Congenital adrenal hyperplasia (CAH) is a rare form of adrenal insufficiency causing deficiency of the highly regulated hormone cortisol and accumulation of its precursors such as 17α-hydroxyprogesterone (17-OHP) and subsequent androgen overproduction. Symptoms associated with CAH are premature pseudo puberty, earlier ending of longitudinal growth, and in female patients, virilisation and hirsutism. CAH patients require life-long cortisol replacement therapy, and dose optimisation through therapy monitoring is crucial to avoid potentially serious adverse events due to cortisol over- or underexposure. Paediatric CAH patients receive hydrocortisone (HC, synthetic cortisol) for cortisol replacement due to its lower risk for adverse effects whereas adult patients receive more potent glucocorticoids, e.g., dexamethasone (Dex). Especially in paediatrics, dried blood spot (DBS) sampling represents a highly advantageous alternative to plasma sampling. The major advantages include minimal invasiveness, low required blood volumes, stability of the analyte and easy storage of the matrix. Thus, DBS sampling has a high potential for facilitating CAH therapy monitoring routine. However, target concentrations of CAH biomarkers such as 17-OHP indicating a successful cortisol replacement are still unknown in DBS. To prevent in utero virilisation of female foetuses with CAH, prenatal therapy with Dex, administered to the pregnant women, has been conducted for decades. Yet, prenatal CAH therapy is still considered experimental since the traditionally administered Dex dose of 20 μg/kg/day is not based on a scientific rationale and is assumed to be too high, causing potential harm to the mother and foetus. In this regard, quantitative approaches such as pharmacometric modelling and simulation are powerful tools to provide a better understanding on pharmacokinetic (PK) and pharmacodynamic (PD) processes and to contribute to the optimisation of drug therapies. This work aimed at paving the way towards an optimised CAH therapy in paediatric and foetal populations by (1) providing insights into the quantitative relationship between cortisol concentrations measured in plasma and in DBS, (2) identifying paediatric target DBS concentrations for the commonly used biomarker 17-OHP and (3) suggesting a rational Dex dose in prenatal CAH therapy. To quantitatively link plasma and DBS cortisol concentrations, a semi-mechanistic nonlinear mixed-effects (NLME) PK model was developed based on data from paediatric CAH patients. The model characterised a nonlinear relationship between cortisol in plasma and DBS with plasma/DBS concentration ratios decreasing from approximately 8 to 2 with increasing DBS cortisol concentrations up to 800 nmol/L. These ratios decreased due to saturation of cortisol binding to corticosteroid-binding globulin and thus higher cortisol fraction associated with red blood cells. In future, more data from neonates and infants can be used to investigate a possible age effect, on the nonlinearity between plasma and DBS cortisol, in addition to the observed concentration effect. For the first time, a target morning DBS 17-OHP concentration range was determined for monitoring paediatric CAH patients. The DBS target range of 2.1-8.3 nmol/L was derived from simulations by applying a developed PK/PD model linking cortisol in plasma to 17-OHP in DBS and by leveraging healthy paediatric cortisol profiles. By extending the PK/PD model, and using the same simulation approach, circadian target concentration profiles, providing DBS biomarker targets for any time of the day, can be derived in future. Furthermore, in Bland-Altman and Passing-Bablok analyses, it was shown that capillary and venous DBS concentrations, which are both commonly obtained in clinical practice, are comparable to each other for cortisol and 17-OHP in paediatric CAH patients. For determining a reduced Dex dose which simultaneously decreases the risk for adverse events in prenatal CAH therapy and still shows sufficient efficacy in the foetus, a target Dex concentration range was identified from literature and a NLME model describing maternal Dex PK was developed. The Dex PK model was used to simulate maternal Dex concentration-time profiles following traditional or reduced Dex doses and to evaluate the tested dosing regimens with regard to the lowest effective dose. Based on the simulation results, a Dex dose of 7.5 μg/kg/day was suggested as a rational dose for prenatal CAH therapy, representing approximately a third of the traditional Dex dose. The suggested rational Dex dose should be evaluated in future clinical trials. In summary, this work provides quantitative insights into DBS measurements for CAH therapy monitoring, presents first target DBS concentrations for the biomarker 17-OHP in paediatrics, and suggests a first model-based dose rationale for Dex in prenatal CAH therapy. Ultimately, this work can help to improve CAH treatment with HC and Dex and therapy monitoring in the highly vulnerable paediatric and foetal populations.

Sensory signals are governed by statistical regularities and carry valuable information about the unfolding of environmental events. The brain is thought to capitalize on the probabilistic nature of sequential inputs to infer on the underlying (hidden) dynamics driving sensory stimulation. Mis-match responses (MMRs) such as the mismatch negativity (MMN) and the P3 constitute prominent neuronal signatures which are increasingly interpreted as reflecting a mismatch between the current sensory input and the brain’s generative model of incoming stimuli. As such, MMRs might be viewed as signatures of probabilistic inference in the brain and their response dynamics can provide insights into the underlying computational principles. However, given the dominance of the auditory modality in MMR research, the specifics of brain responses to probabilistic sequences across sensory modalities and especially in the somatosensory domain are not well characterized. The work presented here investigates MMRs across the auditory, visual and somatosensory modality by means of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). We designed probabilistic stimulus sequences to elicit and characterize MMRs and employed computational modeling of response dynamics to inspect different aspects of the brain’s generative model of the sensory environment. In the first study, we used a volatile roving stimulus paradigm to elicit somatosensory MMRs and performed single-trial modeling of EEG signals in sensor and source space. Model comparison suggested that responses reflect Bayesian inference based on the estimation of transition probability and limited information integration of the recent past in order to adapt to a changing environment. The results indicated that somatosensory MMRs reflect an initial mismatch between sensory input and model beliefs represented by confidence-corrected surprise (CS) followed by model adjustment dynamics represented by Bayesian surprise (BS). For the second and third study we designed a tri-modal roving stimulus paradigm to delineate modality specific and modality general features of mismatch processing. Computational modeling of EEG signals in study 2 suggested that single-trial dynamics reflect Bayesian inference based on estimation of uni-modal transition probabilities as well as cross-modal conditional dependencies. While early mismatch processing around the MMN tended to reflect CS, later MMRs around the P3 rather reflect BS, in correspondence to the somatosensory study. Finally, the fMRI results of study 3 showed that MMRs are generated by an interaction of modality specific regions in higher order sensory cortices and a modality general fronto-parietal network. Inferior parietal regions in particular were sensitive to expectation violations with respect to the cross-modal contingencies in the stimulus sequences. Overall, our results indicate that MMRs across the senses reflect processes of probabilistic inference in a complex and inherently multi-modal environment.

What predicts the acceptance of social innovation (SI), novel ideas, processes, and practices? This is the core question pursued in this thesis. And it is a fundamental issue within the SI literature, dealing with “new social practices created from collective, intentional, and goal-oriented actions” (Cajaiba-Santana, 2014, p. 44), which are intended to respond to individual and collective social needs (Abad & Ezponda, 2022; Cajaiba-Santana, 2014; Grimm et al., 2013; van der Have & Rubalcaba, 2016). Research on innovation acceptance is characterized by a vast landscape of theories, concepts, and models. These consider various factors relating to innovation characteristics, social, organizational and individual factors, which are assumed to shape the process of the innovation decision-making (Kim & Chung, 2017). But what is at the core determining whether novelty emerges and becomes applied? A look at the field of future studies, which I used to pursue, provides an intriguing notion: Research on futures primarily refers to the exploration and discussion of possible, desirable, and probable futures. The common ground of these categories aims at the capacity to attach novel ideas to the individuals involved – to their attitudes, believes and opinions on the nature, desired state, and potential evolution of the subject at hand. Novel ideas are thus linked to the ability of the individuals concerned to recognize and accept this novelty and to create room for it to unfold. In this sense, novelty is always linked to the present, thoughts, believes and conceptions of reality by individuals. The literature on innovation research echoes this perspective, emphasizing the need to take individuals’ characteristics for exploring and predicting the process of an innovation and its’ acceptance by concerned stakeholders into account (Agarwal & Prasad, 1997; Kim & Chung, 2017; van Oorschot et al., 2018). Key models that have had significant influence on subsequent research include Rogers’ (2003) innovation-diffusion model, Triandis’ (1977) model of choice, the Technology Acceptance Model (TAM) (Davis, 1989), the Unified Theory of Acceptance and Use of Technology (UTAUT) (Venkatesh et al., 2003), the Theory of Reasoned Action (TRA) (Fishbein & Ajzen, 1975), and the Theory of Planned Behaviour (TPB) (Ajzen, 1985, 1991; Ajzen & Madden, 1986). These offer a wide range of overarching issues and detailed factors shaping how individuals approach innovation processes and their acceptance (Dedehayir et al., 2017; Kim & Chung, 2017; Lewis et al., 2003; Muthitcharoen et al., 2011). Although these insights were drawn mainly on technological practice and innovations, the findings also shape research on SI (Demirel & Payne, 2018; Małecka et al., 2022; Oeij et al., 2019). 2 Research on innovation acceptance remains dominated by these models (Dedehayir et al., 2017; Kim & Chung, 2017; Lewis et al., 2003; Muthitcharoen et al., 2011; Williams et al., 2015). Building on these studies, a wide variety of studies examine contextual adaptations and extensions. Among others, these consider the relation between organization and individual (Pak et al., 2019) and individuals’ emotions (Choi et al., 2011; Raffaelli et al., 2019). Further, issues like trust (Gefen et al., 2003; Małecka et al., 2022), perception of risk (Arruda Filho et al., 2022), culture (Srite & Karahanna, 2006), and the role of peers (Demirel & Payne, 2018; Małecka et al., 2022) are being explored. However, the majority of these studies relate to technological innovations, calling into consideration their applicability to SI.

Diese Habilitationsschrift beschäftigt sich mit der subjektiven Sicht von Hausärzt*innen auf die Herausforderungen und den Unterstützungsbedarf, die sich sowohl durch die demographische Entwicklung als auch durch die akute Mehrbelastung im Rahmen der Covid-19 Pandemie ergeben. Vier Publikationen sind im Rahmen des regionalen Netzwerkverbundes „Navicare“ entstanden, zwei Publikationen gingen aus dem Strukturaufbaus des hausärztlichen Forschungspraxennetzes „RESPoNsE“ hervor. Das Teilprojekt Compass des Navicare-Verbundes ging in qualitativen und quantitativen Erhebungen der subjektiven Sicht von Hausärzt*innen auf Herausforderungen in der Versorgung multimorbider Patient*innen vor dem Hintergrund der demographischen Entwicklung nach, sowie auf ihren Unterstützungsbedarf und mögliche Lösungsansätze. Die demographische Entwicklung führt zu einer Zunahme der Anzahl multimorbider Patient*innen bei gleichzeitigem Rückgang der Zahlen von tätigen Hausärzt*innen. Dies führt zu Mehrbelastungen in der hausärztlichen Versorgung. Die ersten beiden Publikationen zeigten in qualitativen Interviews und in einer quantitativen Fragebogenerhebung, dass gerade die Versorgung multimorbider Patient*innen hohe Anforderungen an die Koordinierung der Versorgung stellt, da diese sich oftmals durch eine Vielzahl von Versorgern sowie eine häufige Inanspruchnahme auszeichnen. Nicht immer fließen alle Informationen bei den Hausärzt*innen zusammen. Hausärzt*innen wünschen sich Unterstützung, die aus ihrer Sicht sowohl durch die Medizinischen Fachangestellten der eigenen Praxis als auch durch externe Berufsgruppen bzw. Institutionen geleistet werden könnte. Hausärzt*innen benannten zudem die vielen sozialen Beratungsanlässe dieser Patient*innengruppe als herausfordernd. Die dritte Publikation stellt die Ergebnisse einer Fokusgruppen-Diskussion vor, die diesem Aspekt noch vertiefend nachging. Es wurde deutlich, dass die Ressourcen für soziale Beratungsanlässe oftmals nicht ausreichend sind, womöglich aber bereits bestehende Einrichtungen, die diese Beratungen übernehmen könnten, den Hausärzt*innen nicht immer bekannt sind. Die vierte Publikation stellt die Ergebnisse einer Fragebogenerhebung dar, in der dem Bekanntheitsgrad von Pflegestützpunkten unter Hausärzt*innen nachgegangen wurde. Die Mehrheit der teilnehmenden Hausärzt*innen kennt Pflegestützpunkte entweder gar nicht oder fühlt sich nicht vertraut mit deren Angebot. Die Covid-19 Pandemie stellte die Hausärzteschaft vor neue Herausforderungen. Die fünfte Publikation ist ein Studienprotokoll für eine mixed-method Studie, in der die subjektive Sicht von Hausärzt*innen, Medizinische Fachangestellte und Patient*innen auf die hausärztliche Versorgung während der Pandemie untersucht wird, insbesondere für die Regelversorgung von nicht-Covid-bezogenen Beratungsanlässen. Die sechste Publikation stellt die Ergebnisse einer Fragebogenerhebung unter Berliner, Brandenburger und Thüringer Hausärzt*innen und Medizinischen Fachangestellten zu diesem Thema dar. Deutlich wurde, dass zwar einerseits Angebote der Regelversorgung eingeschränkt wurden, aber dennoch aus Sicht der in den Hausarztpraxen Tätigen weiterhin eine gute Versorgung stattfinden konnte. Allerdings kam es dabei zu erheblichen Mehr- und Überlastungen und Stresserleben. Zusammenfassend kommt es durch die demographische Entwicklung anhaltend zu Mehrbelastungen, insbesondere in der Versorgung älterer und multimorbider Patient*innen. Die Covid-19 Pandemie verschärfte diese Situation noch. Hausärztliche Praxen benötigen Unterstützung, um weiterhin eine qualitativ hochwertige hausärztliche Versorgung gewährleisten zu können. Manche Möglichkeiten der Entlastung, wie zum Beispiel eine stärkere Delegation ärztlicher Tätigkeiten an Medizinische Fachangestellte sowie eine Zusammenarbeit mit vorhandenen Einrichtungen wie den Pflegestützpunkten werden noch nicht ausreichend genutzt.

Diese Dissertation untersucht mittels verschiedener Forschungsmethoden die Durchführung des Wertminderungstests des Goodwills gemäß IAS 36. Dabei wird insbesondere der diesbezügliche Entscheidungsprozess tiefgehender beleuchtet, ein Forschungsbereich, der trotz des hohen Grads an individueller Urteilsnotwendigkeit, potenziellen kognitiven Verzerrungen und bedeutenden finanziellen Auswirkungen bisher wenig Beachtung gefunden hat. Der erste Beitrag untersucht explorativ kritische Bereiche der Entscheidungsfindung bei der Durchführung des Wertminderungstests des Goodwills. Hierfür werden halbstrukturierte Experteninterviews mit Abschlussaufstellern und Unternehmensberatern geführt. Im Ergebnis lassen sich kritische Bereiche in Form von Herausforderungen bei der praktischen Handhabung des Wertminderungstests und aufgrund von kognitiven Einflussfaktoren bei der Entscheidungsfindung feststellen. Daneben gibt der Beitrag Einblicke über Teilprozesse der Informationsverarbeitung und Qualitätsmerkmale eines Wertminderungstests. Der zweite Beitrag gibt eine Bestandsaufnahme aus den IFRS-Konzernabschlüssen der DAX30-, MDAX und SDAX-Unternehmen zu den ausgewiesenen Anhaltspunkten für eine Wertminderung. Verglichen wird das durch die Corona-Pandemie geprägte Geschäftsjahr 2020 mit dem Nicht-Krisenjahr 2018. Erwartungsgemäß lassen sich Unterschiede hinsichtlich der Anzahl von Unternehmen mit Wertminderungen (insbesondere auf den Goodwill) und höhere durchschnittliche Wertminderungsintensitäten dokumentieren. Der dritte Beitrag erkundet, wie in der Rechnungslegungspraxis Anhaltspunkte für eine Wertminderung identifiziert (im Sinne einer Suche) und diese im Sinne der Notwendigkeit eines Wertminderungstests beurteilt werden. Auf Basis von Experteninterviews lassen sich insgesamt vier Faktoren identifizieren, welche eine abweichende Einschätzung von ceteris paribus identischen Anhaltspunkten für eine Wertminderung bewirken könnten. Die Identifizierung von Anhaltspunkten wird häufiger als weniger kritisch angesehen als die Beurteilung der identifizierten Anhaltspunkte. Die Informationsverarbeitung von Abschlussaufstellern unterliegt auskunftsgemäß am häufigsten abschlusspolitisch motivierten Einflussfaktoren. Der vierte Beitrag untersucht experimentell kognitive Verzerrungen bei der Wertminderungsentscheidung und der hiermit einhergehenden Informationsverarbeitung sowie die Wirkungsweise zusätzlicher Rechenschaftsmechanismen als mögliche Entzerrungsmechanismen. Die Ergebnisse zeigen, dass eine erhöhte Prozessrechenschaft die Wahrscheinlichkeit für eine Wertminderung des Goodwills positiv beeinflusst. Eine differenzierte Betrachtung der Teilprozesse der Informationsverarbeitung zeigt, dass bei hoher Prozessrechenschaft tendenziell eine ausgewogenere Informationssuche stattfindet und Informationen neutral im Vergleich zu einer Benchmark-Gruppe evaluiert werden. Weiterführende Analysen deuten auf eine zentrale Bedeutung der Rechenschaft gegenüber dem seitens des Aufsichtsrats eingerichteten internen Prüfungsausschusses, unter den in der Fallstudie eingesetzten Rechenschaftsmechanismen, hin.

Glycans are essential molecules for living beings and, in land plants, they play an important structural role as part of the plant cell wall. A major component of the cell wall of many plants is the hemicellulose xylan, which is, after cellulose, the second most abundant glycan in the plant biomass.

Xylan polysaccharides are composed of a linear 1,4-β-linked backbone of xylosyl residues and are decorated with diverse substituents such as glucuronic acid and arabinosyl residues. Only recently, the cohesive role that xylan polysaccharides play between the other major components of the secondary cell wall, cellulose and lignin, is being recognised. Developing synthetic methodologies to produce xylan oligosaccharides that can serve as substrates for enzymatic studies is important for unravelling some of the gaps in the knowledge of its biosynthesis.

Another related xylose-containing polysaccharide was recently revealed in the cell walls of barley. The newly discovered hemicellulose glucoxylan is a linear 1,4-β-linked glycan composed of alternating xylosyl and glucosyl residues. This glycan was previously identified only in the cell wall of a sea lettuce species (a type of green algae). In barley, it is synthesised by genes in the monocot-specific CslF subfamily and is believed to play a structural role in the plant cell wall.

In Chapter 2 of this thesis, a chemoenzymatic synthesis of xylan dodecasaccharides for the study of xylan-modifying enzymes is described. The synthesis of these materials was designed around two central ideas, (a) the implementation of a divergent-convergent iterative synthetic strategy, and (b) the use of a glycosynthase for the glycosylation reactions. Because of the limited solubility of long unprotected glycans in water, two parallel syntheses were performed, one to obtain xylan oligosaccharides with a methyl group at the 3-OH of the reducing-end xylosyl residue and one to obtain xylan oligosaccharides without the methylation. Besides unprotected xylosyl acceptors, the xylan glycosynthase (XynAE265G) employed in these syntheses requires unprotected α-xylosyl fluorides as donors. These donors were equipped with a THP group at the 4-OH of the non-reducing end xylosyl residue to prevent self-condensation of these molecules. The enzymatic glycosylation reactions with this donor gave exclusively the desired 1,4-β-linked glycosyl products, and no sugar-based side-products were detected.

The xylans oligosaccharides equipped with a methyl group showed superior solubility in comparison to the unprotected ones, so the methyl-substituted dodecasaccharide was used for biosynthetic studies using xylan-modifying enzymes. Treatment of this substrate with glucuronosyltransferase AtGUX3 was found to install a single GlcA substituent at the substrate. The data obtained by MS/MS analysis of the reaction products is compatible with the substituent being installed at one of the two central residues of the substrate, which is in agreement with previously reported in vivo studies.

In Chapter 3, a small library of glucoxylan oligosaccharides was produce by chemical synthesis. These molecules have the same structural features as those reported in the literature to be synthesised by the two barley glycosyltransferases HvCslF3 and HvCslF10. The synthesis of these target molecules, ranging from di- to hexasaccharides, was designed to maximize the number of convergent and divergent steps in order to minimize the number of required synthetic transformations. As a temporary protecting group for chain elongation, a TBS group was used with great success to protect the 4-OH glycosylation site. The protected glucoxylan molecules in this small library are equipped with an anomeric azido-pentyl linker, which may be used after reduction to the aminopentyl linker, for immobilization of these molecules as microarrays for biosynthetic studies and the characterization of antibodies.

We give a new, conceptual proof and sharp generalization of a Theorem by Cary Malkiwiech [Mal17] about how the assembly map of the algebraic K-theory of a group ring (spectrum) with respect to a finite group G admits a dual coassembly map, such that the composition of assembly and coassembly is the well-studied norm map of K(R). Using the equivariant perspective on assembly of [DL98] and the precise un- derstanding of the 1-category of genuine G-spectra that the theory of spectral G-Mackey functors of [Bar17] a↵ords, we show the above theorem by contem- plating various universal properties, and that it holds for any additive functor Catperf ! Sp instead of K-theory.

Many geoscientific measurements exhibit significant variability induced by ocean tides that can, if uncorrected, degrade the quality of observations. Thus, tidal variability is usually reduced on the observation level with the help of background models.

The barotropic ocean tide model TiME has been refined to improve this correction process. Major upgrades include updating the bathymetric data, improving the energy dissipation mechanisms, and including the effect of self-attraction of the ocean water and its loading on the solid Earth. These refinements allowed reducing the open ocean root-mean-square deviation from geodetic data by over 70% for the main lunar M2 tide, corresponding to an accuracy on the 80%-level with respect to the mean signal. The model operates independently of empirical satellite altimetry data, so this high relative accuracy also extends to partial tides with minor amplitude, where altimetry-constrained models are less accurate. TiME’s forcing module was augmented by degree-3 spherical harmonic functions and barometric and wind stress acceleration induced by the atmosphere, which enabled the simulation of additional tidal subgroups at the same accuracy level. For degree-3 tides, it could be shown that their gravimetric fingerprints on the level of only 100 pm/s2 can be identified in superconducting gravimeters and agree with the modelling results. This level is close to the threshold of gravimetric detectability and emphasizes TiME’s accuracy for the smallest tidal signals.

As a result of these simulations, the TiME22 ocean tide atlas, which comprises 57 partial ocean tides, has been compiled and is provided in Stokes coefficients for terrestrial and satellite gravimetric applications. Many minor ocean tides from this collection are not included in data-constrained ocean tide atlases. Therefore, they are usually only linearly estimated or completely neglected for gravimetric applications. It is shown for several cases that TiME22 minor tide solutions can improve the accuracy of the tidal correction for geodetic techniques, including satellite and terrestrial gravimetry. More precisely, the model validation conducted within this thesis recommends the utilization of hybrid tidal atlases comprised of altimetry data-constrained ocean tide models for large-signal tides and unconstrained solutions, such as TiME22, for minor tides. The results confirm that purely hydrodynamic ocean tide models can reliably predict tidal variability in cases where empirical data is so sparse or of such low precision that tidal solutions cannot be adequately constrained.

This line of argumentation extends to paleo-ocean tides, where direct observations are impossible, and information can only be extracted by archeological or geological sea-level markers. Within this thesis, TiME is employed to predict paleo tide levels, which indicate the possible height deviation of sea-level markers from the mean sea level at that time. Tidal levels are simulated with dense temporal sampling since the Last Glacial Maximum. The predicted levels (e.g., the mean high water) compare well to available observations and other paleo tidal simulations and represent the first data set with truly-global coverage that allows for interpretation of paleo sea level data.

Die Arbeit untersucht die branchenübergreifende Legalitätskontrollpflicht für Unternehmen, insbesondere im Gesellschaftsrecht. Ausgangspunkt ist die These, dass sich anhand der Entwicklungsstränge der Legalitätskontrolle seit einigen Jahrzehnten ein (innovativer) Wandel der staatlichen regulativen Struktur beobachten lässt, für den hier der Begriff des „regulativen Kapitalismus” benutzt wird. Gleichzeitig soll gezeigt werden, dass dieser Strukturwandel im Privatrecht mit einem liberalen Grundverständnis zusammenstößt. Dieses Grundverständnis soll kritisch und insbesondere kulturtheoretisch rekonstruiert und einem demokratischen Privatrechtsverständnis entgegengestellt werden.

This thesis analyses close social relations among Uyghurs in Kashgar. It discusses and analyses some of the most important practices and concepts pertaining to the constitution of close social relations in lower to higher middle-class urban and semi urban Kashgar. Central to these are kinship (tughqandarchiliq) and marriage (toy qilish, nikahlinish, öylinish ...). Kinship provides the central idiom for expressing and re-presenting close social relations, both in linguistic terms and pertaining to exchange and bodily and spatial practices. Marriage is a central part of kinship practices and has a structural relevance for social organisation. It is the ideal for affnes to be produced as close relatives through the marriage process and lastly unite into one social unit. Thus marriage is not a secondary relation created between genealogically predefned social units, but is primary and central to constructing these units. A bride is not transferred from one unit to the other, as much as she, over the long marriage process involving much visiting and gift giving, combines and unites the two sides into one family. This is an important incentive to marry close, since the affnes need to have the potential of becoming such close relatives. Although this logic is not always adhered to, and many other strategies exist, this logic of close marriage is central to the local understanding of marriage and kinship and is clearly visible in many elements of the marriage process, such as the toy neziri, quda körüshüsh and öy körsitish. The importance and ambivalence of the affnes are also a structurally important element contributing to the relative ease of divorce, since a marriage that does not produce close relatives through affnity can be seen as a failed marriage of which divorce is only a necessary, though painful, logical consequence. On the other hand marriages are also life cycle events celebrated in the local community and contribute to constituting this community through a continuous exchange of gifts including labour help. Both affnity and close neighbourly relations are close social relations based upon exchange, trust and mutual dependency. They are formulated in the idioms of kinship (they are kinship!) and are performed in a number of practices including weddings and other marriage related events. They make up a centre-piece in what kinship, i.e. mutuality of being, means in Kashgar.

One of the most useful tools in the service of communication is language. However, the neuro-cognitive basis of language has often been studied outside of its natural niche and in isolation from its communicative function. This thesis examines the neuro-cognitive processes that are at the basis of processing communicative intention conveyed by language by employing a range of psycho- and neurolinguistic methods. In particular, the present work focuses on two pragmatic phenomena: speech acts and indirect speech acts. The following questions are asked: (1) Can the differences in neural signatures of speech acts previously observed in the comprehension modality also be found in speech production? (2) Is the right temporo-parietal junction, an important node of the ToM network, causally involved in the comprehension of indirect speech acts? (3) Do indirect speech acts systematically differ from direct ones in psycholinguistic properties, whose processing is known to be reflected in different neural processes? The general methodological approach taken here is to use identical words or sentences but alter their pragmatic-communicative roles by embedding them in different dialogic or situational contexts. This way, the communicative function can be examined independently from the linguistic form used to carry it out.

In a first study, the neural representations of naming and request actions were examined. These were performed using the same utterance during speech production, while subjects participated in an interactive communicative task and while participants neural activity was recorded by electroencephalography. The aim was to compare these findings to previous findings in the comprehension modalities. We find that uttering the same words with different speech act functions (naming and request) is associated with different electrophysiological signatures. These differences are similar to those found when comparing the same two speech acts in the comprehension modality. In particular, requests are associated with activations of the motor system, supporting the idea that their intrinsic link to action is also encoded in the brain.

The second study tested whether the comprehension of indirect speech acts relies on the right-temporoparietal junction, a brain region thought to contribute to Theory of Mind processes. To do so, activity in these brain regions was altered by means of (non-invasive) transcranial magnetic stimulation. Subjects were then exposed to indirect speech acts and their matched direct controls, and their comprehension processes were behaviorally monitored. The finding that comprehending indirect speech acts is more costly than comprehending direct ones was replicated. Applying TMS to the right-temporoparietal junction did not affect the processing of indirect speech acts when these were matched to their direct controls in terms of communicative function. However, the speed of comprehension of indirect speech acts was altered relative to the direct controls when they were not matched for communicative function.

In a third study, subjects were asked to provide ratings of several psycholinguistic dimensions for both direct and indirect speech acts to assess the differences between them. Compared to their direct counterparts, indirect speech acts were found to be less predictable, less coherent with their context, less semantically related to their context, and understood with less certainty. Notably, these properties were tightly related to the in/directness of the stimuli.

In summary, it could be shown that (i) communicative function can be encoded in the brain in ways that are similar between comprehension and production modality, (ii) specificities of the neural representations of speech acts can be related to their use in communication, (iii) there was no evidence of the right-temporoparietal junction processing indirect speech acts when compared to well-matched controls, and (iv) contrasting direct and indirect speech acts revealed several differences unrelated to ToM that suggest the (additional) contribution of other brain systems in the comprehension of indirect speech acts. Overall, it was demonstrated that when identical utterances are used with different communicative functions—whether direct or indirect—are associated with different neurocognitive processes. These findings add to the growing literature examining the communicative function of language and argue for greater inclusion of pragmatics in neurocognitive models of language function.

Cancer is the second-most common cause of death for humans and engendered by malignant human cells dividing uncontrollably due to the failure of cell growth control mechanisms. A major bottleneck for the development of new diagnostics and therapeutics is the identification of specific tumor biomarkers and the generation of suitable tools to target these biomarkers. Tumor-associated carbohydrate antigens (TACAs) and aberrant surface thiol groups are promising classes of tumor biomarkers. However, the number of available tools to study them is very limited. I established an approach to generate heavy-chain antibodies targeting TACAs by immunization of an alpaca, thereby expanding the toolbox against TACAs. Conjugates of TACAs and carrier proteins were produced and injected into an alpaca, inducing the formation of glycan-specific conventional and heavy-chain antibodies in the animal. These heavy-chain antibodies formed the basis for the generation of nanobodies binding to the tumor-associated glycan Globo-H. By serendipity, I discovered a new tool for targeting thiol groups on cancer cells, as nanobody CB2 specifically binds to several subtypes of B cell lymphoma and breast cancer via thiol-thiol interactions. I demonstrated that CB2 binding is linked to increased thiol levels on lymphoma cells and requires the presence of an unusual cysteine in the antigen-binding region of the nanobody. CB2 was endowed with additional properties through functionalization, using a combination of chemical and enzymatic conjugation methods. On one hand, I showed that CB2 modified with a rhamnosylated glycopeptide can recruit antibodies to lymphoma cells, resulting in complement activation and cancer cell death. On the other hand, using fluorophore- coupled CB2, I proved that thiol-mediated CB2 binding is followed by internalization into lymphoma cells. Finally, I demonstrated that CB2 internalization can be exploited for the delivery of cytotoxic agents to cancer cells, again leading to cancer cell death. In summary, the results of my work illustrate the potential of combining thiol-binding, internalizing nanobodies with further functionalization, thereby laying the foundation for numerous applications in cancer diagnostics and therapeutics.

Breast cancer is one of the main cancer-associated causes of death in women. While a primary tumor can often be treated well, metastases have a very poor prognosis and the spread to bones is among the most frequent forms of metastasis with very poor outcome. While the cellular involvement of late-stage metastasis in the bone has been studied frequently, early metastatic lesions and associated structural and biophysical parameters, as well as the dynamic bone (re)modeling behavior are not well understood. We hypothesize, that such structural and biophysical changes in the bone microenvironment, influence the establishment and progression of breast cancer induced osteolytic lesions.

Hence, we aim to develop an experimental mouse model of breast cancer bone metastasis to detect and characterize early osteolytic lesions in 3D. In order to study the dynamic bone (re)modeling behavior in a pathological model, a physiological baseline has to be established. In vivo microCT-based time-lapse morphometry is a powerful tool to study temporal and spatial changes in bone (re)modeling. Here we present an advancement of the method to detect and quantify site-specific differences of bone (re)modeling in 12-week-old female BALB/c nude mice. We establish new bone surface interface parameters and show how they are affected by bone curvature. Significant differences in bone (re)modeling baseline parameters between metaphysis and epiphysis, as well as distal femur and proximal tibia, for both cortical and trabecular bone, are described, with important implications for disease models. This baseline of physiological bone (re)modeling using our advanced microCT-based time-lapse morphometry method is then used to study changes in the bone dynamics caused by breast cancer cell bone metastasis. For this we inject mice with breast cancer cells and monitor the bone (re)modeling to detect pathological changes. We show that tumor-injected animals without osteolytic lesions have significantly higher parameters for newly mineralized bone in the trabecular region, compared to healthy control mice and with similar trends for cortical bone. This indicates an influence of cancer cells on the bone (re)modeling even in the absence of detectable lesions and a possible establishment of a pre- or antimetastatic niche. In order to study early osteolytic lesions caused by breast cancer cells in the bone, we develop an eroded bone patch analysis tool. This new mathematical tool allows us to detect and quantify cortical osteolytic lesions already two weeks after cancer cell injection, clearly distinguishing the pathological and physiological eroded bone patches. In addition, we visually identify lesions in the primary spongiosa of trabecular bone, sitting directly under the mineralized growth plate, already two weeks after cancer cell injection. MicroCT-based time-lapse morphometry allows us to describe for the first time three different types of early osteolytic lesions in the bone: 1) cortical lesions initiating at the periosteum, 2) cortical lesions at the endocortial site with additional trabecular erosion and 3) trabecular lesions in the primary spongiosa at the growth plate. We then use our in vivo results to study the homing of cancer cells in the bone using light-sheet fluorescence microscopy and confocal laser scanning microscopy, as well as the tissue changes caused by early osteolytic lesions with the help of backscattered electron microscopy and advanced confocal laser scanning microscopy. We study the size and location of cancer cells in 3D (intact) bones after optical clearing with the help of light-sheet fluorescence microscopy, providing 3D quantification of the homing of cancer cells in the bone marrow and bone surrounding tissue. Within the bone marrow, cancer cells home as small cell clusters close to the endocortical bone, but with no apparent preference for different bone compartments. Further analysis of cancer cell clusters in the marrow revealed that a significant fraction is not proliferating. Additionally, cancer cell clusters have a strong tendency to home in fibronectin-rich areas, providing new implications for the structural features of the cancer cell niche. We last perform a multiscale analysis of the early metastatic lesions with various imaging techniques and are able to show the changes in the mineralized tissue, as well as the organic collagen matrix. To sum up, we use microCT-based time-lapse morphometry to study the dynamics and onset of bone metastasis, including a baseline to differentiate from physiological bone (re)modeling. We quantify changes in pathological bone (re)modeling in the absence of detectable osteolytic lesions. Further, we introduce a new tool to detect and quantify early osteolytic lesions in cortical bone. In addition, we visually detect trabecular lesions and are able to classify three different types of lesions in cortical and trabecular bone. Using advanced ex vivo multimodal tissue analyses, we describe the homing of cancer cells to the bone marrow in 3D and characterize the bone microenvironment in early osteolytic lesion. Our work gives important 3D information and new perspectives on various states of cancer research including the debate on pre- or antimetastatic niches, homing and the onset of metastasis in the long bones.

Einleitung Lebertransplantierte Patient*innen nehmen lebenslang immunsupprimierende Medikamente zu sich. Durch den Ersatz von Cyclosporin A durch Tacrolimus-Präparate konnten diverse Nebenwirkungen minimiert werden, die andauernde Auswirkung auf die parodontale und dentale Gesundheit im postoperativen Langzeitverlauf ist jedoch nicht vollends geklärt. Ziel dieser Studie war die Feststellung einer Veränderung der Mundgesundheit nach Lebertransplantation. Material und Methoden 204 Patient*innen wurden in der Lebertransplantationsambulanz der Charité-Universitätsmedizin Berlin untersucht. Die Datenerhebung umfasste sowohl die medizinische und zahnmedizinische Anamnese als auch den zahnärztlichen Befund mit DMFT und DMFS und einen vollständigen Attachmentstatus zur Befundung des Parodontiums. 159 Patient*innen konnten in die statistische Analyse aufgenommen werden. Es wurde nach vergangener Zeit nach Transplantation stratifiziert (<5 Jahre, 5-10 Jahre, 10-15 Jahre, >15 Jahre). Die Daten wurden innerhalb der Gruppen miteinander verglichen. Des Weiteren wurde der Einfluss von lang- und kurzwirkenden Immunsuppressiva (IS) verglichen, sowie die Mono- und Kombinationstherapie mittels mehrerer IS. Ergebnis 38% der Untersuchten waren Frauen und 62% Männer, durchschnittlich 58,64  12,2 Jahre alt zum Zeitpunkt der zahnärztlichen Untersuchung. Der DMFT betrug im Durchschnitt 19,4. Der DMFT innerhalb der Gruppen betrug: <5 Jahre: 18,1; 5-10 Jahre: 20,34; 10-15 Jahre: 19,65; >15 Jahre: 20,16. Die einfaktorielle ANOVA zeigte keinen signifikanten Zusammenhang der Variablen DMFT (p=0,35), Anzahl der fehlenden Zähne (p=0,99), Anzahl der Füllungen (p=0,77), Anzahl der kariösen Zähne (p=0,39). Die Sondierungstiefen und der klinische Attachmentverlust zeigten ebenfalls keinen Unterschied innerhalb der Jahresgruppen (ANOVA für ST: p=0,99; CAL: p=0,808). Der Chi-Quadrat-Test konnte einen Zusammenhang zwischen den Parodontitisstadien und den Subgruppen nicht statistisch belegen (p=0,964). Einen Unterschied in DMFT, DMFS, ST und CAL in den Subgruppen lang- und kurzwirkende IS, sowie Mono- und Kombinationstherapie war nicht festzustellen (p>0,05). Fazit Keine der untersuchten Variablen zeigte einen signifikanten Zusammenhang zu den stratifizierten Gruppen. Unerwartet waren, die über die Jahre unveränderten Befunde. Durch die Ergebnisse wird die Bedeutung der Immunantwort in der Ätiopathogenese der Parodontitis noch deutlicher. Dies lässt die eingangs formulierte Fragstellung abweisen, ob eine Verschlechterung der Mundgesundheit nach Lebertransplantation stattfindet, und wirft die Hypothese auf, ob Immunsuppressiva möglicherweise einen protektiven Effekt auf die parodontale und dentale Gesundheit haben. Weitere klinische Untersuchungen sind notwendig.

Prostate cancer (PCa) remains the most prevalent cancer in men globally, with an increasing burden worldwide. PCa is unique in its dependence on androgen-androgen receptor (AR) signaling for growth and progression, and hormonal therapies have greatly improved the survival of patients with metastatic prostate cancer (mPCa). However, almost all patients with mPCa are resistant to hormonal treatments and ultimately succumb to metastatic castration-resistant prostate cancer (mCRPC), even when new hormonal agents deplete serum androgen levels. Therefore, novel non-AR dependent therapeutic strategies should be explored. JQ1, a potent and selective Bromodomain and extra terminal domain (BET) inhibitor, is a potentially potent therapy for patients with mCRPC. Compared to new hormonal agents, JQ1 more potently abrogates BRD4 localization to the AR target loci and AR-mediated gene transcription. However, a recent study showed that JQ1 promotes PCa invasion and metastasis in a BET protein-independent manner when PCa cell growth is inhibited. Therefore, combination strategies with JQ1 might be more promising than JQ1 alone. This study shows that JQ1 and docetaxel might serve as an effective combination therapy for patients with mPCa. We assessed the combination therapy in 2D and 3D preclinical models, and we also evaluated the susceptibility of 2D-cultured LNCaP cells and 3D-cultured LNCaP cells/spheroids exposed to the same anti-cancer drug. In contrast to 2D LNCaP cells, the evaluation of LNCaP spheroids’ susceptibility was more complicated. The IC50 curves were not suitable for evaluating the susceptibility to drugs. Specifically for big-sized LNCaP spheroids, a low maximum inhibition and a low R-squared value were observed. Our results identified the different fitness of IC50 curves for 2D and 3D preclinical models and supported a potential combination treatment (docetaxel and JQ1) for PCa patients.

Background: As one of the matrix metalloproteinases, MMP-14 is involved in the deg-radation of the extracellular matrix. In this study, we aim to explore the function of MMP-14 in bladder cancer. Methods: We analyzed MMP-14 expression in various cancers and detected its rela-tionship with the patients’ prognosis with urological cancer from the TCGA database. Additionally, we explored the correlation between MMP-14 expression and the corre-sponding patients’ clinicopathological characteristics in bladder cancer. Next, func-tional enrichment analysis was used to study the biological function and signaling pathways of MMP-14 in bladder cancer. In addition, we used the ssGSEA algorithm and two databases (GEPIA and TIMER) to investigate the effect of MMP-14 on immune infiltration in bladder cancer. Furthermore, Western blotting or immunofluorescence was used to detect the expression of MMP-14, STAT3, p-STAT3 and PD-L1 in bladder cancer cells. The Knock TF and hTFtarget databases were used to predict the transcription factors of MMP-14. We also evaluated the effect of NSC405020 and HO-3867 on bladder cancer cells by proliferation assay, MMP-14 activity assay, cell death detection assay and cell cytotoxicity assay. Moreover, we used CRISPR-Cas9 technology to knockdown MMP-14 expression in bladder cancer cells. Results: The expression level of MMP-14 was significantly up-regulated in bladder cancer, and bladder cancer patients with a high expression level of MMP-14 had shorter overall survival. MMP-14 expression was significantly correlated with some clinicopathological characteristics in bladder cancer. MMP-14 was involved in the negative regulation of the immune response process. Moreover, MMP-14 expression was moderately correlated with Treg cell enrichment, and weakly correlated with CD8+ T cells. The high MMP-14 expression showed more enrichment of Treg cells com-pared with the low expression. Additionally, MMP-14 expression was significantly positively correlated with Treg cell markers and T cell exhaustion markers in bladder cancer. In addition, MMP-14 was positively correlated with PD-L1 expression in blad-der cancer cells, and down-regulation of MMP-14 reduced PD-L1 expression in blad-der cancer cells. STAT3 was predicted to be the transcription factor of MMP-14 and had a significant correlation with MMP-14 expression. Furthermore, the treatment of NSC405020 and HO-3867 decreased the cell proliferation and MMP-14 activity, and they also increased cell apoptosis and cytotoxicity in bladder cancer cells. Inhibiting MMP-14 expression resulted in the decreased expression level and phosphorylation of STAT3. Applying Colivelin resulted in altered expression levels of MMP-14 and PD-L1 in bladder cancer cells. Colivelin upregulated PD-L1 expression in MMP-14 knock-down cells. Conclusion: MMP-14 plays a crucial role in the progress of bladder cancer, and is promised to be a novel target of bladder cancer in the future.

Einleitung: Weltweit werden jährlich mehr als 1,25 Millionen Schrittmacher und 410.000 ICD’s implantiert. Ein großer Teil der Patienten, die sich der Implantation eines kardialen implantierbaren elektronischen Devices (CIED), Aggregataustausches oder ähnlichen Prozeduren unterziehen, werden antikoaguliert. Die Sicherheit der perioperativen kontinuierlichen Gabe von Vitamin-K-Antagonisten (VKA) wurde in mehreren Studien untersucht und im Vergleich zur Bridging-Strategie mit Heparin bevorzugt. Das perioperative Management der direkten oralen Antikoagulanzien (DOAC) Apixaban, Rivaroxaban und Dabigatran war zum Zeitpunkt des Aufkommens der DOAC’s nicht klar definiert. Ziel dieser retrospektiven Analyse ist die Evaluation der Sicherheit der kurzfristig unterbrochenen perioperativen Einnahme von DOAC’s. Dies erfolgte mittels Vergleiches der direkten oralen Antikoagulanzien Apixaban, Rivaroxaban und Dabigatran und den VKA’s hinsichtlich des Auftretens perioperativer Blutungskomplikationen. Methoden: In dieser retrospektiven Studie wurden insgesamt 529 Patienten eingeschlossen, die eine CIED- Implantation, einen Aggregataustausch oder ähnliche Prozeduren erhielten. Die Aufteilung der Patienten erfolgte in 4 Gruppen. In Abhängigkeit der eingenommenen Präparate erfolgte die Zuteilung in die VKA-Gruppe (n = 223), die Apixaban-Gruppe (n = 148), die Rivaroxaban-Gruppe (n = 93) und die Dabigatran-Gruppe (n = 65). Die perioperativen Komplikationen wurden in folgende Gruppen eingeteilt: Major Blutungskomplikationen (Transfusionsbedürftige Hämatome, Hämatome mit verlängerter Hospitalisierungszeit oder stationärer Wiederaufnahme, Hämatome mit Taschenrevision, Hämatothorax, Perikardtamponade), Major thromboembolische Ereignisse (TIA, Schlaganfall, TVT, LAE), Minor Blutungskomplikationen (Perikarderguss ohne Drainage, Hämatome mit Pausierung der Antikoagulation, Hämatome mit verlängerter antibiotischer Therapie) sowie andere Komplikationen (Pneumothorax mit und ohne Notwendigkeit einer Drainagenversorgung, Explantation wegen Device-Infektion, Sondendislokation, Nahtdehiszenz). Ergebnisse: Insgesamt wurden 529 Patienten in die Studie eingeschlossen. Die Patienten unterschieden sich nicht signifikant hinsichtlich des Alters, des CHA2DS2- VASc-Scores (4 [3;5], p = 0,075) und des HAS-BLED-Scores (2 [2;3], p = 0,071). In der gesamten Studienpopulation wurden 20 Major Blutungskomplikationen (3,8%), die vor allem durch eine Verlängerung des Krankenhausaufenthaltes (3,2%) bedingt waren, beobachtet. Es wurden 24 Minor Blutungskomplikationen (4,5%) dokumentiert. So zeigte der Vergleich der VKA-Gruppe mit den DOAC-Gruppen keine statistischen Unterschiede bezüglich des Auftretens von Major oder Minor Blutungskomplikationen. Die Auswertung der Major Blutungskomplikationen ergab einen Patienten (0,7%) in der Apixaban-Gruppe, der bedingt durch ein Hämatom eine Bluttransfusion benötigte. Die Revision eines Taschenhämatoms benötigte ein Patient (0,4%) der VKA-Gruppe und in der Rivaroxaban-Gruppe erlitt ein Patient (1,1%) einen Hämatothorax. Bezüglich der Minor Blutungsereignisse hatten 9 Patienten (1,7%) Hämatome mit Notwendigkeit des Absetzens der Antikoagulation und 12 Patienten (2,3%) Hämatome mit verlängerter Antibiotikatherapie. Perikardergüsse ohne Notwendigkeit einer Perikardiozentese wurden jeweils bei einem Patienten in der VKA- (0,4%), Rivaroxaban- (1,1%) und Dabigatran- Gruppe (1,5%) dokumentiert. Hämatome mit Unterbrechung der Antikoagulation hatten 3 Patienten (2%) in der Apixaban-, 2 Patienten (2,2%) in der Rivaroxaban- und 1 Patient (1,5%) in der Dabigatran-Gruppe im Vergleich zu 3 Patienten (1,3%) in der VKA-Gruppe. Insgesamt zeigte sich eine homogene Verteilung der Minor Blutungskomplikationen auf die verschiedenen Antikoagulationsgruppen. Thromboembolische Ereignisse wurden nicht beobachtet. Schlussfolgerung: Der Einsatz der direkten oralen Antikoagulanzien bei Patienten, die sich der Implantation eines CIED oder ähnlichen Prozeduren unterziehen, zeigte im Vergleich zu den VKA’s kein höheres Risiko für schwere Blutungen oder ischämische Komplikationen.

N-methyl-D-aspartate (NMDA) receptors lay at the core of excitatory glutamatergic transmission and their dysfunction has been implicated in a number of neurological and psychiatric disorders. One such recently described disease is anti-NMDAR encephalitis, characterized by prominent psychiatric, cognitive and autonomic symptoms, which are linked to presence of autoantibodies targeting the NMDARs. To date, the majority of mechanistic studies have focused on antibodies’ action in the hippocampus, where they cause receptor cross-linking and internalization. However, little is known what is the specific contribution of individual antibodies and what are their effects in other brain regions such as cortex, which could help explain dysfunction on higher cognitive level. Here, we employed recently developed monoclonal anti-NMDAR autoantibodies and studied their effects on in vitro rodent neuronal cultures, using electrophysiological and imaging techniques. We report that both affinity-matured and germline, “naïve” NMDAR autoantibodies can pose pathogenic effects and impair NMDAR transmission. Moreover, these autoantibodies show brain regional specificity, exerting different effects in hippocampal versus cortical neurons. While in hippocampus they impair NMDAR currents of excitatory neurons, in cultures from cortex they selectively decrease NMDA currents and synaptic output of inhibitory, but not excitatory, neurons. Consequently, decreased inhibitory drive leads to disinhibition of networks from cortical neurons, bringing them into a hyper-excitable state. This is further associated with lowered levels of crucial pre-synaptic inhibitory proteins, specifically in inhibitory-to-excitatory neuron synapses. Together, these findings deepen our understanding of the pathology of autoimmune encephalitis by showing pathogenic potential of both matured and naïve autoantibodies and providing a novel, cortex specific mechanism of antibody-induced network hyper-excitability. Of note, similar mechanisms of NMDA-mediated cortical disinhibition have been suggested to underlie the etiology of schizophrenia, therefore there is an emerging framework for common mechanisms across neuropsychiatric disorders.

Background: Early sepsis identification can be achieved with the help of effective screening tools and suitable point-of-care biomarkers. With this objective, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) introduced a new screening instrument in 2016 called the quick Sequential Organ Failure Assessment (qSOFA) score. Since the introduction of the qSOFA score, debate has continued over the lack of sensitivity of the score for sepsis recognition in the Emergency Department (ED). The combination of biomarkers of infection like Procalcitonin (PCT) with the qSOFA score might improve the early identification of septic patients in the ED and could be beneficial as a point-of-care biomarker. Main objective: To investigate whether the early measurement of PCT improves the detection of septic patients in an ED population with elevated qSOFA score. Methods: In this large multicentre cohort study, the LIFE-POC study, adult patients presenting with an elevated qSOFA score (≥1) were identified and prospectively recruited at three tertiary care hospital EDs; the Charité - Universitätsmedizin Berlin Campus Mitte and Campus Virchow as well as the University Hospital of Jena. Exclusion criteria were: trauma, acute ST elevation myocardial infarction; pregnancy; suspected stroke and therapy limitation due to short life expectancy. The current analysis included all (n=742) patients from the study sites of the Charité - Universitätsmedizin Berlin. PCT was measured in all enrolled patients upon ED admission. The primary endpoint was sepsis diagnosis within 96 hours after ED admission. The gold standard diagnosis of sepsis was adjudicated according to the sepsis-3 definition by an experts´ panel. Results: Within the first 96 hours, 27.4% (n=202) of the total study population were diagnosed with sepsis. The area under the receiver operating characteristics curve (AUC) for PCT for sepsis prediction was 0.857 (95% CI: 0.83–0.89; p < 0.0001). PCT levels were significantly higher in septic patients (1.15µg/L; interquartile range (IQR): 0.25-5.07) as compared with non-septic patients (0.10µg/L; IQR: 0.06-0.20; p<0.0001). The optimal cut-off value of PCT that achieved the highest accuracy was 0.5µg/L. PCT at this cut-off value had a sensitivity of 63.6% (95%-CI: 56.5-70.2%), a specificity of 89.4% (95%-CI: 86.5-91.9%), a positive predictive value (PPV) of 69.4% (95%-CI: 63.4-74.7%) and a negative predictive value (NPV) of 86.7% (84.4-88.7%). Conclusions: This prospective cohort study showed that PCT, measured in an ED population with elevated qSOFA score, improved early sepsis identification. Based on these results, early measurement of PCT could thus be recommended as an additional and important component of sepsis screening in the ED.

Hintergrund: Die robotergestützte Radiochirurgie (RRS) ermöglicht die präzise Behandlung von kraniellen und extrakraniellen Primärtumoren oder Metastasen mit hohen Einzeldosen. Allerdings können durch Atmung oder Organbewegung verursachte Tumorbewegungen zu Ungenauigkeiten bei der Bestrahlung führen. Daher können Goldmarker (englisch: Fiducial Marker, FM) in den Tumor eingebracht werden, um die Präzision der Bestrahlung weiterhin sicherzustellen. Ziel dieser Studie [1] war es, die potenziellen Komplikationen der FM-Implantationen, die Bewegungsamplitude der Tumoren und etwaige FM-Migrationen auszuwerten. Methodik: Es wurde eine retrospektive Analyse aller Daten von Krebspatient*innen durchgeführt, die in unserem Zentrum zwischen 2011 und 2019 eine FM-Implantation vor der CyberKnife(CK)-Behandlung erhielten. Es wurden deskriptive Patient*innen- und Läsionsmerkmale ausgewertet. Die Evaluation der Komplikationen erfolgte anhand der Richtlinien der Society of Interventional Radiology (SIR). Zudem wurde die radiale Bewegungsamplitude der Tumoren untersucht. Ergebnisse: Insgesamt erhielten 288 Patient*innen eine FM-Implantation zur CK-RRS. Bei 357 Implantationen wurden 725 FM in 350 Tumorläsionen (~50 % jeweils Primärtumore und Metastasen) implantiert, von denen die meisten computertomografisch gestützt implantiert wurden (61,9 %). Die meisten Komplikationen (32,0 %) traten bei Synchrony-getrackten Läsionen auf (62/194 Implantationen), bei den Fiducial-getrackten FM waren es 1,2% (2/163 Implantationen). Insgesamt kam es bei 17,9 % aller Implantationen zu SIR-Komplikationen, davon waren 6,4 % selbstlimitierende Pneumothoraces (SIR A-B), 5,9 % Blutungen und Hämoptysen (SIR A-B) und 5,3 % Pneumothoraces, die eine entsprechende Intervention erforderten (SIR C D). Eine FM-Migration wurde bei 3,6 % der Implantationen beobachtet. Die größten Bewegungsamplituden wurden bei Leberläsionen (20,5 mm, SD=11,0 mm) und Läsionen im Lungenunterlappen (15,4 mm, SD=10,5 mm) gemessen, davon war die größte mediane Bewegungsamplitude von >20 mm bei Läsionen gemessen worden, die mehr als 100,0 mm vom Spinalkanal entfernt waren. Schlussfolgerungen: FM-Implantationen können mit verschiedenen Modalitäten in unterschiedlichen anatomischen Regionen technisch erfolgreich durchgeführt werden. Komplikationen traten fast ausschließlich bei thorakalen Läsionen auf. Pneumothoraces und pulmonale Blutungen waren die häufigsten Komplikationen, waren jedoch selbstlimitierend oder gut behandelbar. FM-Migrationen waren selten. Läsionen im Lungenoberlappen und in den Lymphknoten wiesen jedoch geringere Bewegungsamplituden auf und könnten daher zur Vermeidung potenzieller Komplikationen durch das Xsight® Spine Tracking System bestrahlt werden. Bei allen Leberläsionen und Läsionen des Lungenunterlappens, insbesondere die, die sich >100,0 mm vom Spinalkanal entfernt befinden, hat sich die FM-Platzierung aufgrund ihrer großen medianen Bewegungsamplituden als sehr sinnvoll erwiesen.