Implementation, Feasibility, and Perception of Facilitated Process Groups in Surgical Residency.

OBJECTIVE: Recent studies have demonstrated burnout in surgeons, with trainees affected at alarming levels. However, few studies have focused on specific wellbeing initiatives in surgical residency. We implemented facilitated process groups at our residency program and aimed to understand the feasibility and perception of this program. DESIGN: We recruited a psychologist to conduct weekly process groups. Each postgraduate year (PGY) class was scheduled for a rotating 1-hour session every 6 weeks during protected didactic time. A presurvey was conducted shortly following program commencement for PGY1-5 residents (11/2020-1/2021) and a postsurvey conducted after 9 to 10 months of implementation for PGY2-5 residents. Surveys included demographics, a 2-item Maslach Burnout Inventory, and questions about stress, lifestyle, and perception of the process groups, including qualitative feedback. SETTING: The study took place at within the General Surgery Residency at Massachusetts General Hospital, a tertiary-care institution in Boston, Massachusetts. PARTICIPANTS: Participants in process groups were all General Surgery residents during the timeframe of the study. Participation in the presurvey and postsurvey was voluntary for residents. RESULTS: A total of 32 and 35 residents completed the presurveys and postsurveys, respectively. Groups were similar with regards to gender and race. A total of 97% and 57% of postsurvey respondents attended ≥1 and ≥3 process groups, respectively, with 95% citing clinical/other obligations as the cause of missing sessions. Perception of process groups was highly positive and persisted across both surveys. There were no significant differences in perception or burnout questions, except for a slight decrease in "I think process groups might help me process personal challenges" on postsurvey. Of 15 qualitative postsurvey responses, 73% were positive and the remainder were neutral. CONCLUSIONS: Based on current measures, it is feasible to implement facilitated process groups for surgical residents. Resident perception of these groups was persistently positive.

Knock-out of N-glycolylneuraminic acid attenuates antibody-mediated rejection in xenogenically perfused porcine lungs.

BACKGROUND: Antibody-mediated rejection has long been known to be one of the major organ failure mechanisms in xenotransplantation. In addition to the porcine α1,3-galactose (α1,3Gal) epitope, N-Glycolylneuraminic acid (Neu5Gc), a sialic acid, has been identified as an important porcine antigen against which most humans have pre-formed antibodies. Here we evaluate GalTKO.hCD46 lungs with an additional cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) gene knock-out (Neu5GcKO) in a xenogeneic ex vivo perfusion model METHODS: Eleven GalTKO.hCD46.Neu5GcKO pig lungs were perfused for up to 6 h with fresh heparinized human blood. Six of them were treated with histamine (H) blocker famotidine and 1-thromboxane synthase inhibitor Benzylimidazole (BIA) and five were left untreated. GalTKO.hCD46 lungs without Neu5GcKO (n = 18: eight untreated and 10 BIA+H treated) served as a reference. Functional parameters, blood, and tissue samples were collected at pre-defined time points throughout the perfusion RESULTS: All but one Neu5GcKO organs maintained adequate blood oxygenation and "survived" until elective termination at 6 h whereas two reference lungs failed before elective termination at 4 h. Human anti-Neu5Gc antibody serum levels decreased during the perfusion of GalTKO.hCD46 lungs by flow cytometry (∼40% IgM, 60% IgG), whereas antibody levels in Neu5GcKO lung perfusions did not fall (IgM p = .007; IgG p < .001). Thromboxane elaboration, thrombin generation, and histamine levels were significantly reduced with Neu5GcKO lungs compared to reference in the untreated groups (p = .007, .005, and .037, respectively); treatment with BIA+H masked these changes. Activation of platelets, measured as CD62P expression on circulating platelets, was lower in Neu5GcKO experiments compared to reference lungs (p = .023), whereas complement activation (as C3a rise in plasma) was not altered. MCP-1 and lactotransferin level elevations were blunted in Neu5GcKO lung perfusions (p = .007 and .032, respectively). Pulmonary vascular resistance (PVR) rise was significantly attenuated and delayed in untreated GalTKO.hCD46.Neu5GcKO lungs in comparison to the untreated GalTKO.hCD46 lungs (p = .003) CONCLUSION: Additional Neu5GcKO in GalTKO.hCD46 lungs significantly reduces parameters associated with antibody-mediated inflammation and activation of the coagulation cascade. Knock-out of the Neu5Gc sialic acid should be beneficial to reduce innate immune antigenicity of porcine lungs in future human recipients.

Genetic modifications designed for xenotransplantation attenuate sialoadhesin-dependent binding of human erythrocytes to porcine macrophages.

The phenomenon of diminishing hematocrit after in vivo liver and lung xenotransplantation and during ex vivo liver xenoperfusion has largely been attributed to action by resident liver porcine macrophages, which bind and destroy human erythrocytes. Porcine sialoadhesin (siglec-1) was implicated previously in this interaction. This study examines the effect of porcine genetic modifications, including knockout of the CMAH gene responsible for expression of Neu5Gc sialic acid, on the adhesion of human red blood cells (RBCs) to porcine macrophages. Wild-type (WT) porcine macrophages and macrophages from several strains of genetically engineered pigs, including CMAH gene knockout and several human transgenes (TKO+hTg), were incubated with human RBCs and "rosettes" (≥3 erythrocytes bound to one macrophage) were quantified by microscopy. Our results show that TKO+hTg genetic modifications significantly reduced rosette formation. The monoclonal antibody 1F1, which blocks porcine sialoadhesin, significantly reduced rosette formation by WT and TKO+hTg macrophages compared with an isotype control antibody. Further, desialation of human RBCs with neuraminidase before addition to WT or TKO+hTg macrophages resulted in near-complete abrogation of rosette formation, to a level not significantly different from porcine RBC rosette formation on porcine macrophages. These observations are consistent with rosette formation being mediated by binding of sialic acid on human RBCs to sialoadhesin on porcine macrophages. In conclusion, the data predict that TKO+hTg genetic modifications, coupled with targeting of porcine sialoadhesin by the 1F1 mAb, will attenuate erythrocyte sequestration and anemia during ex vivo xenoperfusion and following in vivo liver, lung, and potentially other organ xenotransplantation.

Pig-to-baboon lung xenotransplantation: Extended survival with targeted genetic modifications and pharmacologic treatments.

Galactosyl transferase knock-out pig lungs fail rapidly in baboons. Based on previously identified lung xenograft injury mechanisms, additional expression of human complement and coagulation pathway regulatory proteins, anti-inflammatory enzymes and self-recognition receptors, and knock-down of the ß4Gal xenoantigen were tested in various combinations. Transient life-supporting GalTKO.hCD46 lung function was consistently observed in association with either hEPCR (n = 15), hTBM (n = 4), or hEPCR.hTFPI (n = 11), but the loss of vascular barrier function in the xenograft and systemic inflammation in the recipient typically occurred within 24 h. Co-expression of hEPCR and hTBM (n = 11) and additionally blocking multiple pro-inflammatory innate and adaptive immune mechanisms was more consistently associated with survival >1 day, with one recipient surviving for 31 days. Combining targeted genetic modifications to the lung xenograft with selective innate and adaptive immune suppression enables prolonged initial life-supporting lung function and extends lung xenograft recipient survival, and illustrates residual barriers and candidate treatment strategies that may enable the clinical application of other organ xenografts.

Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models.

The transplantation of organs across species offers the potential to solve the shortage of human organs. While activation of human platelets by human von Willebrand factor (vWF) requires vWF activation by shear stress, contact between human platelets and porcine vWF (pvWF) leads to spontaneous platelet adhesion and activation. This non-physiologic interaction may contribute to the thrombocytopenia and coagulation pathway dysregulation often associated with xenotransplantation of pig organs in nonhuman primates. Pigs genetically modified to decrease antibody and complement-dependent rejection (GTKO.hCD46) were engineered to express humanized pvWF (h*pvWF) by replacing a pvWF gene region that encodes the glycoprotein Ib-binding site with human cDNA orthologs. This modification corrected for non-physiologic human platelet aggregation on exposure to pig plasma, while preserving in vitro platelet activation by collagen. Organs from pigs with h*pvWF demonstrated reduced platelet sequestration during lung (p ≤ .01) and liver (p ≤ .038 within 4 h) perfusion ex vivo with human blood and after pig-to-baboon lung transplantation (p ≤ .007). Residual platelet sequestration and activation were not prevented by the blockade of canonical platelet adhesion pathways. The h*pvWF modification prevents physiologically inappropriate activation of human or baboon platelets by porcine vWF, addressing one cause of the thrombocytopenia and platelet activation observed with xenotransplantation.

Minimizing Ischemia Reperfusion Injury in Xenotransplantation.

The recent dramatic advances in preventing "initial xenograft dysfunction" in pig-to-non-human primate heart transplantation achieved by minimizing ischemia suggests that ischemia reperfusion injury (IRI) plays an important role in cardiac xenotransplantation. Here we review the molecular, cellular, and immune mechanisms that characterize IRI and associated "primary graft dysfunction" in allotransplantation and consider how they correspond with "xeno-associated" injury mechanisms. Based on this analysis, we describe potential genetic modifications as well as novel technical strategies that may minimize IRI for heart and other organ xenografts and which could facilitate safe and effective clinical xenotransplantation.

Anatomy and Embryology of the Thoracic Outlet.

The thoracic outlet is the space between the thorax and axilla through which the subclavian vein, subclavian artery, and brachial plexus travel from their central origins to their peripheral termini. Its bounds include the clavicle, first thoracic rib, insertion of the pectoralis minor muscle onto the coracoid process of the humerus, and the sternum. It contains three areas: the scalene triangle, the costoclavicular space, and the subcoracoid or pectoralis minor space. Aberrant anatomy is common in the thoracic outlet and may predispose patients to compression of the neurovascular bundle and development of clinical thoracic outlet syndrome (TOS). Much of this aberrancy is explained by the embryologic origins of the structures that comprise the thoracic outlet. A thorough understanding of this anatomy and embryology is therefore critical to the understanding of TOS.

Progress Toward Cardiac Xenotransplantation.

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.

Surgealousy.

Answering the call to care for patients with COVID-19 stirs a range of emotions. This perspective explores an individual surgical resident's early experience in the coronavirus pandemic.