| 21. |
- Gillen, Michael, et al.
(författare)
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Effect of a spacer on total systemic and lung bioavailability in healthy volunteers and in vitro performance of the Symbicort® (budesonide/formoterol) pressurized metered dose inhaler
- 2018
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Ingår i: Pulmonary Pharmacology and Therapeutics. - : Elsevier BV. - 1094-5539 .- 1522-9629. ; 52, s. 7-17
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Many patients with chronic obstructive pulmonary disease or asthma experience difficulties in coordinating inhalation with pressurized metered-dose inhaler (pMDI) actuation. The use of a spacer device can improve drug delivery in these patients. The aim of this study was to establish the relative bioavailability of single doses of Symbicort® (budesonide/formoterol) pMDI 160/4.5 μg/actuation (2 actuations) used with and without a spacer device. In addition, an in vitro study was conducted to characterize performance of the inhaler when used in conjunction with a spacer device. Methods: A Phase I, randomized, open-label, single-dose, single-center, crossover study in 50 healthy volunteers (NCT02934607) assessed the relative bioavailability of single-dose Symbicort® pMDI 160/4.5 μg/actuation (2 actuations) with and without a spacer (AeroChamber Plus® Flow-Vu®). Inhaled doses were administered without or with activated charcoal (taken orally) to estimate total systemic exposure and exposure through the lung, respectively. The in vitro study characterized the effect of the spacer with respect to delivered dose, fine particle dose, and dose during simulated breathing of budesonide and formoterol. Results: In terms of total systemic exposure, use of the spacer increased the relative bioavailability determined by AUC(0-last) and Cmax by 68% (spacer:no spacer treatment ratio, 167.9%; 90% CI, 144.1 to 195.6) and 99% (ratio, 198.7%; 90% CI, 164.4 to 240.2) for budesonide, and 77% (ratio, 176.6%; 90% CI, 145.1 to 215.0) and 124% (ratio, 223.6%; 90% CI, 189.9 to 263.3) for formoterol, respectively, compared with pMDI alone. Similarly, the lung exposure of budesonide and formoterol increased (AUC(0-last) and Cmax by 146% [ratio, 246.0%; 90% CI, 200.7 to 301.6] and 127% [ratio, 226.5%; 90% CI, 186.4 to 275.4] for budesonide, and 173% [ratio, 272.8%; 90% CI, 202.5 to 367.4] and 136% [ratio, 236.2%; 90% CI, 192.6 to 289.6] for formoterol, respectively) when the pMDI was administered through the spacer. When assessed by AUC(0-last) quartile without spacer, subjects in the lowest exposure quartile (indicating poor inhalation technique) with Symbicort® pMDI 160/4.5 μg/actuation (2 actuations) had markedly increased total systemic and lung exposure when the same dose was administered with the spacer. In contrast, for subjects in the highest exposure quartile with pMDI alone, total systemic and lung exposure of formoterol and budesonide was similar with and without the spacer. In the in vitro study, the fine particle dose (<5 μm) of both budesonide and formoterol from the spacer at delay time (i.e. pause period after actuation) = 0 s (instantaneous) after actuation was similar to the fine particle dose when not using the spacer. The delivered doses of budesonide and formoterol from the spacer were both lower compared with the doses administered without the spacer. There was also a decrease in delivered dose with increasing delay time. Conclusions: The clinical study demonstrated that in subjects with poor inhalation technique the use of the AeroChamber Plus® Flow-Vu® spacer increased the bioavailability of Symbicort® pMDI to a level observed in subjects with good inhalation technique without a spacer. The findings from the in vitro study support the fine particle dose characteristics of Symbicort® pMDI with the AeroChamber Plus® Flow-Vu® spacer.
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| 22. |
- Grossi, Mario, et al.
(författare)
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Pyk2 inhibition promotes contractile differentiation in arterial smooth muscle
- 2017
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Ingår i: Journal of Cellular Physiology. - : Wiley. - 0021-9541. ; 232:11, s. 3088-3102
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Tidskriftsartikel (refereegranskat)abstract
- Modulation from contractile to synthetic phenotype of vascular smooth muscle cells is a central process in disorders involving compromised integrity of the vascular wall. Phenotype modulation has been shown to include transition from voltage-dependent toward voltage-independent regulation of the intracellular calcium level, and inhibition of non-voltage dependent calcium influx contributes to maintenance of the contractile phenotype. One possible mediator of calcium-dependent signaling is the FAK-family non-receptor protein kinase Pyk2, which is activated by a number of stimuli in a calcium-dependent manner. We used the Pyk2 inhibitor PF-4594755 and Pyk2 siRNA to investigate the role of Pyk2 in phenotype modulation in rat carotid artery smooth muscle cells and in cultured intact arteries. Pyk2 inhibition promoted the expression of smooth muscle markers at the mRNA and protein levels under stimulation by FBS or PDGF-BB and counteracted phenotype shift in cultured intact carotid arteries and balloon injury ex vivo. During long-term (24–96 hr) treatment with PF-4594755, smooth muscle markers increased before cell proliferation was inhibited, correlating with decreased KLF4 expression and differing from effects of MEK inhibition. The Pyk2 inhibitor reduced Orai1 and preserved SERCA2a expression in carotid artery segments in organ culture, and eliminated the inhibitory effect of PDGF stimulation on L-type calcium channel and large-conductance calcium-activated potassium channel expression in carotid cells. Basal intracellular calcium level, calcium wave activity, and store-operated calcium influx were reduced after Pyk2 inhibition of growth-stimulated cells. Pyk2 inhibition may provide an interesting approach for preserving vascular smooth muscle differentiation under pathophysiological conditions.
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| 23. |
- Hagbom, Marie, et al.
(författare)
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Ionizing air affects influenza virus infectivity and prevents airborne-transmission
- 2015
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Ingår i: Scientific Reports. - : Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group. - 2045-2322. ; 5:11431
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Tidskriftsartikel (refereegranskat)abstract
- By the use of a modified ionizer device we describe effective prevention of airborne transmitted influenza A (strain Panama 99) virus infection between animals and inactivation of virus (greater than 97%). Active ionizer prevented 100% (4/4) of guinea pigs from infection. Moreover, the device effectively captured airborne transmitted calicivirus, rotavirus and influenza virus, with recovery rates up to 21% after 40 min in a 19 m(3) room. The ionizer generates negative ions, rendering airborne particles/aerosol droplets negatively charged and electrostatically attracts them to a positively charged collector plate. Trapped viruses are then identified by reverse transcription quantitative real-time PCR. The device enables unique possibilities for rapid and simple removal of virus from air and offers possibilities to simultaneously identify and prevent airborne transmission of viruses.
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| 24. |
- Hartung, Kerstin, 1989-
(författare)
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Paths to improving atmospheric models across scales : The importance of the unresolved scales
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Correct representation of physical processes, the parametrizations, and their interaction with the resolved circulation is crucial for the performance of numerical models. Here, focus is put on understanding model biases and developing tools to alleviate existing biases. Atmospheric blocking can divert the typical atmospheric flow for several days up to weeks and thereby impacts the mean climate of the region experiencing blocking. Models typically underestimate the frequency of atmospheric blocking. Based on results from the global climate model EC-Earth, it is found that the atmospheric model resolution is not strongly influencing the representation of atmospheric blocking once the grid reaches about 80 km grid length in the horizontal. Updating several physical parametrizations, and thereby the model version, is the largest contributor to advancements in simulating atmospheric blocking. The importance of the topography for the large-scale atmospheric flow is further investigated with the reanalysis ERA-Interim by applying a simplified theoretical analysis. It is found that the idealized topographic forcing theory can explain some part of the observed large-scale properties of the flow, though the method does mainly produce relative results. The explained part of the large-scale structure is increased during periods of northwesterly flow and when the flow impinges the mountain ridge almost orthogonally.Small-scale processes acting in air masses transported from midlatitudes to the Arctic are also discussed. Numerical models often struggle with representing the stable conditions in the Arctic and tend to underestimate the downward longwave impact during cloudy conditions. A comparison of single-column models (SCMs) indicates that most models can capture the bimodal longwave distribution which develops from alternating cloudy and clear-sky conditions. SCMs are often used for model development as they allow to decouple the parametrized physical processes from the large-scale environment and enable many parameter sensitivity tests. A new tool is presented which can be used for the development of physical parametrizations in marine and polar conditions. It combines one-dimensional models of the atmosphere and ocean, including sea-ice, into a coupled atmosphere-ocean SCM (AOSCM). The presented setup constitutes an advantage compared to SCMs of one component because the coupling is directly modelled and the interaction between the respective boundary layers does not dependent on prescribed boundary conditions.
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| 25. |
- Hemmingsson, Jens, 1986, et al.
(författare)
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Autoradiography and biopsy measurements of a resected hepatocellular carcinoma treated with 90 yttrium radioembolization demonstrate large absorbed dose heterogeneities
- 2018
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Ingår i: Advances in Radiation Oncology. - : Elsevier BV. - 2452-1094. ; 3:3, s. 439-446
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 The Authors Purpose: Radioembolization is an alternative palliative treatment for hepatocellular carcinoma. Here, we examine the uptake differences between tumor tissue phenotypes and present a cross-section of the absorbed dose throughout a liver tissue specimen. Methods and materials: A patient with hepatocellular carcinoma was treated with90Y radioembolization followed by liver tissue resection. Gamma camera images and autoradiographs were collected and biopsy tissue samples were analyzed using a gamma well counter and light microscopy. Results: An analysis of 25 punched biopsy tissue samples identified 4 tissue regions: Normal tissue, viable tumor tissue with and without infarcted areas, and tumor areas with postnecrotic scar tissue. Autoradiography and biopsy tissue sample measurements showed large dose differences between viable and postnecrotic tumor tissue (159 Gy vs 23 Gy). Conclusions: Radioembolization of 90 yttrium with resin microspheres produces heterogeneous-absorbed dose distributions in the treatment of unifocal hepatic malignancies that could not be accurately determined with current gamma camera imaging techniques.
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| 26. |
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| 27. |
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| 28. |
- Hofmann, Robin, et al.
(författare)
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Oxygen therapy in ST-elevation myocardial infarction.
- 2018
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 39:29, s. 2730-2739
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine whether supplemental oxygen in patients with ST-elevation myocardial infarction (STEMI) impacts on procedure-related and clinical outcomes.Methods and results: The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial randomized patients with suspected myocardial infarction (MI) to receive oxygen at 6 L/min for 6-12 h or ambient air. In this pre-specified analysis, we included only STEMI patients who underwent percutaneous coronary intervention (PCI). In total, 2807 patients were included, 1361 assigned to receive oxygen, and 1446 assigned to ambient air. The pre-specified primary composite endpoint of all-cause death, rehospitalization with MI, cardiogenic shock, or stent thrombosis at 1 year occurred in 6.3% (86 of 1361) of patients allocated to oxygen compared to 7.5% (108 of 1446) allocated to ambient air [hazard ratio (HR) 0.85, 95% confidence interval (95% CI) 0.64-1.13; P = 0.27]. There was no difference in the rate of death from any cause (HR 0.86, 95% CI 0.61-1.22; P = 0.41), rate of rehospitalization for MI (HR 0.92, 95% CI 0.57-1.48; P = 0.73), rehospitalization for cardiogenic shock (HR 1.05, 95% CI 0.21-5.22; P = 0.95), or stent thrombosis (HR 1.27, 95% CI 0.46-3.51; P = 0.64). The primary composite endpoint was consistent across all subgroups, as well as at different time points, such as during hospital stay, at 30 days and the total duration of follow-up up to 1356 days.Conclusions: Routine use of supplemental oxygen in normoxemic patients with STEMI undergoing primary PCI did not significantly affect 1-year all-cause death, rehospitalization with MI, cardiogenic shock, or stent thrombosis.
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| 29. |
- Hua, Ay-Yen, et al.
(författare)
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Mapping functions in health-related quality of life: mapping from the Achilles Tendon Rupture Score to the EQ-5D.
- 2018
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Ingår i: Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. - : Springer Science and Business Media LLC. - 1433-7347. ; 26:10, s. 3083-3088
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Tidskriftsartikel (refereegranskat)abstract
- Health state utility values are derived from preference-based measurements and are useful in calculating quality-adjusted life years (QALYs), which is a metric commonly used in cost-effectiveness studies. The purpose of this study was to convert the Achilles Tendon Rupture Score (ATRS) to the preference-based European Quality of Life-5 Dimension Questionnaire (EQ-5D) by estimating the relationship between the two scores using mapping.Data were collected from a randomised controlled trial, where 100 patients were treated either surgically or non-surgically for Achilles tendon rupture. Forty-three and forty-four patients in surgical group and non-surgical group completed the ATRS and the EQ-5D alongside each other during follow-up at three time points. Different models of the relationship between the ATRS and the EQ-5D were developed and analysed based on direct mapping and cross-validation. The model with the lowest mean absolute error was observed as the one with the best fit.Among the competing models, mapping based on using a combination of the ATRS items four, five, and six associated with limitation due to pain, during activities of daily living and when walking on uneven ground, produced the best predictor of the EQ-5D score.The present study provides a mapping algorithm to enable the derivation of utility values directly from the ATRS. This approach makes it feasible for researchers, as well as medical practitioners, to obtain preference-based values in clinical studies or settings where only the ATRS is being administered. The algorithm allows for the calculation of QALYs for use in cost-effectiveness analyses, making it valuable in the study of acute Achilles tendon ruptures.II.
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| 30. |
- Högberg, Jonas, 1976, et al.
(författare)
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Increased absorbed liver dose in Selective Internal Radiation Therapy (SIRT) correlates with increased sphere-cluster frequency and absorbed dose inhomogeneity
- 2015
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Ingår i: EJNMMI Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The higher tolerated mean absorbed dose for selective internal radiation therapy (SIRT) with intra-arterially infused 90Y microspheres compared to external beam therapy is speculated to be caused by absorbed dose inhomogeneity, which allows for liver regeneration. However, the complex liver microanatomy and rheology makes modelling less valuable if the tolerance doses are not based on the actual microsphere distribution. The present study demonstrates the sphere distribution and small-scale absorbed dose inhomogeneity and its correlation with the mean absorbed dose in liver tissue resected after SIRT. Methods A patient with marginally resectable cholangiocarcinoma underwent SIRT 9 days prior to resection including adjacent normal liver tissue. The resected specimen was formalin-fixed and sliced into 1 to 2-mm sections. Forty-one normal liver biopsies 6-8 mm in diameter were punched from these sections and the radioactivity measured. Sixteen biopsies were further processed for detailed analyses by consecutive serial sectioning of 15 30-μm sections per biopsy, mounted and stained with haematoxylin-eosin. All sections were scrutinised for isolated or conglomerate spheres. Small-scale dose distributions were obtained by applying a 90Y-dose point kernel to the microsphere distributions. Results A total of 3888 spheres were found in the 240 sections. Clusters were frequently found as strings in the arterioles and as conglomerates in small arteries, with the largest cluster comprising 453 spheres. An increased mean absorbed dose in the punch biopsies correlated with large clusters and a greater coefficient of variation. In simulations the absorbed dose was 5–1240 Gy; 90% were 10-97 Gy and 45% were <30 Gy, the assumed tolerance in external beam therapy. Conclusions Sphere clusters were located in both arterioles and small arteries and increased in size with increasing sphere concentration, resulting in increased absorbed dose inhomogeneity, which contradicts earlier modelling studies.
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