PubMed · 16301892
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Andrew Francis. 2005. ECT and aortic aneurysm.. https://doi.org/10.1097/01.yct.0000191359.07122.59
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Thoracic aortic aneurysm (TAA) is a life-threatening condition characterized by pathological dilation of the aorta. While inflammatory responses have been implicated in TAA pathogenesis, the causal relationships remain elusive. This study aimed to elucidate potential causal associations between inflammatory cytokines, plasma metabolites, and TAA risk using Mendelian randomization (MR) analysis. We conducted bidirectional two-sample MR analysis utilizing genome-wide association study data from 91 inflammatory cytokines (n = 14,824), 1400 plasma metabolites (n = 8299), and TAA (n = 385,857). The inverse-variance weighted method served as the primary analytical approach, with comprehensive sensitivity analyses performed to assess pleiotropy and heterogeneity. Two-step MR analysis was employed to explore potential mediating roles of plasma metabolites. Single-cell sequencing analysis was utilized to detect cell type enrichment and elucidate cellular functions of identified cytokines. Additionally, we conducted an analysis to identify druggable proteins as potential therapeutic targets for TAA. MR analysis revealed that genetically-determined increases in C-X-C motif chemokine 10 (CXCL10) (odds ratios [OR] = 1.149, 95% confidence interval [CI]: 1.009-1.309, P = .037) and fibroblast growth factor 5 (OR = 1.101, 95% CI: 1.013-1.196, P = .024) were associated with elevated TAA risk. Conversely, C-C motif chemokine 20 (CCL20) (OR = 0.870, 95% CI: 0.759-0.996, P = .043) and CD40L receptor (CD40) (OR = 0.906, 95% CI: 0.827-0.992, P = .033) demonstrated inverse associations with TAA risk. Two-step MR analysis identified potential mediating metabolites: the phosphate to linoleoyl-arachidonoyl-glycerol ratio for CXCL10, thyroxine and X-24585 for FGF-5, and the creatine to carnitine ratio for CCL20. Single-cell sequencing analysis revealed enrichment of these cytokines in specific cell types and pathways relevant to TAA pathogenesis. Drug-gene interaction analysis identified CXCL10, CCL20, and CD40 as potential targets for treatment of TAA. This study provides robust genetic evidence supporting causal relationships between specific inflammatory cytokines and TAA risk, with plasma metabolites potentially mediating these effects. CXCL10 and FGF-5 were identified as potential risk factors, while CCL20 and CD40 may confer protective effects. These findings offer novel insights into TAA pathogenesis and suggest potential targets for intervention. Further research is warranted to elucidate the underlying mechanisms and validate these results across diverse populations.
There are several methods available for analysing multireader ROC studies that generalize results to both the reader and case populations. Two of these methods--the Dorfman-Berbaum-Metz (DBM) method and the Obuchowki-Rockette (OR) method--appear to be quite different in their original formulations. However, recently it has been shown that the DBM and OR procedures yield the same test statistic when based on the same accuracy measure and covariance estimation method, but inferences can vary depending on which denominator degrees of freedom (ddf) method, DBM or OR, is used. I show in simulations that there are problems with both ddf methods: OR is ultraconservative with significance levels considerably below the nominal level, and DBM can result in extremely wide confidence intervals because the ddf can be close to zero. I propose a new ddf method that overcomes both of these problems and can be used with either the OR or DBM procedure.
BACKGROUND: The thoracic aortic aneurysm (TAA) is a pathology that involves an expansion of the aortic diameter in the thoracic aorta, leading to risk of rupture. Recent studies have suggested that internal wall stress, which is affected by TAA geometry and the presence or absence of thrombus, is a more reliable predictor of rupture than the maximum diameter, the current clinical criterion. Accurate reconstruction of TAA geometry is a crucial step in patient-specific stress calculations. METHODS: In this work, a novel methodology was developed, which combines data from several sets of magnetic resonance (MR) images with different levels of detail and different resolutions. Two sets of images were employed to create the final model, which has the highest level of detail for each component of the aneurysm (lumen, thrombus, and wall). A reference model was built by using a single set of images for comparison. This approach was applied to two patient-specific TAAs in the descending thoracic aorta. RESULTS: The results of finite element simulations showed differences in stress pattern between the coarse and fine models: higher stress values were found with the coarse model and the differences in predicted maximum wall stress were 30% for patient A and 11% for patient B. CONCLUSION: This paper presents a new approach to the reconstruction of an aneurysm model based on the use of several sets of MR images. This enables more accurate representation of not only the lumen but also the wall surface of a TAA taking account of intraluminal thrombus.