1.Association of thyroid autoimmunity with thyroid function and gestational diabetes mellitus among pregnant women at first-trimester
Chengcheng HAN ; Xiaofeng WANG ; Jing GAO ; Jing YANG ; Lijuan ZHAO ; Changfang HUANG ; Juanjuan ZHANG ; Jingning XU ; Yinli CAO
Chinese Journal of Perinatal Medicine 2025;28(8):675-681
Objective:To analyze the relationship among thyroid autoimmunity (TAI), thyroid function, and gestational diabetes mellitus (GDM) in early pregnant women in Xi'an.Methods:A prospective study included pregnant women who underwent prenatal check-ups at the Northwest Women's and Children's Hospital from November 2020 to October 2021, with a gestational age of 6 to 14 weeks. Thyroid function, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), and urinary iodine levels were measured, and the prevalence of thyroid disease and GDM was monitored. The subjects were divided into four groups: TPOAb positive only, TgAb positive only, both TPOAb and TgAb positive, and both TPOAb and TgAb negative, to compare the differences in the prevalence of thyroid disease and GDM among the groups. Statistical analysis was performed using Kruskal-Wallis rank-sum test, Bonferroni correction, Chi-square test, and a multivariate logistic regression model was used to analyze the relationship between TAI, thyroid disease, and GDM. Results:A total of 20 243 early pregnant women were included in this study, among which 1 615 (7.98%) were positive for TPOAb only; 865 (4.27%) were positive for TgAb only; 1 672 (8.26%) were positive for both TPOAb and TgAb (both positive group); and 16 091 (79.49%) were negative for both TPOAb and TgAb (both negative group). The thyroid stimulating hormone levels in the TPOAb positive only group, TgAb positive only group, and both positive group were significantly higher than those in the both negative group, respectively (Bonferroni correction, all P<0.05); the free thyroxine level in the TPOAb positive only group was significantly lower than that in the both negative group ( P<0.05). After adjusting for age, pre-pregnancy body mass index, and urinary iodine levels, multivariate logistic regression analysis showed that compared to the both negative group, the risk of developing hypothyroidism during pregnancy was significantly increased in the both positive group ( OR=11.49, 95% CI: 2.84-46.39); the risk of developing subclinical hypothyroidism during pregnancy was significantly increased in the TgAb positive only group ( OR=1.99, 95% CI: 1.05-3.76) and the both positive group ( OR=3.74, 95% CI: 2.49-5.63); the risk of developing GDM was significantly increased in the TgAb positive only group ( OR=1.43, 95% CI: 1.04-1.96) and the both positive group ( OR=1.94, 95% CI: 1.53-2.46). Among early pregnant women with normal thyroid function, after adjusting for age, pre-pregnancy body mass index, and urinary iodine levels, multivariate logistic regression analysis showed that compared to the both negative group, the risk of developing GDM was significantly increased in the TgAb positive only group ( OR=1.46, 95% CI: 1.06-2.02) and the both positive group ( OR=1.80, 95% CI: 1.40-2.32). Conclusion:TgAb positive only is a risk factor for subclinical hypothyroidism and GDM. Screening for thyroid autoantibodies, especially TgAb, during pregnancy helps in the early identification of high-risk pregnant women for thyroid dysfunction and GDM.
2.Association of thyroid autoimmunity with thyroid function and gestational diabetes mellitus among pregnant women at first-trimester
Chengcheng HAN ; Xiaofeng WANG ; Jing GAO ; Jing YANG ; Lijuan ZHAO ; Changfang HUANG ; Juanjuan ZHANG ; Jingning XU ; Yinli CAO
Chinese Journal of Perinatal Medicine 2025;28(8):675-681
Objective:To analyze the relationship among thyroid autoimmunity (TAI), thyroid function, and gestational diabetes mellitus (GDM) in early pregnant women in Xi'an.Methods:A prospective study included pregnant women who underwent prenatal check-ups at the Northwest Women's and Children's Hospital from November 2020 to October 2021, with a gestational age of 6 to 14 weeks. Thyroid function, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), and urinary iodine levels were measured, and the prevalence of thyroid disease and GDM was monitored. The subjects were divided into four groups: TPOAb positive only, TgAb positive only, both TPOAb and TgAb positive, and both TPOAb and TgAb negative, to compare the differences in the prevalence of thyroid disease and GDM among the groups. Statistical analysis was performed using Kruskal-Wallis rank-sum test, Bonferroni correction, Chi-square test, and a multivariate logistic regression model was used to analyze the relationship between TAI, thyroid disease, and GDM. Results:A total of 20 243 early pregnant women were included in this study, among which 1 615 (7.98%) were positive for TPOAb only; 865 (4.27%) were positive for TgAb only; 1 672 (8.26%) were positive for both TPOAb and TgAb (both positive group); and 16 091 (79.49%) were negative for both TPOAb and TgAb (both negative group). The thyroid stimulating hormone levels in the TPOAb positive only group, TgAb positive only group, and both positive group were significantly higher than those in the both negative group, respectively (Bonferroni correction, all P<0.05); the free thyroxine level in the TPOAb positive only group was significantly lower than that in the both negative group ( P<0.05). After adjusting for age, pre-pregnancy body mass index, and urinary iodine levels, multivariate logistic regression analysis showed that compared to the both negative group, the risk of developing hypothyroidism during pregnancy was significantly increased in the both positive group ( OR=11.49, 95% CI: 2.84-46.39); the risk of developing subclinical hypothyroidism during pregnancy was significantly increased in the TgAb positive only group ( OR=1.99, 95% CI: 1.05-3.76) and the both positive group ( OR=3.74, 95% CI: 2.49-5.63); the risk of developing GDM was significantly increased in the TgAb positive only group ( OR=1.43, 95% CI: 1.04-1.96) and the both positive group ( OR=1.94, 95% CI: 1.53-2.46). Among early pregnant women with normal thyroid function, after adjusting for age, pre-pregnancy body mass index, and urinary iodine levels, multivariate logistic regression analysis showed that compared to the both negative group, the risk of developing GDM was significantly increased in the TgAb positive only group ( OR=1.46, 95% CI: 1.06-2.02) and the both positive group ( OR=1.80, 95% CI: 1.40-2.32). Conclusion:TgAb positive only is a risk factor for subclinical hypothyroidism and GDM. Screening for thyroid autoantibodies, especially TgAb, during pregnancy helps in the early identification of high-risk pregnant women for thyroid dysfunction and GDM.
3.Identification and analysis of diazepam in fish bait nest material and fish samples by chromatography-mass spectrometry
Yongni FANG ; Guohua XU ; Lan CHU ; Kemei PEI ; Meng ZHAO ; Jianxin CHU ; Zhaohong WANG ; Ling LV ; Minyan MAO ; Yinli DONG
Chinese Journal of Forensic Medicine 2024;39(5):585-589,595
Objective To establish an analytical method combining gas chromatography-tandem mass spectrometry(GC-MS)and liquid chromatography-tandem mass spectrometry(LC-MS)to detect diazepam residue in bait nest materials and fish samples,and improve the pretreatment steps of samples to make the experimental results accurate and the sample processing convenient and fast.Methods Taking diazepam as the research object,samples were extracted with methanol and dichloromethane/n-hexane as solvents according to the type,and the supernatant was taken for detection after centrifugation.Results The diazepam standard sample showed a good linear relationship in the range of 10~10 000 ng/mL.The retention times in methanol and mixed solvent were 13.54 min and 13.83 min,respectively,and the correlation coefficients were 0.998 and 0.999,respectively;The limit of detection(LOD)of using methanol as extraction solvent was 2 ppb,and limit of quantification(LOQ)was 6 ppb.The LOD of using mixed solvents was 5 ppb,and the LOQ was 15 ppb.When the sample is a bait nest material,the GC-MS spectrum was clear and standard,and the peak shape was sharp and prominent;When the sample is biological specimen,the GC-MS spectra are disturbed by matrix,while the LC-MS data is more accurate and faster.Conclusion It is more appropriate to use GC-MS to determine the content of bait nest materialsamples,and it is more accurate to LC-MS to determine the content of fish samples due to the complexity of the organism.
4.Sex differences in systemic lupus erythematosus (SLE): an inception cohort of the Chinese SLE Treatment and Research Group (CSTAR) registry XVII.
Yinli GUI ; Wei BAI ; Jian XU ; Xinwang DUAN ; Feng ZHAN ; Chen ZHAO ; Zhenyu JIANG ; Zhijun LI ; Lijun WU ; Shengyun LIU ; Min YANG ; Wei WEI ; Ziqian WANG ; Jiuliang ZHAO ; Qian WANG ; Xiaomei LENG ; Xinping TIAN ; Mengtao LI ; Yan ZHAO ; Xiaofeng ZENG
Chinese Medical Journal 2022;135(18):2191-2199
BACKGROUND:
The onset and clinical presentation of systemic lupus erythematosus (SLE) are sex-related. Few studies have investigated the distinctions in clinical characteristics and treatment preferences in male and female SLE patients in the initial cohort. This study aimed to improve the understanding of Chinese SLE patients by characterizing the different sexes of SLE patients in the inception cohort.
METHODS:
Based on the initial patient cohort established by the Chinese SLE Treatment and Research Group, a total of 8713 patients (795 men and 7918 women) with newly diagnosed SLE were enrolled between April 2009 and March 2021. Of these, 2900 patients (347 men and 2553 women) were eligible for lupus nephritis (LN). A cross-sectional analysis of the baseline demographic characteristics, clinical manifestations, laboratory parameters, organ damage, initial treatment regimens, and renal pathology classification was performed according to sex.
RESULTS:
In the SLE group, as compared to female patients, male patients had a later age of onset (male vs. female: 37.0 ± 15.8 years vs. 35.1 ± 13.7 years, P = 0.006) and a higher SLE International Collaborative Clinic/American College of Rheumatology damage index score (male vs. female: 0.47 ± 1.13 vs. 0.34 ± 0.81, P = 0.015), LN (male vs. female: 43.6% vs. 32.2%, P < 0.001), fever (male vs. female: 18.0% vs. 14.6%, P = 0.010), thrombocytopenia (male vs. female: 21.4% vs. 18.5%, P = 0.050), serositis (male vs. female: 14.7% vs. 11.7%, P = 0.013), renal damage (male vs. female: 11.1% vs. 7.4%, P < 0.001), and treatment with cyclophosphamide (CYC) (P < 0.001). The frequency of leukopenia (male vs. female: 20.5% vs. 25.4%, P = 0.002) and arthritis (male vs. female: 22.0% vs. 29.9%, P < 0.001) was less in male patients with SLE. In LN, no differences were observed in disease duration, SLE Disease Activity Index score, renal biopsy pathological typing, or 24-h urine protein quantification among the sexes. In comparisons with female patients with LN, male patients had later onset ages (P = 0.026), high serum creatinine (P < 0.001), higher end-stage renal failure rates (P = 0.002), musculoskeletal damage (P = 0.023), cardiovascular impairment (P = 0.009), and CYC use (P = 0.001); while leukopenia (P = 0.017), arthritis (P = 0.014), and mycophenolate usage (P = 0.013) rates were lower.
CONCLUSIONS
Male SLE patients had more severe organ damage and a higher LN incidence compared with female SLE patients; therefore, they may require more aggressive initial treatment compared to female patients.
Humans
;
Female
;
Male
;
Cross-Sectional Studies
;
Sex Characteristics
;
East Asian People
;
Severity of Illness Index
;
Lupus Erythematosus, Systemic/diagnosis*
;
Lupus Nephritis/pathology*
;
Registries
;
Cyclophosphamide/therapeutic use*
;
Thrombocytopenia
;
Leukopenia/drug therapy*
;
Arthritis
5.Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells.
Peilu SONG ; Fan ZHAO ; Dahong LI ; Jiqiang QU ; Miao YAO ; Yuan SU ; Hanxun WANG ; Miaomiao ZHOU ; Yujie WANG ; Yinli GAO ; Feng LI ; Dongmei ZHAO ; Fengjiao ZHANG ; Yu RAO ; Mingyu XIA ; Haitao LI ; Jian WANG ; Maosheng CHENG
Acta Pharmaceutica Sinica B 2022;12(6):2905-2922
The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).
6.Risk Factors and Pregnancy Outcome in Women with a History of Cesarean Section Complicated by Placenta Accreta
Yingyu LIANG ; Lizi ZHANG ; Shilei BI ; Jingsi CHEN ; Shanshan ZENG ; Lijun HUANG ; Yulian LI ; Minshan HUANG ; Hu TAN ; Jinping JIA ; Suiwen WEN ; Zhijian WANG ; Yinli CAO ; Shaoshuai WANG ; Xiaoyan XU ; Ling FENG ; Xianlan ZHAO ; Yangyu ZHAO ; Qiying ZHU ; Hongbo QI ; Lanzhen ZHANG ; Hongtian LI ; Lili DU ; Dunjin CHEN
Maternal-Fetal Medicine 2022;04(3):179-185
Objective::To explore the risk factors and pregnancy outcomes in women with a history of cesarean section complicated by placenta accreta (PA).Methods::This case-control study included clinical data from singleton mothers with a history of cesarean section in 11 public tertiary hospitals in seven provinces of China between January 2017 and December 2017. According to the intraoperative findings after delivery, the study population was divided into PA and non-PA groups. We compared the pregnancy outcomes between the two groups, used multivariate logistic regression to analyze the risk factors for placental accreta.Results::For this study we included 11,074 pregnant women with a history of cesarean section; and of these, 869 cases were in the PA group and 10,205 cases were in the non-PA group. Compared with the non-PA group, the probability of postpartum hemorrhage (236/10,205, 2.31% vs. 283/869, 32.57%), severe postpartum hemorrhage (89/10,205, 0.87% vs. 186/869, 21.75%), diffuse intravascular coagulation (3/10,205, 0.03% vs. 4/869, 0.46%), puerperal infection (33/10,205, 0.32% vs. 12/869, 1.38%), intraoperative bladder injury (1/10,205, 0.01% vs. 16/869, 1.84%), hysterectomy (130/10,205, 1.27% vs. 59/869, 6.79%), and blood transfusion (328/10,205,3.21 % vs. 231/869,26.58%) was significantly increased in the PA group ( P < 0.05). At the same time, the neonatal birth weight (3250.00 (2950.00-3520.00) g vs. 2920.00 (2530.00-3250.00) g), the probability of neonatal comorbidities (245/10,205, 2.40% vs. 61/869, 7.02%), and the rate of neonatal intensive care unit admission (817/10,205, 8.01% vs. 210/869, 24.17%) also increased significantly ( P < 0.05). Weight (odds ratio ( OR)= 1.03, 95% confidence interval ( CI): 1.01-1.05)), parity ( OR= 1.18, 95% CI: 1.03-1.34), number of miscarriages ( OR= 1.31, 95% CI: 1.17-1.47), number of previous cesarean sections ( OR= 2.57, 95% CI: 2.02-3.26), history of premature rupture of membrane ( OR= 1.61, 95% CI: 1.32-1.96), previous cesarean-section transverse incisions ( OR= 1.38, 95% CI: 1.12-1.69), history of placenta previa ( OR= 2.44,95% CI: 1.50-3.96), and the combination of prenatal hemorrhage ( OR= 9.95,95% CI: 8.42-11.75) and placenta previa ( OR= 91.74, 95% CI: 74.11-113.56) were all independent risk factors for PA. Conclusion::There was an increased risk of adverse outcomes in pregnancies complicated by PA in women with a history of cesarean section, and this required close clinical attention. Weight before pregnancy, parity, number of miscarriages, number of previous cesarean sections, history of premature rupture of membranes, past transverse incisions in cesarean sections, a history of placenta previa, prenatal hemorrhage, and placenta previa were independent risk factors for pregnancies complicated with PA in women with a history of cesarean section. These independent risk factors showed a high value in predicting the risk for placentab accreta in pregnancies of women with a history of cesarean section.
7.Risk Factors and Pregnancy Outcome in Women with a History of Cesarean Section Complicated by Placenta Accreta
Yingyu LIANG ; Lizi ZHANG ; Shilei BI ; Jingsi CHEN ; Shanshan ZENG ; Lijun HUANG ; Yulian LI ; Minshan HUANG ; Hu TAN ; Jinping JIA ; Suiwen WEN ; Zhijian WANG ; Yinli CAO ; Shaoshuai WANG ; Xiaoyan XU ; Ling FENG ; Xianlan ZHAO ; Yangyu ZHAO ; Qiying ZHU ; Hongbo QI ; Lanzhen ZHANG ; Hongtian LI ; Lili DU ; Dunjin CHEN
Maternal-Fetal Medicine 2022;04(3):179-185
Objective::To explore the risk factors and pregnancy outcomes in women with a history of cesarean section complicated by placenta accreta (PA).Methods::This case-control study included clinical data from singleton mothers with a history of cesarean section in 11 public tertiary hospitals in seven provinces of China between January 2017 and December 2017. According to the intraoperative findings after delivery, the study population was divided into PA and non-PA groups. We compared the pregnancy outcomes between the two groups, used multivariate logistic regression to analyze the risk factors for placental accreta.Results::For this study we included 11,074 pregnant women with a history of cesarean section; and of these, 869 cases were in the PA group and 10,205 cases were in the non-PA group. Compared with the non-PA group, the probability of postpartum hemorrhage (236/10,205, 2.31% vs. 283/869, 32.57%), severe postpartum hemorrhage (89/10,205, 0.87% vs. 186/869, 21.75%), diffuse intravascular coagulation (3/10,205, 0.03% vs. 4/869, 0.46%), puerperal infection (33/10,205, 0.32% vs. 12/869, 1.38%), intraoperative bladder injury (1/10,205, 0.01% vs. 16/869, 1.84%), hysterectomy (130/10,205, 1.27% vs. 59/869, 6.79%), and blood transfusion (328/10,205,3.21 % vs. 231/869,26.58%) was significantly increased in the PA group ( P < 0.05). At the same time, the neonatal birth weight (3250.00 (2950.00-3520.00) g vs. 2920.00 (2530.00-3250.00) g), the probability of neonatal comorbidities (245/10,205, 2.40% vs. 61/869, 7.02%), and the rate of neonatal intensive care unit admission (817/10,205, 8.01% vs. 210/869, 24.17%) also increased significantly ( P < 0.05). Weight (odds ratio ( OR)= 1.03, 95% confidence interval ( CI): 1.01-1.05)), parity ( OR= 1.18, 95% CI: 1.03-1.34), number of miscarriages ( OR= 1.31, 95% CI: 1.17-1.47), number of previous cesarean sections ( OR= 2.57, 95% CI: 2.02-3.26), history of premature rupture of membrane ( OR= 1.61, 95% CI: 1.32-1.96), previous cesarean-section transverse incisions ( OR= 1.38, 95% CI: 1.12-1.69), history of placenta previa ( OR= 2.44,95% CI: 1.50-3.96), and the combination of prenatal hemorrhage ( OR= 9.95,95% CI: 8.42-11.75) and placenta previa ( OR= 91.74, 95% CI: 74.11-113.56) were all independent risk factors for PA. Conclusion::There was an increased risk of adverse outcomes in pregnancies complicated by PA in women with a history of cesarean section, and this required close clinical attention. Weight before pregnancy, parity, number of miscarriages, number of previous cesarean sections, history of premature rupture of membranes, past transverse incisions in cesarean sections, a history of placenta previa, prenatal hemorrhage, and placenta previa were independent risk factors for pregnancies complicated with PA in women with a history of cesarean section. These independent risk factors showed a high value in predicting the risk for placentab accreta in pregnancies of women with a history of cesarean section.
8.Survey of prevalence of iron deficiency and iron deficiency anemia in pregnant women in urban areas of China
Guolin HE ; Xin SUN ; Jing TAN ; Jing HE ; Xu CHEN ; Caixia LIU ; Ling FAN ; Li ZOU ; Yinli CAO ; Mei XIAO ; Xueqin ZHANG ; Guohua ZHANG ; Wei ZHOU ; Yan CAI ; Xianlan ZHAO ; Yan GAO ; Hongmei LI ; Xiuli LIU ; Hongping ZHANG ; Yun WANG ; Hui TANG ; Ningxia YUAN ; Guifeng DING ; Fang ZHAN ; Chunxia YIN ; Jiewen ZHANG ; Hongmei YANG ; Yana QI ; Xinghui LIU
Chinese Journal of Obstetrics and Gynecology 2018;53(11):761-767
Objective To investigate the prevalence of iron deficiency(ID)and iron deficiency anemia (IDA) in pregnant women in urban areas of China. Methods The study was a national cross-sectional survey conducted from September 19th, 2016 to November 20th, 2016. According to the classification of the National Bureau of Statistics, all survey sites were set up in 6 regions of the country. Pregnant women were continuously selected using multistage stratified sampling. A total of 12 403 pregnant women were collected and examined for serum ferritin and hemoglobin levels. Results The median serum ferritin level during pregnancy was 20.60 μg/L(11.78-36.98 μg/L), the hemoglobin level was(118±12)g/L. With the progress of pregnancy, the levels of serum ferritin and hemoglobin decreased gradually. The median serum ferritin levels in the first, second trimester and third trimester were 54.30 μg/L(34.48-94.01 μg/L), 28.60 μg/L(16.40-50.52 μg/L), and 16.70 μg/L(10.20-27.00 μg/L)respectively(P<0.01). The mean hemoglobin levels were(127 ± 10)g/L,(119 ± 11)g/L and(117 ± 11)g/L respectively(P<0.01). The prevalence of ID in urban pregnant women was 48.16%(5 973/12 403), and IDA prevalence was 13.87% (1 720/12 403). The prevalence of IDA in the first, second trimester and third trimester were 1.96% (20/1 019), 8.40%(293/3 487)and 17.82%(1 407/7 897), respectively(P<0.01). The prevalence of standardized ID and IDA were significantly different in various regions of China(P<0.01). The standardized prevalence of ID were relatively higher in East China and Northeast China, 57.37% and 53.41% respectively, while it was the lowest in Southwest China, 30.51%. The standardized prevalence of IDA in South Central, Northwest, and East China were relatively high, 21.30%, 16.97% and 17.53% respectively, and the standardized prevalence of IDA in Southwest China was the lowest, 5.44%,the differents in various regions were significant(all P<0.01). Conclusion The current phenomenon of ID and IDA in pregnant women is still very common,and nutrition and health care during pregnancy should be strengthened.
9.Current status and influencing factors of spiritual well-being and hope among malignant lymphoma patients
Li ZHU ; Yinli ZHAO ; Yuan TAO
Chinese Journal of Modern Nursing 2018;24(17):2059-2062
Objective To explore the current status and influencing factors of spiritual well-being and hope among malignant lymphoma patients.Methods From May 2012 to May 2015, we selected 90 malignant lymphoma patients treated in Xijing Hospital by convenience sampling. All of the patients were investigated with the Functional Assessment of Chronic Illness Therapy-spiritual Well-being Scale (FACIT-Sp) and the Herth Hope Index (HHI).Results The score of FACIT-Sp and HHI of malignant lymphoma patients was (25.34±12.06) and (26.08±11.87) respectively. Logistic regression analysis showed that the influencing factors of spiritual well-being of patients included the degree of education, social support and tumor stage (P<0.05); the influencing factors of hope of patients included the degree of education, social support, level of income and tumor stage (P<0.05).Conclusions The level of spiritual well-being and hope of malignant lymphoma patients are usually low. They have similar influencing factors.
10.Progress of brucine and its preparations
Cancer Research and Clinic 2017;29(11):784-788
The inhibiting mechanisms of brucine to cancer cells included inducing the apoptosis of cancer cells, inhibiting the proliferation of cancer cells, preventing cell adhesion and transfer. This paper reviews the function of brucine and its anti-tumor preparations, and compares the efficacy and adverse reactions between brucine related preparations and traditional drugs to evaluate its anti-tumor effects. Furthermore, more exploration on the inhibiting mechanisms is necessary for the patients to obtain safe and effective drugs.

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