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Targeted delivery of therapeutics through the use of nanoparticles (NPs) has emerged as a promising method that increases their efficacy and reduces their side effects. NPs can be tailored to localize to selective tissues through conjugation to ligands that bind cell-specific receptors. Although the vast majority of nanodelivery platforms have focused on cancer therapy, efforts have begun to introduce nanotherapeutics to the fields of immunology as well as transplantation. In this article, we provide an overview from a clinician’s perspective of current nanotherapeutic strategies to treat solid organ transplants with NPs during the time interval between organ harvest from the donor and placement into the recipient, an innovative technology that can provide major benefits to transplant patients. The use of ex vivo normothermic machine perfusion (NMP), which is associated with preserving the function of the organ following transplantation, also provides an ideal opportunity for a localized, sustained, and controlled delivery of nanotherapeutics to the organ during this critical time period. Here, we summarize previous endeavors to improve transplantation outcomes by treating the organ with NPs prior to placement in the recipient. Investigations in this burgeoning field of research are promising, but more extensive studies are needed to overcome the physiological challenges to achieving effective nanotherapeutic delivery to transplanted organs discussed in this review.

We conducted a registry-based cohort study of all individuals aged 25-64 years residing in Norway by 1st of January 2008 (N = 2,535,213). This cohort was followed from 2008 through 2014 using inpatient registrations for acute hospitalizations due to all-cause injuries, getting 177,663 cases of hospitalized persons (incidence rate of new cases: 102.1 pr 10,000 person-years at risk). We derived two measures of severity: threat-to-life using the International Classification of Disease-based Injury Severity Score (ICISS) (Stephenson et al 2004; Gedeborg et al 2014), and threat of disability using long-term disability weights (DW) from the Injury-VIBES project (Gabbe et al 2014), also based on the ICD-codes. We found the following distributions of the hospitalized persons (N = 177,663): 1) Threat to life (ICISS): High threat to life: 4,186 (2.4 %); Lower threat to life: 173,477 (97.6%). 2) Threat of disability (Injury Vibes DW): High probability of long-term disability (DW-score < 0.807): 36,573 (20,6 %); Medium probability of long-term disability (DW-score 0.807-0.947): 97,590 (54,9 %); low probability of long-term disability (DW-score >0.947): 43,530 (24.5 %). Correlation between ICISS-score and the Injury Vibes disability weight score was moderate (r = 0.418, p < 0.001). The presentation will end up in a discussion on which of these two severity measures could be used for comparing burden of injuries across countries. References Gabbe BJ, Simpson PM, Lyons RA, et al. (2014) Association between the Number of Injuries Sustained and 12-Months Disability Outcomes: Evidence from the Injury-VIBES Study. PLos ONE, 9(12):e113467. DOI: 10.1371/journal.pone.0113467. Gedeborg R, Warner M, Chen LH, et al. (2014) Internationally comparable diagnosis-specific survival probabilites for calculation of the ICD-10-based Injury Severity Score. J Trauma Acute Care Surg, 76(2):358-65. DOI: 10.1097/ta.0b013e3182a9cd31.

Outcomes following heart transplantation remain suboptimal with acute and chronic rejection being major contributors to poor long-term survival. IL-6 is increasingly recognized as a critical pro-inflammatory cytokine involved in allograft injury and has been shown to play a key role in regulating the inflammatory and alloimmune responses following heart transplantation. Therapies that inhibit IL-6 signaling have emerged as promising strategies to prevent allograft rejection. Here, we review experimental and pre-clinical evidence that supports the potential use of IL-6 signaling blockade to improve outcomes in heart transplant recipients.

Carbon Capture, Utilisation and Storage (CCUS) technologies are utilised to minimise net CO2 emissions and hence mitigate the impact of anthropogenic emissions on the global climate. One example of CO2 utilisation is the production of carbon-neutral methane fuel via catalytic CO2 reduction with H2 (methanation). Thermal activation of a metal impregnated metal-organic framework (MOF), 1 wt%Ru/UiO-66 in the presence of H2 and CO2 provides in situ synthesis of a highly active methanation catalyst: H2 promotes the formation of Ru0 nanoparticles, and CO2 behaves as a mild oxidant to remove framework carbon and promote ZrO2 crystallisation. The nature of the active MOF-derived Ru0/ZrO2 catalyst was studied by PXRD, TEM, and XAS, and the evolution of the parent 1 wt%Ru/UiO-66 during thermal activation monitored in operando by synchrotron PXRD. The Ru impregnated Zr-based MOF collapses on heating in H2 and CO2 to form an amorphous C and Zr containing phase that subsequently crystallises as tetragonal (t-) ZrO2 nanoparticles. These t-ZrO2 nanoparticles undergo a subsequent phase transition to the more stable monoclinic (m-) ZrO2 polymorph. In situ activation of Ru/UiO-66 generates a highly active catalyst for CO2 methanation by transforming the MOF precursor into a (carbon-free) crystalline t-ZrO2 support that stabilises highly dispersed metallic Ru nanoparticles. This insight may guide the rational design of future MOF-derived catalysts.

Donor organ demand continues to outpace supply in heart transplantation. Utilization of donation after circulatory death (DCD) hearts could significantly increase heart donor availability for patients with advanced heart failure.The purpose of this study was to describe hemodynamic and clinical profiles of DCD hearts in comparison to standard of care (SOC) hearts donated after brain death (DBD).This single-center retrospective cohort study of consecutive heart transplant recipients analyzed right heart catheterization measurements, inotrope scores, echocardiograms, and clinical outcomes between DCD and DBD heart recipients.Between April 2016 and February 2022, 47 DCD and 166 SOC hearts were transplanted. Median time from DCD consent to transplant was significantly shorter compared with SOC waiting list time (17 days [6-28 days] vs 70 days [23-240 days]; P 0.001). Right heart function was significantly impaired in DCD recipients compared with SOC recipients 1 week post-transplant (higher median right atrial pressure (10 mm Hg [8-13 mm Hg] vs 7 mm Hg [5-11 mm Hg]; P 0.001), higher right atrial pressure to pulmonary capillary wedge pressure ratio (0.64 [0.54-0.82] vs 0.57 [0.43-0.73]; P = 0.016), and lower pulmonary arterial pulsatility index (1.66 [1.27-2.50] vs 2.52 [1.63-3.82]; P 0.001), but was similar between groups by 3 weeks post-transplant. DCD and SOC recipient mortality was similar at 30 days (DCD 0 vs SOC 2%; P = 0.29) and 1 year post-transplant (DCD 3% vs SOC 8%; P = 0.16).DCD heart utilization is associated with transient post-transplant right heart dysfunction and short-term clinical outcomes otherwise similar to transplantation using DBD hearts.

Fear is an integrated part of predator-prey interactions with cascading effects on the structure and function of ecosystems. Fear of parasitism holds a similar ecological potential but our understanding of the underlying mechanisms in host-parasite interactions is limited by lack of empirical examples. Here, we experimentally test if blue musselsMytilus edulisrespond behaviourally to the mere presence of infective transmission stages of the trematodeHimasthla elongataby ceasing filtration activity, thereby avoiding infection. Our results show that blue mussels reduced clearance rates by more than 30% in presences of parasites. The reduced filtration activity resulted in lower infection rates in experimental mussels. The identified parasite-specific avoidance behaviour can be expected to play a significant role in regulating the ecosystem engineering function of blue mussels in coastal habitats.

A higher risk of hip fracture was found in areas of Norway at higher elevation and farther from the coast. However, the previously seen county variations could not be explained by these geographical factors. Norway is an elongated country extending north of the Arctic Circle with substantial coast-inland variation in topography and climate. Differences in hip fracture incidence between counties and a distinct seasonal variation have previously been shown. The aim of the current study was to explore these variations further by considering associations of height above sea level (elevation) and distance to the coast with hip fracture incidence. All patients with hip fractures admitted to Norwegian hospitals in the period 2009–2018 were included. Individual residential elevation and distance to the coast was calculated in Geographic Information Systems and combined with individual-level population data on all Norwegians 50 years of age or older during the observation period, including hospital information on fractures. Age-standardized incidences rate and incidence rate ratios with 95% confidence intervals (IRR, 95% CI) according to elevation and coastal proximity were estimated. The associations were tested using Poisson models adjusting for sex, urban/rural location of residency, country of birth, and season of hip fracture occurrence. From 2009 to 2018, there were 85,776 first hip fractures. There was an increasing risk with higher residential elevation (above versus below mean) for women: IRR = 1.04, 95% CI: 1.02, 1.05), but not for men (IRR = 1.00, 95% CI: 0.97, 1.02). Incidence of hip fracture increased with distance from the coast. Women residing the farthest away from the coast (above versus below mean distance) had a higher age-adjusted incidence of hip fracture compared to those living closer to the coast (IRR = 1.04 (95% CI: 1.02, 1.06), whereas no association was found in men (IRR = 1.00 (95% CI: 1.00, 1.01). Combining elevation and distance to coast showed a higher incidence in women living at high elevation far from the coast compared with women living at low elevation near the coast (IRR = 1.07, 95% CI: 1.04, 1.10). A similar result was found in men but only for hip fractures occurring during March–May (IRR = 1.07, 95% CI: 1.00, 1.15). The previously shown patterns of county differences and seasonal variations were unchanged when considering geography. We found a somewhat higher incidence of hip fracture in inland residents living in areas of high elevation, as compared to those living in more coastal proximity; however, the geographic variation did not explain county and seasonal differences in fracture incidence in Norway. More in-depth analyses on temperature and climate factors may give further clues.

Consistent survival of life-supporting pig heart xenograft recipients beyond 90 days was recently reported using genetically modified pigs and a clinically applicable drug treatment regimen. If this remarkable achievement proves reproducible, published benchmarks for clinical translation of cardiac xenografts appear to be within reach. Key mechanistic insights are summarized here that informed recent pig design and therapeutic choices, which together appear likely to enable early clinical translation.

Consistent induction of donor‐specific unresponsiveness in the absence of continuous immunosuppressive therapy and toxic effects remains a difficult task in clinical organ transplantation. Transplant immunologists have developed numerous experimental treatments that target antigen‐presentation (signal 1), costimulation (signal 2), and cytokine production (signal 3) to establish transplantation tolerance. While promising results have been obtained using therapeutic approaches that predominantly target the adaptive immune response, the long‐term graft survival rates remain suboptimal. This suggests the existence of unrecognized allograft rejection mechanisms that contribute to organ failure. We postulate that trained immunity stimulatory pathways are critical to the immune response that mediates graft loss. Trained immunity is a recently discovered functional program of the innate immune system, which is characterized by nonpermanent epigenetic and metabolic reprogramming of macrophages. Since trained macrophages upregulate costimulatory molecules (signal 2) and produce pro‐inflammatory cytokines (signal 3), they contribute to potent graft reactive immune responses and organ transplant rejection. In this review, we summarize the detrimental effects of trained immunity in the context of organ transplantation and describe pathways that induce macrophage training associated with graft rejection., Ochando and colleagues describe the detrimental effects of trained immunity in organ transplantation and review mechanistic pathways that induce macrophage training associated with graft rejection.

Background Nutrition guidelines recommend enteral nutrition in the form of gastric feedings for critically ill children and acknowledge a lack of evidence describing an optimal method for providing these feedings. Objective To determine the state of the science regarding the efficacy of bolus (intermittent) or continuous gastric feedings to improve nutrition delivery in critically ill children receiving mechanical ventilation. Methods Five hundred seventy-nine abstracts met the inclusion criteria and were screened by 2 reviewers according to prespecified criteria. Full-text reviews were performed on 28 articles; 11 studies were selected for detailed analysis. Because of the small number of eligible studies, broader searches were conducted. Results Only 5 studies with a collective enrollment of fewer than 200 children closely addressed the specific research question. These 5 studies did not report any similarity in feeding regimens, nor did they report nutritional outcomes. Two of the articles described findings from the same study population. Although 4 of the 5 studies randomized children to bolus versus continuous feedings, only 3 studies described attainment of nutrient delivery goals in both the intervention and the control groups; the remaining study did not report this outcome. The heterogeneity in methodology and outcomes among the 5 studies did not allow for a meta-analysis. Conclusions The dearth of evidence regarding best practices and outcomes related to bolus versus continuous gastric feedings in critically ill children receiving mechanical ventilation requires additional rigorous investigation.

Background DBA/2J kidney allografts, but not heart allografts, are spontaneously accepted indefinitely in C57BL/6 (B6) mice, through regulatory tolerance mechanism dependent on Foxp3 cells. In contrast, B6 kidneys are rejected within a week in DBA/2J recipients. We hypothesized that the tolerogenic difference of the kidneys might be due to differences in number or function of plasmacytoid dendritic cells (pDCs), because these cells are potent inducers of Foxp3 cells. Methods pDCs from murine bone marrow, native kidneys, and spontaneously accepted kidney allografts were analyzed using flow cytometry and immunohistochemical staining. Naive T cells were cocultured with pDCs in specific strain combinations and analyzed for FoxP3 induction and functionality. MEK/ERK and NFκB inhibitors were used to assess the regulatory T-cell induction pathways. pDCs and T-cell cultures were adoptively transferred before heterotopic heart transplantation to assess allograft survival. Results DBA/2J pDCs were more potent in inducing Foxp3 in B6 T cells than the reverse combination, correlating with survival of the kidney allografts. Foxp3 induction by pDCs in vitro was dependent on pDC viability, immaturity, and class II MHC mismatch and blocked by MEK/ERK and NFκB inhibition. pDC-induced Foxp3 T cells suppressed proliferation of B6 T cells in vitro, and adoptive transfer into B6 recipients 2 weeks before heterotopic DBA/2J heart transplantation resulted in prolonged allograft survival. Conclusions These data suggest that pDC-induced regulatory T cells are dependent on downstream signaling effects and on strain-dependent, MHC class II disparity with naive T cells, which may explain organ- and strain-specific differences in spontaneous tolerance.

Intragraft events thought to be relevant to the development of tolerance are here subjected to a comprehensive mechanistic study during long-term spontaneous tolerance that occurs in C57BL/6 mice that receive life sustaining DBA/2 kidneys. These allografts rapidly develop periarterial Treg-rich organized lymphoid structures (TOLS) that form in response to class II but not to class I MHC disparity and form independently of lymphotoxin α and lymphotoxin β receptor pathways. TOLS form in situ in the absence of lymph nodes, spleen, and thymus. Distinctive transcript patterns are maintained over time in TOLS including transcripts associated with Treg differentiation, T cell checkpoint signaling, and Th2 differentiation. Pathway transcripts related to inflammation are expressed in early stages of accepted grafts but diminish with time, while B cell transcripts increase. Intragraft transcript patterns at one week posttransplant distinguish those from kidneys destined to be rejected, that is, C57BL/6 allografts into DBA/2 recipients, from those that will be accepted. In contrast to inflammatory tertiary lymphoid organs (iTLOs) that form in response to chronic viral infection and transgenic Lta expression, TOLS lack high endothelial venules and germinal centers. TOLS represent a novel, pathogenetically important type of TLO that are in situ markers of regulatory tolerance.

Background Almost 9%of deceased donor livers are discarded as marginal donor livers (MDL) due to concern of severe ischemia reperfusion injury (IRI). Emerging data supports ferroptosis (iron regulated hepatocellular death) as an IRI driver, however lack of robust preclinical model limits therapeutic testing. In this manuscript we describe the development of a novel rigorous internal control system utilizing normothermic perfusion of split livers to test ferroptosis regulators modulating IRI. Methods Upon institutional approval, split human MDLs were placed on our normothermic perfusion machine, Perfusion Regulated Organ Therapeutics with Enhanced Controlled Testing (PROTECT), pumping arterial and portal blood. Experiment 1 compared right (UR) and left (UL) lobes to validate PROTECT. Experiment 2 assessed ferroptosis regulator Deferoxamine in Deferoxamine Agent Treated (DMAT) vs. No Agent Internal Control (NAIC) lobes. Liver serology, histology, and ferroptosis genes were assessed. Results Successful MDL perfusion validated PROTECT with no ALT or AST difference between UR and UL (∆ALT UR: 235, ∆ALT UL: 212; ∆AST UR: 576, ∆AST UL: 389). Liver injury markers increased in NAIC vs. DMAT (∆ALT NAIC: 586, ∆ALT DMAT: -405; ∆AST NAIC: 617, ∆AST DMAT: -380). UR and UL had similar expression of ferroptosis regulators RPL8,HO-1 and HIFα. Significantly decreased intrahepatic iron (p = .038), HO-1 and HIFα in DMAT (HO-1 NAIC: 6.93, HO-1 DMAT: 2.74; HIFαNAIC: 8.67, HIFαDMAT: 2.60)and no hepatocellular necrosis or immunohistochemical staining (Ki67/Cytokeratin-7) differences were noted. Conclusion PROTECT demonstrates the therapeutic utility of a novel normothermic perfusion split liver system for drug discovery and rapid translatability of therapeutics, driving a paradigm change in organ recovery and transplant medicine. Our study using human livers, provides preliminary proof of concept for the novel role of ferroptosis regulators in driving IRI.

Background Inflammation plays an important role in atherosclerosis. The neutrophil-to-lymphocyte ratio (NLR) may serve as a clinically useful biomarker of inflammation and cardiovascular (CV) disease, although this relationship has not been studied in people with type 2 diabetes (T2D). Purpose This post hoc analysis investigated the relationship between NLRs and CV outcomes in T2D CV outcomes trials for two formulations of semaglutide, a glucagon-like peptide-1 receptor agonist. Methods In pooled analyses of the SUSTAIN 6 and PIONEER 6 trials, 6,480 patients with T2D at high CV risk received placebo or semaglutide (once-weekly subcutaneously up to 1.0 mg, or once-daily orally up to 14 mg). NLRs were calculated from complete blood counts at randomisation. Adjudicated outcomes included 3-point major adverse CV events (MACE: composite of CV death, non-fatal myocardial infarction [MI] or non-fatal stroke; primary outcome), expanded MACE, CV death and all-cause death (secondary outcomes). Patient characteristics and CV outcomes were analysed according to baseline NLR tertiles using pooled trial data. Estimation of hazard ratios (HRs) for all outcomes across NLR tertiles used a Cox proportional hazards model. A Cox spline regression with continuous NLR as covariate adjusted for treatment was used to predict the event rate of first MACE at 2 years. Results Overall, baseline NLR was recorded in 6,364 patients. Mean baseline NLRs were 1.5, 2.2 and 3.6 in the low, middle and high tertiles, respectively. Patients in the high NLR tertile were older (66.6 years), more likely to be male (70.0%), had longer duration of diabetes (15.3 years), higher body weight (93.3 kg), lower diastolic blood pressure (75.5 mmHg) and estimated glomerular filtration rate (70.4 mL/min/1.73m2) vs those in the lower NLR tertiles (all p5 increased the risk of first MACE substantially (Figure 2). Further analysis of NLR and MACE by tertiles showed a more pronounced association in patients without prior MI and/or stroke (HR [95% CI]: 1.64 [1.07; 2.56]; p=0.03 and 2.09 [1.38; 3.21]; p=0.0006 in the middle and high tertiles, respectively, vs the low tertile). Conclusion Baseline NLR predicts MACE, CV death and all-cause death in patients with T2D and high CV risk. NLR is readily accessible from routinely obtained and inexpensive blood counts; it could offer a convenient, clinically useful inflammatory biomarker for CV risk prediction in this population. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novo Nordisk A/S Figure 1Figure 2

Heart transplantation is the optimal therapy for patients with end-stage heart disease, but its long-term outcome remains inadequate. Recent studies have highlighted the importance of the melanocortin receptors (MCRs) in inflammation, but how MCRs regulate the balance between alloreactive T cells and Tregs, and whether they impact chronic heart transplant rejection, is unknown. Here, we found that Tregs express MC2R, and MC2R expression was highest among all MCRs by Tregs. Our data indicate that adrenocorticotropic hormone (ACTH), the sole ligand for MC2R, promoted the formation of Tregs by increasing the expression of IL-2Rα (CD25) in CD4+ T cells and activation of STAT5 in CD4+CD25+ T cells. ACTH treatment also improved the survival of heart allografts and increased the formation of Tregs in CD28KO mice. ACTH treatment synergized with the tolerogenic effect of CTLA-4-Ig, resulting in long-term survival of heart allografts and an increase in intragraft Tregs. ACTH administration also demonstrated higher prolongation of heart allograft survival in transgenic mouse recipients with both complete KO and conditional KO of PI3Kγ in T cells. Finally, ACTH treatment reduced chronic rejection markedly. These data demonstrate that ACTH treatment improved heart transplant outcomes, and this effect correlated with an increase in Tregs.

Summary Background Donor lung use for transplantation is the lowest among solid organ tranplants because of several complex and multifactorial reasons; one area that could have a substantial role is the limited capabilities of cold ischaemic storage. The aim of the EXPAND trial was to evaluate the efficacy of normothermic portable Organ Care System (OCS) Lung perfusion and ventilation on donor lung use from extended-criteria donors and donors after circulatory death, which are rarely used. Methods In this single-arm, pivotal trial done in eight institutions across the USA, Germany, and Belgium, lungs from extended-criteria donors were included if fulfilling one or more of the following criteria: a ratio of partial pressure of arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (FiO2) in the donor lung of 300 mm Hg or less; expected ischaemic time longer than 6 h; donor age 55 years or older; or lungs from donors after circulatory death that were recruited and assessed using OCS Lung. Lungs were transplanted if they showed stability of OCS Lung variables, PaO2:FiO2 was more than 300 mm Hg, and they were accepted by the transplanting surgeon. Patients were adult bilateral lung transplant recipients. The primary efficacy endpoint was a composite of patient survival at day 30 post-transplant and absence of The International Society for Heart & Lung Tranplantation primary-graft dysfunction grade 3 (PGD3) within 72 h post-transplantation, with a prespecified objective performance goal of 65%. The primary analysis population was all transplanted recipients. This trial is registered with ClinicalTrials.gov, number NCT01963780, and is now complete. Findings Between Jan 23, 2014, and Oct 23, 2016, 93 lung pairs were perfused, ventilated, and assessed on the OCS Lung. 12 lungs did not meet OCS transplantation criteria so 81 lungs were suitable for transplantation. Two lungs were excluded for logistical reasons, hence 79 (87%) of eligible lungs were transplanted. The primary endpoint was achieved in 43 (54%) of 79 patients and did not meet the objective performance goal. 35 (44%) of 79 patients had PGD3 within the initial 72 h. 78 (99%) of 79 patients had survived at 30 days post-transplant. The mean number of lung graft-related serious adverse events (respiratory failure and major pulmonary-related infection) was 0·3 events per patient (SD 0·5). Interpretation Despite missing the objective primary endpoint, the portable OCS Lung resulted in 87% donor lung use for transplantation with excellent clinical outcomes. Many lungs declined by other transplant centres were successfully transplanted using this new technology, which implies its use has the potential to increase the number of lung transplants performed worldwide. Whether similar outcomes could be obtained if these lungs were preserved on ice is unknown and remains an area for future research. Funding TransMedics Inc.

PURPOSE OF REVIEW: There is great variability in how different organ allografts respond to the same tolerance induction protocol. Well known examples of this phenomenon include the protolerogenic nature of kidney and liver allografts as opposed to the tolerance-resistance of heart and lung allografts. This suggests there are organ-specific factors which differentially drive the immune response following transplantation. RECENT FINDINGS: The specific cells or cell products that make one organ allograft more likely to be accepted off immunosuppression than another are largely unknown. However, new insights have been made in this area recently. SUMMARY: The current review will focus on the organ-intrinsic factors that contribute to the organ-specific differences observed in tolerance induction with a view to developing therapeutic strategies to better prevent organ rejection and promote tolerance induction of all organs.

Cardiac allograft vasculopathy (CAV) is a pathologic immune-mediated remodelling of the vasculature in transplanted hearts and, by impairing perfusion, is the major cause of late graft loss. Although best understood following cardiac transplantation, similar forms of allograft vasculopathy occur in other vascularized organ grafts and some features of CAV may be shared with other immune-mediated vasculopathies. Here, we describe the incidence and diagnosis, the nature of the vascular remodelling, immune and non-immune contributions to pathogenesis, current therapies, and future areas of research in CAV.

Introduction/Objective Escherichia coli is an especially dangerous health threat to humans when it develops multi- drug resistance. Decreased sensitivity to quinolone and beta-lactam antibiotics has been documented with antibiotic use in health care and agriculture. Migrating birds interact with wastewater treatment plants colonized with drug resistant Escherichia coli potentially transfer to other wildlife. Anchorage is home to 1500 moose and migrating geese providing a potential risk for Escherichia coli colonization. Because fecal contamination is abundant in Anchorage’s greenspaces, we evaluated the presence of Escherichia coli and antibiotic resistance in urban moose. Methods/Case Report Between 2018-2020, moose fecal samples were ground collected during the spring thaw within Anchorage Alaska, placed in transport media and cultured to MacConkey agar. Lactose fermenting colonies were further identified as Escherichia coli by biochemical testing and sub-cultured to sheep blood agar for antimicrobial evaluation. Using the Kirby Bauer method, antimicrobial sensitivity for cefpodoxime, ampicillin, piperacillin/tazobactam, gentamycin and ciprofloxacin were performed and interpreted using Clinical Laboratory Standards Institute guidelines Results (if a Case Study enter NA) A total of 150 samples were analyzed with 39% positive for Escherichia coli: fourteen in 2018, seventeen in 2019, and twenty-eight in 2020. In 2018, resistance was significant in ampicillin (43%), limited in piperacillin/tazobactam and cefpodoxime (14%). In 2019 found a 40% overall increase of antimicrobial resistance and by 2020 Escherichia coli isolates were resistant in all antibiotics tested: cefpodoxime (100%), ampicillin (96%), piperacillin/tazobactam (43%), gentamycin (35%), and ciprofloxacin (32%). Conclusion Measuring resistant patterns of Escherichia coli in wildlife is essential to understand the risk of colonization. Transmission of infectious agents can occur due to environmental exposure and Anchorage has expanded greenspaces resulting in increased human interaction with urban wildlife. In 2018, we found antimicrobial resistance only to ampicillin but subsequent years discovered decrease sensitivity and by 2020 Escherichia coli isolates resistant to one or more antibiotics including beta-lactams, quinolones, and aminoglycosides. The risk of zoonosis of multi-drug resistant Escherichia coli, especially in our housing insecure, has a significant impact for patient outcome.

T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonality, specificity, and function are incompletely defined. Here we used T cell receptor β chain (TCRB) sequencing to study the T cell repertoire in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in four cases of CAV and compared it to the immunoglobulin heavy chain variable region (IGHV) repertoire from the same samples. High-dimensional flow cytometry coupled with single-cell PCR was also used to define the T cell phenotype. Extensive overlap was observed between intragraft and blood TCRBs in all cases, a finding supported by robust quantitative diversity metrics. In contrast, blood and graft IGHV repertoires from the same samples showed minimal overlap. Coronary infiltrates included CD4+ and CD8+ memory T cells expressing inflammatory (IFNγ, TNFα) and profibrotic (TGFβ) cytokines. These were distinguishable from the peripheral blood based on memory, activation, and tissue residency markers (CD45RO, CTLA-4, and CD69). Importantly, high-frequency rearrangements were traced back to endomyocardial biopsies (2-6 years prior). Comparison with four HLA-mismatched blood donors revealed a repertoire of shared TCRBs, including a subset of recently described cross-reactive sequences. These findings provide supportive evidence for an active local intragraft bystander T cell response in late-stage CAV.

In swine and nonhuman primates, kidney allografts can induce tolerance of heart allografts, leading to their long-term, immunosuppression-free survival. We refer to this phenomenon as kidney-induced cardiac allograft tolerance (KICAT). In this study, we have developed a murine model for KICAT to determine the underlining cellular/molecular mechanisms. Here, we show that spontaneously accepted DBA/2J kidneys in C57BL/6 recipients induce systemic tolerance that results in the long-term acceptance of DBA/2J heart allografts but not third-party cardiac allografts. The state of systemic tolerance of hearts was established 2 weeks after transplantation of the kidney, after which time, the kidney allograft is no longer required. Depletion of Foxp3+ T cells from these mice precipitated rejection of the heart allografts, indicating that KICAT is dependent on Treg function. Acceptance of kidney allografts and cotransplanted heart allografts did not require the thymus. In conclusion, these data show that kidney allografts induce systemic, donor-specific tolerance of cardiac allografts via Foxp3 cells, and that tolerance is independent of the thymus and continued presence of the kidney allograft. This experimental system should promote increased understanding of the tolerogenic mechanisms of the kidney., Accepted DBA/2J kidney allografts can confer acceptance of a co-transplanted DBA/2 heart allograft, which would be rejected when transplanted in the absence of the kidney graft.

The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5-6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed.

Cardiac xenotransplantation has recently taken an important step towards clinical reality. In anticipation of the "first-in-human" heart xenotransplantation trial, we propose a set of patient characteristics that define potential candidates. Our premise is that, to be ethically justified, the risks posed by current state-of-the-art options must outweigh the anticipated risks of a pioneering xenotransplant procedure. Suitable candidates include patients who are at high immunologic risk because of sensitization to alloantigens, including those who have exhibited early onset or accelerated cardiac allograft vasculopathy. In addition, patients should be considered (1) for whom mechanical circulatory support would be prohibitively risky due to a hypercoagulable state, a contraindication to anticoagulation, or restrictive physiology; (2) with severe biventricular dysfunction predicting unsuccessful univentricular left heart support; and (3) adults with complex congenital heart disease. In conclusion, because the published preclinical benchmark for clinical translation of heart xenotransplantation appears within reach, carefully and deliberately defining appropriate trial participants is timely as the basis for ethical clinical trial design.