1. |
- Abbasi, Rasha, et al.
(author)
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IceCube search for neutrinos from GRB 221009A
- 2023
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In: Proceedings of 38th International Cosmic Ray Conference (ICRC 2023). - : Sissa Medialab Srl.
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Conference paper (peer-reviewed)abstract
- GRB 221009A is the brightest Gamma Ray Burst (GRB) ever observed. The observed extremelyhigh flux of high and very-high-energy photons provide a unique opportunity to probe the predictedneutrino counterpart to the electromagnetic emission. We have used a variety of methods to searchfor neutrinos in coincidence with the GRB over several time windows during the precursor, promptand afterglow phases of the GRB. MeV scale neutrinos are studied using photo-multiplier ratescalers which are normally used to search for galactic core-collapse supernovae neutrinos. GeVneutrinos are searched starting with DeepCore triggers. These events don’t have directionallocalization, but instead can indicate an excess in the rate of events. 10 GeV - 1 TeV and >TeVneutrinos are searched using traditional neutrino point source methods which take into accountthe direction and time of events with DeepCore and the entire IceCube detector respectively. The>TeV results include both a fast-response analysis conducted by IceCube in real-time with timewindows of T0 − 1 to T0 + 2 hours and T0 ± 1 day around the time of GRB 221009A, as well asan offline analysis with 3 new time windows up to a time window of T0 − 1 to T0 + 14 days, thelongest time period we consider. The combination of observations by IceCube covers 9 ordersof magnitude in neutrino energy, from MeV to PeV, placing upper limits across the range forpredicted neutrino emission.
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2. |
- Ahlström, Christine, et al.
(author)
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Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions
- 2011
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In: JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS. - 1567-567X. ; 38:1, s. 1-24
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Journal article (peer-reviewed)abstract
- A feedback model was developed to describe the tolerance and oscillatory rebound seen in non-esterified fatty acid (NEFA) plasma concentrations following intravenous infusions of nicotinic acid (NiAc) to male Sprague-Dawley rats. NiAc was administered as an intravenous infusion over 30 min (0, 1, 5 or 20 μmol kg(-1) of body weight) or over 300 min (0, 5, 10 or 51 μmol kg(-1) of body weight), to healthy rats (n = 63), and serial arterial blood samples were taken for measurement of NiAc and NEFA plasma concentrations. Data were analyzed using nonlinear mixed effects modeling (NONMEM). The disposition of NiAc was described by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. The plasma concentration of NiAc was driving NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. The NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M (1)) inhibited the formation of R and the last compartment (M ( N )) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC (50), of NiAc was 45 nmol L(-1), the fractional turnover rate k ( out ) was 0.41 L mmol(-1) min(-1) and the turnover rate of moderator k ( tol ) was 0.027 min(-1). A lower physiological limit of NEFA was modeled as a NiAc-independent release (k ( cap )) of NEFA into plasma and was estimated to 0.032 mmol L(-1) min(-1). This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc. The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues.
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3. |
- Amilon, Carl, et al.
(author)
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Population Pharmacodynamic Modeling of Eflornithine-Based Treatments Against Late-Stage Gambiense Human African Trypanosomiasis and Efficacy Predictions of L-eflornithine-Based Therapy
- 2022
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In: The AAPS journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 24:3
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Journal article (peer-reviewed)abstract
- (Carl Amilon and Mikael Boberg contributed equally to this work) Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers. Our aim was to assess (i) the efficacy of the eflornithine regimens in a time-to-event analysis and (ii) the feasibility of an L-eflornithine-based therapy integrating clinical and preclinical data. A pharmacodynamic time-to-event model was used to estimate the total dose of eflornithine, associated with 50% reduction in baseline hazard, when administered as monotherapy or in the nifurtimox-eflornithine combination therapy. The estimated total doses were 159, 60 and 291 g for intravenous eflornithine monotherapy, nifurtimox-eflornithine combination therapy and oral eflornithine monotherapy, respectively. Simulations suggested that L-eflornithine achieves a higher predicted median survival, compared to when racemate is administered, as treatment against late-stage gambiense human African trypanosomiasis. Our findings showed that oral L-eflornithine-based monotherapy would not result in adequate efficacy, even at high dose, and warrants further investigations to assess the potential of oral L-eflornithine-based treatment in combination with other treatments such as nifurtimox. An all-oral eflornithine-based regimen would provide easier access to treatment and reduce burden on patients and healthcare systems in gambiense human African trypanosomiasis endemic areas. Graphical abstract.
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4. |
- Boberg, Mikael, et al.
(author)
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Chiral Chromatographic Isolation on Milligram Scale of the Human African Trypanosomiasis Treatment D- and L-Eflornithine.
- 2020
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In: ACS omega. - : American Chemical Society (ACS). - 2470-1343. ; 5:37, s. 23885-23891
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Journal article (peer-reviewed)abstract
- Eflornithine is a recommended treatment against the otherwise fatal parasitic disease late stage human African trypanosomiasis (HAT), also known as Gambian sleeping sickness. It is administered repeatedly as a racemic mixture intravenously (IV) together with oral nifurtimox. Racemic eflornithine has been investigated in clinical trials for oral dosing. However, due to low systemic exposures at a maximum tolerated oral dose, the drug is continued to be administered IV. The eflornithine enantiomers, D- and L-eflornithine, have different affinities to the target enzyme ornithine decarboxylase, suggesting that the pharmacodynamics of the enantiomers may differ. The aim of this study was to develop a method for isolation of d- and l-eflornithine from a racemic mixture. Several chiral stationary phases (CSPs) were evaluated for enantioselectivity using supercritical fluid chromatography (SFC) or high-performance liquid chromatography (HPLC). None of the tested CSPs rendered separation of the enantiomers in SFC mode. Separation of the enantiomers with SFC on the CSP Chiralpak IG was only achieved on an analytical scale after derivatization with ortho-phthalaldehyde (OPA). This was the first reported enantioselective SFC method for an eflornithine derivate. However, due to poor stability, the eflornithine-OPA derivates degraded and no chemically pure enantiomers were obtained. The CSP that showed enantioselectivity in HPLC mode was Chirobiotic R, which resulted in a successful isolation on a semipreparative milligram scale. The isolated eflornithine enantiomers will be tested in nonclinical in vitro and in vivo studies to support and assess the feasibility of a future clinical program with an oral HAT treatment.
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5. |
- Boberg, Mikael, et al.
(author)
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Enantiospecific antitrypanosomal in vitro activity of eflornithine. : L-eflornithine against human African trypanosomiasis
- 2021
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In: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2735. ; 15:7
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Journal article (peer-reviewed)abstract
- The polyamine synthesis inhibitor eflornithine is a recommended treatment for the neglected tropical disease Gambian human African trypanosomiasis in late stage. This parasitic disease, transmitted by the tsetse fly, is lethal unless treated. Eflornithine is administered by repeated intravenous infusions as a racemic mixture of L-eflornithine and D-eflornithine. The study compared the in vitro antitrypanosomal activity of the two enantiomers with the racemic mixture against three Trypanosoma brucei gambiense strains. Antitrypanosomal in vitro activity at varying drug concentrations was analysed by non-linear mixed effects modelling. For all three strains, L-eflornithine was more potent than D-eflornithine. Estimated 50% inhibitory concentrations of the three strains combined were 9.1 μM (95% confidence interval [8.1; 10]), 5.5 μM [4.5; 6.6], and 50 μM [42; 57] for racemic eflornithine, L-eflornithine and D-eflornithine, respectively. The higher in vitro potency of L-eflornithine warrants further studies to assess its potential for improving the treatment of late-stage Gambian human African trypanosomiasis.
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7. |
- Fall, David, 1983, et al.
(author)
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Modelling cracking and bending failure of SFRC beams with conventional reinforcement
- 2013
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In: 8th International Conference on Fracture Mechanics of Concrete and Concrete Structures. - 9788494100413 ; , s. 1276-1285
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Conference paper (peer-reviewed)abstract
- In this study three beams, with varying contents of steel fibre reinforcement, were tested in four point bending and compared with results from FE-analysis. The beams were part of a larger experimental programme where relevant material properties were investigated. FE-modelling was performed using a two dimensional model. Concrete was represented by four-node quadrilateral isoperimetric plane stress elements. The smeared crack approach was utilized and the stress-strain relation describing the tensile behavior of the concrete was calculated from uni-axial test results, assuming the crack bandwidth to be equal to the element length. In compression, the concrete was assumed to behave elasto ideal-plastic. The reinforcement was modelled by straight 2-node truss elements connected to the concrete by two-dimensional interface elements providing the bond-slip properties. A material model including hardening effects was derived from tension tests of reinforcement bars and used for modelling the conventional reinforcement. A multi-linear bond-slip model was established through pull-out tests. As an alternative, analyses were also performed taking into account a reduction of the bond stress after yielding of the reinforcement occurred. Loading was applied in two phases: the first comprehending only the self-weight, while incremental loading was applied by deformation control during the second phase. General agreement between experiments and FE-analyses was obtained with regard to load-displacement behaviour. By observing the crack patterns, both from FE-analysis and experiments, it can be concluded that the general behaviour agreed; however, in the analyses not all cracks were fully localized. A higher degree of crack localization was obtained when the bond loss at yielding was included.
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8. |
- Fall, David, 1983, et al.
(author)
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Non-linear Finite Element Analysis of Steel Fibre Reinforced Beams with Conventional Reinforcement
- 2012
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In: 8th RILEM International Symposium on Fiber Reinforced Concrete: challenges and opportunities (BEFIB 2012). - 9782351581322 ; , s. 1033-1045
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Conference paper (peer-reviewed)abstract
- The purpose of this study has been to investigate the behavior of elements reinforced with both conventional steel reinforcement and steel fibres in order to support future applications of such composites. Three beams of varying fibre content were tested in four-point bending. The results were then compared with results from nonlinear FE-analyses and the calculation method suggested in fib Model Code 2010. The beams were a part of a larger experimental programme where relevant properties were investigated in uniaxial tension tests and pull-out tests. The FE-modeling was performed using a two dimensional plane stress model. General agreement between experiments and the FE-analyses was obtained with regard to load-displacement behavior. The crack patterns from the FE-analysis and experiments agreed in general, although the crack patterns in the analysis were more distributed close to the reinforcement. Crack localization was enhanced by modifying the bond-slip behavior to include the bond loss at yielding. Calculations in accordance with fib Model Code 2010 yield conservative results in comparison with both experiments and FE-analysis.
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9. |
- Funehag, Johan, et al.
(author)
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Rock Excavation Cycle and Its Effect on Grouting
- 2019
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In: ISRM 9th Nordic Grouting Symposium. - : International Society for Rock Mechanics and Rock Engineering. - 9789517586481 ; , s. 47-59
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Conference paper (other academic/artistic)abstract
- The drill and blast rock excavation cycle involves several processes that affects the grouting; vibration from drilling, borehole flushing, the blasting itself and water-loss measurements in boreholes. This research project focused on the effects of water-loss measurements, drilling (both vibration and flushing) and blasting on the grout and during the first five hours of the hardening process. A conceptual model was derived to explain what forces acts on the grout and how the forces can be interpreted in order to reveal how these forces effects the grout. The model suggests that the shear modulus of the grout is a key parameter for understanding the degradation of the grout. The different forces/stresses during an excavation effects the grout differently but the blasting is by far the most difficult process to describe. One starting point of the project is that the grout does not reinforce the rock and by that should not hinder the gas expansion. The blasting should generate new fractures around the blast hole and the gas will penetrate these cracks and finally the expansion of gases should cause fragmentation and movement in the rock mass. The paper describes the results from the field test and how the grout has been characterized using a rheometer. The field test was conducted in a short tunnel niche. The effects from the drill- and blast cycle were studied i.e. vibrations from drilling, boreholes flushing/water-loss measurements and vibrations from blasting. Five boreholes with a centrum distance of 1 m were chosen to be monitored, due to its hydraulic connectivity between the boreholes. Four of these boreholes were successfully grouted by following a grouting design and one borehole was left un-grouted and used for blasting. The effect on grouting in the rock mass from hole of blasting was measured using water-loss measurements in adjacent boreholes. One result of the field test is that the grout was not affected by the blasting under the circumstances used. Instead the study revealed that the water loss measurements affected the connected boreholes negatively.
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10. |
- Gennemark, Peter, et al.
(author)
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An oral antisense oligonucleotide for PCSK9 inhibition
- 2021
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In: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:593
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Journal article (peer-reviewed)abstract
- Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
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