1.A phase Ⅲ clinical study to evaluate the efficacy and safety profile of antaitasvir phosphate combined with yiqibuvir in the treatment of adults with chronic hepatitis C
Lai WEI ; Jia SHANG ; Xuan AN ; Guoqiang ZHANG ; Yujuan GUAN ; Hongxin PIAO ; Jinglan JIN ; Lang BAI ; Xingxiang YANG ; Daokun YANG ; Xinhua LUO ; Shufang YUAN ; Yingren ZHAO ; Yingjie MA ; Guangming LI ; Feng LIN ; Xiaoping WU ; Jiawei GENG ; Guizhou ZOU ; Jiabao CHANG ; Zuojiong GONG ; Xiaorong MAO ; Jing ZHU ; Wentao GUO ; Qingwei HE ; Lin LUO ; Yulei ZHUANG ; Hongming XIE ; Yingjun ZHANG
Chinese Journal of Hepatology 2025;33(6):560-569
Objective:To assess the efficacy and safety profile of antaitasvir phosphate combined with yiqibuvir in the treatment of chronic hepatitis C (CHC) of various genotypes, without cirrhosis or with compensated cirrhosis.Methods:394 cases with CHC from 22 centers were collected from October 2021 to April 2023. They were randomly assigned to receive either the experimental drugs (antaitasvir phosphate 100 mg+yiqibuvir 600 mg) or placebo treatment in a 3∶1 ratio. The patients were administered drugs once a day for 12 consecutive weeks, and then followed up for 24 weeks after treatment cessation. All subjects were unblinded at the four-week follow-up following drug discontinuation, with the experimental drug group continuing to complete subsequent post-discontinuation follow-up. The placebo group was switched to receive the experimental drugs for a repeated 12-week treatment period and followed up for another 24 weeks after discontinuation of the drug (placebo delayed treatment phase).The sustained virologic response rate (SVR12) was observed for subjects in the double-blind phase and the placebo delayed-treatment phase at 12 weeks after treatment cessation.Virological resistance analysis was performed on subjects who failed treatment. The primary efficacy endpoint was SVR12. The number and percentage of subjects who achieved "HCV RNA
2.Efficacy and safety of intravenous thrombolysis with tenecteplase in acute ischemic stroke across different time windows: a Meta-analysis
Yejun SHI ; Yulei JING ; Xin NIE ; Le YAO ; Mengjie FAN ; Chaosheng LI
Chinese Journal of Neuromedicine 2025;24(8):806-816
Objective:To systematically evaluate the efficacy and safety of intravenous thrombolysis with tenecteplase (TNK) in acute ischemic stroke (AIS) across different time windows.Methods:Randomized controlled trials investigating TNK in AIS were retrieved from PubMed, Embase, Web of Science, Cochrane Library, CNKI, and Wanfang databases, with data collected up to May 2025. Experimental group received intravenous thrombolysis with 0.25 mg/kg TNK, either alone or in combination with mechanical thrombectomy (MT). Control group received alteplase, placebo, standard medication (containing butylphthalide), MT, or above-mentioned drugs combined with MT. These patients were within 4.5 hours of onset (within-time window) or within 4.5-24 hours of onset (extended-time window). Efficacy indexes included functional outcome excellent rate (modified Rankin scale [mRS] score of 0-1 at 3 months after treatment), early neurological improvement rate (National Institutes of Health Stroke Scale [NIHSS] score improvement≥4 or NIHSS score ranged 0-1 within 72 of treatment), and recanalization rate 24 h after treatment. Safety indexes comprised symptomatic intracranial hemorrhage (sICH) rate within 48 h of treatment, and mortality rate and rate of serious adverse events (SAEs) within 90 d of treatment. Quality of the trials was assessed according to Cochrane handbook for systematic reviews of interventions (version 5.1). Meta-analysis was conducted using Stata software, with pooling data as risk difference ( RD). Results:Sixteen articles (11 were within-time window ones, and 5 were extended-time window ones), involving 9,430 AIS patients, were included. Quality grade of these articles is B-level. (1) In articles of within-time window: the experimental group had a significantly higher functional outcome excellent rate compared with the control group ( RD=0.031, 95% CI: 0.009-0.052, P=0.005); no significant difference was observed in early neurological improvement rate ( RD=0.016, 95% CI: -0.012-0.043, P=0.260), recanalization rate ( RD=0.040, 95% CI: 0.000-0.081, P=0.053), sICH rate ( RD=0.005, 95% CI: -0.002-0.012, P=0.198), mortality rate ( RD=0.000, 95% CI: -0.012-0.013, P=0.950), or SAE rate ( RD=0.003, 95% CI: -0.028-0.033, P=0.870) between the two groups. (2) In articles of extended-time window: the experimental group exhibited significantly higher functional outcome excellent rate ( RD=0.064, 95% CI: 0.016-0.113, P=0.009), early neurological improvement rate ( RD=0.101, 95% CI: 0.023-0.180, P=0.012), and recanalization rate ( RD=0.131, 95% CI: 0.059-0.203, P<0.001) compared with the control group; no significant difference was found in sICH rate ( RD=0.014, 95% CI: -0.003-0.032, P=0.097), mortality rate ( RD=0.006, 95% CI: -0.030-0.041, P=0.752), or SAE rate ( RD=0.030, 95% CI: -0.037-0.097, P=0.385) between the two groups. Conclusion:Intravenous thrombolysis with TNK is safe and effective in AIS patients at both within-time window and extended-time window.
3.A phase Ⅲ clinical study to evaluate the efficacy and safety profile of antaitasvir phosphate combined with yiqibuvir in the treatment of adults with chronic hepatitis C
Lai WEI ; Jia SHANG ; Xuan AN ; Guoqiang ZHANG ; Yujuan GUAN ; Hongxin PIAO ; Jinglan JIN ; Lang BAI ; Xingxiang YANG ; Daokun YANG ; Xinhua LUO ; Shufang YUAN ; Yingren ZHAO ; Yingjie MA ; Guangming LI ; Feng LIN ; Xiaoping WU ; Jiawei GENG ; Guizhou ZOU ; Jiabao CHANG ; Zuojiong GONG ; Xiaorong MAO ; Jing ZHU ; Wentao GUO ; Qingwei HE ; Lin LUO ; Yulei ZHUANG ; Hongming XIE ; Yingjun ZHANG
Chinese Journal of Hepatology 2025;33(6):560-569
Objective:To assess the efficacy and safety profile of antaitasvir phosphate combined with yiqibuvir in the treatment of chronic hepatitis C (CHC) of various genotypes, without cirrhosis or with compensated cirrhosis.Methods:394 cases with CHC from 22 centers were collected from October 2021 to April 2023. They were randomly assigned to receive either the experimental drugs (antaitasvir phosphate 100 mg+yiqibuvir 600 mg) or placebo treatment in a 3∶1 ratio. The patients were administered drugs once a day for 12 consecutive weeks, and then followed up for 24 weeks after treatment cessation. All subjects were unblinded at the four-week follow-up following drug discontinuation, with the experimental drug group continuing to complete subsequent post-discontinuation follow-up. The placebo group was switched to receive the experimental drugs for a repeated 12-week treatment period and followed up for another 24 weeks after discontinuation of the drug (placebo delayed treatment phase).The sustained virologic response rate (SVR12) was observed for subjects in the double-blind phase and the placebo delayed-treatment phase at 12 weeks after treatment cessation.Virological resistance analysis was performed on subjects who failed treatment. The primary efficacy endpoint was SVR12. The number and percentage of subjects who achieved "HCV RNA
4.Efficacy and safety of intravenous thrombolysis with tenecteplase in acute ischemic stroke across different time windows: a Meta-analysis
Yejun SHI ; Yulei JING ; Xin NIE ; Le YAO ; Mengjie FAN ; Chaosheng LI
Chinese Journal of Neuromedicine 2025;24(8):806-816
Objective:To systematically evaluate the efficacy and safety of intravenous thrombolysis with tenecteplase (TNK) in acute ischemic stroke (AIS) across different time windows.Methods:Randomized controlled trials investigating TNK in AIS were retrieved from PubMed, Embase, Web of Science, Cochrane Library, CNKI, and Wanfang databases, with data collected up to May 2025. Experimental group received intravenous thrombolysis with 0.25 mg/kg TNK, either alone or in combination with mechanical thrombectomy (MT). Control group received alteplase, placebo, standard medication (containing butylphthalide), MT, or above-mentioned drugs combined with MT. These patients were within 4.5 hours of onset (within-time window) or within 4.5-24 hours of onset (extended-time window). Efficacy indexes included functional outcome excellent rate (modified Rankin scale [mRS] score of 0-1 at 3 months after treatment), early neurological improvement rate (National Institutes of Health Stroke Scale [NIHSS] score improvement≥4 or NIHSS score ranged 0-1 within 72 of treatment), and recanalization rate 24 h after treatment. Safety indexes comprised symptomatic intracranial hemorrhage (sICH) rate within 48 h of treatment, and mortality rate and rate of serious adverse events (SAEs) within 90 d of treatment. Quality of the trials was assessed according to Cochrane handbook for systematic reviews of interventions (version 5.1). Meta-analysis was conducted using Stata software, with pooling data as risk difference ( RD). Results:Sixteen articles (11 were within-time window ones, and 5 were extended-time window ones), involving 9,430 AIS patients, were included. Quality grade of these articles is B-level. (1) In articles of within-time window: the experimental group had a significantly higher functional outcome excellent rate compared with the control group ( RD=0.031, 95% CI: 0.009-0.052, P=0.005); no significant difference was observed in early neurological improvement rate ( RD=0.016, 95% CI: -0.012-0.043, P=0.260), recanalization rate ( RD=0.040, 95% CI: 0.000-0.081, P=0.053), sICH rate ( RD=0.005, 95% CI: -0.002-0.012, P=0.198), mortality rate ( RD=0.000, 95% CI: -0.012-0.013, P=0.950), or SAE rate ( RD=0.003, 95% CI: -0.028-0.033, P=0.870) between the two groups. (2) In articles of extended-time window: the experimental group exhibited significantly higher functional outcome excellent rate ( RD=0.064, 95% CI: 0.016-0.113, P=0.009), early neurological improvement rate ( RD=0.101, 95% CI: 0.023-0.180, P=0.012), and recanalization rate ( RD=0.131, 95% CI: 0.059-0.203, P<0.001) compared with the control group; no significant difference was found in sICH rate ( RD=0.014, 95% CI: -0.003-0.032, P=0.097), mortality rate ( RD=0.006, 95% CI: -0.030-0.041, P=0.752), or SAE rate ( RD=0.030, 95% CI: -0.037-0.097, P=0.385) between the two groups. Conclusion:Intravenous thrombolysis with TNK is safe and effective in AIS patients at both within-time window and extended-time window.
5.Meta-analysis of efficacy and safety of aspirin versus other anticoagulants in the prevention of thromboembolism after orthopedic surgery
Pei WANG ; Meng WEI ; Yingying TAO ; Yulei ZHAO ; Jing WANG ; Qiang ZHOU
China Pharmacy 2024;35(2):219-225
OBJECTIVE To evaluate the clinical efficacy and safety of aspirin versus other anticoagulants in the prevention of thromboembolism after orthopedic surgery. METHODS Retrieved from PubMed, Embase, the Cochrane Library, CNKI, Wanfang data and VIP, randomized controlled trials (RCTs) and cohort studies about aspirin (trial group) versus other anticoagulants (control group) were collected during the inception and June 1st, 2023. After literature screening, data extraction and quality evaluation, the meta-analysis was conducted by using RevMan 5.4 software. RESULTS A total of 22 studies were included, involving 9 RCTs and 13 cohort studies. RCT results showed that the incidences of deep vein thrombosis (DVT) [RR=1.81, 95%CI(1.36, 2.40), P<0.000 1] and postoperative pulmonary embolism (PE) [RR=1.55, 95%CI(1.01, 2.40), P=0.05] in trial group were significantly higher than control group. There was no statistically significant difference in the incidences of postoperative massive bleeding, postoperative surgical site infection, all-cause death, or any bleeding after surgery between 2 groups. In the cohort study, the incidence of any bleeding in trial group was significantly lower than control group [RR=0.71,95%CI (0.64, 0.79), P<0.000 1], while the differences in other indicators were not statistically significant (P>0.05). The results of subgroup analysis based on different anticoagulants showed that in RCT, the incidences of DVT and PE after surgery in patients using low-molecular-weight heparin (LMWH) were significantly lower than using aspirin (P<0.05); in the cohort study, the incidences of DVT and PE after surgery were significantly lower in patients using direct oral anticoagulants (DOAC) than using aspirin (P<0.05). There was no statistically significant difference in the incidence of major bleeding between patients using aspirin and using DOAC and LWMH (P>0.05) in both RCT and cohort study. CONCLUSIONS Aspirin is equally safe as other anticoagulants for the prevention of thromboembolism after orthopedic surgery, but its efficacy may not be as good as other anticoagulants. After orthopedic surgery, other anticoagulants should be preferred to prevent venous thromboembolism, and aspirin should be carefully considered.
6.A phase Ⅱ clinical study of the efficacy and safety of antaitasvir phosphate combined with yiqibuvir for the treatment of chronic hepatitis C in adults
Lai WEI ; Hongxin PIAO ; Jinglan JIN ; Shufen YUAN ; Xuan AN ; Jia SHANG ; Wenhua ZHANG ; Jiabao CHANG ; Tong SUN ; Yujuan GUAN ; Bo NING ; Jing ZHU ; Wentao GUO ; Qingwei HE ; Lin LUO ; Yulei ZHUANG ; Hongming XIE ; Yingjun ZHANG
Chinese Journal of Hepatology 2024;32(7):637-642
Objective:To evaluate the efficacy and safety of antaitasvir phosphate 100 mg or 200 mg combined with yiqibuvir for 12 weeks in patients with various genotypes of chronic hepatitis C, without cirrhosis or compensated stage cirrhosis.Methods:Patients with chronic hepatitis C (without cirrhosis or compensated stage cirrhosis) were randomly assigned to the antaitasvir phosphate 100 mg+yiqibuvir 600 mg group (100 mg group) or the antaitasvir phosphate 200 mg+yiqibuvir 600 mg group (200 mg group) in a 1∶1 ratio. The drugs were continuously administered once a day for 12 weeks and observed for 24 weeks after drug withdrawal. The drug safety profile was assessed concurrently with the observation of the sustained virological response (SVR12) in the two patient groups 12 weeks following the drug cessation. The intention-to-treat concept was used to define as closely as possible a full analysis set, including all randomized cases who received the experimental drug at least once. The safety set was collected from all subjects who received the experimental drug at least once (regardless of whether they participated in the randomization group) in this study. All efficacy endpoints and safety profile data were summarized using descriptive statistics. The primary efficacy endpoint was SVR12. The primary analysis was performed on a full analysis set. The frequency and proportion of cases were calculated in the experimental drug group (antaitasvir phosphate capsules combined with yiqibuvir tablets) that achieved "HCV RNA
7.Prevention effecacy and safety of PCSK9 inhibitors in stroke in patients with atherosclerotic cardiovascular disease at primary and secondary prevention
Yejun SHI ; Yulei JING ; Shengyi ZHANG ; Chaosheng LI ; Liqun CHENG
Chinese Journal of Neuromedicine 2024;23(8):806-816
Objective:To examine the prevention effecacy and safety of preprotein convertase subtilisin-kexin 9 (PCSK9) inhibitors in stroke in patients with atherosclerotic cardiovascular disease (ASCVD) at primary and secondary prevention.Methods:PubMed, Embase, Web of Science, Cochrane Library, and Wanfang and CNKI databases were searched for randomized controlled trials comparing evolocumab, alirocumab, tafolecimab or inclisiran (experimental group) with placebo or conventional therapy (control group) in hyperlipidemia and ASCVD from inception to March 2024. Valid data were extracted after screening and applying Cochrane Literature quality assessment tool to assess the literature quality. Efficacy outcome (incidences of stroke and ischemic stroke) and safety outcome (cardiovascular mortality, and incidences of aminotransferase increased by more than 3 times, creatine kinase increased by more than 3 times, allergic reaction and hemorrhagic stroke) were recorded. Meta analysis of the extracted data was conducted using Stata software to calculate the risk difference ( RD). Results:Twenty articles (21 randomized controlled trials) were included with 62 799 patients. For primary prevention, no significant difference was found between PCSK9 inhibitors and control groups in stroke incidence ( RD=0.000, 95% CI: -0.002-0.003, P=0.905) or ischemic stroke incidence ( RD=0.001, 95% CI: -0.005-0.006, P=0.824); incidence of creatine kinase increased by more than 3 times in the PCSK9 inhibitors group was significantly decreased compared with that in the control group ( RD=-0.005, 95% CI: -0.010-0.000, P=0.039). For secondary prevention, PCSK9 inhibitors group had significantly reduced stroke incidence ( RD=-0.004, 95% CI: -0.006--0.002, P<0.001) and ischemic stroke incidence ( RD=-0.003, 95% CI: -0.005--0.002, P<0.001) compared with control group; no significant differences in cardiovascular mortality, or incidences of aminotransferase increased by more than 3 times, creatine kinase increased by more than 3 times, allergic reaction and hemorrhagic stroke were noted between the PCSK9 inhibitors group and control group ( P>0.05). Conclusion:PCSK9 inhibitors in primary prevention have no significant effect on stroke or ischemic stroke incidences, but can decrease the incidence of creatine kinase increased by more than 3 times; PCSK9 inhibitors in secondary prevention can reduce stroke and ischemic stroke incidences without increasing complications and thus enjoying certain safety.
8.Prevention and safety of evolocumab and alirocumab in ischemic stroke: a Meta analysis
Yejun SHI ; Yulei JING ; Chaosheng LI ; Lili ZHANG ; Liqun CHENG ; Yong LIU
Chinese Journal of Neuromedicine 2023;22(7):673-682
Objective:To evaluate the preventive role and safety of evolocumab and alirocumab in ischemic stroke in hyperlipidemia and atherosclerotic high-risk cardiovascular patients.Methods:PubMed, Embase, Web of Science, Cochrane Library, Wanfang, and CNKI databases were searched for randomized controlled trials (RCTs) comparing evolocumab or alirocumab (experimental group) with placebo or usual care (control group) in hyperlipidemia and atherosclerotic high-risk cardiovascular patients from database inception to March 2023. References were screened and data were extracted according to the preset inclusion and exclusion criteria; incidence of ischemic stroke was as the efficacy index, and incidences of cardiovascular death, cognitive impairment, aminotransferase increased for more than 3 times and creatine kinase increased for more than 3 times were as the safety index. Cochrane Reviewer Handbook 2.0 was used to evaluate the RCTs literature quality. Meta analysis was performed using Stata software.Results:A total of 11 articles were included, including 12 studies with a total of 53 666 patients. Compared with the control group, the incidence of ischemic stroke in the experimental group was significantly decreased (risk difference [ RD]=-0.004, 95% CI: -0.005--0.002, P<0.001); there were no significant differences in the incidence of cardiovascular death, cognitive impairment, aminotransferase increased for more than 3 times and creatine kinase increased for more than 3 times between the 2 groups ( RD=-0.001, 95% CI: -0.004-0.001, P=0.401; RD=0.000, 95% CI: -0.003-0.002, P=0.638; RD=-0.001, 95% CI: -0.004-0.002, P=0.443; RD=-0.001, 95% CI: -0.003-0.000, P=0.137). Subgroup analysis was performed according to drugs: compared with the control group, the incidence of ischemic stroke was significantly reduced in the evolocumab group and alirocumab group ( RD=-0.004, 95% CI: -0.007--0.001, P=0.006; RD= -0.003, 95% CI: -0.006-0.000, P=0.024); there were no significant differences in incidences of cardiovascular death ( RD=0.001, 95% CI: -0.002-0.004, P=0.619; RD=-0.003, 95% CI: -0.007-0.001, P=0.100), cognitive impairment ( RD=0.001, 95% CI:-0.002-0.004, P=0.463; RD=-0.002, 95% CI: -0.005-0.001, P=0.145), aminotransferase increased for more than 3 times ( RD=0.000, 95% CI: -0.003-0.003, P=0.888; RD=-0.002, 95% CI: -0.007-0.003, P=0.392) or creatine kinase increased for more than 3 times ( RD=0.000, 95% CI: -0.002-0.002, P=0.668; RD=-0.002, 95% CI: -0.005-0.000, P=0.106) between the evolocumab group and alirocumab group. Subgroup analysis was performed according to the medication duration: compared with the control group, no significant differences in incidences of cardiovascular death ( RD=0.000, 95% CI:-0.022-0.022, P=1.000; RD=-0.003, 95% CI: -0.009-0.002, P=0.193; RD=-0.001, 95% CI:-0.004-0.002, P=0.521), cognitive impairment ( RD=-0.003, 95% CI: -0.014-0.008, P=0.569; RD=-0.001, 95% CI: -0.006-0.004, P=0.696; RD=0.000, 95% CI: -0.003-0.002, P=0.735), aminotransferase increased for more than 3 times ( RD=-0.002, 95% CI: -0.016-0.012, P=0.749; RD=-0.002, 95% CI: -0.013-0.010, P=0.773; RD=-0.001, 95% CI: -0.004-0.002, P=0.489) or creatine kinase increased for more than three times ( RD=-0.015, 95% CI: -0.032-0.003, P=0.099; RD= -0.011, 95% CI: -0.025-0.002, P=0.104; RD=0.000, 95% CI: -0.002-0.001, P=0.722) were noted among medication duration<1 year group, medication duration of 1-2 years group and medication duration>2 years group. Conclusion:Both evolocumab and alirocumab can reduce the incidence of ischemic stroke in hyperlipidemia and atherosclerotic high-risk cardiovascular patients, with good safety.
9.Research on the construction of grading nursing care at public hospitals
Yamei BAI ; Qin ZHONG ; Yulei SONG ; Hongmei ZHANG ; Yaqi ZHANG ; Jing ZHU ; Di WANG ; Guihua XU
Chinese Journal of Hospital Administration 2018;34(12):1034-1038
Objective To construct a grading nursing care system at public hospitals based on the severity of illness and activities of daily living ( ADL). Methods Multi-center stratified random sampling was used to investigate the general adult patients hospitalized in 12 wards of six tertiary-level hospitals in the eastern, central and western parts of China from January to December of 2016. The Barthel index and simple clinical score ( SCS) were used to evaluate their ADL and severity of illness, while a customized direct nursing hour scale was applied to record the direct nursing time needed by patients in 24 hours. Nursing grades were defined according to different conditions and ADL and to the difference of patient needs of 24 h direct nursing hours. Results 7 200 patients were investigated in total, and 7 073 effective questionnaires were collected (98. 24% ). Seven new grades of nursing care were defined based on patients′ severity of illness, ADL and different 24 h direct nursing time. These grades match the existing four grading nursing care levels to become refined sub-levels. Conclusions Patients can be graded according to their conditions, ADL and the 24 h direct nursing time needed. Such a new method is more objective, specific and quantitative than before, conducive to upgrading fine management level of nursing.
10.Comparative analysis of nursing needs and actual service status of inpatients
Dandan WANG ; Yamei BAI ; Yulei SONG ; Wei XU ; Jing ZHU ; Qin ZHONG ; Di WANG ; Muran WANG ; Dongmei NI ; Xuefeng LI
Chinese Journal of Hospital Administration 2018;34(2):162-167
Objective To probe into the gaps between the inpatient care needs at public tertiary hospitals and existing nursing services,for measures to improve the quality of nursing service.Methods The simple clinical score(SCS),Barthel index scale,patient care needs questionnaire,and actual service status questionnaire were used in a multi-centered stratified random sampling survey, covering the adult inpatient wards of 72 departments at six tertiary hospitals.The results were subject to a stratified analysis of patient care needs, and a comparative analysis between patient care needs and the actual status of the service.Results Statistically significant differences were found between the nursing needs of patients from among different departments,self-care abilities and those with different conditions(P<0.05); the patient care needs and actual service status in cleaning, eating, excretion, activities, health education, basic treatment and nursing of traditional Chinese medicine in terms of the differences were statistically significant (P<0.05); the comparative analysis found differences between patient care needs and actual service status.The top five patient care needs which were greater than the actual service status were namely temperature measuring,rehabilitation guidance,routine inspection,observation and psychological care.The top five areas with actual service status greater than patient care needs were namely turnover /back flapping, toilet assistance,temperature measuring,hands washing before and after meals,and herbal fumigation.The top five areas with minimal gap between needs and service were namely oral care, moxibustion, perineal care,assistance in using toilet in bed and manicure.Conclusions Departments, self-care abilities and conditions of patients vary with their needs of nursing.Based on the existing problems between patient care needs and the actual service status,nurses should increase their care in such soft indicators as rehabilitation guidance,routine inspection and disease observation, and fully meet the needs of patients.On the other hand,they are expected to enhance patients′health education and health literacy in such hard indicators as temperature measuring,turnover and back flapping.

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