Development and validation of a predicting nomogram for in-hospital mortality of COVID-19 Omicron variant: A cohort study of 1324 cases in Beijing Anzhen Hospital.

Coronavirus disease 2019 (COVID-19) is continuously posing high global public health concerns due to its high morbidity and mortality. This study aimed to construct a convenient risk model for predicting in-hospital mortality of COVID-19 Omicron variant. A total of 1324 hospitalized patients with Omicron variant were enrolled from Beijing Anzhen Hospital. During hospitalization, the Omicron variant mortality rate was found to be 24.4%. Using the datasets of clinical demographics and laboratory tests, three machine learning algorithms, including best subset selection, stepwise selection, and least absolute shrinkage and selection operator regression analyses were employed to identify the potential predictors of in-hospital mortality. The results found that a panel of twenty-four clinical variables (including age, hyperlipemia, stroke, tumor, and several cardiovascular markers) identified by stepwise selection model exhibited significant performances in predicting the in-hospital mortality of COVID-19. The resultant nomogram showed good discrimination, highlighted by the areas under the curve values of 0.88 for 10 days, 0.81 for 20 days, and 0.82 for 30 days, respectively. Furthermore, decision curve analysis showed a significant reliability and precision for the established stepwise selection model. Collectively, this study developed an accurate and convenience risk model for predicting the in-hospital mortality of COVID-19 Omicron.

Association Between Red Blood Cell Distribution Width and Coronary Calcification in Patients Referred for Invasive Coronary Angiography.

This study aimed to determine whether red cell distribution width (RDW) is associated with coronary calcification. A total of 4796 patients who underwent coronary computed tomography angiography and subsequent invasive coronary angiography were consecutively enrolled. Coronary artery calcium score (CACS), demographic, clinical, and laboratory data were collected from electronic medical records. RDW were expressed in two forms, as a coefficient of variation (CV) or as a standard deviation (SD). Multivariable ordinal logistic regression was used to investigate the association of RDW with CACS grades (CACS 0-99, 100-399, 400-999, and >1000). A significant association was found between elevated RDW-SD and higher CACS grades after full adjustment (adjusted OR per 1-SD increase: 1.11, 95% CI: 1.05-1.18; P < .001), while no significant association was found between RDW-CV and CACS grades. When RDW-SD was analyzed as a categorical variable, it was primarily the 4th quartile of RDW-SD that was associated with elevated CACS grades compared with the 1st quartile (adjusted OR: 1.25, 95% CI: 1.07-1.46; P = .006), while the 2nd and 3rd quartiles showed no significantly higher risk. RDW-SD is a more robust biomarker for coronary calcification compared with RDW-CV.

Significance of Aneuploidy in Predicting Prognosis and Treatment Response of Uveal Melanoma.

AIMS: This study aimed to improve personalized treatment strategies and predict survival outcomes for patients with uveal melanoma (UM). BACKGROUND: Copy number aberrations (CNAs) have been considered as a main feature of metastatic UM. OBJECTIVE: This study was designed to explore the feasibility of using copy number variation (CNV) in UM classification, prognosis stratification and treatment response. METHODS: The CNV data in the TCGA-UVM cohort were used to classify the samples. The differentially expressed genes (DEGs) between subtypes were screened by the "Limma" package. The module and hub genes related to aneuploidy score were identified by performing weighted gene co-expression network analysis (WGCNA) on the DEGs. Univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analysis were employed to train the hub genes for developing a prognosis model for UM. Finally, the expression levels of the screened prognostic key genes were verified in UM cells, and the cell migration and invasion abilities were detected using real-time quantitative PCR (qRT-PCR) and transwell assay. RESULTS: The UM samples were divided into 3 CNV subtypes, which differed significantly in overall survival (OS) and disease-specific survival (DSS). C1 had the shortest OS and DSS and the highest level of immune infiltration. A total of 2036 DEGs were obtained from the three subtypes. Eighty hub genes with the closest correlation with aneuploidy scores were selected by WGCNA. Univariate Cox and LASSO regression-based analyses finally determined eight genes as the key prognostic genes, including HES6, RNASEH2C, NQO1, NUDT14, TTYH3, GJC1, FKBP10, and MRPL24. A prognostic model was developed using the eight genes, demonstrating a strong prediction power. Differences in the response to immunotherapy among patients in different risk groups were significant. We found that high-risk patients were more sensitive to two drugs (Palbociclib_ 1054 and Ribociclib_1632), while low-risk patients were more sensitive to AZD1208_1449, ERK_2440_1713, Mirin_1048, and Selumetinib_1736. CONCLUSION: UM in this study was divided into three CNV subtypes, and a model based on eight aneuploidy score-related genes was established to evaluate the prognosis and drug treatment efficacy of UM patients. The current results may have the potential to help the clinical decision-making process for UM management.

Mea6/cTAGE5 cooperates with TRAPPC12 to regulate PTN secretion and white matter development.

Mutations of TRAPPC12 are associated with progressive childhood encephalopathy including abnormal white matter. However, the underlying pathogenesis is still unclear. Here, we found that Trappc12 deficiency in CG4 and oligodendrocyte progenitor cells (OPCs) affects their differentiation and maturation. In addition, TRAPPC12 interacts with Mea6/cTAGE5, and Mea6/cTAGE5 ablation in OPCs affects their proliferation and differentiation, leading to marked hypomyelination, compromised synaptic functionality, and aberrant behaviors in mice. We reveal that TRAPPC12 is associated with COPII components at ER exit site, and Mea6/cTAGE5 cKO disrupts the trafficking pathway by affecting the distribution and/or expression of TRAPPC12, SEC13, SEC31A, and SAR1. Moreover, we observed marked disturbances in the secretion of pleiotrophin (PTN) in Mea6-deficient OPCs. Notably, exogenous PTN supplementation ameliorated the differentiation deficits of these OPCs. Collectively, our findings indicate that the association between TRAPPC12 and MEA6 is important for cargo trafficking and white matter development.

Prognostic Value of a Combined Nomogram Model Integrating 3-Dimensional Deep Learning and Radiomics for Head and Neck Cancer.

OBJECTIVE: The preoperative prediction of the overall survival (OS) status of patients with head and neck cancer (HNC) is significant value for their individualized treatment and prognosis. This study aims to evaluate the impact of adding 3D deep learning features to radiomics models for predicting 5-year OS status. METHODS: Two hundred twenty cases from The Cancer Imaging Archive public dataset were included in this study; 2212 radiomics features and 304 deep features were extracted from each case. The features were selected by univariate analysis and the least absolute shrinkage and selection operator, and then grouped into a radiomics model containing Positron Emission Tomography /Computed Tomography (PET/CT) radiomics features score, a deep model containing deep features score, and a combined model containing PET/CT radiomics features score +3D deep features score. TumorStage model was also constructed using initial patient tumor node metastasis stage to compare the performance of the combined model. A nomogram was constructed to analyze the influence of deep features on the performance of the model. The 10-fold cross-validation of the average area under the receiver operating characteristic curve and calibration curve were used to evaluate performance, and Shapley Additive exPlanations (SHAP) was developed for interpretation. RESULTS: The TumorStage model, radiomics model, deep model, and the combined model achieved areas under the receiver operating characteristic curve of 0.604, 0.851, 0.840, and 0.895 on the train set and 0.571, 0.849, 0.832, and 0.900 on the test set. The combined model showed better performance of predicting the 5-year OS status of HNC patients than the radiomics model and deep model. The combined model was shown to provide a favorable fit in calibration curves and be clinically useful in decision curve analysis. SHAP summary plot and SHAP The SHAP summary plot and SHAP force plot visually interpreted the influence of deep features and radiomics features on the model results. CONCLUSIONS: In predicting 5-year OS status in patients with HNC, 3D deep features could provide richer features for combined model, which showed outperformance compared with the radiomics model and deep model.

A novel enrofloxacin-degrading fungus, Humicola sp. KC0924g, isolated from the rhizosphere sediment of the submerged macrophyte Vallisneria spiralis L.

A novel enrofloxacin-degrading fungus was isolated from a rhizosphere sediment of the submerged macrophyte Vallisneria spiralis L.. The isolate, designated KC0924g, was identified as a member of the genus Humicola based on morphological characteristics and tandem conserved sequence analysis. The optimal temperature and pH for enrofloxacin degradation by strain KC0924g were 28 °C and 9.0, respectively. Under such condition, 98.2% of enrofloxacin with an initial concentration of 1 mg L-1 was degraded after 72 h of incubation, with nine possible degradation products identified. Four different metabolic pathways were proposed, which were initiated by cleavage of the piperazine moiety, hydroxylation of the aromatic ring, oxidative decarboxylation, or defluorination. In addition to enrofloxacin, strain KC0924g also degraded other fluoroquinolone antibiotics (ciprofloxacin, norfloxacin, and ofloxacin), malachite green (an illegal additive in aquaculture), and leucomalachite green. Pretreatment of cells of strain KC0924g with Cu2+ accelerated ENR degradation. Furthermore, it was speculated that a flavin-dependent monooxygenase was involved in ENR degradation, based on the increased transcriptional levels of these two genes after Cu2+ induction. This work enriches strain resources for enrofloxacin remediation and, more importantly, would facilitate studies on the molecular mechanism of ENR degradation with degradation-related transcriptome available.

miR-330-5p Suppress Cell Growth and Invasion via Disrupting HSF4-mediated MACC1/STAT3 Pathway in Colorectal Cancer.

BACKGROUND: Recently, miRNAs are demonstrated to restrain mRNA translation through novel pattern with bind complementary sites in the coding sequence (CDS). Heat Shock Transcription Factor 4 (HSF4) has been newly described as a tumor-associated transcription factor. Therefore, the present study intends to explore miRNAs that bind CDS region of HSF4, and identify the function of their interactions in the malignant biological behavior of colorectal cancer (CRC). METHODS: Prognostic value of HSF4 and correlation between HSF4 and MACC1 expression were estimated via bioinformatics with the Cancer Genome Atlas (TCGA) data. HSF4 and downstream MACC1/STAT3 signaling cascade was characterized by immunoblotting. To characterize the effects of miR-330-5p and HSF4 on the malignant phenotype of CRC cells by functional experiments. The binding activity of miR-330-5p to coding sequence (CDS) of HSF4 was identified using DIANA-microT-CDS algorithm and dual-luciferase reporter assay. RESULTS: HSF4 was aberrantly overexpressed and associated with poor outcomes of CRC patients. Overexpression of HSF4 was correlated with Tumor Node Metastasis stage, and positively regulated malignant behaviors such as growth, migration, invasion of CRC cells. Moreover, miR-330-5p suppressed CRC cell growth, colony formation, migration and invasive. Interestingly, miR-330-5p recognized complementary sites within the HSF4 CDS region to reduce HSF4 expression. In rescue experiments, restoration of HSF4 expression functionally alleviated miR-330-5p-induced inhibition of cell growth, colon formation, invasion, and wound healing of CRC cells. HSF4 was associated positively with the well-known oncogenic factor MACC1 in TCGA cohort CRC samples, and knockdown of HSF4 resulted in downregulation of MACC1. In mechanism, MACC1 was suppressed upon miR-330-5p-induced downregulation of HSF4, leading to inactivation of phosphorylation of downstream STAT3. CONCLUSION: miR-330-5p suppresses tumors by directly inhibiting HSF4 to negatively modify activity of MACC1/STAT3 pathway.

Machine learning-based coronary artery calcium score predicted from clinical variables as a prognostic indicator in patients referred for invasive coronary angiography.

OBJECTIVES: Utilising readily available clinical variables, we aimed to develop and validate a novel machine learning (ML) model to predict severe coronary calcification, and further assessed its prognostic significance. METHODS: This retrospective study enrolled patients who underwent coronary CT angiography and subsequent invasive coronary angiography. Multiple ML algorithms were used to train the models for predicting severe coronary calcification (cardiac CT-measured coronary artery calcium [CT-CAC] score ≥ 400). The ML-based CAC (ML-CAC) score derived from the ML predictive probability was stratified into quartiles for prognostic analysis. The primary endpoint was a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: Overall, 5785 patients were divided into training (80%) and test sets (20%). For clinical practicability, we selected the nine-feature support vector machine model with good and satisfactory performance regarding both discrimination and calibration based on five repetitions of the 10-fold cross-validation in the training set (mean AUC = 0.715, Brier score = 0.202), and based on the test in the test set (AUC = 0.753, Brier score = 0.191). In the test set cohort (n = 1137), the primary endpoint was observed in 50 (4.4%) patients during a median 2.8 years' follow-up. The ML-CAC system was significantly associated with an increased risk of the primary endpoint (adjusted hazard ratio for trend 2.26, 95% CI 1.35-3.79, p = 0.002). There was no significant difference in the prognostic value between the ML-CAC and CT-CAC systems (C-index, 0.67 vs. 0.69; p = 0.618). CONCLUSION: ML-CAC score predicted from clinical variables can serve as a novel prognostic indicator in patients referred for invasive coronary angiography. CLINICAL RELEVANCE STATEMENT: In patients referred for invasive coronary angiography who have not undergone preoperative CT-measured coronary artery calcium scoring, machine learning-based coronary artery calcium score assessment can serve as an alternative for predicting the prognosis. KEY POINTS: • The coronary artery calcium (CAC) score, a solid prognostic indicator, can be predicted using non-CT methods. • We developed a machine learning (ML)-CAC model utilising nine clinical variables to predict severe coronary calcification. • The ML-CAC system offers significant prognostic value in patients referred for invasive coronary angiography.

Genomics-Microbiome Based Assessment of Bidirectional Causality Between Gut Microbiota and Psoriasis.

Background: Traditional observational studies have found a possible risk association of the gut microbiota for psoriasis. Meanwhile, psoriasis may also affect the changes in the gut microbiota. However, the available evidence does not demonstrate a reciprocal relationship between the gut microbiota and psoriasis. This limits our understanding on the role of the gut microbiota in the mechanisms of psoriasis. Methods: To address this question we used Mendelian randomization, a novel epidemiological approach, and acquired the largest current gut microbiota GWAS data from the MiBioGen consortium as well as psoriasis GWAS data from the FinnGen consortium, and performed two-sample bidirectional MR analyses using a multiple MR analysis approach. Finally, the robustness of the results was assessed by sensitivity analysis. Results: Our results indicate that five bacterial genera are causally related to psoriasis and psoriasis is causally related to four bacterial genera. Conclusion: These results suggest a bidirectional causal influence of psoriasis on the gut microbiota. Our results somewhat challenge the causal inferences of previous observational studies. We found that the specific bacterial genera with a risk effect on psoriasis were different from those found to characterize psoriasis in previous observational studies, and that these psoriasis-characterizing genera were inversely associated with psoriasis.

Assessment of dynamic corneal response parameters in Chinese patients of different ages with myopia and orthokeratology lenses using the Corvis ST.

OBJECTIVE: To investigate the effects of orthokeratology lenses (OK lenses) on corneal biomechanics in subjects of different ages. METHODS: Fifty subjects with mild to moderate myopia were categorized into three groups (Group I-III) based on their age. Corvis ST was used to collect dynamic corneal response parameters (DCRs) at different follow-up time points. Repeated measures analysis of variance combined with simple effect analysis was used to analyze the changes in DCRs in different groups during the follow-up period. Multiple linear regression analysis was used to analyze the correlations between axial length growth (ALG) at 6 months (ALG-6M) or 12 months (ALG-12M) and sex, baseline spherical equivalent refraction (SER), and DCRs. RESULTS: The DCRs changed in all three groups after wearing OK lenses. Most DCRs showed significant differences between baseline and 6 months after wearing OK lenses, while the differences between DCRs at 6 months and 12 months were not statistically significant. No significant differences in DCRs were observed among the three groups at the same follow-up time point. Additionally, at 6 months post-OK lens wear, ALG-6M was significantly correlated with velocity of the corneal apex at the first applanation (A1V-6M) (P = 0.002), Corvis biomechanical index (CBI-6M) (P = 0.004), the maximum amount of corneal movement (DAM-6M) (P = 0.010), deformation amplitude ratio of 2 mm (DAR2-6M) (P = 0.010), and stress-strain index (SSI-6M) (P = 0.038) in Group I. Furthermore, ALG-12M showed significant correlations with SSI-6M (P = 0.031), peak distance at the DAM (PD)-6M (P = 0.037), baseline Ambrósio Relational Thickness to the horizontal profile (P = 0.013) in Group I. CONCLUSIONS: The majority of DCRs displayed significant changes within the initial 6 months of OK lens wear. Minimal variation in DCRs was observed across different age groups at the same follow-up time point. Certain DCR parameters exhibited correlations with ALG, suggesting their potential in predicting ALG in myopic children undergoing OK lenses correction.

Autoimmune congenital heart block: a case report and review of the literature related to pathogenesis and pregnancy management.

Autoimmune congenital heart block (ACHB) is a passively acquired immune-mediated disease characterized by the presence of maternal antibodies against components of the Ro/SSA and La/SSB ribonucleoprotein complex that mainly affects the cardiac conducting system. ACHB occurs in 2% of women with positive anti-Ro/SSA and anti-La/SSB antibodies and causes a high risk of intrauterine fetal death, neonatal mortality, and long-term sequelae. In this review, we first describe a case of ACHB to provide preliminary knowledge. Then, we discuss the possible pathogenic mechanisms of ACHB; summarize the pregnancy management of patients with positive anti-Ro/SSA and anti-La/SSB antibodies and/or rheumatic diseases, the prevention of ACHB, and the treatment of ACHB fetuses; and propose routine screening of these antibodies for the general population. Careful follow-up, which consists of monitoring the fetal heart rate, is feasible and reassuring for pregnant women with positive anti-Ro/SSA and/or anti-La/SSB antibodies to lower the risk of ACHB in fetuses. Moreover, maternal administration of hydroxychloroquine may be useful in preventing ACHB in pregnant women with anti-Ro/SSA and/or anti-La/SSB antibodies.

Identification of Reduced mTOR T1262 Phosphorylation as a Novel Mechanism and Therapeutic Target of Apoptosis in Senescent Cardiomyocytes: Aging and Cardiomyocyte Apoptosis.

The mechanisms through which aging increases heart injury remain partially understood. Protein phosphorylation plays a critical regulatory role in cell survival and death. Using an unbiased phosphoproteomics approach, we aimed to identify the proteins whose phosphorylation could be causatively related to aging-related cardiomyocyte apoptosis and elucidate the underlying mechanisms. Comparative phosphoproteomics was conducted on cardiac tissues obtained from young (8 weeks) and aged (24 months) mice. Our findings revealed that the Mammalian Target of Rapamycin phosphorylation at T1262 (mTORT1262) was reduced in the aging heart. Immunohistochemical and Western blot analyses confirmed these findings in aging myocardia and D-galactose-induced senescent AC16 cardiomyocytes. In hypoxia/reoxygenation cardiomyocytes, mTORT1262 phosphorylation deficiency (mTORT1262A, lentivirus-mediated transfection) inhibited AKT1, suppressed NF-κB, activated FOXO1/3a signaling, and ultimately exacerbated apoptosis. Conversely, mTORT1262 pseudophosphorylation (mTORT1262E) exhibited opposite effects. Through bioinformatics and CO-IP, purinergic receptor P2X4 (P2X4R) was found to be the possible receptor responsible for mTORT1262 phosphorylation. Knockdown of P2X4R increased apoptosis, whereas its overexpression decreased it. In senescent cardiomyocytes, P2X4R expression and mTORT1262 and AKT1S473 phosphorylation were reduced, NF-κB signaling was suppressed, and FOXO1/3a signaling was activated. We demonstrated that P2X4R downregulation and the subsequent reduction of mTORT1262 phosphorylation is a novel mechanism contributing to cardiomyocyte apoptosis in aging hearts. The P2X4R-mTOR-AKT1 signaling pathway represents a potential therapeutic target against accelerated cardiac injury in aging.

Association of D-dimer to albumin ratio with adverse cardiovascular outcomes in ischaemic heart failure patients with diabetes mellitus: a retrospective cohort study.

OBJECTIVE: To determine the association of D-dimer to albumin ratio (DAR) with major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) in ischaemic heart failure patients with diabetes mellitus. DESIGN: A retrospective observational cohort study. SETTING: Single centre in Beijing, China, conducted at one of the largest cardiology centres in China. PARTICIPANTS: From June 2017 to June 2019, 3707 patients with heart failure and concomitant multiple vessel disease undergoing elective PCI were screened. A total 1021 of patients were enrolled after exclusion and the follow-up period was up to 36 months. PRIMARY AND SECONDARY OUTCOME MEASURES: The MACE was the primary measured outcome. The secondary outcomes were all-cause mortality, non-fatal myocardial infarction and any revascularisation. METHODS: These participants were grouped according to DAR tertiles. The cumulative incidence functions, Cox regression, restricted cubic spline and receiver operating characteristic curves were used to determine the association between DAR and outcomes. The subgroup analysis was also performed. RESULTS: After follow-up, MACE occurred in 404 (39.6%) participants. The cumulative hazards curve manifested significant differences in MACE, all-cause mortality and any revascularisation (log-rank test: all p<0.001). In adjusted models, DAR was an independent risk factor of MACE (tertile 2: HR 1.82, 95% CI 1.37 to 2.42; tertile 3: HR 1.74, 95% CI 1.28 to 2.36) and all-cause mortality (tertile 2: HR 2.04, 95% CI 1.35 to 3.11; tertile 3: HR 1.89, 95% CI 1.20 to 2.98). The optimal cut-off of DAR was 1.2. In the stratified analysis, sex, age, hypertension, hypercholesterolaemia, total revascularisation and any interfered vessel did not affect the independent predictive ability. CONCLUSION: Higher DAR was independently associated with MACE and all-cause mortality after PCI in ischaemic heart failure patients with diabetes mellitus.

Appropriate time for ejection fraction reassessment after revascularization in patients with left ventricular dysfunction for risk stratification of sudden cardiac death.

BACKGROUND: Appropriate time for ejection fraction (EF) reassessment after revascularization in patients with left ventricular dysfunction has not been investigated comprehensively, although 3 months after revascularization is recommended to stratify the risk of sudden cardiac death (SCD). HYPOTHESIS: EF reassessed within different timeframe after revascularization may have incosistent contribution for risk stratification of SCD. METHODS: Patients who had EF ≤ 40% before revascularization and had EF reassessment at least once during follow-up were included. The role of early (<3 months) versus late (3-12 months) EF measurements in prediction of all-cause mortality and SCD were compared. RESULTS: A total of 1589 patients were identified. EF reassessed <3 months was lower than EF reassessed within 3-12 months (42.1 ± 9.7% vs. 45.8 ± 10.8%; p < .01). Among 1069 patients who had EF reassessed <3 months, EF ≤ 35% was associated with a higher risk of all-cause mortality (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.22-2.29; p < .01), but had no association with the risk of SCD (HR, 1.44; 95% CI, 0.84-2.48; p = .18). By contrast, among 595 patients who had EF reassessed within 3-12 months, EF ≤ 35% was associated with higher risks of both all-cause death (HR, 1.81; 95% CI, 1.06-3.10; p = .03) and SCD (HR, 2.71; 95% CI, 1.31-5.61; p < .01). The relative contribution of SCD to all-cause death was higher in patients with EF ≤ 35% than patients with EF > 35% when EF was reassessed within 3-12 months (p = .04). However, when EF was reassessed <3 months, the mode of death was similar in patients with EF ≤ 35% versus >35% (p = .85). CONCLUSIONS: 3 to 12 months after revascularization may be appropriate for cardiac function reassessment and SCD risk stratification.

PVB exerts anti-inflammatory effects by inhibiting the activation of MAPK and NF-κB signaling pathways and ROS generation in neutrophils.

Pinaverium bromide (PVB) has been shown to protect mice against sepsis, which is predominantly attributed to PVB-mediated anti-inflammatory effects by inhibiting primed neutrophils to produce proinflammatory cytokines. However, the underlying mechanism(s) by which PVB affects neutrophils remains unknown. In this study, we report that treatment with PVB either before or after LPS stimulation attenuated IL-1ß and TNF-α expression at both mRNA and protein levels in LPS-activated murine neutrophils. Further experiments revealed that PVB inhibited the phosphorylation of ERK, JNK, and IκBα in LPS-stimulated murine neutrophils. Moreover, PVB reduced reactive oxygen species (ROS) levels via regulating NADPH oxidase 2 (NOX2) activity, as represented by inhibiting p47phox translocation from the cytoplasm to the cellular membrane. Importantly, PVB significantly attenuated IL-1ß, TNF-α, IL-6, CXCL1 production in both LPS-stimulated low density neutrophils (LDNs) and normal density neutrophils (NDNs) isolated from septic patients. Collectively, we demonstrated that PVB exerts anti-inflammatory effect by attenuating ROS generation and suppressing the activation of MAPK and NF-κB signaling pathways, suggesting that PVB may act as a potential therapeutic agent for sepsis by inhibiting neutrophil priming and activation.

Long-term efficacy and complications of intravitreal anti-vascular endothelial growth factor agents combined with ablative therapies in juvenile Coats disease: a five year follow-up study.

PURPOSE: To evaluate the long-term safety and efficacy of adjuvant intravitreal anti-VEGF therapy in juvenile Coats disease. METHODS: This retrospective, observational study included a total of 62 eyes in 62 pediatric patients with juvenile Coats disease treated with intravitreal anti-VEGF agents followed for a mean of 67.08 months (ranged from 60 to 93 months). All affected eyes were managed initially with one session of ablative treatment plus adjuvant intravitreal anti-VEGF agent (0.5 mg/0.05 ml ranibizumab or conbercept). Ablative treatment was repeated if telangiectatic retinal vessels were not completely regressed or recurred. Anti-VEGF therapy was repeated if subretinal fluid or macular edema still existed. Treatments above were repeated every 2 to 3 months. We reviewed clinical and photographic records of patients including the demographics, clinical characteristics and interventions. RESULTS: At final visit, all 62 affected eyes had partially or completely disease resolution; none progressed to advanced stage namely neovascular glaucoma or phthisis bulbi, respectively. No ocular or systemic side effects related to intravitreal injections were observed during follow-up. In terms of 42 affected eyes that could cooperate with visual examination, best corrected visual acuity improved in 14 (14/42, 33.3%) eyes, stabled in 25 (25/42, 59.5%) eyes, and worsened in 3 (3/42, 7.1%) eyes. In the field of complications, 22 (22/62, 35.5%) eyes developed cataracts; 33 (33/62, 53.2%) eyes developed vitreoretinal fibrosis, of whom 14 (14/33, 42.4%) eyes in the subgroup of stage 3B developed progressive TRD; 40 (40/62, 64.5%) eyes developed subretinal fibrosis. Multivariate regression analysis showed increased clinical stage may be associated with the development of vitreo- and subretinal fibrosis (adjusted odds ratio:16.77,17.59; 95% CI:4.50-62.53, 3.98-77.86, respectively, all P < 0.001). CONCLUSION: Adjuvant intravitreal ranibizumab or conbercept combined with ablative therapies may be a long-term safe and effective treatment for juvenile Coats disease.

Molecular mechanism of Wilms tumour 1-associated protein in diabetes-related dry eye disease by mediating m6A methylation modification of lncRNA NEAT1.

Background: Dry eye disease (DED) is often secondary to diabetes mellitus (DM).Purpose: This study is to explore the action of Wilms tumor 1-associated protein (WTAP) in DM-DED via lncRNA NEAT1 m6A methylation.Methods: DM-DED mouse models were treated with sh-WTAP/sh-NEAT1, followed by assessment of corneal epithelial damage/histopathological changes. HCE-2 cells were exposed to hyperosmotic conditions to establish in vitro DED models and treated with oe-NEAT1/sh-NEAT1/sh-WTAP/nigericin (an NLRP3 inflammasome inducer). Cell viability/apoptosis were evaluated by CCK-8/TUNEL. Levels of WTAP/NEAT1/inflammatory factors/NLRP3 inflammasome- and apoptosis-related markers were determined. m6A modification was examined by MeRIP-qPCR and NEAT1 stability was also detected.Results: DM-DED mice exhibited up-regulated WTAP/NEAT1 expression and severe corneal damage, whereas WTAP/NEAT1 knockdown alleviated inflammation/corneal damage. In hyperosmolarity-induced HCE-2 cells, NEAT1 aggravated inflammation and apoptosis, while NEAT1 knockdown suppressed NLRP3 inflammasome activation and ameliorated cell injury. Hyperosmolarity-induced WTAP expression increased m6A modification and NEAT1 mRNA stability. WTAP mediated m6A methylation of NEAT1 and NLRP3 inflammasome activation in DM-DED mice.

Palmdelphin Deficiency Evokes NF-κB Signaling in Valvular Endothelial Cells and Aggravates Aortic Valvular Remodeling.

Palmd-deficient mice of advanced age manifest increased aortic valve peak velocity, thickened aortic valve leaflets, and excessive extracellular matrix deposition, which are key features of calcific aortic valve disease. PALMD is predominantly expressed in endothelial cells of aortic valves, and PALMD-silenced valvular endothelial cells are prone to oscillatory shear stress-induced endothelial-to-mesenchymal transition. Mechanistically, PALMD is associated with TNFAIP3 interaction protein 1, a binding protein of TNFAIP3 and IKBKG in NF-κB signaling. Loss of PALMD impairs TNFAIP3-dependent deubiquitinating activity and promotes the ubiquitination of IKBKG and subsequent NF-κB activation. Adeno-associated virus-mediated PALMD overexpression ameliorates aortic valvular remodeling in mice with calcific aortic valve disease, indicating protection.

Monocyte to high-density lipoprotein cholesterol ratio predicts poor outcomes in ischaemic heart failure patients combined with diabetes: a retrospective study.

BACKGROUND: The prevalence of ischaemic heart failure (HF) continues to increase. Diabetes mellitus (DM) concomitant with ischaemic HF increases the risk of major adverse cardiovascular events (MACEs). As a promising predictor for cardiovascular diseases, the predictive value of the monocyte to high-density lipoprotein cholesterol ratio (MHR) for MACE in the ischaemic HF with DM cohort has never been investigated before. OBJECTIVE: We aimed to investigate the MHR as a predictor for MACE in ischaemic HF patients with DM who underwent percutaneous coronary intervention (PCI). METHODS: This observational study enrolled 1049 patients with ischaemic HF and DM undergoing PCI from June 2017 to June 2019. The baseline data were collected. MACEs, including all-cause mortality, nonfatal myocardial infarction, and any revascularization, were recorded within the 36-month follow-up. The characteristics and incidence of MACE were analysed in four groups stratified by the quartiles of MHR. The hazard ratio for MACE was analysed with Cox regression models. The incidence of MACE in the four groups was evaluated by Kaplan‒Meier survival analysis. Restricted cubic spline analysis was performed to determine the nonlinear correlation between the MHR and MACE. RESULTS: After the 36-month follow-up, 407 patients (38.8%) experienced MACEs. The incidence of MACE was significantly higher among patients in the upper MHR quartile than among those in the lower MHR quartiles (23.4% vs. 36.0% vs. 41.4% and 54.6%; P < 0.001, respectively), which was consistent with the Kaplan‒Meier survival analyses (P < 0.0001). A multivariate Cox regression model showed that the MHR was an independent risk factor for MACE after variables were adjusted (adjusted HR: 2.11; 95% CI 1.47-3.03; P < 0.001). Its predictive effects on MACE showed no interaction with hypercholesterolemia (P > 0.05). CONCLUSION: The MHR was a significant and independent predictor of MACEs in ischaemic HF patients with DM undergoing PCI.

Point-Based Learnable Query Generator for Human-Object Interaction Detection.

Transformer-based and interaction point-based methods have demonstrated promising performance and potential in human-object interaction detection. However, due to differences in structure and properties, direct integration of these two types of models is not feasible. Recent Transformer-based methods divide the decoder into two branches: an instance decoder for human-object pair detection and a classification decoder for interaction recognition. While the attention mechanism within the Transformer enhances the connection between localization and classification, this paper focuses on further improving HOI detection performance by increasing the intrinsic correlation between instance and action features. To address these challenges, this paper proposes a novel Transformer-based HOI Detection framework. In the proposed method, the decoder contains three parts: learnable query generator, instance decoder, and interaction classifier. The learnable query generator aims to build an effective query to guide the instance decoder and interaction classifier to learn more accurate instance and interaction features. These features are then applied to update the query generator for the next layer. Especially, inspired by the interaction point-based HOI and object detection methods, this paper introduces the prior bounding boxes, keypoints detection and spatial relation feature to build the novel learnable query generator. Finally, the proposed method is verified on HICO-DET and V-COCO datasets. The experimental results show that the proposed method has the better performance compared with the state-of-the-art methods.