1.Constructing a model of degenerative scoliosis using finite element method:biomechanical analysis in etiology and treatment
Kai HE ; Wenhua XING ; Shengxiang LIU ; Xianming BAI ; Chen ZHOU ; Xu GAO ; Yu QIAO ; Qiang HE ; Zhiyu GAO ; Zhen GUO ; Aruhan BAO ; Chade LI
Chinese Journal of Tissue Engineering Research 2025;29(3):572-578
		                        		
		                        			
		                        			BACKGROUND:Degenerative scoliosis is defined as a condition that occurs in adulthood with a coronal cobb angle of the spine>10° accompanied by sagittal deformity and rotational subluxation,which often produces symptoms of spinal cord and nerve compression,such as lumbar pain,lower limb pain,numbness,weakness,and neurogenic claudication.The finite element method is a mechanical analysis technique for computer modelling,which can be used for spinal mechanics research by building digital models that can realistically restore the human spine model and design modifications. OBJECTIVE:To review the application of finite element method in the etiology and treatment of degenerative scoliosis. METHODS:The literature databases CNKI,PubMed,and Web of Science were searched for articles on the application of finite element method in degenerative scoliosis published before October 2023.Search terms were"finite element analysis,biomechanics,stress analysis,degenerative scoliosis,adult spinal deformity"in Chinese and English.Fifty-four papers were finally included. RESULTS AND CONCLUSION:(1)The biomechanical findings from the degenerative scoliosis model constructed using the finite element method were identical to those from the in vivo experimental studies,which proves that the finite element method has a high practical value in degenerative scoliosis.(2)The study of the etiology and treatment of degenerative scoliosis by the finite element method is conducive to the prevention of the occurrence of the scoliosis,slowing down the progress of the scoliosis,the development of a more appropriate treatment plan,the reduction of complications,and the promotion of the patients'surgical operation.(3)The finite element method has gradually evolved from a single bony structure to the inclusion of soft tissues such as muscle ligaments,and the small sample content is increasingly unable to meet the research needs.(4)The finite element method has much room for exploration in degenerative scoliosis.
		                        		
		                        		
		                        		
		                        	
2.Focusing on the evaluation of resectability of bile ducts-Application of medical imaging technology and 3D recon-struction in preoperative planning for radical resection of hi-lar cholangiocarcinoma
Xiang-Min DING ; Dou-Sheng BAI ; Guo-Qing JIANG ; Sheng-Jie JIN ; Chi ZHANG ; Qian WANG ; Bao-Huan ZHOU ; Ao-Qing WANG ; Ren-Jie LIU
Chinese Journal of Current Advances in General Surgery 2024;27(10):789-793
		                        		
		                        			
		                        			Hepatohilar cholangiocarcinoma is a common malignant tumor of the biliary system,and radical surgery is one of the important treatment methods.Due to the narrow space at the hi-lum and the high rate of anatomical variation,radical surgery is challenging.By using medical imag-ing technology and 3D reconstruction,surgeons can accurately determine the stage and classifica-tion of hilar cholangiocarcinoma preoperatively.They can assess the tumor's resectability by Ac-cording to the bile duct separation limit points(U point,P point)and anticipate the impact of portal vein,bile duct,and arterial variations on the surgical plan,thereby improving the rate of radical re-section and reducing complication rates.
		                        		
		                        		
		                        		
		                        	
3.Antiviral Efficacy and Mechanism of BD-77 Against Novel Coronavirus SARS-CoV-2
Lei BAO ; Qinhai MA ; Shanshan GUO ; Ronghua ZHAO ; Wen XIA ; Zihan GENG ; Jing SUN ; Yanyan BAO ; Zhou XU ; Shenglong YAN ; Jinxin XIAO ; Huarong CHEN ; Chenggang HUANG ; Xiaolan CUI
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(13):45-51
		                        		
		                        			
		                        			ObjectiveThe human angiotensin converting enzyme2 (hACE2) transgenic mouse model was used to clarify the antiviral efficacy of BD-77 against a novel coronavirus SARS-CoV-2 and explore the action mechanism of BD-77 against SARS-CoV-2. MethodSARS-CoV-2 Omicron and Delta variant strains-infected VeroE6 cell models were established and administered with BD-77 to observe the antiviral effect of BD-77 in vitro. A kit was used to detect the effect of BD-77 in vitro on the binding of spike S protein of SARS-CoV-2 virus (Delta/Omicron) to angiotensin converting enzyme2 (ACE2). Chromatography was adopted to detect the binding of BD-77 to the S protein and N protein of the novel coronavirus. hACE2 transgenic C57BL/6 mice were divided into a blank control group, SARS-CoV-2 infection group, BD-77 administration groups of 37.5 mg·kg-1 and 75 mg·kg-1, with eight mice in each group. The pneumonia model of SARS-CoV-2-infected hACE2 transgenic mice was built to observe the survival of the mice, detect the virus titer of the lung tissue of the mice, and observe the lesions in the lung tissue. ResultBD-77 had a certain inhibitory effect on Omicron and Delta variant strains in vitro, with median inhibitory concentration (IC50) of 526.3 mg·L-1 and 653.0 mg·L-1, respectively. BD-77 had no significant inhibitory effect on the binding of the S protein of WT, Omicron, and Delta variant strains of SARS-CoV-2 to ACE2 and had no binding effect with the S protein and N protein of the novel coronavirus. No mice in the blank group died, while the mortality rate of SARS-CoV-2-infected mice was 75%. There was a large amount of virus replication in the lung tissue of the mice and large areas of inflammatory infiltration in the lung tissue and interstitium. Compared with the model group, BD-77 administration groups of 37.5 mg·kg-1 and 75 mg·kg-1 could reduce the mortality of mice, significantly lower the virus titer in the lung tissue of mice (P<0.05), and improve lung lesions. ConclusionBD-77 demonstrated significant inhibitory effects against SARS-CoV-2 virus in vitro and in vivo. However, its mechanism of action did not involve direct inhibition of the virus itself or intervention in the virus-host binding process. This finding suggests that the mechanism of action of BD-77 needs to be thoroughly investigated and elucidated by further experiments. 
		                        		
		                        		
		                        		
		                        	
4.Preliminary Proteomics-based Investigation of Inhibitory Effect and Mechanism of BD-77 by Nebulized Inhalation on Respiratory Viral Infections
Lei BAO ; Zihan GENG ; Shanshan GUO ; Lirun ZHOU ; Ronghua ZHAO ; Jing SUN ; Yanyan BAO ; Xing LI ; Cigang HUANG ; Kun JIANG ; Feiyan PENG ; Zhou XU ; Chenggang HUANG ; Xiaolan CUI
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(13):52-59
		                        		
		                        			
		                        			ObjectiveTo observe the therapeutic effect of BD-77 by nebulized inhalation on animal models of various respiratory viral infections and investigate the mechanism of broad-spectrum antiviral action of BD-77 using proteomics. MethodThe influenza virus H1N1/FM1 experiment used ICR mice and divided them into a normal group, model group, Tamiflu group, and BD-77 groups of 75 and 37.5 g·L-1 for inhalation of 20 min and 25 min. Human coronavirus 229E and OC43 experiment divided the BALB/c mice into a normal group, model group, chloroquine phosphate group, and BD-77 groups of 75, 37.5, 18.75, and 9.375 g·L-1, with 10 mice in each group. Influenza virus H1N1/FM1 and human coronaviruses 229E and OC43 infection-induced pneumonia models were used to detect mouse lung index, and real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) was used to detect the viral load in lung tissue. Enzyme-linked immunosorbent assay (ELISA) was used to detect related inflammatory factors in lung tissue, and proteomics analysis was performed on the lung tissue of OC43-infected mice. ResultCompared with that in the normal group, the lung index of mice in each infection group was significantly increased (P<0.01), and viral nucleic acid could be detected in the lung tissue of mice infected with human coronaviruses 229E and OC43. The levels of interleukin-6 (IL-6), IL-10, and tumor necrosis factor-α (TNF-α) in the lung tissue of mice infected with human coronavirus 229E were all significantly increased (P<0.01). BD-77 could significantly reduce the lung index of mice infected with influenza virus H1N1/FM1 and human coronaviruses 229E and OC43 (P<0.05, P<0.01), cut down the viral load in the lungs of mice infected with human coronaviruses 229E and OC43 (P<0.01), and lower the contents of IL-6, IL-10, and TNF-α in the lung tissue of mice infected with human coronavirus 229E (P<0.01). Proteomics analysis of the lung tissue of OC43-infected mice showed that BD-77 regulated the AMPK signaling pathway, TNF signaling pathway, NOD-like signaling pathway, IL-17 signaling pathway, Forkhead box protein O (FoxO) signaling pathway, transforming growth factor-β (TGF-β) signaling pathway, and other signaling pathways. ConclusionNebulized inhalation of BD-77 is effective in treating pneumonia caused by influenza virus H1N1/FM1 and human coronaviruses 229E and OC43 infection in mice and may exert its antiviral effects by regulating the balance of cellular metabolism, enhancing the immune function of the host, and attenuating inflammatory responses. 
		                        		
		                        		
		                        		
		                        	
5.Molluscicidal effect of spraying different formulations of niclosamide ethanolamine salt with drones against Oncomelania hupensis in ditches
Zelin ZHU ; Xia ZHANG ; Junyi HE ; Ying CHEN ; Weisi WANG ; Hehua HU ; Chunli CAO ; Ziping BAO ; Suying GUO ; Liping DUAN ; Yi YUAN ; Jing XU ; Shizhu LI ; Xiaonong ZHOU
Chinese Journal of Schistosomiasis Control 2024;36(5):527-530
		                        		
		                        			
		                        			 Objective To evaluate the molluscicidal effect of spraying different formulations of niclosamide ethanolamine salt with drones against Oncomelania hupensis in ditches. Methods A semi-dry and semi-wet ditch with O. hupensis snails was selected in the second branch field of Jiangbei Farm, Jiangling County, Hubei Province in May 2023, and divided into 4 experimental areas, named groups A1, A2, B1 and B2. Environmental cleaning was performed in groups A1 and B2, and was not conducted in groups A2 or B2. Then, 50% wettable powder of niclosamide ethanolamine salt was sprayed with drones at an effective dose of 2 g/m2 in groups A1 and A2, and 5% niclosamide ethanolamine salt granule was sprayed with drones at an effective dose of 2 g/m2 in groups B1 and B2. O. hupensis snails were surveyed using the systematic sampling method 1, 3, 5, 7, 14 days after spraying, and the natural mortality and corrected mortality of O. hupensis snails were calculated. Results The occurrence of frames with living snails, mean density of living snails and natural mortality of snails were 97.50% (117/120), 6.30 snails/0.1 m2 and 1.18% (9/765) in the test ditch before spraying, respectively. There were significant differences in the mortality of snails among four groups 1, 3, 5, 7 and 14 days after spraying niclosamide formulations with drones (χ2 = 17.230, 51.707, 65.184, 204.050 and 34.435, all P values < 0.01). The overall mortality rates of snails were 94.51% (1 051/1 112), 79.44% (908/1 143), 96.54% (977/1 012) and 88.55% (1 021/1 153) in groups A1, A2, B1 and B2 (χ2 = 207.773, P < 0.05), respectively. In addition, there was no significant difference in the overall snail mortality between groups A1 and B1 (P > 0.05), and the snail mortality in groups A1 and B1 were both statistically different from that in groups A2 and B2 (all P values < 0.05). Conclusion Both 50% wettlable powder of niclosamide ethanolamine salt and 5% niclosamide ethanolamine salt granule sprayed with drones are active against O. hupensis snails in ditches, and environmental cleaning may improve the molluscicidal effect. 
		                        		
		                        		
		                        		
		                        	
6.Molluscicidal effect of spraying 5% niclosamide ethanolamine salt granules with drones against Oncomelania hupensis in marshland areas
Chunli CAO ; Jianfeng ZHANG ; Yefang LI ; Xuehui SHEN ; Junyi HE ; Ziping BAO ; Suying GUO ; Kun YANG ; Jing XU ; Shizhu LI ; Xiaonong ZHOU
Chinese Journal of Schistosomiasis Control 2024;36(5):531-534
		                        		
		                        			
		                        			 Objective To evaluate the molluscicidal effect of spraying 5% niclosamide ethanolamine salt granules with drones against of Oncomelania hupensis snails in snail habitats in marshland areas. Methods From September to October, 2022, marshlands were sampled from Dantu District, Zhenjiang City, Jiangsu Province as study areas, and assigned into four groups, of approximately 3 000 m2 per group. In Group A, environmental cleaning was performed, followed by spraying 5% niclosamide ethanolamine salt granules with knapsack sprayers at a dose of 40 g/m2, and in Group B, 5% niclosamide ethanolamine salt granules were sprayed with knapsack sprayers at a dose of 40 g/m2 without environmental cleaning, while in Group C, environmental cleaning was conducted, followed by spraying 5% niclosamide ethanolamine salt granules with drones at a dose of 40 g/m2, and in Group D, 5% niclosamide ethanolamine salt granules were sprayed with drones at a dose of 40 g/m2 without environmental cleaning. Then, the study areas in each group were equally divided into six blocks, with Block 1 for baseline surveys and blocks 2 to 6 for snail surveys 1, 3, 5, 7, 14 days following chemical treatment. The mortality of snails and the reduction of the density of living snails were calculated. Results A total of 132 frames were surveyed during the period from September to October 2022, and the occurrence of frames with living snails and means density of living snails were 61.36% (81/132) and 1.58 snails/0.1 m2, respectively. The overall mortality rates of snails were 43.02% (77/179), 38.69% (77/199), 47.78% (86/180) and 31.02% (58/187) 14 days following chemical treatment in groups A, B, C and D, respectively (χ2 = 11.646, P < 0.05), and there were differences detected in the snail mortality between group A and D, and between groups C and D (both Padjusted values < 0.05). The adjusted mortality rates of snails were 37.42%, 36.07%, 38.85% and 40.40% in groups A, B, C and D 14 days post-treatment, and the density of living snails decreased by 48.10%, 63.29%, 67.09% and 69.62% 14 days post-treatment relative to pre-treatment, respectively. Conclusions Chemical treatment with drones is feasible for O. hupensis snail control in marshland areas; however, the molluscicidal effect of spraying 5% niclosamide ethanolamine salt granules with drones is comparable to spraying chemicals manually in marshland areas regardless of environmental cleaning. 
		                        		
		                        		
		                        		
		                        	
7.Detection of five tick-borne pathogens in Maanshan City,Anhui Province,China
Guo-Dong YANG ; Kun YANG ; Liang-Liang JIANG ; Ming WU ; Ying HONG ; Ke-Xia XIANG ; Jia HE ; Lei GONG ; Dan-Dan SONG ; Ming-Jia BAO ; Xing-Zhou LI ; Tian QIN ; Yan-Hua WANG
Chinese Journal of Zoonoses 2024;40(4):308-314
		                        		
		                        			
		                        			Here,5 important pathogens carried by ticks in Maanshan City,Anhui Province,China were identified.In to-tal,642 ticks were collected from 13 villages around Maanshan City and identified by morphological and mitochondrial COI genes.The 16S rRNA gene of Francisella tularensis,ssrA gene of Bartonella,16S rRNA,ompA and ompB genes of Rickett-sia,16S rRNA and gltA genes of Anaplasma,and groEL and rpoB genes of Coxiella were sequenced.Reference sequences were retrieved from a public database.Phylogenetic trees were constructed with MEG A1 1.0 software.In total,36 Rickettsiae isolates were detected in 640 Haemaphysalis longicornis ticks,which included 20 isolates of Rickettsia heilongjian-gensis,16 of Candidatus Rickettsia jingxinensis,2 of Ana-plasma bovis,and 186 of Coxiella-like endosymbiont.R.hei-longjiangensis HY2 detected in this study and Anhui B8 strain,Ca.R.jingxinensis QL3 and those from Shanxi Prov-ince and Jiangsu Province,A.bovis JX4 and those from Shanxi Province were clustered on the same branch.Overall,17 ticks had combined infections and none of the 5 bacteria were detected in two Amblyomma testudinarium ticks.This is the first report of Ca.R.jingxinensis detected in H.longicornis ticks from Anhui Province.It is recommended that the two types of Rickettsia that cause spotted fever and A.bovis should be reported to local health authorities to initiate appropriate prevention and control measures.
		                        		
		                        		
		                        		
		                        	
8.Identification of novel candidate genes in East Asian COPD patients by the functional summary-based imputation and the unified test for molecular signatures: a transcriptome-wide association study.
Ye TIAN ; Shufang SHAN ; Qixue BAO ; Siquan ZHOU ; Xia JIANG ; Mengqiao WANG ; Shu YIN ; Jingyuan XIONG ; Guo CHENG
Chinese Medical Journal 2023;136(13):1612-1614
9.Predictive Effects of Different Insulin Resistance Indexes on Diabetes Risk in Hypertensive Population.
Tao WANG ; Chao YU ; Guo-Tao YU ; Wei ZHOU ; Ling-Juan ZHU ; Xiao HUANG ; Hui-Hui BAO ; Xiao-Shu CHENG
Acta Academiae Medicinae Sinicae 2023;45(2):206-212
		                        		
		                        			
		                        			Objective To explore the roles of different insulin resistance indexes[triglyceride-glucose (TyG),triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C),and metabolic score for insulin resistance (METS-IR)]and combinations of two indexes in predicting diabetes risk in hypertensive population. Methods The survey of hypertension was conducted for the residents in Wuyuan county,Jiangxi province from March to August in 2018.The basic information of hypertensive residents was collected by interview.Blood was drawn on an empty stomach in the morning and physical measurements were carried out.Logistic regression model was employed to analyze the relationship between different insulin resistance indexes and diabetes,and the area under the receiver operating characteristic curve was used for evaluating the predictive effects of each index on diabetes risk. Results A total of 14 222 hypertensive patients with an average age of (63.8±9.4) years old were included in this study,including 2616 diabetic patients.The diabetic hypertensive population had higher TyG (t=50.323,P<0.001),TG/HDL-C (Z=17.325,P<0.001),and METS-IR (t=28.839,P<0.001) than the non-diabetic hypertensive population.Multivariate analysis showed that each insulin resistance index was positively correlated with diabetes risk.The area under curve of each insulin index was in a descending order of TyG (0.770)> METS-IR (0.673)> TG/HDL-C (0.620).The difference in the area under curve between two indexes was statistically significant[TyG vs.TG/HDL-C (Z=42.325,P<0.001);TyG vs.METS-IR(Z=17.517,P<0.001);METS-IR vs.TG/HDL-C (Z=10.502,P<0.001)]. Conclusions Elevated insulin resistance indexes can increase the risk of diabetes.TyG and the combination of indexes outperform TG/HDL-C and METS-IR in the prediction of diabetes.
		                        		
		                        		
		                        		
		                        			Humans
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		                        			Middle Aged
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		                        			Aged
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		                        			Insulin Resistance
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		                        			Blood Glucose/metabolism*
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		                        			Biomarkers
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		                        			Diabetes Mellitus
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		                        			Hypertension
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		                        			Glucose
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		                        			Triglycerides
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		                        			Cholesterol, HDL
		                        			
		                        		
		                        	
10.Incidence and prognosis of olfactory and gustatory dysfunctions related to infection of SARS-CoV-2 Omicron strain: a national multi-center survey of 35 566 population.
Meng Fan LIU ; Rui Xia MA ; Xian Bao CAO ; Hua ZHANG ; Shui Hong ZHOU ; Wei Hong JIANG ; Yan JIANG ; Jing Wu SUN ; Qin Tai YANG ; Xue Zhong LI ; Ya Nan SUN ; Li SHI ; Min WANG ; Xi Cheng SONG ; Fu Quan CHEN ; Xiao Shu ZHANG ; Hong Quan WEI ; Shao Qing YU ; Dong Dong ZHU ; Luo BA ; Zhi Wei CAO ; Xu Ping XIAO ; Xin WEI ; Zhi Hong LIN ; Feng Hong CHEN ; Chun Guang SHAN ; Guang Ke WANG ; Jing YE ; Shen Hong QU ; Chang Qing ZHAO ; Zhen Lin WANG ; Hua Bin LI ; Feng LIU ; Xiao Bo CUI ; Sheng Nan YE ; Zheng LIU ; Yu XU ; Xiao CAI ; Wei HANG ; Ru Xin ZHANG ; Yu Lin ZHAO ; Guo Dong YU ; Guang Gang SHI ; Mei Ping LU ; Yang SHEN ; Yu Tong ZHAO ; Jia Hong PEI ; Shao Bing XIE ; Long Gang YU ; Ye Hai LIU ; Shao wei GU ; Yu Cheng YANG ; Lei CHENG ; Jian Feng LIU
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2023;58(6):579-588
		                        		
		                        			
		                        			Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
		                        		
		                        		
		                        		
		                        			Female
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		                        			Humans
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		                        			Adolescent
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		                        			SARS-CoV-2
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		                        			Smell
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		                        			COVID-19/complications*
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		                        			Cross-Sectional Studies
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		                        			COVID-19 Vaccines
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		                        			Incidence
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		                        			Olfaction Disorders/etiology*
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		                        			Taste Disorders/etiology*
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		                        			Prognosis
		                        			
		                        		
		                        	
            
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