TY - JOUR A1 - Reiners, Philipp A1 - Asam, Sarah A1 - Frey, Corinne A1 - Holzwarth, Stefanie A1 - Bachmann, Martin A1 - Sobrino, Jose A1 - Göttsche, Frank-M. A1 - Bendix, Jörg A1 - Kuenzer, Claudia T1 - Validation of AVHRR Land Surface Temperature with MODIS and in situ LST — a TIMELINE thematic processor JF - Remote Sensing N2 - Land Surface Temperature (LST) is an important parameter for tracing the impact of changing climatic conditions on our environment. Describing the interface between long- and shortwave radiation fluxes, as well as between turbulent heat fluxes and the ground heat flux, LST plays a crucial role in the global heat balance. Satellite-derived LST is an indispensable tool for monitoring these changes consistently over large areas and for long time periods. Data from the AVHRR (Advanced Very High-Resolution Radiometer) sensors have been available since the early 1980s. In the TIMELINE project, LST is derived for the entire operating period of AVHRR sensors over Europe at a 1 km spatial resolution. In this study, we present the validation results for the TIMELINE AVHRR daytime LST. The validation approach consists of an assessment of the temporal consistency of the AVHRR LST time series, an inter-comparison between AVHRR LST and in situ LST, and a comparison of the AVHRR LST product with concurrent MODIS (Moderate Resolution Imaging Spectroradiometer) LST. The results indicate the successful derivation of stable LST time series from multi-decadal AVHRR data. The validation results were investigated regarding different LST, TCWV and VA, as well as land cover classes. The comparisons between the TIMELINE LST product and the reference datasets show seasonal and land cover-related patterns. The LST level was found to be the most determinative factor of the error. On average, an absolute deviation of the AVHRR LST by 1.83 K from in situ LST, as well as a difference of 2.34 K from the MODIS product, was observed. KW - Land Surface Temperature KW - AVHRR KW - MODIS KW - time series KW - Europe KW - validation KW - TIMELINE Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246051 SN - 2072-4292 VL - 13 IS - 17 ER - TY - JOUR A1 - Kuhn, Joachim A1 - Gripp, Tatjana A1 - Flieder, Tobias A1 - Dittrich, Marcus A1 - Hendig, Doris A1 - Busse, Jessica A1 - Knabbe, Cornelius A1 - Birschmann, Ingvild T1 - UPLC-MRM Mass Spectrometry Method for Measurement of the Coagulation Inhibitors Dabigatran and Rivaroxaban in Human Plasma and Its Comparison with Functional Assays JF - PLOS ONE N2 - Introduction The fast, precise, and accurate measurement of the new generation of oral anticoagulants such as dabigatran and rivaroxaban in patients' plasma my provide important information in different clinical circumstances such as in the case of suspicion of overdose, when patients switch from existing oral anticoagulant, in patients with hepatic or renal impairment, by concomitant use of interaction drugs, or to assess anticoagulant concentration in patients' blood before major surgery. Methods Here, we describe a quick and precise method to measure the coagulation inhibitors dabigatran and rivaroxaban using ultra-performance liquid chromatography electrospray ionization-tandem mass spectrometry in multiple reactions monitoring (MRM) mode (UPLC-MRM MS). Internal standards (ISs) were added to the sample and after protein precipitation; the sample was separated on a reverse phase column. After ionization of the analytes the ions were detected using electrospray ionization-tandem mass spectrometry. Run time was 2.5 minutes per injection. Ion suppression was characterized by means of post-column infusion. Results The calibration curves of dabigatran and rivaroxaban were linear over the working range between 0.8 and 800 mu g/L (r > 0.99). Limits of detection (LOD) in the plasma matrix were 0.21 mu g/L for dabigatran and 0.34 mu g/L for rivaroxaban, and lower limits of quantification (LLOQ) in the plasma matrix were 0.46 mu g/L for dabigatran and 0.54 mu g/L for rivaroxaban. The intraassay coefficients of variation (CVs) for dabigatran and rivaroxaban were < 4% and 6%; respectively, the interassay CVs were < 6% for dabigatran and < 9% for rivaroxaban. Inaccuracy was < 5% for both substances. The mean recovery was 104.5% (range 83.8-113.0%) for dabigatran and 87.0%(range 73.6-105.4%) for rivaroxaban. No significant ion suppressions were detected at the elution times of dabigatran or rivaroxaban. Both coagulation inhibitors were stable in citrate plasma at -20 degrees C, 4 degrees C and even at RT for at least one week. A method comparison between our UPLC-MRM MS method, the commercially available automated Direct Thrombin Inhibitor assay (DTI assay) for dabigatran measurement from CoaChrom Diagnostica, as well as the automated anti-Xa assay for rivaroxaban measurement from Chromogenix both performed by ACL-TOP showed a high degree of correlation. However, UPLC-MRM MS measurement of dabigatran and rivaroxaban has a much better selectivity than classical functional assays measuring activities of various coagulation factors which are susceptible to interference by other coagulant drugs. Conclusions Overall, we developed and validated a sensitive and specific UPLC-MRM MS assay for the quick and specific measurement of dabigatran and rivaroxaban in human plasma. KW - LC-MS/MS KW - validation KW - serum KW - quantification KW - apixaban KW - diagnostic accuracy KW - performance liquid chromatography KW - factor XA inhibitor KW - direct oral anticoagulants KW - direct thrombin inhibitor Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136023 VL - 10 IS - 12 ER - TY - JOUR A1 - Ermert, Volker A1 - Fink, Andreas H. A1 - Morse, Andrew P. A1 - Paeth, Heiko T1 - The Impact of Regional Climate Change on Malaria Risk due to Greenhouse Forcing and Land-Use Changes in Tropical Africa JF - Environmental Health Perspectives N2 - BACKGROUND: Climate change will probably alter the spread and transmission intensity of malaria in Africa. OBJECTIVES: In this study, we assessed potential changes in the malaria transmission via an integrated weather disease model. METHODS: We simulated mosquito biting rates using the Liverpool Malaria Model (LMM). The input data for the LMM were bias-corrected temperature and precipitation data from the regional model (REMO) on a 0.5 degrees latitude longitude grid. A Plasmodium falciparum infection model expands the LMM simulations to incorporate information on the infection rate among children. Malaria projections were carried out with this integrated weather disease model for 2001 to 2050 according to two climate scenarios that include the effect of anthropogenic land-use and land-cover changes on climate. RESULTS: Model-based estimates for the present climate (1960 to 2000) are consistent with observed data for the spread of malaria in Africa. In the model domain, the regions where malaria is epidemic are located in the Sahel as well as in various highland territories. A decreased spread of malaria over most parts of tropical Africa is projected because of simulated increased surface temperatures and a significant reduction in annual rainfall. However, the likelihood of malaria epidemics is projected to increase in the southern part of the Sahel. In most of East Africa, the intensity of malaria transmission is expected to increase. Projections indicate that highland areas that were formerly unsuitable for malaria will become epidemic, whereas in the lower-altitude regions of the East African highlands, epidemic risk will decrease. CONCLUSIONS: We project that climate changes driven by greenhouse-gas and land-use changes will significantly affect the spread of malaria in tropical Africa well before 2050. The geographic distribution of areas where malaria is epidemic might have to be significantly altered in the coming decades. KW - climate change KW - West Africa KW - highland malaria KW - malaria KW - malaria model KW - malaria projection KW - Sahel KW - transmission KW - model KW - highlands KW - temperatures KW - validation KW - resurgence KW - scenarios KW - epidemic KW - deseases Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135562 VL - 120 IS - 1 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 - 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 - Appel, Patricia A1 - Schuler, Michael A1 - Vogel, Heiner A1 - Oezelsel, Amina A1 - Faller, Hermann T1 - Short Questionnaire for Workplace Analysis (KFZA): factorial validation in physicians and nurses working in hospital settings JF - Journal of Occupational Medicine and Toxicology N2 - Background: In recent years, there has been an increasing interest in psychosocial workplace risk assessments in Germany. One of the questionnaires commonly employed for this purpose is the Short Questionnaire for Workplace Analysis (KFZA). Originally, the KFZA was developed and validated for office workers. The aim of the present study was to examine the factorial validity of the KFZA when applied to hospital settings. Therefore, we examined the factorial structure of a questionnaire that contained all the original items plus an extension adding 11 questions specific to hospital workplaces and analyzed both, the original version and the extended version. Methods: We analyzed questionnaire data of a total of 1731 physicians and nurses obtained over a 10-year period. Listwise exclusion of data sets was applied to account for variations in questionnaire versions and yielded 1163 questionnaires (1095 for the extended version) remaining for factor analysis. To examine the factor structure, we conducted a principal component factor analysis. The number of factors was determined using the Kaiser criterion and scree-plot methods. Factor interpretation was based on orthogonal Varimax rotation as well as oblique rotation. Results: The Kaiser criterion revealed a 7-factor solution for the 26 items of the KFZA, accounting for 62.0% of variance. The seven factors were named: “Social Relationships”, “Job Control”, “Opportunities for Participation and Professional Development”, “Quantitative Work Demands”, “Workplace Environment”, “Variability” and “Qualitative Work Demands”. The factor analysis of the 37 items of the extended version yielded a 9-factor solution. The two additional factors were named “Consequences of Strain” and “Emotional Demands”. Cronbach’s α ranged from 0.63 to 0.87 for these scales. Conclusions: Overall, the KFZA turned out to be applicable to hospital workers, and its content-related structure was replicated well with some limitations. However, instead of the 11 factors originally proposed for office workers, a 7-factor solution appeared to be more suitable when employed in hospitals. In particular, the items of the KFZA factor “Completeness of Task” might need adaptation for the use in hospitals. Our study contributes to the assessment of the validity of this popular instrument and should stimulate further psychometric testing. KW - KFZA KW - mental health KW - work-related stress KW - hospital KW - psychosocial workplace risk assessment KW - validation Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157510 VL - 12 IS - 11 ER - TY - JOUR A1 - Eisele, Marion A1 - Blozik, Eva A1 - Störk, Stefan A1 - Träder, Jens-Martin A1 - Herrmann-Lingen, Christoph A1 - Scherer, Martin T1 - Recognition of depression and anxiety and their association with quality of life, hospitalization and mortality in primary care patients with heart failure - study protocol of a longitudinal observation study JF - BMC Family Practice N2 - Background: International disease management guidelines recommend the regular assessment of depression and anxiety in heart failure patients. Currently there is little data on the effect of screening for depression and anxiety on the quality of life and the prognosis of heart failure (HF). We will investigate the association between the recognition of current depression/anxiety by the general practitioner (GP) and the quality of life and the patients' prognosis. Methods/Design: In this multicenter, prospective, observational study 3,950 patients with HF are recruited by general practices in Germany. The patients fill out questionnaires at baseline and 12-month follow-up. At baseline the GPs are interviewed regarding the somatic and psychological comorbidities of their patients. During the follow-up assessment, data on hospitalization and mortality are provided by the general practice. Based on baseline data, the patients are allocated into three observation groups: HF patients with depression and/or anxiety recognized by their GP (P+/+), those with depression and/or anxiety not recognized (P+/-) and patients without depression and/or anxiety (P-/-). We will perform multivariate regression models to investigate the influence of the recognition of depression and/or anxiety on quality of life at 12 month follow-up, as well as its influences on the prognosis (hospital admission, mortality). Discussion: We will display the frequency of GP-acknowledged depression and anxiety and the frequency of installed therapeutic strategies. We will also describe the frequency of depression and anxiety missed by the GP and the resulting treatment gap. Effects of correctly acknowledged and missed depression/anxiety on outcome, also in comparison to the outcome of subjects without depression/anxiety will be addressed. In case results suggest a treatment gap of depression/anxiety in patients with HF, the results of this study will provide methodological advice for the efficient planning of further interventional research. KW - anxiety KW - depression KW - health care research KW - heart failure KW - prevalence KW - observational study KW - prognosis KW - quality of life KW - hospitalization KW - treatment KW - mortality KW - task force KW - health questionnaire KW - cardiovascular care KW - validity KW - scale KW - validation KW - outcomes KW - standardization KW - population Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121881 SN - 1471-2296 VL - 14 IS - 180 ER - TY - THES A1 - Freitag, Claudia T1 - Quantifizierung von Aminosäuren in Infusionslösungen mittels Hochleistungsflüssigkeitschromatographie-(Tandem) - Massenspektrometrie(HPLC-[MS/]MS) Methodenentwicklung und Validierung T1 - Quantitation of amino acids in infusion solutions by high performance liquid chromatography - (tandem) - mass spectrometry (HPLC-[MS/MS]) - method development and validation N2 - Das Ziel vorliegender Arbeit war die Entwicklung einer HPLC-MS(/MS)-Methode, die im Rahmen der pharmazeutischen Qualitätskontrolle zur direkten Quantifizierung von Aminosäuren (AS) in Infusionslösungen angewendet werden kann. Die Zielset-zung schloss eine Validierung innerhalb der für die Zweckbestimmung vorgesehenen Grenzen ein. Im Rahmen der Methodenentwicklung wurde das ESI-MS/MS-Fragmentierungs-muster von 21 Aminosäuren, von 20 stabil-isotopenmarkierten Aminosäuren, die als interne Standards verwendet wurden, sowie von einigen weiteren Substanzen bestimmt. Nach Kenntnis von Precursor- und Produktionen erstellte man eine SRM-Methode zur spezifischen MS/MS-Analyse. Dabei wurden durch das jeweilige Frag-mentierungsmuster bedingte Interferenzen bei den zu untersuchenden Aminosäuren bestimmt, die bei der zu erarbeitenden HPLC-MS-Methode beachtet werden mussten. Die Methodenentwicklung zur HPLC-MS-Analytik von underivatisierten AS umfasste mit der RP-HPLC unter Verwendung eines Ionenpaarreagenzes (IP) und der hydrophilen Interaktionschromatographie (HILIC) zwei verschiedene chromatographi-sche Ansätze. Bei der Anwendung der RP-HPLC ergaben sich Probleme. Die Verwendung eines IP, im vorliegenden Fall TDFHA (Tridecafluorheptansäure), führte zu langen Equilibrierungs-, Re-Equilibrierungs- und Spülzeiten und damit bei zwar relativ kurzer HPLC-Laufzeit zu einem aber insgesamt hohen Zeitaufwand. Gleich-zeitig war die LC-MS-Anlage auf diese Anwendung fixiert, da das Ionenpaarreagenz das Gerät stark verschmutzte und dadurch andere Analysen erheblich störte. Zudem waren die Retentionszeiten der Analyten trotz langer Equilibrierungszeiten schlecht reproduzierbar, so dass eine solche Methode im Rahmen der pharmazeutischen Qualitätskontrolle schwer validierbar wäre. Weiterführende Untersuchungen erfolgten daher nicht. In nachfolgenden Studien mit der HILIC wurden verschiedene Einflussparameter (Anteil organischer Phase im Fließmittel, pH-Wert des Fließmittels, Temperatur der Säule, Pufferkonzentration im Fließmittel, Gradientenelution) auf die Trennung der AS an einer ZIC®-HILIC-Säule untersucht. Durch Optimierung der Parameter wurde so eine HILIC-HPLC-Methode entwickelt, bei der 21 AS und 20 ihrer isotopen-markierten Referenz-AS innerhalb von 20 min eluierten. Diejenigen AS, bei denen im Rahmen der Fragmentierungsstudien Interferenzen aufgrund gleicher bzw. ähnlicher Massen der Precursor- bzw. Produktionen aufgetreten waren, wurden chroma-tographisch getrennt. Gleichzeitig hat sich die SIM-Analyse als anwendbar erwiesen. Die Anwendung des spezifischeren SRM-Modus und damit der Tandem-Massenspektrometrie war nicht erforderlich. Im Rahmen der nachfolgenden Studien zur Validierung ergab sich, dass die entwickelte Methode über einen weiten Bereich eine lineare Abhängigkeit zwischen Konzentrations- und Messwerten zeigte. Für drei der 21 AS (NAcCys, NAcTyr, Pro) wurde die quadratische Regression mit dem Anpassungstest nach Mandel als geeig-neteres Regressionsmodell ermittelt. Bei Untersuchungen zur Wiederfindung wurde ein Einfluss der Matrix-Lösung der Infusionslösung festgestellt, der zu Abweichungen hinsichtlich des Quotienten AreaAS / AreaIS führte, so dass eine Quantifizierung innerhalb der geforderten Grenzen bei Kalibrierung über reine Standardlösungen nicht möglich war. Die Validierung wurde daher nachfolgend in der Matrixlösung durchgeführt. Dabei wurde gezeigt, dass mit der entwickelten HILIC-HPLC-MS-Methode Aminosäuren in Infusionslösungen mit hoher Präzision und Richtigkeit bestimmt werden können. Neun der 21 untersuchten AS konnten im Bereich von 30% - 350%, zehn weitere im Bereich von 50% - 350% innerhalb der zur Gehaltsbestimmung von pharmazeutischen Formulierungen vorgeschriebenen Grenzen (Wiederfindung Einzelbestimmung: 98% -102.0%, Mittelwert einer Dreifachbestimmung: 98.5% – 101.5%) quantifiziert werden. Für His und Phe gelang allerdings keine Quantifizierung innerhalb der Akzeptanzkriterien, wobei der Grund hierfür in weiteren Studien geklärt werden müsste. Mit der entwickelten Methode ist damit eine gleichzeitige Quantifizierung verschiedener AS-Infusionslösungsformulierungen möglich, die sich bei gleicher Matrix in der Konzentration an AS unterscheiden. Beispielsweise seien hier die Formulierungen „Aminoplasmal® E 5% / 10% /15%“ genannt, die mit der validierten Methode erfassbar sind. Die Probenvorbereitung beschränkt sich dabei auf den Zusatz der IS-Formulierung zur Infusionslösung und einen Verdünnungsschritt. Die Quanti-fizierung erfolgt über eine 5-Punkt-Kalibriergerade, die aus einer AS- und IS-Standardmischung, nach Zusatz der einfach herzustellenden Elektrolyt-Matrix, erstellt wird. Die Analysenzeit der HPLC-MS-Methode beträgt einschließlich Equilibrie-rungszeit 35 min und ist damit deutlich kürzer als die 120 min, die bei der nach wie vor zur AS-Analytik allgemein gebräuchlichen Ionenaustauschchromatographie mit Ninhydrin-Nachsäulenderivatisierung anzusetzen sind. N2 - The aim of this study was to develop an HPLC-MS(/MS) method to be used within pharmaceutical quality control for the direct quantitation of amino acids (AS) in infusion solutions. The validation within the limits of the intended purpose was part of the objective. In the course of the method development the ESI-MS/MS fragmentation pattern of 21 amino acids, 20 stable isotope labelled amino acids, which were used as internal standards, and some further substances were determined. By knowing precursor- and product ions a SRM-method for specific MS/MS analysis was created. Interferences due to the respective fragmentation pattern within the analytes were detected, which had to be considered during the following HPLC-MS method development. The HPLC-MS method development for the analysis of underivatized AS comprised two different approaches: the RP-HPLC using an ion-pair reagent (IP) und the hydrophilic interaction chromatography (HILIC). Problems occurred using the RP-HPLC. Due to the IP, in this study TDFHA (tridecafluoroheptanoic acid), long equilibration-, re-equilibration and rinsing-times were necessary so that this method is very time consuming despite short HPLC run times. Because of the contamination with TDFHA the use of the LC-MS system was limited. Furthermore, despite long equilibration times, retention times of the analytes were poorly reproducible. A validation of the method within the requirements of the pharmaceutical quality control would be therefore hardly to perform. Thus, further studies were not carried out. The following studies were focused on HILIC. Different parameters (percentage of organic solvent in the eluent, pH of the eluent, column temperature, buffer concentration in the eluent, gradient elution) were checked concerning their effects on the separation of AS on a ZIC®-HILIC column. By optimizing the parameters, a HILIC-HPLC method was developed, by which 21 AS and 20 of their stable labelled isotopes were eluted within 20 min. All AS, which interfered with other AS due to their fragmentation pattern, were chromatographically separated. Moreover, the SIM mode was found to be suitable for the separation of AS, thus avoiding SRM mode and tandem mass spectrometry. During the validation studies the HILIC-HPLC-MS method showed linear relation between AS-concentration and measured value over a wide range. Linearity was tested with the Mandel test revealing better fit by quadratic regression for three of 21 AS (NAcCys, NAcTyr and Pro). Recovery studies showed an influence of the matrix of the infusion solution, which led to deviations in the quotients areaAS / areaIS. As a result, quantitation by calibration with pure AS standard solutions was not possible within the given limits. Thus, validation was performed with matrix solution. Thereby it was shown that with the developed HPLC-MS method AS could be deter-mined in infusion solutions with high precision and accuracy. Nine of 21 AS were quantified in the range of 30%-350%, ten AS in the range of 50%-350% within the given requirements of pharmaceutical quality control (individual recovery value: 98% -102.0%, mean recovery value (threefold determination): 98.5% – 101.5%). His and Phe could not be quantified within the acceptance criteria; the reason for this would have to be found out in further studies. With the developed method the simultaneous quantitation of different AS infusion solutions, which differ in analytes concentrations with constant matrix concentration, can be realized. For instance, the formulations „Aminoplasmal® E 5% / 10% /15%“ can be mentioned, which could be determined by using the validated method. Sample preparation is fast and simple, consisting in addition of IS-formulation to the infusion solution and a single dilution step. Quantitation is performed by external standard calibration; the 5-point-regression-line is made by analyzing AS- and IS-standard solution after adding the electrolyte matrix solution, which is easily to produce. HPLC-MS analysis time is 35 min (including equilibration time), thus considerably shorter than the approximately 120 min required with the still common AS analytical method (ion exchange chromatography with postcolumn ninhydrin derivatization). KW - Aminosäuren KW - Qualitätskontrolle KW - HPLC-MS KW - Aminosäuren KW - hydrophile Interaktionschromatographie KW -   HILIC KW - Validierung KW - Methodenentwicklung KW - Infusionslösungen KW - amino acids KW - hydrophilic interaction chromatography KW - HILIC KW - HPLC-MS KW - validation KW - method development KW - infusion solutions Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-65198 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 - 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 - 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 - 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 - JOUR A1 - Dietz, Andreas J. A1 - Conrad, Christopher A1 - Kuenzer, Claudia A1 - Gesell, Gerhard A1 - Dech, Stefan T1 - Identifying Changing Snow Cover Characteristics in Central Asia between 1986 and 2014 from Remote Sensing Data JF - Remote Sensing N2 - Central Asia consists of the five former Soviet States Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan, therefore comprising an area of similar to 4 Mio km(2). The continental climate is characterized by hot and dry summer months and cold winter seasons with most precipitation occurring as snowfall. Accordingly, freshwater supply is strongly depending on the amount of accumulated snow as well as the moment of its release after snowmelt. The aim of the presented study is to identify possible changes in snow cover characteristics, consisting of snow cover duration, onset and offset of snow cover season within the last 28 years. Relying on remotely sensed data originating from medium resolution imagers, these snow cover characteristics are extracted on a daily basis. The resolution of 500-1000 m allows for a subsequent analysis of changes on the scale of hydrological sub-catchments. Long-term changes are identified from this unique dataset, revealing an ongoing shift towards earlier snowmelt within the Central Asian Mountains. This shift can be observed in most upstream hydro catchments within Pamir and Tian Shan Mountains and it leads to a potential change of freshwater availability in the downstream regions, exerting additional pressure on the already tensed situation. KW - AVHRR data KW - satellite KW - Northern Xinjiang KW - cloud KW - products KW - Central Asia KW - climate change KW - Amu Darya KW - Syr Darya KW - Tian Shan KW - snow KW - snow cover KW - snow cover duration KW - Pamir KW - AVHRR KW - MODIS KW - algorithm KW - validation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114470 SN - 2072-4292 VL - 6 IS - 12 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 - 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 - THES A1 - Bleuel, Gabriel T1 - Entwicklung und Validierung eines quantitativen Verfahrens zur Beurteilung der Viabilität von entsprechend der GMP-Richtlinien hergestellter Knorpelimplantate für das Knie T1 - Development and validation of a quantitative assay for a viability test of cultivated knee cartilage implants N2 - Due to the reversing age pyramid in Germany, more and more people are already suffering from joint cartilage damage. But not only age, but also accidents and sports injuries and being overweight can lead to irreversible cartilage defects. Although there are various treatment options, the previous methods cannot be considered a permanent cure. As part of the international research project BIO-CHIP, a promising treatment method with novel drugs was to be investigated. The patient's own cartilage cells from the nose serve as the starting material for the drug, a manufactured cartilage implant. These are isolated, multiplied and ultimately cultivated on a matrix to form a cartilage implant. In addition to toxicological and biological safety tests, an essential prerequisite for the approval of the implant is the assessment of the viability. This was previously carried out on the basis of histology from the pathology department. The aim of the present work was the development and validation of a standardized and objective viability test for the chondrocytes within the cartilage matrix. For this, the LDH was used as a marker for irreversibly damaged cells. The LDH concentration could be measured with the CyQuant LDH assay by measuring the absorption. It could be proven that LDH has the required stability and detectability in the medium. With the help of the lysis, of cultivated mini-cartilage implants, the maximum achievable LDH concentrations could be determined. A calibration curve was generated using these concentrations. This serves to assess the viability of future measured absorptions of the supernatant medium. The developed method does not require any invasive interventions on the implant and is characterized by its simple implementation, since only the protrusion has to be measured. The validation of the method certified a high level of robustness, linearity, accuracy and precision. N2 - Aufgrund der sich umkehrenden Alterspyramide in Deutschland leiden bereits jetzt immer mehr Menschen an Gelenkknorpelschäden. Doch nicht nur das Alter, sondern auch Unfälle und Sportverletzungen und Übergewicht können zu irreversiblen Knorpeldefekten führen. Obwohl es diverse Behandlungsmöglichkeiten gibt, können die bisherige Methoden nicht als dauerhafte Heilung betrachtet werden. Im Rahmen des internationalen Forschungsprojektes BIO-CHIP sollte eine vielsprechende Behandlungsmethode mit neuartigen Arzneimitteln untersucht werden. Als Ausgangsmaterial des Arzneimittels, ein hergestelltes Knorpelimplantat, dienen patienteneigene Knorpelzellen aus der Nase. Diese werden isoliert, vermehrt und letztlich auf einer Matrix zu einem Knorpelimplantat kultiviert. Wesentliche Voraussetzung für die Implantatfreigabe stellt neben toxikologischen und biologischen Unbedenklichkeitstests die Beurteilung der Viabilität dar. Diese wurde bisher anhand von Histologieschnitten von der Pathologie durchgeführt. Ziel der vorliegenden Arbeit war die Entwicklung und Validierung eines standardisierten und objektiven Viabilitätstests für die Chondrozyten innerhalb der Knorpelmatrix. Hierfür wurde die LDH als Marker für irreversibel geschädigte Zellen verwendet. Die LDH Konzentration konnte mit dem CyQuant LDH-Assay durch die Messung der Absorption gemessen werden. Es konnte nachgewiesen werden, dass LDH die erforderliche Stabilität und Nachweisbarkeit im Medium besitzt. Mithilfe der Lyse, analog zum Herstellungsprozess, gezüchteter Mini-Knorpelimplantate, konnten die maximal erreichbaren LDH Konzentrationen ermittelt werden. Mithilfe dieser Konzentrationen wurde eine Eichkurve generiert. Diese dient als Beurteilung der Viabilität zukünftig gemessener Absorptionen des Überstandmediums. Das entwickelte Verfahren erfordert keine invasiven Eingriffe am Implantat und zeichnet sich durch eine einfache Durchführung aus, da nur der Überstand gemessen werden muss. Die durchgeführte Validierung der Methode bescheinigte eine hohe Robustheit, Linearität, Genauigkeit und Präzision. KW - Hyaliner Knorpel KW - Lactatdehydrogenase KW - Kniegelenk KW - Zellkultur KW - Entwicklung KW - development KW - Validierung KW - LDH-assay KW - Knorpelimplantate KW - validation KW - cartilage Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242481 ER - TY - JOUR A1 - Mayr, Stefan A1 - Klein, Igor A1 - Rutzinger, Martin A1 - Kuenzer, Claudia T1 - Determining temporal uncertainty of a global inland surface water time series JF - Remote Sensing N2 - Earth observation time series are well suited to monitor global surface dynamics. However, data products that are aimed at assessing large-area dynamics with a high temporal resolution often face various error sources (e.g., retrieval errors, sampling errors) in their acquisition chain. Addressing uncertainties in a spatiotemporal consistent manner is challenging, as extensive high-quality validation data is typically scarce. Here we propose a new method that utilizes time series inherent information to assess the temporal interpolation uncertainty of time series datasets. For this, we utilized data from the DLR-DFD Global WaterPack (GWP), which provides daily information on global inland surface water. As the time series is primarily based on optical MODIS (Moderate Resolution Imaging Spectroradiometer) images, the requirement of data gap interpolation due to clouds constitutes the main uncertainty source of the product. With a focus on different temporal and spatial characteristics of surface water dynamics, seven auxiliary layers were derived. Each layer provides probability and reliability estimates regarding water observations at pixel-level. This enables the quantification of uncertainty corresponding to the full spatiotemporal range of the product. Furthermore, the ability of temporal layers to approximate unknown pixel states was evaluated for stratified artificial gaps, which were introduced into the original time series of four climatologic diverse test regions. Results show that uncertainty is quantified accurately (>90%), consequently enhancing the product's quality with respect to its use for modeling and the geoscientific community. KW - Earth observation KW - interpolation KW - MODIS KW - optical remote sensing KW - probability KW - reliability KW - validation KW - variability Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245234 SN - 2072-4292 VL - 13 IS - 17 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 - 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 - THES A1 - Baumeister, Joachim T1 - Agile development of diagnostic knowledge systems T1 - Agile Entwicklung von Wissensbasierten Diagnosesystemen N2 - The success of diagnostic knowledge systems has been proved over the last decades. Nowadays, intelligent systems are embedded in machines within various domains or are used in interaction with a user for solving problems. However, although such systems have been applied very successfully the development of a knowledge system is still a critical issue. Similarly to projects dealing with customized software at a highly innovative level a precise specification often cannot be given in advance. Moreover, necessary requirements of the knowledge system can be defined not until the project has been started or are changing during the development phase. Many success factors depend on the feedback given by users, which can be provided if preliminary demonstrations of the system can be delivered as soon as possible, e.g., for interactive systems validation the duration of the system dialog. This thesis motivates that classical, document-centered approaches cannot be applied in such a setting. We cope with this problem by introducing an agile process model for developing diagnostic knowledge systems, mainly inspired by the ideas of the eXtreme Programming methodology known in software engineering. The main aim of the presented work is to simplify the engineering process for domain specialists formalizing the knowledge themselves. The engineering process is supported at a primary level by the introduction of knowledge containers, that define an organized view of knowledge contained in the system. Consequently, we provide structured procedures as a recommendation for filling these containers. The actual knowledge is acquired and formalized right from start, and the integration to runnable knowledge systems is done continuously in order to allow for an early and concrete feedback. In contrast to related prototyping approaches the validity and maintainability of the collected knowledge is ensured by appropriate test methods and restructuring techniques, respectively. Additionally, we propose learning methods to support the knowledge acquisition process sufficiently. The practical significance of the process model strongly depends on the available tools supporting the application of the process model. We present the system family d3web and especially the system d3web.KnowME as a highly integrated development environment for diagnostic knowledge systems. The process model and its activities, respectively, are evaluated in two real life applications: in a medical and in an environmental project the benefits of the agile development are clearly demonstrated. N2 - Wissensbasierte Diagnosesysteme konnten in den letzten Jahrzehnten sehr erfolgreich eingesetzt werden. Intelligente Systeme sind heute in den verschiedensten Domainen zu finden, werden in komplexe Maschinen eingebettet oder interaktiv im Dialog mit dem Benutzer verwendet. Trotz aller Erfolge ist die Entwicklung eines Wissenssystems immer noch eine komplexe Aufgabe. Dies ist darin begründet, dass ähnlich zu der Erstellung von Individual-Software mit einem hohen innovativen Grad eine präzise Spezifikation zu Anfand des Projekt häufig nicht gegeben werden kann. Vielmehr können notwendige Faktoren, welche den Erfolg des Systems maßgeblich bestimmen, nicht vor der Entwicklung identifiziert werden oder sind Änderungen während der Entwicklungsphase unterworfen. Viele Einflussfaktoren können hierbei nur in Rückkopplung mit dem Benutzer abgewogen werden, welches durch vorläufige Versionen des Systems in frühen Stadien ermöglicht werden kann, z.B. bei interaktiven Systemen durch eine Validierung des Dialoges durch den Benutzer. Diese Arbeit stellt heraus, dass klassische, dokument-zentrierte Ansätze in einem solchen Umfeld nicht anwendbar sind, und schlägt ein agiles Vorgehensmodell zur Entwicklung von wissensbasierten Diagnosesystemen als Lösung vor. Das agile Vorgehensmodell wurde wesentlich durch Ideen des im Software Engineering bekannten eXtreme Programming beeinflusst. Als wichtigstes Ziel dieser Arbeit wird die Vereinfachung des Entwicklungsprozesses für den Fachexperten verfolgt, der im Idealfall das benötigte Wissen selbst formalisiert. Dabei wird der Entwicklungsprozess auf einer übergeordneten Ebene durch die Einführung von Wissenscontainern unterstützt, welche eine organisierte Übersicht auf das im System enthaltene Wissen bieten. Weiterhin werden strukturierte Vorgehensweisen für das Füllen der jeweiligen Container empfohlen. Das tatsächliche Wissen wird von Beginn des Projekts an erfasst und formalisiert; eine kontinuierliche Integration von neuen Wissensinhalten in ein lauffähiges System sorgt für eine frühe und konkrete Rückkopplung mit dem Benutzer. Im Gegensatz zu den verwandten Prototyping Ansätzen wird die Validität und Wartbarkeit des erfassten Wissens durch geeignete Test- und Restrukturierungsmethoden sichergestellt. Zusätzlich werden angepasste Lernmethoden diskutiert, welche den Wissensakquisitionsprozess in vielen Bereichen ergänzen können. Die praktische Bedeutung des Vorgehensmodells ist stark mit der Verfügbarkeit von Werkzeugen verknüpft, welche den Fachexperten bei der Entwicklung direkt unterstützen können. Es wird daher die Systemfamilie d3web und im Speziellen die integrierte Entwicklungsumgebung d3web.KnowME vorgestellt. Das Vorgehensmodell und seine Aktivitäten werden in zwei Praxis-Anwendungen, einem medizinischen und einem geo-ökologischen Projekt, evaluiert. KW - Wissensakquisition KW - Wissensentwicklung KW - Wartung KW - Validation KW - Refaktorisierung KW - knowledge engineering KW - knowledge acquisition KW - maintenance KW - validation KW - refactoring Y1 - 2004 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-9698 ER - TY - JOUR A1 - Bischoff, Joakim M. A1 - Ringsted, Thomas K. A1 - Petersen, Marian A1 - Sommer, Claudia A1 - Üçeyler, Nurcan A1 - Werner, Mads U. T1 - A Capsaicin (8%) Patch in the Treatment of Severe Persistent Inguinal Postherniorrhaphy Pain: A Randomized, Double-Blind, Placebo-Controlled Trial JF - PLOS ONE N2 - Background: Persistent pain after inguinal herniorrhaphy is a disabling condition with a lack of evidence-based pharmacological treatment options. This randomized placebo-controlled trial investigated the efficacy of a capsaicin 8% cutaneous patch in the treatment of severe persistent inguinal postherniorrhaphy pain. Methods: Forty-six patients with persistent inguinal postherniorrhaphy pain were randomized to receive either a capsaicin 8% patch or a placebo patch. Pain intensity (Numerical Rating Scale [NRS 0-10]) was evaluated under standardized conditions (at rest, during movement, and during pressure) at baseline and at 1, 2 and 3 months after patch application. Skin punch biopsies for intraepidermal nerve fiber density (IENFD) measurements were taken at baseline and 1 month after patch application. Quantitative sensory testing was performed at baseline and at 1, 2, and 3 months after patch application. The primary outcome was comparisons of summed pain intensity differences (SPIDs) between capsaicin and placebo treatments at 1, 2 and 3 months after patch application (significance level P<0.01). Results: The maximum difference in SPID, between capsaicin and placebo treatments, was observed at 1 month after patch application, but the pain reduction was not significant (NRS, mean difference [95% CI]: 5.0 [0.09 to 9.9]; P=0.046). No differences in SPID between treatments were observed at 2 and 3 months after patch application. Changes in IENFD on the pain side, from baseline to 1 month after patch application, did not differ between capsaicin and placebo treatment: 1.9 [-0.1 to 3.9] and 0.6 [-1.2 to 2.5] fibers/mm, respectively (P=0.32). No significant changes in sensory function, sleep quality or psychological factors were associated with capsaicin patch treatment. Conclusions: The study did not demonstrate significant differences in pain relief between capsaicin and placebo treatment, although a trend toward pain improvement in capsaicin treated patients was observed 1 month after patch application. KW - postherpetic neuralgia KW - long-term pain KW - crossover trial KW - neuropathic pain KW - risk factors KW - cutaneous patch KW - scale KW - hernia repair KW - interference KW - validation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115198 SN - 1932-6203 VL - 9 IS - 10 ER - TY - JOUR A1 - Güder, Gülmisal A1 - Brenner, Susanne A1 - Angermann, Christiane E. A1 - Ertl, Georg A1 - Held, Matthias A1 - Sachs, Alfred P. A1 - Lammers, Jan Willem A1 - Zanen, Peter A1 - Hoes, Arno W. A1 - Störk, Stefan A1 - Rutten, Frans H. T1 - "GOLD or lower limit of normal definition? a comparison with expert-based diagnosis of chronic obstructive pulmonary disease in a prospective cohort-study" N2 - Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed postbronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Agedependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. Methods: In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner’s diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. Results: Compared to the expert panel diagnosis, ‘GOLD-COPD’ misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. Conclusions: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice. KW - Medizin KW - COPD diagnosis KW - lower limit of normal KW - GOLD KW - validation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75193 ER -