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Coming dissertations at MedFak

  • Maternal Death Surveillance and Response in Tanzania : Challenges to successful implementation Author: Ali Said Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-438580 Publication date: 2021-04-28 15:03

    Tanzania has one of the highest maternal mortality ratios (MMR) in the world. Tanzania introduced the Maternal Death Surveillance and Response (MDSR) system to facilitate deaths notification and learning from death reviews inorder to prevent future deaths. The aim was to describe the strengths, challenges and impact of implementing the MDSR system in Tanzania. A mixed methods study was conducted in the Lindi and Mtwara regions in Southern Tanzania. The system’s adequacy was assessed in terms of notification of deaths, categorization of causes of deaths and identification of three delays. The notification of deaths in the MDSR system was compared to other standard estimates. The causes of deaths and delays identified by the MDSR system were compared to an expert panel`s review using Cohen`s K statistic. Community members` perceptions and experiences of events leading to death were explored. The availability and documentation of narrative summaries used in death review meetings and action plans created by the MDSR committees were also assessed. A checklist was used to assess the summaries while the SMART criterion was used for assessing the action plans. Health providers and managers were interviewed through focus group discussions and key informant interviews on their perceptions and experiences in implementing the MDSR system

    The MDSR system performed well in categorizing the causes of maternal deaths (K statistic 0.76). Notification of deaths in the MDSR system was incomplete (MMR 137/100,000 live birth) and there was inadequate identification of all three delays (K statistics < 0.2). Caregivers failed to account for pregnancy complications during birth preparations. They also described challenges in interactions with health providers in health facilities and were excluded from the care of the deceased woman. Families suffered social, psychological and economic consequences from maternal deaths. Most narrative summaries used in death review meetings were not comprehensively written. Less than half of action plans met the SMART criteria. Health providers and managers expressed high ambitions in implementing the system with notable policy, attitude and quality of care changes. They further described many organizational, contextual and individual challenges facing the system.

    Addressing the above challenges will enable the MDSR system to effectively improve quality of care and reduce maternal deaths.

  • Go with your gut : The human intestinal microbiota, international travel, Campylobacter and ESBL-producing Enterobacteriaceae Author: Christian Kampmann Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-438449 Publication date: 2021-04-27 13:51

    Up to 100 million people travel annually from industrialized countries to resource-limited ones. Each traveller contains an internal ecosystem composed of tens of trillions of microbes, known as the intestinal microbiota, which has a large effect on health. The microbiota seems to be highly individual and mostly stable but can be significantly affected by several factors. 

    Many international travellers are at high risk of getting infected by Campylobacter, the most common cause of bacterial enteritis worldwide. Campylobacter infection can cause a wide range of symptoms, with varying severity, for reasons largely unknown. Travel also radically increases the risk of colonization by antibiotic-resistant intestinal bacteria, notably Extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (EPE). To date, there are no therapies available for EPE-decolonization. 

    In this thesis, it was investigated whether the bacterial intestinal microbiota affected susceptibility to Campylobacter and if international travel as such had an impact on the microbiota. In a prospective, observational study, 67 healthy Swedes, travelling in groups to countries with a high risk of Campylobacter infection, were followed. The travellers answered questionnaires and delivered two faecal samples before and three samples after the trip. These samples were cultured for enteropathogens and analysed for the microbiota composition. Low diversity of microbiota seemed to increase the risk of Campylobacter jejuni infection, whereas a high relative abundance of Lachnospiraceae might decrease the risk (Paper I). Furthermore, the overall bacterial diversity did not seem to change in connection with travelling. However, the bacterial family Enterobacteriaceae (otherwise connected with inflammation, infection and antibiotic-resistance) was shown to be dramatically increased in abundance immediately after travel, and the family Christensenellaceae (otherwise connected with beneficial health conditions) simultaneously decreased (Paper II). 

    Eight travellers, from two different destinations, were infected with closely related C. jejuni isolates (ST353CC). The bacterial analysis of genomic and phenotypic characteristics revealed that the C. jejuni isolates of the travellers returning from one of the destinations and with more severe symptoms actually showed less pathogenic potential, compared to the isolates of travellers from the other destination and with milder symptoms. However, the travellers with more severe symptoms had much higher relative abundances of Bacteroidetes in their intestinal microbiota and, in contrast to the other travellers, excluded meat from their diet. (Paper III) 

    Finally, we investigated in a randomized, placebo-controlled clinical trial of 80 established intestinal carriers of EPE, whether the oral probiotic product Vivomixx® could eradicate EPE. Vivomixx® was not superior to placebo (Paper IV).

  • Regulation of cell differentiation and invasion by members of the TGFß family Author: Kalliopi Tzavlaki Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-438027 Publication date: 2021-04-27 08:35

    Transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signaling pathways are important in embryonic development and tissue homeostasis, but also have complex roles in the context of cancer. TGFβ promotes epithelial to mesenchymal transition (EMT) a physiological developmental process, often hijacked in different types of cancer, eventually leading to cancer cell invasion and metastasis. BMP signaling is involved in bone formation, angiogenesis and neural cell differentiation, but also regulates cancer by inducing EMT and its reversion. 

    Liver kinase B1 (LKB1) is a tumor suppressor protein kinase involved in the regulation of cell metabolism, proliferation and polarity. First, we investigated how LKB1 negatively regulates BMP signaling and we demonstrated that LKB1 interacts with one of the BMP type I receptors and mediates its degradation, leading to the inhibition of BMP-induced cell differentiation.

    We then focused on the role of LKB1 in the establishment of mammary epithelial polarity. Upon LKB1 depletion, normal mammary epithelial cells lost the ability to form polarized acini, and displayed enhanced TGFβ responses. The use of a chemical inhibitor targeting TGFβ type I receptor restored the formation of acini, therefore we concluded that the contribution of LKB1 to mammary epithelial polarity is dependent on the regulation of autogenous TGFβ signaling.

    Glioblastoma (GBM) is a brain malignancy, that is highly invasive and heterogeneous in terms of cell differentiation. TGFβ enhances the self-renewal potential of glioblastoma stem cells (GSCs), while BMP promotes their differentiation towards the astrocytic lineage. In the second part of this thesis, we investigated the role of different effectors downstream of TGFβ/BMP signaling in GBM. 

    Snail is a well-established inducer of EMT in carcinomas but in the context of GBM, we demonstrated that Snail was induced by BMP7, and via its interaction with Smad signaling effectors, enhanced BMP while it suppressed TGFβ signaling, thus promoting the astrocytic differentiation of GSCs and suppressing stemness.

    Finally, the role of the TGFβ/BMP target gene, CXXC5, was investigated in GBM. CXXC5 expression was enriched in GSCs that express high levels of stem cell markers, and depletion of CXXC5 led to reduced self-renewal capacity of GBM cells. Further analysis indicated that CXXC5 epigenetically regulates stemness-related genes by counteracting the activity of the polycomb repressor complex 2 (PRC2), thus affecting the histone modification pattern on the regulatory elements of these genes. 

    Collectively, the thesis provides evidence on mechanisms that regulate cell differentiation by interfering with TGFβ/BMP signaling.

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