Coming dissertations at Uppsala university
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Model-informed antibiotic dose individualisation in clinical practice
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-543031
Antibiotics are life-saving medications, and optimal dosing for each individual is critical to effective and safe treatment. Dose individualisation is needed when routine dosing results in concentrations that vary more than accepted between individuals from an efficacy or safety point of view. A tool for individualisation is model-informed precision dosing (MIPD), which uses software with integrated population pharmacokinetic (PK) models to interpret measured antibiotic concentrations and to optimise dosing.
This thesis aimed to improve antibiotic treatment by evaluating pharmacokinetic/pharmacodynamic (PK/PD) target attainment for alternative dosing strategies, assessing PK variability between individuals, and developing processes for MIPD in clinical practice.
One way to improve target attainment for beta-lactams without increasing the daily dose is to prolong the infusions. Different beta-lactam infusion durations were evaluated for adult intensive care patients. The predicted attainment of PK/PD targets recommended for critically ill was high for primary pathogen scenarios regardless of infusion strategy, indicating that short infusions (15 min) can be used. In situations when worst-case scenario pathogens are suspected, e.g., hospital-acquired infection, short infusions were insufficient, and 3h extended or continuous infusions improved target attainment. However, when evaluating the implemented routine use of extended infusions in critically ill, a large proportion of individuals was still below target. The large PK variability between individuals suggests a need for early monitoring to identify under and over-treated patients. In patients with sub-optimal exposure, MIPD can provide an added value.
This thesis has brought MIPD closer to clinical implementation and the benefit of patients. Barriers to implementation were addressed, including an assessment of how documentation errors can impact dosing decisions based on concentration monitoring. For vancomycin, simulations indicate that target attainment evaluations are robust with respect to locally observed errors in dose administration time. For meropenem, the impact of errors was evident already at normal renal function and pronounced in augmented renal clearance. Extra measures to promote correct documentation are needed when monitoring beta-lactams like meropenem, particularly in intensive care. Further, a novel MIPD workflow and an implementation plan for vancomycin dosing were developed. This work defined a new role for physicians or pharmacists as MIPD consultants and new tasks for clinical pharmacists. The pragmatic development process can guide other institutions aiming to initiate MIPD, and the developed workflow provides an opportunity to expand MIPD to other treatments.
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The islet hormone exocytosis machinery in type-2 diabetes
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-543091
Type-2 diabetes (T2D) is characterized by progressive β-cell dysfunction and impaired insulin secretion, yet the molecular mechanisms remain incompletely understood. In pancreatic β-cells, insulin secretion occurs through exocytosis, a process whereby insulin-containing secretory granules dock at the plasma membrane, recruit proteins that make up the SNARE-dependent exocytosis machinery (priming), and ultimately fuse with the membrane to release their content to the extracellular space. This thesis investigates the molecular machinery governing insulin granule dynamics and exocytosis in both healthy and diabetic conditions. Through analysis of secretory machinery components, we demonstrate distinct roles for SNARE binding protein Munc18 isoforms. Both Munc18 isoforms support granule docking, but Munc18-1 is strikingly required for exocytosis. On a molecular level, both isoforms bind to syntaxin, but are not recruited to the granule release site to the same extent. Our investigation of the v-SNARE protein VAMP8 reveals its predominant localization to endosomal compartments rather than insulin granules. Furthermore, we identify VAMP8 as a negative regulator of insulin secretion, likely by competing with VAMP2 at the release site, suggesting a new regulatory mechanism in β-cell function. We further examine phosphatidylinositol transfer protein alpha (PITPNA) as a critical regulator of insulin granule maturation. Modulation of PITPNA levels in human islets directly impacts insulin granule exocytosis, its silencing impairs secretion while overexpression enhances it. Importantly, restoring PITPNA expression in T2D islets reverses diabetes-related secretory defects, suggesting its loss may contribute to β-cell failure. Finally, using a novel ATP biosensor, we demonstrate that insulin granules can undergo either complete fusion, releasing both peptides and small molecules, or partial fusion that selectively releases only small transmitter molecules. This differential cargo release is regulated through cellular polarity and becomes dysregulated in T2D. Collectively, these findings provide insight into the molecular mechanisms controlling insulin granule trafficking and release, revealing multiple points of dysregulation in T2D.
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A growing concern : Online access to minors’ health records
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-542493
Healthcare worldwide is undergoing a transition where patients are increasingly granted access to their electronic health records (EHRs). However, online record access (ORA) for vulnerable groups like children and adolescents remains a topic of active debate. Minors’ experiences of patient-accessible electronic health records (PAEHRs) and related ethical questions remain underexplored.
The thesis aim was to explore stakeholder experiences of online access to minors’ EHRs, through six papers: 1) a case study comparing minors’ and guardian use of PAEHRs in Sweden and Finland and the use of country-specific access control practices; 2) a literature review summarising knowledge about stakeholder views and experiences on ORA for minors and parents; 3-4) two survey studies examining Swedish adolescents’ reasons for reading EHRs, utility, the link between use frequency and encouragement, as well as views on EHR security and privacy, attitudes toward information-sharing, and definitions of sensitive information; and 5-6) two mixed-methods studies exploring the views, awareness and benefits and risks with respect to ORA regulations among Swedish adolescents with serious health issues, their parents, and paediatric oncology HCPs. Findings were analysed using a framework of biomedical ethical principles.
Adolescents in Finland, who receive ORA earlier, showed higher PAEHR use than their Swedish counterparts. In Sweden, few applications for extended access were found. Most prior work was US-based that left minors’ experiences, especially beyond chronic illness, largely underexplored. Swedish adolescent portal users viewed information as useful and higher use was related to HCP encouragement. Although security was rated highly, many wished to manage who could access their EHRs. Mental healthcare was the most cited as sensitive. Adolescents with serious health issues, their parents, and oncology HCPs criticised the current gap in ORA during adolescence. Parents were concerned about early adolescent ORA, while HCPs worried about the impact of parental ORA on EHR quality, and lacked knowledge of access extension.
In conclusion, while ORA showed potential for engaging adolescents in their care early and facilitating parental support, risks remain for EHR quality. Education and dialogue among stakeholders, along with addressing HCP concerns, are essential efforts to make ORA an effective tool for enhancing adolescent health outcomes.