1.Manufacture and mechanical property on zirconia abutments with a titanium base in dental implant restoration
Huan WANG ; Jing LU ; Ying LI ; Maohua MENG ; Jiayu SHU ; Yuncai LUO ; Wenjie LI ; Qiang DONG
Chinese Journal of Tissue Engineering Research 2025;29(10):2171-2177
BACKGROUND:With the development of computer-aided design and computer-aided manufacturing technology,zirconia abutments with a titanium base are widely used in clinic due to its good application advantages,but there are still some problems and a lack of consensus design standards. OBJECTIVE:To review the fabrication methods of Ti-base zirconia abutment,and the effect of abutment connection,emergence design,abutment angle,and bonding on mechanical properties of Ti-base zirconia abutment. METHODS:Relevant literature published from 2010 to 2023 was searched in CNKI and PubMed databases with the search terms"zirconia abutment,titanium base"in Chinese and English,respectively.The search time limit was extended for some classical literature.The relevant literature was obtained through inclusion and exclusion criteria,and 57 eligible documents were included for review. RESULTS AND CONCLUSION:It is recommended that clinicians try to select antirotational titanium bases or rotational titanium bases with a Morse taper connection.Implants should be placed in the correct axial angulation of not more than 15° or with an inclination to the palatal side when using angled zirconia abutments.When a≥30° labial inclination is followed for implant placement,the bite force must be decreased effectively to reduce the risk of mechanical and biological complications of implants,abutments,and prostheses.Ti-base zirconia abutments with a higher gingival height should be selected,and its restorative angle should not exceed 40°.Multilink Hybrid Abutment could be the first choice for extraoral bonding of zirconia abutment to titanium bases.
2.Treatment of Diabetes Mellitus with Traditional Chinese Medicine Classic Prescriptions: A Review
Yu WANG ; Hedi WANG ; Qiang CHEN ; Guanqun HOU ; Yanting LU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(4):266-277
As a chronic and lifelong disease, diabetes mellitus occurs across all age groups and gender groups. Since the disease requires lifelong treatment, it seriously affects the quality of life of patients. With the rising incidence on a global scale, diabetes mellitus has become a global problem that seriously affects public health. Moreover, the complications of this disease have aroused concern from the global medical research community, the World Health Organization, and the public. In the past, Western medicine was used in the clinical treatment of diabetes mellitus, which, however, had drug dependence, unsatisfactory efficacy, and side effects. Long-term oral administration of antidiabetics may cause liver and kidney function damage, hypoglycemia and other adverse symptoms. The treatment of diabetes mellitus has been faced with challenges such as limited efficacy and obvious side effects. Therefore, exploring more effective treatment means, especially tapping the potential of traditional Chinese medicine (TCM) in the treatment of diabetes mellitus, is a major issue to be solved. TCM has shown a great application value and a broad prospect in the treatment of diabetes mellitus because of multi-target regulation, a holistic view, synergistic effects, and high safety. TCM has a history of thousands of years in the prevention and treatment of diabetes mellitus, with rich experience accumulated and remarkable results achieved. Particularly, TCM demonstrates definite therapeutic effects on the complications. The application of TCM in the treatment of complications has been recognized and accepted by patients because of the definite therapeutic effect. In recent years, great progress has been achieved in the treatment of diabetes mellitus by the combination of Chinese and western medicine, which has made important contributions to the control of diabetes mellitus. This paper reviews the articles about the treatment of diabetes mellitus with TCM classic prescriptions, summarizes the treatment of clinical cases regarding the indications of these prescriptions, and provides an overview of the treatment mechanisms, aiming to offer fresh insights and strategies for the clinical diagnosis and treatment of diabetes mellitus.
3.Progress on antisense oligonucleotide in the field of antibacterial therapy
Jia LI ; Xiao-lu HAN ; Shi-yu SONG ; Jin-tao LIN ; Zhi-qiang TANG ; Zeng-ming WANG ; Liang XU ; Ai-ping ZHENG
Acta Pharmaceutica Sinica 2025;60(2):337-347
With the widespread use of antibiotics, drug-resistant bacterial infections have become a significant threat to human health. Finding new antibacterial strategies that can effectively control drug-resistant bacterial infections has become an urgent task. Unlike small molecule drugs that target bacterial proteins, antisense oligonucleotide (ASO) can target genes related to bacterial resistance, pathogenesis, growth, reproduction and biofilm formation. By regulating the expression of these genes, ASO can inhibit or kill bacteria, providing a novel approach for the development of antibacterial drugs. To overcome the challenge of delivering antisense oligonucleotide into bacterial cells, various drug delivery systems have been applied in this field, including cell-penetrating peptides, lipid nanoparticles and inorganic nanoparticles, which have injected new momentum into the development of antisense oligonucleotide in the antibacterial realm. This review summarizes the current development of small nucleic acid drugs, the antibacterial mechanisms, targets, sequences and delivery vectors of antisense oligonucleotide, providing a reference for the research and development of antisense oligonucleotide in the treatment of bacterial infections.
4.Effect of Modified of Bazhentang Combined with Guishentang on Th1/Th2 Immune Balance in Mouse Model of Embryo Implantation Dysfunction
Qiang DENG ; Fengying WU ; Lu YIN ; Jun WANG ; Zhaoyang YE ; Jiamei HUANG ; Zhichun JIN
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(18):68-76
ObjectiveTo investigate the mechanism of the modified of Bazhentang combined with Guishentang in improving pregnancy outcomes in mouse models of embryo implantation dysfunction by regulating T helper 1/T helper 2 (Th1/Th2) immune balance. MethodsEighty ICR female mice were randomly divided into four groups (n=20 per group) on gestational day 1 (GD1): control, model, western medicine, and traditional Chinese medicine (TCM) groups. Except for the control group, all mice received mifepristone solution (0.2 mg/mouse) via oral gavage on GD4 to induce embryo implantation dysfunction. The TCM group received a water decoction of the modified of Bazhentang combined with Guishentang (20.8 g·kg-1), with the western medicine group administered dydrogesterone (3.9 mg·kg-1), and the control/model groups given equal volumes of saline. All treatments were administered once daily from GD1 until one day before sample collection. Outcomes included implantation site counts (macroscopic observation), pregnancy rates, body weight, endometrial histopathology (hematoxylin-eosin staining), uterine expression of T-box expressed in T cells (T-bet), GATA-binding protein 3 (GATA3), interferon gamma (IFN-γ), and interleukin-4 (IL-4) at protein (Western blot) and mRNA (real-time polymerase chain reaction, Real-time PCR) levels, serum IFN-γ and IL-4 levels (enzyme-linked immunosorbent assay, ELISA), and Th1/Th2 immune balance evaluated by calculating T-bet/GATA3 and IFN-γ/IL-4 ratios. ResultsCompared to the control group, the model group showed no significant change in pregnancy rate but exhibited a marked reduction in average implantation sites and body weight (P<0.01). Histopathological analysis revealed endometrial abnormalities, including decreased glandular density, stromal compaction, and absence of nucleolar vacuoles. At the molecular level, uterine tissue in the model group demonstrated significantly upregulated expression of T-bet and IFN-γ (P<0.05, P<0.01), alongside markedly downregulated GATA3 and IL-4 expression (P<0.05, P<0.01). Serum analysis confirmed markedly elevated IFN-γ (P<0.01) and reduced IL-4 levels (P<0.01), resulting in significantly increased T-bet/GATA3 and IFN-γ/IL-4 ratios (P<0.01). Compared to the model group, pregnancy rates in all treatment groups showed no significant change. Implantation sites and body weight increased substantially (P<0.01), with restored endometrial morphology characterized by enhanced glandular density, stromal edema, and reappearance of nucleolar vacuoles. Significant downregulation of T-bet and IFN-γ (P<0.01) and upregulation of GATA3 and IL-4 (P<0.05, P<0.01) in uterine tissue were observed. Serum IFN-γ levels were significantly reduced (P<0.05, P<0.01), while IL-4 levels were significantly elevated (P<0.05). The Th1/Th2 ratios were significantly decreased (P<0.01). ConclusionThe modified of Bazhentang combined with Guishentang significantly enhances the number of embryo implantation sites in mice with embryo implantation dysfunction, potentially through modulating T-bet/GATA3 expression, restoring Th1/Th2 immune balance, and improving endometrial receptivity.
5.Stem Cell-Based Hair Cell Regeneration and Therapy in the Inner Ear.
Jieyu QI ; Wenjuan HUANG ; Yicheng LU ; Xuehan YANG ; Yinyi ZHOU ; Tian CHEN ; Xiaohan WANG ; Yafeng YU ; Jia-Qiang SUN ; Renjie CHAI
Neuroscience Bulletin 2024;40(1):113-126
Hearing loss has become increasingly prevalent and causes considerable disability, thus gravely burdening the global economy. Irreversible loss of hair cells is a main cause of sensorineural hearing loss, and currently, the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids, but these are of limited benefit in patients. It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies. At present, how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research. Multiple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells, and in this article, we first review the principal mechanisms underlying hair cell reproduction. We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration, and we summarize current achievements in hair cell regeneration. Lastly, we discuss potential future approaches, such as small molecule drugs and gene therapy, which might be applied for regenerating functional hair cells in the clinic.
Infant, Newborn
;
Humans
;
Hair Cells, Auditory, Inner/physiology*
;
Ear, Inner/physiology*
;
Hair Cells, Auditory/physiology*
;
Regeneration/genetics*
;
Stem Cells
6.Biomechanical characteristics of "All-on-4" concept analyzed by three-dimensional finite element method
Jing LU ; Ying LI ; Maohua MENG ; Huan WANG ; Jiayu SHU ; Wenjie LI ; Yuncai LUO ; Qiang DONG
Chinese Journal of Tissue Engineering Research 2024;28(22):3591-3596
BACKGROUND:With the increasing demand for edentulous jaw restoration,"All-on-4"concept is widely used.The load transfer mode of implant is different from that of natural tooth.The three-dimensional finite element analysis can study the stress distribution of implants and surrounding bone tissues under functional loading.On this basis,it provides research methods for finding suitable implant materials,optimizing implant geometry,and designing clinical surgical protocols. OBJECTIVE:To review researches related to three-dimensional finite element analysis in"All-on-4"concept. METHODS:Relevant literature published from 2003 to 2023 was searched in CNKI and PubMed databases with the search terms of"finite element method;All-on-4;edentulous;biomechanics"in Chinese and English.Finally,65 articles were included for review. RESULTS AND CONCLUSION:(1)In the case of insufficient horizontal bone mass,we can choose to apply narrow diameter implants,but we need to pay attention to the effect of the presence of the cantilever on the stress distribution and reduce the risk of failure.(2)The"All-on-4"concept reduces the stress distribution of bone by tilting the distal middle implant,but the ideal angle of the distal implant tilt in different jaw types requires further study.(3)The presence of cantilevers increases the risk of implant failure,and keeping the cantilever length/AP distance ratio at 0.9 helps to minimize mechanical complications.(4)When a framework is made of a material with a lower elastic modulus,the stress on the framework itself will be smaller,but it will increase the stress on the implant,prosthetic screw,abutment and peri-implant bone.On the contrary,when a material with a higher elastic modulus is used,it can reduce the stress on the prosthetic components,implants and peri-implant bone in the restoration,but the stress on the framework itself is higher.(5)The"All-on-4"concept allows for a better mechanistic balance,but requires the development of a long-term,effective treatment program that is tailored to the patient's specific situation.(6)Proper occlusal scheme is the key to the success of implant treatment,and there is no difference between canine-guide occlusion and group function occlusion in terms of the longevity of the restoration.However,there are many factors that influence occlusal design,and further in vitro experiments as well as a number of clinical studies are needed to explore the ideal occlusal design of the"All-on-4".
7.Incidence of venous thromboembolism in esophageal cancer: a real-world study of 8 458 cases
Kunyi DU ; Xin NIE ; Kexun LI ; Changding LI ; Kun LIU ; Zhiyu LI ; Kunzhi LI ; Simiao LU ; Kunhan NI ; Wenwu HE ; Chenghao WANG ; Jialong LI ; Haojun LI ; Qiang ZHOU ; Kangning WANG ; Guangyuan LIU ; Wenguang XIAO ; Qiang FANG ; Qiuling SHI ; Yongtao HAN ; Lin PENG ; Xuefeng LENG
Chinese Journal of Digestive Surgery 2024;23(1):109-113
Objective:To investigate the incidence of venous thromboembolism (VTE) in patients with esophageal cancer (EC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 8 458 EC patients who were admitted to Sichuan Cancer Hospital from January 2017 to December 2021 were collected. There were 6 923 males and 1 535 females, aged (64±9)years. There were 3 187 patients undergoing surgical treatment, and 5 271 cases undergoing non-surgical treatment. Observation indicators: (1) incidence of VTE in EC patients; (2) treatment and outcomes of patients with VTE. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was analyzed using the t test. Measurement data with skewed distribution were represented as M(range), and comparison between groups was analyzed using the nonparameter rank sum test. Count data were expressed as absolute numbers or percentages, and comparison between groups was analyzed using the chi-square test or Fisher exact probability. Comparison of ordinal data was analyzed using the nonparameter rank sum test. Results:(1) Incidence of VTE in EC patients. Of 8 458 EC patients, 175 cases developed VTE, with an incidence rate of 2.069%(175/8 458). Among 175 VTE patients, there were 164 cases of deep venous thrombosis (DVT), 4 cases of pulmonary embolism (PE), 7 cases of DVT and PE. There were 59 surgical patients and 116 non-surgical patients. There was no significant difference in thrombus type between surgical and non-surgical EC patients with VTE ( χ2=1.95, P>0.05). Of 3 187 surgical patients, the incidence of VTE was 1.851%(59/3 187), including an incidence of 0.157%(5/3 187) of PE. PE accounted for 8.475%(5/59) of surgical patients with VTE. Of 5 271 non-surgical patients, the incidence of VTE was 2.201%(116/5 271), including an incidence of 0.114%(6/5 271) of PE. PE accounted for 5.172%(6/116) of non-surgical patients with VTE. There was no significant difference in the incidence of VTE or PE between surgical patients and non-surgical patients ( χ2=1.20, 0.05, P>0.05). (2) Treatment and outcomes of patients with VTE. Among 175 EC patients with VTE, 163 cases underwent drug treatment, and 12 cases did not receive treatment. Among 163 cases with drug therapy, 158 cases underwent anticoagulant therapy, 5 cases were treated with thrombolysis. All the 163 patients were improved and discharged from hospital. Conclusions:The incidence of VTE in patients with EC is relatively low, as 2.069%. There is no significant difference in the incidence of VTE or thrombus type between surgical EC patients and non-surgical EC patients.
8.National bloodstream infection bacterial resistance surveillance report (2022) : Gram-negative bacteria
Zhiying LIU ; Yunbo CHEN ; Jinru JI ; Chaoqun YING ; Qing YANG ; Haishen KONG ; Haifeng MAO ; Hui DING ; Pengpeng TIAN ; Jiangqin SONG ; Yongyun LIU ; Jiliang WANG ; Yan JIN ; Yuanyuan DAI ; Yizheng ZHOU ; Yan GENG ; Fenghong CHEN ; Lu WANG ; Yanyan LI ; Dan LIU ; Peng ZHANG ; Junmin CAO ; Xiaoyan LI ; Dijing SONG ; Xinhua QIANG ; Yanhong LI ; Qiuying ZHANG ; Guolin LIAO ; Ying HUANG ; Baohua ZHANG ; Liang GUO ; Aiyun LI ; Haiquan KANG ; Donghong HUANG ; Sijin MAN ; Zhuo LI ; Youdong YIN ; Kunpeng LIANG ; Haixin DONG ; Donghua LIU ; Hongyun XU ; Yinqiao DONG ; Rong XU ; Lin ZHENG ; Shuyan HU ; Jian LI ; Qiang LIU ; Liang LUAN ; Jilu SHEN ; Lixia ZHANG ; Bo QUAN ; Xiaoping YAN ; Xiaoyan QI ; Dengyan QIAO ; Weiping LIU ; Xiusan XIA ; Ling MENG ; Jinhua LIANG ; Ping SHEN ; Yonghong XIAO
Chinese Journal of Clinical Infectious Diseases 2024;17(1):42-57
Objective:To report the results of national surveillance on the distribution and antimicrobial resistance profile of clinical Gram-negative bacteria isolates from bloodstream infections in China in 2022.Methods:The clinical isolates of Gram-negative bacteria from blood cultures in member hospitals of national bloodstream infection Bacterial Resistant Investigation Collaborative System(BRICS)were collected during January 2022 to December 2022. Antibiotic susceptibility tests were conducted by agar dilution or broth dilution methods recommended by Clinical and Laboratory Standards Institute(CLSI). WHONET 5.6 and SPSS 25.0 software were used to analyze the data.Results:During the study period,9 035 strains of Gram-negative bacteria were collected from 51 hospitals,of which 7 895(87.4%)were Enterobacteriaceae and 1 140(12.6%)were non-fermenting bacteria. The top 5 bacterial species were Escherichia coli( n=4 510,49.9%), Klebsiella pneumoniae( n=2 340,25.9%), Pseudomonas aeruginosa( n=534,5.9%), Acinetobacter baumannii complex( n=405,4.5%)and Enterobacter cloacae( n=327,3.6%). The ESBLs-producing rates in Escherichia coli, Klebsiella pneumoniae and Proteus spp. were 47.1%(2 095/4 452),21.0%(427/2 033)and 41.1%(58/141),respectively. The prevalence of carbapenem-resistant Escherichia coli(CREC)and carbapenem-resistant Klebsiella pneumoniae(CRKP)were 1.3%(58/4 510)and 13.1%(307/2 340);62.1%(36/58)and 9.8%(30/307)of CREC and CRKP were resistant to ceftazidime/avibactam combination,respectively. The prevalence of carbapenem-resistant Acinetobacter baumannii(CRAB)complex was 59.5%(241/405),while less than 5% of Acinetobacter baumannii complex was resistant to tigecycline and polymyxin B. The prevalence of carbapenem-resistant Pseudomonas aeruginosa(CRPA)was 18.4%(98/534). There were differences in the composition ratio of Gram-negative bacteria in bloodstream infections and the prevalence of main Gram-negative bacteria resistance among different regions,with statistically significant differences in the prevalence of CRKP and CRPA( χ2=20.489 and 20.252, P<0.001). The prevalence of CREC,CRKP,CRPA,CRAB,ESBLs-producing Escherichia coli and Klebsiella pneumoniae were higher in provinicial hospitals than those in municipal hospitals( χ2=11.953,81.183,10.404,5.915,12.415 and 6.459, P<0.01 or <0.05),while the prevalence of CRPA was higher in economically developed regions(per capita GDP ≥ 92 059 Yuan)than that in economically less-developed regions(per capita GDP <92 059 Yuan)( χ2=6.240, P=0.012). Conclusions:The proportion of Gram-negative bacteria in bloodstream infections shows an increasing trend,and Escherichia coli is ranked in the top,while the trend of CRKP decreases continuously with time. Decreasing trends are noted in ESBLs-producing Escherichia coli and Klebsiella pneumoniae. Low prevalence of carbapenem resistance in Escherichia coli and high prevalence in CRAB complex have been observed. The composition ratio and antibacterial spectrum of bloodstream infections in different regions of China are slightly different,and the proportion of main drug resistant bacteria in provincial hospitals is higher than those in municipal hospitals.
9.Neutrophil-to-lymphocyte ratio may help predict pediatric testicular torsion in chlidren with acute scrotal pain before surgery
Xianya HE ; Chen WANG ; Yongjun YANG ; Junjie CHEN ; Xuecheng WU ; Zhuo LI ; Zhe LIU ; Guangqing SONG ; Yili TENG ; Jia CHEN ; Hongwei WANG ; Huayi ZHENG ; Yuanwei LI ; Qiang LU
Journal of Modern Urology 2024;29(9):785-789
Objective To explore the feasibility and accuracy of neutrophil-to-lymphocyte ratio(NLR)in the prediction of testicular torsion(TT)in children with acute scrotal pain.Methods A retrospective case-control study was performed on 158 pediatric patients with ultrasound suspicion of TT who underwent surgical testicular examination during Jan.2017 and Jan.2024.The patients were divided into TT group and non-TT group.Clinical data and laboratory data at admission were analyzed.Sensitivity and specificity of NLR to TT were determined with the area under the curve(AUC)represented on the receiver operating characteristic(ROC)curves.Results There were with no statistically significant differences in clinical data between the two groups(P>0.05).The NLR was significantly higher in the TT group than in the non-TT group[(4.82±2.37)vs.(2.85±0.75),P<0.05].The optimal cut-off value of TT predicted by NLR was 2.07,the AUC was 0.809(95%CI:0.709-0.909),and the sensitivity and specificity were 97.9%and 93.3%,respectively,which were significantly higher than other factors.Conclusion For suspicious ultrasound diagnosis of pediatric acute scrotal pain cases,NLR can be used to predict the possibility of TT and may help to evaluate the urgent surgical treatment in these patients.
10.Clinical study of modified suspension reduction method combined with percutaneous vertebroplasty in the treatment of thoracolumbar osteoporotic compression fracture
Yu-Zhou LU ; Yu WANG ; Xiao-Xu YANG ; Cheng-Qiang WU ; Shou-Cui ZHANG ; Jin-Guo WANG ; Ya-Dong WU ; Dong QIN ; Lin DING
China Journal of Orthopaedics and Traumatology 2024;37(1):21-26
Objective To investigate the clinical effect of modified suspension reduction method combined with percuta-neous vertebroplasty in the treatment of osteoporotic thoracolumbar compression fractures.Methods From February 2020 to October 2021,92 patients with thoracolumbar osteoporotic compression fracture were treated by percutaneous vertebroplasty.According to different treatment methods,they were divided into the observation group and the control group.The observation group was treated with modified suspension reduction and then percutaneous vertebroplasty,while the control group was treated with percutaneous vertebroplasty alone.The observation group(47 cases),including 20 males and 27 females,the age ranged from 59 to 76 years old with an average of(69.74±4.50)years old,fractured vertebral bodies:T10(2 cases),T11(7 cases),T12(19 cases),L1(14 cases),L2(5 cases);the control group(45 cases),including 21 males and 24 females,the age ranged from 61 to 78 years old with an average of(71.02±3.58)years old,fractured vertebral bodies:T10(3 cases),T11(8 cases),T12(17 cas-es),L1(12 cases),L2(5 cases);The leakage of bone cement were observed,the visual analogue scale(VAS),Oswestry lumbar dysfunction index(ODI),anterior vertebrae height(AVH),Cobb angle of kyphosis and the amount of bone cement injected before and after operation were recorded and compared between the two groups.Results All patients were followed up,ranged from 6 to1O with an average of(8.45±1.73)months.Two patients ocurred bone cement leakage in observation group and 3 pa-tients in control group.AVH of observation group increased(P<0.05)and Cobb angle of injured vertebrae decreased(P<0.05).Cobb angle of injured vertebrae and AVH of the control group were not significantly changed(P>0.05).Cobb angle of injured vertebrae of the observation group was lower than that of control group(P<0.05)and AVH was higher than that of the control group(P<0.05).In the observation group,VAS before operation and 1 week,3 and 6 months after operation respective-ly were(7.32±1.05)scores,(3.56±1.18)scores,(1.83±0.67)scores,(1.27±0.34)scores,and ODI were(40.12±14.69)scores,(23.76±10.19)scores,(20.15±6.39)scores,(13.45±3.46)scores.In the control group,VAS before operation and 1 week,3 and 6 months after operation respectively were(7.11±5.26)scores,(3.82±0.68)scores,(1.94±0.88)scores,(1.36± 0.52)scores,and ODI were(41.38±10.23)scores,(25.13±14.22)scores,(20.61±5.82)scores,(14.55±5.27)scores.The scores of VAS and ODI after operation were lower than those before operation(P<0.05),but there was no significant difference between the two groups(P<0.05).Conclusion Modified suspension reduction method combined with PVP surgery for osteo-porotic thoracolumbar compression fractures has achieved good clinical results,which can effectively relieve lumbar back pain,restore vertebral height,correct kyphosis,improve lumbar function and patients'quality of life.

Result Analysis
Print
Save
E-mail