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Sökning: WFRF:(Mathieu David)

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1.
  • 2019
  • Tidskriftsartikel (refereegranskat)
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2.
  • Huyghe, Jeroen R., et al. (författare)
  • Discovery of common and rare genetic risk variants for colorectal cancer
  • 2019
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
  • Tidskriftsartikel (refereegranskat)abstract
    • To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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3.
  • Schmit, Stephanie L, et al. (författare)
  • Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
  • 2019
  • Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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4.
  • Beal, Jacob, et al. (författare)
  • Robust estimation of bacterial cell count from optical density
  • 2020
  • Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
  • 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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5.
  • Saxena, Richa, et al. (författare)
  • Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge
  • 2010
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:2, s. 142-148
  • Tidskriftsartikel (refereegranskat)abstract
    • Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).
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6.
  • Ade, Peter, et al. (författare)
  • The Simons Observatory : science goals and forecasts
  • 2019
  • Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :2
  • Tidskriftsartikel (refereegranskat)abstract
    • The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial con figuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping approximate to 10% of the sky to a white noise level of 2 mu K-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of sigma(r) = 0.003. The large aperture telescope will map approximate to 40% of the sky at arcminute angular resolution to an expected white noise level of 6 mu K-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
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7.
  • Thomas, Minta, et al. (författare)
  • Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
  • 2020
  • Ingår i: American Journal of Human Genetics. - Cambridge : Elsevier BV. - 0002-9297 .- 1537-6605. ; 107:3, s. 432-444
  • Tidskriftsartikel (refereegranskat)abstract
    • Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
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8.
  • Thomas, Minta, et al. (författare)
  • Response to Li and Hopper
  • 2021
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 108:3, s. 527-529
  • Tidskriftsartikel (refereegranskat)
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9.
  • Bousquet, Jean, et al. (författare)
  • ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice
  • 2021
  • Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 76:1, s. 168-190
  • Forskningsöversikt (refereegranskat)abstract
    • Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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10.
  • Cuni-Sanchez, Aida, et al. (författare)
  • High aboveground carbon stock of African tropical montane forests
  • 2021
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 596:7873, s. 536-542
  • Tidskriftsartikel (refereegranskat)abstract
    • Tropical forests store 40–50per cent of terrestrial vegetation carbon. However, spatial variations in aboveground live tree biomass carbon (AGC) stocks remain poorly understood, in particular in tropical montane forests. Owing to climatic and soil changes with increasing elevation, AGC stocks are lower in tropical montane forests compared with lowland forests. Here we assemble and analyse a dataset of structurally intact old-growth forests (AfriMont) spanning 44 montane sites in 12 African countries. We find that montane sites in the AfriMont plot network have a mean AGC stock of 149.4megagrams of carbon per hectare (95% confidence interval 137.1–164.2), which is comparable to lowland forests in the African Tropical Rainforest Observation Network4 and about 70per cent and 32per cent higher than averages from plot networks in montane and lowland forests in the Neotropics, respectively. Notably, our results are two-thirds higher than the Intergovernmental Panel on Climate Change default values for these forests in Africa8. We find that the low stem density and high abundance of large trees of African lowland forests is mirrored in the montane forests sampled. This carbon store is endangered: we estimate that 0.8 million hectares of old-growth African montane forest have been lost since 2000. We provide country-specific montane forest AGC stock estimates modelled from our plot network to helpto guide forest conservation and reforestation interventions. Our findings highlight the need for conserving these biodiverse and carbon-rich ecosystems.
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11.
  • Lévy, Romain, et al. (författare)
  • Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
  • 2023
  • Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 220:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.
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12.
  • Potapov, Anton M., et al. (författare)
  • Global fine-resolution data on springtail abundance and community structure
  • 2024
  • Ingår i: Scientific Data. - : Nature Publishing Group. - 2052-4463. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Springtails (Collembola) inhabit soils from the Arctic to the Antarctic and comprise an estimated ~32% of all terrestrial arthropods on Earth. Here, we present a global, spatially-explicit database on springtail communities that includes 249,912 occurrences from 44,999 samples and 2,990 sites. These data are mainly raw sample-level records at the species level collected predominantly from private archives of the authors that were quality-controlled and taxonomically-standardised. Despite covering all continents, most of the sample-level data come from the European continent (82.5% of all samples) and represent four habitats: woodlands (57.4%), grasslands (14.0%), agrosystems (13.7%) and scrublands (9.0%). We included sampling by soil layers, and across seasons and years, representing temporal and spatial within-site variation in springtail communities. We also provided data use and sharing guidelines and R code to facilitate the use of the database by other researchers. This data paper describes a static version of the database at the publication date, but the database will be further expanded to include underrepresented regions and linked with trait data.
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13.
  • Abazajian, Kevork, et al. (författare)
  • CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
  • 2022
  • Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
  • Tidskriftsartikel (refereegranskat)abstract
    • CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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14.
  • Bousquet, J. Jean, et al. (författare)
  • Next-generation ARIA care pathways for rhinitis and asthma : a model for multimorbid chronic diseases
  • 2019
  • Ingår i: Clinical and Translational Allergy. - : BMC. - 2045-7022. ; 9
  • Forskningsöversikt (refereegranskat)abstract
    • Background: In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy.Main body: As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted "patient activation", (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Sante as a Good Practice in the field of digitally-enabled, integrated, person-centred care.Conclusion: In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.
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15.
  • Charalambidis, Georgios, et al. (författare)
  • A switchable self-assembling and disassembling chiral system based on a porphyrin-substituted phenylalanine-phenylalanine motif
  • 2016
  • Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:12657
  • Tidskriftsartikel (refereegranskat)abstract
    • Artificial light-harvesting systems have until now not been able to self-assemble into structures with a large photon capture cross-section that upon a stimulus reversibly can switch into an inactive state. Here we describe a simple and robust FLFL-dipeptide construct to which a meso-tetraphenylporphyrin has been appended and which self-assembles to fibrils, platelets or nanospheres depending on the solvent composition. The fibrils, functioning as quenched antennas, give intense excitonic couplets in the electronic circular dichroism spectra which are mirror imaged if the unnatural FDFD-analogue is used. By slightly increasing the solvent polarity, these light-harvesting fibres disassemble to spherical structures with silent electronic circular dichroism spectra but which fluoresce. Upon further dilution with the nonpolar solvent, the intense Cotton effects are recovered, thus proving a reversible switching. A single crystal X-ray structure shows a head-to-head arrangement of porphyrins that explains both their excitonic coupling and quenched fluorescence.
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16.
  • Cnossen, Maryse C., et al. (författare)
  • Variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury : a survey in 66 neurotrauma centers participating in the CENTER-TBI study
  • 2017
  • Ingår i: Critical Care. - : Springer. - 1364-8535 .- 1466-609X. ; 21:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: No definitive evidence exists on how intracranial hypertension should be treated in patients with traumatic brain injury (TBI). It is therefore likely that centers and practitioners individually balance potential benefits and risks of different intracranial pressure (ICP) management strategies, resulting in practice variation. The aim of this study was to examine variation in monitoring and treatment policies for intracranial hypertension in patients with TBI.METHODS: A 29-item survey on ICP monitoring and treatment was developed on the basis of literature and expert opinion, and it was pilot-tested in 16 centers. The questionnaire was sent to 68 neurotrauma centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study.RESULTS: The survey was completed by 66 centers (97% response rate). Centers were mainly academic hospitals (n = 60, 91%) and designated level I trauma centers (n = 44, 67%). The Brain Trauma Foundation guidelines were used in 49 (74%) centers. Approximately 90% of the participants (n = 58) indicated placing an ICP monitor in patients with severe TBI and computed tomographic abnormalities. There was no consensus on other indications or on peri-insertion precautions. We found wide variation in the use of first- and second-tier treatments for elevated ICP. Approximately half of the centers were classified as using a relatively aggressive approach to ICP monitoring and treatment (n = 32, 48%), whereas the others were considered more conservative (n = 34, 52%).CONCLUSIONS: Substantial variation was found regarding monitoring and treatment policies in patients with TBI and intracranial hypertension. The results of this survey indicate a lack of consensus between European neurotrauma centers and provide an opportunity and necessity for comparative effectiveness research.
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17.
  • Coincon, Mathieu, et al. (författare)
  • Crystal structures reveal the molecular basis of ion translocation in sodium/proton antiporters
  • 2016
  • Ingår i: Nature Structural & Molecular Biology. - : Springer Science and Business Media LLC. - 1545-9993 .- 1545-9985. ; 23:3, s. 248-255
  • Tidskriftsartikel (refereegranskat)abstract
    • To fully understand the transport mechanism of Na+/H+ exchangers, it is necessary to clearly establish the global rearrangements required to facilitate ion translocation. Currently, two different transport models have been proposed. Some reports have suggested that structural isomerization is achieved through large elevator-like rearrangements similar to those seen in the structurally unrelated sodium-coupled glutamate-transporter homolog Glt(ph). Others have proposed that only small domain movements are required for ion exchange, and a conventional rocking-bundle model has been proposed instead. Here, to resolve these differences, we report atomic-resolution structures of the same Na+/H+ antiporter (NapA from Thermus thermophilus) in both outward- and inward-facing conformations. These data combined with cross-linking, molecular dynamics simulations and isothermal calorimetry suggest that Na+/H+ antiporters provide alternating access to the ion-binding site by using elevator-like structural transitions.
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18.
  • Danila, Ion, et al. (författare)
  • Hierarchical Chiral Expression from the Nano- to Mesoscale in Synthetic Supramolecular Helical Fibers of a Nonamphiphilic C(3)-Symmetrical pi-Functional Molecule
  • 2011
  • Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 133:21, s. 8344-8353
  • Tidskriftsartikel (refereegranskat)abstract
    • The controlled preparation of chiral structures is a contemporary challenge for supramolecular science because of the interesting properties that can arise from the resulting materials, and here we show that a synthetic nonamphiphilic C(3) compound containing pi-functional tetrathiafulvalene units can form this kind of object. We describe the synthesis, characterization, and self-assembly properties in solution and in the solid state of the enantiopure materials. Circular dichroism (CD) measurements show optical activity resulting from the presence of twisted stacks of preferential helicity and also reveal the critical importance of fiber nucleation in their formation. Molecular mechanics (MM) and molecular dynamics (MD) simulations combined with CD theoretical calculations demonstrate that the (5) enantiomer provides the (M) helix, which is more stable than the (P) helix for this enantiomer. This relationship is for the first time established in this family of C(3) symmetric compounds. In addition, we show that introduction of the "wrong" enantiomer in a stack decreases the helical reversal barrier in a nonlinear manner, which very probably accounts for the absence of a "majority rules" effect. Mesoscopic chiral fibers, which show inverted helicity, i.e. (P) for the (S) enantiomer and (M) for the (R) one, have been obtained upon reprecipitation from dioxane and analyzed by optical and electronic microscopy. The fibers obtained with the racemic mixture present, as a remarkable feature, opposite homochiral domains within the same fiber, separated by points of helical reversal. Their formation can be explained through an "oscillating" crystallization mechanism. Although C(3) symmetric disk-shaped molecules containing a central benzene core substituted in the 1,3,5 positions with 3,3'-diamido-2,2'-bipyridine based wedges have shown peculiar self-assembly properties for amphiphilic derivatives, the present result shows the benefits of reducing the nonfunctional part of the molecule, in our case with short chiral isopentyl chains. The research reported herein represents an important step toward the preparation of functional mesostructures with controlled helical architectures.
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19.
  • Ebrahimi-Fakhari, Darius, et al. (författare)
  • Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
  • 2020
  • Ingår i: Brain. - OXFORD ENGLAND : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:10, s. 2929-2944
  • Tidskriftsartikel (refereegranskat)abstract
    • Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 +/- 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 +/- 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 +/- 5.1 years, SD) and later tetraplegia (mean age: 16.1 +/- 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 +/- 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 +/- 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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20.
  • Glas, Gerie J., et al. (författare)
  • Ventilation practices in burn patients-an international prospective observational cohort study
  • 2021
  • Ingår i: BURNS & TRAUMA. - : Oxford University Press. - 2321-3868 .- 2321-3876. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: It is unknown whether lung-protective ventilation is applied in burn patients and whether they benefit from it. This study aimed to determine ventilation practices in burn intensive care units (ICUs) and investigate the association between lung-protective ventilation and the number of ventilator-free days and alive at day 28 (VFD-28). Methods: This is an international prospective observational cohort study including adult burn patients requiring mechanical ventilation. Low tidal volume (V-T) was defined as V-T <= 8 mL/kg predicted body weight (PBW). Levels of positive end-expiratory pressure (PEEP) and maximum airway pressures were collected. The association between V-T and VFD-28 was analyzed using a competing risk model. Ventilation settings were presented for all patients, focusing on the first day of ventilation. We also compared ventilation settings between patients with and without inhalation trauma. Results: A total of 160 patients from 28 ICUs in 16 countries were included. Low V-T was used in 74% of patients, median V-T size was 7.3 [interquartile range (IQR) 6.2-8.3] mL/kg PBW and did not differ between patients with and without inhalation trauma (p= 0.58). Median VFD-28 was 17 (IQR 0-26), without a difference between ventilation with low or high V-T (p= 0.98). All patients were ventilated with PEEP levels >= 5 cmH(2)O; 80% of patients had maximum airway pressures <30 cmH(2)O. Conclusion: In this international cohort study we found that lung-protective ventilation is used in the majority of burn patients, irrespective of the presence of inhalation trauma. Use of low V-T was not associated with a reduction in VFD-28.
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21.
  • Haynes, Roger, et al. (författare)
  • The 4MOST instrument concept overview
  • 2014
  • Ingår i: Ground-based and Airborne Instrumentation for Astronomy V. - : SPIE. - 0277-786X .- 1996-756X. ; 9147, s. 91476-91476
  • Konferensbidrag (refereegranskat)abstract
    • The 4MOST([1]) instrument is a concept for a wide-field, fibre-fed high multiplex spectroscopic instrument facility on the ESO VISTA telescope designed to perform a massive (initially >25x10(6) spectra in 5 years) combined all-sky public survey. The main science drivers are: Gaia follow up of chemo-dynamical structure of the Milky Way, stellar radial velocities, parameters and abundances, chemical tagging; eROSITA follow up of cosmology with x-ray clusters of galaxies, X-ray AGN/galaxy evolution to z similar to 5, Galactic X-ray sources and resolving the Galactic edge; Euclid/LSST/SKA and other survey follow up of Dark Energy, Galaxy evolution and transients. The surveys will be undertaken simultaneously requiring: highly advanced targeting and scheduling software, also comprehensive data reduction and analysis tools to produce high-level data products. The instrument will allow simultaneous observations of similar to 1600 targets at R similar to 5,000 from 390-900nm and similar to 800 targets at R>18,000 in three channels between similar to 395-675nm (channel bandwidth: 45nm blue, 57nm green and 69nm red) over a hexagonal field of view of similar to 4.1 degrees2. The initial 5-year 4MOST survey is currently expect to start in 2020. We provide and overview of the 4MOST systems: opto-mechanical, control, data management and operations concepts; and initial performance estimates.
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22.
  • Holmgaard List, Nanna, et al. (författare)
  • Origin of DNA-Induced Circular Dichroism in a Minor-Groove Binder
  • 2017
  • Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 139:42, s. 14947-14953
  • Tidskriftsartikel (refereegranskat)abstract
    • Induced circular dichroism (ICD) of DNA-binding ligands is well known to be strongly influenced by the specific mode of binding, but the relative importance of the possible mechanisms has remained undetermined. With a combination of molecular dynamics simulations, CD response calculations, and experiments on an AT-sequence, we show that the ICD of minor-groove-bound 4',6-diamidino-2-phenylindole (DAPI) originates from an intricate interplay between the chiral imprint of DNA, off-resonant excitonic coupling to nucleobases, charge-transfer, and resonant excitonic coupling between DAPIs. The significant contributions from charge-transfer and the chiral imprint to the ICD demonstrate the inadequacy of a standard Frenkel exciton theory of the DAPI-DNA interactions.
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23.
  • Huijben, Jilske A, et al. (författare)
  • Changing care pathways and between-center practice variations in intensive care for traumatic brain injury across Europe : a CENTER-TBI analysis
  • 2020
  • Ingår i: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 46:5, s. 995-1004
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: To describe ICU stay, selected management aspects, and outcome of Intensive Care Unit (ICU) patients with traumatic brain injury (TBI) in Europe, and to quantify variation across centers.METHODS: This is a prospective observational multicenter study conducted across 18 countries in Europe and Israel. Admission characteristics, clinical data, and outcome were described at patient- and center levels. Between-center variation in the total ICU population was quantified with the median odds ratio (MOR), with correction for case-mix and random variation between centers.RESULTS: A total of 2138 patients were admitted to the ICU, with median age of 49 years; 36% of which were mild TBI (Glasgow Coma Scale; GCS 13-15). Within, 72 h 636 (30%) were discharged and 128 (6%) died. Early deaths and long-stay patients (> 72 h) had more severe injuries based on the GCS and neuroimaging characteristics, compared with short-stay patients. Long-stay patients received more monitoring and were treated at higher intensity, and experienced worse 6-month outcome compared to short-stay patients. Between-center variations were prominent in the proportion of short-stay patients (MOR = 2.3, p < 0.001), use of intracranial pressure (ICP) monitoring (MOR = 2.5, p < 0.001) and aggressive treatments (MOR = 2.9, p < 0.001); and smaller in 6-month outcome (MOR = 1.2, p = 0.01).CONCLUSIONS: Half of contemporary TBI patients at the ICU have mild to moderate head injury. Substantial between-center variations exist in ICU stay and treatment policies, and less so in outcome. It remains unclear whether admission of short-stay patients represents appropriate prudence or inappropriate use of clinical resources.
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24.
  • Huijben, Jilske A., et al. (författare)
  • Development of a quality indicator set to measure and improve quality of ICU care for patients with traumatic brain injury
  • 2019
  • Ingår i: Critical Care. - : BioMed Central. - 1364-8535 .- 1466-609X. ; 23
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: We aimed to develop a set of quality indicators for patients with traumatic brain injury (TBI) in intensive care units (ICUs) across Europe and to explore barriers and facilitators for implementation of these quality indicators.Methods: A preliminary list of 66 quality indicators was developed, based on current guidelines, existing practice variation, and clinical expertise in TBI management at the ICU. Eight TBI experts of the Advisory Committee preselected the quality indicators during a first Delphi round. A larger Europe-wide expert panel was recruited for the next two Delphi rounds. Quality indicator definitions were evaluated on four criteria: validity (better performance on the indicator reflects better processes of care and leads to better patient outcome), feasibility (data are available or easy to obtain), discriminability (variability in clinical practice), and actionability (professionals can act based on the indicator). Experts scored indicators on a 5-point Likert scale delivered by an electronic survey tool.Results. The expert panel consisted of 50 experts from 18 countries across Europe, mostly intensivists (N=24, 48%) and neurosurgeons (N=7, 14%). Experts agreed on a final set of 42 indicators to assess quality of ICU care: 17 structure indicators, 16 process indicators, and 9 outcome indicators. Experts are motivated to implement this finally proposed set (N=49, 98%) and indicated routine measurement in registries (N=41, 82%), benchmarking (N=42, 84%), and quality improvement programs (N=41, 82%) as future steps. Administrative burden was indicated as the most important barrier for implementation of the indicator set (N=48, 98%).Conclusions: This Delphi consensus study gives insight in which quality indicators have the potential to improve quality of TBI care at European ICUs. The proposed quality indicator set is recommended to be used across Europe for registry purposes to gain insight in current ICU practices and outcomes of patients with TBI. This indicator set may become an important tool to support benchmarking and quality improvement programs for patients with TBI in the future.
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25.
  • Huijben, Jilske A., et al. (författare)
  • Use and impact of high intensity treatments in patients with traumatic brain injury across Europe : a CENTER-TBI analysis
  • 2021
  • Ingår i: Critical Care. - : BioMed Central (BMC). - 1364-8535 .- 1466-609X. ; 25:1
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: To study variation in, and clinical impact of high Therapy Intensity Level (TIL) treatments for elevated intracranial pressure (ICP) in patients with traumatic brain injury (TBI) across European Intensive Care Units (ICUs).METHODS: We studied high TIL treatments (metabolic suppression, hypothermia (< 35 °C), intensive hyperventilation (PaCO2 < 4 kPa), and secondary decompressive craniectomy) in patients receiving ICP monitoring in the ICU stratum of the CENTER-TBI study. A random effect logistic regression model was used to determine between-centre variation in their use. A propensity score-matched model was used to study the impact on outcome (6-months Glasgow Outcome Score-extended (GOSE)), whilst adjusting for case-mix severity, signs of brain herniation on imaging, and ICP.RESULTS: 313 of 758 patients from 52 European centres (41%) received at least one high TIL treatment with significant variation between centres (median odds ratio = 2.26). Patients often transiently received high TIL therapies without escalation from lower tier treatments. 38% of patients with high TIL treatment had favourable outcomes (GOSE ≥ 5). The use of high TIL treatment was not significantly associated with worse outcome (285 matched pairs, OR 1.4, 95% CI [1.0-2.0]). However, a sensitivity analysis excluding high TIL treatments at day 1 or use of metabolic suppression at any day did reveal a statistically significant association with worse outcome.CONCLUSION: Substantial between-centre variation in use of high TIL treatments for TBI was found and treatment escalation to higher TIL treatments were often not preceded by more conventional lower TIL treatments. The significant association between high TIL treatments after day 1 and worse outcomes may reflect aggressive use or unmeasured confounders or inappropriate escalation strategies.TAKE HOME MESSAGE: Substantial variation was found in the use of highly intensive ICP-lowering treatments across European ICUs and a stepwise escalation strategy from lower to higher intensity level therapy is often lacking. Further research is necessary to study the impact of high therapy intensity treatments.TRIAL REGISTRATION: The core study was registered with ClinicalTrials.gov, number NCT02210221, registered 08/06/2014, https://clinicaltrials.gov/ct2/show/NCT02210221?id=NCT02210221&draw=1&rank=1 and with Resource Identification Portal (RRID: SCR_015582).
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26.
  • Huijben, Jilske A., et al. (författare)
  • Variation in general supportive and preventive intensive care management of traumatic brain injury : a survey in 66 neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study
  • 2018
  • Ingår i: Critical Care. - : Springer. - 1364-8535 .- 1466-609X. ; 22:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: General supportive and preventive measures in the intensive care management of traumatic brain injury (TBI) aim to prevent or limit secondary brain injury and optimize recovery. The aim of this survey was to assess and quantify variation in perceptions on intensive care unit (ICU) management of patients with TBI in European neurotrauma centers.METHODS: We performed a survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We analyzed 23 questions focused on: 1) circulatory and respiratory management; 2) fever control; 3) use of corticosteroids; 4) nutrition and glucose management; and 5) seizure prophylaxis and treatment.RESULTS: The survey was completed predominantly by intensivists (n = 33, 50%) and neurosurgeons (n = 23, 35%) from 66 centers (97% response rate). The most common cerebral perfusion pressure (CPP) target was > 60 mmHg (n = 39, 60%) and/or an individualized target (n = 25, 38%). To support CPP, crystalloid fluid loading (n = 60, 91%) was generally preferred over albumin (n = 15, 23%), and vasopressors (n = 63, 96%) over inotropes (n = 29, 44%). The most commonly reported target of partial pressure of carbon dioxide in arterial blood (PaCO2) was 36-40 mmHg (4.8-5.3 kPa) in case of controlled intracranial pressure (ICP) < 20 mmHg (n = 45, 69%) and PaCO2 target of 30-35 mmHg (4-4.7 kPa) in case of raised ICP (n = 40, 62%). Almost all respondents indicated to generally treat fever (n = 65, 98%) with paracetamol (n = 61, 92%) and/or external cooling (n = 49, 74%). Conventional glucose management (n = 43, 66%) was preferred over tight glycemic control (n = 18, 28%). More than half of the respondents indicated to aim for full caloric replacement within 7 days (n = 43, 66%) using enteral nutrition (n = 60, 92%). Indications for and duration of seizure prophylaxis varied, and levetiracetam was mostly reported as the agent of choice for both seizure prophylaxis (n = 32, 49%) and treatment (n = 40, 61%).CONCLUSIONS: Practice preferences vary substantially regarding general supportive and preventive measures in TBI patients at ICUs of European neurotrauma centers. These results provide an opportunity for future comparative effectiveness research, since a more evidence-based uniformity in good practices in general ICU management could have a major impact on TBI outcome.
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27.
  • Luo, Sizuo, et al. (författare)
  • Ultra-stable and versatile high-energy resolution setup for attosecond photoelectron spectroscopy
  • 2023
  • Ingår i: Advances in Physics: X. - 2374-6149. ; 8:1
  • Forskningsöversikt (refereegranskat)abstract
    • Attosecond photoelectron spectroscopy has opened up for studying light–matter interaction on ultrafast time scales. It is often performed with interferometric experimental setups that require outstanding stability. We demonstrate and characterize in detail an actively stabilized, versatile, high spectral resolution attosecond beamline based on a Mach-Zehnder interferometer. The active stabilization keeps the interferometer ultra-stable for several hours with an RMS stability of 13 as and a total pump-probe delay scanning range of (Formula presented.) fs. A tunable femtosecond laser source to drive high-order harmonic generation allows for precisely addressing atomic and molecular resonances. Furthermore, the interferometer includes a spectral shaper in 4f-geometry in the probe arm as well as a tunable bandpass filter in the pump arm, which offer additional high flexibility in terms of tunability as well as narrowband or polychromatic probe pulses. We demonstrate the capabilities of the beamline via experiments using several variants of the RABBIT (reconstruction of attosecond beating by two photon transitions) technique. In this setup, the temporal-spectral resolution of photoelectron spectroscopy can reach a new level of accuracy and precision.
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28.
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29.
  • Phillips, Helen R. P., et al. (författare)
  • Global distribution of earthworm diversity
  • 2019
  • Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 366:6464, s. 480-
  • Tidskriftsartikel (refereegranskat)abstract
    • Soil organisms, including earthworms, are a key component of terrestrial ecosystems. However, little is known about their diversity, their distribution, and the threats affecting them. We compiled a global dataset of sampled earthworm communities from 6928 sites in 57 countries as a basis for predicting patterns in earthworm diversity, abundance, and biomass. We found that local species richness and abundance typically peaked at higher latitudes, displaying patterns opposite to those observed in aboveground organisms. However, high species dissimilarity across tropical locations may cause diversity across the entirety of the tropics to be higher than elsewhere. Climate variables were found to be more important in shaping earthworm communities than soil properties or habitat cover. These findings suggest that climate change may have serious implications for earthworm communities and for the functions they provide.
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30.
  • Pop, Flavia, et al. (författare)
  • Hierarchical Self-Assembly of Supramolecular Helical Fibres from Amphiphilic C3-Symmetrical Functional Tris(tetrathiafulvalenes)
  • 2014
  • Ingår i: Chemistry - A European Journal. - : Wiley-VCH Verlag. - 0947-6539 .- 1521-3765. ; 20:52, s. 17443-17453
  • Tidskriftsartikel (refereegranskat)abstract
    • The preparation and self-assembly of the enantiomers of a series of C-3-symmetric compounds incorporating three tetrathiafulvalene (TTF) residues is reported. The chiral citronellyl and dihydrocitronellyl alkyl chains lead to helical one dimensional stacks in solution. Molecular mechanics and dynamics simulations combined with experimental and theoretical circular dichroism support the observed helicity in solution. These stacks self-assemble to give fibres that have morphologies that depend on the nature of the chiral alkyl group and the medium in which the compounds aggregate. An inversion of macroscopic helical morphology of the citronellyl compound is observed when compared to analogous 2-methylbutyl chains, which is presumably a result of the stereogenic centre being further away from the core of the molecule. This composition still allows both morphologies to be observed, whereas an achiral compound shows no helicity. The morphology of the fibres also depends on the flexibility at the chain ends of the amphiphilic components, as there is not such an apparently persistent helical morphology for the dihydrocitronellyl derivative as for that prepared from citronellyl chains.
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31.
  • Sharrack, Basil, et al. (författare)
  • Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases : updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)
  • 2020
  • Ingår i: Bone Marrow Transplantation. - : Springer Nature. - 0268-3369 .- 1476-5365. ; 55:2, s. 283-306
  • Tidskriftsartikel (refereegranskat)abstract
    • These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.
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32.
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33.
  • Verlaak, Stijn, et al. (författare)
  • Electronic Structure and Geminate Pair Energetics at Organic-Organic Interfaces: The Case of Pentacene/C-60 Heterojunctions
  • 2009
  • Ingår i: Advanced Functional Materials. - : Wiley. - 1616-301X .- 1616-3028. ; 19:23, s. 3809-3814
  • Tidskriftsartikel (refereegranskat)abstract
    • Organic semiconductors are characterized by localized states whose energies are predominantly determined by electrostatic interactions with their immediate molecular environment. As a result, the details of the energy landscape at heterojunctions between different organic semiconductors cannot simply be deduced from those of the individual semiconductors, and they have so far remained largely unexplored. Here, microelectrostatic computations are performed to clarify the nature of the electronic structure and geminate pair energetics at the pentacene/C-60 interface, as archetype for an interface between a donor molecule and a fullerene electron acceptor. The size and orientation of the molecular quadrupole moments, determined by material choice, crystal orientation, and thermodynamic growth parameters of the semiconductors, dominate the interface energetics. Not only do quadrupoles produce direct electrostatic interactions with charge carriers, but, in addition, the discontinuity of the quadrupole field at the interface induces permanent interface dipoles. That discontinuity is particularly striking for an interface with C-60 molecules, which by virtue of their symmetry possess no quadrupole. Consequently, at a pentacene/C-60 interface, both the vacuum-level shift and geminate pair dissociation critically depend on the orientation of the pentacene pi-system relative to the adjacent C-60.
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34.
  • Volovici, Victor, et al. (författare)
  • Comparative effectiveness of intracranial hypertension management guided by ventricular versus intraparenchymal pressure monitoring : a CENTER-TBI study
  • 2022
  • Ingår i: Acta Neurochirurgica. - : Springer. - 0001-6268 .- 0942-0940. ; 164:7, s. 1693-1705
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To compare outcomes between patients with primary external ventricular device (EVD)-driven treatment of intracranial hypertension and those with primary intraparenchymal monitor (IP)-driven treatment.METHODS: The CENTER-TBI study is a prospective, multicenter, longitudinal observational cohort study that enrolled patients of all TBI severities from 62 participating centers (mainly level I trauma centers) across Europe between 2015 and 2017. Functional outcome was assessed at 6 months and a year. We used multivariable adjusted instrumental variable (IV) analysis with "center" as instrument and logistic regression with covariate adjustment to determine the effect estimate of EVD on 6-month functional outcome.RESULTS: A total of 878 patients of all TBI severities with an indication for intracranial pressure (ICP) monitoring were included in the present study, of whom 739 (84%) patients had an IP monitor and 139 (16%) an EVD. Patients included were predominantly male (74% in the IP monitor and 76% in the EVD group), with a median age of 46 years in the IP group and 48 in the EVD group. Six-month GOS-E was similar between IP and EVD patients (adjusted odds ratio (aOR) and 95% confidence interval [CI] OR 0.74 and 95% CI [0.36-1.52], adjusted IV analysis). The length of intensive care unit stay was greater in the EVD group than in the IP group (adjusted rate ratio [95% CI] 1.70 [1.34-2.12], IV analysis). One hundred eighty-seven of the 739 patients in the IP group (25%) required an EVD due to refractory ICPs.CONCLUSION: We found no major differences in outcomes of patients with TBI when comparing EVD-guided and IP monitor-guided ICP management. In our cohort, a quarter of patients that initially received an IP monitor required an EVD later for ICP control. The prevalence of complications was higher in the EVD group.
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35.
  • Volovici, Victor, et al. (författare)
  • Variation in Guideline Implementation and Adherence Regarding Severe Traumatic Brain Injury Treatment : A CENTER-TBI Survey Study in Europe
  • 2019
  • Ingår i: World Neurosurgery. - : Elsevier. - 1878-8750 .- 1878-8769. ; 125, s. e515-e520
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Guidelines may reduce practice variation and optimize patient care. We aimed to study differences in guideline use in the management of traumatic brain injury (TBI) patients and analyze reasons for guideline non-adherence.METHODS: As part of a prospective, observational, multicenter European cohort study, participants from 68 centers in 20 countries were asked to complete 72-item questionnaires regarding their management of severe TBI. Six questions with multiple sub-questions focused on guideline use and implementation.RESULTS: Questionnaires were completed by 65 centers. Of these, 49 (75%) reported use of the Brain Trauma Foundation guidelines for the medical management of TBI or related institutional protocols, 11 (17%) used no guidelines, and 5 used other guidelines (8%). Of 54 centers reporting use of any guidelines, 41 (75%) relied on written guidelines. Four centers of the 54 (7%) reported no formal implementation efforts. Structural attention to the guidelines during daily clinical rounds was reported by 21 centers (38%). The most often reported reasons for non-adherence were "every patient is unique" and the presence of extracranial injuries, both for centers that did and did not report the use of guidelines.CONCLUSIONS: There is substantial variability in the use and implementation of guidelines in neurotrauma centers in Europe. Further research is needed to strengthen the evidence underlying guidelines and to overcome implementation barriers.
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36.
  • Wiegers, Eveline Janine Anna, et al. (författare)
  • Fluid balance and outcome in critically ill patients with traumatic brain injury (CENTER-TBI and OzENTER-TBI) : a prospective, multicentre, comparative effectiveness study
  • 2021
  • Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:8, s. 627-638
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Fluid therapy-the administration of fluids to maintain adequate organ tissue perfusion and oxygenation-is essential in patients admitted to the intensive care unit (ICU) with traumatic brain injury. We aimed to quantify the variability in fluid management policies in patients with traumatic brain injury and to study the effect of this variability on patients' outcomes.METHODS: We did a prospective, multicentre, comparative effectiveness study of two observational cohorts: CENTER-TBI in Europe and OzENTER-TBI in Australia. Patients from 55 hospitals in 18 countries, aged 16 years or older with traumatic brain injury requiring a head CT, and admitted to the ICU were included in this analysis. We extracted data on demographics, injury, and clinical and treatment characteristics, and calculated the mean daily fluid balance (difference between fluid input and loss) and mean daily fluid input during ICU stay per patient. We analysed the association of fluid balance and input with ICU mortality and functional outcome at 6 months, measured by the Glasgow Outcome Scale Extended (GOSE). Patient-level analyses relied on adjustment for key characteristics per patient, whereas centre-level analyses used the centre as the instrumental variable.FINDINGS: 2125 patients enrolled in CENTER-TBI and OzENTER-TBI between Dec 19, 2014, and Dec 17, 2017, were eligible for inclusion in this analysis. The median age was 50 years (IQR 31 to 66) and 1566 (74%) of patients were male. The median of the mean daily fluid input ranged from 1·48 L (IQR 1·12 to 2·09) to 4·23 L (3·78 to 4·94) across centres. The median of the mean daily fluid balance ranged from -0·85 L (IQR -1·51 to -0·49) to 1·13 L (0·99 to 1·37) across centres. In patient-level analyses, a mean positive daily fluid balance was associated with higher ICU mortality (odds ratio [OR] 1·10 [95% CI 1·07 to 1·12] per 0·1 L increase) and worse functional outcome (1·04 [1·02 to 1·05] per 0·1 L increase); higher mean daily fluid input was also associated with higher ICU mortality (1·05 [1·03 to 1·06] per 0·1 L increase) and worse functional outcome (1·04 [1·03 to 1·04] per 1-point decrease of the GOSE per 0·1 L increase). Centre-level analyses showed similar associations of higher fluid balance with ICU mortality (OR 1·17 [95% CI 1·05 to 1·29]) and worse functional outcome (1·07 [1·02 to 1·13]), but higher fluid input was not associated with ICU mortality (OR 0·95 [0·90 to 1·00]) or worse functional outcome (1·01 [0·98 to 1·03]).INTERPRETATION: In critically ill patients with traumatic brain injury, there is significant variability in fluid management, with more positive fluid balances being associated with worse outcomes. These results, when added to previous evidence, suggest that aiming for neutral fluid balances, indicating a state of normovolaemia, contributes to improved outcome.
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37.
  • Yang, Dazhi, et al. (författare)
  • Verification of deterministic solar forecasts
  • 2020
  • Ingår i: Solar Energy. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0038-092X .- 1471-1257. ; 210, s. 20-37
  • Tidskriftsartikel (refereegranskat)abstract
    • The field of energy forecasting has attracted many researchers from different fields (e.g., meteorology, data sciences, mechanical or electrical engineering) over the last decade. Solar forecasting is a fast-growing sub-domain of energy forecasting. Despite several previous attempts, the methods and measures used for verification of deterministic (also known as single-valued or point) solar forecasts are still far from being standardized, making forecast analysis and comparison difficult. To analyze and compare solar forecasts, the well-established Murphy-Winkler framework for distribution-oriented forecast verification is recommended as a standard practice. This framework examines aspects of forecast quality, such as reliability, resolution, association, or discrimination, and analyzes the joint distribution of forecasts and observations, which contains all time-independent information relevant to verification. To verify forecasts, one can use any graphical display or mathematical/statistical measure to provide insights and summarize the aspects of forecast quality. The majority of graphical methods and accuracy measures known to solar forecasters are specific methods under this general framework. Additionally, measuring the overall skillfulness of forecasters is also of general interest. The use of the root mean square error (RMSE) skill score based on the optimal convex combination of climatology and persistence methods is highly recommended. By standardizing the accuracy measure and reference forecasting method, the RMSE skill score allows-with appropriate caveats-comparison of forecasts made using different models, across different locations and time periods.
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38.
  • Young, Linda, et al. (författare)
  • Roadmap of ultrafast x-ray atomic and molecular physics
  • 2018
  • Ingår i: Journal of Physics B: Atomic, Molecular and Optical Physics. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 51:3
  • Forskningsöversikt (refereegranskat)abstract
    • X-ray free-electron lasers (XFELs) and table-top sources of x-rays based upon high harmonic generation (HHG) have revolutionized the field of ultrafast x-ray atomic and molecular physics, largely due to an explosive growth in capabilities in the past decade. XFELs now provide unprecedented intensity (1020 W cm-2) of x-rays at wavelengths down to ∼1 Ångstrom, and HHG provides unprecedented time resolution (∼50 attoseconds) and a correspondingly large coherent bandwidth at longer wavelengths. For context, timescales can be referenced to the Bohr orbital period in hydrogen atom of 150 attoseconds and the hydrogen-molecule vibrational period of 8 femtoseconds; wavelength scales can be referenced to the chemically significant carbon K-edge at a photon energy of ∼280 eV (44 Ångstroms) and the bond length in methane of ∼1 Ångstrom. With these modern x-ray sources one now has the ability to focus on individual atoms, even when embedded in a complex molecule, and view electronic and nuclear motion on their intrinsic scales (attoseconds and Ångstroms). These sources have enabled coherent diffractive imaging, where one can image non-crystalline objects in three dimensions on ultrafast timescales, potentially with atomic resolution. The unprecedented intensity available with XFELs has opened new fields of multiphoton and nonlinear x-ray physics where behavior of matter under extreme conditions can be explored. The unprecedented time resolution and pulse synchronization provided by HHG sources has kindled fundamental investigations of time delays in photoionization, charge migration in molecules, and dynamics near conical intersections that are foundational to AMO physics and chemistry. This roadmap coincides with the year when three new XFEL facilities, operating at Ångstrom wavelengths, opened for users (European XFEL, Swiss-FEL and PAL-FEL in Korea) almost doubling the present worldwide number of XFELs, and documents the remarkable progress in HHG capabilities since its discovery roughly 30 years ago, showcasing experiments in AMO physics and other applications. Here we capture the perspectives of 17 leading groups and organize the contributions into four categories: ultrafast molecular dynamics, multidimensional x-ray spectroscopies; high-intensity x-ray phenomena; attosecond x-ray science.
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39.
  • Zaidi, Syed H., et al. (författare)
  • Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival
  • 2020
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR=0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR=1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.
  •  
40.
  • Adrian-Martinez, S., et al. (författare)
  • The First Combined Search For Neutrino Point-Sources In The Southern Hemisphere With The Antares And Icecube Neutrino Telescopes
  • 2016
  • Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 823:1
  • Tidskriftsartikel (refereegranskat)abstract
    • We present the results of searches for point-like sources of neutrinos based on the first combined analysis of data from both the ANTARES and IceCube neutrino telescopes. The combination of both detectors, which differ in size and location, forms a window in the southern sky where the sensitivity to point sources improves by up to a factor of 2 compared with individual analyses. Using data recorded by ANTARES from 2007 to 2012, and by IceCube from 2008 to 2011, we search for sources of neutrino emission both across the southern sky and from a preselected list of candidate objects. No significant excess over background has been found in these searches, and flux upper limits for the candidate sources are presented for E-2.5 and E-2 power-law spectra with different energy cut-offs.
  •  
41.
  • Alce, Günter, et al. (författare)
  • D3.2 Interface design prototypes and/or mock ups
  • 2013
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • This document is deliverable D3.2 “Interface design prototypes and/or mock ups” and presents tools and prototypes to show new interface and interaction design.
  •  
42.
  • Alferez, Mauricio, et al. (författare)
  • Modeling variability in the video domain : language and experience report
  • 2019
  • Ingår i: Software quality journal. - : Springer. - 0963-9314 .- 1573-1367. ; 27:1, s. 307-347
  • Tidskriftsartikel (refereegranskat)abstract
    • In an industrial project, we addressed the challenge of developing a software-based video generator such that consumers and providers of video processing algorithms can benchmark them on a wide range of video variants. This article aims to report on our positive experience in modeling, controlling, and implementing software variability in the video domain. We describe how we have designed and developed a variability modeling language, called VM, resulting from the close collaboration with industrial partners during 2 years. We expose the specific requirements and advanced variability constructs; we developed and used to characterize and derive variations of video sequences. The results of our experiments and industrial experience show that our solution is effective to model complex variability information and supports the synthesis of hundreds of realistic video variants. From the software language perspective, we learned that basic variability mechanisms are useful but not enough; attributes and multi-features are of prior importance; meta-information and specific constructs are relevant for scalable and purposeful reasoning over variability models. From the video domain and software perspective, we report on the practical benefits of a variability approach. With more automation and control, practitioners can now envision benchmarking video algorithms over large, diverse, controlled, yet realistic datasets (videos that mimic real recorded videos)-something impossible at the beginning of the project.
  •  
43.
  • An, Lu, et al. (författare)
  • Bathymetry of Southeast Greenland From Oceans Melting Greenland (OMG) Data
  • 2019
  • Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 46:11, s. 197-205
  • Tidskriftsartikel (refereegranskat)abstract
    • Southeast Greenland has been a major participant in the ice sheet mass loss over the last several decades. Interpreting the evolution of glacier fronts requires information about their depth below sea level and ocean thermal forcing, which are incompletely known in the region. Here, we combine airborne gravity and multibeam echo sounding data from the National Aeronautics and Space Administration's Oceans Melting Greenland (OMG) mission with ocean probe and fishing boat depth data to reconstruct the bathymetry extending from the glacier margins to the edges of the continental shelf. We perform a three-dimensional inversion of the gravity data over water and merge the solution with a mass conservation reconstruction of bed topography over land. In contrast with other parts of Greenland, we find few deep troughs connecting the glaciers to the sources of warm Atlantic Water, amidst a relatively uniform, shallow (350 m) continental shelf. The deep channels include the Kangerlugssuaq, Sermilik, Gyldenlove, and Tingmiarmiut Troughs.
  •  
44.
  •  
45.
  • Baxter, Amanda L., et al. (författare)
  • Collaborative experience between scientific software projects using Agile Scrum development
  • 2022
  • Ingår i: Software, practice & experience. - : John Wiley & Sons. - 0038-0644 .- 1097-024X. ; 52:10, s. 2077-2096
  • Tidskriftsartikel (refereegranskat)abstract
    • Developing sustainable software for the scientific community requires expertise in software engineering and domain science. This can be challenging due to the unique needs of scientific software, the insufficient resources for software engineering practices in the scientific community, and the complexity of developing for evolving scientific contexts. While open-source software can partially address these concerns, it can introduce complicating dependencies and delay development. These issues can be reduced if scientists and software developers collaborate. We present a case study wherein scientists from the SuperNova Early Warning System collaborated with software developers from the Scalable Cyberinfrastructure for Multi-Messenger Astrophysics project. The collaboration addressed the difficulties of open-source software development, but presented additional risks to each team. For the scientists, there was a concern of relying on external systems and lacking control in the development process. For the developers, there was a risk in supporting a user-group while maintaining core development. These issues were mitigated by creating a second Agile Scrum framework in parallel with the developers' ongoing Agile Scrum process. This Agile collaboration promoted communication, ensured that the scientists had an active role in development, and allowed the developers to evaluate and implement the scientists' software requirements. The collaboration provided benefits for each group: the scientists actuated their development by using an existing platform, and the developers utilized the scientists' use-case to improve their systems. This case study suggests that scientists and software developers can avoid scientific computing issues by collaborating and that Agile Scrum methods can address emergent concerns.
  •  
46.
  • Bocchetta, Martina, et al. (författare)
  • The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey.
  • 2015
  • Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 11:2, s. 195-206
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
  •  
47.
  • Brochet, Mathieu, et al. (författare)
  • Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites
  • 2014
  • Ingår i: PLoS biology. - : Public Library of Science. - 1544-9173 .- 1545-7885. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Many critical events in the Plasmodium life cycle rely on the controlled release of Ca²⁺ from intracellular stores to activate stage-specific Ca²⁺-dependent protein kinases. Using the motility of Plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic guanosine monophosphate (cGMP)-dependent protein kinase, PKG, maintains the elevated level of cytosolic Ca²⁺ required for gliding motility. We find that the same PKG-dependent pathway operates upstream of the Ca²⁺ signals that mediate activation of P. berghei gametocytes in the mosquito and egress of Plasmodium falciparum merozoites from infected human erythrocytes. Perturbations of PKG signalling in gliding ookinetes have a marked impact on the phosphoproteome, with a significant enrichment of in vivo regulated sites in multiple pathways including vesicular trafficking and phosphoinositide metabolism. A global analysis of cellular phospholipids demonstrates that in gliding ookinetes PKG controls phosphoinositide biosynthesis, possibly through the subcellular localisation or activity of lipid kinases. Similarly, phosphoinositide metabolism links PKG to egress of P. falciparum merozoites, where inhibition of PKG blocks hydrolysis of phosphatidylinostitol (4,5)-bisphosphate. In the face of an increasing complexity of signalling through multiple Ca²⁺ effectors, PKG emerges as a unifying factor to control multiple cellular Ca²⁺ signals essential for malaria parasite development and transmission.
  •  
48.
  • Burke, Sinead M., et al. (författare)
  • An experimental and modeling study of propene oxidation. Part 2: Ignition delay time and flame speed measurements
  • 2015
  • Ingår i: Combustion and Flame. - : Elsevier BV. - 0010-2180. ; 162:2, s. 296-314
  • Tidskriftsartikel (refereegranskat)abstract
    • Experimental data obtained in this study (Part II) complement the speciation data presented in Part I, but also offer a basis for extensive facility cross-comparisons for both experimental ignition delay time (IDT) and laminar flame speed (LFS) observables. To improve our understanding of the ignition characteristics of propene, a series of IDT experiments were performed in six different shock tubes and two rapid compression machines (RCMs) under conditions not previously studied. This work is the first of its kind to directly compare ignition in several different shock tubes over a wide range of conditions. For common nominal reaction conditions among these facilities, cross-comparison of shock tube IDTs suggests 20-30% reproducibility (2 sigma) for the IDT observable. The combination of shock tube and RCM data greatly expands the data available for validation of propene oxidation models to higher pressures (2-40 atm) and lower temperatures (750-1750 K). Propene flames were studied at pressures from 1 to 20 atm and unburned gas temperatures of 295-398 K for a range of equivalence ratios and dilutions in different facilities. The present propene-air LFS results at 1 atm were also compared to LFS measurements from the literature. With respect to initial reaction conditions, the present experimental LFS cross-comparison is not as comprehensive as the IDT comparison; however, it still suggests reproducibility limits for the LFS observable. For the LFS results, there was agreement between certain data sets and for certain equivalence ratios (mostly in the lean region), but the remaining discrepancies highlight the need to reduce uncertainties in laminar flame speed experiments amongst different groups and different methods. Moreover, this is the first study to investigate the burning rate characteristics of propene at elevated pressures (>5 atm). IDT and LFS measurements are compared to predictions of the chemical kinetic mechanism presented in Part I and good agreement is observed. (C) 2014 The Combustion Institute. Published by Elsevier Inc. All rights reserved.
  •  
49.
  • Busto, David, et al. (författare)
  • Fano's Propensity Rule in Angle-Resolved Attosecond Pump-Probe Photoionization
  • 2019
  • Ingår i: Physical Review Letters. - : AMER PHYSICAL SOC. - 0031-9007 .- 1079-7114. ; 123:13
  • Tidskriftsartikel (refereegranskat)abstract
    • In a seminal article, Fano predicts that absorption of light occurs preferably with increase of angular momentum. We generalize Fano's propensity rule to laser-assisted photoionization, consisting of absorption of an extreme-ultraviolet photon followed by absorption or emission of an infrared photon. The predicted asymmetry between absorption and emission leads to incomplete quantum interference in attosecond photoelectron interferometry. It explains both the angular dependence of the photoionization time delays and the delay dependence of the photoelectron angular distributions. Our theory is verified by experimental results in Ar in the 20-40 eV range.
  •  
50.
  • Busto, David, et al. (författare)
  • Probing electronic decoherence with high-resolution attosecond photoelectron interferometry
  • 2022
  • Ingår i: European Physical Journal D. - : Springer Science and Business Media LLC. - 1434-6060 .- 1434-6079. ; 76:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract: Quantum coherence plays a fundamental role in the study and control of ultrafast dynamics in matter. In the case of photoionization, entanglement of the photoelectron with the ion is a well-known source of decoherence when only one of the particles is measured. Here, we investigate decoherence due to entanglement of the radial and angular degrees of freedom of the photoelectron. We study two-photon ionization via the 2s2p autoionizing state in He using high spectral resolution photoelectron interferometry. Combining experiment and theory, we show that the strong dipole coupling of the 2s2p and 2p2 states results in the entanglement of the angular and radial degrees of freedom. This translates, in angle-integrated measurements, into a dynamic loss of coherence during autoionization. Graphic Abstract: [Figure not available: see fulltext.]. © 2022, The Author(s).
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