Date Of Transplantation Research Articles

Abstract 4140138: Coronary Artery Vasculopathy in a Cohort of 321 Heart Transplant Recipients: A Single Center Experience

Introduction: Despite advances in surgical techniques, organ preservation methods and immunosuppressant medications, the ten-year survival for orthotropic heart transplantation (OHT) remains around 50%. Coronary artery vasculopathy (CAV), among other factors, seems to have an important role in accelerated organ injury and failure. Aim: To determine the rate of survival and CAV development along with associated factors in a cohort of OHT recipients. Methods: Patients who underwent OHT at Virginia Commonwealth University (VCU) between October 2008 and September 2021 were retrospectively reviewed until June 2024. According to the VCU protocol, right heart biopsies were done weekly for the first month, every other week for the second month and at the first year mark post transplant. Left heart catheterizations were done one year after OHT and then at 2 year intervals. Survival, CAV development and need for percutaneous coronary interventions (PCI) as well as organ rejection rates in CAV patients were surveyed. Results: A total of 321 patients received OHT during that period with a median follow up time of 8.15 years from the date of transplant. Of these, 122 patients had 10-year follow up or more post OHT (53.27% survived) and 240 patients had 5-year follow up or more (66.25% survived). All patients had greater than 2.75 years of follow up. The overall mortality was 29.5%. CAV occurred in 55 patients out of 321 (17%) with median time of 2.82 years for CAV development. Mortality in the CAV group was 40% compared to 27% in the non-CAV group. Out of 55 patients with CAV, 19 required at least 1 PCI with 3 requiring interventions on chronic total occlusions. Evidence of rejection on right ventricle biopsy was observed in 51% of patients with CAV Conclusion: Our cohort had above average 10-year survival rate compared to the national data. Results revealed CAV is common post OHT and has implications on long term survival. Given CAV may develop in the absence of organ rejection, further studies are needed to identify factors associated with CAV and explore optimal treatment options that would potentially improve long-term survival post OHT.

7244 Kidney Donors With Metabolic Syndrome Have Increased Risk For Chronic Kidney Disease

Abstract Disclosure: C.D. Martínez-Franco: None. F.J. Gomez-Perez: None. M. Vilatobá: None. R. Flores-Cárdenas: None. D. Cuevas-Ramos: None. Kidney Donors with Metabolic Syndrome Have Increased Risk for Chronic Kidney Disease Introduction: Metabolic syndrome (MetS) has a prevalence of 56% in Mexico, been a common cause of progressive deterioration of renal function. Renal donors usually have good health at the time of donation, but some cases already present MetS or develop it over time. Objective: to evaluate the risk of MetS on chronic kidney disease (CKD) in kidney donors. Methods: we performed a comparative, longitudinal, observational and prolective study at a tertiary care hospital from 1980 to 2023. MetS was defined with ATPIII criteria. Renal function was assessed with the CKD-EPI formula to obtain the eGFR prior to the date of transplantation and at last follow-up. Student's t test, chi-square test, Kaplan-Meier, and multivariate Cox regression analyses were performed to assess the independent risk of MetS on renal function. Results: A cohort of 406 patients was collected, 283 cases (58% women), where 96 (34%) showed MetS criteria, and 187 (66%) without them used as control. There was no significant baseline difference on CrCl before donation between control group (97±19 ml/min) vs. MetS group (95±17 ml/min, p=0.45). The median follow-up was 25 (20.2-29.7) years. To assess the outcome of CrCl <60 mL/min, 4 groups were analyzed according to their MetS status at baseline - last follow-up. The fastest decreased on CrCl was seen at group 3 (No MetS - With MetS) after 17 (95%CI 14-19) years of follow-up, then group 4 (MetS - MetS) after 19 (3-34) years, followed by group 2 (With MetS - No MetS) with 23 (10-35) years, and finally group 1 (No MetS - No MetS), after 27 (23.7-30.5) years (p<0.0001). Group 1 was taken as reference to calculate CKD risk between groups. MetS showed a statistically significant risk as an independent determinant for CKD at follow-up with a HR=1.6 (0.7-3.3, p=0.21), HR=2.9 (1.2-7.0, p=0.01) and HR=2.2 (1.1-4.4, p=0.02) for group 2, 3 and 4, respectively. Conclusions: Having or developing MetS on kidney donors caused significantly higher risk of presenting CKD at last follow-up. Clinicians should be aware of such risk to implement strategies for prevention and treatment of MetS, with close and chronic surveillance of such patients. Presentation: 6/1/2024

Decreasing chronic graft-versus-host disease rates in all populations

AbstractSince 2005, there has been a steady decline in chronic graft-versus-host disease (cGVHD) at the Fred Hutchinson Cancer Center. To better understand this phenomenon, we studied the risk of cGVHD requiring systemic immunosuppression (cGVHD-IS) as a function of hematopoietic cell transplantation (HCT) date in 3066 survivors from 2005 through 2019. Cox regression models were fit to assess associations of HCT date (as a continuous linear variable) with cause-specific hazards of cGVHD using unadjusted and adjusted models. Median follow-up for study subjects was 7.0 years (range, 1.0-17.2). Two-year probabilities of cGVHD-IS declined among all survivors from 45% to 52% (2005-2007) to ∼40% (2008-2012) and then further to ∼26% by 2017. A decline was also observed when the analysis was restricted to 502 pediatric survivors, with cGVHD-IS probabilities <10% since 2013. Among 305 adult and pediatric survivors who underwent transplantation for nonmalignant diseases, cGVHD rates showed greater fluctuation but remained <20% after 2016. Each 5-year increase in HCT date was associated with a 27% decrease in the cause-specific hazard of cGVHD (unadjusted hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.68-0.78; P < .0001); the HR was 0.81 (95% CI, 0.75-0.87; P < .0001) even after adjusting for various factors (age, donor/stem-cell source, race, sex, conditioning intensity, GVHD prophylaxis, among others) that could lead to cGVHD reduction. The decline in cGVHD was not fully explained by demographic shifts and greater use of HCT approaches that are generally associated with lower cGVHD rates. This observation underscores that single-cohort cGVHD prevention studies should use contemporaneous and not historical controls for comparison.

Effect of Weather Parameters on Disease Severity and Progression of Fusarium Wilt in Chilli (Capsicum anuum L.)

Fusarium wilt incited by Fusarium oxysporum is an economically damaging disease of chilli (Capsicum anuum L.). Field experiments on epidemiological studies were conducted using susceptible variety (Pusa Jwala) to study the effect of weather parameters on the progression of the disease. The study revealed that transplanting chilli during the first half of July reduced the disease severity compared to earliest transplant dates. The area under disease progress curve (AUDPC) and the apparent infection rate were lowest in the crop transplanted on 15th July, 2022 while they were highest in the crop transplanted on 15th June, 2022. The correlation analysis showed a positive correlation between disease severity and bright sunshine hours, and a negative correlation with the other weather parameters. The R2 value obtained from multiple regression equations revealed that the combined effect of weather parameters could explain the prediction of a disease level of 83-86 per cent at all three transplant dates.

Clinical outcomes in elderly patients receiving agalsidase alfa treatment in the Fabry Outcome Survey

Background and objectivesTreatment with agalsidase alfa in patients with Fabry disease is most effective when initiated early in the disease course; however, the clinical benefits in elderly patients are less well established. This analysis assesses outcomes in patients aged 65 years or older from the Fabry Outcome Survey (FOS) who were treated with agalsidase alfa. MethodsFOS data were extracted for adult patients aged 65 years or older who received agalsidase alfa, had baseline data and at least 3 years of post-baseline data, and had undergone no renal transplantation and/or dialysis before treatment. The data of patients who had undergone renal transplantation and/or dialysis during follow-up were excluded from estimated glomerular filtration rate (eGFR) analysis after the date of the renal transplantation and/or dialysis. Adult patients were stratified into two groups: those who started treatment before 65 years of age and who were still being treated when aged 65 years or older (group A), and those who started treatment when aged 65 years or older (group B). Mean annual changes in left ventricular mass index (LVMI), eGFR and proteinuria were assessed in group A (before and after the age of 65 years to understand if there was an age-related effect once patients turned 65 years of age) and in group B. ResultsEstimated mean (standard error [SE]) annual changes in LVMI were 0.46 (0.26) g/m2.7 and 0.21 (0.42) g/m2.7 in patients in group A when they were younger than 65 years and when they were aged 65 years or older, respectively, and 0.12 (0.65) g/m2.7 in patients in group B. For eGFR, mean (SE) annual changes were 0.83 (2.12) mL/min/1.73 m2 and 2.64 (2.18) mL/min/1.73 m2 in patients in group A when they were younger than 65 years and when they were aged 65 years or older, respectively, and 2.31 (1.44) mL/min/1.73 m2 in patients in group B. Proteinuria remained relatively stable in both subgroups of group A (before and after the age of 65 years) and group B. ConclusionsContinuation and initiation of agalsidase alfa treatment in patients aged 65 years or older with Fabry disease were associated with stabilization of proteinuria and minimal increases in cardiac (LVMI) and renal (eGFR) outcomes.

Pulmonary Nocardiosis in Renal Transplant Recipients From Pakistan: Risk Factors, Clinical Presentation, and Mortality.

Nocardia is an opportunistic infection among renal transplant recipients with an incidence of <1% but high mortality. Data from Pakistan are scarce. Our aim was to find the risk factors, clinical and radiographic findings, antimicrobial sensitivity, and outcomes of Nocardia infection among renal transplant recipients in Pakistan. All adult renal transplant recipients diagnosed with nocardiosis between 2013 and 2020 were included. The cases were matched 1:2 with controls based on sex, age (±1 year), and transplant date (±1 year). Risk factors, clinical features, antibiotic sensitivities and outcomes were analyzed. A total of 48 patients developed nocardiosis. Around 25% of patients presented with disseminated disease. Median time from transplant to disease development was 2.68 years. High-dose methylprednisolone and presence of cytomegalovirus infection within 90 days of disease development were independent risk factors for Nocardia infection. The mortality rate was 20%. Central nervous system disease and cytomegalovirus infection within 90 days were significantly associated with mortality. The most susceptible drugs were co-trimoxazole and linezolid. Imipenem susceptibility was only 20%. High-dose methylprednisolone and cytomegalovirus infection were independent risk factors for Nocardia infection. Central nervous system disease was associated with mortality. Nocardia species were highly resistant to ceftriaxone and imipenem in our patient population.

Real world outcomes of high dose melphalan conditioning prior to autologous stem cell transplant in extramedullary multiple myeloma vs. multiple myeloma without extramedullary involvement: A single center experience.

7550 Background: Extramedullary multiple myeloma (EMM) is defined as the presence of multiple myeloma plasma cells, which develop outside of the bone marrow. It is an aggressive form of multiple myeloma that is associated with a poor prognosis. The current standard of care for multiple myeloma consists of induction, high dose melphalan autologous stem cell transplant (ASCT), followed by maintenance. However, there is limited data on the outcome of patients with extramedullary multiple myeloma who undergo ASCT. Therefore, we examined the outcomes of high dose melphalan conditioning prior to ASCT in EMM patients compared to multiple myeloma patients without extramedullary involvement (non-EMM) at an academic institution in Los Angeles. Methods: We retrospectively reviewed 246 multiple myeloma patients who underwent ASCT after receiving high dose melphalan conditioning at USC Norris Comprehensive Cancer Center from Jan 2017 to Dec 2022. The cohort was subdivided into 70 EMM patients and 176 non-EMM patients. Outcomes were measured as the status of disease response, which was evaluated at 100 days (D+100) and 365 days (D+365) after the date of transplant. Results: In the EMM group, 1.43% (n=1) was found to have progression at D+100 and 12.86% (n=9) at D+365. In the non-EMM group, 0.57% (n=1) was found to have progression at D+100 and 11.93% (n=21) at D+365. There was no statistical significance between the EMM and non-EMM groups for progression free survival at D+100 (p-0.50) and D+365 (p-0.75). Regarding overall survival, there were 0 deaths observed at D+100 in both the EMM and non-EMM groups. For D+365, the overall survival was 98.57% (n=69) for the EMM group and 99.43% (n=175) for the non-EMM group. There was no statistical significance between the overall survival at D+365 (p-0.14). Conclusions: The EMM cohort exhibited similar rates of progression free survival (87.14% vs. 88.07%) and overall survival (98.57% vs. 99.43%) compared to the non-EMM cohort at one year post ASCT after receiving high dose melphalan conditioning. We observed that there was no significant statistical difference between the EMM and non-EMM cohorts regarding progression-free survival (p-0.75) and overall survival (p-0.14) on day 365. According to our data, high dose melphalan conditioning prior to autologous stem cell transplant is equally as effective for patients with multiple myeloma with or without extramedullary involvement. Future studies with long-term follow-up are recommended to further explore these findings. [Table: see text]

Good long-term outcomes of primary sclerosing cholangitis in childhood

Background & AimsPrimary sclerosing cholangitis (PSC) is a rare progressive liver disease associated with inflammatory bowel disease (IBD), usually diagnosed in adults but can also present in children. Data on long-term outcome in pediatric PSC is limited. Our aim was to study the natural history of pediatric PSC in Sweden. Methods: This is a cohort study, including all children (<18 years), diagnosed with PSC between January 2000 and December 2015 at the Pediatric Liver Unit at Karolinska University Hospital, Stockholm. Patients were followed until liver transplantation, death or last date of follow-up (August 2021). ResultsWe identified 124 children with a median age of 14 (1.9–17.8) years at PSC diagnosis. Sixty percent were boys, 93% had IBD. Median follow-up time was 13 years (5.7–21.6). Overall event-free survival in the cohort was 91% (95% CI 0.84–0.95) at 5 years and 77% (95% CI 0.68–0.84) at 10 years after diagnosis. Autoimmune hepatitis (AIH) was present in 31% (n=39). Portal hypertension (PHT) developed in 13% (n=16), biliary complications in 24% (n=30), cholangiocarcinoma (CCA) in 0.8% (n=1), 13% (n=16) were liver transplanted and three patients died. Transplant-free survival was 91% after 10 years. Individuals with a high SCOPE index at diagnosis had 2.3 timed increased risk of liver transplantation, HR 2.35 (95% CI 1.18–4.66), c-statistics=0.70. Patients with an additional AIH diagnosis had slightly higher risk of reaching transplantation during follow-up, HR 2.85 (95% CI 1.06–7.67), p=0.038. ConclusionsChildren diagnosed with PSC have a good prognosis during the first decade after diagnosis. A high SCOPE index at diagnosis was associated with a less favorable outcome.

#1718 Infectious complications among early versus late pulse steroid therapy among renal transplant recipients

Abstract Background and Aims Renal transplant recipients are at risk for infectious complications, with opportunistic infections predominating early after transplant and community acquired infections occurring in late transplant period. Pulse steroid is a form of heightened immunosuppression given to a transplant recipient, usually for treatment of rejection. This study aimed to investigate the effects of early and late pulse steroid therapy on the development of infectious complications in renal transplant recipients. Method Study population was drawn from patients undergoing kidney transplantation in the period between 1st January, 2016 and 31st December, 2020 in the study centre. Early and late pulse steroid therapy was defined based on whether pulse steroid was received within or after 90 days from date of transplant respectively. Patients receiving either early or late (but not both) pulse steroids who were more than or equal to 18 years of age and had at least 90 days of follow up were included in the study. Patients were followed up till 31st December, 2021 or till their death (whichever came earlier). Results Total of 516 patients underwent renal transplantation in the study centre in the specified period, out of whom 128 patients (24.8%) fulfilled the inclusion criteria without fulfilling the exclusion criteria. Out of these 128 patients, 83 (64.8%) and 45 (35.2%) patients received early and late pulse steroids respectively. The 2 groups were similar with respect to respect to baseline characteristics and use of other immunosuppressive agents. The mean values (95% confidence interval) for overall infections in early and late pulse steroid categories were 0.46 (0.31-0.61) and 1.16 (0.55-1.78) episodes per year respectively (p = 0.28). Sepsis occurred at higher rate in patients receiving late pulse steroids, with mean values (95% confidence interval) for sepsis in early and late pulse steroid categories being 0.02 (0.00-0.06) and 0.30 (0.04- 0.57) episodes per year respectively (p = 0.01). Viral infections also occurred at higher rate in patients receiving late pulse steroids, with mean values (95% confidence interval) for viral infections in early and late pulse steroid categories being 0.04 (0.02- 0.09) and 0.23 (0.03-0.43) episodes per year respectively (p = 0.01). Rates of other types of infection did not significantly differ between the 2 categories. A greater proportion of patients receiving late pulse steroids died (4.8% and 17.8% in early and late pulse steroid categories respectively, p = 0.02). Conclusion Late pulse steroid therapy is associated with more episodes of sepsis and viral infections compared to early pulse steroid therapy, although rate of overall infections do not significantly differ between the two groups. This study highlights the importance of surveillance for infections after pulse steroid therapy in renal allograft recipients.

#2581 Cryptococcosis in kidney transplant recipients: a nationwide multicenter retrospective cohort study—CRITERE study

Abstract Background and Aims Cryptococcosis stands as the third most common invasive fungal infection in solid organ transplant recipients. Clinical management and prognosis of the disease remains largely unexplored in the context of kidney transplant recipients. Our main objective was to describe the natural history of cryptococcosis after kidney transplantation from the graft patterns of kidney injury to the long term outcomes. Method We established a nationwide cohort of adult kidney transplant recipients diagnosed with cryptococcosis between 2002 and 2019 in France. All data were gathered starting from the transplantation date and encompassed up to the latest follow-up consultation. All putative causes of AKI as claimed by the attending clinicians were recorded. Cases were matched (ratio 1:6) with kidney transplant recipients from the French prospective multicenter cohort DIVAT with parameters at time of transplant including immunosuppression and known risk factors of cryptococcosis such as age, history of smoke, history of cancer and HIV status. Transplant outcomes (graft failure and patient death) were then compared between matched patients. Results 88 patients were included. Patients were predominantly male (n = 61, 69.3%), with a mean age of 57.0 years [SD ±13.3]. The majority of patients were primary kidney transplants (n = 71, 80.7%) with a median time from ESRD to transplantation of 2.8 years [IQ 1.25-5]. The majority of patients received ATG as induction therapy for their transplant (n = 50, 69.4%)Acute kidney injury (AKI) at diagnosis involved 37.3% of the patients with 13.3% requiring renal replacement therapy. AKI staging was distributed as follows, AKI grade 1 in 12.5% of patients, grade 2 in 13.3% of patients, and grade 3 in 11.5% of patients. During the induction stage, 39% of patients developed amphotericin B-related AKI. AKI resulting from tacrolimus overdose subsequent to tacrolimus/fluconazole interaction occurred in 25.7% of patients during the consolidation stage. Among the patients alive at 3 months following the diagnosis of cryptococcosis, 33.7% of patients exhibited graft dysfunction. Following cryptococcosis, 5 patients displayed T cell rejection and 4 patients developed antibody-mediated rejection. A total of 41 patients with cryptococcosis were matched to 246 controls (ratio 1:6), after a median follow-up of 52.3 [28.1-90.2] months, patients with cryptococcosis exhibited a higher risk of mortality with 35.9% compared with 9.8% (p &amp;lt; 0.001) and graft failure with 33.3% compared with 15.0% (p = 0.0005). Conclusion This study has shown that kidney injury manifests itself through a sequential, multi-step process that initially includes pre-renal impairment, ATN and iatrogenic mechanisms. Amphotericin B-related AKI, followed by tacrolimus overdose represent common causes of AKI.

#2867 Is there an interrelationship between the SARS-CoV-2 virus and the BK polyomavirus in kidney transplant recipients?

Abstract Background and Aims Several viral co-infections following SARS-CoV-2 infection have been described. However, there is very limited and inconclusive data on the relationship between COVID-19 and BK polyomavirus (BKV) in kidney transplant (KT) recipients. Method Retrospective analysis of KT recipients with BK infection (BKi) in our centre from March 2020 (first cases of COVID-19) to March 2023. BK viremia is periodically determined prospectively in all KTs performed in our hospital. We carried out a case-control study, choosing two controls without BKi for each case (closest transplant date and similar donor and recipient age). We analyzed clinical characteristics and evolution, as well as previous history of COVID-19 in both groups. A composite outcome including de novo BKi and/or significant increase in BK viremia (increase &amp;gt; 50% in at least 2 consecutive samples) was analyzed. Multivariate analysis was performed using logistic regression for de novo BKi and/or significant increase in BK viremia risk factors. Results During this period 235 KTs were performed in our center, of which 37 were diagnosed with BKi (16.1%). The median time from the date of KT to BKi was 73 days. When comparing cases versus controls, demographic characteristics and donor type were similar in both groups, except for a higher proportion of males in the BKi group (76.3% vs. 55.3%; p = 0.029). The incidence of SARS-CoV-2 infection was significantly higher in patients with de novo/increased viremia BKi than in the control group (44.7% vs. 26.3% p = 0.048). During follow-up, one patient in the BKi group died and one patient in the control group lost the graft due to causes other than viral infections. In multivariate analysis, male gender and SARS-CoV-2 infection were risk factors for the composite outcome. Conclusion As has been described with other viruses, there may be an interrelationship between SARS-CoV-2 and BKV. Our experience suggests that close monitoring for BKV after episodes of COVID-19 may be appropriate.

Amphiregulin, ST2, and REG3α biomarker risk algorithms as predictors of nonrelapse mortality in patients with acute GVHD

AbstractGraft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

Risk factors for Nocardia infection among allogeneic hematopoietic cell transplant recipients: A case-control study of the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation

Nocardiosis is a rare but life-threatening infection after hematopoietic cell transplantation (HCT). We aimed at identifying risk factors for nocardiosis after allogeneic HCT and clarifying the effect of trimethoprim-sulfamethoxazole prophylaxis on its occurrence. We performed a retrospective multicenter case-control study of patients diagnosed with nocardiosis after allogeneic HCT between January 2000 and December 2018. For each case, two controls were matched by center, transplant date, and age group. Multivariable analysis was conducted using conditional logistic regression to identify potential risk factors for nocardiosis. Kaplan-Meier survival curves of cases and controls were compared using log-rank tests. Sixty-four cases and 128 controls were included. Nocardiosis occurred at a median of 9 months after allogeneic HCT (interquartile range: 5-18). After adjustment for potential confounders in a multivariable model, Nocardia infection was associated with tacrolimus use (adjusted odds ratio [aOR] 9.9, 95% confidence interval [95% CI]: 1.6-62.7), lymphocyte count <500/µL (aOR 8.9, 95% CI: 2.3-34.7), male sex (aOR 8.1, 95% CI: 2.1-31.5), recent use of systemic corticosteroids (aOR 7.9, 95% CI: 2.2-28.2), and recent CMV infection (aOR 4.3, 95% CI: 1.2-15.9). Conversely, use of trimethoprim-sulfamethoxazole prophylaxis was associated with a significantly decreased risk of nocardiosis (aOR 0.2, 95% CI: 0.1-0.8). HCT recipients who developed nocardiosis had a significantly decreased survival, as compared with controls (12-month survival: 58% and 90%, respectively; p<0.0001). We identified six factors independently associated with the occurrence of nocardiosis among allogeneic HCT recipients. In particular, trimethoprim-sulfamethoxazole prophylaxis was found to protect against nocardiosis.

Two sides to every story: Reappraising the early history of liver transplantation at Addenbrooke's Hospital, Cambridge.

Over the course of the past six decades, liver transplantation has evolved to become the treatment of choice for chronic end-stage liver disease and some cases of acute hepatic failure. Currently, more than 34,000 liver transplants are conducted worldwide per annum, and overall one year survival rates exceed 90%. However, the early years of human liver transplantation were beset by failure. Eyewitness reports from this period make for tragic, yet compelling reading. Volume 12 of The History of Anaesthesia Society Proceedings contains one such account, written by Dr Elizabeth Gibbs. This outlined the experience of single-handedly anaesthetising the recipient of the first liver transplant to be undertaken at Addenbrooke's Hospital, Cambridge, UK, in June 1967. Despite the best efforts of the team, the patient died from uncontrollable haemorrhage 19 hours after the start of the procedure. While this tragic outcome might have been expected in the early days of liver transplantation, Gibbs included an unsettling postscript in her paper. This stated that all of the patient's records had apparently been 'lost', and the date of the first Cambridge liver transplant was publicly reported as 2 May 1968, some 11 months after the events described. This article outlines the results of research aimed at critically appraising this postscript. In doing so a number of unexpected discoveries were made. These highlight some important lessons for medical historians and demonstrate that if you look hard enough, there really are two sides to every story.

A novel approach to reducing hepatotoxicity related to fungal prophylaxis in pediatric lung transplant recipients.

Pediatric lung transplant patients are at risk for developing invasive fungal infections post-transplant. No consensus exists on optimal antifungal regimens and voriconazole, a common first-line agent, has been shown to cause hepatotoxicity. We describe a single-center experience utilizing a novel antifungal regimen of intravenous micafungin and nebulized amphotericin B immediately post-transplant with conversion to an azole at the time of hospital discharge and compare it to a historical cohort of patients who received voriconazole monotherapy throughout their immediate post-operative course. This is a retrospective review of patients in the age 0-18 who received a lung transplant from June 2016-May 2021. Data points collected included: demographic data, transplant date and discharge date, Aspergillus colonization, type of lung transplant, hospitalization and level of care information, induction and antifungal medication regimen; AST, ALT, GGT, bilirubin, and direct bilirubin at various timepoints; and respiratory and blood culture results. The two patient groups were compared by assessment of changes in LFTs and culture results. Forty-two patients were included in the analysis, with 24 patients receiving micafungin and nebulized amphotericin and 18 patients receiving voriconazole. All patients in both groups experienced a post-operative elevation in at least one transaminase or bilirubin. More patients in the micafungin/amphotericin group had resolution of all abnormal LFTs by 1 month post-transplant (p = .036). Additionally, patients in the micafungin/amphotericin group experienced faster normalization of their LFTs compared with the voriconazole group (p < .001). Ten patients in the micafungin/amphotericin group and five patients in the voriconazole group were found to have fungal growth on culture post-transplant, but this difference was not found to be statistically significant (p = .507). An antifungal regimen of micafungin and nebulized amphotericin B liposomal may be useful at decreasing the duration of elevated liver enzymes in pediatric patients in the immediate post-lung transplant period when compared with voriconazole monotherapy. Larger prospective studies looking at antifungal regimens in pediatric patients post-lung transplant are warranted.

Risk Factors for and Outcomes Following Early Acquisition of Mycobacterium abscessus Complex After Lung Transplantation.

Lung transplant recipients are at increased risk of Mycobacterium abscessus complex (MABC) acquisition and invasive infection. We analyzed risk factors and outcomes of early post-lung transplant MABC acquisition. We conducted a retrospective matched case-control study of patients who underwent lung transplant from 1/1/2012 to 12/31/2021 at a single large tertiary care facility. Cases had de novo MABC isolation within 90 days post-transplant. Controls had no positive MABC cultures and were matched 3:1 with cases based on age and transplant date. Recipient demographics and pre-/peri-operative characteristics were analyzed, and a regression model was used to determine independent risk factors for MABC acquisition. We also assessed 1-year post-transplant outcomes, including mortality. Among 1145 lung transplants, we identified 79 cases and 237 matched controls. Post-transplant mechanical ventilation for >48 hours was independently associated with MABC acquisition (adjusted odds ratio, 2.46; 95% CI, 1.29-4.72; P = .007). Compared with controls, cases required more days of hospitalization after the MABC index date (28 vs 12 days; P = .01) and had decreased 1-year post-transplant survival (78% vs 89%; log-rank P = .02). One-year mortality appeared highest for cases who acquired M. abscessus subsp. abscessus (31% mortality) or had extrapulmonary infections (43% mortality). In this large case-control study, prolonged post-transplant ventilator duration was associated with early post-lung transplant MABC acquisition, which in turn was associated with increased hospital-days and mortality. Further studies are needed to determine the best strategies for MABC prevention, surveillance, and management.

Potential Barriers to Adaptive Actions in Water–Rice Coupled Systems in Japan: A Framework for Predicting Soft Adaptation Limits

AbstractThe changing climate makes it more difficult to manage water resources and food production sustainably. Various adaptation measures have been proposed to moderate the negative impacts of climate change; however, implementation of these measures may be hampered by other factors even if the benefits are acknowledged—a situation termed “soft adaptation limits” by the IPCC. We hypothesized that societal rules can be a potential barrier to adaptive action if they are too fixed, because such rules have coevolved with the interactions between the past climate and human activities. To test this hypothesis, we present a framework based on the assumption that associated societal rules of Japan's matured irrigation systems are potential barriers to adaptation. The framework consisted of two process‐based models, one to evaluate the water deficit risk and one to evaluate the benefits of optimizing rice yield and quality. We applied each model to an experiment in which we shifted the current transplantation date by 1 week for up to 5 weeks before and after the current date under the historical (1981–2000) and RCP 2.6 and 8.5 (2011–2030 and 2031–2050) scenarios. We revealed two contrasting development pathways in the study watershed. Soft adaptation limits imposed by water availability will occur by 2030 if farmers optimize for quality, whereas mutual benefits to farmers and river administrators will be achieved if farmers seek yield. We argue that more participatory research with stakeholder engagement, as well as policy discussions about these possible developments, is needed to ensure successful adaptation.

Automated graded prognostic assessment for patients with hepatocellular carcinoma using machine learning

BackgroundAccurate mortality risk quantification is crucial for the management of hepatocellular carcinoma (HCC); however, most scoring systems are subjective.PurposeTo develop and independently validate a machine learning mortality risk quantification method for HCC patients using standard-of-care clinical data and liver radiomics on baseline magnetic resonance imaging (MRI).MethodsThis retrospective study included all patients with multiphasic contrast-enhanced MRI at the time of diagnosis treated at our institution. Patients were censored at their last date of follow-up, end-of-observation, or liver transplantation date. The data were randomly sampled into independent cohorts, with 85% for development and 15% for independent validation. An automated liver segmentation framework was adopted for radiomic feature extraction. A random survival forest combined clinical and radiomic variables to predict overall survival (OS), and performance was evaluated using Harrell’s C-index.ResultsA total of 555 treatment-naïve HCC patients (mean age, 63.8 years ± 8.9 [standard deviation]; 118 females) with MRI at the time of diagnosis were included, of which 287 (51.7%) died after a median time of 14.40 (interquartile range, 22.23) months, and had median followed up of 32.47 (interquartile range, 61.5) months. The developed risk prediction framework required 1.11 min on average and yielded C-indices of 0.8503 and 0.8234 in the development and independent validation cohorts, respectively, outperforming conventional clinical staging systems. Predicted risk scores were significantly associated with OS (p < .00001 in both cohorts).ConclusionsMachine learning reliably, rapidly, and reproducibly predicts mortality risk in patients with hepatocellular carcinoma from data routinely acquired in clinical practice.Clinical relevance statementPrecision mortality risk prediction using routinely available standard-of-care clinical data and automated MRI radiomic features could enable personalized follow-up strategies, guide management decisions, and improve clinical workflow efficiency in tumor boards.Key Points• Machine learning enables hepatocellular carcinoma mortality risk prediction using standard-of-care clinical data and automated radiomic features from multiphasic contrast-enhanced MRI.• Automated mortality risk prediction achieved state-of-the-art performances for mortality risk quantification and outperformed conventional clinical staging systems.• Patients were stratified into low, intermediate, and high-risk groups with significantly different survival times, generalizable to an independent evaluation cohort.

Pre-Emptive Kidney Retransplantation from Deceased Donors

There is uncertainty about the best approach to replacement treatment for kidney transplant recipients with chronic terminal graft dysfunction, since a retransplant could be performed before the resumption of dialysis, thus avoiding this treatment and the dilemma of whether or not to suspend immunosuppressive therapy. However, there is limited experience in pre-emptive repeat transplantations, and none from deceased donors. This study aims to assess the results of a pre-emptive retransplantation program with brain-dead deceased donors. We designed a retrospective matched cohort study, including 36 recipients in the pre-dialysis group and 36 controls who were already on dialysis, matched for donor age and transplant date, which could not differ by more than 7 days between pairs. The variables used to standardize the cohorts were donor and recipient age and sex, blood group, duration of the first graft, time on the waitlist to receive the second graft, cold ischemia time, induction and maintenance of immunosuppression, and HLA antibodies (-) prior to retransplantation. The efficacy variables were early graft loss, acute rejection, delay in graft function, renal function at the end of follow-up, survival time, and recipient and graft survival at 24 and 48 months’ follow-up. The pre-dialysis group presented a significantly shorter waitlist time, lower immunization status, and a significantly longer duration of the first graft than the control group. The percentage of recipients who presented early graft loss, delayed renal function, or acute rejection was similar between groups. No significant differences were observed in kidney function or in the survival of the recipient or graft. Retransplantation yields good outcomes in patients with terminal chronic dysfunction, helping to avoid recurrence to dialysis, shortening the time spent on the waitlist, reducing the risk of producing antibodies, and resolving the dilemma of whether or not to stop immunosuppression.

Risk of Corneal Graft Rejection and Vaccination: A Matched Case-Control Study From a United States Integrated Health Care System

Data on vaccine-associated corneal transplant rejections are limited. We examined the association between graft rejection and vaccination. Matched case-control METHODS: We used electronic health records to identify corneal transplant recipients between January 2008 and August 2022 at Kaiser Permanente Southern California. Cases were transplant recipients who experienced a graft rejection (outcome) during the study period. Randomly selected controls who did not experience a corneal graft rejection at their matched cases' index date (rejection date) were matched in a 3:1 ratio to cases. For controls, index date was determined by adding the number of days between transplant and graft rejection of their matched case to the control's transplant date. The study included 601 cases and 1803 matched controls (mean age 66 years [s.d. 17.0], 52% female, 47% non-Hispanic white). Twenty-three% of cases and 22% of controls received ≥1 vaccinations within 12 weeks prior to the index date. The adjusted odds ratio (aOR) for vaccination in the 12 weeks prior to index date, comparing cases to controls was 1.17 (95% CI: 0.91, 1.50]). The aOR was 1.09 (0.84, 1.43) for 1 vaccination, 1.53 (0.90, 2.61) for 2 vaccinations, and 1.79 (0.55, 5.57) for ≥3 vaccinations. The aOR was 1.60 (0.81, 3.14) for mRNA vaccines, and 1.19 (0.80, 1.78) for adjuvanted/high dose vaccines. We found no evidence to suggest an association between vaccination and graft rejection. Our findings provide support for the completion of recommended vaccinations for corneal transplant recipients, without significantly increasing the risk of graft rejection.