1.Oral Herombopag Olamine and subcutaneous recombinant human thrombopoietin after haploidentical hematopoietic stem cell transplantation
Dai KONG ; Xinkai WANG ; Wenhui ZHANG ; Xiaohang PEI ; Cheng LIAN ; Xiaona NIU ; Honggang GUO ; Junwei NIU ; Zunmin ZHU ; Zhongwen LIU
Chinese Journal of Tissue Engineering Research 2025;29(1):1-7
		                        		
		                        			
		                        			BACKGROUND:Allogeneic hematopoietic stem cell transplantation is an important treatment for malignant hematological diseases,and delayed postoperative platelet implantation is a common complication that seriously affects the quality of patient survival;however,there are no standard protocols to improve platelet implantation rates and prevent platelet implantation delays. OBJECTIVE:To compare the safety and efficacy of oral Herombopag Olamine versus subcutaneous recombinant human thrombopoietin for promoting platelet implantation in patients with malignant hematological diseases undergoing haploid hematopoietic stem cell transplantation. METHODS:Clinical data of 163 patients with malignant hematological diseases who underwent haploidentical hematopoietic stem cell transplantation from January 2016 to October 2022 were retrospectively analyzed.A total of 72 patients who started to subcutaneously inject recombinant human thrombopoietin at+2 days were categorized into the recombinant human thrombopoietin group;a total of 27 patients who started to orally take Herombopag Olamine at+2 days were categorized into the Herombopag Olamine group;and 64 patients who did not apply Herombopag Olamine or recombinant human thrombopoietin were categorized into the blank control group.The implantation status,incidence of acute graft-versus-host disease of degree II-IV within 100 days,1-year survival rate,1-year recurrence rate,and safety were analyzed in the three groups. RESULTS AND CONCLUSION:(1)The average follow-up time was 52(12-87)months.The implantation time of neutrophils in the blank control group,recombinant human thrombopoietin group,and Herombopag Olamine group was(12.95±3.88)days,(14.04±3.71)days,and(13.89±2.74)days,respectively,with no statistically significant difference(P=0.352);the implantation time of platelets was(15.16±6.27)days,(17.67±6.52)days,and(17.00±4.75)days,with no statistically significant difference(P=0.287).(2)The complete platelet implantation rate on day 60 was 64.06%,90.28%,and 92.59%,respectively,and the difference was statistically significant(P<0.001).The subgroup analysis showed that the difference between the blank control group and the recombinant human thrombopoietin group was statistically significant(P<0.001),and the difference between the blank control group and the Herombopag Olamine group was statistically significant(P=0.004).The difference was not statistically significant between the recombinant human thrombopoietin group and Herombopag Olamine group(P=0.535).(3)100-day II-IV degree acute graft-versus-host disease incidence in the blank control group,recombinant human thrombopoietin group,and Herombopag Olamine group were 25.00%,30.56%,and 25.93%,respectively,and the difference was not statistically significant(P=0.752).(4)The incidence of cytomegalovirus anemia,cytomegalovirus pneumonia,and hepatic function injury had no statistical difference among the three groups(P>0.05).(5)During the follow-up period,there was no thrombotic event in any of the three groups of patients.(6)The results showed that recombinant human thrombopoietin and Herombopag Olamine could improve the platelet implantation rate of malignant hematological disease patients after haploidentical hematopoietic stem cell transplantation,with comparable efficacy and good safety.
		                        		
		                        		
		                        		
		                        	
2.Analysis of Genes Related to Platelet Activation in Essential Thrombocythemia Based on Transcriptomics
Yan SUN ; Er-Peng YANG ; Yu-Meng LI ; Ji-Cong NIU ; Pei ZHAO ; Wei-Yi LIU ; Zhuo CHEN ; Ming-Jing WANG ; Teng FAN ; Xiao-Mei HU
Journal of Experimental Hematology 2024;32(6):1814-1821
		                        		
		                        			
		                        			Objective:To analyze the genes related to platelet activation in essential thrombocythemia (ET)based on transcriptome sequencing technology (RNA-seq ),and to explore the potential targets related to ET thrombosis. Methods:Blood samples from ET patients and healthy individuals were collected for RNA-seq,and differentially expressed lncRNAs,miRNAs,and mRNAs were selected to construct a lncRNA-miRNA-mRNA regulatory network. Differential mRNAs in the regulatory network were enriched and analyzed using Gene Ontology (GO ) and Kyoto Encyclopedia of Genes and Genomes (KEGG).The real-time PCR method was applied to validate differential mRNAs on crucial signaling pathways.Results:A total of 32 lncRNAs (3 up-regulated,29 down-regulated),16 miRNAs (8 up-regulated,8 down-regulated),and 35 mRNAs (27 up-regulated,8 down-regulated)were identified as differentially expressed.Among them,5 lncRNAs,12 miRNAs,and 19 mRNAs constituted the regulatory network.KEGG enrichment analysis showed that the differential mRNAs were related to the platelet activation signaling pathway,and there were 6 differential mRNAs related to platelet activation,namely F2R,ITGA2B,ITGB1,ITGB3,PTGS1,and GP1 BB,which were all up-regulated in their expression.RT-PCR results showed that the expression of five mRNAs including F2R,ITGA2B,ITGB1,ITGB3,and GP1BB were upregulated in ET patients compared with healthy subjects,and consistent with RNA-seq results,while PTGS1 expression was not significantly different.Conclusion:Differential mRNAs in ET patients are related to the platelet activation pathway,and F2R,ITGA2B,ITGB1,ITGB3,and GP1BB mRNAs may serve as novel targets associated with platelet activation in ET.
		                        		
		                        		
		                        		
		                        	
3.Exploring the effects of sildenafil on testicular of rats with erectile dysfunction based on RIP1/RIP3
Yu-Lian LIU ; Li-Pan NIU ; Pei YANG ; Rui ZHANG ; Feng-Xia LIU
The Chinese Journal of Clinical Pharmacology 2024;40(13):1938-1942
		                        		
		                        			
		                        			Objective To investigate the role of programmed necrosis pathway in testicular tissue damage in rats with erectile dysfunction(ED)and the mechanism of sildenafil intervention.Methods An ED rat model was established by high-fat chow feeding,and the rats were randomly divided into model group,experimental group,interleukin 18 group,and experimental+interleukin 18 group;10 rats were randomly selected as the normal control group.The experimental group was gavaged with 20 mg·kg-1sildenafil;the interleukin 18 group was injected intraperitoneally with 0.2 μg·kg-1interleukin 18 recombinant protein;the experimental+interleukin 18 group was gavaged with an equal amount of sildenafil,and the experimental+interleukin 18 group was injected intraperitoneally with an equal amount of interleukin 18 recombinant protein;the normal control and model groups were given with an equal amount of 0.9%NaCl by gavage and intraperitoneally injected with an equal amount of saline;and the experimental group was injected with an equal amount of 0.9%NaCl.Interleukin 18 group was gavaged with an equal amount of 0.9%NaCl,and the five groups of rats were administered once a day at regular intervals for 14 consecutive days.Reverse transcription polymerase chain reaction(RT-qPCR)and Western blotting were used to detect the expression of receptor-interacting protein kinase 1(RIP1),receptor-interacting protein kinase 3(RIP3),mixed-spectrum kinase structural domain-like protein(MLKL),and calcium-calmodulin-dependent protein kinase Ⅱ(CaMKⅡ)in rat testis tissues.Results The relative expression levels of RIP1 protein in the normal control group,model group,experimental group,interleukin 18 group and experimental+interleukin 18 group were 0.58±0.05,0.99±0.09,0.71±0.05,1.23±0.07 and 0.81±0.07;the relative expression levels of RIP3 protein were 0.61±0.05,1.05±0.10,0.77±0.04,1.19±0.07 and 0.84±0.08,respectively;the relative expression levels of MLKL protein were 0.63±0.05,1.13±0.08,0.79±0.05,1.30±0.02 and 1.00±0.04,respectively;the relative expression levels of CaMK Ⅱ protein were 0.54±0.04,1.12±0.07,0.77±0.05,1.36±0.04 and 1.00±0.07;the differences of the above indexes were statistically significant when the model group was compared with the normal control group,the experimental group was compared with the model group,the interleukin 18 group was compared with the model group,and the experimental+interleukin 18 group was compared with the interleukin 18 group(all P<0.05).Conclusion The RIP1/RIP3-mediated necroptosis pathway plays multiple regulatory roles in testicular injury in ED rats,and sildenafil may improve testicular function in rats by inhibiting the above necroptosis signaling pathway.
		                        		
		                        		
		                        		
		                        	
4.Analysis and suggestions on China′s family bed service policy based on grounded theory
Yaqing LIU ; Sixian DU ; Haoran NIU ; Feng JIANG ; Liwen GONG ; Junfeng PEI
Chinese Journal of Hospital Administration 2024;40(8):613-618
		                        		
		                        			
		                        			Objective:To analyze the current status and deficiencies of family bed service policies in China, for references for promoting the construction of China′s home health service system.Methods:Key words such as " family bed" and " home health services" were used to search for relevant policies(from January 1, 1984 to May 31, 2023)in Peking University Treasure Database, the State Council′s policy document repository, and official websites of health administrative departments at all levels. NVivo 11.0 software was utilized for a three-level coding process to establish a policy text analysis framework and to identify deficiencies in the construction of policies.Results:A total of 63 policy documents were included, comprising 53 provincial and municipal documents, which were mainly concentrated in economically developed provinces; After three-level coding, 72 third level nodes, 21 second level nodes, and 8 first level nodes(service objects, service providers, service methods, service content, service fees, subsidy policies, hospital bed configuration, and standardized management) were obtained. Among them, the responsibilities of service providers needed to be further clarified, the technical and innovative nature of service content was still insufficient, the charging standards and medical insurance reimbursement policies needed to be improved, the support for subsidy policies was limited, and the use of intelligent devices in bed configuration needed to be strengthened.Conclusions:China′s family bed service policy focused on eight dimensions, covering a comprehensive range of content, but there were still areas that need to be refined and improved. This study suggested that relevant departments should further clarify the responsibilities of service providers, deepen the construction of service connotations, moderately increase government support, promote the intelligent construction of services, and achieve multi-party collaboration to jointly promote the sustainable development of family bed services in China.
		                        		
		                        		
		                        		
		                        	
5.Possible Risk Factors for Bone Marrow Fibroplasia in Patients with Polycythemia Vera.
De-Hao WANG ; Pei ZHAO ; Zi-Qing WANG ; Er-Peng YANG ; Yu-Meng LI ; Ji-Cong NIU ; Yi CHEN ; Ke CHEN ; Ming-Jing WANG ; Wei-Yi LIU ; Yan LYU ; Xiao-Mei HU
Journal of Experimental Hematology 2023;31(6):1780-1786
		                        		
		                        			OBJECTIVE:
		                        			To understand the biological characteristics of polycythemia vera (PV) patients with myeloid fibroplasia, and further analyze the risk factors affecting myeloid fibroplasia in PV patients, so as to provide ideas for predicting the occurrence of myeloid fibroplasia in PV patients.
		                        		
		                        			METHODS:
		                        			Forty patients with PV in the Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences were collected and divided into two groups, with (hyperplasia group) and without (Non-proliferative group) hyperplasia of bone marrow fibers. The differences of basic clinical characteristics, blood routine, biochemistry, bone marrow cells, coagulation function and other indicators between the two groups were compared, and the independent risk factors affecting the proliferation of bone marrow fibrous tissue in PV patients were further analyzed by multivariate regression.
		                        		
		                        			RESULTS:
		                        			Compared with Non-proliferative group, the JAK2 mutation rate (95% vs 70%,P=0.037), eosinophilic cell count (0.19 vs 0.11, P=0.047) and eosinophilic percentage (1.84 vs 1.27, P=0.001) in PV patients with hyperplasia were significantly increased, triglycerides (1.55 vs 1.91, P=0.038) and low-density lipoprotein (1.50 vs 3.08, P=0.000) were significantly reduced, bone marrow hematopoietic volume (0.85 vs 0.6, P=0.001), granulocyte/erythrocyte ratio (3.40 vs 1.89, P=0.033), lymphocyte/erythrocyte ratio (0.60 vs 0.42, P=0.033), and granulocyte+lymphocyte/erythrocyte ratio (3.72 vs 2.37, P=0.026) were significantly increased, thrombin time (18.84 vs 18.12, P=0.043) was significantly prolonged. Multivariate regression analysis results showed that peripheral blood eosinophil ≥2% and low-density lipoprotein ≤2 mmol/L were independent risk factors for bone marrow fibrous tissue hyperplasia in PV patients (P<0.05).
		                        		
		                        			CONCLUSION
		                        			Increased proportion of peripheral blood eosinophils and decreased low density lipoprotein are risk factors for bone marrow fibrous tissue hyperplasia in PV patients.
		                        		
		                        		
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Bone Marrow/pathology*
		                        			;
		                        		
		                        			Polycythemia Vera
		                        			;
		                        		
		                        			Hyperplasia/pathology*
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		                        			Granulocytes/pathology*
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		                        			Janus Kinase 2/genetics*
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		                        			Risk Factors
		                        			;
		                        		
		                        			Lipoproteins, LDL
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		                        			Polycythemia/pathology*
		                        			
		                        		
		                        	
6.The effect of different stent oversize on lumen remodeling of endovascular repair of type B aortic dissection
Zhigang PEI ; Haijie CHE ; Lubin LI ; Guolong LIU ; Mu YANG ; Wenqiang NIU ; Zhongzhen YANG ; Hengyang DONG ; Benxiang YU
Chinese Journal of General Surgery 2023;38(1):28-32
		                        		
		                        			
		                        			Objective:To investigate the effect of different stent oversize in thoracic endovascular aortic repair (TEVAR) on lumen remodeling of type B aortic dissection (TBAD).Methods:The clinical and follow-up data of 89 TBAD patients receiving TEVAR from Nov 2010 to Jun 2020 at Yantai Yuhuangding Hospital were retrospectively analyzed. According to the difference of proximal stent oversize, 89 patients were divided into: low oversize group (<10%, 47 cases) and high oversize group (≥10%, 42 cases). The changes of the normal vessel diameter and area at the proximal end of the stent and the long diameter, short diameter and area of the true/false lumen at the distal end of the stent at 3, 6, and 12 months after surgery and postoperative complications were analyzed.Results:The change of proximal vessel diameter with time in the low oversize group is smaller than that in the high oversize group ( P<0.05),and the change of the distal false lumen area of the stent in the low oversize group was greater than that in the high oversize group ( P<0.05). The high oversize group was prone to retrograde type A aortic dissection (RTAD) ( P<0.05). Conclusion:Low oversize stents are more conducive to the remodeling of the aortic lumen in the early and mid-term after TEVAR in TBAD patients.
		                        		
		                        		
		                        		
		                        	
7.Predictive Value of Hypodensities and Spot Sign for Hematoma Enlargement in Early Stage of Spontaneous Cerebral Hemorrhage
Shan-shan NIU ; Li-ping ZHONG ; Teng-fei SONG ; Pei-xin QIN ; Ling-mei CHEN ; Ya-qin ZHANG
Journal of Sun Yat-sen University(Medical Sciences) 2022;43(3):496-503
		                        		
		                        			
		                        			ObjectiveTo explore the application of hypodensities on computed tomography (CT) and the spot sign on CT angiography (CTA) in predicting hematoma expansion in patients with acute intracerebral hemorrhage. MethodsA total of 232 patients with acute intracerebral hemorrhage were retrospectively analyzed. All the patients were divided into hematoma expansion group (62) and hematoma non-expansion group (170). All patients were examined with CT and CT angiography within 24 hours after onset to determine the volume,and reexamined with CT to determine whether hematoma expansion occurred. General clinical and imaging data of all patients were collected. Univariate survival analysis, Logistic regression analysis and ROC curve were carried out to compare the diagnostic value of hypodensities on CT and the spot sign on CTA in predicting hematoma expansion in patients with acute intracerebral hemorrhage. ResultsUnivariate survival analysis showed the GCS score, initial CT time, spot sign and hypodensities were significantly different between the two groups (P values are 0.003, 0.012, <0.001, 0.001, respectively). Logistic regression analysis showed the initial CT time, spot sign and hypodensities were significantly different between the two groups (P<0.05). The area under ROC curve of spot sign, hypodensities, spot sign combined with hypodensities were respectively 0.669, 0.606, 0.726; The sensitivity and specificity of spot sign, hypodensities, spot sign combined with hypodensities were 41.9% and 91.8%, 93.5% and 27.6%, 95.2% and 27.6%, respectively. ConclusionsThe spot sign and hypodensities are independent risk factors for hematoma enlargement. The hypodensities shows a higher sensitivity, the spot sign shows a higher specificity, and the prediction ability of spot sign combined with hypodensities is better than that of alternatively single sign. 
		                        		
		                        		
		                        		
		                        	
8.Analysis of intestinal microbial diversity in Leopoldamys edwardsi based on illumina sequencing technique.
Duan Duan XUAN ; Yuan Li LI ; Guan Nan ZHANG ; Lin Wei DING ; Pei Pei CAO ; Rui Jie JIA ; Yu Ai ZHENG ; Xiao Jun ZHOU ; Liang Yuan PAN ; Shou Kui HU ; Li Na NIU
Chinese Journal of Preventive Medicine 2022;56(4):512-518
		                        		
		                        			
		                        			To explore the composition and diversity of the intestinal microflora of Leopoldamys edwardsi in Hainan Island. In November 2019, DNA was extracted from fecal samples of 25 adult Leopoldamys edwardsi (14 males and 11 females) in Hainan Island at the Joint Laboratory of tropical infectious diseases of Hainan Medical College and Hong Kong University. Based on the IonS5TMXL sequencing platform, single-end sequencing (Single-End) was used to construct a small fragment library for single-end sequencing. Based on Reads shear filtration and OTUs clustering. The species annotation and abundance analysis of OTUs were carried out by using mothur method and SSUrRNA database, and further conducted α diversity and β diversity analysis. A total of 1481842 high quality sequences, belonging to 14 Phyla, 85 families and 186 Genera, were obtained from 25 intestinal excrement samples of Leopoldamys edwardsi. At the level of phyla classification, the main core biota of the Leopoldamys edwardsi contained Firmicutes (46.04%),Bacteroidetes (25.34%), Proteobacteria (17.09%), Tenericutes (7.38%) and Actinobacteria (1.67%), these five phyla account for 97.52% of all phyla. The ratio of Helicobacter which occupied the largest proportion at the genus level was 12.44%, followed by Lactobacillus (11.39%), Clostridium (6.19%),Mycoplasma (4.23%) and Flavonifractor (3.52%). High throughput sequencing analysis showed that the intestinal flora of Leopoldamys edwardsi in Hainan Island was complex and diverse, which had the significance of further research.
		                        		
		                        		
		                        		
		                        			Adult
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		                        			Animals
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		                        			Bacteria/genetics*
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		                        			Feces/microbiology*
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		                        			Female
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		                        			Gastrointestinal Microbiome/genetics*
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		                        			High-Throughput Nucleotide Sequencing
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		                        			Humans
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		                        			Intestines
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		                        			Male
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		                        			Murinae/genetics*
		                        			
		                        		
		                        	
9.Characteristics and related factors of viral nucleic acid negative conversion in children infected with Omicron variant strain of SARS-CoV-2.
Rong YIN ; Quan LU ; Jia Li JIAO ; Kai LIN ; Chao WANG ; Lang YUAN ; Ying DING ; Na DONG ; Bing Jie WANG ; Yan Hua NIU ; Yong Shuang FANG ; Wei LIU ; Yi Fan SUN ; Bing ZOU ; Xiao E ZHANG ; Pei XIAO ; Lei SUN ; Xin DU ; Ying Ying ZHU ; Xiao Yan DONG
Chinese Journal of Pediatrics 2022;60(12):1307-1311
		                        		
		                        			
		                        			Objective: To understand the characteristics and associated factors of viral nucleic acid conversion in children infected with Omicron variant strain of SARS-CoV-2 in Shanghai. Methods: The clinical symptoms, laboratory results and other data of 177 children infected with SARS-CoV-2 who were hospitalized in Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University (designated hospital for SARS-CoV-2 infection in Shanghai) from April 25 to June 8, 2022 were retrospectively analyzed. According to the chest imaging findings, the children were divided into mild and common type groups. According to their age, the unvaccinated children were divided into<3 years old group and 3-<18 years old group. According to the vaccination status, the children aged 3-<18 year were divided into non-vaccination group, 1-dose vaccination group and 2-dose vaccination group. Comparison between groups was performed by independent sample t-test and analysis of variance, and multivariate linear regression analysis was used for multivariate analysis. Results: Among the 177 children infected with Omicron variant of SARS-CoV-2, 96 were males and 81 were females, aged 3 (1, 6) years. The time of viral nucleic acid negative conversion was (10.3±3.1) days. The 177 children were 138 cases of mild type and 39 cases of common type. Among the children aged 3-<18 years old, 55 cases were not vaccinated, 5 cases received 1-dose and 36 cases received 2-dose vaccination. Among the 36 children who received 2 doses of vaccination, the time of viral nucleic acid negative conversion was shorter in those vaccinated within 6 months than those over 6 months ((7.1±1.9) vs. (10.8±3.0) d, t=-3.23, P=0.004). Univariate analysis showed that the time of nucleic acid negative conversion of SARS-CoV-2 was associated with age, underlying diseases, gastrointestinal symptoms, white blood cell count, proportion of neutrophils, proportion of lymphocytes, and the number of doses of SARS-CoV-2 vaccine (t=3.87, 2.55, 2.04, 4.24, 3.51, 2.92, F=16.27, all P<0.05). Multiple linear regression analysis showed that older age (β=-0.33, 95% CI -0.485--0.182, P<0.001) and more doses of vaccination (β=-0.79, 95% CI -1.463--0.120, P=0.021) were associated with shortened nucleic acid negative conversion time in children, while lower lymphocyte proportion (β=-0.02, 95% CI -0.044--0.002, P=0.031) and underlying diseases (β=1.52, 95% CI 0.363-2.672, P=0.010) were associated with prolonged nucleic acid negative conversion time in children. Conclusion: The children infected with Omicron variant of SARS-CoV-2 with reduced lymphocyte proportion and underlying diseases may have longer time of viral nucleic acid negative conversion,while children with older age and more doses of vaccination may have shorter time of viral nucleic acid negative conversion.
		                        		
		                        		
		                        		
		                        			Child
		                        			;
		                        		
		                        			Female
		                        			;
		                        		
		                        			Male
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Child, Preschool
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		                        			Adolescent
		                        			;
		                        		
		                        			SARS-CoV-2
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		                        			COVID-19 Vaccines
		                        			;
		                        		
		                        			Nucleic Acids
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		                        			COVID-19
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		                        			Retrospective Studies
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		                        			China/epidemiology*
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		                        			Translocation, Genetic
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		                        			Hospitals, Pediatric
		                        			
		                        		
		                        	
10.Nonlocal low-rank and sparse matrix decomposition for low-dose cerebral perfusion CT image restoration.
Shan Zhou NIU ; Hong LIU ; Pei Yun LIU ; Meng Zhen ZHANG ; Shuo LI ; Li Jing LIANG ; Na LI ; Guo Liang LIU
Journal of Southern Medical University 2022;42(9):1309-1316
		                        		
		                        			OBJECTIVE:
		                        			To present a nonlocal low-rank and sparse matrix decomposition (NLSMD) method for low-dose cerebral perfusion CT image restoration.
		                        		
		                        			METHODS:
		                        			Low-dose cerebral perfusion CT images were first partitioned into a matrix, and the low- rank and sparse matrix decomposition model was constructed to obtain high-quality low-dose cerebral perfusion CT images. The cerebral hemodynamic parameters were calculated from the restored high-quality CT images.
		                        		
		                        			RESULTS:
		                        			In the phantom study, the average structured similarity (SSIM) value of the sequential images obtained by filtered back-projection (FBP) algorithm was 0.9438, which was increased to 0.9765 using the proposed algorithm; the SSIM values of cerebral blood flow (CBF) and cerebral blood volume (CBV) map obtained by FBP algorithm were 0.7005 and 0.6856, respectively, which were increased using the proposed algorithm to 0.7871 and 0.7972, respectively.
		                        		
		                        			CONCLUSION
		                        			The proposed method can effectively suppress noises in low-dose cerebral perfusion CT images to obtain accurate cerebral hemodynamic parameters.
		                        		
		                        		
		                        		
		                        			Algorithms
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		                        			Cerebrovascular Circulation
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		                        			Image Processing, Computer-Assisted/methods*
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		                        			Phantoms, Imaging
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		                        			Tomography, X-Ray Computed/methods*
		                        			
		                        		
		                        	
            
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