1.Effects of Yishen paidu formula on renal fibrosis in rats with chronic renal failure by regulating the ROS/TXNIP/NLRP3 pathway
Li FENG ; Bowen PENG ; Bin PENG ; Xue FENG ; Shuangyi ZHU ; Wei XIONG ; Xi HU ; Xiaohui SUN
China Pharmacy 2026;37(2):174-179
OBJECTIVE To investigate the effects and mechanism of the Yishen paidu formula on renal fibrosis in rats with chronic renal failure (CRF) through the reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway. METHODS Rats were randomly divided into control group, model group, Yishen paidu formula low-dose (Yishen paidu formula-L) group, Yishen paidu formula high-dose (Yishen paidu formula- H) group, Yishen paidu formula-H+pcDNA-NC group, and Yishen paidu formula-H+ pcDNA-TXNIP group, with 10 rats in each group. Except for control group, all other rats were fed a diet containing 0.5% adenine to establish a CRF model; the rats were then administered corresponding drugs or normal saline intragastrically or via tail vein, once daily, for 8 consecutive weeks. After the last administration, the levels of serum creatinine (Scr), blood urea nitrogen (BUN), ROS, superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were measured in each group. Pathological changes in renal tissue were observed, and the protein expression levels of Collagen Ⅲ, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), TXNIP and NLRP3 in renal tissue were detected. RESULTS Compared with model group, the renal histopathological damage and fibrosis of rats in Yishen paidu formula-L group and Yishen paidu formula-H group were significantly alleviated. The levels of Scr, BUN, ROS, MDA, TNF- α, IL-6 and IL-1β, and the protein expressions of Collagen Ⅲ, α-SMA, TGF-β1, TXNIP and NLRP3 were significantly decreased, while SOD levels were significantly increased (P<0.05). Moreover, the changes were more pronounced in the Yishen paidu formula-H group (P<0.05). Compared with Yishen paidu formula-H+pcDNA-NC group, above indexes of rats in Yishen paidu formula-H+pcDNA-TXNIP group were reversed significantly (P<0.05). CONCLUSIONS Yishen paidu formula can inhibit renal fibrosis in CRF rats by suppressing the ROS/TXNIP/NLRP3 pathway.
2.Expert consensus on neoadjuvant PD-1 inhibitors for locally advanced oral squamous cell carcinoma (2026)
LI Jinsong ; LIAO Guiqing ; LI Longjiang ; ZHANG Chenping ; SHANG Chenping ; ZHANG Jie ; ZHONG Laiping ; LIU Bing ; CHEN Gang ; WEI Jianhua ; JI Tong ; LI Chunjie ; LIN Lisong ; REN Guoxin ; LI Yi ; SHANG Wei ; HAN Bing ; JIANG Canhua ; ZHANG Sheng ; SONG Ming ; LIU Xuekui ; WANG Anxun ; LIU Shuguang ; CHEN Zhanhong ; WANG Youyuan ; LIN Zhaoyu ; LI Haigang ; DUAN Xiaohui ; YE Ling ; ZHENG Jun ; WANG Jun ; LV Xiaozhi ; ZHU Lijun ; CAO Haotian
Journal of Prevention and Treatment for Stomatological Diseases 2026;34(2):105-118
Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.
3.Predictive value of lipoprotein(a) for major adverse cardiovascular events in patients with acute coronary syndrome
Chinese Journal of Clinical Medicine 2025;32(5):820-826
Objective To explore the predictive value of lipoprotein(a) (Lp[a]) levels for major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS). Methods A total of 310 ACS patients who were hospitalized in Dalian Friendship Hospital and completed coronary angiography from August 2021 to October 2023 were included in this study. According to the level of Lp(a), the patients were divided into high Lp(a) group (>300 mg/L, n=224) and low Lp(a) group (≤300 mg/L, n=86). All patients undergo outpatient follow-up after discharge, the occurrence of major MACE was recorded, and multivariate Cox regression analysis was performed to analyze the influencing factors of MACE in ACS patients. Results The age, C-reactive protein, total cholesterol, ApoB, proportion of multiple lesions and percutaneous coronary intervention (PCI), Gensini score of the high Lp(a) group were higher than those of the low Lp(a) group, while uric acid and LVEF were lower than those of the low Lp(a) group (all P<0.05). The median follow-up time for all ACS patients was 22 (17, 24) months, with a total of 61 patients (19.68%) experiencing MACE. The high Lp(a) group had a higher readmission rate and cumulative MACE incidence for angina compared to the low Lp(a) group (P=0.009, P=0.001). Single factor analysis showed that high Lp(a) level, diabetes, myocardial infarction, left main artery disease, multi vessel disease, PCI, age, Gensini score, LVEF, and homocysteine were significantly correlated with MACE (all P<0.05). After adjusting for multiple factors, the MACE risk in the high Lp(a) group was 3.42 times higher than that in the low Lp(a) group (HR=3.42, P=0.016). Conclusion Lp(a)>300 mg/L is an independent risk factor for the development of MACE in patients with ACS, and can be used as a predictor for the development of MACE in patients with ACS.
4.Deep learning-driven intelligent radiotherapy for osteosarcoma: recent advances and challenges
Handong ZHANG ; Xiaohui LI ; Luxu YIN ; Huaqiang SUN ; Peng WANG
Chinese Journal of Radiological Health 2025;34(6):912-917
With the widespread application of deep learning technology in radiotherapy, increasing attention has been directed toward enhancing the precision and personalization of intelligent radiotherapy for osteosarcoma. This review summarizes the recent advances in the application of deep learning to osteosarcoma image preprocessing, automatic target volume delineation, dose prediction and treatment plan optimization, early efficacy assessment, and follow-up monitoring. Bottlenecks such as data sharing, model generalization, and interpretability are analyzed. This review aims to provide a comprehensive reference for technological iteration and clinical implementation in this field, as well as a scientific basis for the determination of future research directions and the development of standardized guidelines.
5.The clinical efficacy of artificial pleural effusion combined with radiofrequency ablation in patients with phrenic top liver cancer
Xinglong ZHANG ; Hongmei HE ; Jing ZHANG ; Ya'nan SHI ; Lanchun REN ; Xiaohui QIN ; Jianghua SUN
Tianjin Medical Journal 2025;53(8):856-859
Objective To explore the effect of artificial pleural effusion combined with radiofrequency ablation in patients with phrenic top liver cancer.Methods A total of 92 patients with liver tumors at top of the diaphragm were prospectively selected and divided into the control group(46 cases,radiofrequency ablation)and the observation group(46 cases,radiofrequency ablation+artificial pleural effusion)by the random number table method.Clinical outcomes one month after treatment,time to first surgical ablation,serum alpha-fetoprotein(AFP)levels and complications before treatment and one month after treatment were compared.Both groups were followed up for 2 years after the operation,and survival conditions of patients were compared.Results Enhanced MRI or enhanced CT at 1 month after surgery in the 2 groups showed that the complete tumor ablation rate was lower in the control group than that in the observation group(76.09%vs.93.48%,P<0.05).The surgical ablation time of the observation group was shorter than that of the control group[(9.64±1.22)min vs.(11.15±1.47)min,P<0.05].The survival rates were higher in the observation group than those in the control group at 1 year(82.61%vs.58.70%)and 2 years(71.74%vs.47.83%)after treatment(P<0.05).Serum AFP levels decreased in both groups after treatment,and those were lower in the observation group than those in the control group(P<0.05).The total complication rate of the observation group was lower than that of the control group(8.70%vs.23.91%,P<0.05).The follow-up period of 92 patients ranged from 7 to 29 months,with a mean of(20.17±4.61)months.The local tumor progression rate was higher in the control group than that in the observation group during the follow-up period(36.96%vs.10.87%,P<0.05).Conclusion Artificial pleural effusion combined with radiofrequency ablation can effectively improve the clinical efficacy and survival rate of patients with liver cancer,reduce the level of serum AFP and decrease the occurrence of complications.
6.Seven-step procedure for robot-assisted endoscopic thyroidectomy(BABA approach)
Zheng DING ; Bomin GUO ; Youben FAN ; Xianzhao DENG ; Ling ZHAN ; Xuanbin TAO ; Xiaohui GU ; Zixia TAO ; Zhihua XIA ; Jingfu SUN ; Bo YANG
Chinese Journal of General Surgery 2025;34(5):859-866
Traditional open thyroid surgery often leaves a scar on the neck,which can affect cosmetic outcomes.Therefore,various endoscopic thyroidectomy approaches via extra-cervical approaches have been developed.However,due to the unique anatomical characteristics of the neck and limitations of endoscopic instruments,conventional endoscopic techniques have certain drawbacks.Robot-assisted endoscopic thyroid surgery can help overcome these limitations.At present,robotic surgical systems remain expensive and the associated surgical costs are high,limiting their widespread adoption.Most surgeons are still relatively unfamiliar with the technique.Nevertheless,with ongoing technological advancements and cost reductions,robot-assisted surgery holds great promise for broader application.Based on years of large-scale experience in endoscopic thyroid surgery at our center,and drawing upon both domestic and international experiences with robotic thyroidectomy,this paper summarizes and proposes a seven-step protocol for robot-assisted endoscopic thyroidectomy via the bilateral axillo-breast approach,aiming to provide a practical reference for the clinical adoption of this technique.
7.Guideline for Adult Weight Management in China
Weiqing WANG ; Qin WAN ; Jianhua MA ; Guang WANG ; Yufan WANG ; Guixia WANG ; Yongquan SHI ; Tingjun YE ; Xiaoguang SHI ; Jian KUANG ; Bo FENG ; Xiuyan FENG ; Guang NING ; Yiming MU ; Hongyu KUANG ; Xiaoping XING ; Chunli PIAO ; Xingbo CHENG ; Zhifeng CHENG ; Yufang BI ; Yan BI ; Wenshan LYU ; Dalong ZHU ; Cuiyan ZHU ; Wei ZHU ; Fei HUA ; Fei XIANG ; Shuang YAN ; Zilin SUN ; Yadong SUN ; Liqin SUN ; Luying SUN ; Li YAN ; Yanbing LI ; Hong LI ; Shu LI ; Ling LI ; Yiming LI ; Chenzhong LI ; Hua YANG ; Jinkui YANG ; Ling YANG ; Ying YANG ; Tao YANG ; Xiao YANG ; Xinhua XIAO ; Dan WU ; Jinsong KUANG ; Lanjie HE ; Wei GU ; Jie SHEN ; Yongfeng SONG ; Qiao ZHANG ; Hong ZHANG ; Yuwei ZHANG ; Junqing ZHANG ; Xianfeng ZHANG ; Miao ZHANG ; Yifei ZHANG ; Yingli LU ; Hong CHEN ; Li CHEN ; Bing CHEN ; Shihong CHEN ; Guiyan CHEN ; Haibing CHEN ; Lei CHEN ; Yanyan CHEN ; Genben CHEN ; Yikun ZHOU ; Xianghai ZHOU ; Qiang ZHOU ; Jiaqiang ZHOU ; Hongting ZHENG ; Zhongyan SHAN ; Jiajun ZHAO ; Dong ZHAO ; Ji HU ; Jiang HU ; Xinguo HOU ; Bimin SHI ; Tianpei HONG ; Mingxia YUAN ; Weibo XIA ; Xuejiang GU ; Yong XU ; Shuguang PANG ; Tianshu GAO ; Zuhua GAO ; Xiaohui GUO ; Hongyi CAO ; Mingfeng CAO ; Xiaopei CAO ; Jing MA ; Bin LU ; Zhen LIANG ; Jun LIANG ; Min LONG ; Yongde PENG ; Jin LU ; Hongyun LU ; Yan LU ; Chunping ZENG ; Binhong WEN ; Xueyong LOU ; Qingbo GUAN ; Lin LIAO ; Xin LIAO ; Ping XIONG ; Yaoming XUE
Chinese Journal of Endocrinology and Metabolism 2025;41(11):891-907
Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.
8.The burden of noncommunicable chronic diseases attributable to metabolic factors in China from 1990 to 2021 and projections of mortality trends
Bowen ZHANG ; Yuhong HUANG ; Xi DU ; Hongrui CHEN ; Wei MU ; Yanjun SUN ; Shengwei GAO ; Zichen LYU ; Rongkun XUE ; Xiaohui YU
Chinese Journal of Endocrinology and Metabolism 2025;41(9):761-768
Objective:To analyze the burden and trends of noncommunicable chronic disease(NCD) attributable to metabolic factors in China from 1990 to 2021.Methods:Data from the Global Burden of Diseases(GBD) 2021 database were utilized to describe changes in mortality and disability-adjusted life years(DALYs) of NCD in China from 1990 to 2021. Stratified analyses were conducted by age, sex, sociodemographic index(SDI), and related risk factors. Statistical analyses and predictions were conducted using the age-period-cohort model and the Nordpred model.Results:In 2021, the age-standardized mortality rate and age-standardized DALYs rate of NCD attributable to metabolic factors in China were 227.56 per 100 000 and 4 829.39 per 100 000, respectively. Their average annual percentage changes were -0.76%( P<0.001) and -0.77%( P<0.001). Overall, the burden decreased progressively with higher SDI levels. Analysis using the age-period-cohort model indicated reduced birth cohort and period effects for metabolic factor-attributable NCD, while age effects rose significantly. The minimum relative risk( RR) value was observed in the 15-19 age group( RR=0.01), and the maximum RR value occurred in the 95-99 age group( RR=996.86). The overall rising mortality trend indicated that age effects are the predominant driver at present. Projections estimate that by 2046, deaths from metabolic factor-attributable NCD in China will reach 8 189 563, with an age-standardized mortality rate of 236.95 per 100 000. Conclusions:China continues to face a substantial burden of NCD linked to metabolic factors, with older adults, males, and individuals with hypertension, diabetes, and prediabetes identified as key populations requiring targeted interventions.
9.Clinical characteristics of juvenile dermatomyositis in anti-nuclear matrix protein 2 antibody-positive patients and risk factors for severity: a national multicenter retrospective study
Huiyuan YANG ; Wanzhen GUAN ; Ling2 YANG ; Haimei LIU ; Xiaoqing3 LI ; Haiguo YU ; Meiping LU ; Jun YANG ; Xiaohui LIU ; Hongxia ZHANG ; Wei ZHANG ; Jihong XIAO ; Xiaozhong LI ; Guomin LI ; Hong CHANG ; Sheng HAO ; Yue DU ; Daliang XU ; Ling WU ; Wenjie ZHENG ; Li LIU ; Xinhui JIANG ; Shaohui ZHU ; Dongmei ZHAO ; Xuemei TANG ; Li SUN
Chinese Journal of Pediatrics 2025;63(12):1299-1305
Objective:To investigate the clinical characteristics and independent risk factors of severe disease in patients with anti-nuclear matrix protein (NXP) 2 antibody-positive juvenile dermatomyositis (JDM).Methods:A retrospective cohort study was conducted, including 219 anti-NXP2 antibody-positive JDM patients admitted to 23 children′s hospitals across China from July 2011 to July 2023. Patients were classified into severe and non-severe groups based on classification criteria for severe dermatomyositis. Demographic characteristics, clinical manifestations, and laboratory parameters were compared between the 2 groups using independent sample t-test, Mann-Whitney U test, or χ2 test. Univariate and multivariate Logistic regression analyses were performed to identify risk factors for severe disease. The receiver operating characteristic curve was employed to calculate optimal cut-off values. Results:Among the 219 patients, 108 were male and 111 were female, with an age at onset of 6.3 (3.5, 9.4) years. The severe group comprised 69 patients, and the non-severe group 150 patients. The severe group had significantly higher rates of fever, heliotrope rash, subcutaneous edema, periorbital edema, anti-Ro52 antibody positivity, as well as elevated levels of ferritin-to-albumin ratio (FAR), creatine kinase (CK), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) (all P<0.05). Multivariate analysis identified anti-Ro52 antibody positivity ( OR=13.26, 95% CI 1.37-128.29) and elevated FAR ( OR=1.90, 95% CI 1.09-2.31) as independent risk factors for severe anti-NXP2 antibody-positive JDM (both P<0.05). Receiver operating characteristic curve analysis revealed that a FAR cutoff value of 6.82 predicted severe disease with an area under the curve of 0.87 (95% CI 0.81-0.94, P<0.001), sensitivity of 0.85, and specificity of 0.70. All patients received glucocorticoid therapy, and the severe group received higher proportions of steroid pulse therapy, cyclophosphamide, mycophenolate mofetil, intravenous immunoglobulin, biologics, and adjuvant treatments compared to the non-severe group (all P<0.05). In terms of outcomes, 2 patients (2.9%) in the severe group died (due to neurological involvement and intestinal perforation, respectively), while the remaining patients achieved complete clinical response or remission. All patients in the non-severe group achieved remission. Conclusions:The primary clinical features of anti-NXP2 antibody-positive JDM included fever, heliotrope rash, subcutaneous edema, periorbital edema, anti-Ro52 antibody positivity, and elevated levels of CK, AST, LDH, and FAR. Furthermore, anti-Ro52 antibody positivity and a FAR>6.82 were identified as independent risk factors.
10.Clinical effects of sequential treatment of extensive skin and soft tissue injuries of the lower leg accompanied by large segmental tibial defects by free transplantation of anterolateral thigh perforator flap combined with bone transport
Hailei ZHAO ; Zhigang SUN ; Xiaohui ZHAO ; Bin YANG ; Ming SHI ; Yuming SHEN
Chinese Journal of Burns 2025;41(3):242-250
Objective:To explore the clinical effects of sequential treatment of extensive skin and soft tissue injuries of the lower leg accompanied by large segmental tibial defects by free transplantation of anterolateral thigh perforator flap combined with bone transport.Methods:This study was a retrospective observational study. From April 2020 to January 2024, 8 patients with extensive skin and soft tissue injuries of the lower leg accompanied by large segmental tibial defects who met the inclusion criteria were admitted to Beijing Dawanglu Emergency Rescue Hospital. Among them, there were 6 males and 2 females, aged 17 to 58 years. After debridement, the area was 17 cm×8 cm to 30 cm×12 cm, and the length of tibial defect was 9 to 12 cm. Stage Ⅰ surgery was performed by free transplantation of anterolateral thigh perforator flap to repair the extensive skin and soft tissue injuries of the lower leg and using autologous skin graft from the thigh to repair the remaining wound. Stage Ⅱ surgery was performed after wound healing, the external fixation bracket was removed and replaced with an Orthofix unilateral external fixation lengthening frame (hereinafter referred to as external fixation lengthening frame) to transport the proximal tibial osteotomy for repairing the large segmental bone defects. The intraoperative arteriovenous anastomosis and the blood supply of the flap during stage Ⅰ surgery were documented, along with the survival status of the flap/skin graft in the donor and recipient areas postoperatively, and the wound healing time in the recipient area. The time required for bone transport completion, the duration of external fixation retention, and the occurrence of complications during this period were recorded after stage Ⅱ surgery. During follow-up, the occurrence of adverse events in the recipient area was recorded. At the final follow-up, fracture healing of the affected limb was evaluated according to the Paley score, and limb function was observed.Results:In 2 patients, the descending branch of the lateral circumflex femoral artery and the accompanying vein were end-to-end anastomosed with the proximal anterior tibial or posterior tibial artery and vein for antegrade blood supply and antegrade reflux; in 2 patients, the descending branch of the lateral circumflex femoral artery was end-to-end anastomosed with the distal anterior tibial artery for retrograde blood supply, and the accompanying vein of the descending branch of the lateral circumflex femoral artery was end-to-end anastomosed with the proximal anterior tibial vein for antegrade reflux; in 3 patients, the descending branch of the lateral circumflex femoral artery was end-to-end anastomosed with the distal posterior tibial artery for retrograde blood supply, and the accompanying vein of the descending branch of the lateral circumflex femoral artery was end-to-end anastomosed with the distal posterior tibial vein for retrograde reflux; one patient underwent repair of the injury in the affected lower leg using a free cross-leg vascular pedicle flap from the healthy limb. The flaps/skin grafts in the donor and recipient areas of all 8 patients survived, and the wound healing time in recipient area was 14 to 30 days. The bone transport duration of the patients in this group was 93 to 125 days, and the external fixation lengthening frame was continuously retained for 7 to 14 months after the bone transport was stopped; during the bone transport period, 1 patient had pin tract infection, which was controlled after dressing change and enhanced nursing. During the follow-up, there was no ulceration of the wound surface in recipient area, and no osteomyelitis or fracture developed in the affected limb. At the last follow-up, the bone healing evaluation was all excellent; the walking posture and function of the affected limb were basically normal.Conclusions:The application of free transplantation of anterolateral thigh perforator flap combined with bone transport in the sequential treatment of extensive skin and soft tissue injuries of the lower leg accompanied by large segmental tibial defecst can achieve wound healing and functional reconstruction of bone defects, and has great clinical application value.


Result Analysis
Print
Save
E-mail