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Reduktion der notwendigen Radiofrequenz-Applikationszeit zur Erstellung einer anterioren Linie durch Informationen des Katheteranpressdrucks bei Patienten mit persistierendem Vorhofflimmern
Get PDFArtificial Intelligence for automated decision-making in error-pattern recognition
Get PDFThe demand for integrating Artificial Intelligence (AI) into diverse systems continues to expand rapidly. With growing reliance on AI, there is a constant need to deliver increasingly more dependable and robust solutions. This thesis aims to address common Machine Learning (ML) challenges and offers solutions in the field of automated decision-making and pattern recognition. It explores, presents, and analyzes novel methods and algorithms for Representation Learning, focusing on "Neural Architecture & Data Representation", "Manifold & Embedding Learning", and "Data Integration & Analysis".
The contributions of this thesis include: (1) a novel neural architecture based on complex-valued neural networks, (2) a framework for encoding hierarchical one-to-many relationship databases into contextualized numeric data representations, (3) an adaptive and robust feature normalization and pre-processing technique, (4) a method for synthetic data augmentation on hierarchical databases, (5) a contrastive Representation Learning framework for tree structures, (6) extending and generalizing hierarchical Embedding Learning to multiple data views, (7) methods and diverse loss functions for Manifold Representation Learning and Clustering, (8) approaches for automated textual description generation for cluster groups, (9) a quality evaluation metric for clustering under coarse label uncertainty, (10) methods for determining representative textual labels for clustering accurate sensor data with inexact annotations, (11) a Transfer Learning approach to distilling insights from ML models trained on different data sets, (12) a novel approach to Out-of-Distribution Detection and Novelty Detection by leveraging mismatches in model calibration alignment, and (13) a method for representative sampling within quantile windows in data streams of unknown final length
Präoperativ elektrisch evozierte Hirnstammpotentiale als Prädiktor des postoperativen Verlaufs nach einer Cochleaimplantation
Get PDFObjective: Subjective promontory stimulation is used to evaluate cochlear implant (CI) candidacy, but the test reliability is low. Electrically evoked auditory brainstem response (EABR) can verify the function of the auditory system objectively. This study’s procedure uses a trans-tympanic rounded bent-tip electrode to perform pre-operative EABR under local anaesthesia (LA-TT-EABR) using MED-EL Software and Hardware. This study aimed to determine usability and effectiveness for CI candidates.
Design: We hypothesised that LA-TT-EABR waveforms of good quality would be related to successful hearing outcomes. We assumed that the duration of hearing loss/deafness was a confounding factor to study outcomes.
Study sample: 19 borderline CI candidates.
Results: Positive LA-TT-EABR results were confirmed in 14 patients. LA-TT-EABR’s mean latency was 2.05 ± 0.31 ms (eII/eIII) and 4.24 ± 0.39 ms (eIV/eV). Latencies weren’t statistically different from intra-operative EABR elicited by basal CI contacts. All positive LA-TT-EABR patients benefitted from CI and speech performance improved one year after implantation. One patient with negative LA-TT-EABR was cochlearimplanted and had no hearing sensation.
Conclusions: LA-TT-EABR is a tool in the frame of pre-operative objective testing the auditory pathway. It seems useful for clinical testing CI candidacy. Based on this study’s outcomes, LA-TT-EABR should be recommended for uncertain CI candidates
Molecular mechanisms behind the interactions between Listeria monocytogenes LL195 and a German deli meat "Lyoner"
Get PDFVerbesserung der Diagnostik von diffus-parenchymatösen Lungenerkrankungen (DPLD) im Kindesalter anhand der Erstellung einer pädiatrisch-pneumologischen Ontologie in der Human Phenotype Ontology (HPO) und der Erweiterung des Wissens um die Korrelation von Phänotyp / Krankheitsverlauf und Genotyp bei komplexen, bisher ungeklärten DPLD-Fällen im Kinderlungenregister (chILD-EU)
Get PDFThe fish fauna of Ettling in the late Jurassic Solnhofen Archipelago (Bavaria, Germany)
Get PDFThe Konservat-Lagerstätte of Ettling, excavation site of the Jura-Museum Eichstätt (JME) since 2007, is unique among the Bavarian Late Jurassic Plattenkalk basins (known as the Solnhofen Archipelago) in its abundant, extremely well-preserved fossil vertebrates, almost exclusively fishes. In the past 20 years I have been excavating, preparing, and cataloguing about 4000 fishes from this locality. I published scientific papers about the fish fauna focusing on the following actinopterygians: ginglymodins, pycnodontiforms, halecomorphs, aspidorynchiforms, “pholidophoriforms”, and “true” teleosts. Ettling has yielded six new fish species described so far (Piranhamesodon pinnatomus Kölbl-Ebert, Ebert, Bellwood & Schulbert, 2018; Macrosemimimus fegerti Schröder, López-Arbarello & Ebert, 2012; Aspidorhynchus sanzenbacheri Brito & Ebert, 2009; Bavarichthys incognitus Arratia & Tischlinger, 2010; Orthogonikleithrus hoelli Arratia, 1997 and Ebertichthys ettlingensis Arratia, 2016). Further new taxa are under study. Upper and lower Ettling strata differ in faunal content, with the lower strata dominated by the small teleost Orthogonikleithrus hoelli (absent from the upper strata, where other prey fish, Leptolepides sp., Allothrissops sp. and Tharsis sp., occur instead). Pharyngeal and stomach contents of Ettling fish provide direct evidence that Orthogonikleithrus hoelli was a primary food source during early Ettling times; additional information comes from thousands of coprolites. Scarcity of ammonites and the near absence of coleoids in Ettling differ markedly from the situation at other Upper Jurassic Plattenkalk localities in the region (e.g., Brunn, Eichstätt, Nusplingen, Painten, Schamhaupten, Solnhofen, Zandt, Wattendorf and the Mörnsheim beds), where they are more common. The comparison of the early Tithonian (eigeltingense horizon) fish fauna from Ettling, with the above-mentioned localities of southern Germany and Cerin (France) shows how much the Ettling fish fauna differs from other sites, particularly also from the site Eichstätt, which is of the same stratigraphic age. Such faunal differences and additional sedimentological evidence indicate a significant difference in environment and ecology between these sites and their surroundings. The evidence indicates that the lower part of the Ettling deposits represents an independent, isolated basin within the larger Upper Jurassic “Solnhofen Archipelago”, a shallow subtropical marine environment featuring scattered islands, sponge-microbial and coral reefs, sandbars, and deeper basins on a vast carbonate platform along the northern margin of the Tethys Ocean
Der Zusammenhang zwischen Adipositas und Fettleber mit Parametern der Blutgerinnung in der erwachsenen Bevölkerung
Get PDFMessung von Tau Proteinablagerungen mittels PET bei primären Tauopathien
Get PDFBiomarker für die Tau Pathologie bei Patienten mit Progressiver Supranukleärer Blickparese (PSP) werden als diagnostisches Einschlusskriterium für Therapiestudien und zum Monitoring von krankheitsverändernden Effekten dringend benötigt. Aktuell existieren jedoch keine zugelassenen Methoden um die 4-Repeat Tau Ablagerungen im Gehirn von Patienten mit PSP zuverlässig detektieren zu können. Im Rahmen dieser Promotionsarbeit wurde der Tau-PET Tracer [18F]PI-2620 bei Patienten mit PSP im Vergleich zu Patienten mit anderen neurodegenerativen Erkrankungen und gesunden Kontrollen als neuer Biomarker für die Tau Pathologie evaluiert. Dafür wurde ein multizentrisch erhobener Datensatz harmonisiert und quantitativ analysiert. In einem zweiten Schritt wurde untersucht, ob sich die Tau Pathologie bei PSP anhand funktionell verbundener Hirnareale ausbreitet.
In einem retrospektiven Design wurden die [18F]PI-2620 Tau-PET Scans von 60 Patienten mit klinischer PSP (40 Patienten mit der typischen Variante eines Richardson Syndroms, 20 mit atypischen Varianten der PSP), 10 Patienten mit Alpha-Synuclein assoziierten Erkrankungen (idiopathische Parkinson Erkrankung und Multisystematrophie), 10 Patienten mit Alzheimer Krankheit und 10 gesunden Kontrollen analysiert. Als Zielregionen wurden das Putamen, der innere und äußere Anteil des Globus pallidus, der Nucleus subthalamicus, die Substantia nigra, das dorsale Mittelhirn, der Nucleus dentatus sowie der dorsolaterale präfrontale Cortex und der mediale präfrontale Cortex definiert. Alle Patienten und Probanden erhielten eine dynamische PET Messung über 60 Minuten, so dass die Bilddaten quantitativ mit einem pharmakokinetischen Modell, relativ zur cerbellären grauen Substanz, berechnet werden konnten. Die [18F]PI-2620 Bindung in den PSP Zielregionen wurde zwischen den Studiengruppen verglichen und mit Krank-heitsschwere, Krankheitsdauer, sowie den klinischen Subtypen der PSP korreliert. Abschließend erfolgte in der ersten Studie eine visuelle Beurteilung der [18F]PI-2620 Tau-PET Bilder durch drei nuklearmedizinische Experten. In der zweiten Studie wurde die regionale Kovarianz der [18F]PI-2620 Tau-PET und die regionale Kovarianz der post-mortem Tau Pathologie mit interregionaler funktioneller Konnektivität verglichen. Als Patientenkollektiv dienten dabei 22 Patienten mit typischer PSP und 24 Patienten mit Cortikobasalem Syndrom (CBS) als weitere klinische Manifestationsform der 4-Repeat Tau Neuropathologie. 15 gesunde Kontrollen wurden als Normalkollektiv herangezogen. Für die korrespondierende post-mortem Analyse lagen zwei unabhängige PSP Kollektive aus der LMU München und der University of Pennsylvania vor. Die mittels Tau-PET erhobene quantitative Tau Pathologie im regionalen Epizentrum (Region mit der höchsten Pathologie) wurde zudem mit der regionalen Konnektivität auf Gruppen- und Einzellevel verglichen. Abschließend wurde die Kovarianz der Tau Pathologie im Autopsie-Arm der Studie hinsichtlich dem betroffenen Zelltyp der Tau Pathologie (Neuronen, Astrozyten, Oligodendrozyten) aufgelöst. In beiden Studien wurden autoradiographische Daten an post-mortem Gewebe von verstorbenen Patienten mit PSP und gesunden Kontrollen erhoben und als hochauflösende Validierung der in vivo Tau-PET Ergebnisse herangezogen.
Patienten mit PSP zeigten im Vergleich zu gesunden Kontrollen ein erhöhtes [18F]PI-2620 Tau-PET Signal im inneren und äußeren Anteil des Globus pallidus, im Putamen, im Nucleus subthalamicus, in der Substantia nigra und im Nucleus dentatus. Die deutlichsten Unterschiede waren im inneren Anteil des Globus pallidus zu beobachten (Co-hen’s d = 2,28), wobei sich in dieser Region auch signifikant erhöhte Tau-PET Signale zwischen Patienten mit atypischer PSP und gesunden Kontrollen nachwiesen lassen. In den cortikalen Zielregionen konnten bei Patienten mit PSP keine Änderungen des Tau-PET Signals beobachtet werden. Es zeigte sich aber eine erwartete erhöhte [18F]PI-2620 Bindung bei Patienten mit Alzheimer Krankheit gegenüber allen Vergleichsgruppen. Innerhalb der Gruppe von Patienten mit typischer PSP ergaben sich keine Korrelationen zwischen dem Tau-PET Signal in PSP Zielregionen und der Krankheitsschwere oder der Krankheitsdauer. Es zeigten sich jedoch unterschiedlich starke Signalerhöhungen zwischen den verschiedenen klinischen Subtypen der PSP, wobei die höchsten Tau-PET Signale bei typischer PSP beobachtet wurden. Erwähnenswert waren ähnliche Effektgrößen für das erhöhte Tau-PET Signal bei Patienten mit PSP und einem niedrigen Schweregrad (PSP Skala ≤ 30) im Vergleich zu Patienten mit PSP und einem hohen Schweregrad (PSP Skala > 30). Die visuelle Beurteilung als Konsens von drei nuklearmedizinischen Experten ergab eine Sensitivität von 85% und eine Spezifität von 77% für die Detektion der Patienten mit PSP gegenüber gemischten Kontrollen. Mittels Autoradiographie konnte sowohl in den Basalganglien als auch im frontalen Cortex eine erhöhte [18F]PI-2620 Bindung bei post-mortem Gewebe bei Patienten mit PSP festge-stellt werden. Gesunde Kontrollen und mit kaltem Tracer präinkubierte Schnitte von Patienten mit PSP und gesunden Kontrollen zeigten keine Retention des Radiotracers. Die Analyse der Kovarianz in der Tau-PET zeigte eine hohe Übereinstimmung mit der durch funktionelle Kernspintomographie gemessenen Konnektivität. Dieses Ergebnis konnte sowohl für Patienten mit PSP und CBS, als auch für subcortikale und globale Analysen reproduziert werden (alle β > 0,4, alle p-Werte < 0,001). Durch die Tau-PET konnte außerdem herausgefunden werden, dass Tau-Muster auf Patientenebene mit der Konnektivität subkortikaler Tau-Epizentren verbunden sind. Zwischen der Kovarianz der regionalen Tau Pathologie in post-mortem Gewebe und funktioneller Konnektivität konnte in zwei unabhängigen Datensätzen ein deutlicher Zusammenhang festgestellt werden (LMU München: β = 0,503, p < 0,001; University of Pennsylvania: β = 0,790, p < 0,001). Bei Zelltyp spezifischer Betrachtung der post-mortem Tau Pathologie zeigte sich, dass diese Assoziation für neuronales Tau stärker als für astrogliales oder oli-godendrogliales Tau war. Dies deutet darauf hin, dass Konnektivität in erster Linie mit neuronaler Tau-Akkumulation verbunden ist. Mittels Autoradiographie an post-mortem Gewebe von 16 Patienten mit typischer PSP zeigte sich schließlich eine gute Übereinstimmung der regionalen [18F]PI-2620 Bindung und der durch Immunfärbung erfassten Tau Pathologie, wodurch die in vivo Tau-PET Daten validiert werden konnten.
Die [18F]PI-2620 Tau-PET-Bildgebung bei Patienten mit PSP und bei Kontrollpersonen stellt einen Durchbruch bei dem Versuch dar, die zugrunde liegende Tau Neuropathologie der PSP in vivo darzustellen. Durch die internationale multizentrische Evaluierung dieses Tau-PET Radiotracers der nächsten Generation mit verbesserter Off-Target-Bindung konnte ein großer Fortschritt in der Bildgebung auf dem Gebiet der 4-Repeat-Tauopathien erzielt werden. Die beiden verknüpften Studien zeigen, dass die [18F]PI-2620 Tau-PET Bildgebung zur Diagnose und Differenzierung von Patienten mit Verdacht auf PSP eingesetzt werden kann. Zudem kann auch das Ausbreitungsmuster der Tau Pathologie entlang funktionell verknüpfter Hirnregionen berechnet werden. Die Tau-PET bietet daher bei der PSP möglicherweise eine frühzeitige und zuverlässigere Diagnose, sowie ein verbessertes Erfassen der Krankheitsprogression. Es ist wahrscheinlich, dass dieser Radiotracer für die Stratifizierung klinischer Studien bei PSP verwendet werden kann.Biomarkers for tau pathology in patients with progressive supranuclear palsy (PSP) are urgently needed as diagnostic inclusion criteria for therapy studies and for monitoring disease-modifying effects. However, there are currently no approved methods to reliably detect 4-repeat tau deposits in the brain of patients with PSP. In this thesis, the tau-PET tracer [18F]PI-2620 was evaluated as a new biomarker for tau pathology in patients with PSP compared to patients with other neurodegenerative diseases and healthy controls. For this purpose, a multicenter data set was harmonized and quantitatively analyzed. In a second step, it was investigated whether tau pathology spreads in PSP on the basis of functionally connected brain areas.
In a retrospective design, the [18F]PI-2620 tau-PET scans of 60 patients with PSP (40 patients with the typical variant of Richardson syndrome, 20 with atypical variants of PSP), 10 patients with alpha-synuclein associated diseases (idiopathic Parkinson's disease and multisystem atrophy), 10 patients with Alzheimer's disease and 10 healthy controls were analyzed. The putamen, the inner and outer part of the globus pallidus, the subthalamic nucleus, the substantia nigra, the dorsal midbrain, the dentate nucleus as well as the dorsolateral prefrontal cortex and the medial prefrontal cortex were defined as target regions. All patients and subjects received a dynamic PET emission recording over 60 minutes so that the image data could be quantitatively calculated with a pharmacokinetic model relative to the cerbellar gray matter. The [18F]PI-2620 binding in the PSP target regions was compared between the study groups and correlated with disease severity, disease duration and the clinical subtypes of PSP. Finally, in the first study, a visual assessment of the [18F]PI-2620 tau PET images was performed by three nuclear medicine experts. In the second study, the regional covariance of [18F]PI-2620 tau-PET and the regional covariance of post-mortem tau pathology with interregional functional connectivity were compared. The patient cohort consisted of 22 patients with typical PSP and 24 patients with corticobasal syndrome (CBS) as a further clinical manifestation of 4-repeat tau neuropathology. 15 healthy controls were used as a normal collective. Two independent PSP autopsy samples from the LMU Munich and the University of Pennsylvania were available for the corresponding post-mortem analysis. The quantitative tau pathology in the regional epicenter (region with the highest pathology) assessed by tau-PET was also compared with the regional connectivity at group and individual level. Finally, the covariance of tau pathology in the autopsy arm of the study was resolved with respect to the affected cell type of tau pathology (neurons, astrocytes, oligodendrocytes). In both studies, autoradiographic data on post-mortem tissue from deceased patients with PSP and healthy controls were collected and used as high-resolution validation of the in vivo tau-PET results.
Patients with PSP showed increased [18F]PI-2620 tau-PET signal in the inner and outer portions of the globus pallidus, the putamen, the subthalamic nucleus, the substantia nigra and the dentate nucleus compared to healthy controls. The clearest differences were observed in the inner part of the globus pallidus (Cohen's d = 2.28), whereby significantly increased tau-PET signals were also detected in this region between patients with atypical PSP and healthy controls. In the cortical target regions, no changes in the tau PET signal were observed in patients with PSP. However, there was an expected increased [18F]PI-2620 binding in patients with Alzheimer's disease compared to all control groups. Within the group of patients with typical PSP, there were no correlations between tau-PET signal in PSP target regions and disease severity or duration. However, there were varying degrees of signal elevation between the different clinical sub-types of PSP, with the highest tau-PET signals observed in typical PSP. Of note were similar effect sizes for increased tau PET signal in patients with PSP and low severity (PSP scale ≤ 30) compared to patients with PSP and high severity (PSP scale > 30). The visual assessment as a consensus of three nuclear medicine experts showed a sensitivity of 85% and a specificity of 77% for the detection of patients with PSP versus mixed controls. Using autoradiography, increased [18F]PI-2620 binding was detected in post-mortem tissue in both the basal ganglia and frontal cortex in patients with PSP. Healthy controls and slices pre-incubated with cold tracer from patients with PSP and healthy controls showed no retention of the radiotracer. Analysis of covariance in tau-PET showed high agreement with connectivity measured by functional magnetic resonance imaging. This result could be reproduced for patients with PSP and CBS, as well as for subcortical and global analyses (all β > 0.4, all p-values < 0.001). Tau-PET also revealed that the tau pathology patterns of individual patients are linked to the functional connectivity archetype of tau epicenters in the subcortex. A clear association between the covariance of regional tau pathology in post-mortem tissue and functional connectivity was found in two independent data sets (LMU Munich: β = 0.503, p < 0.001; Uni-versity of Pennsylvania: β = 0.790, p < 0.001). A specific analysis of cell-type related tau pathology in tissue of deceased patients with PSP showed that the association between functional connectivity and tau spread was strongest for neuronal tau, whereas astroglial or oligodendroglial tau did only show weaker correlation. This suggests that the tau spreading pattern is primarily driven by interconnected neurons with axons tau accumulation. Finally, autoradiography of post-mortem tissue from 16 patients with typical PSP showed good agreement between regional [18F]PI-2620 binding and tau pathology detected by immunostaining, validating the in vivo tau-PET data.
[18F]PI-2620 tau-PET imaging in patients with PSP and control subjects represents a breakthrough in the attempt to visualize the underlying tau neuropathology of PSP in vivo. The international multicenter evaluation of this next-generation tau-PET radiotracer with improved off-target binding has enabled a major advance in imaging in the field of 4-repeat tauopathies. The two linked studies show that [18F]PI-2620 tau PET imaging can be used to diagnose and differentiate patients with suspected PSP. In addition, the pattern of spread of tau pathology along functionally linked brain regions can also be calculated. Tau-PET may therefore offer an early and more reliable diagnosis of PSP, as well as improved detection of disease progression. It is likely that this radiotracer can be used for the stratification of clinical trials in PSP
Addressing the impact of phages on gut microbial ecology and functions using a synthetic bacterial community
Get PDFThe human gut is a complex ecosystem, harboring eukaryotic cells, bacteria and viruses. Alterations of the intestinal microbial communities are associated with an increasing number of human diseases. On the other hand, the gut microbiota protects the host against a variety of major human gastrointestinal pathogens. Bacteriophages (phages), viruses that infect bacteria, are important effectors and indicators of human health and disease by managing specific bacterial population structures and by interacting with the mucosal immune system. They are ubiquitous in nature and frequently ingested via food and drinking water. Moreover, bacteriophages are an attractive tool for microbiome engineering due to their specificity and the lack of known serious adverse effects on the host. However, most of our knowledge on phages is based on metagenomic studies and the functional role of virulent phages within the gastrointestinal microbiome remain poorly understood.
To obtain functional insights on the effect of phages in the gastrointestinal microbiome and its function in health and disease, I established a model to investigate the interaction of bacteriophages and cognate host bacteria in the mammalian gut. Therefore, I isolated specific phages targeting members of a synthetic bacterial consortium, the Oligo-MM14, which consists of 14 well-characterized bacterial strains that form a stable community in gnotobiotic mice and provide colonization resistance against the human enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm).
First, I characterized the isolated phages in vitro with respect to plaque morphologies, genomic features, lysis behaviors and host ranges. Further, I developed methods for specific absolute quantification via qPCR for the single phages, which allowed me to track the abundance of phages and host bacteria in the OMM community in vitro and in vivo, revealing that the phages amplify at varying degrees while not disturbing the overall community composition.
Furthermore, I showed, that phages lead to initial depletion of the target population in the mouse gut and thereafter coexist with the bacteria for up to a week after phage challenge. Moreover, the addition of phages targeting Escherichia coli and Enterococcus faecalis, two bacteria previously identified to mediate colonization resistance, led to a significant decrease of colonization resistance against S. Tm. This demonstrates that phages can affect microbial community functions. Infection susceptibility to S. Tm was markedly increased at an early time point after challenge with both phage cocktails but surprisingly, OMM14 mice were also susceptible to S. Tm infection 7 days after a single phage inoculation, when the targeted bacterial populations were back to pre-phage administration density. Since the abundance of the other bacteria in the gut is not affected by administration of the phage cocktails, this effect is specifically attributed to the impact of the phages on their bacterial hosts. This suggests, that phages targeting protective members of the microbiota may in general increase the risk for S. Tm infection.
In summary, this work yields insights into phage-bacterial interactions in the gut and the effect of phages on fundamental microbiome functions, which will be important for evaluating the future use of phages for targeted microbiome manipulation