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As a physiological function of body, immunity can maintain health by identifying itself and excluding others. With economic development and increasingly fierce social competition, the number of sub-healthy population is gradually increasing, and the most basic problem exposed is human hypoimmunity. Hypoimmunity can be manifested as often feeling tired, catching colds, mental depression, etc. In order to enhance immunity, eating healthy foods with the effect of enhancing immunity may become an effective choice. KRG has pharmacological effects of enhancing immunity. Because the screening and evaluation method of immune population are not unified, there are relatively few KRG immunity tests for sub-health population. It is of great significance to study the effect of KRG on people with hypoimmunity to improve sub-health status.

The impact of atrial fibrillation (AF) among patients with amyloidosis on in‐hospital outcomes is not well‐established. We aimed to examine in‐hospital outcomes among patients admitted with a primary diagnosis of AF with and without amyloidosis. We queried the Nationwide Readmissions Database to compare the in‐hospital outcomes among AF patients with and without amyloidosis. Our study demonstrated that in‐hospital all‐cause mortality, adverse events, and 30‐day readmission were comparable between the two groups. Patients with AF and concurrent amyloidosis did not have worse in‐hospital outcomes than those with AF alone. While there was an increasing trend of admission for atrial fibrillation with amyloidosis, patients with atrial fibrillation and concurrent amyloidosis did not have worse in‐hospital outcomes and adverse events than those with atrial fibrillation alone.

Non-toxic, low-cost, and bandgap-direct material Copper Zinc Tin Sulphide (CZTS) is a promising candidate thin film solar cell. As the effort to improve the efficiency of the CZTS solar cell, this work chooses an environmentally friendly tungsten oxide (WO3) as the buffer layer due to its high bandgap and excellent electrical conductivity. Furthermore, Cu2ZnSnSe4(CZTSe) is employed as the back surface field (BSF) layer which is sandwiched between the absorber layer and the back contact layer. A new structure Pt/CZTSe/CZTS/WO3/ZnO is proposed and a comparative study is done between structures with and without BSF layer. The research investigates how the layer thickness, operating temperature, different back contact layer, acceptors, and defects in BSF layer affect the performance of CZTS solar cell using the solar cell capacitance simulator (SCAP-1D) simulation software. Efficiency of CZTS solar cell with WO3is greatly improved with efficiency as high as 29.37 % for the proposed new structure.

Objective: This study utilized the stimulated thyroglobulin (sTg) to thyroid stimulating hormone (TSH) ratio to predict the long-term efficacy of 131I therapy in patients with moderate-to-high-risk differentiated thyroid cancer (DTC). Methods: This study retrospectively analyzed 960 DTC patients with a median follow-up time of 30 months (6–92 months). The median age was 44 years. All patients underwent total thyroidectomy, lymph node dissection, and at least one 131I therapy. Patients were subjected to a final efficacy evaluation according to American Thyroid Association’s 2015 guidelines. Patients were grouped according to their TSH levels before the initial 131I therapy and the final efficacy evaluation, and factors influencing TSH levels and final efficacy were analyzed. Construction of nomograms using independent risk factors affecting long-term outcomes. The cut-offs of sTg and sTg/TSH ratios were calculated for different long-term outcomes. Progression-free survival (PFS) of patients was analyzed by making Kaplan-Meier survival according to the cut-offs of sTg and sTg/TSH ratio. Results: TSH (mU/L) levels were more concentrated at 60–90 in females (71.5%) and 30–60 in males (39.0%), while patients with younger age, more lymph node metastases, shorter time interval between surgery and the first 131I therapy, and lower dose of levothyroxine sodium taken prior to the first 131I therapy would have higher TSH levels (All P< 0.05).Patients who are male, have primary tumor involvement of the strap muscles, lymph node metastasis, distant metastasis, and higher sTg and sTg/TSH are more likely to have poor long-term outcomes (All P< 0.05).The cut-offs of sTg and sTg/TSH for long-term efficacy were 7.515 and 0.095. STg, sTg/TSH, tumor size, lymph node metastasis, and distant metastasis were shown to be independent risk factors for long-term efficacy. The mean PFSs were longer for patients who had sTg/TSH ≤ 0.095 and/or sTg≤7.515 ug/L. Conclusions: For patients with moderate-to-high-risk DTC, when sTg>7.515 ug/L and/or sTg/TSH > 0.095 before the first 131I therapy, patients are more likely to have a poor long-term efficacy after full 131I therapy. This means that this group of patients may require further surgical treatment or targeted drug therapy after 131I therapy.

AbstractBackground:Coronary atherosclerotic heart disease (CAD) is an inflammatory vascular disease caused by atherosclerosis. Long non-coding RNAs are involved in the pathophysiological process of coronary heart disease. Here we investigated the regulatory effects of lncRNA PVT1 (PVT1) in human coronary artery endothelial cells (HCAECs).Methods:qRT-PCR and western blot were performed to detect gene and protein expressions. CCK-8, flow cytometry and wound healing assays were used to determine cell viability, apoptosis and migration of HCAECs. The binding relationship among miR-532-3p, PVT1 and MAPK1 was verified by dual luciferase reporter assay.Results:Overexpression of PVT1 markedly reduced cell apoptosis and increased cell proliferation and migration. However, miR-532-3p upregulation suppressed cell proliferation and migration and promoted apoptosis of HCAECs. PVT1 suppressed the expression of miR-532-3p viadirectly targeting miR-532-3p. And miR-532-3p overexpression abolished the effect of PVT1 upregulation on proliferation and apoptosis in HCAECs. Furthermore, MAPK1 acted as a target gene of miR-532-3p and miR-532-3p inhibited MAPK1 expression.Conclusion:PVT1 promoted MAPK1 expression by targeting miR-532-3p, thus inhibiting HCAECs apoptosis and promoting cell proliferation, suggesting PVT1 might have great potential as a therapeutic target for CAD.

Smart structures realize sequential motion and self-assembly through external stimuli. With the advancement of four-dimensional (4D) printing, the programming of sequential motions of smart structures is endowed with more design and manufacturing possibilities. In this research, we present a method for physically programming the timescale of shape change in 4D-printed bilayer actuators to enable the sequential motion and self-assembly of smart structures. The effects of the geometric and printing parameters on the time-dependent behavior of 4D-printed bilayer actuators are investigated. The results show that the thickness of the active layer directly affects the timescale of motion, and increasing the thickness leads to faster motion until the thickness ratio is close to 4:6. Similarly, a higher printing speed results in faster motion. Conversely, a higher printing temperature and a greater layer height result in a slower shape change. The effects of the length-width ratio, line width, and filling ratio on the timescale of motion are not as straightforward. Finally, we demonstrate several smart structures that exhibit sequential motion, including a labyrinth-like self-folding structure that is choreographed to achieve multi-step self-shaping and a flower-shaped structure where each part completes its movement sequentially to avoid collisions. The presented method extends the programmability and functional capabilities of 4D printing.

AbstractDengue hemorrhagic fever (DHF) is severe dengue with a hallmark of vascular leakage. β-tryptase has been found to promote vascular leakage in DHF patients, which could be a potential target for DHF treatment. This study aims to develop a theoretical background for designing and selecting human β-tryptase inhibitors through computational studies. Thirty-four α-keto-[1,2,3]-oxadiazoles scaffold-based compounds were used to generate 2D-QSAR models and for molecular docking studies with β-tryptase (PDB Code 4A6L). In addition, molecular dynamics (MD) simulation and molecular mechanics generalised born surface area (MM-GBSA) analysis on the binding of the reported most active compound, compound 11e, towards β-tryptase were performed. Finally, a structure-based pharmacophore model was generated. The selected 2D-QSAR models have statistically proven good models by internal and external validation as well as the y-randomization test. The docking results of compound 11e showed lower CDOCKER energy than the 4A6L co-crystallised ligand and a similar binding pattern as the 4A6L co-crystallised ligand. From molecular dynamics simulation, 4A6L in compound 11e bound state has RMSD below 2 Å throughout the 500 ns simulation, indicating the docked complex is stable. Besides, MM-GBSA analysis suggested the 4A6L-compound 11e docked complex (−66.04 Kcal/mol) is structurally as stable as the 4A6L-native ligand co-crystallized structure (−66.84 Kcal/mol). The best pharmacophore model identified features included hydrogen bond acceptor, ionic interaction, hydrophobic interaction, and aromatic ring, which contribute to the inhibitory potency of a compound. This study supplied insight and knowledge for developing novel chemical compounds with improved inhibition of β-tryptase.Communicated by Ramaswamy H. Sarma

Nowadays, heat, ventilation and air conditioning system are an essential part in a building. In order to achieve energy saving, the heating, ventilation, and air conditioning (HVAC) system have to enhance the designs of their various types of integrated electrical and mechanical components so that to control and operate plant optimally. This paper presented the development of smart sensor controller for heat, ventilation and air conditioning system by using Arduino. Smart sensor controller can be regarded a device that can control the speed of the motor based on the number of person detected by the infrared sensor. The motor used in this project will represent the fan motor of the normal air conditioner. The objective of the smart sensor controller is to prove the energy saving concept and to reduce the electrical consumption for the HVAC system. The experiment conducted show that the implementation of the smart sensor controller provides an average energy saving efficiency of 45.13 % compare to HVAC system without smart sensor controller.

Real‐world clinical data on the adverse events related to the use of cryoballoon catheter for pulmonary vein isolation remains limited. To report and describe the adverse events related to the use of Artic Front cryoballoon catheters (Arctic Front, Arctic Front Advance, and Arctic Front Advance Pro) reported in the Food and Drug Administration's (FDA) Manufacturers and User Defined Experience (MAUDE) database. We reviewed all the adverse events reported to the FDA MAUDE database over a 10.7‐year study period from January 01, 2011 to September 31, 2021. All events were independently reviewed by two physicians. During the study period, a total of 320 procedural‐related adverse events reported in the MAUDE database were identified. The most common adverse event was transient or persistent phrenic nerve palsy (PNP), accounting for 48% of all events. This was followed by cardiac perforation (15%), pulmonary vein stenosis (8%), transient ischemic attack or stroke (6%), vascular injury (4%), transient or persistent ST‐elevation myocardial infarction (3%), hemoptysis (2%), pericarditis (2%), and esophageal ulcer or fistula (1%). There were six reported intra‐procedural death events as a result of cardiac perforation. The two most common procedural adverse events associated with cryoballoon ablation were PNP and cardiac perforation. All cases of procedural mortality were due to cardiac perforation.

The dwindling reserves of fossil fuels have spurred the expansion of photovoltaic power systems, widely regarded as an alluring solution. Yet, a formidable challenge arises when it comes to optimizing the output of PV systems exposed to irregular irradiance stemming from external environmental factors. Consequently, this research endeavors to advocate the use of the Moth Flame Optimization (MFO) algorithm to search for the highest power output of a solar energy harvesting system. The distinctive behavior of moths proves instrumental in thorough searching of the feasible space, mitigating the risk of entrapment in local optima. To evaluate its efficacy, this algorithm’s performance is validated by comparing its outcomes with those of the Butterfly Optimization Algorithm (BOA). Both algorithms are subjected to experimentation to search for the Global Maximum Power Points (GMPPs) of the PV system under two distinct Partial Shading Condition (PSC) scenarios: Case 1 and Case 2. The results indicate that BOA tends to produce outcomes with a broader data dispersion range relative to the mean, unlike MFO. Specifically, for Case 1, the standard deviation values for MFO and BOA are 2.327040E−02 and 5.777913E−02, respectively, while for Case 2, they are 5.0567340E−02 and 8.519362E−02, respectively. Hence, the proposed approach demonstrates faster and more precise convergence.

Extensive investigations on the projection of heat waves (HWs) were conducted on the basis of coarse-resolution global climate models (GCMs). However, these investigations still fail to characterise the future changes in HWs regionally over China. PRECIS dynamical downscaling with a horizontal resolution of 25 km × 25 km was employed on the basis of GCM-HadCM3 to provide reliable projections on HWs over the Chinese mainland, and six statistical downscaling methods were used for bias correction under RCP4.5 and RCP8.5 scenarios. The multi-method ensemble (MME) of the top three dynamical downscaling methods with good performance was used to project future changes. Results showed that PRECIS primarily replicated the detailed spatiotemporal pattern of HWs. However, PRECIS overestimated the HWs in the Northwest and Southeast and expanded the areas of HWs in the Northeast and Southwest. Three statistical downscaling methods (quantile mapping, CDF-t and quantile delta mapping) demonstrated good performance in improving PRECIS simulation for reproducing HWs. By contrast, parametric-based trend-preserving approaches such as scaled distribution mapping and ISI-MIP are outperformed by the three aforementioned methods in downscaling HWs, particularly in the high latitudes of China. Based on MME projections, at the end of the 21st century, the national average of the number of HW days each year, the length of the longest HW event in the year and the extreme maximum temperature in HW will increase by 3 times, 1 time and 1.3 °C, respectively, under the RCP4.5 scenario, whilst that under the RCP8.5 scenario will increase by 8 times, 3 times and 3.7 °C, respectively, relative to 1986–2005. The Northwest is regionally projected to suffer long and hot HWs, whilst the South and Southeast will experience frequent consecutive HWs. Thus, HWs projected by the combined dynamical and statistical downscaling method are highly reliable in projecting HWs over China.

This paper presents a predictive defect detection method for prototype additive manufacturing (AM) based on multilayer susceptibility discrimination (MSD). Most current methods are significantly limited by merely captured images, disregarding the differences between layer-by-layer manufacturing approaches, without combining transcendental knowledge. The visible parts, originating from the prototype of conceptual design, are determined based on spherical flipping and convex hull theory, on the basis of which theoretical template image (TTI) is rendered according to photorealistic technology. In addition, to jointly consider the differences in AM processes, the finite element method (FEM) of transient thermal-structure coupled analysis was conducted to probe susceptible regions where defects appeared with a higher possibility. Driven by prior knowledge acquired from the FEM analysis, the MSD with an adaptive threshold, which discriminated the sensitivity and susceptibility of each layer, was implemented to determine defects. The anomalous regions were detected and refined by superimposing multiple-layer anomalous regions and comparing the structural features extracted using the Chan-Vese (CV) model. A physical experiment was performed via digital light processing (DLP) with photosensitive resin of a non-faceted scaled V-shaped engine block prototype with cylindrical holes using a non-contact profilometer. This MSD method is practical for detecting defects and is valuable for a deeper exploration of barely visible impact damage (BVID), thereby reducing the defect of prototypical mechanical parts in engineering machinery or process equipment via intellectualized machine vision.

Management of a nasolabial cyst typically involves surgical excision via a sublabial approach but the thin plane of dissection may lead to a cyst rupture, or a breach of the nasal mucosa. Endoscopic endonasal marsupialization has been recently described, but there is a risk of fistula stenosis and cyst recurrence especially for small nasolabial cysts with small intranasal components. We describe a modification of the endoscopic endonasal marsupialization technique by incorporating an inferiorly based flap that acts as a spacer to prevent recurrence. The procedure is performed under general anesthesia. With endoscopic guidance, the intranasal cyst wall is incised from a posterior superior to anterior inferior direction. The medial cyst wall is left pedicled inferiorly, trimmed to size and is rolled into the cyst cavity to act as a spacer. This technique has been performed in 4 patients with cyst sizes ranging from 9 to 29 mm with no recurrences at least 6 months postoperatively. Previous reports have described recurrence at 6 months after endoscopic marsupialization, despite an intranasal cyst opening of 10 × 10 mm. This simple modification of the previously described endoscopic marsupialization technique has successfully prevented stenosis and recurrence even in patients with small nasolabial cysts. [ABSTRACT FROM AUTHOR]

Evidence on the impact of obesity on catheter ablation for ventricular tachycardia (VT) is scarce. We queried the Nationwide Readmissions Database to determine the hospital outcomes and procedural complications of VT ablation among the obese and nonobese populations. Obesity was associated with a more prolonged length of stay (p< .01), higher cost of hospitalization (p< .01), and higher rates of pericardial effusion or hemopericardium (p= .05) and vascular complications (p= .05). There was no significant difference in early mortality, 30‐day readmissions, and other procedural complications. VT ablation could be performed relatively safely among patients with obesity. Our manuscript analyses the in‐hospital procedural outcomes of catheter ablation for VT between obese and non‐obese patients and found that VT ablation in obese patients has no significant difference in 30‐day mortality or 30‐day readmissions, but they do have increased vascular and pericardial effusion or hemopericardium complication rates, prolonged hospital stay (>7 days), and cost of hospitalization.

It is important to identify atmospheric environmental drivers of childhood asthma because asthma is the most common chronic disease in children globally. We provided an overview of the impacts of exposure to atmospheric environmental factors (e.g., meteorological factors and air pollutants) on childhood asthma, based on a series of studies with the cutting-edge environmental epidemiological methodology in Shanghai, China. Overall, we found that the prevalence of asthma among the children aged 3–7 years had increased by approximately 7 fold, from 2.1% in 1990 to 14.6% in 2019. Most meteorological factors (i.e. daily mean temperature, temperature difference, air pressure, air pressure difference, precipitation, relative humidity, sunshine and wind speed) and air pollutants (PM10, PM2.5, NO2, SO2and O3) were significantly associated with childhood asthma (p < 0.05), but meteorological factors appeared to play more important roles than air pollutants in the occurrence of asthma exacerbations. We also found that temperature variability was significantly associated with the elevated relative risk of daily outpatient visits for childhood asthma (p < 0.05). Furthermore, we conducted a systematic review on climate change adaptation measures and childhood asthma and found that there were a number of adaptation measures proposed for childhood asthma in response to climate change, including vulnerability assessment, improving ventilation and heating, enhancing community education, developing forecast models, and early warning systems. However, the effectiveness of most adaptation measures, except for improving ventilation and heating in winter, have not been explored and quantified. Since asthma is sensitive to the variation of atmospheric environmental conditions, it is critical to develop and implement appropriate climate change mitigation and adaptation strategies as global heating becomes apparent.

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Arising from the extraordinary theoretical energy density, rechargeable lithium-sulfur (Li–S) batteries have been reputed as one of the most appealing options for next-generation high-performance energy storage and conversion devices. Unfortunately, their industrial implementation has been strongly governed by the formation of Li dendrites caused by the unstable solid electrolyte interphase (SEI) film. Herein, we report a novel electrolyte by introducing the Mg(NO3)2additive to suppress the growth of Li dendrites, further improving the cycling lifetime of Li–S batteries. On the one hand, Mg2+can rapidly react with Li atoms to generate Mg atoms, replacing the Li atoms on the top surface of Li metal and forming the Mg center simultaneously. On the other hand, NO3–can be adsorbed in the inner Helmholtz plane and reduced as an inorganic-rich SEI film for stabilizing the Li metal anode when the electrolyte comes in contact with Li metal, effectively mitigating the formation of Li dendrites. Combining the experimental results and theoretical calculations, we confirm that the Mg atom center and the inorganic-rich SEI film are both beneficial for enhancing the electrochemical performance of Li–S batteries. This work provides a new insight into the electrolyte additive and a possible alternative for the design of high-performance Li–S batteries beyond the LiNO3additive.

• Factors affecting different methods for the determination of MSRC are analyzed. • Principles in the determination of MSRC are recommended. • The factor, α , is strongly dependent on the operative creep failure mechanism. • A relation exists between multiaxial factor, α , and damage tolerance parameter, λ. Materials in engineering applications are rarely uniaxially-loaded. In reality, failures under multiaxial loading has been widely observed in engineering structures. The life prediction of a component under multiaxial stresses has long been a challenging issue, particularly for high temperature applications. To distinguish the mode of failure ranging from a maximum principal stress intergranular damage to von Mises effective stress rupture mode a multiaxial stress rupture criterion (MSRC) was originally proposed by Sdobyrev and then Hayhurst and Leckie (SHL MSRC). A multiaxial-factor, α , was developed as a result which was intended to be a material constant and differentiates the bias of the MSRC between maximum principal stress and effective stress. The success of the SHL MSRC relies on accurately calibrating the value of α to quantify the multiaxial response of the material/geometry combination. To find a more suitable approach for determining MSRC, the applicability of different methods are evaluated. Given that the resulting analysis of the various approaches can be affected by the creep failure mechanism, principles in the determination of MSRC with and without using continuum damage mechanics approaches are recommended. The viability of uniaxial material parameters in correlating with α through the analysis of available data in literature is also presented. It is found that the increase of the uniaxial creep damage tolerance parameter λ is accompanied by the decrease of the α –value, which implies that the creep ductility plays an important role in affecting the multiaxial rupture behavior of materials. [Display omitted] [ABSTRACT FROM AUTHOR]

The gut microbiota shapes the response to immune checkpoint inhibitors (ICIs) in cancer, however dietary and geographic influences have not been well-studied in prospective trials. To address this, we prospectively profiled baseline gut (fecal) microbiota signatures and dietary patterns of 103 trial patients from Australia and the Netherlands treated with neoadjuvant ICIs for high risk resectable metastatic melanoma and performed an integrated analysis with data from 115 patients with melanoma treated with ICIs in the United States. We observed geographically distinct microbial signatures of response and immune-related adverse events (irAEs). Overall, response rates were higher in Ruminococcaceae-dominated microbiomes than in Bacteroidaceae-dominated microbiomes. Poor response was associated with lower fiber and omega 3 fatty acid consumption and elevated levels of C-reactive protein in the peripheral circulation at baseline. Together, these data provide insight into the relevance of native gut microbiota signatures, dietary intake and systemic inflammation in shaping the response to and toxicity from ICIs, prompting the need for further studies in this area.

The past decade has witnessed rapid research and developments in wind energy conversion systems and related enabling technologies. The incorporation of wind turbines in the integral design of buildings has become a promising approach to promote on-site renewable energy conversion in urban areas. However, information pertaining the efficiency of the wind turbines, wind speeds and the integration of generated wind power to the grid in urban environments is scarce. This review paper aims to capture the fact that recent advancements in wind energy systems are able to deliver tangible benefits to the renewable energy technology (RET) industry as a whole. A comprehensive review has been carried out on the applied techniques of radial wind turbine (RWTs), contra-rotating wind turbines (CRWTs), hybrid Savonius–Darrieus rotor, piezoelectric generators, flag-type triboelectric nanogenerator and stretching-enhanced triboelectric nanogenerator. This paper provides a knowledge platform for readers to explore possible methods in exploiting the advantages of urban wind profiles with minimal vibration, noise and installation space. Unique approaches pertaining the developments of wind energy system in urban environments are reviewed and reported in this paper. Several research gaps are also identified to guide future study in urban wind energy conversion systems.

Let Xbe a ball quasi-Banach function space on Rnand hX(Rn)the local Hardy space associated with X. In this paper, under some reasonable assumptions on both Xand another ball quasi-Banach function space Y, we aim to derive the boundedness of pseudo-differential operators with symbols in S1,δ-αfrom hX(Rn)to hY(Rn)via applying the extrapolation theorem. In order to prove this result, we also establish the infinite and finite atomic decompositions for the weighted local Hardy space hωp(Rn)and obtain the mapping property of the above pseudo-differential operators from hωpp(Rn)to hωqq(Rn). Moreover, the above results have a wide range of generality. For example, they can be applied to the variable Lebesgue space, the Lorentz space, the mixed-norm Lebesgue space, the local generalized Herz space and the mixed Herz space.

The electric double layer capacitor (EDLC) has been recognized as one of the most appealing electrochemical energy storage devices. Nanoporous materials with relatively high specific surface areas are generally used as the electrode materials for electric double layer capacitors (EDLCs). The past decades have witnessed anomalous phenomena of EDLCs under nanoconfined space, which to a large degree doubt the conventional recognition. However, there are currently still no deep insights and consensus on the mechanism of these striking discoveries. In this Perspective, we start with a brief introduction to contextualize the significance of EDLCs, especially with electrode materials of nanoconfined space. Next, we briefly review the landmark studies in light of the charge storage mechanism of EDLCs, mainly focusing on the study of nanoporous materials for EDLCs. Subsequently, we reexamine the basic concepts under nanoconfined space and some representative in situ characterization techniques applied to understand the charge storage mechanism of EDLCs. Finally, we provide general conclusions and insights into the future research directions in the field of EDLCs.

We present a case (57-year-old man) of infective endocarditis caused by Streptococcus gallolyticusin a patient with incident early-stage colon cancer. Benzylpenicillin treatment was immediately initiated to control bacteremia, and curative cancer resection was conducted 1 week later. The patient was discharged and placed on a 6-week outpatient parenteral anti-biotic therapy program for infective endocarditis but was rehospitalized 2 months later for heart failure. Transesophageal echocardiography revealed multiple large vegetations and perforation of the aortic valve. Valve replacement was conducted successfully, and heart failure was alleviated. This case highlights the dilemma of prioritizing the management of two competing interests, one for heart failure caused by valve regurgitation and the other for early-stage colon cancer with a curative intent. In this case, curative resection of the colon cancer was conducted after reasonable control of the endocarditis. Perforation of the aortic valve and heart failure could have been avoided if valve replacement was conducted first, but at the risk of cancer progression.

Sensitivity analysis is used to quantify the contribution of the uncertainty of input variables to the uncertainty of systematic output responses. For tolerance design in manufacturing and assembly, sensitivity analysis is applied to help designers allocate tolerances optimally. However, different sensitivity indices derived from different sensitivity analysis methods will always lead to conflicting results. It is necessary to find a sensitivity index suitable for tolerance allocation to transmission mechanisms so that the sensitivity results can truly reflect the effects of tolerances on kinematic and dynamic performances. In this paper, a variety of sensitivity indices are investigated and compared based on hybrid simulation. Firstly, the hybrid simulation model of the crank-slider mechanism is established. Secondly, samples of the kinematic and dynamic responses of the mechanism with joint clearances and link length errors are obtained, and the surrogate model established using polynomial chaos expansion (PCE). Then, different sensitivity indices are calculated based on the PCE model and are further used to evaluate the effect of joint clearances and link length errors on the output response. Combined with the tolerance-cost function, the corresponding tolerance allocation schemes are obtained based on different sensitivity analysis results. Finally, the kinematic and dynamic responses of the mechanism adopting different tolerance allocation schemes are simulated, and the sensitivity index corresponding to the optimal response is determined as the most appropriate index.