Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipien...Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.展开更多
Liver transplantation(LT)is the standard therapy for individuals afflicted with end-stage liver disease.Despite notable advancements in LT technology,the incidence of early allograft dysfunction(EAD)remains a critical...Liver transplantation(LT)is the standard therapy for individuals afflicted with end-stage liver disease.Despite notable advancements in LT technology,the incidence of early allograft dysfunction(EAD)remains a critical concern,exacerbating the current organ shortage and detrimentally affecting the prognosis of recipients.Unfortunately,the perplexing hepatic heterogeneity has impeded characterization of the cellular traits and molecular events that contribute to EAD.Herein,we constructed a pioneering single-cell transcriptomic landscape of human transplanted livers derived from non-EAD and EAD patients,with 12 liver samples collected from 7 donors during the cold perfusion and portal reperfusion stages.Comparison of the 75231 cells of non-EAD and EAD patients revealed an EAD-associated immune niche comprising mucosal-associated invariant T cells,granzyme B^(+)(GZMB^(+))granzyme K^(+)(GZMK^(+))natural killer cells,and S100 calcium binding protein A12^(+)(S100A12^(+))neutrophils.Moreover,we verified this immune niche and its association with EAD occurrence in two independent cohorts.Our findings elucidate the cellular characteristics of transplanted livers and the EAD-associated pathogenic immune niche at the single-cell level,thus,offering valuable insights into EAD onset.展开更多
Behavioral recovery using(viable)peripheral nerve allografts to repair ablation-type(segmental-loss)peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration.Furthermore,such peripher...Behavioral recovery using(viable)peripheral nerve allografts to repair ablation-type(segmental-loss)peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration.Furthermore,such peripheral nerve allografts undergo immunological rejection by the host immune system.In contrast,peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks,reduced immune responses,and many axons do not undergo Wallerian degeneration.The relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this study.We hypothesized that polyethylene glycol might have some immune-protective effects,but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral recovery.We examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal fusion.Ablation-type sciatic nerve injuries in outbred Sprague–Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts,but peripheral nerve allografts were loose-sutured(loose-sutured polyethylene glycol)with an intentional gap of 1–2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host axons.Similar to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts,animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days postoperatively.Other morphological signs of rejection,such as collapsed Schwann cell basal lamina tubes,were absent in polyethylene glycol-fused peripheral nerve allografts but commonly observed in negative control and loose-sutured polyethylene glycol peripheral nerve allografts at 21 days postoperatively.Loose-sutured polyethylene glycol peripheral nerve allografts had more pro-inflammatory and less anti-inflammatory macrophages than negative control peripheral nerve allografts.While T cell counts were similarly high in loose-sutured-polyethylene glycol and negative control peripheral nerve allografts,loose-sutured polyethylene glycol peripheral nerve allografts expressed some cytokines/chemokines important for T cell activation at much lower levels at 14 days postoperatively.MHCI expression was elevated in loose-sutured polyethylene glycol peripheral nerve allografts,but MHCII expression was modestly lower compared to negative control at 21 days postoperatively.We conclude that,while polyethylene glycol per se reduces some immune responses of peripheral nerve allografts,successful polyethylene glycol-fusion repair of some axons is necessary to prevent Wallerian degeneration of those axons and immune rejection of peripheral nerve allografts,and produce recovery of sensory/motor functions and voluntary behaviors.Translation of polyethylene glycol-fusion technologies would produce a paradigm shift from the current clinical practice of waiting days to months to repair ablation peripheral nerve injuries.展开更多
BACKGROUND Detection of early chronic changes in the kidney allograft is important for timely intervention and long-term survival.Conventional and novel ultrasound-based investigations are being increasingly used for ...BACKGROUND Detection of early chronic changes in the kidney allograft is important for timely intervention and long-term survival.Conventional and novel ultrasound-based investigations are being increasingly used for this purpose with variable results.AIM To compare the diagnostic performance of resistive index(RI)and shear wave elastography(SWE)in the diagnosis of chronic fibrosing changes of kidney allograft with histopathological results.METHODS This is a cross-sectional and comparative study.A total of 154 kidney transplant recipients were included in this study,which was conducted at the Departments of Transplantation and Radiology,Sindh Institute of Urology and Transplantation,Karachi,Pakistan,from August 2022 to February 2023.All consecutive patients with increased serum creatinine levels and reduced glomerular filtration rate(GFR)after three months of transplantation were enrolled in this study.SWE and RI were performed and the findings of these were evaluated against the kidney allograft biopsy results to determine their diagnostic utility.RESULTS The mean age of all patients was 35.32±11.08 years.Among these,126(81.8%)were males and 28(18.2%)were females.The mean serum creatinine in all patients was 2.86±1.68 mg/dL and the mean estimated GFR was 35.38±17.27 mL/min/1.73 m2.Kidney allograft biopsy results showed chronic changes in 55(37.66%)biopsies.The sensitivity,specificity,positive predictive value(PPV),and negative predictive value(NPV)of SWE for the detection of chronic allograft damage were 93.10%,96.87%%,94.73%,and 95.87%,respectively,and the diagnostic accuracy was 95.45%.For RI,the sensitivity,specificity,PPV,and NPV were 76.92%,83.33%,70.17%,and 87.62%,respectively,and the diagnostic accuracy was 81.16%.CONCLUSION The results from this study show that SWE is more sensitive and specific as compared to RI in the evaluation of chronic allograft damage.It can be of great help during the routine follow-up of kidney transplant recipients for screening and early detection of chronic changes and selecting patients for allograft biopsy.展开更多
BACKGROUND Liver grafts from donation after circulatory death(DCD)are associated with a higher risk of early graft dysfunction,determined by the warm ischemia and cold ischemia times.It is essential to have precise cr...BACKGROUND Liver grafts from donation after circulatory death(DCD)are associated with a higher risk of early graft dysfunction,determined by the warm ischemia and cold ischemia times.It is essential to have precise criteria to identify this complication in order to guide therapeutic strategies.AIM To validate different graft and recipient survival scores in patients undergoing liver transplantation(LT)with DCD grafts.METHODS A retrospective and observational unicentric study was conducted on 65 LT patients with grafts obtained from controlled DCD donors from November 2013 to November 2022.The United Kingdom(UK)risk score,early allograft dysfunction(EAD)Olthoff score,and model for early allograft function(MEAF)score were used to evaluate the risk of graft and recipient survival post-transplant.For survival analysis purposes,we used the Kaplan-Meier method,and the differences between subgroups were compared using the log-rank(Mantel-Cox)test.RESULTS Sixty-five patients were included in the study.The UK risk score did not demonstrate predictive capacity for recipient or graft survival.However,in donors aged over 70 years old(18.4%),it significantly predicted graft survival(P<0.05).According to Kaplan-Meier survival curves,graft survival rates at 6 months,2 years,and 5 years in the futility group dramatically decreased to 50%compared to the other groups(log-rank 8.806,P<0.05).The EAD Olthoff and MEAF scores did not demonstrate predictive capacity for recipient or graft survival.Based on Kaplan-Meier survival curves,patients with a MEAF score≥7 had a lower graft survival rate at 6 months,2 years,and 5 years compared to patients with a lower MEAF score(log-rank 4.667,P<0.05).CONCLUSION In our series,both UK DCD risk score and MEAF score showed predictive capability for graft survival.展开更多
The second half of the previous century witnessed a tremendous rise in the number of clinical kidney transplants worldwide.This activity was,however,accompanied by many issues and challenges.An accurate diagnosis and ...The second half of the previous century witnessed a tremendous rise in the number of clinical kidney transplants worldwide.This activity was,however,accompanied by many issues and challenges.An accurate diagnosis and appropriate management of causes of graft dysfunction were and still are,a big challenge.Kidney allograft biopsy played a vital role in addressing the above challenge.However,its interpretation was not standardized for many years until,in 1991,the Banff process was started to fill this void.Thereafter,regular Banff meetings took place every 2 years for the past 30 years.Marked changes have taken place in the interpretation of kidney allograft biopsies,diagnosis,and classification of rejection and other non-rejection pathologies from the original Banff 93 classification.This review attempts to summarize those changes for increasing the awareness and understanding of kidney allograft pathology through the eyes of the Banff process.It will interest the transplant surgeons,physicians,pathologists,and allied professionals associated with the care of kidney transplant patients.展开更多
Renal transplantation is the treatment of choice for end stage kidney disease.However,despite all the efforts to expand the donor pool,the shortage of donors is increasing and as a consequence,there has been a signifi...Renal transplantation is the treatment of choice for end stage kidney disease.However,despite all the efforts to expand the donor pool,the shortage of donors is increasing and as a consequence,there has been a significant increase in the number of patients on transplant waiting lists globally.Societies worldwide have employed different methods to address this,each with specific ethical concerns surrounding them.Over three decades ago,a governmentally regulated program of kidney transplantation from living unrelated donors was introduced in Iran and since practiced which has been the subject of hot debate in the literature.Nevertheless,despite all these extensive discussions and publications,several key aspects of the program have still not been properly elucidated and addressed.In this article,the author aims to illuminate some dark corners related to this issue that have largely escaped the notice of ethicists.展开更多
BACKGROUND Fibrous dysplasia is a congenital disorder in which normal bone is replaced by fibro-osseous tissue or irregular trabeculae of woven bone intermixed with mature collagenous tissue.A single or multiple bones...BACKGROUND Fibrous dysplasia is a congenital disorder in which normal bone is replaced by fibro-osseous tissue or irregular trabeculae of woven bone intermixed with mature collagenous tissue.A single or multiple bones are affected.This rare bone disorder has three clinical patterns including monostotic,polyostotic,and that associated with McCune-Albright syndrome.Most studies report primary fibrous dysplasia.However,a few cases of recurrent monostotic fibular fibrous dysplasia have been reported.Here,we report a therapeutic strategy for recurrent fibular fibrous dysplasia.CASE SUMMARY A 4-year-old boy was admitted for persistent pain in the left lower limb and abnormal gait over the previous 9 mo.He had no history of present or past illness.Preoperative imaging data showed erosion-like changes with bone expansion of the left middle and lower fibular segment.Tumor tissue in the fibular bone marrow cavity was removed by curettage,and rapid intraoperative pathological examination suggested fibular fibrous dysplasia.An allograft was implanted into the fibular medullary cavity.However,he was readmitted with clinical symptoms including persistent pain,abnormal gait,and local swelling at the age of 6 years.He was diagnosed with recurrent fibular fibrous dysplasia based on the second medical examination.He underwent fibular bone tumor radical resection and longus fibular allograft transplantation combined with fibular bone locking plate and screws.Good host bone to allogenic bone graft fusion was observed by the physician on postoperative regular follow-up.CONCLUSION Radical resection of fibrous dysplasia and longus fibula allograft combined with internal fixation for reconstruction are suitable for the treatment of recurrent monostotic fibular fibrous dysplasia.展开更多
Currently,the most feasible and widely practiced option for patients with endstage organ failure is the transplantation of part of or whole organs,either from deceased or living donors.However,organ shortage has posed...Currently,the most feasible and widely practiced option for patients with endstage organ failure is the transplantation of part of or whole organs,either from deceased or living donors.However,organ shortage has posed and is still posing a big challenge in this field.Newer options being explored are xenografts and engineered/bioengineered tissues/organs.Already small steps have been taken in this direction and sooner or later,these will become a norm in this field.However,these developments will pose different challenges for the diagnosis and management of problems as compared with traditional allografts.The approach to pathologic diagnosis of dysfunction in these settings will likely be significantly different.Thus,there is a need to increase awareness and prepare transplant diagnosticians to meet this future challenge in the field of xenotransplantation/regenerative medicine.This review will focus on the current status of transplant pathology and how it will be changed in the future with the emerging scenario of routine xenotransplantation.展开更多
BACKGROUND Exosomes are 30-150 nm nanovesicles with sophisticated nucleic acids cargo,actively secreted by all cells within human body,and found in abundance in all body fluids,including urine.These extracellular vesi...BACKGROUND Exosomes are 30-150 nm nanovesicles with sophisticated nucleic acids cargo,actively secreted by all cells within human body,and found in abundance in all body fluids,including urine.These extracellular vesicles have tremendous potential for next generation diagnostics,theoretically enabling noninvasive assessment of organ and tissue function via liquid biopsy analysis.AIM Recently,feasibility of an exosomal molecular test was demonstrated for postorgan transplant monitoring:Analysis of urine-derived exosomal mRNA cargo allowed early detection of kidney allograft rejection.Here,we further studied urine-derived exosomes and their mRNA content as a highly promising diagnostic modality.This included stability studies of urine samples and exosomal mRNA upon transportation from the point of collection to a centralized testing facility,short-term storage of urine at different conditions upon receipt till the point molecular assay is performed,and effects of various potentially interfering substances on the downstream quantitative polymerase chain reaction(qPCR)assay.METHODS The urine specimens were stored at various conditions and pre-processed in different ways.Next,samples were passed through the columns to capture all extracellular vesicles,the vesicles were lysed to release their content and the exosomal RNA was purified on the mini-columns,reverse transcription was performed,next pre-amplification,followed by a qPCR analysis for a panel of RESULTS To ensure exosomal RNA integrity,the harvested urine specimens should be shipped refrigerated,by overnight delivery.Urine can next be stored at the test site for up to 1 wk at 4°C,and long term should be frozen at-80°C.Urine specimens must be centrifuge at low G-force to deplete cells and debris,to ensure consistent top results in downstream molecular assays.All commonly used medications(tacrolimus,cyclosporin A,mycophenolic acid,everolimus,sirolimus,ascomycin,teriflunomide)were tested and confirmed that they do not cause assay interference.CONCLUSION mRNA from urine-derived exosomes was shown to be stable across a broad range of conditions and produced accurate results when analyzed via qPCR assay for detection of kidney allograft rejection.We identified the most optimal conditions for every step of the process,ensuring pre-analytical sample integrity and robust qPCR results.展开更多
BACKGROUND Liver transplantation(LT)is a life-saving intervention for patients with end-stage liver disease.However,the equitable allocation of scarce donor organs remains a formidable challenge.Prognostic tools are p...BACKGROUND Liver transplantation(LT)is a life-saving intervention for patients with end-stage liver disease.However,the equitable allocation of scarce donor organs remains a formidable challenge.Prognostic tools are pivotal in identifying the most suitable transplant candidates.Traditionally,scoring systems like the model for end-stage liver disease have been instrumental in this process.Nevertheless,the landscape of prognostication is undergoing a transformation with the integration of machine learning(ML)and artificial intelligence models.AIM To assess the utility of ML models in prognostication for LT,comparing their performance and reliability to established traditional scoring systems.METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines,we conducted a thorough and standardized literature search using the PubMed/MEDLINE database.Our search imposed no restrictions on publication year,age,or gender.Exclusion criteria encompassed non-English studies,review articles,case reports,conference papers,studies with missing data,or those exhibiting evident methodological flaws.RESULTS Our search yielded a total of 64 articles,with 23 meeting the inclusion criteria.Among the selected studies,60.8%originated from the United States and China combined.Only one pediatric study met the criteria.Notably,91%of the studies were published within the past five years.ML models consistently demonstrated satisfactory to excellent area under the receiver operating characteristic curve values(ranging from 0.6 to 1)across all studies,surpassing the performance of traditional scoring systems.Random forest exhibited superior predictive capabilities for 90-d mortality following LT,sepsis,and acute kidney injury(AKI).In contrast,gradient boosting excelled in predicting the risk of graft-versus-host disease,pneumonia,and AKI.CONCLUSION This study underscores the potential of ML models in guiding decisions related to allograft allocation and LT,marking a significant evolution in the field of prognostication.展开更多
BACKGROUND Prolonged donor hepatectomy time may be implicated in early and late complications of liver transplantation.AIM To evaluate the impact of donor hepatectomy time on outcomes of liver transplant recipients,ma...BACKGROUND Prolonged donor hepatectomy time may be implicated in early and late complications of liver transplantation.AIM To evaluate the impact of donor hepatectomy time on outcomes of liver transplant recipients,mainly early allograft dysfunction.METHODS This multicenter retrospective study included brain-dead donors and adult liver graft recipients.Donor-recipient matching was obtained through a crossover list.Clinical and laboratory data were recorded for both donors and recipients.Donor hepatectomy,cold ischemia,and warm ischemia times were recorded.Primary outcome was early allograft dysfunction.Secondary outcomes included need for retransplantation,length of intensive care unit and hospital stay,and patient and graft survival at 12 months.RESULTS From January 2019 to December 2021,a total of 243 patients underwent a liver transplant from a brain-dead donor.Of these,57(25%)developed early allograft dysfunction.The median donor hepatectomy time was 29(23–40)min.Patients with early allograft dysfunction had a median hepatectomy time of 25(22–38)min,whereas those without it had a median time of 30(24–40)min(P=0.126).CONCLUSION Donor hepatectomy time was not associated with early allograft dysfunction,graft survival,or patient survival following liver transplantation.展开更多
基金supported by grants from the National Nat-ural Science Foundation of China (81570587 and 81700557)the Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology (2013A061401007 and 2017B030314018)+3 种基金Guangdong Provincial Natural Science Funds for Major Basic Science Culture Project (2015A030308010)Science and Technology Program of Guangzhou (201704020150)the Natural Science Foundations of Guangdong province (2016A030310141 and 2020A1515010091)Young Teachers Training Project of Sun Yat-sen University (K0401068) and the Guangdong Science and Technology Innovation Strategy (pdjh2022b0010 and pdjh2023a0002)。
文摘Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.
基金supported by the National Natural Science Foundation of China(82200725)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-D-202002)+4 种基金the Fundamental Research Funds for the Central Universities(226-2023-00114,226-2022-00226,and 226-2023-00059)the Key Program of National Natural Science Foundation of China(81930016)the Key Research and Development Program of China(2021YFA1100500)the Major Research Plan of the National Natural Science Foundation of China(92159202)the Ningbo Top Medical and Health Research Program(2022030309).
文摘Liver transplantation(LT)is the standard therapy for individuals afflicted with end-stage liver disease.Despite notable advancements in LT technology,the incidence of early allograft dysfunction(EAD)remains a critical concern,exacerbating the current organ shortage and detrimentally affecting the prognosis of recipients.Unfortunately,the perplexing hepatic heterogeneity has impeded characterization of the cellular traits and molecular events that contribute to EAD.Herein,we constructed a pioneering single-cell transcriptomic landscape of human transplanted livers derived from non-EAD and EAD patients,with 12 liver samples collected from 7 donors during the cold perfusion and portal reperfusion stages.Comparison of the 75231 cells of non-EAD and EAD patients revealed an EAD-associated immune niche comprising mucosal-associated invariant T cells,granzyme B^(+)(GZMB^(+))granzyme K^(+)(GZMK^(+))natural killer cells,and S100 calcium binding protein A12^(+)(S100A12^(+))neutrophils.Moreover,we verified this immune niche and its association with EAD occurrence in two independent cohorts.Our findings elucidate the cellular characteristics of transplanted livers and the EAD-associated pathogenic immune niche at the single-cell level,thus,offering valuable insights into EAD onset.
基金supported by grants from the Lone Star Paralysis Foundation,NIH R01NS081063Department of Defense award W81XWH-19-2-0054 to GDB+2 种基金supported by University of Wyoming Startup funds,Department of Defense grant W81XWH-17-1-0402the University of Wyoming Sensory Biology COBRE under National Institutes of Health(NIH)award number 5P20GM121310-02the National Institute of General Medical Sciences of the NIH under award number P20GM103432 to JSB。
文摘Behavioral recovery using(viable)peripheral nerve allografts to repair ablation-type(segmental-loss)peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration.Furthermore,such peripheral nerve allografts undergo immunological rejection by the host immune system.In contrast,peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks,reduced immune responses,and many axons do not undergo Wallerian degeneration.The relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this study.We hypothesized that polyethylene glycol might have some immune-protective effects,but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral recovery.We examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal fusion.Ablation-type sciatic nerve injuries in outbred Sprague–Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts,but peripheral nerve allografts were loose-sutured(loose-sutured polyethylene glycol)with an intentional gap of 1–2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host axons.Similar to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts,animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days postoperatively.Other morphological signs of rejection,such as collapsed Schwann cell basal lamina tubes,were absent in polyethylene glycol-fused peripheral nerve allografts but commonly observed in negative control and loose-sutured polyethylene glycol peripheral nerve allografts at 21 days postoperatively.Loose-sutured polyethylene glycol peripheral nerve allografts had more pro-inflammatory and less anti-inflammatory macrophages than negative control peripheral nerve allografts.While T cell counts were similarly high in loose-sutured-polyethylene glycol and negative control peripheral nerve allografts,loose-sutured polyethylene glycol peripheral nerve allografts expressed some cytokines/chemokines important for T cell activation at much lower levels at 14 days postoperatively.MHCI expression was elevated in loose-sutured polyethylene glycol peripheral nerve allografts,but MHCII expression was modestly lower compared to negative control at 21 days postoperatively.We conclude that,while polyethylene glycol per se reduces some immune responses of peripheral nerve allografts,successful polyethylene glycol-fusion repair of some axons is necessary to prevent Wallerian degeneration of those axons and immune rejection of peripheral nerve allografts,and produce recovery of sensory/motor functions and voluntary behaviors.Translation of polyethylene glycol-fusion technologies would produce a paradigm shift from the current clinical practice of waiting days to months to repair ablation peripheral nerve injuries.
文摘BACKGROUND Detection of early chronic changes in the kidney allograft is important for timely intervention and long-term survival.Conventional and novel ultrasound-based investigations are being increasingly used for this purpose with variable results.AIM To compare the diagnostic performance of resistive index(RI)and shear wave elastography(SWE)in the diagnosis of chronic fibrosing changes of kidney allograft with histopathological results.METHODS This is a cross-sectional and comparative study.A total of 154 kidney transplant recipients were included in this study,which was conducted at the Departments of Transplantation and Radiology,Sindh Institute of Urology and Transplantation,Karachi,Pakistan,from August 2022 to February 2023.All consecutive patients with increased serum creatinine levels and reduced glomerular filtration rate(GFR)after three months of transplantation were enrolled in this study.SWE and RI were performed and the findings of these were evaluated against the kidney allograft biopsy results to determine their diagnostic utility.RESULTS The mean age of all patients was 35.32±11.08 years.Among these,126(81.8%)were males and 28(18.2%)were females.The mean serum creatinine in all patients was 2.86±1.68 mg/dL and the mean estimated GFR was 35.38±17.27 mL/min/1.73 m2.Kidney allograft biopsy results showed chronic changes in 55(37.66%)biopsies.The sensitivity,specificity,positive predictive value(PPV),and negative predictive value(NPV)of SWE for the detection of chronic allograft damage were 93.10%,96.87%%,94.73%,and 95.87%,respectively,and the diagnostic accuracy was 95.45%.For RI,the sensitivity,specificity,PPV,and NPV were 76.92%,83.33%,70.17%,and 87.62%,respectively,and the diagnostic accuracy was 81.16%.CONCLUSION The results from this study show that SWE is more sensitive and specific as compared to RI in the evaluation of chronic allograft damage.It can be of great help during the routine follow-up of kidney transplant recipients for screening and early detection of chronic changes and selecting patients for allograft biopsy.
文摘BACKGROUND Liver grafts from donation after circulatory death(DCD)are associated with a higher risk of early graft dysfunction,determined by the warm ischemia and cold ischemia times.It is essential to have precise criteria to identify this complication in order to guide therapeutic strategies.AIM To validate different graft and recipient survival scores in patients undergoing liver transplantation(LT)with DCD grafts.METHODS A retrospective and observational unicentric study was conducted on 65 LT patients with grafts obtained from controlled DCD donors from November 2013 to November 2022.The United Kingdom(UK)risk score,early allograft dysfunction(EAD)Olthoff score,and model for early allograft function(MEAF)score were used to evaluate the risk of graft and recipient survival post-transplant.For survival analysis purposes,we used the Kaplan-Meier method,and the differences between subgroups were compared using the log-rank(Mantel-Cox)test.RESULTS Sixty-five patients were included in the study.The UK risk score did not demonstrate predictive capacity for recipient or graft survival.However,in donors aged over 70 years old(18.4%),it significantly predicted graft survival(P<0.05).According to Kaplan-Meier survival curves,graft survival rates at 6 months,2 years,and 5 years in the futility group dramatically decreased to 50%compared to the other groups(log-rank 8.806,P<0.05).The EAD Olthoff and MEAF scores did not demonstrate predictive capacity for recipient or graft survival.Based on Kaplan-Meier survival curves,patients with a MEAF score≥7 had a lower graft survival rate at 6 months,2 years,and 5 years compared to patients with a lower MEAF score(log-rank 4.667,P<0.05).CONCLUSION In our series,both UK DCD risk score and MEAF score showed predictive capability for graft survival.
文摘The second half of the previous century witnessed a tremendous rise in the number of clinical kidney transplants worldwide.This activity was,however,accompanied by many issues and challenges.An accurate diagnosis and appropriate management of causes of graft dysfunction were and still are,a big challenge.Kidney allograft biopsy played a vital role in addressing the above challenge.However,its interpretation was not standardized for many years until,in 1991,the Banff process was started to fill this void.Thereafter,regular Banff meetings took place every 2 years for the past 30 years.Marked changes have taken place in the interpretation of kidney allograft biopsies,diagnosis,and classification of rejection and other non-rejection pathologies from the original Banff 93 classification.This review attempts to summarize those changes for increasing the awareness and understanding of kidney allograft pathology through the eyes of the Banff process.It will interest the transplant surgeons,physicians,pathologists,and allied professionals associated with the care of kidney transplant patients.
文摘Renal transplantation is the treatment of choice for end stage kidney disease.However,despite all the efforts to expand the donor pool,the shortage of donors is increasing and as a consequence,there has been a significant increase in the number of patients on transplant waiting lists globally.Societies worldwide have employed different methods to address this,each with specific ethical concerns surrounding them.Over three decades ago,a governmentally regulated program of kidney transplantation from living unrelated donors was introduced in Iran and since practiced which has been the subject of hot debate in the literature.Nevertheless,despite all these extensive discussions and publications,several key aspects of the program have still not been properly elucidated and addressed.In this article,the author aims to illuminate some dark corners related to this issue that have largely escaped the notice of ethicists.
基金The Scientific and Technological Innovation Platform of Huaihua,China,No.2022F2701The Science and Technology Planning Project of Huaihua,China,No.2021R3117.
文摘BACKGROUND Fibrous dysplasia is a congenital disorder in which normal bone is replaced by fibro-osseous tissue or irregular trabeculae of woven bone intermixed with mature collagenous tissue.A single or multiple bones are affected.This rare bone disorder has three clinical patterns including monostotic,polyostotic,and that associated with McCune-Albright syndrome.Most studies report primary fibrous dysplasia.However,a few cases of recurrent monostotic fibular fibrous dysplasia have been reported.Here,we report a therapeutic strategy for recurrent fibular fibrous dysplasia.CASE SUMMARY A 4-year-old boy was admitted for persistent pain in the left lower limb and abnormal gait over the previous 9 mo.He had no history of present or past illness.Preoperative imaging data showed erosion-like changes with bone expansion of the left middle and lower fibular segment.Tumor tissue in the fibular bone marrow cavity was removed by curettage,and rapid intraoperative pathological examination suggested fibular fibrous dysplasia.An allograft was implanted into the fibular medullary cavity.However,he was readmitted with clinical symptoms including persistent pain,abnormal gait,and local swelling at the age of 6 years.He was diagnosed with recurrent fibular fibrous dysplasia based on the second medical examination.He underwent fibular bone tumor radical resection and longus fibular allograft transplantation combined with fibular bone locking plate and screws.Good host bone to allogenic bone graft fusion was observed by the physician on postoperative regular follow-up.CONCLUSION Radical resection of fibrous dysplasia and longus fibula allograft combined with internal fixation for reconstruction are suitable for the treatment of recurrent monostotic fibular fibrous dysplasia.
文摘Currently,the most feasible and widely practiced option for patients with endstage organ failure is the transplantation of part of or whole organs,either from deceased or living donors.However,organ shortage has posed and is still posing a big challenge in this field.Newer options being explored are xenografts and engineered/bioengineered tissues/organs.Already small steps have been taken in this direction and sooner or later,these will become a norm in this field.However,these developments will pose different challenges for the diagnosis and management of problems as compared with traditional allografts.The approach to pathologic diagnosis of dysfunction in these settings will likely be significantly different.Thus,there is a need to increase awareness and prepare transplant diagnosticians to meet this future challenge in the field of xenotransplantation/regenerative medicine.This review will focus on the current status of transplant pathology and how it will be changed in the future with the emerging scenario of routine xenotransplantation.
文摘BACKGROUND Exosomes are 30-150 nm nanovesicles with sophisticated nucleic acids cargo,actively secreted by all cells within human body,and found in abundance in all body fluids,including urine.These extracellular vesicles have tremendous potential for next generation diagnostics,theoretically enabling noninvasive assessment of organ and tissue function via liquid biopsy analysis.AIM Recently,feasibility of an exosomal molecular test was demonstrated for postorgan transplant monitoring:Analysis of urine-derived exosomal mRNA cargo allowed early detection of kidney allograft rejection.Here,we further studied urine-derived exosomes and their mRNA content as a highly promising diagnostic modality.This included stability studies of urine samples and exosomal mRNA upon transportation from the point of collection to a centralized testing facility,short-term storage of urine at different conditions upon receipt till the point molecular assay is performed,and effects of various potentially interfering substances on the downstream quantitative polymerase chain reaction(qPCR)assay.METHODS The urine specimens were stored at various conditions and pre-processed in different ways.Next,samples were passed through the columns to capture all extracellular vesicles,the vesicles were lysed to release their content and the exosomal RNA was purified on the mini-columns,reverse transcription was performed,next pre-amplification,followed by a qPCR analysis for a panel of RESULTS To ensure exosomal RNA integrity,the harvested urine specimens should be shipped refrigerated,by overnight delivery.Urine can next be stored at the test site for up to 1 wk at 4°C,and long term should be frozen at-80°C.Urine specimens must be centrifuge at low G-force to deplete cells and debris,to ensure consistent top results in downstream molecular assays.All commonly used medications(tacrolimus,cyclosporin A,mycophenolic acid,everolimus,sirolimus,ascomycin,teriflunomide)were tested and confirmed that they do not cause assay interference.CONCLUSION mRNA from urine-derived exosomes was shown to be stable across a broad range of conditions and produced accurate results when analyzed via qPCR assay for detection of kidney allograft rejection.We identified the most optimal conditions for every step of the process,ensuring pre-analytical sample integrity and robust qPCR results.
文摘BACKGROUND Liver transplantation(LT)is a life-saving intervention for patients with end-stage liver disease.However,the equitable allocation of scarce donor organs remains a formidable challenge.Prognostic tools are pivotal in identifying the most suitable transplant candidates.Traditionally,scoring systems like the model for end-stage liver disease have been instrumental in this process.Nevertheless,the landscape of prognostication is undergoing a transformation with the integration of machine learning(ML)and artificial intelligence models.AIM To assess the utility of ML models in prognostication for LT,comparing their performance and reliability to established traditional scoring systems.METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines,we conducted a thorough and standardized literature search using the PubMed/MEDLINE database.Our search imposed no restrictions on publication year,age,or gender.Exclusion criteria encompassed non-English studies,review articles,case reports,conference papers,studies with missing data,or those exhibiting evident methodological flaws.RESULTS Our search yielded a total of 64 articles,with 23 meeting the inclusion criteria.Among the selected studies,60.8%originated from the United States and China combined.Only one pediatric study met the criteria.Notably,91%of the studies were published within the past five years.ML models consistently demonstrated satisfactory to excellent area under the receiver operating characteristic curve values(ranging from 0.6 to 1)across all studies,surpassing the performance of traditional scoring systems.Random forest exhibited superior predictive capabilities for 90-d mortality following LT,sepsis,and acute kidney injury(AKI).In contrast,gradient boosting excelled in predicting the risk of graft-versus-host disease,pneumonia,and AKI.CONCLUSION This study underscores the potential of ML models in guiding decisions related to allograft allocation and LT,marking a significant evolution in the field of prognostication.
文摘BACKGROUND Prolonged donor hepatectomy time may be implicated in early and late complications of liver transplantation.AIM To evaluate the impact of donor hepatectomy time on outcomes of liver transplant recipients,mainly early allograft dysfunction.METHODS This multicenter retrospective study included brain-dead donors and adult liver graft recipients.Donor-recipient matching was obtained through a crossover list.Clinical and laboratory data were recorded for both donors and recipients.Donor hepatectomy,cold ischemia,and warm ischemia times were recorded.Primary outcome was early allograft dysfunction.Secondary outcomes included need for retransplantation,length of intensive care unit and hospital stay,and patient and graft survival at 12 months.RESULTS From January 2019 to December 2021,a total of 243 patients underwent a liver transplant from a brain-dead donor.Of these,57(25%)developed early allograft dysfunction.The median donor hepatectomy time was 29(23–40)min.Patients with early allograft dysfunction had a median hepatectomy time of 25(22–38)min,whereas those without it had a median time of 30(24–40)min(P=0.126).CONCLUSION Donor hepatectomy time was not associated with early allograft dysfunction,graft survival,or patient survival following liver transplantation.
