1.Predictive value of the percentage of Gleason pattern 4 in biopsy for adverse pathological features and biochemical recurrence after radical prostatectomy in ISUP grade group 2-3 non-metastatic prostate cancer
Haoyu WU ; Tianyu XIONG ; Yanning ZHANG ; Yunpeng FAN ; Tianyu ZHANG ; Zhanliang LIU ; Song JIN ; Guangyong CHEN ; Ping XIE ; Yinong NIU
Chinese Journal of Urology 2025;46(4):267-274
Objective:To assess the predictive value of the percentage of Gleason pattern 4 (G4%) in prostate biopsy for adverse pathology and biochemical recurrence.Methods:We retrospectively analyzed consecutive patients who underwent radical prostatectomy in our institution between January 2019 and December 2023, and included those who were diagnosed with ISUP 2-3 cancer at biopsy. A total of 109 patients were included in this study. The average age of patients was (67.40±6.11) years, and the average BMI of patients was (25.36±2.97) kg/m 2. 49 Cases (45.0%) had a PI-RADS score of 5, and the median prostate volume was 32.60 (24.57, 45.63) ml. The median of most recent tPSA before biopsy was 9.76 (6.89, 12.95) ng/ml, the median PSAD was 0.28 (0.17, 0.44) ng/ml 2, and the median f/tPSA was 0.11 (0.08, 0.16). Clinical T 2b or higher stage was found in 84 cases (77.1%). The total biopsy core length was (22.91±5.18) cm, with a median of 24 (20, 24) biopsy cores and a median of 6 (4, 9) positive cores. Gleason score 3+ 4 was found in 52 cases (47.7%), and Gleason score 4+ 3 in 57 cases (52.3%). Cribriform was present in 30 cases (27.5%). G4% was calculated based on the proportion of Gleason grade 4 tumor relative to total tumor, tumor proportion relative to total tissue, and tissue length. Patients were divided into high-G4% (≥2.45%) and low-G4% (<2.45%) groups based on the median G4% value, with 55 and 54 cases, respectively. No significant differences were observed in baseline characteristics between the two groups ( P>0.05). The main risk factor of adverse pathology was analyzed by logistic regression, and receiver operating characteristic (ROC) curve and area under curve (AUC) were performed. Patients were further stratified by the G4% cutoff value from ROC, and Kaplan-Meier survival curves were plotted to compare biochemical recurrence free survival (BCRFS) between groups. The main risk factor affecting BCRFS was analyzed by Cox regression. Adverse pathology was defined as postoperative Gleason score ≥4+ 3 or pathological stage ≥T 3a. Results:Adverse pathology occurred in 44 (80.0%) high-G4% and 16 (29.6%) low-G4% patients ( P<0.01). Multivariate analysis identified G4% as an independent risk factor for adverse pathology ( OR=1.23, 95% CI 1.02-1.50, P=0.033). The highest ROC AUC value was seen for G4% (0.799), significantly outperforming Gleason score (0.799 vs. 0.641, P=0.003), tPSA (0.799 vs. 0.615, P=0.003), PSAD (0.799 vs. 0.679, P=0.038), positive cores (0.799 vs. 0.677, P=0.009), clinical T stage (0.799 vs. 0.607, P=0.001) and cribriform (0.799 vs. 0.639, P=0.001). The G4% cutoff value for predicting biochemical recurrence was 10.97%. The median BCRFS was significantly higher in the low G4% (<10.97%) group than that in the high G4% (≥10.97%) group (55 vs. 28 months, P=0.002). Cumulative recurrence free survival rates at 1 and 3 years were 94.6% vs. 74.1% and 78.0% vs. 47.6%, respectively. Multivariate Cox regression analysis indicates that G4% was an independent risk factor affecting BCRFS ( HR=1.11, 95% CI 1.00-1.23, P=0.041). Conclusions:For patients with ISUP 2-3 nmPCa, a higher G4% in biopsy specimens demonstrates strong predictive ability for adverse pathology and biochemical recurrence, outperforming traditional clinical indicators such as Gleason score and PSA.
2.Analysis of the levels and food source of cadmium exposure by dietary pathway among middle-aged and elderly populations in cadmium-contaminated areas of China
Xiaochen WANG ; Yi ZHANG ; Xiaojie DONG ; Ruiting HAO ; Xiu YE ; Wenli ZHANG ; Ying ZHU ; Ailing LIU ; Yuan WEI ; Bing WU ; Yufei LUO ; Changzi WU ; Yanning MA ; Zhengxiong YANG ; Yuebin LYU ; Gangqiang DING ; Dongqun XU ; Xiaoming SHI
Chinese Journal of Preventive Medicine 2025;59(5):597-603
Objective:To evaluate the levels and source of cadmium exposure by dietary pathway among middle-aged and elderly people ≥40 in cadmium-contaminated areas of China.Methods:A total of 7 193 people aged 40-89 years from four typical cadmium-contaminated areas in China were selected as the study subjects. Food Frequency Questionnaire (FFQ), Total Diet Study (TDS) and a 3-day-24-hour dietary recall survey were conducted. Dietary cadmium intake and food sources through dietary pathways were assessed based on cadmium content in foods, consumption amounts and intake frequencies.Results:The mean age of the participants was 63.39±12.21 years, with 50.05% being males. The average monthly dietary cadmium intake was 7.39 μg/(kg·BW). Staple foods and vegetables were the primary sources of dietary cadmium intake, accounting for 57.51% and 32.48%, respectively. The monthly dietary cadmium intake in all surveyed regions did not exceed the Provisional Tolerable Monthly Intake (PTMI) recommended by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).Conclusion:The monthly dietary cadmium intake among middle-aged and elderly people in cadmium-contaminated areas of China is relatively low, with the risk remaining at an acceptable level. Staple foods and vegetables are the most significant contributors to dietary cadmium intake.
3.Predictive value of the percentage of Gleason pattern 4 in biopsy for adverse pathological features and biochemical recurrence after radical prostatectomy in ISUP grade group 2-3 non-metastatic prostate cancer
Haoyu WU ; Tianyu XIONG ; Yanning ZHANG ; Yunpeng FAN ; Tianyu ZHANG ; Zhanliang LIU ; Song JIN ; Guangyong CHEN ; Ping XIE ; Yinong NIU
Chinese Journal of Urology 2025;46(4):267-274
Objective:To assess the predictive value of the percentage of Gleason pattern 4 (G4%) in prostate biopsy for adverse pathology and biochemical recurrence.Methods:We retrospectively analyzed consecutive patients who underwent radical prostatectomy in our institution between January 2019 and December 2023, and included those who were diagnosed with ISUP 2-3 cancer at biopsy. A total of 109 patients were included in this study. The average age of patients was (67.40±6.11) years, and the average BMI of patients was (25.36±2.97) kg/m 2. 49 Cases (45.0%) had a PI-RADS score of 5, and the median prostate volume was 32.60 (24.57, 45.63) ml. The median of most recent tPSA before biopsy was 9.76 (6.89, 12.95) ng/ml, the median PSAD was 0.28 (0.17, 0.44) ng/ml 2, and the median f/tPSA was 0.11 (0.08, 0.16). Clinical T 2b or higher stage was found in 84 cases (77.1%). The total biopsy core length was (22.91±5.18) cm, with a median of 24 (20, 24) biopsy cores and a median of 6 (4, 9) positive cores. Gleason score 3+ 4 was found in 52 cases (47.7%), and Gleason score 4+ 3 in 57 cases (52.3%). Cribriform was present in 30 cases (27.5%). G4% was calculated based on the proportion of Gleason grade 4 tumor relative to total tumor, tumor proportion relative to total tissue, and tissue length. Patients were divided into high-G4% (≥2.45%) and low-G4% (<2.45%) groups based on the median G4% value, with 55 and 54 cases, respectively. No significant differences were observed in baseline characteristics between the two groups ( P>0.05). The main risk factor of adverse pathology was analyzed by logistic regression, and receiver operating characteristic (ROC) curve and area under curve (AUC) were performed. Patients were further stratified by the G4% cutoff value from ROC, and Kaplan-Meier survival curves were plotted to compare biochemical recurrence free survival (BCRFS) between groups. The main risk factor affecting BCRFS was analyzed by Cox regression. Adverse pathology was defined as postoperative Gleason score ≥4+ 3 or pathological stage ≥T 3a. Results:Adverse pathology occurred in 44 (80.0%) high-G4% and 16 (29.6%) low-G4% patients ( P<0.01). Multivariate analysis identified G4% as an independent risk factor for adverse pathology ( OR=1.23, 95% CI 1.02-1.50, P=0.033). The highest ROC AUC value was seen for G4% (0.799), significantly outperforming Gleason score (0.799 vs. 0.641, P=0.003), tPSA (0.799 vs. 0.615, P=0.003), PSAD (0.799 vs. 0.679, P=0.038), positive cores (0.799 vs. 0.677, P=0.009), clinical T stage (0.799 vs. 0.607, P=0.001) and cribriform (0.799 vs. 0.639, P=0.001). The G4% cutoff value for predicting biochemical recurrence was 10.97%. The median BCRFS was significantly higher in the low G4% (<10.97%) group than that in the high G4% (≥10.97%) group (55 vs. 28 months, P=0.002). Cumulative recurrence free survival rates at 1 and 3 years were 94.6% vs. 74.1% and 78.0% vs. 47.6%, respectively. Multivariate Cox regression analysis indicates that G4% was an independent risk factor affecting BCRFS ( HR=1.11, 95% CI 1.00-1.23, P=0.041). Conclusions:For patients with ISUP 2-3 nmPCa, a higher G4% in biopsy specimens demonstrates strong predictive ability for adverse pathology and biochemical recurrence, outperforming traditional clinical indicators such as Gleason score and PSA.
4.Analysis of the levels and food source of cadmium exposure by dietary pathway among middle-aged and elderly populations in cadmium-contaminated areas of China
Xiaochen WANG ; Yi ZHANG ; Xiaojie DONG ; Ruiting HAO ; Xiu YE ; Wenli ZHANG ; Ying ZHU ; Ailing LIU ; Yuan WEI ; Bing WU ; Yufei LUO ; Changzi WU ; Yanning MA ; Zhengxiong YANG ; Yuebin LYU ; Gangqiang DING ; Dongqun XU ; Xiaoming SHI
Chinese Journal of Preventive Medicine 2025;59(5):597-603
Objective:To evaluate the levels and source of cadmium exposure by dietary pathway among middle-aged and elderly people ≥40 in cadmium-contaminated areas of China.Methods:A total of 7 193 people aged 40-89 years from four typical cadmium-contaminated areas in China were selected as the study subjects. Food Frequency Questionnaire (FFQ), Total Diet Study (TDS) and a 3-day-24-hour dietary recall survey were conducted. Dietary cadmium intake and food sources through dietary pathways were assessed based on cadmium content in foods, consumption amounts and intake frequencies.Results:The mean age of the participants was 63.39±12.21 years, with 50.05% being males. The average monthly dietary cadmium intake was 7.39 μg/(kg·BW). Staple foods and vegetables were the primary sources of dietary cadmium intake, accounting for 57.51% and 32.48%, respectively. The monthly dietary cadmium intake in all surveyed regions did not exceed the Provisional Tolerable Monthly Intake (PTMI) recommended by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).Conclusion:The monthly dietary cadmium intake among middle-aged and elderly people in cadmium-contaminated areas of China is relatively low, with the risk remaining at an acceptable level. Staple foods and vegetables are the most significant contributors to dietary cadmium intake.
5.Gene mutation characteristics of clinical stage ⅠA lung adenocarcinoma and their relations with patients′ long-term prognosis
Li ZHANG ; Mengwen LIU ; Lin LI ; Shuang ZHAO ; Lihong WU ; Zhaohua YIN ; Meng LI ; Yanning GAO ; Ning WU
Chinese Journal of Oncology 2024;46(8):755-763
Objective:To explore the gene mutation characteristics and the relationship between gene mutations and long-term prognosis in clinical stage ⅠA lung adenocarcinoma patients.Methods:A retrospective analysis was conducted on 63 clinical stage ⅠA lung adenocarcinoma patients who underwent surgical resection at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2007 to October 2012, with documented postoperative recurrence or metastasis, as well as those who had a follow-up duration of 10 years or more without recurrence or metastasis. Whole exome sequencing (WES) technology was used to analyze the gene mutation profiles in tumor tissues and univariate and multivariate Cox regression analysis were used to clarify the influencing factors for patient prognosis.Results:After long term follow-up, 13 out of the 63 patients (21%) experienced recurrence or metastasis. WES technology analysis revealed that the most common tumor related gene mutations occurred in epidermal growth factor receptor (EGFR), with a mutation rate of 65.1% (41/63), followed by tumor protein p53 (TP53), fatatypical cadherin 1 (FAT1), low density lipoprotein receptor-related protein 1B (LRP1B), mechanistic target of rapamycin (MTOR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG), and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), with mutation rates of 30.2% (19/63), 20.6% (13/63), 15.9% (10/63), 15.9% (10/63), 15.9% (10/63), and 15.9% (10/63), respectively. Multivariate Cox regression analysis showed that PIK3CG mutations ( HR=21.52, 95% CI: 3.19-145.01),smoothened (SMO) mutations ( HR=35.28, 95% CI: 3.12-398.39), catenin beta 1 (CTNNB1) mutations ( HR=332.86, 95% CI: 15.76-7 029.05), colony stimulating factor 1 receptor (CSF1R) mutations ( HR=8 109.60, 95% CI: 114.19-575 955.17), and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations ( HR=23.65, 95% CI: 1.86-300.43) were independent risk factors affecting the prognosis of clinical stage ⅠA lung adenocarcinoma patients. Conclusions:PIK3CG, SMO, CTNNB1, CSF1R, BRAF gene mutations are closely related to long-term recurrence or metastasis in clinical stage ⅠA lung adenocarcinoma. Patients with these gene mutations should be given closer clinical attention.
6.Research on the diagnosis and treatment path of acute vestibular syndrome patients under the concept of humanistic care
Yingying LIU ; Yanning YUN ; Qun WU ; Pan YANG ; Zixuan YUN ; Li LU ; Juanli XING
Chinese Medical Ethics 2024;37(4):466-469
At present,there are many difficulties in the diagnosis and treatment of acute vestibular syndrome(AVS).For example,complex and difficult identification of the cause of disease,uneven diagnosis and treatment levels of clinical doctors,weak humanistic care awareness,lack of communication skills,intrinsic affinity and other reasons,which make it difficult for AVS patients in the process of diagnosis and treatment,and cannot receive timely and effective treatment,resulting in an exacerbation of doctor-patient conflicts.Therefore,it is recommended to explore new paths of AVS diagnosis and treatment work using the humanistic care concept,respect each other between doctors and patients,build a team of medical staff with the value orientation of"humanistic care",and promote the organic unity of theory and practice of"humanistic care",with a view to better promoting the implementation of AVS diagnosis and treatment work,helping more patients rebuild confidence,enhancing quality of life,and improving the doctor-patient relationship.
7.Design and Construction of a Specialized Clinical Research Database for Inflammatory Demyelinating Diseases of the Central Nervous System
Lei WU ; Bing WANG ; Qian YU ; Hui SUN ; He ZHAO ; Sai GAO ; Hena GUO ; Yanning HUANG ; Zhaoyou MENG ; Li-Anchen XIAO ; Haizhen XU ; Dehui HUANG
Journal of Medical Informatics 2024;45(5):83-88
Purpose/Significance To construct a specialized database for inflammatory demyelinating disease of the central nervous system(CNS),so as to contribute to clinical research and improve the diagnostic and treatment capabilities of primary healthcare institu-tions.Method/Process Using the internet to collect medical data,after processing and analysis,the CNS inflammatory demyelinating disease database is constructed.Using statistical analysis,natural language processing(NLP),artificial intelligence(AI)image recog-nition and data visualization and other technologies,the database information is integrated and analyzed.Result/Conclusion A standard-ized big database for CNS inflammatory demyelinating diseases is constructed,which enables visualization of clinical research data,pro-vides patient education and specialist training,and facilitates multi-center teleconsultations.The establishment of a specialized database for the CNS inflammatory demyelinating disease can promote the transformation of medical research achievements,provide references for future real-world clinical research,optimize the process of diagnosis and treatment,and improve the clinical capability of primary healthcare institutions.
8.Characteristics of peripheral blood lymphocyte subsets in patients with relapsed neuromyelitis optica spectrum disorder during rituximab treatment
Yanning HUANG ; Lei WU ; Hui SUN ; Sai GAO ; Dehui HUANG ; Xi ZHANG
Chinese Journal of Neuromedicine 2024;23(4):372-378
Objective:To analyze the characteristics of peripheral blood lymphocyte subsets in patients with relapsed neuromyelitis optica spectrum disorder (NMOSD) during rituximab (RTX) treatment and to clarify the influence of these lymphocyte subsets in NMOSD relapse.Methods:The monitoring data of lymphocyte subsets (175 times) in 76 patients diagnosed as having aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive NMOSD during RTX treatment at Department of Neurology, General Hospital of Chinese People's Liberation Army from August 2018 to August 2023 were collected. A relapse group ( n=26) and a non-relapse group ( n=149) were divided based on states at data collection (relapse or not). Two-sample t-test or Mann-Whitney U test were used to compare the differences in RTX administration intervals and lymphocyte subsets between the 2 groups. Additionally, a point biserial correlation analysis was performed to investigate the correlations of lymphocyte subsets and RTX administration intervals with NMOSD relapse. Results:The relapse group had significantly longer RTX administration intervals (10.00 [6.73, 14.37] months vs. 7.27[6.30, 9.10] months), statistically lower percentage of CD3 -CD56 + natural killer lymphocytes (10.72% [7.06%, 15.34%) vs. 13.85% [9.42%, 20.13%]), and significantly higher CD19 + B lymphocytes (7.41% [1.18%, 15.70%] vs. 3.55% [0.38%, 8.74%]) than the non-relapse group ( P<0.05). Positive correlations were noted between RTX administration intervals and NMOSD relapse and between CD3 -D19 +B lymphocytes and NMOSD relapse ( r=0.363, P<0.001; r=0.218, P=0.004); negative correlation was noted between CD3 -CD56 + NK lymphocytes and NMOSD relapse ( r=-0.193, P=0.011). Conclusion:Extended RTX administration interval can increase NMOSD relapse; CD3 -CD56 + natural killer lymphocytes and CD19 +B lymphocytes may regulate the disease states of NMOSD patients.
9.Gene mutation characteristics of clinical stage ⅠA lung adenocarcinoma and their relations with patients′ long-term prognosis
Li ZHANG ; Mengwen LIU ; Lin LI ; Shuang ZHAO ; Lihong WU ; Zhaohua YIN ; Meng LI ; Yanning GAO ; Ning WU
Chinese Journal of Oncology 2024;46(8):755-763
Objective:To explore the gene mutation characteristics and the relationship between gene mutations and long-term prognosis in clinical stage ⅠA lung adenocarcinoma patients.Methods:A retrospective analysis was conducted on 63 clinical stage ⅠA lung adenocarcinoma patients who underwent surgical resection at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2007 to October 2012, with documented postoperative recurrence or metastasis, as well as those who had a follow-up duration of 10 years or more without recurrence or metastasis. Whole exome sequencing (WES) technology was used to analyze the gene mutation profiles in tumor tissues and univariate and multivariate Cox regression analysis were used to clarify the influencing factors for patient prognosis.Results:After long term follow-up, 13 out of the 63 patients (21%) experienced recurrence or metastasis. WES technology analysis revealed that the most common tumor related gene mutations occurred in epidermal growth factor receptor (EGFR), with a mutation rate of 65.1% (41/63), followed by tumor protein p53 (TP53), fatatypical cadherin 1 (FAT1), low density lipoprotein receptor-related protein 1B (LRP1B), mechanistic target of rapamycin (MTOR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG), and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), with mutation rates of 30.2% (19/63), 20.6% (13/63), 15.9% (10/63), 15.9% (10/63), 15.9% (10/63), and 15.9% (10/63), respectively. Multivariate Cox regression analysis showed that PIK3CG mutations ( HR=21.52, 95% CI: 3.19-145.01),smoothened (SMO) mutations ( HR=35.28, 95% CI: 3.12-398.39), catenin beta 1 (CTNNB1) mutations ( HR=332.86, 95% CI: 15.76-7 029.05), colony stimulating factor 1 receptor (CSF1R) mutations ( HR=8 109.60, 95% CI: 114.19-575 955.17), and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations ( HR=23.65, 95% CI: 1.86-300.43) were independent risk factors affecting the prognosis of clinical stage ⅠA lung adenocarcinoma patients. Conclusions:PIK3CG, SMO, CTNNB1, CSF1R, BRAF gene mutations are closely related to long-term recurrence or metastasis in clinical stage ⅠA lung adenocarcinoma. Patients with these gene mutations should be given closer clinical attention.
10.Mechanism of Polysaccharides from Two Spleen-invigorating Chinese Medicine Prescriptions in Regulating Growth of Bacteroides fragilis in vitro: Based on Differential Expression of Polysaccharide Utilization Loci
Yanning WU ; Li WU ; Hejie WU ; Qinglong SHU
Chinese Journal of Experimental Traditional Medical Formulae 2023;29(22):21-28
ObjectiveTo investigate the effects of using the polysaccharides from two Chinese medicine compound prescriptions as the carbon source on the growth of Bacteroides fragilis and to decipher the mechanism from the perspective of differential expression of polysaccharide utilization loci (PULs) based on transcriptomics. MethodThe media with different carbon sources [20% polysaccharides of Lizhongtang, polysaccharides of Shenling Baizhusan, glucose, and brain heart infusion (BHI) Broth] were used for the anaerobic culture of B. fragile ATCC25285. The effects of different carbon sources on the growth of B. fragilis ATCC25285 were determined by continuous sampling and spectrophotometry. Then, transcriptome sequencing was performed for the cultures obtained with different carbon sources to study the mechanism of different carbon sources in regulating bacterial growth. ResultThe concentration of bacteria with the polysaccharide of Lizhongtang, polysaccharide of Shenling Baizhusan, BHI Broth, and glucose as the carbon sources peaked at 26, 32, 26, 38 h, respectively, and the bacteria in all the four groups achieved robust growth. Gene ontology (GO) enrichment indicated that the differentially expressed genes in the Lizhongtang polysaccharide group and Shenling Baizhusan polysaccharide group were concentrated in the transport and transmembrane transport of dicarboxylic acid. The Shenling Baizhusan polysaccharide and BHI Broth groups showed high expression of PUL 4 and 27, glycoside hydrolase 13 (GH13), and glycosyl transferases 5 (GT5). PUL9 was highly expressed in Shenling Baizhusan polysaccharide group, and PUL 17, 19, and 20, GH3, and GH144 in the BHI Broth group. PUL27 and GT5 were highly expressed in Shenling Baizhusan polysaccharide and glucose groups. PUL 4 and 9 and GH13 were only highly expressed in Shenling Baizhusan polysaccharide group, and PUL 2, 17, and 19 and GH2 in the glucose group. Both Lizhongtang polysaccharide group and BHI group highly expressed PUL 4, 17, 19, 20, and 27, GH3, and GH144. PUL 2, 8, 23, and 27, GH2, and GH57 were highly expressed in Lizhongtang polysaccharide group, while GH13 showed high expression in the BHI group. Both the glucose and Lizhongtang polysacharride groups showed high expression of PUL 4 and 27 and GH2. PUL 4, 8, 20, and 23, GH3, and GH144 were highly expressed in Lizhongtang polysaccharide group, while PUL30 was highly expressed in the glucose group. ConclusionThe in vitro experiments and transcriptome sequencing results confirmed that the expression of PULs and GH may provide benefits or costs to the adaptive growth of Bacteroides fragilis ATCC25285 cultured with different carbon sources, which may be one of the mechanisms by which polysaccharides from Chinese medicine compound prescriptions regulate the growth of B. fragilis ATCC25285. The findings can provide a reference for further research on the relationship between B. fragilis metabolic pathway and polysaccharides of Chinese medicine compound prescriptions.

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