Coming theses from other universities
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Pharmacometric tools to support translational drug development
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-524851
The use of model-informed drug development has been shown to save significant costs and improve decision making early in the drug development process. The work in this PhD thesis aimed to employ pharmacometric tools to support translational drug development from the preclinical to the late clinical stages.
Pharmacometric modeling was used to characterize the treatment-shortening potential of different anti tuberculosis regimens. The results provided additional evidence in favor of the treatment-shortening capacity of the BPaMZ regimen over BPaL and standard of care, HRZE.
Pharmacokinetic-pharmacodynamic (PKPD) modeling was used to enable the evaluation of the exposure-response of a new anti-tubercular drug, MPL-447, in C3HeB/FeJ mice, thought to be of a translational value in tuberculosis drug development. Model-based evaluation revealed a significant impact of necrotic lesion development in mice on both bacterial growth and sensitivity to treatment with MPL-447, highlighting the significance of accounting for the heterogenous lesion profile in the C3HeB/FeJ mouse model when evaluating drug efficacy.
Pharmacokinetic (PK) modeling was employed to perform interspecies PK scaling of the CB 4332 protein using information from three preclinical species. This approach accounted for the impact of immunogenicity and species-related differences in elimination. Simulations predicted the protein plasma concentrations in humans after different dosing regimens and suggested that a 7 mg/kg dose would be required to reach the target at steady-state.
Using combined biomarker data, PKPD modeling was employed to simultaneously analyze two tuberculosis efficacy biomarkers. The final biomarker model facilitated the prediction of the relationship between the two biomarkers over time. With this modeling framework, missing biomarker data can be predicted using information from the other biomarker.
Several model-based approaches were also explored to evaluate pediatric study power in rare diseases. These approaches were performed analyzing pediatric data alone or combined with the adult data. While Bayesian priors performed well when analyzing pediatric data alone, less technical modeling approaches proved sufficient when pediatric and adult data were combined.
In conclusion, the research presented in this thesis has addressed various challenges encountered in translational drug development. The work has contributed to the evaluation of new anti-tubercular drugs and regimens, the assessment of newly proposed animal models, and optimizing the utilization of biomarker information. Furthermore, this thesis has provided insights into the selection of First-in-Human dose for a protein, showcasing the applicability of model-based approaches in this critical decision-making process. The research has contributed to improving analysis approaches for pediatrics in rare diseases.
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Novel Endpoints To Unravel Developmental Neurotoxicity : From DNA methylation responses to methylmercury to the in vitro identification of endocrine disruptors
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523935
The developing brain is especially sensitive to environmental stressors due to its dependence on the precise spatiotemporal regulation of multiple signals, and the long time period required for its formation. Some chemicals can interfere with molecular and cellular processes driving brain development, including epigenetic processes such as DNA methylation. Hence, identification of DNA methylation changes induced by chemical exposure may serve as early molecular markers for developmental neurotoxicity (DNT). Chemicals known as endocrine disruptors (EDCs) can produce adverse effects due to their capability to alter the endocrine system. Since brain development is highly dependent on endocrine signals, the potential adverse effects of EDCs on brain development needs to be addressed. Detection of DNT in the regulatory context has been based on in vivo testing, however, the financial costs and time intensive characteristics of these methods have resulted in a limited assessment of the DNT hazard of chemicals. In addition, in order to regulate EDCs, it is paramount to demonstrate that their adverse effects are a product of disruption of endocrine signals. Yet, at the moment, there are no approved methods which address both an endocrine mode of action and adverse neurodevelopmental outcomes. This doctoral thesis had two main aims: Firstly, to identify epigenetic changes, at the level of DNA methylation, underlying DNT induced by exposure to methylmercury (MeHg); and secondly, to develop new approach methods (NAMs) for the detection of DNT induced by endocrine disruption. Epigenetic effects were studied both in epidemiological data and experimentally in vitro. Associations between prenatal MeHg exposure and DNA methylation of GRIN2B and NR3C1 were found in children. In vitro validation of DNA methylation changes found in epigenome-wide association studies of populations exposed to MeHg, uncovered the potential involvement of the Mediator Complex Subunit 31 (MED31) in MeHg DNT. To contribute to the endocrine disruption (ED)-induced DNT field, the applicability of an in vitro model composed of murine neural progenitor cells (the C17.2 cell-line) was evaluated. We found that C17.2 neural differentiation and morphology were sensitive to retinoic acid (RAR), retinoic X (RXR), peroxisome proliferator-activated β/δ (PPARβ/δ), and glucocorticoid (GR) agonism. Furthermore, two out of 25 tested EDCs decreased neurite outgrowth and branching in the C17.2 system. These effects were recovered by co-exposure of the chemicals with antagonists of RAR, RXR, or PPARβ/δ, indicating that their DNT effect is mediated by hormonal disruption. Altogether, this thesis contributed to the development of new methodologies and endpoints for the assessment of DNT induced by MeHg and EDCs.
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Nurses' caring struggle : Stress in caring within hospital emergency care during the COVID-19 pandemic
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-66373
Nurses took a frontline caregiving role in pervasively altered conditions in Swedish hospital emergency healthcare during the COVID-19 pandemic. Little is known about nurses’ experiences of the stress they were subjected to. By the means of individual in-depth interviews with both newly graduated registered nurses (NGRNs) and experienced nurses (ERNs) and by a web-based questionnaire findings illuminate nurses’ lived experiences of stress in caring during the COVID-19 pandemic. Three studies employed qualitative methods (I, II, IV), and one a mixed methods approach (III). Study I aimed to describe NGRNs’ experiences of encountering stress in EDs during the COVID-19 pandemic. Findings illuminate how dedicated NGRNs struggle to develop into the nurse they want to be whilst battling extraordinary situations and conflicting emotions. Loss of control and experiences of shortcomings by work overload in combination with understaffing force NGRNs into an independent role at an early point in their career. Study II aimed to illuminate the meaning of NGRNs' experiences of caring for patients in EDs during the COVID-19 pandemic. Findings comprise caring being bestowed through spatial, emotional, and temporal barriers. NGRNs want to be present, relieve suffering yet describe caring during the pandemic being a hidden activity, less acknowledged and left to the recognition of each nurse. Study III aimed to explore healthcare workers’ (HCWs’) experiences of the changed caring reality by the COVID-19 pandemic. Findings disclose traumatic experiences and having to sacrifice moral values and harbour dilemmas in isolation. Experiencing stress was significantly correlated to lower Sense of Coherence. Study IV aimed to explore nurses’ lived experiences of stress in the transformed caring reality during the COVID-19 pandemic. The interpreted meaning comprise the dilemma of enduring the unbearable, meaning having to silence one's inner ethical, caring compass. In conclusion, stress in caring during the COVID-19 pandemic from nurses’ perspective, can be understood as a caring struggle entailing bodily, ethical, and knowledge stress in a search for meaning found in togetherness with patients, with colleagues, with dear ones and in nature.