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Coming dissertations at MedFak

  • New strategies and tools for Plasmodium falciparum case management and surveillance in the era of imminent resistance to artemisinin-based combination therapy in Tanzania. Author: Lwidiko E Mhamilawa Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-407806 Publication date: 2020-04-29 14:58

    Artemether-lumefantrine has been an efficacious first line treatment for uncomplicated Plasmodium falciparum malaria in Tanzania since its introduction in 2006. Interest has developed in understanding the observation of high residual PCR determined positivity rates on day 3 after supervised artemether-lumefantrine treatment in the magnitude of almost 30% in previous assessments from 2015 in Bagamoyo district, Tanzania. Deep sequencing has recently been used to study these Bagamoyo parasites with delayed clearance, and the clearance times by PCR of some P. falciparum sub-populations were similar to artemisinin resistant parasites in Myanmar as assessed by microscopy, albeit lacking the described mutations in the Kelch13 propeller gene associated with artemisinin resistance. Moreover, molecular epidemiological studies from Bagamoyo, have shown temporal selection of lumefantrine associated genetic tolerance/resistance markers (pfmdr1 - N86, 184F, D1246 and pfcrt - K76) in the parasite population following wide scale use of artemether-lumefantrine but without signs of compromised treatment efficacy. On the other hand, traditional epidemiological studies have reported that imported malaria cases in Zanzibar from Tanzania mainland contribute to regressing the malaria elimination efforts in this pre-elimination part of the country.

    This PhD project explored efficacy and safety of extending the artemether-lumefantrine regimen from standard 3 days to 6 days and adding single low dose primaquine (0.25mg/kg) as a new strategy that can be used in order to protect the therapeutic lifespan of artemether-lumefantrine. Also, whole-genome sequencing was used to study genomic epidemiology of P. falciparum population between Tanzania mainland and Zanzibar.

    The results revealed that extended artemether-lumefantrine treatment did not have superior efficacy in the current context of artemether-lumefantrine sensitive P. falciparum parasites. However, the safety profile was excellent and similar to standard 3 days treatment. Parasite detection by molecular methods was 84% on day 3 after artemether-lumefantrine treatment. Meanwhile, significant decreases in the effective population sizes were inferred in both Tanzania mainland and Zanzibar parasite populations, that coincide with a period of decreasing malaria transmission in Tanzania. The parasite population from Tanzania mainland and Zanzibar were found to be connected, implying importation of cases from high transmission mainland to pre elimination regions of Zanzibar.

    Utility of these results is during exploring options of alternative artemisinin-based combination therapy regimens to protect their therapeutic efficacy in an era of imminent artemisinin resistance in sub Saharan Africa. Moreover, the genomic epidemiological findings in this project may be of interest for malaria elimination programs, in the incorporation of molecular tools in future malaria elimination strategies and resistance surveillance, in the context of understanding importation of malaria from high to low transmission regions.

  • 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.

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