| 1. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 2. |
- Vieira-Silva, S., et al.
(författare)
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Statin therapy is associated with lower prevalence of gut microbiota dysbiosis
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 581:7808, s. 310-315
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Tidskriftsartikel (refereegranskat)abstract
- Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n=888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n=2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
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| 3. |
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| 4. |
- Pellegrinelli, V, et al.
(författare)
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Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance
- 2022
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Ingår i: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 4:4, s. 476-
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Tidskriftsartikel (refereegranskat)abstract
- Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes. Obesity-associated AT fibro-inflammation and metabolic disturbances are linked to PEPD activity and PEPD extracellular levels.
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| 5. |
- Peloso, Gina M, et al.
(författare)
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Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 223-232
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Tidskriftsartikel (refereegranskat)abstract
- Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121(∗)], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
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| 6. |
- Ben-Avraham, Dan, et al.
(författare)
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The complex genetics of gait speed : Genome-wide meta-analysis approach
- 2017
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Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 9:1, s. 209-246
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
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| 7. |
- Fromentin, S., et al.
(författare)
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Microbiome and metabolome features of the cardiometabolic disease spectrum
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:2, s. 303-314
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Tidskriftsartikel (refereegranskat)abstract
- By studying individuals along a spectrum of cardiometabolic disease and adjusting for effects of lifestyle and medication, this investigation identifies alterations of the metabolome and microbiome from dysmetabolic conditions, such as obesity and type 2 diabetes, to ischemic heart disease. Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.
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| 8. |
- Belda, E., et al.
(författare)
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Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism
- 2022
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 71:12
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
- Andrikopoulos, Petros, et al.
(författare)
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Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide
- 2023
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Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.
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| 14. |
- Bel Lassen, P., et al.
(författare)
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Protein intake, metabolic status and the gut microbiota in different ethnicities: Results from two independent cohorts
- 2021
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Protein intake has been associated with the development of pre-diabetes (pre-T2D) and type 2 diabetes (T2D). The gut microbiota has the capacity to produce harmful metabolites derived from dietary protein. Furthermore, both the gut microbiota composition and metabolic status (e.g., insulin resistance) can be modulated by diet and ethnicity. However, to date most studies have predominantly focused on carbohydrate and fiber intake with regards to metabolic status and gut microbiota composition. Objectives: To determine the associations between dietary protein intake, gut microbiota composition, and metabolic status in different ethnicities. Methods: Separate cross-sectional analysis of two European cohorts (MetaCardis, n = 1759; HELIUS, n = 1528) including controls, patients with pre-T2D, and patients with T2D of Caucasian/non-Caucasian origin with nutritional data obtained from Food Frequency Questionnaires and gut microbiota composition. Results: In both cohorts, animal (but not plant) protein intake was associated with pre-T2D status and T2D status after adjustment for confounders. There was no significant association between protein intake (total, animal, or plant) with either gut microbiota alpha diversity or beta diversity, regardless of ethnicity. At the species level, we identified taxonomical signatures associated with animal protein intake that overlapped in both cohorts with different abundances according to metabolic status and ethnicity. Conclusions: Animal protein intake is associated with pre-T2D and T2D status but not with gut microbiota beta or alpha diversity, regardless of ethnicity. Gut microbial taxonomical signatures were identified, which could function as potential modulators in the association between dietary protein intake and metabolic status. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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| 15. |
- Lehtipalo, Katrianne, et al.
(författare)
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The effect of acid-base clustering and ions on the growth of atmospheric nano-particles
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The growth of freshly formed aerosol particles can be the bottleneck in their survival to cloud condensation nuclei. It is therefore crucial to understand how particles grow in the atmosphere. Insufficient experimental data has impeded a profound understanding of nano-particle growth under atmospheric conditions. Here we study nano-particle growth in the CLOUD (Cosmics Leaving OUtdoors Droplets) chamber, starting from the formation of molecular clusters. We present measured growth rates at sub-3 nm sizes with different atmospherically relevant concentrations of sulphuric acid, water, ammonia and dimethylamine. We find that atmospheric ions and small acid-base clusters, which are not generally accounted for in the measurement of sulphuric acid vapour, can participate in the growth process, leading to enhanced growth rates. The availability of compounds capable of stabilizing sulphuric acid clusters governs the magnitude of these effects and thus the exact growth mechanism. We bring these observations into a coherent framework and discuss their significance in the atmosphere.
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| 16. |
- Yates, James A. Fellows, et al.
(författare)
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The evolution and changing ecology of the African hominid oral microbiome
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 118:20
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Tidskriftsartikel (refereegranskat)abstract
- The oral microbiome plays key roles in human biology, health, and disease, but little is known about the global diversity, variation, or evolution of this microbial community. To better understand the evolution and changing ecology of the human oral microbiome, we analyzed 124 dental biofilm metagenomes from humans, including Neanderthals and Late Pleistocene to present-day modern humans, chimpanzees, and gorillas, as well as New World howler monkeys for comparison. We find that a core microbiome of primarily biofilm structural taxa has been maintained throughout African hominid evolution, and these microbial groups are also shared with howler monkeys, suggesting that they have been important oral members since before the catarrhine-platyrrhine split ca. 40 Mya. However, community structure and individual microbial phylogenies do not closely reflect host relationships, and the dental biofilms of Homo and chimpanzees are distinguished by major taxonomic and functional differences. Reconstructing oral metagenomes from up to 100 thousand years ago, we show that the microbial profiles of both Neanderthals and modern humans are highly similar, sharing functional adaptations in nutrient metabolism. These include an apparent Homo-specific acquisition of salivary amylase-binding capability by oral streptococci, suggesting microbial coadaptation with host diet. We additionally find evidence of shared genetic diversity in the oral bacteria of Neanderthal and Upper Paleolithic modern humans that is not observed in later modern human populations. Differences in the oral microbiomes of African hominids provide insights into human evolution, the ancestral state of the human microbiome, and a temporal framework for understanding microbial health and disease.
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| 17. |
- Andrighetto, Giulia, et al.
(författare)
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Changes in social norms during the early stages of the COVID-19 pandemic across 43 countries
- 2024
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Ingår i: Nature Communications. - : NATURE PORTFOLIO. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- The emergence of COVID-19 dramatically changed social behavior across societies and contexts. Here we study whether social norms also changed. Specifically, we study this question for cultural tightness (the degree to which societies generally have strong norms), specific social norms (e.g. stealing, hand washing), and norms about enforcement, using survey data from 30,431 respondents in 43 countries recorded before and in the early stages following the emergence of COVID-19. Using variation in disease intensity, we shed light on the mechanisms predicting changes in social norm measures. We find evidence that, after the emergence of the COVID-19 pandemic, hand washing norms increased while tightness and punishing frequency slightly decreased but observe no evidence for a robust change in most other norms. Thus, at least in the short term, our findings suggest that cultures are largely stable to pandemic threats except in those norms, hand washing in this case, that are perceived to be directly relevant to dealing with the collective threat. Tightness-looseness theory predicts that social norms strengthen following threat. Here the authors test this and find that, after the emergence of the COVID-19 pandemic, hand washing norms increased, but no evidence was observed for a robust change in most other norms.
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| 18. |
- Cornell, David H., 1948, et al.
(författare)
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Zircon xenocrysts obscured the zircon date for the lower Koras Group, southern Africa
- 2023
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Ingår i: South African Journal of Geology. - 1012-0750. ; 126:2, s. 177-194
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Tidskriftsartikel (refereegranskat)abstract
- The Koras Group is a bimodal volcanosedimentary group located in post-tectonic grabens in a foreland thrust complex in the Kaaien Terrane of the Mesoproterozoic Namaqua-Natal Province of southern Africa. It contains two sequences of mafic and felsic volcanic rocks with an unconformity between them, only the lower sequence being slightly folded. The Koras Group was long regarded as having formed at the end of the 1 210 to 1 000 Ma Namaqua Orogeny, because it lacks the severe deformation and metamorphism of the underlying rocks, with igneous minerals preserved in many samples. Following years of unsuccessful attempts to precisely date the volcanic rocks, the first two ion probe U-Pb zircon studies both reported ages of-1 172 Ma for the Swartkopsleegte Formation felsic lava in the slightly folded lower sequence (based on relatively few dated zircons) and-1 100 Ma for the Leeuwdraai Formation rhyolite in the undeformed upper sequence. Thus a major 70 m.y. hiatus seemed apparent between the lower and upper sequences despite their similar geochemistry and rift-related setting. This gave rise to models which envisaged the Kaaien Terrane being unaffected by the syn-to late-tectonic deformation, migmatisation and granite intrusions, documented between 1 200 and 1 150 Ma in the adjoining Namaqua-Natal terranes to the west.A high-pressure (10 kbar) metamorphic event, recognised in the Kaaien Terrane basement just south of hardly deformed Koras Group exposures and dated at 1 150 Ma, is inconsistent with such models. A re-investigation and microbeam dating campaign on the Koras Group confirms the 1 101 & PLUSMN; 2 Ma (n = 6) age for felsic volcanic rocks of the upper sequence, but establishes a new reliable age of 1 114 & PLUSMN; 4 Ma for the lower one (n = 2). The 1 170 ages obtained in the earlier two studies were revisited and are now considered to reflect the age of zircon xenocrysts from the source rocks, which dominate the zircon population of some Swartkopsleegte Formation samples.Several criteria to distinguish autocrystic (magmatic) from antecrystic (age-overlappping xenocrystic) data points were investigated. One sample had high Th levels in only the younger zircons, but histograms of sufficiently precise 207Pb/206Pb ages provided the main criterion. Calculations of zircon crystallisation temperature intervals were not useful in predicting the abundance or proportions of magmatic and antecryst zircons. A multi-episode model of magmatic generation and crystallisation events is probably appropriate. In cases when felsic volcanic samples yield few zircons, care must be taken to avoid the problem exposed in this study.The Koras Group sediments have similar detrital zircon U/Pb age distributions to those of the Rehoboth Basement Inlier. This supports the concept that the Kaaien Terrane originated as the southern part of the Rehoboth Province.
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| 19. |
- Evilevitch, Alex, et al.
(författare)
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Effects of salt concentrations and bending energy on the extent of ejection of phage genomes
- 2008
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Ingår i: Biophysical Journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 94:3, s. 1110-1120
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Tidskriftsartikel (refereegranskat)abstract
- Recent work has shown that pressures inside dsDNA phage capsids can be as high as many tens of atmospheres; it is this pressure that is responsible for initiation of the delivery of phage genomes to host cells. The forces driving ejection of the genome have been shown to decrease monotonically as ejection proceeds, and hence to be strongly dependent on the genome length. Here we investigate the effects of ambient salts on the pressures inside phage-l, for the cases of mono-, di-, and tetravalent cations, and measure how the extent of ejection against a fixed osmotic pressure (mimicking the bacterial cytoplasm) varies with cation concentration. We find, for example, that the ejection fraction is halved in 30 mM Mg21 and is decreased by a factor of 10 upon addition of 1 mM spermine. These effects are calculated from a simple model of genome packaging, using DNA-DNA repulsion energies as determined independently from x-ray diffraction measurements on bulk DNA solutions. By comparing the measured ejection fractions with values implied from the bulk DNA solution data, we predict that the bending energy makes the d- spacings inside the capsid larger than those for bulk DNA at the same osmotic pressure.
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| 20. |
- Forslund, Sofia K., et al.
(författare)
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Combinatorial, additive and dose-dependent drug–microbiome associations
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 600:7889, s. 500-505
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Tidskriftsartikel (refereegranskat)abstract
- During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1–5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.
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| 21. |
- Goeijenbier, Marco, et al.
(författare)
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Emerging Viruses in the Republic of Suriname : Retrospective and Prospective Study into Chikungunya Circulation and Suspicion of Human Hantavirus Infections, 2008-2012 and 2014
- 2015
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Ingår i: Vector Borne and Zoonotic Diseases. - : Mary Ann Liebert Inc. - 1530-3667 .- 1557-7759. ; 15:10, s. 611-618
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Suriname is a country on the northeastern Atlantic coast of South America. It is unique in the sense that different ethnic cultures live together within the country, resulting in high levels of transport of both humans and products between the Asian, African, and European continents as well as the Caribbean. Travel is only one of the many factors present in Suriname contributing to the risk for the emergence or introduction of any infectious disease. Recently, circulation of both chikungunya virus (CHIKV) and hantavirus was reported in areas neighboring Suriname. Here we report a retrospective and prospective study into chikungunya and hantavirus circulation. Methods: A chikungunya and hantavirus retrospective serological study was conducted on samples submitted for dengue, leptospirosis, and/or influenza virus diagnostics between 2008 and 2012 to the Bureau of Public Health in Suriname. This was followed by a prospective CHIKV serological and molecular surveillance study until the detection of the first autochthonous CHIKV cases in Suriname in May and June of 2014. Results: None of the tested samples showed the presence of CHIKV antibodies in the retrospective serological study. Prospective testing of CHIKV-suspected patients resulted in the detection of the first autochthonous CHIKV cases in Suriname in May, 2015. In one sample, we were able to isolate and sequence the virus. Retrospective testing for the presence of hantavirus antibodies showed a relative high response in both pan-hantavirus enzyme-linked immunosorbent assay (ELISA) and immunofluorescence assay (IFA). However, neutralization tests did not yield any evidence for infection with either Seoul or Andes hantavirus. Conclusion: Here we report the presence of CHIKV in the republic of Suriname and the first serological indication of hantavirus infections in symptomatic patients.
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| 22. |
- Guerini-Rocco, Elena, et al.
(författare)
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Genomic aberrations and late recurrence in postmenopausal women with hormone receptor-positive early breast cancer: Results from the SOLE Trial.
- 2021
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 27:2, s. 504-512
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Tidskriftsartikel (refereegranskat)abstract
- Women with hormone-receptor-positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late recurrence risk.In a secondary analysis of Study of Letrozole Extension (SOLE) trial, a case-cohort-like sampling selected 598 primary breast cancer for targeted next-generation sequencing (NGS) analysis of gene mutations and copy number gains (CNG). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence free-intervals (BCFI and DRFI) were analyzed using weighted Cox models.Analysis of mutations and CNG was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time: 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%) and MYC (8%). PIK3CA mutations and MYC CNG were associated with lower (p=0.03) and higher (p=0.004) tumor grade respectively; a higher Ki67 was seen in tumor with CCND1, ERBB2 and MYC CNGs (p=0.01, <0.001 and 0.03 respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses (17/29 patients; BCFI: HR=3.2, 95%CI: 1.48-6.92, p =0.003; DRFI: HR=3.5, 95%CI: 1.61-7.75, p=0.002) and in multivariable models adjusted for clinicopathologic factors.Postmenopausal women with hormone receptor-positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.
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| 23. |
- Luambano, M. M., et al.
(författare)
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IoT enabled smart meter design for demand response program
- 2020
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Ingår i: 6th IEEE International Energy Conference, ENERGYCon 2020. - : Institute of Electrical and Electronics Engineers Inc.. ; , s. 853-857
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Konferensbidrag (refereegranskat)abstract
- The smart grid is a new revolution in the energy sector in which information and communication system is integrated within the conventional electric power generation and distribution system. A key component of this system is the Advanced Metering Infrastructure (AMI), which enables two-way communication between consumer and utility company via a smart meter. In the smart home energy management system (SHEMS), the smart meter is commissioned to monitor, control, trade, and log the energy consumption. Due to the diversification of the appliances in SHEMS, manufactured by different vendors with uncommon standards and deregulation of the communication protocol, then applications and devices in SHEMS become difficult to interoperate. With IoT invention, the smart meter should be able to address the heterogeneity issues. This paper propose an IoT smart meter architecture that addresses the heterogeneity problem in SHEMS by making use of middleware platform which solves interoperability problem in any IoT scenarios. A prototype system using Raspberry Pi and Kaa IoT middleware is reported.
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| 24. |
- Olsson, Lisa M., 1984, et al.
(författare)
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Gut microbiota of obese subjects with Prader-Willi syndrome is linked to metabolic health
- 2020
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 69:7, s. 1229-1238
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The gut microbiota has been implicated in the aetiology of obesity and associated comorbidities. Patients with Prader-Willi syndrome (PWS) are obese but partly protected against insulin resistance. We hypothesised that the gut microbiota of PWS patients differs from that of non-genetically obese controls and correlate to metabolic health. Therefore, here we used PWS as a model to study the role of gut microbiota in the prevention of metabolic complications linked to obesity. Design: We conducted a case-control study with 17 adult PWS patients and 17 obese subjects matched for body fat mass index, gender and age. The subjects were metabolically characterised and faecal microbiota was profiled by 16S ribosomal RNA gene sequencing. The patients' parents were used as a non-obese control group. Stool samples from two PWS patients and two obese controls were used for faecal microbiota transplantations in germ-free mice to examine the impact of the microbiota on glucose metabolism. Results: The composition of the faecal microbiota in patients with PWS differed from that of obese controls, and was characterised by higher phylogenetic diversity and increased abundance of several taxa such as Akkermansia, Desulfovibrio and Archaea, and decreased abundance of Dorea. Microbial taxa prevalent in the PWS microbiota were associated with markers of insulin sensitivity. Improved insulin resistance of PWS was partly transmitted by faecal microbiota transplantations into germ-free mice. Conclusion: The gut microbiota of PWS patients is similar to that of their non-obese parents and might play a role for the protection of PWS patients from metabolic complications. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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| 25. |
- Onerup, Aron, 1983, et al.
(författare)
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Lifestyle and Subsequent Malignant Neoplasms in Childhood Cancer Survivors: A Report from the St. Jude Lifetime Cohort Study
- 2024
-
Ingår i: CANCERS. - 2072-6694. ; 16:5
-
Tidskriftsartikel (refereegranskat)abstract
- Simple Summary It has been shown that lifestyle factors such as smoking, alcohol consumption, diet, and physical activity affect the risk of developing cancer in older adults. While this is not the case for childhood cancers, survivors of childhood cancer are at increased risk of developing cancer in adulthood, called subsequent malignant neoplasms, due to the cancer treatment they received in childhood. We aimed to assess whether the risk of developing subsequent malignant neoplasms in young adulthood was associated with lifestyle factors. We could not see any association between lifestyle factors and subsequent malignant neoplasms in young adult childhood cancer survivors. This suggests that while lifestyle has other health benefits, it is possible that the risk of subsequent malignant neoplasms in young adult childhood cancer survivors cannot be modified with lifestyle behaviors.Abstract Introduction: This study aimed to assess longitudinal associations between lifestyle and subsequent malignant neoplasms (SMNs) in young adult childhood cancer survivors. Methods: Members of the St. Jude Lifetime Cohort (SJLIFE) aged >= 18 years and surviving >= 5 years after childhood cancer diagnosis were queried and evaluated for physical activity, cardiorespiratory fitness (CRF), muscle strength, body mass index (BMI), smoking, risky drinking, and a combined lifestyle score. Time to first SMN, excluding nonmalignant neoplasms and nonmelanoma skin cancer, was the outcome of longitudinal analysis. Results: Survivors (n = 4072, 47% female, 29% smokers, 37% risky drinkers, 34% obese, and 48% physically inactive) had a mean (SD) time between baseline evaluation and follow-up of 7.0 (3.3) years, an age of 8.7 (5.7) years at diagnosis, and an age of 30 (8.4) years at baseline lifestyle assessment. Neither individual lifestyle factors nor a healthy lifestyle score (RR 0.8, 0.4-1.3, p = 0.36) were associated with the risk of developing an SMN. Conclusions: We did not identify any association between lifestyle factors and the risk of SMN in young adult childhood cancer survivors.
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| 26. |
- Onerup, Aron, 1983, et al.
(författare)
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Lifestyle and subsequent meningioma in childhood cancer survivors: A report from the St. Jude Lifetime Cohort study
- 2024
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Ingår i: Cancer Reports. - 2573-8348. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Lifestyle is associated with meningioma risk in the general population. Aims: We assessed longitudinal associations between lifestyle-associated factors and subsequent meningiomas in childhood cancer survivors. Methods and results: Childhood cancer survivors age ≥18 years in the St. Jude Lifetime Cohort Study were evaluated for body composition, self-reported physical activity, cardiopulmonary fitness, muscle strength, smoking, and alcohol consumption at baseline. Time to first meningioma analyses were performed, adjusted for sex, age at diagnosis and baseline assessment, treatment decade, and childhood cancer treatment exposures. The study included 4,072 survivors (47% female; [mean (SD)] 9 (6) years at diagnosis; 30 (8.5) years at the start of follow-up, with 7.0 (3.3) years of follow-up). 30% of the participants were survivors of acute lymphoblastic leukemia and 29% of the participants had received cranial radiation. During follow-up, 90 participants developed ≥1 meningioma, of whom 73% were survivors of acute lymphoblastic leukemia, with cranial radiation being the strongest risk factor (relative risk [RR] 29.7, 95% confidence interval [CI] 10.6-83.2). Muscle strength assessed by knee extension was associated with a lower risk of developing a meningioma in the adjusted analyses (RR 0.5, 95% CI 0.2-1.0, p = 0.04 for quartiles 3-4 vs. 1). No other lifestyle-associated variable was associated with subsequent meningioma. Conclusion: Independent of cranial radiation, muscle strength was associated with a lower risk of developing a subsequent meningioma in childhood cancer survivors.
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| 27. |
- Onerup, Aron, 1983, et al.
(författare)
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Movement efficiency in survivors of childhood acute lymphoblastic leukemia: a report from the St. Jude lifetime cohort study
- 2024
-
Ingår i: JOURNAL OF CANCER SURVIVORSHIP. - 1932-2259 .- 1932-2267.
-
Tidskriftsartikel (refereegranskat)abstract
- PurposeMovement efficiency, a measure of neuromuscular biomechanics, may be modified by physical activity. We aimed to assess the risk of and risk factors for low movement efficiency in survivors of childhood acute lymphoblastic leukemia (ALL).MethodsParticipants underwent an assessment of activity energy expenditure (AEE) with actigraphy, and the gold standard doubly labeled water, where the differences between elimination rates of oxygen and hydrogen from body water are evaluated over a week. Movement efficiency was assessed using the raw residuals of a linear regression between AEEs from accelerometers and doubly labeled water. Elastic-net logistic regressions were used to identify demographic, treatment, and functional variables associated with movement efficiency.ResultsThe study cohort included 256 non-cancer controls and 302 ALL survivors (48% female), categorized as efficient (N = 24), normal (N = 245), or inefficient (N = 33) based on their movement efficiency. There was no difference in the odds for poor movement efficiency between survivors (n = 33, 10.9%) compared to controls (n = 23, 9.0%, odds ratio [OR]: 1.19, 95% confidence interval [CI]: 0.67, 2.10; p = 0.55). In survivors, neuropathy was associated with a higher risk of being inefficient compared to efficient (OR 4.30, 95% CI 1.03-17.96), while obesity (>= 30 kg/m2) had a protective association (OR 0.18, 95% CI 0.04-0.87).ConclusionsNeuropathy was associated with a higher risk of poor movement efficiency in survivors of childhood ALL.Implications for cancer survivorsThese results further highlight impairments associated with treatment-induced neuropathy in survivors of childhood ALL.
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| 28. |
- Osborn, A., et al.
(författare)
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TOI-332 b: a super dense Neptune found deep within the Neptunian desert
- 2023
-
Ingår i: Monthly Notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 526:1, s. 548-566
-
Tidskriftsartikel (refereegranskat)abstract
- To date, thousands of planets have been discovered, but there are regions of the orbital parameter space that are still bare. An example is the short period and intermediate mass/radius space known as the 'Neptunian desert', where planets should be easy to find but discoveries remain few. This suggests unusual formation and evolution processes are responsible for the planets residing here. We present the discovery of TOI-332 b, a planet with an ultra-short period of 0.78 d that sits firmly within the desert. It orbits a K0 dwarf with an effective temperature of 5251 ± 71 K. TOI-332 b has a radius of R, smaller than that of Neptune, but an unusually large mass of 57.2 ± 1.6 M. It has one of the highest densities of any Neptune-sized planet discovered thus far at g cm-3. A 4-layer internal structure model indicates it likely has a negligible hydrogen-helium envelope, something only found for a small handful of planets this massive, and so TOI-332 b presents an interesting challenge to planetary formation theories. We find that photoevaporation cannot account for the mass-loss required to strip this planet of the Jupiter-like envelope it would have been expected to accrete. We need to look towards other scenarios, such as high-eccentricity migration, giant impacts, or gap opening in the protoplanetary disc, to try and explain this unusual discovery.
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| 29. |
- van Son, J., et al.
(författare)
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Plasma Imidazole Propionate Is Positively Correlated with Blood Pressure in Overweight and Obese Humans
- 2021
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 13:8
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The gut microbiota and its metabolites are essential for host health and dysbiosis has been involved in several pathologic conditions such as type 2 diabetes (T2D) and cardiovascular disease (CVD). Recent studies have identified that plasma imidazole propionate (ImP), a microbial-produced metabolite, is increased in patients with prediabetes and T2D. More recently, ImP was found to be significantly increased in patients with overt CVD. Here, we aimed to investigate the association between ImP and CVD risk factors: blood pressure, HDL-cholesterol, LDL-cholesterol and insulin-resistance in overweight and obese subjects without T2D or use of any metabolic diseases-related medication. Methods: Plasma metabolites, including ImP, were determined in 107 male or post-menopausal women with overweight/obesity, but without T2D. Insulin-sensitivity was assessed with the gold standard method: the hyperinsulinemic-euglycemic clamp using the isotope [6,6-H-2(2)] glucose and expressed as glucose rate of disposal (Rd) for peripheral insulin sensitivity and suppression of endogenous glucose production (EGP) for hepatic insulin sensitivity. Results: Partial correlation analysis controlled for BMI and age showed a significant correlation between ImP and diastolic blood pressure (r(s) = 0.285, p = 0.004) and a borderline significance with systolic blood pressure (r(s) = 0.187, p = 0.060); however, systolic and diastolic blood pressure did not correlate with ImP precursor histidine (r(s) = 0.063, p = 0.526 and r = -0.038, p = 0.712, respectively). We did not find a correlation between ImP with LDL-cholesterol or HDL-cholesterol (r(s) = -0.181, p = 0.064 and r(s) = 0.060, p = 0.546, respectively). Furthermore, there was no association between plasma ImP concentrations and Rd and EGP suppression. Conclusion: In this cohort with overweight/obese subjects without T2D, plasma ImP concentrations were positively correlated with diastolic blood pressure but not with insulin-sensitivity.
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| 30. |
- Verberk, Janneke D. M., et al.
(författare)
-
The augmented value of using clinical notes in semi-automated surveillance of deep surgical site infections after colorectal surgery
- 2023
-
Ingår i: Antimicrobial Resistance and Infection Control. - 2047-2994. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn patients who underwent colorectal surgery, an existing semi-automated surveillance algorithm based on structured data achieves high sensitivity in detecting deep surgical site infections (SSI), however, generates a significant number of false positives. The inclusion of unstructured, clinical narratives to the algorithm may decrease the number of patients requiring manual chart review. The aim of this study was to investigate the performance of this semi-automated surveillance algorithm augmented with a natural language processing (NLP) component to improve positive predictive value (PPV) and thus workload reduction (WR).MethodsRetrospective, observational cohort study in patients who underwent colorectal surgery from January 1, 2015, through September 30, 2020. NLP was used to detect keyword counts in clinical notes. Several NLP-algorithms were developed with different count input types and classifiers, and added as component to the original semi-automated algorithm. Traditional manual surveillance was compared with the NLP-augmented surveillance algorithms and sensitivity, specificity, PPV and WR were calculated.ResultsFrom the NLP-augmented models, the decision tree models with discretized counts or binary counts had the best performance (sensitivity 95.1% (95%CI 83.5-99.4%), WR 60.9%) and improved PPV and WR by only 2.6% and 3.6%, respectively, compared to the original algorithm.ConclusionsThe addition of an NLP component to the existing algorithm had modest effect on WR (decrease of 1.4-12.5%), at the cost of sensitivity. For future implementation it will be a trade-off between optimal case-finding techniques versus practical considerations such as acceptability and availability of resources.
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| 31. |
- Almeida, Joao, et al.
(författare)
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Molecular understanding of sulphuric acid-amine particle nucleation in the atmosphere
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 502:7471, s. 359-
-
Tidskriftsartikel (refereegranskat)abstract
- Nucleation of aerosol particles from trace atmospheric vapours is thought to provide up to half of global cloud condensation nuclei(1). Aerosols can cause a net cooling of climate by scattering sunlight and by leading to smaller but more numerous cloud droplets, which makes clouds brighter and extends their lifetimes(2). Atmospheric aerosols derived from human activities are thought to have compensated for a large fraction of the warming caused by greenhouse gases(2). However, despite its importance for climate, atmospheric nucleation is poorly understood. Recently, it has been shown that sulphuric acid and ammonia cannot explain particle formation rates observed in the lower atmosphere(3). It is thought that amines may enhance nucleation(4-16), but until now there has been no direct evidence for amine ternary nucleation under atmospheric conditions. Here we use the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber at CERN and find that dimethylamine above three parts per trillion by volume can enhance particle formation rates more than 1,000-fold compared with ammonia, sufficient to account for the particle formation rates observed in the atmosphere. Molecular analysis of the clusters reveals that the faster nucleation is explained by a base-stabilization mechanism involving acid-amine pairs, which strongly decrease evaporation. The ion-induced contribution is generally small, reflecting the high stability of sulphuric acid-dimethylamine clusters and indicating that galactic cosmic rays exert only a small influence on their formation, except at low overall formation rates. Our experimental measurements are well reproduced by a dynamical model based on quantum chemical calculations of binding energies of molecular clusters, without any fitted parameters. These results show that, in regions of the atmosphere near amine sources, both amines and sulphur dioxide should be considered when assessing the impact of anthropogenic activities on particle formation.
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| 32. |
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| 33. |
- Aron, R.M., et al.
(författare)
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Supremum norms for quadratic polynomials
- 2001
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Ingår i: ARCHIV DER MATHEMATIK. - : BIRKHAUSER VERLAG AG. - 0003-889X. ; 76:1, s. 73-80
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Tidskriftsartikel (refereegranskat)abstract
- We define two norms on R-3 as follows. For (a, b,c) is an element of R-3, we let parallel to (a, b, c)parallel to (R) = sup {/ax(2) + bx + c/ : x is an element of [-1, 1]} and parallel to (a, b, c)parallel to (C) = sup "/az(2) +bz +c/ : z is an element of
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| 34. |
- Ascher, Aron, et al.
(författare)
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Use of implant-supported prostheses in edentulous mandibles among prosthodontists in Sweden.
- 2014
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Ingår i: Swedish Dental Journal. - 0347-9994. ; 38:4, s. 161-167
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the production of mandibular implant-supported fixed and removable prostheses among prosthodontic specialists in Sweden and to compare the results with findings in a similar study made in 2001 (16). Questionnaires regarding treatment with mandibular implant prostheses during 2011 were sent to all specialists in prosthodontics in Sweden (n = 156, according to available data). A total of 129 questionnaires were received from 129 (83 %) prosthodontists of which 114 were completed. The reported number of treatments with mandibular implant-supported prostheses varied much among the specialists. Fixed implant prostheses were more common than overdentures, but the range was large. Tio (9 %) of the specialists reported no treatment with fixed implant prostheses while 29 (25 %) had not made any implant overdentures during 2011. The most common anchorage system for overdentures in 2011 and in 2001 respectively, was two un-splinted implants with ball attachments or locators The most common reasons for the choice of overdenture treatment in 2011, as well as in 2001, were the reduced cost and the patient’s main wish to improve denture retention. In 2011, 58% of the prosthodontists responded that patients with implant overdentures were as satisfied as those with fixed implant-supported prostheses, whereas 40 % claimed they were less satisfied. Two respondents (2 %) considered that overdenture patients were more satisfied than those with a fixed prosthesis. It can be concluded that the general attitude among Swedish prosthodontists towards implant overdentures has not changed much during the 10-year period between the present and the previous investigation. An overdenture is still a seldom-used option in implant treatment of patients with edentulous mandibles. A fixed implant-supported prosthesis continues to be the preferred option.
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| 35. |
- Asres, Georgies Alene, et al.
(författare)
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High photoresponse of individual WS2 nanowire-nanoflake hybrid materials
- 2018
-
Ingår i: Applied Physics Letters. - : AMER INST PHYSICS. - 0003-6951 .- 1077-3118. ; 112:23
-
Tidskriftsartikel (refereegranskat)abstract
- van der Waals solids have been recognized as highly photosensitive materials that compete conventional Si and compound semiconductor based devices. While 2-dimensional nanosheets of single and multiple layers and 1-dimensional nanowires of molybdenum and tungsten chalcogenides have been studied, their nanostructured derivatives with complex morphologies are not explored yet. Here, we report on the electrical and photosensitive properties of WS2 nanowire-nanoflake hybrid materials we developed lately. We probe individual hybrid nanostructured particles along the structure using focused ion beam deposited Pt contacts. Further, we use conductive atomic force microscopy to analyze electrical behavior across the nanostructure in the transverse direction. The electrical measurements are complemented by in situ laser beam illumination to explore the photoresponse of the nanohybrids in the visible optical spectrum. Photodetectors with responsivity up to similar to 0.4 AW(-1) are demonstrated outperforming graphene as well as most of the other transition metal dichalcogenide based devices. Published by AIP Publishing.
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| 36. |
- Borgquist, Signe, et al.
(författare)
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Cholesterol, cholesterol-lowering medication use, and breast cancer outcome in the BIG 1-98 study
- 2017
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 35:11, s. 1179-1188
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose Cholesterol-lowering medication (CLM) has been reported to have a role in preventing breast cancer recurrence. CLM may attenuate signaling through the estrogen receptor by reducing levels of the estrogenic cholesterol metabolite 27-hydroxycholesterol. The impact of endocrine treatment on cholesterol levels and hypercholesterolemia per se may counteract the intended effect of aromatase inhibitors. Patients and Methods The Breast International Group (BIG) conducted a randomized, phase III, double-blind trial, BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor-positive invasive breast cancer from 1998 to 2003. Systemic levels of total cholesterol and use of CLM were measured at study entry and every 6 months up to 5.5 years. Cumulative incidence functions were used to describe the initiation of CLM in the presence of competing risks. Marginal structural Cox proportional hazards modeling investigated the relationships between initiation of CLM during endocrine therapy and outcome. Three time-to-event end points were considered: disease-freesurvival, breast cancer-free interval, and distant recurrence-free interval. Results Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen-letrozole (n = 189), letrozole-tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer-free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence-free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03). Conclusion Cholesterol-lowering medication during adjuvant endocrine therapy may have a role in preventing breast cancer recurrence in hormone receptor-positive early-stage breast cancer. We recommend that these observational results be addressed in prospective randomized trials.
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| 37. |
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| 38. |
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| 39. |
- Chernyshev, Mark, et al.
(författare)
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Vaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages
- 2023
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Vaccination of SARS-CoV-2 convalescent individuals generates broad and potent antibody responses. Here, we isolate 459 spike-specific monoclonal antibodies (mAbs) from two individuals who were infected with the index variant of SARS-CoV-2 and later boosted with mRNA-1273. We characterize mAb genetic features by sequence assignments to the donors' personal immunoglobulin genotypes and assess antibody neutralizing activities against index SARS-CoV-2, Beta, Delta, and Omicron variants. The mAbs used a broad range of immunoglobulin heavy chain (IGH) V genes in the response to all sub-determinants of the spike examined, with similar characteristics observed in both donors. IGH repertoire sequencing and B cell lineage tracing at longitudinal time points reveals extensive evolution of SARS-CoV-2 spike-binding antibodies from acute infection until vaccination five months later. These results demonstrate that highly polyclonal repertoires of affinity-matured memory B cells are efficiently recalled by vaccination, providing a basis for the potent antibody responses observed in convalescent persons following vaccination.
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| 40. |
- Colleoni, Marco, et al.
(författare)
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Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial.
- 2018
-
Ingår i: The Lancet. Oncology. - : Elsevier. - 1474-5488 .- 1470-2045. ; 19:1, s. 127-138
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Tidskriftsartikel (refereegranskat)abstract
- In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women.We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing.Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group).In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them.Novartis and the International Breast Cancer Study Group.
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| 41. |
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| 42. |
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| 43. |
- Ekenberg, Love, et al.
(författare)
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Second order effects in interval valued decision graph models
- 2005
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Ingår i: Proceedings of the Eighteenth International Florida Artificial Intelligence Research Society Conference, FLAIRS 2005 - Recent Advances in Artifical Intelligence. - : AAAI Press. - 1577352343 ; , s. 728-733
-
Konferensbidrag (refereegranskat)abstract
- Second-order calculations may significantly increase a decision maker's understanding of a decision situation when handling aggregations of imprecise representations, as is the case in decision trees or influence diagrams, while the use of only first-order results gives an incomplete picture. The results apply also to approaches which do not explicitly deal with second-order distributions, instead using only first-order concepts such as upper and lower bounds.
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| 44. |
- Ekenberg, Love, et al.
(författare)
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Second-order risk constraints
- 2008
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Ingår i: Proceedings of the 21th International Florida Artificial Intelligence Research Society Conference, FLAIRS-21. - Menlo Park : AAAI Press. - 9781577353652 ; , s. 637-642
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Konferensbidrag (refereegranskat)abstract
- This paper discusses how numerically imprecise information can be modelled and how a risk evaluation process can be elaborated by integrating procedures for numerically imprecise probabilities and utilities. More recently, representations and methods for stating and analysing probabilities and values (utilities) with belief distributions over them (second order representations) have been suggested. In this paper, we are discussing some shortcomings in the use of the principle of maximising the expected utility and of utility theory in general, and offer remedies by the introduction of supplementary decision rules based on a concept of risk constraints taking advantage of second-order distributions.
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| 45. |
- Große, Christine, 1974-, et al.
(författare)
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Collaboration and Decision-making in Response Planning for Power Shortages : The Swedish Policy
- 2017
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Electricity is a key resource for the majority of societal functions and constitutes an important sector in the critical infrastructure of modern societies. Disturbances in power supply can have cascading effects on interdependent public sectors and ordinary citizens. However, it seems nearly impossible to completely prevent the occurrence of power shortages. Strategies to address temporary power losses are therefore essential. This paper aims to increase the understanding of national policies to manage the early consequences of power outages. Therefore, we critically review the Swedish national policy called Styrel as part of Swedish Crisis Management System. In the scientific literature, there are few examples similar to Styrel for handling emergencies in the electricity system. Particularly, we seek to discover related risks and benefits, conditions and constraints, as well as effects for specific stakeholders. We argue that the approach cannot yet be considered as fully developed. Three areas requiring improvement are identified. First, the scope and terms of the process must be specified. Second, (better) quality management seems necessary. Third, people responsible for identifying and prioritizing power consumers critical to local society need better decision aid. Improvements could facilitate risk-communication and collaboration among actors as well as decision-making and organisational learning.
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| 46. |
- Große, Christine, 1974-
(författare)
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Strategic Objectives in Complex Planning Environments : Insights from a Swedish Case for Critical Infrastructure Protection
- 2018
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Large-scale and long-term planning imposes extensive requirements on governance efforts regardless of whether it involves public organisations, private organisations, or both. The proportions of such planning entangle many actors and stakeholders as system components within and around a complex system. These system components and conditions in a complex planning environment introduce a diverse variety of strategic objectives into the planning. This study investigates how strategic objectives can affect the governance of complex planning systems, particularly in the context of national critical infrastructure protection. For this purpose, this thesis concentrates on a national planning procedure, STYREL, which Sweden has recently implemented for the case of power shortages. This case involves various actors from the national, regional and local levels who act on behalf of both public and private organisations in a planning process with four-year intervals, and it thus constitutes a relevant subject for this study. The investigation entailed the collection of evidence from documents and interviews. First, publicly available Swedish documents regarding the case provided an understanding of the planning. Second, interviews with decision-makers who are entrusted with this planning at municipalities and county administrative boards as well as with a few planners from power grid providers offered a deeper comprehension of both the proceedings in practice and the strategic objectives involved in this complex system for planning of critical infrastructure protection. Particularly, the findings resulted in several conceptual models that demonstrate these understandings in more detail. A soft system model visualises the problem situation and contains several elements, such as the system components, interrelations and conditions. Moreover, a multi-level planning model specifies sources of uncertainty in the planning and decision-making process that are associated with an insufficient alignment of strategic objectives in the STYREL case. These decompositions of the Swedish planning environment – both horizontal and vertical – further enabled this study to identify significant parameters of the systemic conditions and strategic objectives involved in such complex planning environments that challenge their governance. The findings of this study suggest that the Swedish process is not yet fully developed. The investigation particularly indicates that a better alignment of strategic objectives is necessary to ensure a selection of adequate goals and means that advances the future usability of the produced plan, which in turn would legitimate and strengthen this complex planning process for critical infrastructure protection.
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| 47. |
- Große, Christine, Fil.Lic, 1974-
(författare)
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Towards Systemic Governance of Critical Infrastructure Protection : State and Relevance of a Swedish Case
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The protection of infrastructure that is critical to society’s functionality, survival and progression has gained significance for both national security and research because of its large-scale and interdependent nature. Critical infrastructure can be viewed as a complex, socio-technical system-of-systems that imposes extensive requirements on governance efforts to foster critical infrastructure protection (CIP), regardless of whether it involves public organisations, private organisations or both.This dissertation investigates how systemic thinking can develop understandings of CIP and its governance. For this purpose, the dissertation presents research that was conducted in the context of an unexplored Swedish governance approach for CIP against power shortages.The dissertation consists of a three-part thesis and six peer-reviewed publications.Part A of this thesis presents the results of a substantial review of scientific literature on the concepts of systems, infrastructure and governance. Because of their recursive nature, the concepts encounter a common challenge in characterising their key elements, structures and processes. The multi-level character of CIP provokes governance to systemically address the behaviours of adaption, emergence and entropy which the complex system exhibits. Apart from contributing nuanced knowledge of systems, infrastructure and governance, Part A provides a novel frame of reference for research in the area in the form of a kaleidoscope for integrative system analysis – KISA.Part B presents the key results of a case study on the Swedish Styrel approach. The investigation is based on an examination of documents that relate to the case, interviews with 66 responsible experts and a survey among all 21 County Administrative Boards and 10 power grid operators that are responsible for stabilising the power grid during disturbances. The contri¬bution of Part B is threefold. First, it originates an extensive representation of an unexplored case of CIP governance. Second, it offers a new comprehen¬sion of practical challenges in CIP governance due to the complex nature of the system and the entangled processes. Third, it provides empirical evidence that indicates areas for development of CIP governance practices.Part C presents the results of the synthesis of theoretical and practical findings. It coalesces perspectives of critical infrastructure and system protection to elaborate on the concept of systemic governance. Fundamentally, systemic governance of CIP integrates the nexus of governance, management and leadership to address challenges regarding key properties of complex systems: entropy, emergence and adaption. Part C defines the theoretical contribution of this dissertation, namely the concept of systemic governance of CIP.
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| 48. |
- Gruber, Günther, et al.
(författare)
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Prognostic value of extracapsular tumor spread for locoregional control in premenopausal patients with node-positive breast cancer treated with classical cyclophosphamide, methotrexate, and fluorouracil: long-term observations from International Breast Cancer Study Group Trial VI.
- 2005
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 0732-183X. ; 23:28, s. 7089-97
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: We sought to determine retrospectively whether extracapsular spread (ECS) might identify a subgroup that could benefit from radiotherapy after mastectomy, especially patients with 1 to 3 positive lymph nodes (LN1-3+). PATIENTS AND METHODS: We randomized 1,475 premenopausal women with node-positive breast cancer to three, six, or nine courses of "classical" CMF (cyclophosphamide, methotrexate, and fluorouracil). After a review of all pathology forms, 933 patients (63%) had information on the presence or absence of ECS. ECS was present in 49.5%. The median follow-up was 10 years. RESULTS: In univariate analyses, ECS was associated with worse disease-free survival (DFS) and overall survival (OS). In multivariate analyses adjusting for tumor size, vessel invasion, surgery type, and age group, ECS remained significant (DFS: hazard ratio, 1.61; 95% CI, 1.34 to 1.93; P < .0001; OS: 1.67; 95% CI, 1.34 to 2.08; P < .0001). However, ECS was not significant when the number of positive nodes was added. The locoregional failure rate +/- distant failure (LRF +/- distant failure) within 10 years was estimated at 19% (+/- 2%) without ECS, versus 27% (+/- 2%) with ECS. The difference was statistically significant in univariate analyses, but not after adjusting for the number of positive nodes. No independent effect of ECS on DFS, OS, or LRF could be confirmed within the subgroup of 382 patients with LN1-3+ treated with mastectomy without radiotherapy. CONCLUSION: Our results do not support an independent prognostic value of ECS, nor its use as an indication for irradiation in premenopausal patients with LN1-3+ treated with classical CMF. However, we could not examine whether extensive ECS is of prognostic importance.
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| 49. |
- Gueymard, Christian A., et al.
(författare)
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A posteriori clear-sky identification methods in solar irradiance time series : Review and preliminary validation using sky imagers
- 2019
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Ingår i: Renewable & sustainable energy reviews. - : Elsevier BV. - 1364-0321 .- 1879-0690. ; 109, s. 412-427
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Forskningsöversikt (refereegranskat)abstract
- This study examines all known methods that have been proposed in the literature to identify clear-sky periods in historical solar irradiance time series. Two different types of clear-sky detection (CSD) methods are discussed: those (16 total) that attempt to isolate periods of 1-min or more cloudless conditions, and those (5 total) that only attempt to detect clear-sun periods. All methods are found to rely on a diversity of inputs and on a variety of tests that typically examine the smoothness of the temporal variation of global and/or direct irradiance. Using samples of a few days with variable cloudiness, it is shown that these methods all have obvious strengths and weaknesses. Although this justifies a detailed validation to determine which method(s) could be best suited in the practice of solar radiation modeling or other applications, the current lack of appropriate equipment at high-quality reference radiometric stations prevents such an endeavor. Only a preliminary study is conducted here at seven stations of the SURFRAD network in the U.S., where 1-min irradiance measurements are available, along with sky data from a Total Sky Imager (TSI). The many limitations of the latter prevent its data to be considered "ground truth" here. Nevertheless, the comparison of the results from all CSD methods and 1.2 million TSI observations from all SURFRAD sites provides important qualitative and quantitative information, using a variety of performance indicators. Overall, two CSD methods appear more robust and are recommended, pending better high-resolution and high-performance cloud observations from modern sky cameras to redo these tests.
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| 50. |
- Hakonen, Aron, 1970, et al.
(författare)
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Explosive and chemical threat detection by surface-enhanced Raman scattering: A review
- 2015
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Ingår i: Analytica Chimica Acta. - : Elsevier BV. - 0003-2670 .- 1873-4324. ; 893, s. 1-13
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Forskningsöversikt (refereegranskat)abstract
- Acts of terror and warfare threats are challenging tasks for defense agencies around the world and of growing importance to security conscious policy makers and the general public. Explosives and chemical warfare agents are two of the major concerns in this context, as illustrated by the recent Boston Marathon bombing and nerve gas attacks on civilians in the Middle East. To prevent such tragic disasters, security personnel must be able to find, identify and deactivate the threats at multiple locations and levels. This involves major technical and practical challenges, such as detection of ultra-low quantities of hazardous compounds at remote locations for anti-terror purposes and monitoring of environmental sanitation of dumped or left behind toxic substances and explosives. Surface-enhanced Raman scattering (SERS) is one of todays most interesting and rapidly developing methods for label-free ultrasensitive vibrational "fingerprinting" of a variety of molecular compounds. Performance highlights include atto-molar detection of TNT and DNT explosives, a sensitivity that few, if any, other technique can compete with. Moreover, instrumentation needed for SERS analysis are becoming progressively better, smaller and cheaper, and can today be acquired for a retail price close to 10,000 US$. This contribution aims to give a comprehensive overview of SERS as a technique for detection of explosives and chemical threats. We discuss the prospects of SERS becoming a major tool for convenient in-situ threat identification and we summarize existing SERS detection methods and substrates with particular focus on ultra-sensitive real-time detection. General concepts, detection capabilities and perspectives are discussed in order to guide potential users of the technique for homeland security and anti-warfare purposes. (C) 2015 Elsevier B.V. All rights reserved.
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