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  • Journal article
    Glaysher M, Mohanaruban A, Prechtl CG, Goldstone AP, Miras AD, Lord J, Chhina N, Falaschetti E, Johnson NA, Al-Najim W, smith C, Li JV, Patel M, Ahmed AR, Moore M, Poulter NR, Bloom S, Darzi A, Le Roux C, Byrne JP, teare Jet al., 2017,

    A randomised controlled trial of a duodenal-jejunal bypass sleeve device (EndoBarrier) compared with standard medical therapy for the management of obese subjects with type 2 diabetes mellitus

    , BMJ Open, Vol: 7, ISSN: 2044-6055

    Introduction The prevalence of obesity and obesity-related diseases, including type 2 diabetes mellitus (T2DM), is increasing. Exclusion of the foregut, as occurs in Roux-en-Y gastric bypass, has a key role in the metabolic improvements that occur following bariatric surgery, which are independent of weight loss. Endoscopically placed duodenal-jejunal bypass sleeve devices, such as the EndoBarrier (GI Dynamics, Lexington, Massachusetts, USA), have been designed to create an impermeable barrier between chyme exiting the stomach and the mucosa of the duodenum and proximal jejunum. The non-surgical and reversible nature of these devices represents an attractive therapeutic option for patients with obesity and T2DM by potentially improving glycaemic control and reducing their weight.Methods and analysis In this multicentre, randomised, controlled, non-blinded trial, male and female patients aged 18–65 years with a body mass index 30–50 kg/m2 and inadequately controlled T2DM on oral antihyperglycaemic medications (glycosylated haemoglobin (HbA1c) 58–97 mmol/mol) will be randomised in a 1:1 ratio to receive either the EndoBarrier device (n=80) for 12 months or conventional medical therapy, diet and exercise (n=80). The primary outcome measure will be a reduction in HbA1c by 20% at 12 months. Secondary outcome measures will include percentage weight loss, change in cardiovascular risk factors and medications, quality of life, cost, quality-adjusted life years accrued and adverse events. Three additional subgroups will investigate the mechanisms behind the effect of the EndoBarrier device, looking at changes in gut hormones, metabolites, bile acids, microbiome, food hedonics and preferences, taste, brain reward system responses to food, eating and addictive behaviours, body fat content, insulin sensitivity, and intestinal tissue gene expression.

  • Journal article
    Lally PJ, Montaldo P, Oliveira V, Swamy RS, Soe A, Shankaran S, Thayyil Set al., 2017,

    Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy

    , Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 103, Pages: F383-F387, ISSN: 1359-2998

    We examined the brain injury and neurodevelopmental outcomes in a prospective cohort of 10 babies with mild encephalopathy who had early cessation of cooling therapy. All babies had MRI and spectroscopy within 2 weeks after birth and neurodevelopmental assessment at 2 years. Cooling was prematurely discontinued at a median age of 9 hours (IQR 5-13) due to rapid clinical improvement. Five (50%) had injury on MRI or spectroscopy, and two (20%) had an abnormal neurodevelopmental outcome at 2 years. Premature cessation of cooling therapy in babies with mild neonatal encephalopathy does not exclude residual brain injury and adverse long-term neurodevelopmental outcomes. This study refers to babies recruited into the MARBLE study (NCT01309711, pre-results stage).

  • Journal article
    Timmermann C, Spriggs MJ, Kaelen M, Leech R, Nutt DJ, Moran RJ, Carhart-Harris RL, Muthukumaraswamy SDet al., 2017,

    LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm.

    , Neuropharmacology, ISSN: 0028-3908

    Under the predictive coding framework, perceptual learning and inference are dependent on the interaction between top-down predictions and bottom-up sensory signals both between and within regions in a network. However, how such feedback and feedforward connections are modulated in the state induced by lysergic acid diethylamide (LSD) is poorly understood. In this study, an auditory oddball paradigm was presented to healthy participants (16 males, 4 female) under LSD and placebo, and brain activity was recorded using magnetoencephalography (MEG). Scalp level Event Related Fields (ERF) revealed reduced neural adaptation to familiar stimuli, and a blunted neural 'surprise' response to novel stimuli in the LSD condition. Dynamic causal modelling revealed that both the presentation of novel stimuli and LSD modulate backward extrinsic connectivity within a task-activated fronto-temporal network, as well as intrinsic connectivity in the primary auditory cortex. These findings show consistencies with those of previous studies of schizophrenia and ketamine but also studies of reduced consciousness - suggesting that rather than being a marker of conscious level per se, backward connectivity may index modulations of perceptual learning common to a variety of altered states of consciousness, perhaps united by a shared altered sensitivity to environmental stimuli. Since recent evidence suggests that the psychedelic state may correspond to a heightened 'level' of consciousness with respect to the normal waking state, our data warrant a re-examination of the top-down hypotheses of conscious level and suggest that several altered states may feature this specific biophysical effector.

  • Journal article
    Vaghi MM, Hampshire A, Fineberg NA, Kaser M, Brühl AB, Sahakian BJ, Chamberlain SR, Robbins TWet al., 2017,

    Hypoactivation and Dysconnectivity of a Frontostriatal Circuit During Goal-Directed Planning as an Endophenotype for Obsessive-Compulsive Disorder

    , Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Vol: 2, Pages: 655-663, ISSN: 2451-9022

    © 2017 Society of Biological Psychiatry Background The symptoms of obsessive-compulsive disorder (OCD) have been postulated to result from impaired executive functioning and excessive habit formation at the expense of goal-directed control and have been objectively demonstrated using neuropsychological tests in such patients. This study tested whether there is functional hypoactivation as well as dysconnectivity of discrete frontostriatal pathways during goal-directed planning in patients with OCD and in their unaffected first-degree relatives. Methods In total, 21 comorbidity-free patients with OCD, 19 clinically asymptomatic first-degree relatives of these patients, and 20 control participants were tested on a functional magnetic resonance optimized version of the Tower of London task. Group differences in brain activation during goal-directed planning were measured together with associated frontostriatal functional connectivity. Results Patients with OCD and their clinically asymptomatic relatives manifested hypoactivation of the right dorsolateral prefrontal cortex during goal-directed planning coupled with reduced functional connectivity between this cortical region and the basal ganglia (putamen). Conclusions Hypoactivation of cortical regions associated with goal-directed planning and associated frontostriatal dysconnectivity represent a candidate endophenotype for OCD. These findings accord with abnormalities in neural networks supporting the balance between goal-directed and habitual behavior, with implications for recent neuropsychological theories of OCD and the major neurobiological model for this disorder.

  • Journal article
    Fallon SJ, Bor D, Hampshire A, Barker RA, Owen AMet al., 2017,

    Spatial structure normalises working memory performance in Parkinson's disease.

    , Cortex, Vol: 96, Pages: 73-82

    Cognitive deficits are a frequent symptom of Parkinson's disease (PD), particularly in the domain of spatial working memory (WM). Despite numerous demonstrations of aberrant WM in patients, there is a lack of understanding about how, if at all, their WM is fundamentally altered. Most notably, it is unclear whether span - the yardstick upon which most WM models are built - is compromised by the disease. Moreover, it is also unknown whether WM deficits occur in all patients or only exist in a sub-group who are executively impaired. We assessed the factors that influenced spatial span in medicated patients by varying the complexity of to-be-remembered items. Principally, we manipulated the ease with which items could enter - or be blocked from - WM by varying the level of structure in memoranda. Despite having similar levels of executive performance to controls, PD patients were only impaired when remembering information that lacked spatial, easy-to-chunk, structure. Patients' executive function, however, did not influence this effect. The ease with which patients could control WM was further examined by presenting irrelevant information during encoding, varying the level of structure in irrelevant information and manipulating the amount of switching between relevant and irrelevant information. Disease did not significantly alter the effect of these manipulations. Rather, patients' executive performance constrained the detrimental effect of irrelevant information on WM. Thus, PD patients' spatial span is predominantly determined by level of structure in to-be-remembered information, whereas their level of executive function may mitigate against the detrimental effect of irrelevant information.

  • Journal article
    Van Zoest RA, Underwood J, De Francesco D, Sabin CA, Cole JH, Wit FW, Caan MWA, Kootstra NA, Fuchs D, Zetterberg H, Majoie CBLM, Portegies P, Winston A, Sharp DJ, Gisslén M, Reiss P, Co-morBidity in Relation to AIDS COBRA Collaborationet al., 2017,

    Structural brain abnormalities in successfully treated HIV infection: associations with disease and cerebrospinal fluid biomarkers.

    , Journal of Infectious Diseases, Vol: 217, Pages: 69-81, ISSN: 0022-1899

    Background: Brain structural abnormalities have been reported in persons with HIV (PWH) on suppressive combination antiretroviral therapy (cART), but their pathophysiology remains unclear. Methods: We investigated factors associated with brain tissue volumes and white matter microstructure (fractional anisotropy) in 134 PWH on suppressive cART and 79 comparable HIV-negative controls, aged ≥45 years from the Co-morBidity in Relation to AIDS (COBRA) cohort, using multimodal neuroimaging and cerebrospinal fluid (CSF) biomarkers. Results: Compared to controls, PWH had lower grey matter volumes (-13.7 mL [95%-confidence interval -25.1, -2.2 mL]) and fractional anisotropy (-0.0073 [-0.012, -0.0024]), with the largest differences observed in those with prior clinical AIDS. Hypertension and CSF soluble CD14 concentration were associated with lower fractional anisotropy. These associations were independent of HIV serostatus (Pinteraction=0.32 and Pinteraction=0.59, respectively) and did not explain the greater abnormalities in brain structure in relation to HIV. Conclusions: The presence of lower grey matter volumes and more white matter microstructural abnormalities in well-treated PWH partly reflect a combination of historical effects of AIDS, as well as the more general influence of systemic factors such as hypertension and ongoing neuroinflammation. Additional mechanisms explaining the accentuation of brain structure abnormalities in treated HIV infection remain to be identified.

  • Conference paper
    Sharp D, 2017,

    Long-term inflammatory and neurodegenerative consequences of traumatic brain injury

    , 23rd World Congress of Neurology (WCN), Publisher: ELSEVIER SCIENCE BV, Pages: 11-11, ISSN: 0022-510X
  • Conference paper
    Sharp D, 2017,

    Precision medicine in TBI: Lessons from dopaminergic treatment of cognitive impairment

    , 23rd World Congress of Neurology (WCN), Publisher: ELSEVIER SCIENCE BV, Pages: 1-2, ISSN: 0022-510X
  • Conference paper
    Sinclair M, Bai W, Puyol-Antón E, Oktay O, Rueckert D, King APet al., 2017,

    Fully automated segmentation-based respiratory motion correction of multiplanar cardiac magnetic resonance images for large-scale datasets

    , International Conference On Medical Image Computing & Computer Assisted Intervention, Pages: 332-340, ISSN: 0302-9743

    © Springer International Publishing AG 2017. Cardiac magnetic resonance (CMR) can be used for quantitative analysis of heart function. However, CMR imaging typically involves acquiring 2D image planes during separate breath-holds, often resulting in misalignment of the heart between image planes in 3D. Accurate quantitative analysis requires a robust 3D reconstruction of the heart from CMR images, which is adversely affected by such motion artifacts. Therefore, we propose a fully automated method for motion correction of CMR planes using segmentations produced by fully convolutional neural networks (FCNs). FCNs are trained on 100 UK Biobank subjects to produce short-axis and long-axis segmentations, which are subsequently used in an iterative registration algorithm for correcting breath-hold induced motion artifacts. We demonstrate significant improvements in motion-correction over image-based registration, with strong correspondence to results obtained using manual segmentations. We also deploy our automatic method on 9,353 subjects in the UK Biobank database, demonstrating significant improvements in 3D plane alignment.

  • Journal article
    Oktay O, Ferrante E, Kamnitsas K, Heinrich M, Bai W, Caballero J, Cook S, de Marvao A, Dawes T, O'Regan D, Kainz B, Glocker B, Rueckert D, Oktay O, Ferrante E, Kamnitsas K, Heinrich M, Bai W, Caballero J, Cook S, de Marvao A, Dawes T, O'Regan D, Kainz B, Glocker B, Rueckert Det al., 2017,

    Anatomically Constrained Neural Networks (ACNN): application to cardiac image enhancement and segmentation

    , IEEE Transactions on Medical Imaging, Vol: 37, Pages: 384-395, ISSN: 0278-0062

    Incorporation of prior knowledge about organ shape and location is key to improve performance of image analysis approaches. In particular, priors can be useful in cases where images are corrupted and contain artefacts due to limitations in image acquisition. The highly constrained nature of anatomical objects can be well captured with learning based techniques. However, in most recent and promising techniques such as CNN based segmentation it is not obvious how to incorporate such prior knowledge. State-of-the-art methods operate as pixel-wise classifiers where the training objectives do not incorporate the structure and inter-dependencies of the output. To overcome this limitation, we propose a generic training strategy that incorporates anatomical prior knowledge into CNNs through a new regularisation model, which is trained end-to-end. The new framework encourages models to follow the global anatomical properties of the underlying anatomy (e.g. shape, label structure) via learnt non-linear representations of the shape. We show that the proposed approach can be easily adapted to different analysis tasks (e.g. image enhancement, segmentation) and improve the prediction accuracy of the state-of-the-art models. The applicability of our approach is shown on multi-modal cardiac datasets and public benchmarks. Additionally, we demonstrate how the learnt deep models of 3D shapes can be interpreted and used as biomarkers for classification of cardiac pathologies.

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