Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes

The splicing factor SF3B1 is the most frequently mutated gene in myelodysplastic syndromes (MDS), and is strongly associated with the presence of ring sideroblasts (RS). We have performed a systematic analysis of cryptic splicing abnormalities from RNA sequencing data on hematopoietic stem cells (HSCs) of SF3B1-mutant MDS cases with RS. Aberrant splicing events in many downstream target genes were identified and cryptic 3' splice site usage was a frequent event in SF3B1-mutant MDS. The iron transporter ABCB7 is a well-recognized candidate gene showing marked downregulation in MDS with RS. Our analysis unveiled aberrant ABCB7 splicing, due to usage of an alternative 3' splice site in MDS patient samples, giving rise to a premature termination codon in the ABCB7 mRNA. Treatment of cultured SF3B1-mutant MDS erythroblasts and a CRISPR/Cas9-generated SF3B1-mutant cell line with the nonsense-mediated decay (NMD) inhibitor cycloheximide showed that the aberrantly spliced ABCB7 transcript is targeted by NMD. We describe cryptic splicing events in the HSCs of SF3B1-mutant MDS, and our data support a model in which NMD-induced downregulation of the iron exporter ABCB7 mRNA transcript resulting from aberrant splicing caused by mutant SF3B1 underlies the increased mitochondrial iron accumulation found in MDS patients with RS.Leukemia advance online publication, 17 June 2016; doi:10.1038/leu.2016.149.

A realist synthesis of educational interventions to improve nutrition care competencies and delivery by doctors and other healthcare professionals

Objective: To determine what, how, for whom, why, and in what circumstances educational interventions to improve the delivery of nutrition care by doctors and other healthcare professionals work?

Design: Realist synthesis following a published protocol and reported following Realist and Meta-narrative Evidence Synthesis: Evolving Standards (RAMESES) guidelines. A multidisciplinary team searched Medline, CINAHL, ERIC, EMBASE, PsyINFO, Sociological Abstracts, Web of Science, Google Scholar, and Science Direct for published and unpublished (grey) literature. The team identified studies with varied designs; appraised their ability to answer the review question; identified relationships between contexts, mechanisms, and outcomes (CMOs); and entered them into a spreadsheet configured for the purpose. The final synthesis identified commonalities across CMO configurations.

Results: Over half of the 46 studies from which we extracted data originated from the US. Interventions that improved the delivery of nutrition care improved skills and attitudes rather than just knowledge; provided opportunities for superiors to model nutrition care; removed barriers to nutrition care in health systems; provided participants with local, practically relevant tools and messages; and incorporated non-traditional, innovative teaching strategies. Operating in contexts where student and qualified healthcare professionals provided nutrition care in both developed and developing countries, these interventions yielded health outcomes by triggering a range of mechanisms, which included: feeling competent; feeling confident and comfortable; having greater self-efficacy; being less inhibited by barriers in healthcare systems; and feeling that nutrition care was accepted and recognised.

Conclusion: These findings show how important it is to move education for nutrition care beyond the simple acquisition of knowledge. They show how educational interventions embedded within systems of healthcare can improve patients’ health by helping health students and professionals to appreciate the importance of delivering nutrition care and feel competent to deliver it.

Session organiser/chair: The architecture of coal and other energies

Coal ignited the industrial revolution. An organic sedimentary rock that energized the globe, transforming cities, landscapes and societies for generations, the importance of ‘King Coal’ to the development and consolidation of modernity has been well-recognised. And yet, as a critical factor in the production of modern architecture, coal—as well as other forms of energy—has been mostly overlooked.

From Appalachia to Lanarkshire, from the pits of northern France, Belgium and the Ruhr valley, to the monumental opencast excavations of Russia, China, Africa and Australia, mining operations have altered the immediate social and physical landscapes of coal-rich areas. But in contrast to its own underground conditions of production, the winning of coal, especially in the twentieth-century, has produced conspicuously enlightened and humane approaches to architecture and urbanism. In the twentieth century, educational buildings, holiday camps, hospitals, swimming pools, convalescent homes and housing prevailed alongside model collieries in mining settlements and areas connected to them. In 1930s Britain, pit head baths—funded by a levy on each ton produced—were often built in the International Style. Many won praise for architectural merit, appearing in Nicholas Pevsner’s guides to the buildings of England alongside cathedrals, village manors and Masonic halls as testimonies to the public good.

The deep relationships between coal and modernity, and the expressions of architecture it has articulated, in the collieries from which it was hewn, the landscape and towns it shaped, and the power stations and other infrastructure where it was used, offer innumerable opportunities to explore how coal produced architectures which embodied and expressed both social and technological conditions. While proposals on coal are preferred, we also welcome papers that interrogate the complexity, heterogeneity and hybridity of other forms of energy production and how these have also interceded into architectural form at a range of scales.