| 1. |
- Abbott, Benjamin W., et al.
(author)
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Biomass offsets little or none of permafrost carbon release from soils, streams, and wildfire : an expert assessment
- 2016
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In: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 11:3
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Journal article (peer-reviewed)abstract
- As the permafrost region warms, its large organic carbon pool will be increasingly vulnerable to decomposition, combustion, and hydrologic export. Models predict that some portion of this release will be offset by increased production of Arctic and boreal biomass; however, the lack of robust estimates of net carbon balance increases the risk of further overshooting international emissions targets. Precise empirical or model-based assessments of the critical factors driving carbon balance are unlikely in the near future, so to address this gap, we present estimates from 98 permafrost-region experts of the response of biomass, wildfire, and hydrologic carbon flux to climate change. Results suggest that contrary to model projections, total permafrost-region biomass could decrease due to water stress and disturbance, factors that are not adequately incorporated in current models. Assessments indicate that end-of-the-century organic carbon release from Arctic rivers and collapsing coastlines could increase by 75% while carbon loss via burning could increase four-fold. Experts identified water balance, shifts in vegetation community, and permafrost degradation as the key sources of uncertainty in predicting future system response. In combination with previous findings, results suggest the permafrost region will become a carbon source to the atmosphere by 2100 regardless of warming scenario but that 65%-85% of permafrost carbon release can still be avoided if human emissions are actively reduced.
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| 2. |
- Ahn, Jae Eun, et al.
(author)
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Likelihood based approaches to handling data below the quantification limit using NONMEM VI
- 2008
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In: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 35:4, s. 401-421
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Journal article (peer-reviewed)abstract
- PURPOSE: To evaluate the likelihood-based methods for handling data below the quantification limit (BQL) using new features in NONMEM VI. METHODS: A two-compartment pharmacokinetic model with first-order absorption was chosen for investigation. Methods evaluated were: discarding BQL observations (M1), discarding BQL observations but adjusting the likelihood for the remaining data (M2), maximizing the likelihood for the data above the limit of quantification (LOQ) and treating BQL data as censored (M3), and like M3 but conditioning on the observation being greater than zero (M4). These four methods were compared using data simulated with a proportional error model. M2, M3, and M4 were also compared using data simulated from a positively truncated normal distribution. Successful terminations and bias and precision of parameter estimates were assessed. RESULTS: For the data simulated with a proportional error model, the overall performance was best for M3 followed by M2 and M1. M3 and M4 resulted in similar estimates in analyses without log transformation. For data simulated with the truncated normal distribution, M4 performed better than M3. CONCLUSIONS: Analyses that maximized the likelihood of the data above the LOQ and treated BQL data as censored provided the most accurate and precise parameter estimates.
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| 3. |
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| 4. |
- Baptista, Marisa A. P., et al.
(author)
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Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells
- 2016
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Journal article (peer-reviewed)abstract
- Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8(+) T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFN gamma-producing CD8(+) T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8(+) T cells at the expense of CD4(+) T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8(+) T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells.
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| 5. |
- Bayati, Zahra, 1958, et al.
(author)
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Nytt centrum mot rasism får fel vetenskaplig inriktning
- 2015
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In: Göteborgs Posten. - 1103-9345. ; :2015-06-14
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Journal article (pop. science, debate, etc.)abstract
- När rasism ska förstås som något som kan lösas genom att lära ut tolerans undergrävs förtroendet för regeringens satsning. Dessutom saknas det etnisk/rasifierad mångfald bland forskargruppen.
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| 6. |
- Dwibedi, Chinmay Kumar, et al.
(author)
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Long-range dispersal moved Francisella tularensis into Western Europe from the East
- 2016
-
In: Microbial Genomics. - : Microbiology Society. - 2057-5858. ; 2:12
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Journal article (peer-reviewed)abstract
- For many infections transmitting to humans from reservoirs in nature, disease dispersal patterns over space and time are largely unknown. Here, a reversed genomics approach helped us understand disease dispersal and yielded insight into evolution and biological properties of Francisella tularensis, the bacterium causing tularemia. We whole-genome sequenced 67 strains and characterized by single-nucleotide polymorphism assays 138 strains, collected from individuals infected 1947-2012 across Western Europe. We used the data for phylogenetic, population genetic and geographical network analyses. All strains (n= 205) belonged to a monophyletic population of recent ancestry not found outside Western Europe. Most strains (n= 195) throughout the study area were assigned to a star-like phylogenetic pattern indicating that colonization of Western Europe occurred via clonal expansion. In the East of the study area, strains were more diverse, consistent with a founder population spreading from east to west. The relationship of genetic and geographic distance within the F. tularensis population was complex and indicated multiple long-distance dispersal events. Mutation rate estimates based on year of isolation indicated null rates; in outbreak hotspots only, there was a rate of 0.4 mutations/genome/year. Patterns of nucleotide substitution showed marked AT mutational bias suggestive of genetic drift. These results demonstrate that tularemia has moved from east to west in Europe and that F. tularensis has a biology characterized by long-range geographical dispersal events and mostly slow, but variable, replication rates. The results indicate that mutation-driven evolution, a resting survival phase, genetic drift and long-distance geographical dispersal events have interacted to generate genetic diversity within this species.
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| 7. |
- Ekman, Petter, 1988-
(author)
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Important Factors for Accurate Scale-Resolving Simulations of Automotive Aerodynamics
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Road transports are responsible for almost 18 % of the greenhouse gas emission in Europe and are today the leading cause of air pollution in cities. Aerodynamic resistance has a significant effect on fuel consumption and hence the emission of vehicles. For electric vehicles, emissions are not affected by the aerodynamics as such but instead have a significant effect on the effective range of the vehicle.In 2017, a new measurement procedure was introduced, Worldwide Harmonized Light Vehicles Test Procedure (WLTP), for measuring emissions, fuel consumption, and range. This procedure includes a new test cycle with increased average driving speed compared to the former procedure, which thereby increases the importance of the aerodynamic resistance, as it drastically increases with speed. A second effect is that the exact car configuration sold to the customer needs to be certified in terms of fuel consumption and emissions. The result is that every possible combination of optional extras, which might affect the aerodynamic resistance, needs to be aerodynamically analyzed and possibly improved. From 2021, the European Commission will introduce stricter emission regulations for new passenger cars, with the fleet-wide average lowered to 95 grams CO2=km, which puts an even higher demand on achieving efficient aerodynamics.Virtual development of the aerodynamics of road vehicles is today used to a great extent, using Computational Fluid Dynamics, as it enables faster and cheaper development. However, achieving high accuracy for the prediction of the flow field and aerodynamic forces is challenging, especially given the complexity of both the vehicle geometry in itself and the surrounding flow field. Even for a simplified generic bluff body, accurately predicting the flow field and aerodynamic forces is a challenge. The main reason for this challenge of achieving results with high accuracy is the prediction of the complex behavior of turbulence. Scale-resolving simulation (SRS) methods, such as Large Eddy Simulation (LES), where most of the turbulent structures are resolved has in many studies shown high accuracy but unfortunately to a very high computational cost. It is primarily the small turbulent structures within the near-wall region that requires a _ne resolution in both space (the mesh) and in time. This fine resolution is the reason for the very high computational cost and makes LES unfeasible for practical use in industrial aerodynamic development at present and in the near future. By modeling the turbulent structures within the near-wall region using a Reynolds-Averaged Navier-Stokes (RANS) model, and resolving the turbulence outside the region with a LES model, a coarser resolution is possible to use, resulting in significantly lower computational cost. Which used RANS model is of high importance, and especially how much turbulent viscosity the model generates, as too high values can result in suppression of the resolved turbulence.The transitioning between the RANS and LES regions have a significant effect on the results. Faster transition enables more resolved turbulence, favorable for higher accuracy, but needs to be balanced with sufficient shielding of the RANS region. If resolving the turbulence occurs within the near-wall region, and the mesh is not sufficiently fine, it can result in poor accuracy.By increasing the time-step size and disregarding best-practice guides, the computational cost can be significantly reduced. The accuracy is reasonably insensitive to the larger time step sizes until a certain degree, thereby enabling computationally cheaper SRS to achieve high accuracy of aerodynamic predictions needed to meet present and future emission regulations.
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| 8. |
- Granstam, Elisabet, et al.
(author)
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Reduced occurrence of severe visual impairment after introduction of anti-Vascular Endothelial Growth Factor in wet age-related macular degeneration : a population- and register-based study from northern Sweden
- 2016
-
In: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 94:7, s. 646-651
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Journal article (peer-reviewed)abstract
- PurposeTo study the occurrence of severe visual impairment (SVI) and treatment outcome at 12months in patients treated for wet age-related macular degeneration (AMD) by use of data from the Swedish Macula Register (SMR) and referrals to the regional low vision clinics in five northern counties. MethodsReferrals to low vision clinics during 2005, 2009 and 2013 and treatment outcome at 12months from the SMR database from 2008 until 2013 in patients >65years of age in five northern counties were included in the survey. ResultsThe rate of referral due to AMD was significantly reduced during the time period (-48%; p<0.001). At 12months, a significant slight mean improvement in logMAR visual acuity (VA) was observed (-0.01, SD 0.37; p<0.001) after a mean of 5.02.3 anti-vascular endothelial growth factor (VEGF)-injections were administered. Age and low baseline VA was associated with less favourable visual outcome (p<0.001). ConclusionReferral rate to low vision clinic is a valuable tool for estimating occurrence of SVI and fell between the years 2005 until 2013. Data from the SMR showed improvement in visual acuity on the whole, but also identified patients at high risk for developing SVI during anti-VEGF-treatment.
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| 9. |
- Hiltonen, Thomas, et al.
(author)
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A cDNA coding for glutathione S-transferase from the unicellular green algae Coccomyxa sp
- 1996
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In: Gene. - 0378-1119 .- 1879-0038. ; 176:1-2, s. 263-264
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Journal article (peer-reviewed)abstract
- A cDNA coding for glutathione S-transferase (GST) was cloned and sequenced from the unicellular green algae Coccomyxa sp. The predicted 215 amino acid polypeptide (23.9 kDa, pI 5.3) is most similar to the theta-type GSTs found in a variety of different eukaryotic organisms. Within this sub-class, the Coccomyxa GST is 42% identical (63% similar) to the flatfish Pleuronectes platessa homologue, and 24 to 35% (49-57%) to other theta-type GST's.
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| 10. |
- Karlsson, Adrian, et al.
(author)
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Extended treatment in cerebral ischemia score 2c or 3 as goal of successful endovascular treatment is associated with clinical benefit.
- 2024
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In: Journal of neuroradiology = Journal de neuroradiologie. - 0150-9861. ; 51:2, s. 190-195
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Journal article (peer-reviewed)abstract
- Successful reperfusion, defined as a modified treatment in cerebral ischemia (mTICI) score 2b or 3, is an important goal for endovascular treatment (EVT) of stroke. Recently, an extension of the mTICI score with an additional grade 2c indicating near-complete reperfusion (expanded TICI, eTICI) and a revised definition of success as eTICI 2c or 3 were proposed. We evaluate whether eTICI 2c translates into improved clinical outcome compared to eTICI 2b.Consecutive patients with large vessel occlusion in the anterior circulation who underwent EVT between December 2013 and December 2020 were included. Clinical outcome measures were favorable functional outcome at 90 days (modified Rankin Scale [mRS] scores 0 to 2 or return to pre-stroke mRS) and early neurological improvement (National Institutes of Health Stroke Scale [NIHSS] improvement ≥4 points or a score of 0-1 at 24h).Of 1282 included patients (median age 76, median NIHSS 16), reperfusion was classified as eTICI 2b in 410 (32%), eTICI 2c in 242 (19%) and eTICI 3 in 464 (36%). eTICI 2c differed significally from 2b with respect to early neurological improvement (aOR=1.49, 95% CI=1.01-2.19). No statistically significant difference in favorable functional outcome at 90 days was found (eTICI 2c vs 2b, aOR=1.31, 95% CI=0.88-2.00).Our study indicates early clinical benefit at 24h of achieving eTICI 2c compared to eTICI 2b, but no significant difference was seen in favorable functional outcome at 90 days. Our results support eTICI 2c and 3 as the goal of a successful thrombectomy but do not exclude eTICI 2b as an acceptable result.
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| 11. |
- Karlsson, Anders, et al.
(author)
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Numerical scattering simulations for estimating soot aggregate morphology from nephelometer scattering measurements
- 2022
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In: Journal of Aerosol Science. - : Elsevier BV. - 0021-8502. ; 159
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Journal article (peer-reviewed)abstract
- Nephelometers are regularly used for air quality monitoring through scattering measurements of aerosols in the atmosphere. Less attention has been paid to the potential of estimating soot morphological parameters from nephelometer measurements in combination with scattering theory. In this work, we perform a fundamental laboratory study where an Ecotech Aurora 3000 nephelometer is used for measuring the scattering properties of soot with different characteristics. The nephelometer monitors the forward and backward scattering at three wavelengths (450 nm, 525 nm, and 635 nm) to retrieve information on the ratio of forward and backward scattering intensities, as well as the scattering wavelength dependence. An inverse scattering method, based on the Rayleigh–Debye–Gans theory, for determination of the equivalent fractal dimension (Df) and radius of gyration (Rg) of soot particles from the experimental scattering data was developed. It is shown that the inverse method can estimate Rg and Df when Rg<185nm and from the wavelength dependence, information on the relative amount of organic soot could be obtained. For validation, estimated parameters are compared with the morphological parameters of soot sampled from the mini-CAST soot generator and evaluated using transmission electron microscopy (TEM). Uncertainties and limitations of the procedure are discussed.
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| 12. |
- Karlsson, Edvin, et al.
(author)
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Clonality of erythromycin resistance in Francisella tularensis
- 2016
-
In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 71:10, s. 2815-2823
-
Journal article (peer-reviewed)abstract
- Objectives: We analysed diverse strains of Francisella tularensis subsp. holarctica to assess if its division into biovars I and II is associated with specific mutations previously linked to erythromycin resistance and to determine the distribution of this resistance trait across this subspecies. Methods:Three-hundred and fourteen F. tularensis subsp. holarctica strains were tested for erythromycin susceptibility and whole-genome sequences for these strains were examined for SNPs in genes previously associated with erythromycin resistance. Each strain was assigned to a global phylogenetic framework using genome-wide canonical SNPs. The contribution of a specific SNP to erythromycin resistance was examined using allelic exchange. The geographical distribution of erythromycin-resistant F. tularensis strains was further investigated by literature search. Results:There was a perfect correlation between biovar II strains (erythromycin resistance) and the phylogenetic group B.12. Only B.12 strains had an AaEuroS -> aEuroSC SNP at position 2059 in the three copies of the rrl gene. Introducing 2059C into an rrl gene of an erythromycin-susceptible F. tularensis strain resulted in resistance. An additional 1144 erythromycin-resistant strains were identified from the scientific literature, all of them from Eurasia. Conclusions:Erythromycin resistance in F. tularensis is caused by an A2059C rrl gene mutation, which exhibits a strictly clonal inheritance pattern found only in phylogenetic group B.12. This group is an extremely successful clone, representing the most common type of F. tularensis throughout Eurasia.
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| 13. |
- Karlsson, Jan, 1966-, et al.
(author)
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A novel α-type carbonic anhydrase associated with the thylakoid membrane in Chlamydomonas reinhardtii is required for growth at ambient CO2
- 1998
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In: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 17:5, s. 1208-1216
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Journal article (peer-reviewed)abstract
- A 29.5 kDa intracellular α-type carbonic anhydrase, designated Cah3, from the unicellular green alga Chlamydomonas reinhardtii is the first of this type discovered inside a photosynthetic eukaryote cell. We describe the cloning of a cDNA which encodes the protein. Immunoblot studies with specific antibodies raised against Cah3 demonstrate that the polypeptide is associated exclusively with the thylakoid membrane. The putative transit peptide suggests that Cah3 is directed to the thylakoid lumen, which is confirmed further by the presence of mature sized Cah3 after thermolysin treatment of intact thylakoids. Complementation of the high inorganic carbon concentration-requiring mutant, cia-3, with a subcloned cosmid containing the cah3 gene yielded transformants that grew on atmospheric levels of CO2 (0.035%) and contained an active 29.5 kDa alpha-type carbonic anhydrase. Although, cia-3 has reduced internal carbonic anhydrase activity, unexpectedly the level of Cah3 was similar to that of the wild-type, suggesting that the mutant accumulates an inactive Cah3 polypeptide. Genomic sequence analysis of the mutant revealed two amino acid changes in the transit peptide. Results from photosynthesis and chlorophyll a fluorescence parameter measurements show that the cia-3 mutant is photosynthetically impaired. Our results indicate that the carbonic anhydrase, extrinsically located within the chloroplast thylakoid lumen, is essential for growth of C.reinhardtii at ambient levels of CO2, and that at these CO2 concentrations the enzyme is required for optimal photosystem II photochemistry.
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| 14. |
- Karlsson, Lars O, 1975, et al.
(author)
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Opioid receptor agonist Eribis peptide 94 reduces infarct size in different porcine models for myocardial ischaemia and reperfusion
- 2011
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In: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 651:1-3, s. 146-151
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Journal article (peer-reviewed)abstract
- Eribis peptide 94 (EP 94) is a novel enkephalin analog, thought to interact with the and delta-opioid receptors. The purpose of the present study was to examine the cardioprotective potential of EP 94 in two clinically relevant porcine models of myocardial ischaemia and reperfusion, and to investigate if such an effect is associated with an increased expression of endothelial nitric oxide synthase (eNOS). Forty-one anesthetized pigs underwent 40 min of coronary occlusion followed by 4 h of reperfusion. In Protocol I, balloon occlusion of the left anterior descending artery was performed with concurrent intravenous administration of (A) vehicle (n = 7), (B) EP 94 (1 ug/kg) after 5, 12, 19 and 26 min of ischaemia (n = 4) or (C) EP 94 (1 ug/kg) after 26, 33, 40 min of ischaemia (n = 6). In Protocol II, open-chest pigs were administered (D) vehicle (n = 6) or (E) 0.2 ug/kg/min of EP 94 (n = 6) through an intracoronary infusion into the jeopardized myocardium, started after 30 min of ischaemia and maintained for 15 min. The hearts were stained and the protein content of eNOS measured. EP 94 reduces infarct size when administered both early and late during ischaemia compared with vehicle (infarct size group A 61.6 +/- 2%, group B 50.2 +/- 3% and group C 49.2 +/- 2%, respectively, P < 0.05), as well as when infused intracoronary (infarct size group D 82.2 +/- 3.9% and group E 61.2 +/- 2.5% respectively, P < 0.01). Phosphorylated eNOS Ser(I177) in relation to total eNOS was significantly increased in the group administered EP 94. indicating activation of nitric oxide production.
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| 15. |
- Karlsson, Max, et al.
(author)
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Phenotypic and genotypic adaptations in a riverine green alga (Chlorophyceae, Selenastraceae) as a response to long-term exposure to chemical stress
- 2019
-
In: SETAC Helsinki - SETAC Europe 29th Annual Meeting, 26 - 30 May 2019, Helsinki, Finland.
-
Conference paper (other academic/artistic)abstract
- Herbicide pollution is a common problem in agricultural streams due to their extensive use and their unwanted effects on non-target species inhabiting these systems. Selanastraceae is a family of green algae that are particularly dominant in freshwater, making them a key component in the base of the food chain and an important part of the oxygen production. Therefore, it is crucial from a conservation point of view to accurately monitor the ecotoxicological impact of herbicides on this group of algae, not only on a short-term scale (e.g. days or weeks), but also in a long-term perspective (e.g. months and years). In this work, phenotypic and genotypic differences are studied between different strains of a population of Kirchneriella (Chlorophyceae, Selenastraceae) isolated from a stream polluted by herbicides over a 20-year period (Skivarpsån, SE Sweden). According to mixture toxicity modelling performed on data obtained from the Swedish pesticide monitoring program, the main drivers of algal toxicity in this river are the herbicides diflufenican (carotenoid synthesis inhibitor) and isoproturon (PSII inhibitor). Three strains of the isolated algae are examined in this study: two strains from the field that have been exposed to different levels of herbicides and one laboratory strain that has never been exposed to herbicide pollution. The taxonomy of this algae is investigated by light microscopy and DNA barcoding analyses (chloroplast 23S rRNA gene). Phenotypic differences between the strains are examined as impacts on growth rate, cell size, photosynthetic activity (chl fluorescence measurements), pigment content and sensitivity to the specific herbicides mentioned earlier (EC50s). Genotypic differences are studied as single nucleotide polymorphisms thought to be induced through exposure to diflufenican and isoproturon on pds and psbA genes via PCR amplification, cloning and sequencing. The results obtained from this project will contribute to a better understanding of genetic and phenotypic adaptations in green algae as a response to herbicide pollution (evolutionary toxicology) and their implications for ecological functions.
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| 16. |
- Kenworthy, Matthew A., et al.
(author)
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High contrast imaging for the enhanced resolution imager and spectrometer (ERIS)
- 2018
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In: GROUND-BASED AND AIRBORNE INSTRUMENTATION FOR ASTRONOMY VII. - : SPIE-INT SOC OPTICAL ENGINEERING. - 9781510619586
-
Conference paper (peer-reviewed)abstract
- ERIS is a diffraction limited thermal infrared imager and spectrograph for the Very Large Telescope UT4. One of the science cases for ERIS is the detection and characterization of circumstellar structures and exoplanets around bright stars that are typically much fainter than the stellar diffraction halo. Enhanced sensitivity is provided through the combination of (i) suppression of the diffraction halo of the target star using coronagraphs, and (ii) removal of any residual diffraction structure through focal plane wavefront sensing and subsequent active correction. In this paper we present the two coronagraphs used for diffraction suppression and enabling high contrast imaging in ERIS.
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| 17. |
- Lärkeryd, Adrian, et al.
(author)
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CanSNPer : a hierarchical genotype classifier of clonal pathogens
- 2014
-
In: Bioinformatics. - : Oxford University Press. - 1367-4803 .- 1367-4811. ; 30:12, s. 1762-1764
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Journal article (peer-reviewed)abstract
- Advances in typing methodologies have recently reformed the field of molecular epidemiology of pathogens. The falling cost of sequencing technologies is creating a deluge of whole genome sequencing data that burdens bioinformatics resources and tool development. In particular, single nucleotide polymorphisms in core genomes of pathogens are recognized as the most important markers for inferring genetic relationships because they are evolutionarily stable and amenable to high-throughput detection methods. Sequence data will provide an excellent opportunity to extend our understanding of infectious disease when the challenge of extracting knowledge from available sequence resources is met. Here, we present an efficient and user-friendly genotype classification pipeline, CanSNPer, based on an easily expandable database of predefined canonical single nucleotide polymorphisms.
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| 18. |
- Marriott, Ross J., et al.
(author)
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Factors Associated With Circulating Sex Hormones in Men
- 2023
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In: Annals of Internal Medicine. - 0003-4819. ; 176:9, s. 1221-1234
-
Research review (peer-reviewed)abstract
- Background: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. Purpose: To clarify factors associated with variations in sex hormone concentrations. Data Sources: Systematic literature searches (to July 2019). Study Selection: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. Data Extraction: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. Data Synthesis: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone–binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. Limitation: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. Conclusion: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.
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| 19. |
- Marriott, Ross J, et al.
(author)
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Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.
- 2023
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In: Annals of internal medicine. - 1539-3704. ; 176:9, s. 1221-1234
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Research review (peer-reviewed)abstract
- Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements.To clarify factors associated with variations in sex hormone concentrations.Systematic literature searches (to July 2019).Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry.Individual participant data (IPD) (9 studies; n= 21074) and aggregate data (2 studies; n= 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted.Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years.Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data.Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).
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| 20. |
- Michelsen, Brigitte, et al.
(author)
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Differences and similarities between the EULAR/ASAS-EULAR and national recommendations for treatment of patients with psoriatic arthritis and axial spondyloarthritis across Europe
- 2023
-
In: The Lancet Regional Health - Europe. - 2666-7762. ; 33
-
Research review (peer-reviewed)abstract
- This is the first report comparing EULAR and national treatment recommendations for PsA patients across Europe, and the first this decade to compare ASAS-EULAR and national treatment recommendations in axSpA patients. An electronic survey was completed from October 2021–April 2022 by rheumatologists in 15 European countries. One and four countries followed all EULAR and ASAS-EULAR recommendations, respectively. Five countries had no national treatment recommendations for PsA and/or axSpA, but followed other regulations. In several countries, national treatment recommendations predated the most recent EULAR/ASAS-EULAR recommendations. Entry criteria for starting biologic/targeted synthetic disease-modifying anti-rheumatic drugs varied considerably. In several countries, for PsA patients with significant skin involvement, interleukin-17 inhibitors were not given preference. The positioning of Janus Kinase inhibitors differed and Phosphodiesterase-4 inhibitors were not in use/reimbursed in most countries. This study may motivate European countries to update their national treatment recommendations, to align them better with the latest international recommendations.
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| 21. |
- Paternoster, Lavinia, et al.
(author)
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Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.
- 2013
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In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 9:2
-
Journal article (peer-reviewed)abstract
- Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n=5,878) followed by replication (n=1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p=3.6×10⁻¹⁴; LOC285735, rs271170, p=2.7×10⁻¹²; OPG, rs7839059, p=1.2×10⁻¹⁰; and ESR1/C6orf97, rs6909279, p=1.1×10⁻⁹). The trabecular vBMD GWA meta-analysis (n=2,500) followed by replication (n=1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p=1.9×10⁻⁹). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n=729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
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| 22. |
- Paternoster, Lavinia, et al.
(author)
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Genome-Wide Association Meta-Analysis of Cortical Bone Mineral Density Unravels Allelic Heterogeneity at the RANKL Locus and Potential Pleiotropic Effects on Bone
- 2010
-
In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 6:11, s. e1001217-
-
Journal article (peer-reviewed)abstract
- Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMDC) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMDC, as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density. After initial GWA meta-analysis of two cohorts (ALSPAC n = 999, aged similar to 15 years and GOOD n = 935, aged similar to 19 years), we attempted to replicate the BMDC associations that had p<1 x 10(-5) in an independent sample of ALSPAC children (n = 2803) and in a cohort of elderly men (MrOS Sweden, n = 1052). The rs1021188 SNP (near RANKL) was associated with BMDC in all cohorts (overall p = 2 x 10(-14), n = 5739). Each minor allele was associated with a decrease in BMDC of similar to 0.14SD. There was also evidence for an interaction between this variant and sex (p = 0.01), with a stronger effect in males than females (at age 15, males -6.77mg/cm(3) per C allele, p = 2 x 10(-6); females -2.79 mg/cm(3) per C allele, p = 0.004). Furthermore, in a preliminary analysis, the rs1021188 minor C allele was associated with higher circulating levels of sRANKL (p<0.005). We show this variant to be independent from the previously aBMD associated SNP (rs9594738) and possibly from a third variant in the same RANKL region, which demonstrates important allelic heterogeneity at this locus. Associations with skeletal parameters reflecting bone dimensions were either not found or were much less pronounced. This finding implicates RANKL as a locus containing variation associated with volumetric bone density and provides further insight into the mechanism by which the RANK/RANKL/OPG pathway may be involved in skeletal development.
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| 23. |
- Pöppelwerth, Adrian, et al.
(author)
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Scale size estimation and flow pattern recognition around a magnetosheath jet
- 2024
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In: Annales Geophysicae. - : Copernicus GmbH. - 0992-7689 .- 1432-0576. ; 42:1, s. 271-284
-
Journal article (peer-reviewed)abstract
- Transient enhancements in the dynamic pressure, so-called magnetosheath jets or simply jets, are abundantly found in the magnetosheath. They travel from the bow shock through the magnetosheath towards the magnetopause. On their way through the magnetosheath, jets disturb the ambient plasma. Multiple studies already investigated their scale size perpendicular to their propagation direction, and almost exclusively in a statistical manner. In this paper, we use multi-point measurements from the Time History of Events and Macroscale Interactions during Substorms (THEMIS) mission to study the passage of a single jet. The method described here allows us to estimate the spatial distribution of the dynamic pressure within the jet. Furthermore, the size perpendicular to the propagation direction can be estimated for different cross sections. In the jet event investigated here, both the dynamic pressure and the perpendicular size increase along the propagation axis from the front part towards the center of the jet and decrease again towards the rear part, but neither monotonically nor symmetrically. We obtain a maximum diameter in the perpendicular direction of about 1 RE and a dynamic pressure of about 6 nPa at the jet center.
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| 24. |
- Qazi, S. Junaid S., et al.
(author)
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Dispersions of plate-like colloidal particles : Cubatic order?
- 2010
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In: Journal of Colloid and Interface Science. - : Elsevier BV. - 0021-9797 .- 1095-7103. ; 348:1, s. 80-84
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Journal article (peer-reviewed)abstract
- Experimental evidence for the existence of 'cubatic' order in a colloidal dispersion of plate-like particles is presented. In a 'cubatic' phase, disk-like particles self-assemble with domains of a few parallel plates and the director tends to be orthogonal in adjacent domains. This phase has been predicted previously by computer simulation. The domains are approximately equiaxial and are predicted to exist only within a limited range of aspect ratios and volume fractions. This locally ordered structure cannot be identified readily using scattering techniques, since the patterns are expected to be similar to those of isotropic liquid phases. For this reason, we have used a real-space technique of cryo-transmission electron microscopy that directly probes such locally ordered structures to study dispersions of nickel hydroxide particles. Polydispersity of particle size is expected to require some local tilting in order to include larger particles in a dense structure and this is discussed with respect to the concentration range for which cubatic order is observed. This new structure offers the possibility of novel materials that could be prepared by self-assembly and have applications in a wide range of fields.
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| 25. |
- Qazi, S. Junaid S., et al.
(author)
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Self-Assembled Structures of Disc-Like Colloidal Particles
- 2011
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In: Trends in colloid andinterface science XXIV. - Berlin, Heidelberg : Springer. - 9783642190377 ; , s. 61-65
-
Conference paper (peer-reviewed)abstract
- Self-assembly is an important phenomenon that leads to formation of interesting and novel structures in colloidal dispersions. We present experimental evidence for the existence of a ‘cubatic’ phase in a colloidal dispersion of disc-like particles of nickel hydroxide colloidal dispersions. In this structure, disc-like particles self-assemble as domains of a few parallel discs and the orientation tends to be orthogonal in adjacent domains. This phase has been predicted previously by computer simulations. The domains are approximately equiaxial and are predicted to exist only within a limited range of aspect ratios and volume fractions. We have used the real space technique of cryo-transmission electron microscopy in our studies as this locally ordered structure could not be identified readily using scattering techniques, since the patterns are expected to be similar to those of isotropic liquid phases.
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| 26. |
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| 27. |
- Ruilope, LM, et al.
(author)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
-
Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 28. |
- Samuelsson, Jennifer, et al.
(author)
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Risk of de novo aneurysm formation in patients previously diagnosed with a ruptured or unruptured aneurysm: 18-year follow-up.
- 2023
-
In: Clinical neurology and neurosurgery. - 0303-8467 .- 1872-6968. ; 233
-
Journal article (peer-reviewed)abstract
- Data on de novo aneurysm formation after treatment for intracranial aneurysms remains scarce. We studied the incidence of de novo aneurysm formation in patients who had undergone aneurysm treatment more than 18 years prior to follow-up. As it is a disease affecting a younger patient population more specific guidelines are needed when planning a follow-up regime.The rate of de novo aneurysm formation was assessed with Magnetic Resonance Angiography (MRA) follow-up >18 years after endovascular or microsurgical treatment for an intracranial aneurysm. Variables associated with de novo aneurysm formation were studied using logistic regression. Missing data were imputed using chained random forests. A data-driven model for the prediction of de novo aneurysm was created to calculate the relative variable importance of ten clinical features.De novo aneurysms were identified in 11/81 (13.6 %) patients, of whom 1 was male, over a median follow-up of 20 years. Sex was the most important variable associated with de novo aneurysm formation. Regarding the development of de novo aneurysm, men displayed an odds ratio (OR) of 0.16 (0.01-0.97), compared with women. OR for mRS score 2 or more was 0.20 (95 % CI 0.01-1.34), and OR for smokers was 3.70 (0.54-31.18). Six out of 11 patients (54.5 %) needed treatment; 1 underwent endovascular treatment (EVT) and 5 underwent microsurgical treatment (MST). The overall annual de novo aneurysm formation rate was 0.92 %.This study highlights the need for a longer follow-up imaging monitoring of patients that have previously undergone treatment for an intracranial aneurysm. These data are useful to take into consideration when planning a follow-up strategy.
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| 29. |
- Schmidt, Bernard, 1981-, et al.
(author)
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Augmented Reality Approach for a User Interface in a Robotic Production System
- 2022
-
In: SPS2022. - Amsterdam; Berlin; Washington, DC : IOS Press. - 9781643682686 - 9781643682693 ; , s. 240-251
-
Conference paper (peer-reviewed)abstract
- In a Cyber-physical system, the information flow from the cyber part to the physical part plays a crucial role. This paper presents the work of development and initial testing of an augmented reality approach to provide a user interface for operators that could be a part of a robotic production system. The solution is distributed and includes a communication hub that allows the exchange of data and information between multiple clients e.g. robot controllers, an optimization platform, and visualization devices. The main contributions of the presented work are visualization of optimization results and visualization of information obtained from the robot controller and the integrated communication framework. The paper also presents challenges faced during the development work and opportunities related to the presented approach. The implemented interface uses HoloLens 2 mixed reality device to visualize in real-time information obtained from a robot controller as well as from simulation. Information regarding the placement of work objects and targets or currently executed lines of code can be useful for robotic cell programmers and commissioning teams to validate robot programs and to select more optimal solutions toward sustainable manufacturing. The operator can simulate the execution of the robot program and visualize it by overlying the robot cell with the 3D model of the simulated robot. Moreover, visualization of future robot motion could support human-robot collaboration. Furthermore, the interface allows providing the user with details from multi-objective optimization performed on a digital twin of the robotic cell with the aim to reduce cycle time and energy consumption. It allows visualizing selected scenarios to support decision-making by allowing comparison of proposed solutions and the initial one. The visualization includes cell layout, robot path, cycle time, robot energy consumption. The presented approach is demonstrated in industry-inspired cases and with the use of an industrial ABB robot.
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| 30. |
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| 31. |
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| 32. |
- Tiensuu, Kiira, et al.
(author)
-
RAVEN: a student rocket program at Luleå University of Technology, Sweden
- 2021
-
In: IAC 2021 Congress Proceedings, 72nd International Astronautical Congress (IAC), Dubai, United Arab Emirates. - : International Astronautical Federation (IAF).
-
Conference paper (peer-reviewed)abstract
- RAVEN, Rocketry and Aerospace Vehicle Engineering in Norrbotten, is the first rocket project at Luleå University of Technology (LTU), Sweden. The project started in early 2020, and it aims to design, build, test and launch a hybrid propulsion rocket. The initial objectives are to reach an altitude of 10 km with an accompanying payload of 10 kg. The RAVEN team is based at the Kiruna Space Campus and consists of approximately 30 graduate students. The main goal of the first RAVEN rocket is to demonstrate its technology. The team is designing the entire rocket from scratch, including the hybrid propulsion system that uses nitrous oxide as the oxidising agent and paraffin as the solid fuel component, to produce approximately 6 kN of thrust. A modular rocket structure will offer customisation, enabling simple design changes in future iterations. Thus, the layout allows individual subsystems to be re-designed without changes directly affecting others. The project is meant to create a foundation for future student and research rocket projects at LTU. The follow-up developments could further iterate on the first rocket design, increasing hands-on education and providing more collaboration opportunities between the university and the aerospace industry – and eventually provide an in-house platform for research and education at the university or even for commercial start-ups. The infrastructure and resources, such as the proximity to the Esrange Space Center launch facility and support from the university and industry, make Northern Sweden an ideal location to establish a continuous rocket program.
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| 33. |
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| 34. |
- Westborg, Inger, et al.
(author)
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Treatment for neovascular age-related macular degeneration in Sweden : outcomes at seven years in the Swedish Macula Register
- 2017
-
In: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 95:8, s. 787-795
-
Journal article (peer-reviewed)abstract
- Purpose: To present Swedish Macula Register (SMR) data regarding treatment of neovascular age-related macular degeneration (AMD) in clinical practice since 2008.Methods: A retrospective register-based study was conducted. Evaluation of baseline demographics, visual outcome and number of injections during this period is presented.Results: Mean age at diagnosis was 79 ± (SD) 8 years; 65% were female. The proportion of patients with <2 months' duration of symptoms increased from 26% in 2008 to 41% in 2014 (p = 0.001). Mean visual acuity (VA) at baseline increased from 54.3 ± 15.0 early treatment diabetic retinopathy study (ETDRS) letters in 2008 to 57.8 ± 15.6 letters in 2014 (CI95 2.6; 4.3; p < 0.001). Mean VA after 1 year of treatment increased from 57.8 ± 17.7 ETDRS letters for patients who started the treatment in 2008 to 62.8 ± 16.4 ETDRS letters in patients starting treatment in 2014 (CI95 2.67; 4.64; p < 0.001). During all study years, the proportion of patients with an improvement in VA of between 5 and 15 letters was around 30%, while 14% had VA improvement of more than 15 letters. The mean number of injections during the first treatment year increased from 4.3 ± 1.9 in 2008 to 5.9 ± 2.9 in 2014 (CI95 1.40; 1.67; p < 0.001). Seven-year follow-up of 322 eyes showed a mean change of -1 letters from baseline, with a mean of 21 injections for the entire period.Conclusion: The duration of symptoms before treatment decreased, while VA at baseline and after 1 year of treatment increased over the years and so did the number of injections. Long-term follow-up demonstrated stable VA.
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| 35. |
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| 36. |
- Xu, Xu Steven, et al.
(author)
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Shrinkage in Nonlinear Mixed-Effects Population Models : Quantification, Influencing Factors, and Impact
- 2012
-
In: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 14:4, s. 927-936
-
Journal article (peer-reviewed)abstract
- Shrinkage of empirical Bayes estimates (EBEs) of posterior individual parameters in mixed-effects models has been shown to obscure the apparent correlations among random effects and relationships between random effects and covariates. Empirical quantification equations have been widely used for population pharmacokinetic/pharmacodynamic models. The objectives of this manuscript were (1) to compare the empirical equations with theoretically derived equations, (2) to investigate and confirm the influencing factor on shrinkage, and (3) to evaluate the impact of shrinkage on estimation errors of EBEs using Monte Carlo simulations. A mathematical derivation was first provided for the shrinkage in nonlinear mixed effects model. Using a linear mixed model, the simulation results demonstrated that the shrinkage estimated from the empirical equations matched those based on the theoretically derived equations. Simulations with a two-compartment pharmacokinetic model verified that shrinkage has a reversed relationship with the relative ratio of interindividual variability to residual variability. Fewer numbers of observations per subject were associated with higher amount of shrinkage, consistent with findings from previous research. The influence of sampling times appeared to be larger when fewer PK samples were collected for each individual. As expected, sample size has very limited impact on shrinkage of the PK parameters of the two-compartment model. Assessment of estimation error suggested an average 1:1 relationship between shrinkage and median estimation error of EBEs.
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| 37. |
- Zheng, Hou-Feng, et al.
(author)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
-
Journal article (peer-reviewed)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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| 38. |
- Zheng, Hou-Feng, et al.
(author)
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WNT16 influences bone mineral density, Cortical bone thickness, bone strength, and Osteoporotic fracture risk
- 2012
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In: PLoS genetics. - SAN FRANCISCO, USA : PUBLIC LIBRARY SCIENCE. - 1553-7404. ; 8:7, s. e1002745-
-
Journal article (peer-reviewed)abstract
- We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10(-12), and -0.16 SD per G allele, P = 1.2×10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10(-6) and rs2707466: OR = 1.22, P = 7.2×10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10(-13)
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