22455 research outputs found
Sort by
Argonaute 2: Der Einfluss von Staufen 2 und Phosphorylierung auf die Lokalisation in Neuronen
Get PDFAnalgesie und Anästhesie bei der experimentellen Kraniotomie an Mäusen und Ratten in den Jahren 2009 und 2019: ein systematisches Scoping-Review
Get PDF
Concepts and syntheses towards substrates with autocatalytic potential in asymmetric diorganozinc alkylations
Get PDFInvestigating generalized Kitaev magnets using machine learning
Get PDFFrustration in Kitaev-Materialien führt zu einem sehr reichhaltigen und komplexen Phasendiagramm, einschließlich der klassischen Spinflüssigkeitsphase. Die Suche nach und das Verständnis von Spinflüssigkeiten und weiteren neuartigen komplexen Phasen der Materie stehen im Mittelpunkt der heutigen Forschung zu kondensierter Materie. Mittels analytischer Methoden Ordnungsparameter zur Charakterisierung dieser Phasen zu finden, ist nahezu unmöglich. Bei niedrigen Temperaturen ordnen sich die meisten klassischen Spinsysteme in komplizierte Strukturen, die große magnetische Elementarzellen belegen, was die Komplexität des Problems noch weiter erhöht und außerhalb des Anwendungsbereichs der meisten herkömmlichen Methoden liegt.
In dieser Arbeit untersuchen wir die Hamilton-Operatoren realitätsnaher Kitaev-Materialien mithilfe maschinellen Lernens. Hauptmerkmale des zugrundeliegenden Algorithmus sind unbeaufsichtigtes Lernen, welches ermöglicht die Topologie eines Phasendiagramms ohne jegliche Vorkenntnisse erforschen, und Interpretierbarkeit, welche zur Analyse der Struktur der klassischen Grundzustände notwendig ist.
In den ersten drei Kapiteln werden wir den Algorithmus des maschinellen Lernens auf verschiedene Hamilton-Operatoren anwenden, die zur Modellierung von Kitaev-Materialien eingesetzt werden, um zu untersuchen inwieweit die Quantenmodelle und die experimentellen Beobachtungen allein durch deren klassischen Grenzfall erklärt werden können. Darüber hinaus erforschen wir weitere Features dieses Algorithmus, die es uns ermöglichen, verborgene Symmetrien, lokale Einschränkungen der klassischen Spinflüssigkeiten, sowie bisher unbekannte Phasen im hochdimensionalen Phasenraum aufzudecken.
In den letzten beiden Kapiteln werden wir uns mit dem Verständnis der Struktur der klassischen Grundzustände befassen, welche durch die Verflechtung mehrerer Helices charakterisiert sind. Wir werden auch versuchen, die Signatur dieser Phasen in Experimenten zu verstehen, indem wir die Dynamik und den Transport durch Kitaev-Magnete untersuchen.
Diese Arbeit beweist die Tauglichkeit von maschinellem Lernen, hochkomplexe Phasendiagramme mit wenig bis gar keinem Vorwissen aufzudecken und hochfrustrierten Magnetismus zu erforschen. Die Kombination aus maschinellem und menschlichem Einsatz ebnet den Weg zu neuen und spannenden physikalischen Erkenntnissen.Bond frustration in Kitaev materials leads to a very rich phase diagram with highly intricate phases including the classical spin liquid phase. The search and understanding of spin liquids and novel complex phases of matter is at the heart pf present day condensed matter research. To search and design order parameters to characterize these phases using analytical approaches is a nearly impossible task. At low temperatures, most of the classical spins order into complicated spin structures occupying large magnetic unit cells which further adds to the complication and is out of the realm of most traditional methods.
In this thesis we investigate realistic Kitaev material Hamiltonians using a machine learning framework whose key features, of unsupervised learning which helps us study the topology of the phase diagram without prior knowledge and interpretability which helps us analyse the structure of the classical ground states, are exploited.
In the first three chapters, we shall use this framework on different Hamiltonians used to model Kitaev materials and understand to what extent the quantum limit and experimental results could be explained just by the classical limit of these models. We in addition explore other features of this framework which lets us uncover hidden symmetries as well as local constraints for the classical spin liquids and hitherto unreported new phases in the high dimensional phase space.
In the last two chapters we shall dwell on the understanding the structure of the classical ground states which is quite complicated as it hosts a tangle of multiple helices. We shall also try and understand the signature of these phases on experiments by studying the dynamics and transport through Kitaev magnets thus bridging the gap between experiment and theory.
This thesis proves instances of using machine learning to uncover highly complex phase diagrams with little to no previous knowledge and serve as a paradigm to explore highly frustrated magnetism. Through a combination of machine and human effort we are on the way to uncover new and exciting physics
Fundamentals for the journey towards an enhanced understanding of human patello-femoral joint mechanics
Get PDFBackground
Anterior knee pain (AKP) is one of the main reasons for patient dissatisfaction after total knee arthroplasty (TKA). Since AKP is localised to the patello-femoral joint and its direct surroundings, it is likely that the causes for AKP are related to this joint. Review of the existing literature on patello-femoral contact forces and patello-femoral wear testing points towards failure-conducing mechanics. This, however, evidently conflicts with the compa-rably low revision rates reported by several national joint registries for patellar implants. This contradiction highlights the need for an improved understanding of the mechanics of the patello-femoral joint in vivo, as herein may lie the key to successful reduction of AKP after TKA.
Objectives
The first aim of this dissertation was to improve the understanding of the patello-femoral joint by focusing on a new approach to simulate the knee joint. This approach aimed to reduce the dependency of the model on assumptions which are based on non-accurate estimations. In order to validate this model, patello-femoral kinematics need to be further investigated. Therefore, the second aim of this dissertation was to lay the foundation to work with patello-femoral kinematic data with mathematical diligence. Finally, a deeper investigation of the factors influencing patellar kinematics was undertaken by first focusing on analysing the effect of patellar resurfacing in a human donor study.
Materials and Methods
In a first step, a finite element model including the patella was developed based on stand-ardized in vivo load data for the isolated tibio-femoral joint. Since these data implicitly in-clude all forces and moments induced by gravity, dynamics and soft tissue crossing be-tween the proximal and distal segments of the joint, explicit modelling of most of these factors can be avoided without weakening the validity of the model. This model was ap-plied to analyse the effects of the initial proximo-distal patellar position and the stiffness of the patellar tendon on patellar kinematics.
The second part of this dissertation addressed a more fundamental issue, re-establishing solid basic principles with which to analyse and interpret patellar kinematics accurately. The representation of kinematics data, especially of relative patello-femoral rotations, is highly dependent on the underlying mathematical conventions used and their exact exe-cution. A detailed summary of the most common methods to describe patello-femoral rota-tions was formulated and more importantly, accurate conversions between these conven-tions were derived. These were provided to the biomechanical research community in the shape of a virtual computation tool.
To improve our understanding of the impact of the parameters which influence patellar kinematics, the effects of patellar resurfacing were isolated from in vitro testing with eight fresh frozen knee specimens on a well-established knee rig at the Musculoskeletal Uni-versity Center Munich (MUM). To identify the specific effects of patellar resurfacing, knee kinematics were measured both pre- and post-TKA, with and without patellar resurfacing, for two tibio-femoral implant variants (posterior stabilised PS and PS+).
Results
The finite element model made it possible to run comparative studies with different im-plants or parameter variants. For the tibio-femoral joint, both kinematics and contact loads are in good accordance with the values previously reported in the relevant literature. For the patello-femoral joint, it was shown that a proximal initial patellar position and a weak patellar tendon causes more patello-femoral flexion and spin, while patellar tilt and shift are mainly influenced by the initial patellar position.
The analysis of underlying mathematical conventions on the representation of patello-femoral rotations showed that both magnitude and the characteristics of the rotation curves can be modified fundamentally by switching between conventions. The derived transformation methods between the presented conventions were shown to be valid by way of mathematical proofs and comparison to benchmark data.
In the experimental part of this dissertation, no significant effects of patellar resurfacing on patello-femoral rotations were found. For the translations, it was shown that patellar resur-facing had significant effects on patellar shift. For cases in which the patellar implant was placed in the medio-lateral centre of the patellar cut, this change in patellar shift proved to be significantly correlated to the lateral facet angle of the native patella.
Conclusion and Outlook
The developed model provides valid results for the tibio-femoral joint. Furthermore, it ena-bles qualitative and comparative analyses between different implant and model configura-tions. Nevertheless, for accurate quantitative results of patellar kinematics and kinetics, additional data for validation are needed, namely in vivo data of patello-femoral kinematics and loads. To handle such kinematic data from different sources, a solid mathematical foundation was established.
The relation shown between the native lateral patellar facet angle and the effect of patellar resurfacing on medio-lateral shift shall be taken into account for clinical applications. In addition, the basic research on patellar kinematics brought forward by this dissertation can be used in future projects for further validation of the newly developed model, especially once a combined dataset of in vivo tibial loads and patello-femoral kinematic data be-comes available
A cohort study evaluating the efficacy and safety of vedolizumab for patients, refractory to anti-TNF-α treatment in inflammatory bowel disease
Get PDFInflammatory bowel disease (IBD) is a chronic illness and is considered as one of the most challenging gastrointestinal diseases to manage. IBD involves both Crohn’s disease (CD) and ulcerative colitis (UC). The disease manifests by bouts of relapse and remission. Management approaches introduced over the years are still inadequate and induce a distinct response in individual patients. Such approaches focus mainly on controlling inflammation, employing a broad-spectrum of anti-inflammatory drugs or immunosuppressants agents as well as biologicals. Surgical intervention becomes necessary if the pharmacological treatment fails and disease-associated complications occur. Novel IBD treatments shift towards early therapeutic intervention to eliminate inflammation to prevent disease-related symptoms. Recent studies revealed that early use of the biological agents, which are also known as antibodies targeting tumor necrosis factor alpha (TNF-α-AB), can improve clinical outcomes by halting the development of the disease. Nonetheless, the efficacy of TNF-α-AB varies; approximately 10–30% of patients were found to be non-responsive to the initial therapy (primary non-response/PNR) and around 23–46% of patients became resistant to treatment over time and required an increased dosage (secondary loss of response/LOR). A higher dosage of medication might induce side-effects and/or a further LOR, leading to a discontinuation of the treatment. Therefore, new agents which mediate the immune response through directly targeting the intestinal mucosa with the help of the effector T-lymphocytes have been introduced. Vedolizumab (VDZ, targets α4β7 integrin), which received approval in 2014 for the management for both UC and CD, is such an agent. Nonetheless, data as far as mid-to long-term results are concerned is still limited.
The aim of this study was to assess efficacy and safety of VDZ treatment of refractory IBD patients in daily clinical practice, and to evaluate the mid-to-long term outcome of these patients and their tolerance of VDZ treatment.
The cohort-collected data were obtained from IBD patients who had started VDZ treatment between October 2014 and January 2016 in two academic IBD centres in Munich (Germany), the IBD Division at the University Hospital in Munich-Grosshadern and the IBD Division at the Municipal Hospital (“IsarKlinikum”). The primary end point of the study was declared as clinical remission in UC and CD patients at week 14 of treatment according to the Colitis Activity Index (CAI) and Crohn’s Disease Activity
6
Index (CDAI). The clinical response evaluation was based on C-reactive protein levels, white blood cell counts, and calprotectin levels. As part of the standardized follow-up protocol, patients were clinically assessed at baseline and after induction of VDZ treatment at weeks 2, 6 and 14. Data was collected at baseline and at week 14. Patients were followed during maintenance therapy until the end of the study. The assessment of clinical outcome together with the assessment of the IBD outcome regarding the efficacy and safety of VDZ were carried out by two senior gastroenterologists (Thomas Ochsenkühn and Fabian Schnitzler).
Overall, 102 adult patients (56 with UC, 46 with CD) were enrolled in the study. All patients received VDZ as a treatment for IBD after being treated with at least one TNF-α-AB treatment. The indication for switch to VDZ treatment was either due to side effects from TNF-α-AB treatment or to being refractory to TNF-α-AB treatment. All patients received treatment according to an international-established protocol: dosage of 300 mg VDZ as an infusion over 30 minutes at baseline, repeated at week 2 and week 6 after treatment initiation, followed by 300 mg VDZ as maintenance therapy every 8 weeks.
Our study showed that CD patients who were intolerant of or refractory to TNF-α-AB treatment seemed to benefit, however, not significantly, from VDZ treatment in terms of a slight improvement of clinical remission from a rate of 54.3% to 60.9%. This resulted in an achieved clinical remission of 6.6% (p=0.549). In terms of clinical response, the achieved reduction of active disease with a drop of ≥70 points of CDAI was 59.1%.
Patients with UC who were intolerant or refractory to TNF-α-AB treatment seemed to significantly benefit from VDZ treatment with a considerable improvement in terms of clinical remission from a rate of 17.8% to 41.1%. This resulted in a significant achieved clinical remission of 23.3% (p<0.001). Regarding clinical response, the achieved reduction of active disease with a drop of CAI ≥ 3 points was 34.1%.
In addition, among 42.1% of IBD patients who had initially received steroids as a complementary therapy, 24.5% of those patients were able to cease steroid treatment by the end of the study. We could also observe that VDZ therapy had no significant effect on C-reactive protein and white blood cell levels in either groups of patients (for CD p=0.447 and p=0.199 and for UC p=0.555 and p=0.266 respectively). On the other
7
side, Calprotectin levels were significantly decreased under VDZ treatment in UC patients (p=0.006) but not in CD patients (p=0.845). As far as medication related adverse events are concerned, only mild side effects appeared in 12.8% of all patients with malaise and headache being the most frequent of them.
The presented study also provides clinical maintenance data on the treatment of refractory IBD with VDZ, with a median follow-up duration of approximately one year.
VDZ showed acceptable clinical efficacy among the treatment-refractory cohort of 90 IBD patients, particularly those with UC. Most IBD patients (i.e. 87.5% of UC (n=43/49) and 85.3% of CD patients (n=35/41)) continued VDZ treatment for up one year which was the end of the follow-up.
Furthermore, VDZ demonstrated a good safety profile without any severe adverse events or the need for discontinuation.
In conclusion, VDZ appears to be a valuable choice in IBD patients in case of therapy failure or intolerance under TNF-α-AB treatment especially in UC patients. Further clinical studies are necessary to outline the role of VDZ treatment in daily clinical practice, not only in TNF-α-AB refractory cases but also in patients without any TNF-α-AB treatment before.Zu den chronisch-entzündlichen Darmerkrankungen (CED) gehören die Colitis ulcerosa (CU) und Morbus Crohn (MC). CED zeigen in den meisten Fällen einen rezidivierenden Verlauf und die verfügbaren Behandlungsstrategien sind was langfristige Therapieerfolge und kurative Intention noch immer unzureichend. Zudem zeigen diese ein unterschiedliches Ansprechen bei den einzelnen Patienten. Behandlungsziel der momentan verfügbaren therapeutischen Ansätze ist die frühzeitige Entzündungskontrolle durch Einsatz von antiinflammatorischen Medikamente, Immunsuppressiva oder Biologika. Ein chirurgischer Eingriff wird dann notwendig, wenn die medikamentöse Behandlung versagt und sich Komplikationen entwickeln. Moderne IBD-Behandlungen basieren sich auf eine frühe Intervention, um krankheitsbedingte Symptome zu beseitigen oder diese vorzubeugen. Studien deuten darauf hin, dass der Einsatz von Biologika, insbesondere von Antikörpern (Ak) gegen Tumor-Nekrose-Faktor alpha (TNF-α), den Krankheitsprogress verhindern und das Ergebnis verbessern können. Allerdings liegt der Wirkungsverlust und die Intoleranz gegenüber TNF-α-Ak Behandlungen von CED-Patienten bei etwa 30%. Daher wurden neue Medikamente entwickelt, die auf die Auswanderung von Effektor-T-Lymphozyten in die Darmschleimhaut abzielen. Vedolizumab (VDZ), ein Antikörper gegen das α4β7-Integrin ist ein solcher Wirkstoff, der 2014 die Zulassung für die Behandlung von CU und MC erhielt. Dennoch sind die verfügbaren Daten zum Einsatz und den dieses Wirkstoffs in der klinischen Praxis, insbesondere zu den Langzeitergebnissen begrenzt.
Ziel der vorliegenden Studie ist, die Wirksamkeit und Sicherheit von VDZ bei der Behandlung von refraktären CED-Patienten in der täglichen Praxis zu untersuchen sowie das Langzeitergebnis dieser Patienten und die Verträglichkeit der VDZ-Behandlung zu evaluieren.
Hierfür wurde eine retrospektive Analyse in zwei akademischen IBD-Zentren in München (Deutschland) (CED-Zentrum des Universitätsklinikums München-Großhadern und CED-Zentrum des IsarKlinikums) durchgeführt. CED-Patienten, die zwischen Oktober 2014 und Januar 2016 eine VDZ-Behandlung in diesen Zentren bekommen haben, wurden in die Analyse eingeschlossen. Als primärer Endpunkt wurde die klinische Remission bei CU- und MC-Patienten in der 14. Behandlungswoche entsprechend dem Crohn's Disease Activity Index (CDAI) und
9
Lichtiger Colitis Activity Index (CAI) definiert. Das klinische Ansprechen wurde bei jeder ambulanten „follow-up“- Untersuchung anhand der C-reaktiven-Protein-Werte im Serum, der Anzahl der weißen Blutkörperchen (Leukozytenanzahl), und der Calprotectin-Werte evaluiert und beurteilt. Im Rahmen des standardisierten Nachbeobachtungsprotokolls wurden die Patienten zu Beginn und nach Induktion der VDZ-Behandlung in den Wochen 2, 6 und 14 klinisch untersucht. Die Patienten wurden während der Erhaltungstherapie bis zum Ende der Nachbeobachtung verfolgt. Die klinische Beurteilung und die Bewertung des CED-Therapieergebnisses hinsichtlich der Wirksamkeit und Sicherheit von VDZ wurden von zwei leitenden Gastroenterologen durchgeführt (Thomas Ochsenkühn und Fabian Schnitzler).
Insgesamt wurden 102 erwachsene Patienten (56 mit CU, 46 mit MC) in der Studie rekrutiert. Die Patienten erhielten VDZ als CED-Behandlung gemäß den internationalen Richtlinien und hatten zuvor eine Behandlung mit mindestens einer TNF-α-Ak Gabe erhalten. Die Umstellung auf die VDZ-Behandlung erfolgte aufgrund von Nebenwirkungen und/ oder einer Therapierefraktärität gegenüber TNF-α-Ak. Alle Patienten erhielten zu Beginn der Behandlung eine Dosis von 300 mg VDZ als Infusion über 30 Minuten. Diese Behandlung wurde in Woche 2 und Woche 6 nach Behandlungsbeginn wiederholt, gefolgt von 300 mg VDZ als Erhaltungstherapie alle 8 Wochen.
Die wichtigsten Ergebnisse zum primären Endpunkt in der Woche 14 zeigten, dass Patienten mit MC, die intolerant oder refraktär gegenüber einer TNF-α-Ak -Behandlung waren, eine moderate Verbesserung durch die VDZ-Behandlung, jedoch nicht signifikant in Bezug zur klinischen Remission aufwiesen. Die klinische Remission stieg von 54,3 % auf 60,9 %, also einem Anstieg des Anteils der Patienten in klinischer Remission um 6, 6 % (p=0.549). In Bezug auf das klinische Ansprechen betrug die erreichte Reduktion der aktiven Erkrankung mit einem Rückgang der CDAI um ≥70 Punkte 59,1 %.
Patienten mit UC hingegen, die intolerant oder refraktär zur Anti-TNF-α-Behandlung waren, profitierten nach 14 Wochen von der VDZ-Behandlung: Die klinische Remission stieg von 17,8 % % auf 41,1 %. Der Anstieg des Anteils der Patienten in klinischer Remission betrug somit 23,3 % (p<0.001).
10
In Bezug zur Aktivität der Erkrankung zeigen UC-Patienten, die intolerant oder refraktär zur TNF-α-Ak Behandlung waren, einen signifikanten Effekt: Die erreichte klinische “Response”-Rate mit einer Reduktion der aktiven Erkrankung um CAI ≥ 3 Punkte war 34,1 %. Ein weiteres Ergebnis dieser Studie war dass bei einem großen Anteil der CED-Patienten (42,1% des Kollektivs), die Steroide als ergänzende Therapie erhalten hatten, die Steroidbehandlung bis zum Studienende absetzen konnte. Weiterhin zeigte sich keine signifikante Auswirkung auf die Werte des C-reaktiven Proteins [MC (p=0,447), CU (p=0,555)] oder die Leukozytenzahl [MC (p=0,199), CU (p=0,266)] unter VDZ-Behandlung. Auf der anderen Seite wurde eine signifikante Regredienz der Calprotectin-Werte wurden durch die VDZ-Behandlung bei CU-Patienten (p=0,006) registriert, allerdings nicht bei CD-Patienten (p=0,845). Was das Nebenwirkungsprofil, angeht, wurden nur seltene und leichte Nebenwirkungen berichtet. Nur 12,8 % der Patienten waren betroffen, wobei Unwohlsein und Kopfschmerzen als häufigste Nebenwirkungen auftraten.
In der vorliegenden Studie wurden zusätzlich Daten zur klinischen Erhaltungstherapie von refraktärer CED mit VDZ, mit einer medianen Nachbeobachtungsdauer von fast einem Jahr generiert. VDZ zeigte eine klinische Wirksamkeit bei behandlungsrefraktären CED-Patienten, insbesondere bei denen mit CU. Die meisten CED-Patienten, im Einzelnen 87,5 % der CU- (n=43/49) sowie 85,3 % der MC-Patienten (n=35/41) setzten die Behandlung mit VDZ bis zum Ende der Nachbeobachtungszeit fort.
Zusammenfassend scheint VDZ eine geeignete alternative Behandlungsoption für die refraktäre CED, insbesondere im Fall einer Therapierefraktärität und/oder Intoleranz gegenüber einer Anti-TNF-α-Behandlung zu sein, vor allem bei Vorliegen einer CU. Weitere klinische Studien sind notwendig, um die Rolle der VDZ-Behandlung in der täglichen klinischen Praxis zu definieren, nicht nur bei TNF-α-Ak refraktären Fällen, sondern auch bei Patienten, die keine TNF-α-Ak-Therapie erhalten haben
Etablierung von BMP-überexprimierenden humanen mesenchymalen Stammzellen für die zelltherapeutische Anwendung
Get PDF
Quantum/classical simulation of molecular excited state dynamics and spectroscopy
Get PDFThe ability of modern quantum chemistry to answer ever more complex questions rises steadily. In this thesis, a comprehensive exploration of molecular photochemistry using high-level electronic structure methods for quantum-classical dynamics is presented.
The first chapter introduces theoretical methods for simulating photodynamical processes, focussing on the relaxation of molecules in explicit atomistic environments. These approaches include nuclear wavepacket dynamics embedded within classical molecular dynamics. The presented Ehrenfest and multi-configurational Ehrenfest approaches are applied to small molecules surrounded by noble gas atoms. Furthermore, trajectory surface hopping is discussed, as, in later chapters, the program SHARC is used to perform such simulations. During this thesis, adaptive time-stepping and two new interfaces to electronic structure codes were implemented. These methods facilitate efficient and accurate dynamics calculations on a variety of photochemically relevant systems ranging from simulations in the gas phase with high-level XMS-CASPT2 electronic structure (including spin-orbit couplings) to QM/MM simulations in the condensed phase.
The second chapter focuses on the energy transfer between an infrared laser and solvated molecules, combining the traditional harmonic approximation to calculate infrared spectra with methods based on \textit{ab initio} molecular dynamics. This methodology is used to elucidate the coherent energy transfer dynamics from the field to the molecule in field-resolved spectroscopic measurements.
The third chapter of this thesis surveys the intricate world of 2-enone photochemistry. By exploring and reactivity using high-level electronic structure methods, insights are gained into the \textit{Z}/\textit{E} isomerization of cyclohept-2-enone and the photoinduced rearrangement of 5,5-dimethylcyclopent-2-enone to a ketene.
In the final chapter, mechanistic investigations are extended to Lewis acid\hyp coordinated enones, uncovering the impact of coordination on the electronic states, UV-Vis spectra, and reactivity. Trajectory surface hopping calculations are used in combination with ultrafast transient absorption spectroscopy to uncover the dynamics of the relaxation of cyclohex-2-enone-BF to the reactive triplet states and the photo-induced B\textendash Cl bond dissociation in benzaldehyde-BCl.
Collectively, this work exemplifies the potent synergy of computational and spectroscopic techniques in unraveling photochemical mechanisms. From explicit solvent relaxation to multi-step organic reactions and from spectroscopic signatures to intricate electronic transitions, this thesis advances our understanding of photochemical processes across a spectrum of molecular examples. The findings have implications for the design and understanding of photochemical reactions and spectroscopic studies in complex environments