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Patients who had discontinued statins because of side effects received four bottles of a statin, four bottles of placebo, and four empty bottles, each to be used for 1 month in a random sequence for 12 months. The symptom burden with placebo was 90% of the symptom burden with the statin.

Augmentation index (AIx) is widely used as a measure of wave reflection. We compared the relationship between AIx and age, height and sex with 'gold standard' measures of wave reflection derived from measurements of pressure and flow to establish how well AIx measures wave reflection. Measurements of carotid pressure and flow velocity were made in the carotid artery of 65 healthy normotensive individuals (age 21-78 yr; 43 male) and pulse wave analysis, wave intensity analysis and wave separation was performed; waveforms were classified into type A, B or C. AIx, the time of the first shoulder (T(s)), wave reflection index (WRI) and the ratio of backward to forward pressure (P(b)/P(f)) were calculated. AIx did not correlate with log WRI or P(b)/P(f). When AIx was restricted to positive values AIx and log WRI were positively correlated (r = 0.33; p = 0.04). In contrast log WRI and P(b)/P(f) were closely correlated (r = 0.66; p<0.001). There was no correlation between the T(s) and the timing of Pb or the reflected wave identified by wave intensity analysis. Wave intensity analysis showed that the morphology of type C waveforms (negative AIx) was principally due to a forward travelling (re-reflected) decompression wave in mid-systole. AIx correlated positively with age, inversely with height and was higher in women. In contrast log WRI and P(b)/P(f) showed negative associations with age, were unrelated to height and did not differ significantly by gender. AIx has serious limitations as a measure of wave reflection. Negative AIx values derived from Type C waves should not be used as estimates of wave reflection magnitude.

Purpose This study establishes a multiphysics simulation platform for both conventional and targeted thrombolysis using tissue plasminogen activator (tPA). Based on our computational results, the effects of therapeutic parameters on the dynamics of thrombolysis and the risk of side effects are investigated. Methods The model extends our previously developed one-dimensional(1D) mathematical models for fibrinolysis by incorporating targeted thrombolysis. It consists of two parts: (i) a coupled mathematical model of systemic pharmacokinetics (PK) and pharmacodynamics (PD) and local PD in a 1D occluded artery, and (ii) a mechanistic model for a targeted thrombolytic system via activated platelet-targeted tPA-loaded nanovesicles (tPA-NV), with model parameters derived from our in vitro experiments. A total of 16 therapeutic scenarios are simulated by varying the clot location and composition as well as the dosing regimen with free tPA or tPA-NV. Results Our simulation results indicate that tPA-NV offers several advantages over free tPA for thrombolysis. It reduces systemic exposure of tPA, thereby minimising the risk of bleeding complications. Simulations with different tPA-NV doses reveal that tPA-NV at 10% of the recommended dose can be as effective as the standard regimen with the full recommended dose of free tPA, demonstrating the potential of our tPA-NV as a new thrombolytic strategy with a reduced tPA dose. Moreover, faster recanalisation can be achieved with tPA-NV, especially for platelet-rich(or fibrin-poor) clots. Conclusions Our simulation platform for thrombolysis with well-tuned model parameters can be used to evaluate and optimise treatment regimens of existing and new thrombolytic therapies via benefit/risk assessment under various therapeutic scenarios.

Diets low in seafood omega-3 polyunsaturated fatty acids (PUFAs) are very prevalent. Such diets have recently been ranked as the sixth most important dietary risk factor—1.5 million deaths and 33 million disability-adjusted life-years worldwide are attributable to this deficiency. Wild oily fish stocks are insufficient to feed the world’s population, and levels of eicosapentaenoic acid and docosahexaenoic acid (DHA) in farmed fish have more than halved in the last 20 years. Here we report on a double-blinded, controlled trial, where 161 healthy normotensive adults were randomly allocated to eat at least three portions/week of omega-3-PUFA enriched (or control) chicken-meat, and to eat at least three omega-3-PUFA enriched (or control) eggs/week, for 6 months. We show that regular consumption of omega-3-PUFA enriched chicken-meat and eggs significantly increased the primary outcome, the red cell omega-3 index (mean difference [98.75% confidence interval] from the group that ate both control foods, 1.7% [0.7, 2.6]). Numbers of subjects with a very high-risk omega-3 index (index < 4%) were more than halved amongst the group that ate both enriched foods. Furthermore, eating the enriched foods resulted in clinically relevant reductions in diastolic blood pressure (− 3.1 mmHg [− 5.8, − 0.3]). We conclude that chicken-meat and eggs, naturally enriched with algae-sourced omega-3-PUFAs, may serve as alternative dietary sources of these essential micronutrients. Unlike many lifestyle interventions, long-term population health benefits do not depend on willingness of individuals to make long-lasting difficult dietary changes, but on the availability of a range of commonly eaten, relatively inexpensive, omega-3-PUFA enriched foods.

Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593. ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI −8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group. In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy. NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.

The optic disc (OD) in retinal fundus images is widely used as a reference in computer-based systems for the measurement of the severity of retinal disease. A number of algorithms have been published in the past 5 years to locate and measure the OD in digital fundus images. Our proposed algorithm, automatically: (i) uses the three channels (RGB) of the digital colour image to locate the region of interest (ROI) where the OD lies, (ii) measures the Shannon information content per channel in the ROI, to decide which channel is most appropriate for searching for the OD centre using the circular Hough transform. A series of evaluations were undertaken to test our hypothesis that using the three channels gives a better performance than a single channel. Three different databases were used for evaluation purposes with a total of 2,371 colour images giving a misdetection error of 3% in the localisation of the centre of the OD. We find that the area determined by our algorithm which assumes that the OD is circular, is similar to that found by other algorithms that detected the shape of the OD. Five metrics were measured for comparison with other recent studies. Combining the two databases where expert delineation of the OD is available (1,240 images), the average results for our multispectral algorithm are: TPR = 0.879, FPR = 0.003, Accuracy = 0.994, Overlap = 80.6% and Dice index = 0.878.

To promote the primary prevention of hypertension and cardiovascular disease by changes in the diet and lifestyle of the whole population To increase the detection and treatment of undiagnosed hypertension by routine screening and increase awareness of hypertension among the public To ensure that patients taking antihypertensive drugs are controlled to optimal blood pressure levels To reduce the risk of cardiovascular disease of treated hypertensive patients by non-pharmacological measures, and by appropriate use of statin and aspirin treatment To increase the identification and treatment of patients with mild hypertension who are at high risk of cardiovascular disease-for example, elderly patients, patients with ischaemic heart disease, people with diabetes, people with target organ damage, or people with multiple risk factors To promote continued adherence to drug treatment, by optimising the choice and use of drugs, minimising side effects, and increasing information and choice for patients. Blood pressure measurement by standard mercury sphygmomanometer or semiautomated device Use a properly maintained, calibrated, and validated device Measure sitting blood pressure routinely: standing blood pressure should be recorded at least at the initial estimation in elderly or diabetic patients Remove tight clothing, support arm at heart level, ensure arm relaxed and avoid talking during the measurement procedure Use cuff of appropriate size (see box 3 in the full guidelines, 3 http://www.bhsoc.org/ ) Lower mercury column slowly (2 mm per second) Read blood pressure to the nearest 2 mm Hg Measure diastolic blood pressure as disappearance of sounds (phase V) Take the mean of at least two readings, more recordings are needed if marked differences between initial measurements are found Do not treat on the basis of an isolated reading For full details of methods see http://www.bhsoc.org/ and reference 8 Absolute risk of cardiovascular disease estimation The treatment of hypertension and the primary prevention of cardiovascular disease should be informed by assessment of total risk of cardiovascular disease.\\n The minimum acceptable level of control (audit standard) recommended is < 150/ < 90 mm Hg In people with diabetes mellitus, initiate antihypertensive drug treatment if systolic blood pressure is sustained â[per thousand]¥ 140 mm Hg or diastolic blood pressure is sustained â[per thousand]¥ 90 mm Hg In hypertensive people with diabetes, chronic renal disease, or established cardiovascular disease optimal blood pressure goals are systolic blood pressure < 130 mm Hg and diastolic blood pressure < 80 mm Hg.

Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs. We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill—a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis. Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14–23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen. The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability. National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.

Mechanical forces, such as low wall shear stress (WSS), are implicated in endothelial dysfunction and atherogenesis. The accumulation of low density lipoprotein (LDL) and hypoxia are also considered as main contributing factors in the development of atherosclerosis. The objective of this study was to investigate the influences of WSS on arterial mass transport by modelling the flow of blood and solute transport in the lumen and arterial wall. The Navier-Stokes equations and Darcy's Law were used to describe the fluid dynamics of the blood in the lumen and wall respectively. Convection-diffusion-reaction equations were used to model LDL and oxygen transport. The coupling of fluid dynamics and solute dynamics at the endothelium was achieved by the Kedem-Katchalsky equations. A shear-dependent hydraulic conductivity relation extracted from experimental data in the literature was employed for the transport of LDL and a shear-dependent permeability was used for oxygen. The integrated fluid-wall model was implemented in Comsol Multiphysics 3.2 and applied to an axisymmetric stenosis. The results showed elevated LDL concentration and reduced oxygen concentration in the subendothelial layer of the arterial wall in areas where WSS is low, suggesting that low WSS might be responsible for lipid accumulation and hypoxia in the arterial wall.

The aim of this study was to develop a fully subject-specific model of the right coronary artery (RCA), including dynamic vessel motion, for computational analysis to assess the effects of cardiac-induced motion on hemodynamics and resulting wall shear stress (WSS). Vascular geometries were acquired in the right coronary artery (RCA) of a healthy volunteer using a navigator-gated interleaved spiral sequence at 14 time points during the cardiac cycle. A high temporal resolution velocity waveform was also acquired in the proximal region. Cardiac-induced dynamic vessel motion was calculated by interpolating the geometries with an active contour model and a computational fluid dynamic (CFD) simulation with fully subject-specific information was carried out using this model. The results showed the expected variation of vessel radius and curvature throughout the cardiac cycle, and also revealed that dynamic motion of the right coronary artery consequent to cardiac motion had significant effects on instantaneous WSS and oscillatory shear index. Subject-specific MRI-based CFD is feasible and, if scan duration could be shortened, this method may have potential as a non-invasive tool to investigate the physiological and pathological role of hemodynamics in human coronary arteries.