Leber Congenital Amaurosis Associated with AIPL1: Challenges in Ascribing Disease Causation, Clinical Findings, and Implications for Gene Therapy

Leber Congenital Amaurosis (LCA) and Early Childhood Onset Severe Retinal Dystrophy are clinically and genetically heterogeneous retinal disorders characterised by visual impairment and nystagmus from birth or early infancy. We investigated the prevalence of sequence variants in AIPL1 in a large cohort of such patients (n = 392) and probed the likelihood of disease-causation of the identified variants, subsequently undertaking a detailed assessment of the phenotype of patients with disease-causing mutations. Genomic DNA samples were screened for known variants in the AIPL1 gene using a microarray LCA chip, with 153 of these cases then being directly sequenced. The assessment of disease-causation of identified AIPL1 variants included segregation testing, assessing evolutionary conservation and in silico predictions of pathogenicity. The chip identified AIPL1 variants in 12 patients. Sequencing of AIPL1 in 153 patients and 96 controls found a total of 46 variants, with 29 being novel. In silico analysis suggested that only 6 of these variants are likely to be disease-causing, indicating a previously unrecognized high degree of polymorphism. Seven patients were identified with biallelic changes in AIPL1 likely to be disease-causing. In the youngest subject, electroretinography revealed reduced cone photoreceptor function, but rod responses were within normal limits, with no measurable ERG in other patients. An increasing degree and extent of peripheral retinal pigmentation and degree of maculopathy was noted with increasing age in our series. AIPL1 is significantly polymorphic in both controls and patients, thereby complicating the establishment of disease-causation of identified variants. Despite the associated phenotype being characterised by early-onset severe visual loss in our patient series, there was some evidence of a degree of retinal structural and functional preservation, which was most marked in the youngest patient in our cohort. This data suggests that there are patients who have a reasonable window of opportunity for gene therapy in childhood

Post-Franco Theatre

In the multiple realms and layers that comprise the contemporary Spanish theatrical landscape, “crisis” would seem to be the word that most often lingers in the air, as though it were a common mantra, ready to roll off the tongue of so many theatre professionals with such enormous ease, and even enthusiasm, that one is prompted to wonder whether it might indeed be a miracle that the contemporary technological revolution – coupled with perpetual quandaries concerning public and private funding for the arts – had not by now brought an end to the evolution of the oldest of live arts, or, at the very least, an end to drama as we know it

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

We performed a multistage genome-wide association study (GWAS) including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT; per-allele odds ratio [OR] = 0.79; 95% confidence interval [CI] = 0.74–0.84; P = 3.0×10−12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2; OR = 1.46; 95% CI = 1.30–1.65; P = 1.1×10−10), rs9581943 at 13q12.2 (PDX1; OR = 1.15; 95% CI = 1.10–1.20; P = 2.4×10−9), and rs16986825 at 22q12.1 (ZNRF3; OR = 1.18; 95% CI = 1.12–1.25; P = 1.2×10−8). An independent signal was identified in exon 2 of TERT at the established region 5p15.33 (rs2736098; OR = 0.80; 95% CI = 0.76–0.85; P = 9.8×10−14). We also identified a locus at 8q24.21 (rs1561927; P = 1.3×10−7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study has identified multiple new susceptibility alleles for pancreatic cancer worthy of follow-up studies

Dimensões do subdesenvolvimento econômico na Colômbia, 1980-2015

El objetivo de este trabajo es identificar las condiciones de subdesarrollo que presenta la economía colombiana en el período 1980-2015. Se asume como marco teórico del subdesarrollo el enfoque estructuralista latinoamericano, estudiando especialmente el concepto de heterogeneidad estructural y la incorporación del progreso tecnológico. En consecuencia, se examina la política agropecuaria en Colombia, frente a la in­corporación del progreso tecnológico y la dinámica estructural. Para hallar evidencia empírica se construyen índices de crecimiento y tasas de participación, y se estiman coeficientes de correlación, cuyos resultados permiten concluir que la economía colombiana presenta condiciones de subdesarrollo en el período de observación.The objective of this article is to identify the underdevelopment conditions of the Colombian economy between 1980 and 2015. The Latin American structuralism approach is assumed as the theoretical framework of the underdevelopment, specifically studying the concept of structural heterogeneity and incorporation of technological progress. Hence, the agricultural and livestock breeding policy in Colombia is evaluated versus the incorporation of technological progress and structural dynamic. In order to find empirical evidence, growth indices and participation rates are built and correlation coefficients are estimated, results of which allow concluding that Colombian economy showed underdevelopment conditions during the period subject matter of this research.O objetivo deste trabalho é identificar as condições de subdesenvolvimento que a economia colombiana apresenta no período 1980-2015. Assume-se como referencial teórico do subdesenvolvimento a abordagem estruturalista latino-americana, estudando especialmente o conceito de heterogeneidade estrutural e a incorporação do progresso tecnológico. Em consequência, examina-se a política agropecuária na Colômbia ante a incorporação do progresso tecnológico e da dinâmica estrutural. Para encontrar provas empíricas, constroem-se índices de crescimento e taxas de participação, bem como se estimam coeficientes de correlação, cujos resultados permitem concluir que a economia colombiana apresenta condições de subdesenvolvimento no período de observação. Albán, Álvaro (2011). Reforma y contrareforma agraria en Colombia. En: Economía Institucional, Vol. 13, No. 24, Universidad Externado de Colombia, p. 327-35

Innovation in consulting firms: an area to explore

Services are the most representative sector in developed economies due to their contribution to GDP and employment. Consulting firms are classified as part of the Knowledge Intensive Business Services (KIBS) and provide professional services to all types of organizations. Consulting firms usually innovate with their customers and suppliers in a nurturing environment for value co-creation. This environment is project-based, process-oriented and with intensive knowledge exchange among all stakeholders. Based on literature review, it has been found that despite the existence of frameworks for service innovation, none of them have specifically focused on consulting firms. Further implications on this issue are addressed for both academics and practitioners