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Sökning: WFRF:(Burger J.)

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51.
  • Schwertel, S., et al. (författare)
  • One-neutron knockout from Sc51-55
  • 2012
  • Ingår i: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-601X .- 1434-6001. ; 48:Dec., s. 191-10
  • Tidskriftsartikel (refereegranskat)abstract
    • Results are presented from a one-neutron knockout experiment at relativistic energies of approximate to 420 A MeV on Sc51-55 using the GSI Fragment Separator as a two-stage magnetic spectrometer and the Miniball array for gamma-ray detection. Inclusive longitudinal momentum distributions and cross-sections were measured enabling the determination of the contributions corresponding to knockout from the nu p(1/2), nu p(3/2), (L = 1) and nu f(7/2), nu f(5/2) (L = 3) neutron orbitals. The observed L = 1 and L = 3 contributions are compared with theoretical cross-sections using eikonal knockout theory and spectroscopic factors from shell model calculations using the GXPF1A interaction. The measured inclusive knockout cross-sections generally follow the trends expected theoretically and given by the spectroscopic strength predicted from the shell model calculations. However, the deduced L = 1 cross-sections are generally 30-40% higher while the L = 3 contributions are about a factor of two smaller than predicted. This points to a promotion of neutrons from the nu f(7/2) to the nu p(3/2) orbital indicating a weakening of the N = 28 shell gap in these nuclei. While this is not predicted for the phenomenological GXPF1A interaction such a weakening is predicted by recent calculations using realistic low-momentum interactions V-lowk obtained by evolving a chiral N3LO nucleon-nucleon potential.
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52.
  • Witjes, J. Alfred, et al. (författare)
  • EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer – An International Collaborative Multistakeholder Effort : Under the Auspices of the EAU-ESMO Guidelines Committees
  • 2020
  • Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 77:2, s. 223-250
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.SETTING: Online Delphi survey and consensus conference.PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.PATIENT SUMMARY: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
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53.
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54.
  • Banu, A, et al. (författare)
  • 108Sn Studied with Intermediate-energy Coulomb Excitation
  • 2005
  • Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 72:6
  • Tidskriftsartikel (refereegranskat)abstract
    • The unstable neutron-deficient Sn-108 isotope has been studied in inverse kinematics by intermediate-energy Coulomb excitation using the RISING/FRS experimental setup at GSI. This is the highest Z nucleus studied so far with this method. Its reduced transition probability B (E2;0(g.s.)(+)-> 2(1)(+)) has been measured for the first time. The extracted B(E2) value of 0.230(57)e(2) b(2) has been determined relative to the known value in the stable Sn-112 isotope. The result is discussed in the framework of recent large-scale shell model calculations performed with realistic effective interactions. The roles of particle-hole excitations of the Sn-100 core and of the Z=50 shell gap for the E2 polarization are investigated.
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55.
  • Becker, F, et al. (författare)
  • Status of the RISING Project at GSI
  • 2005
  • Ingår i: European Physical Journal A. Hadrons and Nuclei. - : Springer Science and Business Media LLC. - 1434-6001. ; 25:Suppl 1, s. 719-722
  • Tidskriftsartikel (refereegranskat)abstract
    • The FRS-RISING set-up at GSI uses secondary radioactive beams at relativistic energies for nuclear structure studies. At GSI the fragmentation or fission of stable primary beams up to U-238 provide secondary beams with sufficient intensity to perform gamma-ray spectroscopy. The RISING set-up is described and results of the first RISING campaign are presented. New experimental methods at relativistic energies are being investigated. Future experiments focus on state-of-the art nuclear structure physics covering exotic nuclei all over the nuclear chart.
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56.
  • Bednarczyk, P, et al. (författare)
  • Status of the RISING Project at Relativistic Energies
  • 2005
  • Ingår i: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 36:4, s. 1235-1244
  • Tidskriftsartikel (refereegranskat)abstract
    • The RISING project was designed to perform high-resolution gamma-ray spectroscopy with radioactive beams at GSI. Unstable beams were produced by fragmentation of relativistic heavy ion projectiles provided by the SIS synchrotron. The fragment separator FRS was used to select and to focus the exotic fragments at about 100A MeV energy on a secondary target. Various charged particle detectors enabled an event-by-event tracking of the incoming radioactive projectiles and the reaction products, thus allowing for a selection of the nuclei of interest and their velocity vector reconstruction. The gamma-ray detection system consisting of the EUROBALL Cluster Ge detectors and the large volume HECTOR BaF2 detectors measured prompt gamma-radiation from nuclei excited in the secondary target. Despite the huge Doppler shift due to the high recoil velocity (beta approximate to 40%), RISING achieved a gamma-energy resolution below 2%. The paper reviews the present status of the RISING project.
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57.
  • Cserni, G, et al. (författare)
  • Consistency in recognizing microinvasion in breast carcinomas is improved by immunohistochemistry for myoepithelial markers.
  • 2016
  • Ingår i: Virchows Archiv: an international journal of pathology. - : Springer Science and Business Media LLC. - 1432-2307. ; 468:4, s. 473-481
  • Tidskriftsartikel (refereegranskat)abstract
    • Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and distinction from in situ carcinoma may have therapeutic implications, and clinical staging also requires the recognition of this phenomenon. Microinvasion is established on the basis of several morphological criteria, which may be difficult and not perfectly reproducible among pathologists. The aim of this study was to assess the consistency of diagnosing microinvasion in the breast on traditional haematoxylin and eosin (HE) stained slides and to evaluate whether immunohistochemistry (IHC) for myoepithelial markers could improve this. Digital images were generated from representative areas of 50 cases stained with HE and IHC for myoepithelial markers. Cases were specifically selected from the spectrum of in situ to microinvasive cancers. Twenty-eight dedicated breast pathologists assessed these cases at different magnifications through a web-based platform in two rounds: first HE only and after a washout period by both HE and IHC. Consistency in the recognition of microinvasion significantly improved with the use of IHC. Concordance rates increased from 0.85 to 0.96, kappa from 0.5 to 0.85, the number of cases with 100 % agreement rose from 9/50 to 25/50 with IHC and the certainty of diagnosis also increased. The use of IHC markedly improves the consistency of identifying microinvasion. This corroborates previous recommendations to use IHC for myoepithelial markers to clarify cases where uncertainty exists about the presence of microinvasion. Microinvasive carcinoma is a rare entity, and seeking a second opinion may avoid overdiagnosis.
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58.
  • Hurst, A. M., et al. (författare)
  • Measurement of the sign of the spectroscopic quadrupole moment for the 2(1)(+) state in Se-70: No evidence for oblate shape
  • 2007
  • Ingår i: Physical Review Letters. - 1079-7114. ; 98:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Using a method whereby molecular and atomic ions are independently selected, an isobarically pure beam of Se-70 ions was postaccelerated to an energy of 206 MeV using REX-ISOLDE. Coulomb-excitation yields for states in the beam and target nuclei were deduced by recording deexcitation gamma rays in the highly segmented MINIBALL gamma-ray spectrometer in coincidence with scattered particles in a silicon detector. At these energies, the Coulomb-excitation yield for the first 2(+) state is expected to be strongly sensitive to the sign of the spectroscopic quadrupole moment through the nuclear reorientation effect. Experimental evidence is presented here for a prolate shape for the first 2(+) state in Se-70, reopening the question over whether there are, as reported earlier, deformed oblate shapes near to the ground state in the light selenium isotopes.
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59.
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60.
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61.
  • Maierbeck, P., et al. (författare)
  • Probing the single particle structure around Ca-54 with one-neutron knock-out
  • 2008
  • Ingår i: AIP Conference Proceedings. - 1551-7616 .- 0094-243X. ; 1012, s. 89-93
  • Konferensbidrag (refereegranskat)abstract
    • The nuclei Ca-47 and Ti-55 were populated in one-neutron knock-out reactions at relativistic energies. Momentum distributions of the residual nuclei as well as gamma-ray spectra were measured at the GSI fragment separator (FRS). Preliminary results of the ongoing analysis including cross sections and spin/parity assignments are presented.
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62.
  • AMAUDRUZ, P, et al. (författare)
  • A REEVALUATION OF THE NUCLEAR-STRUCTURE FUNCTION RATIOS FOR D, HE, LI-6, C AND CA
  • 1995
  • Ingår i: NUCLEAR PHYSICS B. - : ELSEVIER SCIENCE BV. - 0550-3213. ; 441:1-2, s. 3-11
  • Tidskriftsartikel (refereegranskat)abstract
    • We present a re-evaluation of the structure function ratios F-2(He)/F-2(D), F-2(C)/F-2(D) and F-2(Ca)/F-2(D) measured in deep inelastic muon-nucleus scattering at an incident muon momentum of 200 GeV. We also present the ratios F-2(C)/F-2(Li), F-2(Ca)/F-2
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63.
  • Bukkems, V. E., et al. (författare)
  • Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments
  • 2022
  • Ingår i: Clinical Pharmacokinetics. - : Springer Nature. - 0312-5963 .- 1179-1926. ; 61:8, s. 1129-1141
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Objective Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling.Methods Ex vivo placenta perfusions were performed in a closed-closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration (C-trough) values were compared with the target (0.23 mg/L) derived from in vivo exposure-response analysis.Results A decrease of 55% in maternal doravirine area under the plasma concentration-time curve (AUC)(0-24h) was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM C-trough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure.Conclusion Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data.
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64.
  • Einspieler, C, et al. (författare)
  • Cerebral Palsy: Early Markers of Clinical Phenotype and Functional Outcome
  • 2019
  • Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 8:10
  • Tidskriftsartikel (refereegranskat)abstract
    • The Prechtl General Movement Assessment (GMA) has become a cornerstone assessment in early identification of cerebral palsy (CP), particularly during the fidgety movement period at 3–5 months of age. Additionally, assessment of motor repertoire, such as antigravity movements and postural patterns, which form the Motor Optimality Score (MOS), may provide insight into an infant’s later motor function. This study aimed to identify early specific markers for ambulation, gross motor function (using the Gross Motor Function Classification System, GMFCS), topography (unilateral, bilateral), and type (spastic, dyskinetic, ataxic, and hypotonic) of CP in a large worldwide cohort of 468 infants. We found that 95% of children with CP did not have fidgety movements, with 100% having non-optimal MOS. GMFCS level was strongly correlated to MOS. An MOS > 14 was most likely associated with GMFCS outcomes I or II, whereas GMFCS outcomes IV or V were hardly ever associated with an MOS > 8. A number of different movement patterns were associated with more severe functional impairment (GMFCS III–V), including atypical arching and persistent cramped-synchronized movements. Asymmetrical segmental movements were strongly associated with unilateral CP. Circular arm movements were associated with dyskinetic CP. This study demonstrated that use of the MOS contributes to understanding later CP prognosis, including early markers for type and severity.
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65.
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66.
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67.
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68.
  • Modamio, V., et al. (författare)
  • Lifetime measurements in neutron-rich Co-63,Co-65 isotopes using the AGATA demonstrator
  • 2013
  • Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 88:4, s. 044326-
  • Tidskriftsartikel (refereegranskat)abstract
    • Lifetimes of the low-lying (11/2(-)) states in Co-63,Co-65 have been measured employing the recoil distance doppler shift method (RDDS) with the AGATA gamma-ray array and the PRISMA mass spectrometer. These nuclei were populated via a multinucleon transfer reaction by bombarding a U-238 target with a beam of Ni-64. The experimental B(E2) reduced transition probabilities for Co-63,Co-65 are well reproduced by large-scale shell-model calculations that predict a constant trend of the B(E2) values up to the N = 40 Co-67 isotope.
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69.
  • Ruiz-Solani, N., et al. (författare)
  • Arabidopsis metacaspase MC1 localizes in stress granules, clears protein aggregates, and delays senescence
  • 2023
  • Ingår i: Plant Cell. - 1040-4651. ; 35:9, s. 3325-3344
  • Tidskriftsartikel (refereegranskat)abstract
    • The Arabidopsis metacaspase MC1 is recruited to stress granules upon proteotoxic stress, participates in clearance of pathological protein aggregates, and delays senescence. Stress granules (SGs) are highly conserved cytoplasmic condensates that assemble in response to stress and contribute to maintaining protein homeostasis. These membraneless organelles are dynamic, disassembling once the stress is no longer present. Persistence of SGs due to mutations or chronic stress has been often related to age-dependent protein-misfolding diseases in animals. Here, we find that the metacaspase MC1 is dynamically recruited into SGs upon proteotoxic stress in Arabidopsis (Arabidopsis thaliana). Two predicted disordered regions, the prodomain and the 360 loop, mediate MC1 recruitment to and release from SGs. Importantly, we show that MC1 has the capacity to clear toxic protein aggregates in vivo and in vitro, acting as a disaggregase. Finally, we demonstrate that overexpressing MC1 delays senescence and this phenotype is dependent on the presence of the 360 loop and an intact catalytic domain. Together, our data indicate that MC1 regulates senescence through its recruitment into SGs and this function could potentially be linked to its remarkable protein aggregate-clearing activity.
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70.
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71.
  • Balaz, M., et al. (författare)
  • Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation
  • 2019
  • Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 29:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.
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72.
  • Beijert, Irene J., et al. (författare)
  • International Opinions on Grading of Urothelial Carcinoma : A Survey Among European Association of Urology and International Society of Urological Pathology Members
  • 2023
  • Ingår i: European Urology Open Science. - 2666-1691. ; 52, s. 154-165
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Grade of non–muscle-invasive bladder cancer (NMIBC) is an important prognostic factor for progression. Currently, two World Health Organization (WHO) classification systems (WHO1973, categories: grade 1–3, and WHO2004 categories: papillary urothelial neoplasm of low malignant potential [PUNLMP], low-grade [LG], high-grade [HG] carcinoma) are used. Objective: To ask the European Association of Urology (EAU) and International Society of Urological Pathology (ISUP) members regarding their current practice and preferences of grading systems. Design, setting, and participants: A web-based, anonymous questionnaire with ten questions on grading of NMIBC was created. The members of EAU and ISUP were invited to complete an online survey by the end of 2021. Thirteen experts had previously answered the same questions. Outcome measurements and statistical analysis: The submitted answers from 214 ISUP members, 191 EAU members, and 13 experts were analyzed. Results and limitations: Currently, 53% use only the WHO2004 system and 40% use both systems. According to most respondents, PUNLMP is a rare diagnosis with management similar to Ta-LG carcinoma. The majority (72%) would consider reverting back to WHO1973 if grading criteria were more detailed. Separate reporting of WHO1973-G3 within WHO2004-HG would influence clinical decisions for Ta and/or T1 tumors according the majority (55%). Most respondents preferred a two-tier (41%) or a three-tier (41%) grading system. The current WHO2004 grading system is supported by a minority (20%), whereas nearly half (48%) supported a hybrid three- or four-tier grading system composed of both WHO1973 and WHO2004. The survey results of the experts were comparable with ISUP and EAU respondents. Conclusions: Both the WHO1973 and the WHO2004 grading system are still widely used. Even though opinions on the future of bladder cancer grading were strongly divided, there was limited support for WHO1973 and WHO2004 in their current formats, while the hybrid (three-tier) grading system with LG, HG-G2, and HG-G3 as categories could be considered the most promising alternative. Patient summary: Grading of non–muscle-invasive bladder cancer (NMIBC) is a matter of ongoing debate and lacks international consensus. We surveyed urologists and pathologists of European Association of Urology and International Society of Urological Pathology on their preferences regarding NMIBC grading to generate a multidisciplinary dialogue. Both the “old” World Health Organization (WHO) 1973 and the “new” WHO2004 grading schemes are still used widely. However, continuation of both the WHO1973 and the WHO2004 system showed limited support, while a hybrid grading system composed of both the WHO1973 and the WHO2004 classification system may be considered a promising alternative.
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73.
  • Breznau, Nate, et al. (författare)
  • Observing many researchers using the same data and hypothesis reveals a hidden universe of uncertainty
  • 2022
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:44
  • Tidskriftsartikel (refereegranskat)abstract
    • This study explores how researchers analytical choices affect the reliability of scientific findings. Most discussions of reliability problems in science focus on systematic biases. We broaden the lens to emphasize the idiosyncrasy of conscious and unconscious decisions that researchers make during data analysis. We coordinated 161 researchers in 73 research teams and observed their research decisions as they used the same data to independently test the same prominent social science hypothesis: that greater immigration reduces support for social policies among the public. In this typical case of social science research, research teams reported both widely diverging numerical findings and substantive conclusions despite identical start conditions. Researchers expertise, prior beliefs, and expectations barely predict the wide variation in research outcomes. More than 95% of the total variance in numerical results remains unexplained even after qualitative coding of all identifiable decisions in each teams workflow. This reveals a universe of uncertainty that remains hidden when considering a single study in isolation. The idiosyncratic nature of how researchers results and conclusions varied is a previously underappreciated explanation for why many scientific hypotheses remain contested. These results call for greater epistemic humility and clarity in reporting scientific findings.
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74.
  • Chahal, Harvinder S., et al. (författare)
  • Brief Report : AIP Mutation in Pituitary Adenomas in the 18th Century and Today
  • 2011
  • Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 364:1, s. 43-50
  • Tidskriftsartikel (refereegranskat)abstract
    • Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, *RF 1-3* he noted an enlarged pituitary fossa. We extracted DNA from the patient's teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.
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75.
  • Hammond, G, et al. (författare)
  • Spectroscopy of T=3/2 Mirror Nuclei via Two-step Fragmentation using RISING
  • 2005
  • Ingår i: Acta Physica Polonica. Series B: Elementary Particle Physics, Nuclear Physics, Statistical Physics, Theory of Relativity, Field Theory. - 0587-4254. ; 36:4, s. 1253-1257
  • Tidskriftsartikel (refereegranskat)abstract
    • Two two-step fragmentation reactions were performed using RISING to populate excited states in A approximate to 50 mirror nuclei near to the proton-drip line, in order to test isospin symmetry. The experiments were designed to observe gamma decays of excited states in the mirror nuclei Ni-53(28)25/Mn-53(25)28, which have a large value of total isospin (T = 3/2). In the continuing off-line analysis, gamma transitions have been observed in Ni-54 indicating that two-step fragmentation is a successful technique for spectroscopic investigations of proton-rich nuclear systems in this mass region.
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76.
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77.
  • Sehgal, B. R., et al. (författare)
  • Assessment of reactor vessel integrity (ARVI)
  • 2003
  • Ingår i: Nuclear Engineering and Design. - 0029-5493 .- 1872-759X. ; 221:03-jan, s. 23-53
  • Tidskriftsartikel (refereegranskat)abstract
    • The cost-shared project ARVI (assessment of reactor vessel integrity) involves a total of nine organisations from Europe and USA. The objective of the ARVI Project is to resolve the safety issues that remain unresolved for the melt vessel interaction phase of the in-vessel progression of a severe accident. The work consists of experiments and analysis development. Four tests were performed in the EC-FOREVER Programme, in which failure was achieved in-vessels employing the French pressure vessel steel. The tests were analysed with the commercial code ANSYS-Multiphysics, and the codes SYSTUS+ and PASULA, and quite good agreement was achieved for the failure location. Natural convection experiments in stratified pools have been performed in the SIMECO and the COPO facilities, which showed that much greater heat is transferred downwards for immiscible layers or before layers mix. A model for gap cooling and a set of simplified models for the system codes have been developed. MVITA code calculations have been performed for the Czech and Hungarian VVERs, towards evaluation of the in-vessel melt retention accident management scheme. Tests have been performed at the ULPU facility with organised flow for vessel external cooling. Considerable enhancement of the critical heat flux (CHF) was obtained. The ARVI Project has reached the halfway stage. This paper presents the results obtained thus far from the project.
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78.
  • Spillmann, Dorothe, et al. (författare)
  • Characterization of a novel pyruvylated carbohydrate unit implicated in the cell aggregation of the marine sponge Microciona prolifera
  • 1993
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 268:18, s. 13378-13387
  • Tidskriftsartikel (refereegranskat)abstract
    • The species-specific Ca(2+)-dependent reaggregation of dissociated cells of the marine sponge Microciona prolifera is mediated by a large extracellular adhesion proteoglycan. The glycans of this molecule are involved in the interactions of the proteoglycan with itself and with the sponge cells. Monoclonal antibodies against the glycans block the aggregation of sponge cells (Misevic, G. N., Finne, J., and Burger, M. M. (1987) J. Biol. Chem. 262, 5870-5877). Proteoglycan oligosaccharides were prepared by partial acid hydrolysis of the isolated glycans, and their reactivity with the monoclonal antibodies was monitored after linkage to phospholipid and immunostaining of thin layer chromatograms. One major antibody-reactive oligosaccharide was detected and purified by ion-exchange chromatography and high performance liquid chromatography. 1H NMR spectroscopy, fast atom bombardment-mass spectrometry, methylation analysis, and sequential chemical and enzymatic degradation studies indicated the structure [formula: see text] for the oligosaccharide. The depyruvylated derivative of the oligosaccharide did not react with the aggregation-blocking antibody, which indicates that the pyruvate acetal is an essential part of the epitope.
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79.
  • Spillmann, Dorothe, et al. (författare)
  • Characterization of a Novel Sulfated Carbohydrate Unit Implicated in the Carbohydrate­Carbohydrate-mediated Cell Aggregation of the Marine Sponge Microciona prolifera
  • 1995
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 270, s. 5089-5097
  • Tidskriftsartikel (refereegranskat)abstract
    • Species-specific cell reaggregation in the marine sponge Microciona prolifera is mediated by an adhesion proteoglycan. Two interactions are involved in the process: a Ca(2+)-dependent homophilic binding between proteoglycan molecules and a Ca(2+)-independent binding between the molecule and cells. Both interactions are mediated by the glycan moieties of the proteoglycan. The interaction of the proteoglycan with itself has been characterized as a carbohydrate-carbohydrate interaction of multiple low affinity sites. The monoclonal antibodies Block 1 and Block 2 raised against the purified aggregation proteoglycan and selected for inhibition of aggregation bind to these glycans. In a previous report the structure, [formula: see text] was assigned to the oligosaccharide reacting with Block 1 antibody (Spillmann, D., Hård, K., Thomas-Oates, J., Vliegenthart, J. F. G., Misevic, G., Burger, M. M., and Finne, J. (1993) J. Biol. Chem. 268, 13378-13387). By the technique of attaching the water-soluble acid-degraded fragments to a lipid carrier for immunochemical detection and by chemical, enzymatic and spectroscopic methods the structure, [formula: see text] was assigned to the oligosaccharide reacting with the aggregation-blocking monoclonal antibody Block 2. The structure, [formula: see text] was assigned to a major nonreactive oligosaccharide, which outlined the molecular requirements of antibody binding of the two aggregation-associated epitopes. These data demonstrate that two different functional sites with distinct structural characteristics and antibody reactivities are involved in the reaggregation of sponge cells, a model of carbohydrate-carbohydrate-mediated cell interactions.
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80.
  • Taylor, MJ, et al. (författare)
  • Spectroscopy of Nuclei Approaching the Proton Drip-line Using a Secondary-fragmentation Technique with the RISING Detector Array
  • 2005
  • Ingår i: Journal of Physics G: Nuclear and Particle Physics. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 31:10, s. 1527-1530
  • Tidskriftsartikel (refereegranskat)abstract
    • An experiment utilizing a double fragmentation reaction was performed to study isobaric analogue states in A similar to 50 nuclei approaching the proton drip-line. gamma-ray spectroscopy will be used to identify excited states in the neutron-deficient nuclei produced in the second fragmentation reaction. Excited state level schemes will be obtained, through comparison with states in their well-known mirror partners, along with information on Coulomb effects through measurements of the Coulomb energy differences between isobaric analogue excited states. The validity of isospin symmetry for nuclei approaching the proton drip-line can also be investigated and the information gained will aid in testing and improving fp shell model calculations. The analysis of the collected data is at a preliminary stage and current status of this work is reported.
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81.
  • Welsh, Joshua A., et al. (författare)
  • Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches
  • 2024
  • Ingår i: Journal of Extracellular Vesicles. - : John Wiley and Sons Inc. - 2001-3078. ; 13:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its ‘Minimal Information for Studies of Extracellular Vesicles’, which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.
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82.
  • Alsmeyer, H, et al. (författare)
  • Ex-vessel core melt stabilization research (ECOSTAR)
  • 2005
  • Ingår i: Nuclear Engineering and Design. - : Elsevier BV. - 0029-5493 .- 1872-759X. ; 235:2-4, s. 271-284
  • Tidskriftsartikel (refereegranskat)abstract
    • The project on ex-vessel core melt stabilization research (ECOSTAR) started in January 2000 to be concluded by end of 2003. The project is performed by 14 partner institutions from five European countries and involves a large number of experiments with low- and high-temperature simulant melts and real corium at different scales. Model development and scaling analysis allows application of the research results to existing and to future LWRs in the area of reactor design and accident mitigation. The project is oriented toward the analysis and mitigation of severe accident sequences that could occur in the ex-vessel phase of a postulated core melt accident. The issues are: (1) the release of melt form the pressure vessel, (2) the transfer and spreading of the melt on the basement, (3) the analysis of the physical-chemical processes that are important for corium behavior especially during concrete erosion with onset of solidification, and (4) stabilization of the melt by cooling through direct water contact. The results achieved so far resolve a number of important issues: the amount of melt that could be transferred at RPV failure from the RPV into the containment can be substantially reduced by lowering the residual pressure in the primary circuit. It is found that melt dispersion also strongly depends on the location of the RPV failure, and that lateral failure results in substantially less melt dispersion. During melt release, the impinging melt jet could erode parts of the upper basement surface. Jet experiments and a derived heat transfer relation allow estimation of its contribution to concrete erosion. Spreading of the corium melt on the available basement surface is an important process, which defines the initial conditions for concrete attack or for the efficiency of cooling in case of water contact, respectively. Validation of the spreading codes based on a large-scale benchmark experiment is underway and will allow determination of the initial conditions, for which a corium melt can be assumed to spread homogeneously over the available surface. Experiments with UO(2)-based corium melts highlight the role of phase segregation during onset of melt solidification and during concrete erosion. To cool the spread corium melt, the efficacy of top flooding and bottom flooding is investigated in small-scale and in large-scale experiments, supported by model developments. Project assessment is continuing to apply the results to present and future reactors.
  •  
83.
  • Arneodo, M, et al. (författare)
  • Accurate measurement of F-2(d)/F-2(p) and R(d)-R(p)
  • 1997
  • Ingår i: NUCLEAR PHYSICS B. - : ELSEVIER SCIENCE BV. - 0550-3213. ; 487:1-2, s. 3-26
  • Tidskriftsartikel (refereegranskat)abstract
    • Results are presented for F-2(d)/F-2(p) and R(d) - R(p) from simultaneous measurements of deep inelastic muon scattering on hydrogen and deuterium targets, at 90, 120, 200 and 280 GeV. The difference R(d) - R(p), determined in the range 0.002 < x < 0.4 at
  •  
84.
  •  
85.
  •  
86.
  • Arneodo, M, et al. (författare)
  • The A dependence of the nuclear structure function ratios
  • 1996
  • Ingår i: NUCLEAR PHYSICS B. - : ELSEVIER SCIENCE BV. - 0550-3213. ; 481:1-2, s. 3-22
  • Tidskriftsartikel (refereegranskat)abstract
    • Results are presented for six nuclei from Be to Pb on the structure function ratios F-2(A)/F-2(C)(X) and their A dependence in deep inelastic muon scattering at 200 GeV incident: muon energy. The data cover the kinematic range 0.01 < x < 0.8 with Q(2) ran
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87.
  •  
88.
  • ARNEODO, M, et al. (författare)
  • THE STRUCTURE-FUNCTION RATIOS F-2(LI)/F-2(D) AND F-2(C)/F-2(D) AT SMALL-X
  • 1995
  • Ingår i: NUCLEAR PHYSICS B. - : ELSEVIER SCIENCE BV. - 0550-3213. ; 441:1-2, s. 12-30
  • Tidskriftsartikel (refereegranskat)abstract
    • We present the structure function ratios F-2(Li)/F-2(D) and F-2(C)/F-2(D) measured in deep inelastic muon-nucleus scattering at a nominal incident muon energy of 200 GeV. The kinematic range 10(-4) < x < 0.7 and 0.01 < Q(2) < 70 GeV2 is covered. For value
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89.
  • Arrowsmith, C. D., et al. (författare)
  • Laboratory realization of relativistic pair-plasma beams
  • 2024
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Relativistic electron-positron plasmas are ubiquitous in extreme astrophysical environments such as black-hole and neutron-star magnetospheres, where accretion-powered jets and pulsar winds are expected to be enriched with electron-positron pairs. Their role in the dynamics of such environments is in many cases believed to be fundamental, but their behavior differs significantly from typical electron-ion plasmas due to the matter-antimatter symmetry of the charged components. So far, our experimental inability to produce large yields of positrons in quasi-neutral beams has restricted the understanding of electron-positron pair plasmas to simple numerical and analytical studies, which are rather limited. We present the first experimental results confirming the generation of high-density, quasi-neutral, relativistic electron-positron pair beams using the 440 GeV/c beam at CERN’s Super Proton Synchrotron (SPS) accelerator. Monte Carlo simulations agree well with the experimental data and show that the characteristic scales necessary for collective plasma behavior, such as the Debye length and the collisionless skin depth, are exceeded by the measured size of the produced pair beams. Our work opens up the possibility of directly probing the microphysics of pair plasmas beyond quasi-linear evolution into regimes that are challenging to simulate or measure via astronomical observations.
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90.
  • Bravender, T., et al. (författare)
  • Classification of Eating Disturbance in Children and Adolescents: Proposed Changes for the DSM-V
  • 2010
  • Ingår i: European Eating Disorders Review. - : Wiley. - 1072-4133 .- 1099-0968. ; 18:2, s. 79-89
  • Tidskriftsartikel (refereegranskat)abstract
    • Childhood and adolescence are critical periods of neural development and physical growth. The malnutrition and related medical complications resulting from eating disorders such as anorexia nervosa (AN), bulimia nervosa (BN) and eating disorder not otherwise specified may have more severe and potentially more protracted consequences during youth than during other age periods. The consensus opinion of an international workgroup of experts on the diagnosis and treatment of child and adolescent eating disorders is that (a) lower and more developmentally sensitive threshold's of symptom seventy (e.g lower frequency of purging behaviours, significant deviations from growth curves as indicators of clinical seventy) be used as diagnostic boundaries for children and adolescents, (b) behavioural indicators of psychological features of eating disorders be considered even in the absence of direct self-report of such symptoms and (C) multiple informants (e.g parents) be used to ascertain symptom profiles. Collectively, these recommendations will permit earlier identification and intervention to prevent the exacerbation of eating disorder symptoms. Copyright (C) 2010 John Wiley & Sons, Ltd and Eating Disorders Association
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91.
  • Burger, Antoinette, et al. (författare)
  • The impact of acute and short-term methamphetamine abstinence on brain metabolites : A proton magnetic resonance spectroscopy chemical shift imaging study
  • 2018
  • Ingår i: Drug And Alcohol Dependence. - : Elsevier BV. - 0376-8716 .- 1879-0046. ; 185, s. 226-237
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundAbuse of methamphetamine (MA) is a global health concern. Previous H-1-MRS studies have found that, with methamphetamine abstinence (MAA), there are changes in n-acetyl-aspartate (NAA/Cr), myo-inositol (mI/Cr), choline (Cho/Cr and Cho/NAA), and glutamate with glutamine (Glx) metabolites. Limited studies have investigated the effect of acute MAA, and acute-to-short-term MAA on brain metabolites.MethodsAdults with chronic MA dependence (n = 31) and healthy controls (n = 22) were recruited. Two-dimensional chemical shift H-1-MRS imaging (TR2000 ms, TE30 ms) slice was performed and included voxels in bilateral anterior-cingulate (ACC), frontal-white-matter (FWM), and dorsolateral-prefrontal-cortices (DLPFC). Control participants were scanned once. The MA group was scanned twice, with acute (1.5 +/- 0.6 weeks, n = 31) and short-term MAA (5.1 +/- 0.8 weeks, n = 22). The change in H-1-MRS metabolites over time (n = 19) was also investigated. Standard H-1-MRS metabolites are reported relative to Cr + PCr.ResultsAcute MAA showed lower n-acetyl-aspartate (NAA) and n-acetyl-aspartate with n-acetyl-aspartyl-glutamate (NAA + NAAG) in left DLPFC, and glycerophosphocholine with phosphocholine (GPC + PCh) in left FWM. Short-term MAA showed lower NAA + NAAG and higher myo-inositol (mI) in right ACC, lower NAA and NAA + NAAG in the left DLPFC, and lower GPC + PCh in left FWM. Over time, MAA showed decreased NAA and NAA + NAAG and increased mI in right ACC, decreased NAA and NAA + NAAG in right FWM, and decreased in mI in left FWM.ConclusionIn acute MAA, there was damage to the integrity of neuronal tissue, which was enhanced with short-term MAA. From acute to short-term MAA, activation of neuroinflammatory processes are suggested. This is the first H-1-MRS study to report the development of neuroinflammation with loss of neuronal integrity in MAA.
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92.
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93.
  • Burger, Koert N. J., et al. (författare)
  • Dietary Fiber, Carbohydrate Quality and Quantity, and Mortality Risk of Individuals with Diabetes Mellitus
  • 2012
  • Ingår i: PLoS ONE. - San Fransisco : Public Library of Science (PLoS). - 1932-6203. ; 7:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Dietary fiber, carbohydrate quality and quantity are associated with mortality risk in the general population. Whether this is also the case among diabetes patients is unknown. Objective: To assess the associations of dietary fiber, glycemic load, glycemic index, carbohydrate, sugar, and starch intake with mortality risk in individuals with diabetes. Methods: This study was a prospective cohort study among 6,192 individuals with confirmed diabetes mellitus (mean age of 57.4 years, and median diabetes duration of 4.4 years at baseline) from the European Prospective Investigation into Cancer and Nutrition (EPIC). Dietary intake was assessed at baseline (1992-2000) with validated dietary questionnaires. Cox proportional hazards analysis was performed to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality, while adjusting for CVD-related, diabetes-related, and nutritional factors. Results: During a median follow-up of 9.2 y, 791 deaths were recorded, 306 due to CVD. Dietary fiber was inversely associated with all-cause mortality risk (adjusted HR per SD increase, 0.83 [95% CI, 0.75-0.91]) and CVD mortality risk (0.76[0.64-0.89]). No significant associations were observed for glycemic load, glycemic index, carbohydrate, sugar, or starch. Glycemic load (1.42[1.07-1.88]), carbohydrate (1.67[1.18-2.37]) and sugar intake (1.53[1.12-2.09]) were associated with an increased total mortality risk among normal weight individuals (BMI <= 25 kg/m(2); 22% of study population) but not among overweight individuals (P interaction <= 0.04). These associations became stronger after exclusion of energy misreporters. Conclusions: High fiber intake was associated with a decreased mortality risk. High glycemic load, carbohydrate and sugar intake were associated with an increased mortality risk in normal weight individuals with diabetes.
  •  
94.
  • Burger, N., et al. (författare)
  • ND3 Cys39 in complex I is exposed mitochondrial
  • 2022
  • Ingår i: Cell Chemical Biology. - : Elsevier BV. - 2451-9448 .- 2451-9456. ; 29:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Mammalian complex I can adopt catalytically active (A-) or deactive (D-) states. A defining feature of the reversible transition between these two defined states is thought to be exposure of the ND3 subunit Cys39 residue in the D-state and its occlusion in the A-state. As the catalytic A/D transition is important in health and disease, we set out to quantify it by measuring Cys39 exposure using isotopic labeling and mass spectrometry, in parallel with complex I NADH/CoQ oxidoreductase activity. To our surprise, we found significant Cys39 exposure during NADH/CoQ oxidoreductase activity. Furthermore, this activity was unaffected if Cys39 alkylation occurred during complex I-linked respiration. In contrast, alkylation of catalytically inactive complex I irreversibly blocked the reactivation of NADH/CoQ oxidoreductase activity by NADH. Thus, Cys39 of ND3 is exposed in complex I during mitochondrial respiration, with significant implications for our understanding of the A/D transition and the mechanism of complex I.
  •  
95.
  • de Rouw, Nikki, et al. (författare)
  • Rethinking the Application of Pemetrexed for Patients with Renal Impairment : A Pharmacokinetic Analysis
  • 2021
  • Ingår i: Clinical Pharmacokinetics. - : ADIS INT LTD. - 0312-5963 .- 1179-1926. ; 60:5, s. 649-654
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Pemetrexed is used for the treatment for non-small cell lung cancer and mesothelioma. Patients with renal impairment are withheld treatment with this drug as it is unknown what dose is well tolerated in this population. Objective The purpose of our study was to investigate the pharmacokinetics (PK) of pemetrexed in patients with renal impairment. Methods A population PK analysis of pemetrexed was performed using non-linear mixed-effects modelling with phase I data obtained from the manufacturer. Additionally, the impact of renal function on pemetrexed PK was assessed with a simulation study using the developed PK model and a previously developed PK model lacking the phase I data. Results The dataset included 548 paired observations of 47 patients, with a wide range of estimated glomerular filtration rates (eGFR; 14.4-145.6 mL/min). Pemetrexed PK were best described by a three-compartment model with eGFR (calculated using the Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] formula) as a linear covariate on renal pemetrexed clearance. Using the developed model, we found that renal clearance accounts for up to 84% (95% confidence interval 69-98%) of total pemetrexed clearance, whereas the manufacturer previously reported a 50% contribution of renal clearance. Conclusion Renal function is more important for the clearance of pemetrexed than previously thought and this should be taken into account in patients with renal impairment. Furthermore, a third compartment may contribute to prolonged exposure to pemetrexed during drug washout.
  •  
96.
  • Frantz, Laurent A. F., et al. (författare)
  • Ancient pigs reveal a near-complete genomic turnover following their introduction to Europe
  • 2019
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:35, s. 17231-17238
  • Tidskriftsartikel (refereegranskat)abstract
    • Archaeological evidence indicates that pig domestication had begun by similar to 10,500 y before the present ( BP) in the Near East, and mitochondrial DNA ( mtDNA) suggests that pigs arrived in Europe alongside farmers similar to 8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.
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97.
  • Lacy, Michael, et al. (författare)
  • Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease
  • 2021
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Atherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. As CD40L exerts multiple functions depending on the cell-cell interactions involved, we sought to investigate the function of the most relevant CD40L-expressing cell types in atherosclerosis: T cells and platelets. Atherosclerosis-prone mice with a CD40L-deficiency in CD4+ T cells display impaired Th1 polarization, as reflected by reduced interferon-γ production, and smaller atherosclerotic plaques containing fewer T-cells, smaller necrotic cores, an increased number of smooth muscle cells and thicker fibrous caps. Mice with a corresponding CD40-deficiency in CD11c+ dendritic cells phenocopy these findings, suggesting that the T cell-dendritic cell CD40L-CD40 axis is crucial in atherogenesis. Accordingly, sCD40L/sCD40 and interferon-γ concentrations in carotid plaques and plasma are positively correlated in patients with cerebrovascular disease. Platelet-specific deficiency of CD40L does not affect atherogenesis but ameliorates atherothrombosis. Our results establish divergent and cell-specific roles of CD40L-CD40 in atherosclerosis, which has implications for therapeutic strategies targeting this pathway.
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98.
  • Litjens, Carlijn H. C., et al. (författare)
  • Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling
  • 2022
  • Ingår i: Journal of clinical pharmacology. - : John Wiley & Sons. - 0091-2700 .- 1552-4604. ; 62:3, s. 385-396
  • Tidskriftsartikel (refereegranskat)abstract
    • Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed [P/O] ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement.
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99.
  • Litjens, Carlijn H. C., et al. (författare)
  • Protein binding of rifampicin is not saturated when using high-dose rifampicin
  • 2019
  • Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 986-990
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)in vivo was 13.3% (range=8.1%-24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
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100.
  • Martial, Lisa C, et al. (författare)
  • Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure.
  • 2016
  • Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 55:6, s. 723-733
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND OBJECTIVES: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies.METHODS: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW <80 kg) or 70/70 mg (for BW >80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs).RESULTS: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg·h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 µg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 µg/mL.CONCLUSION: The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 µg/mL.
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