Coming dissertations at MedFak
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The open lung in assisted spontaneous breathing
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539582
Background: Mechanical ventilation is essential for managing acute respiratory distress syndrome (ARDS). The implementation of assisted spontaneous breathing may improve diaphragm function and blood oxygenation. However, the optimal protective settings for assisted spontaneous breathing and positive end-expiratory pressure (PEEP) remain uncertain. During the weaning phase from ventilation, assisted spontaneous breathing is commonly used; however, the relationship between applied PEEP levels, transpulmonary pressure, and atelectasis formation during this process is not well understood. We hypothesised that 1) higher PEEP levels may mitigate injurious lung phenomena and 2) atelectasis formation is linearly correlated with transpulmonary pressure during ventilator weaning.
Method: The effects of six different PEEP levels on atelectasis, tidal recruitment–derecruitment (R/D), lung stress and tidal volume distribution were tested in two studies involving experimental ARDS (Studies I and II). Furthermore, the effects of PEEP on inspiratory efforts and the effort-to-drive ratio were analysed retrospectively (Study III). The correlation between atelectasis volume and transpulmonary pressure was assessed during a ramp procedure in patients weaning from mechanical ventilation (Study IV).
Results: In experimental ARDS, lung weight affected by atelectasis and tidal R/D decreased significantly with increasing PEEP levels (PEEP 0 vs 15 cmH2O, p < 0.01). Higher PEEP levels shifted the tidal volume distribution dorsally. The oesophageal pressure swing and the effort-to-drive ratio showed a significant association with the applied PEEP level (p < 0.01). Shifting PEEP from 0 to 15 cmH2O resulted in a decrease in the mean (SD) oesophageal pressure swing from -4.2 (3.1) to -1.9 (1.5) cmH2O (p < 0.01). In humans, the end-expiratory volume of atelectasis decreased significantly with reduced positive pressures (p < 0.05) and was linearly correlated with end-expiratory transpulmonary pressure (p < 0.05).
Conclusion: Higher PEEP levels limit atelectasis and tidal recruitment–derecruitment. PEEP improves ventilation homogeneity by distributing tidal volume dorsally and modulates large inspiratory efforts through the effort-to-drive ratio, potentially protecting against further lung injury. These results were found in experimental ARDS using NAVA ventilation. Further studies are required to determine their applicability in human ARDS. Additionally, the volume of end-expiratory atelectasis is linearly correlated with end-expiratory transpulmonary pressure during a ramp procedure in humans weaning from mechanical ventilation.
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Enterobacterial colonization of enteroids and colonoids : Interplay with the epithelial surface and inflammasomes
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539529
The model enteropathogens Salmonella enterica serovar Typhimurium (S.Tm) and Shigella flexneri (S. flexneri) colonize the intestinal lumen and target the apical surface of intestinal epithelial cells (IECs) for invasion. Intraepithelial bacterial populations are restricted by IEC inflammasomes, cytosolic multiprotein complexes that assemble upon detection of bacterium-derived molecules and induce infected IEC death and extrusion. The recent development of non-transformed, purely epithelial enteroid and colonoid models has opened up venues for physiologically relevant mechanistic studies at high spatial and temporal resolution. In this thesis, we employed live-cell imaging in enteroids and colonoids to study how virulence factor modules governing host cell surface targeting and interaction with inflammasomes shape S.Tm and S. flexneri epithelial colonization strategies.
In Paper I, we found that S.Tm invasion induced tissue-scale epithelial contractions via activation of the IEC-intrinsic NAIP/NLRC4 inflammasome, and myosin-based propagation of the contractile response to surrounding IECs. This response preceded infected IEC extrusion and resulted in local tissue compaction to prevent loss of epithelial integrity during infection. In Paper II, enteroid microinjection was employed to map the stages of S.Tm epithelial colonization and identify luminal expansion and cycles of IEC invasion, intraepithelial replication and infected IEC extrusion as collaborative pathways to ensure efficient colonization of both luminal and epithelial niches. In Paper III, parallel enteroid and colonoid infections characterized an S.Tm apical targeting module comprised of flagellar motility and the SPI-4-encoded SiiE adhesin system to foster abundant, but short-lived, invasion foci, terminated by prompt induction of IEC death and extrusion. Low S. flexneri invasion efficiency, in contrast, is compensated by an intraepithelial expansion module coupling OspC3-mediated inflammasome suppression with IcsA-driven lateral spread to evade restriction by IEC death and extrusion. In Paper IV, we developed a simplistic high-throughput infection model to assess host cell surface determinants involved in S.Tm targeting. Chemical cell surface manipulations and ectopic glycoprotein expression established that glycocalyx constituents and bacterial cell surface appendages represent size-dependent steric barriers towards invasion. Hence, while adhesins are necessary to penetrate the apical IEC glycocalyx, a naked host cell membrane rich in cholesterol would be the preferred surface for S.Tm targeting.
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Periprosthetic bone and uncemented total hip arthroplasty
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539036
Uncemented total hip arthroplasty (THA) has continuously increased in recent decades. Biological fixation of the implant is achieved initially by press-fit and secondary by osseointegration. However, uncemented THA is associated with loss of periprosthetic bone mineral density (pBMD), reduced mechanical strength and increased risk of periprosthetic fractures. The goals of this thesis were to study the short-term results of treatment with an antiresorptive drug for an uncemented THA (studies I and II) and the 8-year follow-up of an uncemented acetabular implant (study III). In addition, the reliability, agreement and precision for the periprosthetic standardized uptake value (pSUV) with [18F] fluoride PET/CT (F-PET) were evaluated (study IV).
We conducted a randomized controlled trial (RCT) to investigate the effect of 2 subcutaneous injections of denosumab, 6 months apart postoperatively, on pBMD by dual-energy x-ray absorptiometry (DXA), pSUV by F-PET and serum markers for bone turnover for an uncemented THA with the collum femoris preserving (CFP) stem and the Continuum cup. Our results show that denosumab prevents early pBMD loss around the stem (study I) and the cup (study II), but the effect is transient upon treatment discontinuation. Additionally, denosumab reduces periprosthetic and systemic bone turnover, but the effect is unsustainable.
Study III is a prospective study to evaluate the 8-year results of the trabeculae-oriented pattern (TOP) cup in terms of implant survival, pBMD measured by DXA and clinical outcomes. We found an overall implant survival for the TOP cup of 83% and that pBMD continued to decrease in the proximal regions around the cup. The clinical outcome in patients with unrevised cups was excellent.
Study IV is a methodological study investigating F-PET's reliability, agreement and precision. 2 independent observers analyzed all F-PET scans from study II on 2 occasions, with a minimum interval of 3 weeks between each analysis. We found good reliability, high agreement and moderate precision between and within observers.
This thesis concludes that 2 doses of denosumab effectively prevent pBMD loss around the CFP stem and the Continuum cup while also reducing bone turnover. However, the effect on pBMD is not enduring, and a rebound effect on bone turnover markers appears after treatment discontinuation. Moreover, the TOP cup shows inferior 8-year survival rates compared to other uncemented implants and continuous pBMD loss proximally. Finally, the F-PET of acetabular cups can be reliably performed with strong agreement and moderate precision.