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Coming theses from other universities

  • Pharmacometric models to inform dose selection and study design : Applied in hemophilia and tuberculosis Author: Alan Faraj Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-521052 Publication date: 2024-02-15 12:55

    While tuberculosis is a global pandemic, hemophilia is a rare disease which many have not heard of. Due to tuberculosis mainly being a problem in developing countries and hemophilia being a rare disease, they are not as heard of as other diseases such as cancer or metabolic diseases which are on the rise in Western societies. The quality of life for patients suffering from these diseases is notably impaired and novel drugs are warranted to further improve the treatment and management of both diseases. As market incentives are a limiting factor, it is important that the efforts that are taken to develop novel drugs are carried out in an informative manner.   One strategy to incorporate as much information as possible to inform decision making in drug development is to use pharmacometric methods. Such strategies enable simultaneous analysis of different types of data that are generated during drug development programs. In this thesis, the aim was to develop and apply pharmacometric models to facilitate dose selection and study designs in clinical programs that aim at developing new drugs for tuberculosis and hemophilia.   A standardized analysis approach of early clinical trials studying drugs against tuberculosis was presented including power calculations that showed the number of patients needed to detect drug effects. Such efforts are important as showing drug effect in early trials will aid decision making into significantly longer and costlier late trials. The approach was used to analyze a clinical trial studying if the current dose of meropenem can be lowered without negatively impacting drug effects and improving the already poor tolerability of the drug. The study found that lowering the dose may lower activity without any improvement of the tolerability properties. Furthermore, population pharmacokinetic models were developed for two novel hemostatic drugs in development for prophylactic and on-demand treatment of hemophilia. Based on the models, clinical trials in adult and pediatric subjects were supported. One of the trials were performed and it was showed with a model-based analysis that the new drug which is given subcutanously has similar efficacy as current intravenously given standard of care alternatives. Using the developed models, different strategies for designing pharmacokinetic trials in children was also presented.   In conclusion, the work performed within this thesis has contributed to the development of new drugs against tuberculosis and hemophilia.

  • Return to work after long-term sick leave for common mental disorders : Women’s beliefs, intentions, health and psychological well-being Author: Åsa Hedlund Link: http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-43469 Publication date: 2024-02-14 11:15

    Background: Long-term sick leaves due to common mental disorders (CMDs)are common in Sweden today, especially among women. Return-to-work (RTW) support usually includes work-related factors and treatment for the CMD. Despite this, the way back to work is often long with an increased risk of relapse into sick leave afterwards. The overall aim of this thesis was to generate knowledge about women’s RTW after long-term sick leave for CMDs by investigating their beliefs, intentions, perceived health and psychological wellbeing.

    Methods: Study I reported on the development and psychometric evaluation of the RTW Beliefs Questionnaire based on the Theory of Planned Behaviour (TPB). It contain items about attitude towards, social pressure to, perceived behavioural control over, and intentions to RTW. Study II was a cross-sectional study investigating determinants (RTW beliefs and perceived health) of RTW intentions. Study III was a 1-year follow-up investigating predictors of RTW and psychological well-being. Study IV was a qualitative study describing women’s health and psychological well-being in the RTW process from women’s and first-line managers’ perspectives.

    Results: Beliefs about RTW mainly concerned health, psychological well-being, the work situation and relations in private life. The RTW Beliefs Questionnaire showed varied psychometric qualities and a distinct division between work and private life. Women with a more positive attitude, stronger social pressure and higher perceived behavioural control had stronger RTW intentions. The follow-up showed that the only predictor of having RTW one year later was stronger RTW intentions at baseline. However, these intentions were not associated with higher psychological well-being. In the qualitative study, women’s health and psychological well-being were described to be dependent on the individual characteristics of the women themselves, their private life, work and RTW stakeholders.

    Conclusions: Women’s RTW after long-term sick leave for CMDs concerned three core aspects: Private-, personal- and work-related. It is important that RTW is compatible with good health and high psychological well-being and that health promotion continue after the end of sick leave. Future studies in the area should consider private life aspects in addition to personal- and work-related aspects.

  • Toxicological studies of di-n-butyl phthalate (DBP) : Impact on the reproductive system and gut microbiota Author: Radwa Almamoun Link: http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-225853 Publication date: 2024-02-14 08:00

    The potential health impact of exposure to anthropogenic chemicals has raised major concerns worldwide. Phthalates are mainly used in the plastic industry and have been associated with adverse effects in humans. Di-n-butyl phthalate (DBP) is one of the dominant phthalates with a ubiquitous presence in the environment. While many studies have examined the endocrine disrupting properties of DBP, with a focus on developmental and reproductive dysfunctions, studies of its effects on the adult reproductive system and gut microbiota are limited. This thesis aimed to determine persistent effects of DBP on the adult male reproductive system, provide a high-throughput screening tool for identifying reproductive toxicants, and characterize the effects of DBP on the gut microbiota.

       Paper I investigated if adult DBP exposure can induce persistent effects on the mature reproductive system. Adult male mice were orally exposed to 10 or 100 mg/kg/day for five weeks and testes were collected one week after the last dose. The results demonstrated a significant decrease in testosterone levels in the DBP-exposed groups. Mechanistically, the levels of steroidogenic enzymes, cell-specific markers and oxidative stress were increased. In paper II, elements of the in vivo testicular microenvironment, including functional testosterone production, were modeled using a three-dimensional (3D) heterogenous testicular cell co-culture derived from neonatal mice. Automated high-content imaging of cell-specific markers confirmed the presence of germ cells (DAZL+), Leydig cells (CYP11A1+), and Sertoli cells (SOX9+). DBP exposure decreased testosterone production, as well as levels of the steroidogenic enzyme CYP11A1, and the steroidogenic regulator StAR. Overall, this in vitro 3D model recapitulates the testicular pathways involved in DBP toxicity, making it a relevant tool for assessing reprotoxic effects of chemicals.

       Paper III investigated the impact of oral DBP exposure on the gut microbiota and the potential interplay with immune and testicular toxicity using 16S rRNA sequencing. DBP-treated mice showed a distinct microbial composition and numerous differentially abundant amplicon sequence variants. Interestingly, the microbial alterations correlated with an increase in non-classical monocytes observed in DBP-exposed mice. In paper IV, a shotgun metagenomic analysis was conducted to achieve a more comprehensive characterization of the DBP-induced effects on gut microbiota composition and function. The DBP-exposed mice had a higher abundance of Adlercreutzia mucosicola, a bacterium linked with intestinal inflammation. In contrast, the beneficial Akkermansia muciniphila was less abundant in DBP-exposed mice. Functional analysis demonstrated that DBP exposure increased the abundance of genes involved in environmental sensing and antimicrobial resistance.

       In conclusion, this doctoral thesis demonstrates the antiandrogenic effects of DBP as well as potential underlying mechanisms of testicular dysfunction in adult mice. In addition, we established a powerful in vitro tool for screening reprotoxic effects. The gut microbiota was also impaired by DBP exposure, which may play a potential role in initiating or exacerbating the DBP-induced toxicity. Overall, this work highlights the potential health impact of the interplay between the two exposome components, chemical exposure and gut microbiota.

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