The Sonata Form and its Use in Beethoven\u27s First Seventeen Piano Sonatas

Beethoven\u27s piano sonatas are possibly the greatest achievement in piano literature, perhaps in all musical literature. It has been said that if the forty-eight preludes and fuges of Bach\u27s Well-tempered Clavier were to be considered the Old Testament of music, then Beethoven\u27s thirty-two sonatas would have to be the New Testament

Combined high-resolution genotyping and geospatial analysis reveals modes of endemic urban typhoid fever transmission

Typhoid is a systemic infection caused by Salmonella Typhi and Salmonella Paratyphi A, human-restricted bacteria that are transmitted faeco-orally. Salmonella Typhi and S. Paratyphi A are clonal, and their limited genetic diversity has precluded the identification of long-term transmission networks in areas with a high disease burden. To improve our understanding of typhoid transmission we have taken a novel approach, performing a longitudinal spatial case–control study for typhoid in Nepal, combining single-nucleotide polymorphism genotyping and case localization via global positioning. We show extensive clustering of typhoid occurring independent of population size and density. For the first time, we demonstrate an extensive range of genotypes existing within typhoid clusters, and even within individual households, including some resulting from clonal expansion. Furthermore, although the data provide evidence for direct human-to-human transmission, we demonstrate an overwhelming contribution of indirect transmission, potentially via contaminated water. Consistent with this, we detected S. Typhi and S. Paratyphi A in water supplies and found that typhoid was spatially associated with public water sources and low elevation. These findings have implications for typhoid-control strategies, and our innovative approach may be applied to other diseases caused by other monophyletic or emerging pathogens

Social isolation, vital exhaustion, and incident heart failure: findings from the Atherosclerosis Risk in Communities Study

Prospective studies have shown that social isolation (i.e. lack of social contacts) predicts incident coronary heart disease (CHD), but it is unclear whether it predicts incident heart failure (HF) and what factors might mediate this association. HF patients may be more susceptible to social isolation as they tend to be older and may have disrupted social relationships due to life course factors (e.g. retirement or bereavement). We prospectively examined whether individuals with higher vs. low social isolation have a higher incidence of HF and determined whether this association is mediated by vital exhaustion

Low-dose (0.01%) atropine eye drops to reduce progression of myopia in children: a multi-centre placebo-controlled randomised trial in the United Kingdom (CHAMP-UK) – study protocol

Background/aims To report the protocol of a trial designed to evaluate the efficacy, safety and mechanism of action of low-dose atropine (0.01%) eye-drops for reducing progression of myopia in UK children. Methods Multicentre, double-masked, superiority, placebo-controlled, randomised trial. We will enrol children aged 6–12 years with myopia of −0.50 dioptres or worse in both eyes. We will recruit 289 participants with an allocation ratio of 2:1 (193 atropine; 96 placebo) from five centres. Participants will instil one drop in each eye every day for 2 years and attend a research centre every 6 months. The vehicle and preservative will be the same in both study arms. The primary outcome is SER of both eyes measured by autorefractor under cycloplegia at 2 years (adjusted for baseline). Secondary outcomes include axial length, best corrected distance visual acuity, near visual acuity, reading speed, pupil diameter, accommodation, adverse event rates and allergic reactions, quality of life (EQ-5D-Y) and tolerability at 2 years. Mechanistic evaluations will include: peripheral axial length, peripheral retinal defocus, anterior chamber depth, iris colour, height and weight, activities questionnaire, ciliary body biometry and chorioretinal thickness. Endpoints from both eyes will be pooled in combined analysis using generalised estimating equations to allow for the correlation between eyes within participant. Three years after cessation of treatment, we will also evaluate refractive error and adverse events. Conclusions The Childhood Atropine for Myopia Progression in the UK study will be the first randomised trial reporting outcomes of low-dose atropine eye-drops for children with myopia in a UK population. Trial registration number ISRCTN99883695 , NCT0369008

A survey of intelligence analysts’ strategies for solving analytic tasks

Analytic performance may be assessed by the nature of the process applied to intelligence tasks and analysts are expected to use a 'critical' or deliberative mindset. However, there is little research on how analysts do their work. We report the findings of a quantitative survey of 113 intelligence analysts who were asked to report how often they would apply strategies involving more or less critical thinking when performing representative tasks along the analytic workflow. Analysts reported using ‘deliberative’ strategies significantly more often than ‘intuitive’ ones when capturing customer requirements, processing data, and communicating conclusions. Years of experience working in the intelligence community, skill level, analytic thinking training, and time spent working collaboratively (opposed to individually) were largely unrelated to reported strategy use. We discuss the implications of these findings for both improving intelligence analysis and developing an evidence-based approach to policy and practice in this domain

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article

Time spent outdoors in childhood is associated with reduced risk of myopia as an adult

Myopia (near-sightedness) is an important public health issue. Spending more time outdoors can prevent myopia but the long-term association between this exposure and myopia has not been well characterised. We investigated the relationship between time spent outdoors in childhood, adolescence and young adulthood and risk of myopia in young adulthood. The Kidskin Young Adult Myopia Study (KYAMS) was a follow-up of the Kidskin Study, a sun exposure-intervention study of 1776 children aged 6–12 years. Myopia status was assessed in 303 (17.6%) KYAMS participants (aged 25–30 years) and several subjective and objective measures of time spent outdoors were collected in childhood (8–12 years) and adulthood. Index measures of total, childhood and recent time spent outdoors were developed using confirmatory factor analysis. Logistic regression was used to assess the association between a 0.1-unit change in the time outdoor indices and risk of myopia after adjusting for sex, education, outdoor occupation, parental myopia, parental education, ancestry and Kidskin Study intervention group. Spending more time outdoors during childhood was associated with reduced risk of myopia in young adulthood (multivariable odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69, 0.98). Spending more time outdoors in later adolescence and young adulthood was associated with reduced risk of late-onset myopia (≥ 15 years of age, multivariable OR 0.79, 95% CI 0.64, 0.98). Spending more time outdoors in both childhood and adolescence was associated with less myopia in young adulthood.Te authors thank the participants of the Kidskin Study and their families. Te Kidskin Young Adult Myopia Study was supported by Perpetual Impact Philanthropy (IPAP2015/0230) and the National Health and Medical Research Council (1121979). Te Kidskin Study was supported by the National Health and Medical Research Council (954601, 110221, 209057) and by the Cancer Foundation of Western Australia. GL receives fnancial support through an Australian Government Research Training Program Scholarship

NKp46⁺CD3⁺ Cells: A Novel Nonconventional T Cell Subsetin Cattle Exhibiting Both NK Cell and T Cell Features

The NKp46 receptor demonstrates a high degree of lineage-specificity, being expressed almost exclusively in natural killer cells. Previous studies have demonstrated NKp46 expression by T-cells, but NKp46(+)CD3(+) cells are rare and almost universally associated with NKp46 acquisition by T-cells following stimulation. In this study we demonstrate the existence of a population of NKp46(+)CD3(+) cells resident in normal bovine PBMC which include cells of both the αβ TCR(+) and γδ TCR(+) lineages and is present at a frequency of 0.1-1.7%. NKp46(+)CD3(+) cells express transcripts for a broad repertoire of both natural killer (NKR) and T-cell receptors (TCR) and also the CD3ζ, DAP10 and FcεR1γ but not DAP12 adaptor proteins. In vitro functional analysis of NKp46(+)CD3(+) cells confirm that NKp46, CD16 and CD3 signalling pathways are all functionally competent and capable of mediating-re-direct cytolysis. However, only CD3 cross-ligation elicits IFN-γ release. NKp46(+)CD3(+) cells exhibit cytotoxic activity against autologous Theileria parva infected cells in vitro and during in vivo challenge with this parasite an expansion of NKp46(+)CD3(+) cells was observed in some animals, indicating the cells have the potential to act as an anti-pathogen effector population. The results presented herein identifies and describes a novel non-conventional NKp46(+)CD3(+) T-cell subset that is phenotypically and functionally distinct from conventional NK and T-cells. The ability to exploit both NKR and TCR suggests these cells may fill a functional niche at the interface of innate and adaptive immune responses

Generation of Priority Research Questions to Inform Conservation Policy and Management at a National Level

Integrating knowledge from across the natural and social sciences is necessary to effectively address societal tradeoffs between human use of biological diversity and its preservation. Collaborative processes can change the ways decision makers think about scientific evidence, enhance levels of mutual trust and credibility, and advance the conservation policy discourse. Canada has responsibility for a large fraction of some major ecosystems, such as boreal forests, Arctic tundra, wetlands, and temperate and Arctic oceans. Stressors to biological diversity within these ecosystems arise from activities of the country's resource-based economy, as well as external drivers of environmental change. Effective management is complicated by incongruence between ecological and political boundaries and conflicting perspectives on social and economic goals. Many knowledge gaps about stressors and their management might be reduced through targeted, timely research. We identify 40 questions that, if addressed or answered, would advance research that has a high probability of supporting development of effective policies and management strategies for species, ecosystems, and ecological processes in Canada. A total of 396 candidate questions drawn from natural and social science disciplines were contributed by individuals with diverse organizational affiliations. These were collaboratively winnowed to 40 by our team of collaborators. The questions emphasize understanding ecosystems, the effects and mitigation of climate change, coordinating governance and management efforts across multiple jurisdictions, and examining relations between conservation policy and the social and economic well-being of Aboriginal peoples. The questions we identified provide potential links between evidence from the conservation sciences and formulation of policies for conservation and resource management. Our collaborative process of communication and engagement between scientists and decision makers for generating and prioritizing research questions at a national level could be a model for similar efforts beyond Canada