Fibrinolysis: Its relationship to coronary heart disease and "risk factors"

This thesis reviews the Literature relating to the various factors which are important in the development of clinically significant coronary artery atherosclerosis. The pathogenesis and progress of atherosclerotic lesions are considered and the Literature regarding the various so-called coronary heart disease (C.H.D.) "risk factors" examined. The importance of two main non-modifiable "risk factors", age and sex, and three main modifiable "risk factors", cigarette-smoking, hypertension and increased plasma Lipid levels, is discussed. A possible relationship between poor plasma fibrinolytic activity and the risk of developing C.H.D. is postulated. Current knowledge about the various components of the fibrinolytic system is presented and evidence of physiological and pathological variations in fibrinolysis consi -dered. A standardised procedure for measuring plasma fibrinolytic activity in euglobulin fractions applied to fibrin plates was introduced and details of this procedure are presented along with the results of a number of experiments carried out to examine the effect of varying different aspects of the standardised procedure. As previously reported by other researchers, plasma fibrinolytic activity has been shown, normally to increase locally in response to venous occlusion of a limb. A fifteen minute venous occlusion test of an arm was developed and assessed as a means of studying the fibrinolytic response to a challenge. This test has been found to be reproducible and acceptable to both healthy male volunteers and male patients. In agreement with other workers, plasma fibrinolytic activity, resting and post venous occlusion, has been found to vary in relation to the existence of a number of the C.H.D. "risk factors" - in particular to plasma lipid levels but also, probably, to age and to diastolic blood pressure. No direct relationship between cigarette smoking habit and plasma fibrinolytic activity could be defined. Male subjects only were studied. The relationships between plasma fibrinolytic activity and C.H.D. "risk factors" were present both in healthy controls and in men known to have C.H.D. Results are presented which suggest that C.H.D. itself is associated with reduced plasma fibrinolytic activity at rest and, possibly, post venous occlusion. This impaired fibrinolytic activity appears to be independent of co-existing C.H.D. "risk factors". It is not possible, from the evidence obtained in this study, to comment on whether impaired plasma fibrinolytic activity is an important factor contributing to the risk of developing C.H.D. or is a secondary effect of the disease

Successful elimination of factor VIII inhibitor using cyclosporin A

No abstract available

Exploring the spectral diversity of low-redshift Type Ia supernovae using the Palomar Transient Factory

We present an investigation of the optical spectra of 264 low-redshift (z < 0.2) Type Ia supernovae (SNe Ia) discovered by the Palomar Transient Factory, an untargeted transient survey. We focus on velocity and pseudo-equivalent width measurements of the Si II 4130, 5972, and 6355 A lines, as well those of the Ca II near-infrared (NIR) triplet, up to +5 days relative to the SN B-band maximum light. We find that a high-velocity component of the Ca II NIR triplet is needed to explain the spectrum in ~95 per cent of SNe Ia observed before -5 days, decreasing to ~80 per cent at maximum. The average velocity of the Ca II high-velocity component is ~8500 km/s higher than the photospheric component. We confirm previous results that SNe Ia around maximum light with a larger contribution from the high-velocity component relative to the photospheric component in their Ca II NIR feature have, on average, broader light curves and lower Ca II NIR photospheric velocities. We find that these relations are driven by both a stronger high-velocity component and a weaker contribution from the photospheric Ca II NIR component in broader light curve SNe Ia. We identify the presence of C II in very-early-time SN Ia spectra (before -10 days), finding that >40 per cent of SNe Ia observed at these phases show signs of unburnt material in their spectra, and that C II features are more likely to be found in SNe Ia having narrower light curves.Comment: 18 page, 10 figures, accepted for publication in MNRA

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

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

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Abstract: Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating