Early Experience With a Novel Dissection-Specific Stent-Graft to Prevent Distal Stent-Graft-Induced New Entry Tears After Thoracic Endovascular Repair of Chronic Type B Aortic Dissections

Background: The aim was to report short and mid-term outcomes of a novel, investigational, dissection-specific stent-graft (DSSG), specifically designed to address the features of chronic type B aortic dissection (CTBAD) and reduce the risk of distal stent-graft-induced new entry tears (dSINE). Materials and Methods: A retrospective single center cohort study of all patients undergoing TEVAR with the DSSG for CTBAD from January 1, 2017 to January 31, 2020. The DSSG, which is a modified stent-graft based on the Cook Zenith Alpha Thoracic platform, has no proximal barbs, and a customized longer body length with substantial taper. The second and third distal Z-stents are sited internally to avoid any contact of the metal skeleton with the dissection membrane and have reduced radial force, while the most distal stent was removed creating a distal 30 mm unsupported Dacron graft. Results: Sixteen patients (13 males, 3 females) with a median age of 66 years (range 31–79 years) underwent elective TEVAR of CTBAD using the DSSG. Six patients (38%) had an underlying connective tissue disorder. The median tapering was 10 mm (range 4 mm–21 mm) and median length 270 mm (range 210–380 mm). Technical success was achieved in all but one case (96%). One patient died within 30 days, due to retrograde type A dissection with cardiac tamponade. The 30-day rate of stroke, spinal cord ischemia, and re-interventions was 0%. After median imaging follow-up time of 17 months (range 1–31 months), one patient developed a dSINE 4 months after the index procedure. After median survival follow-up of 23 months (range 2–35 months), one late death occurred due to traumatic brain injury, while no aortic-related death occurred during follow-up. Complete false lumen (FL) thrombosis was achieved in 9 patients while the remaining 6 showed partial FL thrombosis. No instances of diameter increase at the level oftreated aortic segment were noted with serial measurements showing either stable (n = 7) or decreased (n = 8) maximal transverse diameter. Conclusions: Use of a novel DSSG with low radial force for TEVAR in the setting of CTBAD is safe and feasible. This early real-world experience shows promising mid-term effectiveness with low rates of dSINE or unplanned re-interventions and satisfactory aortic remodeling during follow-up. Longer follow-up is needed, however, before any firm conclusions can be drawn

Itaconate confers tolerance to late NLRP3 inflammasome activation

Itaconate is a unique regulatory metabolite that is induced upon Toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production in activated macrophages. We show that endogenous itaconate is a key regulator of the signal 2 of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation after long lipopolysaccharide (LPS) priming, which establishes tolerance to late NLRP3 inflammasome activation. We show that itaconate acts synergistically with inducible nitric oxide synthase (iNOS) and that the ability of various TLR ligands to establish NLRP3 inflammasome tolerance depends on the pattern of co-expression of IRG1 and iNOS. Mechanistically, itaconate accumulation upon prolonged inflammatory stimulation prevents full caspase-1 activation and processing of gasdermin D, which we demonstrate to be post-translationally modified by endogenous itaconate. Altogether, our data demonstrate that metabolic rewiring in inflammatory macrophages establishes tolerance to NLRP3 inflammasome activation that, if uncontrolled, can result in pyroptotic cell death and tissue damage

Single-cell atlas of healthy human blood unveils age-related loss of NKG2C+GZMB−CD8+ memory T cells and accumulation of type 2 memory T cells

Extensive, large-scale single-cell profiling of healthy human blood at different ages is one of the critical pending tasks required to establish a framework for the systematic understanding of human aging. Here, using single-cell RNA/T cell receptor (TCR)/BCR-seq with protein feature barcoding, we profiled 317 samples from 166 healthy individuals aged 25-85 years old. From this, we generated a dataset from ∼2 million cells that described 55 subpopulations of blood immune cells. Twelve subpopulations changed with age, including the accumulation of GZM

Distributed cerebellar plasticity implements generalized multiple-scale memory components in real-robot sensorimotor tasks

The cerebellum plays a crucial role in motor learning and it acts as a predictive controller. Modeling it and embedding it into sensorimotor tasks allows us to create functional links between plasticity mechanisms, neural circuits and behavioral learning. Moreover, if applied to real-time control of a neurorobot, the cerebellar model has to deal with a real noisy and changing environment, thus showing its robustness and effectiveness in learning. A biologically inspired cerebellar model with distributed plasticity, both at cortical and nuclear sites, has been used. Two cerebellum-mediated paradigms have been designed: an associative Pavlovian task and a vestibulo-ocular reflex, with multiple sessions of acquisition and extinction and with different stimuli and perturbation patterns. The cerebellar controller succeeded to generate conditioned responses and finely tuned eye movement compensation, thus reproducing human-like behaviors. Through a productive plasticity transfer from cortical to nuclear sites, the distributed cerebellar controller showed in both tasks the capability to optimize learning on multiple time-scales, to store motor memory and to effectively adapt to dynamic ranges of stimuli.This work was supported by grants of European Union: REALNET (FP7-ICT270434) and Human Brain Project (HBP-604102)

Perioperative platelet and monocyte activation in patients with critical limb ischemia

BackgroundPatients with critical limb ischemia (CLI) have a high rate of adverse cardiovascular events, particularly when undergoing surgery. We sought to determine the effect of surgery and vascular disease on platelet and monocyte activation in vivo in patients with CLI.MethodsAn observational, cross-sectional study was performed at a tertiary referral hospital in the southeast of Scotland. Platelet and monocyte activation were measured in whole blood in patients with CLI scheduled for infrainguinal bypass and compared with matched healthy controls, patients with chronic intermittent claudication, patients with acute myocardial infarction, and those undergoing arthroplasty (n = 30 per group). Platelet and monocyte activation were quantified using flow cytometric assessment of platelet-monocyte aggregation, platelet P-selectin expression, platelet-derived microparticles, and monocyte CD40 and CD11b expression.ResultsCompared with those with intermittent claudication, subjects with CLI had increased platelet-monocyte aggregates (41.7% ± 12.2% vs 32.6% ± 8.5%, respectively), platelet microparticles (178.7 ± 106.9 vs 116.9 ± 53.4), and monocyte CD40 expression (70.0% ± 12.2% vs 52.4% ± 15.2%; P < .001 for all). Indeed, these levels were equivalent (P-selectin, 4.4% ± 2.0% vs 4.9% ± 2.2%; P > .05) or higher (platelet-monocyte aggregation, 41.7% ± 12.2% vs 33.6% ± 7.0%; P < .05; platelet microparticles, 178.7 ± 106.9 vs 114.4 ± 55.0/μL; P < .05) than in patients with acute myocardial infarction. All platelet and monocyte activation markers remained elevated throughout the perioperative period in patients with CLI (P < .01) but not those undergoing arthroplasty.ConclusionsPatients undergoing surgery for CLI have the highest level of in vivo platelet and monocyte activation, and these persist throughout the perioperative period. Additional antiplatelet therapy may be of benefit in protecting vascular patients with more severe disease during this period of increased risk.Clinical RelevancePeripheral arterial disease is increasingly common and is associated with a significant risk of cardiovascular complications, especially at the time of surgery. Despite this, patients are poorly provided with evidence-based therapies such as antiplatelet and lipid-lowering medications. Platelets play a key role in the pathogenesis of atherothrombosis, with elevated levels of in vivo platelet activation prognostic of adverse clinical events. This study demonstrates, for the first time to our knowledge, significantly greater levels of platelet activation in patients with severe peripheral arterial disease compared with patients with acute myocardial infarction or patients undergoing other moderate- to high-risk surgical procedures. This further emphasizes the need for improved risk stratification and cardioprotection of this vulnerable group

Harnessing the preconditioning phenomenon: does remote organ ischaemia provide the answer?

Despite progress in defining the cellular mechanisms of the ischaemic preconditioning phenomenon, its conversion into convenient clinical practice has been slow. The possibility that an innate mechanism of tissue resistance to ischaemia could be harnessed as a clinical tool is an attractive and enticing prospec