| 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. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- Jansson, August, 1994, et al.
(author)
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Experimental design for shotcrete tunnel lining with distributed optical fibre monitoring
- 2022
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Conference paper (other academic/artistic)abstract
- As the demand for expanding the transport infrastructure increases, sustainable solutions for ensuring the service life and safety of new and existing structures are crucial. By introducing state-of-the art-monitoring solutions and advanced AI-algorithms, continuous verification and prediction of the structural integrity becomes possible. In this paper, the SensIT 2.0 project at Chalmers University of Technology is described and initial experimental design for applying Distributed Optical Fibers Sensing (DOFS) systems to a Fibre Reinforced Shotcrete (FRS) tunnel lining is presented.
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| 7. |
- Jansson, August, 1994, et al.
(author)
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Investigation of the Impact of Concrete Surface Treatment Methods on the Interfacial Bond Strength
- 2023
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In: RILEM Bookseries. - 2211-0844 .- 2211-0852. ; 43, s. 925-934
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Conference paper (peer-reviewed)abstract
- Fibre-reinforced shotcrete (FRS) tunnel linings in hard rock are structurally intricate due to the complexity of rock mechanics and the interaction between shotcrete and rock. As the consequences of tunnel failure can be severe, maintaining the structural safety is vital in an operating tunnel. However, to satisfy safety demands, design- and maintenance measures can be conservative, as empirical methods and worst-case scenarios are commonly used in design and repair to account for the complexity of the system. A novel method for verification of tunnel linings, combining experiments, state-of-the-art distributed optical fibre sensing systems embedded in the shotcrete, advanced finite element modelling, and machine learning algorithms is in development. For the experiments, the characterisation of bond strength between rock and FRS are crucial to simulate trustworthy data. In this paper, a literature review and experiments are presented aiming to characterise a high and a low, non-zero, interfacial bond strength between two layers of concrete. The properties of the substrate surface in terms of roughness, microcracks, cleanliness and free water are investigated before casting. The experiments study four different surface treatments, including jackhammering, grinding, grinding and adding a layer of sand to the surface, and grinding and adding free water to the surface. The literature review showed hydrodemolition as a surface treatment method to have a consistently high bond strength, while the experiments showed a lower bond strength for ground surfaces than for jackhammered specimens. The inclusion of sand did not significantly decrease the bond strength, while the addition of water slightly increased the strength.
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| 8. |
- Karlsson, Cecilia, 1968, et al.
(author)
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Gastric Bypass vs Diet and Cardiovascular Risk Factors A Nonrandomized Controlled Trial
- 2024
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In: JAMA SURGERY. - 2168-6254 .- 2168-6262.
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Journal article (peer-reviewed)abstract
- IMPORTANCE Roux-en-Y gastric bypass (RYGB) is associated with reduced cardiovascular (CV) risk factors, morbidity, and mortality. Whether these effects are specifically induced by the surgical procedure or the weight loss is unclear. OBJECTIVE To compare 6-week changes in CV risk factors in patients with obesity undergoing matching caloric restriction and weight loss by RYGB or a very low-energy diet (VLED). DESIGN, SETTING, AND PARTICIPANTS This nonrandomized controlled study (Impact of Body Weight, Low Calorie Diet, and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors, and Metabolic Biomarkers [COCKTAIL]) was conducted at a tertiary care obesity center in Norway. Participants were individuals with severe obesity preparing for RYGB or a VLED. Recruitment began February 26, 2015; the first patient visit was on March 18, 2015, and the last patient visit (9-week follow-up) was on August 9, 2017. Data were analyzed from April 30, 2021, through June 29, 2023. INTERVENTIONS VLED alone for 6 weeks or VLED for 6 weeks after RYGB; both interventions were preceded by 3-week LED. MAIN OUTCOMES AND MEASURES Between-group comparisons of 6-week changes in CV risk factors. RESULTS Among 78 patients included in the analyses, the mean (SD) age was 47.5 (9.7) years; 51 (65%) were women, and 27 (35%) were men. Except for a slightly higher mean (SD) body mass index of 44.5 (6.2) in the RYGB group (n = 41) vs 41.9 (5.4) in the VLED group (n = 37), baseline demographic and clinical characteristics were similar between groups. Major atherogenic blood lipids (low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein[a]) were reduced after RYGB in comparison with VLED despite a similar fat mass loss. Mean between-group differences were -17.7 mg/dL (95% CI, -27.9 to -7.5), -17.4 mg/dL (95% CI, -29.8 to -5.0) mg/dL, -9.94 mg/dL (95% CI, -15.75 to -4.14), and geometric mean ratio was 0.55 U/L (95% CI, 0.42 to 0.72), respectively. Changes in glycemic control and blood pressure were similar between groups. CONCLUSIONS AND RELEVANCE This study found that clinically meaningful reductions in major atherogenic blood lipids were demonstrated after RYGB, indicating that RYGB may reduce CV risk independent of weight loss.
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| 9. |
- Kvitne, Kine Eide, et al.
(author)
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Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals
- 2024
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In: Clinical Pharmacokinetics. - : Springer. - 0312-5963 .- 1179-1926. ; 63:1, s. 109-120
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Journal article (peer-reviewed)abstract
- Background and Objective: Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals.Methods: This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery.Results: The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 +/- 2.3% and 11 +/- 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 mu g h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 mu g h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 +/- 0.33 hours at week 3 to 0.77 +/- 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 mu g h/L [-0.94, 3.2]) or the diet group (0.94 mu g h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 +/- 7%, diet: 3 +/- 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 mu g h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/mu g [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals.Conclusions: Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.
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| 10. |
- Rigal, Sophie, et al.
(author)
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Normoglycemia and physiological cortisone level maintain glucose homeostasis in a pancreas-liver microphysiological system
- 2024
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In: Communications Biology. - : NATURE PORTFOLIO. - 2399-3642. ; 7:1
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Journal article (peer-reviewed)abstract
- Current research on metabolic disorders and diabetes relies on animal models because multi-organ diseases cannot be well studied with standard in vitro assays. Here, we have connected cell models of key metabolic organs, the pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based in vitro system. Aided by mechanistic mathematical modeling, we demonstrate that hyperglycemia and high cortisone concentration induce glucose dysregulation in the pancreas-liver microphysiological system (MPS), mimicking a diabetic phenotype seen in patients with glucocorticoid-induced diabetes. In this diseased condition, the pancreas-liver MPS displays beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic gene expression. Conversely, a physiological culture condition maintains glucose tolerance and beta-cell function. This method was reproducible in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic proteins, as demonstrated with a combined transcriptome and proteome analysis. A human-cell-based pancreas-liver microphysiological system serves as a preclinical platform for studying glucose-insulin homeostasis and disease mechanisms of glucose dysregulation, offering a tool for identifying targets and testing drugs.
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