Trials Of Transplantation Research Articles

Effects of biological sex mismatch on neural progenitor cell transplantation for spinal cord injury in mice

Despite advancement of neural progenitor cell transplantation to spinal cord injury clinical trials, there remains a lack of understanding of how biological sex of transplanted cells influences outcomes after transplantation. To address this, we transplanted GFP-expressing sex-matched, sex-mismatched, or mixed donor cells into sites of spinal cord injury in adult male and female mice. Biological sex of the donor cells does not influence graft neuron density, glial differentiation, formation of the reactive glial cell border, or graft axon outgrowth. However, male grafts in female hosts feature extensive hypervascularization accompanied by increased vascular diameter and perivascular cell density. We show greater T-cell infiltration within male-to-female grafts than other graft types. Together, these findings indicate a biological sex-specific immune response of female mice to male donor cells. Our work suggests that biological sex should be considered in the design of future clinical trials for cell transplantation in human injury.

248.12: Critically Important Outcomes for Infection in Trials in Kidney Transplantation: An International Survey of Patients, Caregivers and Health Professionals

Background: Infections are a common complication following kidney transplantation, but are reported inconsistently in clinical trials. This study aimed to identify the infection outcomes of highest priority for patients/caregivers and health professionals to inform a core outcome set to be reported in all kidney transplant clinical trials. Methods: In an international online survey, participants rated the absolute importance of 16 infections and 8 severity dimensions on 9-point Likert Scales, with 7-9 being critically important. Relative importance was determined using a best-worst scale. Means and proportions of the Likert-scale ratings and best-worst preference scores were calculated. Results: 353 healthcare professionals (19 who identified as both patients/caregiver and healthcare professionals) and 220 patients/caregivers (190 patients, 22 caregivers, 8 who identified as both) from 55 countries completed the survey. Both healthcare professionals and patients/caregivers rated bloodstream (mean 8.4 and 8.5 respectively; aggregate 8.5), kidney/bladder (mean 7.9 and 8.4; aggregate 8.1) and BK virus (mean 8.1 and 8.6; aggregate 8.3) as the top 3 most critically important infection outcomes, whilst infectious death (mean 8.8 and 8.6; aggregate 8.7), impaired graft function (mean 8.4 and 8.7; aggregate 8.5) and admission to the intensive care unit (mean 8.2 and 8.3; aggregate 8.2) were the top 3 severity dimensions. Relative importance (best-worst) scores were consistent. Conclusions: Healthcare professionals and patients/caregivers consistently identified bloodstream infection, kidney/bladder infections and BK virus as the three most important infection outcomes, and infectious death, admission to intensive care unit and infection impairing graft function as the three most important infection severity outcomes.

Choosing to Die.

Two articles in the September-October 2022 issue of the Hastings Center Report discuss health-related reasons that people might have to actively bring their lives to an end. In one, Brent Kious considers the situation of a person who, because of illness, becomes a burden on loved ones. A person in such a situation might prefer to die, and Kious argues that, while there is no obligation to hasten one's death, the choice to do so could sometimes be reasonable. In a second article, Henri Wijsbek and Thomas Nys discuss a case in the Netherlands in which a woman with severe dementia was euthanized at a point when her advance euthanasia directive did not align with what she said, when asked, about death. Wijsbek and Nys defend the authority of her advance directive against a range of objections. In a third article, Henry Silverman and Patrick Odonkor, physicians at the University of Maryland Medical Center, where the first pig-to-human heart transplantation was performed in early 2022, develop recommendations for clinical trials of porcine heart transplantation. And an essay in the issue criticizes the allocation recommendations developed for Covid-19 vaccines by the U.S. Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices.

P2.02: Save the Environment: Liver Transplantation Restores A Circulating Environment That Supports Healthy Platelet Aggregation Within Two Hours of Reperfusion

Introduction: Thrombocytopenia in patients with cirrhosis is common and likely multifactorial secondary to splenic sequestration, decreased thrombopoietin production, shear stress of portal hypertension, and toxic suppression of megakaryocytopoiesis. However, there is no clear association of absolute platelet count with risk of hemorrhage. Rather, platelet dysfunction, in the pro-inflammatory vasodilatory state of chronic liver disease, may be of greater importance. There is evidence that the circulating environment of severe tissue injury and shock impairs platelet aggregation in trauma patients. Using this model as our template, we hypothesized that healthy platelets treated with serum from cirrhotic patients pre-transplant would have impaired aggregation compared to those treated with serum post-portal reperfusion. Methods: Serum was collected from liver transplant recipients prior to incision, and two hours following portal reperfusion as part of the Mild Hypothermia and Acute Kidney Injury in Liver Transplantation trial (NCT03534141). Platelets (from male and female healthy platelet donors) were isolated by centrifugation, pelleted, and mixed with each of the following sera (6 of each group): buffer, autologous, gender matched healthy (heterologous), gender matched pre-transplant, and gender matched post-portal reperfusion (12% v/v) for 20min (Fig1A). Baseline aggregation was measured for 10min via multiple impedance aggregometer, then stimulated with a thrombin analog and measured for 15min. Aggregometry responses were quantified by the area under the impedance aggregation curve (AUC), normalized to autologous treated platelets. Statistical analysis was performed using one way ANOVA, with Tukey’s Honest Significant Difference testing post-hoc for pairwise comparisons. Results: Healthy platelet aggregation was markedly impaired upon treatment with pre-transplant serum, but was restored when treated with serum from the same cohort of patients two hours post-portal reperfusion (to levels similar to treatment with healthy sera, Fig1B). Healthy platelet aggregation upon treatment with post-portal reperfusion serum was significantly higher than with pre-transplant serum treatment (median relative AUC 1.4x vs -0.1x, p<0.05; Fig2). Conclusion: Healthy platelets treated with serum from cirrhotic patients immediately prior to liver transplant have impaired aggregation, while treatment with serum from the same patients two hours post-portal reperfusion restores aggregation. This suggests the circulating environment of cirrhosis may induce platelet dysfunction through soluble inhibitors, and that liver transplantation and the healthy plasma administration accompanying the reperfusion phase, may induce swift recovery of platelet aggregation capacity. Future investigations should focus on implications of this including that platelet transfusion may not achieve hemostasis until post portal-reperfusion.

Extremely small and incredibly close: Gut microbes as modulators of inflammation and targets for therapeutic intervention

Chronic inflammation is a hallmark for a variety of disorders and is at least partially responsible for disease progression and poor patient health. In recent years, the microbiota inhabiting the human gut has been associated with not only intestinal inflammatory diseases but also those that affect the brain, liver, lungs, and joints. Despite a strong correlation between specific microbial signatures and inflammation, whether or not these microbes are disease markers or disease drivers is still a matter of debate. In this review, we discuss what is known about the molecular mechanisms by which the gut microbiota can modulate inflammation, both in the intestine and beyond. We identify the current gaps in our knowledge of biological mechanisms, discuss how these gaps have likely contributed to the uncertain outcome of fecal microbiota transplantation and probiotic clinical trials, and suggest how both mechanistic insight and -omics-based approaches can better inform study design and therapeutic intervention.

Pig heart and lung xenotransplantation: Present status.

The recent pig heart transplant in a patient at the University of Maryland Medical Center has stimulated renewed interest in the xenotransplantation of organs from genetically engineered pigs. The barriers to the use of pigs as sources of organs have largely been overcome by 2 approaches - (1) the deletion of expression of the three known pig carbohydrate xenoantigens against which humans have preformed antibodies, and (2) the transgenic introduction of human 'protective' proteins, such as complement-regulatory proteins. These gene modifications, coupled with immunosuppressive therapy based on blockade of the CD40/CD154 costimulation pathway, have resulted in survival of baboons with life-supporting pig heart grafts for almost 9 months. The initial clinical success at the University of Maryland reinforces encouraging preclinical results. It suggests that pig hearts are likely to provide an effective bridge to an allotransplant, but their utility for destination therapy remains uncertain. Because of additional complex immunobiological problems, the same approach has been less successful in preclinical lung xenograft transplantation, where survival is still measured in days or weeks. The first formal clinical trials of pig heart transplantation may include patients who do not have access to an allotransplant, those with contraindications for mechanical circulatory support, those in need of retransplantation or with a high level of panel-reactive antibodies. Infants with complex congenital heart disease, should also be considered.

Effect of Sirolimus vs. Everolimus on CMV-Infections after Kidney Transplantation-A Network Meta-Analysis.

(1) Background: Following renal transplantation, infection with cytomegalovirus (CMV) is a common and feared complication. mTOR-inhibitor (mTOR-I) treatment, either alone or in combination with calcineurininhibitors (CNIs), significantly reduces the CMV incidence after organ transplantation. As of now, there is no information on which mTOR-I, sirolimus (SIR) or everolimus (ERL), has a stronger anti-CMV effect. (2) Methods: The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 1164 trials screened, of which 27 could be included (11,655 pts.). We performed a network meta-analysis to analyze the relative risk of different types of mTOR-I treatment on CMV infection 12 months after transplantation compared to CNI treatment. (3) Results: Four different types of mTOR-I treatment were analyzed in network meta-analyses—SIR mono, ERL mono, SIR with CNI, ERL with CNI. The mTOR-I treatment with the strongest anti-CMV effect compared to a regular CNI treatment was ERL in combination with a CNI (relative risk (RR) 0.27, confidence interval (CI) 0.22–0.32, p < 0.0001). The other mTOR-I therapy groups showed a slightly decreased anti-CMV efficacy (SIR monotherapy (mono): RR 0.35, CI 0.22–0.57, p < 0.001; SIR with CNI: RR 0.43, CI 0.29–0.64, p < 0.0001; ERL mono: RR 0.46, CI 0.22–0.93, p = 0.031). (4) Conclusions: The anti-CMV effect of both mTOR-Is (SRL and ERL) is highly effective, irrespective of the combination with other immunosuppressive drugs. Certain differences with respect to the potency against the CMV could be found between SRL and ERL. Data gained from this analysis seem to support that a combination of ERL and CNI has the most potent anti-CMV efficacy.

Microplastics-perturbed gut microbiota triggered the testicular disorder in male mice: Via fecal microbiota transplantation

Microplastics (MPs), an emerging environmental pollutant, have been clarified to induce testicular disorder in mammals. And the current studies have delineated a correlation between gut microbiota and male reproduction. However, it's still unclear whether gut microbiota gets involved in MPs-induced reproductive toxicity. In this work, we constructed a mouse model drinking 5 μm polystyrene-MPs (PS-MPs) at the concentrations of 100 μg/L and 1000 μg/L for 90 days. Evident histological damage, spermatogenetic disorder and hormones synthesis inhibition were observed in PS-MPs exposed mice. With fecal microbiota transplantation (FMT) trial, the recipient mice exhibited gut microbial alteration, and the elevated abundance of Bacteroides and Prevotellaceae_UCG-001 were positively correlated with testicular disorder according to spearman correlation analysis. Mechanistically, increased proportion of pro-inflammatory bacteria may drive translocation of T helper 17 (Th17) cells, resulting in overproduced interleukin (IL)-17 A and downstream inflammatory response in both the mice exposed to PS-MPs and corresponding recipient mice. In summary, our findings revealed the critical role of gut microbiota in PS-MPs-induced reproductive toxicity, and tried to elucidate the underlying mechanism of gut microbial dysregulation-mediated IL-17 A signaling pathway. Furthermore, this study also provides the research basis for gut microbiota-targeted treatment of male infertility in the future.

Dampened Inflammatory Signalling and Myeloid-Derived Suppressor-Like Cell Accumulation Reduces Circulating Monocytic HLA-DR Density and May Associate With Malignancy Risk in Long-Term Renal Transplant Recipients

BackgroundMalignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients.MethodsA cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks.ResultsMonocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density.ConclusionsDampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association.

Immunologic risk stratification of pediatric heart transplant patients by combining HLAMatchmaker and PIRCHE-II.

Molecular-level human leukocyte antigen (HLA) mismatch is a powerful biomarker of rejection; however, few studies have explored its use in heart transplant recipients, and none have attempted to use the results of separate algorithms synergistically. Here we tested the hypothesis that a combination of HLAMatchmaker and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) can be used to identify more patients at low risk of rejection. We studied 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC) performing class I and II HLA genotyping by next-generation sequencing to determine eplet mismatch (epMM) load and PIRCHE-II score. Correlation with clinical outcomes was performed on 131 cases. Of the 131 patients, 100 without pre-formed donor specific antibody (DSA) were used to identify cutoffs for the Class I, HLA-DR, and HLA-DQ epMM load and PIRCHE-II score for risk of developing post-transplant DSA (epMM: Class I/DR/DQ=9/9/6; PIRCHE-II: 141/116/111) and antibody-mediated rejection (ABMR) (epMM: 9/8/8; PIRCHE-II: 157/80/201). Patients with above cut-off epMM load appear to be less likely to develop DSA and ABMR if their PIRCHE-II score is below cut-off (high epMM/high PIRCHE-II: 12.3%-20.3% DSA and 9%-13.5% ABMR vs high epMM/low PIRCHE-II: 4%-10% DSA and 0%-2% ABMR). For the first time in a pediatric heart transplant cohort, immunologic risk cut-offs for DSA and ABMR have been established. When used together, epMM load and PIRCHE-II score allow us to reclassify a portion of cases with high epMM load as having a lower risk for developing DSA and ABMR.

Human IL-17 and TNF-α Additively or Synergistically Regulate the Expression of Proinflammatory Genes, Coagulation-Related Genes, and Tight Junction Genes in Porcine Aortic Endothelial Cells.

Immune rejection is the major limitation for porcine xenograft survival in primate recipients. Proinflammatory cytokines play important roles in immune rejection and have been found to mediate the pathological effects in various clinical and experimental transplantation trials. IL-17 and TNF-α play critical pathological roles in immune disorders, such as psoriasis and rheumatoid arthritis. However, the pathological roles of human IL-17 (hIL-17) and human TNF-α (hTNF-α) in xenotransplantation remain unclear. Here we found that hIL-17 and hTNF-α additively or synergistically regulate the expression of 697 genes in porcine aortic endothelial cells (PAECs). Overall, 415 genes were found to be synergistically regulated, while 282 genes were found to be additively regulated. Among these, 315 genes were upregulated and 382 genes were downregulated in PAECs. Furthermore, we found that hIL-17 and hTNF-α additively or synergistically induced the expression of various proinflammatory cytokines and chemokines (e.g., IL1α, IL6, and CXCL8) and decreased the expression of certain anti-inflammatory genes (e.g., IL10). Moreover, hIL-17 plus hTNF-α increased the expression of IL1R1 and IL6ST, receptors for IL1 and IL6, respectively, and decreased anti-inflammatory gene receptor expression (IL10R). hIL-17 and hTNF-α synergistically or additively induced CXCL8 and CCL2 expression and consequently promoted primary human neutrophil and human leukemia monocytic cell migration, respectively. In addition, hIL-17 and hTNF-α induced pro-coagulation gene (SERPINB2 and F3) expression and decreased anti-coagulation gene (TFPI, THBS1, and THBD) expression. Additionally, hIL-17 and hTNF-α synergistically decreased occludin expression and consequently promoted human antibody-mediated complement-dependent cytotoxicity. Interestingly, hTNF-α increased swine leukocyte antigen (SLA) class I expression; however, hIL-17 decreased TNF-α-mediated SLA-I upregulation. We concluded that hIL-17 and hTNF-α likely promote the inflammatory response, coagulation cascade, and xenoantibody-mediated cell injury. Thus, blockade of hIL-17 and hTNF-α together might be beneficial for xenograft survival in recipients.

A Systematic Review and Meta-Analysis of Randomized Controlled Trials of Fecal Microbiota Transplantation for the Treatment of Inflammatory Bowel Disease.

Objectives Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease of the gastrointestinal tract, and its prevalence is increasing worldwide. Fecal microbiota transplantation (FMT) is an emerging therapy that modifies the patient's gut microbiota by transplanting feces from a healthy donor to achieve disease remission. However, its efficacy and safety need to be further investigated. Methods PubMed, the Cochrane Library, Web of Science, Embase, and Google Scholar databases (up to 8th November 2021) were searched and literature was screened by title and abstract as well as full text. The primary outcome was clinical remission, with the clinical response as a secondary outcome. Risk ratios (RR) with 95% confidence intervals (CI) were reported. Results A total of 14 trials were included in this study. In terms of clinical remission, FMT had a significant effect compared to placebo (RR = 1.44, 95 CI%: 1.03 to 2.02, I2 = 38%, P=0.03), with no significant risk of study heterogeneity. Moreover, FMT led to significant results in clinical response compared to placebo with moderate between-study heterogeneity (RR = 1.34, 95 CI%: 0.92 to 1.94, I2 = 51%, P=0.12). Subgroup analysis showed a higher clinical remission for fresh fecal FMT (40.9%) than that for frozen fecal FMT (32.2%); the efficacy of gastrointestinal (GI) pretreatment, the severity of disease, route of administration, and the donor selection remain unclear and require more extensive study. Safety analysis concluded that most adverse events were mild and self-resolving. The microbiological analysis found that the patient's gut microbiota varied in favor of the donor, with increased flora diversity and species richness. Conclusion FMT is a safe, effective, and well-tolerated therapy. Studies have found that fresh fecal microbiota transplant can increase clinical remission rates. However, more randomized controlled trials and long-term follow-ups are needed to assess its long-term effectiveness and safety.

One-year immunologic outcomes of lung transplantation utilizing hepatitis C-viremic donors.

Little is known about the effects of hepatitis C viremia on immunologic outcomes in the era of direct-acting antivirals. We conducted a prospective, single-arm trial of lung transplantation from hepatitis C-infected donors into hepatitis C-naïve recipients (n=21). Recipients were initiated on glecaprevir-pibrentasvir immediately post-transplant and were continued on therapy for a total of 8weeks. A control group of recipients of hepatitis C-negative lungs were matched 1:1 on baseline variables (n=21). The primary outcome was the frequency of acute cellular rejection over 1-year post-transplant. Treatment with glecaprevir-pibrentasvir was well tolerated and resulted in viremia clearance after a median of 16 days of therapy (IQR 10-24 days). At one year, there was no difference in incidence of acute cellular rejection (71.4%vs. 85.7%, P=.17) or rejection requiring treatment (33.3%vs. 57.1%, P=.12). Mean cumulative acute rejection scores were similar between groups (.46 [SD ± .53] vs. .52 [SD± .37], P=.67). Receipt of HCV+ organs was not associated with acute rejection on unadjusted Cox regression analysis (HR .55, 95% CI .28-1.11, P=.09), or when adjusted for risk factors known to be associated with acute rejection (HR .57, 95% CI .27-1.21, P=.14). Utilization of hepatitis C infected lungs with immediate treatment leads to equivalent immunologic outcomes at 1 year.

Regenerative and restorative medicine for eye disease.

Causes of blindness differ across the globe; in higher-income countries, most blindness results from the degeneration of specific classes of cells in the retina, including retinal pigment epithelium (RPE), photoreceptors, and retinal ganglion cells. Advances over the past decade in retinal regenerative medicine have allowed each of these cell types to be produced ex vivo from progenitor stem cells. Here, we review progress in applying these technologies to cell replacement - with the goal of vision restoration in degenerative disease. We discuss the landscape of human clinical trials for RPE transplantation and advanced preclinical studies for other cell types. We also review progress toward in situ repair of retinal degeneration using endogenous progenitor cells. Finally, we provide a high-level overview of progress toward prosthetic ocular vision restoration, including advanced photovoltaic devices, opsin-based gene therapy, and small-molecule photoswitches. Progress in each of these domains is at or near the human clinical-trial stage, bringing the audacious goal of vision restoration within sight.

Enrollment disparities in non-Hodgkin lymphoma clinical trials.

e18594 Background: Disparities in cancer clinical trials limit the real-world reproducibility of their results while remaining inapplicable to excluded patients (pts) like those living with chronic viral infections. Non-Hodgkin lymphoma (NHL) has an incidence distributed heterogeneously among races and is associated with chronic viral infections such as HIV, Hepatitis B (Hep B) and Hepatitis C (Hep C). Given these epidemiological characteristics, we assessed demographic representation in NHL clinical trials to identify areas for improvement. Methods: Clinicaltrials.gov was queried for NHL trials and specified for completed, interventional, phase 2, 3 &amp; 4 trials, with results and with recruitment in the US. Trials including malignancies other than NHL, with enrollment outside of the US or lacking reported demographics on clinicaltrials.gov or trial publications were excluded. SEER 21 and the 2020 US census were used to calculate incident cases for each specified subgroup. Enrollment fraction (EF) was defined as the number of trial enrollees divided by the estimated US cases in each subgroup. We compared EF between subgroups utilizing odds ratios (OR) with p-value &lt; 0.05 deemed significant. Results: Of 176 trials meeting criteria, 64 (36.4%) reported ethnicity and 79 (44.9%) reported race. EF of Black, Asian/Pacific Islander, American Indian and Hispanic (HSP) pts were significantly lower compared to White and non-HSP pts (Table). Racial minorities were less likely to be enrolled in relapsed/refractory trials (OR 0.31 - 0.57 p &lt; 0.008) compared to White pts but all were equally likely to be enrolled in front-line trials. HSP pts had a lower EF compared to non-HSP pts in both relapsed/refractory and front-line trials (OR 0.57, 0.46 p &lt; 0.0001). Black and HSP pts were also less likely to be enrolled in hematopoietic stem cell transplant (HSCT) trials (OR 0.27, 0.74, p &lt; 0.003). Women had a significantly lower EF compared to men (Table). 150 trials had inclusion/exclusion criteria specific for chronic viral infections: 141 (94%) excluded pts with HIV, 108 (72%) with chronic Hep B and 103 (69%) with Hep C. Conclusions: Our study demonstrates underrepresentation of not only women, but also of Black, Asian/Pacific Islanders, American Indian and HSP pts in NHL trials, especially in relapsing/refractory and HSCT trials. Moreover, pts living with chronic viral infections are systematically excluded by trial criteria. It is essential that trials reporting on safety, toxicity and efficacy represent the true patient population to limit ascertainment bias and improve external validity of results.[Table: see text]

Whole transcriptome profiling of prospective endomyocardial biopsies reveals prognostic and diagnostic signatures of cardiac allograft rejection.

Heart transplantation provides a significant improvement in survival and quality of life for patients with end-stage heart disease, however many recipients experience different levels of graft rejection that can be associated with significant morbidities and mortality. Current clinical standard-of-care for the evaluation of heart transplant acute rejection (AR) consists of routine endomyocardial biopsy (EMB) followed by visual assessment by histopathology for immune infiltration and cardiomyocyte damage. We assessed whether the sensitivity and/or specificity of this process could be improved upon by adding RNA sequencing (RNA-seq) of EMBs coupled with histopathological interpretation. Up to 6 standard-of-care, or for-cause EMBs, were collected from 26 heart transplant recipients from the prospective observational Clinical Trials of Transplantation (CTOT)-03 study, during the first 12-months post-transplant and subjected to RNA-seq (n=125 EMBs total). Differential expression and random-forest-based machine learning were applied to develop signatures for classification and prognostication. Leveraging the unique longitudinal nature of this study, we show that transcriptional hallmarks for significant rejection events occur months before the actual event and are not visible using traditional histopathology. Using this information, we identified a prognostic signature for 0R/1R biopsies that with 90% accuracy can predict whether the next biopsy will be 2R/3R. RNA-seq-based molecular characterization of EMBs shows significant promise for the early detection of cardiac allograft rejection.

A phase I/IIa clinical trial of autologous hematopoietic stem cell transplantation in amyotrophic lateral sclerosis.

To verify the safety and potential effect on ALS progression of a low-intensity immunosuppressive regimen followed by autologous hematopoietic stem cell transplantation (aHSCT) in amyotrophic lateral sclerosis (ALS) patients. ALS eligible patients underwent a set of clinical and laboratory evaluations at T-4 (screening), T-1 (pre-treatment visit), and for the 12 consecutive months after treatment (T3, T6, T9, T12). We evaluated the tolerability of the procedure, its efficacy on clinical course and quality of life (QoL). Eight of the 11 ALS patients enrolled received the established immunoablative protocol. The procedure was well tolerated and side effects were those expected. One patient died 4months after the conditioning regimen and another patient underwent tracheotomy just before T3 for a sudden respiratory failure, but he is still alive 4years after the procedure without being ventilated any more. A third patient died 10months after conditioning. In the other cases, there was no statistical difference in all functional measures and QoL pre- and post-treatment; however, a transitory slopes' reduction of ALSFRS-R and seated SVC% after the conditioning procedures was reported. Moreover, although not statistically significant, trends of reduction of CD4 + and increment of CD8 + were found. aHSCT was overall well tolerated, but it was not followed by any significant modification in disease progression. Considering the negative results of this small trial, further studies aimed to evaluate the possible efficacy of the aHSCT using a higher-intensity regimen should be carefully and with caution evaluated.

Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson\u2019s disease

In pursuit of treating Parkinson’s disease with cell replacement therapy, differentiated induced pluripotent stem cells (iPSC) are an ideal source of midbrain dopaminergic (mDA) cells. We previously established a protocol for differentiating iPSC-derived post-mitotic mDA neurons capable of reversing 6-hydroxydopamine-induced hemiparkinsonism in rats. In the present study, we transitioned the iPSC starting material and defined an adapted differentiation protocol for further translation into a clinical cell transplantation therapy. We examined the effects of cellular maturity on survival and efficacy of the transplants by engrafting mDA progenitors (cryopreserved at 17 days of differentiation, D17), immature neurons (D24), and post-mitotic neurons (D37) into immunocompromised hemiparkinsonian rats. We found that D17 progenitors were markedly superior to immature D24 or mature D37 neurons in terms of survival, fiber outgrowth and effects on motor deficits. Intranigral engraftment to the ventral midbrain demonstrated that D17 cells had a greater capacity than D24 cells to innervate over long distance to forebrain structures, including the striatum. When D17 cells were assessed across a wide dose range (7,500-450,000 injected cells per striatum), there was a clear dose response with regards to numbers of surviving neurons, innervation, and functional recovery. Importantly, although these grafts were derived from iPSCs, we did not observe teratoma formation or significant outgrowth of other cells in any animal. These data support the concept that human iPSC-derived D17 mDA progenitors are suitable for clinical development with the aim of transplantation trials in patients with Parkinson’s disease.

The Jarvik 2000 Left Ventricular Assist Device: Results of the United States Bridge to Transplant Trial.

The Jarvik 2000 bridge to transplant investigational device exemption study was a multicentered, prospective study of 150 UNOS status I patients implanted with the Jarvik 2000 between 2005 and 2012. During the study period, there were numerous modifications of the system that included converting from pin to cone bearings. Results were analyzed for three cohorts: total (n = 150), pin (n = 128), and cone (n = 22). Baseline demographics included age (52 ± 13), gender (79% male), size (BSA 1.98), and etiology (37% idiopathic dilated cardiomyopathy; 43% Ischemic). Seventy percent of patients were either INTERMACS 1 or 2. The primary endpoint-defined as successful transplantation or listing at 180 days (prespecified at 65%; 95% lower CI: 57%)-was successfully achieved for the total cohort (67.3%; 95% CI: 59.5%-74.3%; p = 0.006). In subgroup analysis of the more contemporary, cone-bearing group, the primary endpoint was met in 91% (95% CI: 72%-97.5%; p = 0.001). Compared with pin patients, cone-bearing patients had less hemolysis as well as decreased end-organ dysfunction. Functional and quality of life scores improved after implantation independent type of bearing. In conclusion, despite a particularly sick patient population, the Jarvik 2000 was shown to be effective in supporting the advanced HF patient.

Critically important outcomes for infection in trials in kidney transplantation: An international survey of patients, caregivers, and health professionals.

Infections are a common complication following kidney transplantation, but are reported inconsistently in clinical trials. This study aimed to identify the infection outcomes of highest priority for patients/caregivers and health professionals to inform a core outcome set to be reported in all kidney transplant clinical trials. In an international online survey, participants rated the absolute importance of 16 infections and eight severity dimensions on 9-point Likert Scales, with 7-9 being critically important. Relative importance was determined using a best-worst scale. Means and proportions of the Likert-scale ratings and best-worst preference scores were calculated. 353 healthcare professionals (19 who identified as both patients/caregiver and healthcare professionals) and 220 patients/caregivers (190 patients, 22 caregivers, eight who identified as both) from 55 countries completed the survey. Both healthcare professionals and patients/caregivers rated bloodstream (mean 8.4 and 8.5, respectively; aggregate 8.5), kidney/bladder (mean 7.9and 8.4; aggregate 8.1), and BK virus (mean 8.1 and 8.6; aggregate 8.3) as the top three most critically important infection outcomes, whilst infectious death (mean 8.8 and 8.6; aggregate 8.7), impaired graft function (mean 8.4 and 8.7; aggregate 8.5) and admission to the intensive care unit (mean 8.2 and 8.3; aggregate 8.2) were the top three severity dimensions. Relative importance (best-worst) scores were consistent. Healthcare professionals and patients/caregivers consistently identified bloodstream infection, kidney/bladder infections, and BK virus as the three most important infection outcomes, and infectious death, admission to intensive care unit and infection impairing graft function as the three most important infection severity outcomes.