| 1. |
- Abrahamsson, B., et al.
(författare)
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Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER. - 0939-6411 .- 1873-3441. ; 152, s. 236-247
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Tidskriftsartikel (refereegranskat)abstract
- OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.
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| 2. |
- Ekström, Magnus P., et al.
(författare)
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Mild to Moderate Cognitive Impairment Does Not Affect the Ability to Self-Report Important Symptoms in Patients With Cancer : A Prospective Longitudinal Multinational Study (EPCCS)
- 2020
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Ingår i: Journal of Pain and Symptom Management. - : Elsevier BV. - 0885-3924. ; 60:2, s. 2-354
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Tidskriftsartikel (refereegranskat)abstract
- Context: Patients with advanced cancer commonly suffer from both distressing symptoms and cognitive impairment, but the effect of cognitive impairment on the reliability and validity of symptom self-report is unknown. Objectives: To evaluate the reliability and validity of symptom self-report in cancer outpatients with and without mild to moderate cognitive impairment. Methods: This was an analysis of the longitudinal European Palliative Care Cancer Symptom study of adults with incurable cancer in specialized palliative care (30 centers across 12 countries). Patients who could not comply with the study because of severe cognitive impairment were excluded. Cognitive status on the Mini-Mental State Examination short version and nine symptoms (pain, tiredness, drowsiness, nausea, appetite, breathlessness, depression, anxiety, and well-being) using the revised Edmonton Symptom Assessment System were self-reported at baseline and one-month follow-up. Reliability was analyzed using intraclass correlation coefficients and validity using regression of each symptom with health-related quality of life (HrQoL) measured with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 for Palliative Care. Results: A total of 1047 patients were included: mean age of 62.9 years; 54.4% women; main cancer types were of digestive organs (26.6%), breast (21.6%), and lungs (21.2%). Cognitive impairment was present in 181 (17.3%) at baseline and associated with worse self-reported tiredness, drowsiness, appetite, and depression. Reliability (intraclass correlation coefficient) and validity (associations with HrQoL) were similar between people with/without cognitive impairment across the nine symptoms, except breathlessness, which showed a weaker relation to HrQoL in patients with cognitive impairment. Findings were robust in sensitivity analyses and after controlling for potential confounders. Conclusion: In advanced cancer, self-report of nine major symptoms was reliable and valid also in people with mild-to-moderate cognitive impairment.
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| 3. |
- Oudin Åström, Daniel, et al.
(författare)
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Temperature effects on incidence of surgery for acute type A aortic dissection in the Nordics
- 2022
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Ingår i: Global health action. - : Informa UK Limited. - 1654-9880 .- 1654-9880 .- 1654-9716. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to investigate a hypothesised association between daily mean temperature and the risk of surgery for acute type A aortic dissection (ATAAD). For the period of 1 January 2005 until 31 December 2019, we collected daily data on mean temperatures and date of 2995 operations for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Using a two-stage time-series approach, we investigated the association between hot and cold temperatures relative to the optimal temperature and the rate of ATAAD repair in the selected cities. The relative risks (RRs) of cold temperatures (<=-5 degrees C) and hot temperatures (>= 21 degrees C) compared to optimal temperature were 1.47 (95% CI: 0.72-2.99) and 1.43 (95% CI: 0.67-3.08), respectively. In line with previous studies, we observed increased risk at cold and hot temperatures. However, the observed associations were not statistically significant, thus only providing weak evidence of an association.
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| 4. |
- Berntsen, P., et al.
(författare)
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Complex modulus and compliance for airway smooth muscle cells
- 2020
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Ingår i: Physical Review E. - 2470-0045 .- 2470-0053. ; 101:3
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Tidskriftsartikel (refereegranskat)abstract
- A cell can be described as a complex viscoelastic material with structural relaxations that is modulated by thermal and chemically nonequilibrium processes. Tissue morphology and function rely upon cells' physical responses to mechanical force. We measured the frequency-dependent mechanical relaxation response of adherent human airway smooth muscle cells under adenosine triphosphate (ATP) depletion and normal ATP conditions. The frequency dependence of the complex compliance J* and modulus G* was measured over the frequencies 10(-1) < f < 10(3) Hz at selected temperatures between 4 < T < 54 degrees C. Our results show characteristic relaxation features which can be interpreted by the mode-coupling theory (MCT) of viscoelastic liquids. We analyze the shape of the spectra in terms of a so-called A(4) scenario with logarithmic scaling laws. Characteristic timescales tau(beta) and tau(alpha) appear with corresponding energy barriers E-beta approximate to (10-20)k(B) T and E-alpha approximate to (20-30)k(B)T. We demonstrate that cells are close to a glass transition. We find that the cell becomes softer around physiological temperatures, where its surface structure is more liquid-like with a plateau modulus around 0.1-0.8 kPa compared with the more solid-like interior cytoskeletal structures with a plateau modulus 1-15 kPa. Corresponding values for the viscosity are 10(2)-10(3) Pa s for the surface structures closer to the membrane and 10(4)-10(6) Pa s for the core cytoskeletal structures.
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| 5. |
- Casarino, V., et al.
(författare)
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On the maximal operator of a general Ornstein-Uhlenbeck semigroup
- 2022
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Ingår i: Mathematische Zeitschrift. - : Springer Science and Business Media LLC. - 0025-5874 .- 1432-1823. ; 301, s. 2393-2413
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Tidskriftsartikel (refereegranskat)abstract
- If Q is a real, symmetric and positive definite n x n matrix, and B a real n x n matrix whose eigenvalues have negative real parts, we consider the Ornstein-Uhlenbeck semigroup on R-n with covariance Q and drift matrix B. Our main result says that the associated maximal operator is of weak type (1, 1) with respect to the invariant measure. The proof has a geometric gist and hinges on the "forbidden zones method" previously introduced by the third author.
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| 6. |
- Casarino, V., et al.
(författare)
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On the orthogonality of generalized eigenspaces for the Ornstein-Uhlenbeck operator
- 2021
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Ingår i: Archiv der Mathematik. - : Springer Science and Business Media LLC. - 0003-889X .- 1420-8938. ; 117, s. 547-556
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Tidskriftsartikel (refereegranskat)abstract
- We study the orthogonality of the generalized eigenspaces of an Ornstein-Uhlenbeck operator L in R-N, with drift given by a real matrix B whose eigenvalues have negative real parts. If B has only one eigenvalue, we prove that any two distinct generalized eigenspaces of L are orthogonal with respect to the invariant Gaussian measure. Then we show by means of two examples that if B admits distinct eigenvalues, the generalized eigenspaces of L may or may not be orthogonal.
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| 7. |
- Casarino, V., et al.
(författare)
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On the variation operator for the Ornstein-Uhlenbeck semigroup in dimension one
- 2024
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Ingår i: Annali Di Matematica Pura Ed Applicata. - 0373-3114 .- 1618-1891. ; 203:1, s. 205-219
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Tidskriftsartikel (refereegranskat)abstract
- Consider the variation seminorm of the Ornstein-Uhlenbeck semigroup Ht in dimension one, taken with respect to t. We show that this seminorm defines an operator of weak type (1, 1) for the relevant Gaussian measure. The analogous Lp estimates for 1 < p < 8 were already known.
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| 8. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 9. |
- Lattanzi, Lucia, et al.
(författare)
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The possibility of using secondary alloys for producing aluminium matrix composite components
- 2023
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Konferensbidrag (refereegranskat)abstract
- Aluminium-based metal matrix composites (MMCs) are valid candidates to substitute cast iron in the production of automobile brake discs. These materials provide good tribological performance and suitable thermophysical properties combined in a lightweight solution. The two main challenges lie in the high-temperature mechanical properties and the recyclability of the composite at the product’s end-of-life. Aluminium gives the opportunity of using secondary alloys in the production of these MMCs. The drawback is that secondary aluminium alloys usually include several impurities and oxides that can harm mechanical and thermophysical properties. The present study focuses on characterising Al-Si-based MMCs reinforced with 20 wt.% of SiC particles. The composites are produced by squeeze casting using 100 % of secondary alloy for the matrix and are compared to the current solution developed for light brake discs. The critical material properties for brake discs are good thermal conductivity and suitable coefficient of friction. The microstructure of the MMC produced with secondary alloy presented a higher number of clustered SiC particles, probably related to the presence of oxide films that wrap the carbides and hinder their dispersion in the melt. The presence of oxide-related porosities affected the thermal conductivity of the composites produced with secondary alloys, with a reduction in thermal conductivity of 15 % from 147 to 125 W/m*K at room temperature. The reduction was maintained with increasing temperature up to 500 °C. The wear performance was tested at room temperature with a pin-on-plate tribometer against the brake pad material. The coefficient of friction did not change with the presence of the recycled matrix alloy, reaching a maximum value of 0.2 over 4 hours of testing. The wear surface on the MMC presents a tribo-layer that develops at the beginning of the wear test and maintains a stable coefficient of friction over time.
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| 10. |
- Lawenius, Lina, et al.
(författare)
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Pasteurized Akkermansia muciniphila protects from fat mass gain but not from bone loss
- 2020
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 318:4
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Tidskriftsartikel (refereegranskat)abstract
- Probiotic bacteria can protect from ovariectomy (ovx)-induced bone loss in mice. Akkermansia muciniphila is considered to have probiotic potential due to its beneficial effect on obesity and insulin resistance. The purpose of the present study was to determine if treatment with pasteurized Akkermansia muciniphila (pAkk) could prevent ovx-induced bone loss. Mice were treated with vehicle or pAkk for 4 wk, starting 3 days before ovx or sham surgery. Treatment with pAkk reduced fat mass accumulation confirming earlier findings. However, treatment with pAkk decreased trabecular and cortical bone mass in femur and vertebra of gonadal intact mice and did not protect from ovx-induced bone loss. Treatment with pAkk increased serum parathyroid hormone (PTH) levels and increased expression of the calcium transporter Trpv5 in kidney suggesting increased reabsorption of calcium in the kidneys. Serum amyloid A 3 (SAA3) can suppress bone formation and mediate the effects of PTH on bone resorption and bone loss in mice and treatment with pAkk increased serum levels of SAA3 and gene expression of Saa3 in colon. Moreover, regulatory T cells can be protective of bone and pAkk-treated mice had decreased number of regulatory T cells in mesenteric lymph nodes and bone marrow. In conclusion, treatment with pAkk protected from ovx-induced fat mass gain but not from bone loss and reduced bone mass in gonadal intact mice. Our findings with pAkk differ from some probiotics that have been shown to protect bone mass, demonstrating that not all prebiotic and probiotic factors have the same effect on bone.
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| 11. |
- Sanchez-Fernandez, Adrian, et al.
(författare)
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An integrative toolbox to unlock the structure and dynamics of protein-surfactant complexes
- 2020
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Ingår i: Nanoscale Advances. - : Royal Society of Chemistry (RSC). - 2516-0230. ; 2:9, s. 4011-4023
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Tidskriftsartikel (refereegranskat)abstract
- The interactions between protein and surfactants play an important role in the stability and performance of formulated products. Due to the high complexity of such interactions, multi-technique approaches are required to study these systems. Here, an integrative approach is used to investigate the various interactions in a model system composed of human growth hormone and sodium dodecyl sulfate. Contrast variation small-angle neutron scattering was used to obtain information on the structure of the protein, surfactant aggregates and surfactant-protein complexes. 1H and 1H-13C HSQC nuclear magnetic resonance spectroscopy was employed to probe the local structure and dynamics of specific amino acids upon surfactant addition. Through the combination of these advanced methods with fluorescence spectroscopy, circular dichroism and isothermal titration calorimetry, it was possible to identify the interaction mechanisms between the surfactant and the protein in the pre- and post-micellar regimes, and interconnect the results from different techniques. As such, the protein was revealed to evolve from a partially unfolded conformation at low SDS concentration to a molten globule at intermediate concentrations, where the protein conformation and local dynamics of hydrophobic amino acids are partially affected compared to the native state. At higher surfactant concentrations the local structure of the protein appears disrupted, and a decorated micelle structure is observed, where the protein is wrapped around a surfactant assembly. Importantly, this integrative approach allows for the identification of the characteristic fingerprints of complex transitions as seen by each technique, and establishes a methodology for an in-detail study of surfactant-protein systems. This journal is
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| 12. |
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| 13. |
- Tannergren, C., et al.
(författare)
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Physiologically based biopharmaceutics modeling of regional and colon absorption in humans
- 2023
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Ingår i: European Journal of Pharmaceutics and Biopharmaceutics. - : Elsevier. - 0939-6411 .- 1873-3441. ; 186, s. 144-159
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Tidskriftsartikel (refereegranskat)abstract
- Colon absorption is a key determinant for successful development of extended release and colon targeted drug products. This is the first systematic evaluation of the ability to predict in vivo regional differences in absorption and the extent of colon absorption in humans using mechanistic physiologically based biopharmaceutics modeling (PBBM). A new dataset, consisting of 19 drugs with a wide range of biopharmaceutics properties and extent of colon absorption in humans, was established. Mechanistic predictions of the extent of absorption and plasma exposure after oral, or jejunal and direct colon administration were performed in GastroPlus and GI-Sim using an a priori approach. Two new colon models developed in GI-Sim, were also evaluated to assess if the prediction performance could be improved. Both GastroPlus and GI-Sim met the pre-defined criteria for accurate predictions of regional and colon absorption for high permeability drugs irrespective of formulation type, while the prediction performance was poor for low permeability drugs. For solutions, the two new GI-Sim colon models improved the colon absorption prediction performance for the low permeability drugs while maintaining the accurate prediction performance for the high permeability drugs. In contrast, the prediction performance decreased for non-solutions using the two new colon models. In conclusion, PBBM can be used with sufficient accuracy to predict regional and colon absorption in humans for high permeability drugs in candidate selection as well as early design and development of extended release or colon targeted drug products. The prediction performance of the current models needs to be improved to allow high accuracy predictions for commercial drug product applications including highly accurate predictions of the entire plasma concentration-time profiles as well as for low permeability drugs.
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| 14. |
- Westin, Olof, et al.
(författare)
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Treatment of acute Achilles tendon rupture - a multicentre, non-inferiority analysis
- 2020
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Ingår i: BMC Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background While numerous clinical studies have compared the surgical and non-surgical treatment of acute Achilles tendon rupture (ATR), there are no studies that have performed a non-inferiority analysis between treatments. Methods Data from patients who were included in five randomised controlled trials from two different centres in Sweden were used. Outcomes at 1 year after ATR consisted of the patient-reported Achilles tendon Total Rupture Score (ATRS) and the functional heel-rise tests reported as the limb symmetry index (LSI). The non-inferiority statistical 10% margin was calculated as a reflection of a clinically acceptable disadvantage in ATRS and heel-rise outcome when comparing treatments. Results A total of 422 patients (350 males and 72 females) aged between 18 and 71 years, with a mean age of 40.6 (standard deviation 8.6), were included. A total of 363 (86%) patients were treated surgically. The ATRS (difference (Delta) = - 0.253 [95% confidence interval (CI); - 5.673;5.785]p = 0.36) and LSI of heel-rise height (difference = 1.43 [95% CI; - 2.43;5.59]p = 0.81), total work (difference = 0.686 [95% CI; - 4.520;6.253]p = 0.67), concentric power (difference = 2.93 [95% CI; - 6.38;11.90]p = 0.063) and repetitions (difference = - 1.30 [95% CI; - 6.32;4.13]p = 0.24) resulted in non-inferiority within a Delta - 10% margin for patients treated non-surgically. Conclusion The non-surgical treatment of Achilles tendon ruptures is not inferior compared with that of surgery in terms of 1-year patient-reported and functional outcomes.
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