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Coming dissertations at MedFak

  • Diet and common neurological disorders: cohort studies on dementia, Parkinson’s disease, and stroke Author: Erika Olsson Link: Publication date: 2021-11-26 08:35

    Risk factors for dementia, Parkinson’s disease, and stroke have been widely studied but there are still research gaps concerning the role of diet for the development of these diseases. The overall aim of this thesis was to investigate whether various aspects of diet are associated with common disorders and diseases in the brain. 

    Paper I and II are based on the Uppsala Longitudinal Study of Adult Men (ULSAM). Paper III and IV are based on the Swedish Mammography Cohort (SMC) and the Cohort of Swedish Men (COSM). 

    In paper I, we investigated the associations between three different dietary patterns and incidence of Alzheimer’s disease (AD), dementia, and cognitive impairment. We observed no associations between adherence to the Healthy Diet Indicator and any of the outcomes studied, or between adherence to a Mediterranean-like diet (mMDS) and AD or dementia. There was a tendency towards a lower risk of cognitive impairment with higher adherence to the mMDS, and a weak association between adherence to a Low Carbohydrate High Protein score and higher risk of all-type dementia. Overall, there were no strong associations with the studied dietary patterns and development of dementia or cognitive impairment. 

    In paper II, we found no associations of vitamin D measured as vitamin D intake, plasma 25-hydroxyvitamin D concentrations, or a vitamin D synthesis genetic risk score with incident AD, vascular dementia, dementia, or performance in the Mini-Mental State Examination.

    In paper III, we observed a weak higher risk of PD associated with milk consumption but there was no dose-response relationship. Thus, this association needs to be interpreted with caution. Fermented milk intake was not associated with PD.

    In paper IV, we found that a higher long-term milk consumption based on repeated measures of intake was not associated with total stroke, weakly and non-linearly associated with lower risk of cerebral infarction and higher risk of hemorrhagic stroke. Fermented milk consumption was not associated with any stroke type. Our results highlight the importance of repeated measurements of food intake, separate analyses of milk and fermented milk consumption, and to study stroke types separately.

    Despite the lack of strong associations, the findings of this thesis have increased our knowledge about the potential role of overall diet, vitamin D, and milk and fermented consumption in the prevention or development of common neurodegenerative diseases and stroke.

  • Thoracic Endovascular Aortic Repair : Clinical and morphological outcomes Author: Tina Hellgren Link: Publication date: 2021-11-25 12:11

    In the years following its introduction in the late 1980’s, thoracic endovascular aortic repair (TEVAR) rose as a minimally invasive alternative to open surgical repair of thoracic aortic disease. As a result, an expanding group of patients are receiving invasive treatment, even though evidence in the area is still scarce. The overall aim of this thesis was to study the outcomes of modern treatment of thoracic aortic disease – TEVAR and hybrid repair – by analyzing data from local and international cohorts.

    Paper I includes an evaluation of outcomes of TEVAR for intact and ruptured thoracic aortic aneurysm (TAA) at a tertiary referral center (1999 to 2014). Survival was unexpectedly poor after ruptured TAA repair, only one third of the patients were alive at 3-years follow-up. Intact TAA repair was associated with low perioperative mortality and acceptable 5-year survival.

    Paper II analyses aortic remodelling, complications, reinterventions and survival after TEVAR for subacute and chronic type B aortic dissection at a tertiary aortic center (1999-2015). TEVAR induced positive remodelling, characterized by false lumen thrombosis and shrinkage accompanied by true lumen expansion, of the thoracic but not the abdominal aorta. Reintervention due to aortic dilatation distal to the stent graft was common.

    Paper III, an international registry-based multicenter study of 9518 TEVAR cases from 2012 to 2016, demonstrated substantial international differences in practice patterns. The large dataset provides a point of reference for short-term outcome after TEVAR in current practice.   

    Paper IV, a single-center study of 50 consecutive patients who underwent frozen elephant trunk repair of the aortic arch (2006 to 2020), confirmed that whilst this procedure is associated with morbidity and mortality, the technique provides an adequate bridge to endovascular repair of the downstream aortic segments, which was common during follow-up. The repair was shown to induce positive aortic remodeling in the thoracic but not abdominal aorta, in patients with chronic aortic dissection.

    In conclusion, this thesis provides insights into the rapidly evolving field of TEVAR, including an overview of current practice as well as clinical and morphological outcomes.

  • Exploring the interactions of antibiotic combinations against multidrug-resistant Gram-negative bacteria Author: Anna Olsson Link: Publication date: 2021-11-25 09:05

    Antimicrobial resistance is emerging and available treatment options are lacking. Antibiotics is a cornerstone in modern medicine where medical procedures such as surgery, care of premature babies or treatment of cancer is dependent on efficient drugs. The need for novel treatment alternatives is increasing as bacteria continue to develop new resistance mechanisms.

    The main goal of this thesis was to screen for antimicrobial combinations efficient against Gram-negative bacteria. The complex membrane structure of Gram-negative bacteria is very protective against antimicrobial activity making many antibiotics ineffective. Polymyxin B was therefore used as a main component in the combinations evaluated due to its membrane disruptive mode of action. Previously neglected or disused antibiotics was used in combination with polymyxin B as a part of a Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) called CO-ACTION. The prevailing theory of polymyxin B combinations is that the membrane disruptive effect will facilitate entry of a second antibiotic and reduce efflux activity. In contrast, the combination will not be as efficient in the presence of bacterial enzymatic activity as the resistance mechanism is not affected by changes in the membrane composition. To increase knowledge on underlying mechanisms behind the success of antimicrobial combinations an extensive genetic analysis was performed. 

    Several promising polymyxin B combinations were found which could offer a treatment option in caring for severely ill patients for which few alternatives exist. Associations between genetic background and efficient bacterial killing was also established. The chance of synergistic effect by the combination was increased if the antibiotic used in combination with polymyxin B could normally not enter the bacterial cell or in presence of resistance mechanisms increasing efflux activity. This thesis highlights the fact that only phenotypical antimicrobial susceptibility testing would not be used in forecasting the success of antimicrobial combinations. Information on antimicrobial susceptibility in combination with knowledge on resistance mechanisms present and how it influences the antibiotics used in combination is equally important.  

    With this work increased knowledge on genetic background of resistance mechanisms and bacterial killing by polymyxin B combinations and was provided. Antimicrobial combinations offer an interesting feature when no other treatment alternatives are available. The lack of diagnostics in forecasting the success of combination therapy in a clinical microbiology lab is of concern. The knowledge obtained in this work contributes to the general knowledge on antimicrobial combinations and provides an example of how to evaluate their effect.