Quantum Monte Carlo : some theoretical and numerical studies

In Part I, theoretical derivations for Variational Monte Carlo calculations are compared with results from a numerical calculation of He; both indicate that minimization of the ratio estimate of Evar , denoted EMC ' provides different optimal variational parameters than does minimization of the variance of E MC • Similar derivations for Diffusion Monte Carlo calculations provide a theoretical justification for empirical observations made by other workers. In Part II, Importance sampling in prolate spheroidal coordinates allows Monte Carlo calculations to be made of E for the vdW molecule var He2' using a simplifying partitioning of the Hamiltonian and both an HF-SCF and an explicitly correlated wavefunction. Improvements are suggested which would permit the extension of the computational precision to the point where an estimate of the interaction energy could be made

High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria

Acknowledgements We are grateful for the assistance provided by both the Microscopy and Histology Core Facility, and the Iain Fraser Cytometry Centre, at the University of Aberdeen. We thank Ann Wheeler and Matt Pearson from Edinburgh Super-Resolution Imaging Consortium for technical support with 3D SIM microscopy. We also thank Janet A. Willment and Bernard Kerscher, supervised by G.D.B., for providing the Fc fusion proteins, Jeanette A. Wagener, supervised by Neil A.R.G. Gow, for providing high purity chitin, Jan Westland for obtaining blood samples and Paul Crocker for useful discussions. Principal funding for this project was provided by Wellcome Trust grant 094847 (R.N.B, L.P.E, M.A.V). In addition, support was provided by Biotechnology and Biological Sciences Research Council grants BBF0083091 (A.D. and S.M.H.) and BBK0161641 (A.D. and S.M.H.), Wellcome Trust grant 082098 (A.D.), Wellcome Trust grants 97377, 102705 (G.D.B) and funding for the MRC Centre for Medical Mycology at the University of Aberdeen MR/N006364/1 (G.D.B).Non peer reviewe

Red blood cell mannoses as phagocytic ligands mediating both sickle cell anaemia and malaria resistance

Acknowledgements We are grateful for the assistance provided by both the Microscopy and Histology Core Facility, and the Iain Fraser Cytometry Centre, at the University of Aberdeen. We thank Ann Wheeler and Matt Pearson from Edinburgh Super-Resolution Imaging Consortium for technical support with 3D SIM microscopy. We also thank Janet A. Willment and Bernard Kerscher, supervised by G.D.B., for providing the Fc fusion proteins, Jeanette A. Wagener, supervised by Neil A.R.G. Gow, for providing high purity chitin, Jan Westland for obtaining blood samples and Paul Crocker for useful discussions. Principal funding for this project was provided by Wellcome Trust grant 094847 (R.N.B., L.P.E., M.A.V.). In addition, support was provided by Biotechnology and Biological Sciences Research Council grants BBF0083091 (A.D. and S.M.H.) and BBK0161641 (A.D. and S.M.H.), Wellcome Trust grant 082098 (A.D.), Wellcome Trust grants 97377, 102705 (G.D.B.), and funding for the MRC Centre for Medical Mycology at the University of Aberdeen MR/N006364/1 (G.D.B.).Peer reviewedPublisher PD

Radical cystectomy (bladder removal) against intravesical BCG immunotherapy for high-risk non-muscle invasive bladder cancer (BRAVO): a protocol for a randomised controlled feasibility study

INTRODUCTION: High-risk non-muscle invasive bladder cancer (HRNMIBC) is a heterogeneous disease that can be difficult to predict. While around 25% of cancers progress to invasion and metastases, the remaining majority of tumours remain within the bladder. It is uncertain whether patients with HRNMIBC are better treated with intravesical maintenance BCG (mBCG) immunotherapy or primary radical cystectomy (RC). A definitive randomised controlled trial (RCT) is needed to compare these two different treatments but may be difficult to recruit to and has not been attempted to date. Before undertaking such an RCT, it is important to understand whether such a comparison is possible and how best to achieve it. METHODS AND ANALYSIS: BRAVO is a multi-centre, parallel-group, mixed-methods, individually randomised, controlled, feasibility study for patients with HRNMIBC. Participants will be randomised to receive either mBCG immunotherapy or RC. The primary objective is to assess the feasibility and acceptability of performing the definitive phase III trial via estimation of eligibility and recruitment rates, assessing uptake of allocated treatment and compliance with mBCG, determining quality-of-life questionnaire completion rates and exploring reasons expressed by patients for declining recruitment into the study. We aim to recruit 60 participants from six centres in the UK. Surgical trials with disparate treatment options find recruitment challenging from both the patient and clinician perspective. By building on the experiences of other similar trials through implementing a comprehensive training package aimed at clinicians to address these challenges (qualitative substudy), we hope that we can demonstrate that a phase III trial is feasible. ETHICS AND DISSEMINATION: The study has ethical approval (16/YH/0268). Findings will be made available to patients, clinicians, the funders and the National Health Service through traditional publishing and social media. TRIAL REGISTRATION NUMBER: ISRCTN12509361; Pre results

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

First-trimester ultrasound detection of fetal heart anomalies: systematic review and meta-analysis

Objectives: To determine the diagnostic accuracy of ultrasound at 11–14 weeks' gestation in the detection of fetal cardiac abnormalities and to evaluate factors that impact the detection rate. Methods: This was a systematic review of studies evaluating the diagnostic accuracy of ultrasound in the detection of fetal cardiac anomalies at 11–14 weeks' gestation, performed by two independent reviewers. An electronic search of four databases (MEDLINE, EMBASE, Web of Science Core Collection and The Cochrane Library) was conducted for studies published between January 1998 and July 2020. Prospective and retrospective studies evaluating pregnancies at any prior level of risk and in any healthcare setting were eligible for inclusion. The reference standard used was the detection of a cardiac abnormality on postnatal or postmortem examination. Data were extracted from the included studies to populate 2 × 2 tables. Meta-analysis was performed using a random-effects model in order to determine the performance of first-trimester ultrasound in the detection of major cardiac abnormalities overall and of individual types of cardiac abnormality. Data were analyzed separately for high-risk and non-high-risk populations. Preplanned secondary analyses were conducted in order to assess factors that may impact screening performance, including the imaging protocol used for cardiac assessment (including the use of color-flow Doppler), ultrasound modality, year of publication and the index of sonographer suspicion at the time of the scan. Risk of bias and quality assessment were undertaken for all included studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Results: The electronic search yielded 4108 citations. Following review of titles and abstracts, 223 publications underwent full-text review, of which 63 studies, reporting on 328 262 fetuses, were selected for inclusion in the meta-analysis. In the non-high-risk population (45 studies, 306 872 fetuses), 1445 major cardiac anomalies were identified (prevalence, 0.41% (95% CI, 0.39–0.43%)). Of these, 767 were detected on first-trimester ultrasound examination of the heart and 678 were not detected. First-trimester ultrasound had a pooled sensitivity of 55.80% (95% CI, 45.87–65.50%), specificity of 99.98% (95% CI, 99.97–99.99%) and positive predictive value of 94.85% (95% CI, 91.63–97.32%) in the non-high-risk population. The cases diagnosed in the first trimester represented 63.67% (95% CI, 54.35–72.49%) of all antenatally diagnosed major cardiac abnormalities in the non-high-risk population. In the high-risk population (18 studies, 21 390 fetuses), 480 major cardiac anomalies were identified (prevalence, 1.36% (95% CI, 1.20–1.52%)). Of these, 338 were detected on first-trimester ultrasound examination and 142 were not detected. First-trimester ultrasound had a pooled sensitivity of 67.74% (95% CI, 55.25–79.06%), specificity of 99.75% (95% CI, 99.47–99.92%) and positive predictive value of 94.22% (95% CI, 90.22–97.22%) in the high-risk population. The cases diagnosed in the first trimester represented 79.86% (95% CI, 69.89–88.25%) of all antenatally diagnosed major cardiac abnormalities in the high-risk population. The imaging protocol used for examination was found to have an important impact on screening performance in both populations (P < 0.0001), with a significantly higher detection rate observed in studies using at least one outflow-tract view or color-flow Doppler imaging (both P < 0.0001). Different types of cardiac anomaly were not equally amenable to detection on first-trimester ultrasound. Conclusions: First-trimester ultrasound examination of the fetal heart allows identification of over half of fetuses affected by major cardiac pathology. Future first-trimester screening programs should follow structured anatomical assessment protocols and consider the introduction of outflow-tract views and color-flow Doppler imaging, as this would improve detection rates of fetal cardiac pathology. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology

Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials

Background: Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages. Methods: In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups. Findings: 14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0·01), and remained non-significant for major vascular events (ptrend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence. Interpretation: Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials. Funding: Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

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