Research and Prediction of Factors Related to High Degree Atrioventricular Block after TAVI Surgery Based on Logistic Regression Model.

OBJECTIVE: Based on the logistic regression model, analyze the risk factors for high degree atrioventricular block after transcatheter aortic valve replacement (TAVI) surgery and further analyze its predictive value. METHODS: 402 patients who underwent TAVI surgery at Henan Thoracic Hospital for "aortic stenosis" between January 2020 and January 2023 were selected as the study subjects. The study subjects were divided into A group (N = 89) and B group (N = 313) based on whether high degree atrioventricular block occurred after surgery. The age, biochemistry and other general data of patients were systematically collected through inpatient cases, and the preoperative Right bundle branch block, I degree atrioventricular block, QRS duration, and indoor block were collected through our hospital's electrocardiogram (ECG) system, Calcification integral of Aortic valve was calculated by computed tomography (CT) results. Logistic regression analysis was performed on the clinical data, and the predictive value of related factors was further analyzed through the Receiver operating characteristic. RESULTS: The preoperative QRS wave duration in the A group (165.06 ± 61.25) was significantly higher than that in the B group (108.30 ± 16.30), and the difference was statistically significant (p < 0.05). Compared with the B group, the incidence of Right bundle branch block in the A group was significantly higher before operation. The calcification score of Aortic valve in the A group (97.58 ± 61.25) was significantly higher than that in the B group (43.59 ± 7.56), with a statistically significant difference (p < 0.05). Further multivariate logistic regression analysis showed that the duration of QRS wave before operation and Aortic valve calcification score were independent risk factors for high atrioventricular block after TAVI (p < 0.05). Through Receiver operating characteristic analysis, it was found that preoperative QRS wave duration and Aortic valve calcification score had a high predictive value for the occurrence of high atrioventricular block after TAVI. The optimal cutoff value of QRS wave duration for predicting high atrioventricular block was 152, area under curve (AUC): 0.780 (95% CI: 0.718-0.841, p < 0.001). The optimal cutoff value for predicting high degree atrioventricular block with aortic calcification score is 61.5, AUC: 0.997 (95% CI: 0.992-1.000, p < 0.001). CONCLUSIONS: Preoperative QRS wave duration and Aortic valve calcification score are independent risk factors for high degree atrioventricular block after TAVI, and they have high predictive value. In clinical work, risk factors should be found early and responded in time.

Cost-effectiveness analysis of an orphan drug tebentafusp in patients with metastatic uveal melanoma and a call for value-based pricing.

The normative regimens recommendations for treating metastatic uveal melanoma (mUM) are absent in the US. Recently, a phase III randomized clinical trial revealed that tebentafusp yielded a conspicuously longer overall survival than the control group. Based on the prominent efficacy, this study aimed to assess whether tebentafusp is cost-effective compared to the control group in patients with untreated mUM. A three-state partitioned survival model was developed to assess the costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) from the perspective of US payers. Scenario analyses and sensitivity analyses were conducted to explore the conclusion uncertainty. Compared with control group, tebentafusp therapy yielded an additional 0.47 QALYs (1.19 vs. 0.72 QALYs) and an incremental cost of $444 280 ($633 822 vs. $189 542). The resultant ICER of $953 230/QALY far outweighed the willingness-to-pay threshold of $200 000/QALY. The ICER was always more than $750 000/QALY in all the univariable and probabilistic sensitivity analyses. Scenario analyses indicated that reducing the unit price of tebentafusp to $33.768/µg was associated with a favorable result of tebentafusp being cost-effective. For treatment-naive patients with mUM, the cost of tebentafusp therapy was not worth the improvement in survival benefits at the current price compared to the investigator's choice of therapy. The cost-effectiveness of tebentafusp could be promoted using value-based pricing.

Potential Role and Expression Level of Urinary CXCL8 in Different Stages of Incipient Diabetic Nephropathy with Undiminished Creatinine Clearance: A Pilot Study.

Background: Diabetic nephropathy (DN) is one of the most devastating microvascular complications of diabetes, with a high prevalence and poor prognosis. Early intervention is crucial to improve the outcomes of DN. CXCL8 is related to podocyte damage in incipient DN; however, the role and expression level of CXCL8 have never been elucidated, especially in those with undiminished creatinine clearance. Methods: Consecutive inpatients with type 2 diabetes were included in this study. Patients were assigned into four groups based on the Mogensen stage, reflecting pathological features through clinical manifestations: non-DN group, hyperfiltration group, microalbuminuria group and overt DN group. Clinical and laboratory data were retrospectively collected and analyzed. Urinary CXCL8 (uCXCL8) was measured using an enzyme-linked immunosorbent assay (ELISA) method and adjusted for urinary creatinine (Cr) from the same urine sample. Results: In total, 88 eligible consecutive inpatients with type 2 diabetes were included in this study. uCXCL8 was differentially expressed in different stages of incipient DN; it decreased in the hyperfiltration phase of incipient DN (1.40±1.01 pg/µmol Cr) and was highly expressed in patients in the microalbuminuria stage (5.01±4.01 pg/µmol Cr). uCXCL8 was positively correlated with age, diabetes course, cystatin C and urinary albuminuria-to-creatinine ratio, but negatively correlated with estimated glomerular filtration rate (P<0.05). uCXCL8 was a risk factor for classic DN after adjusting for age, diabetes course and cystatin C (OR=1.17, 95% CI 0.98-1.4, P=0.045). Conclusion: CXCL8 played an important role in the progression of incipient DN. The unique expression profile of uCXCL8 may provide a reference for understanding the prognosis and mechanisms of incipient DN progression. uCXCL8 was an independent risk factor for the development of classic DN.

MicroRNA expression profiles in familial hypertrophic cardiomyopathy with myosin-binding protein C3 (MYBPC3) gene mutations.

Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant inherited disease caused by mutations in genes encoding cardiac sarcomere proteins. MicroRNAs (miRNAs) play an important role in the pathogenesis of FHCM. In the present study, we aimed to determine the miRNA profile in FHCM patients with myosin-binding protein C3 (MYBPC3) gene mutations. We recruited three FHCM patients and age- and sex-matched controls. The three probands all had hypertrophic obstructive cardiomyopathy with severe myocardial hypertrophy, and two of the three had a history of sudden cardiac death, representing a "malignant" phenotype. We then compared the miRNA expression profiles of three FHCM patients carrying MYBPC3 gene mutations with those of the normal control group using miRNA sequencing technology. Differentially expressed miRNAs were verified using real-time polymerase chain reaction (qPCR). Target genes and signaling pathways of the identified differentially expressed miRNAs were predicted using bioinformatics analysis. A total of 33 significantly differentially expressed miRNAs were detected in the peripheral blood of the three probands, of which 28 were upregulated, including miR-208b-3p, and 5 were downregulated. Real-time PCR confirmed the upregulated expression of miR-208b-3p in FHCM patients (P < 0.05). Bioinformatics analysis showed that miR-208b-3p was mainly enriched in 79 target genes including UBE2V2, MED13, YBX1, CNKSR2, GATA4, andSOX5/6, et al. Gene ontology (GO) analysis of target genes showed that miR-208b was mainly involved in the processes of negative regulation of transcription from RNA polymerase II promoter, and regulation of transcription, DNA templated. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the target genes regulated by miR-208b-3p were mainly involved in the Wnt signaling pathway. These findings suggest that FHCM patients with MYBPC3 gene mutations have a specific miRNA expression profile, and that miR-208b-3p is significantly upregulated in cardiac hypertrophy. Our results also indicate that miRNA-208b-3p activates the Wnt signaling pathway through its target gene to promote cardiac hypertrophy.

DNMT3A inhibits E2F1-induced arterial marker expression and impairs angiogenesis in human umbilical artery endothelial cells.

Arterial marker genes EphrinB2 and HEY2 are essential for cardiovascular development and postnatal neovascularization. Our previous study confirmed that E2F1 could activate the transcription of EphrinB2 and HEY2 in human mesenchymal stem cells; however, the detailed mechanism has not been resolved yet. In this study, we focused on the interaction between E2F1 and DNMT3A, a de novo DNA methyltransferase, on regulating the expression of EphrinB2 and HEY2, and explored the potential mechanisms. Gain- and loss-of-function experiments implicated the positive effect of E2F1 on the expression of EphrinB2 and HEY2 and tube formation in human umbilical artery endothelial cells. Accumulation of DNMT3A decreased the levels of EphrinB2 and HEY2, and impaired tube formation induced by E2F1, while inhibiting DNMT3A by RNA interference augmented their expression and angiogenesis in E2F1-trasfected cells. We then asked whether the low expressions of EphrinB2 and HEY2 induced by DNMT3A are related to the methylation status of their promoters. Surprisingly, the methylation status of the CpG islands in the promoter region was not significantly affected by overexpression of exogenous DNMT3A. Furthermore, the interaction between E2F1 and DNMT3A was confirmed by co-immunoprecipitation. DNMT3A could inhibit the transcription of EphrinB2 and HEY2 promoters by affecting the binding of E2F1 to its recognition sequences as revealed by luciferase reporter assay and chromatin immunoprecipitation. These results identified a novel mechanism underlying the cooperation of DNMT3A with E2F1 on regulating target gene expression, and revealed their roles in the angiogenic process.

The Effect of TNF Inhibitors on Cardiovascular Events in Psoriasis and Psoriatic Arthritis: an Updated Meta-Analysis.

TNF inhibitors have been used in psoriasis (Pso) and psoriatic arthritis (PsA), which were associated with increased risk of cardiac and cerebrovascular events. However, whether TNF inhibitors reduce cardiovascular event is still unclear. Therefore, we aimed to evaluate the effect of TNF inhibitors on adverse cardiovascular events (CVEs) in Pso with or without PsA. We undertook a meta-analysis of clinical trials identified in systematic searches of MEDLINE, EMBASE, Wanfang database, Cochrane Database, and Google scholar through December 31, 2015. Five studies (49,795 patients) were included. Overall, compared with topical/photo treatment, TNF inhibitors were associated with a significant lower risk of CVE (RR, 0.58; 95 % CI, 0.43 to 0.77; P < 0.001; I (2) = 66.2 %). Additionally, compared with methotrexate (MTX) treatment, risk of CVE was also markedly decreased in the TNF inhibitor group (RR, 0.67; 95 % CI, 0.52 to 0.88; P = 0.003; I (2) = 9.3 %). Meanwhile, TNF inhibitors were linked to reduced incidence of myocardial infarction compared with topical/photo or MTX treatment (RR, 0.73; 95 % CI, 0.59 to 0.90; P = 0.003; I (2) = 56.2 % and RR, 0.65; 95 % CI, 0.48 to 0.89; P = 0.007; I (2) = 0.0 %, respectively). Furthermore, there was a trend of decreased rate of mortality in the TNF inhibitor group compared with other therapy (RR, 0.90; 95 % CI, 0.54 to 1.50; P = 0.68; I (2) = 70.9 %). TNF inhibitors appear to have net clinical benefits with regard to adverse cardiovascular events in Pso and/or PsA. Rigorous randomized controlled trials will need to evaluate whether TNF inhibitors truly result in reduction of cardiovascular diseases.

Homocysteine induces cytotoxicity and proliferation inhibition in neural stem cells via DNA methylation in vitro.

Mild to moderate hyperhomocysteinemia has been implicated in neurodevelopmental disorders and neurodegenerative diseases in human studies. Although the molecular mechanisms underlying the effects of homocysteine (Hcy) neurotoxicity on the nervous system are not yet fully understood, inhibition of neural stem cell (NSC) proliferation and alterations in DNA methylation may be involved. The aim of the present study was to characterize the effects of Hcy on DNA methylation in NSCs, and to explore how Hcy-induced changes in DNA methylation patterns affect NSC proliferation. We found that D,L-Hcy (30-1000 µm) but not L-cysteine inhibited cell proliferation and reduced levels of global DNA methylation in NSCs from neonatal rat hippocampus and increased cell injury. High levels of Hcy also induced an increase in S-adenosylhomocysteine (SAH), a decrease in the ratio of S-adenosylmethionine (SAM) to SAH, and a reduction in protein expression of the DNA methyltransferases DNMT1, DNMT3a and DNMT3b and their enzymatic activity. Moreover, the DNMT inhibitor zebularine reduced the global DNA methylation level and inhibited NSC proliferation. Our results suggest that alterations in DNA methylation may be an important mechanism by which high levels of Hcy inhibit NSC viability in vitro. Hcy-induced DNA hypomethylation may be caused by a reduction in the DNMT activity which is regulated by the cellular concentrations of SAM and SAH, or their protein expression levels. Our results also suggest that Hcy may play a role in the pathogenesis of certain nervous system diseases via a molecular mechanism that involves negative regulation of NSC proliferation and alterations in DNA methylation.