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Coming dissertations at MedFak

  • Antibiotic resistance in the pan-genome of E. coli Author: Jennifer Jagdmann Link: Publication date: 2022-09-14 10:35

    The pan-genome of a species is made up of all gene families that can be included in any individual isolate of the species. Escherichia coli (E. coli) has an open pan-genome including at least 128000 gene families, while only about half of the genes found in each individual isolate are common to all isolates. This indicates a great intraspecies genetic diversity that is not often considered when studying antibiotic resistance. This thesis uses a comparatively large collection of isolates to include more intraspecies genetic diversity and assess its impact on resistance.

    One angle of this approach was to study the impact of the pan-genome on spontaneous resistance development. For this, we compared the development of resistance to several antibiotics in a 35-strain collection of E. coli isolates. We found that frequencies of resistant mutants varied greatly between strains, that this variation was largely independent from the initial resistance level of the isolates, and that an isolate’s frequency of mutants for one antibiotic was a poor predictor of the mutant frequencies for other antibiotics. In conclusion, there was a clear impact of genetic diversity on spontaneous antibiotic resistance development. 

    Using this approach, we observed a previously undescribed pattern of resistance development for tigecycline, a last-line antibiotic, via amplifications of a known efflux pump. In addition, we found a mutated allele of the pump with a reduced level of induction that did not allow for resistance development through amplifications. We showed that a fitness advantage at low antibiotics concentrations and clonal spread were likely contributing to the high occurrence of the mutated pump among E. coli isolates. While this efflux pump is common and well-studied, the lack of pre-existing knowledge of the mutated allele highlights the value of including many isolates in studies of antibiotic resistance. 

    Another angle of this thesis was to determine whether intraspecies genetic diversity also impacts plasmid-borne resistance. For this, we transferred several multiresistance plasmids into a collection of E. coli hosts and characterized the plasmid-host combinations. We observed strain- and plasmid-dependent variations in resistance as well as inconsistencies in the clinical resistance categorization of different hosts with the same plasmid.

    In conclusion, this work reveals the impact of intraspecies genetic diversity on the development of antibiotic resistance, both through spontaneous mutations and the acquisition of resistance plasmids, highlighting the need to include intraspecies genetic diversity in studies of antibiotic resistance.

  • A Behavioral Medicine Perspective on Pain Disability in a Work Context : Prevention, Assessment, and Tailored Physiotherapy Author: Hedvig Zetterberg Link: Publication date: 2022-09-13 13:06

    Chronic pain (>3 months) is associated with work limitations and sick leave. This thesis aimed to evaluate assessments and interventions targeting work disability for individuals at risk of or with chronic pain. Specific aims for studies I and II were to compare the preventive effects of a brief psychosocial program with an active educational control. Study III aimed to evaluate the construct validity and internal consistency of the Work Ability Index (WAI). Study IV aimed to systematically replicate a behavioral medicine physiotherapy intervention within a return-to-work context and evaluate its effects on an individual level.  

    Methods: Studies I and II were based on a cluster-randomized controlled trial, including 191 employees with reported pain and/or stress-related ill-health and 53 supervisors. Study I reported on the primary outcome of sick leave and secondary health-related outcomes on employees at 6-months follow-up; study II reported on the supervisors’ communication behavior and perceived stress. Study III was a cross-sectional study including 118 patients with chronic pain referred to specialized care. Study IV was a single case experimental design study including five participants with chronic pain on long-term sick leave. 

    Results: In studies I and II, no effects of the brief psychosocial program were found on outcomes on employees or supervisors. In study III, the construct validity and internal consistency of the WAI were supported. In study IV, the physiotherapy protocol was successfully replicated, and the results indicated an effect on task-specific self-efficacy for target activities at work, but not on experience of target activities or work ability.

    Conclusion: The results highlight the importance of selecting participants for preventive workplace interventions based on their assessed risk profiles for long-term pain disability, and that targeting mainly the supervisors might be insufficient. The WAI appears to be a valid measurement of work ability for patients with chronic pain in specialized care. Accordingly, behavioral medicine physiotherapy can be successfully adapted to work disability needs for patients with chronic pain. Large-scale trials are needed to evaluate its effects on return-to-work. A behavioral medicine perspective on pain disability in a work context motivates a focus on target activities at work, which can be seen to mediate the incorporation of behavioral knowledge in assessments and interventions for individuals with pain.

  • The effect of mechanical ventilation on the abdominal organs Author: Silvia Marchesi Link: Publication date: 2022-09-08 13:40

    During mechanical ventilation (MV), the interplay between abdomen and thorax has been studied unilaterally focusing on the effect that an increased abdominal pressure would have on the thorax. Only a small cluster of studies offered a different perspective showing a lower inflammation and a better lymphatic clearance of edema in abdominal organs when spontaneous breathing was applied compared to MV. Apart from these insights, a deeper understanding of the effect of different MV features on the abdominal organs remains uninvestigated.The aims of the thesis were: to investigate how changes in perfusion and edema influence inflammation and affect each other, and to examine how the management of ARDS could affect abdominal organs by comparing MV with spontaneous breathing and prone with supine position. All the studies were conducted using a porcine model. In three studies, a septic-like status was generated with an infusion of endotoxin; while in one study, a VILI model was used to simulate ARDS.In the first two studies, perfusion and lymphatic drainage were modified in different groups of animals and the impact of the changes on the abdominal organs was assessed. In the other two studies the effect of different ventilation settings on the abdominal organs was investigated: in Paper III, spontaneous breathing(CPAP) was compared with MV (maintaining positive end expiratory pressure – PEEP – and respiratory rate similar in both groups), and, in Paper IV, MV in prone position was compared with MV in supine position. The main findings were that low perfusion increased inflammation in the abdominal organs, but the hemodynamic parameters could not affect intestinal perfusion or edema. Similarly, increased edema was not associated with a decreased perfusion, but it enhanced inflammation in duodenum. MV increased systemic inflammation compared to CPAP, but did not increased inflammation or edema in the abdominal organs. Prone position reduced renal perfusion and was associated to extensive renal micro-thrombosis. In conclusion, both perfusion and edema influence inflammation in the abdomen, even if they seem not to affect one another. Besides, spontaneous breathing develops less systemic inflammation compared to MV, but it was not associated to a lower edema or inflammation in the abdomen; on the other side, prone positioning resulted in a possibly dangerous decrease of renal perfusion.