1.Clinical guidelines for the treatment of ankylosing spondylitis combined with lower cervical fracture in adults (version 2024)
Qingde WANG ; Yuan HE ; Bohua CHEN ; Tongwei CHU ; Jinpeng DU ; Jian DONG ; Haoyu FENG ; Shunwu FAN ; Shiqing FENG ; Yanzheng GAO ; Zhong GUAN ; Hua GUO ; Yong HAI ; Lijun HE ; Dianming JIANG ; Jianyuan JIANG ; Bin LIN ; Bin LIU ; Baoge LIU ; Chunde LI ; Fang LI ; Feng LI ; Guohua LYU ; Li LI ; Qi LIAO ; Weishi LI ; Xiaoguang LIU ; Hongjian LIU ; Yong LIU ; Zhongjun LIU ; Shibao LU ; Yong QIU ; Limin RONG ; Yong SHEN ; Huiyong SHEN ; Jun SHU ; Yueming SONG ; Tiansheng SUN ; Yan WANG ; Zhe WANG ; Zheng WANG ; Hong XIA ; Guoyong YIN ; Jinglong YAN ; Wen YUAN ; Zhaoming YE ; Jie ZHAO ; Jianguo ZHANG ; Yue ZHU ; Yingjie ZHOU ; Zhongmin ZHANG ; Wei MEI ; Dingjun HAO ; Baorong HE
Chinese Journal of Trauma 2024;40(2):97-106
Ankylosing spondylitis (AS) combined with lower cervical fracture is often categorized into unstable fracture, with a high incidence of neurological injury and a high rate of disability and morbidity. As factors such as shoulder occlusion may affect the accuracy of X-ray imaging diagnosis, it is often easily misdiagnosed at the primary diagnosis. Non-operative treatment has complications such as bone nonunion and the possibility of secondary neurological damage, while the timing, access and choice of surgical treatment are still controversial. Currently, there are no clinical practice guidelines for the treatment of AS combined with lower cervical fracture with or without dislocation. To this end, the Spinal Trauma Group of Orthopedics Branch of Chinese Medical Doctor Association organized experts to formulate Clinical guidelines for the treatment of ankylosing spondylitis combined with lower cervical fracture in adults ( version 2024) in accordance with the principles of evidence-based medicine, scientificity and practicality, in which 11 recommendations were put forward in terms of the diagnosis, imaging evaluation, typing and treatment, etc, to provide guidance for the diagnosis and treatment of AS combined with lower cervical fracture.
2.Mechanism of Qianyang Yuyin Granules Regulating NR3C2/ROS/ERK Pathway to Alleviate Aldosterone-induced Podocyte Injury
Yin LI ; Fang YUAN ; Junyao XU ; Cheng NING ; Yixuan WANG ; Lichao QIAN ; Haitao LI ; Jie LI
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(13):95-105
ObjectiveTo investigate the protective mechanism of Qianyang Yuyin granules (QYYY) on aldosterone-induced podocyte injury. MethodA total of 30 C57BL/6J mice were randomly divided into five groups: control group, model group, QYYY low dose (QYYY-L) group, QYYY high dose (QYYY-H) group, and spironolactone (SPL) group, with six mice in each group. Except for the control group, mice were implanted with osmotic minipumps and injected continuously with aldosterone (300 μg·kg-1·d-1) to induce renal injury. The drug administration group was given low and high doses (2.6, 5.2 g·kg-1·d-1) of QYYY and SPL (18 mg·kg-1·d-1) for 28 days. The renal pathological changes of mice were observed by hematoxylin-eosin (HE) staining and Masson staining. The expression levels of Nephrin, Desmin, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), cleaved Caspase-3, nuclear receptor subfamily 3 group C member 2 (NR3C2), extracellular regulated protein kinases (ERK), and phospho-ERK (p-ERK) in kidney tissue were detected by Western blot. The apoptosis levels of kidney tissue were detected by TdT-mediated dUTP nick and labeling (TUNEL) staining, and the superoxide dismutase (SOD) levels were detected. In vitro, the mice were divided into five groups: Control group, model group (aldosterone concentration of 200 nmol·L-1), QYYY-L group, QYYY medium dose (QYYY-M) group, and QYYY-H group (25, 50, and 100 mg·L-1). The effect of different concentrations of QYYY on the relative viability of aldosterone-induced podocytes was detected by cell proliferation and viability assay (CCK-8). The expressions of Nephrin, Desmin, Bax, Bcl-2, cleaved Caspase-3, NR3C2, and p-ERK/ERK were detected by Western blot. AnnexinV-FITC/PI flow cytometry was used to detect the apoptosis levels of podocytes. Reactive oxygen species (ROS) in podocytes were observed by DCFH-DA. ResultCompared with the control group, the model group showed structural pathological changes and fibrotic conditions in the kidney, increased apoptosis levels (P<0.01), and decreased SOD levels (P<0.01). Aldosterone concentration at 200 nmol·L-1 showed a significant decrease in podocyte activity (P<0.05). Podocytes in the model group showed structural pathological changes, disordered arrangement of intercellular microfilaments, increased apoptosis levels (P<0.01), and increased intracellular ROS levels (P<0.01). The protein expressions of Nephrin, Bcl-2, and p-ERK/ERK in kidney tissue and podocytes were decreased (P<0.05, P<0.01). The protein expressions of Desmin, Bax, cleaved Caspase-3, and NR3C2 were increased (P<0.05, P<0.01). Compared with the model group, QYYY alleviated the structural damage and fibrosis of the kidney, decreased the apoptosis levels (P<0.05, P<0.01), and enhanced the SOD content of the kidney (P<0.05, P<0.01). QYYY improved the activity of podocytes (P<0.05, P<0.01), restored the foot process structure of podocytes, and decreased apoptosis levels (P<0.01) and ROS levels of podocytes (P<0.01). The protein expressions of Nephrin, Bcl-2, and p-ERK/ERK in kidney tissue and podocytes were increased (P<0.05, P<0.01), and the protein expressions of Desmin, Bax, cleaved Caspase-3, and NR3C2 were down-regulated (P<0.05, P<0.01). ConclusionQYYY improves aldosterone-induced podocyte injury by regulating the NR3C2/ROS/ERK pathway.
3.MoS2 nanozyme attenuated inflammation-related endothelial cell injury by regulating mitochondrial dynamics and mitophagy
Dong-mei PAN ; Sun-kui KE ; Qian-hao YIN ; Pei-yan YANG ; Chao LI ; She-fang YE
Acta Pharmaceutica Sinica 2024;59(10):2791-2799
To explore the protective mechanisms of a novel molybdenum disulfide (MoS2) nanozyme in alleviating inflammation-related endothelial cell injury by regulating mitochondrial dynamic, flower like-MoS2 nanosheets were prepared by hydrothermal method, and its antioxidant enzyme-mimic activities were assessed
4.Evaluation of Burosumab in the treatment of X-linked hypophosphatemic rickets in children
Shaohan FANG ; Fang DENG ; Yue YUAN ; Xu LI ; Zhen ZHAO ; Ying ZHU ; Yin PENG ; Luodan ZHANG
Chinese Journal of Endocrinology and Metabolism 2024;40(1):11-16
Objective:To evaluate the efficacy and safety of Burosumab in patients with X-linked hypophosphatemic rickets.Methods:Clinical data of 9 children diagnosed with X-linked hypophosphatemic rickets and treated with Burosumab in the Department of Pediatric Nephrology, Anhui Children′s Hospital from November 2021 to September 2023 were retrospectively analyzed, including the general information, clinical manifestations, auxiliary examination, Burosumab treatment and follow-up.Results:Among the 9 cases, there were 5 males and 4 females, with a median age at diagonosis of 2 years. After traditional treatment, the fluctuation of serum phosphorus ranged from 0.7 to 0.9 mmol/L. The median age at the initiation of Burosumab treatment was 2.8 years, and the initial dosage was 0.8 mg/kg, administrated subcutaneously every 2 weeks. The laboratory and imaging indexes were improved after 6 months of Burosumab treatment, and the mean serum phosphorus level increased from(0.81±0.14) mmol/L to(1.02±0.10) mmol/L at 1 month( t=3.85, P=0.001) and(1.14±0.25) mmol/L at 6 months( t=3.58, P=0.002). The average alkaline phosphatase(ALP) level decreased from(509.89±110.10) U/L before treatment to(447.89±106.76) U/L after 1 month( t=1.21, P=0.243). After 6 months, the ALP level significantly decreased to(385.89±60.33) U/L ( t=2.96, P=0.009). The average height percentile increased from 18.42±10.09 before treatment to 26.56±16.59 after 6 months( t=1.26, P=0.227). Rachitis severity scores of both lower limbs ranged from 4.61±1.36 before treatment to 3.06±1.51 after 6 months( t=2.29, P=0.036). No serious adverse events occurred during treatment. Conclusion:Burosumab is safe and effective in treating X-linked hypophosphatemic rickets, exhibiting minimal side effects and significant clinical applicability value.
5.Advances in Clinical Genetics of the Ehlers-Danlos Syndromes
Kexin XU ; Guozhuang LI ; Qing LI ; Xiangjie YIN ; Kun FANG ; Zhihong WU ; Jianguo ZHANG ; DISCO(Deciphering Disorders Involving Scoliosis & COmorbidities)Study Group ; Nan WU
JOURNAL OF RARE DISEASES 2024;3(3):295-303
The Ehlers-Danlos syndromes(EDS)are a group of rare hereditary connective tissue disorders characterized by joint hypermobility,skin hyperextensibility,and tissue fragility.The clinical and genetic hetero-geneity of EDS frequently leads to underdiagnosis and misdiagnosis.Genetic testing is an essential approach to clarify the underlying diagnosis.Recent research has preliminarily established genotype-phenotype correlations and introduced the novel concept of"disease spectrum"in some subtypes.These studies deepen our under-standing of EDS etiology and provide important insights into clinical management.Published in 2023,the Chinese Guidelines for Diagnosis and Treatment of the Ehlers-Danlos Syndromes(the Guidelines)recommend performing genetic testing with deep phenotyping for patients who meet the clinical diagnostic criteria or are sus-pected of having EDS.However,it should be noted that the clinical diagnosis might differ from the molecular diagnosis.Furthermore,cutting-edge approaches such as periodic data reanalysis,integration of RNA sequen-cing into family-based whole-genome sequencing,and third-generation sequencing may facilitate the reclassifi-cation of variants of uncertain significance or resolve undiagnosed cases.This article summarizes recent progress in the genetics research of EDS,with the hope of offering a valuable resource for clinical diagnosis,treatment and scientific research to optimize the quality of life of patients with EDS.
6.Research status of anti-inflammatory effect of traditional Chinese medicine based on NLRP3 inflammatory body
Fu-Mei XU ; Jun-Yuan ZENG ; Lei ZHAO ; Qi-Li ZHANG ; Peng-Fei XIA ; Yin-Qiang JIA ; Jie WANG ; Peng-Xia FANG ; Yan-Li XU
The Chinese Journal of Clinical Pharmacology 2024;40(6):923-927
Inflammasome is a kind of intracellular polyprotein complex,which is an important component of the complex system of local inflammatory microenvironment after human tissue damage.When the inflammasome is activated,it induces the activation of cysteine aspartate proteinase 1(caspase-1),mediates the maturation and secretion of proinflammatory cytokines,such as interleukin(IL)-1 β and IL-18,and induces cell death,which plays an important role in regulating the host immune response to pathogen infection and tissue repair of cell damage.Nod-like receptor protein 3(NLRP3)inflammatory body,which is composed of NLRP3,pro-cysteine aspartic acid specific protease-1(pro-caspase-1)and apoptosis-related spot-like protein(ASC),is the most deeply and widely studied type of inflammatory body,which plays an important role in the regulation of inflammation.When NLRP3 inflammatory bodies are activated,inflammatory mediators are produced and released,which participate in the occurrence and development of a variety of inflammatory diseases.Some studies have shown that traditional Chinese medicine can improve the pathological state of a variety of diseases by inhibiting NLRP3 inflammatory bodies,and play a role in the prevention and treatment of a variety of inflammatory diseases,including cardiovascular diseases,joint inflammation,diabetes and so on.This paper systematically combs the mechanism of NLRP3 inflammatory bodies,and summarizes the latest research reports on the effects of traditional Chinese medicine compound prescription,traditional Chinese medicine monomers and traditional Chinese medicine extracts on NLRP3 inflammatory bodies in the treatment of inflammatory diseases,in order to provide new ideas for the further study of the pathogenesis and drug treatment of many inflammatory diseases.
7.Development and external validation of a quantitative diagnostic model for malignant gastric lesions in clinical opportunistic screening: A multicenter real-world study
Hongchen ZHENG ; Zhen LIU ; Yun CHEN ; Ping JI ; Zhengyu FANG ; Yujie HE ; Chuanhai GUO ; Ping XIAO ; Chengwen WANG ; Weihua YIN ; Fenglei LI ; Xiujian CHEN ; Mengfei LIU ; Yaqi PAN ; Fangfang LIU ; Ying LIU ; Zhonghu HE ; Yang KE
Chinese Medical Journal 2024;137(19):2343-2350
Background::Clinical opportunistic screening is a cost-effective cancer screening modality. This study aimed to establish an easy-to-use diagnostic model serving as a risk stratification tool for identification of individuals with malignant gastric lesions for opportunistic screening.Methods::We developed a questionnaire-based diagnostic model using a joint dataset including two clinical cohorts from northern and southern China. The cohorts consisted of 17,360 outpatients who had undergone upper gastrointestinal endoscopic examination in endoscopic clinics. The final model was derived based on unconditional logistic regression, and predictors were selected according to the Akaike information criterion. External validation was carried out with 32,614 participants from a community-based randomized controlled trial.Results::This questionnaire-based diagnostic model for malignant gastric lesions had eight predictors, including advanced age, male gender, family history of gastric cancer, low body mass index, unexplained weight loss, consumption of leftover food, consumption of preserved food, and epigastric pain. This model showed high discriminative power in the development set with an area under the receiver operating characteristic curve (AUC) of 0.791 (95% confidence interval [CI]: 0.750–0.831). External validation of the model in the general population generated an AUC of 0.696 (95% CI: 0.570–0.822). This model showed an ideal ability for enriching prevalent malignant gastric lesions when applied to various scenarios.Conclusion::This easy-to-use questionnaire-based model for diagnosis of prevalent malignant gastric lesions may serve as an effective prescreening tool in clinical opportunistic screening for gastric cancer.
8.Anticoagulation after revascularization therapy for atrial fibrillation-related acute ischemic stroke:current status
Fang LI ; Tinghao GUO ; Kai WANG ; Zhijuan CHENG ; Weiping CHEN ; Min YIN ; Jianglong TU
Academic Journal of Naval Medical University 2024;45(11):1381-1389
Objective To investigate the anticoagulation status of patients with atrial fibrillation(AF)-related acute ischemic stroke(AIS)after revascularization therapy in the real world.Methods A retrospective study was performed on patients diagnosed as AIS and AF from Jan.2019 to Jan.2022 at The Second Affiliated Hospital of Nanchang University.Patients treated with intravenous thrombolysis(IVT),endovascular thrombectomy(EVT),or both were enrolled.Clinical information,timing of anticoagulation initiation,treatment regimens,and outcomes were documented and statistically analyzed.Additionally,a questionnaire was administered to the primary physicians to understand reasons for delaying or not initiating anticoagulation.Results A total of 189 patients with AF-related AIS met the screening criteria,including 86(45.5%)cases in the IVT group,63(33.3%)cases in the EVT group,and 40(21.2%)cases in the IVT+EVT group.The mean age of 189 patients was(72.90±9.23)years old.There were 93(49.2%)female patients.Anticoagulation was initiated within 14 d after revascularization therapy in 36.0%(68/189)of patients,with the highest rate in the IVT group(58.8%,40/68),followed by the EVT group(22.1%,15/68)and IVT+EVT group(19.1%,13/68).A significant difference was found in the proportion of patients receiving anticoagulation within 14 d among the 3 groups(P=0.020).Univariate analysis was performed on the clinical data of patients who initiated anticoagulation within 14 d after revascularization therapy(68 cases)and those who delayed or did not initiate anticoagulation(121 cases).The results showed that there were significant differences in the stroke history,National Institutes of Health stroke scale(NIHSS)score before revascularization therapy,Alberta Stroke Program early computed tomography score,modified Rankin scale(mRs)score before revascularization therapy,imaging characteristics(lesions near cortex,large infarction,severe stenosis or occlusion of major intracranial arteries),revascularization therapy method,NIHSS score 3 d after revascularization therapy,and intracranial hemorrhagic transformation after revascularization therapy between the 2 groups(all P<0.05).Multivariate logistic regression analysis indicated that higher NIHSS scores 3 d after revascularization therapy(odds ratio[OR]=1.113,95%confidence interval[CI]1.053-1.176,P<0.001)and the presence of intracranial hemorrhage after revascularization therapy(OR=6.098,95%CI 2.004-18.193,P=0.001)were significant factors that contraindicated the initiation of anticoagulation.Large infarcts(40.8%),infarct location(35.8%),and hemorrhagic transformation after stroke(40.8%)were the common reasons cited by physicians for not initiating anticoagulation.In the 90-d prognosis of patients with AF-related AIS,6 patients had bleeding events,and 116 patients had a good prognosis(mRS score of 0-2).The 90-d good prognosis rate in the initiated anticoagulation group within 14 d after revascularization therapy(89.7%,61/68)was significantly higher than that in the delayed or non-anticoagulation group(45.5%,55/121;P<0.001).Conclusion For patients with AF-related AIS who receive IVT,EVT or IVT+EVT,it is safe to initiate anticoagulation early after revascularization therapy,but the timing of anticoagulation in most patients is later than the currently recommended anticoagulation timing.
9.Effect of Xiao Chaihu Decoction and Xiangsha Liujunzi Decoction on the Changes of Gastric Mucosal Pathological Scores and Gastrointestinal Hormones in Patients with Chronic Atrophic Gastritis of Liver Stagnation and Spleen Deficiency Type
Ming-He LIU ; Dong-Qing YIN ; Yong-Qing ZHANG ; Xiao BAI ; Chen MO ; Li XU ; Jing ZHAO ; Jian-Tang GUO ; Shu-Fang FENG
Journal of Guangzhou University of Traditional Chinese Medicine 2024;41(9):2326-2332
Objective To investigate the effect of Xiao Chaihu Decoction and Xiangsha Liujunzi Decoction on the changes of gastric mucosal pathological score and gastrointestinal hormones in patients with chronic atrophic gastritis(CAG)of liver stagnation and spleen deficiency type.Methods A total of 156 cases of CAG patients with liver stagnation and spleen deficiency syndrome were randomly divided into a control group and an observation group,78 cases in each group.The control group was treated with conventional western medicine,and the observation group was treated with Xiao Chaihu Decoction and Xiangsha Liujunzi Decoction on the basis of treatment for the control group.The course of treatment covered four weeks.The changes in the scores of traditional Chinese medicine(TCM)symptoms such as epigastric distention and pain,poor appetite,loose stools,limb weakness,belching and acid regurgitation,gastric mucosal pathological scores and serum levels of gastrointestinal hormones of motilin(MTL)and gastrin(GAS)in the two groups were observed before and after treatment.The negative conversion rate of Helicobacter pylori(Hp)in the two groups was compared,and the clinical efficacy and safety of the two groups were evaluated.Results(1)After four weeks of treatment,the total effective rate of the observation group was 93.59%(73/78),which was significantly higher than 82.05%(64/78)of the control group,and the difference between the two groups was statistically significant(P<0.05).(2)After treatment,the scores of TCM symptoms such as epigastric distention and pain,poor appetite,loose stool,limb weakness,belching and acid regurgitation in the two groups were significantly decreased compared with those before treatment(P<0.05),and the decrease in the observation group was significantly superior to that in the control group(P<0.05).(3)After treatment,the pathological scores of gastric mucosa in the two groups were significantly decreased when compared with those before treatment(P<0.05),and the decrease in the observation group was more significant than that in the control group(P<0.01).(4)After four weeks of treatment,the negative conversion rate of Hp in the observation group was 91.03%(71/78),which was significantly higher than that in the control group(75.64%,59/78),and the difference between the two groups was statistically significant(P<0.05).(5)After treatment,the level of serum GAS in the two groups was significantly decreased(P<0.05)and the serum MTL level was significantly increased compared with that before treatment(P<0.05);the decrease of serum GAS level and the increase of serum MTL level in the observation group were significantly superior to those in the control group(P<0.05).(6)There were no obvious abnormalities in the routine test of blood,urine,stool,kidney function,and liver function,electrocardiograph and other safety indicators during the treatment of the two groups of patients,no adverse reactions such as dizziness,rash and chest distress occurred either,with high safety.Conclusion Xiao Chaihu Decoction combined with Xiangsha Liujunzi Decoction exerts a significant therapeutic effect on GAS of liver stagnation and spleen deficiency type,which can effectively relieve the clinical symptoms,improve the pathological changes of gastric mucosa and promote Hp negative conversion.The therapeutic mechanism may be related to the regulation of gastrointestinal hormone levels.
10.The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection
Ruo-Bai QIAO ; Wei-Hong DAI ; Wei LI ; Xue YANG ; Dong-Mei HE ; Rui GAO ; Yin-Qin CUI ; Ri-Xing WANG ; Xiao-Yuan MA ; Fang-Jie WANG ; Hua-Ping LIANG
Chinese Journal of Traumatology 2024;27(5):295-304
Purpose::Vibrio vulnificus ( V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. Methods::An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. Results::In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival ( p = 0.014), reduced the serum creatinine ( p = 0.002), urea nitrogen ( p = 0.030), aspartate aminotransferase ( p = 0.029), and alanine aminotransferase ( p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1β: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1β, IL-6, TNF-α in liver (IL-1β: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1β: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid ( p = 0.225), liver ( p = 0.186), or kidney ( p = 0.637). Conclusion::Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.

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