| 1. |
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| 2. |
- Skoglund, Elisabeth, et al.
(författare)
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Longitudinal Muscle and Myocellular Changes in Community-Dwelling Men Over Two Decades of Successful Aging : The ULSAM Cohort Revisited
- 2020
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Ingår i: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press (OUP). - 1079-5006 .- 1758-535X. ; 75:4, s. 654-663
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Tidskriftsartikel (refereegranskat)abstract
- Participants of the population-based Uppsala longitudinal study of adult men (ULSAM) cohort reaching more than 88 years of age (survivors, S) were investigated at age 70, 82, and 88-90 and compared at 70 years with non-survivors (NS) not reaching 82 years. Body composition, muscle mass and muscle histology were remarkably stable over 18 years of advanced aging in S. Analysis of genes involved in muscle remodeling showed that S had higher mRNA levels of myogenic differentiation factors (Myogenin, MyoD), embryonic myosin (eMyHC), enzymes involved in regulated breakdown of myofibrillar proteins (Smad2, Trim32, MuRF1,) and NCAM compared with healthy adult men (n = 8). S also had higher mRNA levels of eMyHC, Smad 2, MuRF1 compared with NS. At 88 years, S expressed decreased levels of Myogenin, MyoD, eMyHC, NCAM and Smad2 towards those seen in NS at 70 years. The gene expression pattern of S at 70 years was likely beneficial since they maintained muscle fiber histology and appendicular lean body mass until advanced age. The expression pattern at 88 years may indicate a diminished muscle remodeling coherent with a decline of reinnervation capacity and/or plasticity at advanced age.
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| 3. |
- Ali, Mohamed Atiya, et al.
(författare)
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Polyamines in foods : development of a food database
- 2011
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Ingår i: Food & Nutrition Research. - : SNF Swedish Nutrition Foundation. - 1654-6628 .- 1654-661X. ; 55, s. 5572-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Knowing the levels of polyamines (putrescine, spermidine, and spermine) in different foods is of interest due to the association of these bioactive nutrients to health and diseases. There is a lack of relevant information on their contents in foods. Objective: To develop a food polyamine database from published data by which polyamine intake and food contribution to this intake can be estimated, and to determine the levels of polyamines in Swedish dairy products. Design: Extensive literature search and laboratory analysis of selected Swedish dairy products. Polyamine contents in foods were collected using an extensive literature search of databases. Polyamines in different types of Swedish dairy products (milk with different fat percentages, yogurt, cheeses, and sour milk) were determined using high performance liquid chromatography (HPLC) equipped with a UV detector. Results: Fruits and cheese were the highest sources of putrescine, while vegetables and meat products were found to be rich in spermidine and spermine, respectively. The content of polyamines in cheese varied considerably between studies. In analyzed Swedish dairy products, matured cheese had the highest total polyamine contents with values of 52.3, 1.2, and 2.6 mg/kg for putrescine, spermidine, and spermine, respectively. Low fat milk had higher putrescine and spermidine, 1.2 and 1.0 mg/kg, respectively, than the other types of milk. Conclusions: The database aids other researchers in their quest for information regarding polyamine intake from foods. Connecting the polyamine contents in food with the Swedish Food Database allows for estimation of polyamine contents per portion.
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| 4. |
- Cui, Weiyingqi, et al.
(författare)
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High expression of cytoplasmic FOXO3 protein associated with poor prognosis of rectal cancer patients : A study from Swedish clinical trial of preoperative radiotherapy to big database analysis
- 2023
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Ingår i: Heliyon. - : Elsevier. - 2405-8440. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Accumulating evidence has implicated a pivotal role for FOXO3, FOXM1 and SIRT6 in cancer progression. The majority of researches focused on the functions of these proteins in drug resistance, but their relationships with radiotherapy (RT) response remain unclear. In this study, we examined protein expression of FOXO3, FOXM1 and SIRT6 and their clinical significance in a Swedish rectal cancer trial of preoperative RT.METHODS: Expression of FOXO3, FOXM1 and SIRT6 protein was examined by immunohistochemistry in patient samples. Genetic analysis of FOXO3, FOXM1 and SIRT6 were performed by cBioportal and MEXPRESS database. Gene-gene network analysis was conducted using GeneMANIA. Functional enrichment analysis was performed based on LinkedOmics and Metascape online software.RESULTS: FOXO3 and FOXM1were mainly expressed in the cytoplasm in both normal and tumour tissues, and SIRT6 in both the cytoplasm and nucleus in normal and tumour tissues. FOXO3 and FOXM1 expression increased from normal mucosa to primary cancer (P < 0.001), while SIRT6 expression decreased from normal mucosa to primary cancer (P < 0.001). High FOXO3 expression correlated with late TNM stage (P = 0.040), distant metastasis (P = 0.032) and independently with disease free survival (DFS) in the RT patients (HR = 7.948; P = 0.049; 95% CI = 1.002-63.032) but not in non-RT patients (P > 0.05). Genetic analysis indicated that DNA methylation status contributed to FOXO3 overexpression. Functional enrichment analysis demonstrated that FOXO3 was closely related to metabolism-related signalling pathway which in turn associated with cancer radioresistance. Moreover, there were strong gene-gene interactions between FOXO3 and metabolism-related signalling.CONCLUSIONS: Our findings suggest that FOXO3 may be a prognostic factor in rectal cancer patients with RT.
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| 5. |
- Drobni, Mirva, 1976-
(författare)
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Adhesion-related interactions of Actinomyces and Streptococcus biofilm bacteria
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adhesion of bacteria is a key event in biofilm formation and is mediated by bacterial adhesins recognising host or bacterial partner receptors. In oral biofilm formation, primary Actinomyces and Streptococcus colonizers adhere to salivary pellicle proteins such as proline-rich proteins (PRPs) as well as to mucosal surfaces. Subsequently, Actinomyces and Streptococcus strains and other bacteria, such as Veillonella, Fusobacterium and Porphyromonas, adhere to each other. The nature of this community is highly important for the health or disease status, although specific pathogenic species may also have been implicated. The aim of this thesis was to study key players in early oral colonisation, Actinomyces and Streptococcus species, and more specifically the nature of their adhesins and ligands. A further aim was to study the function of the salivary PRP proteins and an innate peptide derived thereof on bacterial adhesion, proliferation and regulation of pH, i.e. key factors in biofilm formation. In paper I and II, adhesion, proliferation and pH affecting features of the RGRPQ (arginine-glycine-arginine-proline-glutamine) peptide, derived from PRP-1, were demonstrated. By use of an alanine-scan (I), motifs for adhesion inhibition and desorption of Actinomyces naeslundii, and proliferation stimulation, ammonia production and inhibition of sucrose induced pH drop by Streptococcus gordonii were indicated. The RGRPQ peptide also stimulated S. gordonii colonisation in vivo. In paper II, a more sophisticated quantitative structure-activity relationship (QSAR) study, using statistical molecular design (SMD) and multivariate modelling (partial least squares projections to latent structures, PLS), further narrowed down the RGRPQ peptide motifs. The R and Q amino acids were crucial for activity. For proliferation a hydrophobic and large size third position amino acid was crucial, while adhesion inhibition and desorption needed a small hydrophilic second position amino acid. All functions depended on a low polarity hydrophobic fourth position. Accordingly, activities could be optimized separately, with decreased function in the others. In paper III and IV, focus was on the bacterial adhesins and their binding epitopes. The genes for FimA major subunit proteins of type-2 fimbriae were sequenced from A. naeslundii genospecies 1 and 2 and Actinomyces odontolyticus, each with unique carbohydrate binding specificities (III). Three major subtypes of FimA proteins were found that correlated with binding specificity, including a novel fimA gene in A. odontolyticus. All subtypes contained a pilin, LPXTG and E box motif. In paper IV, multiple PRP binding patterns for Actinomyces and Streptococcus strains were mapped using a hybrid peptide construct. The two most deviating binding groups deviated in type-1 fimbriae mediated binding to milk and saliva protein ligands. In conclusion, differences in bacterial adhesins and their ability to utilise salivary proteins may render bacteria tropism for different niches. Peptides derived from protein receptors, such as RGRPQ, may be important modulators of biofilm formation, giving commensal bacteria a competitive edge in the bacterial community.
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| 6. |
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| 7. |
- Glöss, Mareike, et al.
(författare)
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New mobilities: A workshop on mobility beyond the car
- 2020
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Ingår i: Conference on Human Factors in Computing Systems - Proceedings. - New York, NY, USA : ACM. - 9781450368193 ; , s. 1-8
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Konferensbidrag (refereegranskat)abstract
- HCI research on mobility and transport has been dominated by a focus on the automobile. Yet urgent environmental concerns, along with new transport technologies, have created an opportunity for new ways of thinking about how we get from A to B. App-based services, innovations in electric motors, along with changing urban transport patterns, are transforming public transit. Technology is creating new collective transit services, as well as new ways for individuals to move, such as through rental, free-floating e-scooters, so called 'micro-mobility'. This workshop seeks to discuss and establish HCI perspectives on these new mobilities - engaging with and even inventing new modes of transport, fostering collaboration between scholars with varied topical interests around mobility. We seek to bring together a group of industry and academic collaborators, bringing new competences to HCI around the exciting opportunities of redesigning our contemporary mobilities.
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| 8. |
- Hernandez, Danilo, et al.
(författare)
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Respiratory Symptoms among Waste-Picking Child Laborers A Cross-Sectional Study
- 2010
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Ingår i: International Journal of Occupational and Environmental Health. - 1077-3525. ; 16:2, s. 124-135
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Tidskriftsartikel (refereegranskat)abstract
- This study evaluates respiratory symptoms, lung function, and exposure to airborne particles among waste-picking children. We enrolled 103 waste-picking children at a dump in Managua, Nicaragua and 103 children who do not pick waste. Exposure to airborne particles was assessed by area sampling. Health data were obtained from a questionnaire, clinical examination, and spirometry. Exposure effects were evaluated with multivariate regression analysis. Exposure to particles exceeded national and international standards. Wheezing among children was related to exposure status, with waste-picking children who are both "never highly exposed" and "ever highly exposed" having greater prevalence of wheezing compared to the children who do not pick waste. FEV1 among "ever highly exposed" waste-picking children with wheeze was 13% lower than non-waste-picking children with wheeze. Exposure to small particles was unacceptably high and associated with wheeze and decreased lung function.
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| 9. |
- Hochhaus, Andreas, et al.
(författare)
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Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia : primary results of the phase 4 BYOND study
- 2020
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 34:8, s. 2125-2137
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Tidskriftsartikel (refereegranskat)abstract
- Bosutinib is approved for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and for Ph+ CP, accelerated (AP), or blast (BP) phase CML after prior treatment with tyrosine kinase inhibitors (TKIs). In the ongoing phase 4 BYOND study (NCT02228382), 163 CML patients resistant/intolerant to prior TKIs (n = 156 Ph+ CP CML, n = 4 Ph+ AP CML, n = 3 Ph-negative/BCR-ABL1+ CML) received bosutinib 500 mg once daily (starting dose). As of ≥1 year after last enrolled patient (median treatment duration 23.7 months), 56.4% of Ph+ CP CML patients remained on bosutinib. Primary endpoint of cumulative confirmed major cytogenetic response (MCyR) rate by 1 year was 75.8% in Ph+ CP CML patients after one or two prior TKIs and 62.2% after three prior TKIs. Cumulative complete cytogenetic response (CCyR) and major molecular response (MMR) rates by 1 year were 80.6% and 70.5%, respectively, in Ph+ CP CML patients overall. No patient progressed to AP/BP on treatment. Across all patients, the most common treatment-emergent adverse events were diarrhea (87.7%), nausea (39.9%), and vomiting (32.5%). The majority of patients had confirmed MCyR by 1 year and MMR by 1 year, further supporting bosutinib use for Ph+ CP CML patients resistant/intolerant to prior TKIs.
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| 10. |
- Horkoff, Jennifer, 1980, et al.
(författare)
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Modeling support for strategic API planning and analysis
- 2018
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Ingår i: Lecture Notes in Business Information Processing. - Cham : Springer International Publishing. - 1865-1356 .- 1865-1348. ; 336, s. 10-26
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Konferensbidrag (refereegranskat)abstract
- APIs provide value beyond technical functionality. They enable and manage access to strategic business assets and play a key role in enabling software ecosystems. Existing work has begun to consider the strategic business value of software APIs, but such work has limited analysis capabilities and has not made use of established, structured modeling techniques from software and requirements engineering. Such modeling languages have been used for strategic analysis of ecosystems and value exchange. We believe these techniques expand analysis possibilities for APIs, and we apply them as part of a cross-company case study focused on strategic API planning and analysis. Results show that goal, value, and workflow modeling provide new, API-specific benefits that include mapping the API ecosystem, facilitating incremental API planning, understanding dynamic API-specific roles, identifying bottlenecks in API change workflows, and identifying API value.
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| 11. |
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| 12. |
- Markljung, Ellen, et al.
(författare)
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ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth
- 2009
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 7:12, s. e1000256-
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Tidskriftsartikel (refereegranskat)abstract
- A single nucleotide substitution in intron 3 of IGF2 in pigs abrogates a binding site for a repressor and leads to a 3-fold up-regulation of IGF2 in skeletal muscle. The mutation has major effects on muscle growth, size of the heart, and fat deposition. Here, we have identified the repressor and find that the protein, named ZBED6, is previously unknown, specific for placental mammals, and derived from an exapted DNA transposon. Silencing of Zbed6 in mouse C2C12 myoblasts affected Igf2 expression, cell proliferation, wound healing, and myotube formation. Chromatin immunoprecipitation (ChIP) sequencing using C2C12 cells identified about 2,500 ZBED6 binding sites in the genome, and the deduced consensus motif gave a perfect match with the established binding site in Igf2. Genes associated with ZBED6 binding sites showed a highly significant enrichment for certain Gene Ontology classifications, including development and transcriptional regulation. The phenotypic effects in mutant pigs and ZBED6-silenced C2C12 myoblasts, the extreme sequence conservation, its nucleolar localization, the broad tissue distribution, and the many target genes with essential biological functions suggest that ZBED6 is an important transcription factor in placental mammals, affecting development, cell proliferation, and growth.
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| 13. |
- Marklund, Matti, et al.
(författare)
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Chain length of dietary alkylresorcinols affects their in vivo elimination kinetics in rats
- 2013
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Ingår i: Journal of Nutrition. - : Elsevier BV. - 0022-3166 .- 1541-6100. ; 143:10, s. 1573-1578
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Tidskriftsartikel (refereegranskat)abstract
- Two phenolic acids, 3,5-dihydroxybenzoic acid (DHBA) and 3-(3,5-dihydroxyphenyl)- propanoic acid (DHPPA), are the major metabolites of cereal alkylresorcinols (ARs). Like their precursors, AR metabolites have been suggested as biomarkers for intake of whole-grain wheat and rye and as such could aid the understanding of diet-disease associations. This study estimated and compared pharmacokinetic parameters of ARs and their metabolites in rats and investigated differences in metabolite formation after ingestion of different AR homologs. Rats were i.v. infused for 30 min with 2, 12, or 23 μmol/kg DHBA or DHPPA or orally given the same amounts of the AR homologs, C17:0 and C25:0. Repeated plasma samples, obtained from rats for 6 h (i.v.) or 36 h (oral), were simultaneously analyzed for ARs and their metabolites by GC-mass spectrometry. Pharmacokinetic parameters were estimated by population-based compartmental modeling and noncompartmental calculation. A 1-compartment model best described C25:0 pharmacokinetics, whereas C17:0 and AR metabolites best fitted 2-compartment models. Combined models for simultaneous prediction of AR and metabolite concentration were more complex, with less reliable estimates of pharmacokinetic parameters. Although the AUC of C17:0 was lower than that of C25:0 (P < 0.05), the total amount and composition of AR metabolites did not differ between rats given C17:0 or C25:0. The elimination half-life of ARs and their metabolites increased with length of the side chain (P-trend < 0.001) and ranged from 1.2 h (DHBA) to 8.8 h (C25:0). The formation of AR metabolites was slower than their elimination, indicating that the rate of AR metabolism and not excretion of DHBA and DHPPA determines their plasma concentrations in rats.
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| 14. |
- Marklund, Matti, et al.
(författare)
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Simultaneous pharmacokinetic modeling of alkylresorcinols and their main metabolites indicates dual absorption mechanisms and enterohepatic elimination in humans
- 2014
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Ingår i: Journal of Nutrition. - : Elsevier BV. - 0022-3166 .- 1541-6100. ; 144:11, s. 1674-1680
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alkylresorcinols have proven to be useful biomarkers of whole-grain wheat and rye intake in many nutritional studies. To improve their utility, more knowledge regarding the fate of alkylresorcinols and their metabolites after consumption is needed.OBJECTIVE: The objective of this study was to develop a combined pharmacokinetic model for plasma concentrations of alkylresorcinols and their 2 major metabolites, 3,5-dihydroxybenzoic acid (DHBA) and 3-(3,5-dihydroxyphenyl)-propanoic acid (DHPPA).METHODS: The model was established by using plasma samples collected from 3 women and 2 men after a single dose (120 g) of rye bran and validated against fasting plasma concentrations from 8 women and 7 men with controlled rye bran intake (23, 45, or 90 g/d). Alkylresorcinols in the lymph and plasma of a pig fed a single alkylresorcinol dose (1.3 mmol) were quantified to assess absorption. Human ileostomal effluent and pig bile after high and low alkylresorcinol doses were analyzed to evaluate biliary alkylresorcinol metabolite excretion.RESULTS: The model contained 2 absorption compartments: 1 that transferred alkylresorcinols directly to the systematic circulation and 1 in which a proportion of absorbed alkylresorcinols was metabolized before reaching the systemic circulation. Plasma concentrations of alkylresorcinols and their metabolites depended on absorption and formation, respectively, and the mean ± SEM terminal elimination half-life of alkylresorcinols (1.9 ± 0.59 h), DHPPA (1.5 ± 0.26 h), and DHBA (1.3 ± 0.22 h) did not differ. The model accurately predicted alkylresorcinol and DHBA concentrations after repeated alkylresorcinol intake but DHPPA concentration was overpredicted, possibly because of poorly modeled enterohepatic circulation. During the 8 h following administration, <2% of the alkylresorcinol dose was recovered in the lymph. DHPPA was identified in both human ileostomal effluent and pig bile, indicating availability of DHPPA for absorption and enterohepatic circulation.CONCLUSION: Intact alkylresorcinols have advantages over DHBA and DHPPA as plasma biomarkers for whole-grain wheat and rye intake because of lower susceptibility to factors other than alkylresorcinol intake.
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| 15. |
- Nyberg, Joakim, et al.
(författare)
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PopED : An extended, parallelized, nonlinear mixed effects models optimal design tool
- 2012
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Ingår i: Computer Methods and Programs in Biomedicine. - : Elsevier BV. - 0169-2607 .- 1872-7565. ; 108:2, s. 789-805
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Tidskriftsartikel (refereegranskat)abstract
- Several developments have facilitated the practical application and increased the general use of optimal design for nonlinear mixed effects models. These developments include new methodology for utilizing advanced pharmacometric models, faster optimization algorithms and user friendly software tools. In this paper we present the extension of theoptimal design software PopED, which incorporates many of these recent advances into aneasily useable enhanced GUI. Furthermore, we present new solutions to problems related to the design of experiments such as: faster and more robust FIM calculations and optimizations, optimizing over cost/utility functions and diagnostic tools and plots to evaluate designperformance. Examples for; (i) Group size optimization and efficiency translation, (ii) Cost/constraint optimization, (iii) Optimizations with different FIM approximations and (iv) optimization with parallel computing demonstrate the new features in PopED and underline the potential use of this tool when designing experiments.
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| 16. |
- Rullman, Eric, et al.
(författare)
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Endurance exercise activates matrix metalloproteinases in human skeletal muscle
- 2009
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 106:3, s. 804-812
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, the effect of exercise training on the expression and activity of matrix metalloproteinases (MMPs) in the human skeletal muscle was investigated. Ten subjects exercised one leg for 45 min with restricted blood flow and then exercised the other leg at the same absolute workload with unrestricted blood flow. The exercises were conducted four times per week for 5 wk. Biopsies were taken from the vastus lateralis muscles of both legs at rest before the training period, after 10 days and 5 wk of training, and 2 h after the first exercise bout for analysis of MMP and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA, enzyme activity, and protein expression. Levels of MMP-2, MMP-14, and TIMP-1 mRNA in muscle tissue increased after 10 days of training regardless of blood flow condition. MMP-2 mRNA level in laser-dissected myofibers and MMP-2 activity in whole muscle increased with training. The level of MMP-9 mRNA and activity increased after the first bout of exercise. Although MMP-9 mRNA levels appeared to be very low, the activity of MMP-9 after a single bout of exercise was similar to that of MMP-2 after 10 days of exercise. MMP-2 and MMP-9 protein was both present throughout the extracellular matrix of the muscle, both around fibers and capillaries, but MMP-2 was also present within the skeletal muscle fibers. These results show that MMPs are activated in skeletal muscle in nonpathological conditions such as voluntary exercise. The expression and time pattern indicate differences between the MMPs in regards of production sites as well as in the regulating mechanism
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| 17. |
- Strömberg, Anna, et al.
(författare)
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Bone marrow derived cells in adult skeletal muscle tissue in humans
- 2013
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Ingår i: Skeletal Muscle. - : Springer Science and Business Media LLC. - 2044-5040. ; 3:1, s. 12-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:During the past decade, several animal studies have demonstrated that in addition to local cells, cells from the bone marrow (BM) possess the ability to contribute to regeneration of injured skeletal muscle tissue. In addition, in mice, regular physical activity has been displayed to be a sufficient stimulus for BM-derived cell contribution to the muscle, indicating that this is part of the ongoing physiological remodeling of skeletal muscle. However, whether BM-derived cells participate in human skeletal muscle remodeling is not known. To this end, we analyzed the incorporation of BM-derived cells in healthy human skeletal muscle in women transplanted with male BM.METHODS:Skeletal muscle biopsies were obtained from the m. vastus lateralis of women transplanted with male donor hematopoietic stem cells 6 to 12 years earlier. Healthy women served as controls. Immunohistochemical staining for skeletal muscle fibers, satellite cells (SCs) or endothelial cells (ECs) combined with fluorescent in situ hybridization (FISH) of X and Y chromosomes was used to identify cells of BM origin within the biopsies. Three dimensional confocal imaging was performed to demonstrate colocalization of Y chromosome and DAPI within muscle fibers. To further investigate whether BM-derived cells incorporate into the SC niche, myoblasts were extracted from the biopsies from the transplanted women, cultured, and analyzed using XY FISH and immunocytochemistry.RESULTS:Three dimensional confocal imaging indisputably demonstrated colocalization of Y chromosome and DAPI within muscle fibers. Some Y chromosomes were found within centrally located nuclei. No Y chromosomes were detected in CD56+ SCs in the tissue sections nor in the myoblasts cultured from the extracted SCs. Y chromosome+ ECs were found in all sections from the transplanted subjects. No Y chromosomes were found in the skeletal muscle biopsies obtained from healthy control women.CONCLUSIONS:We demonstrate that BM-derived cells contribute to skeletal muscle fibers and ECs. Our results support that BM contribution to skeletal muscle occurs via direct fusion to muscle fibers, and that the contributing cells derive from the hematopoietic lineage. Thus, the present findings encourage further studies of the importance of this process for the physiological adaptation occurring throughout life.
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| 18. |
- Strömberg, Eric
(författare)
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Applied Adaptive Optimal Design and Novel Optimization Algorithms for Practical Use
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The costs of developing new pharmaceuticals have increased dramatically during the past decades. Contributing to these increased expenses are the increasingly extensive and more complex clinical trials required to generate sufficient evidence regarding the safety and efficacy of the drugs. It is therefore of great importance to improve the effectiveness of the clinical phases by increasing the information gained throughout the process so the correct decision may be made as early as possible. Optimal Design (OD) methodology using the Fisher Information Matrix (FIM) based on Nonlinear Mixed Effect Models (NLMEM) has been proven to serve as a useful tool for making more informed decisions throughout the clinical investigation. The calculation of the FIM for NLMEM does however lack an analytic solution and is commonly approximated by linearization of the NLMEM. Furthermore, two structural assumptions of the FIM is available; a full FIM and a block-diagonal FIM which assumes that the fixed effects are independent of the random effects in the NLMEM. Once the FIM has been derived, it can be transformed into a scalar optimality criterion for comparing designs. The optimality criterion may be considered local, if the criterion is based on singe point values of the parameters or global (robust), where the criterion is formed for a prior distribution of the parameters. Regardless of design criterion, FIM approximation or structural assumption, the design will be based on the prior information regarding the model and parameters, and is thus sensitive to misspecification in the design stage. Model based adaptive optimal design (MBAOD) has however been shown to be less sensitive to misspecification in the design stage. The aim of this thesis is to further the understanding and practicality when performing standard and MBAOD. This is to be achieved by: (i) investigating how two common FIM approximations and the structural assumptions may affect the optimized design, (ii) reducing runtimes complex design optimization by implementing a low level parallelization of the FIM calculation, (iii) further develop and demonstrate a framework for performing MBAOD, (vi) and investigate the potential advantages of using a global optimality criterion in the already robust MBAOD.
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| 19. |
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| 20. |
- Strömberg, Eric, 1987-, et al.
(författare)
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The effect of Fisher information matrix approximation methods in population optimal design calculations
- 2016
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 43:6, s. 609-619
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Tidskriftsartikel (refereegranskat)abstract
- With the increasing popularity of optimal design in drug development it is important to understand how the approximations and implementations of the Fisher information matrix (FIM) affect the resulting optimal designs. The aim of this work was to investigate the impact on design performance when using two common approximations to the population model and the full or block-diagonal FIM implementations for optimization of sampling points. Sampling schedules for two example experiments based on population models were optimized using the FO and FOCE approximations and the full and block-diagonal FIM implementations. The number of support points was compared between the designs for each example experiment. The performance of these designs based on simulation/estimations was investigated by computing bias of the parameters as well as through the use of an empirical D-criterion confidence interval. Simulations were performed when the design was computed with the true parameter values as well as with misspecified parameter values. The FOCE approximation and the Full FIM implementation yielded designs with more support points and less clustering of sample points than designs optimized with the FO approximation and the block-diagonal implementation. The D-criterion confidence intervals showed no performance differences between the full and block diagonal FIM optimal designs when assuming true parameter values. However, the FO approximated block-reduced FIM designs had higher bias than the other designs. When assuming parameter misspecification in the design evaluation, the FO Full FIM optimal design was superior to the FO block-diagonal FIM design in both of the examples.
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| 21. |
- Strömberg, Eric, et al.
(författare)
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The effect of using a robust optimality criterion in model based adaptive optimization.
- 2017
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 44:4, s. 317-324
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Tidskriftsartikel (refereegranskat)abstract
- Optimizing designs using robust (global) optimality criteria has been shown to be a more flexible approach compared to using local optimality criteria. Additionally, model based adaptive optimal design (MBAOD) may be less sensitive to misspecification in the prior information available at the design stage. In this work, we investigate the influence of using a local (lnD) or a robust (ELD) optimality criterion for a MBAOD of a simulated dose optimization study, for rich and sparse sampling schedules. A stopping criterion for accurate effect prediction is constructed to determine the endpoint of the MBAOD by minimizing the expected uncertainty in the effect response of the typical individual. 50 iterations of the MBAODs were run using the MBAOD R-package, with the concentration from a one-compartment first-order absorption pharmacokinetic model driving the population effect response in a sigmoidal EMAX pharmacodynamics model. The initial cohort consisted of eight individuals in two groups and each additional cohort added two individuals receiving a dose optimized as a discrete covariate. The MBAOD designs using lnD and ELD optimality with misspecified initial model parameters were compared by evaluating the efficiency relative to an lnD-optimal design based on the true parameter values. For the explored example model, the MBAOD using ELD-optimal designs converged quicker to the theoretically optimal lnD-optimal design based on the true parameters for both sampling schedules. Thus, using a robust optimality criterion in MBAODs could reduce the number of adaptations required and improve the practicality of adaptive trials using optimal design.
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| 22. |
- Ståhl, Jan Eric, et al.
(författare)
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Relationship Between Tool Temperature Distribution and Stagnation Point Behavior for Different Process Factors in Machining Operations
- 2024
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Ingår i: Moving Integrated Product Development to Service Clouds in the Global Economy - Proceedings of the 21st ISPE Inc. International Conference on Concurrent Engineering, CE 2014. - 2352-7528 .- 2352-751X. - 9781643685106 ; 52, s. 69-89
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Konferensbidrag (refereegranskat)abstract
- Metal cutting is physically defined by a tool separating a chip by developing a stagnation point after the work material has passed a shear plane. This distinguishes the method group metal cutting or machining from shearing and wedging processes. The development of the stagnation point is central to the functioning of a metal cutting process. The stagnation point and its behavior has a great influence on the different load conditions of the tool as it controls both the temperature distribution and the mechanical load distribution around the tool's edge-line. This publication shows that there is a temperature drop at the stagnation point where the shear stress changes sign, which means that the shear stress at this point assumes the value zero. Furthermore, it is demonstrated that there is a correlation between the position of the temperature dip, its size and the selected cutting data as well as tool geometry and current work material. The knowledge of the interaction between the position of the stagnation point and the tool coating type in combination with the tool's micro- and macro-geometry will be of importance for the development of high-performance tools optimized for different machining applications.
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