Michael Abecassis

Background Research on posttransplant care has predominantly focused on predictors of readmission with little attention to emergency department (ED) visits. The goal of this study was to describe early postoperative ED care of transplant recipients. Methods A secondary database analysis of adult patients who underwent abdominal organ transplantation between January 1, 2008, and December 31, 2013, and sought ED care within 1 year after transplantation was conducted. Survival was compared using the Kaplan-Meier method with log-rank test. Cox proportional hazards regression analysis was performed to adjust for pertinent covariates Results A total of 1900 abdominal organ transplants were performed during the study period. Of these, 37% (N = 711) transplant recipients sought care in the ED (1343 total visits) with 1.89 mean ED visits per recipient. Of recipients seen in the ED, 58% received a kidney transplant and 28% received a liver transplant, with 45% of recipients presenting within the first 60 postoperative days. The most common chief complaints were gastroenterological (17%) and abnormal laboratory values or vital signs (17%). In total, 74% of recipients were readmitted and 50% of admitted patients were discharged in less than 24 hours. Transplant recipients with ED visits had lower 3-year graft (81% vs 87%; P < 0.001) and patient (89% vs 93%; P = 0.002) survival. Conclusions Transplant recipients have a high frequency of ED visits in the first posttransplantation year and high rates of subsequent hospital admission. Further investigation is needed to understand what drives recipient presentation to the ED and create care models that achieve the best outcomes.

Cytomegalovirus (CMV) gene expression is repressed in latency due to heterochromatinization of viral genomes. In murine CMV (MCMV) latently infected mice, viral genomes are bound to histones with heterochromatic modifications, to enzymes that mediate these modifications, and to adaptor proteins that may recruit co-repressor complexes. Kinetic analyses of repressor binding show that these repressors are recruited at the earliest time of infection, suggesting that latency may be the default state. Kidney transplantation leads to epigenetic reprogramming of latent viral chromatin and reactivation of immediate early gene expression. Inflammatory signaling pathways, which activate transcription factors that regulate the major immediate early promoter (MIEP), likely mediate the switch in viral chromatin.

Proteomic technology has advanced steadily since the development of 'soft-ionization' techniques for mass-spectrometry-based molecular identification more than two decades ago. Now, the large-scale analysis of proteins (proteomics) is a mainstay of biological research and clinical translation, with researchers seeking molecular diagnostics, as well as protein-based markers for personalized medicine. Proteomic strategies using the protease trypsin (known as bottom-up proteomics) were the first to be developed and optimized and form the dominant approach at present. However, researchers are now beginning to understand the limitations of bottom-up techniques, namely the inability to characterize and quantify intact protein molecules from a complex mixture of digested peptides. To overcome these limitations, several laboratories are taking a whole-protein-based approach, in which intact protein molecules are the analytical targets for characterization and quantification. We discuss these top-down techniques and how they have been applied to clinical research and are likely to be applied in the near future. Given the recent improvements in mass-spectrometry-based proteomics and stronger cooperation between researchers, clinicians and statisticians, both peptide-based (bottom-up) strategies and whole-protein-based (top-down) strategies are set to complement each other and help researchers and clinicians better understand and detect complex disease phenotypes.

Immunosuppression (IS) withdrawal from calcineurin inhibitors is only possible in ˜20% of liver transplant recipients. However, mammalian target of rapamycin inhibitors (e.g., sirolimus; SRL) appear to be more immunoregulatory and might promote a tolerant state for withdrawal. Our aim was to determine whether systemic (i.e., blood, marrow, and allograft) signatures of immunoregulation are promoted by conversion from tacrolimus (TAC) to SRL. We therefore performed the following serial assays before and after SRL conversion in liver transplant recipients to test for enhanced markers of immunoregulation: (1) flow-cytometry immunophenotyping of peripheral blood mononuclear cells (PBMCs) and bone marrow aspirates for regulatory T cells (Tregs) (e.g., CD4⁺CD25⁺⁺⁺FOXP3⁺) and regulatory dendritic cells (DCregs) (immunoglobulin-like transcript 3⁺/4⁺); (2) liver biopsy immunohistochemical staining (e.g., FOXP3:CD3 and CD4:CD8 ratios) and immunophenotyping of biopsy-derived Tregs after growth in culture; (3) effects of pre- versus postconversion sera on Treg generation in mixed lymphocyte reactions; (4) peripheral blood nonspecific CD4 responses; and (5) peripheral blood gene transcripts and proteomic profiles. We successfully converted 20 nonimmune, nonviremic recipients (age, 57.2 ± 8.0; 3.5 ± 2.1 years post–liver transplantation) from TAC to SRL for renal dysfunction. Our results demonstrated significant increases in Tregs in PBMCs and marrow and DCregs in PBMCs (P < 0.01) after conversion. In biopsy staining, FOXP3:CD3 and CD4:CD8 ratios were significantly higher after conversion and a number of biopsy cultures developed new or higher FOXP3⁺ cell growth. Nonspecific CD4 responses did not change. Both pre- and postconversion sera inhibited mixed lymphocyte reactions, although only TAC sera suppressed Treg generation. Finally, 289 novel genes and 22 proteins, several important in immunoregulatory pathways, were expressed after conversion. Conclusions: TAC to SRL conversion increases systemic Tregs, DCregs, and immunoregulatory proteogenomic signatures in liver transplant recipients and may therefore facilitate IS minimization or withdrawal. (Hepatology 2013)