1.Analysis of constraints and policy recommendations for the development of pediatric drugs in China:Based on the perspective of pharmaceutical enterprises
Rui-Lin DING ; Ming-Yu BAI ; Jia-Nan FU ; Xin-Yu LI ; Rong SHAO
Chinese Journal of Health Policy 2024;17(2):59-65
Objective:To provide a basis for improving the design and implementation of policies for ensuring the supply of pediatric drugs in China.Method:Based on the perspective of pharmaceutical enterprises,reviewed literature and conducts questionnaire surveys to identify the constraints in the development of pediatrict drugs throughout the entire drug lifecycle,and analyzes the constraints'concentration and urgency.Result:The main constraints include:difficulty in conducting clinical trials for children;the current registration and approval rules lack consideration for the specificity of pediatric drugs and specific requirements for application materials;lack of implementation rules and measures in the implementation process of incentive policies for pediatric drug production;The market interest mechanism of pediatric drugs is not yet perfect.Among them,research and development and payment for use are currently relatively concentrated issues.Discussion and suggestions:It is recommended that China fully utilize existing clinical trial data of pediatric and broaden sources,take multiple measures to increase investment in pediatric drug R&D;Develop special guidelines for pediatric drug application and encourage adult drug registration to submit pediatric research plans;Explore the optimization path of pediatrict drug production and supply based on typical cases;Provide more space for pediatric drugs in the rules of drug use and payment.
2.Construct course of exercise therapy technology for vocational college of rehabilitation therapy techenology based on ICF and RCF
Junwu YU ; Zhongbing DING ; Qinglan FU ; Haizhou LI ; Ji-Won PARK ; Yan WANG ; Jie HU ; Jianjuan BAI ; Zuojun SHI
Chinese Journal of Rehabilitation Theory and Practice 2024;30(12):1400-1406
ObjectiveTo analyze and construct a curriculum framework and content system of the vocational college rehabilitation therapy technology exercise therapy technology course, based on World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) and rehabilitation competency framework (RCF). MethodsUsing educational psychology and curriculum theory, and applying the ICF and RCF, the curriculum system for rehabilitation therapy technology curriculum system was constructed. A systematic analysis of the existing exercise therapy technology course content was conducted to identify the core elements related to ICF and RCF. Through the design of course modules, these core elements were integrated into theoretical courses, skills training and practical courses to form a comprehensive curriculum structure. ResultsCombining the ICF and RCF, a curriculum system for rehabilitation therapy technology curriculum system was constructed, covering theoretical courses, skills training and practical courses. This system enabled students to systematically master rehabilitation assessment and treatment techniques and develop clinical decision-making abilities and interdisciplinary collaboration skills. The introduction of the ICF framework allowed students to acquire knowledge, skills and abilities in the field of exercise therapy technology through the course. Developing competency-oriented courses based on RCF framework helped students develop comprehensive professional competencies through learning. ConclusionBy integrating the ICF and RCF, a curriculum for exercise therapy technology course in vocational colleges has been constructed. Based on the ICF framework, the content of the course has been aligned with the bio-psycho-social theory of functioning and health, covering three levels: body function, activity and participation, and environmental factors. The curriculum content should include the analysis, assessment and intervention of these functioning. RCF provides a theoretical structure and methodology for developing competency-oriented courses. When designing the course modules, teaching objectives have been established based on the core competency framework, aiming to develop students' comprehensive professional competence and professionalism through theoretical courses, practical training and clinical internships.
3.Inheritance,Innovation and Research Application of Lingnan Liver-Soothing and Spirit-Regulating Acupuncture and Moxibustion Technique
Wen-Bin FU ; Bai-Le NING ; Qian WU ; Cong WANG ; Rui MA ; Ding LUO ; Jun-He ZHOU ; Xue-Song LIANG ; Shan-Ze WANG
Journal of Guangzhou University of Traditional Chinese Medicine 2024;41(10):2740-2745
The lingnan liver-soothing and spirit-regulating acupuncture and moxibustion technique,developed by Professor FU Wen-Bin,a renowned traditional Chinese medicine expert in Guangdong Province,represents an innovative achievement in acupuncture therapy for depression-related disorders.Drawing upon the rich legacy of master scholars,meticulous study of medical literature,and over three decades of continuous research and innovation,Professor FU has formulated this technique with profound influence and widespread application.By tracing the developmental trajectory of the Lingnan liver-soothing and spirit-regulating technique,this paper sheds light on its significant guiding principles and reference value for the development of other distinctive acupuncture techniques.Furthermore,it offers insights and inspiration for advancement in various fields of traditional Chinese medicine.
4.Influence of different processing motivation on the intergroup interaction willingness of college students
Yatong LI ; Haoyang BAI ; Xiaolong FU ; Xiaobin DING
Chinese Journal of Behavioral Medicine and Brain Science 2023;32(4):334-340
Objective:To explore the effect and mechanism of different processing motivation on college students' intergroup interaction willingness by technology of eye movement.Methods:Sixty college students conforming to the study conditions were selected from Northwest Normal University and randomly divided into ingroup motivation group ( n=30) and outgroup motivation group ( n=30) according to the random number table method. Subjects of the two groups first participated in the eye movement task, and then participated in the partner selection task.In the eye movement task, the percentage of time that subjects looked at faces of different groups was recorded.And in the partner selection task, the number of selections that subjects selected faces from different groups was recorded.SPSS 20.0 software was used for repeated measurement analysis of variance. Results:(1) In the eye movement task, there was a significant interaction of group and face group type ( F=13.37, P<0.001), but the main effects of group( F=3.23, P=0.077), and face group type ( F=0.09, P>0.05) were not significant. Further simple effect analysis showed that the percentage of time that the ingroup motors looked at the yellow race((16.00±0.06)%) was significantly higher than that of the outgroup motors ((12.00±0.04)%), and the percentage of time that the outgroup motors looked at the white race((17.00±0.06)%) was significantly higher than that of the ingroup motors ((9.00±0.04)%). (2) In the task of partner selection, there was a significant interaction among group, face group type and face old and new types( F=4.38, P=0.041), and the main effect of face group type was significant( F=14.87, P<0.001). The main effect of old and new types of face was significant( F=8.88, P=0.004), but the main effect of group was not significant ( P>0.05). Further simple effect analysis showed that the two groups of college students had statistically significant differences in the selection times of familiar faces from different groups( F=11.51, P=0.001). The number of times that the ingroup generator (5.51±1.14) selected the familiar yellow race as its partner was significantly greater than that of the outgroup generator (2.30±0.65). The number of times that the outgroup generator (5.40±1.00) selected the familiar white race as its partner was significantly greater than that of the ingroup generator (3.47±0.94). (3)Preferential attention to the ingroup members was a mediator between processing motivation and intergroup interaction willingness (mediating effect=0.20, 95% CI=0.02-0.31). Conclusion:Ingroup processing motivation has a threatening effect on college students' intergroup interaction willingness, outgroup processing motivation has a promoting effect on college students' intergroup interaction willingness, and processing motivation affects intergroup interaction willingness through ingroup bias.
5.Comparisons of the efficacy of drug injections for the treatment of keloid: a network meta-analysis
Hongfan DING ; Xiao XU ; Shiyi LI ; Yichen WANG ; Qian WU ; Ruiqi BAI ; Guiwen ZHOU ; Qiang FU ; Yue LIU ; Minliang CHEN
Chinese Journal of Plastic Surgery 2023;39(12):1311-1323
Objective:To conduct a network meta-analysis comparing the efficacy and safety of various drug injections for treating keloids.Methods:The search terms of "triamcinolone acetonide, 5-fluorouracil, verapamil, botulinum toxin, platelet rich plasma, keloid, scar, drug injection" were retrieved in PubMed, Embase, Web of Science, CNKI and Wanfang database to obtain the publicly published randomized controlled trials comparing single or combined drug injection for treating keloid from January 2010 to February 2023. The outcome index was the effective proportion of treatment, incidence proportion of adverse reactions, and recurrence proportion. NoteExpress, RevMan 5.4, and Stata 16.0 statistical software were utilized to perform a network meta-analysis of eligible studies that met the inclusion and exclusion criteria.Results:A total of 1 679 patients were enrolled in 21 studies that evaluated nine treatment modalities: triamcinolone (TAC), 5-fluorouracil (5-FU), botulinum toxin type A (BTA), platelet-rich plasma (PRP), Verapamil, BTA+ 5-FU, TAC+ 5-FU, TAC+ BTA, and TAC+ PRP. The network diagram revealed that there were 36 pairwise comparisons among the 9 treatment measures, with direct comparisons in 13 of them. The funnel plot demonstrated a symmetrical distribution of effect size points, and both Beggs test and Eggers test yielded P values greater than 0.05, indicating a low likelihood of publication bias. Nine treatment measures formed five closed loops with good consistency. The result of the network meta-analysis indicated that BTA+ 5-FU was more effective than TAC, 5-FU, or PRP alone; TAC+ 5-FU was more effective than TAC, 5-FU, or PRP alone; TAC+ BTA was more effective than TAC, 5-FU, BTA, or PRP alone; Verapamil was more effective than 5-FU and BTA was more effective than 5-FU. All result were found to be statistically significant ( P<0.05). A surface under the cumulative ranking area (SUCRA) map was generated, displaying the efficacy ranking and corresponding SUCRA values for each treatment: BTA+ 5-FU (85.6%)>TAC+ 5-FU (84.8%)>BTA+ TAC (76.7%)>Verapamil (48.9%)>BTA (45.0%)>TAC+ PRP (43.8%)>PRP (32.1%)>TAC (24.7%)>5-FU(8.3%). In terms of recurrence rate, the incidence of recurrence was higher with 5-FU compared to BTA or TAC+ 5-FU, and the incidence of recurrence was higher with TAC compared to TAC+ 5-FU; these differences were statistically significant ( P<0.05). A SUCRA map was generated with the ranking and SUCRA value for each treatment as follows: 5-FU (80.4%)>TAC (73.5%)>Verapamil (65.7%)>TAC+ BTA (52.5%)>PRP (34.8%)>BTA+ 5-FU (33.7%)>TAC+ 5-FU (30.2%)>BTA (29.3%). The qualitative analysis revealed a significantly lower incidence of systemic and local adverse reactions following combined drug injection compared to single drug injection. Conclusion:In the treatment of keloids using drug injection, combination therapy utilizing multiple drugs has demonstrated superior efficacy, lower recurrence rates, and fewer adverse reactions in comparison to single-drug therapy. Notably, the utilization of BAT, 5-FU, and TAC in combination may yield the most favorable outcomes.
6.Comparisons of the efficacy of drug injections for the treatment of keloid: a network meta-analysis
Hongfan DING ; Xiao XU ; Shiyi LI ; Yichen WANG ; Qian WU ; Ruiqi BAI ; Guiwen ZHOU ; Qiang FU ; Yue LIU ; Minliang CHEN
Chinese Journal of Plastic Surgery 2023;39(12):1311-1323
Objective:To conduct a network meta-analysis comparing the efficacy and safety of various drug injections for treating keloids.Methods:The search terms of "triamcinolone acetonide, 5-fluorouracil, verapamil, botulinum toxin, platelet rich plasma, keloid, scar, drug injection" were retrieved in PubMed, Embase, Web of Science, CNKI and Wanfang database to obtain the publicly published randomized controlled trials comparing single or combined drug injection for treating keloid from January 2010 to February 2023. The outcome index was the effective proportion of treatment, incidence proportion of adverse reactions, and recurrence proportion. NoteExpress, RevMan 5.4, and Stata 16.0 statistical software were utilized to perform a network meta-analysis of eligible studies that met the inclusion and exclusion criteria.Results:A total of 1 679 patients were enrolled in 21 studies that evaluated nine treatment modalities: triamcinolone (TAC), 5-fluorouracil (5-FU), botulinum toxin type A (BTA), platelet-rich plasma (PRP), Verapamil, BTA+ 5-FU, TAC+ 5-FU, TAC+ BTA, and TAC+ PRP. The network diagram revealed that there were 36 pairwise comparisons among the 9 treatment measures, with direct comparisons in 13 of them. The funnel plot demonstrated a symmetrical distribution of effect size points, and both Beggs test and Eggers test yielded P values greater than 0.05, indicating a low likelihood of publication bias. Nine treatment measures formed five closed loops with good consistency. The result of the network meta-analysis indicated that BTA+ 5-FU was more effective than TAC, 5-FU, or PRP alone; TAC+ 5-FU was more effective than TAC, 5-FU, or PRP alone; TAC+ BTA was more effective than TAC, 5-FU, BTA, or PRP alone; Verapamil was more effective than 5-FU and BTA was more effective than 5-FU. All result were found to be statistically significant ( P<0.05). A surface under the cumulative ranking area (SUCRA) map was generated, displaying the efficacy ranking and corresponding SUCRA values for each treatment: BTA+ 5-FU (85.6%)>TAC+ 5-FU (84.8%)>BTA+ TAC (76.7%)>Verapamil (48.9%)>BTA (45.0%)>TAC+ PRP (43.8%)>PRP (32.1%)>TAC (24.7%)>5-FU(8.3%). In terms of recurrence rate, the incidence of recurrence was higher with 5-FU compared to BTA or TAC+ 5-FU, and the incidence of recurrence was higher with TAC compared to TAC+ 5-FU; these differences were statistically significant ( P<0.05). A SUCRA map was generated with the ranking and SUCRA value for each treatment as follows: 5-FU (80.4%)>TAC (73.5%)>Verapamil (65.7%)>TAC+ BTA (52.5%)>PRP (34.8%)>BTA+ 5-FU (33.7%)>TAC+ 5-FU (30.2%)>BTA (29.3%). The qualitative analysis revealed a significantly lower incidence of systemic and local adverse reactions following combined drug injection compared to single drug injection. Conclusion:In the treatment of keloids using drug injection, combination therapy utilizing multiple drugs has demonstrated superior efficacy, lower recurrence rates, and fewer adverse reactions in comparison to single-drug therapy. Notably, the utilization of BAT, 5-FU, and TAC in combination may yield the most favorable outcomes.
7.Modern research thoughts and methods on bio-active components of TCM formulae.
Yu-Ping TANG ; Ding-Qiao XU ; Shi-Jun YUE ; Yan-Yan CHEN ; Rui-Jia FU ; Xue BAI
Chinese Journal of Natural Medicines (English Ed.) 2022;20(7):481-493
TCM formulae are the important guidances for clinical application of traditional Chinese medicines, which follow the principles of diagnosis and treatment in TCM. Elucidating the bio-active components of TCM formulae is the key to the modernization and internationalization of traditional Chinese medicines. With the rapid development of modern instruments and technology, many new theories, methods and strategies are emerging, which upgrade the research of TCM formulae into a higher level. Only when the medicinal efficacy, bio-active components, function mechanism of TCM formulae are understood, we can guarantee TCM safety and quality control. In this paper, we summarized the latest modern research thoughts and methods on bio-active components of TCM formulae including formula decomposition study, serum pharmacology and serum pharmacochemistry, association analysis, biochromatography, network pharmacology, metabolomics and proteomics, so as to provide reference for the research and development of TCM in the future.
Biological Products
;
Drugs, Chinese Herbal/chemistry*
;
Medicine, Chinese Traditional/methods*
;
Metabolomics
;
Proteomics
8.Clinical value of radiomics based on CT examination in preoperative differential diagnosis of pancreatic serous cystadenoma and mucinous cystadenoma
Wenjie LIANG ; Wuwei TIAN ; Yubizhuo WANG ; Jingwen XIA ; Shijian RUAN ; Jiayuan SHAO ; Zhihao FU ; Na LU ; Yong DING ; Wenbo XIAO ; Xueli BAI
Chinese Journal of Digestive Surgery 2021;20(5):555-563
Objective:To investigate the clinical value of radiomics based on computed tomography (CT) examination in preoperative differential diagnosis of pancreatic serous cystadenoma (SCA) and mucinous cystadenoma (MCA).Methods:The retrospective case-control study was conducted. The clinicopathological and imaging data of 154 patients with pancreatic cystic neoplasms who were admitted to the First Affiliated Hospital, Zhejiang University School of Medicine from January 2012 to December 2019 were collected. There were 24 males and 130 females, aged (50±13)years. Of the 154 patients, 99 cases were diagnosed as SCA and 55 cases were diagnosed as MCA. All the 154 patients underwent plain and enhanced CT scan of pancreas before operation. The clinical characteristics, radiology features and radiomics features of all patients were collected to construct the clinical characteristics model, radiology model, radiomics model and fused model. The receiver operating characteristic (ROC) curve of each model was drawn, and those constructed models were evaluated by area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value and negative predictive value. Based on the optimal model, the nomogram was constructed. Observation indicators: (1) establishment and validation of clinical characteristics model; (2) establishment and validation of radiology model; (3) establishment and validation of radiomics model; (4) establishment and validation of fused model; (5) nomogram of fused model. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was analyzed using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and comparison between groups was analyzed using the chi-square test or Fisher exact probability. Results:(1) Establishment and validation of clinical characteristics model: 3 clinical characteristics, including age, symptoms and preoperative serum CA19-9, were selected using multinomial logistic linear regression analysis to construct the clinical characteristics model. Result of the multinomial logistic linear regression analysis was expressed by formula ①: clinical characteristics model score=0.635-0.007×age+0.054×clinical symptoms+0.108×preoperative serum CA19-9. The ROC curve for the test dataset of clinical characteristics model was drawn. The AUC, accuracy, sensitivity, specificity, positive predictive value and negative predictive value of clinical characteristics model were 0.611(95% confidence interval as 0.488?0.734, P<0.05), 56.6%, 66.7%, 56.3%, 41.5%, 78.4% for the training dataset and 0.771(95% confidence interval as 0.624?0.919, P<0.05), 77.8%, 63.1%, 88.5%, 80.1%, 76.7% for the test dataset, respectively. (2) Establishment and validation of radiology model: 5 radiology characteristics, including tumor location, the number of tumors, tumor diameter of cross section, lobulated tumor and polycystic tumor (more than 6), were selected using multinomial logistic linear regression analysis to construct the radiology model. Result of the multinomial logistic linear regression analysis was expressed by formula ②: radiology model score=?0.034+0.300×tumor location+0.202×the number of tumors+0.014×tumor diameter of cross section?0.251×lobulated tumor?0.170×polycystic tumor (more than 6). The ROC curve for the test dataset of radiology model was drawn. The AUC, accuracy, sensitivity, specificity, positive predictive value and negative predictive value of radiology model were 0.862(95% confidence interval as 0.791?0.932, P<0.05), 78.8%, 81.8%, 77.5%, 62.8%, 90.2% for the training dataset and 0.853(95% confidence interval as 0.713?0.994), P<0.05), 88.9%, 89.4%, 88.5%, 85.0%, 92.0% for the test dataset, respectively. (3) Establishment and validation of radiomics model: 4 categories of a total 1 067 radiomics features were extracted from 154 patients with pancreatic cystic neoplasms, including 7 first-order histogram features, 53 texture features, 848 wavelet features and 159 local binary pattern features. A total of 896 stable radiomics features were retained to construct the model, based on the condition of intraclass correlation coefficient >0.9. After selected by variance threshold and correlation coefficient threshold, 350 radiomics features were retained. Fifty synthetic radiomics features were constructed based on the original features in order to obtain potential radiomics features, and the total number of radiomics features was 400. After analyzed by the five-fold recursive feature elimination, 22 radiomics features were screened out, including 13 wavelet features, 7 synthetic radiomics features and 2 local binary pattern features. The support vector machine algorithm was used to construct the radiomics model. The penalty coefficient 'C' and parameter 'γ' of the radiomics model were 35.938 and 0.077, respectively. The kernel function of the radiomics model was 'radial basis function kernel'. The ROC curve of radiomics model using 5-fold cross validation was drawn. The average AUC, accuracy, sensitivity, specificity, positive predictive value and negative predictive value of the radiomics model were 0.870 ( P<0.05), 83.1%, 81.8%, 83.8%, 73.8% and 89.2%, respectively. (4) Establishment and validation of fused model: the fused model was constructed after selecting the tumor location and lobulated tumor of radiology characteristics and radiomics score. Result of the multinomial logistic linear regression analysis was expressed by formula ③: fused model socre=?0.154+0.218×tumor location?0.223×lobulated tumor+0.621×radiomics score. The ROC curve for the test dataset of fused model was drawn. The AUC, accuracy, sensitivity, specificity, positive predictive value and negative predictive value of fused model were 0.893(95% confidence interval as 0.828?0.958, P<0.05), 83.7%, 81.8%, 84.5%, 71.1%, 90.9% for the training dataset and 0.966(95% confidence interval as 0.921?0.999, P<0.05), 91.1%, 84.2%, 96.2%, 94.1%, 89.3% for the test dataset, respectively. (5) Nomogram of fused model: the nomogram of fused model was illustrated with the Youden index of 0.416. Conclusion:The prediction model based on the radiomics signature and radiological features extracted from preoperative CT examination can make the differential diagnosis of pancreatic SCA from MCA.
9.Transurethral resection of the prostate versus transurethral holmium laser enucleation of the prostate for benign prostatic hyperplasia with bladder detrusor overactivity.
Jun-Wen SHEN ; Chuan-Jun DU ; Fu-Ding BAI ; Rong-Jiang WANG
National Journal of Andrology 2016;22(8):720-724
ObjectiveTo compare and analyze the effects of transurethral resection of the prostate (TURP) and transurethral holmium laser enucleation of the prostate (HoLEP) in the treatment of benign prostatic hyperplasia (BPH) with bladder detrusor overactivity.
METHODShis study included 51 cases of BPH with bladder detrusor overactivity treated by TURP and another 58 treated by HoLEP. We evaluated the urination of the two groups of patients during the recovery period and at 3 and 6 months postoperatively.
RESULTSThere were no statistically significant differences in such baseline data as the blood PSA level, prostate volume, International Prostate Symptom Score (IPSS), and quality of life (QOL) between the two groups of patients, except in effective bladder capacity, which was higher in the TURP than in the HoLEP group ([315±59] vs [287±76] ml, P<0.05). Urine storage symptoms were obviously improved in both of the groups postoperatively, with the storage symptoms score significantly decreased from 12.6±4.9 preoperatively to 7.5±3.9 at 3 months and 6.1±4.2 at 6 months after surgery in the TURP group (P<0.01) and from 13.7±5.7 to 7.9±4.2 and 7.0±5.1 in the HoLEP group (P<0.01). HoLEP manifested significant advantages over TURP in the postoperative urethral catheterization time ([2.7±0.8] vs [5.1±1.2] d, P<0.05), postoperative bladder contracture time ([4.1±1.9] vs [5.8±2.4] d, P<0.05), postoperative hospital stay ([4.4±1.8] vs [5.9±2.5] d, P<0.05), and improvement of the maximum urinary flow rate, which was increased from (7.9±3.7) ml/s preoperatively to (16.8±4.3) ml/s at 3 months after surgery in the HoLEP group and from (8.6±3.2) ml/s to (14.6±4.3) ml/s in the TURP group (P<0.05).
CONCLUSIONSBoth TURP and HoLEP can improve bladder function and detrusor overactivity in BPH patients, with similar effects in improving urination at 3 to 6 months after surgery. However, HoLEP has more advantages over TURP during the period of postoperative recovery.
Humans ; Lasers, Solid-State ; therapeutic use ; Length of Stay ; Male ; Prostate ; surgery ; Prostatic Hyperplasia ; surgery ; Quality of Life ; Transurethral Resection of Prostate ; methods ; Treatment Outcome ; Urinary Bladder Neck Obstruction ; surgery ; Urinary Bladder, Overactive ; surgery ; Urinary Catheterization ; statistics & numerical data ; Urination ; physiology
10.A widely adaptable approach to generate integration-free iPSCs from non-invasively acquired human somatic cells.
Zhichao DING ; Lina SUI ; Ruotong REN ; Yanjun LIU ; Xiuling XU ; Lina FU ; Ruijun BAI ; Tingting YUAN ; Ying HAO ; Weiqi ZHANG ; Huize PAN ; Wensu LIU ; Han YU ; Concepcion Rodriguez ESTEBAN ; Xiaobing YU ; Ze YANG ; Jian LI ; Xiaomin WANG ; Juan Carlos IZPISUA BELMONTE ; Guang-Hui LIU ; Fei YI ; Jing QU
Protein & Cell 2015;6(5):386-389
Adolescent
;
Adult
;
Aged
;
Aged, 80 and over
;
Cell Culture Techniques
;
methods
;
Child
;
Female
;
Humans
;
Induced Pluripotent Stem Cells
;
cytology
;
metabolism
;
Male
;
Middle Aged

Result Analysis
Print
Save
E-mail