Transplant Research Research Articles

Precision medicine results from equitable representation.

In this special issue of Bone Marrow Transplantation, investigators report the impact of IDH1 [1], IDH2 [2], and FLT3-TKD [3] measurable residual disease (MRD) pre-hematopoietic cell transplantation (HCT) in predicting relapse of acute myeloid leukemia (AML) in adults receiving allogeneic HCT. The patient population for these retrospective cohorts, reflecting clinical transplant practice patterns and research biobank participation, was 84-86% non-Hispanic White (NHW) in each study. In this commentary, we explore the implications of racial and ethnic disparities in access to both HCT and HCT-related research and propose strategies to promote representation in precision medicine, given the emerging impact of the field on HCT outcomes.

Novel machine learning technique further clarifies unrelated donor selection to optimize transplantation outcomes

AbstractWe investigated the impact of donor characteristics on outcomes in allogeneic hematopoietic cell transplantation (HCT) recipients using a novel machine learning approach, the Nonparametric Failure Time Bayesian Additive Regression Trees (NFT BART). NFT BART models were trained on data from 10 016 patients who underwent a first HLA-A, B, C, and DRB1 matched unrelated donor HCT between 2016 and 2019, reported to the Center for International Blood and Marrow Transplant Research, then validated on an independent cohort of 1802 patients. The NFT BART models were adjusted based on recipient, disease, and transplant variables. We defined a clinically meaningful impact on overall survival (OS) or event-free survival (EFS; survival without relapse, graft failure, or moderate to severe chronic graft-versus-host disease) as >1% difference in predicted outcome at 3 years. Characteristics with <1% impact (within a zone of indifference) were not considered to be clinically relevant. Donor cytomegalovirus, parity, HLA-DQB1, and HLA-DPB1 T-cell epitope matching fell within the zone of indifference. The only significant donor factor that associated with OS was age, in which, compared with 18-year-old donors, donors aged ≥31 years old were associated with lower OS. Both donor age (≤32 years) and use of a male donor, regardless of recipient sex, improved EFS. We, therefore, recommend selecting the earliest available donor within the 18 to 30 years age range for HCT to optimize OS. If several donors in the 18 to 30 years age range are available, a male donor may be chosen to optimize EFS.

Navigating the changing landscape of transplant research: Trends, topics, and gender disparities

BackgroundTransplantation is a rapidly evolving field, reflecting advances in medical science and changing healthcare needs. This study aims to elucidate shifts in research focus over a decade, providing insights into emerging trends in transplant research. MethodsWe conducted a comprehensive analysis of 9,250 articles published in five high-impact transplant journals from 2012 to 2021. Article titles were processed to extract keywords using R Studio (v. 4.3.0). STATA 18 was used for t-tests and logistic regressions, with significance set at p ​< ​0.05. ResultsEmerging topics over the decade included outcomes and survival, surgical innovations, and lung transplantation. There was a downward trend in research on immunosuppression, genetics, and immunology. Over the decade, the odds of women's first authorship were higher for subjects such as public health, pediatric transplantation, infectious diseases, renal transplantation, and psychological aspects. Similarly, there were lower odds for women as first authors on surgical innovations, organ preservation, living donor transplantation, liver and lung transplantation, and multiorgan transplantation. Senior women authors had higher odds of publishing on the same topics as first author, plus immunology, kidney and heart transplantation. There were lower odds that a woman would be last author of regenerative medicine and xenotransplantation. Over the decade, there were higher odds of funding for research published on xenotransplantation, regenerative medicine, and immunology. Living donor, infectious diseases, and liver transplantation had lower odds of being funded over time. ConclusionThis cross-sectional study highlights the dynamic nature of transplant research, underscoring the importance of continuous observation of trends to anticipate future directions and needs in the field. The emergence of new focal areas, especially those related to technological advancements and social issues, reflects a broader trend in medical research responding to evolving challenges and opportunities. Notably, women's authorship was more prevalent in public health but less in surgical innovation. These insights can guide future research priorities, funding allocation, and clinical practices in transplantation.

Understanding What Patients and Families Living with Kidney Failure Want and Need to Know about Xenotransplantation: A Kidney Transplant Research Possibility

Understanding What Patients and Families Living with Kidney Failure Want and Need to Know about Xenotransplantation: A Kidney Transplant Research Possibility

Optimal Trough Concentration of Tacrolimus in Pediatric Patients With Primary Nephrotic Syndrome.

The trough concentration (C0) of tacrolimus in children with nephrotic syndrome (NS) has rarely been explored, so its target level was based on transplant research. This study aimed to determine the optimal tacrolimus C0 in NS children. Data from primary NS children treated with tacrolimus at Wuhan Children's Hospital in the last 10 years were retrospectively collected. According to the cutoff C0 analyzed by receiver-operator characteristics (ROC) analysis, patients were divided into very low- (< 4 ng/mL), low- (4-5 ng/mL), medium- (5-7 ng/mL), and high-concentration (7-10 ng/mL) groups. A total of 196 patients were enrolled for primary outcome analysis. Compared to medium-concentration group, only the very low-concentration group obtained significant inferior primary outcomes, including overall remission rate, relapse-free survival rate, and relapse rate at 6 months. For secondary outcomes, the very low-concentration group experienced more frequent treatment failure in 12 months, whereas the high-concentration group suffered a higher risk of adverse events than the medium-concentration group. For steroid-resistant NS, very low- and low-concentration groups required longer time to achieve remission compared to medium-concentration group. For steroid-sensitive NS, the very low-concentration group suffered a higher relapse frequency than medium-concentration group. Lastly, the dose of tacrolimus required for children with different CYP3A5 genotypes with or without Wuzhi capsules was analyzed. In conclusion, tacrolimus may be targeted to C0 of 4-7 ng/mL during the first 6 months in children with NS. For steroid-resistant NS, C0 of 5-7 ng/mL can achieve a rapid remission.

EndoC-βH3 pseudoislets are suitable for intraportal transplantation in diabetic mice

ABSTRACT Background Islet or β-cell transplantation is a therapeutical approach to substitute the insulin-producing cells which are abolished in type 1 diabetes mellitus. The shortage of human islets as well as the complicated and costly isolation process limit the application of these techniques in daily clinical practice. EndoC-βH is a human β-cell line that readily forms aggregates termed pseudoislets, providing an alternative to primary human islets or β-cells. Methods EndoC-βH3 cells were seeded and incubated to form pseudoislets. Their insulin secretion was analyzed by ELISA and compared with cell monolayers. Pseudoislets were transplanted into streptozotocin-treated NMRi nu/nu mice. Blood glucose was monitored before and after transplantation and compared with wild types. Grafts were analyzed by immunohistology. Results This study shows that EndoC-βH cells are able to form pseudoislets by aggregation, leading to an enhanced glucose stimulated insulin secretion in vitro. These pseudoislets were then successfully transplanted into the livers of diabetic mice and produced insulin in vitro. Blood glucose levels of the streptozocin-treated recipient mice were significantly decreased when compared to pre-transplantation and matched the levels found in control mice. Conclusion We suggest pseudoislets aggregated from EndoC-βH cells as a valuable and promising model for islet transplantation research.

Japanese Perception of Brain Death and Implications for New Medical Technologies: Quantitative and Qualitative Social Media Analysis.

Brain death has been used to decide whether to keep sustained care and treatment. It can facilitate tissue, organ, and body donation for several purposes, such as transplantation and medical education and research. In Japan, brain death has strict diagnostic criteria and family consent is crucial, but it has been a challenging concept for the public since its introduction, including knowledge and communication issues. We analyzed data across YouTube and Twitter in Japan to uncover actors and assess the quality of brain death communication, providing recommendations to communicate new medical technologies. Using the keyword "" (brain death), we collected recent data from YouTube and Twitter, classifying the data into 5 dimensions: time, individuality (type of users), place, activity, and relations (hyperlinks). We employed a scale to evaluate brain death information quality. We divided YouTube videos into 3 groups and assessed their differences through statistical analysis. We also provided a text-based analysis of brain death-related narratives. Most videos (20/61, 33%) were uploaded in 2019, while 10,892 tweets peaked between July 3 and 9, 2023, and June 12 and 18, 2023. Videos about brain death were mostly uploaded by citizens (18/61, 27%), followed by media (13/61, 20%) and unknown actors (10/61, 15%). On the other hand, most identified users in a random sample of 100 tweets were citizens (73/100, 73%), and the top 10 retweeted and liked tweets were also mostly authored by citizens (75/100, 75%). No specific information on location was uncovered. Information videos contained guides for accreditation of the National Nursing Exam and religious points of view, while misinformation videos mostly contained promotions by spirituality actors and webtoon artists. Some tweets involved heart transplantation and patient narratives. Most hyperlinks pointed to YouTube and Twitter. Brain death has become a common topic in everyday life, with some actors disseminating high-quality information, others disseminating no medical information, and others disseminating misinformation. Recommendations include partnering with interested actors, discussing medical information in detail, and teaching people to recognize pseudoscience.

Use of Hematopoietic Cell Transplant for Hematologic Cancers by Race, Ethnicity, and Age.

Utilization of hematopoietic cell transplantation (HCT) for hematologic cancers previously demonstrated race, ethnicity, and age-based disparities. To evaluate utilization over time by race, ethnicity, and age to determine if disparities persist in light of recent significant increases in HCT volume. This US population-based retrospective cohort study includes patients who received transplants from January 2009 to December 2018. Data collection and cleaning occurred from February 2019 to November 2021, and data analysis occurred from January 2022 to October 2023. Method 1 restricted the analysis to Surveillance, Epidemiology and End Results (SEER) reporting areas for cases and transplants. Method 2 applied SEER age-, race-, and ethnicity-specific incidence rates to corresponding US census population and included all transplants reported to the Center for International Blood and Marrow Transplant Research. Race and ethnicity groups were hierarchically defined as Hispanic (any race), non-Hispanic White, non-Hispanic Black, and non-Hispanic Other (Asian and American Indian). Receipt of HCT. Utilization rate of autologous or allogeneic HCT for patients with hematologic cancers by age, race, and ethnicity. From 2009 to 2018, 136 280 HCTs were analyzed for 6 hematologic cancers comprising 16.7% pediatric/adolescent/young adults (0-39 years), 83.3% adults (40-84 years), 58% male, 10.3% Hispanic, 11.4% non-Hispanic Black, 3.8% non-Hispanic Other, and 74.5% non-Hispanic White patients, with 49 385 allogeneic and 86 895 autologous HCTs performed. HCT utilization increased over time for all disease, age, race, and ethnic groups. From 2017 to 2018, adult (40-84 years) allogeneic transplant utilization for acute myeloid leukemia and myelodysplastic syndrome (MDS) was similar for Hispanic and non-Hispanic White or Other patients but was lower for non-Hispanic Black patients (acute myeloid leukemia: 19% vs 13%; MDS: 9%-10% vs 5%). Similarly, autologous transplant utilization for lymphoma was similar for all race and ethnicity groups; however, autologous transplant for multiple myeloma was highest for non-Hispanic White patients and lower for all other groups (31% vs 26%-27%). In patients aged 0 to 39 years, utilization of allogeneic transplant for acute lymphoblastic leukemia was highest in Hispanic patients, followed by non-Hispanic White, Black, and Other races (acute lymphoblastic leukemia: 19%, 18%, 17%, and 16%, respectively). In this cohort study of autologous and allogeneic transplant utilization for hematologic cancers, disparities persisted for non-Hispanic Black patients. Hispanic, non-Hispanic Other, and younger age groups had increased utilization over time that was on par with non-Hispanic White patients in the most recent cohort.

Walter Brendel and the dawn of transplantation research in Germany.

Walter Brendel was a physiologist who headed the Institut of Experimental Surgery at the University of Munich (LMU) from 1961 until 1989. His legendary career began with the development of an anti-human lymphocyte globulin (ALG) at his Institute during the late 1960s. The initial successful treatment of a small number of patients culminated in the co-treatment of the first successfully heart-transplanted patient in Capetown, South Africa (successful reversal with ALG of an acute allograft rejection). Walter Brendel was a pioneering personality whose work has laid a wide platform for the promotion of interdisciplinarily conducted innovative research programs in various domains of translational science and medicine. Among the many innovative achievements, the most notable are: discovery of involvement of the alternative pathway of complement activation in hyperacute xenograft rejection; induction of immunological tolerance to horse IgG as a means to prevent anaphylactic reactions during ALG therapy; development and clinical implementation of the extracorporeal shock wave lithotripsy for extracorporeal destruction of renal and ureteral calculi. The legacy of Brendel continues with the foundation of the Walter-Brendel Kolleg für Transplantationsmedizin (i.e., the German Transplant School for Transplantation Medicine), which has been held annually since 1994.

Building a successful transplant research center: Blueprints and barriers.

A successful multidisciplinary research center depends on the quality of the science being conducted and the quality of the center's design, culture, infrastructure, and institutional support. In this perspective, we describe our experience building and maintaining a multidisciplinary transplant research center with a large focus on transplant infectious diseases. We identify principles that we believe contributed to our success including: taking inventory, defining culture, creating a multidisciplinary shared leadership model, establishing expertise in a multiple method approach, investing in operations and management, building and sharing resources, and securing institutional support. We share our experience putting these principles into practice and highlight potential roadblocks.

The current landscape of in situ and ex situ machine perfusion utilization for liver grafts from cardiac donation after circulatory death donors in the US

Donation after circulatory death (DCD) is driving the increase in deceased organ donors in the United States. Normothermic regional perfusion (NRP) and ex situ machine perfusion (es-MP) have been instrumental in improving liver transplant outcomes and graft utilization. This study examines the current landscape of liver utilization from cardiac DCD donors in the United States. Using the United Network for Organ Sharing Standard Transplant Analysis and Research file, all adult (≥18 years old) DCD donors in the United States from which the heart was used for transplantation from October 1, 2020, to September 30, 2023, were compared by procurement technique (NRP versus super rapid recovery [SRR]) and storage strategy (es-MP versus static cold storage). One hundred eighty-eight livers were transplanted from 309 thoracoabdominal NRP donors (61% utilization) versus 305 (56%) liver transplants from 544 SRR donors. es-MP was used in 20% (n = 38) of NRP cases versus 32% (98) of SRR cases. Of the liver grafts, 281 (59%) were exposed to NRP, es-MP, or both. While there is widespread utilization of machine perfusion, more research is needed to determine optimal graft management strategies, particularly concerning the use of multiple technologies in complementary ways. More complete data collection is necessary at a national level to address these important research questions.

Four Decades of Research Productivity and Hot Spots in Pancreas Transplantation.

Background: The field of pancreas transplantation has undergone transformative phases, progressing from its promising inception in 1966 to becoming a standard treatment for patients with insulin-dependent diabetes. This bibliometric analysis explores the progression of pancreas transplantation research over a period of four decades, mapping milestones, contributors, and emerging trends. Methods: Our bibliometric analysis utilizes the comprehensive Scopus database, which includes publication titles, author information, affiliations, abstracts, keywords, and journal details. The search strategy was centered on research related to pancreas and pancreas-kidney transplantation. The analysis encompasses the time frame spanning from 1983 to 2023, with the data extraction taking place on October 7th, 2023. Results: The analysis of 4,897 articles uncovered unique trends in the field of pancreas transplantation research. The years 1989, 1996, and 2021 saw significant increases in the number of publications, which corresponded to the responses to clinical challenges and advancements. Contributions by authors from the United States of America were the most numerous, with 1,905 publications and 49,949 citations. The research topics were highlighted by keywords such as "graft survival," "graft rejection," and" Immunosuppressive treatment." Conclusion: The fluctuations in publication trends that have been identified indicate dynamic reactions to changing priorities and challenges. Although it has limitations, this analysis provides valuable insights for researchers, clinicians, and policymakers who are dealing with the complex field of pancreas transplantation literature. Further bibliometric research may advance our knowledge and direct future initiatives in this developing field.

Late effects after allogeneic haematopoietic cell transplantation in children and adolescents with non-malignant disorders: a retrospective cohort study

Continued advances in haematopoietic cell transplantation (HCT) for children with non-malignant diseases (NMDs) have led to a growing population of survivors in whom late occurring toxic effects remain a challenge. We investigated the incidence of and risk factors for post-transplant toxicities in a contemporary cohort of children and adolescents undergoing HCT for NMDs. In this retrospective cohort study, we extracted data from the Center for International Blood and Marrow Transplantation Research (CIBMTR) database to analyse timing and incidence of effects and risk factors associated with late effects of HCT for treatment of NMDs at age 21 years or younger. Late effects of interest were avascular necrosis, cataracts, congestive heart failure, myocardial infarction, diabetes, gonadal dysfunction, growth hormone deficiency, hypothyroidism, renal failure requiring dialysis, and neurological events (stroke and seizure). Cumulative incidence of each late effect was calculated at 5 years and 7 years after HCT. Risk factors were evaluated in Cox proportional hazards regression analyses. Main exposures were primary NMD, age, sex, ethnicity and race, insurance, donor and graft type, myoablative conditioning, total-body irradiation exposure, graft-versus-host disease (GVHD), and transplant year. Primary outcomes were rates, cumulative incidence probability (95% CI), and risk-factors for organ-specific late effects. Between Jan 1, 2000, and Dec 31, 2017, 7785 patients aged 21 years or younger underwent HCT. 1995 patients were ineligible or did not consent to be included. 5790 patients from 171 centres were included in the analysis. 3505 (60·5%) of 5790 patients were male and 2285 (39·5%) were female. 2106 (36·4%) patients were White, 771 (13·3%) were Hispanic, and 773 (12·7%) were Black. 1790 (30·9%) patients were non-USA residents. Median age at HCT was 5·5 years (range 0·0-21·0). 1127 (19%) of 5790 patients had one late effect, and 381 (7%) had at least two. At 7 years post-HCT, the cumulative incidence probability was 1·9 (95% CI 1·5-2·3) for cataracts, 4·9 (4·3-5·6) for diabetes, 2·6 (2·1-3·1) for gonadal dysfunction, 3·2 (2·7-3·8) for hypothyroidism, 5·0 (4·4-5·7) for growth disturbance, 8·1 (7·4-8·9) for renal failure, 1·6 (1·3-2·0) for avascular necrosis, 0·6 (0·4-0·8) for congestive heart failure, 0·2 (0·1-0·3) for myocardial infarction, and 9·4 (8·6-10·2) for neurological effects. Age 10 years or older at HCT, unrelated donor source, total-body irradiation, and GVHD were identified as risk factors for long-term effects. The findings highlight the need for, and access to, multidisciplinary and lifelong follow-up for children undergoing HCT for NMDs. As more children undergo treatment with cellular therapies for non-malignant conditions, further analyses of post-transplant data could increasingly guide treatment decisions and subsequent long-term surveillance. National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Allergy and Infectious Diseases, Health Resources and Services Administration, and Office of Naval Research.

CAST Regimen for GvHD Prophylaxis: A CIBMTR Propensity Score-Matched Analysis

Previously, we reported excellent results with the combination of post-transplant cyclophosphamide (PTCy), abatacept, and a short course of tacrolimus (CAST) for the prevention of graft-versus-host disease (GvHD) following peripheral blood haploidentical transplantation. To further substantiate these results, we performed a propensity score-matched analysis. Patients enrolled in the CAST trial were matched with patients from a contemporaneous cohort from the Center for International Blood and Marrow Transplant Research database who received PTCy, tacrolimus, and mycophenolate mofetil, using nearest neighbor propensity score matching. An excellent balance between pairs was achieved as measured by the density distribution and standardized differences of covariates (median 0.09). The rates of acute GvHD grades II to IV at day +120 and 1-year GvHD- and relapse-free survival were 16.7% and 66.7% in the CAST cohort versus 28.6% and 47.6% in the control group, respectively. This trend did not reach statistical significance (P = .14 and .07), possibly due to the small numbers of patients and events. On the other hand, CAST was associated with a statistically significant reduction in the incidence of relapse (9.5% versus 26.2%, P = .045) with improved disease-free survival (85.7% versus 61.9%, P = .01). Our data provides a strong impetus to examine CAST in a randomized clinical trial.

Utilization of allogeneic hematopoietic stem cell transplantation among patients with newly diagnosed acute myeloid leukemia in California: a population-based linked dataset study.

Acute myeloid leukemia (AML) often requires allogeneic hematopoietic cell transplantation (alloHCT) for cure, but historically alloHCT has been strikingly underutilized. Reasons for this remain uncertain at the population level. We examined alloHCT utilization over time and explored associations between demographic/healthcare factors and use of alloHCT by age group (AYA 15-39y, adult 40-64y, older adult 65-79y) using a linked dataset merging the Center for International Blood and Marrow Transplant Research, California Cancer Registry, and California Patient Discharge Database. Eligibility included patients newly diagnosed with AML in California between 2001-2016 who received induction therapy and had no prior HCT. Multivariable Fine-Gray regression analyses were fitted separately across age groups. Among 7,925 patients with AML, alloHCT utilization increased over time across all age groups; however, in the most recent time period studied (2011-2016), utilization within 2 years of diagnosis remained lowest in older adults (13%) relative to adults (41%) and AYAs (49%). Factors statistically significantly associated with lower alloHCT utilization: (1) AYAs: female sex, lower neighborhood socioeconomic status (nSES), uninsured or Indian Health Services (IHS) coverage; (2) adults: older age, male sex, non-Hispanic Black or Asian race and ethnicity, unmarried, lower nSES, uninsured or covered by Medicaid, Medicare, or IHS, higher comorbidity, and living 100+ miles from a transplant center; and (3) older adults: older age, Asian race, and unmarried. In conclusion, using a population-based linked dataset, we demonstrate that utilization of alloHCT among older patients newly diagnosed with AML remains low in California, and factors associated with utilization vary by age group.

Pre-transplant Loco-Regional Therapy for Hepatocellular Carcinoma and Post-transplant Outcomes: A National Study.

The ultimate preferred treatment for hepatocellular carcinoma (HCC) complicated with cirrhosis and portal hypertension is an orthotopic liver transplant (OLT). Loco regional therapy (LRT) has emerged to prevent tumor growth and progression of disease beyond the Milan criteria to achieve transplant. There is a paucity of data regarding safety, posttransplant survival benefits, and tumor recurrence rate achieved by these LRT modalities. We aim to assess and compare the five-year survival rate and tumor recurrence rate with or without LRT in patients after OLT with diagnosed HCC utilizing the nation's largest dataset. This is a retrospective observational study approved by Saint Louis University institutional review board. We utilized the largest dataset from the years 2003-2013 where pertaining data were gathered from Organ Procurement Transplant Network (OPTN) standard analysis and research files (STAR) through novel linkages with Medicare bills. Descriptive and comparative statistics were performed. 2412 (51.6%) patients received any form of locoregional therapy (single or combination) out of 4669 total study sample size. The overall five-year survival in the study sample was 76.1%. There was statistically no significant improvement seen in five-year posttransplant survival in the group that received one mode of LRT (adjusted hazard ratio (aHR) 0.97, P<0.64) or a combination of LRT (aHR 0.94, P<0.58) in comparison to those that received none after adjusting donor and recipient clinical characteristics. However, five-year survival trended higher among those treated with combination therapy over those treated with single LRT or none. Overall HCC recurrence was 4.8%, while no significant difference was noted when comparing above-mentioned groups. Five-year posttransplant survival and HCC recurrence rate were also found to have no difference when compared between above-mentioned groups after adjusting explant pathology. This is the largest retrospective study comparing liver transplant patients with HCC who received LRT to none. Although it did not show any statistically significant benefit of single or combination of LRT on survival or tumor recurrence after liver transplant for HCC patients, the outcomes encourage the safe and feasible use of LRT as a bridging therapy. Our study also suggests an observed pattern of improved posttransplant survival and tumor recurrence rate with combination loco-regional therapy. Larger multicenter prospective studies will be required to achieve the effect size to determine the best therapies for maximizing patient survival cost-effectively.

Using established biorepositories for emerging research questions: a feasibility study

BackgroundProteomics and metabolomics offer substantial potential for advancing kidney transplant research by providing versatile opportunities for gaining insights into the biomolecular processes occurring in donors, recipients, and grafts. To achieve this, adequate quality and numbers of biological samples are required. Whilst access to donor samples is facilitated by initiatives such as the QUOD biobank, an adequately powered biobank allowing exploration of recipient-related aspects in long-term transplant outcomes is missing. Rich, yet unverified resources of recipient material are the serum repositories present in the immunological laboratories of kidney transplant centers that prospectively collect recipient sera for immunological monitoring. However, it is yet unsure whether these samples are also suitable for -omics applications, since such clinical samples are collected and stored by individual centers using non-uniform protocols and undergo an undocumented number of freeze–thaw cycles. Whilst these handling and storage aspects may affect individual proteins and metabolites, it was reasoned that incidental handling/storage artifacts will have a limited effect on a theoretical network (pathway) analysis. To test the potential of such long-term stored clinical serum samples for pathway profiling, we submitted these samples to discovery proteomics and metabolomics.MethodsA mass spectrometry-based shotgun discovery approach was used to obtain an overview of proteins and metabolites in clinical serum samples from the immunological laboratories of the Dutch PROCARE consortium. Parallel analyses were performed with material from the strictly protocolized QUOD biobank.ResultsFollowing metabolomics, more than 800 compounds could be identified in both sample groups, of which 163 endogenous metabolites were found in samples from both biorepositories. Proteomics yielded more than 600 proteins in both groups. Despite the higher prevalence of fragments in the clinical, non-uniformly collected samples compared to the biobanked ones (42.5% vs 26.5% of their proteomes, respectively), these fragments could still be connected to their parent proteins. Next, the proteomic and metabolomic profiles were successfully mapped onto theoretical pathways through integrated pathway analysis, which showed significant enrichment of 79 pathways.ConclusionsThis feasibility study demonstrated that long-term stored serum samples from clinical biorepositories can be used for qualitative proteomic and metabolomic pathway analysis, a notion with far-reaching implications for all biomedical, long-term outcome-dependent research questions and studies focusing on rare events.

Five decades of clinical ABO-incompatible liver transplantation research: a bibliometric analysis.

Five decades of clinical ABO-incompatible liver transplantation research: a bibliometric analysis.

Unveiling Hidden Disparities: Evaluating US Multiple Listing Practices in Lung Transplantation

BackgroundMultiple listing (ML) is a practice utilized to increase the potential for transplant but is controversial due to concerns that it disproportionately benefits patients with greater access to healthcare resources. Research QuestionIs there disparity in ML practices based on social deprivation in the United States and does ML lead to quicker time to transplant? Study design and methodsA retrospective cohort study of adult (>18 years old) lung transplant candidates listed for transplant (2005-2018) was conducted. Exclusion criteria included heart only or heart and lung transplant and patients relisted during the observation period. Data were obtained from the UNOS Standard Transplant Analysis and Research File. The first exposure of interest was social deprivation index (SDI) with a primary outcome of ML status, to assess disparities between ML and SL participants. The second exposure of interest was ML status with a primary outcome of time to transplant, to assess whether implementation of ML leads to quicker time to transplant. Results35,890 subjects were included in the final analysis, of whom 791 (2.2%) were ML and 35,099 (97.8%) were SL. ML participants had lower median level of social deprivation (5 units, more often female (60.0% vs 42.3%), and had lower median LAS (35.3 vs 37.3). ML patients were more likely to be transplanted compared to SL patients (OR=1.42, 95%CI [1.17-1.73]), but there was a significantly quicker time to transplant only for whom ML was early (within 6 months of initial listing) (sHR=1.17, 95%CI [1.04-1.32]). InterpretationML is an uncommon practice with disparities existing between ML and SL patients on the basis of several factors including social deprivation. ML patients are more likely to be transplanted, but only if they ML early in their transplant candidacy. With changing allocation guidelines, it is yet to be seen how ML will change with the implementation of continuous distribution.

Epidemiology of Diffuse Alveolar Hemorrhage in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary toxicity that can arise after hematopoietic cell transplantation (HCT). Risk factors and outcomes are not well understood owing to a sparsity of cases spread across multiple centers. The objectives of this epidemiologic study were to characterize the incidence, outcomes, transplantation-related risk factors and comorbid critical care diagnoses associated with post-HCT DAH. Retrospective analysis was performed in a multicenter cohort of 6995 patients age ≤21 years who underwent allogeneic HCT between 2008 and 2014 identified through the Center for International Blood and Marrow Transplant Research registry and cross-matched with the Virtual Pediatric Systems database to obtain critical care characteristics. A multivariable Cox proportional hazard model was used to determine risk factors for DAH. Logistic regression models were used to determine critical care diagnoses associated with DAH. Survival outcomes were analyzed using both a landmark approach and Cox regression, with DAH as a time-varying covariate. DAH occurred in 81 patients at a median of 54 days post-HCT (interquartile range, 23 to 160 days), with a 1-year post-transplantation cumulative incidence probability of 1.0% (95% confidence interval [CI], .81% to 1.3%) and was noted in 7.6% of all pediatric intensive care unit patients. Risk factors included receipt of transplantation for nonmalignant hematologic disease (reference: malignant hematologic disease; hazard ratio [HR], 1.98; 95% CI, 1.22 to 3.22; P = .006), use of a calcineurin inhibitor (CNI) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis (referent: CNI plus methotrexate; HR, 1.89; 95% CI, 1.07 to 3.34; P = .029), and grade III-IV acute GVHD (HR, 2.67; 95% CI, 1.53-4.66; P < .001). Critical care admitted patients with DAH had significantly higher rates of systemic hypertension, pulmonary hypertension, pericardial disease, renal failure, and bacterial/viral/fungal infections (P < .05) than those without DAH. From the time of DAH, median survival was 2.2 months, and 1-year overall survival was 26% (95% CI, 17% to 36%). Among all HCT recipients, the development of DAH when considered was associated with a 7-fold increase in unadjusted all-cause post-HCT mortality (HR, 6.96; 95% CI, 5.42 to 8.94; P < .001). In a landmark analysis of patients alive at 2 months post-HCT, patients who developed DAH had a 1-year overall survival of 33% (95% CI, 18% to 49%), compared to 82% (95% CI, 81% to 83%) for patients without DAH (P < .001). Although DAH is rare, it is associated with high mortality in the post-HCT setting. Our data suggest that clinicians should have a heightened index of suspicion of DAH in patients with pulmonary symptoms in the context of nonmalignant hematologic indication for HCT, use of CNI + MMF as GVHD prophylaxis, and severe acute GVHD. Further investigations and validation of modifiable risk factors are warranted given poor outcomes.