Coming dissertations at Uppsala university
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The open lung in assisted spontaneous breathing
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539582
Background: Mechanical ventilation is essential for managing acute respiratory distress syndrome (ARDS). The implementation of assisted spontaneous breathing may improve diaphragm function and blood oxygenation. However, the optimal protective settings for assisted spontaneous breathing and positive end-expiratory pressure (PEEP) remain uncertain. During the weaning phase from ventilation, assisted spontaneous breathing is commonly used; however, the relationship between applied PEEP levels, transpulmonary pressure, and atelectasis formation during this process is not well understood. We hypothesised that 1) higher PEEP levels may mitigate injurious lung phenomena and 2) atelectasis formation is linearly correlated with transpulmonary pressure during ventilator weaning.
Method: The effects of six different PEEP levels on atelectasis, tidal recruitment–derecruitment (R/D), lung stress and tidal volume distribution were tested in two studies involving experimental ARDS (Studies I and II). Furthermore, the effects of PEEP on inspiratory efforts and the effort-to-drive ratio were analysed retrospectively (Study III). The correlation between atelectasis volume and transpulmonary pressure was assessed during a ramp procedure in patients weaning from mechanical ventilation (Study IV).
Results: In experimental ARDS, lung weight affected by atelectasis and tidal R/D decreased significantly with increasing PEEP levels (PEEP 0 vs 15 cmH2O, p < 0.01). Higher PEEP levels shifted the tidal volume distribution dorsally. The oesophageal pressure swing and the effort-to-drive ratio showed a significant association with the applied PEEP level (p < 0.01). Shifting PEEP from 0 to 15 cmH2O resulted in a decrease in the mean (SD) oesophageal pressure swing from -4.2 (3.1) to -1.9 (1.5) cmH2O (p < 0.01). In humans, the end-expiratory volume of atelectasis decreased significantly with reduced positive pressures (p < 0.05) and was linearly correlated with end-expiratory transpulmonary pressure (p < 0.05).
Conclusion: Higher PEEP levels limit atelectasis and tidal recruitment–derecruitment. PEEP improves ventilation homogeneity by distributing tidal volume dorsally and modulates large inspiratory efforts through the effort-to-drive ratio, potentially protecting against further lung injury. These results were found in experimental ARDS using NAVA ventilation. Further studies are required to determine their applicability in human ARDS. Additionally, the volume of end-expiratory atelectasis is linearly correlated with end-expiratory transpulmonary pressure during a ramp procedure in humans weaning from mechanical ventilation.
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The Dominant Divide : Innovation in Project-Based Organisations
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-538049
Projects, temporary organisations, have long been lauded as creative hotspots and as innovative workshops. Project-based organisations on the other hand are often seen in the literature as slow innovators, as being conservative. This "innovation paradox", the creative projects within conservative organisations seems to be related to the way that the firms are structured and the different logics which arise in the permanent organisation and its temporary projects respectively.
The aim of this study is to understand and explain the challenges surrounding innovation which comes from being a project-based organisation. The aim is reached by asking two questions: What are the ways in which innovations are (or are not) spread and adopted in a project-based organisation; and, how does the existence of separate logics within a project-based organisation affect innovation adoption? Through primarily semi-structured interviews, six embedded sub-cases in a large Swedish construction firm are presented. Using the framework of Dominant Logic, the study sets out to identify both manifested and cognitive dimensions of the two organisation’s logics.
The analysis shows how the permanent organisation often looks for strategic, long-term returns from innovation and that they use the projects to identify the value of an innovation. At the same time the time-bound projects expect their own investments to give returns within their limited existence. This can create a logical misalignment. When an innovation “makes sense” within both organisations however, innovation adoption can be rather quick. The co-existence of different organisational values is also shown to affect the strategy of adoption. While project autonomy was important, certain values such as sustainability and worker safety afforded the permanent organisation greater ability to steer the projects to adopt.
By understanding the logics in the firm, a divide between the temporary and permanent organisations appears, and it seems able to explain the difficulties of innovation. The idea of construction and project-based organisations as conservative is thus challenged in this thesis and a main finding is that to make innovations widely used they must align with existing logics. Furthermore, certain individuals who are placed at the borderline between the organisations are better able to understand both logics, something which could facilitate innovation alignment. This ability does not completely overcome the chasm however, and actors in project-based organisations seem to have to get used to the existence of a divide.
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Oral Multidrug Amorphous Formulations : Impact of Solution Components on Drug Supersaturation, Solution Chemistry, and Thermodynamic Activity
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539689
Combination drug therapy offers substantial clinical benefits by enhancing treatment efficacy and improving patient compliance. However, it presents complex challenges from a dosage form development perspective, particularly for drugs with low water solubility. To enhance solubility and bioavailability, amorphous formulations are an attractive formulation strategy. This thesis aimed to optimize and implement a rational design approach for amorphous multidrug formulations with a robust and predictable performance after oral administration. This was achieved by investigating the influence of drugs, formulation excipients, and biorelevant intestinal media on solution chemistry, colloidal precipitate stability, and membrane transport of drug combinations.
Dissolution, solubility, and supersaturation of drug combinations were investigated in buffer and fasted state simulated intestinal fluids (FaSSIF). The solution behavior of the drugs was the same for structurally related compounds, highlighting the impact of their molecular properties and chemical diversity on the solubility profiles. A reduction in the maximum achievable concentration of drugs in combination was observed in buffer and FaSSIF, but the extent of reduction in FaSSIF was affected by the degree of solubilization by media components. Membrane transport studies demonstrated that drug transport across membranes is dominated by the degree of supersaturation, rather than solubilization. The colloidal particles formed as a result of liquid-liquid phase separation underwent uncontrolled coarsening. Polymers, in comparison to surfactants and small molecules, were more effective in controlling the particle size of this colloidal phase.
The mechanistic studies on multidrug combinations led to the development of a novel approach for preparing amorphous formulations using spray drying. The developed formulation successfully maintained drug supersaturation and ensured controlled colloidal particle size upon dissolution.
The undertaken scientific efforts contribute to the knowledge in the evolving field of amorphous multidrug formulations. These findings highlight the potential of particle engineering, where a mechanistically informed selection of excipients is combined with an appropriate spray drying process, to achieve stable amorphous multidrug formulations—critical for ensuring robust drug performance and enabling intestinal absorption.