New Score Models for Predicting Bleeding and Ischemic of Ticagrelor Therapy in Patients with Diabetes Mellitus.

PURPOSE: Ticagrelor is an antiplatelet drug, and its use increases the risk of bleeding. Coronary artery disease is significantly influenced by the widespread occurrence of diabetes mellitus. In order to decrease the incidence of clinical adverse events, a novel bleeding and thrombosis score is developed in this research. METHODS: We conducted a retrospective analysis of patient data from two medical centers who were diagnosed with diabetes mellitus and treated with ticagrelor. We gathered information on every patient from the electronic database of the hospital and follow-up. The collected data were statistically analyzed to obtain risk factors for bleeding and ischemic events. RESULTS: A total of 851 patients with diabetes mellitus who have been administered ticagrelor are included in our investigation. A total of 76 patients have bleeding events and 80 patients have ischemic events. The analysis of multiple variables indicates that characteristics like the age of >65, having a previous occurrence of bleeding, experiencing anemia, using aspirin, and taking atorvastatin are linked to a higher likelihood of bleeding. Additionally, the age of >65, smoking, having a history of blood clots, and having a BMI ≥ 30 are found to increase the risk of ischemia. CONCLUSION: The A4B score established in this study was better than the HAS-BLED score，and the same is true for the ABST score to the CHA2DS-VASc score. This new risk assessment model can potentially detect patients who are at high risk for bleeding and ischemic events. For high-risk patients, the dose of ticagrelor can be adjusted appropriately or the medication can be adjusted.(2023-09-11, ChiCTR2300075627).

Low-dose IL-2 treatment confers anti-inflammatory effect against subarachnoid hemorrhage in mice.

Objective: Subarachnoid hemorrhage (SAH) was a stroke with high occurrence and mortality. At the early stage, SAH patients have severe cerebral injury which is contributed by inflammation. In this study, we aimed to explore the anti-inflammation effect of low-dose IL-2 in SAH mice. Methods: The 12-week-old C57BL/6J male mice were conducted with SAH surgery (Internal carotid artery puncture method). Different dose of IL-2 was injected intraperitoneally for 1 h, 1 day, and 2 days after SAH. Single-cell suspension and flow cytometry were used for the test of regulatory T (Treg) cells. Immunofluorescence staining was used to investigate the phenotypic polarization of microglia and inflammation response around neurons. Enzyme-Linked Immuno-sorbent Assay (ELISA) was applied to detect the level of pro-inflammatory factors. Results: Low-dose IL-2 could enrich the Treg cells and drive the microglia polarizing to M2. The level of pro-inflammatory factors, IL-1α, IL-6, and TNF-α decreased in the low-dose IL-2 group. The inflammation response around neurons was attenuated. Low-dose IL-2 could increase the number of Treg cells, which could exert a neuroprotective effect against inflammation after SAH. Conclusion: Low-dose IL-2 had the potential to be an effective clinical method to inhibit inflammation after SAH.

Clinical research progress of ridaforolimus (AP23573, MK8668) over the past decade: a systemic review.

Rapamycin, an established mTOR inhibitor in clinical practice, is widely recognized for its therapeutic efficacy. Ridaforolimus, a non-prodrug rapalog, offers improved aqueous solubility, stability, and affinity compared to rapamycin. In recent years, there has been a surge in clinical trials involving ridaforolimus. We searched PubMed for ridaforolimus over the past decade and selected clinical trials of ridaforolimus to make a summary of the research progress of ridaforolimus in clinical trials. The majority of these trials explored the application of ridaforolimus in treating various tumors, including endometrial cancer, ovarian cancer, prostate cancer, breast cancer, renal cell carcinoma, and other solid tumors. These trials employed diverse drug combinations, incorporating agents such as ponatinib, bicalutamide, dalotuzumab, MK-2206, MK-0752, and taxanes. The outcomes of these trials unveiled the diverse potential applications of ridaforolimus in disease treatment. Our review encompassed analyses of signaling pathways, ridaforolimus as a single therapeutic agent, its compatibility in combination with other drugs, and an assessment of adverse events (AEs). We conclude by recommending further research to advance our understanding of ridaforolimus's clinical applications.

Thymoma with immunodeficiency, combined diffuse panbronchiolitis, and latent autoimmune diabetes in adults- case report and systematic review.

Thymoma with Immunodeficiency (Good's Syndrome, GS) is a rare association between thymoma and immunodeficiency, first described over 60 years ago. Patients with GS typically present with thymomas, reduced or absent B cells in the peripheral blood, hypogammaglobulinemia, and defects in cell-mediated immunity. We report the case of a 67-year-old woman diagnosed with GS following the development of a progressive, severe, refractory pulmonary infection and diffuse panbronchiolitis (DPB). She also had diabetes, characterized by anti-glutamic acid decarboxylase antibody positivity, leading to a diagnosis of latent autoimmune diabetes in adults (LADA). A thorough review of existing literature revealed that GS is often confirmed after multiple episodes of opportunistic infections or autoimmune diseases post-thymoma surgery. Due to their immunodeficiency, GS patients frequently suffer from recurrent infections over extended periods, and some succumb to severe infections. Regular immunoglobulin infusions may be effective in treating GS.

Expression, Significance, and Correlation of Histone Deacetylase 1/RE-1 Silencing Transcription Factor and Neuronal Markers in Glioma.

BACKGROUND: Inducing the differentiation of glioma cells into neuron-like cells may be an effective strategy to combat glioma. The histone deacetylase 1/RE-1 silencing transcription factor (HDAC1/REST) complex regulates the expression of multiple neuronal genes. In this study, we analyzed the presence and significance of this regulatory effect in glioma based on bioinformatics methods. METHODS: The Human Protein Atlas database was used to obtain immunohistochemical staining images. The Gene Expression Profiling Interactive Analysis and Chinese Glioma Genome Atlas databases were used to analyze the expression of HDAC1/REST and neuronal markers in glioma, their effects on survival, and the association between HDAC1/REST and the expression of neuronal markers and stem cell markers. The differentially expressed genes between the high and low HDAC1/REST groups were explored. The Database for Annotation, Visualization and Integrated Discovery database was used for gene ontology and kyoto encyclopedia of genes and genomes pathway enrichment analysis. RESULTS: The results showed that the expression of HDAC1 and REST increased with the grade of glioma, while the expression of neuronal markers decreased with the grade of glioma. High expression of HDAC1/REST and low expression of neuronal markers were associated with poor prognosis. HDAC1/REST expression was negatively correlated with the expression of neuronal markers, and positively correlated with the expression of neural stem cell markers. The genes up-regulated in the high HDAC1/REST group were mainly related to extracellular matrix and inflammation, and the down-regulated genes were mainly related to synapsis. CONCLUSIONS: This study suggested that HDAC1/REST may be involved in maintaining the malignant phenotype of glioma cells and the stem cell status of glioma stem cells by inhibiting the expression of neuronal markers, which promote the progression of glioma.

Predicting Glioma Cell Differentiation-inducing Drugs Using a Drug Repositioning Strategy.

BACKGROUND: Currently, there are no effective differentiation-inducing agents for gliomas. Drug repositioning is a time-saving, low-risk, and low-cost drug development strategy. In this study, drugs that could induce the differentiation of glioma cells were searched by using a drug repositioning strategy. METHODS: Data mining was used to screen for differentially expressed genes (DEGs). The STRING 11.0 database was used for enrichment analysis. The Connectivity Map database was used for drug screening. The ChEMBL and STITCH databases were used to search for drug targets. The SwissDock database was used for molecular docking. RESULTS: A total of 45 DEGs were identified. The biological processes in which the DEGs were enriched mainly involved nervous system development and the regulation of biological processes. The enriched molecular functions mainly involved transcription-related molecular binding. The enriched cellular components mainly involved membrane-bound organelles and cellular protrusions. The enriched local network clusters mainly involved autophagy, the retinoic acid signalling pathway, and DNA methylation. The drug screening results showed that the drug with the highest score was acenocoumarol. A total of 12 acenocoumarol targets were obtained, among which histone deacetylase 1 (HDAC1) was the target with the highest degree value; the lowest ΔG value for acenocoumarol docked with HDAC1 was -7.52 kcal/mol, which was between those of the HDAC1 inhibitors romidepsin and vorinostat. CONCLUSION: Acenocoumarol may be a potential differentiation-inducing agent for glioma cells.

Correlation between Mean Platelet Volume and Gensini Score in Patients with Coronary Heart Disease in Different Diabetic States.

SUBJECT: To investigate the correlation between mean platelet volume (MPV) levels and Gensini scores in stable coronary heart disease (CHD) patients with or without diabetes. METHODS: A retrospective analysis was conducted on 2525 patients with stable CHD in Zhongshan Hospital, Fudan University. There were 1274 in the low MPV group and 1251 in the high MPV group, divided by a median MPV level of 10.9 fL. In the total population, 1605 patients were non-diabetic and 920 were diabetic. The severity of coronary artery disease was quantified using the Gensini score. RESULTS: The Gensini score was significantly higher in the high MPV group than in the low MPV group (p < 0.001). MPV levels increased significantly with the number of stenotic (>50%) coronary vessels (p < 0.001). The Spearman analysis showed a positive correlation between MPV and Gensini score (r = 0.189, p < 0.001), which was more significant in the diabetic subgroup (r = 0.232, p < 0.001). Receiver operating characteristic (ROC) curves were employed to assess the predictive value of MPV for high Gensini scores, using the median value of 32 points as the cutoff. MPV levels in the diabetes cohort exhibited a higher predictive value for high Gensini scores (area under the curve: 0.635 [0.614-0.657], p < 0.001). Multivariate linear regression analysis showed that diabetes and MPV were independently associated with Gensini scores. CONCLUSION: MPV levels in stable CHD patients can predict the severity of coronary artery stenosis. This correlation is more significant in the presence of diabetes.

Nocardiosis: A two-center analysis of clinical characteristics.

Objective: The objective of the present study was to describe and analyze the clinical characteristics of nocardiosis. Materials and methods: We described and analyzed the clinical characteristics of nocardiosis cases from two centers over the past 5 years from the following aspects: age and sex, Nocardia species, sites of Nocardia infection, test specimens, detection methods, concurrent pathogens, symptoms, imaging features, co-conditions, drug susceptibility tests, antibiotic therapy/duration, outcomes, and follow-up. Results: The median age of the 19 cases was 64 years, with an interquartile range (IQR) of 56-68 years. Eight cases (42.1%) were immunocompromised [those who had been on corticosteroid use (62.5%), those who had used immunosuppressants (50.0%), or those who had suffered from chronic nephrosis (37.5%) or diabetes mellitus (DM) (25.0%)]. The plethora of comorbidities of these cases included diabetes (10.5%), chronic kidney disease (CDK) (15.8%), chronic lung disease (36.8%), and rheumatic diseases (10.5%). Cough and expectoration (73.7%) was the most common symptom of nocardiosis. The respiratory tract (89.5%) was the most common site of the clinical disease. Nearly half (9 cases, 47.3%) of these patients had concurrent infections. The most common Nocardia isolation site was the respiratory tract (73.7%). All patients were given antibiotic therapies, out of whom as many as 63.6% of patients were treated with two concurrent antimicrobial agents, 15.8% of patients were treated under monotherapy and 21.1% of patients were treated with three or more concurrent antimicrobial agents. Conclusions: An uncommon life-threatening infection, nocardiosis, affects those patients with structural lung disease or immunosuppression. Although nocardiosis is capable of progressing into a serious and metastatic disease, early recognition and prompt treatment usually result in successful outcomes benefitting the patient.

Preoperative treatment with clopidogrel and ticagrelor on bleeding complications in off-pump coronary artery bypass grafting.

BACKGROUND: Dual antiplatelet therapy (DAPT) consisting of acetylsalicylic acid and clopidogrel or ticagrelor increased bleeding complications in patients undergoing coronary artery bypass grafting (CABG). We aimed to compare the bleeding risks between patients treated with clopidogrel and ticagrelor preoperatively and investigate the influence of discontinuation of clopidogrel and ticagrelor on bleeding risk in off-pump CABG (OPCABG). METHODS: We conducted a retrospective analysis of patients with DAPT who underwent OPCABG. The propensity score matching was performed given the baseline differences between clopidogrel- and ticagrelor-treated patients. Bleeding was assessed by chest tube drainage volume and universal definition of perioperative bleeding. RESULTS: This study included 836 patients. Five hundred and fifty patients were treated with clopidogrel and 286 patients treated with ticagrelor before surgery. After matching, 275 patients treated with clopidogrel and 275 patients with ticagrelor were included. There were no significant differences in bleeding between clopidogrel and ticagrelor group. Patients who discontinued clopidogrel before surgery <3 d had a higher risk of severe perioperative bleeding compared with those who discontinued ≥5 d (16.4 % vs. 5.0 %, P = 0.045). By contrast, the risk of severe perioperative bleeding was comparable among patients who discontinued ticagrelor for <3 d, ≥3-5 d and ≥5 d preoperatively (16.2 % vs. 9.1 % vs. 10.1 %, P = 0.317). The multivariable analysis confirmed that time since discontinuation (<3 d vs. ≥5 d: OR = 2.732, 95 % CI: 1.332-5.605, P = 0.006) but not the types of P2Y12 receptor antagonist was an independent predictor for severe perioperative bleeding. CONCLUSIONS: There were no significant differences in severe perioperative bleeding between clopidogrel and ticagrelor groups. Discontinuation of clopidogrel <3 d before OPCABG increased the risk of severe perioperative bleeding.

Does thromboelastography predict bleeding in patients treated with clopidogrel or ticagrelor in off-pump coronary artery bypass grafting?

OBJECTIVES: We sought to investigate the predictive value of platelet function assessment for bleeding in clopidogrel- or ticagrelor-treated patients undergoing off-pump coronary artery bypass grafting (OPCABG). METHODS: This prospective study included patients treated with acetylsalicylic acid and clopidogrel or acetylsalicylic acid and ticagrelor and scheduled for OPCABG. The percentage of platelet aggregation was evaluated by thromboelastography. Postoperative blood loss was measured as the chest tube drainage (CTD) and excessive blood loss was settled as CTD with more than 600 mL at first postoperative 12 h. Major bleeding complications were defined by Bleeding Academic Research Consortium (BARC) type 4-CABG related bleeding or class 3 or class 4 bleeding in universal definition of perioperative bleeding (UDPB) in adult cardiac surgery. RESULTS: A total of 434 consecutive patients were included. There was a negative correlation (r = -0.133, P = 0.0056) between ADP-induced platelet aggregation and CTD at 12 h. The platelet aggregation exhibited a moderate performance (AUC = 0.616) for predicting excessive postoperative blood loss. Multivariable analysis showed that ADP-induced platelet aggregation <33.45% (OR = 2.976, 95% CI: 1.325-6.711, P = 0.008) was independently associated with excessive postoperative blood loss. However, the percentage of ADP-induced platelet aggregation predicted neither UDPB-defined nor BARC-defined major bleeding. Instead, P2Y12 receptor antagonist discontinuation time was independently related to the risk of major bleeding complication. CONCLUSIONS: ADP-induced platelet aggregation detected by thromboelastography was negatively related to postoperative blood loss and platelet aggregation <33.45% was associated with excessive postoperative blood loss. However, platelet function assessment by thromboelastography failed to predict major bleeding complications.

A risk factor-based predictive model for linezolid-induced anaemia: A 7-year retrospective study.

WHAT IS KNOWN AND OBJECTIVE: The primary adverse reaction of linezolid is haematological toxicity, leading to thrombocytopenia and anaemia. This study aimed to investigate the risk factors of linezolid-induced anaemia (LI-AN) and establish a predictive model by multivariate logistic regression model analysis to predict LI-AN risks in Chinese adult patients. METHODS: Demographic and clinical data of patients who underwent linezolid therapy for more than three days between January 2014 and December 2020 in Zhongshan Hospital, Fudan University, were retrieved from the hospital's electronic medical record for analysis. Multivariate logistic regression analysis was employed to establish a predictive model, whose predictability was further evaluated by the area under the receiver operating characteristic (ROC) curve. RESULTS AND DISCUSSION: The study comprised 298 patients among the 2322 patients who underwent linezolid treatment between 2014 and 2020. Among the 298 patients, 32 (10.7%) developed anaemia with an average of 11.4 (SD 6.2) days after the initiation of linezolid therapy. Multivariate logistic analysis revealed that age ≥60 years (odds ratio [OR] 2.815, 95% confidence interval [CI] 1.242-6.379), higher total bilirubin (TBi) (OR 1.031, 95% CI 1.011-1.051), eGFR < 60 ml/(min·1.73 m2 ) (OR 2.537, 95% CI 1.054-6.106), duration of linezolid therapy (DLT) (OR 1.091, 95% CI 1.023-1.163) and intensive care unit (ICU) admittance (OR 2.664, 95% CI 1.150-6.174) were the independent risk factors for anaemia occurrence among patients receiving linezolid therapy. A logistic regression equation based on the five risk factors was subsequently established and transformed to obtain the calculation formula of the combined predictor: Y(Combined predictor)  = XTBi  + 34.5 × XAge≥60  + 31.1 × XeGFR<60  + 32.7 × XICU  + 2.9 × XDLT , (where Age ≥60 years, yes = 1, no = 0; eGFR < 60 ml/(min·1.73 m2 ), yes = 1, no = 0; ICU admittance, yes = 1, no = 0). The area under the ROC curve of the combined predictors equation was 0.773 with an optimal cut-off point value of 92.4, corresponding to a 75.0% sensitivity and 76.7% specificity. WHAT IS NEW AND CONCLUSION: LI-AN is associated with age (≥60 years), higher TBi, eGFR < 60 ml/(min·1.73 m2 ), DLT and ICU admittance. Physicians should thus calculate the combined predictor value at the beginning of linezolid treatment to predict and evaluate the risk of LI-AN. An optimal cut-off value larger than 92.4 indicates that the patient has a higher LI-AN risk. As such, Hb levels should be monitored regularly, and dosage regimens adjusted accordingly to prevent anaemia occurrence. This study provides an evidence-based logistic model that reduces LI-AN incidences and promotes the safe clinical use of linezolid.

Development and validation of a four-lipid metabolism gene signature for diagnosis of pancreatic cancer.

Abnormal lipid metabolism is closely related to the malignant biological behavior of tumor cells. Such abnormal lipid metabolism provides energy for rapid proliferation, and certain genes related to lipid metabolism encode important components of tumor signaling pathways. In this study, we analyzed pancreatic cancer datasets from The Cancer Genome Atlas and searched for prognostic genes related to lipid metabolism in the Molecular Signature Database. A risk score model was built and verified using the GSE57495 dataset and International Cancer Genome Consortium dataset. Four molecular subtypes and 4249 differentially expressed genes (DEGs) were identified. The DEGs obtained by Weighted Gene Coexpression Network Construction analysis were intersected with 4249 DEGs to obtain a total of 1340 DEGs. The final prognosis model included CA8, CEP55, GNB3 and SGSM2, and these had a significant effect on overall survival. The area under the curve at 1, 3 and 5 years was 0.72, 0.79 and 0.87, respectively. These same results were obtained using the validation cohort. Survival analysis data showed that the model could stratify the prognosis of patients with different clinical characteristics, and the model has clinical independence. Functional analysis indicated that the model is associated with multiple cancer-related pathways. Compared with published models, our model has a higher C-index and greater risk value. In summary, this four-gene signature is an independent risk factor for pancreatic cancer survival and may be an effective prognostic indicator.