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Spatiotemporal immune atlas of the first clinical-grade, gene-edited pig-to-human kidney xenotransplant

Porrett, Paige; Cheung, Matthew; Asiimwe, Rebecca; Erman, Elise; Fucile, Christopher; Liu, Shanrun; Sun, Chiao-Wang; Hanumanthu, Vidya; Pal, Harish; Wright, Emma; Ghajar-Rahimi, Gelare; Epstein, Daniel; Orandi, Babak; Kumar, Vineeta; Anderson, Douglas; Greene, Morgan; Bell, Markayla; Yates, Stefani; Moore, Kyle; Lafontaine, Jennifer; Killian, John; Baker, Gavin; Perry, Jackson; Reed, Rhiannon; Little, Shawn; Rosenberg, Alexander; George, James; Locke, Jayme
Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. We transplanted a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and studied the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells were uncommon in the porcine kidney cortex early after xenotransplantation and consisted of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages expressed genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft was detected. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression is sufficient to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.
PMID: 36711785
ISSN: n/a
CID: 5520062

First clinical-grade porcine kidney xenotransplant using a human decedent model

Porrett, Paige M; Orandi, Babak J; Kumar, Vineeta; Houp, Julie; Anderson, Douglas; Cozette Killian, A; Hauptfeld-Dolejsek, Vera; Martin, Dominique E; Macedon, Sara; Budd, Natalie; Stegner, Katherine L; Dandro, Amy; Kokkinaki, Maria; Kuravi, Kasinath V; Reed, Rhiannon D; Fatima, Huma; Killian, John T; Baker, Gavin; Perry, Jackson; Wright, Emma D; Cheung, Matthew D; Erman, Elise N; Kraebber, Karl; Gamblin, Tracy; Guy, Linda; George, James F; Ayares, David; Locke, Jayme E
A radical solution is needed for the organ supply crisis, and the domestic pig is a promising organ source. In preparation for a clinical trial of xenotransplantation, we developed an in vivo pre-clinical human model to test safety and feasibility tenets established in animal models. After performance of a novel, prospective compatible crossmatch, we performed bilateral native nephrectomies in a human brain-dead decedent and subsequently transplanted two kidneys from a pig genetically engineered for human xenotransplantation. The decedent was hemodynamically stable through reperfusion, and vascular integrity was maintained despite the exposure of the xenografts to human blood pressure. No hyperacute rejection was observed, and the kidneys remained viable until termination 74 h later. No chimerism or transmission of porcine retroviruses was detected. Longitudinal biopsies revealed thrombotic microangiopathy that did not progress in severity, without evidence of cellular rejection or deposition of antibody or complement proteins. Although the xenografts produced variable amounts of urine, creatinine clearance did not recover. Whether renal recovery was impacted by the milieu of brain death and/or microvascular injury remains unknown. In summary, our study suggests that major barriers to human xenotransplantation have been surmounted and identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans.
PMID: 35049121
ISSN: 1600-6143
CID: 5519922

COVID-19 Vaccination and Remdesivir are Associated With Protection From New or Increased Levels of Donor-Specific Antibodies Among Kidney Transplant Recipients Hospitalized With COVID-19

Killian, John T; Houp, Julie A; Burkholder, Greer A; Roman Soto, Salomon A; Killian, A Cozette; Ong, Song C; Erdmann, Nathaniel B; Goepfert, Paul A; Hauptfeld-Dolejsek, Vera; Leal, Sixto M; Zumaquero, Esther; Nellore, Anoma; Agarwal, Gaurav; Kew, Clifton E; Orandi, Babak J; Locke, Jayme E; Porrett, Paige M; Levitan, Emily B; Kumar, Vineeta; Lund, Frances E
Alloimmune responses in kidney transplant (KT) patients previously hospitalized with COVID-19 are understudied. We analyzed a cohort of 112 kidney transplant recipients who were hospitalized following a positive SARS-CoV-2 test result during the first 20 months of the COVID-19 pandemic. We found a cumulative incidence of 17% for the development of new donor-specific antibodies (DSA) or increased levels of pre-existing DSA in hospitalized SARS-CoV-2-infected KT patients. This risk extended 8 months post-infection. These changes in DSA status were associated with late allograft dysfunction. Risk factors for new or increased DSA responses in this KT patient cohort included the presence of circulating DSA pre-COVID-19 diagnosis and time post-transplantation. COVID-19 vaccination prior to infection and remdesivir administration during infection were each associated with decreased likelihood of developing a new or increased DSA response. These data show that new or enhanced DSA responses frequently occur among KT patients requiring admission with COVID-19 and suggest that surveillance, vaccination, and antiviral therapies may be important tools to prevent alloimmunity in these individuals.
PMID: 35928347
ISSN: 1432-2277
CID: 5520002

How Does Mission Ground Time Impact on Population Coverage of Aeromedical Retrieval Systems?

Smedley, Weston Andrew; Killian, John; Stone, Kelly Lorraine; Stephens, Shannon W; Griffin, Russell L; Cox, Daniel B; Kerby, Jeffrey D; Jansen, Jan O
BACKGROUND:Aeromedical retrieval is an essential component of contemporary emergency care systems. However, in many locations, ground emergency medical services are dispatched to the scene of an incident first to assess the patient and then call for a helicopter if needed. The time to definitive care therefore includes the helicopter's flight to the scene, flight to the trauma center, and nonflying time. Mission ground time (MGT) includes the time required to get the helicopter airborne, as well as time spent at the scene, packaging and loading the casualty into the aircraft. Estimates of MGT typically vary from 10 to 30 min. The impact of MGT duration on population coverage-the number of residents that could be taken to a trauma center within a set time-is not known. The aim of this study was to compare population coverage for different durations of MGT in a single state. METHODS:Coverage was calculated using elliptical coverage areas ("isochrones") based on the location of helicopter bases and Level I and Level II trauma centers. The calculations were performed using Microsoft Excel, assuming a cruising speed of 133 knots (246 km/h), and mapped using arcGIS. The access time threshold was set at 60 min, and we evaluated MGTs of 10, 15, 20, 25, and 30 min. RESULTS:MGT has a marked impact on population coverage. The effect is, furthermore, not linear. When considering the state's three Level I trauma centers, decreasing MGT from 30 to 10 min increased population coverage from 61.2% to 84.2%. When also considering Level II centers, decreasing MGT from 30 min to 10 min increased coverage by 20%. CONCLUSIONS:Elliptical isochrones, with allowance for MGT, provide realistic estimates of population coverage. MGT significantly impacts the proportion of the population that can be taken to a Level I and/or Level II Trauma Center within a set time. The impact is not linear, reflecting the uneven distribution of the population. Consideration should be given to minimizing MGT to preserve the benefits of aeromedical retrieval.
PMID: 33069390
ISSN: 1095-8673
CID: 5030532

Aeromedical retrieval of trauma patients: Impact of flight path model on estimates of population coverage

Stone, K Lorraine; Smedley, W Andrew; Killian, John; Stephens, Shannon W; Griffin, Russell L; Cox, Daniel B; Kerby, Jeffrey D; Jansen, Jan O
BACKGROUND:The aim of this study was to compare the impact of different flight path models on the calculated population coverage of aeromedical retrieval systems, using the state of Alabama as a case study. METHODS:Geospatial analysis of U.S. Census Bureau population data using helicopter bases and trauma centers as foci of either circular or elliptical coverage areas. RESULTS:Circular isochrone models around helicopter bases or trauma centers suggest that the entire population of Alabama could reach a level I or II trauma center within 60 min. Elliptical isochrones, incorporating outbound and inbound flights, suggest that only 78.8% of the population have ready access to level I or II trauma centers. CONCLUSION:While all three flight path models described have some validity and utility, simplistic circular flight time isochrones around trauma centers and helicopter bases provide overly optimistic estimates of population coverage. The elliptical model provides a more realistic evaluation.
PMID: 32037046
ISSN: 1879-1883
CID: 5030522

Population Coverage of Trauma Systems: What Do Helicopters Add?

Smedley, W Andrew; Stone, K Lorraine; Killian, John; Brown, Allison; Farley, Paige; Griffin, Russell L; Cox, Daniel B; Kerby, Jeffrey D; Jansen, Jan O
Trauma is a time-critical condition. Helicopters are thought to enhance the accessibility to trauma centers, but this benefit is poorly quantified. The aim of this study was to conduct a geographical analysis of the added benefit provided by helicopters, over ground transport. This study uses geospatial analysis. Helicopter bases and Level I and II designated trauma centers were geocoded. 60-minute drive-time and elliptical flight-time isochrones were mapped with ArcGISâ„¢ (Esri, Redlands, CA). Calculations included allowance for mission ground time (MGT). We compared the proportion of the population that could be taken to Level I and II trauma centers, within 60 minutes, by road and by air. Using a 30-minute MGT model, helicopters permit 279,317 additional residents (5.8%) access to a Level I trauma center within 60 minutes. Using the 20-minute MGT model, 1,089,177 more residents (22.8%) would have access to Level I trauma center care. The benefits were marginally greater for access to Level I and II trauma center care. Helicopters enhance access to specialist trauma center care, but the benefit is small and dependent on MGT. Consideration should be given to the siting of helicopters, particularly in relation to trauma patients, MGT, and the timely response of EMS when determining the triage for helicopter transport.
PMID: 31638527
ISSN: 1555-9823
CID: 5030512

A Predictive Model for a Reputation-Based General Surgery Residency Match and a Novel Online Calculator

Killian, John T; Leeper, James D; Xu, Qiong; Sauer, Paul F; Porterfield, John R
OBJECTIVE:This study aimed to identify medical student characteristics that predict a successful categorical match into a general surgery residency and a match based upon Doximity program rankings. DESIGN:This was a retrospective study that analyzed academic and personal predictors of a successful general surgery residency match. SETTING:This study was set at the University of Alabama at Birmingham School of Medicine, a public medical school. PARTICIPANTS:This study included 173 fourth-year medical students at a public medical school who matched into general surgery residency programs. METHODS:Our cohort comprised students graduating from our institution between 2004 and 2015 that matched into preliminary or categorical general surgery positions. We collected academic variables and performed univariate analyses and logistic regression to examine the likelihood of specific match outcomes. RESULTS:= 0.35). Models for a match based upon Doximity ranking lacked the same predictive power. CONCLUSIONS:This research identifies students that are at risk for not matching into a categorical position and predicts competitiveness for certain programs. It provides a novel calculator to give applicants easily interpretable match probabilities.
PMID: 29033024
ISSN: 1878-7452
CID: 5030562

Caretaker Quality of Life in Rett Syndrome: Disorder Features and Psychological Predictors

Killian, John T; Lane, Jane B; Lee, Hye-Seung; Pelham, James H; Skinner, Steve A; Kaufmann, Walter E; Glaze, Daniel G; Neul, Jeffrey L; Percy, Alan K
OBJECTIVE:Rett syndrome is a severe neurodevelopmental disorder affecting approximately one in 10,000 female births. The clinical features of Rett syndrome are known to impact both patients' and caretakers' quality of life in Rett syndrome. We hypothesized that more severe clinical features would negatively impact caretaker physical quality of life but would positively impact caretaker mental quality of life. METHODS:Participants were individuals enrolled in the Rett Natural History Study with a diagnosis of classic Rett syndrome. Demographic data, clinical disease features, caretaker quality of life, and measures of family function were assessed during clinic visits. The Optum SF-36v2 Health Survey was used to assess caretaker physical and mental quality of life (higher scores indicate better quality of life). Descriptive, univariate, and multivariate analyses were used to characterize relationships between child and caretaker characteristics and caretaker quality of life. RESULTS:Caretaker physical component scores (PCS) were higher than mental component scores (MCS): 52.8 (9.7) vs 44.5 (12.1). No differences were demonstrated between the baseline and 5-year follow-up. In univariate analyses, disease severity was associated with poorer PCS (P = 0.006) and improved MCS (P = 0.003). Feeding problems were associated with poorer PCS (P = 0.007) and poorer MCS (P = 0.018). In multivariate analyses, limitations in caretaker personal time and home conflict adversely affected PCS. Feeding problems adversely impacted MCS. CONCLUSIONS:Caretaker quality of life in Rett syndrome is similar to that for caretakers in other chronic diseases. Disease characteristics significantly impact quality of life, and feeding difficulties may represent an important clinical target for improving both child and caretaker quality of life. The stability of quality-of-life scores between baseline and five years adds important value.
PMID: 26995066
ISSN: 1873-5150
CID: 5030552

Delays in Surgery for Patients With Coronary Stents Placed After Diagnosis of Colorectal Cancer

Killian, John T; Holcomb, Carla N; Graham, Laura A; Richman, Joshua S; Hawn, Mary T
PMID: 26501344
ISSN: 2168-6262
CID: 5030542

Relationships among musculoskeletal impairments and functional health status in ambulatory cerebral palsy

Abel, Mark F; Damiano, Diane L; Blanco, John S; Conaway, Mark; Miller, Freeman; Dabney, Kirk; Sutherland, David; Chambers, Henry; Dias, Luciano; Sarwark, John; Killian, John; Doyle, Scott; Root, Leon; LaPlaza, Javier; Widmann, Roger; Snyder, Brian
Orthopedic surgery for patients with cerebral palsy addresses motion impairments, assuming that this will improve motor function. This study evaluates the relationships among clinical impairment measures with standardized assessments of function and disability as an initial step in testing this assumption. A total of 129 ambulatory children and adolescents across six institutions participated in a prospective evaluation that consisted of passive motion and spasticity examination of the lower extremities, three-dimensional gait temporal-spatial and kinematic analysis, and administration of the Gross Motor Function Measure (GMFM) and the Pediatric Outcomes Data Collection Instrument (PODCI). The analysis found that isolated impairment measures of motion and spasticity were only weakly related to motor function in cerebral palsy and even when averaged across multiple joints yielded no more than a fair correlation with functional scores, nor did a combination of impairments emerge that could predict substantial variance in motor function. These findings suggest that caution should be exercised when anticipating functional change through the treatment of isolated impairment and that addressing multiple impairments may be needed to produce appreciable effects.
PMID: 12826956
ISSN: 0271-6798
CID: 5030502