↓ Direkt till sidans innehåll
↓ Direkt till sidans sekundära innehåll (sidomenyn)

Träfflista för sökning "WFRF:(Gary J W) srt2:(2015-2019)"

Sökning: WFRF:(Gary J W) > (2015-2019)

Resultat 1-50 av 61

Sortera/gruppera träfflistan

Sortering: Träffar per sida:

Numrering	Referens	Omslagsbild	Hitta
1.	Aad, G, et al. (författare) 2015 swepub:Mat__t
2.	Corbalan, R, et al. (författare) Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation: A Report From the GARFIELD-AF Registry 2019 Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6591 .- 2380-6583. ; 4:6, s. 526-548 Tidskriftsartikel (refereegranskat)
3.	Klionsky, Daniel J, et al. (författare) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). 2016 Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 12:1, s. 1-222 Tidskriftsartikel (refereegranskat)
4.	2019 Tidskriftsartikel (refereegranskat)
5.	Arndt, D. S., et al. (författare) STATE OF THE CLIMATE IN 2017 2018 Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310 Forskningsöversikt (refereegranskat)
6.	Arndt, D. S., et al. (författare) State of the Climate in 2016 2017 Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 98:8, s. S1-S280 Tidskriftsartikel (refereegranskat)abstract In 2016, the dominant greenhouse gases released into Earth's atmosphere-carbon dioxide, methane, and nitrous oxide-continued to increase and reach new record highs. The 3.5 +/- 0.1 ppm rise in global annual mean carbon dioxide from 2015 to 2016 was the largest annual increase observed in the 58-year measurement record. The annual global average carbon dioxide concentration at Earth's surface surpassed 400 ppm (402.9 +/- 0.1 ppm) for the first time in the modern atmospheric measurement record and in ice core records dating back as far as 800000 years. One of the strongest El Nino events since at least 1950 dissipated in spring, and a weak La Nina evolved later in the year. Owing at least in part to the combination of El Nino conditions early in the year and a long-term upward trend, Earth's surface observed record warmth for a third consecutive year, albeit by a much slimmer margin than by which that record was set in 2015. Above Earth's surface, the annual lower troposphere temperature was record high according to all datasets analyzed, while the lower stratospheric temperature was record low according to most of the in situ and satellite datasets. Several countries, including Mexico and India, reported record high annual temperatures while many others observed near-record highs. A week-long heat wave at the end of April over the northern and eastern Indian peninsula, with temperatures surpassing 44 degrees C, contributed to a water crisis for 330 million people and to 300 fatalities. In the Arctic the 2016 land surface temperature was 2.0 degrees C above the 1981-2010 average, breaking the previous record of 2007, 2011, and 2015 by 0.8 degrees C, representing a 3.5 degrees C increase since the record began in 1900. The increasing temperatures have led to decreasing Arctic sea ice extent and thickness. On 24 March, the sea ice extent at the end of the growth season saw its lowest maximum in the 37-year satellite record, tying with 2015 at 7.2% below the 1981-2010 average. The September 2016 Arctic sea ice minimum extent tied with 2007 for the second lowest value on record, 33% lower than the 1981-2010 average. Arctic sea ice cover remains relatively young and thin, making it vulnerable to continued extensive melt. The mass of the Greenland Ice Sheet, which has the capacity to contribute similar to 7 m to sea level rise, reached a record low value. The onset of its surface melt was the second earliest, after 2012, in the 37-year satellite record. Sea surface temperature was record high at the global scale, surpassing the previous record of 2015 by about 0.01 degrees C. The global sea surface temperature trend for the 21st century-to-date of +0.162 degrees C decade(-1) is much higher than the longer term 1950-2016 trend of +0.100 degrees C decade(-1). Global annual mean sea level also reached a new record high, marking the sixth consecutive year of increase. Global annual ocean heat content saw a slight drop compared to the record high in 2015. Alpine glacier retreat continued around the globe, and preliminary data indicate that 2016 is the 37th consecutive year of negative annual mass balance. Across the Northern Hemisphere, snow cover for each month from February to June was among its four least extensive in the 47-year satellite record. Continuing a pattern below the surface, record high temperatures at 20-m depth were measured at all permafrost observatories on the North Slope of Alaska and at the Canadian observatory on northernmost Ellesmere Island. In the Antarctic, record low monthly surface pressures were broken at many stations, with the southern annular mode setting record high index values in March and June. Monthly high surface pressure records for August and November were set at several stations. During this period, record low daily and monthly sea ice extents were observed, with the November mean sea ice extent more than 5 standard deviations below the 1981-2010 average. These record low sea ice values contrast sharply with the record high values observed during 2012-14. Over the region, springtime Antarctic stratospheric ozone depletion was less severe relative to the 1991-2006 average, but ozone levels were still low compared to pre-1990 levels. Closer to the equator, 93 named tropical storms were observed during 2016, above the 1981-2010 average of 82, but fewer than the 101 storms recorded in 2015. Three basins-the North Atlantic, and eastern and western North Pacific-experienced above-normal activity in 2016. The Australian basin recorded its least active season since the beginning of the satellite era in 1970. Overall, four tropical cyclones reached the Saffir-Simpson category 5 intensity level. The strong El Nino at the beginning of the year that transitioned to a weak La Nina contributed to enhanced precipitation variability around the world. Wet conditions were observed throughout the year across southern South America, causing repeated heavy flooding in Argentina, Paraguay, and Uruguay. Wetter-than-usual conditions were also observed for eastern Europe and central Asia, alleviating the drought conditions of 2014 and 2015 in southern Russia. In the United States, California had its first wetter-than-average year since 2012, after being plagued by drought for several years. Even so, the area covered by drought in 2016 at the global scale was among the largest in the post-1950 record. For each month, at least 12% of land surfaces experienced severe drought conditions or worse, the longest such stretch in the record. In northeastern Brazil, drought conditions were observed for the fifth consecutive year, making this the longest drought on record in the region. Dry conditions were also observed in western Bolivia and Peru; it was Bolivia's worst drought in the past 25 years. In May, with abnormally warm and dry conditions already prevailing over western Canada for about a year, the human-induced Fort McMurray wildfire burned nearly 590000 hectares and became the costliest disaster in Canadian history, with $3 billion (U.S. dollars) in insured losses.
7.	Hibar, Derrek P., et al. (författare) Novel genetic loci associated with hippocampal volume 2017 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8 Tidskriftsartikel (refereegranskat)abstract The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
8.	Wang, Li-San, et al. (författare) Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States. 2015 Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2 Tidskriftsartikel (refereegranskat)abstract Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
9.	Pattaro, Cristian, et al. (författare) Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function 2016 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Tidskriftsartikel (refereegranskat)abstract Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
10.	Block, Keith I., et al. (författare) Designing a broad-spectrum integrative approach for cancer prevention and treatment 2015 Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304 Forskningsöversikt (refereegranskat)abstract Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
11.	Klein, Alison P., et al. (författare) Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer 2018 Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9 Tidskriftsartikel (refereegranskat)abstract In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 x 10(-8)). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PAN-DoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 x 10(-14)), rs2941471 at 8q21.11 (HNF4G, P = 6.60 x 10(-10)), rs4795218 at 17q12 (HNF1B, P = 1.32 x 10(-8)), and rs1517037 at 18q21.32 (GRP, P = 3.28 x 10(-8)). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
12.	Freitag, Daniel F., et al. (författare) Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis 2015 Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253 Tidskriftsartikel (refereegranskat)abstract Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
13.	Jones, Lesley, et al. (författare) Convergent genetic and expression data implicate immunity in Alzheimer's disease 2015 Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671 Tidskriftsartikel (refereegranskat)abstract Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
14.	Bousquet, J. Jean, et al. (författare) Next-generation ARIA care pathways for rhinitis and asthma : a model for multimorbid chronic diseases 2019 Ingår i: Clinical and Translational Allergy. - : BMC. - 2045-7022. ; 9 Forskningsöversikt (refereegranskat)abstract Background: In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy.Main body: As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted "patient activation", (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Sante as a Good Practice in the field of digitally-enabled, integrated, person-centred care.Conclusion: In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.
15.	Lakens, Daniel, et al. (författare) Justify your alpha 2018 Ingår i: Nature Human Behaviour. - : Nature Publishing Group. - 2397-3374. ; 2:3, s. 168-171 Tidskriftsartikel (refereegranskat)abstract In response to recommendations to redefine statistical significance to P ≤ 0.005, we propose that researchers should transparently report and justify all choices they make when designing a study, including the alpha level.
16.	Liu, Ke, et al. (författare) X Chromosome Dose and Sex Bias in Autoimmune Diseases 2016 Ingår i: Arthritis & Rheumatology. - : WILEY-BLACKWELL. - 2326-5191 .- 2326-5205. ; 68:5, s. 1290-1300 Tidskriftsartikel (refereegranskat)abstract Objective. More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47, XXX; occurring in similar to 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods. All subjects in this study were female. We identified subjects with 47, XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47, XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results. We found 47, XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47, XXX. There was an excess of 47, XXX among SLE and SS patients. Conclusion. The estimated prevalence of SLE and SS in women with 47, XXX was similar to 2.5 and similar to 2.9 times higher, respectively, than that in women with 46, XX and similar to 25 and similar to 41 times higher, respectively, than that in men with 46, XY. No statistically significant increase of 47, XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.
17.	Liu, Ke, et al. (författare) X Chromosome Dose and Sex Bias in Autoimmune Diseases : Increased 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome 2016 Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 68:5, s. 1290-1300 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE:More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls.METHODS:We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR).RESULTS:We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects.CONCLUSION:The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.
18.	Zamora, Juan Carlos, et al. (författare) Considerations and consequences of allowing DNA sequence data as types of fungal taxa 2018 Ingår i: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185 Tidskriftsartikel (refereegranskat)abstract Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
19.	Braasch, Ingo, et al. (författare) The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons 2016 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:4, s. 427-437 Tidskriftsartikel (refereegranskat)abstract To connect human biology to fish biomedical models, we sequenced the genome of spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before teleost genome duplication (TGD). The slowly evolving gar genome has conserved in content and size many entire chromosomes from bony vertebrate ancestors. Gar bridges teleosts to tetrapods by illuminating the evolution of immunity, mineralization and development (mediated, for example, by Hox, ParaHox and microRNA genes). Numerous conserved noncoding elements (CNEs; often cis regulatory) undetectable in direct human-teleost comparisons become apparent using gar: functional studies uncovered conserved roles for such cryptic CNEs, facilitating annotation of sequences identified in human genome-wide association studies. Transcriptomic analyses showed that the sums of expression domains and expression levels for duplicated teleost genes often approximate the patterns and levels of expression for gar genes, consistent with subfunctionalization. The gar genome provides a resource for understanding evolution after genome duplication, the origin of vertebrate genomes and the function of human regulatory sequences.
20.	Koivula, Robert W., et al. (författare) Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium 2019 Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:9, s. 1601-1615 Tidskriftsartikel (refereegranskat)abstract Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.
21.	Sako, Masao, et al. (författare) The Data Release of the Sloan Digital Sky Survey-II Supernova Survey 2018 Ingår i: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 130:988 Tidskriftsartikel (refereegranskat)abstract This paper describes the data release of the Sloan Digital Sky Survey-II (SDSS-II) Supernova Survey conducted between 2005 and 2007. Light curves, spectra, classifications, and ancillary data are presented for 10,258 variable and transient sources discovered through repeat ugriz imaging of SDSS Stripe 82, a 300 deg(2) area along the celestial equator. This data release is comprised of all transient sources brighter than r similar or equal to 22.5 mag with no history of variability prior to 2004. Dedicated spectroscopic observations were performed on a subset of 889 transients, as well as spectra for thousands of transient host galaxies using the SDSS-III BOSS spectrographs. Photometric classifications are provided for the candidates with good multi-color light curves that were not observed spectroscopically, using host galaxy redshift information when available. From these observations, 4607 transients are either spectroscopically confirmed, or likely to be, supernovae, making this the largest sample of supernova candidates ever compiled. We present a new method for SN host-galaxy identification and derive host-galaxy properties including stellar masses, star formation rates, and the average stellar population ages from our SDSS multi-band photometry. We derive SALT2 distance moduli for a total of 1364 SN. Ia with spectroscopic redshifts as well as photometric redshifts for a further 624 purely photometric SN. Ia candidates. Using the spectroscopically confirmed subset of the three-year SDSS-II SN. Ia sample and assuming a flat.CDM cosmology, we determine Omega(M) = 0.315 +/- 0.093 (statistical error only) and detect a non-zero cosmological constant at 5.7 sigma.
22.	Stephens, Lucas, et al. (författare) Archaeological assessment reveals Earth’s early transformation through land use 2019 Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 365:6456, s. 897-902 Tidskriftsartikel (refereegranskat)abstract Humans began to leave lasting impacts on Earth’s surface starting 10,000 to 8000 years ago. Through a synthetic collaboration with archaeologists around the globe, Stephens et al. compiled a comprehensive picture of the trajectory of human land use worldwide during the Holocene (see the Perspective by Roberts). Hunter-gatherers, farmers, and pastoralists transformed the face of Earth earlier and to a greater extent than has been widely appreciated, a transformation that was essentially global by 3000 years before the present.Science, this issue p. 897; see also p. 865Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth’s transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon.
23.	Yeates, Alison J., et al. (författare) PUFA status and methylmercury exposure are not associated with leukocyte telomere length in mothers or their children in the seychelles child development study 2017 Ingår i: Journal of Nutrition. - : Elsevier BV. - 0022-3166 .- 1541-6100. ; 147:11, s. 2018-2024 Tidskriftsartikel (refereegranskat)abstract Background: Leukocyte telomere length (TL) is associated with age-related diseases and early mortality, but there is a lack of data on the determinants of TL in early life. Evidence suggests that dietary intake ofmarine n-3 (v-3) polyunsaturated fatty acids (PUFAs) is protective of telomere attrition, yet the effect of methylmercury exposure, also found in fish, on TL is unknown. Objective: The aim of this study was to investigate the associations between prenatal PUFA status, methylmercury exposure, and TL in mothers and children in the SCDS (Seychelles Child Development Study), for whom fish consumption is high. Methods: Blood samples collected from 229 mothers (at 28 wk gestation and delivery) and children (at 5 y of age) in the SCDS first nutrition cohort were analyzed for PUFA concentrations. Prenatal mercury was measured in maternal hair collected at delivery. Postnatalmercury was alsomeasured in children's hair samples with the use of a cumulativemetric derived from values obtained at 3-5 y of age. Relative TL wasmeasured in blood obtained from mothers at delivery, in cord blood, and in children at 5 y of age by quantitative polymerase chain reaction. Linear regression models were used to investigate the associations between PUFA status, methylmercury exposure, and TL. Results: Neither prenatal PUFA status or methylmercury exposure was associated with TL of the mother or child or with TL attrition rate. However, a higher prenatal n-6:n-3 PUFA ratiowas significantly associated with longer TLs in the mothers (β = 0.001, P = 0.048). Child PUFA status andmethylmercury exposurewere not associated with child TL. However, higher family Hollingshead socioeconomic status (SES) scores at 9 mo of agewere significantly associatedwith longer TLs in cord blood (β = 0.005, P=0.03). Conclusions: We found no evidence that PUFA status or methylmercury exposure are determinants of TL in either the mother or child. However, our results support the hypothesis that family SES may be associated with child TL.
24.	Zhu, Ying, et al. (författare) Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer : A Mendelian Randomization Analysis 2019 Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:5, s. 935-942 Tidskriftsartikel (refereegranskat)abstract Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall nonsmall cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.
25.	Ade, Peter, et al. (författare) The Simons Observatory : science goals and forecasts 2019 Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :2 Tidskriftsartikel (refereegranskat)abstract The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial con figuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping approximate to 10% of the sky to a white noise level of 2 mu K-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of sigma(r) = 0.003. The large aperture telescope will map approximate to 40% of the sky at arcminute angular resolution to an expected white noise level of 6 mu K-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
26.	Hart, Robert G., et al. (författare) Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source : Design of the NAVIGATE ESUS randomized trial 2016 Ingår i: European Stroke Journal. - : SAGE Publications. - 2396-9873 .- 2396-9881. ; 1:3, s. 146-154 Tidskriftsartikel (refereegranskat)abstract Background: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source. Main hypothesis: In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily. Design: Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRI-determined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches. Summary: The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018.
27.	Jelenkovic, Aline, et al. (författare) Zygosity Differences in Height and Body Mass Index of Twins From Infancy to Old Age : A Study of the CODATwins Project 2015 Ingår i: Twin Research and Human Genetics. - : Cambridge University Press. - 1832-4274 .- 1839-2628. ; 18:5, s. 557-570 Tidskriftsartikel (refereegranskat)abstract A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m(2) in childhood and adolescence and up to 0.2 kg/m(2) in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
28.	McKay, James D., et al. (författare) Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes 2017 Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132 Tidskriftsartikel (refereegranskat)abstract Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
29.	Silventoinen, Karri, et al. (författare) The CODATwins Project : The Cohort Description of Collaborative Project of Development of Anthropometrical Measures in Twins to Study Macro-Environmental Variation in Genetic and Environmental Effects on Anthropometric Traits 2015 Ingår i: Twin Research and Human Genetics. - : Cambridge University Press. - 1832-4274 .- 1839-2628. ; 18:4 Tidskriftsartikel (refereegranskat)abstract For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
30.	Andersson, Leif, et al. (författare) Coordinated international action to accelerate genome-to-phenome with FAANG, the Functional Annotation of Animal Genomes project 2015 Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X .- 1474-7596. ; 16 Tidskriftsartikel (refereegranskat)abstract We describe the organization of a nascent international effort, the Functional Annotation of Animal Genomes (FAANG) project, whose aim is to produce comprehensive maps of functional elements in the genomes of domesticated animal species.
31.	Carreras-Torres, Robert, et al. (författare) Obesity, metabolic factors and risk of different histological types of lung cancer : a Mendelian randomization study 2017 Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 12:6 Tidskriftsartikel (refereegranskat)abstract Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95% CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m(2)]), but not for adenocarcinoma (OR [95% CI] = 0.93 [0.79-1.08]) (P-heterogeneity = 4.3x10(-3)). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10(-3)), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95% CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95% CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.
32.	Desnick, Robert J., et al. (författare) Roscoe Owen Brady, MD : Remembrances of co-investigators and colleagues 2017 Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192. ; 120:1-2, s. 1-7 Tidskriftsartikel (refereegranskat)abstract To celebrate the research visions and accomplishments of the late Roscoe O. Brady (1923-2016), remembrance commentaries were requested from several of his postdoctoral research fellows and colleagues. These commentaries not only reflect on the accomplishments of Dr. Brady, but they also share some of the backstories and experiences working in the Brady laboratory. They provide insights and perspectives on Brady's research activities, and especially on his efforts to develop an effective treatment for patients with Type 1 Gaucher disease. These remembrances illuminate Brady's efforts to implement the latest scientific advances with an outstanding team of young co-investigators to develop and demonstrate the safety and effectiveness of the first enzyme replacement therapy for a lysosomal storage disease. Brady's pursuit and persistence in accomplishing his research objectives provide insights into this remarkably successful physician scientist who paved the way for the development of treatments for patients with other lysosomal storage diseases.
33.	Lee, Crystal Man Ying, et al. (författare) Comparing different definitions of prediabetes with subsequent risk of diabetes: an individual participant data meta-analysis involving 76 513 individuals and 8208 cases of incident diabetes. 2019 Ingår i: BMJ open diabetes research & care. - : BMJ. - 2052-4897. ; 7:1 Tidskriftsartikel (refereegranskat)abstract There are currently five widely used definition of prediabetes. We compared the ability of these to predict 5-year conversion to diabetes and investigated whether there were other cut-points identifying risk of progression to diabetes that may be more useful.We conducted an individual participant meta-analysis using longitudinal data included in the Obesity, Diabetes and Cardiovascular Disease Collaboration. Cox regression models were used to obtain study-specific HRs for incident diabetes associated with each prediabetes definition. Harrell's C-statistics were used to estimate how well each prediabetes definition discriminated 5-year risk of diabetes. Spline and receiver operating characteristic curve (ROC) analyses were used to identify alternative cut-points.Sixteen studies, with 76513 participants and 8208 incident diabetes cases, were available. Compared with normoglycemia, current prediabetes definitions were associated with four to eight times higher diabetes risk (HRs (95% CIs): 3.78 (3.11 to 4.60) to 8.36 (4.88 to 14.33)) and all definitions discriminated 5-year diabetes risk with good accuracy (C-statistics 0.79-0.81). Cut-points identified through spline analysis were fasting plasma glucose (FPG) 5.1mmol/L and glycated hemoglobin (HbA1c) 5.0% (31 mmol/mol) and cut-points identified through ROC analysis were FPG 5.6mmol/L, 2-hour postload glucose 7.0mmol/L and HbA1c 5.6% (38 mmol/mol).In terms of identifying individuals at greatest risk of developing diabetes within 5years, using prediabetes definitions that have lower values produced non-significant gain. Therefore, deciding which definition to use will ultimately depend on the goal for identifying individuals at risk of diabetes.
34.	Zhang, W, et al. (författare) Systems thinking : an approach for understanding 'eco-agri-food systems' 2018 Ingår i: TEEB for Agriculture & Food : Scientific and Economic Foundations - Scientific and Economic Foundations. - 9789280737028 ; , s. 17-56 Bokkapitel (övrigt vetenskapligt/konstnärligt)
35.	Bartlett, Sofia R., et al. (författare) Sequencing of Hepatitis C Virus for Detection of Resistance to Direct-Acting Antiviral Therapy : A Systematic Review 2017 Ingår i: HEPATOLOGY COMMUNICATIONS. - : JOHN WILEY & SONS LTD. - 2471-254X. ; 1:5, s. 379-390 Forskningsöversikt (refereegranskat)abstract The significance of the clinical impact of direct-acting antiviral (DAA) resistance-associated substitutions (RASs) in hepatitis C virus (HCV) on treatment failure is unclear. No standardized methods or guidelines for detection of DAA RASs in HCV exist. To facilitate further evaluations of the impact of DAA RASs in HCV, we conducted a systematic review of RAS sequencing protocols, compiled a comprehensive public library of sequencing primers, and provided expert guidance on the most appropriate methods to screen and identify RASs. The development of standardized RAS sequencing protocols is complicated due to a high genetic variability and the need for genotype- and subtype-specific protocols for multiple regions. We have identified several limitations of the available methods and have highlighted areas requiring further research and development. The development, validation, and sharing of standardized methods for all genotypes and subtypes should be a priority.
36.	Berge, Eivind, et al. (författare) Methods to improve patient recruitment and retention in stroke trials 2016 Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 11:6, s. 663-676 Tidskriftsartikel (refereegranskat)abstract Background: The success of randomized-controlled stroke trials is dependent on the recruitment and retention of a sufficient number of patients, but fewer than half of all trials meet their target number of patients. Methods: We performed a search and review of the literature, and conducted a survey and workshop among 56 European stroke trialists, to identify barriers, suggest methods to improve recruitment and retention, and make a priority list of interventions that merit further evaluation. Results: The survey and workshop identified a number of barriers to patient recruitment and retention, from patients’ incapacity to consent, to handicaps that prevent patients from participation in trial-specific follow-up. Methods to improve recruitment and retention may include simple interventions with individual participants, funding of research networks, and reimbursement of new treatments by health services only when delivered within clinical trials. The literature review revealed that few methods have been formally evaluated. The top five priorities for evaluation identified in the workshop were as follows: short and illustrated patient information leaflets, nonwritten consent, reimbursement for new interventions only within a study, and monetary incentives to institutions taking part in research (for recruitment); and involvement of patient groups, remote and central follow-up, use of mobile devices, and reminders to patients about their consent to participate (for retention). Conclusions: Many interventions have been used with the aim of improving recruitment and retention of patients in stroke studies, but only a minority has been evaluated. We have identified methods that could be tested, and propose that such evaluations may be nested within on-going clinical trials.
37.	Callier, Myriam D., et al. (författare) Attraction and repulsion of mobile wild organisms to finfish and shellfish aquaculture: A review 2018 Ingår i: Reviews in Aquaculture. - : Wiley. - 1753-5123 .- 1753-5131. ; 10:4, s. 924-949 Tidskriftsartikel (refereegranskat)abstract © 2017 Wiley Publishing Asia Pty Ltd. Knowledge of aquaculture-environment interactions is essential for the development of a sustainable aquaculture industry and efficient marine spatial planning. The effects of fish and shellfish farming on sessile wild populations, particularly infauna, have been studied intensively. Mobile fauna, including crustaceans, fish, birds and marine mammals, also interact with aquaculture operations, but the interactions are more complex and these animals may be attracted to (attraction) or show an aversion to (repulsion) farm operations with various degrees of effects. This review outlines the main mechanisms and effects of attraction and repulsion of wild animals to/from marine finfish cage and bivalve aquaculture, with a focus on effects on fisheries-related species. Effects considered in this review include those related to the provision of physical structure (farm infrastructure acting as fish aggregating devices (FADs) or artificial reefs (ARs), the provision of food (e.g. farmed animals, waste feed and faeces, fouling organisms associated with farm structures) and some farm activities (e.g. boating, cleaning). The reviews show that the distribution of mobile organisms associated with farming structures varies over various spatial (vertical and horizontal) and temporal scales (season, feeding time, day/night period). Attraction/repulsion mechanisms have a variety of direct and indirect effects on wild organisms at the level of individuals and populations and may have implication for the management of fisheries species and the ecosystem in the context of marine spatial planning. This review revealed considerable uncertainties regarding the long-term and ecosystem-wide consequences of these interactions. The use of modelling may help better understand consequences, but long-term studies are necessary to better elucidate effects.
38.	Dyson, Kylie, et al. (författare) International variation in survival after out-of-hospital cardiac arrest : A validation study of the Utstein template. 2019 Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 138, s. 168-181 Tidskriftsartikel (refereegranskat)abstract INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) survival varies greatly between communities. The Utstein template was developed and promulgated to improve the comparability of OHCA outcome reports, but it has undergone limited empiric validation. We sought to assess how much of the variation in OHCA survival between emergency medical services (EMS) across the globe is explained by differences in the Utstein factors. We also assessed how accurately the Utstein factors predict OHCA survival.METHODS: We performed a retrospective analysis of patient-level prospectively collected data from 12 OHCA registries from 12 countries for the period 1 Jan 2006 through 31 Dec 2011. We used generalized linear mixed models to examine the variation in survival between EMS agencies (n=232).RESULTS: Twelve registries contributed 86,759 cases. Patient arrest characteristics, EMS treatment and patient outcomes varied across registries. Overall survival to hospital discharge was 10% (range, 6% to 22%). Overall survival with Cerebral Performance Category of 1 or 2 (available for 8/12 registries) was 8% (range, 2% to 20%). The area-under-the-curve for the Utstein model was 0.85 (Wald CI: 0.85-0.85). The Utstein factors explained 51% of the EMS agency variation in OHCA survival.CONCLUSIONS: The Utstein factors explained 51% of the variation in survival to hospital discharge among multiple large geographically separate EMS agencies. This suggests that quality improvement and public health efforts should continue to target modifiable Utstein factors to improve OHCA survival. Further study is required to identify the reasons for the variation that is incompletely understood.
39.	Furman, David, et al. (författare) Chronic inflammation in the etiology of disease across the life span 2019 Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 25:12, s. 1822-1832 Tidskriftsartikel (refereegranskat)abstract Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.
40.	Jack, Alison A, et al. (författare) Cellulose Nanofibril Formulations Incorporating a Low-Molecular-Weight Alginate Oligosaccharide Modify Bacterial Biofilm Development. 2019 Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 20:8, s. 2953-2961 Tidskriftsartikel (refereegranskat)abstract Cellulose nanofibrils (CNFs) from wood pulp are a renewable material possessing advantages for biomedical applications because of their customizable porosity, mechanical strength, translucency, and environmental biodegradability. Here, we investigated the growth of multispecies wound biofilms on CNF formulated as aerogels and films incorporating the low-molecular-weight alginate oligosaccharide OligoG CF-5/20 to evaluate their structural and antimicrobial properties. Overnight microbial cultures were adjusted to 2.8 × 109 colony-forming units (cfu) mL-1 in Mueller Hinton broth and growth rates of Pseudomonas aeruginosa PAO1 and Staphylococcus aureus 1061A monitored for 24 h in CNF dispersions sterilized by γ-irradiation. Two CNF formulations were prepared (20 g m-2) with CNF as air-dried films or freeze-dried aerogels, with or without incorporation of an antimicrobial alginate oligosaccharide (OligoG CF-5/20) as a surface coating or bionanocomposite, respectively. The materials were structurally characterized by scanning electron microscopy (SEM) and laser profilometry (LP). The antimicrobial properties of the formulations were assessed using single- and mixed-species biofilms grown on the materials and analyzed using LIVE/DEAD staining with confocal laser scanning microscopy (CLSM) and COMSTAT software. OligoG-CNF suspensions significantly decreased the growth of both bacterial strains at OligoG concentrations >2.58% (P < 0.05). SEM showed that aerogel-OligoG bionanocomposite formulations had a more open three-dimensional structure, whereas LP showed that film formulations coated with OligoG were significantly smoother than untreated films or films incorporating PEG400 as a plasticizer (P < 0.05). CLSM of biofilms grown on films incorporating OligoG demonstrated altered biofilm architecture, with reduced biomass and decreased cell viability. The OligoG-CNF formulations as aerogels or films both inhibited pyocyanin production (P < 0.05). These novel CNF formulations or bionanocomposites were able to modify bacterial growth, biofilm development, and virulence factor production in vitro. These data support the potential of OligoG and CNF bionanocomposites for use in biomedical applications where prevention of infection or biofilm growth is required.
41.	Ji, Xuemei, et al. (författare) Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk 2018 Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9, s. 1-15 Tidskriftsartikel (refereegranskat)abstract Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
42.	Jones, Robert P., et al. (författare) Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma : A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial 2019 Ingår i: JAMA Surgery. - : AMER MEDICAL ASSOC. - 2168-6254 .- 2168-6262. ; 154:11, s. 1038-1048 Tidskriftsartikel (refereegranskat)abstract Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear.Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival.Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019.Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine.Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence.Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P=.03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P=.04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P=.27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P=.85 and P=.35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P=.03).Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection.Trial Registration: ClinicalTrials.gov identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434. This secondary analysis of a randomized clinical trial investigates patterns of recurrence after adjuvant chemotherapy in pancreatic cancer and the association with survival.
43.	Kachuri, Linda, et al. (författare) Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci 2016 Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 37:1, s. 96-105 Tidskriftsartikel (refereegranskat)abstract Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000x) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73x10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64x10(-6)), rs112290073 (OR = 1.85, P = 1.27x10(-5)), rs138895564 (OR = 2.16, P = 2.06x10(-5); among young cases, OR = 3.77, P = 8.41x10(-4)). In addition, we found that rs139852726 (P = 1.44x10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84x10(-7)) and lung cancer (P = 2.37x10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.
44.	Kasner, Scott E., et al. (författare) Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial 2018 Ingår i: Journal of Stroke and Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057. ; 27:6, s. 1673-1682 Tidskriftsartikel (refereegranskat)abstract Background: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. Aims: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. Methods: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. Results: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. Conclusions: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research.
45.	Langefeld, Carl D., et al. (författare) Transancestral mapping and genetic load in systemic lupus erythematosus 2017 Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8 Tidskriftsartikel (refereegranskat)abstract Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
46.	Li, Yafang, et al. (författare) Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development 2019 Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 10:19, s. 1760-1774 Tidskriftsartikel (refereegranskat)abstract The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.
47.	Li, Yafang, et al. (författare) Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population 2018 Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 39:3, s. 336-346 Tidskriftsartikel (refereegranskat)abstract Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13 336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13 970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.
48.	Neoptolemos, John P., et al. (författare) Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4) : a multicentre, open-label, randomised, phase 3 trial 2017 Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 389:10073, s. 1011-1024 Tidskriftsartikel (refereegranskat)abstract Background: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer.Methods: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1: 1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m(2) gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m(2) oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434.Findings: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28.0 months (95% CI 23.5-31.5) compared with 25.5 months (22.7-27.9) in the gemcitabine group (hazard ratio 0.82 [95% CI 0.68-0.98], p=0.032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group.Interpretation: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma.
49.	Petrov, Dmitry, et al. (författare) Machine Learning for Large-Scale Quality Control of 3D Shape Models in Neuroimaging 2017 Ingår i: Machine learning in medical imaging. MLMI (Workshop). - Cham : Springer International Publishing. ; 10541, s. 371-378 Tidskriftsartikel (refereegranskat)abstract As very large studies of complex neuroimaging phenotypes become more common, human quality assessment of MRI-derived data remains one of the last major bottlenecks. Few attempts have so far been made to address this issue with machine learning. In this work, we optimize predictive models of quality for meshes representing deep brain structure shapes. We use standard vertex-wise and global shape features computed homologously across 19 cohorts and over 7500 human-rated subjects, training kernelized Support Vector Machine and Gradient Boosted Decision Trees classifiers to detect meshes of failing quality. Our models generalize across datasets and diseases, reducing human workload by 30-70%, or equivalently hundreds of human rater hours for datasets of comparable size, with recall rates approaching inter-rater reliability.
50.	Simone, Roberto, et al. (författare) G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology invitro and invivo. 2018 Ingår i: EMBO molecular medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 10:1, s. 22-31 Tidskriftsartikel (refereegranskat)abstract Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA-binding proteins and through toxic dipeptide repeat proteins generated by repeat-associated non-ATG translation. GGGGCC repeat RNA folds into a G-quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G-quadruplex RNA We investigated their effect in C9orf72 patient iPSC-derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival invivo, in GGGGCC repeat-expressing Drosophila Therefore, small molecules that target GGGGCC repeat G-quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS These data provide proof of principle thattargeting GGGGCC repeat G-quadruplexes has therapeutic potential.

Skapa referenser, mejla, bekava och länka

Länka till träfflistan

Resultat 1-50 av 61

Avgränsa träffmängd

Typ av publikation: tidskriftsartikel (54); forskningsöversikt (5); bokkapitel (1)

Typ av innehåll: refereegranskat (59); övrigt vetenskapligt/konstnärligt (1)

Författare/redaktör: Amos, Christopher I. (9); Brennan, Paul (8); Johansson, Mattias (7); Duell, Eric J. (7); Chen, Chu (7); Christiani, David C. (7); visa fler...; Field, John K. (7); Liu, Geoffrey (7); Manjer, Jonas (6); Melander, Olle (6); Grankvist, Kjell (6); Rennert, Gad (6); Bojesen, Stig E. (6); Le Marchand, Loïc (6); Johansson, Mikael (6); Kiemeney, Lambertus ... (6); Goodman, Gary E (6); Holcatova, Ivana (6); Zaridze, David (6); Janout, Vladimir (6); Scelo, Ghislaine (6); Brunnström, Hans (6); Risch, Angela (6); Aldrich, Melinda C (6); Wu, Xifeng (6); Lam, Stephen (6); Lazarus, Philip (6); Taylor, Fiona (5); Cox, Angela (5); Lissowska, Jolanta (5); Han, Younghun (5); Landi, Maria Teresa (5); Overvad, Kim (4); Trichopoulou, Antoni ... (4); Tumino, Rosario (4); Carreras-Torres, Rob ... (4); Muller, David C. (4); Pelosi, Paolo (4); Bakke, Per (4); Wichmann, H. Erich (4); Martin, Nicholas G. (4); Mukeria, Anush (4); Montgomery, Grant W. (4); Hofman, Albert (4); Gudnason, Vilmundur (4); Schultz, Marcus J (4); Wrigge, Hermann (4); Smith, Albert V (4); Hiesmayr, Michael (4); Caporaso, Neil E. (4); visa färre...

Lärosäte: Uppsala universitet (21); Lunds universitet (21); Karolinska Institutet (19); Umeå universitet (15); Göteborgs universitet (8); Stockholms universitet (8); visa fler...; Linköpings universitet (5); Sveriges Lantbruksuniversitet (4); Örebro universitet (3); Jönköping University (2); Högskolan i Skövde (2); Linnéuniversitetet (2); RISE (2); Kungliga Tekniska Högskolan (1); Högskolan i Halmstad (1); Chalmers tekniska högskola (1); Högskolan i Borås (1); Högskolan Dalarna (1); Naturhistoriska riksmuseet (1); visa färre...

Språk: Engelska (61)

Forskningsämne (UKÄ/SCB): Medicin och hälsovetenskap (48); Naturvetenskap (17); Lantbruksvetenskap (3); Samhällsvetenskap (2); Humaniora (1)

År

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

LIBRIS.kb.se

Stäng

Kopiera och spara länken för att återkomma till aktuell vy