect of social support on anxiety symptoms via family care and emotional management was significant (β=-0.137, 95%CI: -0.167 to -0.109), and the direct effect of social support on anxiety symptoms remained significant (P<0.05). Family care and emotional management served as significant chain mediators in the relationship between social support and anxiety symptoms (β=-0.025,95%CI:-0.032 to -0.018), accounting for 14.5% of the total effect. CONCLUSIONS Social support can directly affect anxiety symptoms among rural primary school students and can also indirectly influence anxiety symptoms through the chain mediating effects of family care and emotional management. These findings provide scientific evidence for the prevention of anxiety in primary school students from multiple perspectives.
Humans ; Female ; Male ; Social Support ; Anxiety/etiology* ; Child ; Students/psychology* ; Emotions ; Logistic Models

OBJECTIVE: To investigate the short-term efficacy and safety of low-dose venetoclax combined with CHG (cytarabine+homoharringtonine+G-CSF) priming regimen in patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy. METHODS: The data of 14 patients with AML or high-risk MDS admitted to the department of hematology/oncology of the First Hospital of Tsinghua University and 2 cooperative institutions from July 2022 to August 2023 were retrospectively analyzed. All the patients were treated with low-dose venetoclax combined with CHG priming regimen and the early induction (one course) efficacy and adverse reactions were observed. RESULTS: Among the 14 patients, 10 were males and 4 were females, with a median age of 69.5 (46-83) years. After 1 cycle of induction chemotherapy, the complete remission (CR) rate was 64.3% (9/14) and overall response rate (ORR) was 78.6% (11/14). Among the 10 patients with adverse prognosis according to cytogenetics and molecular genetics, the CR rate was 50.0% (5/10), and ORR was 70.0% (7/10). In 7 patients with TP53 mutation, the CR rate was 42.9% (3/7) and ORR was 71.4% (5/7). In the 6 patients with complex karyotype, CR rate was 33.3% (2/6) and ORR was 66.7% (4/6). While the CR rate and ORR of 8 non-complex karyotype patients were both 87.5% (7/8), and the difference in CR rate between patients with complex karyotype and non-complex karyotype was statistically significant ( P < 0.05). The adverse reactions of chemotherapy were tolerable, without early treatment-related deaths. CONCLUSION Low-dose venetoclax combined with CHG priming regimen can be used as an effective treatment for AML and high-risk MDS patients who are ineligible for intensive chemotherapy, and it is safe and worthy of clinical application.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Aged ; Male ; Female ; Sulfonamides/therapeutic use* ; Middle Aged ; Myelodysplastic Syndromes/drug therapy* ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use* ; Aged, 80 and over ; Retrospective Studies ; Cytarabine/administration & dosage* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Homoharringtonine/therapeutic use*

OBJECTIVE: To investigate the clinical features and prognosis of central nervous system (CNS) invasion in peripheral T-cell lymphoma (PTCL) and construct a risk prediction model for CNS invasion. METHODS: Clinical data of 395 patients with PTCL diagnosed and treated in the First Affiliated Hospital of Zhengzhou University from 1st January 2013 to 31st December 2022 were analyzed retrospectively. RESULTS: The median follow-up time of 395 PTCL patients was 24(1-143) months. There were 13 patients diagnosed CNS invasion, and the incidence was 3.3%. The risk of CNS invasion varied according to pathological subtype. The incidence of CNS invasion in patients with anaplastic large cell lymphoma (ALCL) was significantly higher than in patients with angioimmunoblastic T-cell lymphoma (AITL) (P <0.05). The median overall survival was significantly shorter in patients with CNS invasion than in those without CNS involvement, with a median survival time of 2.4(0.6-127) months after diagnosis of CNS invasion. The results of univariate and multivariate analysis showed that more than 1 extranodal involvement (HR=4.486, 95%CI : 1.166-17.264, P =0.029), ALCL subtype (HR=9.022, 95%CI : 2.289-35.557, P =0.002) and ECOG PS >1 (HR=15.890, 95%CI : 4.409-57.262, P <0.001) were independent risk factors for CNS invasion in PTCL patients. Each of these risk factors was assigned a value of 1 point and a new prediction model was constructed. It could stratify the patients into three distinct groups: low-risk group (0-1 point), intermediate-risk group (2 points) and high-risk group (3 points). The 1-year cumulative incidence of CNS invasion in the high-risk group was as high as 50.0%. Further evaluation of the model showed good discrimination and accuracy, and the consistency index was 0.913 (95%CI : 0.843-0.984). CONCLUSION The new model shows a precise risk assessment for CNS invasion prediction, while its specificity and sensitivity need further data validation.
Humans ; Lymphoma, T-Cell, Peripheral/pathology* ; Prognosis ; Retrospective Studies ; Central Nervous System Neoplasms/pathology* ; Neoplasm Invasiveness ; Male ; Female ; Central Nervous System/pathology* ; Middle Aged ; Adult