Subject(s)
Cell-Free Nucleic Acids , Graft Rejection , Organ Transplantation , Humans , Graft Rejection/diagnosis , Graft Rejection/immunology , Graft Rejection/blood , Cell-Free Nucleic Acids/blood , Organ Transplantation/adverse effects , Tissue Donors , Heart Transplantation/adverse effects , Biomarkers/bloodABSTRACT
Since the first liver transplant was performed over six decades ago, the landscape of liver transplantation in the US has seen dramatic evolution. Numerous advancements in perioperative and operative techniques have resulted in major improvements in graft and patient survival rates. Despite the increase in transplants performed over the years, the waitlist mortality rate continues to remain high. The obesity epidemic and the resultant metabolic sequelae continue to result in more marginal donors and challenging recipients. In this review, we aim to highlight the changing characteristics of liver transplant recipients and liver allograft donors. We focus on issues relevant in successfully transplanting a high model for end stage liver disease recipient. We provide insights into the current use of terms and definitions utilized to discuss marginal allografts, discuss the need to look into more consistent ways to describe these organs and propose two new concepts we coin as "Liver Allograft Variables" (LAV) and "Liver Allograft Composite Score" (LACS) for this. We discuss the development of spectrum of risk indexes as a dynamic tool to characterize an allograft in real time. We believe that this concept has the potential to optimize the way we allocate, utilize and transplant livers across the US.
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BACKGROUND: Mandibular reconstruction has historically been challenging due to the complex, highly functional, and esthetic nature of the anatomy. The most common etiologies of these defects requiring resection include trauma, benign tumors, and malignant pathology. Mandibular defects have been treated with little consideration for neural reconstruction, leaving patient's orally incompetent with associated social stigma. Although recent advances in reconstructive techniques improve oral rehabilitation, immediate inferior alveolar nerve (IAN) reconstruction has not been widely adapted. OBJECTIVE: Here-in we seek to discuss the innovations of neural reconstruction of large segment mandibular defects and associated IAN defects and present an example case performed at Naval Medical Center San Diego (NMCSD). METHODS: Pertinent literature discussing maxillofacial reconstruction and nerve repair using autogenous nerve harvest and allograft was queried from available online resources. RESULTS: Six patients have received immediate reconstruction of the IAN using processed nerve allograft over the past three years. All obtained sensation to S3 within six months of surgery. CONCLUSION: IAN repair using nerve allografts in conjunction with free flap reconstruction for large mandibular defects is a viable treatment and should be the new paradigm in maxillofacial reconstruction as it provides substantial quantifiable and qualitative improvements in social, functional, and esthetic outcomes of care.
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Background: Variation in stiffness, fixation methods, and donor-site morbidity after anterior cruciate ligament reconstruction (ACLR) with different graft types and with anterior cruciate ligament suture repair (ACLSR) can lead to differences in dynamic knee laxity and consequent differences in posttraumatic osteoarthritis (PTOA) development. Purpose: To compare the incidence of PTOA between different graft types used for primary ACLR and between primary ACLR and ACLSR. It was hypothesized that the incidence of PTOA would vary between ACLR with different autografts and allografts and between ACLR and ACLSR. Study Design: Systematic review; Level of evidence, 1. Methods: A search of the literature was performed to identify all randomized controlled trials (RCTs) comparing radiographic evidence of PTOA after ACLR between different graft types-hamstring tendon (HT) autograft, bone-patellar tendon-bone (BPTB) autograft, quadriceps tendon autograft, and allograft-and between ACLR and ACLSR. The minimum follow-up was 2 years. Study quality was assessed using the modified Coleman Methodology Score. A meta-analysis was performed to determine whether there was a difference in the incidence of PTOA between the different graft types and between ACLR and ACLSR. Results: Eleven randomized controlled trials were included in the meta-analysis-HT: 440 patients (mean follow-up, 9.7 years); BPTB: 307 patients (mean follow-up, 11.8 years); allograft: 246 patients (mean follow-up, 5 years); ACLSR, 22 patients (5 years). No study reporting the incidence after ACLR with quadriceps tendon was included. The study quality ranged from 70 to 88. The meta-analysis indicated no significant difference in the incidence of PTOA between graft types used for ACLR and between ACLR and ACLSR (risk ratios: HT vs BPTB, 1.05; HT vs allograft, 0.81; BPTB vs allograft, 0.82; HT vs ACLSR, not estimable [P > .05 for all]). The combined number of patients with PTOA in all studies per graft type showed that patients who underwent ACLR with a BPTB autograft had the highest percentage of PTOA (HT, 23.4%; BPTB, 29.6%; allograft, 8.1%; ACLSR, 0%). However, excluding studies with a follow-up <5 years resulted in similar outcomes for patients with an HT autograft and a BPTB autograft. Conclusion: This meta-analysis reported no difference in the incidence of PTOA between graft types used for ACLR and between ACLR and ACLSR. More research is necessary to make a reliable conclusion about which technique is associated with the lowest incidence of PTOA after ACL surgery.
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Background: Selecting an appropriate graft for anterior cruciate ligament (ACL) reconstruction requires consideration of a patient's preferences, goals, age, and physical demands alongside the risks and benefits of each graft choice. Purpose: To determine the most popular ACL reconstruction grafts among patients and the most important factors influencing their decisions. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patients undergoing ACL reconstruction between October 2022 and April 2023 completed a survey either before (nonconsult group) or after (consult group) speaking with their surgeon, who provided an evidence-based description of the pros and cons of an allograft and the following autografts: bone-patellar tendon-bone (BPTB), hamstring tendon (HT), and quadriceps tendon (QT). Patient characteristics, graft choice, information influencing their graft choice, and surgeon recommendation were collected and compared between the groups. Results: Among the 100 included patients, 59.0% were male, and the mean age was 28.3 ± 10.4 years. The most popular grafts were the BPTB (56.0%), followed by the QT (29.0%), HT (8.0%), and allograft (7.0%). No significant difference was observed in the graft selection between the consult group (n = 60; BPTB, 46.7%; QT, 38.3%; HT, 8.3%; allograft, 6.7%) and nonconsult group (n = 40; BPTB, 70.0%; QT, 15.0%; HT, 7.5%; allograft, 7.5%) (P = .0757). In the consult group, 81.7% of patients selected the graft recommended to them by their surgeon. The top 2 graft selection reasons were usage in professional athletes and failure rates, while the top 2 ACL surgery concerns were returning to their desired level of athletics and graft failure risk. Among the 93 patients who researched their ACL graft options before their visit, the most popular information source was some form of media (72.0% [67/93]). Conclusion: The study findings underscore the importance of patient preference and surgeon recommendation in a patient's graft selection and highlight the need to be cognizant of the information sources available to patients when researching their graft options.
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Fractures of the proximal humerus account for 4%-8% of injuries to the appendicular skeleton. Most are stable, minimally displaced osteoporotic fractures in the elderly, and are the result of low-energy falls. A large majority of these patients regain adequate shoulder function without operative intervention. Surgery is considered in approximately 20% of patients because they require improved shoulder function for their activities of daily living or because of the significant deformity of their fracture and the need to restore functional alignment, length, and rotation in active, higher demand individuals. However, fixation of these fractures can pose a challenge due to poor bone quality and displacing forces of the rotator cuff. This is especially true in 3-part and 4-part fractures. These factors lead to the high failure rates seen with early attempts at osteosynthesis. In the last 2 decades, locking plate technology has been an innovation in treating these complex fractures. Despite the improvements in torsional strength and rigidity, outcome studies on locking plate technology demonstrate equivocal results with complication rates as high as 20%-30% and a revision rate of 10%. Specifically, these complications include avascular necrosis, varus collapse, intra-articular screw penetration, and postoperative stiffness. Varus collapse occurs when the weak osteoporotic bone fails around the implant. In turn, fibular strut endosteal augmentation was introduced to provide additional support and decrease implant failure rates in displaced fractures with varus coronal malalignment and significant metaphyseal bone loss. Although clinically successful and biomechanically superior to plate-only constructs, a few concerns remain. In turn, we introduce a novel technique of creating individual cancellous femoral head allograft struts or "French fries" that provides structural support for the humeral head but does not have the potential problems of a cortical fibular strut.
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Background: Determine the effect of a novel acellular cannulated dermal allograft on tendon-to-bone healing, retear rates, and clinical outcomes over a 12-month period. Methods: This was a single surgeon prospective nonrandomized case series. Patients with medium sized full-thickness superior and posterosuperior rotator cuff tears, as confirmed by magnetic resonance imaging, were consented. Patients were excluded if they had fatty atrophy indicative of Goutallier grade III or IV. The allograft is a cannulated rectangular prism that has a 5-year shelf life, does not require prehydration, and does not need to be trimmed to size. Outcome metrics included ultrasound assessment at 1-year as well as 6-month patient-reported outcomes (PROs) scores. Results: 31 patients consented and enrolled in this consecutive cohort series. 9 patients were excluded, and statistical analysis was performed on the remaining 22 patients. There were 9 females and 13 males. The average age was 59.27 ± 7.48 year old. The average supraspinatus short axis measurement in males was 0.56 ± 0.12 cm and 0.52 ± 0.09 cm in females (P = .44). The average supraspinatus long axis measurement in males was 0.61 ± 0.18 cm and 0.55 ± 0.14 cm in females (P = .46). The average infraspinatus short axis measurement in males was 0.48 ± 0.10 cm and 0.50 ± 0.13 in females (P = .74). The average infraspinatus long axis measurement in males was 0.44 ± 0.12 cm and 0.43 ± 0.08 cm in females (P = .84). Of the 19 patients who completed baseline and 6-month PRO's, 17 achieved the minimal clinical important difference for American Shoulder and Elbow Surgeons and Patient-Reported Outcomes Measurement Information SystemUE 7a. Retear occurred in 2 cases. The remaining 20 cases have all demonstrated healing or fully healed repairs at their most recent clinical visits with no additional cases of retears. Conclusion: This study is the first to report the results of a novel acellular dermal allograft for rotator cuff repair augmentation. Satisfactory PRO measures and robust tendon healing at 1 year, as measured by ultrasound, demonstrate the utility of a cannulated human acellular dermal allograft as a viable biologic augmentation device for rotator cuff repair.
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Background: Tendon transfers in conjunction with reverse total shoulder arthroplasty can significantly improve functional outcomes in patients with glenohumeral arthritis and irreparable rotator cuff deficiency. There have been multiple promising new techniques described within the last 20 years that shoulder surgeons should become familiar with. Methods: The authors reviewed the literature on tendon transfers in the setting of reverse total shoulder arthroplasty. Procedures to restore various shoulder functions were described including surgical anatomy, techniques, pearls and pitfalls, and photos. Results: Subscapularis insufficiency can be reconstructed with a pectoralis major transfer or latissimus dorsi transfer, with the latter having better clinical outcomes and a more anatomic line of pull. Posterosuperior rotator cuff deficiency can be reconstructed with a latissimus transfer (L'Episcopo transfer) or lower trapezius transfer, with the latter proving superior in biomechanical and short-term studies. Deltoid deficiency can be reconstructed with a pedicled upper pectoralis major transfer. Massive proximal humerus bone loss can be reconstructed with an allograft-prosthetic composite, and any of the aforementioned transfers can be utilized in this setting as well. Conclusion: Tendon transfers in conjunction with reverse shoulder arthroplasty can significantly improve functional outcomes in patients with glenohumeral arthritis and irreparable rotator cuff deficiency. There have been multiple promising new techniques described within the last 20 years that shoulder surgeons should become familiar with.
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OBJECTIVES: Previous studies elucidated that capecitabine (CAP) works as an anti-tumor agent with putative immunosuppressive effects. However, the intricate mechanisms underpinning these effects remain to be elucidated. In this study, we aimed to unravel the molecular pathways by which CAP exerts its immunosuppressive effects to reduce allograft rejection. METHODS: Hearts were transplanted from male BALB/c donors to male C57BL/6 recipients and treated with CAP for seven days. The rejection of these heart transplants was assessed using a range of techniques, including H&E staining, immunohistochemistry, RNA sequencing, LS-MS/MS, and flow cytometry. In vitro, naïve CD4+ T cells were isolated and cultured under Th1 condition medium with varying treatments, flow cytometry, LS-MS/MS were employed to delineate the role of thymidine synthase (TYMS) during Th1 differentiation. RESULTS: CAP treatment significantly mitigated acute allograft rejection and enhanced graft survival by reducing graft damage, T cell infiltration, and levels of circulating pro-inflammatory cytokines. Additionally, it curtailed CD4+ T cell proliferation and the presence of Th1 cells in the spleen. RNA-seq showed that TYMS, the target of CAP, was robustly increased post-transplantation in splenocytes. In vitro, TYMS and its metabolic product dTMP were differentially expressed in Th0 and Th1, and were required after activation of CD4+ T cell and Th1 differentiation. TYMS-specific inhibitor, raltitrexed, and the metabolite of capecitabine, 5-fluorouracil, could inhibit the proliferation and differentiation of Th1. Finally, the combined use of CAP and the commonly used immunosuppressant rapamycin can induce long-term survival of allograft. CONCLUSION: CAP undergoes metabolism conversion to interfere pyrimidine metabolism, which targets TYMS-mediated differentiation of Th1, thereby playing a significant role in mitigating acute cardiac allograft rejection in murine models.
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Early allograft dysfunction (EAD) is a frequent phenomenon, leading to increased graft loss and higher mortality after liver transplantation (LT). Despite significant efforts for early diagnosis of EAD, there is no existing approach that can predict EAD on the first post-operative day. The aim is to define a metabolite-based biomarker on the first day after LT complicated with EAD. Ten patients diagnosed with EAD and 26 non-EAD are recruited for the study. A HPLC-MS/MS is used to determine 14 amino acids and 15 bile acids serum concentration. Comparative analyses are conducted between EAD and non-EAD groups. Arginine is identified as the most significant metabolite distinguishing the EAD and non-EAD groups, and therefore, is identified as a potential biomarker of EAD. The optimal cut-off value for arginine is 52.09 µmol L-1, with an AUROC of 0.804 (95% confidence interval: 0.638-0.917, p < 0.001), yielding a sensitivity of 100%, specificity of 53.8%, and Youden index of 0.54, NPVof 100%, and PPV of 45.45%. In summary, the study indicated that targeted metabolomics analysis would be a promising strategy for discovering novel biomarkers to predict EAD. The identified arginine may be helpful in developing an objective diagnostic method for EAD.
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Background: Little is known regarding the opinions of the general population on anterior cruciate ligament (ACL) graft options. Purpose: To evaluate the general population's perception of the use of allografts versus autografts in ACL reconstruction using a previously validated online marketplace platform. Methods: A prospective 34-question survey was distributed via the online marketplace. After collecting baseline demographics, participant preferences for ACL reconstruction with an allograft or autograft were established. All respondents completed a preeducation survey, reviewed an evidence-based education sheet, and completed a posteducation survey to assess their understanding. Upon completion, participants were asked which graft they would prefer. Participants were then asked if they would be willing to change their preference based on surgeon recommendation. Finally, participants were asked to rank the factors from the education sheet that were most influential. Study Design: Cross-sectional study. Results: There were 491 participants that completed the survey (mean age, 39.9 years [range, 19-72 years]; 244 male, 241 female, and 6 nonbinary/third-gender participants). Before reading the education sheet, 276 (56%) reported no graft preferences, 146 (30%) preferred autograft, and 69 (14%) preferred allograft. After reading the provided sheet, 226 (46%) participants preferred autograft, 185 (38%) preferred allograft, and 80 (16%) had no preference. The mean score on the preeducation test was 45%, and the mean score on the posteducation test was significantly greater (61%; P < .01). Overall, 345 participants (83.9%) stated they would change their preference for autograft or allograft if their surgeon recommended it. Surgeon preference (n = 330; 67%), educational information provided (n = 117; 24%), and previous knowledge (n = 44; 9%) were the most important factors for making graft selections. The mean ages of the participants selecting each graft type before and after education were as follows: allograft (37.8 ± 10.1 vs 40.6 ± 11.8 years; P = .05), autograft (38 ± 11.5 vs 39.5 ± 10.1 years; P = .21), and no preference (41.5 ± 11.2 vs 39.4 ± 11.8 years; P = .16). Conclusion: Education resulted in a greater number of individuals' reporting a preference in graft type (either allograft or autograft) compared with preinformation questioning. In addition, 83.9% of the participants were willing to switch their graft choice if recommended by their surgeon.
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Renal transplantation is a life-saving treatment for patients with end-stage renal disease. However, the challenge of transplant rejection and the complications associated with immunosuppressants necessitates a deeper understanding of the underlying immune mechanisms. T cell exhaustion, a state characterized by impaired effector functions and sustained expression of inhibitory receptors, plays a dual role in renal transplantation. While moderate T cell exhaustion can aid in graft acceptance by regulating alloreactive T cell responses, excessive exhaustion may impair the recipient's ability to control viral infections and tumors, posing significant health risks. Moreover, drugs targeting T cell exhaustion to promote graft tolerance and using immune checkpoint inhibitors for cancer treatment in transplant recipients are areas deserving of further attention and research. This review aims to provide a comprehensive understanding of the changes in T cell exhaustion levels after renal transplantation and their implications for graft survival and patient outcomes. We discuss the molecular mechanisms underlying T cell exhaustion, the role of specific exhaustion markers, the potential impact of immunosuppressive therapies, and the pharmaceutical intervention on T cell exhaustion levels. Additionally, we demonstrate the potential to modulate T cell exhaustion favorably, enhancing graft survival. Future research should focus on the distinctions of T cell exhaustion across different immune states and subsets, as well as the interactions between exhausted T cells and other immune cells. Understanding these dynamics is crucial for optimizing transplant outcomes and ensuring long-term graft survival while maintaining immune competence.
Subject(s)
Graft Rejection , Kidney Transplantation , T-Lymphocytes , Kidney Transplantation/adverse effects , Humans , T-Lymphocytes/immunology , Graft Rejection/immunology , Graft Rejection/prevention & control , Graft Survival/immunology , Graft Survival/drug effects , Animals , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/adverse effects , Kidney Failure, Chronic/surgery , Kidney Failure, Chronic/immunology , Transplantation Tolerance/immunologyABSTRACT
Background: Renal transplant recipients confront a substantially elevated susceptibility to renal cell carcinoma (RCC), particularly in their native kidneys as opposed to allografts. Methods: In this systematic scoping review, exhaustive searches were conducted of the MEDLINE and EMBASE databases. Information was gathered on clinical manifestations, donor demographics, diagnostic intervals, tumor dimensions, histopathological characteristics, and therapeutic outcomes associated with RCC arising in allograft kidneys. Results: The searches yielded a corpus of 42 case reports and 11 retrospective cohorts, encompassing a cohort of 274 patients. The majority of cases (75.4%) were clinically latent, discerned primarily through imaging modalities. Symptomatic presentations encompassed manifestations such as hematuria, elevated serum creatinine levels, abdominal discomfort, and graft-related pain. The mean temporal interval between renal transplantation and RCC diagnosis was calculated at 11.6 years, albeit displaying considerable variance. Notably, papillary and clear cell RCC emerged as the prevailing histopathological subtypes. However, the paucity of longitudinal follow-up data represents a notable caveat. Conclusion: This investigation underscores the imperative of rigorous posttransplant surveillance regimes owing to the substantial prevalence of asymptomatic RCC instances. Future research should focus on clinical outcomes and cost-effectiveness of screening practices to develop preventive strategies.
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Post-transplantation immune rejection remains an important factor for transplant patients. However, conventional immunosuppressants are associated with substantial adverse effects. Natural immunosuppressants present a promising alternative to conventional counterparts, boasting exceptional biological activity, minimal toxicity and reduced side effects. We identified carvacrol as a prospective immunosuppressive agent following T cell proliferation experiment and validated carvacrol's immunosuppressive efficacy in the murine allogeneic skin graft model. T cell proliferation assay was used to screen natural small molecule compounds and the immunosuppressive effect of compounds was evaluated in MHC-mismatched murine allogeneic skin graft model. H&E and immunohistochemical staining were applied to evaluate the pathological grade. Furthermore, flow cytometry was uitlized to analyse the immunophenotype changes of immune cells. Western blotting and q-PCR were used to detect the expression of key molecules in macrophages. In vitro, carvacrol demonstrates significant inhibition of the proliferation of CD4+ T and CD8+ T cells. It notably reduces inflammatory factor expression within the allografts, suppresses T cell differentiation toward Th1 phenotype and expansion. Furthermore, carvacrol prominently hinders M1-type macrophages polarization by activating Wnt signaling. Notably, the anti-rejection efficacy of carvacrol was significantly weakened upon the removal of macrophages in mice using chlorophosphate liposomes. Carvacrol could significantly inhibit T cell proliferation, alleviate graft rejection and has outstanding toxicological safety. The molecular mechanism of the anti-rejection effect of carvacrol is closely related to its mediating activation of macrophage Wnt pathway, inhibiting M1 polarization and inducing T cell differentiation.
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BACKGROUND: Bone defects around the teeth affect a large portion of the population. Bone regeneration in the area of existing teeth is completely different from that in an edentulous area. To date, no method has been developed for three-dimensional (3D) bone reconstruction in regions with preserved teeth. OBJECTIVES: This study aimed to radiologically evaluate the results of the new method of 3D mandibular bone reconstruction in preserved dentition using a custom-made allogeneic bone block with a 6-month follow-up. MATERIAL AND METHODS: Alveolar ridge dimensions were radiographically assessed before and 6 months after reconstruction using cone beam computed tomography (CBCT) scans in 32 patients (192 teeth). Reconstruction used a bone block that had been previously planned and prepared using CAD/CAM technology. RESULTS: The observed changes in alveolar bone dimensions were highly significant in most cases (p < 0.001). The closer to the tooth root apex, the lower the bone growth in the sagittal dimension (average of the mean values for each tooth examined in the measured heights): CEJ2: 2.9 mm, ½ CEJ2: 2.7 mm, » CEJ2: 1.9 mm, and API: 1.4 mm. The maximum bone growth in the vertical dimension was observed on tooth 43 (9.9 mm), followed by 32 (9.8 mm), 33 (8.5 mm), 31 (8.4 mm), 42 (8 mm), and 41 (7 mm). The degree of decrease in vestibular dehiscence of the bone was greater the closer the tooth was to the midline (average of -3.8 mm and -3.4 mm for the central incisors; average of -2.8 mm and -2.6 mm for the lateral incisors; average of -2.6 mm and -2.5 mm for the canines). CONCLUSIONS: The results prove that it is possible to prevent bone dehiscence in patients undergoing orthodontic treatment, increasing the ability and effectiveness of covering recessions and improving the morphology of the lower part of the face.
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BACKGROUND: Long-term clinical outcomes of early intravascular ultrasound (IVUS) findings in a prospective cohort of heart transplantation (HTx) patients have not been evaluated. METHODS: This study included patients from 20 centers across Europe and North and South America among the original cohort of the RAD B253 study. Among these patients, 91 had paired IVUS images at baseline and 1-year post-transplant: everolimus 1.5 mg group (n = 25), everolimus 1.5 mg group (n = 33), and azathioprine 3.0 group (n = 33). The primary outcome was a composite of cardiovascular death, retransplantation, myocardial infarction (MI), coronary revascularization, and cardiac allograft vasculopathy (CAV) within a 10-year follow-up period. The secondary outcome was all-cause death, cardiovascular death, retransplantation, MI, coronary revascularization, and CAV. Donor disease was defined as baseline maximal intimal thickness (MIT) >0.66 mm, and rapid progression was defined as a change in MIT > 0.59 mm at 1 year. RESULTS: Donor disease (46 patients) was associated with a higher incidence of the primary outcome (hazard ratio (HR) 4.444, 95% confidence interval [CI] 1.946-10.146, p < 0.001). Rapid progression (44 patients) was associated with a significantly higher incidence of the primary outcome (HR 2.942, 95% CI 1.383-6.260, p = 0.005). Higher-risk features on IVUS (positive both donor disease and rapid progression) were independently associated with poor clinical outcomes (HR 4.800, 95% CI 1.816-12.684, p = 0.002). CONCLUSIONS: An increase in baseline MIT and a change in first-year MIT in IVUS post HTx was associated with poor outcomes up to 10 years. Early IVUS findings can be considered as surrogate endpoints for evaluating long-term outcomes in HTx clinical trials.