Heart and en-bloc thymus transplantation in miniature swine

BackgroundDonor-specific tolerance to organ allografts might be induced by cotransplantation of a sufficient amount of vascularized donor thymus. To facilitate donor thymus-induced cardiac allograft tolerance, we have developed a novel technique for heart and en-bloc thymus transplantation in swine.MethodsDonor heart and en-bloc thymus grafts were prepared by a technique that preserves the entire arterial supply and venous drainage of the right thymic lobe. En-bloc grafts (n = 4) were transplanted heterotopically into the abdomens of major histocompatibility complex-matched miniature swine. Recipients received 12 days of cyclosporine intravenously. Grafts were monitored by palpation, electrocardiographic monitoring, and periodic open biopsy. Engraftment of the donor thymus was demonstrated by measuring the proportion of recipient-type thymocytes in the donor thymus with flow cytometry.ResultsAll of the heart and en-bloc thymus grafts had normal cardiac contractility and immediate perfusion of the thymus. All en-bloc grafts were accepted for more than 200 days without significant acute cellular rejection or cardiac allograft vasculopathy. Thymic tissue of en-bloc grafts displayed normal architecture and supported thymopoiesis of recipient-type cells.ConclusionWe have validated a new technique of donor thymus transplantation that could have utility in human heart transplantation

Stability and collapse of rapidly rotating, supramassive neutron stars: 3D simulations in general relativity

We perform 3D numerical simulations in full general relativity to study the stability of rapidly rotating, supramassive neutron stars at the mass-shedding limit to dynamical collapse. We adopt an adiabatic equation of state with $\Gamma = 2$ and focus on uniformly rotating stars. We find that the onset of dynamical instability along mass-shedding sequences nearly coincides with the onset of secular instability. Unstable stars collapse to rotating black holes within about one rotation period. We also study the collapse of stable stars which have been destabilized by pressure depletion (e.g. via a phase transition) or mass accretion. In no case do we find evidence for the formation of massive disks or any ejecta around the newly formed Kerr black holes, even though the progenitors are rapidly rotating.Comment: 16 pages, to appear in Phys. Rev.

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding: Novo Nordisk

Spatial patterns of large African cats : a large-scale study on density, home range size, and home range overlap of lions Panthera leo and leopards Panthera pardus

SUPPORTING INFORMATION : APPENDIX S1. Site information. APPENDIX S2. Intuitive explanation of the autocorrelated kernel density estimator. APPENDIX S3. Sources of density data. APPENDIX S4. Mathematical modifications of Jetz et al.’s (2014) overlap equation. APPENDIX S5. Lion pride size data.1. Spatial patterns of and competition for resources by territorial carnivores are typically explained by two hypotheses: 1) the territorial defence hypothesis and 2) the searching efficiency hypothesis. 2. According to the territorial defence hypothesis, when food resources are abundant, carnivore densities will be high and home ranges small. In addition, carnivores can maximise their necessary energy intake with minimal territorial defence. At medium resource levels, larger ranges will be needed, and it will become more economically beneficial to defend resources against a lower density of competitors. At low resource levels, carnivore densities will be low and home ranges large, but resources will be too scarce to make it beneficial to defend such large territories. Thus, home range overlap will be minimal at intermediate carnivore densities. 3. According to the searching efficiency hypothesis, there is a cost to knowing a home range. Larger areas are harder to learn and easier to forget, so carnivores constantly need to keep their cognitive map updated by regularly revisiting parts of their home ranges. Consequently, when resources are scarce, carnivores require larger home ranges to acquire sufficient food. These larger home ranges lead to more overlap among individuals’ ranges, so that overlap in home ranges is largest when food availability is the lowest. Since conspecific density is low when food availability is low, this hypothesis predicts that overlap is largest when densities are the lowest. 4. We measured home range overlap and used a novel method to compare intraspecific home range overlaps for lions Panthera leo (n = 149) and leopards Panthera pardus (n = 111) in Africa. We estimated home range sizes from telemetry location data and gathered carnivore density data from the literature. 5. Our results did not support the territorial defence hypothesis for either species. Lion prides increased their home range overlap at conspecific lower densities whereas leopards did not. Lion pride changes in overlap were primarily due to increases in group size at lower densities. By contrast, the unique dispersal strategies of leopards led to reduced overlap at lower densities. However, when human-caused mortality was higher, leopards increased their home range overlap. Although lions and leopards are territorial, their territorial behaviour was less important than the acquisition of food in determining their space use. Such information is crucial for the future conservation of these two iconic African carnivores.The Natural Sciences and Engineering Research Council of Canada and a Hugh Kelly Fellowship from Rhodes University, Grahamstown, SA.https://onlinelibrary.wiley.com/journal/13652907am2024Centre for Wildlife ManagementMammal Research InstituteZoology and EntomologySDG-15:Life on lan

Controls on Coastal Dune Morphology, Shoreline Erosion and Barrier Island Response to Extreme Storms

The response of a barrier island to an extreme storm depends in part on the surge elevation relative to the height and extent of the foredunes which can exhibit considerable variability alongshore. While it is recognized that alongshore variations in dune height and width direct barrier island response to storm surge, the underlying causes of the alongshore variation remain poorly understood. This study examines the alongshore variation in dune morphology along a 11 km stretch of Santa Rosa Island in northwest Florida and relates the variation in morphology to the response of the island during Hurricane Ivan and historic and storm-related rates of shoreline erosion. The morphology of the foredune and backbarrier dunes was characterized before and after Hurricane Ivan using Empirical Orthogonal Function (EOF) analysis and related through Canonical Correlation Analysis (CCA). The height and extent of the foredune, and the presence and relative location of the backbarrier dunes, varied alongshore at discrete length scales (of ~ 750, 1450 and 4550 m) that are statistically significant at the 95% confidence level. Cospectral analysis suggests that the variation in dune morphology is correlated with transverse ridges on the inner-shelf, the backbarrier cuspate headlands, and the historical and storm-related trends in shoreline change. Sections of the coast with little to no dune development before Hurricane Ivan were observed in the narrowest portions of the island (between headlands), west of the transverse ridges. Overwash penetration tended to be larger in these areas and island breaching was common, leaving the surface close to the watertable and covered by a lag of shell and gravel. In contrast, large foredunes and the backbarrier dunes were observed at the widest sections of the island (the cuspate headlands) and at crest of the transverse ridges. Due to the large dunes and the presence of the backbarrier dunes, these areas experienced less overwash penetration and most of the sediment from the beachface and dunes was deposited within the upper-shoreface. It is argued that this sediment is returned to the beachface through nearshore bar migration following the storm and that the areas with larger foredunes and backbarrier dunes have smaller rates of historical shoreline erosion compared to areas with smaller dunes and greater transfer of sediment to the washover terrace. Since the recovery of the dunes will vary depending on the availability of sediment from the washover and beachface, it is further argued that the alongshore pattern of dune morphology and the response of the island to the next extreme storm is forced by the transverse ridges and island width through alongshore variations in storm surge and overwash gradients respectively. These findings may be particularly important for coastal managers involved in the repair and rebuilding of coastal infrastructure that was damaged or destroyed during Hurricane Ivan

Higher frequency of high-grade rejections in cardiac allograft patients after Quilty B lesions or grade 2/4 rejections

To better understand how different histologic patterns of allograft inflammation found on biopsies of human cardiac allografts progress to high-grade rejection, we undertook a statistical analysis of our institutional database to detect statistical patterns among different types of myocardial allograft inflammations found on sequential biopsies. Biopsies were analyzed for statistical associations between high-grade rejections (International Society of Heart and Lung Transplantation [ISHLT] grade > or = 3A/4) and the type of cardiac allograft inflammation found on prior biopsies. Case cross-over and case control designs were used to compare the antecedent patterns of inflammation on biopsies with high-grade rejection compared to biopsies with low-grade rejection, all within the same subject. Quilty lesions were correlated with cyclosporine levels. Patients with Quilty B lesions or ISHLT grade 2/4 rejections show an increased risk for high-grade rejection on their next biopsies (Odds ratio 5.9 to 11.2). The presence of two pathological findings, especially Quilty B and grade 2/4 rejection, creates additional risk in excess of that found independently (Odds ratio >14). Quilty lesions are found only in cardiac allografts, and do not correlate with trough cyclosporine levels. The morphological patterns of several types of human cardiac allograft inflammation found on sequential protocol biopsies are not randomly associated. Patients with grade 2/4 rejections and Quilty B lesions show an increased risk for high-grade rejections on their next biopsies. Quilty B lesions, similar to ISHLT grade 2/4 rejections, may represent subclinical rejection. Both are more likely to progress to a high-grade rejection

Pig kidney transplantation in baboons treated intravenously with a bovine serum albumin-Galalpha1-3Gal conjugate

The maintenance of depletion of antibody (Ab) reactive with Galalpha1-3Gal (Gal) on pig vascular endothelial cells by the intravenous (i.v.) infusion of a synthetic Gal conjugate has been proposed as a means of delaying Ab-mediated rejection of transplanted pig organs in primates. We have therefore studied the effect of the continuous i.v. infusion of bovine serum albumin conjugated to multiple synthetic Gal type 6 oligosaccharides (BSA-Gal) on anti-Gal Ab levels and on graft survival in baboons undergoing pig kidney transplantation. Group 1 baboons (n=3) underwent extracorporeal immunoadsorption of anti-Gal Ab, a cyclophosphamide (CPP)-based immunosuppressive regimen, and a non-transgenic pig kidney transplant. Group 2 (n=2) were treated identically to Group 1 but, in addition, received a continuous i.v. infusion of BSA-Gal. Group 3 (n=2) were treated identically to Group 2, but without CPP. A single baboon (Group 4) underwent extracorporeal immunoadsorption, a CPP-based regimen, and continuous i.v. BSA-Gal therapy for 28 days, but did not receive a pig kidney transplant. Two of the transplanted pig kidneys in Group 1 were excised on post transplant days 7 and 13 for a rejected ureter, and disseminated intravascular coagulation (DIC), respectively. The third baboon died of sepsis on day 6. All transplanted ureters and kidneys showed some histopathologic features of acute humoral xenograft rejection. Group 2 baboons were euthanized on days 8 and 11, respectively, for liver failure. At autopsy, there were histopathological features of widespread liver necrosis, but the pig kidneys and ureters showed no features of rejection. The pig kidneys in Group 3 baboons were excised for renal vein thrombosis (day 9) and DIC (day 12); there was no histological signs of rejection in the pig kidneys or ureter, although there were focal areas of modest liver injury in one baboon on biopsy. The single Group 4 baboon showed no biochemical or histological features of liver injury. Anti-Gal Ab levels returned in Group 1, but were maintained at negligible levels in the baboons in Groups 2 to 4 that received BSA-Gal therapy. Continuous i.v. therapy with BSA-Gal is largely successful in maintaining depletion of circulating anti-Gal antibodies and in preventing or delaying Ab deposition and acute humoral xenograft rejection in porcine grafts, but may be associated with liver injury when administered in the presence of a pig kidney transplant and CPP therapy. The mechanism of the hepatic injury remains uncertain