718 research outputs found

    CV4: USING UK OBSERVATIONAL DATA TO IDENTIFY POSSIBILITIES FOR THE COST-EFFECTIVE IMPROVEMENT OF THE TREATMENT OF ATRIAL FIBRILLATION

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    Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy

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    Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational ā€œhotspotā€ in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD

    Monte Carlo Transmission Line Modeling of Multilayer Optical Coatings for Performance Sensitivity of a Dichroic Filter for the ARIEL Space Telescope

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    Dichroic beamsplitters, or dichroics, are filters that rely on the optical interference that occurs within thin layers to ensure the transmission and reflection of selective wavelengths of an incident beam of light. These optical components consist of a substrate coated on one or both surfaces with multiple layers of thin films, the spectral design and construction of which determine the isolation of particular wavebands. Discrepancies between the measured and expected spectral performance of optical elements with such coatings can largely be attributed to depositions errors and uncertainties in the refractive indices of the materials. Our model uses two-dimensional transmission line modeling to evaluate the transmittance of light through multilayer coatings deposited on a substrate material for given materials, angle of incidence and polarisation. This model allows us to perform Monte Carlo simulations to obtain statistical information about the tolerance of the coating performance to systematic and random uncertainties from the manufacturing process, as well as from environmental changes in space. With the aid of accurate manufacturing recipes and uncertainty amplitudes from commercial manufacturers, this tool can predict variations in the optical performance that result from the propagation of each of these uncertainties for various hypothetical scenarios. One particular application of this study are the dichroics of the ARIEL space telescope. We compare the predicted optical performance with transmission measurements at cryogenic temperatures for one of the ARIEL dichroics, which show the specification compliance of this prototype after many thermal cycles

    Lesbian and bisexual women's human rights, sexual rights and sexual citizenship: negotiating sexual health in England.

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    Lesbian and bisexual women's sexual health is neglected in much Government policy and practice in England and Wales. This paper examines lesbian and bisexual women's negotiation of sexual health, drawing on findings from a small research project. Themes explored include invisibility and lack of information, influences on decision-making and sexual activities and experiences of services and barriers to sexual healthcare. Key issues of importance in this respect are homophobic and heterosexist social contexts. Drawing on understandings of lesbian, gay and bisexual human rights, sexual rights and sexual citizenship, it is argued that these are useful lenses through which to examine and address lesbian and bisexual women's sexual health and related inequalities

    Multiplex in situ hybridization within a single transcript: RNAscope reveals dystrophin mRNA dynamics

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    Dystrophin plays a vital role in maintaining muscle health, yet low mRNA expression, lengthy transcription time and the limitations of traditional in-situ hybridization (ISH) methodologies mean that the dynamics of dystrophin transcription remain poorly understood. RNAscope is highly sensitive ISH method that can be multiplexed, allowing detection of individual transcript molecules at sub-cellular resolution, with different target mRNAs assigned to distinct fluorophores. We instead multiplex within a single transcript, using probes targeted to the 5ā€™ and 3ā€™ regions of muscle dystrophin mRNA. Our approach shows this method can reveal transcriptional dynamics in health and disease, resolving both nascent myonuclear transcripts and exported mature mRNAs in quantitative fashion (with the latter absent in dystrophic muscle, yet restored following therapeutic intervention). We show that even in healthy muscle, immature dystrophin mRNA predominates (60ā€“80% of total), with the surprising implication that the half-life of a mature transcript is markedly shorter than the time invested in transcription: at the transcript level, supply may exceed demand. Our findings provide unique spatiotemporal insight into the behaviour of this long transcript (with implications for therapeutic approaches), and further suggest this modified multiplex ISH approach is well-suited to long genes, offering a highly tractable means to reveal complex transcriptional dynamics

    Development and validation of risk prediction model for venous thromboembolism in postpartum women: multinational cohort study

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    Objective: To develop and validate a risk prediction model for venous thromboembolism in the first six weeks after delivery (early postpartum). Design: Cohort study. Setting: Records from England based Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and data from Sweden based registry. Participants: All pregnant women registered with CPRD-HES linked data between 1997 and 2014 and Swedish medical birth registry between 2005 and 2011 with postpartum follow-up. Main outcome measure: Multivariable logistic regression analysis was used to develop a risk prediction model for postpartum venous thromboembolism based on the English data, which was externally validated in the Swedish data. Results: 433 353 deliveries were identified in the English cohort and 662 387 in the Swedish cohort. The absolute rate of venous thromboembolism was 7.2 per 10 000 deliveries in the English cohort and 7.9 per 10 000 in the Swedish cohort. Emergency caesarean delivery, stillbirth, varicose veins, pre-eclampsia/eclampsia, postpartum infection, and comorbidities were the strongest predictors of venous thromboembolism in the final multivariable model. Discrimination of the model was similar in both cohorts, with a C statistic above 0.70, with excellent calibration of observed and predicted risks. The model identified more venous thromboembolism events than the existing national English (sensitivity 68% v 63%) and Swedish guidelines (30% v 21%) at similar thresholds. Conclusion: A new prediction model that quantifies absolute risk of postpartum venous thromboembolism has been developed and externally validated. It is based on clinical variables that are available in many developed countries at the point of delivery and could serve as the basis for real time decisions on obstetric thromboprophylaxis

    High temporal resolution sampling reveals reef fish settlement is highly clustered

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    Coral reef fish larvae settle on reefs predominantly at night around the new-moon phase, after an early developmental period spent in the pelagic environment. Most sampling is conducted across whole nights, and any studies that have examined the frequency of arrival within nights have typically been limited to coarse sampling time scales of 1ā€“5 h. Here, we present results for arrival numbers of fish caught between dusk and midnight from light traps sampled every 15 min at an Indonesian coral reef, providing the finest temporal resolution for this type of study to date. A spatial analysis by distance indices analysis, adapted to temporal data, revealed clustering of reef arrival times for many species, with an increase in catches immediately after dusk dropping off towards midnight. Importantly, the timing of clusters differed among species, indicating that different factors determine the timing of arrival among taxa. Our results support the hypothesis that larval behaviour influences the timing of arrival at a coral reef for different fish species
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