Transcatheter non-contact microwave ablation may enable circumferential renal artery denervation while sparing the vessel intima and media

Aims: Trials of transcatheter renal artery denervation (RDN) have failed to show consistent antihypertensive efficacy. Procedural factors and limitations of radiofrequency ablation can lead to incomplete denervation. The aim of the study was to show that non-contact microwave catheter ablation could produce deep circumferential perivascular heating while avoiding injury to the renal artery intima and media. Methods and results: A novel microwave catheter was designed and tested in a renal artery model consisting of layers of phantom materials embedded with a thermochromic liquid crystal sheet, colour range 50-78°C. Ablations were performed at 140 W for 180 sec and 120 W for 210 sec, delivering 25,200 J with renal arterial flow at 0.5 L/min and 0.1 L/min. Transcatheter microwave ablations 100-160 W for 180 sec were then performed in the renal arteries of five sheep. In vitro, ablations at 140 W and 0.5 L/min flow produced circumferential lesions 5.9±0.2 mm deep and 19.2±1.5 mm long with subendothelial sparing depth of 1.0±0.1 mm. In vivo, transcatheter microwave ablation was feasible with no collateral visceral thermal injury. There was histological evidence of preferential outer media and adventitial ablation. Conclusions: Transcatheter microwave ablation for RDN appears feasible and provides a heating pattern that may enable more complete denervation while sparing the renal arterial intima and media

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Inflammatory Mechanisms and the Utility of Colchicine in Atherosclerotic Cardiovascular Disease

Atherosclerosis is a chronic, pro-inflammatory condition that significantly contributes towards the global burden of cardiovascular disease. Vascular smooth muscle cells (VSMC), in response to inflammatory stimuli, play an important role in the formation of atherosclerotic plaque and clinical manifestations of the disease process. Despite tremendous advances in medical therapy and coronary revascularisation techniques, the current therapeutic options for patients with atherosclerotic cardiovascular disease do not adequately suppresses the panvascular inflammatory process, leaving patients with a residual risk of disease progression and recurrence of major adverse cardiovascular events. Therefore, there is a current therapeutic gap in the management of this high-risk cohort of patients. Colchicine, an inexpensive immunomodulatory drug used traditionally to treat gout and familial Mediterranean fever, has recently emerged as a promising candidate to address this therapeutic gap but its mechanistic properties in atherosclerosis are yet to be fully understood. This thesis aimed to examine the mechanistic effects of colchicine on de novo atherosclerotic plaque formation and advanced plaque regression using a hyperlipidaemic apolipoprotein E knockout (ApoE-/-) murine model of atherosclerosis. These in vivo studies included both a prevention and late-stage intervention treatment strategy. In addition to this, in vitro studies were performed to investigate colchicine’s effects on vascular smooth muscle cell behaviour under inflammatory and hyperlipidaemic conditions. For the final chapter, a pilot clinical study was undertaken to assess colchicine’s acute effects on inflammatory chemokine and metabolite expression in patients with atherosclerotic cardiovascular disease. The major findings of this thesis were firstly, early colchicine treatment reduced de novo atherosclerotic plaque formation and resulted in plaque features associated with increased stability. In addition, early colchicine treatment was also able to suppress atherosclerosis related vascular inflammation. Secondly, colchicine attenuated proatherogenic VSMC behaviours, including cholesterol induced phenotypic switching, lipid uptake and foam cell formation. Thirdly, late-stage colchicine did not induce the regression of mature, advanced atherosclerotic lesions. Finally, the clinical study demonstrated that acute coronary syndrome patients had elevated levels of inflammatory chemokines and vasospastic mediators compared to patients with stable coronary artery disease. Importantly, colchicine treatment acutely reduced circulating levels of the inflammatory chemokines, CCL2, CCL5 and CX3CL1, in ACS patients and reduced macrophage CCL2 production and VSMC migration. In summary, this thesis illustrates colchicine’s ability to modulate atherosclerosis mediated vascular inflammation and early plaque formation as well as its specific beneficial effects on atherogenic vascular smooth muscle cell behaviour. Taken together, this work provides novel mechanistic insights and lends further support for the use of colchicine in atherosclerotic cardiovascular disease

Neutrophils in Acute Coronary Syndrome

Acute coronary syndrome (ACS) encompasses a spectrum of clinical disorders of myocardial ischaemia or infarction, with atherosclerosis leading to coronary plaque formation the predominant disease process. Alterations of endothelial cell integrity involving atherosclerotic plaque surfaces, such as plaque rupture or erosion, can lead to atherothrombosis with subsequent interruption to myocardial blood supply. Over the past two decades, it has become increasingly apparent that inflammation plays a pivotal role in the initiation and progression of atherosclerosis. Inflammatory cytokines have been shown to correlate with the risk and burden of coronary artery disease and there is a growing body of evidence demonstrating the presence of various immune cells in atherosclerotic plaques and coronary thrombus specimens. Due to improved cellular detection methods compared to earlier studies, neutrophils are being increasingly recognised as a key player in the process of athero-inflammation. The aim of this review is to: i) outline the role of neutrophils in ACS and atherothrombosis, ii) describe the process of inflammasome-mediated release of inflammatory cytokines from neutrophils, and iii) discuss multiple parameters of neutrophil activity in ACS, including peripheral neutrophil/lymphocyte ratio; neutrophil microparticle release; expression of neutrophilic granular proteins, including myeloperoxidase, neutrophil elastase, and metalloproteinases; neutrophil extracellular traps release; tissue factor; and neutrophil-macrophage interactions

Gravitational footprints of massive neutrinos and lepton number breaking

We investigate the production of primordial Gravitational Waves (GWs) arising from First Order Phase Transitions (FOPTs) associated to neutrino mass generation in the context of type-I and inverse seesaw schemes. We examine both “high-scale” as well as “low-scale” variants, with either explicit or spontaneously broken lepton number symmetry U(1) in the neutrino sector. In the latter case, a pseudo-Goldstone majoron-like boson may provide a candidate for cosmological dark matter. We find that schemes with softly-broken U(1) and with single Higgs-doublet scalar sector lead to either no FOPTs or too weak FOPTs, precluding the detectability of GWs in present or near future measurements. Nevertheless, we found that, in the majoron-like seesaw scheme with spontaneously broken U(1) at finite temperatures, one can have strong FOPTs and non-trivial primordial GW spectra which can fall well within the frequency and amplitude sensitivity of upcoming experiments, including LISA, BBO and u-DECIGO. However, GWs observability clashes with invisible Higgs decay constraints from the LHC. A simple and consistent fix is to assume the majoron-like mass to lie above the Higgs-decay kinematical threshold. We also found that the majoron-like variant of the low-scale seesaw mechanism implies a different GW spectrum than the one expected in the high-scale seesaw. This feature will be testable in future experiments. Our analysis shows that GWs can provide a new and complementary portal to test the neutrino mass generation mechanism.The work of R.P. was also sup-ported in part by The Ministry of Education, Youth and Sportsof the Czech Republic, project LT17018. The work of A.P.M. has been performed in the framework of COST Action CA16201 “Un-raveling new physics at the LHC through the precision frontier” (PARTICLEFACE). A.P.M.is supported by the Center for Research and Development in Mathematics and Applications (CIDMA) through the Portuguese Foundation for Science and Technology (FCT -Fun-dação para a Ciência e a Tecnologia), references UIDB/04106/2020 and UIDP/04106/2020 and by national funds (OE), through FCT, I.P., in the scope of the framework contract foreseen in the numbers 4, 5 and 6 of the article 23, of the Decree-Law 57/2016, of August 29, changed by Law 57/2017, of July 19.A.P.M.is also supported by the Enabling Green E-science for the Square Kilometer Array Research Infras-tructure(ENGAGESKA), POCI-01-0145-FEDER-022217, and by the projects PTDC/FIS-PAR/31000/2017 and CERN/FIS-PAR/0027/2019. R.V. and J.W.F.V. are supported by the Spanish grants SEV-2014-0398 and FPA2017-85216-P (AEI/FEDER, UE), PROMETEO/2018/165 (Generalitat Valenciana) and the Spanish Red Consolider MultiDark FPA2017-90566-REDC