Uric acid levels and heart failure: A mendelian randomization study.

BACKGROUND AND AIMS: Uric acid, the end-product of purine metabolism within the human body, has been the subject of studies exploring its potential association with cardiovascular and cerebrovascular diseases. However, the precise relationship between uric acid levels and heart failure remains elusive. METHODS AND RESULTS: In this particular study, aggregated data from genome-wide association studies on uric acid and heart failure were utilized to perform a two-sample Mendelian randomization (MR) analysis utilizing R software. The aim was to uncover any causal link between these variables. The primary outcome was assessed using inverse variance weighted (IVW) methodology, while sensitivity analyses employed MR-Egger, weighted median (WME), and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) techniques. IVW results revealed a possible causal relationship between elevated uric acid levels and an increased risk of heart failure (OR: 1.09, 95 % CI: 1.01-1.17, P < 0.05). Encouragingly, the directions provided by MR-Egger and WME aligned with IVW findings, and no anomalies were detected in the remaining sensitivity analyses. CONCLUSION: These outcomes indicate the stability of the results of the study, thereby suggesting that heightened uric acid levels may contribute to an augmented risk of heart failure.

The effects of self-esteem and parental phubbing on adolescent internet addiction and the moderating role of the classroom environment: a hierarchical linear model analysis.

BACKGROUND: With the advent of the new media era, the understanding of adolescent internet addiction needs to be enriched. It is also necessary to distinguish the related factors of adolescent internet addiction at different levels to clarify the mechanisms of this phenomenon. METHODS: This study used hierarchical linear model analysis to explore the effects of student-level factors and school-level factors on adolescent internet addiction, along with cross-level moderating effects. A total of 1,912 students between the 4th and 8th grades in China participated in the study. Participants completed the Self-Esteem Scale, Parents Phubbing Scale, Classroom Environment Scale, and the Diagnostic Questionnaire of Internet Addiction. RESULTS: Correlational analyses revealed that internet addiction was found to be negatively correlated with both self-esteem and the teacher-student relationship (p < 0.01), while father phubbing, mother phubbing, and learning burden were shown to positively correlate with internet addiction (p < 0.01). Hierarchical linear model analysis suggested that student-level variables, including self-esteem, and mother phubbing, were significant predictors of internet addiction (ß = -0.077, p < 0.001 and ß = 0.028, p < 0.01, respectively). At the school level, learning burden significantly and negatively predicted internet addiction (ß = 0.073, p < 0.05). Furthermore, the relationship between self-esteem and internet addiction was significantly moderated by learning burden (ß = -0.007, p < 0.05). Meanwhile, the teacher-student relationship also had a significant moderating effect on the association between mother phubbing and internet addiction (ß = -0.005, p < 0.01). CONCLUSIONS: This study revealed the relationships between self-esteem, parental phubbing, and classroom environment with adolescent internet addiction, and these findings could provide insights into reducing adolescent internet addiction from the perspective of individuals, families, and schools.

Antiplatelet therapy for secondary prevention of lacunar stroke: a systematic review and network meta-analysis.

PURPOSE: To comprehensively compare the efficacy of different antiplatelet therapies for secondary prevention of lacunar stroke (LS). METHODS: The relevant studies were identified by searching PubMed, EMBASE, Web of Science, and Cochrane Collaboration Database up to May 2022. Cardiovascular and cerebrovascular events were chosen to evaluate the efficacy of antiplatelet therapy for secondary prevention. Loop-specific approach and node-splitting analysis were used to evaluate consistency and inconsistency, respectively. The value of the surface under the cumulative ranking (SUCRA) was calculated and ranked. Funnel-plot symmetry was used to evaluate publication bias. The meta-analysis was performed by using STATA 16.0. RESULTS: Thirteen studies with a total of 33,011 subjects were included in this network meta-analysis. Compared with placebo, aspirin, clopidogrel, cilostazol, ticlopidine, aspirin plus dipyridamole, and aspirin plus clopidogrel were associated with reducing cardiovascular and cerebrovascular events. The SUCRA estimated relative ranking of treatments showed that cilostazol may be the most effective (RR 0.56, 95% CI 0.42-0.74, SUCRA 95.8). No significant inconsistency or publication bias was found in the study. CONCLUSIONS: This meta-analysis suggests that cilostazol may be a priority option for secondary prevention of patients with LS. These findings still need further study in the future.

Uric acid levels and their association with vascular dementia and Parkinson's disease dementia: a meta-analysis.

OBJECTIVES: To explore the association between uric acid (UA) levels and vascular dementia (VaD) and Parkinson's disease dementia (PDD), a meta-analysis was conducted. METHODS: The relevant studies were identified by searching PubMed, Embase, Web of Science, and Cochrane Collaboration Database up to May 2022. Pooled analysis, sensitivity analysis, and publication bias examination were all conducted. All analyses were performed by using STATA 16. RESULTS: Twelve studies with a total of 2097 subjects were included. The pooled analysis showed that UA levels were not associated with VaD (WMD = - 10.99 µmol/L, 95% CI (- 48.05, 26.07), P = 0.561) but were associated with PDD (WMD = - 25.22 µmol/L, 95% CI (- 43.47, - 6.97), P = 0.007). The statistical stability and reliability were evaluated using sensitivity analysis and publication bias outcomes. CONCLUSION: UA levels are associated with PDD but not with VaD. This study will help to strengthen our knowledge of the pathophysiologies of VaD and PDD, and promote the development of prevention and treatment strategies.

Risk Factors for Primary Angle-closure Glaucoma: A Systematic Review and Meta-analysis of 45 Studies.

SIGNIFICANCE: This study summarized primary angle-closure glaucoma (PACG)-related factors across different dimensions. OBJECTIVES: This review aimed at systematically summarizing the associated factors of PACG in published literatures. METHODS: A systematic review and meta-analysis were conducted by searching the electronic databases including PubMed, EMBASE, and Web of Science from their inception to November 2021. The pooled risk estimates of continuous and categorical variables were calculated using weighted mean difference (WMD) and odds ratio (OR; 95% confidence intervals [CIs]), respectively. RESULTS: We included 45 studies in this review. In the meta-analysis, intraocular pressure (WMD, 3.13; 95% CI, 2.37 to 3.89), anterior chamber depth (WMD, -0.52; 95% CI, -0.70 to -0.34), axial length (WMD, -0.77; 95% CI, -1.26 to -0.28), retinal nerve fiber layer (WMD, -21.23; 95% CI, -30.21 to -12.25), and spherical equivalent (WMD, 1.02; 95% CI, 0.66 to 1.38) were the most common ophthalmic anatomic factors, and lower body weight (WMD, -3.65; 95% CI, -6.48 to -0.82) was the most significant general morphological indicators. The presence of cataract (OR, 3.77; 95% CI, 3.46 to 4.11) and hyperlipidemia (OR, 1.10; 95% CI, 1.02 to 1.20) were significantly associated with PACG. Increased level of triglyceride (WMD, 0.17; 95% CI, 0.06 to 0.27) was associated with PACG. In addition, an association between short-term antidepressant exposure (OR, 1.36; 95% CI, 1.08 to 1.70) and acute angle-closure glaucoma was observed. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: This review identified a few consistent factors related to PACG, providing important information for primary care physicians, general ophthalmologists, and public health professionals to counsel their patients on PACG risks.

A review of study designs and data analyses in metabolomics studies in myopia.

Metabolomics analyzes the entire range of small molecule metabolites in biological systems to reveal the response signals that are transmitted from "genetics and environment", which could help us understand complex phenotypes of diseases. Metabolomics has been successfully applied to the study of eye diseases including age-related macular degeneration, glaucoma, and diabetic retinopathy. In this review, we summarize the findings of myopic metabolomics and discuss them from a design and analysis perspective. Finally, we provide new ideas for the future development of myopia metabolomics research based on the broader ocular metabolomics study.

Mechanical Thrombectomy for Mild Acute Ischemic Stroke with Large-Vessel Occlusion: A Systematic Review and Meta-Analysis.

BACKGROUND: The functional prognosis of mechanical thrombectomy (MT) for mild acute ischemic stroke (AIS) with large-vessel occlusion (LVO) is controversial. To explore a more precise estimation, a meta-analysis was conducted. METHODS: The relevant studies were identified by searching PubMed, Embase, Web of Science, and Cochrane Collaboration Database until October 2021. The pooled analysis, subgroup analysis, sensitivity analysis, and publication bias examination were all conducted. The meta-analysis was performed by using Stata 12.0. RESULTS: Eleven studies were included with a total of 1,929 subjects, including 794 patients receiving MT and 1,135 patients receiving medical management. The pooled analysis showed that MT might be not associated with functional prognosis among mild AIS with LVO (excellent functional prognosis: risk ratio (RR) = 1.07, 95% confidence interval (CI) = 0.94-1.21, p = 0.294; favorable functional prognosis: RR = 1.01, 95% CI = 0.96-1.06, p = 0.823). The statistical stability and reliability were demonstrated by the sensitivity analysis and publication bias outcomes. CONCLUSION: Our meta-analysis suggests that MT may be not associated with functional prognosis of mild AIS with LVO.

Rope Jumping Strength Monitoring on Smart Devices via Passive Acoustic Sensing.

Rope jumping, as a fitness exercise recommended by many sports medicine practitioners, can improve cardiorespiratory capacity and physical coordination. Existing rope jump monitoring systems have limitations in terms of convenience, comfort, and exercise intensity evaluation. This paper presents a rope jump monitoring system using passive acoustic sensing. Our system exploits the off-the-shelf smartphone and headphones to capture the user's rope-jumping sound and breathing sound after exercise. Given the captured acoustic data, the system uses a short-time energy-based approach and the high correlation between rope jumping cycles to detect the rope-jumping sound frames, then applies a dual-threshold endpoint detection algorithm to calculate the number of rope jumps. Finally, our system performs regression predictions of exercise intensity based on features extracted from the jumping speed and the mel spectrograms of the user's breathing sound. The significant advantage of the system lies in the solution of the problem of poorly characterized mel spectrograms. We employ an attentive mechanism-based GAN to generate optimized breathing sound mel spectrograms and apply domain adversarial adaptive in the network to improve the migration capability of the system. Through extensive experiments, our system achieves (on average) 0.32 and 2.3% error rates for the rope jumping count and exercise intensity evaluation, respectively.

[The acceleration algorithm for projection decomposition of dual-energy computed tomography image reconstruction based on projection matching].

Dual-energy computed tomography (CT) reconstruction imaging technology is an important development direction in the field of CT imaging. The mainstream model of dual-energy CT reconstruction algorithm is the basis material decomposition model, and the projection decomposition is the crucial technique. The projection decomposition algorithm based on projection matching was a general method. With establishing the energy spectrum lookup table, we can obtain the stable solution by the least squares matching method. But the computation cost will increase dramatically when size of lookup table enlarges and it will slow down the computer. In this paper, an acceleration algorithm based on projection matching is proposed. The proposed algorithm makes use of linear equations and plane equations to fit the lookup table data, so that the projection value of the decomposition coefficients can be calculated quickly. As the result of simulation experiment, the acceleration algorithm can greatly shorten the running time of the program to get the stable and correct solution.

Prognostic value of glycated hemoglobin among patients with ST-segment elevation myocardial infarction: a systematic review and meta-analysis.

Many studies have shown the prognostic significance of glycated hemoglobin (HbA1c) for overall coronary artery disease (CAD). But less is known about the role that HbA1c played in the prognosis of patients diagnosed with ST-segment elevation myocardial infarction (STEMI). Results from previous studies were controversial. Therefore, a meta-analysis was conducted to investigate whether admission HbA1c level was a predictor of short- and long-term mortality rates among patients diagnosed with STEMI. Relevant literatures were retrieved from the electronic databases up to March 2016. Reference lists were hand searched to identify eligible studies. Articles were included if they provided sufficient information for the calculation of pooled relative risk (RR) and its corresponding 95% confidence interval (CI). Finally, we got 19 prospective studies involving a total of 35,994 STEMI patients to evaluate the associations between HbA1c level and their in-hospital, 30-day and long-term mortality. Among STEMI patients, HbA1c level was not significantly associated with in-hospital mortality (RR 1.20, 95% CI 0.95-1.53, p=0.13). However, elevated HbA1c level was positively associated with risk of 30-day and long-term mortality (for 30-day mortality, RR 1.25, 95% CI 1.03-1.52, p=0.02; for long-term mortality, RR 1.45, 95% CI 1.20-1.76, p<0.01). In conclusion, our findings suggested elevated HbA1c level among STEMI patients was an indicator of 1.25-fold 30-day mortality risk and 1.45-fold long-term mortality risk, respectively. STEMI patients with high HbA1c level should have their chronic glucose dysregulation under intensive control.

Associations between CLCNKA_B tag SNPs with essential hypertension and interactions between genetic and environmental factors in an island population in China.

OBJECTIVE: Essential hypertension (EH) is known as the result from the interaction of environmental and genetic factors. We selected tag SNPs of CLCNKA_B genes as gene markers, to elucidate the relationship between CLCNKA_B and EH, and to determine the possible interaction among tag SNPs and dietary factors in island of China. METHODS: A case-control study was conducted in Changshan islands of China, blood samples of 806 participants were genotyped, and the general characteristics and dietary habits of them were collected. Unconditional logistic regression (ULR) was used to assess the effects of CLCNKA_B tag SNPs and dietary factors on EH. Generalized multifactor dimensionality reduction (GMDR) was used to test gene-environment interaction for EH risk. RESULTS: Four SNPs were identified as the tag SNPs of CLCNKA_B. Recessive model for rs5253 and rs2275166 were marginal associated with the decrease risk of EH (OR = 0.36, 95% CI = 0.12-1.07 for rs5253; OR = 0.40, 95% CI = 0.16-1.05 for rs2275166). In GMDR, the five-factor interaction model of rs1010069, salt, marine products, meat and edible oil consumption was the best model, with a maximum CVC of 10/10 and a TBA of 0.638 (p = 0.001). In ULR, compared with subjects carried wild genotypes and null dietary risk factor, those with three or more dietary risk factors and mutation genotypes had 5.90-fold EH risk (95% CI:2.24-15.53). CONCLUSION: Though the single loci of tag SNPs of CLCNKA_B are not enough to significantly increase the EH susceptibility, the combination of CLCNKA tag SNP, salt, marine products, meat and edible oil consumption is associated with elevated risk.

Quantity of Cerebral Microbleeds, Antiplatelet Therapy, and Intracerebral Hemorrhage Outcomes: A Systematic Review and Meta-analysis.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) increase future intracerebral hemorrhage (ICH) risk after ischemic stroke (IS) or transient ischemic attack (TIA). However, whether CMB-related ICH risk depends on CMB quantity, CMB location, or antithrombotic agents is unclear. We performed a systematic review and meta-analysis to investigate CMB-related ICH risk, stratifying patients according to the quantity of CMB, the location of CMB, and the type of antithrombotic therapy used. METHODS: Literature databases were searched for prospective cohorts reporting ICH outcomes in patients with IS or TIA with baseline CMB evaluation. We calculated pooled relative ratios (RRs) for ICH among patients with and without CMBs. Pooled RRs of CMB-related ICH were further calculated in subgroups stratified by CMB quantity, CMB location, and antithrombotic therapy. RESULTS: Among the 10 included studies, the pooled RR of future ICH was 7.73 (95% confidence interval [CI], 4.07-14.70; P < .001) in CMB versus non-CMB patients. Subgroup analysis revealed that compared with non-CMB patients, multiple-CMB patients were at an increased risk for future ICH (RR = 8.02; 95% CI, 3.21-20.01; P < .001), whereas single-CMB patients did not incur this risk (RR = 2.33; 95% CI, .63-8.63; P = .205). A strong association was found between CMB presence and subsequent ICH in antiplatelet users (RR = 16.56; 95% CI, 3.68-74.42; P < .001). Studies on CMB-related ICH according to CMB locations and in anticoagulant users are lacking for subgroup analysis. CONCLUSION: Our study revealed that patients with IS or TIA with multiple CMBs may incur a higher risk of future ICH, and the presence of CMBs in patients with IS or TIA using antiplatelet agents may significantly increase the subsequent ICH risk.

Gene polymorphism of cytochrome P450 2C19*2 and clopidogrel resistance reflected by platelet function assays: a meta-analysis.

BACKGROUND: The relationship between CYP2C19*2 gene polymorphism and clopidogrel resistance reflected by platelet function assays has been studied extensively in the past several years, while no clear conclusion can be drawn from the previous studies. To explore a more precise estimation of the relationship, a meta-analysis was conducted in the present study. METHODS: The relevant studies were identified by searching PubMed, EMBASE, the Web of Science, Cochrane Collaboration Database, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, and China Biological Medicine (CBM) up to February, 2014. The meta-analysis was performed by the STATA 11. RESULTS: Eight studies with a total of 2,331 subjects, including 1,066 patients with clopidogrel resistance and 1,265 patients without clopidogrel resistance were included. The pooled analysis showed that CYP2C19*2 gene polymorphism was probably associated with clopidogrel resistance (OR (95% CI): GA vs. GG: 2.10 (1.74-2.53); AA vs. GG: 3.05 (2.10-4.45); dominant model: 2.22 (1.85-2.65); recessive model: 2.33 (1.62-3.36)). No statistically significant difference was found in the analysis of the three subgroups. The statistical stability and reliability was also demonstrated by the sensitivity analysis and publication bias outcomes. CONCLUSION: The meta-analysis suggests that CYP2C19*2 gene polymorphism may be associated with clopidogrel resistance.

[Tumor segmentation of brain MRI with adaptive bandwidth mean shift].

In order to get the adaptive bandwidth of mean shift to make the tumor segmentation of brain magnetic resonance imaging (MRI) to be more accurate, we in this paper present an advanced mean shift method. Firstly, we made use of the space characteristics of brain image to eliminate the impact on segmentation of skull; and then, based on the characteristics of spatial agglomeration of different tissues of brain (includes tumor), we applied edge points to get the optimal initial mean value and the respectively adaptive bandwidth, in order to improve the accuracy of tumor segmentation. The results of experiment showed that, contrast to the fixed bandwidth mean shift method, the method in this paper could segment the tumor more accurately.

Evaluating the Causal Effects of Low Density Lipoprotein Cholesterol Levels on Ischemic Stroke: A Mendelian Randomization Study.

Background: Ischemic stroke (IS) is the leading cause of disability and mortality worldwide. Low-density lipoprotein cholesterol (LDL-C) levels hadno potential risk on ischemic stroke. However, higher LDL-C levels were closely related to IS. Based on two antagonistic viewpoints, a Mendelian randomization (MR) study was designed to evaluate the causal effects of LDL-C levels on IS. Methods: Datasets of LDL-C levels and ischemic stroke were acquired from genome-wide association studies (GWAS). Weighted median method was conducted for main analysis, and MR-Egger and inverse-variance weighted (IVW) methods were performed for auxiliary analyses. Heterogeneity and pleiotropic tests were utilized to confirm the reliability of this study. Results: A total of 359 single nucleotide polymorphisms (SNPs) were associated with LDL-C levels (P < 5 × 10-8) and 337 SNPs were available in ischemic stroke with eliminating outliers. LDL-C levels were significantly associated with ischemic stroke (OR = 1.104, 95%CI = 1.019 - 1.195, P = 1.52 × 10-2). MR-Egger and IVW showed directionally similar estimates (MR-Egger: OR = 1.120, 95%CI = 1.040 - 1.207, P = 3.12 × 10-3; IVW: OR = 1.120, 95%CI = 1.064 - 1.178, P = 1.17 × 10-5). Conclusion: LDL-C levels had causal effects on IS, providing insights into the design of future interventions to reduce the burden of ischemic stroke.

Genome-wide analyses reveal a role for peptide hormones in planarian germline development.

Bioactive peptides (i.e., neuropeptides or peptide hormones) represent the largest class of cell-cell signaling molecules in metazoans and are potent regulators of neural and physiological function. In vertebrates, peptide hormones play an integral role in endocrine signaling between the brain and the gonads that controls reproductive development, yet few of these molecules have been shown to influence reproductive development in invertebrates. Here, we define a role for peptide hormones in controlling reproductive physiology of the model flatworm, the planarian Schmidtea mediterranea. Based on our observation that defective neuropeptide processing results in defects in reproductive system development, we employed peptidomic and functional genomic approaches to characterize the planarian peptide hormone complement, identifying 51 prohormone genes and validating 142 peptides biochemically. Comprehensive in situ hybridization analyses of prohormone gene expression revealed the unanticipated complexity of the flatworm nervous system and identified a prohormone specifically expressed in the nervous system of sexually reproducing planarians. We show that this member of the neuropeptide Y superfamily is required for the maintenance of mature reproductive organs and differentiated germ cells in the testes. Additionally, comparative analyses of our biochemically validated prohormones with the genomes of the parasitic flatworms Schistosoma mansoni and Schistosoma japonicum identified new schistosome prohormones and validated half of all predicted peptide-encoding genes in these parasites. These studies describe the peptide hormone complement of a flatworm on a genome-wide scale and reveal a previously uncharacterized role for peptide hormones in flatworm reproduction. Furthermore, they suggest new opportunities for using planarians as free-living models for understanding the reproductive biology of flatworm parasites.

[Three-dimensional mini-type permanent magnetic resonance imaging device and medical imaging of mice].

We developed a three-dimensional mini-type permanent magnetic resonance imaging (MRI) device in our lab. The purposes of this study were (1) for further development of MRI technologies, (2) for support of broadening practices of animal test modeling in medical research, and (3) for training more specialists from colleges or universities in the field of MRI. This paper describes the research and development at our lab(s), especially stressing on the design of the main magnet, the gradient coil and the radio frequency coil. In addition, the specific methodologies used in our lab(s) and the related data are emphasized. The 3D MRI technologies have met the needs of using small animals, super thin sections of live animal body and high imaging resolutions. MRI images of mice head and abdominal have been obtained successfully by using the imager that we developed. The imaging results and analyses have also been discussed.

Metabolomics facilitates the discovery of metabolic profiles and pathways for myopia: A systematic review.

BACKGROUND: Myopia is one of the major eye disorders and the global burden is increasing rapidly. Our purpose is to systematically summarize potential metabolic biomarkers and pathways in myopia to facilitate the understanding of disease mechanisms as well as the discovery of novel therapeutic measures. METHODS: Myopia-related metabolomics studies were searched in electronic databases of PubMed and Web of Science until June 2021. Information regarding clinical and demographic characteristics of included studies and metabolomics findings were extracted. Myopia-related metabolic pathways were analysed for differential metabolic profiles, and the quality of included studies was assessed based on the QUADOMICS tool. Pathway analyses of differential metabolites were performed using bioinformatics tools and online software such as the Metaboanalyst 5.0. RESULTS: The myopia-related metabolomics studies included in this study consisted of seven human and two animal studies. The results of the study quality assessment showed that studies were all phase I studies and all met the evaluation criteria of 70% or more. The myopia-control serum study identified 23 differential metabolites with the Sphingolipid metabolism pathway beings enriched. The high myopia-cataract aqueous humour study identified 40 differential metabolites with the Arginine biosynthesis pathway being enriched. The high myopia-control serum study identified 43 differential metabolites and 4 pathways were significantly associated with metabolites including Citrate cycle; Alanine, aspartate and glutamate metabolism; Glyoxylate and dicarboxylate metabolism; Biosynthesis of unsaturated fatty acids (all P value < 0.05). CONCLUSIONS: This study summarizes potential metabolic biomarkers and pathways in myopia, providing new clues to elucidate disease mechanisms.

X-ray CT image denoising with MINF: A modularized iterative network framework for data from multiple dose levels.

In clinical applications, multi-dose scan protocols will cause the noise levels of computed tomography (CT) images to fluctuate widely. The popular low-dose CT (LDCT) denoising network outputs denoised images through an end-to-end mapping between an LDCT image and its corresponding ground truth. The limitation of this method is that the reduced noise level of the image may not meet the diagnostic needs of doctors. To establish a denoising model adapted to the multi-noise levels robustness, we proposed a novel and efficient modularized iterative network framework (MINF) to learn the feature of the original LDCT and the outputs of the previous modules, which can be reused in each following module. The proposed network can achieve the goal of gradual denoising, outputting clinical images with different denoising levels, and providing the reviewing physicians with increased confidence in their diagnosis. Moreover, a multi-scale convolutional neural network (MCNN) module is designed to extract as much feature information as possible during the network's training. Extensive experiments on public and private clinical datasets were carried out, and comparisons with several state-of-the-art methods show that the proposed method can achieve satisfactory results for noise suppression of LDCT images. In further comparisons with modularized adaptive processing neural network (MAP-NN), the proposed network shows superior step-by-step or gradual denoising performance. Considering the high quality of gradual denoising results, the proposed method can obtain satisfactory performance in terms of image contrast and detail protection as the level of denoising increases, which shows its potential to be suitable for a multi-dose levels denoising task.