| 1. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 2. |
- Gardner, Michael, et al.
(författare)
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Gender and telomere length : Systematic review and meta-analysis
- 2014
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Ingår i: Experimental Gerontology. - : Elsevier. - 0531-5565 .- 1873-6815. ; 51, s. 15-27
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Forskningsöversikt (refereegranskat)abstract
- Background: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. Methods: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. Results: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. Conclusions: Telomere length is longer in females thanmales, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required. (C) 2013 Published by Elsevier Inc.
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| 3. |
- Jones, Robert P., et al.
(författare)
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Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma : A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial
- 2019
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Ingår i: JAMA Surgery. - : AMER MEDICAL ASSOC. - 2168-6254 .- 2168-6262. ; 154:11, s. 1038-1048
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Tidskriftsartikel (refereegranskat)abstract
- Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear.Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival.Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019.Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine.Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence.Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P=.03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P=.04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P=.27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P=.85 and P=.35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P=.03).Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection.Trial Registration: ClinicalTrials.gov identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434. This secondary analysis of a randomized clinical trial investigates patterns of recurrence after adjuvant chemotherapy in pancreatic cancer and the association with survival.
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| 4. |
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| 5. |
- Akiyama, Kazunori, et al.
(författare)
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First Sagittarius A* Event Horizon Telescope Results. II. EHT and Multiwavelength Observations, Data Processing, and Calibration
- 2022
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
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Tidskriftsartikel (refereegranskat)abstract
- We present Event Horizon Telescope (EHT) 1.3 mm measurements of the radio source located at the position of the supermassive black hole Sagittarius A* (Sgr A*), collected during the 2017 April 5-11 campaign. The observations were carried out with eight facilities at six locations across the globe. Novel calibration methods are employed to account for Sgr A*'s flux variability. The majority of the 1.3 mm emission arises from horizon scales, where intrinsic structural source variability is detected on timescales of minutes to hours. The effects of interstellar scattering on the image and its variability are found to be subdominant to intrinsic source structure. The calibrated visibility amplitudes, particularly the locations of the visibility minima, are broadly consistent with a blurred ring with a diameter of similar to 50 mu as, as determined in later works in this series. Contemporaneous multiwavelength monitoring of Sgr A* was performed at 22, 43, and 86 GHz and at near-infrared and X-ray wavelengths. Several X-ray flares from Sgr A* are detected by Chandra, one at low significance jointly with Swift on 2017 April 7 and the other at higher significance jointly with NuSTAR on 2017 April 11. The brighter April 11 flare is not observed simultaneously by the EHT but is followed by a significant increase in millimeter flux variability immediately after the X-ray outburst, indicating a likely connection in the emission physics near the event horizon. We compare Sgr A*'s broadband flux during the EHT campaign to its historical spectral energy distribution and find that both the quiescent emission and flare emission are consistent with its long-term behavior.
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| 6. |
- Bach, Lennart T, et al.
(författare)
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Influence of Ocean Acidification on a Natural Winter-to-Summer Plankton Succession: First Insights from a Long-Term Mesocosm Study Draw Attention to Periods of Low Nutrient Concentrations
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Every year, the oceans absorb about 30% of anthropogenic carbon dioxide (CO2) leading to a re-equilibration of the marine carbonate system and decreasing seawater pH. Today, there is increasing awareness that these changes-summarized by the term ocean acidification (OA)-could differentially affect the competitive ability of marine organisms, thereby provoking a restructuring of marine ecosystems and biogeochemical element cycles. In winter 2013, we deployed ten pelagic mesocosms in the Gullmar Fjord at the Swedish west coast in order to study the effect of OA on plankton ecology and biogeochemistry under close to natural conditions. Five of the ten mesocosms were left unperturbed and served as controls (similar to 380 mu atm pCO(2)), whereas the others were enriched with CO2-saturated water to simulate realistic end-of-the-century carbonate chemistry conditions (mu 760 mu atm pCO(2)). We ran the experiment for 113 days which allowed us to study the influence of high CO2 on an entire winter-to-summer plankton succession and to investigate the potential of some plankton organisms for evolutionary adaptation to OA in their natural environment. This paper is the first in a PLOS collection and provides a detailed overview on the experimental design, important events, and the key complexities of such a "long-term mesocosm" approach. Furthermore, we analyzed whether simulated end-of-the-century carbonate chemistry conditions could lead to a significant restructuring of the plankton community in the course of the succession. At the level of detail analyzed in this overview paper we found that CO2-induced differences in plankton community composition were non-detectable during most of the succession except for a period where a phytoplankton bloom was fueled by remineralized nutrients. These results indicate: (1) Long-term studies with pelagic ecosystems are necessary to uncover OA-sensitive stages of succession. (2) Plankton communities fueled by regenerated nutrients may be more responsive to changing carbonate chemistry than those having access to high inorganic nutrient concentrations and may deserve particular attention in future studies.
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| 7. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 8. |
- Berger, Uta, et al.
(författare)
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Towards reusable building blocks for agent-based modelling and theory development
- 2024
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Ingår i: Environmental Modelling & Software. - 1364-8152 .- 1873-6726. ; 175
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Tidskriftsartikel (refereegranskat)abstract
- Despite the increasing use of standards for documenting and testing agent -based models (ABMs) and sharing of open access code, most ABMs are still developed from scratch. This is not only inefficient, but also leads to ad hoc and often inconsistent implementations of the same theories in computational code and delays progress in the exploration of the functioning of complex social -ecological systems (SES). We argue that reusable building blocks (RBBs) known from professional software development can mitigate these issues. An RBB is a submodel that represents a particular mechanism or process that is relevant across many ABMs in an application domain, such as plant competition in vegetation models, or reinforcement learning in a behavioural model. RBBs need to be distinguished from modules, which represent entire subsystems and include more than one mechanism and process. While linking modules faces the same challenges as integrating different models in general, RBBs are atomic enough to be more easily re -used in different contexts. We describe and provide examples from different domains for how and why building blocks are used in software development, and the benefits of doing so for the ABM community and to individual modellers. We propose a template to guide the development and publication of RBBs and provide example RBBs that use this template. Most importantly, we propose and initiate a strategy for community -based development, sharing and use of RBBs. Individual modellers can have a much greater impact in their field with an RBB than with a single paper, while the community will benefit from increased coherence, facilitating the development of theory for both the behaviour of agents and the systems they form. We invite peers to upload and share their RBBs via our website - preferably referenced by a DOI (digital object
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| 9. |
- Bindler, Richard, 1963-, et al.
(författare)
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Reshaping the landscape: mining, metallurgy and a millennium of environmental changes in south-central Sweden
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Before the recognition of emerging environmental issues during the 20th century such as acid rain, mercury pollution, climate change and biodiversity loss, human activities had already significantly altered landscapes around the globe. As elsewhere in Europe, the introduction of agriculture into Sweden during the Bronze and Iron Ages led to changes in forest cover, especially in southern areas, but also more limited impacts in central and northern Sweden along river valleys and coastal areas. In central Sweden the rise and rapid spread of ore mining and metallurgy from the 12th and especially 13th century initiated a widespread reshaping of the landscape named after its mining heritage –Bergslagen (mining laws). This mineral rich 89,000 km2 region encompasses ~5000 metallurgical sites (furnaces, smelters, foundries, forges) and ~10000 mines registered in the Swedish National Antiquities Board’s database.Analyses of >30 lake-sediment records using a combination of geochemical, diatom and pollen analyses, in combination with archaeological and historical records and toponyms, add important details to the early, poorly documented history of mining/metallurgy as well as provide insights into some of the environmental impacts across this large landscape. These impacts included damming of lakes and regulation of watercourses for waterpower, increase in erosion, emission of metals to surface waters and the atmosphere (and leaching from slag piles), decrease in forest cover and changes in water quality. The discontinuous appearance of pollen from cultivated plants (cereals) indicates some limited settlement before the 12th century, but the regular occurrence thereafter of cereal pollen together with a sharp increase in charcoal particles and geochemical evidence of mining/metallurgical activities, indicates mining/metallurgy was a driving force for settlement. Decline in forest cover was gradual from the 13th century, but was more significant from the late 16th century when iron and copper production increased exponentially. The increased demand for charcoal and increased agriculture, including an expansion of summer forest farms, contributed to a reduction in inferred forest cover to 40–80% – as compared to pre-anthropogenic (≤2000 BP) values of 84–95%. From the 16th century charcoal became the limiting resource within Bergslagen and metallurgy expanded to regions adjoining Bergslagen, contributing to a more widespread decline in forest cover also beyond the Bergslagen landscape.In association with the increase in land-use activities and resulting changes in vegetation cover, there was a decline (20–50%) in spectrally inferred lake-water total organic carbon, which we hypothesize resulted from a decreased pool of labile soil carbon. In some lakes closely connected with blast furnaces, where the peasant-miners also lived and farmed, there was an increase in diatom-inferred lake-water pH – as observed previously in SW Sweden in association with Iron Age land use. Only in a suite of lakes in close proximity to the smelting of copper sulfide ores in the surroundings of Falun was there evidence for pre-20th century acidification.While current rates of environmental change may be unprecedented, they build on an already modified landscape. Because pre-industrial conditions, i.e., pre-19th century, are often used as a reference level the scale of current changes may underestimate the full extent of ecosystem and environmental impacts.
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| 10. |
- Birkhofer, Klaus, et al.
(författare)
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General Relationships between Abiotic Soil Properties and Soil Biota across Spatial Scales and Different Land-Use Types.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- Very few principles have been unraveled that explain the relationship between soil properties and soil biota across large spatial scales and different land-use types. Here, we seek these general relationships using data from 52 differently managed grassland and forest soils in three study regions spanning a latitudinal gradient in Germany. We hypothesize that, after extraction of variation that is explained by location and land-use type, soil properties still explain significant proportions of variation in the abundance and diversity of soil biota. If the relationships between predictors and soil organisms were analyzed individually for each predictor group, soil properties explained the highest amount of variation in soil biota abundance and diversity, followed by land-use type and sampling location. After extraction of variation that originated from location or land-use, abiotic soil properties explained significant amounts of variation in fungal, meso- and macrofauna, but not in yeast or bacterial biomass or diversity. Nitrate or nitrogen concentration and fungal biomass were positively related, but nitrate concentration was negatively related to the abundances of Collembola and mites and to the myriapod species richness across a range of forest and grassland soils. The species richness of earthworms was positively correlated with clay content of soils independent of sample location and land-use type. Our study indicates that after accounting for heterogeneity resulting from large scale differences among sampling locations and land-use types, soil properties still explain significant proportions of variation in fungal and soil fauna abundance or diversity. However, soil biota was also related to processes that act at larger spatial scales and bacteria or soil yeasts only showed weak relationships to soil properties. We therefore argue that more general relationships between soil properties and soil biota can only be derived from future studies that consider larger spatial scales and different land-use types.
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| 11. |
- Brandão, Rita D., et al.
(författare)
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Targeted RNA-seq successfully identifies normal and pathogenic splicing events in breast/ovarian cancer susceptibility and Lynch syndrome genes
- 2019
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 145:2, s. 401-414
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Tidskriftsartikel (refereegranskat)abstract
- A subset of genetic variants found through screening of patients with hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome impact RNA splicing. Through target enrichment of the transcriptome, it is possible to perform deep-sequencing and to identify the different and even rare mRNA isoforms. A targeted RNA-seq approach was used to analyse the naturally-occurring splicing events for a panel of 8 breast and/or ovarian cancer susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, PTEN, STK11, CDH1, TP53), 3 Lynch syndrome genes (MLH1, MSH2, MSH6) and the fanconi anaemia SLX4 gene, in which monoallelic mutations were found in non-BRCA families. For BRCA1, BRCA2, RAD51C and RAD51D the results were validated by capillary electrophoresis and were compared to a non-targeted RNA-seq approach. We also compared splicing events from lymphoblastoid cell-lines with those from breast and ovarian fimbriae tissues. The potential of targeted RNA-seq to detect pathogenic changes in RNA-splicing was validated by the inclusion of samples with previously well characterized BRCA1/2 genetic variants. In our study, we update the catalogue of normal splicing events for BRCA1/2, provide an extensive catalogue of normal RAD51C and RAD51D alternative splicing, and list splicing events found for eight other genes. Additionally, we show that our approach allowed the identification of aberrant splicing events due to the presence of BRCA1/2 genetic variants and distinguished between complete and partial splicing events. In conclusion, targeted-RNA-seq can be very useful to classify variants based on their putative pathogenic impact on splicing.
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| 12. |
- Brenner, David, et al.
(författare)
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Hot-spot KIF5A mutations cause familial ALS
- 2018
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 141, s. 688-697
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Tidskriftsartikel (refereegranskat)abstract
- Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
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| 13. |
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| 14. |
- Brigham-Grette, Julie, et al.
(författare)
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Pliocene warmth, polar amplification, and stepped pleistocene cooling recorded in NE arctic russia
- 2013
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 340:6139, s. 1421-1427
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the evolution of Arctic polar climate from the protracted warmth of the middle Pliocene into the earliest glacial cycles in the Northern Hemisphere has been hindered by the lack of continuous, highly resolved Arctic time series. Evidence from Lake El'gygytgyn, in northeast (NE) Arctic Russia, shows that 3.6 to 3.4 million years ago, summer temperatures were similar to 8 degrees C warmer than today, when the partial pressure of CO2 was similar to 400 parts per million. Multiproxy evidence suggests extreme warmth and polar amplification during the middle Pliocene, sudden stepped cooling events during the Pliocene-Pleistocene transition, and warmer than present Arctic summers until similar to 2.2 million years ago, after the onset of Northern Hemispheric glaciation. Our data are consistent with sea-level records and other proxies indicating that Arctic cooling was insufficient to support large-scale ice sheets until the early Pleistocene.
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| 15. |
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| 16. |
- Cherniack, Martin, et al.
(författare)
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The Hand-Arm Vibration International Consortium (HAVIC) : prospective studies on the relationship between power tool exposure and health effects.
- 2007
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Ingår i: Journal of Occupational and Environmental Medicine. - 1076-2752 .- 1536-5948. ; 49:3, s. 289-301
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The Hand-Arm Vibration International Consortium (HAVIC) is a collaboration of investigators from Europe and North America studying health effects from hand-arm vibration (HAV). Features include prospective design, cross-cohort exposure, and health assessment methods. METHODS: Two new cohorts (dental hygienists and dental hygiene students), two existing cohorts (Finnish forest workers, and Swedish truck cab assemblers), and a previous population (US shipyard workers) are included. Instruments include surveys, quantitative medical tests, physical examination, and work simulation and data logging to assess exposure. New methods were developed for nerve conduction and data logging. RESULTS: Findings on the relationship between nerve conduction and skin temperature in HAV-exposed subjects resulted in a new approach to subject warming. CONCLUSIONS: Integrating established cohorts has advantages over de novo cohort construction. Complex laboratory tests can be successfully adapted for field use.
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| 17. |
- Demichev, Vadim, et al.
(författare)
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A time-resolved proteomic and prognostic map of COVID-19
- 2021
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Ingår i: Cell Systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 12:8, s. 780-794.e7
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Tidskriftsartikel (refereegranskat)abstract
- COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.
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| 18. |
- Dima, Danai, et al.
(författare)
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Subcortical volumes across the lifespan : Data from 18,605 healthy individuals aged 3-90 years.
- 2022
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Ingår i: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 43:1, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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| 19. |
- Ding, Li, et al.
(författare)
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Somatic mutations affect key pathways in lung adenocarcinoma
- 2008
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7216, s. 1069-1075
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Tidskriftsartikel (refereegranskat)abstract
- Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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| 20. |
- Feddermann-Demont, Nina, et al.
(författare)
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Recommendations for initial examination, differential diagnosis, and management of concussion and other head injuries in high-level football
- 2020
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : John Wiley & Sons. - 0905-7188 .- 1600-0838. ; 30:10, s. 1846-1858
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Forskningsöversikt (refereegranskat)abstract
- Head injuries can result in substantially different outcomes, ranging from no detectable effect to transient functional impairments to life-threatening structural lesions. In high-level international football (soccer) tournaments, on average, one head injury occurs in every third match. Making the diagnosis and determining the severity of a head injury immediately on-pitch or off-field is a major challenge for team physicians, especially because clinical signs of a brain injury can develop over several minutes, hours, or even days after the injury. A standardized approach is useful to support team physicians in their decision whether the player should be allowed to continue to play or should be removed from play after head injury. A systematic, football-specific procedure for examination and management during the first 72 hours after head injuries and a graduated Return-to-Football program for high-level players have been developed by an international group of experts based on current national and international guidelines for the management of acute head injuries. The procedure includes seven stages from the initial on-pitch examination to the graduated Return-to-Football program. Details of the assessments and the consequences of different outcomes are described for each stage. Criteria for emergency management (red flags), removal from play (orange flags), and referral to specialists for further diagnosis and treatment (persistent orange flags) are provided. The guidelines for return to sport after concussion-type head injury are specified for football. Thus, the present paper presents a comprehensive procedure for team physicians after a head injury in high-level football.
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| 21. |
- Ferolla, Piero, et al.
(författare)
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Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA) : an open-label, multicentre, randomised, phase 2 trial
- 2017
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 18:12, s. 1652-1664
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThere are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus.MethodsLUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0–2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing.FindingsBetween Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2–55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6–49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1–73·7) in the combination group. The most common grade 1–2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3–4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related.InterpretationThe study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids.
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| 22. |
- Frazier-Wood, Alexis C., et al.
(författare)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Tidskriftsartikel (refereegranskat)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 23. |
- Freischmidt, Axel, et al.
(författare)
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Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
- 2015
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 18:5, s. 631-
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
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| 24. |
- Gallo, Selene, et al.
(författare)
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Functional connectivity signatures of major depressive disorder: machine learning analysis of two multicenter neuroimaging studies
- 2023
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Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; 28:7, s. 3013-3022
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Tidskriftsartikel (refereegranskat)abstract
- The promise of machine learning has fueled the hope for developing diagnostic tools for psychiatry. Initial studies showed high accuracy for the identification of major depressive disorder (MDD) with resting-state connectivity, but progress has been hampered by the absence of large datasets. Here we used regular machine learning and advanced deep learning algorithms to differentiate patients with MDD from healthy controls and identify neurophysiological signatures of depression in two of the largest resting-state datasets for MDD. We obtained resting-state functional magnetic resonance imaging data from the REST-meta-MDD (N = 2338) and PsyMRI (N = 1039) consortia. Classification of functional connectivity matrices was done using support vector machines (SVM) and graph convolutional neural networks (GCN), and performance was evaluated using 5-fold cross-validation. Features were visualized using GCN-Explainer, an ablation study and univariate t-testing. The results showed a mean classification accuracy of 61% for MDD versus controls. Mean accuracy for classifying (non-)medicated subgroups was 62%. Sex classification accuracy was substantially better across datasets (73-81%). Visualization of the results showed that classifications were driven by stronger thalamic connections in both datasets, while nearly all other connections were weaker with small univariate effect sizes. These results suggest that whole brain resting-state connectivity is a reliable though poor biomarker for MDD, presumably due to disease heterogeneity as further supported by the higher accuracy for sex classification using the same methods. Deep learning revealed thalamic hyperconnectivity as a prominent neurophysiological signature of depression in both multicenter studies, which may guide the development of biomarkers in future studies.
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| 25. |
- Germovsek, Eva, et al.
(författare)
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Plasma and CSF pharmacokinetics of meropenem in neonates and young infants : results from the NeoMero studies
- 2018
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 73:7, s. 1908-1916
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking.Objectives: To determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS).Methods: Data were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed.Results: A one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome.Conclusions: Simulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.
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