1.Effect of Optimized New Shengmai Powder (优化新生脉散方) on Exercise Tolerance in Patients with Chronic Heart Failure of Qi Deficiency,Blood Stasis and Fluid Retention Syndrome:A Randomized,Double-Blind,Placebo-Controlled Trial
Xianliang WANG ; Jingyi ZHANG ; Zhao GE ; Tongzuo LIU ; Maozhe ZHANG ; Shuai WANG ; Zhiqiang ZHAO ; Yingfei BI ; Ruijuan ZHOU ; Ying ZHENG ; Jingyuan MAO
Journal of Traditional Chinese Medicine 2026;67(4):425-431
ObjectiveTo evaluate the effects and safety of the optimized new Shengmai Powder (优化新生脉散方) on exercise tolerance in patients with chronic heart failure (CHF) of qi deficiency, blood stasis, and fluid retention syndrome. MethodsA randomized, double-blind, placebo-controlled trial was conducted. A total of 78 CHF patients with qi deficiency, blood stasis, and fluid retention syndrome were recruited and randomly assigned to a treatment group (39 cases) and a control group (39 cases). On the basis of conventional western medical therapy, patients in the treatment group additionally received the optimized new Shengmai Powder granules, while the control group was given an oral placebo of optimized new Shengmai Powder granules. Patients in both groups took 30.6 g each time, twice a day, mixed with water for administration, with a total treatment course of 4 weeks. The primary outcomes were 6-minute walk distance (6MWD) and peak oxygen uptake (Peak VO2) measured by cardiopulmonary exercise testing. Secondary outcomes included New York Heart Association (NYHA) functional classification, B-type natriuretic peptide (BNP) levels, cardiac function indexes including left ventricular ejection fraction (LVEF), left ventri-cular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD), Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores, and scores of four diagnostic information of traditional Chinese medicine (TCM). All indicators were assessed once before and after treatment respectively. Safety indicators were evaluated, and adverse events during the trial were recorded. ResultsAll patients in both groups were included in the full ana-lysis set (FAS) and safety set (SS). Compared with baseline, the 6MWD and Peak VO₂ of cardiopulmonary exercise test in the treatment group significantly increased after treatment, while the MLHFQ scores, serum BNP levels and scores of TCM four diagnostic information significantly decreased, and the NYHA cardiac function grade significantly improved (P<0.01). After treatment, the 6MWD and Peak VO₂ of cardiopulmonary exercise test, as well as their changes from baseline in the treatment group were higher than those in the control group; the MLHFQ scores, serum BNP levels and scores of TCM four diagnostic information in the treatment group were lower than those in the control group; and the improvement of NYHA cardiac function grade in the treatment group was superior to that in the control group (P<0.01). There was no statistically significant differences in all indicators after treatment in the control group (P>0.05). The incidence of adverse events was 5.1% (2/39) in the treatment group and 2.6% (1/39) in the control group, with no statistically significant difference between groups (P>0.05). ConclusionOn the basis of conventional western medicine treatment, the addition of the optimized new Shengmai Powder can further improve exercise tolerance, cardiac function and quality of life in patients with CHF of qi deficiency, blood stasis and fluid retention syndrome, and show good safety.
2.Analysis of the disease burden of hypertensive heart disease among individuals aged≥60 years globally and in China from 1990 to 2021
Jiali LI ; Chunzhen REN ; Fan LIU ; Keyan WANG ; Zhijiang BI ; Xiaoxiao ZHAO ; Lixin KE ; Haibo WANG ; Wenxi PENG ; Zhifei WANG ; Qiang ZHANG ; Peng XU ; Yingdong LI ; Xiuxiu DENG ; Xinke ZHAO ; Cuncun LU
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2026;33(02):281-290
Objective To systematically analyze the characteristics of the disease burden of hypertensive heart disease (HHD) in the elderly (≥60 years) globally and in China from 1990 to 2021, and to predict its future trends from 2022 to 2040, with the aim of providing data support for optimizing comprehensive prevention and control strategies for HHD. Methods Based on the Global Burden of Disease (GBD) 2021 database, the number of prevalent cases and disability-adjusted life years (DALYs) of HHD in the elderly were extracted for the world, China, and five regions categorized by sociodemographic index (SDI). Joinpoint regression was used to analyze the temporal trends of age-standardized prevalence rate and age-standardized DALYs rate of HHD in the elderly. A three-factor decomposition method was applied to evaluate the relative contributions of aging, population growth, and epidemiological changes to the variations in the elderly HHD burden. Additionally, a Bayesian age-period-cohort model was used to predict the elderly HHD burden from 2022 to 2040. Results In 2021, the number of prevalent elderly HHD cases reached 10 283 000 globally and 3 412 400 in China, representing increases of 179.20% and 159.20% respectively, compared with 1990. The DALYs of elderly HHD were 18 812 700 person-years globally and 4 731 400 person-years in China, rising by 76.08% and 29.45% respectively from 1990. Meanwhile, the growth rates of the number of prevalent cases and DALYs of elderly HHD varied across different SDI regions. From 1990 to 2021, the age-standardized prevalence rate of elderly HHD in China, as well as the age-standardized DALYs rate of elderly HHD both globally and in China, showed significant downward trends (all average annual percentage changes<0, all P<0.001). In 2021, the 70-74 years age group accounted for the highest proportion of prevalent cases and DALYs of elderly HHD, both globally and in China. Decomposition analysis revealed that population growth was the dominant factor driving the increase in the elderly HHD burden across all regions. The prediction model results indicated that the number of prevalent cases and DALYs of elderly HHD would continue to rise globally and in China from 2022 to 2040, with the growth rate of the elderly HHD burden in China between 2021 and 2040 expected to exceed the global average. Conclusion Over the past 32 years, although the age-standardized disease rates of elderly HHD have mainly shown a downward trend globally and in China, the absolute number of the disease burden has increased substantially. The projection model indicates a continued upward trajectory, with the growth rate in China higher than the global average. Therefore, there is an urgent need to implement precise prevention and control strategies to effectively mitigate the disease burden of elderly HHD.
3.Comparative analyses of the detection performance of five multiplex polymerase chain reaction nucleic acid detection kits for respiratory pathogens
Fang YUAN ; Lei BI ; Jiajing LIU ; Huanru WANG ; Jun FENG ; Yuan ZHUANG ; Min CHEN ; Zheng TENG
Shanghai Journal of Preventive Medicine 2026;38(2):165-169
ObjectiveTo evaluate the detection specificity for clinical samples and the detection capability for standard substances of five commercially available multiplex polymerase chain reaction (PCR) nucleic acid detection kits (hereinafter referred to as the kits) for respiratory pathogens, and to provide a reference for selecting appropriate detection kits for multi-pathogen nucleic acid testing of respiratory infections. MethodsA total of 60 respiratory pathogen-positive clinical samples with known redults were selected and tested using the five kits (labeled as A, B, C, D, and E). The detection rates and Kappa coefficients were calculated to evaluate the consistency between the results from these kits and those from single-pathogen PCR kits. According to the limit of detection (LOD) provided by the kits, standard substances of respiratory pathogens (including 12 types such as influenza virus, Mycoplasma pneumoniae, and Bordetella pertussis) were diluted to four concentrations (250, 500, 1 000, and 2 000 copies·mL⁻¹). All five kits were used for detection to evaluate their respective detection capabilities. ResultsCompared with the results from single-pathogen PCR kits, the five tested kits demonstrated good consistency (all Kappa >0.80). Among them, Kit A had the highest detection rate (100.00%), followed by Kits C and E (98.33%), and then Kits B and D (95.00%). All five kits showed a relatively low false negative rate (FNR) for samples with a cycle threshold (Ct) value ≤35 (≤2.38%). However, for samples with Ct values>35, the FNR increased accordingly(average FNR=6.67%, P=0.029). Kit C exhibited the highest detection sensitivity for the tested standard substances (average LOD: 458.33 copies·mL⁻¹), followed by Kit D, then Kits A/E, and finally Kit B. ConclusionThe five multiplex PCR kits showed good consistency with single-pathogen detection results, but each had its own performance emphasis. Kit A, with the highest detection rate and high throughput, is suitable for targeted viral screening. Kit B, covering the broadest pathogen spectrum (including fungi/bacteria), is suitable for comprehensive respiratory pathogen screening. Kits C, D and E, are applicable for rapid detection. It is important to note that the detection efficacy of all kits decreases for low viral load samples with Ct values >35. In practical application, selection should be based on specific screening objectives, throughput requirements, and sample types.
4.Development and validation of a blood-based differential diagnosis model for pulmonary tuberculosis and community-acquired pneumonia
Xiaolan SU ; Rui ZHANG ; Zeqing YANG ; Xinrui WANG ; Ziyu BI ; Nian LIU ; Yunyan HAN ; Qi REN
Acta Universitatis Medicinalis Anhui 2026;61(6):1143-1150
ObjectiveTo develop and validate a diagnostic prediction model for differentiating pulmonary tuberculosis from community-acquired pneumonia based on routine blood parameters. MethodsA total of 642 patients with pulmonary tuberculosis and 503 patients with community-acquired pneumonia were retrospectively enrolled from the Seventh Hospital of Tangshan. They were randomly divided into a training set and an internal validation set at a 7∶3 ratio. Additionally, 218 patients from the 981st Hospital were independently included as an external validation set. The Boruta algorithm and recursive feature elimination were employed to select predictors from 82 blood parameters, sex, and age. A multivariate Logistic regression model was established and evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. ResultsThe final model incorporated eight predictors, namely uric acid, urea nitrogen, alkaline phosphatase, monoamine oxidase, alanine aminotransferase, glutathione, neutrophil percentage, and age. The model achieved areas under the curve (AUCs) of 0.800 (95%CI: 0.769-0.830), 0.787 (95%CI: 0.738-0.836), and 0.736 (95%CI: 0.667-0.835) in the training, internal validation, and external validation sets, respectively. The model demonstrated good calibration, and decision curve analysis showed clinical net benefit within the threshold probability range of 10%-80%. ConclusionThe developed model exhibits good discriminative ability and clinical utility, serving as an effective early screening tool for primary healthcare institutions.
5.Exploration on the mechanism of Lanqin Granules in the treatment of respiratory tract infection based on UPLC-Q-TOF-MS/MS and network pharmacology
Zhenzhen BI ; Gang ZHU ; Xin ZHOU ; Jianfang WANG ; Jianbiao YAO ; Hao LIU
International Journal of Traditional Chinese Medicine 2025;47(3):348-356
Objective:To analyze the main chemical components of Lanqin Granules based on UPLC-Q-TOF-MS/MS; To explore the potential targets, core components and related pathways of Lanqin Granules in the treatment of respiratory tract infection through network pharmacology.Methods:Using UPLC-Q-TOF-MS/MS secondary fragment cleavage information, combined with literature and database, the chemical components of Lanqin Granules were analyzed; the related action targets of Lanqin Granules were obtained by PharmMapper; The related targets of respiratory tract infection were obtained from GeneCards and OMIM databases, and the common targets were selected by intersection with the relevant action targets of Lanqin Granules. The common targets were imported into string database, and the protein interaction data were downloaded and input into Cytoscape 3.7.2 software to obtain hub gene; Go function and KEGG pathway enrichment analysis were carried out on DAVID platform, and chemical components closely related to hub gene were obtained by using the Network Anlyzer plug-in.Results:53 chemical constituents of Lanqin Granules were obtained, including 11 alkaloids, 20 flavonoids, 5 terpenoids, 7 organic esters, 2 amino acids and 8 other compounds. 28 hub genes and 38 related core components were obtained. The results of GO analysis showed that the treatment of respiratory tract infection with Lanqin Granules was related to neutrophil degranulation, negative regulation of apoptosis, protein hydrolysis and other biological processes; extracellular exosomes, cytoplasm, extracellular components and other cellular components; the same protein binding, RNA polymerase Ⅱtranscription factor activity, ligand activated sequence specific DNA binding, protein serine/ threonine/ tyrosine kinase activity and other molecular processes. KEGG analysis results mainly involved cancer pathway, lipid and atherosclerosis, metabolic pathway and other signaling pathways.Conclusion:Lanqin Granules can treat respiratory tract infection through multi-component, multi-target and multi-channel, and play the role of anti-inflammatory, antibacterial and anti-virus.
6.Clinical characteristics and influencing factors of cognitive impairment in non-dialysis patients with chronic kidney disease
Hongxia LI ; Xia XU ; Jie JIANG ; Mengxue JIA ; Wenjin LIU ; Zhe HAN ; Yushuang LIU ; Yijiao ZHU ; Dafeng HE ; Chunlei LU ; Mengyue ZHU ; Hongbin MOU ; Guangyu BI ; Rong WANG
Journal of Clinical Medicine in Practice 2025;29(11):1-6,13
Objective To explore the influencing factors of cognitive impairment in non-dialysis patients with chronic kidney disease(CKD).Methods A total of 60 hospitalized non-dialysis patients with CKD in the Department of Nephrology of Northern Jiangsu People's Hospital Affiliated to Yangzhou University from September 2022 to September 2023 were enrolled as research objects.According to the estimated glomerular filtration rate(eGFR),they were divided into stage 1 to 2 of CKD group[eGFR ≥60 mL/(min·1.73 m2)]with 23 cases,the stage 3 of CKD group[eGFR 30~<60 mL/(min·1.73 m2)]with 20 cases,and stage 4 to 5 of CKD group[eGFR<30 mL/(min·1.73 m2)]with 17 cases.The Montreal Cognitive Assessment Scale(MoCA)was used to evaluate the cognitive function of the patients.Basic data and common clinical laboratory in-dicators on hospital admission were collected to analyze the differences in cognitive function levels under different renal function statuses and to explore the influencing factors of cognitive impairment.Results The incidence rates of cognitive impairment in the stage 1 to 2 of CKD group,stage 3 of CKD group,and stage 4 to 5 of CKD group were 47.8%,85.0%,and 94.1%respectively,the median MoCA scored 26,24 and 20 respectively,with statistically significant between-group differ-ences(P<0.05).Cognitive function was significantly negatively correlated with age(r=-0.634,P<0.001),blood urea nitrogen(BUN)(r=-0.574,P<0.001),serum creatinine(Cr)(r=-0.417,P<0.001),cystatin C(Cys-C)(r=-0.327,P=0.011),serum β2-microglobulin(β2-MG)(r=-0.259,P=0.046),and N-terminal pro-brain natriuretic peptide(NT-proBNP)(r=-0.474,P<0.001),and was significantly positively correlated with hemoglobin(HB)(r=0.401,P=0.001)and eGFR(r=0.485,P<0.001).Multivariate Logistic regression analysis showed that age(P=0.006)and NT-proBNP(P=0.041)were influencing factors of cognitive im-pairment in non-dialysis patients with CKD.Receiver operating characteristic(ROC)curve analysis showed that the area under the curve(AUC),sensitivity,and specificity of age for prediction were 0.860,0.864 and 0.812 respectively,the AUC,sensitivity,and specificity of NT-proBNP for pre-diction were 0.808,0.795 and 0.875 respectively,and the combined prediction of age and NT-proBNP had an AUC,sensitivity,and specificity of 0.893,0.955,and 0.750,respectively.Conclusion As renal function deteriorates,the incidence rate and severity of cognitive impairment in non-dialysis patients with CKD tend to increase.Advanced age,renal function deterioration,high NT-proBNP level,and anemia are associated with the occurrence of cognitive impairment in non-di-alysis patients with CKD,among which age and NT-proBNP are influencing factors for cognitive im-pairment.
7.Comparative transcriptome profiling of three different murine modelsof metabolic dysfunction-associated steatohepatitis
Tianwen Liu ; Ziyi Guo ; Hanqi Bi ; Bing Zhou ; Yan Lu ; Fei Mao ; Hua Wang
Acta Universitatis Medicinalis Anhui 2025;60(8):1445-1453
Objective:
To compare the transcriptomic profiles between three distinct metabolic dysfunction⁃associat⁃mal murine model that more closely resembles human MASH progression .
Methods:
Forty 8 ⁃week⁃old male C57BL/6J mice were randomly assigned to either a control group fed normal chow diet ( NCD) or one of three MASH model groups receiving high⁃fat high⁃cholesterol diet (HFHCD) , choline⁃deficient high⁃fat diet (CDHFD) ,from three randomly selected mice per group were collected for mRNA sequencing ( mRNA⁃seq) analysis . Mean⁃bases . Overlap of functional profiles was analyzed by gene set enrichment analysis (GSEA) profiles to compare the mouse transcriptome with that of human patients at different stages of the disease . Additionally , Pearson ′s correla⁃tion analysis was used to explore the correlation between gene expression of murine models and human MASH .
Results:
Seven commonly up⁃regulated genes (Col1a1 , Smoc2 , Col6a1 , Gpx3 , Col16a1 , Spp1 and Crtap) were de⁃ways involving steatosis , hepatocellular injury and fibrosis were detected in the three MASH models at the pathway level . HFHCD and MCD might share more common traits . In comparing gene expression and pathway profiles be⁃tween different murine models and patients with different stages of MASH , all three murine MASH models showed a closer resemblance to the human progressive stages of MASH . Notably , the transcriptomic features of the CDHFD model were more consistent with those of human MASH .
Conclusion
There are certain similarities and differences among the transcriptional profiles of the three MASH models . The MASH models are more similar to the advanced stage of MASH in human patients . Compared to the other two models , the CDHFD model ′ s transcriptome profile more closely resembles human MASH .
8.Mediating role of emotional intelligence between nursing work environment and work engagement among nurses in hematopoietic stem cell transplantation units
Yue LIU ; Yani WANG ; Huifen WANG ; Shan LIU ; Yaping BI ; Jia SUN ; Tingting LIU
China Occupational Medicine 2025;52(5):516-521
Objective To explore the status of nursing work engagement, nursing work environment and emotional intelligence and their relationship among nurses who work in hematopoietic stem cell transplantation (HSCT) units. Methods A total of 225 HSCT nurses were selected as study subjects by convenience sampling method. Utrecht Work Engagement Scale, Nursing Work Environment Scale and Emotional Intelligence Scale were used to assess the work engagement, work environment and emotional intelligence among these nurses. AMOS 23.0 software was used to construct the structural equation model. Results The median and 25th and 75th percentiles of the score of work engagement of the research subjects were 59.0 (54.0, 64.0) points. The average scores of the nursing work environment and emotional intelligence were (117.8±21.5) and (58.8±10.7) points, respectively. The score of work engagement was positively correlated with the scores of the nursing work environment and emotional intelligence (rank correlation coefficients were 0.550 and 0.431, respectively, both P<0.01). The total score of the nursing work environment was positively correlated with the total score of emotional intelligence (correlation coefficient was 0.271, P<0.01). The nursing work environment influenced the work engagement status of HSCT nurses through the mediating effect of emotional intelligence, with an indirect effect of 0.115 (95% confidence interval: 0.201-0.365), accounting for 20.4% of the total effect. Conclusion Emotional intelligence is a mediating variable between the nursing work environment and work engagement of HSCT nurses.
9.Prognostic value of single PET-CT after chemotherapy combined with immunotherapy in patients with non-small cell lung cancer treated with radiotherapy
Zhenghui MA ; Yuqi WU ; Guangqian JI ; Zongmei ZHOU ; Qinfu FENG ; Zefen XIAO ; Jima LYU ; Xin WANG ; Jianyang WANG ; Wenyang LIU ; Lei DENG ; Wenqing WANG ; Nan BI ; Junlin YI ; Tao ZHANG
Chinese Journal of Radiation Oncology 2025;34(11):1111-1116
Objective:To evaluate the role of a single PET-CT scan in predicting survival and prognosis in patients with non-small cell lung cancer (NSCLC) who did not undergo surgery but received radiotherapy after neoadjuvant chemotherapy combined with immunotherapy.Methods:A retrospective analysis was conducted on the data of 23 NSCLC patients treated at the Cancer Hospital of the Chinese Academy of Medical Sciences from May 2022 to June 2024. All patients were pathologically confirmed, received neoadjuvant chemotherapy combined with immunotherapy, did not undergo surgery for various reasons, and instead received radiotherapy. Each patient underwent only one PET-CT scan after neoadjuvant chemotherapy combined with immunotherapy and before radiotherapy. According to the maximum standardized uptake value (SUV max) on PET-CT, patients were divided into the low-uptake group (SUV max < 8, n=12) and high-uptake group (SUV max ≥ 8, n=11). Survival analysis was performed using the Kaplan-Meier method with survival curves plotted. Univariate analysis of influencing factors of survival was conducted using the Cox proportional hazards regression model. Clinical characteristics and survival outcomes of the two groups were compared, including progression-free survival (PFS) and overall survival (OS). Results:The 1-year PFS rates were 100% in the low-uptake group, 54.5% in the high-uptake group. This difference was statistically significant ( P=0.007). The 1-year and 2-year OS rates were both 100% in the low-uptake group, the 1-year and 2-year OS rates were both 90.9% in the high-uptake group, with no statistically significant difference ( P=0.394). Univariate Cox analysis identified age as an independent factor affecting PFS. Conclusions:For NSCLC patients who did not undergo surgical resection but received radiotherapy after neoadjuvant chemotherapy combined with immunotherapy, a single PET-CT scan before radiotherapy has potential value in predicting PFS. However, clinical studies with larger sample size and longer follow-up are required to evaluate its predictive value for OS.
10.Systemic inflammatory score predicts survival of patient with unresectable stage Ⅲ non-small cell lung cancer treated by definitive chemoradiotherapy combined with consolidation immunotherapy
Shihong LUO ; Yupei YUAN ; Yu WANG ; Yin YANG ; Tao ZHANG ; Lei DENG ; Wenyang LIU ; Wenqing WANG ; Xin WANG ; Jima LYU ; Zongmei ZHOU ; Jianyang WANG ; Nan BI
Chinese Journal of Radiation Oncology 2025;34(10):993-1000
Objective:To analyze the prognostic value of systemic inflammatory score (SIS) in patients with unresectable stage Ⅲ non-small cell lung cancer (NSCLC) treated by definitive chemoradiotherapy (dCRT) combined with or without consolidation immunotherapy with immune checkpoint inhibitor (ICI).Methods:The medical record data of 229 patients who received dCRT from January 2014 to December 2017 and 183 patients who received dCRT combined with any form of ICI (induction, concurrent, consolidation or combination) from August 2018 to August 2022 in the Cancer Hospital, Chinese Academy of Medical Sciences were retrospectively analyzed. Upon admission, 1 and 3 months after treatment (efficacy evaluation) and upon tumor recurrence, peripheral blood count was collected, and neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and SIS were calculated, respectively. The SIS before, 1 and 3 months after treatment was defined as SIS 0, SIS 1 and SIS 3, respectively. Overall survival (OS) was considered as the primary endpoint. All patients were divided into dCRT group and dCRT+ICI group according to whether received immunotherapy, and then divided into different subgroups based on the cutoff value of SIS determined by X-Tile software. The prognostic value of SIS was evaluated by Kaplan-Meier survival analysis. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the predictive efficiency. The predictive value of SIS was compared with inflammatory indexes (NLR, PLR) and independent prognostic factors. Results:In the dCRT group, the optimal cutoff value of SIS 0 was 590×10 9 and 530×10 9 in the dCRT+ICIs group. Univariate and multivariate analyses indicated that SIS 0 was an independent predictive factor of OS, progression - free survival (PFS), local - recurrence free survival (LRFS) and distant metastasis free survival (DMFS) in the dCRT group, but not associated with DMFS in the dCRT+ICI group. In the dCRT group, SIS 1>970×10 9 (optimal cutoff value) predicted poor OS ( HR=2.512, 95% CI=1.622-3.198, P<0.001), PFS ( HR=1.726, 95% CI=1.187-2.509, P=0.004), and DMFS ( HR=1.625, 95% CI=1.029-2.564, P=0.037). In the dCRT+ICI group, SIS 3>1570×10 9 (optimal cutoff value) indicated poor OS ( HR=5.107, 95% CI=1.731-15.069, P=0.003). In both groups, the AUC of SIS was higher than NLR, PLR and other traditional clinicopathological predictive indexes except T stage. Conclusions:SIS before treatment can be considered as an independent, dependable and easily acquired prognostic marker in patients with unresectable stage Ⅲ NSCLC treated by dCRT or dCRT+ICI. In the dCRT+ICI group, the optimal time point of post-radiotherapy SIS (3 months after treatment) is postponed than that (1 month after treatment) in the dCRT group.


Result Analysis
Print
Save
E-mail