Search Results (1,693)

Background: Inflammation plays a critical role in myocardial infarction as a critical process in the development of heart failure, involving the development of cardiac fibrosis. Colchicine is a well-established anti-inflammatory drug, but its scientific application in controlling post-acute myocardial infarction (AMI) inflammatory processes has not been established. IL-10 is a key cytokine in modulating inflammatory responses, underscoring its potential as a crucial therapeutic target of colchicine. The objective was to explore the protective role of IL-10 modulated by colchicine in myocardial healing and repair following AMI, particularly cardiac fibrosis. Methods: The predicted protein of colchicine was assessed using WAY2DRUG PASS as probability active value. Proteins associated with colchicine, cardiac fibrosis, and acute myocardial infarction were analyzed with DisGeNET and Open Target databases. Analysis and visualization of protein–protein interactions were conducted using STRING and Cytoscape. A 3T3 cell line treated with CoCl₂ was used to mimic hypoxic. HIF-1α and IL-10 expression were measured by flow cytometry and analyzed using a one-way ANOVA test. This observational clinical trial examined acute myocardial infarction patients undergoing immediate and delayed primary percutaneous coronary interventions. Subjects were randomized into control groups receiving placebo and intervention groups treated with colchicine. Assessments occurred at 24 h and five days after the intervention. IL-10 expression in the clinical trial was measured by ELISA and analyzed using a T-test. Results: Colchicine demonstrates promising bioactivity in treating acute myocardial infarction, with notably activity values highlighting its probable role as a tubulin antagonist (0.744), beta-tubulin antagonist (0.673), and NOS2 inhibitor (0.529). Its primary action targets IL-10, with the protein–protein interactions analysis indicating interactions between IL-10 and key inflammatory mediators—IL-1β, IFN-γ, CCL2, TNF, and TGF-β1—during acute myocardial infarction and cardiac fibrosis. Hypoxic conditions in the CoCl₂-induced 3T3 cell model show significantly elevated HIF-1α compared to controls (p < 0.0001). Colchicine use significantly increased IL-10 expression in CoCl₂-treated cells (p < 0.0001) and in AMI patients within five days (p < 0.05). Conclusions: Colchicine may bolster the anti-inflammatory response post-myocardial infarction by activating IL-10 pathways in fibroblasts and in clinical settings, potentially reducing inflammation after AMI. Further investigation into broader aspects of this pathway, particularly in cardiac fibroblasts, is required. Full article

The tailings from gold beneficiation can cause various negative impacts, necessitating measures to prevent their transport and environmental contamination. Geomembranes serve as hydraulic barriers in mining tailings reservoirs, thereby supporting the Sustainable Development Goals (SDGs). To ensure that the geomembrane effectively mitigates environmental impact, it is essential to study its durability when applied in the field. This article examines the long-term performance of an HDPE geomembrane exposed for 7 and 11 years at a gold mining tailing site in Brazil. Samples were exhumed from different locations at the dam, and their properties were evaluated. Non-parametric statistics were employed using the Kernel Density Estimator (KDE). For the 11-year-old geomembranes, the probability of the geomembrane reaching nominal failure in terms of tensile strength was 0.4%. The peel separation values exceeded the maximum allowable by the GRI GM13 standard. Although the geomembranes showed significant antioxidant depletion, suggesting they were close to or had already reached their residual stages, they approached nominal failure based on their stress crack resistance but did not rupture. The environmental analysis indicated no significant contamination in the area, corroborating that the geomembrane is fulfilling its function. The non-parametric methodology proved promising for durability analysis and could be applied to other engineering projects with geosynthetics, thereby adding reliability to decision-making in alignment with sustainable development. Full article

Background: Real-world data on the use of lipid-lowering therapy (LLT) in clinical practice show that about 80% of (very) high-cardiovascular (CV)-risk patients disregard the 2019 European Society of Cardiology (ESC) Guidelines’ recommendations on dyslipidemias. The availability of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9mAb) should reduce this gap. Our aim was to provide data on PCSK9mAb use in clinical practice, investigating the achievement of the ESC Guidelines’ recommendations in the real world. Methods: Between April 2018 and December 2022, patients who started on PCSK9mAb therapy (140 mg of evolocumab or 75 mg or 150 mg of alirocumab, subcutaneous injection every 2 weeks) were included in a prospective registry. Our cohort consisted of 256 patients: 95 (37.1%) were women (mean age: 65.43 ± 11.12 yrs), 53 (20.7%) were at high CV risk, and 203 (79.3%) were at very high CV risk. Results: After one year of PCSK9mAb treatment, nearly 60% of patients demonstrated full adherence to the ESC Guidelines’ recommendations, defined as achieving at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C) levels along with reaching LDL-C target levels (≤55 and ≤70 mg/dL for very high and high risk, respectively). Concomitant high-dose statin therapy emerged as the primary predictor of LDL-C target attainment. Heterozygous familial hypercholesterolemia (HeFH), statin intolerance, and female gender were associated with a significant lower probability of achieving LDL-C target levels. Conclusions: Our analysis confirms that PCSK9mAb treatment is safe and effective, enabling 60% of our cohort to fully achieve the LDL-C guideline recommendations. The use of high-intensity statins emerged as a significant predictor of efficacy. Conversely, familial hypercholesterolemia and female gender were identified as predictors of therapeutic failure. Hence, it is crucial to address disparities in cardiovascular disease prevention between genders and to enhance strategies for managing elevated LDL-C in HeFH patients. Full article

Background: Destructive aortic prosthetic valve endocarditis portends a high morbidity and mortality, and requires complex high-risk surgery. Homograft root replacement is the most radical and biocompatible operation and, thus, the preferred option. Methods: A retrospective analysis was conducted on 61 consecutive patients who underwent a cardiac reoperation comprising homograft aortic root replacement since 2010. The probabilities of survival were calculated with the Kaplan–Meier method, whereas multivariable regression served to outline the predictors of adverse events. The endpoints were operative/late death, perioperative low cardiac output and renal failure, and reoperations. Results: The operative (cumulative hospital and 30-day) mortality was 13%. The baseline aspartate transaminase (AST) and associated mitral procedures were predictive of operative death (p = 0.048, OR [95% CIs] = 1.03 [1–1.06]) and perioperative low cardiac output, respectively (p = 0.04, OR [95% CIs] = 21.3 [2.7–168.9] for valve replacement). The latter occurred in 12 (20%) patients, despite a normal ejection fraction. Survival estimates (±SE) at 3 months, 6 months, 1 year, and 3 years after surgery were 86.3 ± 4.7%, 82.0 ± 4.9%, 75.2 ± 5.6, and 70.0 ± 6.3%, respectively. Survival was significantly lower in the case of AST ≥ 40 IU/L (p = 0.04) and aortic cross-clamp time ≥ 180 min (p = 0.01), but not when excluding operative survivors. Five patients required early (two out of the five, within 3 months) or late (three out of the five) reoperation. Conclusions: Homograft aortic root replacement for destructive prosthetic valve endocarditis can currently be performed with a near 90% operative survival and reasonable 3-year mortality and reoperation rate. AST might serve to additionally stratify the operative risk. Full article

Large-tow carbon fiber-reinforced polymer composites (CFRP) have great application potential in civil engineering due to their low price, but their basic mechanical properties are still unclear. The tensile properties of large-tow CFRP rods and plates were investigated in this study. First, the tensile properties of unidirectional CFRP rods and plates were studied, and the test results of the relevant mechanical properties were statistically analyzed. The tensile strength of the CFRP rod and plate are 2005.97 MPa and 2069.48 MPa. Second, the surface of the test specimens after failure was observed using a scanning electron microscope to analyze the type of failure and damage evolution process. Finally, the probabilistic characteristics of the mechanical properties were analyzed using normal, lognormal, and Weibull distributions for parameter fitting. Quasi-optimality tests were performed, and a probability distribution model was proposed for the mechanical properties of large-tow CFRP rods and plates. Full article

The avionics network supports high-safety-level flight operations, with the analysis of transmission failures serving as a crucial means for its safety evaluation. Due to the time-dependent nature of the failure probability in avionics networks, traditional constant and unchangeable probability values can deviate from the actual situation under specific conditions. This deviation may lead to inadequate responses to occasional events and potentially cause flight accidents. A Dynamic Fault Tree (DFT) model for civil aircraft avionics network transmission failures, based on an optimized extended fuzzy algorithm, is introduced in this paper. Initially focusing on event correlations, a DFT is established for the transmission failure of the Avionics Full Duplex Switched Ethernet (AFDX). Subsequently, considering the variations between events, triangular fuzzy processing is applied to the event failure rates based on relative confidence levels. Finally, by optimizing the weakest t-norm operator, the failure probability intervals are aggregated and the fuzzy scale is regulated. Experimental results demonstrate that, compared to the static-minimum t-norm and traditional weakest t-norm methods, the proposed approach enhances the accuracy of the fuzzy failure probability intervals by 66.15% and 40.59%, respectively. Concurrently, it maintains consistency in the ranking of event importance, highlighting the superior effectiveness of the proposed method in analyzing transmission failures in avionics networks. Full article

Background: The purpose of this paper is to address how to handle uncertainty when performing an economic valuation of a medical innovation R&D project in orphan diseases from the perspective of the investor. Methods: We describe the specific uncertainty related to cash flows and the cost of capital for innovation in orphan diseases. The uncertainty in cash flows relates to sales, manufacturing and R&D costs, and probabilities of failure for each phase in the clinical trial program. We consider different net present values (NPVs) and higher standard deviations for orphan drugs compared to non-orphan drugs. Results: Numerical case base examples showed the differences in trade-off by an investor for R&D projects with differences in NPV and level of uncertainty. The investor will transfer the additional uncertainty in cash flows in a higher cost of capital. An alternative approach is the application of an “acceptability curve” based on a probabilistic sensitivity analysis, which displays the cumulative probabilities at a range of different values for the NPV. Finally, we consider uncertainty in the cost of capital itself by applying the Capital Asset Pricing Model (CAPM). Conclusions: In this paper, we described various types of uncertainty and explored various approaches to how to handle uncertainty in the economic valuation of medical innovation in orphan diseases. The bridging of health economics with economic valuation theory in the healthcare market is to our knowledge a novel approach for the valuation of medical innovation by investors. Full article

Aviation networks exhibit multi-layer characteristics and heterogeneity of nodes and edges. Identifying key nodes in a multi-layer heterogeneous aviation network (MHAN) and elucidating its cascading failure process are of great practical significance for enhancing the ability to resist failure and strengthening network resilience. Therefore, this paper first establishes the basic model of MHAN and then designs an intra-layer node importance evaluation method based on the improved TOPSIS-grey correlation analysis (ITG) method and an inter-layer influence weight quantification method based on the gravity model. By integrating the information transmission characteristics between network nodes, a key node identification method in MHAN through aggregating multi-source information is proposed. Finally, based on the actual overload operation of aviation networks, the initial load adjustment coefficient, capacity limit, and overload coefficient are introduced based on the traditional capacity–load model, a cascading failure model of MHAN considering overload condition and failure probability is constructed, and a node influence index based on this model is defined to verify the accuracy of the key node identification results. The instance analysis conducted on the aviation network in western China demonstrates that the intra-layer node importance evaluation method based on ITG yields results with better distinguishability and higher accuracy. The key nodes are predominantly hub en-route nodes and sector nodes. In the cascading failure model, increasing the overload coefficient and capacity limit within a specific range while reducing the initial load adjustment coefficient helps reduce the network failure scale. The key nodes identified by the node influence index are consistent with those identified by the method proposed in this paper, validating the accuracy and effectiveness of the key node identification method in MHAN through aggregating multi-source information herein. Full article

During devastating earthquakes, soil liquefaction has disastrous outcomes on bridge foundations, as mentioned in books and published research. To avoid foundation failure when the surrounding soil is fully liquefied, a bridge’s pile foundation design could be such that the bridge pier is directly resting on the top of a large-diameter monopile instead of the traditional multiple small-diameter piles. This paper discusses the gap of insufficient studies on large-diameter monopiles to support railway bridges subjected to buckling instability and the lack of simplified tools to quickly assess structural reliability. A framework could quickly assess the structural reliability by formulating a simplified reliability analysis. This study focused on pure buckling with shear deformation and reliability assessment to calculate a monopile’s failure probability in fully liquefied soils. In reliability assessment, with the critical pile length (L_crit) and the unsupported pile length (L_uns), the limit state function g(x) = [L_crit − L_uns] thus forms the basis for assessing the safety and reliability of a structure, indicating the state of success or failure. The L_crit formulation is accomplished with a differential equation. Here, L_uns assumes various depths of liquefied soil. The reliability index’s (β) formulation is achieved through the Hasofer–Lind concept and then double-checked through a normal or Gaussian distribution. A case study was conducted using a high-speed railway bridge model from a published research to demonstrate the application of the proposed methodology. To validate the minimum pile diameter for buckling instability when a fully liquefied soil’s thickness reaches the condition that L_crit = L_uns, this study applies the published research of Bhattacharya and Tokimatsu. The validation results show good agreement for 0.85–0.90 m monopile diameters. With a monopile diameter smaller than 0.85 m, the L_crit = L_uns limit was at lesser depths, while with a monopile diameter larger than 0.90 m, the L_crit = L_uns limit was at deeper depths. A load increase notably affected the large-diameter monopiles because the L_crit movement required a longer range. In fully liquefied soil, buckling will likely happen in piles with a diameter between 0.50 m and 1.60 m because the calculated probability of failure (Pf) value is nearly one. Conversely, buckling instability will likely not happen in monopiles with a diameter of 1.80–2.20 m because the Pf value is zero. Hence, the outcome of this case study suggests that the reliable monopile minimum diameter is 1.80 m for supporting a high-speed railway bridge. Lastly, this paper analyzed the shear deformation effect on large-diameter monopiles, the result of which was 0.30% of L_crit. Shear deformation makes minimal contributions to large-diameter monopile buckling. Full article

In order to obtain stable and reliable configuration transformation ability, reliability optimization design is regarded as an effective way to reduce the probability of kinematic function failure for the constrained metamorphic mechanism. Based on the structural composition principle of multi-configuration source metamorphic mechanism that can operate in an under-actuated state, the modularized calculation methods are established for the force analysis of augmented Assur groups including metamorphic kinematic joints. According to the equivalent resistance gradient model of metamorphic mechanisms, with considering the uncertainties in the link dimensions, masses, and compliance parameters et al., a probabilistic evaluation method for describing the configuration transformation ability of the constrained metamorphic mechanism is established. Based on reliability evaluation and reliability sensitivity analysis, a reliability optimization design method for improving the configuration transformation ability is proposed, and then the optimization design is carried out for tolerances of random variables focusing on those structural parameters with higher reliability sensitivity, so that the optimized results can satisfy the requirements of both reliability and economic simultaneously. Finally, the feasibility and effectiveness of the proposed method is verified by the illustration of a paper folding metamorphic mechanism. The research provides the foundation of reliability design of metamorphic mechanisms to obtain the high-probability repeated execution ability of configuration transformation, it also has theoretical and practical significance to promote the engineering application of metamorphic mechanisms. Full article

In this paper, we generalize two new statistical distributions, to improve the ability to model failure rates with non-monotonic, monotonic, and mainly bathtub curve behaviors. We call these distributions Generalized Powered Uniform Distribution and MOE-Powered Uniform. The proposed distributions’ approach is based on incorporating a parameter k in the power of the values of the random variables, which is associated with the Probability Density Function and includes an operator called the Powered Mean. Various statistical and mathematical features focused on reliability analysis are presented and discussed, to make the models attractive to reliability engineering or medicine specialists. We employed the Maximum Likelihood Estimator method to estimate the model parameters and we analyzed its performance through a Monte Carlo simulation study. To demonstrate the flexibility of the proposed approach, a comparative analysis was carried out on four case studies with the proposed MOE-Powered Uniform distribution, which can model failure times as a bathtub curve. The results showed that this new model is more flexible and useful for performing reliability analysis. Full article

A comparative analysis between Bidirectional Evolutionary Structural Optimization (BESO) and Smoothing-ESO (SESO), simultaneously considering Reliability-Based Topology Optimization (RBTO) and the structure’s self-weight in the case of three-dimensional elasticity, is presented in this study. Due to the important role of the existence of uncertainties in making the structural design more realistic, geometry, volumetric fraction, modulus of elasticity, compliance, and loading are considered random variables with normal probability distribution. When adopting the First Order Reliability Method (FORM), the failure probability is calculated based on the reliability index. Furthermore, considering the influence of self-weight in problems involving large structures in civil engineering, especially in the case of bridges, this makes the optimal configuration more reliable for design. A series of examples are covered to validate the methods presented, showing their efficiency and robustness. Full article

Considering the worldwide impact of heart failure, it is crucial to develop approaches that can help us comprehend its root cause and make accurate predictions about its outcome. This is essential for lowering the suffering and death rates connected with this widespread illness. Cardiomyopathies frequently result from genetic factors, and the study of heart failure genetics is advancing quickly. Dilated cardiomyopathy (DCM) is the most prevalent kind of cardiomyopathy, encompassing both genetic and nongenetic abnormalities. It is distinguished by the enlargement of the left ventricle or both ventricles, accompanied by reduced contractility. The discovery of the molecular origins and subsequent awareness of the molecular mechanism is broadening our knowledge of DCM development. Additionally, it emphasizes the complicated nature of DCM and the necessity to formulate several different strategies to address the diverse underlying factors contributing to this disease. Genetic variants that can be transmitted from one generation to another can be a significant contributor to causing family or sporadic hereditary DCM. Genetic variants also play a significant role in determining susceptibility for acquired triggers for DCM. The genetic causes of DCM can have a large range of phenotypic expressions. It is crucial to select patients who are most probable to gain advantages from genetic testing. The purpose of this research is to emphasize the significance of identifying genetic DCM, the relationships between genotype and phenotype, risk assessment, and personalized therapy for both those affected and their relatives. This approach is expected to gain importance once treatment is guided by genotype-specific advice and disease-modifying medications. Full article

Background: Impaired gastric motility in the form of constipation may often occur in elderly patients with chronic heart failure. Candidates for trans-catheter aortic replacement (TAVR) are of old age and have multiple comorbidities, probably including constipation. However, the clinical implication of a history of constipation in patients receiving TAVR remains unknown. Methods: Patients who underwent TAVR at our large academic center between 2015 and 2022 were eligible. The prognostic impact of the prescribed laxative type and number, which was assumed as the severity of constipation, on the incidence of death or heart failure readmission two years after index discharge was investigated. Results: A total of 344 patients were included. Median age was 85 years, and 99 patients were men. Patients with any laxatives (N = 166) had higher systolic blood pressure, higher plasma B-type natriuretic peptide levels, and a lower prescription rate of renin–angiotensin system inhibitors at the time of index discharge after TAVR (p < 0.05 for all). The number of laxative types was independently associated with the composite primary outcome with an adjusted hazard ratio of 1.83 (95% confidence interval 1.27–2.63, p = 0.001) with a cutoff of one type of laxative used, which significantly stratified the 2-year cumulative incidence of the primary outcome (18% versus 7%, p = 0.001). Conclusions: The presence of constipation was associated with worse clinical outcomes following TAVR. The prognostic impact of an aggressive intervention for constipation remains a future concern in this cohort. Full article

This paper investigates the possible failure modes of the product development process in production companies that are active in the B2C markets with a focus on household products. Since these cases require short lead times and are difficult to differentiate, in many instances the result will not be the desired one and could affect profitability for a season or for good. A model of these possibilities is created and an approach to plan contingencies for their solutions is proposed in the article. The main guideline is to switch from failure probability determination to accepting failure as inevitable and using digital solutions to reinforce the development process to offset its impact. For this goal, an Industry 5.0 Abatement Factor (abbreviated IFAF) is introduced in the contingency planning approach, which factors in the evaluation of the low cost of digital instruments and the proper mix of Technology, Humans, and AI (abbreviated THAI). The new working procedure based on these concepts and their interlinkages is discussed based on specific examples. Full article