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Strengthening vaccine pharmacovigilance in low- and middle-income countries using a multi-centre hospital based prospective surveillance approach
No full textThe capacity to rapidly detect and respond to emerging vaccine safety signals is critical for assuring public confidence in vaccination programmes. Clinical trials, despite their increasing size, cannot detect very rare or long-term adverse events following immunization (AEFIs) and do not represent the diversity of real-world populations, highlighting the need for effective post-licensure safety surveillance of vaccines. Spontaneous reporting remains the mainstay of vaccine safety monitoring in low- and middle-income countries (LMICs). Such passive surveillance systems are susceptible to under- and biased reporting and lack the capacity to identify long-term sequelae following vaccinations.
The present thesis aims to evaluate the potential of multi-centre hospital-based active surveillance approaches towards strengthening capacity for vaccine pharmacovigilance in LMICs. To achieve these objectives, the thesis established two prospective observational active vaccine safety surveillance networks across seven countries. The two large, multi-centre studies underpinning this thesis, collectively screened a cohort of over 160,000 individuals and identified over 40,000 serious perinatal, neonatal and paediatric adverse outcomes, syndromes and diseases in one primary, five secondary and 32 tertiary care hospitals across seven countries, over a span of 34 months. By generating background rates of adverse perinatal, neonatal, and paediatric conditions across diverse geographies and healthcare settings, it shows that hospitals in resource-constrained settings can effectively classify adverse outcomes and vaccine exposures using standardized definitions.
The thesis demonstrates the feasibility and potential of tailored multi-centre hospital-based active surveillance systems in India and other LMICs. These findings offer operational and scientific guidance for building robust and responsive post-licensure active vaccine safety surveillance systems in the future
Charge control of biomolecules by photocleavage in high vacuum
No full textThis thesis summarizes the work performed from March 2020 – April 2024 as part of a collaboration between the Köhler group (University of Basel), Marcel Mayor (University of Basel) and the Arndt group (University of Vienna). The author YH designed experiments in collaboration with the Arndt group and performed synthesis of photocleavable tags and bioconjugation at the University of Basel. The gas-phase cleavage experiments were carried out by the collaborating group of Markus Arndt at the University of Vienna.
Different photocleavable tags, which can be cleaved under different wavelengths, were designed and synthesized. The optimized tags were then attached to a series of biomolecules. Charged particles can be generated by ESI/MALDI, after which positive/negative charges can be removed by photo-induced cleavage with a laser to achieve neutralization.
In chapter 1, a BODIPY-based photocleavable tag was designed and synthesized for the application with 532 nm laser under positive mode.
In chapter 2, redesigned Ru(II) complexes were investigated for the application with 355 nm laser under positive mode.
In chapter 3, a new photocleavage mechanism of Ru(II) complexes under concomitant electron transfer was explored.
In chapter 4, two generations of rotaxanes stoppered with a Ru(II)-photocage were explored for the removal of multiple charges with a single bond cleavage.
In chapter 5, a nitrodibenzofuran-based photocleavable tag was investigated for the application with 355 nm laser under negative mode.
In parallel, new bioconjugation methods were developed for the attachment of photocleavable tags in chapter 6
Characterization of the laminin receptors integrin α3β1, integrin α6β1, integrin α7β1 and basal cell adhesion molecule in acute myeloid leukemia
Get PDFAcute myeloid leukemia (AML) is a rapidly progressing type of blood cancer characterized by the accumulation of immature myeloid blasts in the bone marrow (BM) or peripheral blood (PB) that interfere with healthy hematopoiesis. During leukemogenesis, healthy hematopoietic stem and progenitor cells acquire genetic and epigenetic lesions leading to the transformation into their malignant counterpart, the leukemic stem cells (LSC). Despite tremendous progress in AML research over the past few decades, as well as refined chemotherapeutic treatment strategies, AML remains a disease with a poor prognosis and a five-year overall survival rate of only 30%.
One major challenge in treating AML patients is the persistence of drug-resistant LSC that survive chemotherapy and cause relapse. The BM niche has recently gained attention as a protective environment for leukemic cells and it has been recognized that interactions with the BM niche are crucial for promoting self-renewal and survival of AML cells. At the same time, AML cells remodel the BM niche, adapt it to their needs and create a pro-leukemic microenvironment. Consequently, AML cells express a variety of surface receptors to engage with BM niche cells and extracellular matrix proteins, such as laminins. Despite the association of laminin receptor expression with stemness in healthy hematopoiesis and with poor prognosis in several cancer entities, the role of laminin receptors in AML remains poorly understood.
This thesis provides a comprehensive characterization of the laminin receptors integrin α3β1, integrin α6β1, integrin α7β1 and basal cell adhesion molecule (BCAM) in AML. In addition to analyzing publicly available datasets, we used a flow cytometry approach to determine laminin receptor expression on primary BM and PB samples from a cohort of 60 AML patients, also in relation to stemness and prognosis. We found that high mRNA expression of all four laminin receptors correlated with poor overall survival. Notably, integrin α6 and α7 displayed the highest cell surface presentation among the laminin receptors examined and were expressed at higher levels on AML cells in comparison to healthy controls. Moreover, our results indicated that integrin α7 expression allows to distinguish between LSC and non-LSC populations and that integrin α7 surface expression further identifies a cell population with enhanced migratory potential. In contrast, integrin α6 contributed to laminin adhesion and therefore presumably to AML cell retention to the BM niche. Both, interfering with ECM interactions and targeting the migratory cell population may have therapeutic potential
Amyloid oligomer formation and interferences
Get PDFAs the global population is aging, the growing prevalence of progressive neurodegenerative diseases places a huge burden on our society. A wide range of amyloid-forming proteins or peptides, such as Alzheimer's amyloid-beta (Aβ) and Parkinson's α-Synuclein, have the inherent tendency to undergo protein homeostasis collapse under the misfolding conditions, in which these proteins or peptides fail to keep native conformations, followed by self-assembling into a diverse array of aggregates including the initial oligomers or protofibrils (or early aggregates) and mature fibrils. Though one of the hallmarks of these age-related diseases is the fibrillar deposits in the brain, numerous evidence has shown that it is the soluble early aggregates rather than these fibrils that are the main contributing factors to neurotoxicity. One of the prevalently accepted mechanisms states that early aggregates interact with lipid membranes, permeabilize and disrupt the integrity of cellular membranes, resulting in uncontrolled extracellular Ca2+ influx and imbalance of other biomolecules. However, these early aggregates are structurally heterogeneous, transient, and metastable, making them difficult to characterize their biophysical properties, such as the size distributions, the structural information, the interaction with other molecules (metal ions or extracellular globular proteins), and the permeabilization with cellular membranes.
To make a deep understanding of the above conspicuous feature of the toxicity-induced amyloid aggregates in the pathogenesis of neurodegenerative diseases, in this thesis, we discussed two main aspects of the involvement of different amyloid-forming proteins, that is amyloid oligomer formation in chapters 2-4 and oligomer interference in chapters 5-6 to discuss amyloid aggregation neurotoxic mechanisms, structural features, membrane permeabilization, and intermolecular interactions. In chapter 2, we proposed that single-molecule techniques can be taken as complementary tools for the characterization of heterogeneous amyloid aggregates and provide diagnostic perspectives for neurodegenerative diseases. Additionally, we showed a structurally and functionally relevant scaffold to stabilize Aβ oligomers in chapter 3, which enable us to determine the structure in a membrane-mimic environment, and we explored the membrane permeabilization mechanism of truncated prion protein in lipid membranes in chapter 4. Moreover, our results in chapters 5-6 reveal the effects of globular proteins on amyloid protein aggregation or the dynamic influence of lipids or metal ions on binding and unbinding to lipid membranes. Our results expand our knowledge about the toxic molecular mechanisms of amyloid aggregates and present the new directions to design
or screen the oligomer-based nanobody or antibody, which can further contribute to putting forward the diagnosis and drug design for subsequent therapy of these diseases
Contribution of LicB to the adaptation of Streptococcus pneumoniae to host niche conditions
Get PDFCholine Binding Proteins (CBP) play a fundamental role in the infection mechanism of S. pneumoniae by promoting adhesion, endocytosis, and evasion of the host immune system (Figure 1) (1–4). CBPs bind to teichoic acids by their phosphorylcholine decoration moieties, a feature that is key to performing their functions. S. pneumoniae is auxotrophic for choline, a necessary precursor for teichoic acid decoration, and the protein that mediates choline import is LicB (Figure 1), a proton-coupled symporter essential for bacterial growth and survival (5,6). Understanding the function of LicB can contribute to the development of new approaches for the treatment and prevention of S. pneumoniae infection (7). In this study, I aimed to uncover the contribution of LicB to S. pneumoniae adaptation to host niche pH conditions. I used solid supported membrane (SSM)- based electrophysiology to investigate LicB function under different pH conditions to assess its impact on choline import mediated by LicB. I showed that low pH conditions boost the transport rate activity of LicB, which might play an essential role in the adaptation mechanism to the physiological pH of the host that ranges from 5.0 to 6.5 (8,9). I also evaluated the impact of the enhanced transport rate activity of LicB on the composition of the cell wall and showed that the phosphorylcholine content of teichoic acids is increased under low pH conditions.
Due to the essential role of LicB in cell wall biosynthesis and S. pneumoniae pathogenicity, obtaining inhibitors against this protein is highly relevant. I have tested the effect of two compounds that are known to inhibit the human choline transporter CHT1: hemicholinium 3 (HC3) and hemicholinium 15 (HC15) (6,10–13). I showed that both compounds inhibit LicB activity in proteoliposomes, however, no inhibitory effect was observed in vivo. I showed that HC3 impacts the S. pneumoniae growth pattern by hindering the transition into the autolysis phase. Autolysis is a crucial process in the infection cycle of S. pneumoniae, as it allows for the release of virulent factors such as pneumolysin, which initiates the inflammatory process (14 16). These results indicate that compounds such as HC3 are valuable molecules that could serve as templates for the synthesis of new molecules for the prevention of detrimental effects of inflammation caused by S. pneumoniae
Antimicrobial resistance in humans and animals in the Somali region of Ethiopia: a one-health approach
Get PDFThe rampant spread of antimicrobial resistance (AMR) in humans, food-producing animals, agriculture and the environment presents an alarming and significant global crisis. Unless action is taken, AMR is projected to claim 10 million lives annually by 2050, disproportionally impacting low- and middle income countries (LMICs). Due to the severity, vastness, intricacy and multifaceted nature of AMR, a holist One Health approach is widely considered the strategy to address and combat AMR. However, prior evidence to this thesis, demonstrated the dearth of studies that truly applied a One Health approach implementing genomic analysis in LMICs. The broad goal of this research was to provide evidence on AMR genes in children and animals, as well as the knowledge and attitude of rural communities regarding AMR.
The first part of the research provides an overview of the existing evidence of molecular AMR studies utilizing a One Health approach in Africa, aiming to determine the prevalence of resistance genes in humans, animals and the environment. The findings from the systematic review and meta-analysis showed very limited studies truly implementing this approach in Africa. However, within the limited studies, sul1, sul2, tetA, strB, and blaTEM were the most prevalent genes identified in humans and animals.
Thus, due the scarcity of studies utilizing unified approach in Africa, we examined the genetic characterization of fecal carriage of ESBL-producing E. coli in rural children and livestock, studied diarrheagenic pathogens and their resistance genes in urban children, as well as assessed the communities’ knowledge and attitude regarding AMR and climate change in the Somali region of Ethiopia. The results showed a high prevalence of ESBL-producing E.coli in rural and urban children, and a low prevalence in livestock, predominantly harboring blaCTX-M-15. Conversely, the carbapenemase-producing diarrheagenic E. coli, Salmonella spp. and Shigella spp. were exclusively detected in urban children. Moreover, the first whole genome sequencing analysis employed in rural communities in Ethiopia, revealed a high diversity of sequence types (ST), with ST2353 being among the most prevalent, harboring multiple resistance genes. Notably, this is the first study to report ST2353 in Ethiopia. The findings also shed light on Shigella spp. harboring blaNDM and blaOXA-48, which has been rarely described to date, indicating the widespread of AMR genes in both rural and urban children aged less than five years. These findings are concerning as the identified genes confer resistance to most commonly used antibiotics, potentially hampering treatment of infections caused by these bacteria.
In addition to the spread of AMR genes, a significant association between ESBL carriage in rural children and being both wasted and stunted, water treatment (with chlorine), and chicken ownership were found. Furthermore, the findings highlighted the limited knowledge of AMR and climate change, with noticeable gender disparity, where females showed lower levels of knowledge compared to males. Further, the limited knowledge of mothers was seen to significantly increase the odds of ESBL-producing E. coli carriage in children.
The overall findings indicated the wide spread of AMR resistance genes in urban and rural children, showcasing diverse sequence types such as ST2353, a first report in Ethiopia. Additionally, this research identified Shigella spp. harboring carbapenemase genes, rarely reported globally. This is alarming, as these strains might complicate treatment options, possibly prolong hospital stay and increase costs. Moreover, the limited knowledge of AMR and climate change, mainly among females, adds to the burden. Therefore, with the emergence and spread of AMR in the country, it is imperative to implement an integrated AMR surveillance system using a One Health approach that involves both hospital and community settings in order to mitigate and control AMR. Addressing other relevant issues such as malnutrition and water, sanitation and hygiene (WASH) is also of paramount importance. Further, we recommend comprehensive community-based educational programs tailored for women to promote responsible antimicrobial use and environmental conservation.
In addition, the research of this thesis provided the foundation for future research work on various aspects of AMR. Furthermore, the research showed the need for robust study designs suitable for determining the acquisition and dynamics of AMR
On multidimensional nonlocal conservation laws with BV kernels
Get PDFWe establish local-in-time existence and uniqueness results for nonlocal conservation laws in several space dimensions under weak (that is, Sobolev or BV) differentiability assumptions on the convolution kernel. In contrast to the case of a smooth kernel, in general the solution experiences finite-time blow-up. We provide an explicit example showing that solutions corresponding to different smooth approximations of the convolution kernel in general converge to different measures after the blow-up time. This rules out a fairly natural strategy for extending the notion of solution of the nonlocal conservation law after the blow-up time
Welches Potential hat Sensomotoriktraining zur Symptomreduktion neuropathischer Symptome nach einer neurotoxischen Chemotherapie? – ein Case Report
No full textDie Chemotherapie-induzierte periphere Polyneuropathie (CIPN) ist eine zentrale Nebenwir-kung der Krebstherapie, die sich in vielen Bereichen negativ auf die Gesundheit und die Le-bensqualität der Patient:innen auswirkt. Bei Erwachsenen gibt es viel Evidenz, die für ein Sen-somotoriktraining (SMT) zur Linderung der CIPN spricht. Untersuchungen im pädiatrischen Bereich fehlen jedoch noch. Das SMT scheint aber auch bei ihnen eine wirkungsvolle Behand-lungsmethode zu sein. Aus diesem Anlass absolvierte eine 16-jährige CIPN-Patientin regel-mässig ein SMT. Die Auswirkungen davon werden in dieser Arbeit analysiert.
Methode
Aufgrund der relativ limitierten Patientenzahl in der pädiatrischen Onkologie wird in dieser Ar-beit über eine einzelne Patientin berichtet, was einem klassischen Case-Report entspricht. Die Patientin besuchte vier Monate lang regelmässig ein spielerisches SMT und führte zusätzlich zwei- bis dreimal wöchentlich Übungen zuhause durch. Arztberichte und Assessments doku-mentierten den Verlauf ihrer CIPN und dessen Einfluss auf die Gleichgewichtsfähigkeit, Dor-salflexion der Füsse und Gehfähigkeit. Die Resultate wurden mit einer gesunden Referenz-gruppe verglichen. Die Lebensqualität wurde mittels Fragebögen erfasst.
Ergebnisse
Das SMT führte zu einer Verbesserung des Ganges, des Gleichgewichts und des Bewegungs-umfangs der Dorsalflexion der Füsse. Der Achilles- und Patellarsehenreflex waren wieder aus-lösbar. Das SMT wirkte sich auch positiv auf die Lebensqualität aus.
Schlussfolgerung
Ein regelmässiges, spielerisches SMT mit einer 16-jährigen CIPN-Patientin ist gut durchführ-bar. Es könnte für krebskranke Kinder und Jugendliche eine vielversprechende Behandlungs-methode der CIPN sein
Akuter Einfluss einer Sporteinheit auf das retrospektive und prospektive Gedächtnis bei Kindern
No full textHintergrund: Das retrospektive Gedächtnis ermöglicht das Speichern und Abrufen von Wissen und Fähigkeiten, was für alle Altersgruppen wichtig ist. Das prospektive Gedächtnis hilft Erwachsenen, sich an zukünftige Aufgaben zu erinnern und unterstützt Kinder dabei, ein unabhängiges Leben zu führen. Es stellt sich daher die Frage, ob eine akute Sporteinheit das retrospektive und das prospektive Gedächtnis verbessern kann.
Zahlreiche Studien haben gezeigt, dass eine akute Sporteinheit das retrospektive Gedächtnis bei Erwachsenen verbessert. Auch bei Kindern konnte dieser positive Effekt nachgewiesen werden. Der Einfluss auf das prospektive Gedächtnis bei Erwachsenen ist bisher wenig erforscht und die Ergebnisse sind uneinheitlich. Bei Kindern und Jugendlichen gibt es noch keine Studie dazu. Diese Lücke soll durch diese Arbeit geschlossen werden.
Methoden: Die randomisierte kontrollierte Studie umfasste Schülerinnen und Schüler im Alter von 8 bis 13 Jahren, welche eine 3./4. Klasse oder 5./6. Klasse besuchten. Die Interventionsgruppe absolvierte eine einmalige Intervallausdauereinheit. In dieser Zeit machte die Kontrollgruppe Dehnübungen. Vor und direkt nach der Einheit wurden kognitive Aufgaben am Laptop gelöst (N-Back Aufgabe, ereignisbasierte prospektive Aufgabe und Flanker-Aufgabe). Zusätzlich wurden vier Fragebögen ausgefüllt.
Ergebnisse: Insgesamt haben 89 Proband*innen (51w/38m) vollständig an der Studie teilgenommen. Die Interventionsgruppe zeigte im Vergleich zur Kontrollgruppe keine besseren Leistungen, weder im retrospektiven Gedächtnis (N-Back Test) noch im prospektiven Gedächtnis (ereignisbasierte prospektive Aufgabe).
Schlussfolgerungen: Die Studie zeigt keine signifikanten Unterschiede in den kognitiven Tests zwischen der Interventions- und Kontrollgruppe. Aus diesem Grund sollten weitere Studien mit unterschiedlichen Parametern durchgeführt werden, um die Ergebnisse zu bestätigen oder zu widerlegen
Einfluss von Kraft- und Ausdauertraining auf das psychische Wohlbefinden, den Schlaf und die körperliche Leistungsfähigkeit bei Patienten und Patientinnen mit hochgradigem Gliom (WHO III° und IV°)
No full textHintergrund: In zahlreichen Studien wurde bereits belegt, dass Sport und körperliche Aktivität einen positiven Einfluss auf die Prävention, die Therapie und das Rezidivrisiko bei verschie-denen Krebserkrankungen haben. Trotz dieser breiten Evidenzlage besteht noch eine deutli-che Forschungslücke im Bereich von Sportinterventionen bei Hirntumoren. Aus diesem Grund wurde die vorliegende Studie initiiert, um die Effekte von Kraft- und Ausdauertraining auf das psychische Wohlbefinden, den Schlaf sowie die physische Verfassung von Patienten mit re-zidivierenden hochgradigen Gliomen nach Tumorresektion und während der (kombinierten) Radio- und Chemotherapie zu untersuchen. Dies geschieht im direkten Vergleich mit einer aktiven Kontrollgruppe.
Methode: In die vorliegende Studie wurden insgesamt 47 Patienten (51,2% Männer) einbezo-gen. Nach der Tumorresektion erfolgte die Randomisierung der Patienten in eine der drei In-terventionsgruppen: Kraft (n= 16), Ausdauer (n= 17) und aktive Kontrolle (n= 14). Die Teilneh-mer nahmen ab Beginn der (kombinierten) Radio- und Chemotherapie zweimal wöchentlich für sechs Wochen an den entsprechenden Trainings oder der Kontrollbedingung teil. Während des gesamten Beobachtungszeitraums, der sich über 24 Wochen erstreckte, wurden zu ver-schiedenen Zeitpunkten (Baseline, Woche 3, Woche 6, Woche 12, Woche 24) Tests und Be-fragungen durchgeführt. Diese umfassten verschiedene Dimensionen, darunter depressive Symptome, Angst, Stressempfinden, Schlafqualität, Lebensqualität, Fatigue, Ausdauer und Handkraft.
Ergebnisse: Während des sechswöchigen Interventionszeitraums zeigten sich in der Ausdau-ergruppe positive Effekte auf bestimmte Dimensionen, darunter subjektives Stressempfinden, Angst und Schlaf. Auf die Fatigue scheint sich ein Ausdauertraining hingegen eher negativ auszuwirken. Die aktive Kontrollbedingung hatte auf alle gemessenen und getesteten Variab-len positive Auswirkungen, während ein Krafttraining keine oder sogar negative Effekte auf die Variablen zu haben scheint. Bei den Messzeitpunkten in der anschliessenden Beobachtungs-phase zeigte sich hingegen auch in der Kraftgruppe eine positive Tendenz, insbesondere in den Dimensionen Fatigue, subjektives Stressempfinden und Angst.
Schlussfolgerung: Die Ergebnisse zeigen komplexe und vielfältige Auswirkungen der Interven-tionen auf die abhängigen Variablen. Besonders effektiv für eine begleitende Therapie bei re-zidivierenden hochgradigen Gliomen scheinen Ausdauertrainings und die aktive Kontrollbe-dingung zu sein. In Zukunft sind weiterführende Studien erforderlich, um die Komplexität der Effekte genauer zu verstehen und differenzierte Empfehlungen für das Training bei Gliom-Patienten ableiten zu können