Coming dissertations at MedFak
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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.
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The leading and following brain
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-538396
Leading and following are daily activities for most individuals, as these behaviors are crucial for social interactions. When these interactions fail, they can negatively affect the individuals and the activity. The driving force behind this thesis was to understand more about the neural underpinnings of leading and following. The accomplishment of this aim required a fundamental examination of leadership and followership. A thorough and rigorous process was followed to develop a minimal model for study I to investigate neural reactivity during leading and following. This model aims to analyze leader and follower behavior in a standardized manner. The model used finger tapping of rhythms representing the core of the interactions during leading and following. Participants were invited to assume the roles of both leaders and followers, with no requirement for prior expertise. The model did not incorporate a status difference between leaders and followers.
Data collection occurred in Japan, but most analyses were conducted in Sweden. Study II translated the Swedish Universities Scales of Personality from Swedish to Japanese. Its three dimensions represent personality facets for emotional stability, extraversion, and agreeableness. Study II resulted in SSPJ-11 with 11 reliable personality scales of these three facets that are most probably relevant for leading and following. In study III and IV, participants were paired to engage in the minimal model for leading and following while their brain activity was recorded using hyperscanning EEG. For study III, a graph-based algorithm was introduced to analyze directed causal connections in time series data. It was combined with hyperscanning EEG prefrontal cortex activation of single and two interacting brains. The PCMCI algorithm effectively detected directed causal connections within and between participants. In study IV, PCMCI assessed whole brain-directed causal networks of leading and following within and between brains. The results of Study I and IV indicate a significant overlap in neural reactivation between the roles of leading and following, albeit with certain role-specific differences. Leadership activations indicate focus on decision-making, task performance, social cognition, and effective processing and followership activation stipulate social adaptivity and task focus. These results could be a first step towards elucidating the pivotal components of neural reactivations in the context of leading and following. Ultimately, these discoveries could provide a foundation for the creation of novel, sustainable, and effective cross-cultural training techniques designed to enhance both performance and well-being in leadership and followership, thereby presenting a promising vision for the future.
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Spatial characterization of proteins in reproductive tissues : Insights into health and disease states
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-536635
The molecular building blocks of human cells have been increasingly mapped in large-scale projects by emerging high-throughput antibody profiling and sequencing methods. These transformational efforts have shown remarkable progress in resolving the expression levels and spatial locations of proteins in many human cells. This thesis aimed to characterize the spatial protein expression at the single-cell level in human reproductive tissues, testis and fallopian tube (FT), and additionally study how aberrantly expressed testis-proteins repurposed in non-small cell lung cancer (NSCLC) affect the immune microenvironment.
In Paper I, more than 500 proteins with elevated RNA expression levels in the testis were profiled in eight different cell types with immunohistochemistry (IHC). Several poorly characterized proteins, so-called “missing proteins,” were localized at the cell-type level at various stages of spermatogenesis, providing novel insights into their possible function.
In Paper II, a spatiotemporal map of human spermatogenesis was created by combining single-cell transcriptomics and multiplex IHC. High-throughput image analysis determined the cell state-specific protein expression for almost 500 proteins. By examining RNA and protein correlation dynamics, we highlighted the complex spatiotemporal landscape of the human testis. These proteins serve as targets for functional studies.
In Paper III, protein-coding genes elevated in FT based on RNA levels were profiled by IHC, and most proteins were functionally related to cilia motility, a mechanism necessary for creating the tubal flow essential for fertilization. Of 133 proteins annotated at the cell-type level, most were exclusive to ciliated cells, including several proteins previously not described in motile cilia.
In Paper IV, cancer-testis antigens (CTA) were characterized by IHC on more than 300 immunophenotyped NSCLC patients. CTAs are typically expressed in the testis and harbor immunogenic properties that may be used as treatment targets due to aberrant expression in NSCLC. CTAs were associated with immune profiles, such as macrophage and plasma cell infiltration, possibly demonstrating an in situ immunogenic effect. These associations can be studied and exploited as potential immunotherapy targets.
This thesis defines the spatial proteome of reproductive tissues at the single-cell resolution and identifies many proteins with previously unknown functions in reproduction. The integrative approach to mapping tissue-specific cellular diversity at the molecular level shows the importance of combining RNA and protein detection methods. The thesis developed emerging methods like multiplexed staining and bioimage analysis, which hold promise for large-scale efforts. This work significantly contributes to the cellular atlas of reproductive tissues, which historically have not been well-studied.