Donor-derived regulatory dendritic cell infusion modulates effector CD8+ T cell and NK cell responses after liver transplantation.

Immune cell-based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor liver transplant (LDLT) recipients up to 12 months (M) after transplant. Thirteen patients were given a single infusion of donor-derived DCreg 1 week before transplant (STUDY) and were compared with 40 propensity-matched standard-of-care (SOC) patients. Donor-derived DCreg infusion was well tolerated in all STUDY patients. There were no differences in postoperative complications or biopsy-confirmed acute rejection compared with SOC patients up to 12M. DCreg administration was associated with lower frequencies of effector T-bet+Eomes+CD8+ T cells and CD16bright natural killer (NK) cells and an increase in putative tolerogenic CD141+CD163+ DCs compared with SOC at 12M. Antidonor proliferative capacity of interferon-γ+ (IFN-γ+) CD4+ and CD8+ T cells was lower compared with antithird party responses in STUDY participants, but not in SOC patients, at 12M. In addition, lower circulating concentrations of interleukin-12p40 (IL-12p40), IFN-γ, and CXCL10 were detected in STUDY participants compared with SOC patients at 12M. Analysis of 12M allograft biopsies revealed lower frequencies of graft-infiltrating CD8+ T cells, as well as attenuation of cytolytic TH1 effector genes and pathways among intragraft CD8+ T cells and NK cells, in DCreg-infused patients. These reductions may be conducive to reduced dependence on immunosuppressive drug therapy or immunosuppression withdrawal.

Transcriptomic Profiling Identifies Ferroptosis-Related Gene Signatures in Ischemic Muscle Satellite Cells Affected by Peripheral Artery Disease-Brief Report.

BACKGROUND: We hypothesized that transcriptomic profiling of muscle satellite cells in peripheral artery disease (PAD) would identify damage-related pathways contributing to skeletal muscle myopathy. We identified a potential role for ferroptosis-a form of programmed lytic cell death by iron-mediated lipid peroxidation-as one such pathway. Ferroptosis promotes myopathy in ischemic cardiac muscle but has an unknown role in PAD. METHODS: Muscle satellite cells from donors with PAD were obtained during surgery. cDNA libraries were processed for single-cell RNA sequencing using the 10X Genomics platform. Protein expression was confirmed based on pathways inferred by transcriptomic analysis. RESULTS: Unsupervised cluster analysis of over 25 000 cells aggregated from 8 donor samples yielded distinct cell populations grouped by a shared unique transcriptional fingerprint. Quiescent cells were diminished in ischemic muscle while myofibroblasts and apoptotic cells were prominent. Differential gene expression demonstrated a surprising increase in genes associated with iron transport and oxidative stress and a decrease in GPX4 (glutathione peroxidase 4) in ischemic PAD-derived cells. Release of the danger signal HMGB1 (high mobility group box-1) correlated with ferroptotic markers including surface transferrin receptor and were higher in ischemia. Furthermore, lipid peroxidation in muscle satellite cells was modulated by ferrostatin, a ferroptosis inhibitor. Histology confirmed iron deposition and lipofuscin, an inducer of ferroptosis in PAD-affected muscle. CONCLUSIONS: This report presents a novel finding that genes known to be involved in ferroptosis are differentially expressed in human skeletal muscle affected by PAD. Targeting ferroptosis may be a novel therapeutic strategy to reduce PAD myopathy.

Carbonyls and Aerosol Mass Generation from Vaping Nicotine Salt Solutions Using Fourth- and Third-Generation E-Cigarette Devices: Effects of Coil Resistance, Coil Age, and Coil Metal Material.

Aerosol formation and production yields from 11 carbonyls (carbonyl concentration per aerosol mass unit) were investigated (1) from a fourth-generation (4th gen) e-cigarette device at different coil resistances and coil age (0-5000 puffs) using unflavored e-liquid with 2% benzoic acid nicotine salt, (2) between a sub-ohm third-generation (3rd gen) tank mod at 0.12 Ω and a 4th gen pod at 1.2 Ω using e-liquid with nicotine salt, together with nicotine yield, and (3) from 3rd gen coils of different metals (stainless steel, kanthal, nichrome) using e-liquid with freebase nicotine. Coil resistance had an inverse relationship with coil temperature, and coil temperature was directly proportional to aerosol mass formation. Trends in carbonyl yields depended on carbonyl formation mechanisms. Carbonyls produced primarily from thermal degradation chemistry (e.g., formaldehyde, acetaldehyde, acrolein, propionaldehyde) increased per aerosol mass with higher coil resistances, despite lower coil temperature. Carbonyls produced primarily from chemistry initiated by reactive oxygen species (ROS) (e.g., hydroxyacetone, dihydroxyacetone, methylglyoxal, glycolaldehyde, lactaldehyde) showed the opposite trend. Coil age did not alter coil temperature nor aerosol mass formation but had a significant effect on carbonyl formation. Thermal carbonyls were formed optimally at 500 puffs in our study and then declined to a baseline, whereas ROS-derived carbonyls showed a slow rise to a maximum trend with coil aging. The 3rd gen versus 4th gen device comparison mirrored the trends in coil resistance. Nicotine yields per aerosol mass were consistent between 3rd and 4th gen devices. Coil material did not significantly alter aerosol formation nor carbonyl yield when adjusted for wattage. This work shows that sub-ohm coils may not necessarily produce higher carbonyl yields even when they produce more aerosol mass. Furthermore, carbonyl formation is dynamic and not generalizable during the coil's lifetime. Finally, studies that compare data across different e-cigarette devices, coil age, and coil anatomy should account for the aerosol chemistry trends that depend on these parameters.

The role of eye banking with cell-based therapies.

PURPOSE OF REVIEW: Cell-based therapies are an exciting new frontier in managing corneal diseases. The introduction of these novel therapies may provide new alternatives to corneal transplantation and decrease the dependence on donor corneal tissue. These changes have the potential to significantly impact eye banking in the future. RECENT FINDINGS: The current article reviews current research involving cell-based therapy for treating corneal disorders, including cultivated limbal stem cell transplantation, limbal mesenchymal stem cells for stromal regeneration, and the use of human-cultivated endothelial cells. We will look at barriers to the development and implementation of these therapies. SUMMARY: As corneal surgery expands to include cell-based therapies; eye banks will need to redefine their role to support the everchanging landscape of corneal surgery and the decreased demand for corneal donor tissue.

Second-Order Kinetic Rate Coefficients for the Aqueous-Phase Sulfate Radical (SO4•-) Oxidation of Some Atmospherically Relevant Organic Compounds.

The sulfate anion radical (SO4•-) is a reactive oxidant formed in the autoxidation chain of sulfur dioxide, among other sources. Recently, new formation pathways toward SO4•- and other reactive sulfur species have been reported. This work investigated the second-order rate coefficients for the aqueous SO4•- oxidation of the following important organic aerosol compounds (kSO4): 2-methyltetrol, 2-methyl-1,2,3-trihydroxy-4-sulfate, 2-methyl-1,2-dihydroxy-3-sulfate, 1,2-dihydroxyisoprene, 2-methyl-2,3-dihydroxy-1,4-dinitrate, 2-methyl-1,2,4-trihydroxy-3-nitrate, 2-methylglyceric acid, 2-methylglycerate, lactic acid, lactate, pyruvic acid, pyruvate. The rate coefficients of the unknowns were determined against that of a reference in pure water in a temperature range of 298-322 K. The decays of each reagent were measured with nuclear magnetic resonance (NMR) and high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS). Incorporating additional SO4•- reactions into models may aid in the understanding of organosulfate formation, radical propagation, and aerosol mass sinks.

Sulfur radical formation from the tropospheric irradiation of aqueous sulfate aerosols.

The sulfate anion radical (SO4•-) is known to be formed in the autoxidation chain of sulfur dioxide and from minor reactions when sulfate or bisulfate ions are activated by OH radicals, NO3 radicals, or iron. Here, we report a source of SO4•-, from the irradiation of the liquid water of sulfate-containing organic aerosol particles under natural sunlight and laboratory UV radiation. Irradiation of aqueous sulfate mixed with a variety of atmospherically relevant organic compounds degrades the organics well within the typical lifetime of aerosols in the atmosphere. Products of the SO4•- + organic reaction include surface-active organosulfates and small organic acids, alongside other products. Scavenging and deoxygenated experiments indicate that SO4•- radicals, instead of OH, drive the reaction. Ion substitution experiments confirm that sulfate ions are necessary for organic reactivity, while the cation identity is of low importance. The reaction proceeds at pH 1-6, implicating both bisulfate and sulfate in the formation of photoinduced SO4•-. Certain aromatic species may further accelerate the reaction through synergy. This reaction may impact our understanding of atmospheric sulfur reactions, aerosol properties, and organic aerosol lifetimes when inserted into aqueous chemistry model mechanisms.

Intravascular ultrasound evaluation during iliofemoral venous stenting is associated with improved midterm patency outcomes.

OBJECTIVE: Intravascular ultrasound (IVUS) examination is increasingly used in the treatment of iliofemoral venous disease and provides more sensitive and specific detection of stenotic lesions when compared with traditional multiplanar venography alone. Correlations with deep venous stent patency, however, have not yet been investigated. The objective of the study was to evaluate the impact of the use of IVUS examination in addition to multiplanar venography on iliofemoral venous patency. METHODS: Consecutive patients who underwent stenting for symptomatic thrombotic or nonthrombotic iliofemoral venous lesions (NIVLs) between 2014 and 2020 at a single institution were identified and divided into two groups based on whether IVUS examination was used before stent deployment in addition to multiplanar venography compared with venography alone. A retrospective review of demographic, operative, and follow-up data was performed. Thirty-day and 2-year stent patency were measured as primary end points. χ2 analysis, logistic regression models, and Kaplan-Meier survival analysis were used to determine outcomes. Technical details and outcomes were additionally examined among patients treated for acute deep venous thrombosis, post-thrombotic syndrome, or NIVLs separately on subgroup analysis. RESULTS: We identified 150 patients (173 limbs, 23 bilateral) who underwent iliofemoral stenting during the study period at our institution (mean age: 48.8 ± 16.8 years, 61% female). Adjunctive IVUS utilization before stent deployment was reported in 69 of 173 (39.9%) treated limbs. IVUS examination was more likely to be used in patients who underwent stenting for NIVLs compared with thrombotic disease (41.0% vs 11.2%, P < .01). There was no difference in the number of stents deployed between IVUS and non-IVUS cohorts. However, IVUS examination was associated with the increased total length of the stent deployed (126 ± 56 vs 112 ± 48 mm, P = .04) and a higher rate of infrainguinal stent extension (17.4% vs 6.7%, P = .03). In addition, mean stent diameter was significantly higher when IVUS examination was performed before stent placement (16.3 ± 3.7 vs 15.2 ± 1.9 mm, P < .01). Both 30-day (98.5% vs 89.4%, P = .02) and 2-year (90.3% vs 78.7%, P = .03) primary patency were significantly higher in the IVUS cohort. Adjunctive IVUS use was found to significantly protect against stent reintervention at 2 years on adjusted Cox regression analysis (hazard ratio: 0.22, 95% confidence interval: 0.07-0.71, P = .01). CONCLUSIONS: Adjunctive IVUS utilization is associated with differences in stent diameter and length selections as well as landing segments in the treatment of thrombotic and nonthrombotic iliofemoral venous disease. IVUS examination before stent deployment significantly protects against 30-day and 2-year stent reintervention when compared with the use of multiplanar venography alone. These data provide stronger evidence for routine IVUS use in addition to venography before iliofemoral venous stenting.

Vaping Aerosols from Vitamin E Acetate and Tetrahydrocannabinol Oil: Chemistry and Composition.

The popularity of vaping cannabis products has increased sharply in recent years. In 2019, a sudden onset of electronic cigarette/vaping-associated lung injury (EVALI) was reported, leading to thousands of cases of lung illness and dozens of deaths due to the vaping of tetrahydrocannabinol (THC)-containing e-liquids that were obtained on the black market. A potential cause of EVALI has been hypothesized due to the illicit use of vitamin E acetate (VEA) in cannabis vape cartridges. However, the chemistry that modifies VEA and THC oil, to potentially produce toxic byproducts, is not well understood under different scenarios of use. In this work, we quantified carbonyls, organic acids, cannabinoids, and terpenes in the vaping aerosol of pure VEA, purified THC oil, and an equal volume mixture of VEA and THC oil at various coil temperatures (100-300 °C). It was found under the conditions of our study that degradation of VEA and cannabinoids, including Δ9-THC and cannabigerol (CBG), occurred via radical oxidation and direct thermal decomposition pathways. Evidence of terpene degradation was also observed. The bond cleavage of aliphatic side chains in both VEA and cannabinoids formed a variety of smaller carbonyls. Oxidation at the ring positions of cannabinoids formed various functionalized products. We show that THC oil has a stronger tendency to aerosolize and degrade compared to VEA at a given temperature. The addition of VEA to the e-liquid nonlinearly suppressed the formation of vape aerosol compared to THC oil. At the same time, toxic carbonyls including formaldehyde, 4-methylpentanal, glyoxal, or diacetyl and its isomers were highly enhanced in VEA e-liquid when normalized to particle mass.

Symptomatic human immunodeficiency virus infection is associated with advanced presentation and perioperative mortality in patients undergoing surgery for peripheral arterial disease.

OBJECTIVE: Prior studies have demonstrated an increased risk of developing cardiovascular and peripheral arterial disease (PAD) in patients with human immunodeficiency virus (HIV). However, the effect of chronic HIV infection in patients with preexisting PAD and requiring vascular intervention is unclear. In the present study, we assessed the differences in clinical presentation and perioperative outcomes for patients with PAD who had undergone revascularization or amputation with and without HIV infection. METHODS: International Classification of Diseases, 9th and 10th Revisions, Clinical Modification, codes were used to identify patients with a prior diagnosis of PAD who had undergone lower extremity revascularization or amputation in the National Inpatient Sample (2003-2017). From this group, the patients were divided for analysis into those with and without HIV infection. Of the patients with HIV infection (PWHs), we identified additional subsets of patients: those with any prior or current diagnosis of an HIV-related illness, including acquired immunodeficiency syndrome, designated as symptomatic HIV, and those without such a diagnosis, designated as asymptomatic HIV infection. Propensity score matching was performed to create matched cohorts. Population-based comparative analyses were performed of the clinical characteristics of the HIV-infected and HIV-uninfected groups. Univariate and multivariate logistic regression analyses of the perioperative in-hospital outcomes were performed on the matched cohorts. RESULTS: A total of 224,912 patients aged 18 to 85 years were identified who had been admitted with an established diagnosis of PAD and had undergone a lower extremity procedure. Of these patients, 1264 (0.56%) also had a diagnosis of HIV infection. Symptomatic PWHs were more likely to present with critical limb ischemia than were the HIV-uninfected patients or asymptomatic PWHs (66.2% vs 46.3% and 43.6%; P < .01). However, both asymptomatic and symptomatic PWHs were more likely to have required minor (7.5% and 6.7% vs 2.6%; P < .01) and major (12.9% and 27.4% vs 7.0%; P < .01) amputations than were matched HIV-uninfected controls. Although adjusted multivariate logistic regression analysis demonstrated symptomatic HIV infection to be a significant, independent predictor of in-hospital mortality (odds ratio, 2.46; 95% confidence interval, 1.37-4.40; P = .003), the perioperative mortality for the asymptomatic PWH was comparable to that of matched HIV-uninfected controls. CONCLUSIONS: Symptomatic PWHs, including patients living with acquired immunodeficiency syndrome, who had required a PAD-related procedure had presented with more advanced vascular disease and were most at risk of early perioperative mortality. However, the presentation and mortality between asymptomatic PWHs with well-controlled disease and HIV-uninfected patients were comparable. All PWHs with PAD were more likely to undergo lower extremity amputations than were HIV-uninfected matched controls. Asymptomatic, well-controlled HIV infection should not be a contraindication to elective PAD-related procedures because the mortality was similar to that of HIV-uninfected controls. However, the limb salvage rates might be lower for all PWHs with PAD, regardless of HIV disease severity. Taken together, these findings can improve perioperative risk stratification and surgical management of PAD in this high-risk population.

Hospital-based delays to revascularization increase risk of postoperative mortality and short bowel syndrome in acute mesenteric ischemia.

OBJECTIVE: Acute mesenteric ischemia (AMI) is a surgical emergency for which delays in treatment have been closely associated with high morbidity and mortality. Although the duration of ischemia as a determinant of outcomes for AMI is well known, the objective of this study was to identify hospital-based determinants of delayed revascularization and their effects on postoperative morbidity and mortality in AMI. METHODS: All patients who underwent any surgery for AMI from a multi-center hospital system between 2010 and 2020 were divided into two groups based on timeliness of mesenteric revascularization after presentation. Early revascularization (ER) was defined as having both vascular consultation ≤12 hours of presentation and vascular surgery performed at the patient's initial operation. Delayed revascularization (DR) was defined as having either delays to vascular consultation or vascular surgery. A retrospective review of demographic and postoperative data was performed. The effect of DR on major postoperative outcomes, including 30-day and 2-year mortality, total length of bowel resection, and development of short bowel syndrome, were analyzed. Effects of delayed vascular consultation alone, delayed vascular surgery alone, no revascularization during admission, and admitting service on outcomes were also examined on subgroup analyses. RESULTS: A total of 212 patients were analyzed. Ninety-nine patients received ER, whereas the remaining 113 patients experienced a DR after hospital presentation. Among the DR group, 55 patients (25.9%) had delayed vascular consultation, whereas vascular surgery was deferred until after the initial operation in 37 patients (17.4%). Fifty-one patients (24.0%) were never revascularized during admission. DR was a significant predictor of 30-day (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.4-4.9; P = .03) and 2-year mortality (hazard ratio, 1.55, 95% CI, 1.0-2.3; P = .04). DR was also independently associated with increased bowel resection length (OR, 7.47; P < .01) and postoperative short bowel syndrome (OR, 2.4; P = .03) on multivariate analyses. When examined separately on subgroup analysis, both delayed vascular consultation (OR, 3.38; P = .03) and vascular surgery (OR, 4.31; P < .01) independently increased risk of 30-day mortality. Hospital discharge after AMI without mesenteric revascularization was associated with increased risk of short bowel syndrome (OR, 2.94; P < .01) and late mortality (hazard ratio, 1.60; P = .04). CONCLUSIONS: Delayed vascular consultation and vascular surgery are both significant hospital-based determinants of postoperative mortality and short bowel syndrome in patients with AMI. Timing-based management protocols that emphasize routine evaluation by a vascular surgeon and early, definitive mesenteric revascularization should be established and widely adopted for all patients with clinically suspected AMI at presentation.

Contemporary management of acute and chronic mesenteric ischemia: 10-year experience from a multihospital healthcare system.

OBJECTIVE: Endovascular and hybrid methods have been increasingly used to treat mesenteric ischemia. However, the long-term outcomes and risk of symptom recurrence remain unknown. The objective of the present study was to define the predictors of postoperative morbidity, mortality, and patency loss for acute mesenteric ischemia (AMI) and chronic mesenteric ischemia (CMI). METHODS: The inpatient and follow-up records for all patients who had undergone revascularization for AMI and CMI from 2010 to 2020 at a multicenter hospital system were reviewed. Patency and mortality were evaluated with Cox regression, visualized with Kaplan-Meier curves, and compared using log-rank testing. Patency was further evaluated using Fine-Gray regression with death as a competing risk. The postoperative major adverse events (MAE) and 30-day mortality were evaluated with logistic regression. RESULTS: A total of 407 patients were included, 148 with AMI and 259 with CMI. For the AMI group, the 30-day mortality was 31%. Open surgery was associated with lower rates of bowel resection (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.13-0.61). The etiology of AMI also did not change the outcomes (OR, 1.30; 95% CI, 0.77-2.19). Adjusted analyses indicated that a history of diabetes (OR, 2.77; 95% CI, 1.37-5.61) and sepsis on presentation (OR, 2.32; 95% CI, 1.18-4.58) were independently associated with an increased risk of 30-day MAE. In the CMI group, open surgery and chronic kidney disease were associated with a higher incidence of MAE (OR, 3.03; 95% CI, 1.14-8.05; OR, 2.37; 95% CI, 1.31-4.31). In contrast, chronic kidney disease (OR, 3.02; 95% CI, 1.10-8.37) and inpatient status before revascularization (OR, 2.78; 95% CI, 1.01-7.61) were associated with increased 30-day mortality. For the CMI group, the endovascular cohort had experienced greater rates of symptom recurrence (29% vs 13%) with a faster onset (endovascular, 64 days; vs bypass, 338 days). CONCLUSIONS: AMI remains a morbid disease despite the evolving revascularization techniques. An open approach should remain the reference standard because it reduces the likelihood of bowel resection. For CMI, endovascular interventions have improved the postoperative morbidity but have also resulted in early symptom recurrence and reintervention. An endovascular-first approach should be the standard of care for CMI with close surveillance.

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection.

Liver allograft recipients are more likely to develop transplantation tolerance than those that receive other types of organ graft. Experimental studies suggest that immune cells and other non-parenchymal cells in the unique liver microenvironment play critical roles in promoting liver tolerogenicity. Of these, liver interstitial dendritic cells (DCs) are heterogeneous, innate immune cells that appear to play pivotal roles in the instigation, integration and regulation of inflammatory responses after liver transplantation. Interstitial liver DCs (recruited in situ or derived from circulating precursors) have been implicated in regulation of both ischemia/reperfusion injury (IRI) and anti-donor immunity. Thus, livers transplanted from mice constitutively lacking DCs into syngeneic, wild-type recipients, display increased tissue injury, indicating a protective role of liver-resident donor DCs against transplant IRI. Also, donor DC depletion before transplant prevents mouse spontaneous liver allograft tolerance across major histocompatibility complex (MHC) barriers. On the other hand, mouse liver graft-infiltrating host DCs that acquire donor MHC antigen via "cross-dressing", regulate anti-donor T cell reactivity in association with exhaustion of graft-infiltrating T cells and promote allograft tolerance. In an early phase clinical trial, infusion of donor-derived regulatory DCs (DCreg) before living donor liver transplantation can induce alterations in host T cell populations that may be conducive to attenuation of anti-donor immune reactivity. We discuss the role of DCs in regulation of warm and liver transplant IRI and the induction of liver allograft tolerance. We also address design of cell therapies using DCreg to reduce the immunosuppressive drug burden and promote clinical liver allograft tolerance.

Impact of e-Liquid Composition, Coil Temperature, and Puff Topography on the Aerosol Chemistry of Electronic Cigarettes.

E-cigarette aerosol is a complex mixture of gases and particles with a composition that is dependent on the e-liquid formulation, puffing regimen, and device operational parameters. This work investigated mainstream aerosols from a third generation device, as a function of coil temperature (315-510 °F, or 157-266 °C), puff duration (2-4 s), and the ratio of propylene glycol (PG) to vegetable glycerin (VG) in e-liquid (100:0-0:100). Targeted and untargeted analyses using liquid chromatography high-resolution mass spectrometry, gas chromatography, in situ chemical ionization mass spectrometry, and gravimetry were used for chemical characterizations. PG and VG were found to be the major constituents (>99%) in both phases of the aerosol. Most e-cigarette components were observed to be volatile or semivolatile under the conditions tested. PG was found almost entirely in the gas phase, while VG had a sizable particle component. Nicotine was only observed in the particle phase. The production of aerosol mass and carbonyl degradation products dramatically increased with higher coil temperature and puff duration, but decreased with increasing VG fraction in the e-liquid. An exception is acrolein, which increased with increasing VG. The formation of carbonyls was dominated by the heat-induced dehydration mechanism in the temperature range studied, yet radical reactions also played an important role. The findings from this study identified open questions regarding both pathways. The vaping process consumed PG significantly faster than VG under all tested conditions, suggesting that e-liquids become more enriched in VG and the exposure to acrolein significantly increases as vaping continues. It can be estimated that a 30:70 initial ratio of PG:VG in the e-liquid becomes almost entirely VG when 60-70% of e-liquid remains during the vaping process at 375 °F (191 °C). This work underscores the need for further research on the puffing lifecycle of e-cigarettes.

Current status of adult liver transplantation: utilization of living donor versus deceased donor graft.

PURPOSE OF REVIEW: This article will summarize prior and recent studies comparing outcomes between living donor and deceased donor liver transplantation (LT) in adults and provide a rationale and framework for expanding living donor liver transplantation (LDLT) in Western countries to address the growing critical organ shortage. RECENT FINDINGS: There is a growing body of evidence demonstrating superior survival outcomes in LDLT in addition to a multitude of other advantages including shorter cold ischemia times, opportunity for pretransplant medical optimization, and expansion of transplant eligibility. Additionally, these outcomes continue to improve with center volume and experience. SUMMARY: LDLT in adults emerged in response to an effective donor organ shortage created by the critical discrepancy between donor graft supply and demand. Overcoming this organ shortage and an increasing waitlist mortality requires a liver transplant framework that fully integrates LDLT into liver disease management although continuing to fully maximize deceased donor graft utilization at experience, capable centers. Optimizing both living and deceased donor graft utilization will drastically increase patients' access to LT.

Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients.

Regulatory dendritic cells (DCreg) promote transplant tolerance following their adoptive transfer in experimental animals. We investigated the feasibility, safety, fate, and impact on host T cells of donor monocyte-derived DCreg infused into prospective, living donor liver transplant patients, 7 days before transplantation. The DCreg expressed a tolerogenic gene transcriptional profile, high cell surface programed death ligand-1 (PD-L1):CD86 ratios, high IL-10/no IL-12 productivity and poor ability to stimulate allogeneic T cell proliferation. Target DCreg doses (range 2.5-10 × 106 cells/kg) were achieved in all but 1 of 15 recipients, with no infusion reactions. Following DCreg infusion, transiently elevated levels of donor HLA and immunoregulatory PD-L1, CD39, and CD73 were detected in circulating small extracellular vesicles. At the same time, flow and advanced image stream analysis revealed intact DCreg and "cross-dressing" of host DCs in blood and lymph nodes. PD-L1 co-localization with donor HLA was observed at higher levels than with recipient HLA. Between DCreg infusion and transplantation, T-bethi Eomeshi memory CD8+ T cells decreased, whereas regulatory (CD25hi CD127- Foxp3+ ): T-bethi Eomeshi CD8+ T cell ratios increased. Thus, donor-derived DCreg infusion may induce systemic changes in host antigen-presenting cells and T cells potentially conducive to modulated anti-donor immune reactivity at the time of transplant.

Systematic review of plasma/packed red blood cell ratio on survival in ruptured abdominal aortic aneurysms.

BACKGROUND: The ideal perioperative fluid resuscitation for patients with ruptured abdominal aortic aneurysms (rAAAs) is unknown. It has been shown in trauma studies that a higher ratio of plasma and platelets to packed red blood cells confers a mortality benefit. Controversy remains whether this is true also in the rAAA population. The objective of the present study was to investigate the benefit of a greater ratio of plasma/packed red blood cells in patients with rAAAs. METHODS: A health sciences librarian searched four electronic databases, including PubMed, Embase, Cochrane, and ClinicalTrials.gov, using concepts for the terms "fluid resuscitation," "survival," and "ruptured abdominal aortic aneurysm." Two reviewers independently screened the studies that were identified through the search strategy and read in full any study that was potentially relevant. Studies were included if they had compared the mortality of patients with rAAAs who had received a greater ratio of plasma to other component therapy with that of patients who had received a lower ratio. The risk of bias was assessed using the ROBINS-I (risk of bias in nonrandomized studies of interventions) validated tool, and evidence quality was rated using the GRADE (grades of recommendation assessment, development, and evaluation) profile. No data synthesis or meta-analysis was planned or performed, given the anticipated paucity of research on this topic and the high degree of heterogeneity of available studies. RESULTS: Our search identified seven observational studies for inclusion in the present review. Of these seven studies, three found an associated decrease in mortality with a greater ratio of plasma to packed red blood cells. The remaining four found no significant differences. The overall risk of bias was serious, and the evidence quality was very low. CONCLUSIONS: Overall, the findings from the available studies would suggest that for patients who have undergone open surgery for a rAAA, mortality tends to be decreased when the amount of plasma transfused perioperatively is similar to the amount of packed red blood cells. However, the included studies reported very low-quality evidence based solely on highly heterogeneous observational studies, and further research is warranted.

Detection and Monitoring of Regulatory Immune Cells Following Their Adoptive Transfer in Organ Transplantation.

Application of cell-based immunotherapy in organ transplantation to minimize the burden of immunosuppressive medication and promote allograft tolerance has expanded significantly over the past decade. Adoptively transferred regulatory immune cells prolong allograft survival and transplant tolerance in pre-clinical models. Many cell products are currently under investigation in early phase human clinical trials designed to assess feasibility and safety. Despite rapid advances in manufacturing practices, defining the appropriate protocol that will optimize in vivo conditions for tolerance induction remains a major challenge and depends heavily on understanding the fate, biodistribution, functional stability and longevity of the cell product after administration. This review focuses on in vivo detection and monitoring of various regulatory immune cell types administered for allograft tolerance induction in both pre-clinical animal models and early human clinical trials. We discuss the current status of various non-invasive methods for tracking regulatory cell products in the context of organ transplantation and implications for enhanced understanding of the therapeutic potential of cell-based therapy in the broad context of control of immune-mediated inflammatory disorders.

Eyelid and orbital trauma for the primary care physician.

Patients who experience trauma to the eyelid or the orbit may present to their primary care providers or directly to the emergency room for evaluation of their injuries. These patients will often be in pain and may have bleeding around the eye, which can make evaluation of these patients difficult. Many traumatic injuries to the eye require quick and immediate intervention. In this article, we will review the background, anatomy, exam and management of some of the most common eye traumas including eyelid lacerations, orbital hemorrhages, intraorbital foreign bodies, and orbital fractures.

Tolerance studies in liver transplantation: are we fooling ourselves?

PURPOSE OF REVIEW: This article will summarize outcomes of prior immunosuppression withdrawal trials in pediatric and adult liver transplantation and provide updates on the current status of ongoing clinical tolerance studies including evolving strategies, such as identification of reliable biomarkers or immunomodulation to achieve an earlier onset and more robust level of operational tolerance. RECENT FINDINGS: Clinical tolerance studies in liver transplantation have previously been limited by inconsistent and delayed success of immunosuppressive withdrawal, lack of substantial histological analysis from liver tissue biopsy, and the inability to translate mechanistic studies to reproducible clinical outcomes. Current clinical trials are attempting to overcome these hurdles through more comprehensive and guided immunosuppression withdrawal protocols. Novel and emerging technologies are enabling investigators to identify and validate potential biomarkers of tolerance in order to predict patient subpopulations disposed towards operational tolerance. Immune cell therapy using the adoptive transfer of various cell products have been shown to be feasible and well tolerated in early phase clinical trials and ongoing. SUMMARY: Tolerance studies in liver transplantation are evolving and substantial progress has been made in overcoming the challenges that have prevented the widespread implementation of immunosuppression withdrawal protocols in the clinic. Identifying more sensitive and specific predictors of immunosuppression withdrawal success and tolerance induction strategies that will allow for early tolerance will advance the field tremendously towards the goal of promoting long-term allograft survival without immunosuppression.