| 1. |
- Maksimovic, M., et al.
(author)
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First observations and performance of the RPW instrument on board the Solar Orbiter mission
- 2021
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 656
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Journal article (peer-reviewed)abstract
- The Radio and Plasma Waves (RPW) instrument on the ESA Solar Orbiter mission is designed to measure in situ magnetic and electric fields and waves from the continuum up to several hundred kHz. The RPW also observes solar and heliospheric radio emissions up to 16 MHz. It was switched on and its antennae were successfully deployed two days after the launch of Solar Orbiter on February 10, 2020. Since then, the instrument has acquired enough data to make it possible to assess its performance and the electromagnetic disturbances it experiences. In this article, we assess its scientific performance and present the first RPW observations. In particular, we focus on a statistical analysis of the first observations of interplanetary dust by the instrument's Thermal Noise Receiver. We also review the electro-magnetic disturbances that RPW suffers, especially those which potential users of the instrument data should be aware of before starting their research work.
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| 2. |
- Maksimovic, M., et al.
(author)
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The Solar Orbiter Radio and Plasma Waves (RPW) instrument
- 2020
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In: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 642
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Journal article (peer-reviewed)abstract
- The Radio and Plasma Waves (RPW) instrument on the ESA Solar Orbiter mission is described in this paper. This instrument is designed to measure in-situ magnetic and electric fields and waves from the continuous to a few hundreds of kHz. RPW will also observe solar radio emissions up to 16 MHz. The RPW instrument is of primary importance to the Solar Orbiter mission and science requirements since it is essential to answer three of the four mission overarching science objectives. In addition RPW will exchange on-board data with the other in-situ instruments in order to process algorithms for interplanetary shocks and type III langmuir waves detections.
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| 3. |
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| 4. |
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| 5. |
- Brekkan, Ari, et al.
(author)
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Characterization of anti-drug antibody dynamics using a bivariate mixed hidden-markov model by nonlinear-mixed effects approach
- 2024
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In: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer. - 1567-567X .- 1573-8744. ; 51:1, s. 65-75
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Journal article (peer-reviewed)abstract
- Biological therapies may act as immunogenic triggers leading to the formation of anti-drug antibodies (ADAs). Population pharmacokinetic (PK) models can be used to characterize the relationship between ADA and drug disposition but often rely on the ADA bioassay results, which may not be sufficiently sensitive to inform on this characterization.In this work, a methodology that could help to further elucidate the underlying ADA production and impact on the drug disposition was explored. A mixed hidden-Markov model (MHMM) was developed to characterize the underlying (hidden) formation of ADA against the biologic, using certolizumab pegol (CZP), as a test drug. CZP is a PEGylated Fc free TNF-inhibitor used in the treatment of rheumatoid arthritis and other chronic inflammatory diseases.The bivariate MHMM used information from plasma drug concentrations and ADA measurements, from six clinical studies (n = 845), that were correlated through a bivariate Gaussian function to infer about two hidden states; production and no-production of ADA influencing PK. Estimation of inter-individual variability was not supported in this case. Parameters associated with the observed part of the model were reasonably well estimated while parameters associated with the hidden part were less precise. Individual state sequences obtained using a Viterbi algorithm suggested that the model was able to determine the start of ADA production for each individual, being a more assay-independent methodology than traditional population PK. The model serves as a basis for identification of covariates influencing the ADA formation, and thus has the potential to identify aspects that minimize its impact on PK and/or efficacy.
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| 6. |
- Bukkems, Laura H., et al.
(author)
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Association between Sports Participation, Factor VIII Levels and Bleeding in Hemophilia A
- 2023
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In: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 123:03, s. 317-325
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Journal article (peer-reviewed)abstract
- BackgroundLittle is known on how sports participation affects bleeding risk in hemophilia. This study aimed to examine associations between sports participation, factor VIII (FVIII) levels and bleeding in persons with hemophilia A.MethodsIn this observational, prospective, single-center study, persons with hemophilia A who regularly participated in sports were followed for 12 months. The associations of patient characteristics, FVIII levels, and type/frequency of sports participation with bleeding were analyzed by repeated time-to-event modelling.ResultsOne hundred and twelve persons (median age: 24 years [interquartile range:16-34], 49% severe, 49% on prophylaxis) were included. During follow-up, 70 bleeds of which 20 sports-induced were observed. FVIII levels were inversely correlated with the bleeding hazard; a 50% reduction of the baseline bleeding hazard was observed at FVIII levels of 3.1 and a 90% reduction at 28.0 IU/dL. The bleeding hazard did not correlate with sports participation. In addition, severe hemophilia, prestudy annual bleeding rate, and presence of arthropathy showed a positive association with the bleeding hazard.ConclusionsThis analysis showed that FVIII levels were an important determinant of the bleeding hazard, but sports participation was not. This observation most likely reflects the presence of adequate FVIII levels during sports participation in our study. Persons with severe hemophilia A exhibited a higher bleeding hazard at a similar FVIII levels than nonsevere, suggesting that the time spent at lower FVIII levels impacts overall bleeding hazard. These data may be used to counsel persons with hemophilia regarding sports participation and the necessity of adequate prophylaxis.
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| 7. |
- Bukkems, Laura, et al.
(author)
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Relationship between factor VIII levels and bleeding for rFVIII-SingleChain in severe hemophilia A : A repeated time-to-event analysis
- 2023
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In: CPT. - : Wiley-Blackwell. - 2163-8306. ; 12:5, s. 706-718
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Journal article (peer-reviewed)abstract
- Publications on the exposure-effect relationships of factor concentrates for hemophilia treatment are limited, whereas such analyses give insight on treatment efficacy. Our objective was to examine the relationship between the dose, factor VIII (FVIII) levels and bleeding for rFVIII-SingleChain (lonoctocog alfa, Afstyla). Data from persons with severe hemophilia A on rFVIII-SingleChain prophylaxis from three clinical trials were combined. The published rFVIII-SingleChain population pharmacokinetic (PK) model was evaluated and expanded. The probability of bleeding was described with a parametric repeated time-to-event (RTTE) model. Data included 2080 bleeds, 2545 chromogenic stage assay, and 3052 one-stage assay FVIII levels from 241 persons (median age 19 years) followed for median 1090 days. The majority of the bleeds occurred in joints (65%) and the main bleeding reason was trauma (44%). The probability of bleeding decreased during follow-up and a FVIII level of 8.9 IU/dL (95% confidence interval: 6.9-10.9) decreased the bleeding hazard by 50% compared to a situation without FVIII in plasma. Variability in bleeding hazard between persons with similar FVIII levels was large, and the pre-study annual bleeding rate explained part of this variability. When a FVIII trough level of 1 or 3 IU/dL is targeted during prophylaxis, simulations predicted two (90% prediction interval [PI]: 0-17) or one (90% PI: 0-11) bleeds per year, respectively. In conclusion, the developed PK-RTTE model adequately described the relationship between dose, FVIII levels and bleeds for rFVIII-SingleChain. The obtained estimates were in agreement with those published for the FVIII concentrates BAY 81-8973 (octocog alfa) and BAY 94-9027 (damoctocog alfa pegol), indicating similar efficacy to reduce bleeding.
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| 8. |
- Centanni, Maddalena, et al.
(author)
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Optimization of blood pressure measurement practices for pharmacodynamic analyses of tyrosine-kinase inhibitors
- 2023
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In: Clinical and Translational Science. - : John Wiley & Sons. - 1752-8054 .- 1752-8062. ; 16:1, s. 73-84
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Journal article (peer-reviewed)abstract
- Blood pressure measurements form a critical component of adverse event monitoring for tyrosine kinase inhibitors, but might also serve as a biomarker for dose titrations. This study explored the impact of various sources of within-individual variation on blood pressure readings to improve measurement practices and evaluated the utility for individual- and population-level dose selection. A pharmacokinetic-pharmacodynamic modeling framework was created to describe circadian blood pressure changes, inter- and intra-day variability, changes from dipper to non-dipper profiles, and the relationship between drug exposure and blood pressure changes over time. The framework was used to quantitatively evaluate the influence of physiological and pharmacological aspects on blood pressure measurements, as well as to compare measurement techniques, including office-based, home-based, and ambulatory 24-h blood pressure readings. Circadian changes, as well as random intra-day and inter-day variability, were found to be the largest sources of within-individual variation in blood pressure. Office-based and ambulatory 24-h measurements gave rise to potential bias (>5 mmHg), which was mitigated by model-based estimations. Our findings suggest that 5-8 consecutive, home-based, measurements taken at a consistent time around noon, or alternatively within a limited time frame (e.g., 8.00 a.m. to 12.00 p.m. or 12.00 p.m. to 5.00 p.m.), will give rise to the most consistent blood pressure estimates. Blood pressure measurements likely do not represent a sufficiently accurate method for individual-level dose selection, but may be valuable for population-level dose identification. A user-friendly tool has been made available to allow for interactive blood pressure simulations and estimations for the investigated scenarios.
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| 9. |
- Chen, Po-Wei, et al.
(author)
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Evaluation of the effect of erenumab on migraine-specific questionnaire in patients with chronic and episodic migraine
- 2023
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In: CPT. - : John Wiley & Sons. - 2163-8306. ; 12:12, s. 1988-2000
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Journal article (peer-reviewed)abstract
- Erenumab is a fully human anti-canonical calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. The Migraine-Specific Quality-of-Life Questionnaire (MSQ) is a 14-item patient-reported outcome instrument that measures the impact of migraine on health-related quality of life. Erenumab data from four phase II/III clinical trials were used to develop an item response theory (IRT) model within a nonlinear mixed effects framework, (i) evaluate the MSQ item information with respect to patient disability, (ii) characterize the longitudinal progression of the MSQ, and (iii) quantify the effect of erenumab on the MSQ in patients with migraine. The majority (80%) of information was found to be contained in 9 out of 14 items, extending the current knowledge on the reliability of the MSQ as a psychometric tool. Simulations across three MSQ domains show significant improvement from baseline, exceeding minimally important differences. Overall, the IRT model platform developed herein allows for systematic quantification of the effect of erenumab on the MSQ in patients with migraine.
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| 10. |
- Dreesen, Erwin, et al.
(author)
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Ceftriaxone dosing based on the predicted probability of augmented renal clearance in critically ill patients with pneumonia
- 2022
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In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 77:9, s. 2479-2488
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Journal article (peer-reviewed)abstract
- Objectives: PTA of protein-unbound ceftriaxone may be compromised in critically ill patients with community-acquired pneumonia (CAP) with augmented renal clearance (ARC). We aimed to determine an optimized ceftriaxone dosage regimen based on the probability of developing ARC on the next day (P-ARC,P-d+1; www.arcpredictor.com). Patients and methods: Thirty-three patients enrolled in a prospective cohort study were admitted to the ICU with severe CAP and treated with ceftriaxone 2 g once daily. Patients contributed 259 total ceftriaxone concentrations, collected during 1 or 2 days (+/- 7 samples/day). Unbound fractions of ceftriaxone were determined in all peak and trough samples (n= 76). Population pharmacokinetic modelling and simulation were performed using NONMEM7.4. Target attainment was defined as an unbound ceftriaxone concentration >4 mg/L throughout the dosing interval. Results: A two-compartment population pharmacokinetic model described the data well. The maximal protein-bound ceftriaxone concentration decreased with lower serum albumin. Ceftriaxone clearance increased with body weight and P-ARC,P-d+1 determined on the previous day. A high P-ARC,P-d+1 was identified as a clinically relevant predictor for underexposure on the next day (area under the receiver operating characteristics curve 0.77). Body weight had a weak predictive value and was therefore considered clinically irrelevant. Serum albumin had no predictive value. An optimal P-ARC,P-d+1 threshold of 5.7% was identified (sensitivity 73%, specificity 69%). Stratified once- or twice-daily 2 g dosing when below or above the 5.7% P-ARC,P-d+1 cut-off, respectively, was predicted to result in 81% PTA compared with 47% PTA under population-level once-daily 2 g dosing. Conclusions: Critically ill patients with CAP with a high P-ARC,P-d+1 may benefit from twice-daily 2 g ceftriaxone dosing for achieving adequate exposure on the next day.
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| 11. |
- Garcia-Prats, Anthony J., et al.
(author)
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Pharmacokinetics and safety of high-dose rifampicin in children with TB : the Opti-Rif trial
- 2021
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In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 76:12, s. 3237-3246
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Journal article (peer-reviewed)abstract
- Background: Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. Objectives: To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. Patients and methods: The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L.h, the geometric mean area under the concentration-time curve from 0 to 24h (AUC(0-24)) among adults receiving a 35mg/kg dose]. Results: Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range=0.4-11.7). Evaluated doses were similar to 35 mg/kg (days 1-14) and similar to 50 mg/kg (day 15) for cohort 2 and similar to 60 mg/kg (days 1-14) and similar to 75mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure. Conclusions: High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.
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| 12. |
- Germovsek, Eva, et al.
(author)
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A Time-to-Event Model Relating Integrated Craving to Risk of Smoking Relapse Across Different Nicotine Replacement Therapy Formulations
- 2021
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In: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 109:2, s. 416-423
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Journal article (peer-reviewed)abstract
- Smoking increases the risk of cancer and other diseases, causing an estimated 7 million deaths per year. Nicotine replacement therapy (NRT) reduces craving for smoking, therefore, increasing an individual's probability to remain abstinent. In this work, we for the first time quantitatively described the relationship between craving and smoking abstinence, using retrospectively collected data from 19 studies, including 3 NRT formulations (inhaler, mouth spray, and patch) and a combination of inhaler and patch. Smokers motivated to quit were included in the NRT or placebo arms. Integrated craving (i.e., craving over a period of time) was assessed with 4-category, 5-category, or 100-mm visual analogue scale. The bounded integer model was used to assess latent craving from all scales. A time-to-event model linked predicted integrated craving to the hazard of smoking relapse. Available data included 9,323 adult subjects, observed for 3 weeks up to 2 years. At the study end, 9% (11% for NRT and 5% for placebo), on average, remained abstinent according to the protocol definition. A Gompertz-Makeham hazard best described the data, with a hazard of smoking relapse decreasing over time. Latent integrated craving was positively related to the hazard of smoking relapse, through a sigmoidal maximum effect function. For the same craving, being on NRT was found to reduce the hazard of relapse by an additional 30% compared with placebo. This work confirmed that low craving is associated with a high probability of remaining smoking abstinent and that NRT, in addition to reducing craving, increases the probability of remaining smoking abstinent.
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| 13. |
- Gomes, João, 1979-
(author)
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Development of Concentrating Photovoltaic-Thermal Solar Collectors
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Fossil fuels have greatly improved human living standards and saved countless lives. However, today, their continued use threatens human survival, as CO2 levels rise at an unprecedented pace to levels never seen during human existenceon earth.This thesis aims at gathering knowledge on solar energy in general and photovoltaic thermal (PVT) and concentrating photovoltaic thermal (C-PVT) in particular. This thesis establishes several key research questions for PVTs and C-PVT collectors and attempts to answer them.A comprehensive market study of solar thermal (ST), photovoltaic (PV) and PVT was conducted to obtain prices and performance. Simulations of the energy output around the world were conducted. A ratio between ST and PV annual output was defined to serve as a tool for comparison and plotted on a world map.A key issue for PVT collectors is how to encapsulate the solar cells in a way that, amongst other things, protects the cell from the thermal expansion of the receiver, has a high transparency, and insulates electrically while at the same time conducts the heat to the receiver. In order to be useful, this analysis must also consider the impacts on the production processes. Several prototypes were constructed, a test methodology was created, and the analysis of the results enabled several conclusions on the validity of the different silicon encapsulations methods.This thesis relies heavily on collector testing with 30 different prototypes of C-PVTs being designed and constructed. Most testing was conducted using steady state method but quasi dynamic was also carried out. From this work, several guidelines were created for the design of collectors in terms of reflector geometry, cell size, string configuration, encapsulation method and several other design aspects. These analyses were complemented with thermal simulations (COMSOL & ANSYS), string layout (LT SPICE) and evaluation of existing installations. Two novel design ideas came from this thesis work, which the author will patent in the coming year. Additionally, raytracing work has been conducted and a new reflector geometry more appropriate for C-PVTs has been found to significantly improve the annual performance. Finally, the current and future position of PVTs in the global energy market is discussed.
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| 14. |
- Hoffman, Tove, et al.
(author)
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Association between guilds of birds in the African-Western Palaearctic region and the tick species Hyalomma rufipes, one of the main vectors of Crimean-Congo hemorrhagic fever virus.
- 2022
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In: Microorganisms. - : MDPI AG. - 2076-2607. ; 10
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Journal article (peer-reviewed)abstract
- The migratory behavior of wild birds contributes to the geographical spread of ticks and their microorganisms. In this study, we aimed to investigate the dispersal and co-occurrence of Francisella and spotted fever group Rickettsia (SFGR) in ticks infesting birds migrating northward in the African-Western Palaearctic region (AWPR). Birds were trapped with mist nests across the Mediterranean basin during the 2014 and 2015 spring migration. In total, 575 ticks were collected from 244 birds. We screened the ticks for the species Francisella tularensis, the genus Francisella, and SFGR by microfluidic real-time PCR. Confirmatory analyses and metagenomic sequencing were performed on tick samples that putatively tested positive for F. tularensis during initial screenings. Hyalomma rufipes was the most common tick species and had a high prevalence of Francisella, including co-occurrence of Francisella and SFGR. Metagenomic analysis of total DNA extracted from two H. rufipes confirmed the presence of Francisella, Rickettsia, and Midichloria. Average nucleotide identity and phylogenetic inference indicated the highest identity of the metagenome-assembled genomes to a Francisella-like endosymbiont (FLE), Rickettsia aeschlimannii, and Midichloria mitochondrii. The results of this study suggest that (i) FLE- and SFGR-containing ticks are dispersed by northbound migratory birds in the AWPR, (ii) H. rufipes likely is not involved in transmission of F. tularensis in the AWPR, and (iii) a dual endosymbiosis of FLEs and Midichloria may support some of the nutritional requirements of H. rufipes.
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| 15. |
- Hoffman, Tove, et al.
(author)
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Co-Occurrence of Francisella, Spotted Fever Group Rickettsia, and Midichloria in Avian-Associated Hyalomma rufipes
- 2022
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In: Microorganisms. - : MDPI. - 2076-2607. ; 10:7
-
Journal article (peer-reviewed)abstract
- The migratory behavior of wild birds contributes to the geographical spread of ticks and their microorganisms. In this study, we aimed to investigate the dispersal and co-occurrence of Francisella and spotted fever group Rickettsia (SFGR) in ticks infesting birds migrating northward in the African-Western Palaearctic region (AWPR). Birds were trapped with mist nests across the Mediterranean basin during the 2014 and 2015 spring migration. In total, 575 ticks were collected from 244 birds. We screened the ticks for the species Francisella tularensis, the genus Francisella, and SFGR by microfluidic real-time PCR. Confirmatory analyses and metagenomic sequencing were performed on tick samples that putatively tested positive for F. tularensis during initial screenings. Hyalomma rufipes was the most common tick species and had a high prevalence of Francisella, including co-occurrence of Francisella and SFGR. Metagenomic analysis of total DNA extracted from two H. rufipes confirmed the presence of Francisella, Rickettsia, and Midichloria. Average nucleotide identity and phylogenetic inference indicated the highest identity of the metagenome-assembled genomes to a Francisella-like endosymbiont (FLE), Rickettsia aeschlimannii, and Midichloria mitochondrii. The results of this study suggest that (i) FLE- and SFGR-containing ticks are dispersed by northbound migratory birds in the AWPR, (ii) H. rufipes likely is not involved in transmission of F. tularensis in the AWPR, and (iii) a dual endosymbiosis of FLEs and Midichloria may support some of the nutritional requirements of H. rufipes.
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| 16. |
- Karlsson, Lars O, 1975, et al.
(author)
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Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Contribute to Exercise-Induced Neurogenesis.
- 2021
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In: Molecular neurobiology. - : Springer Science and Business Media LLC. - 1559-1182 .- 0893-7648. ; 58, s. 1465-1481
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Journal article (peer-reviewed)abstract
- Physical exercise can improve age-dependent decline in cognition, which in rodent is partly mediated by restoration of an age-dependent decline in neurogenesis. Exercise-inducible myokines in the circulation present a link in muscle-brain crosstalk. The transcription factor PGC-1α regulates the release of such myokines with neurotrophic properties into the circulation. We study how chronic muscular overexpression of PGC-1α could contribute to exercise-induced effects on hippocampal neurogenesis and if this effect could be enhanced in a running wheel paradigm. We used 3- and 11-month-old transgenic mice with overexpression of PGC-1α under the control of muscle creatinine kinase promoter (MCK-PGC-1α), which have a constitutively developed endurance muscle phenotype. Wild-type and MCK-PGC-1α mice were single housed with free access to running wheels. Four weeks of running in female animals increased the levels of newborn cells, immature neurons, and, for young animals, new mature neurons, compared to sedentary controls. However, no difference in these parameters was observed between wild-type and transgenic mice under sedentary or running conditions. Multiplex analysis of serum cytokines, chemokines, and myokines suggested several differences in serum protein concentrations between genotypes with musclin found to be significantly upregulated 4-fold in male MCK-PGC-1α animals. We conclude that constitutive muscular overexpression of PGC-1α, despite systemic changes and difference in serum composition, does not translate into exercise-induced effects on hippocampal neurogenesis, independent of the age of the animal. This suggests that chronic activation of PGC-1α in skeletal muscle is by itself not sufficient to mimic exercise-induced effects or to prevent decline of neurogenesis in aging.
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| 17. |
- Krishnan, Sreenath M., et al.
(author)
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Multistate model for pharmacometric analyses of overall survival in HER2-negative breast cancer patients treated with docetaxel
- 2021
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In: CPT. - : John Wiley & Sons. - 2163-8306. ; 10:10, s. 1255-1266
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Journal article (peer-reviewed)abstract
- The aim of this study was to develop a multistate model for overall survival (OS) analysis, based on parametric hazard functions and combined with an investigation of predictors derived from a longitudinal tumor size model on the transition hazards. Different states - stable disease, tumor response, progression, second-line treatment, and death following docetaxel treatment initiation (stable state) in patients with HER2-negative breast cancer (n = 183) were used in model building. Past changes in tumor size prospectively predicts the probability of state changes. The hazard of death after progression was lower for subjects who had longer treatment response (i.e., longer time-to-progression). Young age increased the probability of receiving second-line treatment. The developed multistate model adequately described the transitions between different states and jointly the overall event and survival data. The multistate model allows for simultaneous estimation of transition rates along with their tumor model derived metrics. The metrics were evaluated in a prospective manner so not to cause immortal time bias. Investigation of predictors and characterization of the time to develop response, the duration of response, the progression-free survival, and the OS can be performed in a single multistate modeling exercise. This modeling approach can be applied to other cancer types and therapies to provide a better understanding of efficacy of drug and characterizing different states, thereby facilitating early clinical interventions to improve anticancer therapy.
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| 18. |
- Krämer, Eva, et al.
(author)
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Waves in Magnetosheath Jets-Classification and the Search for Generation Mechanisms Using MMS Burst Mode Data
- 2023
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In: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 128:7
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Journal article (peer-reviewed)abstract
- Magnetosheath jets are localized dynamic pressure enhancements in the magnetosheath. We make use of the high time resolution burst mode data of the Magnetospheric Multiscale mission for an analysis of waves in plasmas associated with three magnetosheath jets. We find both electromagnetic and electrostatic waves over the frequency range from 0 to 4 kHz that can be probed by the instruments on board the MMS spacecraft. At high frequencies we find electrostatic solitary waves, electron acoustic waves, and whistler waves. Electron acoustic waves and whistler waves show the typical properties expected from theory assuming approximations of a homogeneous plasma and linearity. In addition, 0.2 Hz waves in the magnetic field, 1 Hz electromagnetic waves, and lower hybrid waves are observed. For these waves the approximation of a homogeneous plasma does not hold anymore and the observed waves show properties from several different basic wave modes. In addition, we investigate how the various types of waves are generated. We show evidence that, the 1 Hz waves are connected to gradients in the density and magnetic field. The whistler waves are generated by a butterfly-shaped pitch-angle distribution and the electron acoustic waves by a cold electron population. The lower hybrid waves are probably generated by currents at the boundary of the jets. As for the other waves we can only speculate about the generation mechanism due to limitations of the instruments. Studying waves in jets will help to address the microphysics in jets which can help to understand the evolution of jets better.
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| 19. |
- Liu, Han, et al.
(author)
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A multistate modeling and simulation framework to learn dose-response of oncology drugs : Application to bintrafusp alfa in non‐small cell lung cancer
- 2023
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In: CPT. - : John Wiley & Sons. - 2163-8306. ; 12:11, s. 1738-1750
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Journal article (peer-reviewed)abstract
- The dose/exposure-efficacy analyses are often conducted separately for oncology end points like best overall response, progression-free survival (PFS) and overall survival (OS). Multistate models offer to bridge these dose-end point relationships by describing transitions and transition times from enrollment to response, progression, and death, and evaluating transition-specific dose effects. This study aims to apply the multistate pharmacometric modeling and simulation framework in a dose optimization setting of bintrafusp alfa, a fusion protein targeting TGF-β and PD-L1. A multistate model with six states (stable disease [SD], response, progression, unknown, dropout, and death) was developed to describe the totality of endpoints data (time to response, PFS, and OS) of 80 patients with non-small cell lung cancer receiving 500 or 1200 mg of bintrafusp alfa. Besides dose, evaluated predictor of transitions include time, demographics, premedication, disease factors, individual clearance derived from a pharmacokinetic model, and tumor dynamic metrics observed or derived from tumor size model. We found that probabilities of progression and death upon progression decreased over time since enrollment. Patients with metastasis at baseline had a higher probability to progress than patients without metastasis had. Despite dose failed to be statistically significant for any individual transition, the combined effect quantified through a model with dose-specific transition estimates was still informative. Simulations predicted a 69.2% probability of at least 1 month longer, and, 55.6% probability of at least 2-months longer median OS from the 1200 mg compared to the 500 mg dose, supporting the selection of 1200 mg for future studies.
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| 20. |
- Llanos-Paez, Carolina C., et al.
(author)
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Improved Confidence in a Confirmatory Stage by Application of Item-Based Pharmacometrics Model : Illustration with a Phase III Active Comparator-Controlled Trial in COPD Patients
- 2022
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In: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 39:8, s. 1779-1787
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Journal article (peer-reviewed)abstract
- Purpose The current study aimed to illustrate how a non-linear mixed effect (NLME) model-based analysis may improve confidence in a Phase III trial through more precise estimates of the drug effect. Methods The FULFIL clinical trial was a Phase III study that compared 24 weeks of once daily inhaled triple therapy with twice daily inhaled dual therapy in patients with chronic obstructive pulmonary disease (COPD). Patient reported outcome data, obtained by using The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) questionnaire, from the FULFIL study were analyzed using an NLME item-based response theory model (IRT). The change from baseline (CFB) in E-RS:COPD total score over 4-week intervals for each treatment arm was obtained using the IRT and compared with published results obtained with a mixed model repeated measures (MMRM) analysis. Results The IRT included a graded response model characterizing item parameters and a Weibull function combined with an offset function to describe the COPD symptoms-time course in patients receiving either triple therapy (n = 907) or dual therapy (n = 894). The IRT improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of at least 3.64 times larger for the MMRM analysis to achieve the IRT precision in the CFB estimate. Conclusion This study shows the advantage of IRT over MMRM with a direct comparison of the same primary endpoint for the two analyses using the same observed clinical trial data, resulting in an increased confidence in Phase III.
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| 21. |
- Llanos-Paez, Carolina, et al.
(author)
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Improved Decision-Making Confidence Using Item-Based Pharmacometric Model : Illustration with a Phase II Placebo-Controlled Trial
- 2021
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In: AAPS Journal. - : Springer. - 1550-7416. ; 23:4
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Journal article (peer-reviewed)abstract
- This study aimed to illustrate how a new methodology to assess clinical trial outcome measures using a longitudinal item response theory-based model (IRM) could serve as an alternative to mixed model repeated measures (MMRM). Data from the EXACT (Exacerbation of chronic pulmonary disease tool) which is used to capture frequency, severity, and duration of exacerbations in COPD were analyzed using an IRM. The IRM included a graded response model characterizing item parameters and functions describing symptom-time course. Total scores were simulated (month 12) using uncertainty in parameter estimates. The 50th (2.5th, 97.5th) percentiles of the resulting simulated differences in average total score (drug minus placebo) represented the estimated drug effect (95%CI), which was compared with published MMRM results. Furthermore, differences in sample size, sensitivity, specificity, and type I and II errors between approaches were explored. Patients received either oral danirixin 75 mg twice daily (n=45) or placebo (n=48) on top of standard of care over 52 weeks. A step function best described the COPD symptoms-time course in both trial arms. The IRM improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of 2.5 times larger for the MMRM analysis to achieve the IRM precision. The IRM showed a higher probability of a positive predictive value (34%) than MMRM (22%). An item model-based analysis data gave more precise estimates of drug effect than MMRM analysis for the same endpoint in this one case study.
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| 22. |
- Llanos-Paez, Carolina, et al.
(author)
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Joint longitudinal model-based meta-analysis of FEV1 and exacerbation rate in randomized COPD trials
- 2023
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In: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Nature. - 1567-567X .- 1573-8744. ; 50:4, s. 297-314
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Journal article (peer-reviewed)abstract
- Model-based meta-analysis (MBMA) is an approach that integrates relevant summary level data from heterogeneously designed randomized controlled trials (RCTs). This study not only evaluated the predictability of a published MBMA for forced expiratory volume in one second (FEV1) and its link to annual exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) but also included data from new RCTs. A comparative effectiveness analysis across all drugs was also performed. Aggregated level data were collected from RCTs published between July 2013 and November 2020 (n = 132 references comprising 156 studies) and combined with data used in the legacy MBMA (published RCTs up to July 2013 - n = 142). The augmented data (n = 298) were used to evaluate the predictive performance of the published MBMA using goodness-of-fit plots for assessment. Furthermore, the model was extended including drugs that were not available before July 2013, estimating a new set of parameters. The legacy MBMA model predicted the post-2013 FEV1 data well, and new estimated parameters were similar to those of drugs in the same class. However, the exacerbation model overpredicted the post-2013 mean annual exacerbation rate data. Inclusion of year when the study started on the pre-treatment placebo rate improved the model predictive performance perhaps explaining potential improvements in the disease management over time. The addition of new data to the legacy COPD MBMA enabled a more robust model with increased predictability performance for both endpoints FEV1 and mean annual exacerbation rate.
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| 23. |
- Lyauk, Yassine Kamal, et al.
(author)
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Integrated Item Response Theory Modeling of Multiple Patient-Reported Outcomes Assessing Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia
- 2020
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In: AAPS Journal. - : SPRINGER. - 1550-7416. ; 22:5
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Journal article (peer-reviewed)abstract
- In clinical trials within lower urinary tract symptoms due to benign prostatic hyperplasia (BPH-LUTS), the International Prostate Symptom Score (IPSS) is commonly the primary efficacy outcome while the Quality of Life (QoL) score and the BPH Impact Index (BII) are common secondary efficacy markers. The current study aimed to characterize BPH-LUTS progression using responses to the IPSS, the QoL, and the BII in an integrated item response theory (IRT) framework and assess the Fisher information of each scale. The power of this approach to detect a drug effect was compared with an IRT approach considering only IPSS responses. A unidimensional and a bidimensional pharmacometric IRT model, based on item-level IPSS responses in a clinical trial with 403 patients, were extended by incorporating patients' QoL and summary BII scores over the 6-month trial period. In the developed unidimensional integrated model, the QoL score was found to be the most informative, representing 17% of the total Fisher information, while the combined information content of the seven IPSS items represented 70.6%. In the bidimensional model, "storage" and both storage and "voiding" disability drove QoL and summary BII responses, respectively. Sample size reduction of 16% to detect a drug effect at 80% power was obtained with the unidimensional integrated IRT model compared with its counterpart IPSS IRT model. This study shows that utilizing the information content across the IPSS, QoL, and BII scales in an integrated IRT framework results in a modest but meaningful increase in power to detect a drug effect.
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| 24. |
- Minichmayr, Iris K., et al.
(author)
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Pharmacometrics-Based Considerations for the Design of a Pharmacogenomic Clinical Trial Assessing Irinotecan Safety
- 2021
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In: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 38:4, s. 593-605
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Journal article (peer-reviewed)abstract
- Purpose Pharmacometric models provide useful tools to aid the rational design of clinical trials. This study evaluates study design-, drug-, and patient-related features as well as analysis methods for their influence on the power to demonstrate a benefit of pharmacogenomics (PGx)-based dosing regarding myelotoxicity. Methods Two pharmacokinetic and one myelosuppression model were assembled to predict concentrations of irinotecan and its metabolite SN-38 given different UGT1A1 genotypes (poor metabolizers: CLSN-38: -36%) and neutropenia following conventional versus PGx-based dosing (350 versus 245 mg/m(2) (-30%)). Study power was assessed given diverse scenarios (n = 50-400 patients/arm, parallel/crossover, varying magnitude of CLSN-38, exposure-response relationship, inter-individual variability) and using model-based data analysis versus conventional statistical testing. Results The magnitude of CLSN-38 reduction in poor metabolizers and the myelosuppressive potency of SN-38 markedly influenced the power to show a difference in grade 4 neutropenia (<0.5 center dot 10(9) cells/L) after PGx-based versus standard dosing. To achieve >80% power with traditional statistical analysis (chi(2)/McNemar's test, alpha = 0.05), 220/100 patients per treatment arm/sequence (parallel/crossover study) were required. The model-based analysis resulted in considerably smaller total sample sizes (n = 100/15 given parallel/crossover design) to obtain the same statistical power. Conclusions The presented findings may help to avoid unfeasible trials and to rationalize the design of pharmacogenetic studies.
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| 25. |
- Nyberg, Joakim, et al.
(author)
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Properties of the full random-effect modeling approach with missing covariate data
- 2024
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In: Statistics in Medicine. - : John Wiley & Sons. - 0277-6715 .- 1097-0258. ; 43:5, s. 935-952
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Journal article (peer-reviewed)abstract
- During drug development, a key step is the identification of relevant covariates predicting between-subject variations in drug response. The full random effects model (FREM) is one of the full-covariate approaches used to identify relevant covariates in nonlinear mixed effects models. Here we explore the ability of FREM to handle missing (both missing completely at random (MCAR) and missing at random (MAR)) covariate data and compare it to the full fixed-effects model (FFEM) approach, applied either with complete case analysis or mean imputation. A global health dataset (20 421 children) was used to develop a FREM describing the changes of height for age Z-score (HAZ) over time. Simulated datasets (n = 1000) were generated with variable rates of missing (MCAR) covariate data (0%-90%) and different proportions of missing (MAR) data condition on either observed covariates or predicted HAZ. The three methods were used to re-estimate model and compared in terms of bias and precision which showed that FREM had only minor increases in bias and minor loss of precision at increasing percentages of missing (MCAR) covariate data and performed similarly in the MAR scenarios. Conversely, the FFEM approaches either collapsed at ≥70% of missing (MCAR) covariate data (FFEM complete case analysis) or had large bias increases and loss of precision (FFEM with mean imputation). Our results suggest that FREM is an appropriate approach to covariate modeling for datasets with missing (MCAR and MAR) covariate data, such as in global health studies.
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