Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation:systematic review, network meta-analysis and cost-effectiveness analysis

BACKGROUND: Warfarin is effective for stroke prevention in atrial fibrillation (AF), but anticoagulation is underused in clinical care. The risk of venous thromboembolic disease during hospitalisation can be reduced by low-molecular-weight heparin (LMWH): warfarin is the most frequently prescribed anticoagulant for treatment and secondary prevention of venous thromboembolism (VTE). Warfarin-related bleeding is a major reason for hospitalisation for adverse drug effects. Warfarin is cheap but therapeutic monitoring increases treatment costs. Novel oral anticoagulants (NOACs) have more rapid onset and offset of action than warfarin, and more predictable dosing requirements.OBJECTIVE: To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE.DESIGN: Four systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials.SETTING: Hospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention).PARTICIPANTS: Patients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE).INTERVENTIONS: NOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network.MAIN OUTCOME MEASURES: Efficacy Stroke, symptomatic VTE, symptomatic deep-vein thrombosis and symptomatic pulmonary embolism. Safety Major bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness.DATA SOURCES: MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library, reference lists of published NMAs and trial registries. We searched MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. The stroke prevention in AF review search was run on the 12 March 2014 and updated on 15 September 2014, and covered the period 2010 to September 2014. The search for the three reviews in VTE was run on the 19 March 2014, updated on 15 September 2014, and covered the period 2008 to September 2014.REVIEW METHODS: Two reviewers screened search results, extracted and checked data, and assessed risk of bias. For each outcome we conducted standard meta-analysis and NMA. We evaluated cost-effectiveness using discrete-time Markov models.RESULTS: Apixaban (Eliquis(rcledR), Bristol-Myers Squibb, USA; Pfizer, USA) [5 mg bd (twice daily)] was ranked as among the best interventions for stroke prevention in AF, and had the highest expected net benefit. Edoxaban (Lixiana(rcledR), Daiichi Sankyo, Japan) [60 mg od (once daily)] was ranked second for major bleeding and all-cause mortality. Neither the clinical effectiveness analysis nor the CEA provided strong evidence that NOACs should replace postoperative LMWH in primary prevention of VTE. For acute treatment and secondary prevention of VTE, we found little evidence that NOACs offer an efficacy advantage over warfarin, but the risk of bleeding complications was lower for some NOACs than for warfarin. For a willingness-to-pay threshold of > £5000, apixaban (5 mg bd) had the highest expected net benefit for acute treatment of VTE. Aspirin or no pharmacotherapy were likely to be the most cost-effective interventions for secondary prevention of VTE: our results suggest that it is not cost-effective to prescribe NOACs or warfarin for this indication.CONCLUSIONS: NOACs have advantages over warfarin in patients with AF, but we found no strong evidence that they should replace warfarin or LMWH in primary prevention, treatment or secondary prevention of VTE.LIMITATIONS: These relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs.FUTURE WORK: Calculating the expected value of sample information to clarify whether or not it would be justifiable to fund one or more head-to-head trials.STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330.FUNDING: The National Institute for Health Research Health Technology Assessment programme

JWST/NIRCam Coronagraphy of the Young Planet-hosting Debris Disk AU Microscopii

High-contrast imaging of debris disk systems permits us to assess the composition and size distribution of circumstellar dust, to probe recent dynamical histories, and to directly detect and characterize embedded exoplanets. Observations of these systems in the infrared beyond 2--3 $\mu$m promise access to both extremely favorable planet contrasts and numerous scattered-light spectral features -- but have typically been inhibited by the brightness of the sky at these wavelengths. We present coronagraphy of the AU Microscopii (AU Mic) system using JWST's Near Infrared Camera (NIRCam) in two filters spanning 3--5 $\mu$m. These data provide the first images of the system's famous debris disk at these wavelengths and permit additional constraints on its properties and morphology. Conducting a deep search for companions in these data, we do not identify any compelling candidates. However, with sensitivity sufficient to recover planets as small as $\sim 0.1$ Jupiter masses beyond $\sim 2^{\prime\prime}$ ($\sim 20$ au) with $5\sigma$ confidence, these data place significant constraints on any massive companions that might still remain at large separations and provide additional context for the compact, multi-planet system orbiting very close-in. The observations presented here highlight NIRCam's unique capabilities for probing similar disks in this largely unexplored wavelength range, and provide the deepest direct imaging constraints on wide-orbit giant planets in this very well studied benchmark system.Comment: 27 pages, 14 figure

Quantum Dots for Multiplexed Detection and Characterisation of Prostate Cancer Cells Using a Scanning Near-Field Optical Microscope

In this study scanning near-field optical microscopy (SNOM) has been utilised in conjunction with quantum dot labelling to interrogate the biomolecular composition of cell membranes. The technique overcomes the limits of optical diffraction found in standard fluorescence microscopy and also yields vital topographic information. The technique has been applied to investigate cell-cell adhesion in human epithelial cells. This has been realised through immunofluorescence labelling of the cell-cell adhesion protein E-cadherin. Moreover, a dual labelling protocol has been optimised to facilitate a comparative study of the adhesion mechanisms and the effect of aberrant adhesion protein expression in both healthy and cancerous epithelial cells. This study reports clear differences in the morphology and phenotype of healthy and cancerous cells. In healthy prostate epithelial cells (PNT2), E-cadherin was predominantly located around the cell periphery and within filopodial extensions. The presence of E-cadherin appeared to be enhanced when cell-cell contact was established. In contrast, examination of metastatic prostate adenocarcinoma cells (PC-3) revealed no E-cadherin labelling around the periphery of the cells. This lack of functional E-cadherin in PC-3 cells coincided with a markedly different morphology and PC-3 cells were not found to form close cell-cell associations with their neighbours. We have demonstrated that with a fully optimised sample preparation methodology, multiplexed quantum dot labelling in conjunction with SNOM imaging can be successfully applied to interrogate biomolecular localisation within delicate cellular membranes

Oral anticoagulants for prevention of stroke in atrial fibrillation : systematic review, network meta-analysis, and cost effectiveness analysis

Objective To compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation.Design Systematic review, network meta-analysis, and cost effectiveness analysis. Data sources Medline, PreMedline, Embase, and The Cochrane Library.Eligibility criteria for selecting studies Published randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation.Results 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin.Conclusions The network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A Novel Engineering Tool for Creative Design of Fluid Systems

Computational fluid dynamics is not often used early in the conceptual design stage of product development due to the lengthy computation times involved with solving complex computational fluid dynamics models. At this early stage, design options are being explored and significant changes are common, and therefore updated solutions must be found quickly to make these models effective. Because of this, computational fluid dynamics models are often reduced to analysis tools used later in the process and are used for refinement rather than for creative engineering design. This paper presents a novel method to create computational fluid dynamics models that can be used earlier in the engineering design process. The key aspects of analysis models used in the initial, creative phase of design are the ability to make changes and re-analyze the altered model quickly. Typically, computational fluid dynamics analysts choose to re-analyze the entire altered model to maintain the same level of accuracy. This can take a significant amount of time because the entire domain must be recalculated. Much of this time is devoted to fine-tuning the model, i.e., improving the accuracy of details of the domain that are sometimes non-essential to the bulk characteristics of the flowfield. However, in the early stage of the design process, decisions are often made based on the large-scale behavior of the fluid flow; fine details are often inconsequential. We have taken advantage of this premise to decrease the turnaround time required to re-analyze a computational fluid dynamics model using the Adaptive Modeling by Evolving Blocks Algorithm. The Adaptive Modeling by Evolving Blocks Algorithm is a genetic programming-based optimization program that segregates a flowfield and places minimal cost solvers in regions with simple flow dynamics while placing full-scale computational fluid dynamics solvers in the more complex regions to preserve accuracy. The program evolves the combined segregation scheme and solver placement until a reliably accurate, faster multi-solver model is found. Substantial reductions in solution times have been found in some cases. The results show an improvement in the speed of the multi-solver when compared with a single-model solution with no significant loss of accuracy

Relative efficacy and safety of simeprevir and telaprevir in treatment-naïve hepatitis C-infected patients in a Japanese population: a Bayesian network meta-analysis

Aim: Simeprevir (SMV) is an oral, once‐daily protease inhibitor for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. In phase II/III randomized controlled trials (RCT) conducted in Japan, SMV, in combination with peginterferon‐α and ribavirin (PEG IFN/RBV), demonstrated potent efficacy in HCV genotype 1‐infected patients relative to PEG IFN/RBV and was generally well tolerated. Telaprevir (TVR) in combination with PEG IFN/RBV is licensed for the treatment of HCV in Japan. In the absence of head‐to‐head comparisons of TVR and SMV in a Japanese population, we undertook a network meta‐analysis (NMA) to examine the relative efficacy and safety of SMV and TVR in combination with PEG IFN/RBV. Methods: A systematic review identified SMV and TVR RCT in Japanese treatment‐naïve patients. Bayesian NMA was performed assuming fixed study effects. Results: Three studies met our inclusion criteria: two SMV and one TVR. SMV showed a higher mean odds ratio (OR) of achieving SVR versus TVR (OR, 1.68 (95% credible interval 0.66–4.26)). SMV showed a lower mean OR of discontinuation: overall, 0.35 (0.12–1.00); and due to AE, 0.87 (0.23–3.34) versus TVR. SMV showed a lower mean OR of experiencing anemia 0.20 (0.07–0.56) and rash 0.41 (0.17–0.99) but a higher mean OR of experiencing pruritus 1.26 (0.46–3.47) versus TVR. Conclusion: In this indirect treatment comparison, SMV, in combination with PEG IFN/RBV, showed a favorable risk–benefit profile compared with TVR with PEG IFN/RBV in Japanese treatment‐naïve HCV patients

Metabolic fate of intravenously administered N-acetylneuraminic acid-6-¹⁴C in newborn piglets

Background: Sialic acid (N-acetylneuraminic acid), a component of gangliosides and sialylglycoproteins, may be a conditional nutrient in early life because endogenous synthesis is limited. The aim of this study was to investigate the metabolic fate of intravenously administrated N-acetylneuraminic acid 6¹⁴C (sialic acid) in piglets. Method: Three-day-old male domestic piglets (Sus scrofa) were injected via the jugular vein with 5 µCi (11-12x10⁶ cpm) of N-acetylneuraminic acid-6¹⁴C (specific activity of 55 mCi/mmol). Blood samples were collected at regular intervals over the next 120 min. The organs were then removed and the urine collected for determination of residual radioactivity. Results: Within 2 min of injection, 80% of the activity was removed from the blood and by 120 min the remaining activity approached 8%. At 120 min, the brain contained significantly more radioactivity (cpm/g tissue) than the liver, pancreas, heart and spleen, but less than the kidneys. Within the brain, the percentage of total injected activity was highest in the cerebrum (0.175 ± 0.008) followed by the cerebellum (0.0295 ± 0.006, p = 0.00006) and the thalamus (0.029 ± 0.006, p = 0.00003). Conclusions: An exogenous source of sialic acid is capable of crossing the blood-brain barrier and being taken up into various tissues. The findings suggest that dietary sources of sialic acid may contribute to early brain development in newborn mammals.6 page(s