Introduction

Since Starzl et al.[1] first reported 11 cases of ABO-incompatible(ABO-I)liver transplantation(LT)in 1979,there have been numerous advances.In countries with a severe lack of deceased donors,such as South Korea and Japan,ABO-I living donors have been crucial in expanding the pool of donors.Concerns about ABO-I-related complications,such as antibody-mediated rejection(AMR),biliary stricture,hepatic artery thrombosis,infection,poor graft and patient survival,have continually been raised[2–7].However,the scope of applications for ABO-I LT has gradually broadened,and outcomes have improved considerably with the introduction of treatment strategies such as plasmapheresis,splenectomy,graft local infusion,rituximab,mycophenolate mofetil,and intravenous immunoglobulin,which can prevent AMR by lowering the titer level and inhibiting the production of anti-blood type isoagglutinin[8–13].

The most representative example of treatment strategies for ABO-I LT is rituximab with plasmapheresis.Rituximab is a monoclonal antibody targeting CD20 proteins on the surface of B cells.It was first introduced in Japan for prophylactic use in ABO-I LT patients during the early 2000s and used continuously for ABOI LT at many centers,dramatically improving outcomes[10,14,15].Plasmapheresis usually begins 1–2 weeks before ABO-I LT,with the aim of removing the preformed anti-blood type isoagglutinins.

Although plasmapheresis contributes to reducing anti-blood type isoagglutinin titers for ABO-I LT,there has been a lack of study on its usefulness in the rituximab era.This study aimed to evaluate the reliability,safety,and limitation of current desensitization protocols by comparing changes in anti-blood type isoagglutinin titers and peripheral blood B cells over time,patient survival,and ABO-I-related complications between a group undergoing rituximab only therapy and a group undergoing rituximab and plasmapheresis therapy in ABO-I LT.

Methods

Patients

This study was a single-center,retrospective study of 56 consecutive adult patients(18 years or over)who underwent ABO-I living donor liver transplantation(LDLT)at the National Cancer Center in Korea between January 2012 and October 2015.Between January 2012 and February 2014,26 patients underwent desensitization with rituximab and several rounds of plasmapheresis(RP group)prior to ABO-I LDLT;30 patients between March 2014 and October 2015 underwent preoperative desensitization with rituximab only,without plasmapheresis(RO group).Medical records,including demographics,anti-blood type isoagglutinin titers,CD19+lymphocyte(B cell)subpopulations,and surgical outcomes such as patient survival and complications,were reviewed.This study was approved by our Institutional Review Board(IRB number:NCC2016-0157).

Desensitization and immunosuppression

A single dose of rituximab(300 mg/m2)was administered approximately 2 weeks before surgery,but all patients prior to February 2014 also underwent plasmapheresis 1–2 weeks before the operation;patients from March 2014 onward were only administered rituximab.No other methods,such as splenectomy,graft local infusion(e.g.with prostaglandin E1,methylprednisolone,and gabexate mesilate),and preoperative mycophenolate mofetil,were used.Intravenous immunoglobulin(0.8 g/kg)was administered on postoperative days 1 and 4.

For induction therapy,basiliximab(20 mg)was administered on the day of the surgery and postoperative day 4.Immunosuppressive agents were a combination of tacrolimus,mycophenolate mofetil,and corticosteroids.Tacrolimus was started within 2 days after ABO-I LDLT with a goal trough of 8–12 ng/mL,and mycophenolate mofetil was started from postoperative day 2 at a dose of 1.5 g/day.The dose of corticosteroids was gradually reduced up to discontinuation 6 months after ABO-I LDLT.

Operation

In all cases,the right lobe of the liver donor was used.After full mobilization of the recipient’s liver,the left and right portal veins were clamped before resection.The middle hepatic vein and left hepatic vein were resected with a surgical stapler,and the right hepatic vein was clamped before removing any diseased liver left in the peritoneal cavity after resection.

Continuous variables are given as mean±standard deviation(SD)or median(interquartile range)and compared with a Student’s t test or Mann–Whitney U test,depending on the normality of the distribution.For categorical variables,comparisons between groups were done with a Chi-square test or Fisher’s exact test,as appropriate.Analyses for AMR,biopsy-proven acute cellular rejection,and other ABO-I-related complications between groups were made using a Mantel–Haenszel test strati fied by the initial isoagglutinin titers 16.Cut-off values for continuous variables were de fined as the point with the most signi ficant(log-rank test)split using the “maxstat”and “survival”packages of R software.Survival was estimated using the Kaplan–Meier method and compared using the log-rank test.Cox’s proportional hazard model was used for multivariate analysis.A P value of less than 0.05 was considered statistically signi ficant.All calculations were made using the SPSS 24.0(IBM,Inc.,Chicago,IL,USA)and R 3.3.3(https://www.r-project.org).The statistical methods were checked by the Biometric Research Branch,Research Institute and Hospital,National Cancer Center,Korea.

Perioperative management and follow-up

食堂从业人员资质触发的安全风险。高校食堂被承包后，承包方来自全国各地，生产、销售、加工、采购人员来源更加宽泛；各种地方特色美食和小吃开始进入食堂，各地区、各民族饮食的专技人员大量到食堂就业，成分更趋复杂；承包方更迭愈加频繁，管理经营、销售、生产、加工、采购人员流动性加大。为追求超额利润，降低人力成本成为必然选项，这就导致食品安全的风险增加。再加上从业人员文化层次不高、工资待遇不高，食品安全工作经验和食品安全责任意识不足，就更加导致风险的存在。在实际情况中，多数从业人员未取得从业资格证，更有甚者连健康证都不具备，因此，这就需要对食堂从业人员的资质进行重点审核和把关。

Six patients in the RP group showed abnormal liver function and elevated isoagglutinin titers with no abnormalities in imaging tests;since rejection could not be excluded,a biopsy was performed in these patients,but AMR or acute cellular rejection was not con firmed in the pathology reports.There was no mortality within 30 postoperative days for either group.

Anti-blood type isoagglutinin titers were measured using the immediate spin technique[22,23];these were measured immediately before rituximab administration,and continually from after the start of plasmapheresis until discharge.Following discharge,measurements were taken every week during the first postoperative month,and every 2 weeks to 1 month after that.

B cell(CD19+)subpopulations were measured by flow cytometry immediately before rituximab administration,and immediately before ABO-I LDLT[24,25].Further measurements were taken twice a week from ABO-I LDLT to discharge,once a week from discharge to the end of the first postoperative month,and once per month after that.

太阳能电池板通过螺栓固定在垃圾箱顶盖，垃圾箱顶盖与顶盖的支撑柱焊接固定，顶盖的支撑柱与垃圾箱焊接固定。垃圾箱顶盖通过螺栓固定有红外传感器、单片机、窄带物联网通信模块。空气质量检测器、异味传感器与单片机电连接，单片机与窄带物联网通信模块电连接，窄带物联网通信模块通过无线信号与云端服务器连接，云端服务器通过无线信号与移动终端连接。太阳能电池板通过导线与蓄电池连接，蓄电池通过导线与单片机、红外传感器、空气质量检测器、异味传感器、窄带物联网通信模块电连接。

1) 集叶率与作业效率都与手持作业时移动剪叶器的速度有关，过快虽作业效率高，但集叶率相对要低一些；过慢作业效率低，但集叶效果要好。因此，在具体操作过程中，要兼顾效率和集叶效果，掌握好移动速度。

Statistical analysis

After the recipient’s total hepatectomy,implantation began with right hepatic vein anastomosis using a modi fied right liver graft.In cases with an inferior right hepatic vein of at least 5 mm,that was directly anastomosed to the inferior vena cava.Based on its size and redundancy,the right portal vein of the graft was anastomosed to either the right or main portal vein of the recipient.Following reperfusion,hepatic artery anastomosis was achieved using surgical microscopy to anastomose the right hepatic artery of the graft with either the right or left hepatic artery of the recipient.Ductto-duct biliary reconstruction was performed in all cases[16–21].

Results

Demographics

A total of 56 patients underwent ABO-I LDLT.These patients were divided into two groups according to the desensitization method,with 46.4%(n=26)in the RP group and 53.6%(n=30)in the RO group.The mean age of the recipients was 52.3±8.1 years for the RP group and 54.3±6.7 years for the RO group(P=0.312).The proportion of male and female recipients was 69.2%(n=18)and 30.8%(n=8)in the RP group,and was 60.0%(n=18)and 40.0%(n=12)in the RO group(P=0.472).

In terms of the ABO type of donor to recipient,the most common combination in the RP group was A to O in 23.1%of patients(n=6),while the most common combination in the RO group was AB to B in 30.0%of patients(n=9)(P=0.413).The median value for initial isoagglutinin titers prior to desensitization was 32(8–32)in the RP group and 8(4–16)in the RO group(P＜0.001).

合理利用信息化手段，便于轻松了解资产的使用现状，根据掌握的状况和闲置信息情况，做到科学部署、合理调配，实现资源共享，确保固定资产高效运用于教学、科研、行政、后勤服务中，从而进一步提高固定资产的使用和管理效率。

Table 1 Basal characteristics of patients who underwent ABO-I LDLT.

Values are presented as number(%),mean±SD or median(interquartile range). ABO-I:ABO-incompatible;BMI:body mass index;HBV:hepatitis B virus;HCC:hepatocellular carcinoma;HCV:hepatitis C virus;INR:international normalized ratio;LDLT:living donor liver transplantation;MELD:model for end-stage liver disease;PT:prothrombin time;RO:rituximab without plasmapheresis;RP:rituximab with plasmapheresis;TBil:total bilirubin. ∗ Wilson’s disease(n=1),metastatic adenocarcinoma from colon(n=1).

Characteristics RP group(n=26) RO group(n=30) P value Age(yr)Recipient 52.3±8.1 54.3±6.7 0.312 Donor 36.5±14.5 31.9±13.6 0.230 Gender(male/female)Recipient 18/8 18/12 0.472 Donor 12/14 23/7 0.019 Disease(HCC/cirrhosis/others) 21/5/0 23/5/2∗ 0.404 Viral status(HBV/HCV/none) 19/1/6 19/2/9 0.722 BMI(kg/m2)Recipient 23.4±4.0 22.5±2.5 0.286 Donor 22.7±2.8 22.4±2.7 0.667 Albumin(g/dL) 3.4±0.6 3.5±0.7 0.820 TBil(mg/dL) 1.3(0.8–2.9) 1.6(0.9–3.6) 0.599 PT(INR) 1.25(1.15–1.66) 1.28(1.13–1.67) 0.967 Creatinine(mg/dL) 0.9(0.8–1.1) 0.7(0.6–0.8) ＜0.001 Child-Pugh score 6(5–8) 7(5–9) 0.212 MELD score 10.5(8.0–16.0) 12.0(8.8–18.0) 0.468 ABO type(donor to recipient) 0.413 A→B 5(19.2%) 1(3.3%)A→O 6(23.1%) 6(20.0%)B→A 3(11.5%) 4(13.3%)B→O 4(15.4%) 5(16.7%)AB→A 3(11.5%) 5(16.7%)AB→B 4(15.4%) 9(30.0%)AB→O 1(3.8%) 0 Isoagglutinin titer Initial 32(8–32) 8(4–16) ＜0.001≥256 1(3.8%) 0 128 3(11.5%) 0 64 1(3.8%) 1(3.3%)32 10(38.5%) 1(3.3%)16 4(15.4%) 8(26.7%)＜16 7(26.9%) 20(66.7%)At the time of LDLT 2(2–4) 2(1–4) 0.514≥16 1(3.8%) 3(10.0%)8 4(15.4%) 3(10.0%)4 4(15.4%) 5(16.7%)2 12(46.2%) 8(26.7%)1 4(15.4%) 7(23.3%)0 1(3.8%) 4(13.3%)CD19+lymphocyte(B cells)subpopulation(%)Initial 13.5(10.9–18.1) 14.0(9.3–19.7) 0.657 At the time of LDLT 0.5(0.2–1.2) 0.2(0–0.5) 0.079 Plasmapheresis(times)Before ABO-I LDLT 2(1–2.3) 0 ＜0.001 After ABO-I LDLT 0 0 NA

B cell subpopulations were not different in the two groups at the time of initial point(P=0.657)and ABO-I LDLT(P=0.079).Plasmapheresis was performed a median of 2 times(1–2.3)before surgery in the RP group(Table 1).

Surgical outcomes

The median operative time was 410 min(377–487)for the RP group and 354 min(332–378)for the RO group(P=0.001).Cold ischemia time(CIT)was 100 min(79–117)for the RP group and 71 min(62–77)for the RO group(P＜0.001).Warm ischemia time was 24 min(20–30)for the RP group and 17 min(15–21)for the RO group(P=0.001).The actual graft weights in the RP and RO groups were 544.8±114.2 g and 668.6±144.7 g,respectively(P=0.001),and graft recipient weight ratio was 0.89±0.24 and 1.11±0.25,respectively(P=0.001).

For patients with hepatitis B virus infection,hepatitis B immunoglobulin,and entecavir or tenofovir were used for hepatitis B prophylaxis after LDLT.In patients with suspected recurrence of hepatitis C virus,pegylated-interferon and ribavirin were used after con firming hepatitis C virus RNA levels and elevated liver enzyme levels.Other infection prophylaxis consisted of ticarcillin-clavulanate for 1 week, fluconazole for 1 month,and trimethoprim-sulfamethoxazole for 1 year.

Among the complications,biliary stricture was most common in both groups,occurring in 23.1%of patients(n=6)in the RP group and 16.7%of patients(n=5)in the RO group(P=0.990).Meanwhile,all biliary strictures were observed at the anastomosis site,and diffuse intrahepatic biliary stricture was not observed.Hepatic artery thrombosis occurred in 6.7%of patients(n=2)in the RO group only.Infection occurred in 7.7%of patients(n=2)in the RP group and 6.7%of patients(n=2)in the RO group(P=0.791)(Table 2).

Table 2 Surgical outcomes of patients who underwent ABO-I LDLT.

Values are presented as number(%),mean±SD or median(interquartile range). ABO-I:ABO-incompatible;AMR:antibody-mediated rejection;BPACR:biopsy-proven acute cellular rejection;TIT:total ischemia time;CIT:cold ischemia time;WIT:warm ischemia time;EBL:estimated blood loss;FFP:fresh frozen plasma;GRWR:graft recipient weight ratio;HAT:hepatic artery thrombosis;LDLT:living donor liver transplantation;PC:platelet concentrates;RBC:red blood cell;RO:rituximab without plasmapheresis;RP:rituximab with plasmapheresis. ∗Strati fied P values by the initial anti-blood type isoagglutinin titers 16 using the Mantel–Haenszel test.

Characteristics RP group(n=26) RO group(n=30) P value Operation time(min) 410(377–487) 354(332–378) 0.001 TIT(min) 124(102–145) 88(81–94) ＜0.001 CIT(min) 100(79–117) 71(62–77) ＜0.001 WIT(min) 24(20–30) 17(15–21) 0.001 EBL(mL) 2000(925–3850) 2150(700–3500) 0.598 Transfusion RBC 18(69.2%) 20(66.7%) 0.838 FFP 17(65.4%) 21(70.0%) 0.712 PC 14(53.8%) 18(60.0%) 0.643 Actual graft weight(g) 544.8±114.2 668.6±144.7 0.001 GRWR 0.89±0.24 1.11±0.25 0.001 Steatosis on pathology 0.302＜5% 16(61.5%) 20(66.7%)5−33% 8(30.8%) 10(33.3%)＞33% 2(7.7%) 0 AMR 0 0 NA∗BPACR 0 0 NA∗Complications 0.690∗Absent 15(57.7%) 21(70.0%)Present 11(42.3%) 9(30.0%)Biliary stricture 6(23.1%) 5(16.7%) 0.990∗Bile leakage 1(3.8%) 4(13.3%) 0.152∗Bleeding 4(15.4%) 1(3.3%) 0.237∗HAT 0 2(6.7%) NA∗Infection 2(7.7%) 2(6.7%) 0.791∗Others 1(3.8%) 1(3.3%) 0.439∗30-day mortality 0 0 NA Postoperative hospital stay(day) 14(12–15) 15(14–19) 0.038

Table 3 Analysis of predictors of patient survival after ABO-I LDLT.

ABO-I:ABO-incompatible;BMI:body mass index;CIT:cold ischemia time;EBL:estimated blood loss;LDLT:living donor liver transplantation. a Variables with P less than 0.05 in the univariate analysis were noted. b Reference is＜105 min.

Variablesa Univariate analysis Multivariate analysis P value Hazard ratio 95%CI P value Recipient BMI 0.015(＜25 kg/m2 vs ≥25 kg/m2)Operative time 0.020(＜6 h vs ≥6 h)CIT ＜0.001 10.0b 2.658–37.872 0.001(＜105 min vs≥105 min)EBL 0.028(＜5000 mL vs≥5000 mL)Donor Gender 0.027(male vs female)

Predictors of overall survival

There was no rebound rise of isoagglutinin titers after ABOI LDLT in patients with initial isoagglutinin titers＜16 in either group,and there was no difference in isoagglutinin titers between the RP and RO groups(Fig.3A).There was also no difference in the two groups in overall survival rate(P=0.953;Fig.4A).

该品种春季幼叶黄绿色，夏季成熟叶片深绿色，椭圆形，叶面革质有光泽。树姿开张，枝条节间短，无针刺。幼树生长势较强，喜肥，干性强，枝条直立生长，进入结果期后，骨干枝自然开张，树势中庸。丰产期亩产可达4 200 kg。

Kinetics of anti-blood type isoagglutinin titers and CD19+(B cell)lymphocytes

Initial isoagglutinin titers showed a median value of 32(8–32)in the RP group and 8(4–16)in the RO group(P＜0.001;Table 1;Fig.2A).Although there was no difference in isoagglu-tinin titers between the RP and RO groups at the time of ABOI LDLT(P=0.514),a rebound rise of isoagglutinin titers was observed in the RP group,and this difference was observed continually from postoperative week 1(P=0.002)to postoperative week 11(P=0.017),and then week 16(Fig.2A).In the two groups,no difference was observed in B cell subpopulations at any time point(Fig.2B).

In ABO-I LT,AMR can present in 2 broad forms:hepatic necrosis within the first postoperative week,or diffuse intrahepatic biliary stricture 1–2 months after transplantation[26,27].Diffuse intrahepatic biliary stricture was considered if multiple strictures or sporadic dilatation of intrahepatic bile ducts was observed in computed tomography scans.AMR was suspected and a biopsy was performed in cases with a 4-fold or greater increase in antiblood type isoagglutinin titers compared to surgery or anti-blood type isoagglutinin titers higher than 1:32,abnormal liver function test results exceeding normal values by 2–3-fold for serum aspartate aminotransferase,alanine aminotransferase,and total bilirubin,and a lack of abnormal findings by imaging tests.Also,in these cases,plasmapheresis was performed prior to liver biopsy results.

The 6-,12-,and 18-month overall survival rates were 92.3%,80.8%,and 76.9%in the RP group,and 96.6%,85.4%,and 85.4%in the RO group(P=0.574;Fig.1A),respectively.In the univariate analysis for overall survival rate after ABO-I LDLT,signi ficant differences were observed according to the recipient’s body mass index(BMI)(P=0.015),operative time(P=0.020),CIT(P＜0.001),estimated blood loss(P=0.028),and the donor’s gender(P=0.027)(Table 3),but there was no difference in the overall survival rate between the RP and RO groups(P=0.574;Fig.1A).Multivariate analysis showed that overall survival rate was signi ficantly lower in the case of CIT≥105 min compared with those of CIT＜105 min(hazard ratio=10.0;95%CI:2.658–37.872;P=0.001)(Table 3;Fig.1B).

However,in patients with initial isoagglutinin titers≥16,the rebound rise of isoagglutinin titers after ABO-I LDLT was more prominent in the RP group,and this difference was observed continually from postoperative week 1(P=0.019)to postoperative week 20(P=0.021),only excluding postoperative week 8(Fig.3B).In these patients,there was no difference in overall survival rate between the RP and the RO group(P=0.652;Fig.4B).

Apart from the desensitization methods,all other procedures were identical to ABO-compatible(ABO-C)LDLT,including routine laboratory and imaging tests such as computed tomography,magnetic resonance imaging,and positron emission tomographycomputed tomography.

Fig.1.Overall survival rate according to plasmapheresis(A)and CIT(B)after ABOI LDLT.ABO-I:ABO-incompatible;CIT:cold ischemia time;LDLT:living donor liver transplantation;RO:rituximab without plasmapheresis;RP:rituximab with plasmapheresis.

Fig.2.The changes of the isoagglutinin titers(A)and the CD19+lymphocyte(B cell)subpopulations(B)over time.Data are presented in box plots.∗:P＜0.05;∗∗:P＜0.001.RO:rituximab without plasmapheresis;RP:rituximab with plasmapheresis.

Fig.3.The changes of the isoagglutinin titers over time when the initial isoagglutinin titers＜16(A)and ≥16(B).Data are presented in box plots.∗:P＜0.05.RO:rituximab without plasmapheresis;RP:rituximab with plasmapheresis.

Discussion

Based on animal experiments,Starzl et al.reported in 1969 that transplantation of the liver was less susceptible to acute rejection than that of the kidney or heart[28],the same group in 1979 reported 11 cases of successful ABO-I LT without graft rejection[1].However,since then,many problems such as AMR,lower graft survival,hepatic artery thrombosis,and cholangitis have persistently been reported for ABO-I LT patients compared to ABO-C or ABO-identical LT patients[4–6,29].As a result,LT across the ABO blood type barrier was not recommended,except in a very small fraction of emergencies.In cases of LDLT,however,the donor is usually restricted to family,which can make it impossible to avoid breaking the ABO blood type barrier.In particular,in Asian countries with a serious shortage of deceased donors,ABO-I living donors are key to broadening the donor pool.

Fig.4.Overall survival rate after ABO-I LDLT when the initial isoagglutinin titers＜16(A)and≥16(B).ABO-I:ABO-incompatible;LDLT:living donor liver transplantation;RO:rituximab without plasmapheresis;RP:rituximab with plasmapheresis.

Rituximab is a monoclonal chimeric human anti-CD20 antibody that destroys B cells via antibody-dependent cell-mediated cytotoxicity,complement-dependent cytotoxicity,and a direct antigen–antibody reaction[2,30,31].According to Genberg et al.[32],following a single dose of rituximab(375 mg/m2),the number of peripheral blood B cells decreased after only 3 days and were cleared completely after 3 or more weeks.

“大蒜”是人们日常生活中的美蔬和佳料，过日子离不开它。据《本草纲目》记载：“其气熏烈，能通五脏，达诸窍，去寒湿，辟邪恶，消痈肿，化症积肉食，此其功也。”足见它的药用价值。

Plasmapheresis has been reported to be useful for rapidly reducing anti-blood type isoagglutinin titers for ABO-I LT[33].However,it has also been reported that even if antibody titers are reduced by plasmapheresis prior to ABO-I LT,isoagglutinin titers can rise again within 3–7 days after operation[33,34].This occurs because,although plasmapheresis is able to remove antibodies from the peripheral blood prior to ABO-I LT,it cannot suppress the production of new antibodies by preexisting plasma cells,which are not affected by rituximab administration.For this reason,repetitive plasmapheresis can be considered a more efficient therapeutic method than rituximab in patients with rebound rise of isoagglutinin titers after ABO-I LT[33].

In this study,there was no difference in the overall survival rates between the RP and RO groups,either for patients with initial isoagglutinin titers＜16(P=0.953;Fig.4A)or for those with initial isoagglutinin titers≥16(P=0.652;Fig.4B).Furthermore,there was no signi ficant difference in two groups in ABO-I-related complications such as AMR,biliary stricture,hepatic artery thrombosis,and infection,even when a strati fied analysis by the initial anti-blood type isoagglutinin titers was performed.

Interestingly,patients with initial isoagglutinin titers＜16 did not experience a rebound rise of isoagglutinin titers after ABO-I LDLT in either group,and no difference was observed in the two groups’isoagglutinin titers at any time point(Fig.3A).However,in patients with initial isoagglutinin titers≥16,the rebound rise of isoagglutinin titers after ABO-I LDLT was more prominent in the RP group(Fig.3B).It suggests at least that there is no evidence that rituximab alone therapy increases the rebound rise of isoagglutinin titers after ABO-I LT,although differences in initial isoagglutinin titers exist in the two groups.

These results lead to the conclusion that sufficient desensitization can be achieved with rituximab alone,and that this desensitization strategy does not affect patient survival,ABO-I-related complications,and the rebound rise of isoagglutinin titers after ABO-I LDLT.However,it should be still noted that in patients with initial isoagglutinin titers≥16,there was a difference in the distribution of initial isoagglutinin titers between the RP and RO groups,which could not be adjusted because of the limited sample size.Further studies considering this point are needed to con firm our preliminary results.

In this study,the only important prognostic factor for overall survival was not the desensitization methods but the prolonged CIT.There have previously been several reports of an association between prolonged CIT and worse outcomes[35–40].However,most studies have been conducted on ABO-C deceased donor liver transplants,and so they differ in some ways from the present study on ABO-I LDLT.Because of shorter CIT during LDLT relative to deceased donor liver transplants,there have been only a small number of reports regarding the in fluence of CIT on the patient and graft outcomes in LDLT.In the present study entirely composed of ABO-I LDLT,CIT was the only poor prognostic factor for patients’overall survival.This finding suggests that ABO-I living donor allografts are much more susceptible to the prolonged CIT than ABO-C living donor allografts.The immunological response elicited and ampli fied by prolonged CIT may unfavorably affect the occurrence of graft damage in ABO-I LDLT.Additional studies will be needed to clarify the impact of CIT on graft outcomes and patient survival in ABO-I LDLT.

This study has several limitations.First,it was a single-center,retrospective study.Second,the difference in the distribution of initial isoagglutinin titers between the RP and RO groups resulted in an inability to compare the two groups using a cutoff value of initial isoagglutinin titers of 32 or higher.

In conclusion,sufficient desensitization is possible using rituximab alone for initial isoagglutinin titers in ABO-I LDLT.This approach has no effect on patient survival,and there is no increase in rebound rise of anti-blood type isoagglutinin titers and ABO-I-related complications such as AMR,biliary stricture,hepatic artery thrombosis,and infection rate.However,for initial isoagglutinin titers≥16,further studies are still needed to verify our results.

在进入二十一世纪后，世界形成了更健康、更科学、更完美的社会文明，此时，绿色已经成为人们的一种价值观念，全方面改变了人们的衣食住行，有效改善了生态环境。对此，在畜牧业方面，为推动其的可持续发展，也应积极发展生态畜牧业，充分利用生态系统中的生物工程和谐技术，将物质能量进行多层次的循环，以此降低废物的产生，推动畜牧业生产的系统化，促进畜牧业可持续发展。

朗格在陀飞轮发明逾200年后，实现了如何在旋转陀飞轮框架内掣停振动摆轮，使陀飞轮腕表也能精确设计时间。拉出表冠，复杂的杠杆系统便驱动可动的V形弹簧转向摆轮边缘。摆轮随即停止。按下表冠，“制动器”便松开，摆轮随即再度开始摆动。此专利装置与其它装置搭载于Lange 1Tourbillon Perpetual Calendar、1815 Tourbillon、Datograph Perpetual Tourbillon之上。

中职生年龄一般为15～17岁，不仅有青春期中学生的普遍特征，还有一些自身所特有的心理特点。中职生基本上是中考失败的学生，都有考试失败、家人责骂、老师不重视以及认为中职学校学生低人一等的感受，他们频繁出现的课堂问题行为，与其自卑、焦虑、紧张、敏感和自我保护心理是分不开的。有的中职生为了引起老师和同学的关注，故意扰乱课堂秩序；有的学生则因多次受到老师责骂而心怀怨恨；一些学生无法静下心来学习。这样便形成了中职生比较特殊且严重的课堂问题行为。此外，厌学情绪也是不容忽视的原因。

Contributors

LEC,KSH,SJR and PSJ designed the research.LEC and SJR performed the research.LEC analyzed the data and wrote the paper.KSH supervised the study and revised the manuscript.KSH is the guarantor.

Funding

None.

在“十一五”期间，没有建立独立儿童福利院的地级以上城市和部分人口多、孤残儿童数量大的县级市，纷纷新建独立儿童福利机构；已经建立儿童福利机构的地级以上城市，对现有儿童福利机构进行改建、扩建或重建；已经建立社会福利院的县（市、区），新建、改扩建相对独立儿童部，旨在为孤残儿童提供养护、教育、康复、娱乐于一体的多功能综合性服务[3][4]。儿童爱心庄园结合自身实际，抓住契机，积极探索教、康、保三位一体整合服务模式。

Ethical approval

This study was approved by Institutional Review Board of National Cancer Center,Korea(NCC2016-0157).

Competing interest

No bene fits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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