| 1. |
- Bar, N., et al.
(författare)
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A reference map of potential determinants for the human serum metabolome
- 2020
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Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Tidskriftsartikel (refereegranskat)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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| 2. |
- Browne, F., et al.
(författare)
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Pairing Forces Govern Population of Doubly Magic Ca-54 from Direct Reactions
- 2021
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Ingår i: Physical Review Letters. - : American Physical Society (APS). - 0031-9007 .- 1079-7114. ; 126:25
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Tidskriftsartikel (refereegranskat)abstract
- Direct proton-knockout reactions of Sc-55 at similar to 220 MeV/nucleon were studied at the RIKEN Radioactive Isotope Beam Factory. Populated states of Ca-54 were investigated through -ray and invariant-mass spectroscopy. Level energies were calculated from the nuclear shell model employing a phenomenological intemucleon interaction. Theoretical cross sections to states were calculated from distorted-wave impulse approximation estimates multiplied by the shell model spectroscopic factors, which describe the wave function overlap of the Sc-55 ground state with states in Ca-54. Despite the calculations showing a significant amplitude of excited neutron configurations in the ground-state of Sc-55, valence proton removals populated predominantly the ground state of Ca-54. This counterintuitive result is attributed to pairing effects leading to a dominance of the ground-state spectroscopic factor. Owing to the ubiquity of the pairing interaction, this argument should be generally applicable to direct knockout reactions from odd-even to even-even nuclei.
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| 3. |
- Wilman, H. R., et al.
(författare)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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| 4. |
- Storck, Sonja, et al.
(författare)
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Lifetime measurement of the 26 0 g.s. At SAMURAI
- 2020
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 1643:1
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Konferensbidrag (refereegranskat)abstract
- The ground state of the neutron unbound nucleus O is speculated to have a lifetime in the pico-second regime. In order to determine the decay lifetime of the O ground state with high sensitivity and precision, a new method has been applied. The experiment was performed in December 2016 at the Superconducting Analyzer for MUlti-particle from Radio Isotope Beams (SAMURAI) at the Radioactive Isotope Beam Factory (RIBF) at RIKEN. A F beam was produced in the fragment separator BigRIPS and impinged on a W/Pt target stack where O was produced. According to the lifetime, the decay of O happens either in or outside the target. Thus, the velocity difference between the decay neutrons and the fragment O delivers a characteristic spectrum from which the lifetime can be extracted.
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| 5. |
- Heil, M., et al.
(författare)
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A new Time-of-flight detector for the R 3 B setup
- 2022
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Ingår i: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-601X .- 1434-6001. ; 58:12
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Tidskriftsartikel (refereegranskat)abstract
- We present the design, prototype developments and test results of the new time-of-flight detector (ToFD) which is part of the R3B experimental setup at GSI and FAIR, Darmstadt, Germany. The ToFD detector is able to detect heavy-ion residues of all charges at relativistic energies with a relative energy precision σΔE/ ΔE of up to 1% and a time precision of up to 14 ps (sigma). Together with an elaborate particle-tracking system, the full identification of relativistic ions from hydrogen up to uranium in mass and nuclear charge is possible.
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| 6. |
- Gobel, K., et al.
(författare)
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Coulomb dissociation of 16O into 4He and 12C
- 2020
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 1668:1
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Konferensbidrag (refereegranskat)abstract
- We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(a,?)16O fusion reaction and to reach lower center-ofmass energies than measured so far. The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-To-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.
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| 7. |
- Wamers, F., et al.
(författare)
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Comparison of electromagnetic and nuclear dissociation of Ne-17
- 2018
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Ingår i: Physical Review C. - : AMER PHYSICAL SOC. - 2469-9985 .- 2469-9993. ; 97:3
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Tidskriftsartikel (refereegranskat)abstract
- The Borromean drip-line nucleus Ne-17 has been suggested to possess a two-proton halo structure in its ground state. In the astrophysical rp-process, where the two-proton capture reaction O-15(2p,gamma) Ne-17 plays an important role, the calculated reaction rate differs by several orders of magnitude between different theoretical approaches. To add to the understanding of the Ne-17 structure we have studied nuclear and electromagnetic dissociation. A 500 MeV/u Ne-17 beam was directed toward lead, carbon, and polyethylene targets. Oxygen isotopes in the final state were measured in coincidence with one or two protons. Different reaction branches in the dissociation of Ne-17 were disentangled. The relative populations of s and d states in F-16 were determined for light and heavy targets. The differential cross section for electromagnetic dissociation (EMD) shows a continuous internal energy spectrum in the three-body system O-15 + 2p. The Ne-17 EMD data were compared to current theoretical models. None of them, however, yields satisfactory agreement with the experimental data presented here. These new data may facilitate future development of adequate models for description of the fragmentation process.
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| 8. |
- Lehr, C., et al.
(författare)
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Unveiling the two-proton halo character of 17 Ne: Exclusive measurement of quasi-free proton-knockout reactions
- 2022
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Ingår i: Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 827
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Tidskriftsartikel (refereegranskat)abstract
- The proton drip-line nucleus 17Ne is investigated experimentally in order to determine its two-proton halo character. A fully exclusive measurement of the 17Ne(p,2p)16F→15⁎O+p quasi-free one-proton knockout reaction has been performed at GSI at around 500 MeV/nucleon beam energy. All particles resulting from the scattering process have been detected. The relevant reconstructed quantities are the angles of the two protons scattered in quasi-elastic kinematics, the decay of 16F into 15O (including γ decays from excited states) and a proton, as well as the 15O+p relative-energy spectrum and the 16F momentum distributions. The latter two quantities allow an independent and consistent determination of the fractions of l=0 and l=2 motion of the valence protons in 17Ne. With a resulting relatively small l=0 component of only around 35(3)%, it is concluded that 17Ne exhibits a rather modest halo character only. The quantitative agreement of the two values deduced from the energy spectrum and the momentum distributions supports the theoretical treatment of the calculation of momentum distributions after quasi-free knockout reactions at high energies by taking into account distortions based on the Glauber theory. Moreover, the experimental data allow the separation of valence-proton knockout and knockout from the 15O core. The latter process contributes with 11.8(3.1) mb around 40% to the total proton-knockout cross section of 30.3(2.3) mb, which explains previously reported contradicting conclusions derived from inclusive cross sections.
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| 9. |
- Wamers, F., et al.
(författare)
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Comparison of electromagnetic and nuclear dissociation of Ne 17
- 2018
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Ingår i: Physical Review C. - 2469-9985 .- 2469-9993. ; 97:3
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Tidskriftsartikel (refereegranskat)abstract
- The Borromean drip-line nucleus Ne17 has been suggested to possess a two-proton halo structure in its ground state. In the astrophysical rp-process, where the two-proton capture reaction O15(2p,γ)Ne17 plays an important role, the calculated reaction rate differs by several orders of magnitude between different theoretical approaches. To add to the understanding of the Ne17 structure we have studied nuclear and electromagnetic dissociation. A 500 MeV/u Ne17 beam was directed toward lead, carbon, and polyethylene targets. Oxygen isotopes in the final state were measured in coincidence with one or two protons. Different reaction branches in the dissociation of Ne17 were disentangled. The relative populations of s and d states in F16 were determined for light and heavy targets. The differential cross section for electromagnetic dissociation (EMD) shows a continuous internal energy spectrum in the three-body system O15+2p. The Ne17 EMD data were compared to current theoretical models. None of them, however, yields satisfactory agreement with the experimental data presented here. These new data may facilitate future development of adequate models for description of the fragmentation process.
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| 10. |
- Wamers, F., et al.
(författare)
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Diverse mechanisms in proton knockout reactions from the Borromean nucleus Ne-17
- 2023
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Ingår i: European Physical Journal A. - : Springer. - 1434-6001 .- 1434-601X. ; 59
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Tidskriftsartikel (refereegranskat)abstract
- Nucleon knockout experiments using beryllium or carbon targets reveal a strong dependence of the quenching factors, i.e., the ratio (Rs) of theoretical to the experimental spectroscopic factors (C2S), on the proton-neutron asymmetry in the nucleus under study. However, this dependence is greatly reduced when a hydrogen target is used. To understand this phenomenon, exclusive H-1(Ne-17, 2p F-16) and inclusive C-12(Ne-17, 2p 1(6)F)X, 1(2)C(Ne-17, F-16)X as well as 1H(Ne-17,(16) F)X(X-denotes undetected reaction products) reactions with F-16 in the ground and excited states were anal- ysed. The longitudinal momentum distribution of F-16 and the correlations between the detached protons were studied. In the case of the carbon target, there is a significant deviation from the predictions of the eikonal model. The eikonal approximation was used to extract spectroscopic factor values (CS)-S-2. The experimental (CS)-S-2 value obtained with C target is markedly lower than that for H target. This is interpreted as rescattering due to simultaneous nucleon knockout from both reaction partners, Ne-17 and C-12.
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| 11. |
- Wamers, F., et al.
(författare)
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New insight into knockout reactions from the two-proton halo nucleus Ne 17
- 2024
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Ingår i: Physical Review C. - 2469-9985 .- 2469-9993. ; 109:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: The unexplained disagreement in the dependence of spectroscopic factors (C2Sexp) on the binding energy obtained by nucleon knockout using different targets is still a puzzle that needs to be addressed. Purpose: To find an explanation of this riddle through exclusive measurements using different targets. Method: The exclusive measurements were performed by using a Ne17 beam with an energy of 500 MeV/u incident on C and CH2 targets. Through the standard theoretical approach, C2Sexp were derived from the analysis of the experimental data on proton ejection from the proton halo in Ne17 as well as from its core O15. Result: For the C target, proton ejection from the proton halo gave C2Sexp about 37% smaller than for the H target. But when protons are ejected from the core of Ne17, C2Sexp are identical within statistical uncertainties. Conclusion: An explanation for the difference in C2Sexp could be the removal of both halo protons, a more important reaction pathway for the C target. The C2Sexp values obtained by analyzing the proton ejection from the core indicate that it is not affected by the interaction with the halo protons.
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| 12. |
- Allesøe, Rosa Lundbye, et al.
(författare)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 13. |
- Pelaz, B, et al.
(författare)
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Diverse Applications of Nanomedicine
- 2017
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Ingår i: ACS nano. - : American Chemical Society (ACS). - 1936-086X .- 1936-0851. ; 11:3, s. 2313-2381
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Tidskriftsartikel (refereegranskat)
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| 14. |
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| 15. |
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| 16. |
- Stöber, T M, et al.
(författare)
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Selective neuromodulation and mutual inhibition within the CA3–CA2 system can prioritize sequences for replay
- 2020
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 30:11, s. 1228-1238
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Tidskriftsartikel (refereegranskat)abstract
- To make optimal use of previous experiences, important neural activity sequences must be prioritized during hippocampal replay. Integrating insights about the interplay between CA3 and CA2, we propose a conceptual framework that allows the two regions to control which sequences are reactivated. We suggest that neuromodulatory-gated plasticity and mutual inhibition enable discrete assembly sequences in both regions to support each other while suppressing competing sequences. This perspective provides a coherent interpretation for a variety of seemingly disconnected functional properties of CA2 and paves the way for a more general understanding of CA2.
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| 17. |
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| 18. |
- Bott, Lukas Thomas, et al.
(författare)
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Coulomb dissociation of O-16 into He-4 and C-12
- 2023
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Ingår i: NUCLEAR PHYSICS IN ASTROPHYSICS - X, NPA-X 2022. - : EDP Sciences. - 2100-014X. ; 279
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Konferensbidrag (refereegranskat)abstract
- We measured the Coulomb dissociation of O-16 into He-4 and C-12 within the FAIR Phase-0 program at GSI Helmholtzzentrum fur Schwerionenforschung Darmstadt, Germany. From this we will extract the photon dissociation cross section O-16(alpha,gamma)C-12, which is the time reversed reaction to C-12(alpha,gamma)O-16. With this indirect method, we aim to improve on the accuracy of the experimental data at lower energies than measured so far. The expected low cross section for the Coulomb dissociation reaction and close magnetic rigidity of beam and fragments demand a high precision measurement. Hence, new detector systems were built and radical changes to the (RB)-B-3 setup were necessary to cope with the high-intensity O-16 beam. All tracking detectors were designed to let the unreacted O-16 ions pass, while detecting the C-12 and He-4.
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| 19. |
- Ebert, D. D., et al.
(författare)
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Does Internet-based guided-self-help for depression cause harm? An individual participant data meta-analysis on deterioration rates and its moderators in randomized controlled trials
- 2016
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Ingår i: Psychological Medicine. - : Cambridge University Press. - 0033-2917 .- 1469-8978. ; 46:13, s. 2679-2693
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Forskningsöversikt (refereegranskat)abstract
- Almost nothing is known about the potential negative effects of Internet-based psychological treatments for depression. This study aims at investigating deterioration and its moderators within randomized trials on Internet-based guided self-help for adult depression, using an individual patient data meta-analyses (IPDMA) approach.Studies were identified through systematic searches (PubMed, PsycINFO, EMBASE, Cochrane Library). Deterioration in participants was defined as a significant symptom increase according to the reliable change index (i.e. 7.68 points in the CES-D; 7.63 points in the BDI). Two-step IPDMA procedures, with a random-effects model were used to pool data.A total of 18 studies (21 comparisons, 2079 participants) contributed data to the analysis. The risk for a reliable deterioration from baseline to post-treatment was significantly lower in the intervention v. control conditions (3.36 v. 7.60; relative risk 0.47, 95% confidence interval 0.29–0.75). Education moderated effects on deterioration, with patients with low education displaying a higher risk for deterioration than patients with higher education. Deterioration rates for patients with low education did not differ statistically significantly between intervention and control groups. The benefit–risk ratio for patients with low education indicated that 9.38 patients achieve a treatment response for each patient experiencing a symptom deterioration.Internet-based guided self-help is associated with a mean reduced risk for a symptom deterioration compared to controls. Treatment and symptom progress of patients with low education should be closely monitored, as some patients might face an increased risk for symptom deterioration. Future studies should examine predictors of deterioration in patients with low education.
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| 20. |
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| 21. |
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| 22. |
- Liesenfeld, K-H, et al.
(författare)
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Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial
- 2011
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 9:11, s. 2168-2175
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity. Objectives: To characterize the pharmacokinetics of dabigatran in patients with non-valvular atrial fibrillation (AF) from the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters. Patients and methods: A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non-linear mixed-effects modeling. Results: The pharmacokinetics of dabigatran were best described by a two-compartment disposition model with first-order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup 'South Asian' exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton-pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15-30 mL min(-1) and patients with normal renal function receiving 150 mg twice daily. Conclusions: The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE-LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment.
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