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American Journal of Transplantation 2006; 6: 2556–2562 Blackwell Munksgaard

 C 2006 The Authors C 2006 The American Society of Journal compilation  Transplantation and the American Society of Transplant Surgeons

Meeting Report

doi: 10.1111/j.1600-6143.2006.01514.x

Disparities in Solid Organ Transplantation for Ethnic Minorities: Facts and Solutions R. S. D. Higginsa and J. A. Fishmanb, ∗ a Rush University Medical Center, Department of Cardiovascular and Thoracic Surgery, Chicago, Illinois, USA b Massachusetts General Hospital, Harvard Medical School, Infectious Disease Division, Boston, Massachusetts, USA ∗ Corresponding author: Jay A. Fishman, [email protected]

The Diversity and Minority Affairs Committee of the American Society of Transplantation (AST) convened a symposium to examine organ transplantation in underserved and minority populations. The goals of the meeting included ‘benchmarking’ of solid organ transplantation among minority populations, review of the epidemiology of end-organ damage, exploration of barriers to transplantation services and development of approaches to eliminate disparities. Participants noted that minority populations were more likely to be adversely affected by limited preventive medical care, lack of counseling regarding transplant options, and delays in transplant referrals for organ transplantation. These features largely reflect economic disadvantage as well as the reduced presence of minority professionals with training in transplant-related specialties. Participants in the conference noted that recent changes in organ allocation policies had improved access to minority individuals once listed for renal transplantation. Similar advances will be needed for other organs to address inequities in pretransplant care and underrepresentation of minorities among transplant professionals. The biologic basis of differences in transplant outcomes for minority recipients has not been adequately studied. Research funds must be targeted to address biologic mechanisms underlying disparate transplant outcomes including the impacts of environment, education, poverty and lifestyle choices. Key words: Disparity, education, ethnicity, genomics, minority, race, transplantation Received 6 March 2006, revised 19 June 2006 and accepted for publication 30 June 2006

Introduction Racial and ethnic disparities in healthcare extend to specialty fields including solid organ transplantation. The Diversity and Minority Affairs Committee of the American Society of Transplantation (AST) sponsored a symposium (Diversity and Disparity in Solid Organ Transplantation: Bench to Bedside, Facts and Solutions) to examine disparities in transplantation for underserved and minority populations (1–3).

Epidemiology Most of the available data on the epidemiology of organ failure relate to renal transplantation, although participants believed that the major themes apply to all forms of solid organ transplantation. In 2002, end stage renal disease (ESRD) Medicare (CMS) program costs $17 billion or 6.7% of the overall budget (3). In the United States, ethnic minorities suffer disproportionately from kidney disease (Table 1). African Americans comprise 35% of the Medicare dialysis population. Compared to Caucasians, the incidence of ESRD in African Americans is 4-fold higher than that of Caucasian counterparts. This is also true for Native Americans among Zuni Indians in the American Southwest in whom renal disease is 18-fold more prevalent than for Caucasians. Hispanic Americans have 2-fold the rate of ESRD of non-Hispanic Caucasians. The excess burden of kidney disease in minority populations reflects, in part, the higher rate of known medical and environmental risk factors for ESRD and for other end-organ failure, including genetic predisposition, diet, lifestyle, Type II diabetes mellitus and hypertension and delays in receiving appropriate treatment (4). In the Native American dialysis population, 73% are diabetic and 83% are hypertensive (5). In African Americans, hypertension is prevalent and less well controlled by conventional medical therapies (6).

Access to Transplantation Services

Proceedings of an AST Conference September 21–22, 2005 Washington, D.C.

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Medicare reimbursement policies make renal replacement therapy an entitlement for most U.S. citizens. Socioeconomically disadvantaged minorities have reduced access to preventative medical care and are more likely to

Disparities in Solid Organ Transplantation for Ethnic Minorities Table 1: Point prevalence rates of reported ESRD, as of December 31, 2002 (USRDS 2004) Race/Ethnicity

Prevalence, per million

Caucasian African American Native American Asian Hispanic Non-Hispanic

1060 4467 2569 1571 1991 1404

Rates per million U.S. population, adjusted for age and gender. Hispanic may include people of any race or combination of races. Other categories are non-Hispanic. Adapted from USRDS Annual Data Report: Atlas of End-Stage Renal Disease in the United States. 2004; Table B.5.

Figure 1: Waiting list, by organ and ethnicity (UNOS, 2005).

receive care from physicians less knowledgeable in specialized areas including organ transplantation (7–11). Access to transplantation is also affected by overall severity of illness, general health status, transplant center activity and for kidney transplantation, patient and physician attitudes about dialysis and transplantation. Resulting disparities are most evident in renal, rather than thoracic organ or hepatic transplantation. Lack of private health insurance appears to be a major barrier to transplantation care, although this may be a surrogate for other socioeconomic factors (7). Those without insurance avoid frequent interactions with the healthcare system, leading to the perception that they are noncompliant or disinterested and delaying preventative care (8,9). Ethnic minorities, notably Hispanic Americans, are less likely than non-Hispanic White Americans to possess health insurance, notably among the working poor (12). African Americans are also less likely to possess private or employment-sponsored insurance and they are more likely to be covered by Medicaid or other publicly funded insurance. Approximately 33% of American Indians and Alaskan natives lack health insurance and less than half have employment-based insurance, while 25% have either Medicaid, are uninsured or rely upon only Indian Health Services services. As a result, the majority of eligible Native Americans in urban or nonreservation areas have reduced access to medical care (13). High-income patients are more likely than low and middleincome patients to be listed for renal transplantation, often before the need for dialysis (11,14). Minority patients experience low referral rates to kidney and liver transplant centers (even if expressing a preference for transplantation), fewer completed evaluations and fewer become candidates after screening than Caucasian patients (15–17). Referral rates for minorities are lower both for initial evaluation of transplantation (African American [AA] vs. whites, 90.1% vs. 98% respectively, p = 0.008) and for placement on the transplant waitlist (AA 71% vs. whites 86.7%) (17,18). Thus, African American, Hispanic and Native AmerAmerican Journal of Transplantation 2006; 6: 2556–2562

ican patients remain underrepresented on kidney waiting lists relative to the composition of the chronic kidney disease population (Figure 1) (16). Counseling may be complicated by data that suggest that African Americans and Native Americans fare better (initially) than non-Hispanic whites on dialysis (4). These factors may reduce the impetus for healthcare providers and patients to pursue transplantation (19,20). Scientific Registry of Transplant Recipients data for dialysis patients under age 70 (1995–2003) confirm the existence of delays in transplant referrals for minority patients. African Americans, Hispanics and Native Americans have lower rates of placement on the waiting list than Caucasians and Asians. As a result, African Americans and Native Americans are more likely to enter the healthcare system with more advanced renal disease. In the United States, 17% of blacks and 11% of Hispanics have completed 4 or more years of higher education compared to 44% of Asian Americans and 26% of Caucasians (14). These factors affect the ability to understand and to pay for preventive medical care and transplantation. Several factors account for differences in transplantation rates between races after listing. These include: HLA differences as a barrier to organ allocation; the Organ Procurement Organization (OPO) or donation service area of waitlisting; and patient insurance type. However, even with correction of these characteristics, there is an 18% lower transplantation rate for African Americans (RR = 0.82) compared with non-Hispanic whites (21). African American patients are 70% less likely than Caucasians to receive preemptive transplantation before dialysis or to receive a living donor kidney. Retransplantation for African American individuals sensitized after a first kidney transplant was significantly delayed compared to Caucasian patients (21). An apparently successful policy change affecting organ availability was made by the Organ Procurement and Transplant Network, which implemented a change in the kidney 2557

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allocation policy in May 2003 based on the observation that certain HLA antigens (notably, HLA-B) were less common among donors than among candidates in certain minority groups and contributed to the reduced rate of transplantation among minorities. By removing the criteria for matching of these antigens, this policy change improved access to transplantation for African American candidates within the first year of the new policy without adversely affecting the general population (22,23). Rates of referral for liver transplantation at a Veterans Affairs medical center were adversely impacted by factors including older age (adjusted odds ratio [OR] 0.31; 95% confidence interval [CI] 0.13–0.77, p = 0.01), alcoholic liver disease (adjusted OR: 0.10; 95% CI 0.02–0.57, p = 0.01) and Black race (OR 0.15; 95% CI 0.02–0.96, p = 0.045) (17). Contraindications to transplantation were often undocumented. Such deficiencies at the referral level diminish access to liver transplantation for African American adults (24). African American orthotopic liver transplant (OLT) recipients tend to be younger and sicker than white candidates, more likely to die or become too ill for OLT while waiting (p < 0.001), and are less likely to receive OLT within 4 years (p < 0.001) (18,24). Once waitlisted, Hispanics, African Americans, Asians and Other Race candidates have unadjusted transplantation rates from the time of wait listing that are 35%, 43%, 41% and 39% lower, respectively, than non-Hispanic whites. However, although transplantation rates remain widely disparate (African American 16.9% vs. whites 52%, P < 0.001), after adjustment for disease severity and other factors, time to liver transplantation after listing did not differ by race (18). For lung recipients, there is a slightly lower probability of being transplanted within 1 year for blacks compared to whites and Hispanics.

Outcomes of Solid Organ Transplantation Outcomes of transplantation are inferior in minority recipients compared to the general population (Table 2). In all ethnic groups studied, transplantation reduced the longterm risk of death compared with dialysis; higher initial mortality after transplantation disappears within 6 months. Transplantation reduces the long-term relative risk of death

more among Asians and whites than among Native Americans and blacks (20). Asian Americans, who had the lowest mortality rate on dialysis and on the waiting list, required 2 years after transplantation to accrue a mortality benefit. For heart recipients, the probability of transplantation within 1 year after listing was similar for all ethnic groups, as was the probability of death on the waiting list or being classified as too sick for transplant, a measure of disease severity (5). After heart transplantation, increased mortality was observed among African Americans, females, those with prior pregnancies, preoperative valvular heart disease, prior transplantation, LVAD requirement and ventilator dependence (25–27). African American females with prior pregnancy had the highest relative risk of mortality (RR = 1.9, p < 0.0001) followed by African American females without prior pregnancy, African American males and Caucasian females with prior pregnancy (RR = 1.24, p < 0.0004). HLA sensitization increased from 4.9% to 50% after multiple pregnancies. Outcomes may relate to the underlying conditions necessitating transplantation. Non-Hispanic white heart registrants less often had cardiomyopathy, were less likely to have been in the intensive care unit at the time of listing or to be transplanted as Status 1A, and were more likely to have had cardiac surgery before transplantation. African American lung registrants had sarcoidosis more frequently as a predisposing condition to respiratory failure compared with Caucasians who most often had chronic obstructive pulmonary disease. In spite of these differences, outcomes for lung transplantation were not significantly different between minority and nonminority recipients. For abdominal organs, the adjusted 3-year graft survival rates for African Americans are worse for recipients of non-ECD kidneys and livers compared to non-Hispanic Whites. By contrast kidney recipients of Asian or Hispanic(Latino background had better 3-year graft survival than non-Hispanic Whites. For living donor kidney transplant recipients, the 3-year graft survival was 83.4% among African Americans versus. 88.4% for non-Hispanic whites. Similar observations apply to pediatric recipients. The percentage of nonwhite pediatric recipients (African

Table 2: Adjusted 3-year graft survival, deceased donor transplants by race/ethnicity and transplanted organ, 2000–2003 Transplanted Organ

White, non-Hispanic

African American

Hispanic/Latino

Asian American

Other/Multi-race

Kidney, non-ECD Pancreas only, PTA Liver Intestine Heart Lung

81.6% 63.5% 73.6% 55.0% 80.4% 62.6%

73.9%1 58.6% 66.9%∗1 37.9% 72.8%1 61.0%

83.6%1 78.1% 74.0% 50.0% 78.9% 62.3%

85.5%1 74.1% 50.5% 81.5% 77.5%

83.0% 28.2% 71.7% 81.7% 39.8%

(∗) Insufficient numbers; 1 significantly different from Non-Hispanic White (p < 0.05) (5)

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American and Hispanics) increased from 28% to 43% in 2001. African American ethnicity was associated with increased risk of first rejection in both living (relative risk [RR] = 1.22, p = 0.005) and deceased donor renal transplants (RR = 1.27, p < 0.001) and of chronic rejection compared with non-African Americans (North American Pediatric Renal Transplant Cooperative Study , 8713 pediatric recipients (18 years of age) (28). The etiologies of inferior transplant outcomes for ethnic minorities are unclear. Lifestyle and general health issues including obesity and nutritional status have exaggerated impacts on minority populations and transplant outcomes (29). The prevalence of overweight and obese individuals is greater in men and women of all ethnic minority populations (other than Asian Americans) compared to Caucasians (30). Smaller studies have shown increased prevalence of obesity in Puerto Ricans, Cuban Americans, Pacific-Islander Americans and Native Americans (31). The metabolic consequences of obesity include increased rates of insulin resistance, diabetes, hypertension, dyslipidemia, proteinuria, increased cardiovascular risk and mortality (32). Obesity is associated with worse transplant outcomes—increased risk of death, death-censored graft loss, wound infections and dehiscence, donor graft failure and posttransplant diabetes (PTDM). Risk factors for PTDM include family history, history of glucose intolerance, increasing age, ethnic minority (blacks, Hispanics and Native Americans), obesity, hepatitis C and immunosuppression (steroids and calcineurin inhibitors). New-onset diabetes after transplant, in particular, is increased among ethnic minorities beyond the normally elevated risk profile. The ability to effect lifestyle changes may be one of the most significant interventions to improve transplant outcomes. Studies are needed to understand the mechanisms underlying the impacts of modifiable risk factors in transplant outcomes in diverse populations.

Future Directions Biologic issues and research priorities ‘Race’ is a social construct defined by history, geography and culture. Given that ∼99.9% of the human genome are conserved, genetic variants and the effects of environmental factors, including lifestyle, on gene regulation and protein expression and processing must be examined in the context of transplantation (33). This interface between basic science, clinical medicine, environment and lifestyle is termed ‘complex genomics’. Among the factors affecting outcomes of transplantation are the genetics and regulation of immune responses, pharmacokinetics (PKs) and pharmacogenomics (e.g. drug metabolism and polymorphisms affecting drug absorbance and delivery). Ethnicity may correlate with some of these processes. For example, polymorphisms in expression of B7 costimulatory molecules and in regulatory regions of cyAmerican Journal of Transplantation 2006; 6: 2556–2562

tokine genes (including IL-6, IL-10, TNF-a, TGF-b) may modulate alloimmune responses following transplantation and may contribute to the apparent influence of ethnicity on organ transplant outcomes (34–36). Antigen-presenting cells from African Americans exhibit increased B7 family member (CD80, CD86) costimulatory molecule expression that may contribute to enhanced alloreactive T-cell responses compared with Caucasians (37). Similarly, HLA sensitization negatively impacts African Americans and women more than males and Caucasians (26). The links between enhanced alloreactivity and transplant outcomes have not been fully elucidated. Pharmacogenetic studies suggest that gene polymorphisms affecting drug transport, metabolism and elimination exist between ethnic groups. Two polymorphisms affecting disposition of immunosuppressive agents have different allelic frequencies in Caucasians and African Americans. These polymorphisms are in the genes ABCB1 (MDR1) and cytochrome P450 3A5 (CYP3A5), which encode production of the membrane pump P-glycoprotein and a major enzyme in the metabolism of calcineurin inhibitors, prednisone, sirolimus and other agents (38). CYP3A5∗ 1 expressors require more tacrolimus to achieve therapeutic drug levels (39); 50% of African Americans express CYP3A5 in comparison to only 10–30% of Caucasians (40). The membrane pump encoded by ABCB1 affects drug absorption, drug distribution into tissues, drug and metabolite elimination and steroidresistant immunologic rejection (41–43). In African Americans, 84% are ‘high pumpers’ in comparison with 22% of Caucasians (44) and absorb immunosuppressive drug substrates less well and are more likely to have drug-resistant graft rejection. Thus, pharmacogenetic profiles may contribute to steroid resistance, the incidence of acute rejection and increased requirements for immunosuppressive drugs in African American transplant patients. PK differences for immunosuppressive drugs related to ethnicity have not been well studied; most data come from post hoc analyses of small numbers of subjects from various ethnic groups (45). Although inclusion of diverse patient populations is mandated by federal statute, racial, ethnic and population data collection and reporting have not achieved enrollment goals (46). Consensus observations: Participants stressed that studies that examine the biologic basis of outcome differences in diverse ethnic populations, including studies of the genetics of immune responses and pharmacogenetic profiles, will provide rational approaches to drug therapies in transplant patients for prevention of graft rejection. Such assessments will also define alternative endpoints for clinical studies that may have greater applicability to diverse populations (47–53).

Public policy and social strategies Conferees identified disparities in organ transplantation which excessively disadvantage minority patients in terms of transplant evaluations and referrals, 2559

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pretransplant disease management, organ allocation and treatment outcomes. The roles of the level of educational attainment, occupation, income and insurance status considerations, relative to attaining the benefits of transplantation, are incompletely understood. The Secretary’s Advisory Committee on Transplantation has made a number of specific recommendations to the U.S. Secretary of Health and Human Services to address issues of disparity in transplantation including increasing the education and awareness of patients at dialysis centers regarding transplant options; research into the causes of existing disparities in transplant rates and outcomes; requests for research proposals to collect data from OPOs and transplant centers to better explain the relative risk of graft loss after transplantation; legislation to eliminate current 3-year time limits on Medicare coverage for immunosuppressive drugs for renal allografts; reporting of factors affecting multicultural donation and presentation of data on transplantation by race, ethnicity sex and religion. These recommendations have not been addressed to date. Consensus observations: Inability to pay for healthcare services remains a barrier to equal access and delivery of transplant care. Race, ethnicity and socioeconomic variables, including income and insurance coverage, should be measured in prospective clinical trials in transplantation. In the absence of political will, economic disparities will continue to provide an insurmountable hurdle to redressing inequity in the healthcare system.

Professional development and training opportunities: The transplant community must confront the need for minority healthcare providers. This is illustrated by the central role of nonspecialists in the primary medical care of African American, Hispanic and Native Americans. Diversity and cultural awareness of healthcare providers have a profound impact on the effectiveness of care delivered to minority patients by allaying distrust and improved communication (54,55). African American healthcare providers are significantly more likely to serve minority and medically underserved communities, improving access to care for these individuals (56). Minorities tend to have greater participation in their care when the patient and the provider are of the same ethnicity (57). Therefore, an increase in the training of minority transplant professionals may help to address disparities in the care of patients with end-organ failure who would benefit from solid organ transplantation. The education of minority healthcare providers and developing the cultural competence of all physicians are critically important to narrowing the healthcare gaps between minority and majority communities. Consensus observations: The AST, HHS and other professional societies must take leadership roles in the development of educational programs specifically aimed at the training of minority transplant professionals and primary care providers. 2560

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44. Zheng HX, Zeevi A, McCurry K et al. The impact of pharmacogenomic factors on acute persistent rejection in adult lung transplant patients. Transpl Immunol 2005; 14: 37–42. 45. Kovarik JM, Kahan BD, Rajagopalan PR et al. Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation. The U.S. simulect renal transplant study group. Transplantation 1999; 68: 1288–1294. 46. Perot RT, Youdelman M. Racial, ethnic and primary language data collection in the health care system: An assessment of federal policies and practices. The Commonwealth Fund. In: Smedley BD, Stith A, Nelson A (eds). Unequal treatment; Confronting Racial and Ethnic Disparities in Health. Washington DC: National Academy Press; 2003. 47. Hariharan S, McBride M, Cherik H et al. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 2002; 62: 311–318. 48. Kasiske B, Gaston R, Gourishankar S, Halloran P et al. Long-term deterioration of kidney allograft function. Am J Transpl 2005; 5: 1405–1414. 49. Vincenti F, Larsen C, Durrbach A et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353: 770–781. 50. Rabb H. Surrogate endpoints for long-term allograft survival: An AST(ASTS sponsored consensus conference. Am J Transpl 2004; 4: 1170–1170. 51. Bowdish ME, Arcasoy SM, Wilt JS et al. Surrogate markers and risk factors for chronic lung allograft dysfunction. Am J Transpl 2004; 4: 1171–1178. 52. Hariharan S, Kasiske B, Matas A, Cohen A, Harmon W, Rabb H. Surrogate markers for long-term renal allograft survival. Am J Transpl 2004; 4: 1179–1183. 53. Mehra MR, Benza R, Deng MC, Russell S, Webber S. Surrogate markers for late cardiac allograft survival. Am J Transpl 2004; 4: 1184–1191. 54. Institute of Medicine of the National Academies. The healthcare environment and its relation to disparities. In: Smedley BD, Stith A, Nelson A (eds). Unequal treatment: Confronting Racial and Ethnic Disparities in Health. Washington DC: National Academy Press, 2003. 55. Churak J. Racial and ethnic disparities in renal transplantation. JAMA 2005; 97: 153–160. 56. National Institute of General Medical Sciences (NIGMS), NIGMS Committee on Minority Recruitment, Approaches to Recruiting and Retaining Underrepresented Minority Students and Postdoctoral Fellows on NRSA Institutional Research Training Grants. 57. Smedley B, Butler A, Bristow Leds. In The nation’s compelling interest: Ensuring diversity in the health-care workforce. Washington, DC: National Academy Press, 2004.

Conference Participants Upton Allen, M.D., University of Toronto, Hospital for Sick Children, Toronto,Canada; Denise Alveranga, M.D., Tampa, FL; Nancy Ascher, M.D., Ph.D., University of California, San Francisco;

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Higgins and Fishman Hugh Auchincloss, M.D., Massachusetts General Hospital, Harvard Medical School; Yolanda Becker, M.D., University Wisconsin Hospitals & Clinics; Gilbert Burckart, Pharm.D., F.C.P,. F.C.C.P., University of Southern California; Clive Callender, M.D., Howard University Hospital; Blanche Chavers, M.D., University of Minnesota; Jeffrey Crippin, M.D., Washington University School of Medicine; Connie Davis, M.D., University of Washington Medical Center; Francis Delmonico, M.D., Massachusetts General Hospital, Harvard Medical School; Leah Edwards, Ph.D., United Network for Organ Sharing; Roger Evans, Ph.D., Consultant in Health Care; Gregory Fant, Ph.D., F.R.I.P.H., Division of Transplantation, Health Resources and Services Administration, U.S. Department of Health and Human Services; Richard Fine, M.D., Children’s Medical Center at Stony Brook, State University of New York at Stony Brook; Jay Fishman, M.D.(Co-Chair), Massachusetts General Hospital, Harvard Medical School; Robert Gaston, M.D., University of Alabama at Birmingham,

Ross Isaacs, M.D., University of Virginia; Michael Ishitani, M.D., Mayo Clinic; Lynt Johnson, M.D., Georgetown University Hospital; David Lederer, M.D., Columbia University College of Physicians and Surgeons; Arthur Matas, M.D., University of Minnesota Hospital; Clifton McClenney, ASMHTP, United Network for Organ Sharing; Andrew Narva, M.D., F.A.C.P., Albuquerque Indian Hospital; Silas Norman, M.D., University of Michigan; Mark Pescovitz, M.D., Indiana University; Friedrich Port, M.D., M.S., F.A.C.P., University Renal Research and Education Association, Ann Arbor, MI; Shiv Prasad, Ph.D., National Institute of Alergy and Infectious Diseases, National institutes of Health; Velma Scantlebury, M.D., University of South Alabama Medical Center; Paul Schwab, Association of Organ Procurement Organizations; Starlette Sharp, B.S., Auburn University; Angus Thomson, Ph.D., D.Sc., University of Pittsburgh Medical Center;

Sundaram Hariharan, M.D., Medical College of Wisconsin;

Winfred Williams, Jr., M.D., MGH, Massachusetts General Hospital, Harvard Medical School;

Robert Higgins, M.D.(Co-Chair), Rush Presbyterian Medical Center;

Carlton Young, M.D., University of Alabama Health Services Foundation;

Rodney Hood, M.D., National Medical Education Association;

Adriana Zeevi, Ph.D., University of Pittsburgh Medical Center

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