Faculty Bibliography

BACKGROUND AIMS/UNASSIGNED:In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic Oxygenated Machine Perfusion (HMP-O2) has shown benefit compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O2 device in the first US randomized control trial. APPROACH RESULTS/UNASSIGNED:The PILOT™ trial (NCT03484455) was a multicenter, randomized, open-label, non-inferiority trial, with participants randomized to HMP-O2 or SCS. HMP-O2 livers were preserved using the Lifeport® Liver Transporter and Vasosol® perfusion solution. Primary outcome was early allograft dysfunction (EAD). Non-inferiority margin was 7.5%. From 4/3/19-7/12/22, 179 patients were randomized to HMP-O2 (n=90) or SCS (n=89). Per protocol cohort included 63 HMP-O2 and 73 SCS. EAD occurred in 11.1% HMP-O2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. Risk of graft failure as predicted by L-GrAFT7 was lower with HMP-O2 (median [IQR] 3.4% [2.4-6.5] vs. 4.5% [2.9-9.4], p=0.024). Primary nonfunction occurred in 2.2%, all SCS (n=3, p=0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O2 (p=0.18). Non-anastomotic biliary strictures occurred only in SCS (n=4). CONCLUSIONS:HMP-O2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. EAD by L-GrAFT7 was lower in HMP-O2, suggesting improved early clinical function. Recipients of HMP-O2 livers also demonstrated a lower incidence PNF and biliary strictures, although this difference did not reach significance.

Digital health technologies (DHTs) can transform neurological assessments, improving quality and continuity of care. In the United States, the Food & Drug Administration (FDA) oversees the safety and efficacy of these technologies, employing a detailed regulatory process that classifies devices based on risk and requires rigorous review and post-market surveillance. Following FDA approval, DHTs enter the Current Procedural Terminology, Relative Value Scale Update Committee, and Centers for Medicare & Medicaid Services coding and valuation processes leading to coverage and payment decisions. DHT adoption is challenged by rapid technologic advancements, an inconsistent evidence base, marketing discrepancies, ambiguous coding guidance, and variable health insurance coverage. Regulators, policymakers, and payers will need to develop better methods to evaluate these promising technologies and guide their deployment. This includes striking a balance between patient safety and clinical effectiveness versus promotion of innovation, especially as DHTs increasingly incorporate artificial intelligence. Data validity, cybersecurity, risk management, societal, and ethical responsibilities should be addressed. Regulatory advances can support adoption of these promising tools by ensuring DHTs are safe, effective, accessible, and equitable.

OBJECTIVE:The aim of this study was to compare portal venous phase photon-counting CT (PCCT) using 20 cc less than weight-based contrast dosing with energy-integrating detector CT (EID-CT) using weight-based dosing by quantitative and qualitative analysis. METHODS:Fifty adult patients who underwent a reduced intravenous contrast dose portal venous phase PCCT from May 1, 2023, to August 10, 2023, and a prior portal-venous EID-CT with weight-based contrast dosing were retrospectively identified. Hounsfield units (HU) and noise (SD of HU) were obtained from region-of-interest measurements on 70-keV PCCT and EID-CT in 4 hepatic segments, the main and right portal vein, and both paraspinal muscles. Signal-to-noise and contrast-to-noise ratios were computed. Three abdominal radiologists qualitatively assessed overall image quality, hepatic enhancement, and confidence for metastasis identification on 5-point Likert scales. Readers also recorded the presence/absence of hepatic metastases. Quantitative variables were compared with paired t tests, and multiple comparisons were accounted for with a Bonferroni-adjusted α level of .0016. Ordinal logistic regression was used to evaluate qualitative assessments. Interreader agreement for hepatic metastases was calculated using Fleiss' κ. RESULTS:Fifty patients (32 women; mean [SD] age, 64 [13] years) were included. There was no significant difference in hepatic HU, portal vein HU, noise, and signal-to-noise or contrast-to-noise ratio between reduced contrast dose portal venous phase PCCT versus EID-CT (all Ps > 0.0016). Image quality, degree of hepatic enhancement, and confidence for metastasis identification were not different for reduced dose PCCT 70-keV images and EID-CT (P = 0.06-0.69). κ Value for metastasis identification was 0.86 (95% confidence interval, 0.70-1.00) with PCCT and 0.78 (95% confidence interval, 0.59-0.98) with EID-CT. CONCLUSION/CONCLUSIONS:Reduced intravenous contrast portal venous phase PCCT 70-keV images had similar attenuation and image quality as EID-CT with weight-based dosing. Metastases were identified with near-perfect agreement in reduced dose PCCT 70-keV images.

IMPORTANCE/UNASSIGNED:Identifying the mechanisms of structural racism, such as racial and ethnic segregation, is a crucial first step in addressing the persistent disparities in access to live donor kidney transplantation (LDKT). OBJECTIVE/UNASSIGNED:To assess whether segregation at the candidate's residential neighborhood and transplant center neighborhood is associated with access to LDKT. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:In this cohort study spanning January 1995 to December 2021, participants included non-Hispanic Black or White adult candidates for first-time LDKT reported in the US national transplant registry. The median (IQR) follow-up time for each participant was 1.9 (0.6-3.0) years. MAIN OUTCOME AND MEASURES/UNASSIGNED:Segregation, measured using the Theil H method to calculate segregation tertiles in zip code tabulation areas based on the American Community Survey 5-year estimates, reflects the heterogeneity in neighborhood racial and ethnic composition. To quantify the likelihood of LDKT by neighborhood segregation, cause-specific hazard models were adjusted for individual-level and neighborhood-level factors and included an interaction between segregation tertiles and race. RESULTS/UNASSIGNED:Among 162 587 candidates for kidney transplant, the mean (SD) age was 51.6 (13.2) years, 65 141 (40.1%) were female, 80 023 (49.2%) were Black, and 82 564 (50.8%) were White. Among Black candidates, living in a high-segregation neighborhood was associated with 10% (adjusted hazard ratio [AHR], 0.90 [95% CI, 0.84-0.97]) lower access to LDKT relative to residence in low-segregation neighborhoods; no such association was observed among White candidates (P for interaction = .01). Both Black candidates (AHR, 0.94 [95% CI, 0.89-1.00]) and White candidates (AHR, 0.92 [95% CI, 0.88-0.97]) listed at transplant centers in high-segregation neighborhoods had lower access to LDKT relative to their counterparts listed at centers in low-segregation neighborhoods (P for interaction = .64). Within high-segregation transplant center neighborhoods, candidates listed at predominantly minority neighborhoods had 17% lower access to LDKT relative to candidates listed at predominantly White neighborhoods (AHR, 0.83 [95% CI, 0.75-0.92]). Black candidates residing in or listed at transplant centers in predominantly minority neighborhoods had significantly lower likelihood of LDKT relative to White candidates residing in or listed at transplant centers located in predominantly White neighborhoods (65% and 64%, respectively). CONCLUSIONS/UNASSIGNED:Segregated residential and transplant center neighborhoods likely serve as a mechanism of structural racism, contributing to persistent racial disparities in access to LDKT. To promote equitable access, studies should assess targeted interventions (eg, community outreach clinics) to improve support for potential candidates and donors and ultimately mitigate the effects of segregation.

BACKGROUND:Evidence suggests that older patients are less frequently placed on the waiting list for kidney transplantation (KT) than their younger counterparts. The trends and magnitude of this age disparity in access to first KT and repeat KT (re-KT) remain unclear. METHODS:Using the US Renal Data System, we identified 2 496 743 adult transplant-naive dialysis patients and 110 338 adult recipients with graft failure between 1995 and 2018. We characterized the secular trends of age disparities and used Cox proportional hazard models to compare the chances of listing and receiving first KT versus re-KT by age (18-64 y versus ≥65 y). RESULTS:Older transplant-naive dialysis patients were less likely to be listed (adjusted hazard ratio [aHR] = 0.18; 95% confidence interval [CI], 0.17-0.18) and receive first KT (aHR = 0.88; 95% CI, 0.87-0.89) compared with their younger counterparts. Additionally, older patients with graft failure had a lower chance of being listed (aHR = 0.40; 95% CI, 0.38-0.41) and receiving re-KT (aHR = 0.76; 95% CI, 0.72-0.81). The magnitude of the age disparity in being listed for first KT was greater than that for re-KT ( Pinteraction  < 0.001), and there were no differences in the age disparities in receiving first KT or re-KT ( Pinteraction  = 0.13). Between 1995 and 2018, the age disparity in listing for first KT reduced significantly ( P  < 0.001), but the age disparities in re-KT remained the same ( P  = 0.16). CONCLUSIONS:Age disparities exist in access to both first KT and re-KT; however, some of this disparity is attenuated among older adults with graft failure. As the proportion of older patients with graft failure rises, a better understanding of factors that preclude their candidacy and identification of appropriate older patients are needed.

BACKGROUND:Older adults with frailty and kidney failure face higher waitlist mortality and are more likely to be listed as inactive on the kidney transplant (KT) wait list. Photovoice is a qualitative participatory research method where participants use photographs to represent their environment, needs and experiences. It offers unique insight into the lived environment and experience of patients and may offer direction in how to improve functional independence, symptom burden, and kidney transplant outcomes in adults with frailty. METHODS:This photovoice study was embedded within a larger intervention adaptation project. Participants with pre-frailty or frailty awaiting a KT or recently post-transplant took photos with Polaroid cameras and wrote short descriptions for 11 prompts. Each participant completed a semi-structured interview wherein their photos were discussed. The team coded and discussed photos and interviews to determine overarching themes and implications. Focus groups were used to triangulate visual data findings. RESULTS:Sixteen participants completed both the photovoice and interview. Participants were a mean age of 60.5 years, 31.2% female, 43.4% self-identifying as Black, and 69% were frail. Outcomes were categorized into seven themes: functional space, home safety, medication management, adaptive coping, life changing nature of dialysis, support and communication. Visual data clarified and sometimes changed the interpretations of the text alone. Especially within the themes of home safety and functional space, safety hazards not previously recognized in the literature, like dialysis fluid storage, were identified. CONCLUSIONS:Photovoice contextualizes the living conditions and experiences of adults with frailty on the kidney transplant journey and could be a useful tool in geriatric nephrology and transplant. Addressing issues of home storage, organization, and accessibility should be explored as potential intervention targets. Incorporating participant values and goals into care decisions and interventional design should be further explored.

Despite well-studied associations of state firearm laws with lower state- and county-level firearm homicide, there is a shortage of studies investigating differences in the effects of distinct state firearm law categories on various cities within the same state using identical methods. We examined associations of 5 categories of state firearm laws-pertaining to buyers, dealers, domestic violence, gun type/trafficking, and possession-with city-level firearm homicide, and then tested differential associations by city characteristics. City-level panel data on firearm homicide cases of 78 major cities from 2010 to 2020 was assessed from the Centers for Disease Control and Prevention's National Vital Statistics System. We modeled log-transformed firearm homicide rates as a function of firearm law scores, city, state, and year fixed effects, along with time-varying city-level confounders. We considered effect measure modification by poverty, unemployment, vacant housing, and income inequality. A one z-score increase in state gun type/trafficking, possession, and dealer law scores was associated with 25% (95% confidence interval [CI]:-0.37,-0.1), 19% (95% CI:-0.29,-0.07), and 17% (95% CI:-0.28, -0.4) lower firearm homicide rates, respectively. Protective associations were less pronounced in cities with high unemployment and high housing vacancy, but more pronounced in cities with high income inequality. In large US cities, state-level gun type/trafficking, possession, and dealer laws were associated with lower firearm homicide rates, but buyers and domestic violence laws were not. State firearm laws may have differential effects on firearm homicides based on city characteristics, and city-wide policies to enhance socioeconomic drivers may add benefits of firearm laws.

Type 2 diabetes (T2D) is a chronic metabolic disorder in which insulin resistance and impaired insulin secretion result in altered metabolite balance, specifically elevated levels of circulating glucose and succinate, which increases the risk of many pathologies, including periodontitis. Succinate, a tricarboxylic acid (TCA) cycle intermediate, can be produced and metabolized by both host cells and host microbiota, where elevated levels serve as an inflammation and pathogen threat signal through activating the succinate G protein-coupled receptor, SUCNR1. Modulating succinate-induced SUCNR1 signaling remains a promising therapeutic approach for pathologies resulting in elevated levels of succinate, such as T2D and periodontitis. Here, we demonstrate hyperglycemia and elevated intracellular succinate in a T2D mouse model and determine gut microbiome composition. Drawing on previous work demonstrating the ability of a novel SUCNR1 antagonist, compound 7a, to block inflammation and alleviate dysbiosis in a mouse model, we examined if compound 7a has an impact on the growth and virulence gene expression of bacterial and fungal human microbiota in vitro, and if 7a could reduce bone loss in a periodontitis-induced mouse model. T2D mice harbored a significantly different gut microbiome, suggesting the altered metabolite profile of T2D causes shifts in host-microbial community structure, with enrichment in succinate producers and consumers and mucin-degrading bacteria. Bacterial and fungal cultures showed that 7a did not influence growth or virulence gene expression, suggesting the therapeutic effects of 7a are a direct result of 7a interacting with host cells and that alterations in microbial community structure are driven by reduced host SUCNR1 signaling. This work further suggests that targeting SUCNR1 signaling is a promising therapeutic approach in metabolic, inflammatory, or immune disorders with elevated succinate levels.

The first 2 living recipients of pig hearts died unexpectedly within 2 months, despite both recipients receiving what over 30 years of nonhuman primate (NHP) research would suggest were the optimal gene edits and immunosuppression to ensure success. These results prompt us to question how faithfully data from the NHP model translate into human outcomes. Before attempting any further heart xenotransplants in living humans, it is highly advisable to gain a more comprehensive understanding of why the promising preclinical NHP data did not accurately predict outcomes in humans. It is also unlikely that additional NHP data will provide more information that would de-risk a xenoheart clinical trial because these cases were based on the best practices from the most successful NHP results to date. Although imperfect, the decedent model offers a complementary avenue to determine appropriate treatment regimens to control the human immune response to xenografts and better understand the biologic differences between humans and NHP that could lead to such starkly contrasting outcomes. Herein, we explore the potential benefits and drawbacks of the decedent model and contrast it to the advantages and disadvantages of the extensive body of data generated in the NHP xenoheart transplantation model.