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Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss
Hearing loss is the most common sensory deficit in humans, affecting 1 in 500 newborns. Due to its genetic heterogeneity, comprehensive diagnostic testing has not previously been completed in a large multiethnic cohort. To determine the aggregate contribution inheritance makes to non-syndromic hearing loss, we performed comprehensive clinical genetic testing with targeted genomic enrichment and massively parallel sequencing on 1119 sequentially accrued patients. No patient was excluded based on phenotype, inheritance or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 patients (39 %). Pathogenic variants were found in 49 genes and included missense variants (49 %), large copy number changes (18 %), small insertions and deletions (18 %), nonsense variants (8 %), splice-site alterations (6 %), and promoter variants (<1 %). The diagnostic rate varied considerably based on phenotype and was highest for patients with a positive family history of hearing loss or when the loss was congenital and symmetric. The spectrum of implicated genes showed wide ethnic variability. These findings support the more efficient utilization of medical resources through the development of evidence-based algorithms for the diagnosis of hearing loss.
Journal Article
Rational policymaking during a pandemic
Policymaking during a pandemic can be extremely challenging. As COVID-19 is a new disease and its global impacts are unprecedented, decisions are taken in a highly uncertain, complex, and rapidly changing environment. In such a context, in which human lives and the economy are at stake, we argue that using ideas and constructs from modern decision theory, even informally, will make policymaking a more responsible and transparent process.
Journal Article
Bizet's Carmen uncovered
What were the forces that brought Carmen to the Operatic stage? There were certainly many: for example, the liberation of Spain from the Napoleonic rule in 1813; the subsequent emigration of Spanish artists and musicians to form an active community in Paris; the mid-century mushrooming of interest in visiting Spain facilitated by the establishment of railways. The first part of this book explores the reasons behind the French mania for Spain, and the second demonstrates how the travels and writings of Prosper Mérimée, particularly in his novella Carmen, but also in his earlier writings sent back to Paris from his first visit to Spain in the 1830s, were incorporated into the opera. What were the stories he incorporated into the fateful tale of the soldier who murders his gypsy lover? And how important was the Spanish background to this tragic tale? This book explores how the stereotypes of Andalusian-gypsy spectacle, banditry, and the fiestas of the bullfight contributed to the eventual success of Bizet's opera. How did Bizet and his librettists, Meilhac and Halévy--and the scenographic team--capture the spirit of Spain so strongly as to seduce opera-goers around the world? And how did it hybridise real Spanish music and French Opera with the essential 'moments' of Spanish life so important to Mérimée and his librettists? The original staging of the opera is used to examine both 'places' and characters, in particular of realities and mythologies about gypsies in the nineteenth century. It concludes with the first ways in which the opera reached the stage, both in terms of its scenography and how it was sung, played, and acted. Copiously illustrated with materials emanating from before the first production, the book reveals some of the realities of the Spain which went into this ground-breaking opera, to this day continually re-invented with new angles, new settings, and new interpretations.
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Chronic kidney disease enhances alternative pathway activity: a new paradigm
Reduced kidney function is associated with increased risk of cardiovascular disease in addition to kidney disease progression. Kidney disease is considered an inflammatory state, based on elevated levels of C-reactive protein and inflammatory cytokines. A key mediator of cardiovascular and kidney disease progression in the setting of reduced kidney function is systemic and vascular inflammation. However, the exact pathways that link chronic kidney disease (CKD) with inflammation remain incompletely understood. For decades it has been known that factor D, the main activator of the alternative complement pathway, is increased in the plasma of patients with reduced kidney function. Recent biomarker evidence suggests alternative pathway activation in this setting. CKD, therefore, seems to alter the balance of alternative pathway proteins, promoting inflammation and potentially exacerbating complement-mediated diseases and CKD-associated complications. In this manuscript, we review the impact of reduced kidney function on biomarkers of the alternative complement pathway and the implications of alternative pathway activation on cardiovascular disease and kidney disease progression. Importantly, we highlight the need for ongoing research efforts that may lead to opportunities to target the alternative pathway of complement withx the goal of improving kidney and cardiovascular outcomes in persons with reduced kidney function.
Journal Article
