Background Ultrasound imaging is able to quantify carotid arterial wall structure for the assessment of cerebral and cardiovascular disease risks. We describe a protocol and quality assurance process ...to enable carotid imaging at large scale that has been developed for the UK Biobank Imaging Enhancement Study of 100,000 individuals. Design An imaging protocol was developed to allow measurement of carotid intima-media thickness from the far wall of both common carotid arteries. Six quality assurance criteria were defined and a web-based interface (Intelligent Ultrasound) was developed to facilitate rapid assessment of images against each criterion. Results and conclusions Excellent inter and intra-observer agreements were obtained for image quality evaluations on a test dataset from 100 individuals. The image quality criteria then were applied in the UK Biobank Imaging Enhancement Study. Data from 2560 participants were evaluated. Feedback of results to the imaging team led to improvement in quality assurance, with quality assurance failures falling from 16.2% in the first two-month period examined to 6.4% in the last. Eighty per cent had all carotid intima-media thickness images graded as of acceptable quality, with at least one image acceptable for 98% of participants. Carotid intima-media thickness measures showed expected associations with increasing age and gender. Carotid imaging can be performed consistently, with semi-automated quality assurance of all scans, in a limited timeframe within a large scale multimodality imaging assessment. Routine feedback of quality control metrics to operators can improve the quality of the data collection.
UK Biobank is a prospective cohort study with 500,000 participants aged 40 to 69. Recently an enhanced imaging study received funding. Cardiovascular magnetic resonance (CMR) will be part of a ...multi-organ, multi-modality imaging visit in 3-4 dedicated UK Biobank imaging centres that will acquire and store imaging data from 100,000 participants (subject to successful piloting). In each of UK Biobank's dedicated bespoke imaging centres, it is proposed that 15-20 participants will undergo a 2 to 3 hour visit per day, seven days a week over a period of 5-6 years. The imaging modalities will include brain MRI at 3 Tesla, CMR and abdominal MRI at 1.5 Tesla, carotid ultrasound and DEXA scans using carefully selected protocols. We reviewed the rationale, challenges and proposed approaches for concise phenotyping using CMR on such a large scale. Here, we discuss the benefits of this imaging study and review existing and planned population based cardiovascular imaging in prospective cohort studies. We will evaluate the CMR protocol, feasibility, process optimisation and costs. Procedures for incidental findings, quality control and data processing and analysis are also presented. As is the case for all other data in the UK Biobank resource, this database of images and related information will be made available through UK Biobank's Access Procedures to researchers (irrespective of their country of origin and whether they are academic or commercial) for health-related research that is in the public interest.
Objective To describe the factors that contributed to successful recruitment of more than 200 000 women to the UK Collaborative Trial of Ovarian Cancer Screening, one of the largest ever randomised ...controlled trials.Design Descriptive study.Setting 13 NHS trusts in England, Wales, and Northern Ireland.Participants Postmenopausal women aged 50-74; exclusion criteria included ovarian malignancy, bilateral oophorectomy, increased risk of familial ovarian cancer, active non-ovarian malignancy, and participation in other ovarian cancer screening trials.Main outcome measures Achievement of target recruitment, acceptance rates of invitation, and recruitment rates.Results The trial was set up in 13 centres with 27 adjoining local health authorities. The coordinating centre team was led by one of the senior investigators, who was closely involved in planning and day to day trial management. Of 1 243 282 women invited, 23.2% (288 955) replied that they were eligible and would like to participate. Of those sent appointments, 73.6% (205 090) attended for recruitment. The acceptance rate varied from 19% to 33% between trial centres. Measures to ensure target recruitment included named coordinating centre staff supporting and monitoring each centre, prompt identification and resolution of logistic problems, varying the volume of invitations by centre, using local non-attendance rates to determine the size of recruitment clinics, and organising large ad hoc clinics supported by coordinating centre staff. The trial randomised 202 638 women in 4.3 years.Conclusions Planning and trial management are as important as trial design and require equal attention from senior investigators. Successful recruitment needs constant monitoring by a committed proactive management team that is willing to explore individual solutions for different centres and use central resources to improve local recruitment. Automation of trial processes with web based trial management systems is crucial in large multicentre randomised controlled trials. Recruitment can be further enhanced by using information videos and group discussions.Trial registration Current Controlled Trials ISRCTN22488978.
A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size ...descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.
Extreme Ultraviolet (EUV) lithography is a leading technology option for manufacturing at the 22nm half pitch node and beyond. Implementation of the technology will require continued progress on ...several key supporting infrastructure challenges, including EUV photoresist materials. The main development issue regarding EUV photoresists is simultaneously achieving the high resolution, high sensitivity, and low line width roughness (LWR) required. This paper describes our strategy, the current status of EUV materials, and some integrated post-development LWR reduction efforts. Data collected utilizing Intel′s Micro-Exposure Tool (MET) is presented in order to examine the feasibility of establishing a resist process that simultaneously exhibits ≤22nm half-pitch (HP) L/S resolution at ≤11.3mJ/cm2 with ≤3nm LWR
Today, DIY -- do-it-yourself -- describes more than self-taught carpentry. Social media enables DIY citizens to organize and protest in new ways (as in Egypt's "Twitter revolution" of 2011) and to ...repurpose corporate content (or create new user-generated content) in order to offer political counternarratives. This book examines the usefulness and limits of DIY citizenship, exploring the diverse forms of political participation and "critical making" that have emerged in recent years. The authors and artists in this collection describe DIY citizens whose activities range from activist fan blogging and video production to knitting and the creation of community gardens. Contributors examine DIY activism, describing new modes of civic engagement that include Harry Potter fan activism and the activities of the Yes Men. They consider DIY making in learning, culture, hacking, and the arts, including do-it-yourself media production and collaborative documentary making. They discuss DIY and design and how citizens can unlock the black box of technological infrastructures to engage and innovate open and participatory critical making. And they explore DIY and media, describing activists' efforts to remake and reimagine media and the public sphere. As these chapters make clear, DIY is characterized by its emphasis on "doing" and making rather than passive consumption. DIY citizens assume active roles as interventionists, makers, hackers, modders, and tinkerers, in pursuit of new forms of engaged and participatory democracy.ContributorsMike Ananny, Chris Atton, Alexandra Bal, Megan Boler, Catherine Burwell, Red Chidgey, Andrew Clement, Negin Dahya, Suzanne de Castell, Carl DiSalvo, Kevin Driscoll, Christina Dunbar-Hester, Joseph Ferenbok, Stephanie Fisher, Miki Foster, Stephen Gilbert, Henry Jenkins, Jennifer Jenson, Yasmin B. Kafai, Ann Light, Steve Mann, Joel McKim, Brenda McPhail, Owen McSwiney, Joshua McVeigh-Schultz, Graham Meikle, Emily Rose Michaud, Kate Milberry, Michael Murphy, Jason Nolan, Kate Orton-Johnson, Kylie A. Peppler, David J. Phillips, Karen Pollock, Matt Ratto, Ian Reilly, Rosa Reitsamer, Mandy Rose, Daniela K. Rosner, Yukari Seko, Karen Louise Smith, Lana Swartz, Alex Tichine, Jennette Weber, Elke Zobl
L-745,870,(3-(4-(4-chlorophenyl)piperazin-1-ylmethyl)-1H- pyrollo2,3-b pyridine, was identified as a selective dopamine D4 receptor antagonist with excellent oral bioavailability and brain ...penetration. L-745,870 displaced specific binding of 0.2 nM 3H spiperone to cloned human dopamine D4 receptors with a binding affinity (Ki) of 0. 43 nM which was 5- and 20-fold higher than that of the standard antipsychotics haloperidol and clozapine, respectively. L-745,870 exhibited high selectivity for the dopamine D4 receptor (>2000 fold) compared to other dopamine receptor subtypes and had moderate affinity for 5HT2, sigma and alpha adrenergic receptors(IC50 < 300 nM). In vitro, L-745,870 (0.1-1 microM) exhibited D4 receptor antagonist activity, reversing dopamine (1 microM) mediated 1) inhibition of adenylate cyclase in hD4HEK and hD4CHO cells; 2) stimulation of 35S GTPgammaS binding and 3) stimulation of extracellular acidification rate, but did not exhibit any significant intrinsic activity in these assays. Although standard antipsychotics increase dopamine metabolism or plasma prolactin levels in rodents, L-745,870 (</=30 mg/kg p.o.) had no effect in these assays. The lack of a suitable in vivo assay for D4 receptor activation prompted the use of in vivo surrogate marker assays which confirmed that doses of 5-60 microg/kg L-745,870 would be sufficient to occupy 50% D4 receptors in the brain. These results show that dopamine D4 receptor antagonism in the brain does not result in the same neurochemical consequences (increased dopamine metabolism or hyperprolactinemia) observed with typical neuroleptics.
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified ...by compound
8.
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound
8.
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