A pig kidney supporting human physiology.

Because of the global shortage of donor kidneys, xenotransplantation emerges as a potential solution for individuals with kidney failure who face challenges in securing a suitable donor kidney. A study featured in this month's issue of Kidney International assesses the kidney physiology of a porcine kidney transplanted into a brain-dead human with kidney failure, demonstrating life-sustaining physiological function for 7 days. Together with preclinical nonhuman primate studies, decedent models provide complementary data for development of clinical kidney xenotransplantation.

Late graft failure of pig-to-rhesus renal xenografts has features of glomerulopathy and recipients have anti-swine leukocyte antigen class I and class II antibodies.

Prolonged survival in preclinical renal xenotransplantation demonstrates that early antibody mediated rejection (AMR) can be overcome. It is now critical to evaluate and understand the pathobiology of late graft failure and devise new means to improve post xenograft outcomes. In renal allotransplantation the most common cause of late renal graft failure is transplant glomerulopathy-largely due to anti-donor MHC antibodies, particularly anti-HLA DQ antibodies. We evaluated the pig renal xenograft pathology of four long-surviving (>300 days) rhesus monkeys. We also evaluated the terminal serum for the presence of anti-SLA class I and specifically anti-SLA DQ antibodies. All four recipients had transplant glomerulopathy and expressed anti-SLA DQ antibodies. In one recipient tested for anti-SLA I antibodies, the recipient had antibodies specifically reacting with two of three SLA I alleles tested. These results suggest that similar to allotransplantation, anti-MHC antibodies, particularly anti-SLA DQ, may be a barrier to improved long-term xenograft outcomes.

The Surgical Clerkship in the COVID Era: A Natural Language Processing and Thematic Analysis.

INTRODUCTION: Responses to COVID-19 within medical education prompted significant changes to the surgical clerkship. We analyzed the changes in medical student end of course feedback before and after the COVID-19 outbreak. METHODS: Postclerkship surveys from 2017 to 2022 were analyzed including both Likert scale data and free text, excluding the COVID outbreak year 2019-2020. Likert scale questions were compared between pre-COVID (2017-2019) and COVID-era cohorts (2020-2022) with the Mann-Whitney U-test. Free-text comments were analyzed using both thematic analysis and natural language processing including sentiment, word and phrase frequency, and topic modeling. RESULTS: Of the 483 medical students surveyed from 2017 to 2022, 297 responded (61% response rate) to the included end of clerkship surveys. Most medical students rated the clerkship above average or excellent with no significant difference between the pre-COVID and COVID-era cohorts (70.4% Versus 64.8%, P = 0.35). Perception of grading expectations did significantly differ, 51% of pre-COVID students reported clerkship grading standards were almost always clear compared to 27.5% of COVID-era students (P = 0.01). Pre-COVID cohorts more frequently mentioned learning and feedback while COVID-era cohorts more frequently mentioned case, attending, and expectation. Natural language processing topic modeling and formal thematic analysis identified similar themes: team, time, autonomy, and expectations. CONCLUSIONS: COVID-19 presented many challenges to undergraduate medical education. Despite many changes, there was no significant difference in clerkship satisfaction ratings. Unexpectedly, the greater freedom and autonomy of asynchronous lectures and choice of cases became a highlight of the new curriculum. Future research should investigate if there are similar associations nationally with a multi-institutional study.

Surgical Residents as Clerkship Scholars May Improve Student Perception of the Surgery Clerkship.

INTRODUCTION: The surgical clerkship is a formative experience in the medical school curriculum and can leave a lasting impression on students' perception of surgery. Given the historical negative stereotypes of surgeons, the clerkship represents an opportunity to impact students in a meaningful way. METHODS: Our institution developed a program in which research residents can serve as junior clerkship coordinators and educators; working closely with medical students on their surgery clerkship. At the end of their clerkship, students were administered a survey with Likert-scale and free text responses regarding satisfaction with the rotation, lectures, feedback, and value of the clerkship. Student survey results were compared before (2015-2016) and after (2017-2019) the implementation of the scholar program with nonparametric statistical analysis and qualitative text analysis. RESULTS: A total of 413 students responded to the survey with no significant difference in response rate by term (P = 0.88). We found no statistical difference with respect to overall course perception (92.3% versus 91.2%, P = 0.84), but a statistically significant difference was noted for the clarity of the provided written clerkship materials (80.3% versus 91.3%, P = 0.02) and usefulness of the feedback (57.5% versus 78.7%, P = 0.01). Qualitative analysis demonstrated an overall positive shift in perception of the clerkship, improvement in the course materials, and organization. CONCLUSIONS: The scholar program was overall well received by the students with improvements in certain aspects of the clerkship: organization, feedback, and course materials. This program represents a potential strategy to improve certain portions of the medical school clerkship experience.

The Association Between Altmetric Attention Scores and Public Engagement in the Medical Literature.

INTRODUCTION: With the advent of social media and the associated increase in connectivity between scientists and the lay public, the Altmetric Attention Score has been created as a way to measure these interactions between scholarly publications and media dissemination. Little is known, however, whether these types of media exchanges measured by Altmetrics may serve as a proxy for public engagement. As such, we have sought to determine whether or not an association exists between Altmetric scores and public engagement, as measured by article citation in a health policy document. METHODS: The top 100 highest scoring articles in the medical and health sciences with respect to Altmetric Attention Scores were selected from each of 3 y (2014, 2015, and 2016). Each article was then matched to an article from the same year and journal with the highest Relative Citation Ratio (RCR) for comparison. Bivariate analysis compared article groups with respect to citation in a public policy document, open-access status, and funding status, as well as Altmetric and RCR scores. A multivariable model was then constructed to identify significant factors associated with citation in a public policy document. Finally, a contour plot was generated in order to estimate the interaction between Altmetric Scores and RCR and their comparative effects on the probability of inclusion in a health policy document. RESULTS: Of the 600 articles included in the analysis, 286 (48%) had been cited by a public policy article. The only difference that existed between the cohorts was for funding status, with 55 articles (40%) in the RCR cohort having received funding compared to 81 (60%) in the Altmetric cohort (P = 0.011). On bivariate analysis, both Altmetric (P = 0.0018) and RCR (P < 0.0001) scores were independently predictive of policy citation. In a multivariable model, the interaction between Altmetric Scores and RCR with respect to policy inclusion was significant (OR = 1.22; 95% CI = 1.08-1.38) and a contour plot demonstrates that either high Altmetric score or RCR alone is sufficient to generate a high probability of policy inclusion. CONCLUSIONS: Scholarly article Altmetric Scores may serve as a novel means to explore public engagement in scientific research and health policy. In addition, journals that aim to impact public policy through article dissemination may benefit from engagement in social media avenues in addition to traditional citation pathways in order to encourage broader inclusion.

The Influence of an Acting or Subintern on Third-Year Medical School Surgery Clerkship Students.

BACKGROUND: Previous reports demonstrated a positive relationship between the surgical clerkship and student likelihood of pursuing a surgical career, but no studies have examined the influence a peer has on comfort during a surgical clerkship. We hypothesized that a fourth-year acting intern (AI) would positively impact third-year medical students' experience during their surgical clerkship. METHODS: All third-year medical students at our institution who completed their surgical clerkship in 2019 were surveyed regarding the preclerkship and postclerkship perceptions. RESULTS: Of the 110 students surveyed, 52 responded (47.3% response rate), and 25 students (48.1%) reported having an AI during their clerkship rotation, and 27 did not (51.9%). Presence of an AI had no significant effect on the postclerkship perception of surgery, likelihood of pursuing general surgery, or comfort in the OR. Analysis of all responses demonstrated the surgery clerkship had no significant impact on students' perception of surgery or likelihood of pursuing general surgery but did statistically increase students' comfort in the OR. CONCLUSIONS: The results of this study suggest that AI presence did not significantly influence a student's clerkship experience or comfort in the OR. Further studies are needed to determine what, if any effect, an AI could have on third-year clerkship students.

Efficacy of ATG and Rituximab in capuchin monkeys (a New World monkey)-An in vitro study relevant to xenotransplantation.

While Old World monkeys, for example, baboons, have antibodies against triple-knockout (TKO) pig cells, thus complicating pig organ transplantation studies, capuchin monkeys (a New World monkey) do not, thus more closely mimicking humans in respect to the response to TKO pig cells. Whether drugs such as anti-thymocyte globulin (ATG) and Rituximab are effective in capuchin monkeys remains uncertain. We measured the binding and cytotoxicity of ATG and Rituximab to human (n = 7), baboon (n = 7), and capuchin monkey (n = 5) peripheral blood mononuclear cells (PBMCs), T cells or B cells by flow cytometry.The effect in vitro of ATG in depleting PBMCs in capuchin monkeys and baboons was significantly less than in humans, but the depletion in capuchin monkeys was not significantly different from that in baboons. In contrast, the effect in vitro of Rituximab in depleting B cells in capuchin monkeys was very limited, and significantly less than in humans and baboons.Although capuchin monkeys mimic the human antibody response to TKO pig cells more closely than baboons, Rituximab had a minimal effect in capuchin monkeys in vitro. This observation may limit the value of New World Monkeys as recipients of pig organs, tissues, or cells in experimental studies of xenotransplantation or, indeed, in allotransplantation.

Examining the Biosynthesis and Xenoantigenicity of Class II Swine Leukocyte Antigen Proteins.

Genetically engineered pig organs could provide transplants to all patients with end-stage organ failure, but Ab-mediated rejection remains an issue. This study examines the class II swine leukocyte Ag (SLA) as a target of epitope-restricted Ab binding. Transfection of individual α- and ß-chains into human embryonic kidney cells resulted in both traditional and hybrid class II SLA molecules. Sera from individuals on the solid organ transplant waiting list were tested for Ab binding and cytotoxicity to this panel of class II SLA single-Ag cells. A series of elution studies from an SLA-DQ cell line were performed. Our results indicate that human sera contain Abs specific for and cytotoxic against class II SLA. Our elution studies revealed that sera bind the SLA-DQ molecule in an epitope-restricted pattern. Site-specific mutation of one of these epitopes resulted in statistically decreased Ab binding. Humans possess preformed, specific, and cytotoxic Abs to class II SLA that bind in an epitope-restricted fashion. Site-specific epitope mutagenesis may decrease the Ab binding of highly sensitized individuals to pig cells.

Examining epitope mutagenesis as a strategy to reduce and eliminate human antibody binding to class II swine leukocyte antigens.

Xenotransplantation of pig organs into people may help alleviate the critical shortage of donors which faces organ transplantation. Unfortunately, human antibodies vigorously attack pig tissues preventing the clinical application of xenotransplantation. The swine leukocyte antigens (SLA), homologs of human HLA molecules, can be xenoantigens. SLA molecules, encoded by genes in the pig major histocompatibility complex, contribute to protective immune responses in pig. Therefore, simply inactivating them through genome engineering could reduce the ability of the human immune system to surveil transplanted pig organs for infectious disease or the development of neoplasms. A potential solution to this problem is to identify and modify epitopes in SLA proteins to eliminate their contribution to humoral xenoantigenicity while retaining their biosynthetic competence and ability to contribute to protective immunity. We previously showed that class II SLA proteins were recognized as xenoantigens and mutating arginine at position 55 to proline, in an SLA-DQ beta chain, could reduce human antibody binding. Here, we extend these observations by creating several additional point mutants at position 55. Using a panel of monoclonal antibodies specific for class II SLA proteins, we show that these mutants remain biosynthetically competent. Examining antibody binding to these variants shows that point mutagenesis can reduce, eliminate, or increase antibody binding to class II SLA proteins. Individual mutations can have opposite effects on antibody binding when comparing samples from different people. We also performed a preliminary analysis of creating point mutants near to position 55 to demonstrate that manipulating additional residues also affects antibody reactivity.

Xenoantigen Deletion and Chemical Immunosuppression Can Prolong Renal Xenograft Survival.

OBJECTIVE: Xenotransplantation using pig organs could end the donor organ shortage for transplantation, but humans have xenoreactive antibodies that cause early graft rejection. Genome editing can eliminate xenoantigens in donor pigs to minimize the impact of these xenoantibodies. Here we determine whether an improved cross-match and chemical immunosuppression could result in prolonged kidney xenograft survival in a pig-to-rhesus preclinical model. METHODS: Double xenoantigen (Gal and Sda) knockout (DKO) pigs were created using CRISPR/Cas. Serum from rhesus monkeys (n = 43) was cross-matched with cells from the DKO pigs. Kidneys from the DKO pigs were transplanted into rhesus monkeys (n = 6) that had the least reactive cross-matches. The rhesus recipients were immunosuppressed with anti-CD4 and anti-CD8 T-cell depletion, anti-CD154, mycophenolic acid, and steroids. RESULTS: Rhesus antibody binding to DKO cells is reduced, but all still have positive CDC and flow cross-match. Three grafts were rejected early at 5, 6, and 6 days. Longer survival was achieved in recipients with survival to 35, 100, and 435 days. Each of the 3 early graft losses was secondary to IgM antibody-mediated rejection. The 435-day graft loss occurred secondary to IgG antibody-mediated rejection. CONCLUSIONS: Reducing xenoantigens in donor pigs and chemical immunosuppression can be used to achieve prolonged renal xenograft survival in a preclinical model, suggesting that if a negative cross-match can be obtained for humans then prolonged survival could be achieved.

Efficient generation of targeted and controlled mutational events in porcine cells using nuclease-directed homologous recombination.

BACKGROUND: Nuclease-based genome editing has rapidly sped the creation of new models of human disease. These techniques also hold great promise for the future of clinical xenotransplantation and cell-based therapies for cancer or immunodeficient pathology. However, to fully realize the potential of nuclease editing tools, the efficiency and precision of their application must be optimized. The object of this study was to use nonintegrating selection and nuclease-directed homologous recombination to efficiently control the genetic modification of the porcine genome. METHODS: Clustered randomly integrating spaced palindromic repeats and associated Cas9 protein (CRISPR/Cas9)-directed mutagenesis with a single-guide RNA target was designed to target the alpha-1,3-galactosyltransferase locus (GGTA1) of the porcine genome. A vector expressing a single-guide RNA, Cas9 protein, and green fluorescent protein was used to increase plasmid-delivered mutational efficiency when coupled with fluorescence sorting. Single and double-strand DNA oligonucleotides with a restriction site replacing the start codon were created with variable homology lengths surrounding the mutational event site. Finally, a transgene construct was flanked with 50 base pairs of homology directed immediately 5' to a nuclease cut site. These products were introduced to cells with a constant concentration of CRISPR/cas9 vector. Phenotype-specific mutational efficiency was measured by flow cytometer. Controlled homologous insertion was measured by Sanger sequence, restriction enzyme digest and flow cytometry. RESULTS: Expression of a fluorescence protein on the Cas9 vector functioned as a nonintegrating selection marker. Selection by this marker increased phenotype-silencing mutation rates from 3.5% to 82% (P = 0.0002). Insertion or deletion mutation increased from 11% to 96% (P = 0.0007). Co-transfection with homologous DNA oligonucleotides increased the aggregate phenotype-silencing mutation rates up to 22% and increased biallelic events. Single-strand DNA was twice as efficient as double-strand DNA. Furthermore, nuclease-mediated insertion by homology-directed repair successfully drove locus-specific transgene expression in the porcine genome. CONCLUSIONS: A nonintegrating selection strategy based on fluorescence expression can increase the mutational efficiency of the CRISPR/Cas9 system. The precision of this system can be increased by the addition of a very short homologous template sequence and can serve as a method for locus-specific transgene delivery. Together these strategies may be used to efficiently control mutational events. This system may be used to better use the potential of nuclease-mediated genomic editing.

Silencing porcine genes significantly reduces human-anti-pig cytotoxicity profiles: an alternative to direct complement regulation.

UNLABELLED: The future of solid organ transplantation is challenged by an increasing shortage of available allografts. Xenotransplantation of genetically modified porcine organs offers an answer to this problem. Strategies of genetic modification have 'humanized' the porcine model towards clinical relevance. Most notably, these approaches have aimed at either antigen reduction or human transgene expression. The object of this study was to evaluate the relative effects of both antigen reduction and direct complement regulation on the human-anti-porcine complement dependent cytotoxicity response. Genetically modified animals were created through CRISPR/Cas9-directed mutation and human transgene delivery. Pigs doubly deficient in GGTA1 and CMAH genes were compared to pigs of the same background that expressed a human complement regulatory protein (hCRP). A third animal was made deficient in GGTA1, CMAH and B4GalNT2 gene expression. Cells from these animals were subjected to measures of human antibody binding and antibody-mediated complement-dependent cytotoxicity by flow cytometry. Human IgG and IgM antibody binding was unchanged between the double knockout and the transgenic hCRP double knockout pig. IgG and IgM binding was reduced by 49.1 and 43.2 % respectively by silencing the B4GalNT2 gene. Compared to the double knockout, human anti-porcine cytotoxicity was reduced by 8 % with the addition of a hCRP (p = .032); It was reduced by 21 % with silencing the B4GalNT2 gene (p = .012). CONCLUSIONS: Silencing the GGTA1, CMAH and B4GalNT2 genes in pigs achieved a significant antigen reduction. Changing the porcine carbohydrate profile effectively mediates human antibody-mediated complement dependent cytoxicity.

Silencing the porcine iGb3s gene does not affect Galα3Gal levels or measures of anticipated pig-to-human and pig-to-primate acute rejection.

BACKGROUND: The Galα(1,3)Gal epitope (α-GAL), created by α-1,3-glycosyltransferase-1 (GGTA1), is a major xenoantigen causing hyperacute rejection in pig-to-primate and pig-to-human xenotransplantation. In response, GGTA1 gene-deleted pigs have been generated. However, it is unclear whether there is a residual small amount of α-Gal epitope expressed in GGTA1(-/-) pigs. Isoglobotrihexosylceramide synthase (iGb3s), another member of the glycosyltransferase family, catalyzes the synthesis of isoglobo-series glycosphingolipids with an α-GAL-terminal disaccharide (iGb3), creating the possibility that iGb3s may be a source of α-GAL epitopes in GGTA1(-/-) animals. The objective of this study was to examine the impact of silencing the iGb3s gene (A3GalT2) on pig-to-primate and pig-to-human immune cross-reactivity by creating and comparing GGTA1(-/-) pigs to GGTA1(-/-) - and A3GalT2(-/-) -double-knockout pigs. METHODS: We used the CRISPR/Cas 9 system to target the GGTA1 and A3GalT2 genes in pigs. Both GGTA1 and A3GalT2 genes are functionally inactive in humans and baboons. CRISPR-treated cells used directly for somatic cell nuclear transfer produced single- and double-gene-knockout piglets in a single pregnancy. Once grown to maturity, the glycosphingolipid profile (including iGb3) was assayed in renal tissue by normal-phase liquid chromatography. In addition, peripheral blood mononuclear cells (PBMCs) were subjected to (i) comparative cross-match cytotoxicity analysis against human and baboon serum and (ii) IB4 staining for α-GAL/iGb3. RESULTS: Silencing of the iGb3s gene significantly modulated the renal glycosphingolipid profile and iGb3 was not detected. Moreover, the human and baboon serum PBMC cytotoxicity and α-GAL/iGb3 staining were unchanged by iGb3s silencing. CONCLUSIONS: Our data suggest that iGb3s is not a contributor to antibody-mediated rejection in pig-to-primate or pig-to-human xenotransplantation. Although iGb3s gene silencing significantly changed the renal glycosphingolipid profile, the effect on Galα3Gal levels, antibody binding, and cytotoxic profiles of baboon and human sera on porcine PBMCs was neutral.

The fate of human platelets exposed to porcine renal endothelium: a single-pass model of platelet uptake in domestic and genetically modified porcine organs.

BACKGROUND: Thrombocytopenia may represent a significant challenge to the clinical application of solid-organ xenotransplantation. When studied in a pig-to-primate model, consumptive coagulopathy has challenged renal xenografts. New strategies of genetic manipulation have altered porcine carbohydrate profiles to significantly reduce human antibody binding to pig cells. As this process continues to eliminate immunologic barriers to clinical xenotransplantation, the relationship between human platelets and pig organs must be considered. METHODS: Genetically modified pigs that were created by the CRISPR/Cas9 system with α-1,3-galactosyltransferase (GGTA1)(-/-) or GGTA1(-/-) cytidine monophosphate-N-acetylneuraminic acid hydroxylase(-/-) phenotype, as well as domestic pigs, were used in this study. Autologous porcine platelets were isolated from donor animal blood collection, and human platelets were obtained from a blood bank. Platelets were fluorescently labeled and in a single-pass model, human, or autologous platelets were perfused through porcine organs at a constant concentration and controlled temperature. Platelet uptake was measured by sampling venous output and measuring sample florescence against input florescence. In vitro study of the interaction between human platelets and porcine endothelial cells was accomplished by immunohistochemical stain and confocal microscopy. RESULTS: Differences between human and autologous platelet loss through the porcine kidney were not significant in any genetic background tested (WT P = 0.15, GGTA1(-/-)P = 0.12, GGTA1(-/-) cytidine monophosphate-N-acetylneuraminic acid hydroxylase(-/-)P = 0.25). The unmodified porcine liver consumed human platelets in a single-pass model of platelet perfusion in fewer than 10 min. WT suprahepatic inferior vena cava fluoresce reached a maximum of 76% of input fluoresce within the human platelet cohort and was significantly lower than the autologous platelet control cohort (P = 0.001). Confocal microscopic analysis did not demonstrate a significant association between human platelets and porcine renal endothelial cells compared with porcine liver endothelial positive controls. CONCLUSIONS: Our results suggest that in the absence of immunologic injury, human platelets respond in a variable fashion to organ-specific porcine endothelial surfaces. Human platelets are not removed from circulation by exposure to porcine renal endothelium but are removed by unmodified porcine hepatic endothelium. Kidneys possessing genetic modifications currently relevant to clinical xenotransplantation failed to consume human platelets in an isolated single-pass model. Human platelets did not exhibit significant binding to renal endothelial cells by in vitro assay.

Normothermic Preservation of the Intestinal Allograft.

Intestinal allotransplantation was first described in the 1960s and successfully performed in the 1980s. Since that time, less progress has been made in the preservation of the allograft before transplantation and static cold storage remains the current standard. Normothermic machine perfusion represents an opportunity to simultaneously preserve, assess, and recondition the organ for transplantation and improve the procurement radius for allografts. The substantial progress made in the field during the last 60 years, coupled with the success of the preclinical animal model of machine perfusion-preserved intestinal transplantation, suggest we are approaching the point of clinical application.

The Role of Autophagy in Vascular Endothelial Cell Health and Physiology.

Autophagy is a highly conserved cellular recycling process which enables eukaryotes to maintain both cellular and overall homeostasis through the catabolic breakdown of intracellular components or the selective degradation of damaged organelles. In recent years, the importance of autophagy in vascular endothelial cells (ECs) has been increasingly recognized, and numerous studies have linked the dysregulation of autophagy to the development of endothelial dysfunction and vascular disease. Here, we provide an overview of the molecular mechanisms underlying autophagy in ECs and our current understanding of the roles of autophagy in vascular biology and review the implications of dysregulated autophagy for vascular disease. Finally, we summarize the current state of the research on compounds to modulate autophagy in ECs and identify challenges for their translation into clinical use.

Subnormothermic Oxygenated Machine Perfusion (24 h) in DCD Kidney Transplantation.

Background: Ex vivo kidney perfusion is an evolving platform that demonstrates promise in preserving and rehabilitating the kidney grafts. Despite this, there is little consensus on the optimal perfusion conditions. Hypothermic perfusion offers limited functional assessment, whereas normothermic perfusion requires a more complex mechanical system and perfusate. Subnormothermic machine perfusion (SNMP) has the potential to combine the advantages of both approaches but has undergone limited investigation. Therefore, the present study sought to determine the suitability of SNMP for extended kidney preservation. Methods: SNMP at 22-25 °C was performed on a portable device for 24 h with porcine kidneys. Graft assessment included measurement of mechanical parameters and biochemical analysis of the perfusate using point-of-care tests. To investigate the viability of kidneys preserved by SNMP, porcine kidney autotransplants were performed in a donation after circulatory death (DCD) model. SNMP was also compared with static cold storage (SCS). Finally, follow-up experiments were conducted in a subset of human kidneys to test the translational significance of findings in porcine kidneys. Results: In the perfusion-only cohort, porcine kidneys all displayed successful perfusion for 24 h by SNMP, evidenced by stable mechanical parameters and biological markers of graft function. Furthermore, in the transplant cohort, DCD grafts with 30 min of warm ischemic injury demonstrated superior posttransplant graft function when preserved by SNMP in comparison with SCS. Finally, human kidneys that underwent 24-h perfusion exhibited stable functional and biological parameters consistent with observations in porcine organs. Conclusions: These observations demonstrate the suitability and cross-species generalizability of subnormothermic machine perfusion to maintain stable kidney perfusion and provide foundational evidence for improved posttransplant graft function of DCD kidneys after SNMP compared with SCS.

Contemporary trends and outcomes after liver transplantation and resection for intrahepatic cholangiocarcinoma.

BACKGROUND: Liver transplantation (LT) has been shown to be superior to resection in highly selected patients with perihilar cholangiocarcinoma (CCA), yet has traditionally been contraindicated for intrahepatic CCA (iCCA). Herein, we aimed to examine contemporary trends and outcomes for surgical resection and LT for iCCA. METHODS: The National Cancer Database was queried for patients presenting with stage I-III iCCA between 2010 and 2018 who underwent resection or LT. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods stratified by management. Secondary analysis of patients undergoing transplant for CCA was performed with the United Network for Organ Sharing database. RESULTS: Of 2565 patients, 2412 (94.0%) underwent resection and 153 (5.96%) LT of whom 84 (54.9%) received neoadjuvant therapy. Utilization of LT remained between 3.9% and 7.8% annually. Unadjusted 5-year OS was higher for LT than resection (59.8% vs 39.9%, P = .0067), yet adjusted analysis revealed no significant difference in mortality (hazard ratio, 0.91; 95% CI, 0.66-1.27; P = .58). On secondary analysis including 437 patients with all subtypes of CCA, unadjusted 5-year OS was higher for non-CCA indications (79% vs 52%-54%, P < .001). CONCLUSION: Utilization of LT for iCCA remains low and many cases are likely incidental. Although partial hepatectomy remains the standard of care for patients with resectable disease, our findings suggest that highly selected patients with unresectable iCCA may achieve favorable outcomes after LT. Granular, prospective data are needed to identify patients most likely to benefit from transplant and allocate scarce liver grafts.

A novel low-cost model of superficial abscess for trainee education in incision and drainage.

Background: Proficiency in ultrasound usage is quickly becoming an expectation in multiple residency programs: emergency medicine, obstetrics-gynecology, surgery, and internal medicine. There is a lack of affordable training devices for ultrasound training and identification of superficial fluid collections. We sought to develop a model for trainee education in ultrasound usage, identification of superficial fluid collection, aspiration, and incision & drainage (I&D). Materials & methods: Commercially available products were used to develop a novel, low-cost model for ultrasound-guided aspiration and I&D of an abscess. A latex balloon embedded in silicone gel construct simulated a superficial fluid collection when examined with an ultrasound probe and monitor. A 18-gauge needle on a 10-cc syringe were used for aspiration, and a 15-blade disposal scalpel with 0.25″ packing strip used for I&D. Results: Approximately six hours are required to generate 24 individual models of a superficial abscess. Following an initial investment, each model costs less than $1 USD to produce. Compared to commercially available models, this represents a significant savings. This model was utilized during the medical school academic year as a teaching aid for medical students to simulate ultrasound-guided identification, aspiration, and incision and drainage of a superficial abscess. Conclusions: We successfully produced an affordable, low-cost model of a superficial fluid collection for training in ultrasound usage, aspiration, and I&D. The model represents significant savings over commercially available alternatives and can be easily replicated for trainee education.

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates.

Prior studies of anti-CD40 ligand (CD40L)-based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501-based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.