Amino acid and lipid profiles following pig-to-primate liver xenotransplantation.

As outcomes in clinical liver transplantation steadily improve, demand continues to exceed supply, leading to a substantial disparity in organ availability. The translation of porcine liver xenotransplantation (LXT) into a clinical reality aims to address this dilemma. Our laboratory has previously established an applicable model of α-1,3-galactosyltransferase knockout (GalT-KO) pig-to-primate LXT with continuous human coagulation factor infusion and costimulation blockade. This report aims to further investigate the post-LXT lipid and amino acid metabolism profile in our longest surviving recipients (25 and 29 days). Experimental samples and control samples, consisting of pre-transplant porcine and baboon serum and plasma, were analyzed for standard lipid profiles and for amino acid levels. Lipid profiles of LXT recipients remained stable following xenotransplantation compared to donor porcine baseline levels. Amino acid concentrations also remained similar to baseline controls, with the exception of a 3-fold increase in l-ornithine and more than a 10-fold decrease in l-arginine post-transplant when compared to both porcine and baboon baseline levels. The observed changes in l-arginine are consistent with prior studies investigating the effects of graft preservation injury following liver transplantation. These results indicate that the porcine liver can maintain most biochemical profiles stably post-operatively in baboons and suggest that arginine supplementation post-LXT may potentially be useful for further prolongation of xenograft survival.

GalT-KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels.

BACKGROUND: Despite recent progress in survival times of xenografts in non-human primates, there are no reports of survival beyond 5 days of histologically well-aerated porcine lung grafts in baboons. Here, we report our initial results of pig-to-baboon xeno-lung transplantation (XLTx). METHODS: Eleven baboons received genetically modified porcine left lungs from either GalT-KO alone (n = 3), GalT-KO/humanCD47(hCD47)/hCD55 (n = 3), GalT-KO/hD47/hCD46 (n = 4), or GalT-KO/hCD39/hCD46/hCD55/TBM/EPCR (n = 1) swine. The first 2 XLTx procedures were performed under a non-survival protocol that allowed a 72-hour follow-up of the recipients with general anesthesia, while the remaining 9 underwent a survival protocol with the intention of weaning from ventilation. RESULTS: Lung graft survivals in the 2 non-survival animals were 48 and >72 hours, while survivals in the other 9 were 25 and 28 hours, at 5, 5, 6, 7, >7, 9, and 10 days. One baboon with graft survival >7 days, whose entire lung graft remained well aerated, was euthanized on POD 7 due to malfunction of femoral catheters. hCD47 expression of donor lungs was detected in both alveoli and vessels only in the 3 grafts surviving >7, 9, and 10 days. All other grafts lacked hCD47 expression in endothelial cells and were completely rejected with diffuse hemorrhagic changes and antibody/complement deposition detected in association with early graft loss. CONCLUSIONS: To our knowledge, this is the first evidence of histologically viable porcine lung grafts beyond 7 days in baboons. Our results indicate that GalT-KO pig lungs are highly susceptible to acute humoral rejection and that this may be mitigated by transgenic expression of hCD47.

Liver xenotransplantation.

PURPOSE OF REVIEW: There continues to be an inadequate organ supply and lack of effective temporary support, for patients with liver failure. The purpose of this review is to discuss recent progress in the field of orthotopic pig-to-nonhuman primate (NHP) liver xenotransplantation (LXT). RECENT FINDINGS: From 1968 to 2012, survival in pig-to-NHP LXT was limited to 9 days, initially due to hyperacute rejection which has been ameliorated through use of genetically engineered donor organs, but ultimately because of profound thrombocytopenia, thrombotic microangiopathy, and bleeding. Most recently, however, demise secondary to lethal coagulopathy has been avoided with LXT of α(1,3)-galactosyltransferase knockouts and cytomegalovirus-negative porcine xenografts into baboons receiving exogenous administration of coagulation factors and co-stimulation blockade, establishing that a porcine liver is capable of supporting NHP life for nearly a month. SUMMARY: Continued consistent achievement of pig-to-NHP LXT survival beyond 2 weeks justifies consideration of a clinical application as a bridge to allotransplantation for patients with acute hepatic failure. Further genetic modifications to the donor, as well as additional studies, are required in order to apply LXT as destination therapy.

Mobile Integrated Health Interventions for Older Adults: A Systematic Review.

Background and Objectives: Mobile integrated health (MIH) interventions have not been well described in older adult populations. The objective of this systematic review was to evaluate the characteristics and effectiveness of MIH programs on health-related outcomes among older adults. Research Design and Methods: We searched Ovid MEDLINE, Ovid EMBASE, CINAHL, AgeLine, Social Work Abstracts, and The Cochrane Library through June 2021 for randomized controlled trials or cohort studies evaluating MIH among adults aged 65 and older in the general community. Studies were screened for eligibility against predefined inclusion/exclusion criteria. Using at least 2 independent reviewers, quality was appraised using the Downs and Black checklist and study characteristics and findings were synthesized and evaluated for potential bias. Results: Screening of 2,160 records identified 15 studies. The mean age of participants was 67 years. The MIH interventions varied in their focus, community paramedic training, types of assessments and interventions delivered, physician oversight, use of telemedicine, and post-visit follow-up. Studies reported significant reductions in emergency call volume (5 studies) and immediate emergency department (ED) transports (3 studies). The 3 studies examining subsequent ED visits and 4 studies examining readmission rates reported mixed results. Studies reported low adverse event rates (5 studies), high patient and provider satisfaction (5 studies), and costs equivalent to or less than usual paramedic care (3 studies). Discussion and Implications: There is wide variability in MIH provider training, program coordination, and quality-based metrics, creating heterogeneity that make definitive conclusions challenging. Nonetheless, studies suggest MIH reduces emergency call volume and ED transport rates while improving patient experience and reducing overall health care costs.

Simulation-Based Orientation for Emergency Medicine Residents Participating in EMS Ride-Alongs.

Introduction: Emergency medicine resident physicians are required to complete observational ride-alongs with emergency medical services (EMS) units as part of their curriculum as per the ACGME. We created this curriculum to expose emergency medicine residents to the equipment they will encounter in the prehospital setting, discuss basic EMS operations and the challenges of working in the prehospital environment, and review the limitations that restrict care provided by EMS professionals. Methods: We created a series of five simulation cases for resident physicians participating in an EMS ride-along rotation. Each case was implemented with three to four residents at a time. A critical action checklist was used to assess participants during the scenarios. Following each simulation, a debriefing was conducted to discuss EMS operations and the impact on providers. At the conclusion of the session, participants completed a course evaluation survey. Results: Thirteen emergency medicine resident physicians took part in this curriculum from October 2020 through January 2021. Results indicated that the participants gained insight into the prehospital environment, felt more prepared to complete their ride-alongs, and were engaged and satisfied with the introduction to EMS program. Discussion: Simulation allowed emergency medicine residents to be exposed to the complex nature of prehospital care and prepared them for their ride-along sessions. The five cases provided significant breadth and depth of potential prehospital care issues, and the residents were able to discuss the medical, policy, and operational challenges presented as part of each case.

Dosing optimization of CCR4 immunotoxin for improved depletion of CCR4+ Treg in nonhuman primates.

Recently, we have developed a diphtheria toxin-based recombinant anti-human CCR4 immunotoxin for targeting CCR4+ tumors and Tregs. In this study, we further optimized the dosing schedule for improved CCR4+ Treg depletion. We have demonstrated that up to a 90% depletion was achieved and the depletion extended to approximately 2 weeks in the peripheral blood and more than 48 days in the lymph node at 25 µg·kg-1 , BID for 8 consecutive days in cynomolgus monkeys. Expansion was observed including monocytes and NK cells. Antibody against the CCR4 immunotoxin was detected after approximately 2 weeks, affecting further depletion efficacy for multiple course treatment.

Nontrauma surgeons can safely take call at an academic, rural level I trauma center.

BACKGROUND: Care protocols can facilitate effective management of injured patients across a spectrum of providers. It is uncertain whether patient care is compromised when a full time trauma surgeon is not on call in the rural setting, where manpower may be a challenge. METHODS: A retrospective cohort study was performed at an academic medical center with a level I trauma center. Patients admitted to the trauma service from 2007 to 2012 were compared with respect to mortality, missed injuries, delay in diagnosis, and length of stay based on whether they were admitted to the trauma service when a full-time trauma surgeon was on call. RESULTS: A total of 2,571 injured patients were admitted during the study period; 1,621 directly to the trauma service. Of those, 1,415 patients were initially seen by a trauma surgeon (group A) and 206 by a nontrauma surgeon (group B). Demographics were similar except that the trauma attending patients were somewhat older (44.7 vs 39.4 years, P = .002). There was no difference in the mean injury severity score (17.0 vs 16.0, P = .13) or Glasgow Coma Scale (12.7 vs 12.3, P = .7) between the 2 groups. There were 128 deaths; mortality rate in group A was 7.9% versus 7.7% for group B (P = .54). There was no difference in the incidence of delayed diagnosis or missed injuries (3.0 vs 3.4%, P = .8; .4 vs .9%, P = .27, respectively). The mean length of stay was shorter (7.9 vs 6.3, P = .016) in group B. CONCLUSIONS: There was no increase in mortality, delayed diagnosis, or missed injuries when nontrauma surgeons took call. Systems of care and algorithms can be developed that provide staffing flexibility yet maintain safe and effective care to trauma patients in the rural setting.