1.Efficacy and safety of Chinese herbal compounds for pulmonary nodules: A systematic review and meta-analysis
Yanlong LI ; Xinze ZHENG ; Lingyan LAN ; Ying WANG ; Wei SU ; Jiahui CHEN ; Xiangjun QI ; Xuewei LI ; Bo AN ; Ling YU ; Lingling SUN ; Lizhu LIN
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2026;33(07):1119-1128
Objective To systematically evaluate the efficacy and safety of traditional Chinese medicine (TCM) compound in treating pulmonary nodules, providing evidence-based medical evidence for TCM intervention in pulmonary nodules. Methods Computer search of PubMed, CNKI, Wanfang, VIP, and SinoMed was conducted to select randomized controlled trials (RCTs) of TCM compound intervention in pulmonary nodules, with the retrieval time from the inception to November 29, 2023. The Cochrane bias risk assessment tool was used to evaluate the quality of the included studies, and Review Manager 5.4 was used for Meta-analysis. Results A total of 18 RCTs were included, covering 8 provinces across the country, with a total sample size of 1301 patients. The TCM compounds used in the included studies all incorporated the method of dissolving phlegm and dissipating nodules. There was a high risk of bias uncertainty in the included studies. Meta-analysis results suggested that TCM compound could significantly reduce the diameter of pulmonary nodules [MD=−1.41, 95%CI (−1.70, −1.13), P<0.001], decrease the number of nodules [MD=−0.37, 95%CI (−0.73, −0.01), P=0.05], alleviate clinical symptoms [MD=−4.84, 95%CI (−6.04, −3.64), P<0.001], and improve lung function [forced expiratory volume in one second (FEV1), MD=0.55, 95%CI (0.09, 1.01), P=0.02; FEV1/forced vital capacity, MD=6.12, 95%CI (4.47, 7.78), P<0.001]. However, there was no statistically significant difference in the probability of malignancy between the experimental group and the control group [MD=−0.01, 95%CI (−0.01, 0.00), P=0.09]. Conclusion TCM compound can significantly reduce the diameter of pulmonary nodules, decrease the number of nodules, alleviate clinical symptoms, and improve lung function, but future multicenter, large-sample, high-quality RCTs are still needed to further explore and verify this conclusion.
2.Clinical and Radiological Outcomes of Transarterial Embolization for Adhesive Capsulitis
Keng-Wei LIANG ; Hsuan Yin LIN ; Kai-Lan HSU ; Fa-Chuan KUAN ; Chia-Yu GEAN ; Chien-Kuo WANG ; Wei-Ren SU ; Bow WANG
Korean Journal of Radiology 2025;26(3):230-238
Objective:
To assess the effect of transarterial embolization (TAE) for adhesive capsulitis (AC) by evaluating clinical outcomes and changes in inflammation using magnetic resonance imaging (MRI).
Materials and Methods:
Patients who had undergone TAE between August 2020 and August 2023 for AC refractory to conservative treatments without any invasive procedures for more than 3 months, and had undergone baseline and 3-month post-AC follow-up contrast-enhanced MRI evaluations, were included. A suspension mixture of 500 mg imipenem/cilastatin in 10 mL of iodinated contrast agent was used for TAE. MRI results were analyzed to assess periarticular capsule/ligament inflammation. Clinical assessments included pain scores using the numeric rating scale (NRS) and functional scores using the quick disabilities of the arm, shoulder, and hand (Quick DASH) questionnaire.
Results:
Twenty-five patients (female:male, 14:11; age, 54.9 ± 7.1 years) were included. Significant reductions in average NRS pain scores as well as improvements in Quick DASH scores and range of motion, including anterior flexion and abduction, were observed at 1, 3, and 6 months after TAE (all P < 0.001). MRI analyses revealed that TAE significantly decreased the grades of axillary recess capsule enhancement, rotator interval (RI) capsule T2 signal intensity, and RI capsule enhancement (all P ≤ 0.004).
Conclusion
TAE may be an effective and safe therapeutic approach for AC refractory to conservative treatments, alleviating pain and supporting functional recovery. The observed MRI findings suggest that the effectiveness of TAE for AC may be attributed to the reduction of inflammation and the elimination of angiogenesis.
3.The impact of lesions in different nuclei of the basal ganglia on speech processing function in patients with post-stroke dysarthria
Juan LIU ; Shuzhi ZHAO ; Rongfeng SU ; Shaofeng ZHAO ; Yumei ZHANG ; Lan WANG ; Nan YAN
Chinese Journal of Behavioral Medicine and Brain Science 2025;34(6):517-524
Objective:To investigate the impact of lesions in different nuclei of the subcortical basal ganglia on speech processing functions in patients with post-stroke dysarthria.Methods:From July 2022 to September 2023, a total of 20 patients with post-stroke dysarthria (patient group) and 22 healthy individuals (control group) were recruited. Brain imaging data, including structural magnetic resonance imaging(MRI) and diffusion-weighted imaging (DWI), as well as behavioral data of speech fluency task and picture association task were collected. Structural MRI data was analyzed using SPM12 software to perform voxel-based morphometry (VBM), measuring cortical thickness and gray matter volume (VGM) in specific nuclei of the basal ganglia. Behavioral metrics, such as reaction time (RT) and the number of valid responses were extracted for each task. Statistical analysis was conducted using SPSS 27.0 and R 4.0 softwares. Spearman correlation analysis was applied to examine relationships between neuroimaging parameters and behavioral performance indicators.Results:The patient group exhibited significantly smaller gray matter volumes in both left and right caudate nuclei((2.69±0.92)mm 3, (3.17±0.91)mm 3 ) and putamen (3.31±1.08)mm 3, (3.66±0.91)mm 3) compared to the control group (caudate nuclei (3.19±0.36)mm 3, (3.49±0.52)mm 3 putamen (4.52±0.54)mm 3, (4.72±0.64)mm 3), with statistically significant differences ( t=-2.83, 1.68; t=-3.59, 3.52, both P<0.05). Behavioral experiments revealed that the patient group exhibited significantly prolonged reaction time during picture association and naming tasks (1 910.50(1 214.25, 3 806.75) ms, 1 362.00(978.00, 2 297.00) ms) compared to the control group (1 618.00(1 162.75, 2 401.75) ms, 1 224.00(984.25, 1 661.50) ms; Z=-5.20, -4.61, both P<0.05). Gray matter volumes in the left caudate nucleus and left putamen exhibited negative correlations with reaction times during the picture naming task ( r=-0.52, -0.54, both P<0.05). Additionally, the gray matter volume of the left putamen demonstrated a positive correlation with the number of valid responses in speech fluency task-T2 ( r=0.46, P<0.05), whereas the left globus pallidus volume showed a negative correlation with speech fluency task-T1 ( r=-0.51, P<0.05) with the same measure. Conclusion:Lesions in the left subnuclei of the basal ganglia directly impair early-stage speech functions, including conceptual preparation and lexical selection, whereas right-side lesions exert less pronounced effects on linguistic performance compared to their left counterparts. Furthermore, the basal ganglia's involvement in higher-order linguistic processing may represent an indirect consequence of cognitive decline.
4.Clinical distribution and trend of drug resistance of Klebsiella pneumoniae isolates from a three-A hospital of Suzhou from 2019 to 2023
Jingjing GAO ; Ning SU ; Lu YUAN ; Lan HUANG ; Li-jun XU ; Wei-dong XU ; Ya-nan WANG
Chinese Journal of Nosocomiology 2025;35(13):2007-2012
OBJECTIVE To investigate the clinical distribution and dynamic change of drug resistance of K.pneu-moniae and carbapenem-resistant Klebsiella pneumoniae(CRKP)isolated from a three-A hospital of Suzhou so as to provide scientific bases for prevention and control of hospital-associated infections and reasonable application of antibiotics.METHODS The K.pneumoniae and CRKP strains that were isolated from the submitted specimens were collected from the patients who treated in the Affiliated Suzhou Hospital of Nanjing Medical University from 2019 to 2023.The clinical characteristics of the patients with infection and the trend of drug resistance were statis-tically analyzed.RESULTS Totally 5631 strains of K.pneumoniae were isolated,1205(21.40%)of which were CRKP,and the isolation rate of CRKP showed an upward trend in the five years(x2=236.352,P<0.001).Among the K.pneumoniae isolates,51.59%were isolated from sputum,13.51%from urine;19.43%were isolated from intensive care unit(ICU),7.64%from emergency department,and 7.19%from respiratory department.There were significant differences in gender,age and season between the patients detected with CRKP and the patients detected with non-CRKP(P<0.05).The drug resistance rates of the K.pneumoniae strains to cephalosporins,quinolones and carbapenems con-tinuously increased from 2019 to 2023(P<0.001),the drug resistance rate to imipenem increased from 11.69%to 34.24%,meropenem from 10.92%to 34.24%.CONCLUSIONS The K.pneumoniae isolates show severe drug re-sistance from 2019 to 2023,and the isolation rate of CRKP strains rises increasingly.It is necessary for the hospi-tal to focus on the continuous monitoring of key populations and departments and optimize the management of an-tibiotics and infection control strategies so as to provide guidance for reasonable clinical use of antibiotics,effective control of transmission of drug-resistant strains and cope with the increasingly severe drug resistance.
5.Relationship between SOD2 lactylation and NCOA4-mediated ferritinophagy-ferroptosis during cerebral ischemia-reperfusion in mice
Xue QI ; Yanan LI ; Su WANG ; Lan ZHAO ; Mopu LI ; Jing LI ; Wenwei GAO ; Bo ZHAO
Chinese Journal of Anesthesiology 2025;45(10):1286-1290
Objective:To evaluate the relationship between superoxide dismutase 2 (SOD2) lactylation and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy-ferroptosis during cerebral ischemia-reperfusion (IR) in mice.Methods:Thirty-six clean-grade male C57BL/6 mice, aged 8-10 weeks, weighing 22-25 g, were divided into 4 groups ( n=9 each) using a table of random numbers: sham operation group (Sham group), cerebral IR group (IR group), IR+ glycolysis inhibitor 2-DG group (IR+ 2-DG group), and IR+ 2-DG+ NCOA4 overexpression group (IR+ 2-DG+ LvNCOA4 group). The model of cerebral IR injury was established by occlusion of the middle cerebral artery for 1 h followed by 24 h of reperfusion using the intraluminal suture method in anesthetized animals. 2-DG 250 mg/kg was intraperitoneally injected at 90 min before ischemia in IR+ 2-DG and IR+ 2-DG+ LvNCOA4 groups. The lentivirus overexpressing NCOA4 2 μl was injected into the ventricles at 7 days before ischemia in IR+ 2-DG+ LvNCOA4 group. The percentage of cerebral infarct volume was determined, the viable neurons were counted, and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) were measured by enzyme-linked immunosorbent assay. The expression of SOD2, lysine 114 lactylation of superoxide dismutase 2 (SOD2-K114la), NCOA4, microtubule-associated protein 1 light chain 3β (LC3B), and acyl-CoA synthetase long-chain family member 4 (ACSL4) was determined by Western blot. Mitochondrial morphology was examined by electron microscopy. Results:Compared with Sham group, the percentage of cerebral infarct volume was significantly increased, the number of viable neurons was decreased, the levels of ROS and MDA were elevated, the content of GSH was reduced, the expression of SOD2-K114la, NCOA4, LC3B and ACSL4 was up-regulated, the expression of SOD2 was down-regulated ( P<0.05), and the mitochondrial injury was aggravated in IR group. Compared with IR group, the percentage of cerebral infarct volume was significantly decreased, the number of viable neurons was increased, the mitochondrial injury was alleviated, the levels of ROS and MDA were decreased, the content of GSH was increased, the expression of SOD2-K114la, NCOA4 and ACSL4 was down-regulated, and the expression of SOD2 and LC3B was up-regulated in IR+ 2-DG group ( P<0.05). Compared with IR+ 2-DG group, the percentage of cerebral infarct volume was significantly increased, the number of viable neurons was decreased, the levels of ROS and MDA were elevated, the content of GSH was reduced, and the expression of NCOA4, LC3B and ACSL4 was up-regulated ( P<0.05), no significant change was found in the expression of SOD2 and SOD2-K114la ( P>0.05), and the mitochondrial injury was aggravated in IR+ 2-DG+ LvNCOA4 group. Conclusions:SOD2 lactylation promotes NCOA4-mediated ferritinophagy-ferroptosis by enhancing oxidative stress, thereby contributing to the cerebral IR injury in mice.
6.The impact of lesions in different nuclei of the basal ganglia on speech processing function in patients with post-stroke dysarthria
Juan LIU ; Shuzhi ZHAO ; Rongfeng SU ; Shaofeng ZHAO ; Yumei ZHANG ; Lan WANG ; Nan YAN
Chinese Journal of Behavioral Medicine and Brain Science 2025;34(6):517-524
Objective:To investigate the impact of lesions in different nuclei of the subcortical basal ganglia on speech processing functions in patients with post-stroke dysarthria.Methods:From July 2022 to September 2023, a total of 20 patients with post-stroke dysarthria (patient group) and 22 healthy individuals (control group) were recruited. Brain imaging data, including structural magnetic resonance imaging(MRI) and diffusion-weighted imaging (DWI), as well as behavioral data of speech fluency task and picture association task were collected. Structural MRI data was analyzed using SPM12 software to perform voxel-based morphometry (VBM), measuring cortical thickness and gray matter volume (VGM) in specific nuclei of the basal ganglia. Behavioral metrics, such as reaction time (RT) and the number of valid responses were extracted for each task. Statistical analysis was conducted using SPSS 27.0 and R 4.0 softwares. Spearman correlation analysis was applied to examine relationships between neuroimaging parameters and behavioral performance indicators.Results:The patient group exhibited significantly smaller gray matter volumes in both left and right caudate nuclei((2.69±0.92)mm 3, (3.17±0.91)mm 3 ) and putamen (3.31±1.08)mm 3, (3.66±0.91)mm 3) compared to the control group (caudate nuclei (3.19±0.36)mm 3, (3.49±0.52)mm 3 putamen (4.52±0.54)mm 3, (4.72±0.64)mm 3), with statistically significant differences ( t=-2.83, 1.68; t=-3.59, 3.52, both P<0.05). Behavioral experiments revealed that the patient group exhibited significantly prolonged reaction time during picture association and naming tasks (1 910.50(1 214.25, 3 806.75) ms, 1 362.00(978.00, 2 297.00) ms) compared to the control group (1 618.00(1 162.75, 2 401.75) ms, 1 224.00(984.25, 1 661.50) ms; Z=-5.20, -4.61, both P<0.05). Gray matter volumes in the left caudate nucleus and left putamen exhibited negative correlations with reaction times during the picture naming task ( r=-0.52, -0.54, both P<0.05). Additionally, the gray matter volume of the left putamen demonstrated a positive correlation with the number of valid responses in speech fluency task-T2 ( r=0.46, P<0.05), whereas the left globus pallidus volume showed a negative correlation with speech fluency task-T1 ( r=-0.51, P<0.05) with the same measure. Conclusion:Lesions in the left subnuclei of the basal ganglia directly impair early-stage speech functions, including conceptual preparation and lexical selection, whereas right-side lesions exert less pronounced effects on linguistic performance compared to their left counterparts. Furthermore, the basal ganglia's involvement in higher-order linguistic processing may represent an indirect consequence of cognitive decline.
7.Combination of hyaluronidase and pH-responsive, IR780-loaded photosensitive micelle enhanced anticancer effect in triple-negative breast cancer
Rui YANG ; Qinghua WANG ; Lan MING ; Su LI ; Zhen JIA ; Jiuda ZHAO ; Daozhen CHEN
Chinese Journal of Oncology 2025;47(9):885-895
Objectives:To investigate the enhancement of tumor penetration and photodynamic therapy (PDT) efficacy in triple-negative breast cancer by hyaluronidase (HAase) using a novel pH-responsive IR780-loaded photosensitive micelle.Methods:The pH-responsive IR780-loaded photosensitive micelles were prepared using the nanoprecipitation method, and their morphology, size, and encapsulation efficiency were characterized. The in vitro stability and pH-responsive drug release of the micelles were also evaluated. The cytotoxicity of the micelles on triple-negative breast cancer cells (MDA-MB-231) was assessed using a cell counting kit. A nude mouse breast cancer model was established, and HAase was injected intratumorally 24 hours before intravenous injection of the photosensitive micelles. The effect of HAase on the biodistribution and tumor uptake of the micelles was detected using small animal in vivo imaging. CD31 and HIF-1α immunofluorescence staining were performed to investigate the mechanism of HAase-enhanced tumor penetration. The body weight and tumor volume of the mice were measured, and necrosis and apoptosis of tumor tissues were assessed using HE staining and TUNEL staining, respectively. Results:Transmission electron microscopy showed that the micelles had a uniform particle size of approximately 60-70 nm, with a hydrated particle size of (98.03±0.22) nm. The IR780 encapsulation efficiency was 74.15%, with a drug loading content of 2.07%. After 7 days at 4 ℃, there was no significant change in hydrated particle size ( P=0.062). The 24-hour release rates of the micelles in PBS at pH 7.4 and 6.5 were (2.41±0.21)% and (43.69±2.09)%, respectively, showing a significant difference ( P<0.000 1). The cytotoxicity assay revealed that the cell viability in the micelles group without light exposure was significantly higer than that in the micelles group under light exposure [(97.00±5.38)% vs. (53.27±9.00)%, P=0.000 2]. The micelles were able to target and accumulate in the tumor tissue, and this accumulation increased significantly with HAase treatment. CD31 and HIF-1α immunofluorescence staining indicated that the CD31 signal was enhanced [(0.27±0.05)% vs. (4.57±0.27)%, P<0.000 1] and the HIF-1α signal was reduced [(5.14±0.38)% vs. (0.08±0.04)%, P<0.000 1] in the HAase-treated group compared to that in the micelle-only group. After 11 days of treatment with HAase combined with photosensitive micelles, there was no statistically significant difference in mouse body weight ( P>0.05). However, the tumor volume inhibition rate in the HAase-micelle-mediated PDT group was significantly higher than that in the micelle-mediated PDT group [(87.66±6.37)% vs. (25.34±12.63)%, P=0.002]. Histological staining showed a significant increase in tumor cell necrosis and apoptosis in the HAase-micelle-mediated PDT group. Conclusion:HAase enhances the deep tumor penetration and targeted accumulation of pH-responsive IR780-loaded photosensitive micelles, significantly improves the efficacy of photodynamic therapy in triple-negative breast cancer.
8.Clinical and Radiological Outcomes of Transarterial Embolization for Adhesive Capsulitis
Keng-Wei LIANG ; Hsuan Yin LIN ; Kai-Lan HSU ; Fa-Chuan KUAN ; Chia-Yu GEAN ; Chien-Kuo WANG ; Wei-Ren SU ; Bow WANG
Korean Journal of Radiology 2025;26(3):230-238
Objective:
To assess the effect of transarterial embolization (TAE) for adhesive capsulitis (AC) by evaluating clinical outcomes and changes in inflammation using magnetic resonance imaging (MRI).
Materials and Methods:
Patients who had undergone TAE between August 2020 and August 2023 for AC refractory to conservative treatments without any invasive procedures for more than 3 months, and had undergone baseline and 3-month post-AC follow-up contrast-enhanced MRI evaluations, were included. A suspension mixture of 500 mg imipenem/cilastatin in 10 mL of iodinated contrast agent was used for TAE. MRI results were analyzed to assess periarticular capsule/ligament inflammation. Clinical assessments included pain scores using the numeric rating scale (NRS) and functional scores using the quick disabilities of the arm, shoulder, and hand (Quick DASH) questionnaire.
Results:
Twenty-five patients (female:male, 14:11; age, 54.9 ± 7.1 years) were included. Significant reductions in average NRS pain scores as well as improvements in Quick DASH scores and range of motion, including anterior flexion and abduction, were observed at 1, 3, and 6 months after TAE (all P < 0.001). MRI analyses revealed that TAE significantly decreased the grades of axillary recess capsule enhancement, rotator interval (RI) capsule T2 signal intensity, and RI capsule enhancement (all P ≤ 0.004).
Conclusion
TAE may be an effective and safe therapeutic approach for AC refractory to conservative treatments, alleviating pain and supporting functional recovery. The observed MRI findings suggest that the effectiveness of TAE for AC may be attributed to the reduction of inflammation and the elimination of angiogenesis.
9.The effects and mechanisms of silica on alveolar epithelial cell apoptosis
Yali LAN ; Wenyao SU ; Zhiming HU ; Ping WANG ; Bizhu ZHANG ; Na ZHAO
China Occupational Medicine 2025;52(1):10-16
Objective To investigate the effects and mechanisms of silica dust on the apoptosis of alveolar epithelial cell (AEC) through in vitro and animal experiments. Methods i) In vitro experiment. A549 cells were stimulated with 100 mg/L silica suspension for 0, 12, 24 and 48 hours. The cell apoptosis rate was detected by flow cytometry. ii) Animal experiment. Specific pathogen-free male C57BL/6 mice were randomly divided into control, 14-day, 28-day, and 56-day groups, with five mice in each group. The mice in the control group were sacrificed at 56 days after being treated with 40.0 μL 0.9% sodium chloride solution, and the mice in the last three groups were sacrificed at 14, 28 and 56 days after being treated with 40.0 μL silica suspension with a mass concentration of 125 g/L via tracheal exposure method. The lung tissues of mice were collected to measure lung organ coefficients. Masson staining was used to detect the degree of pulmonary fibrosis, and Ashcroft scores were evaluated. The apoptosis of AEC in mice was observed by TUNEL immunofluorescence assay. iii) The mRNA relative expression of apoptosis-related genes in A549 cells and mouse lung tissue was detected using reverse transcription and real-time fluorescence quantitative polymerase chain reaction. Results i) In vitro experiment. The apoptosis rate of A549 cells increased with longer silica exposure (all P<0.05). The relative expression of B cell lymphoma-2 (BCL-2) mRNA in A549 cells in 24 h group and 48 h group decreased (both P<0.05), and the relative expression of BCL-2 associated X protein (BAX) mRNA increased (both P<0.05), compared with 0 h group. The mRNA relative expression of caspase (CASP) -3 and CASP-9 in A549 cells increased with longer silica exposure (all P<0.05). ii) Animal experiment. The lung organ coefficients and Ashcroft score in mice progressively increased (all P<0.05), the degree of pulmonary fibrosis was gradually aggravated, and TUNEL positive cells in lung tissue were gradually increased, while Bax, Casp-3 and Casp-9 mRNA relative expression increased with longer silica exposure (all P<0.05). Conclusion Silica dust may cause pulmonary fibrosis by inducing apoptosis of AEC, with a time-dependent effect. The mechanism may be related to the effect of silica dust on mitochondrial apoptosis through Bcl-2/Bax/Caspase-3 signaling pathway.
10.Clinical and Radiological Outcomes of Transarterial Embolization for Adhesive Capsulitis
Keng-Wei LIANG ; Hsuan Yin LIN ; Kai-Lan HSU ; Fa-Chuan KUAN ; Chia-Yu GEAN ; Chien-Kuo WANG ; Wei-Ren SU ; Bow WANG
Korean Journal of Radiology 2025;26(3):230-238
Objective:
To assess the effect of transarterial embolization (TAE) for adhesive capsulitis (AC) by evaluating clinical outcomes and changes in inflammation using magnetic resonance imaging (MRI).
Materials and Methods:
Patients who had undergone TAE between August 2020 and August 2023 for AC refractory to conservative treatments without any invasive procedures for more than 3 months, and had undergone baseline and 3-month post-AC follow-up contrast-enhanced MRI evaluations, were included. A suspension mixture of 500 mg imipenem/cilastatin in 10 mL of iodinated contrast agent was used for TAE. MRI results were analyzed to assess periarticular capsule/ligament inflammation. Clinical assessments included pain scores using the numeric rating scale (NRS) and functional scores using the quick disabilities of the arm, shoulder, and hand (Quick DASH) questionnaire.
Results:
Twenty-five patients (female:male, 14:11; age, 54.9 ± 7.1 years) were included. Significant reductions in average NRS pain scores as well as improvements in Quick DASH scores and range of motion, including anterior flexion and abduction, were observed at 1, 3, and 6 months after TAE (all P < 0.001). MRI analyses revealed that TAE significantly decreased the grades of axillary recess capsule enhancement, rotator interval (RI) capsule T2 signal intensity, and RI capsule enhancement (all P ≤ 0.004).
Conclusion
TAE may be an effective and safe therapeutic approach for AC refractory to conservative treatments, alleviating pain and supporting functional recovery. The observed MRI findings suggest that the effectiveness of TAE for AC may be attributed to the reduction of inflammation and the elimination of angiogenesis.

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