Cardiovascular magnetic resonance imaging in severe aortic stenosis: impact of surgical and trans-catheter aortic valve replacement on reverse remodelling and fibrosis

Introduction: Aortic stenosis (AS) is the commonest valvular lesion in the developed world and is associated with adverse cardiac remodelling. With its excellent accuracy and reproducibility, cardiovascular magnetic resonance (CMR) imaging is an ideal tool to assess cardiac remodelling and reverse remodelling following surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI). The aims of this thesis were: 1) to evaluate gender differences in AS and following aortic valve replacement, 2) to evaluate the incidence of post-procedural myocardial infarction following SAVR and TAVI, 3) to describe the immediate effect of TAVI on reverse remodelling and 4) to assess the impact of TAVI-induced left bundle branch block (LBBB) . Methods: Between January 2009 and April 2015, patients with severe AS undergoing either TAVI or SAVR were prospectively recruited. Patients underwent comprehensive 1.5T CMR evaluation pre-procedure, prior to hospital discharge and 6m post-procedure. Results: 1) Women with severe AS have a lower indexed left ventricular (LV) mass than men (65.3± 18.4 vs. 81.5±21.3g/m2, p<0.001). 6m following valve replacement, LV mass regression is similar between genders (men 21.7±10.1 vs. women 18.4±11.0%, p=0.121). 2) Myocardial infarction (MI) is more frequent following SAVR than TAVI (n=10 (26%) vs. n=3 (5%), p=0.004). 3) Over 10% of LV mass regression occurs prior to hospital discharge following TAVI and is more pronounced in the absence of myocardial fibrosis (p=0.005). 4) TAVI-induced LBBB is associated with a reduced LVEF 6m following TAVI compared with those with a narrow QRS (-2.1±6.9 vs. +4.6±7.8%, p=0.002). Conclusions: TAVI and SAVR are associated with favourable cardiac reverse remodelling which does not differ according to gender and begins prior to hospital discharge. SAVR is associated with a higher incidence of post-procedural MI than TAVI. TAVI-induced LBBB should be avoided where possible due to its unfavourable effects on cardiac reverse remodelling

Climate-Related Hazards: A Method for Global Assessment of Urban and Rural Population Exposure to Cyclones, Droughts, and Floods

Global climate change (GCC) has led to increased focus on the occurrence of, and preparation for, climate-related extremes and hazards. Population exposure, the relative likelihood that a person in a given location was exposed to a given hazard event(s) in a given period of time, was the outcome for this analysis. Our objectives were to develop a method for estimating the population exposure at the country level to the climate-related hazards cyclone, drought, and flood; develop a method that readily allows the addition of better datasets to an automated model; differentiate population exposure of urban and rural populations; and calculate and present the results of exposure scores and ranking of countries based on the country-wide, urban, and rural population exposures to cyclone, drought, and flood. Gridded global datasets on cyclone, drought and flood occurrence as well as population density were combined and analysis was carried out using ArcGIS. Results presented include global maps of ranked country-level population exposure to cyclone, drought, flood and multiple hazards. Analyses by geography and human development index (HDI) are also included. The results and analyses of this exposure assessment have implications for country-level adaptation. It can also be used to help prioritize aid decisions and allocation of adaptation resources between countries and within a country. This model is designed to allow flexibility in applying cyclone, drought and flood exposure to a range of outcomes and adaptation measures

Salicylic acid treatment and expression of an RNA-dependent RNA polymerase 1 transgene inhibit lethal symptoms and meristem invasion during tobacco mosaic virus infection in Nicotiana benthamiana.

BACKGROUND: Host RNA-dependent RNA polymerases (RDRs) 1 and 6 contribute to antiviral RNA silencing in plants. RDR6 is constitutively expressed and was previously shown to limit invasion of Nicotiana benthamiana meristem tissue by potato virus X and thereby inhibit disease development. RDR1 is inducible by salicylic acid (SA) and several other phytohormones. But although it contributes to basal resistance to tobacco mosaic virus (TMV) it is dispensable for SA-induced resistance in inoculated leaves. The laboratory accession of N. benthamiana is a natural rdr1 mutant and highly susceptible to TMV. However, TMV-induced symptoms are ameliorated in transgenic plants expressing Medicago truncatula RDR1. RESULTS: In MtRDR1-transgenic N. benthamiana plants the spread of TMV expressing the green fluorescent protein (TMV.GFP) into upper, non-inoculated, leaves was not inhibited. However, in these plants exclusion of TMV.GFP from the apical meristem and adjacent stem tissue was greater than in control plants and this exclusion effect was enhanced by SA. TMV normally kills N. benthamiana plants but although MtRDR1-transgenic plants initially displayed virus-induced necrosis they subsequently recovered. Recovery from disease was markedly enhanced by SA treatment in MtRDR1-transgenic plants whereas in control plants SA delayed but did not prevent systemic necrosis and death. Following SA treatment of MtRDR1-transgenic plants, extractable RDR enzyme activity was increased and Western blot analysis of RDR extracts revealed a band cross-reacting with an antibody raised against MtRDR1. Expression of MtRDR1 in the transgenic N. benthamiana plants was driven by a constitutive 35S promoter derived from cauliflower mosaic virus, confirmed to be non-responsive to SA. This suggests that the effects of SA on MtRDR1 are exerted at a post-transcriptional level. CONCLUSIONS: MtRDR1 inhibits severe symptom development by limiting spread of virus into the growing tips of infected plants. Thus, RDR1 may act in a similar fashion to RDR6. MtRDR1 and SA acted additively to further promote recovery from disease symptoms in MtRDR1-transgenic plants. Thus it is possible that SA promotes MtRDR1 activity and/or stability through post-transcriptional effects.We thank Zhixiang Chen for his advice on the RDR assay protocol. Xiaoqiang Wang and Zhentian Lei at the Samuel Roberts Noble Foundation for the AKTA purification protocol and analysis of recombinant MBP:MtRDR1 fusion protein, respectively. David Baulcombe, Peter Palukaitis, Joel Milner and Lydia Hunter are thanked for stimulating discussions and useful advice and Adrienne Pate for expert technical assistance. FSF was funded by grants from the Cambridge Overseas Trust and the Ministry of Education of Taiwan, and WSL was funded by a studentship from the Biotechnology and Biological Sciences Research Council (BBSRC) and work in the Carr lab was funded by BBSRC grants (BB/D008204/1, BB/D014376/1, BB/J011762/1), The Leverhulme Trust (F/09 741/F, RPG-2012-667), and Cambridge University Isaac Newton Trust. RSN and SRC were funded by the Samuel Roberts Noble Foundation, Inc

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

Early Spectroscopy and Dense Circumstellar Medium Interaction in SN~2023ixf

We present the optical spectroscopic evolution of SN~2023ixf seen in sub-night cadence spectra from 1.18 to 14 days after explosion. We identify high-ionization emission features, signatures of interaction with material surrounding the progenitor star, that fade over the first 7 days, with rapid evolution between spectra observed within the same night. We compare the emission lines present and their relative strength to those of other supernovae with early interaction, finding a close match to SN~2020pni and SN~2017ahn in the first spectrum and SN~2014G at later epochs. To physically interpret our observations we compare them to CMFGEN models with confined, dense circumstellar material around a red supergiant progenitor from the literature. We find that very few models reproduce the blended \NC{} emission lines observed in the first few spectra and their rapid disappearance thereafter, making this a unique diagnostic. From the best models, we find a mass-loss rate of $10^{-3}-10^{-2}$ \mlunit{}, which far exceeds the mass-loss rate for any steady wind, especially for a red supergiant in the initial mass range of the detected progenitor. These mass-loss rates are, however, similar to rates inferred for other supernovae with early circumstellar interaction. Using the phase when the narrow emission features disappear, we calculate an outer dense radius of circumstellar material $R_\mathrm{CSM, out}\sim5\times10^{14}~\mathrm{cm}$ and a mean circumstellar material density of $\rho=5.6\times10^{-14}~\mathrm{g\,cm^{-3}}$. This is consistent with the lower limit on the outer radius of the circumstellar material we calculate from the peak \Halpha{} emission flux, $R_\text{CSM, out}\gtrsim9\times10^{13}~\mathrm{cm}$.Comment: Submitted to ApJ

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

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention