TY - JOUR A1 - Wertgen, Andreas G. A1 - Richter, Tobias T1 - Source credibility modulates the validation of implausible information JF - Memory & Cognition N2 - Validation of text information as a general mechanism for detecting inconsistent or false information is an integral part of text comprehension. This study examined how the credibility of the information source affects validation processes. Two experiments investigated combined effects of source credibility and plausibility of information during validation with explicit (ratings) and implicit (reading times) measurements. Participants read short stories with a high-credible versus low-credible person that stated a consistent or inconsistent assertion with general world knowledge. Ratings of plausibility and ratings of source credibility were lower when a credible source stated a world-knowledge inconsistent assertion compared with a low-credible source. Reading times on target sentences and on spillover sentences were slower when a credible source stated an assertion inconsistent with world knowledge compared with a low-credible source, suggesting that source information modulated the validation of implausible information. These results show that source credibility modulates validation and suggest a bidirectional relationship of perceived plausibility and source credibility in the reading process. KW - validation KW - plausibility KW - sourcing KW - credibility KW - text comprehension Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234825 SN - 0090-502X VL - 48 ER - TY - JOUR A1 - Urlaub, Jonas A1 - Kaiser, Reinhard P. A1 - Scherf‐Clavel, Oliver A1 - Bolm, Carsten A1 - Holzgrabe, Ulrike T1 - Investigation of isomerization of dexibuprofen in a ball mill using chiral capillary electrophoresis JF - Electrophoresis N2 - Besides the racemate, the S‐enantiomer of ibuprofen (Ibu) is used for the treatment of inflammation and pain. Since the configurational stability of S‐Ibu in solid state is of interest, it was studied by means of ball milling experiments. For the evaluation of the enantiomeric composition, a chiral CE method was developed and validated according to the ICH guideline Q2(R1). The addition of Mg\(^{2+}\), Ca\(^{2+}\), or Zn\(^{2+}\) ions to the background electrolyte (BGE) was found to improve Ibu enantioresolution. Chiral separation of Ibu enantiomers was achieved on a 60.2 cm (50.0 cm effective length) x 75 μm fused‐silica capillary using a background electrolyte (BGE) composed of 50 mM sodium acetate, 10 mM magnesium acetate tetrahydrate, and 35 mM heptakis‐(2,3,6‐tri‐O‐methyl)‐β‐cyclodextrin (TM‐β‐CD) as chiral selector. The quantification of R‐Ibu in the mixture was performed using the normalization procedure. Linearity was evaluated in the range of 0.68–5.49% R‐Ibu (R\(^{2}\) = 0.999), recovery was found to range between 97 and 103%, the RSD of intra‐ and interday precision below 2.5%, and the limit of quantification for R‐ in S‐Ibu was calculated to be 0.21% (extrapolated) and 0.15% (dilution of racemic ibuprofen), respectively. Isomerization of S‐Ibu was observed under basic conditions by applying long milling times and high milling frequencies. KW - capillary electrophoresis KW - chiral separation KW - Ibuprofen KW - isomerization KW - validation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225852 VL - 42 IS - 17-18 SP - 1790 EP - 1799 ER - TY - JOUR A1 - Timmermans, Wim J. A1 - van der Tol, Christiaan A1 - Timmermans, Joris A1 - Ucer, Murat A1 - Chen, Xuelong A1 - Alonso, Luis A1 - Moreno, Jose A1 - Carrara, Arnaud A1 - Lopez, Ramon A1 - Fernando de la Cruz, Tercero A1 - Corcoles, Horacio L. A1 - de Miguel, Eduardo A1 - Sanchez, Jose A. G. A1 - Perez, Irene A1 - Belen, Perez A1 - Munoz, Juan-Carlos J. A1 - Skokovic, Drazen A1 - Sobrino, Jose A1 - Soria, Guillem A1 - MacArthur, Alasdair A1 - Vescovo, Loris A1 - Reusen, Ils A1 - Andreu, Ana A1 - Burkart, Andreas A1 - Cilia, Chiara A1 - Contreras, Sergio A1 - Corbari, Chiara A1 - Calleja, Javier F. A1 - Guzinski, Radoslaw A1 - Hellmann, Christine A1 - Herrmann, Ittai A1 - Kerr, Gregoire A1 - Lazar, Adina-Laura A1 - Leutner, Benjamin A1 - Mendiguren, Gorka A1 - Nasilowska, Sylwia A1 - Nieto, Hector A1 - Pachego-Labrador, Javier A1 - Pulanekar, Survana A1 - Raj, Rahul A1 - Schikling, Anke A1 - Siegmann, Bastian A1 - von Bueren, Stefanie A1 - Su, Zhongbo (Bob) T1 - An Overview of the Regional Experiments for Land-atmosphere Exchanges 2012 (REFLEX 2012) Campaign JF - Acta Geophysica N2 - The REFLEX 2012 campaign was initiated as part of a training course on the organization of an airborne campaign to support advancement of the understanding of land-atmosphere interaction processes. This article describes the campaign, its objectives and observations, remote as well as in situ. The observations took place at the experimental Las Tiesas farm in an agricultural area in the south of Spain. During the period of ten days, measurements were made to capture the main processes controlling the local and regional land-atmosphere exchanges. Apart from multi-temporal, multi-directional and multi-spatial space-borne and airborne observations, measurements of the local meteorology, energy fluxes, soil temperature profiles, soil moisture profiles, surface temperature, canopy structure as well as leaf-level measurements were carried out. Additional thermo-dynamical monitoring took place at selected sites. After presenting the different types of measurements, some examples are given to illustrate the potential of the observations made. KW - multi scale heterogeneity KW - quantitative remote sensing KW - remote KW - evapotranspiration KW - validation KW - issues KW - energy KW - models KW - water KW - flux KW - land-atmosphere interaction KW - turbulence KW - calibration and validation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136491 VL - 63 IS - 6 ER - TY - JOUR A1 - Szymski, Dominik A1 - Aschenbach, Leonard A1 - Krutsch, Volker A1 - Alt, Volker A1 - Meffert, Rainer A1 - Krutsch, Werner A1 - Fehske, Kai T1 - Injury epidemiology in men's professional team sports: is media analysis helpful? JF - Archives of Orthopaedic and Trauma Surgery N2 - Introduction Epidemiological injury surveillance in professional sports is often based on online media analysis in order to collect necessary data. However, the validation of this study protocol is lacking. Therefore, this study aimed to identify the validity of injury surveillance in men's professional team sports based on media reports. Methods In a retrospective cohort study, the validity of media-data-relating injuries was investigated in participating teams of the highest two German divisions in men's professional basketball (BB) and handball (HB) in the season 2018/2019. Injury protocols completed by the team physicians were compared to those of sports media injury reports. Results The study population was composed of 133 athletes (54 BB and 79 HB). Of 343 injuries reported by the team physicians, 151 (44%) could be identified by means of sports media reports. Severe injuries (n = 75, 72%) were reported more likely in sports media compared to less severe injuries (n = 76, 32%, p < 0.00001). Odds ratio (OR) was 5.33 (95% CI 3.22-8.82). No differences regarding injury reporting could be seen between the two team sports. Conclusion For severe injuries, media analysis may be a sufficient method for data collection in popular men's professional ball sports. An underestimation of true injury prevalence lies within the range of previous reported investigations concerning the validation of injury surveillance methods. Non-severe injuries could not be verified via media analysis in professional handball and basketball. KW - severe injury KW - professional KW - injury KW - media-based KW - evidence KW - validation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266690 SN - 1434-3916 VL - 141 IS - 4 ER - TY - THES A1 - Stiefl, Nikolaus Johannes T1 - Entwicklung, Validierung und Anwendung einer neuen translations- und rotationsinvarianten 3D-QSAR-Methodik T1 - Development, validation and application of a novel translational and rotational invariant 3D-QSAR-technique N2 - Die vorliegende Arbeit beschreibt die Entwicklung und Validierung der neuartigen 3D-QSAR Technik Mapping Property Distributions of Molecular Surfaces (MaP). Die Methode ist gegenüber Translation und Rotation invariant, d. h. eine Überlagerung der Moleküle, wie sie zum Beispiel für CoMFA nötig ist, entfällt. MaP basiert auf der Charakterisierung der Moleküle nach ihrer Fähigkeit Wasserstoffbrücken auszubilden, sowie ihrer Hydrophobie / Hydrophilie. Dabei werden jedoch nicht nur die atombasierten Eigenschaften, sondern auch die Oberflächeneigenschaften der Moleküle zur Charakterisierung genutzt. Diese Loslösung von der chemischen Struktur der Verbindungen erlaubt es, die für die Ligand-Rezeptor-Interaktion (bzw. Substrat-Enzym-Interaktion) wichtigen Grenzflächen zu charakterisieren. Die wichtigsten methodischen Elemente der MaP-Technik, sowie die erhaltenen Ergebnisse der untersuchten Datensätze sollen hier noch einmal in kurzer Form dargestellt werden: Die theoretische Basis des MaP-Deskriptors bilden so genannte Radialverteilungsfunktionen. Mittels dieser selektiven Distanz-Zählstatistiken (SDZS) können sowohl die Form der Moleküle, als auch die Verteilung der einzelnen Oberflächeneigenschaften zueinander, in einem einzelnen Vektor beschrieben werden. Die MaP-Variablen kodieren dabei die Größe (absolute Anzahl an Einträgen), sowie die Orientierung (Distanz) verschiedener Oberflächeneigenschaften zueinander. Die Grundlage der Oberflächeneigenschaften stellen atomare Charakteristika wie das Wasserstoffbrückenbindungspotential sowie die atomare Hydrophobie / Hydrophilie dar. Diese Eigenschaften werden den Atomen mittels einfacher Regeln (Wasserstoffbrücken) bzw. einer Substruktursuche (Hydrophobie / Hydrophilie) zugewiesen und dann auf die Oberfläche projiziert. Um die mathematische Transformation der Rohdaten in die SDZS zu ermöglichen, muss die Moleküloberfläche durch gleichverteilte Oberflächenpunkte diskretisiert werden. Da diese Anforderung von gebräuchlichen analytischen Oberflächenberechnungsmethoden, wie zum Beispiel dem GEPOL-Algorithmus, nicht erfüllt wird, wurde der GEPOL-Algorithmus so modifiziert, dass ein Zusammenhang zwischen der Oberflächengröße und der Anzahl an Oberflächenpunkten gegeben ist. Da es aufgrund dieser Diskretisierung jedoch zum Verlust der Invarianz gegenüber Translation und Rotation kommen kann, wurde der Bestimmung der Moleküloberflächen eine spezielle Technik zur Ausrichtung der Moleküle im Koordinatensystem (Kanonisierung) vorgeschaltet. Dadurch wird ein identischer MaP-Deskriptor unabhängig von der Position der Moleküle im Raum garantiert. Um den Diskretisierungsfehler der Oberflächenbestimmung weiter zu reduzieren, wurde eine unscharfe Zählweise bei der Berechnung des MaP-Deskriptors adaptiert. Diese erlaubt es, Einträge die an den Kategoriengrenzen des MaP-Vektors liegen, auf die beiden nächsten Zentren zu verteilen. Dadurch werden kleine Schwankungen in den Distanzwerten kompensiert. Zur Modellbildung werden die infomativsten Variablen (MIV) mit Hilfe der ‚Reverse-Elimination-Method’-Tabu-Suche (REM-TS) identifiziert. Die so erhaltenen MIV’s können auf die Moleküle zurückprojiziert werden, was die Interpretation der berechneten Modelle stark vereinfacht. Zur Visualisierung der Ergebnisse können die Variablen unter Zuhilfenahme der unscharfen Zählweise nochmals gefiltert werden, um die Interpretation hoch besetzter Variablen zu vereinfachen. Da es aufgrund der Variablenselektion zu einer Zufallskorrelation in der Modellbildung kommen kann, werden die erhaltenen Modelle einer strengen Validierung unterzogen. Dabei werden neben der sehr anspruchsvollen ‚Lass-mehrere-Objekte-heraus’-Kreuzvalidierung als Gütefunktion der Variablenselektion auch ein Permutationstest der Modelle sowie eine Testdatenvorhersage angewandt. Durchläuft ein Modell all diese Validierungsschritte erfolgreich, so ist die Wahrscheinlichkeit einer Zufallskorrelation sehr gering. Um die Anwendbarkeit und die Güte des MaP-Deskriptors zu überprüfen, wurden verschiedene Datensätze untersucht. Diese können entsprechend ihrer Zielsetzung in unterschiedliche Gebiete aufgeteilt werden. Der erste Datensatz (Steroide) wird in der QSAR häufig als Vergleichsdatensatz eingesetzt. Ein weiterer Datensatz umfasst strukturell sehr heterogene Substanzen, die ein augenirritierendes Potential aufweisen (ECETOC). Inhibitoren des EndothelinA-Rezeptors (ETA) bildeten einen weiteren Datensatz. Die enthaltenen Moleküle sind im Datenraum stark in Untergruppen geklustert. Weiterhin wurden konformell sehr flexible, allostere Modulatoren des muskarinischen M2-Rezeptors (M2-Modulatoren) untersucht. Dieser Datensatz diente aufgrund der hohen Flexibilität der Moleküle auch zur Überprüfung der konformellen Abhängigkeit der Methode. Die Erweiterung des Standardparametersatzes wurde mit Hilfe von Naphthylisochinolin-Derivaten (NIQ) untersucht, die eine Aktivität gegen Plasmodium falciparum aufweisen. Ein weiterer Datensatz, deren Moleküle die Öffnungswahrscheinlickeit ATP-abhängiger Kalium-Kanäle erhöht (KCO), wurde herangezogen, um den Vorteil der mathematischen Transformation der MaP-Technik gegenüber der von GRIND benutzten MACC-2-Transformation herauszustellen. Inhibitoren des nicotinischen Acetylcholin-Rezeptors (CAR) bildeten einen weiteren Datensatz für den bisher keine QSAR-Studie vorlag. Zur strukturbasierten Validierung der Methode wurden Inhibitoren der Acetylcholinesterase (APZ-Datensatz) untersucht. Hierbei wurde geprüft, ob die aus der Kristallstruktur der Acetylcholinesterase wichtigen Ligand-Enzym-Wechselwirkungen durch MaP beschrieben werden. Die Ergebnisse dieser Untersuchungen lassen folgenden Rückschlüsse zu: Im Vergleich mit bereits etablierten 3D-QSAR-Techniken wie CoMFA, CoMSIA oder GRID/PLS führt die MaP-Technik zu vergleichbar guten Modellen (Steroide, ETA, M2-Modulatoren). Durch die Loslösung vom strukturellen Grundgerüst der Substanzen können auch strukturell diverse Datensätze gut modelliert und die relevante Information extrahiert werden (ECETOC). Dies ist mit Deskriptoren, die eine gemeinsame Ausrichtung der Moleküle benötigen (z.B. CoMFA), oft nicht möglich. Auch Datensätze, deren Objekte geklustert vorliegen, können mittels MaP gut modelliert werden. MaP ist dabei in der Lage die relevante Information sowohl zwischen, als auch innerhalb der einzelnen Gruppen zu extrahieren (ETA). Auch für Datensätze, deren Moleküle eine sehr hohe Flexibilität aufweisen, ist es möglich mit MaP gute Modelle zu erhalten (M2-Modulatoren, APZ). Hierbei ist es jedoch wichtig, zu beachten, dass MaP als 3D-QSAR-Technik gegenüber der Konformation der Moleküle nicht invariant ist. Bei der Anwendung der Methode zeigte sich jedoch, dass kleine konformelle Änderungen der Verbindungen oft einen sehr geringen Einfluss auf die Ergebnisse der Methode haben (M2-Modulatoren, APZ). Bei der Untersuchung der NIQ-Daten zeigte sich, dass unter Verwendung der MaP-Standardparameter bereits die relevanten Eigenschaften der Moleküle charakterisiert werden können. Allerdings führte eine Erweiterung dieser Parameter zu einer Vereinfachung der Interpretation der Ergebnisse. Hierbei ist jedoch darauf zu achten, dass die Modellvalidierung strikt eingehalten werden muss. Der Vorteil der mathematischen Transformation der Rohdaten (SDZS) gegenüber der von GRIND verwendeten MACC-2 Transformation konnte mittels der KCO-Daten aufgezeigt werden. Das erhaltene Modell spiegelte sehr schön die bereits bekannten Struktur-Wirkungs-Beziehungen wider. Leider ist die publizierte Datenlage in diesem Falle noch nicht ausreichend, um einen abschließenden Vergleich der beiden konkurrierenden Techniken zu ermöglichen. Beim CAR-Datensatz war MaP in der Lage, neben der bekannten, relevanten strukturellen Allylalkoholgruppe ein weiteres strukturelles Merkmal zu identifizieren. Abschließend konnte gezeigt werden, dass MaP in der Lage ist, die für die Wechselwirkung zwischen Acetylcholinesterase und Ligand wichtigen Interaktionsstellen und Charakteristika eindeutig zu identifizieren (APZ-Datensatz). Diese Eigenschaften wurden zur besseren Interpretation der Ergebnisse in die Bindetasche projiziert. Die Ergebnisse dieser Untersuchungen zeigen, dass die entwickelte Technik ein weites Anwendungsspektrum besitzt, leicht zu interpretieren ist und sich dabei durch ihre Robustheit auszeichnet. Vor allem aber liefert MaP aussagekräftige 3D-QSAR-Modelle. Bei der MaP-Methode handelt es sich jedoch nicht nur um einen neuen Moleküldeskriptor, sondern um eine Kombination aus Deskriptor, mathematischer Modellierung, Modellvalidierung und Modellvisualisierung. Obwohl MaP in Hinsicht auf Modellqualität und Modellinterpretierbarkeit Techniken wie zum Beispiel CoMFA in nichts nachsteht, sind aufgrund der einfachen und trotzdem hocheffizienten mathematischen Grundlagen folgende Erweiterungen denkbar: (1) als dreidimensionale Technik ist MaP von den Ausgangskonformationen der Moleküle abhängig. Findet sich im untersuchten Datensatz ein starres Molekül (M2-Modulatoren) oder aber sind Informationen über einen möglichen Bindungsmodus vorhanden, so können diese Konformationen relativ leicht erhalten werden. Da dies jedoch nicht immer der Fall ist, ist eine Erweiterung der Technik in die vierte Dimension (konformelle Flexibilität) wichtig. Dass dies prinzipiell möglich ist, konnte Hopfinger bereits zeigen. Da die mathematische Grundlage der MaP-Technik sehr einfach ist, sollte diese Art der Erweiterung in die vierte Dimension auch für MaP möglich sein. (2) Momentan ist der MaP-Deskriptor auf Verknüpfungen zwischen zwei Oberflächenpunkten beschränkt. Diese Einschränkung könnte dazu führen, dass Inkremente ein und derselben Variablen aus verschiedenen Teilen des Moleküls stammen. Wenn nur ein Teil davon Eigenschaften kodieren, die relevant für die Ligand-Rezeptor-Interaktion sind, könnte dies theoretisch zu Inkonsistenzen in dem resultierenden Modell führen. Bei den bislang untersuchten Datensätzen konnte dies noch nicht beobachtet werden. Eine mögliche Erklärung hierfür ist, dass die MaP-Variablen zu einem gewissen Grad redundant sind, d.h. das selbe Phänomen kann durch verschiedene Variablen beschrieben werden. Von diesen redundanten Variablen werden durch die strenge Validierung diejenigen vom Suchalgorithmus der Variablenselektion identifiziert, die am wenigsten mit anderen Eigenschaften vermengt sind. Prinzipiell ist eine solche Problematik jedoch denkbar. Um die Wahrscheinlichkeit eines derartigen Phänomens weiter zu reduzieren, sollten die bisher genutzten Zweipunktverknüpfungen auf drei Punkte erweitert werden. N2 - This thesis describes the development and validation of the novel 3D-QSAR technique Mapping Property Distributions of Molecular Surfaces (MaP). The method is invariant to translation and rotation. Hence a superimposition of the molecules prior to analysis is not necessary as opposed to field-based methods such as CoMFA. MaP characterises molecules with respect to their hydrogen bonding capabilities and their hydrophilicity / hydrophobicity. However, in contrast to atom-based approaches, MaP uses molecular surface properties for this description of the noncovalent binding forces relevant for receptor-ligand interaction. This property-based approach allows to describe the important interactions which form between the surfaces of receptor and ligand. In the following, the theoretical fundamentals of the MaP technique as well as the most important applications will be summarised. Radial distribution functions form the basis of the MaP descriptor. These are implemented as selective distance count statistics (SDCS) and allow the description of molecular shape as well as the distribution of different surface properties with a single vector. MaP variables themselves inherently encode the size of surface patches with particular properties in terms of the absolute number of counts and their relative position by the distance which separates the two properties under scrutiny. Surface properties are categorised based on atomic characteristics like the hydrogen bonding potential and the atomic hydrophobicity / hydrophilicity. Firstly, the atomic features are assigned by simple rules (hydrogen bonding) and substructure search routines (hydrophilicity / hydrophobicity), respectively. In a second step, they are projected onto the molecular surface. In order to make the mathematical transformation of the raw data into the SDCS possible, the molecular surface needs to be discretised by equally distributed surface points. Standard surface calculation algorithms like the GEPOL algorithm do not fulfil the requirement of equally distributed surface points. Consequently, the GEPOL algorithm was modified as to ensure a linear correlation between surface size and number of surface points. Unfortunately, this discretisation step bears the potential risk, that the translational and rotational invariance of the descriptor is lost. Hence, to avoid this undesirable feature of the descriptor, the molecules are canonicalised. When canonicalising a molecule its centre of mass is first translated into the origin of the coordinate system. Next a rotation matrix is computed which orients the molecules along their principal moments of inertia. These two steps render the surface (and thus the descriptor) translationally and rotationally invariant. To further reduce the discretisation error, the concept of fuzzy counts was introduced for the calculation of the MaP descriptor. Fuzzy counting means, that the two bins closest to the respective distance are incremented proportionally. That way, minor fluctuations due to the surface discretisation are compensated for. Identification of the most important variables (MIV) by variable selection is one of the key data modelling steps in the MaP procedure. For this task MaP employs a reverse-elemination-method tabu-search (REM-TS). For model interpretation these MIVs are back-projected onto the molecules. To further facilitate interpretation of the graphical output, fuzzy counts can be used to filter densely populated variables. One of the major drawbacks of variable selection in data modelling is the risk of chance correlations. Consequently, a strict validation procedure is applied to the MaP models. Apart from using the highly discriminative leave-multiple-out cross-validation as objective function in variable selection, permutation testing as well as test set prediction is applied. If a model passes all tests (validation steps), the risk of a chance correlation is very low. To validate the MaP descriptor and the quality of the models obtained with it, different data sets were investigated. Depending on the problem investigated, these data sets reflect different aspects of research. The first data set comprises structurally rigid compounds (steroids). It is frequently used as a ‘benchmark’ data set for novel QSAR techniques. The molecules of the second data set are structurally very heterogenous compounds with an eye-irritating potential (ECETOC). Members of the third data set include inhibitors of the endothelin-A receptor, that are highly clustered in data space (ETA). Another set of compounds comprises conformationally very flexible allosteric modulators of the muscarinic M2 receptors (M2-modulators). Due to this high flexibility of the compounds the data set is also used to validate the conformational dependence of the method. The NIQ data set which comprises naphthylisoquinolin derivatives with an antimalarial activity against Plasmodium falciparum was used to investigate the extension of the standard parameter set. To compare the mathematical transformation used by MaP with to the one used by GRIND (MACC-2 transformation), a set of compounds which increase the opening probability of ATP dependent potassium channels (KCO) was used. Another data set consisted of inhibitors of the nicotinic acetylcholine receptor (CAR), for which hitherto no QSAR study was performed. The last data set presented (APZ) was utilised to carry out a structure-based validation of the MaP method. Here it was examined, if the important ligand-enzyme interactions can be correctly identified by MaP. For this task, inhibitors of the actylcholine esterase (AChE) were used since a broad knowledge of the actual interactions are known from the different crystal structures available for AChE. From the obtained results the following conclusions can be drawn. When compared to already established 3D-QSAR techniques like CoMFA, CoMSIA, or GRID/PLS the models obtained with the MaP technique are of similar quality (steroids, ETA, M2-modulators). With the pursued property-based approach, even data sets comprising structurally highly diverse compounds can easily be modelled and the relevant information can be extracted (ECETOC). This is in contrast to techniques that need a superpositioning step of the molecules under study (e.g. CoMFA), for which these kind of data sets are hardly accessible. Furthermore, data sets with highly clustered objects can be modelled with MaP. Here MaP is able to extract not only intercluster, but also relevant intracluster information (ETA). Data sets with conformationally highly flexible molecules can also be modelled with good results employing MaP. However, it is important to keep in mind, that MaP, as every 3D-QSAR technique, is still sensitive to the molecular conformation. Nevertheless, it was found, that minor conformational changes of the molecules under study have a low impact on the results obtained with MaP (M2-modulators, APZ). Studying the NIQ data set it was found, that when applying the default parameters, MaP is already able to characterise the most relevant properties of the molecules under study. Yet, an extension of this parameter set resulted in a simplified interpretation of the obtained models. A necessity when using such an extension, however, is the strict model validation applied within MaP. The advantage of the mathematical transformation of the raw data using SDCS (MaP) over the MACC-2 transformation (GRIND) could be highlighted with the KCO data. Here, the model obtained was in full agreement with the available structure–activity relationships. Unfortunately, a complete comparison of the two techniques is currently not possible owing to comparatively few papers published. For the CAR data set, beside the important allyl alcohol group that was already known to be relevant for biological activity, it was possible to identify an additional important structural feature of the compounds under scrutiny. Finally, MaP is able to identify the relevant features as well as the interaction sites between the AChE and the respective ligand (APZ). To make the latter results easily understandable, a projection into the binding pocket of the enzyme was performed. The findings of these studies allow the conclusion, that MaP is widely applicable, easy to interpret and very robust. Most notably however, MaP produces meaningful and sensible 3D-QSAR models. Additionally, it should be emphasised, that MaP is not just yet another molecular descriptor, but a combination of molecular descriptor, mathematical modelling procedure, model validation and model visualisation. Even though MaP is comparable to standard 3D-QSAR techniques like CoMFA in terms of model quality and model interpretability, the following extension are conceivable owing to MaP’s simple but highly efficient fundamental mathematical principles: (1) As a three-dimensional technique, MaP is dependent on the molecular conformations employed. If the data set includes a rigid molecule (M2-modulators) or if information on a possible binding mode of the molecules is available, these conformations can be obtained comparatively easy. However, since these prerequisites are not always available, an extension of MaP to the fourth dimension (conformational flexibility) is important. Hopfinger showed, that in principle such an extension is possible. With the simple mathematical fundamentals of MaP, making use of this fourth dimension should be an achievable development step. (2) Currently, MaP is restricted to connections between two surface points. A numerical artefact of this constraint is, that the same variable might be incremented by surface areas of completely different parts of the molecule. Theoretically, if only a part of these encode properties that are relevant for the ligand-receptor interactions, this could lead to inconsistencies of the resulting model. One explanation why this was not the case thus far is, that MaP-variables are redundant up to a certain degree. Put differently, the same phenomena is explained by different variables. With the strict validation criteria applied within MaP, the search algorithm currently seems to select those variables, which exhibit the lowest confounding with others. Nevertheless, the aforementioned difficulties are possible. To further reduce the probability of such a situation, the two-point approach should extended to three points. KW - QSAR KW - translations- und rotationsinvariant KW - TRI KW - Chemometrie KW - Validierung KW - QSAR KW - translationally and rotationally invariant KW - TRI KW - chemometrics KW - validation Y1 - 2004 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-8230 ER - TY - JOUR A1 - Steinmann, Diana A1 - Paelecke-Habermann, Yvonne A1 - Geinitz, Hans A1 - Aschoff, Raimund A1 - Bayerl, Anja A1 - Bölling, Tobias A1 - Bosch, Elisabeth A1 - Bruns, Frank A1 - Eichenseder-Seiss, Ute A1 - Gerstein, Johanna A1 - Gharbi, Nadine A1 - Hagg, Juliane A1 - Hipp, Matthias A1 - Kleff, Irmgard A1 - Müller, Axel A1 - Schäfer, Christof A1 - Schleicher, Ursula A1 - Sehlen, Susanne A1 - Theodorou, Marilena A1 - Wypior, Hans-Joachim A1 - Zehentmayr, Franz A1 - van Oorschot, Birgitt A1 - Vordermark, Dirk T1 - Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases JF - BMC Cancer N2 - Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. Results: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information. KW - breast cancer KW - brain tumours KW - survival KW - validation KW - symptoms KW - EORTC-QLQ-C15-PAL KW - EORTC-BN20 KW - whole-brain radiotherapy KW - partitioning analysis RPA KW - cancer patients KW - lung cancer KW - prognostic index KW - radiation oncology KW - clinical trials Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135254 VL - 12 IS - 283 ER - TY - THES A1 - Steinhauer, Sven T1 - Erhebung pharmakokinetischer Daten von Cisaprid, SC-72393, Haloperidol, Linezolid, Methotrexat und Ketoprofen nach Methodenentwicklung und Validierung durch LC-MS/MS-Detektion T1 - Enquiry of pharmacokinetic parameters of Cisapride, SC-72393, Haloperidol, Linezolid, Methotrexat and Ketoprofen after method development and validation by LC-MS/MS N2 - Zur Bestimmung von geringen Wirkstoffkonzentrationen in biologischen, speziell human-biologischen Matrizes wie Blut, Urin oder Mikrodialysat bedarf es einer Analysentechnik, die den Wirkstoff mit einem Höchstmaß an Selektivität, Spezifität und Präzision bestimmen kann. Daneben muß die verwendetete Methode eine hohe Geschwindigkeit aufweisen und sehr robust sein, da bei der heutigen marktwirtschaftlichen Lage Analysensysteme eine optimale Auslastung erfahren müssen. Aus diesem Grund ist der Umbau oder die Umstellung der Methode von einem zum anderen Wirkstoff ohne nennenswerten Zeitverlust ein maßgeblicher Faktor. Als Technik, die diese Anforderungen optimal erfüllt, hat sich in den letzten Jahren die LC-MS/MS-Technik etabliert. Sie ist den bislang überwiegenden Methoden, wie GC-MS-Techniken oder HPLC-UV-Detektion bzw. Fluoreszenztechniken in Bezug auf die oben genannten Parameter deutlich überlegen. In der vorliegenden Arbeit wurden für die Wirkstoffe Cisaprid, SC-72393, Haloperidol, Linezolid, Methotrexat und Ketoprofen LC-MS/MS-Methoden entwickelt oder via unabhängiger Laborvalidierung auf die lokalen Gegebenheiten transferiert und zur Bestimmung pharmakokinetischer Parameter zur Anwendung gebracht. Ziel der Methodenentwicklung war es die hohe Selektivität und Empfindlichkeit des Detektors zu nutzten, um bei geringen Probenvolumina eine Bestimmungsgrenze zu erreichen, die es ermöglichte ausreichend viele Meßwerte zu bestimmen, um die pharmakokinetischen Parameter der Wirkstoffe zu berechnen. Zusätzlich wurde eine Maximierung des Probendurchsatzes und eine Minimierung des personellen und materiellen Aufwandes angestrebt ohne dabei einen Qualitätsverlust der Methode zu erleiden. Eine gelungene Methoden-entwicklung bedurfte daher der Optimierung der Probenaufarbeitung, die sich neben den chemisch-physikalischen Eigenschaften des Wirkstoffes hauptsächlich an der Menge der zur Verfügung stehenden Probe orientierte. Das chromato-graphische System hingegen hing weitestgehend von den chemischen Eigenschaften des Analyten und von den massenspektroskopischen Bedingungen ab, die verdampfbare Puffer im Fließmittel erforderten. Diese drei zu optimierenden Teilbereiche, die miteinander interagieren, wurden jeweils sorgsam aufeinander abgestimmt, um eine Methode zu entwickeln, die die zu erwartenden Wirkstoffkonzentrationen in der jeweiligen Matrix sicher und robust bis hin zum Quantifizierungslimit bestimmen konnte. N2 - In order to quantify low drug concentrations in biological, specifically human matrices as blood, urine or microdialysate it is indispensable to use a technique, that is able to evaluate the drug with a maximum of selectivity, specifity and precision. In addition the used method needs to be fast and robust to meet todays economical requirements. For this reason the used equipment has to be exchangeable within the used methods without any time interuptions worth mentioning. The LC-MS/MS-technique, which has been established as routine technic over the last decade fulfils these requirements. It is superior with regards to selectivity, specifity and precision over methods such as GC-MS or HPLC with UV- or fluorescense-detection. In this thesis method development, validation or independent laboratory validation was done with LC-MS/MS on Cisapride, SC-72393, Haloperidol, Linezolid, Methotrexat and Ketoprofen to determine their concentrations and to calculate pharmakokinetic parameters. The objective of the method development was to use the high selectivity and sensetivity of the detector to reach a low quantification limit with the limited specimen volumes given. Besides that a maximum throughput of specimens with a minimum of personal expense was aspired without decreasing the quality of the produced data by taking into account the phamakokinetic parameters to be determined. Therefore an optimum of the work-up procedure as well as the chromatographic and the mass spectrometric conditions has to be developed for the individual drugs with their physicochemical properties. Limitations were frequently given by the availability of the specimen volume. Those three parts, which interact with each other were carefully coordinated to develop a method that quantifies the specific drug concentrations in the individual matrix with good sensitivity and robustness down to the limit of quantification. KW - Wirkstoff KW - Pharmakokinetik KW - LC-MS KW - Pharmakokinetik KW - Validierung KW - LC-MS/MS KW - Cisaprid KW - Linezolid KW - pharmacokinetic KW - validation KW - LC-MS/MS KW - Cisapride KW - Linezolid Y1 - 2002 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-5803 ER - TY - JOUR A1 - Scharbatke, Eva C. A1 - Behrens, Frank A1 - Schmalzing, Marc A1 - Koehm, Michaela A1 - Greger, Gerd A1 - Gnann, Holger A1 - Burkhardt, Harald A1 - Tony, Hans-Peter T1 - Association of improvement in pain with therapeutic response as determined by individual improvement criteria in patients with rheumatoid arthritis JF - Arthritis Care & Research N2 - Objective To use statistical methods to establish a threshold for individual response in patient-reported outcomes (PROs) in patients with rheumatoid arthritis. Methods We used an analysis of variance model in patients on stable therapy (discovery cohort) to establish critical differences (d(crit)) for the minimum change associated with a significant individual patient response (beyond normal variation) in the PRO measures of pain (0-10), fatigue (0-10), and function (Funktionsfragebogen Hannover questionnaire; 0-100). We then evaluated PRO responses in patients initiating adalimumab in a noninterventional study (treatment cohort). Results In the discovery cohort (n=700), PROs showed excellent long-term retest reliability. The minimum change that exceeded random fluctuation was conservatively determined to be 3 points for pain, 4 points for fatigue, and 16 points for function. In the treatment cohort (n=2,788), 1,483 patients (53.2%) achieved a significant individual therapeutic response as assessed by Disease Activity Score in 28 joints (DAS28)-d(crit) (1.8 points) after 12 months of adalimumab treatment; 68.5% of patients with a DAS28-d(crit) response achieved a significant improvement in pain, whereas approximately 40% achieved significant improvements in fatigue or function. Significant improvements in all 3 PROs occurred in 22.7% of patients; 22.8% did not have any significant PRO responses. In contrast, significant improvements in all 3 PROs occurred in only 4.4% of 1,305 patients who did not achieve a DAS28-d(crit) response at month 12, and 59.1% did not achieve any significant PRO responses. Conclusion The establishment of critical differences in PROs distinguishes true responses from random variation and provides insights into appropriate patient management. KW - health-assessment questionnaire KW - minimally important difference KW - disease-activity score KW - reported outcomes KW - clinical-practice KW - fatigue KW - care KW - discordance KW - validation KW - physicians Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186817 VL - 68 IS - 11 ER - TY - JOUR A1 - Samimi, C. A1 - Fink, A. H. A1 - Paeth, H. T1 - The 2007 flood in the Sahel: causes, characteristics and its presentation in the media and FEWS NET JF - Natural Hazards and Earth System Sciences N2 - During the rainy season in 2007, reports about exceptional rains and floodings in the Sahel were published in the media, especially in August and September. Institutions and organizations like the World Food Programme (WFP) and FEWS NET put the events on the agenda and released alerts and requested help. The partly controversial picture was that most of the Sahel faced a crisis caused by widespread floodings. Our study shows that the rainy season in 2007 was exceptional with regard to rainfall amount and return periods. In many areas the event had a return period between 1 and 50 yr with high spatial heterogeneity, with the exception of the Upper Volta basin, which yielded return periods of up to 1200 yr. Despite the strong rainfall, the interpretation of satellite images show that the floods were mainly confined to lakes and river beds. However, the study also proves the difficulties in assessing the meteorological processes and the demarcation of flooded areas in satellite images without ground truthing. These facts and the somewhat vague and controversial reports in the media and FEWS NET demonstrate that it is crucial to thoroughly analyze such events at a regional and local scale involving the local population. KW - prediction KW - satellite rainfall products KW - tropical North-Africa KW - West-Africa KW - climate change KW - summer rainfall KW - variability KW - SST KW - teleconnection KW - validation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131790 VL - 12 IS - 2 SP - 313 EP - 325 ER - TY - JOUR A1 - Rodrigues, Johannes A1 - Ulrich, Natalie A1 - Mussel, Patrick A1 - Carlo, Gustavo A1 - Hewig, Johannes T1 - Measuring prosocial tendencies in Germany: sources of validity and reliablity of the revised prosocial tendency measure JF - Frontiers in Psychology N2 - The prosocial tendencies measure (PTM; Carlo and Randall, 2002) is a widely used measurement for prosocial tendencies in English speaking participants. This instrument distinguishes between six different types of prosocial tendencies that partly share some common basis, but also can be opposed to each other. To examine these constructs in Germany, a study with 1067 participants was conducted. The study investigated the structure of this German version of the PTM-R via exploratory factor analysis, confirmatory factor analysis, correlations with similar constructs in subsamples as well as via measurement invariance test concerning the original English version. The German translation showed a similar factor structure to the English version in exploratory factor analysis and in confirmatory factor analysis. Measurement invariance was found between the English and German language versions of the PTM and support for the proposed six-factor structure (altruistic, anonymous, compliant, dire, emotional and public prosocial behavior) was also found in confirmatory factor analysis. Furthermore, the expected interrelations of these factors of prosocial behavior tendencies were obtained. Finally, correlations of the prosocial behavior tendencies with validating constructs and behaviors were found. Thus, the findings stress the importance of seeing prosocial behavior not as a single dimension construct, but as a factored construct which now can also be assessed in German speaking participants. KW - measurement invariance KW - prosocial tendency measure KW - prosocial behavior KW - altruism KW - validation KW - German translation Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159351 VL - 8 ER -