31 results on '"Gustafson, S. K."'
Search Results
2. OPTN/SRTR 2016 Annual Data Report: Pancreas
- Author
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Kandaswamy, R., Stock, P. G., Gustafson, S. K., Skeans, M. A., Curry, M. A., Prentice, M. A., Fox, A., Israni, A. K., Snyder, J. J., and Kasiske, B. L.
- Published
- 2018
- Full Text
- View/download PDF
3. OPTN/SRTR 2015 Annual Data Report: Early effects of the new kidney allocation system
- Author
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Hart, A., Gustafson, S. K., Skeans, M. A., Stock, P., Stewart, D., Kasiske, B.L., and Israni, A. K.
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- 2017
- Full Text
- View/download PDF
4. OPTN/SRTR 2015 Annual Data Report: Pancreas
- Author
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Kandaswamy, R., Stock, P. G., Gustafson, S. K., Skeans, M. A., Curry, M. A., Prentice, M. A., Israni, A. K., Snyder, J. J., and Kasiske, B. L.
- Published
- 2017
- Full Text
- View/download PDF
5. OPTN/SRTR 2015 Annual Data Report: Kidney
- Author
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Hart, A., Smith, J. M., Skeans, M. A., Gustafson, S. K., Stewart, D. E., Cherikh, W. S., Wainright, J. L., Kucheryavaya, A., Woodbury, M., Snyder, J. J., Kasiske, B. L., and Israni, A. K.
- Published
- 2017
- Full Text
- View/download PDF
6. Kidney
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Hart, A., Smith, J. M., Skeans, M. A., Gustafson, S. K., Stewart, D. E., Cherikh, W. S., Wainright, J. L., Boyle, G., Snyder, J. J., Kasiske, B. L., and Israni, A. K.
- Published
- 2016
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- View/download PDF
7. Pancreas
- Author
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Kandaswamy, R., Skeans, M. A., Gustafson, S. K., Carrico, R. J., Prentice, M. A., Israni, A. K., Snyder, J. J., and Kasiske, B. L.
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- 2016
- Full Text
- View/download PDF
8. OPTN/SRTR 2013 Annual Data Report: Pancreas
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Kandaswamy, R., Skeans, M. A., Gustafson, S. K., Carrico, R. J., Tyler, K. H., Israni, A. K., Snyder, J. J., and Kasiske, B. L.
- Published
- 2015
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- View/download PDF
9. OPTN/SRTR 2013 Annual Data Report: Kidney
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Matas, A. J., Smith, J. M., Skeans, M. A., Thompson, B., Gustafson, S. K., Stewart, D. E., Cherikh, W. S., Wainright, J. L., Boyle, G., Snyder, J. J., Israni, A. K., and Kasiske, B. L.
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- 2015
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10. Sirolimus Use and Cancer Incidence Among US Kidney Transplant Recipients
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Yanik, E. L., Gustafson, S. K., Kasiske, B. L., Israni, A. K., Snyder, J. J., Hess, G. P., Engels, E. A., and Segev, D. L.
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- 2015
- Full Text
- View/download PDF
11. OPTN/SRTR 2012 Annual Data Report: Kidney
- Author
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Matas, A. J., Smith, J. M., Skeans, M. A., Thompson, B., Gustafson, S. K., Schnitzler, M. A., Stewart, D. E., Cherikh, W. S., Wainright, J. L., Snyder, J. J., Israni, A. K., and Kasiske, B. L.
- Published
- 2014
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- View/download PDF
12. OPTN/SRTR 2012 Annual Data Report: Pancreas
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Israni, A. K., Skeans, M. A., Gustafson, S. K., Schnitzler, M. A., Wainright, J. L., Carrico, R. J., Tyler, K. H., Kades, L. A., Kandaswamy, R., Snyder, J. J., and Kasiske, B. L.
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- 2014
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13. OPTN/SRTR 2011 Annual Data Report: Pancreas
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Kandaswamy, R., Stock, P. G., Skeans, M. A., Gustafson, S. K., Sleeman, E. F., Wainright, J. L., Carrico, R. J., Ghimire, V., Snyder, J. J., Israni, A. K., and Kasiske, B. L.
- Published
- 2013
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14. OPTN/SRTR 2011 Annual Data Report: Kidney
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Matas, A. J., Smith, J. M., Skeans, M. A., Lamb, K. E., Gustafson, S. K., Samana, C. J., Stewart, D. E., Snyder, J. J., Israni, A. K., and Kasiske, B. L.
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- 2013
- Full Text
- View/download PDF
15. OPTN/SRTR 2014 ANNUAL DATA REPORT: KIDNEY
- Author
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Hart, A., Smith, J. M., Skeans, M. A., Gustafson, S. K., Stewart, D. E., Cherikh, W. S., Wainright, J. L., Boyle, G., Snyder, J. J., Kasiske, B. L., and Israni, A. K.
- Subjects
Adult ,Tissue and Organ Procurement ,Adolescent ,Waiting Lists ,Data Collection ,Graft Survival ,Infant ,Middle Aged ,Kidney Transplantation ,Article ,Tissue Donors ,United States ,Young Adult ,Child, Preschool ,Outcome Assessment, Health Care ,Living Donors ,Humans ,Kidney Failure, Chronic ,Registries ,Child ,Immunosuppressive Agents ,Aged - Abstract
Kidney transplant provides significant survival, cost, and quality-of-life benefits over dialysis in patients with end-stage kidney disease, but the number of kidney transplant candidates on the waiting list continues to grow annually. By the end of 2014, nearly 100,000 adult candidates and 1500 pediatric candidates were waiting for kidney transplant. Not surprisingly, waiting times also continued to increase, along with the number of adult candidates removed from the list due to death or deteriorating medical condition. Death censored graft survival has increased after both living and deceased donor transplants over the past decade in adult recipients. The majority of the trends seen over the past 5 years continued in 2014. However, the new allocation system was implemented in late 2014, providing an opportunity to assess changes in these trends in the coming years.
- Published
- 2016
16. OPTN/SRTR 2018 Annual Data Report: Hepatitis C
- Author
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Wang, J.H., Gustafson, S. K., Skeans, M. A., Lake, J. R., Kim, W. R., Kasiske, B. L., Israni, A. K., and Hart, A.
- Abstract
Direct acting antivirals (DAAs) have fundamentally changed the treatment of hepatitis C virus (HCV) infection and reduced the discard rate of HCV‐infected organs by offering a treatment option with a high likelihood of cure posttransplant. This has spurred increased interest in transplanting organs from HCV‐positive donors into recipients both with and without HCV. In this chapter, we examine data from 2007 to 2018 to determine trends in HCV(+) donor transplants across various organ types. Since 2015, willingness to accept HCV(+) organs increased for candidates waitlisted for kidney, lung, heart, and pancreas transplant, but decreased for those listed for intestine transplant. For candidates listed for liver transplant, willingness to accept HCV(+) organs decreased from 2007 to 2017, but began increasing in 2017. Willingness to accept was not concentrated in a single USgeographic area, and there was substantial variation among transplant programs and donation service areas. Numbers of anti‐HCV(+) donor kidney, heart, lung, and liver transplants have increased considerably in the past few years. Short‐term allograft survival for kidney and liver transplant recipients of anti‐HCV(+) organs appears to be comparable to that for recipients of anti‐HCV(‐) organs in an unadjusted analysis. However, an unadjusted analysis indicates that long‐term allograft survival may be worse. Kidney transplant between HCV‐infected donors and uninfected recipients with posttransplant DAAtreatment is an emerging area. Short‐term data are promising, with similar 1‐year allograft survival compared with HCV‐uninfected donor to HCV‐uninfected recipient kidney transplants in unadjusted analyses. However, long‐term data are lacking and close monitoring in the future is warranted.
- Published
- 2020
- Full Text
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17. OPTN/SRTR2018 Annual Data Report: Pancreas
- Author
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Kandaswamy, R., Stock, P. G., Gustafson, S. K., Skeans, M. A., Urban, R., Fox, A., Israni, A. K., Snyder, J. J., and Kasiske, B. L.
- Abstract
The overall number of pancreas transplants continued to increase to 1027 in 2018, after a nadir of 947 in 2015. New additions to waiting list remained stable, with 1485 candidates added in 2018. Proportions of patients with type IIdiabetes waiting for transplant (14.6%) and undergoing transplant (14.8%) have steadily increased since 2016. Waiting times for simultaneous pancreas/kidney transplant have decreased; median months to transplant was 13.5 for simultaneous pancreas/kidney transplant and 19.7 for pancreas transplant alone in 2018. Outcomes, including patient and kidney survival, as well as rejection rates, have improved consistently over the past several years. Pancreas graft survival data are being collected by the Organ Procurement and Transplantation Network and will be included in a future report once there are sufficient cohorts for analysis.
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- 2020
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- View/download PDF
18. OPTN/SRTR2018 Annual Data Report: Kidney
- Author
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Hart, A., Smith, J. M., Skeans, M. A., Gustafson, S. K., Wilk, A. R., Castro, S., Foutz, J., Wainright, J. L., Snyder, J. J., Kasiske, B. L., and Israni, A. K.
- Abstract
Despite the ongoing severe mismatch between organ need and supply, data from 2018 revealed some promising trends. For the fourth year in a row, the number of patients waiting for a kidney transplant in the USdeclined and numbers of both deceased and living donor kidney transplants increased. These encouraging trends are tempered by ongoing challenges, such as a large proportion of listed patients with dialysis time longer than 5 years. The proportion of candidates aged 65 years or older continued to rise, and the proportion undergoing transplant within 5 years of listing continued to vary dramatically nationwide, from 10% to nearly 80% across donation service areas. Increasing trends in the recovery of organs from hepatitis C positive donors and donors with anoxic brain injury warrant ongoing monitoring, as does the ongoing discard of nearly 20% of recovered organs. While the number of living donor transplants increased, racial disparities persisted in the proportion of living versus deceased donors. Strikingly, the total number of kidney transplant recipients alive with a functioning graft is on track to pass 250,000 in the next 1‐2 years. The total number of pediatric kidney transplants remained steady at 756 in 2018. Deeply concerning to the pediatric community is the persistently low level of living donor kidney transplants, representing only 36.2% in 2018.
- Published
- 2020
- Full Text
- View/download PDF
19. OPTN/SRTR 2017 Annual Data Report: Pancreas
- Author
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Kandaswamy, R., Stock, P. G., Gustafson, S. K., Skeans, M. A., Urban, R., Fox, A., Odorico, J. S., Israni, A. K., Snyder, J. J., and Kasiske, B. L.
- Abstract
In 2017, 1492 patients were added to the pancreas transplant waiting list, 964 listed as active, a slight increase from 2016. This is significant because for the first time in the past decade, the steady downward trend in additions to the waiting list has been reversed. Proportions of pancreas donors with cerebrovascular accident as cause of death decreased, with a concomitant increase in proportions with anoxia and head trauma. This is partly a result of the national opioid crisis, and it reflects increasing use of younger donors for pancreas transplant. The 2017 outcome report remains compromised by previous variation in reporting graft failure. Although the OPTNPancreas Transplantation Committee has approved more precise definitions of pancreas graft failure, implementation of these definitions took place recently, and the data are not reflected in this report.
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- 2019
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- View/download PDF
20. OPTN/SRTR 2017 Annual Data Report: Kidney
- Author
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Hart, A., Smith, J. M., Skeans, M. A., Gustafson, S. K., Wilk, A. R., Castro, S., Robinson, A., Wainright, J. L., Snyder, J. J., Kasiske, B. L., and Israni, A. K.
- Abstract
Many positive trends in kidney transplantation were notable in 2017. Deceased donor kidney transplant rates and counts continued to rise, the kidney transplant waiting list declined for the third year in a row after decades of growth, and both short‐ and long‐term allograft survival continued to improve year over year. In total, more than 220,000 patients were living in the United States with a functioning allograft. With 3 years of data available since implementation of the new kidney allocation system, better prediction of longer‐term results of the allocation policy changes became possible. The data also reveal several areas in need of improvement and attention. Overall, the challenge of providing adequate access to kidney transplant persisted nationally, with additional dramatic regional variation. The proportion of living donor kidney transplants in both adults and children continued to fall, and racial disparities in living donor kidney transplant grew in the past decade.
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- 2019
- Full Text
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21. Program‐specific transplant rate ratios: Association with allocation priority at listing and posttransplant outcomes
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Wey, A., Gustafson, S. K., Salkowski, N., Pyke, J., Kasiske, B. L., Israni, A. K., and Snyder, J. J.
- Abstract
The Scientific Registry of Transplant Recipients (SRTR)is considering more prominent reporting of program‐specific adjusted transplant rate ratios (TRRs). To enable more useful reporting of TRRs, SRTRupdated the transplant rate models to adjust explicitly for components of allocation priority. We evaluated potential associations between TRRs and components of allocation priority that could indicate programs' ability to manipulate TRRs by denying or delaying access to low‐priority candidates. Despite a strong association with unadjusted TRRs, we found no candidate‐level association between the components of allocation priority and adjusted TRRs. We found a strong program‐level association between median laboratory Model for End‐stage Liver Disease (MELD) score at listing and program‐specific adjusted TRRs (r= .37; P <.001). The program‐level association was likely confounded by regional differences in donor supply/demand and listing practices. In kidney transplantation, higher program‐specific adjusted TRRs were weakly associated with better adjusted posttransplant outcomes (r= −.14; P =.035) and lower adjusted waitlist mortality rate ratios (r= −.15; P =.022), but these associations were absent in liver, lung, and heart transplantation. Program‐specific adjusted TRRs were unlikely to be improved by listing candidates with high allocation priority and can provide useful information for transplant candidates and programs. Program‐specific adjusted transplant rate ratios are not associated with allocation priority, posttransplant outcomes, or adjusted waitlist mortality rate ratios. See Patzer's editorial on page 1301.
- Published
- 2018
- Full Text
- View/download PDF
22. OPTN/SRTR2016 Annual Data Report: Pancreas
- Author
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Kandaswamy, R., Stock, P. G., Gustafson, S. K., Skeans, M. A., Curry, M. A., Prentice, M. A., Fox, A., Israni, A. K., Snyder, J. J., and Kasiske, B. L.
- Abstract
The number of pancreas transplants performed in the United States increased by 7.0% in 2016 over the previous year, the first such increase in more than a decade, largely attributable to an increase in simultaneous kidney pancreas transplants. Transplant rates increased in 2016, and mortality on the waiting list decreased. The declining enthusiasm for pancreas after kidney (PAK) transplants persisted. The uniform definition of graft failure was approved by the OPTNBoard of Directors in 2015 and will be implemented in early 2018. Meanwhile, SRTRcontinues to refrain from reporting pancreas graft failure data. The OPTN/UNOSPancreas Transplantation Committee is seeking to broaden allocation of pancreata across compatible ABOblood types in a proposal out for public comment July 31 to October 2, 2017. A new initiative to provide guidance on the benefits of PAKtransplants is also out for public comment.
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- 2018
- Full Text
- View/download PDF
23. OPTN/SRTR2016 Annual Data Report: Kidney
- Author
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Hart, A., Smith, J. M., Skeans, M. A., Gustafson, S. K., Wilk, A. R., Robinson, A., Wainright, J. L., Haynes, C. R., Snyder, J. J., Kasiske, B. L., and Israni, A. K.
- Abstract
Data from 2016 show ongoing positive trends in short‐ and long‐term allograft survival, and a decrease in the number of active listed candi‐ dates for the first time in more than a decade, with a concomitant in‐ crease in deceased donor kidney transplants. Transplant rates that had changed dramatically for some groups after implementation of the new kidney allocation system in 2014 are stabilizing, allowing for evaluation of new steady states and trends. Many challenges remain in adult kid‐ ney transplantation, including stagnant rates of living donor transplant, geographic disparities in access to transplant, racial disparities in living donor transplant, and overall a continuing demand for kidneys that far outpaces the supply. For pediatric recipients, a decline in the proportion of living donor transplants is of concern. In 2016, only 34.2% of pediatric transplants were from living donors, compared with 47.2% in 2005. The number of related donors decreased dramatically over the past decade, and the number of unrelated directed transplants performed in pediatric candidates remained low (50).
- Published
- 2018
- Full Text
- View/download PDF
24. Reply to Comment on the Article “OPTN/SRTR2015 Annual Data Report: Pancreas”
- Author
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Kandaswamy, R., Stock, P. G., Gustafson, S. K., Skeans, M., Thompson, B., and Kasiske, B. L.
- Published
- 2017
- Full Text
- View/download PDF
25. OPTN/SRTR 2018 Annual Data Report: Kidney.
- Author
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Hart A, Smith JM, Skeans MA, Gustafson SK, Wilk AR, Castro S, Foutz J, Wainright JL, Snyder JJ, Kasiske BL, and Israni AK
- Subjects
- Graft Survival, Humans, Tissue Donors, Kidney Transplantation methods, Registries, Tissue and Organ Procurement methods, Waiting Lists
- Abstract
Despite the ongoing severe mismatch between organ need and supply, data from 2018 revealed some promising trends. For the fourth year in a row, the number of patients waiting for a kidney transplant in the US declined and numbers of both deceased and living donor kidney transplants increased. These encouraging trends are tempered by ongoing challenges, such as a large proportion of listed patients with dialysis time longer than 5 years. The proportion of candidates aged 65 years or older continued to rise, and the proportion undergoing transplant within 5 years of listing continued to vary dramatically nationwide, from 10% to nearly 80% across donation service areas. Increasing trends in the recovery of organs from hepatitis C positive donors and donors with anoxic brain injury warrant ongoing monitoring, as does the ongoing discard of nearly 20% of recovered organs. While the number of living donor transplants increased, racial disparities persisted in the proportion of living versus deceased donors. Strikingly, the total number of kidney transplant recipients alive with a functioning graft is on track to pass 250,000 in the next 1-2 years. The total number of pediatric kidney transplants remained steady at 756 in 2018. Deeply concerning to the pediatric community is the persistently low level of living donor kidney transplants, representing only 36.2% in 2018., (.)
- Published
- 2020
- Full Text
- View/download PDF
26. OPTN/SRTR 2018 Annual Data Report: Pancreas.
- Author
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Kandaswamy R, Stock PG, Gustafson SK, Skeans MA, Urban R, Fox A, Israni AK, Snyder JJ, and Kasiske BL
- Subjects
- Graft Survival, Humans, United States, Pancreas Transplantation statistics & numerical data, Tissue Donors statistics & numerical data, Tissue and Organ Procurement methods, Waiting Lists
- Abstract
The overall number of pancreas transplants continued to increase to 1027 in 2018, after a nadir of 947 in 2015. New additions to waiting list remained stable, with 1485 candidates added in 2018. Proportions of patients with type II diabetes waiting for transplant (14.6%) and undergoing transplant (14.8%) have steadily increased since 2016. Waiting times for simultaneous pancreas/kidney transplant have decreased; median months to transplant was 13.5 for simultaneous pancreas/kidney transplant and 19.7 for pancreas transplant alone in 2018. Outcomes, including patient and kidney survival, as well as rejection rates, have improved consistently over the past several years. Pancreas graft survival data are being collected by the Organ Procurement and Transplantation Network and will be included in a future report once there are sufficient cohorts for analysis., (.)
- Published
- 2020
- Full Text
- View/download PDF
27. Broadened Allocation of Pancreas Transplants Across Compatible ABO Blood Types.
- Author
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Fridell JA, Gustafson SK, Thompson BW, Fox AC, Prentice MA, Curry MA, and Odorico JS
- Subjects
- Adult, Blood Grouping and Crossmatching standards, Cohort Studies, Female, Graft Survival, Humans, Kidney, Kidney Transplantation, Male, Pancreas, Tissue and Organ Procurement standards, Waiting Lists, ABO Blood-Group System, Blood Grouping and Crossmatching methods, Pancreas Transplantation, Tissue and Organ Procurement methods, Transplants supply & distribution
- Abstract
Background: Current Organ Procurement and Transplantation Network (OPTN) policy restricts certain blood type-compatible simultaneous pancreas and kidney (SPK) transplants. Using the Kidney Pancreas Simulated Allocation Model, we examined the effects of 5 alternative allocation sequences that allowed all clinically compatible ABO transplants., Methods: The study cohort included kidney (KI), SPK, and pancreas alone (PA) candidates waiting for transplant for at least 1 day between January 1, 2010, and December 31, 2010 (full cohort), and kidneys and pancreata recovered for transplant during the same period. Additionally, because the waiting list has shrunk since 2010, the study population was reduced by random sampling to match the volume of the 2015 waiting list (reduced cohort)., Results: Compared with the current allocation sequence, R4 and R5 both showed an increase in SPK transplants, a nearly corresponding decrease in KI transplants, and virtually no change in PA transplants. Life-years from transplant and median years of benefit also increased. The distribution of transplants by blood type changed, with more ABO:A, B, and AB transplants performed, and fewer ABO:O across all transplant types (KI, SPK, PA), with the relative percent changes largest for SPK., Discussion: Broadened ABO compatibility allowances primarily benefitted SPK ABO:A and AB candidates. ABO:O candidates saw potentially reduced access to transplant. The simulation results suggest that modifying the current allocation sequence to incorporate broadened ABO compatibility can result in an increase in annual SPK transplants., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
28. Reply to Comment on the Article "OPTN/SRTR 2015 Annual Data Report: Pancreas".
- Author
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Kandaswamy R, Stock PG, Gustafson SK, Skeans M, Thompson B, and Kasiske BL
- Subjects
- Graft Survival, Pancreas Transplantation
- Published
- 2017
- Full Text
- View/download PDF
29. Partial characterization of a novel avian defect affecting adult muscle function.
- Author
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Velleman SG, Brown SM, Gustafson SK, Faustman LC, Beaurang PA, Craft F, and Hausman RE
- Subjects
- Animals, Chickens, Muscular Diseases physiopathology, Muscular Dystrophy, Animal physiopathology, Pectoralis Muscles physiopathology, Reference Values, Bird Diseases physiopathology, Muscular Diseases veterinary
- Published
- 1993
30. RG 12561 (dalvastatin): a novel synthetic inhibitor of HMG-CoA reductase and cholesterol-lowering agent.
- Author
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Amin D, Gustafson SK, Weinacht JM, Cornell SA, Neuenschwander K, Kosmider B, Scotese AC, Regan JR, and Perrone MH
- Subjects
- Analysis of Variance, Animals, Cholesterol biosynthesis, Cricetinae, Cyclohexanes therapeutic use, Humans, Lactones therapeutic use, Lipoproteins, HDL blood, Lipoproteins, LDL blood, Liver cytology, Liver enzymology, Lovastatin pharmacology, Lovastatin therapeutic use, Male, Pravastatin pharmacology, Rabbits, Rats, Rats, Sprague-Dawley, Tumor Cells, Cultured, Anticholesteremic Agents pharmacology, Cholesterol blood, Cyclohexanes pharmacology, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lactones pharmacology, Liver drug effects
- Abstract
RG 12561 (dalvastatin) is a prodrug which converts to its open hydroxyacid form in the body. The Na salt of RG 12561 (RG 12561-Na) is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. It competitively inhibits rat liver HMG-CoA reductase with an IC50 value of 3.4 nmol/l. In the same assay, the IC50 values for other potent HMG-CoA reductase inhibitors, lovastatin-Na and pravastatin, were 2.3 and 8.9 nmol/l, respectively. In Hep G2 liver cells, RG 12561-Na, lovastatin-Na and pravastatin inhibited cholesterol biosynthesis from radiolabeled octanoate with IC50 values of 4 and 5 nmol/l and 1.1 mumol/l, respectively. In a rat ex vivo assay, orally administered RG 12561, lovastatin and pravastatin inhibited cholesterol biosynthesis in liver slices with ED50 values of 0.9, 0.5 and 12 mg/kg, respectively. In cholestyramine-fed hamsters, RG 12561 (0.1% in food for 18 days) reduced LDL cholesterol, whereas HDL was slightly increased. The reductions in the LDL/HDL ratio for RG 12561, RG 12561-Na, lovastatin and lovastatin-Na were 35, 76, 88 and 88%, respectively. At a higher dose, RG 12561 (0.4% in food) reduced serum cholesterol, LDL and LDL/HDL by 84, 97 and 91%, respectively. In WHHL rabbits, RG 12561 and lovastatin (5 mg/kg, b.i.d., 12 days) reduced serum cholesterol by 17 and 16%, respectively. These results demonstrate that RG 12561 is a potent cholesterol-lowering agent.
- Published
- 1993
- Full Text
- View/download PDF
31. Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis.
- Author
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Amin D, Cornell SA, Gustafson SK, Needle SJ, Ullrich JW, Bilder GE, and Perrone MH
- Subjects
- Animals, Bone Diseases metabolism, Bone Resorption prevention & control, Cell Line, Cell-Free System, In Vitro Techniques, Kinetics, Male, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Rats, Rats, Sprague-Dawley, Bone Diseases drug therapy, Cholesterol biosynthesis, Diphosphonates pharmacology, Farnesyl-Diphosphate Farnesyltransferase antagonists & inhibitors
- Abstract
Some bisphosphonates used for the treatment of bone disorders are also potent inhibitors of squalene synthase, a critical enzyme for sterol biosynthesis. Among seven drugs tested, YM 175 (cycloheptylaminomethylene-1,1-bisphosphonic acid) was the most potent inhibitor of rat liver microsomal squalene synthase (Ki = 57 nM) and sterol biosynthesis from [14C]mevalonate in rat liver homogenate (IC50 = 17 nM). EB 1053 (3-(1-pyrolidino)-1-hydroxypropylidene-1,1-bisphosphonic acid) and PHPBP (3-(1-piperidino)-1-hydroxypropylidene-1,1-bisphosphonic acid) were less potent inhibitors in both these assays. Pamidronate and alendronate were poor inhibitors of squalene synthase (IC50 > 10 microM) but were potent inhibitors of sterol biosynthesis from mevalonate (IC50 = 420 and 168 nM, respectively), suggesting that the latter two agents may have inhibited other enzymes involved in the synthesis of farnesyl pyrophosphate from mevalonate. Etidronate and clodronate were inactive in both these assays. YM 175 also inhibited sterol biosynthesis in mouse macrophage J774 cells (IC50 = 64 microM) and in rats, when administered acutely, it inhibited cholesterol biosynthesis in the liver (ED50 = 30 mg/kg, s.c.). Structural modifications on YM 175 to enhance cell permeability may result in a new class of cholesterol-lowering agents.
- Published
- 1992
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