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Functional genetics on congenital intestinal motility disorders
Get PDFThis thesis explores primary pediatric intestinal pseudo-obstruction (PIPO), focusing on the genetic causes and cellular mechanisms behind the neuropathic (ENS defects) and myopathic (smooth muscle dysfunction) forms of the disorder. Chapter 2 identifies the TFAP2B gene as a new candidate for neuropathic PIPO, showing that a deletion in this gene causes abnormal exon splicing and impaired gastrointestinal function in zebrafish models. Chapter 3 investigates Filamin A (FLNA) mutations in myopathic PIPO, demonstrating that the loss of the long FLNA isoform disrupts smooth muscle contraction and intestinal development, leading to congenital short bowel syndrome and delayed motility.Chapter 4 examines the role of DNA methylation in Hirschsprung disease (HSCR), a common form of neuropathic PIPO, finding hypermethylation in key genes like MAB21L2, which may contribute to the disease by disrupting enteric nervous system (ENS) development. The study suggests that both RET and MAB21L2 interact in the same molecular pathway, offering insights into potential epigenetic influences on HSCR pathogenesis. Finally, Chapter 5 uses patient-derived induced pluripotent stem cells (iPSCs) to model HSCR, highlighting defective migration and proliferation of enteric neural crest cells (ENCCs) caused by genetic variants, and suggesting that genetic correction may be necessary for cell therapy approaches.Taken together, the thesis contributes new genetic insights into PIPO and HSCR, advancing the understanding of their pathogenesis and offering potential strategies for future therapies, including genetic correction and cell replacement therapies for patients with these disorders.<br/
Taking the next steps in unravelling TC-NER
No full textTranscription-coupled nucleotide excision repair (TC-NER) is a specialized DNA repair pathway that removes transcription-blocking lesions from active genes, thereby preventing cellular toxicity and maintaining transcription. TC-NER is initiated by RNA polymerase II stalling, which recruits proteins such as CSB, CSA, and UVSSA to orchestrate repair. While the molecular functions of these proteins have been studied, the precise mechanisms of initiation and regulation remained unclear. Recent advances, including structural insights and the discovery of new repair factors, have provided a more detailed understanding of TC-NER.Using a combination of live cell imaging, functional assays and proteomics approaches, this work uncovered new aspects of TC-NER dynamics, such as regulated chromatin association of CSB and its dependency on the CRL4CSA ubiquitin ligase complex. Novel protein interactors, including proteins involved in chromatin folding, were identified to be important for the removal of endogenous and UV damage, linking chromatin architecture to repair processes. Furthermore, the small protein DDA1 was characterized as a new component of the CRL4CSA complex, where it plays a crucial role in ubiquitylation events and lesion removal.Proximity-labeling experiments expanded the TC-NER interactome, identifying proteins that modulate CSB dynamics and transcription-coupled repair efficiency. Collectively, these findings broaden the understanding of TC-NER regulation, its connections to genome organization, and its implications for aging and disease, while opening new directions for future research.<br/
Noninvasive perioperative monitoring and gas exchange in pediatric anesthesia
No full textThis thesis explores the advancement of non-invasive monitoring in pediatric anesthesia, with a focus on improving gas exchange monitoring to enhance perioperative safety. It begins with a historical overview of anesthesiology, tracing its evolution from fundamental practices to a modern specialty emphasizing safety and monitoring. Technological milestones like pulse oximetry and capnography, along with global safety standards, have shaped current practices.Chapters 2 and 3 focus on non-invasive monitoring modalities. The thesis highlights the challenges of pediatric monitoring, including accuracy and applicability of current technologies. It validates transcutaneous CO₂ sensors as reliable during pediatric anesthesia, though oxygen sensors (tcPO₂) are only dependable for infants under six months.In Chapter 4, a clinical study on transcutaneous CO₂ monitoring during rigid bronchoscopies and microlaryngeal surgeries found no significant differences in ventilation outcomes, but spontaneous breathing led to lower CO₂ levels. These findings show clinical potential, though further refinement is needed.Chapters 5 and 6 critique oxygen management practices. An international survey revealed wide variability in oxygen use, with common intraoperative hyperoxemia. A retrospective analysis confirmed that 89% of pediatric patients experienced excessive oxygen levels, highlighting the need for structured oxygen protocols.Lastly, Chapter 7 introduces hyperspectral imaging as a tool for assessing bowel viability during neonatal surgery, demonstrating feasibility and potential for enhancing tissue perfusion assessment.Overall, the thesis underscores the importance of accurate, continuous, and non-invasive monitoring, and calls for standardized guidelines to improve pediatric anesthesia safety.<br/
Human-centric digital transformation:Exploring human information behavior through three field studies in digital policy, artificial intelligence, and emerging technologies
Get PDFIn today's rapidly evolving digital landscape, organizations often struggle to implement human-centric digital transformation effectively. Despite significant investments in advanced technologies, many digital initiatives fail to resonate with users because they overlook how humans seek, process, and utilize information. This disconnect arises from a gap in aligning technological advancements with the complex informational behaviors and preferences of individuals. Addressing this gap, this thesis investigates human-centric digital transformation through three distinct studies: the implementation of digital policies like General Data Protection Regulation (GDPR) and their reliance on understanding customers’ informational proactiveness; the application of machine learning algorithms such as life-event targeting to address customer uncertainties during decision-making; and the integration of emerging technologies like Artificial Intelligence (AI)-infused Augmented Reality (AR) in industrial settings, focusing on aligning their use with workers’ information processing capabilities. These studies explain how organizations can tailor digital transformation efforts to individuals' informational characteristics, offering insights into achieving human-centric digital strategies.Through three comprehensive studies corresponding to the stages of Digitization, Digitalization, and Digital Innovation, the research examines how aligning technological initiatives with human informational attributes enhances the success of digital transformation efforts. The first study explores how tailoring consent acquisition strategies to customers' information proactiveness under regulations like GDPR enhances compliance and trust, emphasizing the importance of human-centric approaches in the initial digitization stage. The second study investigates how addressing customers' information-seeking needs during uncertain decision-making periods improves the effectiveness of machine learning applications like life-event targeting, highlighting the value of personalized engagement in the digitalization stage. The third study examines how adapting advanced technologies like AI-infused augmented reality to match workers' information processing capabilities enhances productivity in industrial settings, underscoring the necessity of considering human factors in the digital innovation stage.Collectively, these studies affirm that prioritizing human-centric strategies aligned with end-users' informational behaviors will improve specific outcomes within each stage of digital transformation. While effectiveness was measured through stage-specific metrics—such as compliance rates in GDPR implementation, engagement rates in life-event targeting, and productivity enhancements with AR—these findings collectively demonstrate how aligning technology with informational behaviors fosters more impactful digital transformation efforts. By understanding and integrating how individuals seek, process, and utilize information, organizations can design and implement digital solutions that resonate deeply with users, leading to higher engagement, better adoption rates, and meaningful impacts. This thesis concludes that technological advancements alone are insufficient; success in digital transformation depends on the harmonious integration of technology with human informational characteristics. Future work could explore additional informational characteristics and contexts to further refine human-centric strategies, ensuring that digital transformation efforts remain aligned with the evolving ways humans interact with information. By adopting these approaches, organizations can navigate the complexities of the digital landscape more effectively, fostering a more inclusive, efficient, and responsive digital ecosystem.<br/
Navigating treacherous waters:Hemostatic complications in pediatric extracorporeal membrane oxygenation
Get PDFCovid-19 vaccine induced immune responses in patients with kidney disease:a cellular perspective
No full textThis thesis investigates humoral and cellular immune responses to COVID-19 vaccination in patients with chronic kidney disease, dialysis patients, and kidney transplant recipients, who show reduced vaccine responsiveness due to immune impairment. The results highlight the critical role of T-cell immunity, particularly IL-2 and IL-21 responses and memory B cells, when antibody responses are weak, and demonstrate that repeated booster vaccinations can substantially enhance immune protection. These findings support personalized vaccination strategies to optimize protection in immunocompromised populations.<br/
Innovations in neonatal monitoring:From physiology to technology, from concept to implementation
No full textPulmonary valve repair at the time of the Ross procedure:A safe and durable strategy to address postimplantation aortic regurgitation
No full textBackground: Contemporary evidence supports use of the Ross procedure (pulmonary autograft) to treat patients with aortic valve disease. No studies have evaluated the impact of autograft repair to correct residual aortic regurgitation at the index Ross procedure on late outcomes. Methods: This study includes patients undergoing a Ross procedure followed by concomitant autograft valve repair at 2 institutions. Autograft repair was defined as correction of residual aortic regurgitation during the same admission for the Ross procedure. Results: Between 2011 and 2024, 675 patients underwent a Ross procedure in 2 large-volume institutions. Of them, 22 (3%) underwent autograft repair for postprocedural aortic regurgitation (mean age, 52 years; 23% were female). Fourteen patients had a bicuspid valve (64%), and 5 patients had a unicuspid aortic valve (23%). One patient had a bicuspid autograft. Residual aortic regurgitation was eccentric in 8 patients (36%), commissural in 9 patients (41%), and combined in 5 patients (23%). Aortic regurgitation was corrected using central plication sutures in 13 patients (59%) and commissuroplasty in 14 patients (63%). There were no perioperative deaths. One patient required reintervention and conversion to a Bentall procedure 6 days after the index Ross procedure. All patients but 1 (5%; mild aortic regurgitation) had no or trivial aortic regurgitation on discharge. At a median echocardiographic follow-up of 3 years (Q1-Q3: 2-8), 7 patients have mild aortic regurgitation (32%), and 1 patient developed mild-to-moderate aortic regurgitation after 7 years. All other patients have no or trivial aortic regurgitation. At 5 years, the cumulative incidence of aortic regurgitation greater than 2 is 6% ± 6%.Conclusions: Addressing postprocedural aortic regurgitation after autograft implantation is safe and associated with durable outcomes in the first decade. These findings support correction of postprocedural commissural or eccentric jets at the time of index operation.</p