Predicting Incremental and Future Visual Change in Neovascular Age-Related Macular Degeneration Using Deep Learning

PURPOSE: To evaluate the predictive utility of quantitative imaging biomarkers, acquired automatically from optical coherence tomography (OCT) scans, of cross-sectional and future visual outcomes of patients with neovascular age-related macular degeneration (AMD) starting anti-vascular endothelial growth factor (VEGF) therapy. DESIGN: Retrospective cohort study. PARTICIPANTS: Treatment-naïve, first-treated eyes of patients with neovascular AMD between 2007 and 2017 at Moorfields Eye Hospital (a large, UK single-centre) undergoing anti-VEGF therapy METHODS: Automatic segmentation was carried out by applying a deep learning segmentation algorithm to 137,379 OCT scans from 6467 eyes of 3261 patients with neovascular AMD. After applying selection criteria 926 eyes of 926 patients were taken forward for analysis. MAIN OUTCOME MEASURES: Correlation coefficients (R2) and mean absolute error (MAE) between quantitative OCT (qOCT) parameters and cross-sectional visual-function. The predictive value of these parameters for short-term visual change i.e. incremental visual acuity [VA] resulting from an individual injection, as well as, VA at distant timepoints (up to 12 months post-baseline). RESULTS: VA at distant timepoints could be predicted: R2 0.80 (MAE 5.0 ETDRS letters) and R2 0.7 (MAE 7.2) post-injection 3 and at 12 months post-baseline (both p < 0.001), respectively. Best performing models included both baseline qOCT parameters and treatment-response. Furthermore, we present proof-of-principle evidence that the incremental change in VA from an injection can be predicted: R2 0.14 (MAE 5.6) for injection 2 and R2 0.11 (MAE 5.0) for injection 3 (both p < 0.001). CONCLUSIONS: Automatic segmentation enables rapid acquisition of quantitative and reproducible OCT biomarkers with potential to inform treatment decisions in the care of neovascular AMD. This furthers development of point-of-care decision-aid systems for personalized medicine

Feasibility of Automated Deep Learning Design for Medical Image Classification by Healthcare Professionals with Limited Coding Experience

Deep learning has huge potential to transform healthcare. However, significant expertise is required to train such models and this is a significant blocker for their translation into clinical practice. In this study, we therefore sought to evaluate the use of automated deep learning software to develop medical image diagnostic classifiers by healthcare professionals with limited coding – and no deep learning – expertise. We used five publicly available open-source datasets: (i) retinal fundus images (MESSIDOR); (ii) optical coherence tomography (OCT) images (Guangzhou Medical University/Shiley Eye Institute, Version 3); (iii) images of skin lesions (Human against Machine (HAM)10000) and (iv) both paediatric and adult chest X-ray (CXR) images (Guangzhou Medical University/Shiley Eye Institute, Version 3 and the National Institute of Health (NIH)14 dataset respectively) to separately feed into a neural architecture search framework that automatically developed a deep learning architecture to classify common diseases. Sensitivity (recall), specificity and positive predictive value (precision) were used to evaluate the diagnostic properties of the models. The discriminative performance was assessed using the area under the precision recall curve (AUPRC). In the case of the deep learning model developed on a subset of the HAM10000 dataset, we performed external validation using the Edinburgh Dermofit Library dataset. Diagnostic properties and discriminative performance from internal validations were high in the binary classification tasks (range: sensitivity of 73.3-97.0%, specificity of 67-100% and AUPRC of 0.87-1). In the multiple classification tasks, the diagnostic properties ranged from 38-100% for sensitivity and 67-100% for specificity. The discriminative performance in terms of AUPRC ranged from 0.57 to 1 in the five automated deep learning models. In an external validation using the Edinburgh Dermofit Library dataset, the automated deep learning model showed an AUPRC of 0.47, with a sensitivity of 49% and a positive predictive value of 52%. The quality of the open-access datasets used in this study (including the lack of information about patient flow and demographics) and the absence of measurement for precision, such as confidence intervals, constituted the major limitation of this study. All models, except for the automated deep learning model trained on the multi-label classification task of the NIH CXR14 dataset, showed comparable discriminative performance and diagnostic properties to state-of-the-art performing deep learning algorithms. The performance in the external validation study was low. The availability of automated deep learning may become a cornerstone for the democratization of sophisticated algorithmic modelling in healthcare as it allows the derivation of classification models without requiring a deep understanding of the mathematical, statistical and programming principles. Future studies should compare several application programming interfaces on thoroughly curated datasets

Effectiveness and cost-effectiveness of an educational intervention for practice teams to deliver problem focused therapy for insomnia: rationale and design of a pilot cluster randomised trial

Background: Sleep problems are common, affecting over a third of adults in the United Kingdom and leading to reduced productivity and impaired health-related quality of life. Many of those whose lives are affected seek medical help from primary care. Drug treatment is ineffective long term. Psychological methods for managing sleep problems, including cognitive behavioural therapy for insomnia (CBTi) have been shown to be effective and cost effective but have not been widely implemented or evaluated in a general practice setting where they are most likely to be needed and most appropriately delivered. This paper outlines the protocol for a pilot study designed to evaluate the effectiveness and cost-effectiveness of an educational intervention for general practitioners, primary care nurses and other members of the primary care team to deliver problem focused therapy to adult patients presenting with sleep problems due to lifestyle causes, pain or mild to moderate depression or anxiety. Methods and design: This will be a pilot cluster randomised controlled trial of a complex intervention. General practices will be randomised to an educational intervention for problem focused therapy which includes a consultation approach comprising careful assessment (using assessment of secondary causes, sleep diaries and severity) and use of modified CBTi for insomnia in the consultation compared with usual care (general advice on sleep hygiene and pharmacotherapy with hypnotic drugs). Clinicians randomised to the intervention will receive an educational intervention (2 × 2 hours) to implement a complex intervention of problem focused therapy. Clinicians randomised to the control group will receive reinforcement of usual care with sleep hygiene advice. Outcomes will be assessed via self-completion questionnaires and telephone interviews of patients and staff as well as clinical records for interventions and prescribing. Discussion: Previous studies in adults have shown that psychological treatments for insomnia administered by specialist nurses to groups of patients can be effective within a primary care setting. This will be a pilot study to determine whether an educational intervention aimed at primary care teams to deliver problem focused therapy for insomnia can improve sleep management and outcomes for individual adult patients presenting to general practice. The study will also test procedures and collect information in preparation for a larger definitive cluster-randomised trial. The study is funded by The Health Foundation

Exogenous spatial precuing reliably modulates object processing but not object substitution masking

Object substitution masking (OSM) is used in behavioral and imaging studies to investigate processes associated with the formation of a conscious percept. Reportedly, OSM occurs only when visual attention is diffusely spread over a search display or focused away from the target location. Indeed, the presumed role of spatial attention is central to theoretical accounts of OSM and of visual processing more generally (Di Lollo, Enns, & Rensink, Journal of Experimental Psychology: General 129:481–507, 2000). We report a series of five experiments in which valid spatial precuing is shown to enhance the ability of participants to accurately report a target but, in most cases, without affecting OSM. In only one experiment (Experiment 5) was a significant effect of precuing observed on masking. This is in contrast to the reliable effect shown across all five experiments in which precuing improved overall performance. The results are convergent with recent findings from Argyropoulos, Gellatly, and Pilling (Journal of Experimental Psychology: Human Perception and Performance 39:646–661, 2013), which show that OSM is independent of the number of distractor items in a display. Our results demonstrate that OSM can operate independently of focal attention. Previous claims of the strong interrelationship between OSM and spatial attention are likely to have arisen from ceiling or floor artifacts that restricted measurable performance

Evidence for a nuclear compartment of transcription and splicing located at chromosome domain boundaries

The nuclear topography of splicing snRNPs, mRNA transcripts and chromosome domains in various mammalian cell types are described. The visualization of splicing snRNPs, defined by the Sm antigen, and coiled bodies, revealed distinctly different distribution patterns in these cell types. Heat shock experiments confirmed that the distribution patterns also depend on physiological parameters. Using a combination of fluorescencein situ hybridization and immunodetection protocols, individual chromosome domains were visualized simultaneously with the Sm antigen or the transcript of an integrated human papilloma virus genome. Three-dimensional analysis of fluorescence-stained target regions was performed by confocal laser scanning microscopy. RNA transcripts and components of the splicing machinery were found to be generally excluded from the interior of the territories occupied by the individual chromosomes. Based on these findings we present a model for the functional compartmentalization of the cell nucleus. According to this model the space between chromosome domains, including the surface areas of these domains, defines a three-dimensional network-like compartment, termed the interchromosome domain (ICD) compartment, in which transcription and splicing of mRNA occurs

A VLP-based vaccine targeting domain III of the West Nile virus E protein protects from lethal infection in mice

Background. Since its first appearance in the USA in 1999, West Nile virus (WNV) has spread in the Western hemisphere and continues to represent an important public health concern. In the absence of effective treatment, there is a medical need for the development of a safe and efficient vaccine. Live attenuated WNV vaccines have shown promise in preclinical and clinical studies but might carry inherent risks due to the possibility of reversion to more virulent forms. Subunit vaccines based on the large envelope (E) glycoprotein of WNV have therefore been explored as an alternative approach. Although these vaccines were shown to protect from disease in animal models, multiple injections and/or strong adjuvants were required to reach efficacy, underscoring the need for more immunogenic, yet safe DIII-based vaccines. Results. We produced a conjugate vaccine against WNV consisting of recombinantly expressed domain III (DIII) of the E glycoprotein chemically cross-linked to virus-like particles derived from the recently discovered bacteriophage AP205. In contrast to isolated DIII protein, which required three administrations to induce detectable antibody titers in mice, high titers of DIII-specific antibodies were induced after a single injection of the conjugate vaccine. These antibodies were able to neutralize the virus in vitro and provided partial protection from a challenge with a lethal dose of WNV. Three injections of the vaccine induced high titers of virus-neutralizing antibodies, and completely protected mice from WNV infection. Conclusions. The immunogenicity of DIII can be strongly enhanced by conjugation to virus-like particles of the bacteriophage AP205. The superior immunogenicity of the conjugate vaccine with respect to other DIII-based subunit vaccines, its anticipated favourable safety profile and low production costs highlight its potential as an efficacious and cost-effective prophylaxis against WNV

Vaccination against GIP for the Treatment of Obesity

BACKGROUND: According to the WHO, more than 1 billion people worldwide are overweight and at risk of developing chronic illnesses, including cardiovascular disease, type 2 diabetes, hypertension and stroke. Current therapies show limited efficacy and are often associated with unpleasant side-effect profiles, hence there is a medical need for new therapeutic interventions in the field of obesity. Gastric inhibitory peptide (GIP, also known as glucose-dependent insulinotropic polypeptide) has recently been postulated to link over-nutrition with obesity. In fact GIP receptor-deficient mice (GIPR(-/-)) were shown to be completely protected from diet-induced obesity. Thus, disrupting GIP signaling represents a promising novel therapeutic strategy for the treatment of obesity. METHODOLOGY/PRINCIPAL FINDINGS: In order to block GIP signaling we chose an active vaccination approach using GIP peptides covalently attached to virus-like particles (VLP-GIP). Vaccination of mice with VLP-GIP induced high titers of specific antibodies and efficiently reduced body weight gain in animals fed a high fat diet. The reduction in body weight gain could be attributed to reduced accumulation of fat. Moreover, increased weight loss was observed in obese mice vaccinated with VLP-GIP. Importantly, despite the incretin action of GIP, VLP-GIP-treated mice did not show signs of glucose intolerance. CONCLUSIONS/SIGNIFICANCE: This study shows that vaccination against GIP was safe and effective. Thus active vaccination may represent a novel, long-lasting treatment for obesity. However further preclinical safety/toxicology studies will be required before the therapeutic concept can be addressed in humans

Decadal to monthly timescales of magma transfer and reservoir growth at a caldera volcano

International audienceCaldera-forming volcanic eruptions are low-frequency, highimpact events capable of discharging tens to thousands of cubic kilometres of magma explosively on timescales of hours to days, with devastating effects on local and global scales1. Because no such eruption has been monitored during its long build-up phase, the precursor phenomena are not well understood. Geophysical signals obtained during recent episodes of unrest at calderas such as Yellowstone, USA, and Campi Flegrei, Italy, are difficult to interpret, and the conditions necessary for large eruptions are poorly constrained2,3. Here we present a study of pre-eruptive magmatic processes and their timescales using chemically zoned crystals from the 'Minoan' caldera-formingeruption of Santorini volcano,Greece4, which occurred in the late 1600s BC. The results provide insights into how rapidly large silicic systems may pass from a quiescent state to one on the edge of eruption5,6. Despite the large volume of erupted magma4 (40-60 cubic kilometres), and the 18,000-year gestation period between the Minoan eruption and the previous major eruption, most crystals in the Minoan magma record processes that occurred less than about 100 years before the eruption. Recharge of the magma reservoir by large volumes of silicic magma (and some mafic magma) occurred during the century before eruption, and mixing between different silicicmagmabatches was still taking place during the final months. Final assembly of large silicic magma reservoirs may occur on timescales that are geologically very short by comparison with the preceding repose period, with major growth phases immediately before eruption. These observations have implications for the monitoring of long-dormant, but potentially active, caldera systems