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Background Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN–EYE) is to facilitate improvement in diagnosis of RED in European member states. Main body Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. Short conclusion Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED.

Andrew Walkden, James F Young, Anne F Spencer, Jane AshworthManchester Royal Eye Hospital, Manchester, UKProblem: Starting ophthalmic specialty training can be daunting as new basic clinical examination and surgical skills must be acquired before meaningful assessment of patients can begin. No formal clinical induction currently exists with the aim to teach clinical and practical skills to new starters.Aim and objectives: To determine the experience and needs of ophthalmic trainees entering into specialist training. Using this information we developed and implemented a clinical skills training programme for Ophthalmology ST1s.Intervention: Using SMART objectives, PDSA cycles and Chartered Institute of Personnel Development guidance we implemented a clinical skills induction week. Pre-course skills evaluation took place in the form of a questionnaire in order to tailor the course content to the skill level of the group. Course material was made and simulation techniques devised for teaching practical skills. Qualitative data was collected via a pre- and post-course questionnaire.Outcome: All 9 participants rated the course as “extremely useful” it increased their confidence in terms of commencing clinical ophthalmology. 100% of participants felt that this course should be delivered to new ST1s. All participants reported improved confidence in managing ophthalmic emergencies and their clinical skills technique.Lessons learned: A sustainable induction programme was implemented tailored to the prior experience and skills of ST1 trainees. All participants felt it improved their confidence and clinical skills prior to commencing clinical activities. Basic clinical skills can be taught in a cost effective manner early on in postgraduate training.Keywords: ophthalmic training, starting ophthalmology, ophthalmology run-through training, ophthalmic clinical skills, ophthalmic training needs &nbsp

Acidification of the ocean due to high atmospheric CO2 levels may increase the resilience of diatoms causing dramatic shifts in abiotic and biotic cycles with lasting implications on marine ecosystems. Here, we report a potential bioindicator of a shift in the resilience of a coastal and centric model diatom Thalassiosira pseudonana under elevated CO2. Specifically, we have discovered, through EGFP-tagging, a plastid membrane localized putative Na+(K+)/H+ antiporter that is significantly upregulated at >800 ppm CO2, with a potentially important role in maintaining pH homeostasis. Notably, transcript abundance of this antiporter gene was relatively low and constant over the diel cycle under contemporary CO2 conditions. In future acidified oceanic conditions, dramatic oscillation with >10-fold change between nighttime (high) and daytime (low) transcript abundances of the antiporter was associated with increased resilience of T. pseudonana. By analyzing metatranscriptomic data from the Tara Oceans project, we demonstrate that phylogenetically diverse diatoms express homologs of this antiporter across the globe. We propose that the differential between night- and daytime transcript levels of the antiporter could serve as a bioindicator of a shift in the resilience of diatoms in response to high CO2 conditions in marine environments.

There is a growing awareness that cells grown in 3D better model in vivo behavior than those grown in 2D. In this protocol, we describe a simple and tunable 3D hydrogel, suitable for culturing cells and tissue in a setting that matches their native environment. This is particularly important for researchers investigating the initiation, growth, and treatment of cancer where the interaction between cells and their local extracellular matrix is a fundamental part of the model.

Congenital and childhood cataracts are uncommon but regularly seen in the clinics of most paediatric ophthalmology teams in the UK. They are often associated with profound visual loss and a large proportion have a genetic aetiology, some with significant extra-ocular comorbidities. Optimal diagnosis and treatment typically require close collaboration within multidisciplinary teams. Surgery remains the mainstay of treatment. A variety of surgical techniques, timings of intervention and options for optical correction have been advocated making management seem complex for those seeing affected children infrequently. This paper summarises the proceedings of two recent RCOphth paediatric cataract study days, provides a literature review and describes the current UK ‘state of play’ in the management of paediatric cataracts.

Currency usage began a long trend decline in the decades after World War II. This was expected to continue, and even accelerate, owing to payment technology innovations. Surprisingly, however, such usage as a percentage of GDP stopped falling and has increased quite sharply in recent years in most countries, with Sweden the major outlier. We examine to what extent this may have been due to increasing interest elasticity, nearing the zero lower bound, and also to rising tax evasion, as indirect taxes rise. We also show how currency holdings increased temporarily as the financial crisis struck in 2008.

© 2020 Diatoms produce a wide diversity of sterols among different species, the biosynthesis and conservation of which is not yet fully understood. To investigate the conservation and divergence of sterol biosynthesis pathways among diatoms, we performed comparative metabolic profiling and transcriptomics for a centric diatom (Thalassiosira pseudonana), a pennate diatom (Phaeodactylum tricornutum) and a chaetocerid (Chaetoceros muelleri) in response to inhibitors of enzymes involved in sterol biosynthesis. These three model diatoms, which are representative of distinct clades, share a unique core phytosterol biosynthesis pathway that relies on a terbinafine-insensitive alternative squalene epoxidase and the cyclization of 2,3-epoxysqualene into cycloartenol by a conserved oxidosqualene cyclase. Lineage-specific divergence in the synthesis of sterol precursors was found in the species analyzed. Cholesterol synthesis in diatoms seems to occur via cycloartenol rather than lanosterol. The diversification of natural sterols produced by each species appears to occur downstream of all experimentally targeted enzymes, suggesting adaptive specialization in terminal synthesis pathways.

© 2019 Current materials used for in vitro 3D cell culture are often limited by their poor similarity to human tissue, batch-to-batch variability and complexity of composition and manufacture. Here, we present a “blank slate” culture environment based on a self-assembling peptide gel free from matrix motifs. The gel can be customised by incorporating matrix components selected to match the target tissue, with independent control of mechanical properties. Therefore the matrix components are restricted to those specifically added, or those synthesised by encapsulated cells. The flexible 3D culture platform provides full control over biochemical and physical properties, allowing the impact of biochemical composition and tissue mechanics to be separately evaluated in vitro. Here, we demonstrate that the peptide gels support the growth of a range of cells including human induced pluripotent stem cells and human cancer cell lines. Furthermore, we present proof-of-concept that the peptide gels can be used to build disease-relevant models. Controlling the peptide gelator concentration allows peptide gel stiffness to be matched to normal breast (1 kPa), with higher stiffness favouring the viability of breast cancer cells over normal breast cells. In parallel, the peptide gels may be modified with matrix components relevant to human breast, such as collagen I and hyaluronan. The choice and concentration of these additions affect the size, shape and organisation of breast epithelial cell structures formed in co-culture with fibroblasts. This system therefore provides a means of unravelling the individual influences of matrix, mechanical properties and cell-cell interactions in cancer and other diseases.

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The connectivity of rocks’ porous structure and the presence of fractures influence the transfer of fluids in the Earth’s crust. Here, we employed laboratory experiments to measure the influence of macro-fractures and effective pressure on the permeability of volcanic rocks with a wide range of initial porosities (1–41 vol. %) comprised of both vesicles and micro-cracks. We used a hand-held permeameter and hydrostatic cell to measure the permeability of intact rock cores at effective pressures up to 30 MPa; we then induced a macro-fracture to each sample using Brazilian tensile tests and measured the permeability of these macro-fractured rocks again. We show that intact rock permeability increases non-linearly with increasing porosity and decreases with increasing effective pressure due to compactional closure of micro-fractures. Imparting a macro-fracture both increases the permeability of rocks and their sensitivity to effective pressure. The magnitude of permeability increase induced by the macro-fracture is more significant for dense rocks. We finally provide a general equation to estimate the permeability of intact and fractured rocks, forming a basis to constrain fluid flow in volcanic and geothermal systems.

© 2015 Elsevier B.V. Diatoms are important primary producers in the ocean that thrive in diverse and dynamic environments. Their survival and success over changing conditions depend on the complex coordination of gene regulatory processes. Here we present an integrated analysis of all publicly available microarray data for the diatoms Thalassiosira pseudonana and Phaeodactylum tricornutum. This resource includes shared expression patterns, gene functions, and cis-regulatory DNA sequence motifs in each species that are statistically coordinated over many experiments. These data illustrate the coordination of transcriptional responses in diatoms over changing environmental conditions. Responses to silicic acid depletion segregate into multiple distinctly regulated groups of genes, regulation by heat shock transcription factors (HSFs) is implicated in the response to nitrate stress, and distinctly coordinated carbon concentrating, CO2 and pH-related responses are apparent. Fundamental features of diatom physiology are similarly coordinated between two distantly related diatom species, including the regulation of photosynthesis, cellular growth functions and lipid metabolism. These integrated data and analyses can be explored publicly (http://networks.systemsbiology.net/diatom-portal/).

Marine diatoms are important primary producers that thrive in diverse and dynamic environments. They do so, in theory, by sensing changing conditions and adapting their physiology accordingly. Using the model species Thalassiosira pseudonana, we conducted a detailed physiological and transcriptomic survey to measure the recurrent transcriptional changes that characterize typical diatom growth in batch culture. Roughly 40% of the transcriptome varied significantly and recurrently, reflecting large, reproducible cell-state transitions between four principal states: (i) "dawn," following 12 h of darkness; (ii ) "dusk," following 12 h of light; (iii ) exponential growth and nutrient repletion; and (iv) stationary phase and nutrient depletion. Increases in expression of thousands of genes at the end of the reoccurring dark periods (dawn), including those involved in photosynthesis (e.g., ribulose-1,5- bisphosphate carboxylase oxygenase genes rbcS and rbcL), imply large-scale anticipatory circadian mechanisms at the level of gene regulation. Repeated shifts in the transcript levels of hundreds of genes encoding sensory, signaling, and regulatory functions accompanied the four cell-state transitions, providing a preliminary map of the highly coordinated gene regulatory program under varying conditions. Several putative light sensing and signaling proteins were associated with recurrent diel transitions, suggesting that these genes may be involved in light-sensitive and circadian regulation of cell state. These results begin to explain, in comprehensive detail, how the diatom gene regulatory program operates under varying environmental conditions. Detailed knowledge of this dynamic molecular process will be invaluable for new hypothesis generation and the interpretation of genetic, environmental, and metatranscriptomic data from field studies.

GRT9906 is an investigational novel compound with μ-opioid receptor agonism and inhibition of noradrenalin/serotonin re-uptake. In this randomized, double-blind, placebo-controlled, three-way cross-over trial in painful polyneuropathy, the efficacy and safety of GRT9906 was assessed and compared with tramadol. During 4-week treatment periods, daily oral doses of either GRT9906 120-240 mg, or placebo, or tramadol 200-400 mg were given. These were separated by 1-week washout periods. The primary endpoint was the average pain intensity (average of daily current pain intensity over the last 3 days of each treatment period rated on a 0 to 10-point numeric rating scale). One hundred seventeen patients were enrolled and 64 were randomized to one of six treatment sequences. Forty-seven patients qualified for the per protocol analysis. GRT9906 reduced average pain intensity by 2.1 points compared with a reduction of 0.6 points on placebo (p

There are a variety of satellite applications that require application intelligence at intermediate devices for their proper functioning e.g. satellite networks using (Performance Enhancing Proxies, PEPs), real time streaming applications like SIP, H.323 and peer-to-peer applications. Interworking between PEPs and security system has been researched in the past. Multi-layer IPSec (ML-IPSec) resolves the conflict between end-to-end security in standard IPSec and working of PEPs. This paper presents the concept and detailed design of ML-IPSec by breaking the IP datagram into three zones while enabling the intermediate nodes to access the TCP header and HTTP header information. The paper also presents an efficient interworking scheme between ML-IPSec and secure IP multicast using the Logical Key Hierarchy for key distribution.

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Background: The Child Health Utility-9D (CHU-9D) is the only generic preference-based measure specifically developed to elicit health-related quality of life directly from children aged 7–11 years. The aim of this study was to investigate whether the use of animation on a touch screen device (tablet) is a better way of collecting health status information from children aged 4–14 years compared to a traditional paper questionnaire. The specific research questions were firstly, do young children (4–7 years) find an animated questionnaire easier to understand; secondly, independent of age, is completion of an animated questionnaire easier for sick children in hospital settings; and thirdly, do children’s preferences for the different formats of the questionnaire vary by the age of the child. Methods: Using a balanced cross-over trial, we administered different formats of the CHU-9D to 221 healthy children in a school setting and 217 children with health problems in a hospital setting. The study tested five versions of the CHU-9D questionnaire: paper text, tablet text, tablet still image, paper image and tablet animation. Results: Our results indicated that the majority of the children aged 4–7 years found the CHU-9D questions easy to answer independent of the format of the questionnaire administered. Amongst children aged 7–14 with health problems, the format of questionnaire influenced understanding. Children aged 7–11 years found the tablet image and animation formats easier compared to text questionnaires, while the oldest children in hospital found text-based questionnaires easier compared to image and animation. Conclusion: Children in all three age groups preferred animation on a tablet to other methods of assessment. Our results highlight the potential for using an animated preference-based measure to assess the health of children as young as 4 years.

Amid a substantial rise in gabapentin and pregabalin (gabapentinoid) prescribing and increasing concerns with their potential for misuse and diversion, there are anecdotal reports of their use for osteoarthritis. The aim of my thesis was to understand whether osteoarthritis may have contributed to the general rise in the use of the gabapentinoids.\ud A series of scoping literature reviews summarised the context and potential rationale for the off-label use of gabapentinoids for osteoarthritis. An original analysis of data from the Clinical Practice Research Datalink (CPRD) was then undertaken.\ud 383,680 patients aged over 40 years with a new diagnosis of osteoarthritis recorded between 1995 and 2015 were identified and followed for a median of 5.1 years to their first gabapentinoid prescription or other censoring event. 35,031 (9.1%) cohort members received a gabapentinoid prescription. The crude incidence rate of first gabapentinoid prescription among this cohort of osteoarthritis patients increased from 1.71 (95% CI: 1.37, 2.11) per 1,000 person-years in 2000 to 27.92 (27.06, 28.81) in 2015. Age-standardisation resulted in little change to these estimates. Whilst differences in incidence rates were seen by attained age, time since index osteoarthritis consultation, gender, and geographical region, the increasing trend over time was seen in all strata. The proportions of first gabapentinoid prescriptions in this cohort that could be attributed to osteoarthritis, a licensed indication, or an unlicensed indication were estimated as 9-10%, 11-12%, and 1-2%, respectively. This proportion of attribution remained relatively stable throughout the study period.\ud Patients with OA have become increasingly likely to be prescribed a gabapentinoid in the past two decades. Whilst this analysis found that the proportion of first prescriptions attributed to OA is approximately 9-10%, an unknown proportion of unattributed prescriptions may also be for OA. With growing concerns regarding their use, gabapentinoid prescribing in this condition requires careful justification.

International audience; This paper extends the empirical literature about the effects of fiscal decentralization on the growth of government along three dimensions. It distinguishes between the effects of the level of decentralization from the way local governments finance their expenditures (common pool versus own resources); it uses a panel cointegration approach to separate the long run effects of decentralization from the short run dynamics; and it extends and revises the datasets generally used in these empirical analyses. The results show that the amount of revenue raised by sub-national governments leads to a long-term fall in the size of government but grants have the opposite effect. In addition, a greater decentralization of expenditure leads to greater overall spending. When the short-term is considered these influences work slowly, as the speed of adjustment towards the desired government size is relatively sluggish. In addition, in the short run, there is also a clear effect from the role of local revenue raising powers that stimulates the growth of government. These results appear robust to changes in the composition of the variables, countries and periods included the sample.