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- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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- Adam, J., et al.
(författare)
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Fumarate Hydratase Deletion in Pancreatic beta Cells Leads to Progressive Diabetes
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:13, s. 3135-3148
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Tidskriftsartikel (refereegranskat)abstract
- We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic beta cells (Fh1 beta KO mice) appear normal for 6-8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expression of mitochondrial or cytosolic FH but not by deletion of Hif1 alpha or Nrf2. Progressive hyperglycemia in Fh1bKO mice led to dysregulated metabolism in b cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca2+](i) elevation, and GSIS. Fh1 loss resulted in elevated intracellular fumarate, promoting succination of critical cysteines in GAPDH, GMPR, and PARK 7/DJ-1 and cytoplasmic acidification. Intracellular fumarate levels were increased in islets exposed to high glucose and in islets from human donors with type 2 diabetes (T2D). The impaired GSIS in islets from diabetic Fh1bKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D.
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- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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- Keilwagen, J., et al.
(författare)
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Separating the wheat from the chaff - a strategy to utilize plant genetic resources from ex situ genebanks
- 2014
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- The need for higher yielding and better-adapted crop plants for feeding the world's rapidly growing population has raised the question of how to systematically utilize large genebank collections with their wide range of largely untouched genetic diversity. Phenotypic data that has been recorded for decades during various rounds of seed multiplication provides a rich source of information. Their usefulness has remained limited though, due to various biases induced by conservation management over time or changing environmental conditions. Here, we present a powerful procedure that permits an unbiased trait-based selection of plant samples based on such phenotypic data. Applying this technique to the wheat collection of one of the largest genebanks worldwide, we identified groups of plant samples displaying contrasting phenotypes for selected traits. As a proof of concept for our discovery pipeline, we resequenced the entire major but conserved flowering time locus Ppd-D1 in just a few such selected wheat samples - and nearly doubled the number of hitherto known alleles.
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- Pasam, R. K., et al.
(författare)
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Genetic Diversity and Population Structure in a Legacy Collection of Spring Barley Landraces Adapted to a Wide Range of Climates
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:12
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Tidskriftsartikel (refereegranskat)abstract
- Global environmental change and increasing human population emphasize the urgent need for higher yielding and better adapted crop plants. One strategy to achieve this aim is to exploit the wealth of so called landraces of crop species, representing diverse traditional domesticated populations of locally adapted genotypes. In this study, we investigated a comprehensive set of 1485 spring barley landraces (LRC1485) adapted to a wide range of climates, which were selected from one of the largest genebanks worldwide. The landraces originated from 5 degrees to 62.5 degrees N and 16 degrees to 71 degrees E. The whole collection was genotyped using 42 SSR markers to assess the genetic diversity and population structure. With an average allelic richness of 5.74 and 372 alleles, LRC1485 harbours considerably more genetic diversity than the most polymorphic current GWAS panel for barley. Ten major clusters defined most of the population structure based on geographical origin, row type of the ear and caryopsis type - and were assigned to specific climate zones. The legacy core reference set LRC648 established in this study will provide a long-lasting resource and a very valuable tool for the scientific community. LRC648 is best suited for multi-environmental field testing to identify candidate genes underlying quantitative traits but also for allele mining approaches.
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