Lack of efficacy of aprotinin over tranexamic acid in type A aortic dissection repair.

BACKGROUND: The role of aprotinin in modern cardiac surgery is not well defined. While licensed for use in isolated coronary artery bypass grafting it is more commonly used for cases deemed to be at an increased risk of bleeding. The relative efficacy, and safety profile, of aprotinin as compared to other antifibrinolytics in these high-risk cases is uncertain. STUDY DESIGN AND METHODS: A retrospective observational study with propensity matching to determine whether aprotinin versus tranexamic acid reduced bleeding or transfusion requirements in patients presenting for surgical repair of type A aortic dissection (TAD). RESULTS: Between 2016 and 2022, 250 patients presented for repair of TAD. A total of 231 patients were included in the final analysis. Bleeding and transfusion were similar between both groups in both propensity matched and unmatched cohorts. Compared to tranexamic acid, aprotinin use did not reduce transfusion requirements for any product. Rates of bleeding in the first 12 h, return to theater and return to intensive care unit with an open packed chest were similar between groups. There was no difference in rates of renal failure, stroke, or death. CONCLUSION: Aprotinin did not reduce the risk of bleeding or transfusion requirements in patients undergoing repair of type A aortic dissections. Efficacy of aprotinin may vary depending on the type of surgery performed and the underlying pathology.

Graft function and incidence of cardiac allograft vasculopathy in donation after circulatory-determined death heart transplant recipients.

Experience in donation after circulatory-determined death (DCD) heart transplantation (HTx) is expanding. There is limited information on the functional outcomes of DCD HTx recipients. We sought to evaluate functional outcomes in our cohort of DCD recipients. We performed a single-center, retrospective, observational cohort study comparing outcomes in consecutive DCD and donation after brain death (DBD) HTx recipients between 2015 and 2019. Primary outcome was allograft function by echocardiography at 12 and 24 months. Secondary outcomes included incidence of cardiac allograft vasculopathy, treated rejection, renal function, and survival. Seventy-seven DCD and 153 DBD recipients were included. There was no difference in left ventricular ejection fraction at 12 months (59% vs 59%, P = .57) and 24 months (58% vs 58%, P = .87). There was no significant difference in right ventricular function at 12 and 24 months. Unadjusted survival between DCD and DBD recipients at 5 years (85.7% DCD and 81% DBD recipients; P = .45) was similar. There were no significant differences in incidence of cardiac allograft vasculopathy (odds ratio 1.59, P = .21, 95% confidence interval 0.77-3.3) or treated rejection (odds ratio 0.60, P = .12, 95% confidence interval 0.32-1.15) between DBD and DCD recipients. Post-transplant renal function was similar at 1 and 2 years. In conclusion, cardiac allografts from DCD donors perform similarly to a contemporary population of DBD allografts in the medium term.

Comparative expression analysis of the Atoh7 gene regulatory network in the mouse and chicken auditory hindbrain.

The mammalian and avian auditory brainstem likely arose by independent evolution. To compare the underlying molecular mechanisms, we focused on Atoh7, as its expression pattern in the mammalian hindbrain is restricted to bushy cells in the ventral cochlear nucleus. We thereby took advantage of an Atoh7 centered gene regulatory network (GRN) in the retina including upstream regulators, Hes1 and Pax6, and downstream targets, Ebf3 and Eya2. In situ hybridization demonstrated for the latter four genes broad expression in all three murine cochlear nuclei at postnatal days (P) 4 and P30, contrasting the restricted expression of Atoh7. In chicken, all five transcription factors were expressed in all auditory hindbrain nuclei at embryonic day (E) 13 and P14. Notably, all five genes showed graded expression in the embryonic nucleus magnocellularis (NM). Atoh7 was highly expressed in caudally located neurons, whereas the other four transcription factors were highly expressed in rostrally located neurons. Thus, Atoh7 shows a strikingly different expression between the mammalian and avian auditory hindbrain. This together with the consistent absence of graded expression of GRN components in developing mammalian nuclei provide the first molecular support to the current view of convergent evolution as a major mechanism in the amniote auditory hindbrain. The graded expression of five transcription factors specifically in the developing NM confirms this nucleus as a central organizer of tonotopic features in birds. Finally, the expression of all five retinal GRN components in the auditory system suggests co-options of genes for development of sensory systems of distinct modalities.

Acute aortic regurgitation due to fibrous strand rupture.

A 60-year-old male presented with sudden onset chest pain and pulmonary edema. The investigation confirmed torrential aortic regurgitation of a bicuspid valve. At surgery, a ruptured fibrous strand was identified which had been supporting the left-right cusp commissure with loss of attachment to the aortic wall. This case demonstrates that fibrous strands may be present as a supporting structure of the aortic valve, and rupture can be a rare cause of torrential aortic regurgitation, similar in pathogenesis to how it may be associated with acute severe mitral regurgitation and chordae tendineae rupture.

Aortic valve replacement in patients over 60: Real-world surgical outcomes.

OBJECTIVE: With the advent of transcatheter aortic valve implantation (TAVI) has come an expectation that there will be a decline in surgical aortic valve replacement (SAVR). This has been fueled by trials comparing outcomes between TAVI and SAVR in lower-risk patients. The aim of this study was to examine outcomes following SAVR in patients over the age of 60. MATERIALS AND METHODS: This retrospective cohort study observed 1005 patients ≥60 who underwent isolated primary SAVR from January 2015 to December 2018. The cohort was stratified by surgical risk, defined as European System for Cardiac Operative Risk Evaluation (EuroSCORE) II < 4 versus ≥4. The cohort was also divided by age (60-69, 70-79, ≥80) for additional comparisons. Outcomes included in-hospital complications and patient survival. RESULTS: The median age and EuroSCORE II were 75 years and 1.6, respectively. The overall 30-day mortality was 1.7% and increased significantly with surgical risk (p = .007). The 30-day mortality of elective patients was 1.1%. Overall, 1- and 2-year survival rates were 94.3% and 91.7%, respectively, which significantly decreased with surgical risk (p < .001) and age (p = .002, p = .003). The rates of postoperative stroke and pacemaker implantations were 1.2% and 3.6%, respectively. CONCLUSIONS: SAVR can be performed in patients ≥60 years old with excellent outcomes, which compare favorably with outcomes from TAVI trials, with their highly selected patient cohorts. SAVR remains a reliable, tried and tested, treatment option in these patients.

Minimally invasive extracorporeal circulation is a cost-effective alternative to conventional extracorporeal circulation for coronary artery bypass grafting: propensity matched analysis.

INTRODUCTION: Minimally invasive extracorporeal circulation has developed with the aim of reducing the impact of the adverse effects associated with conventional extracorporeal circulation. The aim of this study was to compare outcomes for patients undergoing coronary artery bypass grafting using minimally invasive extracorporeal circulation with those performed using conventional extracorporeal circulation. METHODS: A retrospective analysis was performed of patients undergoing minimally invasive extracorporeal circulation coronary artery bypass grafting at a single centre. 2:1 propensity matching was performed to identify control patients undergoing conventional extracorporeal circulation coronary artery bypass grafting. Outcomes were compared using univariate analysis. RESULTS: A total of 354 patients were included in the study, with 118 patients undergoing minimally invasive extracorporeal circulation coronary artery bypass grafting. Patients were well matched on baseline characteristics. The mean logistic EuroSCORE was 3.95 ± 4.20. Operative times (3.31 ± 1.52 vs. 3.56 ± 0.73, p = 0.03) were significantly shorter in minimally invasive extracorporeal circulation cases. Patients who underwent surgery with minimally invasive extracorporeal circulation had significantly less 12-hour blood loss (322.3 ± 13.2 mL vs. 380.8 ± 15.2 mL, p < 0.01). Correspondingly, a significantly lower proportion of patients were transfused (25.8% vs. 36%, p = 0.04), and the mean number of red blood cells transfused was lower (0.45 ± 0.95 vs. 0.97 ± 2.13, p = 0.01). Similarly, the number of coagulation products administered was lower (0.161 ± 0.05 vs. 0.40 ± 0.09, p = 0.05). There was a significantly lower incidence of acute kidney injury (11.0% vs. 19.9%, p = 0.03). Minimally invasive extracorporeal circulation was associated with a £679.50 cost saving per patient. DISCUSSION: Minimally invasive extracorporeal circulation for coronary artery bypass grafting is associated with a reduced requirement for blood transfusion, reduced incidence of acute kidney injury and a significant cost saving. Minimally invasive extracorporeal circulation should be considered as an adjunct for all patients undergoing coronary artery bypass grafting.

Spontaneous diaphragmatic rupture as a complication following lung transplantation.

Spontaneous diaphragm rupture is a rare but potentially life-threatening condition, requiring urgent surgical intervention. Here we present two patients who developed spontaneous right hemidiaphragm rupture with abdominal visceral herniation into the thoracic cavity several days following bilateral lung transplantation, as an unusual complication. Both patients' surgeries were performed through bilateral anterior thoracotomies and were uneventful. There may be an association with this complication and patients suffering with emphysema, typically receiving donor lungs smaller than their native lungs, and with significant pretransplant exposure to steroids, factors that when combined may contribute to an increased risk of spontaneous diaphragmatic rupture in the absence of a significant precipitant. If a similar clinical picture is seen, teams managing lung transplant recipients should be aware of this potential complication and recognize the need for urgent intervention.

Geological data indicate that the interpretation for the age-calibrated phylogeny for the Kurixalus-genus frogs of South, South-east and East Asia (Lv et al., 2018) needs to be rethought.

Recently, Lv et al. (2018) published an age-calibrated phylogenetic tree for the Kurixalus frogs, members of which occur across parts of South, South-east and East Asia. A clade on Taiwan, represented by Kurixalus idiootocus and the Kurixalus eiffingeri species complex, is deemed to have been resident since the middle Cenozoic; its closest congeners are in southern Indochina (not in the adjacent parts of south-east China), and the split between the two is dated at 32.8 Ma. Furthermore, a sub-population of Kurixalus eiffingeri is believed to have colonized islands in the western Ryukyus c. 13.5 Ma. There is, however, a problem with this scenario: the landmass regarded as modern-day Taiwan has existed only for 4-5 million years (it results from a young and ongoing tectonic-plate collision). Assuming the Kurixalus phylogeny and the dating of its branchings are correct, then a palaeobiogeographical scenario involving an older, alternative land surface with later transfer to Taiwan, possibly involving over-water dispersal, would reconcile the biology, but testing this may be difficult/impossible. If the ages of the nodes in the proposed tree are found to be significantly overestimated, the geology and biology might more easily be accommodated.

Transfer of Patients With Cardiogenic Shock Using Veno-Arterial Extracorporeal Membrane Oxygenation.

OBJECTIVES: The authors describe the experience of patient transfer on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) used as a salvage therapy for refractory cardiogenic shock, examining feasibility and long-term outcomes. DESIGN: A retrospective case series. SETTING: A tertiary referral cardiothoracic transplantation center. PARTICIPANTS AND INTERVENTIONS: Since 2012, the authors' multidisciplinary team has traveled to the referring center of 15 patients referred with refractory cardiogenic shock. Of these, 13 were instituted on VA ECMO support (8 peripheral and 5 central) and subsequently transferred to the authors' center. A further 11 patients were transferred to the authors' institution by the referring team, already having been placed on VA-ECMO (8 peripheral and 3 central). MEASUREMENTS AND MAIN RESULTS: All patients were safely transferred. The distance travelled ranged from 16 to 341 miles. The median duration of support on VA-ECMO was 4 days, ranging from 1 to 24 days. The VA-ECMO support was weaned, or the patient underwent a definitive surgical management (including 4 undergoing cardiac transplantation and 3 pulmonary endarterectomy) in 15 (62.5%) patients. The median intensive care unit stay was 15 days (range 1-109). Overall 30-day survival for this patient cohort was 69.6% with 1-year survival of 59.8%. For patients who were weaned from VA-ECMO, the 30-day survival was 100% and 1-year survival 92.9%. CONCLUSIONS: The authors' experience demonstrates the feasibility and survival benefit of a salvage VA-ECMO retrieval service for carefully selected patients with refractory cardiogenic shock. The authors suggest that a system based on the model of nationally commissioned severe respiratory failure services could be organized to support the transfer of these patients.

Is carotid screening redundant for patients undergoing coronary artery bypass grafting?

OBJECTIVES: Stroke is a devastating complication following coronary artery bypass grafting, which thankfully occurs with low incidence. The role of preoperative carotid ultrasound remains unclear. Whilst it is a cheap and reliable way of diagnosing carotid stenosis (CS), it is unclear if and how this knowledge should impact on subsequent patient management. METHODS: A systematic review of the literature was performed using the PRISMA guideline. A literature search was conducted on the MEDLINE database from 1950 to May 2020 using the OVID interface. Fifteen papers out of a total of 5931 were identified for inclusion. RESULTS: The evidence overall suggests that patients with severe CS are likely to have an increased incidence of postoperative stroke-however, the prevalence of severe CS is low, and even in this cohort of patients, the incidence is not particularly high. CONCLUSION: In screened patients identified to have severe CS, there appears to be a generally low appetite for undertaking carotid intervention internationally either before or concurrently with the coronary artery bypass grafting. Putting this all together, the widespread screening of asymptomatic patients would appear to not be justified.

Impact of stroke on outcomes following cardiac surgery: Propensity matched analysis.

BACKGROUND: Stroke remains a devastating complication of cardiac surgery. The aim of this study was to characterize the incidence of stroke and analyze the impact of stroke on patient outcomes and survival. METHODS: A retrospective analysis was performed of patients with a computed tomography-confirmed stroke diagnosis between 1 January 2015 and 31 March 2019 at a single center. 2:1 propensity matching was performed to identify a control population. RESULTS: Over the period 165 patients suffered a stroke (1.99%), with an incidence ranging from 0.85% for coronary artery bypass grafting to 8.14% for aortic surgery. The mean age was 70.3 years and 58.8% were male. 18% had experienced a previous stroke or transient ischemic attack. Compared to the comparison group, patients experiencing postoperative stroke had a significantly prolonged period of intensive care unit admission (8.0 vs 1.1 days P < .001) and hospital length of stay (12.94 vs 8.0 days P < .001). Patient survival was also inferior. In-hospital mortality was almost three times as high (17.0% vs 5.9%; P < .001). Longer-term survival was also inferior to Kaplan-Meier estimation (P < .001). The 1-year and 3-year survival were 61.5% and 53.8% respectively compared to 89.4% and 86.1% for the comparison group. CONCLUSION: Perioperative stroke is a devastating complication following cardiac surgery. Perioperative stroke is associated with significantly inferior outcomes in terms of both morbidity and mortality. Notably a 28% reduction in 1-year survival. Efforts should focus on identifying strategies aimed at reducing the incidence, morbidity, and mortality of perioperative stroke following cardiac surgery.

Emergency valve-in-valve transcatheter aortic valve implantation for endocarditis degeneration.

The use of transcatheter aortic valve implantation (TAVI) in the emergency setting has not been widely reported, and TAVI is generally contraindicated in the context of endocarditis. Here we describe a patient developing acute cardiogenic shock due to prosthetic aortic valve degeneration with free-flow aortic regurgitation 8 months after receiving treatment for confirmed infective endocarditis. Due to his clinical status, he was deemed unfit for redo surgery, and he underwent salvage valve-in-valve (ViV)-TAVI. The patient made an excellent recovery. Postprocedure he was treated with a 6-week course of antibiotics, and at 18-months follow-up remains very well with no evidence of reinfection. This case may demonstrate that for selected patients with degenerative prosthetic aortic valve disease, despite a history of infective endocarditis, ViV-TAVI may be considered an alternative to redo surgery in the emergency setting.

Catastrophic sickling crisis in patient undergoing cardiac transplantation with sickle cell trait.

There is debate in the literature regarding management of patients with sickle cell trait (SCT) undergoing cardiac surgery, since it is recognized that cardiopulmonary bypass presents many precipitating risk factors for a sickling crisis. Despite this, many report successful outcomes without any modification to perioperative management. A 49-year-old woman with SCT (HbS 38%) with postpartum cardiomyopathy underwent cardiac transplantation. The patient was cooled to 34.0°C and retrograde cold blood cardioplegia was infused continuously. The cold ischemic time was 219 minutes and warm ischemic time 46 minutes. After weaning from bypass, she developed global cardiac dysfunction requiring veno-arterial extracorporeal membrane oxygenation. The circuit suddenly stopped, requiring emergency reinstitution of bypass; the circuit had clotted. Transesophageal-echocardiogram revealed thrombus within the left atrium and ventricle. There was no recovery of cardiac function and the patient developed multiorgan failure. At postmortem there was extensive myocardial infarction with evidence of widespread catastrophic intravascular red-cell sickling. This case highlights the danger of complacency in patients with SCT, offering a learning opportunity for the cardiothoracic community to highlight the most serious complication that can occur in this group of patients. We have learned that SCT and cardiac surgery is not a benign combination.

Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy.

The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. We examine whether autoimmunity contributes independently to allograft rejection. In a MHC class II-mismatched murine model of chronic humoral rejection, we report that effector antinuclear autoantibody responses were initiated upon graft-versus-host allorecognition of recipient B cells by donor CD4 T-cells transferred within heart allografts. Consequently, grafts were rejected more rapidly, and with markedly augmented autoantibody responses, upon transplantation of hearts from donors previously primed against recipient. Nevertheless, rejection was dependent upon recipient T follicular helper (TFH) cell differentiation and provision of cognate (peptide-specific) help for maintenance as long-lived GC reactions, which diversified to encompass responses against vimentin autoantigen. Heart grafts transplanted into stable donor/recipient mixed haematopoietic chimeras, or from parental strain donors into F1 recipients (neither of which can trigger host adaptive alloimmune responses), nevertheless provoked GC autoimmunity and were rejected chronically, with rejection similarly dependent upon host TFH cell differentiation. Thus, autoantibody responses contribute independently of host adaptive alloimmunity to graft rejection, but require host TFH cell differentiation to maintain long-lived GC responses. The demonstration that one population of helper CD4 T-cells initiates humoral autoimmunity, but that a second population of TFH cells is required for its maintenance as a GC reaction, has important implications for how autoimmune-related phenomena manifest.

CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection.

Adaptive CD8 T-cell immunity is the principal arm of the cellular alloimmune response, but its development requires help. This can be provided by CD4 T cells that recognize alloantigen "indirectly," as self-restricted allopeptide, but this process remains unexplained, because the target epitopes for CD4 and CD8 T-cell recognition are "unlinked" on different cells (recipient and donor antigen presenting cells (APCs), respectively). Here, we test the hypothesis that the presentation of intact and processed MHC class I alloantigen by recipient dendritic cells (DCs) (the "semidirect" pathway) allows linked help to be delivered by indirect-pathway CD4 T cells for generating destructive cytotoxic CD8 T-cell alloresponses. We show that CD8 T-cell-mediated rejection of murine heart allografts that lack hematopoietic APCs requires host secondary lymphoid tissue (SLT). SLT is necessary because within it, recipient dendritic cells can acquire MHC from graft parenchymal cells and simultaneously present it as intact protein to alloreactive CD8 T cells and as processed peptide alloantigen for recognition by indirect-pathway CD4 T cells. This enables delivery of essential help for generating cytotoxic CD8 T-cell responses that cause rapid allograft rejection. In demonstrating the functional relevance of the semidirect pathway to transplant rejection, our findings provide a solution to a long-standing conundrum as to why SLT is required for CD8 T-cell allorecognition of graft parenchymal cells and suggest a mechanism by which indirect-pathway CD4 T cells provide help for generating effector cytotoxic CD8 T-cell alloresponses at late time points after transplantation.

Global Cardioplegia Practices: Results from the Global Cardiopulmonary Bypass Survey.

Despite the ubiquitous use of cardioplegia in cardiac surgery, there is a lack of agreement on various aspects of cardioplegia practice. To discover current cardioplegia practices throughout the world, we undertook a global survey to document contemporary cardiopulmonary bypass practices. A 16-question, Internet-based survey was distributed by regional specialist societies, targeting adult cardiac anesthesiologists. Ten questions concerned caseload and cardioplegia practices, the remaining questions examined anticoagulation and pump-priming practices. The survey was available in English, Spanish, and Portuguese. The survey was launched in June 2015 and remained open until May 2016. A total of 923 responses were analyzed, summarizing practice in Europe (269), North America (334), South America (215), and Australia/New Zealand (105). Inter-regional responses differed for all questions asked (p < .001). In all regions other than South America, blood cardioplegia was the common arrest technique used. The most commonly used cardioplegia solutions were: St. Thomas, Bretschneider, and University of Wisconsin with significant regional variation. The use of additives (most commonly glucose, glutamate, tris-hydroxymethyl aminomethane, and aspartate) varied significantly. This survey has revealed significant variation in international practice with regards to myocardial protection, and is a reminder that there is no clear consensus on the use of cardioplegia. It is unclear why regional practice groups made the choices they have and the clinical impact remains unclear.

Robotic Camera Assistance: The Future of Laparoscopic and Thoracoscopic Surgery?

INTRODUCTION: Minimally invasive techniques have become the standard for a variety of procedures across all surgical specialties. There has been a recent move to integrate robotic technology into standard laparoscopic and thoracoscopic surgery with the aim of improving stability of the visual field with the use of robotic camera assistance. The aim of this study was to report on and examine the use of a headset-controlled robotic camera holder, FreeHand. METHODS: Between May 2013 and Dec 2016, 105 procedures were observed where the FreeHand robotic camera assistant was used. Observations were made of 43 consultant surgeons in 30 hospitals performing 21 different surgical procedures. During the surgery, the number of scope cleans and collisions were quantified, and surgeons were asked to score from 0 to 5 the setup, ergonomics, usability, and overall experience in a questionnaire. RESULTS: Overall surgeon satisfaction was rated as "good" for setup (4.29), ergonomics of the system (4.12), usability (4.39), and overall experience of the system (4.34). In 8 operations (7.6%), there was a conversion from robotic camera assistant to manual assistant. There were no reported adverse events attributable to the use of the system. CONCLUSION: This study demonstrates the breadth of surgical procedures that can be performed with a robotic camera assistant. The robotic camera assistant was found to be safe and simple to use and was positively perceived on assessment in multiple procedures spanning several surgical specialties. This work suggests that robotic camera assistants may offer significant benefits to laparoscopic and thoracoscopic surgeons.

Targeting indirect pathway CD4 T-cell alloresponses in the prevention of chronic transplant rejection.

BACKGROUND: Uniquely, alloantigen is recognised by two pathways: as intact antigen on the surface of donor antigen-presenting cells (direct) and as self-restricted processed allopeptide (indirect). The indirect pathway is believed to be longlasting, and is generally considered to be a single entity. Here we address how indirect responses against different alloantigens differ in their strength and longevity, and how this knowledge could be used to direct immunoregulatory therapy with antigen-specific regulatory T cells (Tregs). METHODS: A murine model of cardiac transplantation was used (bm12.Kd.IE to C57BL/6). Indirect CD4 T-cell allorecognition of mismatched donor MHC class I and II, and of H-Y minor histocompatibility antigen was assessed by quantifying proliferation of adoptively transferred monoclonal T-cell receptor transgenic T cells (TCR75, Tea, Mar). Antigen presentation by dendritic cells and B cells was assessed by selective depletion with diphtheria toxin or depleting anti-CD20 monoclonal antibody. Tregs were generated by in-vitro culture. FINDINGS: Indirect pathway responses were heterogeneous. Whereas the indirect response against class I alloantigen was longlasting and persistently strong, the response against class II alloantigen decayed within 2 weeks. Leucocyte depletion studies confirmed that this difference was due to rapid destruction of MHC class II expressing donor B cells and dendritic cells in the recipient, whereas anti-class I responses were generated by continual processing of graft parenchymal cells; recognition of donor haemopoietic fraction was not required. Notably, transfer of MHC class I specific Tregs at transplant or 3 weeks later abrogated germinal centre alloantibody responses and blocked development of allograft vasculopathy, whereas class II specific Tregs were ineffective when transferred at the late timepoint. INTERPRETATION: Although indirect allorecognition is considered to be a single entity, our results show that it consists of a number of responses that vary in duration and strength according to target alloantigen. The ability of class I allopeptide specific Tregs, but not class II specific Tregs, to prevent rejection when transferred at a late timepoint suggests that antigen-specific targeting of dominant and longlasting pathways might be particularly effective at preventing chronic rejection. FUNDING: Wellcome Trust Clinical Research Training Fellowship.

Recipient natural killer cell allorecognition of passenger donor lymphocytes and its effect on adaptive alloimmunity after transplantation.

BACKGROUND: Memory T cells are known to reside in peripheral non-lymphoid tissue, but how their presence within solid organ allografts affects transplant outcomes is not known. We have previously described how graft-versus-host (GVH) allorecognition by passenger CD4 T cells within MHC class II-mismatched bm12 heart grafts provokes antinuclear humoral autoimmunity in C57BL/6 recipient mice. Here we aimed to examine how such GVH recognition affects the alloresponse to allografts with greater mismatching. METHODS: A MHC class I and II mismatched murine model of cardiac transplantation was developed (bm12.Kd.IE to C57BL/6). After transplantation, cellular and humoral responses against mismatched antigens were measured with ELISPOT and ELISA, and the effect of GVH recognition assessed by depletion of donor CD4 T cells before graft procurement. Antinuclear autoantibody development was assessedwith HeP-2 indirect immunofluorescence. The role of recipient natural killer (NK) cells was examined by depletion with anti-NK1.1 antibody. FINDINGS: Bm12.Kd.IE heart grafts provoked strong germinal centre alloantibody and autoantibody responses in C57BL/6 recipients and developed allograft vasculopathy. By contrast, heart grafts from CD4 T-cell-depleted donors developed only minimal vasculopathy, and the alloantibody responses were weaker, without observable autoantibody. Bm12.Kd.IE CD4 T cells survived long term when transferred to RAG hosts suggesting that avoidance of killing by host NK cells might be essential for autoantibody development. In support, in a model of alloantibody-mediated vasculopathy, depletion of NK cells from a C57BL/6 recipient of a BALB/c heart graft resulted in the development of autoantibody, amplification of the alloantibody response, and rapid allograft rejection. This amplification was abrogated by depletion of donor CD4 T cells. INTERPRETATION: Although host adaptive immunity is expected to bring about destruction of passenger lymphocytes within heart allografts, this process occurs too slowly to prevent GVH-mediated augmentation of the alloresponse to the graft. Rather, rapid killing of donor lymphocytes by host alloreactive NK cells is essential. Passenger CD4 lymphocytes might therefore contribute to chronic rejection in recipients receiving an allograft that does not prompt innate NK cell recognition. FUNDING: Wellcome Trust Clinical Research Training Fellowship.

Outcomes of primary arteriovenous fistulas in patients older than 70 years.

BACKGROUND: The population of elderly hemodialysis patients is increasing, yet the most suitable approach for providing permanent hemodialysis access remains unclear. Here we report outcomes using an approach aimed predominantly at creating radiocephalic (RC) fistulas. METHODS: A single-center retrospective cohort study was performed in which access outcomes for primary arteriovenous fistulas created between January 1, 2005, and December 31, 2012, in patients aged 70 years or older were compared. RESULTS: During the study period, 204 RC, 1 brachiobasilic, and 9 brachiocephalic (BC) primary fistulas were created initially for patients requiring dialysis. Immediate failure rates for RC fistulas were lower than for BC fistulas but not significantly so (12% vs 22%; Fisher's exact text, P = .319). One-year primary and secondary patency for RC fistulas was 54% and 66%, respectively, and similar for those created in patients between 70 and 80 years old and in those older than 80 years. The secondary patency rate at 1 year for RC fistulas using cephalic vein of diameter <2.5 mm was lower than for fistulas created with cephalic vein >2.5 mm (49% vs 72%; log-rank test, P = .005). Creation of a BC fistula was associated with a significantly higher incidence of steal syndrome than with an RC fistula (10% vs 2%; Fisher's exact text, P = .009). CONCLUSIONS: RC fistulas formed in the elderly carry a lower risk of steal syndrome than BC fistulas and offer the potential for further revision surgery, such that acceptable secondary patency is achieved for RC fistulas formed using even small (<2.5 mm) cephalic veins.