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Reactivation of latent cytomegalovirus remains an important complication after transplant. Although immunosuppression (IS) has been implicated as a primary cause, we have previously shown that the implantation response of a kidney allograft can lead to early transcriptional activation of latent murine cytomegalovirus (MCMV) genes in an immune-competent host and to MCMV reactivation and dissemination to other organs in a genetically immune-deficient recipient. We now describe a model that allows us to separately analyze the impact of the implantation effect vs that of a clinically relevant IS regimen. Treatment with IS of latently infected mice alone does not induce viral reactivation, but transplant of latently infected allogeneic kidneys combined with IS facilitates MCMV reactivation in the graft and dissemination to other organs. The IS regimen effectively dampens allo-immune inflammatory pathways and depletes recipient anti-MCMV but does not affect ischemia-reperfusion injury pathways. MCMV reactivation similar to that seen in allogeneic transplants combined with also occurs after syngeneic transplants. Thus, our data strongly suggest that while ischemia-reperfusion injury of the implanted graft is sufficient and necessary to initiate transcriptional reactivation of latent MCMV ("first hit"), IS is permissive to the first hit and facilitates dissemination to other organs ("second hit").

Assessment of major adverse cardiovascular events (MACE) after liver transplantation (LT) has been limited by the lack of a multicenter study with detailed clinical information. An integrated database linking information from the University HealthSystem Consortium and the Organ Procurement and Transplant Network was analyzed using multivariate Poisson regression to assess factors associated with 30- and 90-day MACE after LT (February 2002 to December 2012). MACE was defined as myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), cardiac arrest, pulmonary embolism, and/or stroke. Of 32 810 recipients, MACE hospitalizations occurred in 8% and 11% of patients at 30 and 90 days, respectively. Recipients with MACE were older and more likely to have a history of nonalcoholic steatohepatitis (NASH), alcoholic cirrhosis, MI, HF, stroke, AF and pulmonary and chronic renal disease than those without MACE. In multivariable analysis, age >65 years (incidence rate ratio [IRR] 2.8, 95% confidence interval [95% CI] 1.8-4.4), alcoholic cirrhosis (IRR 1.6, 95% CI 1.2-2.2), NASH (IRR 1.6, 95% CI 1.1-2.4), pre-LT creatinine (IRR 1.1, 95% CI 1.04-1.2), baseline AF (IRR 6.9, 95% CI 5.0-9.6) and stroke (IRR 6.3, 95% CI 1.6-25.4) were independently associated with MACE. MACE was associated with lower 1-year survival after LT (79% vs. 88%, p < 0.0001). In a national database, MACE occurred in 11% of LT recipients and had a negative impact on survival. Pre-LT AF and stroke substantially increase the risk of MACE, highlighting potentially high-risk LT candidates.

The ability of two three-dimensional bioscaffold systems to reverse the primary limitations of induced pluripotent stem cell (iPSC)-derived hepatocytes was compared. Proliferation and function of iPSC hepatocytes were significantly enhanced when cultured within scaffolds made from extracellular matrix (ECM). This ECM scaffold enhanced phenotypic maturation of iPSC hepatocytes compared with other platforms, likely owing to its biologically diverse makeup., Induced pluripotent stem cells (iPSCs) are new diagnostic and potentially therapeutic tools to model disease and assess the toxicity of pharmaceutical medications. A common limitation of cell lineages derived from iPSCs is a blunted phenotype compared with fully developed, endogenous cells. We examined the influence of novel three-dimensional bioartificial microenvironments on function and maturation of hepatocyte-like cells differentiated from iPSCs and grown within an acellular, liver-derived extracellular matrix (ECM) scaffold. In parallel, we also compared a bioplotted poly-l-lactic acid (PLLA) scaffold that allows for cell growth in three dimensions and formation of cell-cell contacts but is infused with type I collagen (PLLA-collagen scaffold) alone as a “deconstructed” control scaffold with narrowed biological diversity. iPSC-derived hepatocytes cultured within both scaffolds remained viable, became polarized, and formed bile canaliculi-like structures; however, cells grown within ECM scaffolds had significantly higher P450 (CYP2C9, CYP3A4, CYP1A2) mRNA levels and metabolic enzyme activity compared with iPSC hepatocytes grown in either bioplotted PLLA collagen or Matrigel sandwich control culture. Additionally, the rate of albumin synthesis approached the level of primary cryopreserved hepatocytes with lower transcription of fetal-specific genes, α-fetoprotein and CYP3A7, compared with either PLLA-collagen scaffolds or sandwich culture. These studies show that two acellular, three-dimensional culture systems increase the function of iPSC-derived hepatocytes. However, scaffolds derived from ECM alone induced further hepatocyte maturation compared with bioplotted PLLA-collagen scaffolds. This effect is likely mediated by the complex composition of ECM scaffolds in contrast to bioplotted scaffolds, suggesting their utility for in vitro hepatocyte assays or drug discovery. Significance Through the use of novel technology to develop three-dimensional (3D) scaffolds, the present study demonstrated that hepatocyte-like cells derived via induced pluripotent stem cell (iPSC) technology mature on 3D extracellular matrix scaffolds as a result of 3D matrix structure and scaffold biology. The result is an improved hepatic phenotype with increased synthetic and catalytic potency, an improvement on the blunted phenotype of iPSC-derived hepatocytes, a critical limitation of iPSC technology. These findings provide insight into the influence of 3D microenvironments on the viability, proliferation, and function of iPSC hepatocytes to yield a more mature population of cells for cell toxicity studies and disease modeling.

We sought to evaluate the prevalence of medication understanding and non-adherence of entire drug regimens among kidney transplantation (KT) recipients and to examine associations of these exposures with clinical outcomes. Structured, in-person interviews were conducted with 99 adult KT recipients between 2011 and 2012 at two transplant centers in Chicago, IL; and Atlanta, GA. Nearly, one-quarter (24%) of participants had limited literacy as measured by the Rapid Estimate of Adult Literacy in Medicine test; patients took a mean of 10 (SD=4) medications and 32% had a medication change within the last month. On average, patients knew what 91% of their medications were for (self-report) and demonstrated proper dosing (via observed demonstration) for 83% of medications. Overall, 35% were non-adherent based on either self-report or tacrolimus level. In multivariable analyses, fewer months since transplant and limited literacy were associated with non-adherence (all P

Recent studies utilizing transcriptomics, metabolomics, and bottom up proteomics have identified molecular signatures of kidney allograft pathology. Although these results make significant progress toward non-invasive differential diagnostics of dysfunction of a transplanted kidney, they provide little information on the intact, often modified, protein molecules present during progression of this pathology. Because intact proteins underpin diverse biological processes, measuring the relative abundance of their modified forms promises to advance mechanistic understanding, and might provide a new class of biomarker candidates. Here, we used top down proteomics to inventory the modified forms of whole proteins in peripheral blood mononuclear cells (PBMCs) taken at the time of kidney biopsy for 40 kidney allograft recipients either with healthy transplants or those suffering acute rejection. Supported by gas-phase fragmentation of whole protein ions during tandem mass spectrometry, we identified 344 proteins mapping to 2,905 distinct molecular forms (proteoforms). Using an initial implementation of a label-free approach to quantitative top down proteomics, we obtained evidence suggesting relative abundance changes in 111 proteoforms between the two patient groups. Collectively, our work is the first to catalog intact protein molecules in PBMCs and suggests differentially abundant proteoforms for further analysis.

Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation.

Background The purpose of this study is to assess operative, post-operative, and long-term outcomes in patients who underwent radiation lobectomy (RL) for tumor control and/or hypertrophy of small future liver remnant (FLR) prior to resection. Methods Right lobar +/− segment 4 radioembolization was performed prior to lobectomy/tri-segmentectomy in patients with hepatic tumor but inadequate FLR. Parenchymal/tumor volumes were calculated from pre/post-RL imaging; FLR/%FLR hypertrophy were determined. Complications were graded by the Clavien-Dindo classification. Results Thirteen patients (HCC n = 10, cholangiocarcinoma n = 2, mCRC n = 1) underwent RL prior to resection. The median time between RL and post-RL imaging was 40 days (23–190 days); the median time to resection was 86 days (30–210 days). Median FLR increased significantly [pre: 33% (22–43%); post: 43% (29–69%), P 50% pathologic necrosis. Median follow up time after surgery was 604 days (144–1,416 days); one death occurred. Conclusions In this preliminary study, radiation lobectomy was a safe and effective method to achieve remnant liver hypertrophy while providing tumor control. This approach may facilitate safe resection and favorable post-operative outcomes.J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

Reactivation of latent human cytomegalovirus is a significant infectious complication of organ transplantation and current therapies target viral replication once reactivation of latent virus has already occurred. The specific molecular pathways that activate viral gene expression in response to transplantation are not well understood. Our studies aim to identify these factors, with the goal of developing novel therapies that prevent transcriptional reactivation in transplant recipients. Murine cytomegalovirus (MCMV) is a valuable model for studying latency and reactivation of CMV in vivo. We previously demonstrated that transplantation of MCMV-latently infected kidneys into allogeneic recipients induces reactivation of immediate early (IE) gene expression and epigenetic reprogramming of the major immediate early promoter (MIEP) within 48 h. We hypothesize that these events are mediated by activation of signalling pathways that lead to binding of transcription factors to the MIEP, including AP-1 and NF-κB. Here we show that transplantation induces rapid activation of several members of the AP-1 and NF-κB transcription factor family and we demonstrate that canonical NF-κB (p65/p50), the junD component of AP-1, and nucleosome remodelling complexes are recruited to the MIEP following transplantation. Proteomic analysis of recipient plasma and transcriptome analysis of kidney RNA identified five extracellular ligands, including TNF, IL-1β, IL-18, CD40L and IL-6, and three intracellular signalling pathways associated with reactivation of IE gene expression. Identification of the factors that mediate activation of these signalling pathways may eventually lead to new therapies to prevent reactivation of CMV and its sequelae.

Portal vein thrombosis (PVT) is common in cirrhotic patients and presents a challenge at the time of transplant. Owing to the increased posttransplant morbidity and mortality associated with complete PVT, the presence of PVT is a relative contraindication to liver transplantation at many centers. Our group began performing portal vein (PV) recanalization and transjugular intrahepatic portostystemic shunt placement (PVR-TIPS) several years ago to optimize the transplant candidacy of patients with PVT. The procedure has evolved to include transsplenic access to assist with recanalization, which is now our preferred method due to its technical success without significant added morbidity. Here, we describe in detail our approach to PVR-TIPS with a focus on the transsplenic method. The procedure was attempted in 61 patients and was technically successful in 60 patients (98%). After transitioning to transsplenic access to assist with recanalization, the technical success rate has improved to 100%. The recanalized portal vein and TIPS have maintained patency during follow-up, or to the time of transplant, in 55 patients (92%) with a mean follow-up of 16.7 months. In total, 23 patients (38%) have undergone transplant, all of whom received a physiologic anastomosis (end-to-end anastomosis in 22 of 23 patients, 96%). PVR-TIPS placement should be considered as an option for patients with chronic PVT in need of transplantation. Transsplenic access makes the procedure technically straightforward and should be considered as the primary method for recanalization.

Objective Efforts to improve patient safety are challenged by the lack of universally agreed upon terms. The International Classification for Patient Safety (ICPS) was developed by the World Health Organization for this purpose. This study aimed to test the applicability of the ICPS to a surgical population. Design A web-based safety debriefing was sent to clinicians involved in surgical care of abdominal organ transplant patients. A multidisciplinary team of patient safety experts, surgeons and researchers used the data to develop a system of classification based on the ICPS. Disagreements were reconciled via consensus, and a codebook was developed for future use by researchers. Results A total of 320 debriefing responses were used for the initial review and codebook development. In total, the 320 debriefing responses contained 227 patient safety incidents (range: 0–7 per debriefing) and 156 contributing factors/hazards (0–5 per response). The most common severity classification was ‘reportable circumstance,’ followed by ‘near miss.’ The most common incident types were ‘resources/organizational management,’ followed by ‘medical device/equipment.’ Several aspects of surgical care were encompassed by more than one classification, including operating room scheduling, delays in care, trainee-related incidents, interruptions and handoffs. Conclusions This study demonstrates that a framework for patient safety can be applied to facilitate the organization and analysis of surgical safety data. Several unique aspects of surgical care require consideration, and by using a standardized framework for describing concepts, research findings can be compared and disseminated across surgical specialties. The codebook is intended for use as a framework for other specialties and institutions.

Purpose The purpose of this study was to present the institutional experience of performing endoscopy, cholangiography, and biliary interventions through the modified Hutson loop by interventional radiology. Materials and Methods A total of 61 of 64 modified Hutson loop access procedures were successful. This single-center retrospective study included 61 successful procedures of biliary interventions using existing modified Hutson loops (surgically affixed subcutaneous jejunal limb adjacent to biliary anastomosis or anastomoses) for diagnostic or therapeutic purposes in 21 patients. Seventeen of 21 patients (81%) had undergone liver transplantation. Indications included biliary strictures (n = 18) and biliary leaks (n = 3). The clinical success and complications were evaluated. Results There were 3 of 26 modified Hutson loop retrograde biliary intervention failures (12%) before introduction of endoscopy and no failures (0 of 38 [0%]) subsequently (P = .06). Endoscopy or cholangioscopy was performed in 19 procedures by interventional radiologists. Retrograde biliary interventions included diagnostic cholangiography (n = 26), cholangioplasty (n = 25), stent placement (n = 29), stent retrieval (n = 25), and biliary drainage catheter placement (n = 5). No procedure-related mortality occurred. There was 1 major complication (duodenal perforation) (1.6%) and 12 minor complications (19%). In the 9 patients undergoing therapeutic interventions for biliary strictures, there was a significant decrease in median alkaline phosphatase (288.5 to 174.5 U/L; P = .03). There was a trend toward decrease in median bilirubin levels (1.7 to 1 mg/dL; P = .06) at 1 month post-intervention. Conclusions The modified Hutson loop provided interventional radiologists a safe and effective alternative access to manage biliary complications in patients with biliary-enteric anastomoses. Introduction of the endoscope in interventional radiology has improved the success rate of these procedures.

Transplantation tolerance is achieved when recipients are unresponsive to donor alloantigen yet mobilize against third-party antigens, including virus. After transplantation, cytomegalovirus (CMV) reactivation in latently-infected transplants reduces allograft viability. To determine if pre-tolerized recipients are resistant to viral dissemination in this setting, we transfused chemically-fixed donor splenocytes (1-ethyl-3- (3&prime, dimethyl-aminopropyl)-carbo-diimide (ECDI)-treated splenocytes (ECDIsp)) to induce donor antigen tolerance without immunosuppression. In parallel, we implanted donor islet cells to validate operational tolerance. These pre-tolerized recipients were implanted with murine CMV (MCMV) latently-infected donor kidneys (a validated model of CMV latency) to monitor graft inflammation and viral dissemination. Our results indicate that tolerance to donor islets was sustained in recipients after implantation of donor kidneys. In addition, kidney allografts implanted after ECDIsp and islet implantation exhibited low levels of fibrosis and tubulitis. In contrast, kidney cellular and innate immune infiltrates trended higher in the CMV group and exhibited increased markers of CD8+ T cell activation. Tolerance induction was unable to prevent increases in MCMV-specific CD8+ T cells or dissemination of viral IE-1 DNA. Our data suggest that latently-infected allografts are inherently more susceptible to inflammation that is associated with viral dissemination in pre-tolerized recipients. Thus, CMV latently-infected allografts require enhanced strategies to protect allograft integrity and viral spread.

Author(s): Marrero, Jorge A; Kulik, Laura M; Sirlin, Claude B; Zhu, Andrew X; Finn, Richard S; Abecassis, Michael M; Roberts, Lewis R; Heimbach, Julie K

Author(s): Heimbach, Julie K; Kulik, Laura M; Finn, Richard S; Sirlin, Claude B; Abecassis, Michael M; Roberts, Lewis R; Zhu, Andrew X; Murad, M Hassan; Marrero, Jorge A

Background Chronic, obliterative portal vein (PV) thrombosis (PVT) represents a relative contraindication to liver transplantation (LT) in some centers. When PV thromboembolectomy is not feasible, alternative techniques (portacaval hemitransposition, portal arterialization, multivisceral transplantation) are associated with suboptimal outcomes. In cases where a chronically thrombosed PV has become obliterated, we developed PV recanalization (PVR)-transjugular intrahepatic portosystemic shunt (TIPS) to potentiate LT. We evaluated the impact of PVR-TIPS on liver function, transplant eligibility, and long-term outcomes after LT. Methods Forty-four patients with chronic obliterative main PVT were identified during our institutional LT selection committee. After joint imaging review by transplant surgery/radiology, these patients underwent PVR-TIPS to potentiate transplant eligibility. Patients were followed by hepatology/transplant until LT, and ultimately in posttransplant clinic. The TIPS venography and serial ultrasound/MRI were used subsequently to document PV patency. Results The main PV (MPV) was completely thrombosed in 17 of 44 (39%) patients; near complete (>95%) occlusion was noted in 27 of 44 (61%) patients. Direct transhepatic and transsplenic punctures were required in 11 of 43 (26%) and 3 of 43 (7%) cases, respectively. Technical success was 43 of 44 (98%) cases. At PVR-TIPS completion, persistence of MPV thrombus was noted in 33 of 43 (77%) cases. One-month TIPS venography demonstrated complete resolution of MPV thrombosis in 22 of 29 (76%) without anticoagulation. Thirty-six patients were listed for transplantation; 18 (50%) have been transplanted. Eighty-nine percent MPV patency rate and 82% survival were achieved at 5 years. Conclusions The PVR-TIPS may be considered for patients with obliterative PVT who are otherwise appropriate candidates for LT. The high rate of MPV patency post-TIPS placement suggests flow reestablishment as the dominant mechanism of thrombus resolution.

Background The goal of this study was to assess systems and processes involved in the operating room (OR) to intensive care unit (ICU) handoff in an attempt to understand the criticality of specific steps of the handoff. Methods We performed a failure modes, effects, and criticality analysis (FMECA) of the OR to ICU handoff of deceased donor liver transplant recipients using in-person observations and descriptions of the handoff process from a multidisciplinary group of clinicians. For each step in the process, failures were identified along with frequency of occurrence, causes, potential effects and safeguards. A Risk Priority Number (RPN) was calculated for each failure (frequency × potential effect × safeguard; range 1-least risk to 1,000-most risk). Results Using FMECA, we identified 37 individual steps in the OR to ICU handoff process. In total, 81 process failures were identified, 22 of which were determined to be critical and 36 of which relied on weak safeguards such as informal human verification. Process failures with the greatest risk of harm were lack of preliminary OR to ICU communication (RPN 504), team member absence during handoff communication (RPN 480), and transport equipment malfunction (Risk Priority Number 448). Conclusion Based on the analysis, recommendations were made to reduce potential for patient harm during OR to ICU handoffs. These included automated transfer of OR data to ICU clinicians, enhanced ICU team member notification processes and revision of the postoperative order sets. The FMECA revealed steps in the OR to ICU handoff that are high risk for patient harm and are currently being targeted for process improvement.

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.

Since publication of the Centers for Medicare and Medicaid Services (CMS) Conditions of Participation Final Rule in 2007, there has been dual regulation of transplant centers by the Organ Procurement and Transplantation Network (OPTN) contractor the United Network for Organ Sharing (UNOS) and CMS. Herein, we summarize the environment leading to the development of the present regulatory framework and identify significant and unintended consequences of the current regulations.

Nineteen subjects have more than 18 months' follow-up in a phase IIb tolerance protocol in HLA-mismatched recipients of living donor kidney plus facilitating cell enriched hematopoietic stem cell allografts (FCRx). Reduced intensity conditioning preceded a kidney allograft, followed the next day by FCRx. Twelve have achieved stable donor chimerism and have been successfully taken off immunosuppression (IS). We prospectively evaluated immune reconstitution and immunocompetence. Return of CD4 and CD8 T central and effector memory cell populations was rapid. T-cell receptor (TCR) Excision Circle analysis showed a significant proportion of chimeric cells produced were being produced de novo. The TCR repertoires posttransplant in chimeric subjects were nearly as diverse as pretransplant donors and recipients, and were comparable to subjects with transient chimerism who underwent autologous reconstitution. Subjects with persistent chimerism developed few serious infections when off IS. The majority of infectious complications occurred while subjects were still on conventional IS. BK viruria and viremia resolved after cessation of IS and no tissue-invasive cytomegalovirus infections occurred. Notably, although 2 of 4 transiently or nonchimeric subjects experienced recurrence of their underlying autoimmune disorders, none of the chimeric subjects have, suggesting that self-tolerance is induced in addition to tolerance to alloantigen. No persistently chimeric subject has developed donor-specific antibody, and renal function has remained within normal limits. Patients were successfully vaccinated per The American Society for Blood and Marrow Transplantation guidelines without loss of chimerism or rejection. Memory for hepatitis vaccination persisted after transplantation. Chimeric subjects generated immune responses to pneumococcal vaccine. These data suggest that immune reconstitution and immunocompetence are maintained in persistently chimeric subjects.

Objective Urgent clinician–clinician communications require routes of contact that are fast and dependable, and allow for the exchange of complex information. Despite the increasing focus on improving healthcare delivery systems over the past decade, few studies have examined the role of technology in clinician–clinician communication. The aim of this study was to review the literature examining the role of devices and technology in facilitating urgent clinician–clinician communication to identify critical areas for future research. Materials and methods A search of Pub Med was performed using the terms ((((“Critical Care”[Mesh] OR “urgent”)))) AND (((hospital communication systems[MeSH Terms]) OR health communication[MeSH Terms]) OR interdisciplinary communication[MeSH Terms]). Commentaries and editorials were excluded. Results The initial search returned 272 articles, which were reviewed to identify articles describing: (1) the role of technological support or devices in clinician–clinician communication, (2) technology-based interventions that improved clinician-to-clinician communication in hospitals or acute care facilities related to critically ill patients, or (3) critical information exchange. A total of 16 articles were included in the final review. These were grouped into three categories: alphanumeric pagers, cellular and smart telephones, and novel uses of technology. Discussion Breakdowns in clinician–clinician communication are complex and cannot be solved through the implementation of devices or technologically advanced systems alone. It is essential to understand the correlation between emerging technologies, a demanding workload, and clinician–clinician interaction. Enhanced communication of clinical ideas, opportunities for team discussion, and a sense of partnership and support require not just increased information, but enhanced delivery.

Background Increasing use of kidney grafts for simultaneous liver and kidney (SLK) transplants is causing concern about the most effective utilization of scarce kidney graft resources. This study evaluated the impact of implementing the proposed United Network for Organ Sharing SLK transplant policy on outcomes for end-stage liver disease (ESLD) and end-stage renal disease (ESRD) patients awaiting transplant. Methods A Markov model was constructed to simulate a hypothetical cohort of ESLD patients over a 30-year time horizon starting from age 50. The model applies the different criteria being considered in the United Network for Organ Sharing policy and tallies outcomes, including numbers of procedures and life years after liver transplant alone (LTA) or SLK transplant. Results When 1-week pretransplant dialysis duration is required, the numbers of SLK transplants and LTAs would be 648 and 9,065, respectively. If the pretransplant dialysis duration is extended to 12 weeks, there would be 240 SLK transplants and 9,426 LTAs. This change results in a decrease of 6,483 life years among SLK transplant recipients and an increase of 4,971 life years among LTA recipients. However, by increasing the dialysis duration to 12 weeks from 1 week, 408 kidney grafts would be released to the kidney waitlist because of the decline in SLK transplants; this yields 796 additional life years gained among ESRD patients. Conclusion Implementation of the proposed SLK transplant policy could restore access to kidney transplants for patients with ESRD albeit at the detriment of patients with ESLD and renal impairment.

Cardiovascular disease (CVD) complications are important causes of morbidity and mortality after orthotopic liver transplantation (OLT). There is currently no preoperative risk assessment tool that allows physicians to estimate the risk for CVD events following OLT. We sought to develop a point-based prediction model (risk score) for CVD complications after OLT, the CAR-OLT risk score, among a cohort of 1024 consecutive patients aged 18-75 years who underwent first OLT in a tertiary-care teaching hospital (2002-2011). The main outcome measures were major 1-year CVD complications, defined as death from a CVD cause or hospitalization for a major CVD event (myocardial infarction, revascularization, heart failure, atrial fibrillation, cardiac arrest, pulmonary embolism, and/or stroke). The bootstrap method yielded bias-corrected 95% confidence intervals for the regression coefficients of the final model.Among 1024 first OLT recipients, major CVD complications occurred in 329 (32.1%). Variables selected for inclusion in the model (using model optimization strategies) included pre-operative recipient age, sex, race, employment status, education status, history of hepatocellular carcinoma, diabetes, heart failure, atrial fibrillation, pulmonary or systemic hypertension, and respiratory failure. The discriminative performance of the CAR-OLT point-based score (C statistic=0.78, bias-corrected C statistic=0.77) was superior to other published risk models for postoperative CVD morbidity and mortality, and it had appropriate calibration (Hosmer-Lemeshow p=0.33). Conclusion: The point-based CAR-OLT risk score can identify patients at risk for CVD complications after OLT surgery (available at: www.carolt.us). This score may be useful for identification of candidates for further risk stratification or other management strategies to improve CVD outcomes after OLT. This article is protected by copyright. All rights reserved.

Introduction Measuring the chemokine CXCL9 in urine by enzyme-linked immunosorbent assay (ELISA) can diagnose acute cellular rejection (ACR) noninvasively after kidney transplantation, but the required 12- to 24-hour turnaround time is not ideal for rapid, clinical decision-making. Methods We developed a biolayer interferometry (BLI)−based assay to rapidly measure urinary CXCL9 in 200 pg/ml in subjects with ACR and ≤100 pg/ml in subjects with stable kidney function without cellular infiltrates. In samples obtained after treatment for ACR, BLI CXCL9 measurements detected biopsy-proven intragraft infiltrates despite treatment-induced reduction in serum creatinine. Discussion Together, our proof-of-principle results demonstrate that BLI-based urinary CXCL9 detection has potential as a point-of-care noninvasive biomarker to diagnose and guide therapy for ACR in kidney transplantation recipients.

Yttrium-90 transarterial radioembolization (TARE) is a locoregional therapy (LRT) for hepatocellular carcinoma (HCC). In this study, we present overall survival (OS) outcomes in a 1,000-patient cohort acquired over a 15-year period. Between December 1, 2003 and March 31, 2017, 1,000 patients with HCC were treated with TARE as part of a prospective cohort study. A comprehensive review of toxicity and survival outcomes was performed. Outcomes were stratified by baseline Child-Pugh (CP) class, United Network for Organ Sharing (UNOS), and Barcelona Clinic Liver Cancer (BCLC) staging systems. Albumin and bilirubin laboratory toxicities were compared to baseline. OS outcomes were reported using censoring and intention-to-treat methodologies. All treatments were outpatient, with a median one treatment per patient. Five hundred six (51%) were CP A, 450 (45%) CP B, and 44 (4%) CP C. Two hundred sixty-three (26%) patients were BCLC A, 152 (15%) B, 541 (54%) C, and 44 (4%) D. Three hundred sixty-eight (37%) were UNOS T1/T2, 169 (17%) T3, 147 (15%) T4a, 223 (22%) T4b, and 93 (9%) N/M. In CP A patients, censored OS for BCLC A was 47.3 (confidence interval [CI], 39.5-80.3) months, BCLC B 25.0 (CI, 17.3-30.5) months, and BCLC C 15.0 (CI, 13.8-17.7) months. In CP B patients, censored OS for BCLC A was 27 (CI, 21-30.2) months, BCLC B 15.0 (CI, 12.3-19.0) months, and BCLC C 8.0 (CI, 6.8-9.5) months. Forty-nine (5%) and 110 (11%) patients developed grade 3/4 albumin and bilirubin toxicities, respectively. Conclusion Based on our experience with 1,000 patients over 15 years, we have made a decision to adopt TARE as the first-line transarterial LRT for patients with HCC. Our decision was informed by prospective data and incrementally reported demonstrating outcomes stratified by BCLC, applied as either neoadjuvant or definitive treatment. (Hepatology 2017).

Myeloid cells are important cell types that carry human cytomegalovirus. Latent viral DNA is present in CD34+ progenitor cells and their derived monocytes. However, differentiation of latently infected monocytes to mature macrophages or dendritic cells causes reactivation of latent viruses. During hematopoietic development, pluripotent genes are repressed, and lineage specific genes are activated in a step-wise manner. This process is governed by cell-type specific chromatin states. Enhancers in the hematopoietic system are highly dynamic and established by pioneer (first tier) transcription factors (TFs), which set the stage for second and third tier TF binding. In this review, we examine the epigenetic mechanisms that regulate myeloid cell development, cell identity, and activation with a special focus on factors that regulate viral gene expression and the status of viral infection in myeloid cells.

Background: Co-management of hospitalized heart failure (HHF) patients by hospitalists and cardiologists may enhance care quality. Aided by an enterprise data warehouse (EDW) screen for HHF patients, we implemented a house surveillance model of heart failure consultation, whereby cardiology consultation and multidisciplinary heart failure intervention was offered for patients meeting criteria. Objective: To analyze the impact of house surveillance for HHF on cardiology consultation rates for patients coding into heart failure diagnosis-related groups (DRGs) on medicine units. Methods: An EDW screen for HHF was deployed, and services with HHF patients were offered cardiology consultation. The intervention was deployed 7/2015; chart review for patients 6 months pre- and post-intervention was conducted to ascertain consultation rate. Results: There were 386 patient discharges from a non-cardiac service with a heart failure DRG. In the six months prior to intervention, 40% of patients had cardiology consultation. This figure rose to 69% post-intervention, a highly statistically significant result. Conclusions: EDW-enabled active surveillance for HHF increases cardiology consultation rate, allowing for multidisciplinary intervention, co-management, and potentially improved outcomes for HHF patients.

Background: TruGraf is a blood test that measures gene expression signatures in kidney transplant recipients, providing information on adequacy of immunosuppression. Signatures derived from peripheral blood using DNA microarrays have been internally and externally validated in two populations of transplant recipients: (i) patients designated as TX (“Transplant eXcellence”) - stable serum creatinine and normal biopsy, indicative of immune quiescence, and (ii) patients designated as not-TX (renal dysfunction and/or histological abnormalities). The test is intended for use in subjects with stable renal function as an alternative to protocol biopsies. Methodology: Simultaneous blood tests and transplant biopsies were performed in 169 patients. The molecular laboratory was blinded to renal function and biopsy results. Results: Biopsy-confirmed clinical phenotype was TX (105 cases), not-TX (64). Renal function was stable in 125 subjects (105 TX, 20 not-TX). Positive predictive value of TruGraf for detecting TX was 86% and 105/125 (84%) had a normal biopsy result. Significance of study: In subjects with stable renal function, TruGraf blood test result of TX corresponded to biopsy findings in 88% of cases. Results indicate that had the blood test been run in place of surveillance biopsies, 107/125 (86%) of patients with stable renal function may have avoided an invasive biopsy and 92/105 (88%) of these patients with biopsy-confirmed TX may have avoided a biopsy for a negative result.

Context: The TruGraf test is a blood-based assay that provides non-invasive, accurate assessment of adequacy of immunosuppression in kidney transplant recipients. TruGraf relies on gene-expression “signatures” that differentiate a state of Transplant eXcellence (TX, indicating adequately immunosuppressed) from not-TX. Objective: To evaluate the performance of the TruGraf test. Design: Analytical performance studies to characterize stability of RNA in blood during collection and shipment, analytical sensitivity (input RNA concentration), analytical specificity (interfering substances) and assay performance (clinical validity, and intra-assay, inter-assay, inter-laboratory reproducibility). Results: Total RNA extracted from whole blood specimens collected in PAXgene Blood RNA tubes was stable up to 3 days at room temperature (stable RNA yield). Under routine ambient shipping conditions, storage and shipping temperatures did not affect results. However, specimen shipments exposed to temperatures >400°C or to ambient temperatures for >3 days were unacceptable for processing. Analytical sensitivity studies demonstrated tolerance to variation in RNA input (50 to 400 ng per 3’ IVT (in vitro transcript] labeling reaction). Specificity studies using genomic DNA spiked into 3 ’IVT reactions at 10-20% demonstrated negligible assay interference. The test was reproducible across operators, runs, reagent lots, and laboratories. External validation demonstrated that the TruGraf blood test accurately classified patients in 72% of 295 samples. Conclusions: Analytical sensitivity, analytical specificity, robustness, quality control, and clinical validity of the TruGraf blood test were successfully verified, indicating its suitability for clinical use.

Kidney transplantation is the treatment of choice for patients with end-stage renal disease, providing a survival and quality of life benefit to the recipient over patients on dialysis. While the survival trend for kidney transplant recipients has steadily improved over the years, the rate of death with a functioning renal allograft remains largely unchanged. Donor and recipient selection impacts both recipient and graft survival and the newly introduced longevity matching-based Kidney Allocation System attempts to capture this association. It is interesting to note that while short-term graft survival has improved significantly over the years, long-term graft survival has not seen an equivalent rise. Various factors including subclinical rejection, immunosuppressive toxicity and chronic allograft dysfunction have been implicated. Protocol renal allograft biopsies serve to provide biological and immunological markers of these factors and biopsy endpoints have been shown to be associated with long-term graft survival. We used laboratory and pathology data after transplant to independently develop a late outcome surrogate score providing a prediction model for graft survival following kidney transplantation. Further effort into developing novel biomarkers and quality predictive models of long-term graft survival is needed.

Cardiovascular disease (CVD) contributes to excessive long-term mortality after liver transplantation (LT); however, little is known about early postoperative CVD mortality in the current era. In addition, there is no model for predicting early postoperative CVD mortality across centers. We analyzed adult recipients of primary LT in the Organ Procurement and Transplantation Network (OPTN) database between February 2002 and December 2012 to assess the prevalence and predictors of early (30-day) CVD mortality, which was defined as death from arrhythmia, heart failure, myocardial infarction, cardiac arrest, thromboembolism, and/or stroke. We performed logistic regression with stepwise selection to develop a predictive model of early CVD mortality. Sex and center volume were forced into the final model, which was validated with bootstrapping techniques. Among 54,697 LT recipients, there were 1576 deaths (2.9%) within 30 days. CVD death was the leading cause of 30-day mortality (40.2%), and it was followed by infection (27.9%) and graft failure (12.2%). In a multivariate analysis, 9 significant covariates (6 recipient covariates, 2 donor covariates, and 1 operative covariate) were identified: age, preoperative hospitalization, intensive care unit status, ventilator status, calculated Model for End-Stage Liver Disease score, portal vein thrombosis, national organ sharing, donor body mass index, and cold ischemia time. The model showed moderate discrimination (C statistic = 0.66, 95% confidence interval = 0.63-0.68). In conclusion, we provide the first multicenter prognostic model for the prediction of early post-LT CVD death, the most common cause of early post-LT mortality in the current transplant era. However, evaluations of additional CVD-related variables not collected by the OPTN are needed in order to improve the model's accuracy and potential clinical utility.

There are complex risk-benefit tradeoffs with different transplantation strategies for end-stage liver disease patients on renal support. Using a Markov discrete-time state transition model, we compared survival for this group with 3 strategies: simultaneous liver-kidney (SLK) transplantation, liver transplantation alone (LTA) followed by immediate kidney transplantation if renal function did not recover, and LTA followed by placement on the kidney transplant wait list. Patients were followed for 30 years from the age of 50 years. The probabilities of events were synthesized from population data and clinical trials according to Model for End-Stage Liver Disease (MELD) scores (21-30 and >30) to estimate input parameters. Sensitivity analyses tested the impact of uncertainty on survival. Overall, the highest survival rates were seen with SLK transplantation for both MELD score groups (82.8% for MELD scores of 21-30 and 82.5% for MELD scores > 30 at 1 year), albeit at the cost of using kidneys that might not be needed. Liver transplantation followed by kidney transplantation led to higher survival rates (77.3% and 76.4%, respectively, at 1 year) than placement on the kidney transplant wait list (75.1% and 74.3%, respectively, at 1 year). When uncertainty was considered, the results indicated that the waiting time and renal recovery affected conclusions about survival after SLK transplantation and liver transplantation, respectively. The subgroups with the longest durations of pretransplant renal replacement therapy and highest MELD scores had the largest absolute increases in survival with SLK transplantation versus sequential transplantation. In conclusion, the findings demonstrate the inherent tension in choices about the use of available kidneys and suggest that performing liver transplantation and using renal transplantation only for those who fail to recover their native renal function could free up available donor kidneys. These results could inform discussions about transplantation policy. Liver Transpl 20:1034-1044, 2014. © 2014 AASLD.

Selectin-selectin ligand interactions mediate the initial steps in leukocyte migration, an integral part of immune responses. Fucosyltransferase-VII (FucT-VII), encoded by Fut7, is essential for biosynthesis of selectin ligands. In an established model of cardiac allograft vasculopathy and chronic rejection, Fut7(-/-) recipients exhibited long-term graft survival with minimal vasculopathy compared with WT controls. Graft survival was associated with CD4 T-cell exhaustion in the periphery, characterized by impaired effector cytokine production, defective proliferation, increased expression of inhibitory receptors programmed death-1 (PD-1) and T cell Ig- and mucin-domain-containing molecule-3 (Tim-3), low levels of IL-7Rα on CD4 T cells, and reduced migration of polyfunctional CD4 memory T cells to the allograft. Blocking PD-1 triggered rejection only in Fut7(-/-) recipients, whereas depleting regulatory T cells had no effect in either Fut7(-/-) or WT recipients. Adoptive transfer experiments confirmed that this CD4 T cell-exhausted phenotype is seen primarily in Fut7(-/-) CD4 T cells. These data suggest that impaired leukocyte recruitment is a novel mechanism leading to CD4 T-cell exhaustion. Our experimental system serves as an excellent model to study CD4 T-cell exhaustion as a dominant mechanism of transplant tolerance. Further, targeting FucT-VII may serve as a promising strategy to prevent chronic allograft rejection and promote tolerance.

BACKGROUND Waiting time to deceased donor kidney transplant varies greatly across the United States. This variation violates the final rule, a federal mandate, which demands geographic equity in organ allocation for transplantation. METHODS Retrospective analysis of the United States Renal Data System and United Network for Organ Sharing database from 2000 to 2009. Median waiting time was calculated for each of the 58 donor service areas (DSA) in the United States. Multivariate regression was performed to identify DSA predictors for long waiting times to kidney transplantation. RESULTS The median waiting time varied between the 58 DSAs from 0.61 to 4.57 years, ranging from 0.59 to 5.17 years for standard criteria donor kidneys and 0.41 to 4.69 years for expanded criteria donor kidneys. The disparity in waiting time between the DSAs grew from 3.26 years (range, 0.41-3.67) in 2000 to 4.72 years (range, 0.50-5.22) in 2009. In DSAs with longer waiting times, there were significantly more patients suffering from end-stage renal disease and more patients listed for kidney transplant, lower kidney procurement rates, and higher transplant center competition. Patients were more likely black, sensitized, with lower educational attainment and less likely to waitlist outside of their DSA of residence. Donor organs used in DSAs with long waiting times were more likely hepatitis C positive and had a higher kidney donor profile index. Graft and patient survival at 5 years was worse for deceased donor kidney transplant, but rates for living donor kidney transplant were higher. CONCLUSION Our analysis demonstrates significant and worsening geographic disparity in waiting time for kidney transplant across the DSAs. Increase in living donor kidney transplant and use of marginal organs has not mitigated the disparity. Changes to the kidney allocation system might be required to resolve this extensive geographic disparity in kidney allocation.

Context Hispanics receive disproportionately fewer live donor kidney transplants than non-Hispanic whites. Increasing Hispanics' knowledge and changing attitudes about live kidney donation may reduce these disparities. Objective To evaluate the effectiveness of culturally and linguistically competent educational sessions delivered through Northwestern University's Hispanic Transplant Program. Design Baseline and postsession questionnaires were used to evaluate changes in patients' and family members' knowledge and attitudes toward live kidney donation and program satisfaction. Knowledge items related to live kidney donation were scaled, and changes in scores were evaluated via a paired t test. Multiple regression analysis of follow-up knowledge scores controlled for baseline scores was used to estimate the effects of patients' and families' sociodemographic characteristics. Changes in attitude items, including comfort with exploring live kidney donation, were analyzed with χ2 tests. Results One-hundred thirteen patients and family members completed surveys before and after an education session. Respondents' knowledge about live kidney donation and transplant increased significantly ( P < .001) between baseline and after the session. Patients' attitudes toward live kidney donation became more favorable ( P < .02), as did family members' attitudes toward being a donor ( P < .001) after participating in the program. All respondents reported high levels of satisfaction with the program and preferences for culturally congruent care. Conclusions The educational sessions provided by the Hispanic Transplant Program effectively addressed commonly shared Hispanic concerns about live kidney donation. Culturally congruent education increased Hispanic patients' and family members' knowledge and improved attitudes about live donor kidney transplants.

The aim of this study was to compare radiological and pathological changes and test the adjunct efficacy of Sorafenib to Y90 as a bridge to transplantation in hepatocellular carcinoma (HCC). 15 patients with 16 HCC lesions were randomized to Y90 without (Group A, n = 9) or with Sorafenib (Group B, n = 7). Size (WHO, RECIST), enhancement (EASL, mRECIST) and diffusion-weighted imaging criteria (apparent diffusion coefficient, ADC) measurements were obtained at baseline, then at 1 and every 3 months after treatment until transplantation. Percentage necrosis in explanted tumors was correlated with imaging findings. 100%, 50%-99% and