| 1. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
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| 4. |
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| 5. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 6. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Pennells, Lisa, et al.
(författare)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 8. |
- Kulmala, M., et al.
(författare)
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General overview: European Integrated project on Aerosol Cloud Climate and Air Quality interactions (EUCAARI) - integrating aerosol research from nano to global scales
- 2011
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 11:24, s. 13061-13143
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Tidskriftsartikel (refereegranskat)abstract
- In this paper we describe and summarize the main achievements of the European Aerosol Cloud Climate and Air Quality Interactions project (EUCAARI). EUCAARI started on 1 January 2007 and ended on 31 December 2010 leaving a rich legacy including: (a) a comprehensive database with a year of observations of the physical, chemical and optical properties of aerosol particles over Europe, (b) comprehensive aerosol measurements in four developing countries, (c) a database of airborne measurements of aerosols and clouds over Europe during May 2008, (d) comprehensive modeling tools to study aerosol processes fron nano to global scale and their effects on climate and air quality. In addition a new Pan-European aerosol emissions inventory was developed and evaluated, a new cluster spectrometer was built and tested in the field and several new aerosol parameterizations and computations modules for chemical transport and global climate models were developed and evaluated. These achievements and related studies have substantially improved our understanding and reduced the uncertainties of aerosol radiative forcing and air quality-climate interactions. The EUCAARI results can be utilized in European and global environmental policy to assess the aerosol impacts and the corresponding abatement strategies.
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| 9. |
- Mansoor, Rashid, et al.
(författare)
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Haematological consequences of acute uncomplicated falciparum malaria : a WorldWide Antimalarial Resistance Network pooled analysis of individual patient data
- 2022
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Ingår i: BMC Medicine. - : Springer Nature. - 1741-7015. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPlasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia.MethodsIndividual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall >= 25% at day 3 and day 7.ResultsA total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0-19.7 g/dL) in Africa, 11.6 g/dL (range 5.0-20.0 g/dL) in Asia and 12.3 g/dL (range 6.9-17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to >= 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39-3.05], p < 0.001).ConclusionsIn patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.
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| 10. |
- Middeldorp, Christel M., et al.
(författare)
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The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects
- 2019
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:3, s. 279-300
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Tidskriftsartikel (refereegranskat)abstract
- The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
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| 11. |
- Stephens, Lucas, et al.
(författare)
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Archaeological assessment reveals Earth’s early transformation through land use
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 365:6456, s. 897-902
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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.
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| 12. |
- Dahal, Prabin, et al.
(författare)
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Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy : an individual participant data meta-analysis
- 2022
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Ingår i: Malaria Journal. - : Springer Nature. - 1475-2875. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria.Methods: Individual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up.Results: Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged < 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47-74%] of recrudescences in African children and 32% [95% CI 15-45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19-90%] in children under 5 years old treated with > 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0-22%] in those treated with <= 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution.Conclusions: Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.
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| 13. |
- Lembrechts, Jonas J., et al.
(författare)
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SoilTemp : A global database of near-surface temperature
- 2020
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 26:11, s. 6616-6629
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Tidskriftsartikel (refereegranskat)abstract
- Current analyses and predictions of spatially explicit patterns and processes in ecology most often rely on climate data interpolated from standardized weather stations. This interpolated climate data represents long-term average thermal conditions at coarse spatial resolutions only. Hence, many climate-forcing factors that operate at fine spatiotemporal resolutions are overlooked. This is particularly important in relation to effects of observation height (e.g. vegetation, snow and soil characteristics) and in habitats varying in their exposure to radiation, moisture and wind (e.g. topography, radiative forcing or cold-air pooling). Since organisms living close to the ground relate more strongly to these microclimatic conditions than to free-air temperatures, microclimatic ground and near-surface data are needed to provide realistic forecasts of the fate of such organisms under anthropogenic climate change, as well as of the functioning of the ecosystems they live in. To fill this critical gap, we highlight a call for temperature time series submissions to SoilTemp, a geospatial database initiative compiling soil and near-surface temperature data from all over the world. Currently, this database contains time series from 7,538 temperature sensors from 51 countries across all key biomes. The database will pave the way toward an improved global understanding of microclimate and bridge the gap between the available climate data and the climate at fine spatiotemporal resolutions relevant to most organisms and ecosystem processes.
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| 14. |
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| 15. |
- Nik-Zainal, Serena, et al.
(författare)
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Landscape of somatic mutations in 560 breast cancer whole-genome sequences
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 534:7605, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
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| 16. |
- Saunois, Marielle, et al.
(författare)
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The Global Methane Budget 2000–2017
- 2020
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Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3516 .- 1866-3508. ; 12:3, s. 1561-1623
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Tidskriftsartikel (refereegranskat)abstract
- Understanding and quantifying the global methane (CH4) budget is important for assessing realistic pathways to mitigate climate change. Atmospheric emissions and concentrations of CH4 continue to increase, making CH4 the second most important human-influenced greenhouse gas in terms of climate forcing, after carbon dioxide (CO2). The relative importance of CH4 compared to CO2 depends on its shorter atmospheric lifetime, stronger warming potential, and variations in atmospheric growth rate over the past decade, the causes of which are still debated. Two major challenges in reducing uncertainties in the atmospheric growth rate arise from the variety of geographically overlapping CH4 sources and from the destruction of CH4 by short-lived hydroxyl radicals (OH). To address these challenges, we have established a consortium of multidisciplinary scientists under the umbrella of the Global Carbon Project to synthesize and stimulate new research aimed at improving and regularly updating the global methane budget. Following Saunois et al. (2016), we present here the second version of the living review paper dedicated to the decadal methane budget, integrating results of top-down studies (atmospheric observations within an atmospheric inverse-modelling framework) and bottom-up estimates (including process-based models for estimating land surface emissions and atmospheric chemistry, inventories of anthropogenic emissions, and data-driven extrapolations).For the 2008–2017 decade, global methane emissions are estimated by atmospheric inversions (a top-down approach) to be 576 Tg CH4 yr−1 (range 550–594, corresponding to the minimum and maximum estimates of the model ensemble). Of this total, 359 Tg CH4 yr−1 or ∼ 60 % is attributed to anthropogenic sources, that is emissions caused by direct human activity (i.e. anthropogenic emissions; range 336–376 Tg CH4 yr−1 or 50 %–65 %). The mean annual total emission for the new decade (2008–2017) is 29 Tg CH4 yr−1 larger than our estimate for the previous decade (2000–2009), and 24 Tg CH4 yr−1 larger than the one reported in the previous budget for 2003–2012 (Saunois et al., 2016). Since 2012, global CH4 emissions have been tracking the warmest scenarios assessed by the Intergovernmental Panel on Climate Change. Bottom-up methods suggest almost 30 % larger global emissions (737 Tg CH4 yr−1, range 594–881) than top-down inversion methods. Indeed, bottom-up estimates for natural sources such as natural wetlands, other inland water systems, and geological sources are higher than top-down estimates. The atmospheric constraints on the top-down budget suggest that at least some of these bottom-up emissions are overestimated. The latitudinal distribution of atmospheric observation-based emissions indicates a predominance of tropical emissions (∼ 65 % of the global budget, < 30∘ N) compared to mid-latitudes (∼ 30 %, 30–60∘ N) and high northern latitudes (∼ 4 %, 60–90∘ N). The most important source of uncertainty in the methane budget is attributable to natural emissions, especially those from wetlands and other inland waters.Some of our global source estimates are smaller than those in previously published budgets (Saunois et al., 2016; Kirschke et al., 2013). In particular wetland emissions are about 35 Tg CH4 yr−1 lower due to improved partition wetlands and other inland waters. Emissions from geological sources and wild animals are also found to be smaller by 7 Tg CH4 yr−1 by 8 Tg CH4 yr−1, respectively. However, the overall discrepancy between bottom-up and top-down estimates has been reduced by only 5 % compared to Saunois et al. (2016), due to a higher estimate of emissions from inland waters, highlighting the need for more detailed research on emissions factors. Priorities for improving the methane budget include (i) a global, high-resolution map of water-saturated soils and inundated areas emitting methane based on a robust classification of different types of emitting habitats; (ii) further development of process-based models for inland-water emissions; (iii) intensification of methane observations at local scales (e.g., FLUXNET-CH4 measurements) and urban-scale monitoring to constrain bottom-up land surface models, and at regional scales (surface networks and satellites) to constrain atmospheric inversions; (iv) improvements of transport models and the representation of photochemical sinks in top-down inversions; and (v) development of a 3D variational inversion system using isotopic and/or co-emitted species such as ethane to improve source partitioning.The data presented here can be downloaded from https://doi.org/10.18160/GCP-CH4-2019 (Saunois et al., 2020) and from the Global Carbon Project.
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| 17. |
- Vogelezang, Suzanne, et al.
(författare)
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Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
- 2020
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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| 18. |
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| 19. |
- Dahal, Prabin, et al.
(författare)
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Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria : a WorldWide Antimalarial Resistance Network individual participant data meta-analysis
- 2019
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Ingår i: Malaria Journal. - : BMC. - 1475-2875. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.
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| 20. |
- El-Sayed, Najib M., et al.
(författare)
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The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.
- 2005
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5733, s. 409-15
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
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| 21. |
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| 22. |
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| 23. |
- Micah, Angela E., et al.
(författare)
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Tracking development assistance for health and for COVID-19 : a review of development assistance, government, out-of-pocket, and other private spending on health for 204 countries and territories, 1990-2050
- 2021
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 398:10308, s. 1317-1343
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Forskningsöversikt (refereegranskat)abstract
- Background The rapid spread of COVID-19 renewed the focus on how health systems across the globe are financed, especially during public health emergencies. Development assistance is an important source of health financing in many low-income countries, yet little is known about how much of this funding was disbursed for COVID-19. We aimed to put development assistance for health for COVID-19 in the context of broader trends in global health financing, and to estimate total health spending from 1995 to 2050 and development assistance for COVID-19 in 2020. Methods We estimated domestic health spending and development assistance for health to generate total health-sector spending estimates for 204 countries and territories. We leveraged data from the WHO Global Health Expenditure Database to produce estimates of domestic health spending. To generate estimates for development assistance for health, we relied on project-level disbursement data from the major international development agencies' online databases and annual financial statements and reports for information on income sources. To adjust our estimates for 2020 to include disbursements related to COVID-19, we extracted project data on commitments and disbursements from a broader set of databases (because not all of the data sources used to estimate the historical series extend to 2020), including the UN Office of Humanitarian Assistance Financial Tracking Service and the International Aid Transparency Initiative. We reported all the historic and future spending estimates in inflation-adjusted 2020 US$, 2020 US$ per capita, purchasing-power parity-adjusted US$ per capita, and as a proportion of gross domestic product. We used various models to generate future health spending to 2050. Findings In 2019, health spending globally reached $8. 8 trillion (95% uncertainty interval [UI] 8.7-8.8) or $1132 (1119-1143) per person. Spending on health varied within and across income groups and geographical regions. Of this total, $40.4 billion (0.5%, 95% UI 0.5-0.5) was development assistance for health provided to low-income and middle-income countries, which made up 24.6% (UI 24.0-25.1) of total spending in low-income countries. We estimate that $54.8 billion in development assistance for health was disbursed in 2020. Of this, $13.7 billion was targeted toward the COVID-19 health response. $12.3 billion was newly committed and $1.4 billion was repurposed from existing health projects. $3.1 billion (22.4%) of the funds focused on country-level coordination and $2.4 billion (17.9%) was for supply chain and logistics. Only $714.4 million (7.7%) of COVID-19 development assistance for health went to Latin America, despite this region reporting 34.3% of total recorded COVID-19 deaths in low-income or middle-income countries in 2020. Spending on health is expected to rise to $1519 (1448-1591) per person in 2050, although spending across countries is expected to remain varied. Interpretation Global health spending is expected to continue to grow, but remain unequally distributed between countries. We estimate that development organisations substantially increased the amount of development assistance for health provided in 2020. Continued efforts are needed to raise sufficient resources to mitigate the pandemic for the most vulnerable, and to help curtail the pandemic for all. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.
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| 24. |
- Abou-Hachem, Maher, et al.
(författare)
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Calcium binding and thermostability of carbohydrate binding module CBM4-2 of Xyn10A from Rhodothermus marinus.
- 2002
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 41:18, s. 5720-5729
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Tidskriftsartikel (refereegranskat)abstract
- Calcium binding to carbohydrate binding module CBM4-2 of xylanase 10A (Xyn10A) from Rhodothermus marinus was explored using calorimetry, NMR, fluorescence, and absorbance spectroscopy. CBM4-2 binds two calcium ions, one with moderate affinity and one with extremely high affinity. The moderate-affinity site has an association constant of (1.3 +/- 0.3) x 10(5) M(-1) and a binding enthalpy DeltaH(a) of -9.3 +/- 0.4 kJ x mol(-1), while the high-affinity site has an association constant of approximately 10(10) M(-1) and a binding enthalpy DeltaH(a) of -40.5 +/- 0.5 kJ x mol(-1). The locations of the binding sites have been identified by NMR and structural homology, and were verified by site-directed mutagenesis. The high-affinity site consists of the side chains of E11 and D160 and backbone carbonyls of E52 and K55, while the moderate-affinity site comprises the side chain of D29 and backbone carbonyls of L21, A22, V25, and W28. The high-affinity site is in a position analogous to the calcium site in CBM4 structures and in a recent CBM22 structure. Binding of calcium increases the unfolding temperature of the protein (T(m)) by approximately 23 degrees C at pH 7.5. No correlation between binding affinity and T(m) change was noted, as each of the two calcium ions contributes almost equally to the increase in unfolding temperature.
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| 25. |
- Leavitt, Peter R., et al.
(författare)
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Paleolimnological evidence of the effects on lakes of energy and mass transfer from climate and humans
- 2009
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Ingår i: Limnology and Oceanography. - 0024-3590 .- 1939-5590. ; 54:6, s. 2330-2348
-
Forskningsöversikt (refereegranskat)abstract
- The premise of this article is that climate effects on lakes can be quantified most effectively by the integration of process-oriented limnological studies with paleolimnological research, particularly when both disciplines operate within a common conceptual framework. To this end, the energy (E)-mass (m) flux framework (Em flux) is developed and applied to selected retrospective studies to demonstrate that climate variability regulates lake structure and function over diverse temporal and spatial scales through four main pathways: rapid direct transfer of E to the lake surface by irradiance, heat, and wind; slow indirect effects of E via changes in terrestrial development and subsequent m subsidies to lakes; direct influx of m as precipitation, particles, and solutes from the atmosphere; and indirect influx of water, suspended particles, and dissolved substances from the catchment. Sedimentary analyses are used to illustrate the unique effects of each pathway on lakes but suggest that interactions among mechanisms are complex and depend on the landscape position of lakes, catchment characteristics, the range of temporal variation of individual pathways, ontogenetic changes in lake basins, and the selective effects of humans on m transfers. In particular, preliminary synthesis suggests that m influx can overwhelm the direct effects of E transfer to lakes, especially when anthropogenic activities alter m subsidies from catchments.
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| 26. |
- Davies, Helen R., et al.
(författare)
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HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures
- 2017
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 23:4, s. 517-525
-
Tidskriftsartikel (refereegranskat)abstract
- Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.
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| 27. |
- Glodzik, Dominik, et al.
(författare)
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A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers
- 2017
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:3, s. 341-348
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Tidskriftsartikel (refereegranskat)abstract
- Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.
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| 28. |
- Margaryan, Ashot, et al.
(författare)
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Population genomics of the Viking world
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 585:7825, s. 390-396
-
Tidskriftsartikel (refereegranskat)abstract
- The maritime expansion of Scandinavian populations during the Viking Age (about ad750–1050) was a far-flung transformation in world history1,2. Here we sequenced the genomes of 442humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci—including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response—in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.
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| 29. |
- Smid, Marcel, et al.
(författare)
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The circular RNome of primary breast cancer
- 2019
-
Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 29:3, s. 356-366
-
Tidskriftsartikel (refereegranskat)abstract
- Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R <0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and RERE in an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2 was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2 levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2 is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer.
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| 30. |
- Terenius, Olle, et al.
(författare)
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RNA interference in Lepidoptera : An overview of successful and unsuccessful studies and implications for experimental design
- 2011
-
Ingår i: Journal of insect physiology. - : Elsevier BV. - 0022-1910 .- 1879-1611. ; 57:2, s. 231-245
-
Tidskriftsartikel (refereegranskat)abstract
- Gene silencing through RNA interference (RNAi) has revolutionized the study of gene function, particularly in non-model insects. However, in Lepidoptera (moths and butterflies) RNAi has many times proven to be difficult to achieve. Most of the negative results have been anecdotal and the positive experiments have not been collected in such a way that they are possible to analyze. In this review, we have collected detailed data from more than 150 experiments including all to date published and many unpublished experiments. Despite a large variation in the data, trends that are found are that RNAi is particularly successful in the family Saturniidae and in genes involved in immunity. On the contrary, gene expression in epidermal tissues seems to be most difficult to silence. In addition, gene silencing by feeding dsRNA requires high concentrations for success. Possible causes for the variability of success in RNAi experiments in Lepidoptera are discussed. The review also points to a need to further investigate the mechanism of RNAi in lepidopteran insects and its possible connection to the innate immune response. Our general understanding of RNAi in Lepidoptera will be further aided in the future as our public database at http://insectacentral.org/RNAi will continue to gather information on RNAi experiments.
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| 31. |
- Wijayatunga, Priyantha, 1967-, et al.
(författare)
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Discussion on the meeting on 'Data visualization'
- 2019
-
Ingår i: Journal of the Royal Statistical Society. - UK : Royal Statistical Society. - 0964-1998 .- 1467-985X. ; 182:2, s. 433-441
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Visualizing both conditional and marginal associations in contingency tables by using simple diagrams is discussed
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| 32. |
- Abou Hachem, Maher, et al.
(författare)
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Carbohydrate-binding modules from a thermostable Rhodothermus marinus xylanase : Cloning, expression and binding studies
- 2000
-
Ingår i: Biochemical Journal. - : Portland Press Ltd.. - 0264-6021. ; 345:1, s. 53-60
-
Tidskriftsartikel (refereegranskat)abstract
- The two N-terminally repeated carbohydrate-binding modules (CBM4-1 and CBM4-2) encoded by xyn10A from Rhodothermus marinus were produced in Escherichia coli and purified by affinity chromatography. Binding assays to insoluble polysaccharides showed binding to insoluble xylan and to phosphoric-acid-swollen cellulose but not to Avicel or crystalline cellulose. Binding to insoluble substrates was significantly enhanced by the presence of Na+ and Ca2+ ions. The binding affinities for soluble polysaccharides were tested by affinity electrophoresis; strong binding occurred with different xylans and β-glucan. CBM4-2 displayed a somewhat higher binding affinity than CBM4-1 for both soluble and insoluble substrates but both had similar specificities. Binding to short oligosaccharides was measured by NMR; both modules bound with similar affinities. The binding of the modules was shown to be dominated by enthalpic forces. The binding modules did not contribute with any significant synergistic effects on xylan hydrolysis when incubated with a Xyn10A catalytic module. This is the first report of family 4 CBMs with affinity for both insoluble xylan and amorphous cellulose.
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| 33. |
- Alahmadi, Fahad, et al.
(författare)
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Measures of adherence in patients with severe asthma prescribed systemic steroids in the U-BIOPRED cohort
- 2018
-
Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 52
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Rates of sub-optimal adherence to medications in asthma range up to 70%; the impact in severe asthma is likely to be particularly high. We measured self-reported adherence in participants in the U-BIOPRED cohort prescribed daily prednisolone using the Medication Adherence Response Scale (MARS), and compared to measured urinary prednisolone and metabolites in order to determine: 1. the prevalence of suboptimal adherence by each method; 2. the ability of MARS to predict urinary steroid detection.Methods: Participants completed the MARS, and/or provided urine samples (analysed for prednisolone and metabolites by LCMS). The performance characteristics of the MARS predicting undetected urinary steroid were calculated in the subgroup having both tests.Results: 181 participants currently taking regular oral corticosteroids were included, 59% female, mean (SD) age 54(12)yrs, FEV1 64.7(20.4)% predicted. Sub-optimal adherence (MARS score < 4.5) was reported in 62 participants, and 76 did not have detectable urinary prednisolone or metabolites. Good adherence by both methods was detected in only 52 participants (34%, see table). There was no difference in daily prednisolone dose between detectable and undetectable metabolites groups (p=0.848).Conclusion: Low levels of adherence to treatment in severe asthma is a common problem, when measured either directly or self-reported. There was very poor agreement (48% concordance) between these two methods, and we suggest that, for now both approaches should be used.
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| 34. |
- Buder, Sven, et al.
(författare)
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The GALAH Survey : second data release
- 2018
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : OXFORD UNIV PRESS. - 0035-8711 .- 1365-2966. ; 478:4, s. 4513-4552
-
Tidskriftsartikel (refereegranskat)abstract
- The Galactic Archaeology with HERMES (GALAH) survey is a large-scale stellar spectroscopic survey of the Milky Way, designed to deliver complementary chemical information to a large number of stars covered by the Gaia mission. We present the GALAH second public data release (GALAH DR2) containing 342 682 stars. For these stars, the GALAH collaboration provides stellar parameters and abundances for up to 23 elements to the community. Here we present the target selection, observation, data reduction, and detailed explanation of how the spectra were analysed to estimate stellar parameters and element abundances. For the stellar analysis, we have used a multistep approach. We use the physics-driven spectrum synthesis of Spectroscopy Made Easy (SME) to derive stellar labels (T-eff, log g, [Fe/H], [X/Fe], v(mic), vsin i, AKS) for a representative training set of stars. This information is then propagated to the whole sample with the data-driven method of The Cannon. Special care has been exercised in the spectral synthesis to only consider spectral lines that have reliable atomic input data and are little affected by blending lines. Departures from local thermodynamic equilibrium (LTE) are considered for several key elements, including Li, O, Na, Mg, Al, Si, and Fe, using 1D MARCS stellar atmosphere models. Validation tests including repeat observations, Gaia benchmark stars, open and globular clusters, and K2 asteroseismic targets lend confidence to our methods and results. Combining the GALAH DR2 catalogue with the kinematic information from Gaia will enable a wide range of Galactic Archaeology studies, with unprecedented detail, dimensionality, and scope.
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| 35. |
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| 36. |
- Ostergaard, Pia, et al.
(författare)
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Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome).
- 2011
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:10
-
Tidskriftsartikel (refereegranskat)abstract
- We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome.
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| 37. |
- Simpson, Phoebe, et al.
(författare)
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Training of Physical Therapists to Deliver Individualized Biopsychosocial Interventions to Treat Musculoskeletal Pain Conditions : A Scoping Review
- 2021
-
Ingår i: Physical Therapy. - : Oxford University Press. - 0031-9023 .- 1538-6724. ; 101:10
-
Forskningsöversikt (refereegranskat)abstract
- OBJECTIVE: Current guidelines recommend management of musculoskeletal pain conditions from a biopsychosocial approach, however biopsychosocial interventions delivered by physical therapists vary considerably in effectiveness. It is unknown whether the differences are explained by the intervention itself, the training and/or competency of physical therapists delivering the intervention, or fidelity of the intervention. The aim was to investigate and map the training, competency assessments and fidelity checking of individualized biopsychosocial interventions delivered by physical therapists to treat musculoskeletal pain conditions.METHODS: A scoping review methodology was employed, using Arksey and O'Malley's framework. Seven electronic databases were searched between January to March 2019, with a bridge search completed in January 2020. Full text peer-reviewed papers, with an individualized biopsychosocial intervention were considered, and thirty-two studies were included.RESULTS: Reporting overall was sparse and highly variable. There was a broad spectrum of the training. More sophisticated training involved workshops combining didactic and experiential learning, over longer durations with supervision and feedback. Less sophisticated training was brief, involving lectures or seminars, with no supervision or feedback. Competency assessments and fidelity testing were underperformed.CONCLUSION: Training in some interventions may not have facilitated the implementation of skills or techniques to enable the paradigm shift and behavior change required for physical therapists to effectively deliver a biopsychosocial intervention. Lack of competency assessments and fidelity checking may have impacted on the methodological quality of biopsychosocial interventions.IMPACT: This study highlighted problematic reporting, training, assessment of competency and fidelity checking of physical therapist delivered individualized biopsychosocial interventions. Findings here highlight why previous interventions may have shown small effect sizes and areas for improvement in future interventions. These findings can help inform future research and facilitate more widespread implementation of physical therapist delivered biopsychosocial interventions for people with musculoskeletal pain and thereby improve their quality of life.
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| 38. |
- Smid, Marcel, et al.
(författare)
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Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA, PTEN, CCND1 and CDH1. We find that CCND3 expression levels do not correlate with amplification, while increased GATA3 expression in mutant GATA3 cancers suggests GATA3 is an oncogene. In luminal cases the total number of substitutions, irrespective of type, associates with cell cycle gene expression and adverse outcome, whereas the number of mutations of signatures 3 and 13 associates with immune-response specific gene expression, increased numbers of tumour-infiltrating lymphocytes and better outcome. Thus, while earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response, our data suggests that substitutions of a particular type are more effective in doing so than others.
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| 39. |
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| 40. |
- Baigent, Colin, et al.
(författare)
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The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection) : a randomised placebo-controlled trial
- 2011
-
Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 377:9784, s. 2181-2192
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Tidskriftsartikel (refereegranskat)abstract
- Background Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. Methods This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and I SRCTN54137607. Findings 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0.85 mmol/L (SE 0.02; with about two-thirds compliance) during a median follow-up of 4.9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11.3%] simvastatin plus ezetimibe vs 619 [13.4%] placebo; rate ratio [RR] 0.83, 95% CI 0.74-0.94; log-rank p=0.0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4.6%] vs 230 [5.0%]; RR 0.92,95% CI 0.76-1.11; p=0.37) and there were significant reductions in non-haemorrhagic stroke (131 [2.8%] vs 174 [3.8%]; RR 0.75,95% CI 0.60-0.94; p=0.01) and arterial revascularisation procedures (284 [6.1%] vs 352 [7.6%]; RR 0.79, 95% CI 0.68-0.93; p=0.0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0.2%] vs 5 [0.1%]). There was no evidence of excess risks of hepatitis (21 [0.5%] vs 18 [0.4%]), gallstones (106 [2.3%] vs 106 [2.3%]), or cancer (438 [9.4%] vs 439 [9.5%], p=0.89) and there was no significant excess of death from any non-vascular cause (668 [14.4%] vs 612 [13.2%], p=0.13). Interpretation Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.
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| 41. |
- Carrod, Andrew J., et al.
(författare)
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Photo- and Electrochemical Dual-Responsive Iridium Probe for Saccharide Detection
- 2022
-
Ingår i: Chemistry - A European Journal. - 0947-6539 .- 1521-3765. ; 28
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Tidskriftsartikel (refereegranskat)abstract
- Dual detection systems are of interest for rapid, accurate data collection in sensing systems and in vitro testing. We introduce an IrIII complex with a boronic acid receptor site attached to the 2-phenylpyridine ligand as an ideal probe with photo- and electrochemical signals that is sensitive to monosaccharide binding in aqueous solution. The complex displays orange luminescence at 618 nm, which is reduced by 70 and 40 % upon binding of fructose and glucose, respectively. The electro-chemiluminescent signal of the complex also shows a direct response to monosaccharide binding. The IrIII complex shows the same response upon incorporation into hydrogel matrices as in solution, thus demonstrating the potential of its integration into a device, as a nontoxic, simple-to-use tool to observe sugar binding over physiologically relevant pH ranges and saccharide concentrations. Moreover, the complex's luminescence is responsive to monosaccharide presence in cancer cells.
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| 42. |
- Diamant, Zuzana, et al.
(författare)
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Toward clinically applicable biomarkers for asthma : An EAACI position paper
- 2019
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 74:10, s. 1835-1851
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best-defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non-type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point-of-care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.
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| 43. |
- Etzold, Sophia, et al.
(författare)
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Nitrogen deposition is the most important environmental driver of growth of pure, even-aged and managed European forests
- 2020
-
Ingår i: Forest Ecology and Management. - : Elsevier BV. - 0378-1127 .- 1872-7042. ; 458
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Tidskriftsartikel (refereegranskat)abstract
- Changing environmental conditions may substantially interact with site quality and forest stand characteristics, and impact forest growth and carbon sequestration. Understanding the impact of the various drivers of forest growth is therefore critical to predict how forest ecosystems can respond to climate change. We conducted a continental-scale analysis of recent (1995–2010) forest volume increment data (ΔVol, m3 ha−1 yr−1), obtained from ca. 100,000 coniferous and broadleaved trees in 442 even-aged, single-species stands across 23 European countries. We used multivariate statistical approaches, such as mixed effects models and structural equation modelling to investigate how European forest growth respond to changes in 11 predictors, including stand characteristics, climate conditions, air and site quality, as well as their interactions. We found that, despite the large environmental gradients encompassed by the forests examined, stand density and age were key drivers of forest growth. We further detected a positive, in some cases non-linear effect of N deposition, most pronounced for beech forests, with a tipping point at ca. 30 kg N ha−1 yr−1. With the exception of a consistent temperature signal on Norway spruce, climate-related predictors and ground-level ozone showed much less generalized relationships with ΔVol. Our results show that, together with the driving forces exerted by stand density and age, N deposition is at least as important as climate to modulate forest growth at continental scale in Europe, with a potential negative effect at sites with high N deposition.
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| 44. |
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| 45. |
- Kalra, Hina, et al.
(författare)
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Vesiclepedia : a compendium for extracellular vesicles with continuous community annotation
- 2012
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Ingår i: PLoS biology. - : Public library of science. - 1544-9173 .- 1545-7885. ; 10:12, s. e1001450-
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.
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| 46. |
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| 47. |
- Simpson, Jeffrey D., et al.
(författare)
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The GALAH survey : co-orbiting stars and chemical tagging
- 2019
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 482:4, s. 5302-5315
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Tidskriftsartikel (refereegranskat)abstract
- We present a study using the second data release of the GALAH survey of stellar parameters and elemental abundances of 15 pairs of stars identified by Oh et al. They identified these pairs as potentially co-moving pairs using proper motions and parallaxes from Gaia DR1. We find that 11 very wide (>1 pc) pairs of stars do in fact have similar Galactic orbits, while a further four claimed co-moving pairs are not truly co-orbiting. Eight of the 11 co-orbiting pairs have reliable stellar parameters and abundances, and we find that three of those are quite similar in their abundance patterns, while five have significant [Fe/H] differences. For the latter, this indicates that they could be co-orbiting because of the general dynamical coldness of the thin disc, or perhaps resonances induced by the Galaxy, rather than a shared formation site. Stars such as these, wide binaries, debris of past star formation episodes, and coincidental co-orbiters, are crucial for exploring the limits of chemical tagging in the Milky Way.
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| 48. |
- Teo, Ian, et al.
(författare)
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Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers
- 2012
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 4:9, s. 866-881
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in β-defensin, IL-10, interferon-β, transforming growth factor-β, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.
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| 49. |
- Woolway, R. Iestyn, et al.
(författare)
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Diel Surface Temperature Range Scales with Lake Size
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Ecological and biogeochemical processes in lakes are strongly dependent upon water temperature. Long-term surface warming of many lakes is unequivocal, but little is known about the comparative magnitude of temperature variation at diel timescales, due to a lack of appropriately resolved data. Here we quantify the pattern and magnitude of diel temperature variability of surface waters using high-frequency data from 100 lakes. We show that the near-surface diel temperature range can be substantial in summer relative to long-term change and, for lakes smaller than 3 km(2), increases sharply and predictably with decreasing lake area. Most small lakes included in this study experience average summer diel ranges in their near-surface temperatures of between 4 and 7 degrees C. Large diel temperature fluctuations in the majority of lakes undoubtedly influence their structure, function and role in biogeochemical cycles, but the full implications remain largely unexplored.
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