Transforming the Future of Surgeon-Scientists.

OBJECTIVE: To create a blueprint for surgical department leaders, academic institutions, and funding agencies to optimally support surgeon-scientists. BACKGROUND: Scientific contributions by surgeons have been transformative across many medical disciplines. Surgeon-scientists provide a distinct approach and mindset toward key scientific questions. However, lack of institutional support, pressure for increased clinical productivity, and growing administrative burden are major challenges for the surgeon-scientist, as is the time-consuming nature of surgical training and practice. METHODS: An American Surgical Association Research Sustainability Task Force was created to outline a blueprint for sustainable science in surgery. Leaders from top NIH-sponsored departments of surgery engaged in video and in-person meetings between January and April 2023. A strength, weakness, opportunities, threats analysis was performed, and workgroups focused on the roles of surgeons, the department and institutions, and funding agencies. RESULTS: Taskforce recommendations: (1) SURGEONS: Growth mindset : identifying research focus, long-term planning, patience/tenacity, team science, collaborations with disparate experts; Skill set : align skills and research, fill critical skill gaps, develop team leadership skills; DEPARTMENT OF SURGERY (DOS): (2) MENTORSHIP: Chair : mentor-mentee matching/regular meetings/accountability, review of junior faculty progress, mentorship training requirement, recognition of mentorship (eg, relative value unit equivalent, awards; Mentor: dedicated time, relevant scientific expertise, extramural funding, experience and/or trained as mentor, trusted advisor; Mentee : enthusiastic/eager, proactive, open to feedback, clear about goals; (3) FINANCIAL SUSTAINABILITY: diversification of research portfolio, identification of matching funding sources, departmental resource awards (eg, T-/P-grants), leveraging of institutional resources, negotiation of formalized/formulaic funds flow investment from academic medical center toward science, philanthropy; (4) STRUCTURAL/STRATEGIC SUPPORT: Structural: grants administrative support, biostats/bioinformatics support, clinical trial and research support, regulatory support, shared departmental laboratory space/equipment; Strategic: hiring diverse surgeon-scientist/scientists faculty across DOS, strategic faculty retention/ recruitment, philanthropy, career development support, progress tracking, grant writing support, DOS-wide research meetings, regular DOS strategic research planning; (5) COMMUNITY AND CULTURE: Community: right mix of faculty, connection surgeon with broad scientific community; Culture: building research infrastructure, financial support for research, projecting importance of research (awards, grand rounds, shoutouts); (6) THE ROLE OF INSTITUTIONS: Foundation: research space co-location, flexible start-up packages, courses/mock study section, awards, diverse institutional mentorship teams; Nurture: institutional infrastructure, funding (eg, endowed chairs), promotion friendly toward surgeon-scientists, surgeon-scientists in institutional leadership positions; Expectations: RVU target relief, salary gap funding, competitive starting salaries, longitudinal salary strategy; (7) THE ROLE OF FUNDING AGENCIES: change surgeon research training paradigm, offer alternate awards to K-awards, increasing salary cap to reflect market reality, time extension for surgeon early-stage investigator status, surgeon representation on study section, focused award strategies for professional societies/foundations. CONCLUSIONS: Authentic recommitment from surgeon leaders with intentional and ambitious actions from institutions, corporations, funders, and society is essential in order to reap the essential benefits of surgeon-scientists toward advancements of science.

Between-hospital care referrals for severe alcohol-related liver disease during the COVID-19 pandemic, 2020 to 2022.

Increased alcohol consumption during the coronavirus disease 2019 pandemic is projected to impact alcohol-related liver disease (ALD) morbidity and mortality. Inter-hospital escalation-of-care referral requests to our tertiary-care hepatology unit were analyzed from January 2020 through December 2022. Most requests to our center were for ALD with an increase in requests from intermediate care units, suggestive of higher acuity illness.

Induction of Skin Allograft Chimerism by Pharmacological Mobilization of Endogenous Bone Marrow-Derived Stem Cells.

Skin substitutes including allografts remain a standard therapeutic approach to promote healing of both acute and chronic large wounds. However, none have resulted in the regrowth of lost and damaged tissues and scarless wound healing. Here, we demonstrate skin allograft chimerism and repair through the mobilization of endogenous bone marrow-derived stem and immune cells in rats and swine. We show that pharmacological mobilization of bone marrow stem cells and immune cells into the circulation promotes host repopulation of skin allografts and restoration of the skin's normal architecture without scarring and minimal contracture. When skin allografts from DA rats are transplanted into GFP transgenic Lewis recipients with a combination of AMD3100 and low-dose FK506 (AF) therapy, host-derived GFP-positive cells repopulate and/or regenerate cellular components of skin grafts including epidermis and hair follicles and the grafts become donor-host chimeric skin. Using AF combination therapy, burn wounds with skin allografts were healed by newly regenerated chimeric skin with epidermal appendages and pigmentation and without contracture in swine.

Managing your human capital in a department of surgery.

Human capital management in the department of surgery represents a heterogeneous array of operational and strategic activities that focus on enhancing the well-being and productivity of all team members. This is not an episodic or reactive effort but rather a constant one that occurs in an ongoing cycle. Awareness of all the human capital in one's department, tending to members with their own best interest in mind, and an approach that is communication-heavy and based on fairness and transparency will serve to elevate the productivity and wellness of the department of surgery members and the organization as a whole.

Discovery and characterization of cross-reactive intrahepatic antibodies in severe alcoholic hepatitis.

The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and Escherichia coli K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and E. coli antigens. Further, both Ig- and E. coli-captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and E. coli-captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers.

A phase I, first-in-human study to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of MRG-001 in healthy subjects.

Preclinical studies demonstrate that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a fixed-dose drug combination (MRG-001) improves wound healing, promotes tissue regeneration, and prevents allograft rejection. In this phase I, first-in-human study, three cohorts receive subcutaneous MRG-001 or placebo, every other day for 5 days. The primary outcome is safety and tolerability of MRG-001. Fourteen subjects received MRG-001 and seven received a placebo. MRG-001 is safe over the selected dose range. There are no clinically significant laboratory changes. The intermediate dose group demonstrates the most significant white blood cell, stem cell, and immunoregulatory cell mobilization. PBMC RNA sequencing and gene set enrichment analysis reveal 31 down-regulated pathways in the intermediate MRG-001 dose group compared with no changes in the placebo group. MRG-001 is safe across all dose ranges. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration (ClinicalTrials.gov: NCT04646603).

Discovery and characterization of cross-reactive intrahepatic antibodies in severe alcoholic hepatitis.

The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We sought to determine if there was antibody deposition in SAH livers and whether antibodies extracted from SAH livers were cross-reactive against both bacterial antigens and human proteins. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissue from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy in an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. Employing human proteome arrays, we profiled the antibodies extracted from explanted SAH, alcoholic cirrhosis (AC), nonalcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), hepatitis B virus (HBV), hepatitis C virus (HCV) and HD livers and found that antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins as autoantigens. The use of an E. coli K12 proteome array revealed the presence of unique anti- E. coli antibodies in SAH, AC or PBC livers. Further, both Ig and E. coli captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion and focal adhesion (IgG). Except IgM from PBC livers, no common autoantigen was recognized by Ig and E. coli captured Ig from AC, HBV, HCV, NASH or AIH suggesting no cross-reacting anti- E. coli autoantibodies. The presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in the liver may participate in the pathogenesis of SAH.

Patient reflections, challenges, and supports related to early liver transplant for severe alcohol-associated liver disease.

Transplant centers conventionally require at least 6 months of alcohol abstinence before offering liver transplants for alcohol-associated liver disease. However, early liver transplant (ELT)-proceeding with a transplant when clinically necessary without first meeting the conventional requirement-is increasingly gaining attention. In our study, we qualitatively assessed ELT recipients' perceived challenges and supports regarding alcohol-associated liver disease, transplant, and posttransplant survivorship. To diversify perspectives based on gender, race/ethnicity, age, time since ELT, and pretransplant abstinence duration, we purposively recruited ELT recipients and conducted semistructured interviews. Recruitment continued until data saturation. We analyzed transcripts using inductive thematic analysis. We interviewed 20 ELT recipients between June and December 2020 and identified themes within 3 participant-characterized time periods. Three themes emerged in life before severe illness: (1) alcohol as a "constant" part of life, (2) alcohol use negatively affecting relationships and work life, and (3) feeling "stuck" in the cycle of drinking. Two themes emerged during the severe illness period: (4) rapidity of health decline and (5) navigating medical care and the 6-month abstinence requirement. Finally, in life after transplant, 4 themes emerged: (6) feelings of shame or stigma and new self-worth, (7) reconnecting with others and redefining boundaries, (8) transplant as a defining point for sobriety, and (9) work-related challenges. Overall, participants expressed gratitude for receiving a gift of life and acknowledged their responsibilities to the new liver. ELT recipient experiences reveal complex psychosocial challenges related to addiction, inadequate support system, and stigma, particularly in the posttransplant period. The care of ELT recipients would be incomplete if focused solely on optimizing patient or graft survival.

Comprehensive quality initiative leads to immediate postoperative extubation following liver transplant.

BACKGROUND: Immediate postoperative extubation (IPE) can reduce perioperative complications and length of stay (LOS), however it is performed variably after liver transplant across institutions and has historically excluded high-risk recipients from consideration. In late 2012, we planned and implemented a single academic institution structured quality improvement (QI) initiative to standardize perioperative care of liver transplant recipients without exceptions. We hypothesized that such an approach would lead to a sustained increase in IPE after primary (PAC) and delayed abdominal closure (DAC). METHODS: We retrospectively studied 591 patients from 2013 to 2018 who underwent liver transplant after initiative implementation. We evaluated trends in incidence of IPE versus delayed extubation (DE), and reintubation, LOS, and mortality. RESULTS: Overall, 476/591 (80.5%) recipients underwent PAC (278 IPE, 198 DE) and 115/591 (19.5%) experienced DAC (39 IPE, 76 DE). When comparing data from 2013 to data from 2018, the incidence of IPE increased from 9/67 (13.4%) to 78/90 (86.7%) after PAC and from 1/12 (8.3%) to 16/23 (69.6%) after DAC. For the same years, the incidence of IPE after PAC for recipients with MELD scores ≥30 increased from 0/19 (0%) to 12/17 (70.6%), for recipients who underwent simultaneous liver-kidney transplant increased from 1/8 (12.5%) to 4/5 (80.0%), and for recipients who received massive transfusion (>10 units of packed red blood cells) increased from 0/17 (0%) to 10/13 (76.9%). Reintubation for respiratory considerations <48 h after IPE occurred in 3/278 (1.1%) after PAC and 1/39 (2.6%) after DAC. IPE was associated with decreased intensive care unit (HR of discharge: 1.92; 95% CI: 1.58, 2.33; P < 0.001) and hospital LOS (HR of discharge: 1.45; 95% CI: 1.20, 1.76; P < 0.001) but demonstrated no association with mortality. CONCLUSION: A structured QI initiative led to sustained high rates of IPE and reduced LOS in all liver transplant recipients, including those classified as high risk.

Prophylactic Recombinant Factor VIIa for Preventing Massive Transfusion During Orthotopic Liver Transplantation.

OBJECTIVES: RecombinanthumanactivatedfactorVIIahas been usedprophylactically to mitigate requirements for transfusion in liver transplant. We explored its effectiveness andrisks amonglivertransplantrecipients at high risk for massive transfusion. MATERIALS AND METHODS: We performed a retrospective study of recipients who underwent liver transplant from 2012 to 2015. Patients considered at risk for massive transfusion received up to two 20 µg/kg doses of recombinant human activated factor VIIa, with rescue use permitted for other patients. We used propensity matching to determine the average treatment effectson patients who received recombinant human activated factor VIIa prophylactically to prevent massive transfusion. We determined thromboembolic events from medical record review. RESULTS: Of 234 liver transplant recipients, 38 received prophylactic and 2 received rescue recombinant human activated factor VIIa. We used a prediction model to readily identify those who would receive prophylactic recombinant human activated factorVIIa (C statistic = 0.885; 95% CI, 0.835-0.935). Propensity matching achieved balance, particularly for massive transfusion. Twenty-three of 38 patients (60.5%) who received recombinant human activated factorVIIa and 47 of 76 matched controls (61.8%) experienced massive transfusion. The coefficient for the average treatment effect of prophylactic administration was - 0.013 (95% CI, -0.260 to 0.233; P = .92). The cohorts exhibited no difference in number ofthromboembolic events (P > .99), although fatal events occurred in 1 patient who had prophylactic and 1 patient who had rescue recombinant human activated factor VIIa. CONCLUSIONS: Prophylactic recombinanthumanactivated factor VIIa use in patients at elevated risk of massive transfusion did not affect incidence of massive transfusion and was not associated with an increase in thromboembolic events overall. The lack of clinical benefit and the potential for fatal throm-boembolic events observed with recombinant human activated factor VIIa precluded its prophylactic use in liver transplant recipients.

Multicenter study of racial and ethnic inequities in liver transplantation evaluation: Understanding mechanisms and identifying solutions.

Racial and ethnic disparities persist in access to the liver transplantation (LT) waiting list; however, there is limited knowledge about underlying system-level factors that may be responsible for these disparities. Given the complex nature of LT candidate evaluation, a human factors and systems engineering approach may provide insights. We recruited participants from the LT teams (coordinators, advanced practice providers, physicians, social workers, dieticians, pharmacists, leadership) at two major LT centers. From December 2020 to July 2021, we performed ethnographic observations (participant-patient appointments, committee meetings) and semistructured interviews (N = 54 interviews, 49 observation hours). Based on findings from this multicenter, multimethod qualitative study combined with the Systems Engineering Initiative for Patient Safety 2.0 (a human factors and systems engineering model for health care), we created a conceptual framework describing how transplant work system characteristics and other external factors may improve equity in the LT evaluation process. Participant perceptions about listing disparities described external factors (e.g., structural racism, ambiguous national guidelines, national quality metrics) that permeate the LT evaluation process. Mechanisms identified included minimal transplant team diversity, implicit bias, and interpersonal racism. A lack of resources was a common theme, such as social workers, transportation assistance, non-English-language materials, and time (e.g., more time for education for patients with health literacy concerns). Because of the minimal data collection or center feedback about disparities, participants felt uncomfortable with and unadaptable to unwanted outcomes, which perpetuate disparities. We proposed transplant center-level solutions (i.e., including but not limited to training of staff on health equity) to modifiable barriers in the clinical work system that could help patient navigation, reduce disparities, and improve access to care. Our findings call for an urgent need for transplant centers, national societies, and policy makers to focus efforts on improving equity (tailored, patient-centered resources) using the science of human factors and systems engineering.

Examination of Racial and Socioeconomic Disparity in Use of Nondirected Kidney Donation in the US.

BACKGROUND: Nondirected donor (NDD) kidney transplant (NDDKT) continues to improve organ access for waitlisted candidates. Although NDDs are becoming increasingly common, there has been no contemporary evaluation of NDD allograft use, and it is vital to understand sociodemographic, as well as center-level, use across the US. STUDY DESIGN: Using national data from the Scientific Registry for Transplant Recipients, this study characterized NDDs, NDDKT recipients, and center-level distribution of NDDKT. Directed donor and NDD characteristics were compared using Fisher's exact and Wilcoxon rank-sum tests for categorical and continuous variables, respectively. Multivariable logistic regression was used to identify characteristics associated with receiving NDDKT, and center distribution of NDDKT was assessed using the Gini coefficient. RESULTS: NDDKT increased from 1.4% (n = 154) of all living donor kidney transplants in 2010 to 6.5% (n = 338) in 2020. Compared with directed living donors, NDDs were older (median [IQR], 44 [33 to 54] vs 43 [33 to 52], p < 0.01), more often male (40.2% vs 36.7%, p < 0.001), and White (91.4% vs 69.5%, p < 0.001). White adult candidates were more likely to receive NDDKT compared with Black (adjusted odds ratio [aOR], 0.300.340.39, p < 0.001), Hispanic/Latino (aOR, 0.360.420.48, p < 0.001), and Other (aOR, 0.410.470.55, p < 0.001) candidates. Black pediatric candidates had lower odds of receiving NDDKT (aOR, 0.090.220.54, p = 0.02). The proportion of centers performing NDDKT has increased from 2010 to 2020 (Gini = 0.77 vs 0.68). CONCLUSIONS: Although more centers are performing NDDKT, racial disparities persist among NDDs and NDDKT recipients. Continued effort is needed to recruit living kidney donors and improve access to living donation for minority groups in the US. (J Am Coll Surg 2022;234:000-00. © 2022 by the American College of Surgeons).

The Landscape of Nondirected Living Liver Donation in the United States.

BACKGROUND: Living donor liver transplants (LDLTs) including those from nondirected donors (NDDs) have increased during the past decade, and center-level variations in LDLTs have not yet been described. We sought to quantify changes in the volume of NDD transplants over time and variation in NDD volume between transplant centers. We further examined characteristics of living liver donors and identified factors potentially associated with receiving an NDD liver transplant. METHODS: Using Scientific Registry of Transplant Recipients data between March 01, 2002, and December 31, 2020, we compared 173 NDDs with 5704 DLDs and 167 NDD recipients with 1153 waitlist candidates. RESULTS: NDDs increased from 1 (0.4% of LDLTs) in 2002 to 58 (12% of LDLTs) in 2020. Of 150 transplant centers, 35 performed at least 1 NDD transplant. Compared with waitlist candidates, adult NDD recipients were less frequently males (39% versus 62%, P < 0.001), had a lower model for end-stage liver disease (16 versus 18, P = 0.01), and spent fewer days on the waitlist (173 versus 246, P = 0.02). Compared with waitlist candidates, pediatric NDD recipients were younger (50% versus 12% age <2 y, P < 0.001) and more often diagnosed with biliary atresia (66% versus 41%, P < 0.001). Compared with DLDs, NDDs were older (40 versus 35 y, P < 0.001), college educated (83% versus 64%, P < 0.001), White (92% versus 78%, P < 0.001), and more frequently donated left-lateral segment grafts (32.0% versus 14%, P < 0.001). CONCLUSIONS: Liver NDD transplants continue to expand but remain concentrated at a few centers. Graft distribution favors female adults and pediatric patients with biliary atresia. Racial inequities in adult or pediatric center-level NDD graft distribution were not observed.

Survival Benefit of Split-Liver Transplantation for Pediatric and Adult Candidates.

Patient and graft survival are similar following whole-liver transplantations (WLTs) versus split-liver transplantations (SLTs) among pediatric and adult recipients, yet SLTs are rarely used. We sought to determine the survival benefit associated with accepting a splittable graft offer for SLT versus declining and waiting for a subsequent offer using 2010 to 2018 Scientific Registry of Transplant Recipients (SRTR) data on 928 pediatric and 1814 adult liver transplantation candidates who were ever offered a splittable graft. We compared eventual mortality, regardless of subsequent transplants, between those patients who accepted versus declined a split liver offer with adjustments for Pediatric End-Stage Liver Disease/Model for End-Stage Liver Disease (MELD) scores, diagnosis, and weight among pediatric candidates and matching for MELD score, height, and offer among adult candidates. Among pediatric candidates ≤7 kg, split liver offer acceptance versus decline was associated with a 63% reduction in mortality (adjusted hazard ratio [aHR], 0.17 0.370.80 [P = 0.01]; 93.1% versus 84.0% 1-year survival after decision). Within 1 year of decline for those ≤7 kg, 6.4% died and 31.1% received a WLT. Among pediatric candidates >7 kg, there was no significant difference associated with acceptance of a split liver offer (aHR, 0.63 1.071.82 [P = 0.81]; 91.7% versus 94.4% 1-year survival after decision). Within 1 year of decline for those >7 kg, 1.8% died and 45.8% received a WLT. Among adult candidates, split liver offer acceptance was associated with a 43% reduction in mortality (aHR, 0.39 0.570.83 [P = 0.005]; 92.2% versus 84.4% 1-year survival after decision). Within 1 year of decline for adult candidates, 7.9% died and 39.3% received a WLT. Accepting split liver offers for SLT could significantly improve survival for small children and adults on the waiting list.

Inter-Hospital Escalation-of-Care Referrals for Severe Alcohol-Related Liver Disease with Recent Drinking During the COVID-19 Pandemic.

Alcohol sales and consumption have increased during the coronavirus disease 2019 pandemic, but their downstream effects on alcohol-related liver disease (ALD) are unclear. We analyzed inter-hospital escalation-of-care referrals to our tertiary care inpatient liver unit across 18 months through December 2020. There was a significant rise in severe ALD with recent unhealthy drinking in our regional community during the pandemic.