A case-control study of drug risk factors for age-related macular degeneration.

OBJECTIVE: To investigate the association between age-related macular degeneration (AMD) and exposure to antacids, antithyroids, thyroid hormones, and thiazide diuretics. DESIGN: Matched case-control study. PARTICIPANTS: Population-based participants were selected from the United Kingdom General Practice Research Database. A total of 18,007 people with diagnosed AMD were compared with 86 169 controls matched for age, gender, and general practice. METHODS: Conditional logistic regression was used to determine the association between exposure to each drug group of interest and a diagnosis of AMD, adjusting for relevant confounding variables. MAIN OUTCOME MEASURES: The primary outcome was the odds ratio for the association between exposure to antacids, antithyroids, thyroid hormones, or thiazide diuretics and AMD. Secondary analyses were conducted to assess the effect of recent exposure to the drugs of interest, the total number of prescriptions received, and restricting the data set to participants with more than 2 years of observation time. RESULTS: The crude odds ratios for association between any record of drug exposure and AMD were as follows: 1.34 (95% confidence interval [CI], 1.29-1.39) for antacids; 1.15 (95% CI, 0.92-1.44) for antithyroids; 1.34 (95% CI, 1.29-1.39) for thyroid hormones; and 1.13 (95% CI, 1.08-1.17) for thiazide diuretics. After adjusting for consultation rate, observation time, diabetes, heart failure, hyperlipidemia, cardiovascular drug use, atherosclerosis, hypertension, aspirin use, hormone replacement therapy use, body mass index, alcohol consumption, and smoking, the odds ratios reduced to: 1.06 (95% CI, 1.02-1.10) for antacids, 0.98 (95% CI, 0.78-1.24) for antithyroids, 0.99 (95% CI, 0.92-1.06) for thyroid hormones, and 0.98 (95% CI, 0.94-1.02) for thiazides. Secondary analyses were consistent with these findings for all 4 drug categories. CONCLUSIONS: No association was detected between short- and medium-term use of antithyroids, thyroid hormones, and thiazide diuretics and the risk of AMD. Short- and medium-term use of antacids seems to be associated with a small increase in the risk of this disease. However, this increased risk is likely the result of residual confounding by smoking or uncontrolled confounding resulting from socioeconomic status. No conclusions could be drawn regarding longer-term use of each drug category

Hybrid electric aircraft : state of the art and key electrical system challenges

In both Europe and the USA, the aerospace sector is actively pursuing revolutionary design concepts to further improve the environmental impact of air travel. This is partly a result of increasing pressure on the industry from government and other organisations to reduce emissions , despite the continuing increase in air traffic [1] . The aggressive targets set by NASA and the EU [1, 2, 3] (e.g. the Advisory Coun cil for Aviation Research and Innovation in Europe has a target of a 75% reduction in CO2 emissions and a 90% reduction of NOx emissions by 2050) cannot be achieved through marginal improvements in turbine technology or aircraft design. Rather, disruptive technologies and more innovative aircraft must be considered

A novel role for GSK3β as a modulator of Drosha microprocessor activity and MicroRNA biogenesis

Regulation of microRNA (miR) biogenesis is complex and stringently controlled. Here, we identify the kinase GSK3β as an important modulator of miR biogenesis at Microprocessor level. Repression of GSK3β activity reduces Drosha activity toward pri-miRs, leading to accumulation of unprocessed pri-miRs and reduction of pre-miRs and mature miRs without altering levels or cellular localisation of miR biogenesis proteins. Conversely, GSK3β activation increases Drosha activity and mature miR accumulation. GSK3β achieves this through promoting Drosha:cofactor and Drosha:pri-miR interactions: it binds to DGCR8 and p72 in the Microprocessor, an effect dependent upon presence of RNA. Indeed, GSK3β itself can immunoprecipitate pri-miRs, suggesting possible RNA-binding capacity. Kinase assays identify the mechanism for GSK3β-enhanced Drosha activity, which requires GSK3β nuclear localisation, as phosphorylation of Drosha at S300 and/or S302; confirmed by enhanced Drosha activity and association with cofactors, and increased abundance of mature miRs in the presence of phospho-mimic Drosha. Functional implications of GSK3β-enhanced miR biogenesis are illustrated by increased levels of GSK3β-upregulated miR targets following GSK3β inhibition. These data, the first to link GSK3β with the miR cascade in humans, highlight a novel pro-biogenesis role for GSK3β in increasing miR biogenesis as a component of the Microprocessor complex with wide-ranging functional consequences

From large-scale loops to the sites of dense flaring loops: Preferential conditions for long-period pulsations in solar flares

Copyright © 2010 American Astronomical Society / IOP PublishingLong-period quasi-periodic pulsations (QPPs) of solar flares are a class apart from shorter period events. By involving an external resonator, the mechanism they call upon differs from traditional QPP models, but has wider applications. We present a multi-wavelength analysis of spatially resolved QPPs, with periods around 10 minutes, observed in the X-ray spectrum primarily at energies between 3 and 25 keV. Complementary observations obtained in Hα and radio emission in the kHz to GHz frequency range, together with an analysis of the X-ray plasma properties provide a comprehensive picture that is consistent with a dense flaring loop subject to periodic energization and thermalization. The QPPs obtained in Hα and type III radio bursts, with similar periods as the QPPs in soft X-rays, have the longest periods ever reported for those types of data sets. We also report 1-2 GHz radio emission, concurrent with but unrestricted to the QPP time intervals, which is multi-structured at regularly separated narrowband frequencies and modulated with ~18 minute periods. This radio emission can be attributed to the presence of multiple "quiet" large-scale loops in the background corona. Large scale but shorter inner loops below may act as preferential resonators for the QPPs. The observations support interpretations consistent with both inner and outer loops subject to fast kink magnetohydrodynamic waves. Finally, X-ray imaging indicates the presence of double coronal sources in the flaring sites, which could be the particular signatures of the magnetically linked inner loops. We discuss the preferential conditions and the driving mechanisms causing the repeated flaring

The direct electrochemistry of ferritin compared with the direct electrochemistry of nanoparticulate hydrous ferric oxide

Horse spleen ferritin is a naturally occurring iron storage protein, consisting of a protein shell encapsulating a hydrous ferric oxide core about 8 nm in diameter. It is known from prior work that the protein can be adsorbed onto the surface of tin-doped indium oxide (ITO) electrodes, where it undergoes voltammetric reduction at about –0.6 V vs Ag/AgCl. This is accompanied by dissolution of Fe(II) through channels in the protein shell. In the present work, it is demonstrated that a pre-wave at about –0.4 V vs Ag/AgCl is due to the reduction of FePO4 also present inside the protein shell. In order to prove that the pre-wave was due to the reduction of FePO4, it was first necessary to prepare 8 nm diameter hydrous ferric oxide nanoparticles without protein shells, adsorb them onto ITO electrodes, and then study their electrochemistry. Having achieved that, it was then necessary to establish that their behaviour was analogous to that of ferritin. This was achieved in several ways, but principally by noting that the same electrochemical reduction reactions occurred at negative potentials, accompanied by the dissolution of Fe(II). Finally, by switching to aqueous phosphate buffer, the pre-wave could be unambiguously identified as the reduction of FePO4 present as a thin layer on the hydrous ferric oxide nanoparticle surfaces. Although the bare and protein-coated hydrous ferric oxide nanoparticles were found to behave identically toward electrochemical reduction, they nevertheless reacted very differently towards H2O2. The bare nanoparticles acted as potent electrocatalysts for both the oxidation and the reduction of H2O2, whereas the horse spleen ferritin had a much lesser effect. It seems likely therefore that the protein shell in ferritin blocks the formation of key intermediates in hydrogen peroxide decomposition

Patient freedom to choose a weight loss diet in the treatment of overweight and obesity: a randomized dietary intervention in type 2 diabetes and pre-diabetes

BackgroundOffering the overweight or obese patient the option of choosing from a selection of weight loss diets has not been investigated in type 2 diabetes. The aim of the study was to investigate if the option to choose from, and interchange between a selection of diets (&ldquo;Choice&rdquo;), as opposed to being prescribed one set diet (&ldquo;No Choice&rdquo;), improves drop out rates and leads to improved weight loss and cardio-metabolic outcomes.MethodsThe study was a 12 month, randomized parallel intervention. A total of 144 volunteers with type 2 diabetes or pre-diabetes and a BMI &gt;27 were randomized to &ldquo;No Choice&rdquo; or &ldquo;Choice&rdquo;. Those in the No Choice group were placed on a set weight loss diet (CSIRO) with no change permitted. Those in the Choice group could choose from, and interchange between, the CSIRO, South Beach or Mediterranean diets.ResultsThere were no differences in attrition rates or weight loss between the &ldquo;Choice&rdquo; and &ldquo;No Choice&rdquo;. In a secondary analysis of the intention-to-treat weight loss data with last measured weight carried forward gave a highly significant diet group by time by gender interaction (p&thinsp;=&thinsp;0.002) with men doing better in the No Choice group overall (maximum difference &ldquo;No Choice &ldquo;-2.9&thinsp;&plusmn;&thinsp;4.6 kg vs. &ldquo;Choice&rdquo;-6.2 kg&thinsp;&plusmn;&thinsp;5.3 kg at 6 months) and women doing better in the Choice group overall (maximum difference Choice -3.1&thinsp;&plusmn;&thinsp;3.7 kg vs. &ldquo;No Choice&rdquo; -2.0 kg&thinsp;&plusmn;&thinsp;2.6 kg at 6 months).ConclusionsMen prefer direction in their weight loss advice and do less well with choice. A gender-specific approach is recommended when prescribing weight loss diets.Trial registrationanzctr.org.au ACTRN12612000310864.<br /

Children's Divergent Thinking Improves When They Understand False Beliefs

This research utilized longitudinal and cross sectional methods to investigate the relation between the development of a representational theory of mind and children's growing ability to search their own minds for appropriate problem solutions. In the first experiment 59 pre-school children were given three false-belief tasks and a divergent thinking task. Those children who passed false-belief tasks produced significantly more items, as well as more original items, in response to divergent thinking questions than those children who failed. This significant association persisted even when chronological age, verbal and nonverbal general ability were partialed out. In a second study 20 children who failed the false-belief tasks in the first experiment were re-tested three months later. Again, those who now passed the false-belief tasks were significantly better at the divergent thinking task than those who continued to fail. The associations between measures of divergent thinking and understanding false-beliefs remained significant when controlling for the covariates. Earlier divergent thinking scores did not predict false-belief understanding three months later. Instead, children who passed false-belief tasks on the second measure improved significantly in relation to their own earlier performance and improved significantly more than children who continued to fail. False-belief task performance was significantly correlated to the amount of intra-individual improvement in divergent thinking even when age, verbal and nonverbal skills were partialed out. These findings suggest that developments in common underlying skills are responsible for the improvement in understanding other minds and searching one's own. Changes in representational and executive skills are discussed as potential causes for the improvement

Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations.

Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity.165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100.There was wide variation in SaO2 on air (78.5-99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up.Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses

Emergent dynamic chirality in a thermally driven artificial spin ratchet

Modern nanofabrication techniques have opened the possibility to create novel functional materials, whose properties transcend those of their constituent elements. In particular, tuning the magnetostatic interactions in geometrically frustrated arrangements of nanoelements called artificial spin ice1, 2 can lead to specific collective behaviour3, including emergent magnetic monopoles4, 5, charge screening6, 7 and transport8, 9, as well as magnonic response10, 11, 12. Here, we demonstrate a spin-ice-based active material in which energy is converted into unidirectional dynamics. Using X-ray photoemission electron microscopy we show that the collective rotation of the average magnetization proceeds in a unique sense during thermal relaxation. Our simulations demonstrate that this emergent chiral behaviour is driven by the topology of the magnetostatic field at the edges of the nanomagnet array, resulting in an asymmetric energy landscape. In addition, a bias field can be used to modify the sense of rotation of the average magnetization. This opens the possibility of implementing a magnetic Brownian ratchet13, 14, which may find applications in novel nanoscale devices, such as magnetic nanomotors, actuators, sensors or memory cells

EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders

BACKGROUND: Genomic variant prioritisation is one of the most significant bottlenecks to mainstream genomic testing in healthcare. Tools to improve precision while ensuring high recall are critical to successful mainstream clinical genomic testing, in particular for whole genome sequencing where millions of variants must be considered for each patient. METHODS: We developed EyeG2P, a publicly available database and web application using the Ensembl Variant Effect Predictor. EyeG2P is tailored for efficient variant prioritisation for individuals with inherited ophthalmic conditions. We assessed the sensitivity of EyeG2P in 1234 individuals with a broad range of eye conditions who had previously received a confirmed molecular diagnosis through routine genomic diagnostic approaches. For a prospective cohort of 83 individuals, we assessed the precision of EyeG2P in comparison with routine diagnostic approaches. For 10 additional individuals, we assessed the utility of EyeG2P for whole genome analysis. RESULTS: EyeG2P had 99.5% sensitivity for genomic variants previously identified as clinically relevant through routine diagnostic analysis (n=1234 individuals). Prospectively, EyeG2P enabled a significant increase in precision (35% on average) in comparison with routine testing strategies (p<0.001). We demonstrate that incorporation of EyeG2P into whole genome sequencing analysis strategies can reduce the number of variants for analysis to six variants, on average, while maintaining high diagnostic yield. CONCLUSION: Automated filtering of genomic variants through EyeG2P can increase the efficiency of diagnostic testing for individuals with a broad range of inherited ophthalmic disorders