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Coming dissertations at MedFak

  • Study of Resistance in Hepatitis C Virus Prior to Treatment with Direct Acting Antivirals Author: Midori Kjellin Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-407561 Publication date: 2020-04-27 14:31

    The rapid advancement of Hepatitis C (HCV) treatment presents a great challenge to clinicians in optimising therapy for their patients. Genotype (GT), efficacy, side-effects, drug combinations and treatment durations must be tailored to individual patients, considering comorbidities, degree of fibrosis, adherence and antiviral resistance.

    Resistance associated substitutions (RASs) may impair treatment response to direct-acting antiviral agents (DAA). Almost all patients who fail treatment acquire RASs that may persist for years. Even treatment-naïve patients can harbour naturally occurring RASs against currently approved DAAs, i.e. resistance at baseline. Prevalence of key NS3 and NS5A-RASs is relatively high (3-9%) at baseline for DAA-treatment-naïve GT1a and 3a patients with population sequencing at 20% cut-off in Sweden and Norway.

    The studies in this thesis comprise investigations on the prevalence and the effects of baseline RASs on treatment outcome in patients with HCV GT1 and GT3 receiving personalised treatment based on results from NS3 and NS5A resistance testing. We developed a pan-genotypic population sequencing method for detecting NS5A RASs (Paper I), which is certified and used in routine diagnostics at our laboratory together with our previously developed NS3 RAS sequencing method.  We acquired data on RAS prevalence and treatment outcome from the early DAA management and carried out a non-randomised, prospective real-life study seeking to examine the impact on treatment outcome in patients receiving treatment tailored to baseline resistance testing.

    The studies were carried out between 2011 and 2017, one retrospective study comprising patients in the Uppsala region (Paper II) and two prospective studies with patients in a multicentre study involving sites in both in Sweden and Norway (Paper III and IV).

    RAS prevalence data from the prospective studies was obtained from a total of 401 patients and was shown to be slightly lower than reported from previous studies. Still, although not statistically significant due to the low prevalence of RASs in the cohort, we could show that there was a trend toward tailoring treatment to baseline RAS testing has a favourable impact on treatment outcome over treatment according to standard recommendations, especially in patients with cirrhosis. The economical and best practise objectives were important factors to consider when treatment costs were high and adverse effects were challenging at the initiation of the studies.

    In summary, this doctoral thesis presents results from real-life studies that indicate that tailoring treatment based on baseline RAS-testing have beneficial impact on patients that are treatment experienced and/or patients with cirrhosis.

  • Perinatal Depressive Symptoms among Women in North-Eastern Thailand : Risk Factors, Support and Prevention Author: Nitikorn Phoosuwan Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-402419 Publication date: 2020-04-23 13:08

    Perinatal depressive symptoms among women remain a global burden. Improvements in self-efficacy among public health professionals (PHPs) in primary healthcare settings to detect and manage perinatal depressive symptoms among women are needed.

    The aims of this thesis were to: identify prevalence and risk factors associated with perinatal depressive symptoms among women; to explore and describe life situation and support among women with antenatal depressive symptoms (ADS) and their partners; and to improve self-efficacy of PHPs in detection and management of perinatal depressive symptoms in Sakonnakhon province in Thailand. Qualitative and quantitative studies with different types of data collection methods were used.

    Study I determined prevalence of ADS and associated risk factors among 449 Thai women in late pregnancy using the Edinburgh Postnatal Depression Scale (EPDS). The prevalence was 46.8% and associated risk factors were insufficient money, being a teenager, low psychological well-being, low self-esteem and low sense of coherence.

    Study II explored and described life situation and support during pregnancy among women with ADS and their partners using semi-structured interviews. Four categories emerged: Having obstacles in life, Facing life situation, Enhancing confidence and Dissatisfaction with help.

    Study III determined risk factors associated with postpartum depressive symptoms at one month among 319 women and at three months among 276 women. Risk factors at one month were antenatal psychological well-being, non-exclusive breastfeeding, low personal income and caregiver not a mother; risk factors at three months were unintended pregnancy, low personal income/month, low self-esteem, low psychological well-being and low maternal competence.

    Study IV evaluated a self-efficacy improvement programme (SIP) intended to increase PHPs’ self-efficacy in efforts to detect and manage perinatal depressive symptoms among women. After the SIP, PHPs in the intervention group (n=33) had higher self-efficacy scores than PHPs in the control group (n=33). Four categories emerged in qualitative evaluation: Having confidence, Changing knowledge and attitudes, Increasing perception of an important role, and Increasing awareness of performed function.

    Women who are at increased risk for perinatal depressive symptoms should be screened using the EPDS. Health care professionals should involve expectant fathers in ANC process. The SIP enhances PHPs’ ability to detect and manage perinatal depressive symptoms.

  • Cdc42, orchestrator of vascular morphogenesis in the retina Author: Alberto Álvarez-Aznar Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-407117 Publication date: 2020-04-23 10:38

    Cdc42 is a small GTPase that controls many cellular functions related to cytoskeletal dynamics, such as migration, polarity, and proliferation. Despite what we know of Cdc42 in other cell types, not much research has been done on the vasculature. This thesis describes the consequences of Cdc42 deletion in two vascular cell types—endothelial and mural cells—during developmental angiogenesis.

    In paper I, we demonstrate through a combination of in vitro, in silico, and in vivo assays, that Cdc42-deficient endothelial cells migrate less and fail to distribute normally in areas of naturally occurring high proliferation during angiogenesis, causing vascular malformations with enlarged lumens. In addition, these cells present impaired filopodia formation, a disadvantage for the tip cell position, disturbed axial polarity and altered junctions.

    With an in vivo approach, in paper III we demonstrate that the deletion of Cdc42 in mural cells has consequences on the morphogenesis of the retinal vasculature. Cdc42-deficient mural cells proliferate less and cannot keep up with the nascent angiogenic vasculature, which results in a complete pericyte loss at the sprouting front. Furthermore, we describe that mural cells contribute to the remodeling of the vasculature, also after the initial phases of angiogenesis.

    The CreERT2 system is frequently used for conditional gene deletion and lineage tracing. Tamoxifen administration allows spatiotemporally controlled recombination of fluorescent reporters, and tracing of the labeled cells. However, in the course of our studies, we observed tamoxifen-independent recombination. In paper II, we describe this phenomenon in detail, using different combinations of CreERT2 and fluorescent reporter lines. We conclude that tamoxifen-independent recombination is a widespread occurrence, and that fluorescent reporter lines present varying levels of susceptibility to it.

    In summary, the work presented here sheds new light on the role of Cdc42 in the vasculature. Additionally, this thesis describes in detail an important feature of CreERT2 and reporter lines that should be taken into account when performing lineage-tracing experiments.

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