ChiCTR2000035969 版本V1.0 版本创建时间2020/08/20 23:52:53 中国临床试验注册中心

审核状态：

Project audit state：

通过审核

Successful

注册号：

Registration number：

ChiCTR2000035969 

最近更新日期：

Date of Last Refreshed on：

2020-08-20 23:50:15 

注册时间：

Date of Registration：

2020-08-20 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

Evaluation of IL10 and TGF-beta levels in blood as a biomarker of peri-prosthetic joint infection

Public title：

Evaluation of IL10 and TGF-beta levels in blood as a biomarker of peri-prosthetic joint infection

注册题目简写：

English Acronym：

研究课题的正式科学名称：

Evaluation of IL10 and TGF-beta levels in blood as a biomarker of peri-prosthetic joint infection

Scientific title：

Evaluation of IL10 and TGF-beta levels in blood as a biomarker of peri-prosthetic joint infection

研究课题代号(代码)：

Study subject ID：

在二级注册机构或其它机构的注册号：

The registration number of the Partner Registry or other register：

申请注册联系人：

cagatay tekin 

研究负责人：

burak günaydin 

Applicant：

cagatay tekin 

Study leader：

burak günaydin 

申请注册联系人电话：

Applicant telephone：

+905556164634

研究负责人电话：

Study leader's telephone：

+905557887965

申请注册联系人传真 ：

Applicant Fax：

研究负责人传真：

Study leader's fax：

申请注册联系人电子邮件：

Applicant E-mail：

cagat87@gmail.com

研究负责人电子邮件：

Study leader's E-mail：

docburak@gmail.com

申请单位网址(自愿提供)：

Applicant website(voluntary supply)：

https://cizredh.saglik.gov.tr

研究负责人网址(自愿提供)：

Study leader's website(voluntary supply)：

http://tip.nku.edu.tr/Ortopedi%20ve%20Travmatoloji%20ABD

申请注册联系人通讯地址：

Cizre state hospital, Sirnak state, Turkey

研究负责人通讯地址：

Namik Kemal Mah. Kampüs Cad. No:1, Merkez, Tekirdag, 59030 Tekirdag, Turkey

Applicant address：

Cizre state hospital, Sirnak state, Turkey

Study leader's address：

Namik Kemal Mah. Kampüs Cad. No:1, Merkez, Tekirdag, 59030 Tekirdag, Turkey

申请注册联系人邮政编码：

Applicant postcode：

73200

研究负责人邮政编码：

Study leader's postcode：

59100

申请人所在单位：

土耳其锡尔纳克州立医院

Applicant's institution：

Cizre state hospital, Sirnak state, Turkey

研究负责人所在单位：

土耳其拉米克科莫大学卫生与应用中心

Affiliation of the Leader：

Namik Kemal University Health and Application Center

是否获伦理委员会批准：

是/Yes

Approved by ethic committee：

Yes

伦理委员会批件文号：

Approved No. of ethic committee：

2018/80/06/01

伦理委员会批件附件：

Approved file of Ethical Committee：

 查看附件View

批准本研究的伦理委员会名称：

Girisimsel Olmayan Klinik Arastirmalar Etik Kurulu

Name of the ethic committee：

Girisimsel Olmayan Klinik Arastirmalar Etik Kurulu

伦理委员会批准日期：

Date of approved by ethic committee：

2018-09-27 00:00:00

伦理委员会联系人：

engin deniz rencber

Contact Name of the ethic committee：

engin deniz rencber

伦理委员会联系地址：

NKU GiRiSiMSEL OLMAYAN ARASTIRMALAR ETiK KuRULU//NAMIK KEMAL University faculty of medicine, Non-Invasive Clinical Research Ethics Committee

Contact Address of the ethic committee：

NKU GiRiSiMSEL OLMAYAN ARASTIRMALAR ETiK KuRULU//NAMIK KEMAL University faculty of medicine, Non-Invasive Clinical Research Ethics Committee

伦理委员会联系人电话：

Contact phone of the ethic committee：

+90 28 22505904

伦理委员会联系人邮箱：

Contact email of the ethic committee：

edrencber@nku.edu.tr

研究实施负责（组长）单位：

namik kemal health application & research center

Primary sponsor：

namik kemal health application & research center

研究实施负责（组长）单位地址：

namik kemal mah NKU saglik arastirma ve uygUlama merkezi

Primary sponsor's address：

namik kemal mah NKU saglik arastirma ve uygUlama merkezi

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：

土耳其

省(直辖市)：

tekirdag

市(区县)：

suleymanpasa

Country：

Türkiye

Province：

tekirdag

City：

suleymanpasa

单位(医院)：

health application & research center

具体地址：

namik kemal mah NKU saglik arastirma ve uygUlama merkezi

Institution
hospital：

health application & research center

Address：

namik kemal mah NKU saglik arastirma ve uygUlama merkezi

经费或物资来源：

Scientific Research Project Coordination Unit of Namik kemal University (Date: 28/03/2019, NKUBAP No: 02.GA.19.200).

Source(s) of funding：

Scientific Research Project Coordination Unit of Namik kemal University (Date: 28/03/2019, NKUBAP No: 02.GA.19.200).

Target disease：

periprosthetic joint infection

Target disease code：

t84.5

研究类型：

诊断试验

Study type：

Diagnostic test

研究所处阶段：

 探索性研究/预试验 

Study phase：

0

研究设计：

连续入组 

Study design：

Sequential 

研究目的：

The most common area of arthrosis is the hip and knee, where excessive load affects joint surfaces. Although conservative treatment is considered in the first stage of arthrosis treatment, surgical (prosthetic) treatment is planned in the presence of advanced arthrosis. Many complications can be seen during or after arthroplasty surgery. One such complication that can be seen after arthroplasty is periprosthetic joint infection (PJI). PJI is an undesirable situation due to its additional surgical intervention and long-term antibiotic treatment, high cost, and morbidity [1]. Laboratory tests, histopathologic/microbiologic data, and imaging methods should be evaluated together with the clinical diagnosis [2]. A single clinical finding and laboratory test with sufficient sensitivity and specificity routinely used in the diagnosis of PJI has not yet been demonstrated [2-3]. The criteria were defined in the diagnosis of PJI in 2011 by the Musculoskeletal Infection Society (MSIS) [4], and these criteria were modified at the International Consensus Meeting (ICM) in 2013, and they were widely accepted worldwide [5]. These criteria consist of major and minor criteria. The major criteria are as follows: pathogen isolated by culture from two separate tissue/fluid samples from the affected joint or sinus tract communicating with the prosthesis. The minor criteria include elevated erythrocyte sedimentation rate (ESR) (>30 mm/h) or C-reactive protein (CRP) (>10 mg/L); elevated white blood cells (WBC) in synovial fluid (>1100 cells/μL for knees, >3000 cells/μL for hips); elevated synovial polymorphonucleocytes (PMN) (>64% for knees, >80% for hips); pathogen isolation in one culture and intraoperative frozen section of periprosthetic tissue microscopic examination; the presence of >5 PMN per high-power field (hpf) in 5 hpf at x400 magnification [5]. For the diagnosis of PJI, one major criterion or three minor criteria are required [5-6]. PJIs are divided into three as early post-surgical, chronic, and late acute infections (7). Late acute infection is defined as the patient's symptoms starting within the last 3 weeks and 3 months have passed after arthroplasty surgery [7]. In previous studies, it was emphasized that the success rate was high with debridement and insert replacement treatment after the early diagnosis of PJI [3]. If PJI is diagnosed within the first 3 weeks following the development of infection, surgical treatment can be successfully performed without early removal of the prosthesis with early surgical intervention. Early diagnosis of infections that develop after prosthetic surgery is very important because it affects the success of treatment. Today, biomarkers that can be used in early diagnosis of PJI are the subject of research. New clinical methods such as microbiologic culture techniques, molecular methods, and serologic tests used to detect biomarkers from blood and/or joint fluid are used in the diagnosis because milder symptoms are seen in chronic PJI compared with acute infections. The use of biomarkers such as IL-6, CRP, ESR, and alpha defensin is increasing in the diagnosis of PJIs [8,9]. However, accurate and reliable test methods are still required for the early diagnosis of PJIs. IL-10 is a cytokine with an anti-inflammatory effect, suppressing the immune system by inhibiting the activity of Th-1 helper cells, macrophages, and natural killer (NK) cells [10,11]. However, the effects of some cytokines such as IL-10 may not be universally anti-inflammatory. IL-10 also enhances B cell functions and promotes the development of cytotoxic T cells. IL-10 has a regulatory role in immunity against viral, bacterial, fungal, protozoal, and helminth infections [11]. The main sources of IL-10 are helper T cells 2 (Th2), Tr1 cells (a subset of regulatory T cells), Th1, and Th17 cells. However, cytotoxic T cells, monocytes, macrophages, some dendritic cell subgroups (DCs), B cells, and some granulocytes (eosinophils and mast cells) are other important cells that secrete IL-10. IL-10 has effects on the suppression of the immune response by inhibiting the differentiation and maturation of dendritic cells, inhibiting antigen presentation, and inhibiting the production of pro-inflammatory cytokines [IL-1, IL-6, IL-12, and tumor necrosis factor-alpha (TNF-α)]. Moreover, IL-10 is thought to play a regulatory role in B cell activation, NK cell proliferation, and cytokine secretion [12]. TGF-β is an immunomodulatory cytokine, like IL-10. TGF-β is produced by leukocytes, including lymphocytes, macrophages, and dendritic cells, and is a growth factor with many functions that play a role in controlling the differentiation, proliferation, and activation status of these cells. It benefits from the immunosuppressive effect of TGF-β in many chronic diseases [13]. It is important in maintaining pro-inflammatory and anti-inflammatory balance by inhibiting the cellular growth of numerous immune cell precursors. It plays a role in the differentiation of some T cell subgroups, the stimulation of Treg cells, and immune tolerance [14,15]. Also, TGF-β inhibits the release of immunoglobulins from lymphocytes and inhibits the cytotoxicity of mononuclear phagocytes and NK cells [16]. In this study, it was aimed to prospectively investigate the effectiveness of using serum levels of IL-10 and TGF-β for detecting PJIs.  

Objectives of Study：

The most common area of arthrosis is the hip and knee, where excessive load affects joint surfaces. Although conservative treatment is considered in the first stage of arthrosis treatment, surgical (prosthetic) treatment is planned in the presence of advanced arthrosis. Many complications can be seen during or after arthroplasty surgery. One such complication that can be seen after arthroplasty is periprosthetic joint infection (PJI). PJI is an undesirable situation due to its additional surgical intervention and long-term antibiotic treatment, high cost, and morbidity [1]. Laboratory tests, histopathologic/microbiologic data, and imaging methods should be evaluated together with the clinical diagnosis [2]. A single clinical finding and laboratory test with sufficient sensitivity and specificity routinely used in the diagnosis of PJI has not yet been demonstrated [2-3]. The criteria were defined in the diagnosis of PJI in 2011 by the Musculoskeletal Infection Society (MSIS) [4], and these criteria were modified at the International Consensus Meeting (ICM) in 2013, and they were widely accepted worldwide [5]. These criteria consist of major and minor criteria. The major criteria are as follows: pathogen isolated by culture from two separate tissue/fluid samples from the affected joint or sinus tract communicating with the prosthesis. The minor criteria include elevated erythrocyte sedimentation rate (ESR) (>30 mm/h) or C-reactive protein (CRP) (>10 mg/L); elevated white blood cells (WBC) in synovial fluid (>1100 cells/μL for knees, >3000 cells/μL for hips); elevated synovial polymorphonucleocytes (PMN) (>64% for knees, >80% for hips); pathogen isolation in one culture and intraoperative frozen section of periprosthetic tissue microscopic examination; the presence of >5 PMN per high-power field (hpf) in 5 hpf at x400 magnification [5]. For the diagnosis of PJI, one major criterion or three minor criteria are required [5-6]. PJIs are divided into three as early post-surgical, chronic, and late acute infections (7). Late acute infection is defined as the patient's symptoms starting within the last 3 weeks and 3 months have passed after arthroplasty surgery [7]. In previous studies, it was emphasized that the success rate was high with debridement and insert replacement treatment after the early diagnosis of PJI [3]. If PJI is diagnosed within the first 3 weeks following the development of infection, surgical treatment can be successfully performed without early removal of the prosthesis with early surgical intervention. Early diagnosis of infections that develop after prosthetic surgery is very important because it affects the success of treatment. Today, biomarkers that can be used in early diagnosis of PJI are the subject of research. New clinical methods such as microbiologic culture techniques, molecular methods, and serologic tests used to detect biomarkers from blood and/or joint fluid are used in the diagnosis because milder symptoms are seen in chronic PJI compared with acute infections. The use of biomarkers such as IL-6, CRP, ESR, and alpha defensin is increasing in the diagnosis of PJIs [8,9]. However, accurate and reliable test methods are still required for the early diagnosis of PJIs. IL-10 is a cytokine with an anti-inflammatory effect, suppressing the immune system by inhibiting the activity of Th-1 helper cells, macrophages, and natural killer (NK) cells [10,11]. However, the effects of some cytokines such as IL-10 may not be universally anti-inflammatory. IL-10 also enhances B cell functions and promotes the development of cytotoxic T cells. IL-10 has a regulatory role in immunity against viral, bacterial, fungal, protozoal, and helminth infections [11]. The main sources of IL-10 are helper T cells 2 (Th2), Tr1 cells (a subset of regulatory T cells), Th1, and Th17 cells. However, cytotoxic T cells, monocytes, macrophages, some dendritic cell subgroups (DCs), B cells, and some granulocytes (eosinophils and mast cells) are other important cells that secrete IL-10. IL-10 has effects on the suppression of the immune response by inhibiting the differentiation and maturation of dendritic cells, inhibiting antigen presentation, and inhibiting the production of pro-inflammatory cytokines [IL-1, IL-6, IL-12, and tumor necrosis factor-alpha (TNF-α)]. Moreover, IL-10 is thought to play a regulatory role in B cell activation, NK cell proliferation, and cytokine secretion [12]. TGF-β is an immunomodulatory cytokine, like IL-10. TGF-β is produced by leukocytes, including lymphocytes, macrophages, and dendritic cells, and is a growth factor with many functions that play a role in controlling the differentiation, proliferation, and activation status of these cells. It benefits from the immunosuppressive effect of TGF-β in many chronic diseases [13]. It is important in maintaining pro-inflammatory and anti-inflammatory balance by inhibiting the cellular growth of numerous immune cell precursors. It plays a role in the differentiation of some T cell subgroups, the stimulation of Treg cells, and immune tolerance [14,15]. Also, TGF-β inhibits the release of immunoglobulins from lymphocytes and inhibits the cytotoxicity of mononuclear phagocytes and NK cells [16]. In this study, it was aimed to prospectively investigate the effectiveness of using serum levels of IL-10 and TGF-β for detecting PJIs.

药物成份或治疗方案详述：

 

Description for medicine or protocol of treatment in detail：

 

纳入标准：

A healthy control group and patients who underwent primary total arthroplasty surgery between October 2018 and November 2019, and who were hospitalized and treated with the diagnosis of chronic PJI was included in this study. The diagnosis of PJI in patients was determined according to the criteria determined by the MSIS and modified by the ICM

Inclusion criteria

A healthy control group and patients who underwent primary total arthroplasty surgery between October 2018 and November 2019, and who were hospitalized and treated with the diagnosis of chronic PJI was included in this study. The diagnosis of PJI in patients was determined according to the criteria determined by the MSIS and modified by the ICM

排除标准：

Patients with chronic disease or acute infection findings that might affect cytokine levels were excluded from the study. The primary arthroplasty surgery of the patients in group 2 and group 4 was performed in our clinic.
Patients with a previous history of additional surgical intervention of the knee or hip, patients who had undergone unicondylar knee or partial hip replacement, patients aged over 80 years, and patients with outpatient follow-up less than 6 months were not included in the study. Patients with additional diseases that might predispose to infection and therefore PJI, other than hypertension, were excluded from the study.

Exclusion criteria：

Patients with chronic disease or acute infection findings that might affect cytokine levels were excluded from the study. The primary arthroplasty surgery of the patients in group 2 and group 4 was performed in our clinic.
Patients with a previous history of additional surgical intervention of the knee or hip, patients who had undergone unicondylar knee or partial hip replacement, patients aged over 80 years, and patients with outpatient follow-up less than 6 months were not included in the study. Patients with additional diseases that might predispose to infection and therefore PJI, other than hypertension, were excluded from the study.

研究实施时间：

Study execute time：

从 From 2018-10-01 00:00:00至 To 2019-11-26 00:00:00  

征募观察对象时间：

Recruiting time：

从From 2018-10-02 00:00:00 至 To 2019-11-19 00:00:00  

诊断试验：

Diagnostic Tests：

金标准或参考标准（即可准确诊断某疾病的单项方法或多项联合方法，在本研究中用于诊断是否有该病的临床参考标准）：

Preoperative CRP, ESR, WBC, complete blood count (CBC) parameters, urinalysis, total protein, and albumin values of patients

Gold Standard or Reference Standard (The clinical reference standards required to establish the presence or absence of the target condition in the tested population in present study):

Preoperative CRP, ESR, WBC, complete blood count (CBC) parameters, urinalysis, total protein, and albumin values of patients

指标试验（即本研究的待评估诊断试验，无论为方法、生物标志物或设备，均请列出名称）：

Preoperative CRP, ESR, WBC, complete blood count (CBC) parameters, urinalysis, total protein, and albumin values of patients

Index test:

Preoperative CRP, ESR, WBC, complete blood count (CBC) parameters, urinalysis, total protein, and albumin values of patients

目标人群（可以是某种疾病患者或正常人群，详细描述其疾病特征，注意应纳入符合分布特点的全序列病例，具有良好的代表性）

The serum IL-10 and TGF-beta levels of patients with chronic PJI were examined once when it was determined that infection had developed. In group 2 and group 4, cytokine levels were examined one day before and 15 days after surgery. Serum cytokine levels were examined once in the healthy control gro

例数:

Sample size:

60

Target condition (The target condition is a particular disease or disease stage that the index test will be intended to identify. Please specify the characteristics in detail; the population should has a complete spectrum and good representative):

The serum IL-10 and TGF-beta levels of patients with chronic PJI were examined once when it was determined that infection had developed. In group 2 and group 4, cytokine levels were examined one day before and 15 days after surgery. Serum cytokine levels were examined once in the healthy control gro

容易混淆的疾病人群（即与目标疾病不易区分的一种或多种不同疾病，应避免采用正常人群对照的病例-对照设计）：

例数:

Sample size:

60

Population with condition difficult to distinguish from the target condition, the normal population in a case-control study design should be avoid:

研究实施地点：

Countries of recruitment and research settings：

国家：

 土耳其

省(直辖市)：

 tekirda 

市(区县)：

 suleymanpasa 

Country：

Türkiye 

Province：

tekirda 

City：

suleymanpasa 

单位(医院)：

namik kemal university health and application center 

单位级别：

三级医院 

Institution
hospital：

namik kemal university health and application center

Level of the institution：

Tertiary Hospital

测量指标：

Outcomes：

指标中文名：

comparison TGF-B and IL-10 levels and other serum infection markers

指标类型：

主要指标

Outcome：

comparison TGF-B and IL-10 levels and other serum infection markers

Type：

Primary indicator

测量时间点：

9 months

测量方法：

blood samples

Measure time point of outcome：

9 months

Measure method：

blood samples

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：

blood

组织：

muscles and periarthritic structures

Sample Name：

blood

Tissue：

muscles and periarthritic structures

人体标本去向

 使用后保存  

说明

Fate of sample：

Preservation after use  

Note：

征募研究对象情况：

Recruiting status：

结束

/Completed

年龄范围：

Participant age：
最小 Min age 54 岁 years
最大 Max age 80 岁 years

性别：

男女均可

Gender：

Both

随机方法（请说明由何人用什么方法产生随机序列）：

All patients who have appropriate follow up were included thus no randomization procedure was performed

Randomization Procedure (please state who generates the random number sequence and by what method)：

All patients who have appropriate follow up were included thus no randomization procedure was performed

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

公开/Public

盲法：

N/A

Blinding：

N/A

试验完成后的统计结果（上传文件）：

Calculated Results after
the Study Completed(upload file)：

是否共享原始数据：

IPD sharing

No

共享原始数据的方式（说明：请填入公开原始数据日期和方式，如采用网络平台，需填该网络平台名称和网址）：

we will publish an issue of one of the most remarkable orthopaedic surgery journal at following months

The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：

we will publish an issue of one of the most remarkable orthopaedic surgery journal at following months

数据采集和管理（说明：数据采集和管理由两部分组成，一为病例记录表(Case Record Form, CRF)，二为电子采集和管理系统(Electronic Data Capture, EDC)，如ResMan即为一种基于互联网的EDC：

CASE REPORT FORMS COULD NOT SHAR?NG BEFORE PUBLICATION BUT CRF COMPLETION GUIDELINES (CGG) AS WRITTEN BELOW The mean serum IL-10 and TGF-β levels were as follows: group 1, 1.01 pg/mL (0-3.8), 11.78 pg/mL (1.38-36); group 2a, 1.15 pg/mL (0-4.6), 9.28 pg/mL (0.93-24.3); group 2b, 1.16 pg/mL (0-4.2), 12.38 pg/mL (1.29-40.5); group 3, 1.53 pg/mL (0-4.6), 7.68 pg/mL (0.18-27); group 4a, 0.6 pg/mL (0-0.14), 14.06 pg/mL (7.2-19.5); and group 4b, 0.33 pg/mL (0-0.1), 5.08 pg/mL (3-8.5), respectively) (Table 3) (Figure 1-2). CRP, WBC, and ESR values of all groups and subgroups are shown in Table 3 (Figure 3-5). IL-10 values of patients with arthroplasty in group 2 who did not develop infection preoperatively (group 2a) and postoperatively were (group 2b) 1.15 ± 1.62 (0-4.6), 1.16 ± 1.18 (0-4.2), respectively, (p=0.86), and TGF-β values were 9.28 ± 6.89 (0.93-24.3), 12.38 ± 11.8 (1.29-40.5) (p=0.25) and cytokine levels were not statistically significant. Similarly, no statistically significant difference was found between preoperative (4a) and postoperative (4b) serum levels of patients with PJI in group 4. IL-10 levels were 0.60 ± 0.72 (0-1.4), 0.33 ± 0.57 (0-1.0), respectively (p=0.15), and TGF-β levels were 14.06 ± 6.27 (7.2-19.5), 5.08 ± 2.98 (3-8.5), respectively (p=0.11).

Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：

CASE REPORT FORMS COULD NOT SHAR?NG BEFORE PUBLICATION BUT CRF COMPLETION GUIDELINES (CGG) AS WRITTEN BELOW The mean serum IL-10 and TGF-β levels were as follows: group 1, 1.01 pg/mL (0-3.8), 11.78 pg/mL (1.38-36); group 2a, 1.15 pg/mL (0-4.6), 9.28 pg/mL (0.93-24.3); group 2b, 1.16 pg/mL (0-4.2), 12.38 pg/mL (1.29-40.5); group 3, 1.53 pg/mL (0-4.6), 7.68 pg/mL (0.18-27); group 4a, 0.6 pg/mL (0-0.14), 14.06 pg/mL (7.2-19.5); and group 4b, 0.33 pg/mL (0-0.1), 5.08 pg/mL (3-8.5), respectively) (Table 3) (Figure 1-2). CRP, WBC, and ESR values of all groups and subgroups are shown in Table 3 (Figure 3-5). IL-10 values of patients with arthroplasty in group 2 who did not develop infection preoperatively (group 2a) and postoperatively were (group 2b) 1.15 ± 1.62 (0-4.6), 1.16 ± 1.18 (0-4.2), respectively, (p=0.86), and TGF-β values were 9.28 ± 6.89 (0.93-24.3), 12.38 ± 11.8 (1.29-40.5) (p=0.25) and cytokine levels were not statistically significant. Similarly, no statistically significant difference was found between preoperative (4a) and postoperative (4b) serum levels of patients with PJI in group 4. IL-10 levels were 0.60 ± 0.72 (0-1.4), 0.33 ± 0.57 (0-1.0), respectively (p=0.15), and TGF-β levels were 14.06 ± 6.27 (7.2-19.5), 5.08 ± 2.98 (3-8.5), respectively (p=0.11).

数据与安全监察委员会：

Data and Safety Monitoring Committee：

有/Yes

注册人：

Name of Registration：

  2020-08-20 23:50:15