Racial disparities in patient survival after liver transplantation in the United States

Background. Racial disparities in healthcare span such areas as access, outcomes after procedures, and patient satisfaction. Previous work suggested that minorities experience less healthcare and worse survival rates. In adult orthotopic liver transplantation (OLT) mixed results have been reported, with some showing African-American recipients having poor survival compared to Caucasians, and others finding no such discrepancy. ^ Purpose. This study’s purpose was to analyze the most recent United Network for Organ Sharing (UNOS) data, both before and after the implementation of the Model for End-Stage Liver Disease (MELD)/Pediatric End-Stage Liver Disease (PELD) scoring system, to determine if minority racial groups still experience poor outcomes after OLT. ^ Methods. The UNOS dataset for 1992-2001 (Era I) and 2002-2007 (Era II) was used. Patient survival rates for each Era and for adult and pediatric recipients were analyzed with adjustment. A separate multivariate analysis was performed on African-American adult patients in Era II in order to identify unique predictors for poor patient survival. ^ Results. The overall study included 66,118 OLT recipients. The majority were Caucasian (78%), followed by Hispanics (13%) and African-Americans (9%). Hispanic and African-American adults were more likely to be female, have Hepatitis C, to be in the intensive care unit (ICU) or ventilated at time of OLT, to have a MELD score ≥23, to have a lower education level, and to have public insurance when compared to Caucasian adults (all p-values < 0.05). Hispanic and African-American pediatric recipients were more likely have public insurance and less likely to receive a living donor OLT than were Caucasian pediatric OLT recipients (p <0.05). There was no difference in the likelihood of having a PELD score ≥21 among racial groups (p >0.40). African-American adults in Era I and Era II had worse patient survival rates than both Caucasians and Hispanic (pair-wise p-values <0.05). This same disparity was seen for pediatric recipients in Era I, but not in Era II. Multivariate analysis of African-American recipients revealed no unique predictors of patient death. ^ Conclusions. African-American race is still a predictor of poor outcome after adult OLT, even after adjustment for multiple clinical, demographic, and liver disease severity variables. Although African-American and Hispanic subgroups share many characteristics previously thought to increase risk of post-OLT death, only African-American patients have poor survival rates when compared to Caucasians. ^

Prevalence and risk factors for polyomavirus reactivation in solid-organ transplantation

Background. Polyomavirus reactivation is common in solid-organ transplant recipients who are given immunosuppressive medications as standard treatment of care. Previous studies have shown that polyomavirus infection can lead to allograft failure in as many as 45% of the affected patients. Hypothesis. Ubiquitous polyomaviruses when reactivated by post-transplant immunosuppressive medications may lead to impaired renal function and possibly lower survival prospects. Study Overview. Secondary analysis of data was conducted on a prospective longitudinal study of subjects who were at least 18 years of age and were recipients of liver and/or kidney transplant at Mayo Clinic Scottsdale, Arizona. Methods. DNA extractions of blinded urine and blood specimens of transplant patients collected at Mayo Clinic during routine transplant patient visits were performed at Baylor College of Medicine using Qiagen kits. Virologic assays included testing DNA samples for specific polyomavirus sequences using QPCR technology. De-identified demographic and clinical patient data were merged with laboratory data and statistical analysis was performed using Stata10. Results. 76 patients enrolled in the study were followed for 3.9 years post transplantation. The prevalence of BK virus and JC virus urinary excretion was 30% and 28%. Significant association was observed between JC virus excretion and kidney as the transplanted organ (P = 0.039, Pearson Chi-square test). The median urinary JCV viral loads were two logs higher than those of BKV. Patients that excreted both BKV and JCV appeared to have the worst renal function with a mean creatinine clearance value of 71.6 millimeters per minute. A survival disadvantage was observed for dual shedders of BKV and JCV, log-rank statistics, p = 0.09; 2/5 dual-shedders expired during the study period. Liver transplant and male sex were determined to be potential risk factors for JC virus activation in renal and liver transplant recipients. All patients tested negative for SV40 and no association was observed between polyomavirus excretion and type of immunosuppressive medication (tacrolimus, mycophenolate mofetil, cyclosporine and sirolimus). Conclusions. Polyomavirus reactivation was common after solid-organ transplantation and may be associated with impaired renal function. Male sex and JCV infection may be potential risk factors for viral reactivation; findings should be confirmed in larger studies.^

Children with acute leukemia: A comparison of outcomes and cost-effectiveness from allogeneic blood stem cell and bone marrow transplantation

The relative merits of PBSCT versus BMT for children with standard and high risk hematologic malignancies remain unclear. In a retrospective single center study, we compared allogeneic peripheral blood stem cell transplantation (PBSCT) (n=30) with bone marrow transplantation (BMT) (n=110) in children with acute leukemia. We studied recipients of HLA matched sibling stem cells, and of stem cells from alternative donors (HLA mismatched and/or unrelated) and determined whether sourcing the stem cells from PB or marrow affected engraftment, incidence of acute and chronic GvHD, and disease-free survival at 1 year. Our results show a modest reduction in time to engraftment from PB stem cells and no greater risk of GvHD, but illustrate that the severity of the underlying disease is by far the greatest determinant of 1 year survival. Patients in the BMT group had a higher treatment success rate and lower costs than the recipients of the PBSCT within the standard but not the high risk disease group, where the treatment success rate and the cumulative costs were lower in the PBSCT group compared to the BMT group. Our current incremental cost-effectiveness ratio and analysis of uncertainty suggest that allogeneic transplantation of bone marrow grafts was a more cost-effective treatment option compared to peripheral blood stem cells in patients with standard risk childhood acute leukemia disease. For high risk disease our data are less prescriptive, since the differences were more limited and the range of costs much larger. Neither option demonstrated a clear advantage from a cost-effectiveness standpoint.^

Impact of donor-recipient gender and race mismatching on patient survival in patients with end-stage liver diseases undergoing liver transplantation

Background. End-stage liver disease (ESLD) is an irreversible condition that leads to the imminent complete failure of the liver. Orthotopic liver transplantation (OLT) has been well accepted as the best curative option for patients with ESLD. Despite the progress in liver transplantation, the major limitation nowadays is the discrepancy between donor supply and organ demand. In an effort to alleviate this situation, mismatched donor and recipient gender or race livers are being used. However, the simultaneous impact of donor and recipient gender and race mismatching on patient survival after OLT remains unclear and relatively challenging to surgeons. ^ Objective. To examine the impact of donor and recipient gender and race mismatching on patient survival after OLT using the United Network for Organ Sharing (UNOS) database. ^ Methods. A total of 40,644 recipients who underwent OLT between 2002 and 2011 were included. Kaplan-Meier survival curves and the log-rank tests were used to compare the survival rates among different donor-recipient gender and race combinations. Univariate Cox regression analysis was used to assess the association of donor-recipient gender and race mismatching with patient survival after OLT. Multivariable Cox regression analysis was used to model the simultaneous impact of donor-recipient gender and race mismatching on patient survival after OLT adjusting for a list of other risk factors. Multivariable Cox regression analysis stratifying on recipient hepatitis C virus (HCV) status was also conducted to identify the variables that were differentially associated with patient survival in HCV + and HCV − recipients. ^ Results. In the univariate analysis, compared to male donors to male recipients, female donors to male recipients had a higher risk of patient mortality (HR, 1.122; 95% CI, 1.065–1.183), while in the multivariable analysis, male donors to female recipients experienced an increased mortality rates (adjusted HR, 1.114; 95% CI, 1.048–1.184). Compared to white donors to white recipients, Hispanic donors to black recipients had a higher risk of patient mortality (HR, 1.527; 95% CI, 1.293–1.804) in the univariate analysis, and similar result (adjusted HR, 1.553; 95% CI, 1.314–1.836) was noted in multivariable analysis. After the stratification on recipient HCV status in the multivariable analysis, HCV + mismatched recipients appeared to be at greater risk of mortality than HCV − mismatched recipients. Female donors to female HCV − recipients (adjusted HR, 0.843; 95% CI, 0.769–0.923), and Hispanic HCV + recipients receiving livers from black donors (adjusted HR, 0.758; 95% CI, 0.598–0.960) had a protective effect on patient survival after OLT. ^ Conclusion. Donor-recipient gender and race mismatching adversely affect patient survival after OLT, both independently and after the adjustment for other risk factors. Female recipient HCV status is an important effect modifier in the association between donor-recipient gender combination and patient survival.^

Evaluation of a transplantation algorithm for expressive speech synthesis

When designing human-machine interfaces it is important to consider not only the bare bones functionality but also the ease of use and accessibility it provides. When talking about voice-based inter- faces, it has been proven that imbuing expressiveness into the synthetic voices increases signi?cantly its perceived naturalness, which in the end is very helpful when building user friendly interfaces. This paper proposes an adaptation based expressiveness transplantation system capable of copying the emotions of a source speaker into any desired target speaker with just a few minutes of read speech and without requiring the record- ing of additional expressive data. This system was evaluated through a perceptual test for 3 speakers showing up to an average of 52% emotion recognition rates relative to the natural voice recognition rates, while at the same time keeping good scores in similarity and naturality.

Towards speaking style transplantation in speech synthesis

One of the biggest challenges in speech synthesis is the production of naturally sounding synthetic voices. This means that the resulting voice must be not only of high enough quality but also that it must be able to capture the natural expressiveness imbued in human speech. This paper focus on solving the expressiveness problem by proposing a set of different techniques that could be used for extrapolating the expressiveness of proven high quality speaking style models into neutral speakers in HMM-based synthesis. As an additional advantage, the proposed techniques are based on adaptation approaches, which means that they can be used with little training data (around 15 minutes of training data are used in each style for this paper). For the final implementation, a set of 4 speaking styles were considered: news broadcasts, live sports commentary, interviews and parliamentary speech. Finally, the implementation of the 5 techniques were tested through a perceptual evaluation that proves that the deviations between neutral and speaking style average models can be learned and used to imbue expressiveness into target neutral speakers as intended.

Development of a genre-dependent TTS system with cross-speaker speaking-style transplantation

One of the biggest challenges in speech synthesis is the production of contextually-appropriate naturally sounding synthetic voices. This means that a Text-To-Speech system must be able to analyze a text beyond the sentence limits in order to select, or even modulate, the speaking style according to a broader context. Our current architecture is based on a two-step approach: text genre identification and speaking style synthesis according to the detected discourse genre. For the final implementation, a set of four genres and their corresponding speaking styles were considered: broadcast news, live sport commentaries, interviews and political speeches. In the final TTS evaluation, the four speaking styles were transplanted to the neutral voices of other speakers not included in the training database. When the transplanted styles were compared to the neutral voices, transplantation was significantly preferred and the similarity to the target speaker was as high as 78%.

Emotion transplantation through adaptation in HMM-based speech synthesis

This paper proposes an emotion transplantation method capable of modifying a synthetic speech model through the use of CSMAPLR adaptation in order to incorporate emotional information learned from a different speaker model while maintaining the identity of the original speaker as much as possible. The proposed method relies on learning both emotional and speaker identity information by means of their adaptation function from an average voice model, and combining them into a single cascade transform capable of imbuing the desired emotion into the target speaker. This method is then applied to the task of transplanting four emotions (anger, happiness, sadness and surprise) into 3 male speakers and 3 female speakers and evaluated in a number of perceptual tests. The results of the evaluations show how the perceived naturalness for emotional text significantly favors the use of the proposed transplanted emotional speech synthesis when compared to traditional neutral speech synthesis, evidenced by a big increase in the perceived emotional strength of the synthesized utterances at a slight cost in speech quality. A final evaluation with a robotic laboratory assistant application shows how by using emotional speech we can significantly increase the students’ satisfaction with the dialog system, proving how the proposed emotion transplantation system provides benefits in real applications.

Calpain is a mediator of preservation-reperfusion injury in rat liver transplantation

Proteases as well as alterations in intracellular calcium have important roles in hepatic preservation-reperfusion injury, and increased calpain activity recently has been demonstrated in liver allografts. Experiments were designed to evaluate (i) hepatic cytosolic calpain activity during different periods of cold ischemia (CI), rewarming, or reperfusion, and (ii) effects of inhibition of calpain on liver graft function using the isolated perfused rat liver and arterialized orthotopic liver transplantation models. Calpain activity was assayed using the fluorogenic substrate Suc-Leu-Leu-Val-Tyr-7-amino-4-methyl coumarin (AMC) and expressed as mean ± SD pmol AMC released/min per mg of cytosolic protein. Calpain activity rose significantly after 24 hr of CI in University of Wisconsin solution and further increased with longer preservation. Activity also increased within 30 min of rewarming, peaking at 120 min. Increased durations of CI preceding rewarming resulted in significantly higher activity (P < 0.01). Calpain activity increased rapidly upon reperfusion and was significantly enhanced by previous CI (P < 0.01). Calpain inhibition with Cbz-Val-Phe methyl ester significantly decreased aspartate aminotransferase released in the isolated perfused rat liver perfusate (P < 0.05). Duration of survival after orthotopic liver transplantation using livers cold-preserved for 40 hr was also significantly increased (P < 0.05) with calpain inhibitor. In conclusion, calpain proteases are activated during each phase of transplantation and are likely to play an important role in the mechanisms of preservation-reperfusion injury.

Prevention of development of autoimmune disease in BXSB mice by mixed bone marrow transplantation

Transplantations of fully allogeneic, autoimmune-resistant T-cell-depleted marrow (TCDM) plus syngeneic, autoimmune-prone TCDM into lethally irradiated BXSB mice were carried out to investigate the ability of the mixed bone marrow transplantation (BMT) to prevent development of autoimmune disease and, at the same time, to reconstitute fully the immunity functions of heavily irradiated BXSB recipients. Male BXSB mice were engrafted with mixed TCDM from both allogeneic, autoimmune-resistant BALB/c mice and syngeneic, autoimmune-prone BXSB mice. BMT with mixed TCDM from both resistant and susceptible strains of mice (mixed BMT) prolonged the median life span and inhibited development of glomerulonephritis in BXSB mice. BMT with mixed TCDM also prevented the formation of anti-DNA antibodies that is typically observed in male mice of this strain. Moreover, mixed BMT reconstituted primary antibody production in BXSB recipients, so that no annoying immunodeficiencies that are regularly observed in fully allogeneic chimeras were present in the recipient of the mixed TCDM. These findings indicate that transplanting allogeneic, autoimmune-resistant TCDM plus syngeneic, autoimmune-prone TCDM into lethally irradiated BXSB mice prevents development of autoimmune disease in this strain of mice. In addition, this dual BMT reconstitutes the immunity functions and avoids the immunodeficiencies that occur regularly in fully allogeneic chimeras after total-body irradiation.

Differentiation of pancreatic epithelial progenitor cells into hepatocytes following transplantation into rat liver

The ability to identify, isolate, and transplant progenitor cells from solid tissues would greatly facilitate the treatment of diseases currently requiring whole organ transplantation. In this study, cell fractions enriched in candidate epithelial progenitor cells from the rat pancreas were isolated and transplanted into the liver of an inbred strain of Fischer rats. Using a dipeptidyl dipeptidase IV genetic marker system to follow the fate of transplanted cells in conjunction with albumin gene expression, we provide conclusive evidence that, after transplantation to the liver, epithelial progenitor cells from the pancreas differentiate into hepatocytes, express liver-specific proteins, and become fully integrated into the liver parenchymal structure. These studies demonstrate the presence of multipotent progenitor cells in the adult pancreas and establish a role for the liver microenvironment in the terminal differentiation of epithelial cells of foregut origin. They further suggest that such progenitor cells might be useful in studies of organ repopulation following acute or chronic liver injury.

Purified hematopoietic stem cells without facilitating cells can repopulate fully allogeneic recipients across entire major histocompatibility complex transplantation barrier in mice

We report herein the successful long term engraftment of highly purified hematopoietic stem cells (HSCs) without any facilitating cells in fully allogeneic recipient mice across the entire major histocompatibility complex (MHC) transplantation barrier. This finding challenges the assumption that highly purified marrow HSCs alone cannot produce long-lived allogeneic bone marrow chimeras across the MHC barrier. In the present experiments, 1 × 105 HSCs from 5-fluorouracil (5-FU)-treated donors, without any facilitating cells, have been found to repopulate lethally irradiated fully allogeneic recipients. Low density, lineage-negative (CD4−, CD8−, B220−, Mac-1−, Gr-1−), CD71-negative, class I highly positive, FACS-sorted cells from 5-FU-treated C57BL/6 (B6) donor mice were transplanted into lethally irradiated BALB/c recipients. (BALB/c → BALB/c) → BALB/c T cell-depleted marrow cells used as compromised cells were also transplanted into the recipients to permit experiments to be pursued over a long period of time. Cells of donor origin in all recognized lineages of hematopoietic cells developed in these allogeneic chimeras. One thousand HSCs were sufficient to repopulate hemiallogeneic recipients, but 1 × 104 HSCs alone from 5-FU-treated donors failed to repopulate the fully allogeneic recipients. Transplantation of primary marrow stromal cells or bones of the donor strain into recipient, together with 1 × 104 HSCs, also failed to reconstitute fully allogeneic recipients. Suppression of resistance of recipients by thymectomy or injections of granulocyte colony-stimulating factor before stem cell transplantation enhanced the engraftment of allogeneic HSCs. Our experiments show that reconstitution of all lymphohematopoietic lineages across the entire MHC transplantation barriers may be achieved by transplanting allogeneic HSCs alone, without any facilitating cells, as long as a sufficient number of HSCs is transplanted.