Gatto A.,CSIC - National Center for Metallurgical Research |
Torroja-Fungairino C.,Bioinformatics Unit |
Mazzarotto F.,Imperial College London |
Mazzarotto F.,Cardiovascular Biomedical Research Unit |
And 8 more authors.
Nucleic Acids Research | Year: 2014
Alternative splicing is the main mechanism governing protein diversity. The recent developments in RNA-Seq technology have enabled the study of the global impact and regulation of this biological process. However, the lack of standardized protocols constitutes a major bottleneck in the analysis of alternative splicing. This is particularly important for the identification of exon-exon junctions, which is a critical step in any analysis workflow. Here we performed a systematic benchmarking of alignment tools to dissect the impact of design and method on the mapping, detection and quantification of splice junctions from multi-exon reads. Accordingly, we devised a novel pipeline based on TopHat2 combined with a splice junction detection algorithm, which we have named FineSplice. FineSplice allows effective elimination of spurious junction hits arising from artefactual alignments, achieving up to 99% precision in both real and simulated data sets and yielding superior F1 scores under most tested conditions. The proposed strategy conjugates an efficient mapping solution with a semi-supervised anomaly detection scheme to filter out false positives and allows reliable estimation of expressed junctions from the alignment output. Ultimately this provides more accurate information to identify meaningful splicing patterns. FineSplice is freely available at https://sourceforge.net/p/finesplice/. © 2014 © The Author(s) 2014. Published by Oxford University Press.
News Article | December 19, 2016
Genetic cause that identifies dystonia patients who can benefit from Deep Brain Stimulation uncovered by UCL, Great Ormond Street Hospital and University of Cambridge researchers using the NIHR Rare Disease Bioresource DNA sequencing has defined a new genetic disorder that affects movement, enabling patients with dystonia -- a disabling condition that affects voluntary movement -- to be targeted for treatment that brings remarkable improvements, including restoring independent walking. A team of researchers from UCL Great Ormond Street Institute of Child Health, University of Cambridge and the NIHR Rare Disease Bioresource have identified mutations in a gene, called KMT2B, in 28 patients with dystonia. In most cases, the patients -- many of whom were young children who were thought to have a diagnosis of cerebral palsy -- were unable to walk without difficulty. Remarkably, for some patients, treatment with Deep Brain Stimulation, in which electrical impulses are delivered to a specific brain region involved in movement, either restored or significantly improved independent walking and improved hand and arm movement. In one patient, improvements have been sustained over six years. Given these observations, the team now suggest that testing for mutations in the gene should form part of standard testing for patients with dystonia, as this is emerging to be one of the commonest genetic causes of childhood-onset dystonia. The research is published in Nature Genetics on Monday 19 December 2016. Dystonia is one of the commonest movement disorders and is thought to affect 70,000 people in the UK alone. It can cause a wide range of disabling symptoms, including painful muscle spasms and abnormal postures, and can affect walking and speech. Through research testing of patients, the team discovered a region of chromosome 19 that was deleted from the genome of some patients with childhood-onset dystonia. Together with the NIHR Rare Disease Bioresource and international collaborators, the team then identified abnormal genetic changes in genomes from a further 18 patients in one gene, called KMT2B, where affected patients carried a mutated in their DNA. "Through DNA sequencing, we have identified a new genetic movement disorder that can be treated with Deep Brain Stimulation. This can dramatically improve the lives of children with the condition and enable them to have a wider range of movement with long-lasting effects," says Dr Manju Kurian, paediatric neurologist at Great Ormond Street Hospital and Wellcome Trust-funded researcher at UCL Great Ormond Street Institute of Child Health. "Our results, though in a relatively small group of patients, show the power of genomic research not only to identify new diseases, but also to reveal possible approaches that will allow other patients to benefit." The KMT2B protein is thought to alter the activity of other genes. The team believes that the mutations impair the ability of the KMT2B protein to carry out its normal, crucial role in controlling the expression of genes involved in voluntary movement. A number of patients were previously thought to have cerebral palsy prior to confirmation of their genetic diagnosis. Such uncertainty could be addressed by looking for KMT2B mutations as part of a diagnostic approach. Although affected patients have been found to have a mutation in their DNA, this severe condition is rarely inherited from either parent but usually occurs for the first time in the affected child. "Most patients show a progressive disease course with worsening dystonia over time," continues Dr Kurian. "Many patients did not show any response to the usual medications that we use for dystonia so we knew we would have to consider other strategies. We know, from our experience with other patients with dystonia, that Deep Brain Stimulation might improve our patient's symptoms, so were keen to see what response patients would have to this type of treatment." "Remarkably nearly all patients who had Deep Brain Stimulation showed considerable improvements. One patient was able to walk independently within two weeks; in five patients, the improvement has lasted for more than three years. It is an astounding result." Given the dramatic effects seen in their patients with this newly defined genetic condition, the team propose that referral for assessment of Deep Brain Stimulation should be considered for all patients with a mutation in KMT2B. In the future, the team hopes that, by diagnosing additional patients, the full spectrum of this new condition will be more apparent and patients and their families might see real benefit. "It is only through the amazing generosity and efforts of patients and their families that we can begin to search for better answers and treatments: we admire their contribution," says Professor Raymond, Assistant Director of the NIHR Bioresource for Rare Diseases and Professor of Medical Genetics and Neurodevelopment at the University of Cambridge. "Through participating in our research, they have helped us to identify patients with KMT2B-related dystonia, meaning we can aim for a more "precision medicine approach" to target treatment with Deep Brain Stimulation to those likely to benefit: most importantly, we would anticipate improvement in many of those treated. "The lesson from our study is simple and clear: because confirming this diagnosis has implications for therapy, we should test all patients with suspected genetic dystonia for mutations in KMT2B." Meyer E, Carss KJ, Rankin J et al. (2016) Mutations in the Histone Methyltransferase Gene, KMT2B Cause Early Onset Dystonia. Nature Genetics. doi: 10.1038/ng.3740 A full list of participating centres can be found at the Nature Genetics website. About the UCL Great Ormond Street Institute of Child Health (ICH) The UCL Great Ormond Street Institute of Child Health is part of the Faculty of Population Health Sciences within the School of Life and Medical Sciences at UCL. Together with its clinical partner Great Ormond Street Hospital for Children (GOSH), it forms the largest concentration of children's health research in Europe. The research studies were undertaken as part of the NIHR BioResource. The NIHR BioResource (http://bioresource. ) functions as a partnership between the NIHR Biomedical Research Centres at Imperial College London, King's/Guy's and St Thomas' Hospitals London, Newcastle Hospitals, South London and Maudsley Hospitals, Oxford University Hospitals, University College London Hospitals and the Cardiovascular Biomedical Research Unit in Leicester. The NIHR BioResource, which currently includes over 100,000 research patients and volunteers and over 10,000 Individuals with rare genetic diseases most of whom have undergone analysis of their genome. About the University of Cambridge The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 96 affiliates of the University have won the Nobel Prize. Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America. The University sits at the heart of one of the world's largest technology clusters. The 'Cambridge Phenomenon' has created 1,500 hi-tech companies, 14 of them valued at over US$1 billion and two at over US$10 billion. Cambridge promotes the interface between academia and business, and has a global reputation for innovation. http://www. About Cambridge University Hospitals and the Cambridge Biomedical Research Centre Based within the most outstanding NHS and University partnerships in the country, the NIHR Biomedical Research Centres are leaders in scientific translation. They receive substantial levels of funding from the National Institute for Health Research (NIHR) to translate fundamental biomedical research into clinical research that benefits patients and they are early adopters of new insights in technologies, techniques and treatments for improving health. The Cambridge Biomedical Research Centre (http://www. ) coordinates the NIHR BioResource.
Transcatheter aortic valve implantation in the United Kingdom: Temporal trends, predictors of outcome, and 6-year follow-up: A report from the UK transcatheter aortic valve implantation (TAVI) registry, 2007 to 2012
Ludman P.F.,Queen Elizabeth Hospital |
Moat N.,Royal Brompton and Harefield Hospital |
De Belder M.A.,James Cook University |
Blackman D.J.,Leeds Teaching Hospitals |
And 14 more authors.
Circulation | Year: 2015
Background - We assessed trends in the performance of transcatheter aortic valve implantation in the United Kingdom from the first case in 2007 to the end of 2012. We analyzed changes in case mix, complications, outcomes to 6 years, and predictors of mortality. Methods and Results - Annual cohorts were examined. Mortality outcomes were analyzed in the 92% of patients from England and Wales for whom independent mortality tracking was available. A total of 3980 transcatheter aortic valve implantation procedures were performed. In successive years, there was an increase in frequency of impaired left ventricular function, but there was no change in Logistic EuroSCORE. Overall 30-day mortality was 6.3%; it was highest in the first cohort (2007-2008), after which there were no further significant changes. One-year survival was 81.7%, falling to 37.3% at 6 years. Discharge by day 5 rose from 16.7% in 2007 and 2008 to 28% in 2012. The only multivariate preprocedural predictor of 30-day mortality was Logistic EuroSCORE ≥40. During long-term follow-up, multivariate predictors of mortality were preprocedural atrial fibrillation, chronic obstructive pulmonary disease, creatinine >200 μmol/L, diabetes mellitus, and coronary artery disease. The strongest independent procedural predictor of long-term mortality was periprocedural stroke (hazard ratio=3.00; P<0.0001). Nonfemoral access and postprocedural aortic regurgitation were also significant predictors of adverse outcome. Conclusions - We analyzed transcatheter aortic valve implantation in an entire country, with follow-up over 6 years. Although clinical profiles of enrolled patients remained unchanged, longer-term outcomes improved, and patients were discharged earlier. Periprocedural stroke, nonfemoral access, and postprocedural aortic regurgitation are predictors of adverse outcome, along with intrinsic patient risk factors. © 2015 American Heart Association, Inc.
Secco G.G.,Cardiovascular Biomedical Research Unit |
Secco G.G.,University of Piemonte Orientale |
Foin N.,Imperial College London |
Viceconte N.,Cardiovascular Biomedical Research Unit |
And 3 more authors.
EuroIntervention | Year: 2011
Aims: The treatment of in-stent restenosis (ISR) remains a challenge with poor immediate results and higher restenosis rate than in de novo lesions. We propose, based on a consecutive series of patients treated with cutting balloon, a strategy of aggressive device selection based on the results of serial FD-OCT assessment. Methods and results: Fourteen consecutive ISR lesions were evaluated both angiographically and with frequency domain optical coherence tomography (FD-OCT) (C7; LightLab Imaging Inc., Westford, MA, USA). Cutting balloon (CB) was used in all cases, sized firstly according to conventional angiographic criteria and then upgraded based on OCT assessment with the aim of creating cuts as close as possible to the struts. OCT data analysis included measurements of lumen and stent area, minimal distance lumen-struts and residual plaque neointimal hyperplasia. With an OCT guided CB strategy, the final minimal lumen cross-sectional area (MLCSA) after the final treatment reached 6.68±1.14 mm 2, with a reduction from 69% to 25% of neointimal hyperplasia. In the patients with a two-step strategy using a first CB guided by angiography and a second CB guided by OCT, the increase in CB diameter was 0.5 mm, achieving an increase in MLCSA area from 4.9±0.42 to 6.35±0.92 mm 2 with a reduction from 41% to 27% of neointimal hyperplasia. Conclusions: The OCT measurements of strut-to-strut distance allow safe upsizing of the CB with an acceptable lumen increase before deployment of a new DES. The strategy appears of particular usefulness for a DEB strategy with no intention to implant new stents. © Europa Edition 2011. All rights reserved.
Keegan J.,Cardiovascular Biomedical Research Unit |
Jhooti P.,Cardiovascular Biomedical Research Unit |
Jhooti P.,University of Basel |
Babu-Narayan S.V.,Cardiovascular Biomedical Research Unit |
And 5 more authors.
Magnetic Resonance in Medicine | Year: 2014
Purpose Acquisition durations of navigator-gated high-resolution three-dimensional late gadolinium enhancement studies may typically be up to 10 min, depending on the respiratory efficiency and heart rate. Implementation of the continuously adaptive windowing strategy (CLAWS) could increase respiratory efficiency, but the resulting non-smooth k-space acquisition order during gadolinium wash-out could result in increased artifact. Methods Navigator-gated three-dimensional late gadolinium enhancement acquisitions were performed in 18 patients using tracking end-expiratory accept/reject (EE-ARA) and CLAWS algorithms in random order. Results Retrospective analysis of the stored navigator data shows that CLAWS scan times are very close to (within 1%) or equal to the fastest achievable scan times while EE-ARA significantly extends the acquisition duration (P < 0.0001). EE-ARA acquisitions are 26% longer than CLAWS acquisitions (378 ± 104 s compared to 301 ± 85 s, P = 0.002). Image quality scores for CLAWS and EE-ARA acquisitions are not significantly different (4.1 ± 0.6 compared to 4.3 ± 0.6, P = ns). Numerical phantom simulations show that the non-uniform k-space ordering introduced by CLAWS results in slight, but not statistically significant, reductions in both blood signal-to-noise ratio (10%) and blood-myocardium contrast-to-noise ratio (12%). Conclusions CLAWS results in markedly reduced acquisition durations compared to EE-ARA without significant detriment to the image quality. © 2013 Wiley Periodicals, Inc.
Foin N.,Imperial College London |
Secco G.G.,Cardiovascular Biomedical Research Unit |
Ghilencea L.,Cardiovascular Biomedical Research Unit |
Krams R.,Imperial College London |
Di Mario C.,Cardiovascular Biomedical Research Unit
EuroIntervention | Year: 2011
Aims: High rates of restenosis and stent thrombosis are still often observed after bifurcation stenting despite the recommended stent post-dilatation using the kissing balloon (KB) technique. We investigated the potential benefits of a final post-dilatation step in bifurcation stenting with a balloon that respects the natural diameter ratio of the proximal and distal vessels in bifurcations (Murray's law). Methods and results: Fourteen commercially available stents (Xience V, Taxus Liberté and Presillion) were deployed in a silicone model of a coronary bifurcation using a provisional stenting approach. After side branch (SB) ostium dilatation and KB inflation, stent geometry and strut apposition was analysed using micro-CT. A final proximal inflation step was then performed to post-dilate only the proximal segment of the main vessel (MV). KB inflation produces an asymmetrical dilatation of the stent in the proximal part of the bifurcation with a number of struts left malapposed in the MV. Using the proposed final proximal inflation (FPI) step reduces the average stent eccentricity index from 0.72 to 0.90 (p<0.001) and the percentage of malapposed struts in the proximal part of the MV from 33.4% to 0.6% (p=0.02), while increasing the minimum stent area from 6.8 mm 2 to 8.5 mm 2 (p < 0.0001). Conclusions: A final dilatation of the stent only in the MV proximal to the SB with a balloon sized according to the mother vessel is suggested to prevent stent malapposition and optimise stent deployment in bifurcation stenting. © Europa Edition 2011. All rights reserved.
Gutierrez-Chico J.L.,Erasmus Medical Center |
Wykrzykowska J.,Erasmus Medical Center |
Nuesch E.,University of Bern |
Van Geuns R.J.,Erasmus Medical Center |
And 9 more authors.
Circulation: Cardiovascular Interventions | Year: 2012
Background-The vascular tissue reaction to acute incomplete stent apposition (ISA) is not well known. The aim of this study was to characterize the vascular response to acute ISA in vivo and to look for predictors of incomplete healing. Methods and Results-Optical coherence tomography studies of 66 stents of different designs, implanted in 43 patients enrolled in 3 randomized trials, were analyzed sequentially after implantation and at 6 to 13 months. Seventy-eight segments with acute ISA were identified in 36 of the patients and matched with the follow-up study by use of fiduciary landmarks. The morphological pattern of healing in the ISA segments was categorized as homogeneous, layered, crenellated, bridged, partially bridged, or bare, depending on the persistence of ISA and on the coverage. After 6 months, acute ISA volume decreased significantly, and 71.5% of the ISA segments were completely integrated into the vessel wall. Segments with acute ISA had higher risk of delayed coverage than well-apposed segments (relative risk 2.37, 95% confidence interval 2.01-2.78). Acute ISA size (estimated as ISA volume or maximum ISA distance per strut) was an independent predictor of ISA persistence and of delayed healing at follow-up. Conclusions-Neointimal healing tends to reduce ISA, with the malapposed stent struts often integrated completely into the vessel wall, resulting in characteristic morphological patterns. Coverage of ISA segments is delayed with respect to well-apposed segments. The larger the acute ISA, the greater the likelihood of persistent malapposition at follow-up and delayed healing. Clinical Trial Registration-URL: http://www.clinicaltrials. gov. Unique identifier: NCT00617084 and NCT00934752. © 2012 American Heart Association, Inc.
Ware J.S.,Imperial College London |
Roberts A.M.,Imperial College London |
Cook S.A.,Imperial College London |
Cook S.A.,Cardiovascular Biomedical Research Unit
Heart | Year: 2012
The fast moving field of genomic medicine is already impacting on clinical care and cardiologists are fortunate to be in a position to benefit early from the transformative advances in genomics. However, the challenges associated with genomics in the clinic in general, and with next generation sequencing technologies in particular, are significant and cardiologists need to be prepared if they wish to surf the wave of genomic opportunity. This paper presents an overview of the implications of next generation sequencing for clinical diagnostics and personalised medicine in the cardiology clinic.
Keegan J.,Cardiovascular Biomedical Research Unit
Journal of Magnetic Resonance Imaging | Year: 2015
Like X-Ray contrast angiography, MR coronary angiograms show the vessel lumens rather than the vessels themselves. Consequently, outward remodeling of the vessel wall, which occurs in subclinical coronary disease before luminal narrowing, cannot be seen. The current gold standard for assessing the coronary vessel wall is intravascular ultrasound, and more recently, optical coherence tomography, both of which are invasive and use ionizing radiation. A noninvasive, low-risk technique for assessing the vessel wall would be beneficial to cardiologists interested in the early detection of preclinical disease and for the safe monitoring of the progression or regression of disease in longitudinal studies. In this review article, the current state of the art in MR coronary vessel wall imaging is discussed, together with validation studies and recent developments. J. Magn. Reson. Imaging 2015;41:1190-1202. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.
Keegan J.,Cardiovascular Biomedical Research Unit |
Drivas P.,Cardiovascular Biomedical Research Unit |
Firmin D.N.,Cardiovascular Biomedical Research Unit
Magnetic resonance in medicine | Year: 2014
PURPOSE: Navigator-gated three-dimensional (3D) late gadolinium enhancement (LGE) imaging demonstrates scarring following ablation of atrial fibrillation. An artifact originating from the slice-selective navigator-restore pulse is frequently present in the right pulmonary veins (PVs), obscuring the walls and making quantification of enhancement difficult. We describe a simple sequence modification to greatly reduce or remove this artifact.METHODS: A navigator-gated inversion-prepared gradient echo sequence was modified so that the slice-selective navigator-restore pulse was delayed in time from the nonselective preparation (NAV-restore-delayed). Both NAV-restore-delayed and conventional 3D LGE acquisitions were performed in 11 patients and the results compared.RESULTS: One patient was excluded due to severe respiratory motion artifact in both NAV-restore-delayed and conventional acquisitions. Moderate to severe artifact was present in 9 of the remaining 10 patients using the conventional sequence and was considerably reduced when using the NAV-restore-delayed sequence (ostial PV to blood pool ratio, 1.7 ± 0.5 versus 1.1 ± 0.2, respectively [P < 0.0001]; qualitative artifact scores, 2.8 ± 1.1 versus 1.2 ± 0.4, respectively [P < 0.001]). While navigator signal-to-noise ratio was reduced with the NAV-restore-delayed sequence, respiratory motion compensation was unaffected.CONCLUSIONS: Shifting the navigator-restore pulse significantly reduces or eliminates navigator artifact. This simple modification improves the quality of 3D LGE imaging and potentially aids late enhancement quantification in the atria. Copyright © 2013 Wiley Periodicals, Inc.