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Alrawi, Sura, and Manar Younan. "High Molecular Weight (HMW) snabbtypning av Clostridium difficile med MALDI-TOF MS : Genom två metoder direkt och proteinextraktion." Thesis, Hälsohögskolan, Högskolan i Jönköping, HHJ. Biomedicinsk plattform, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:hj:diva-31515.
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Aluwihare, Lihini Indira. "High molecular weight (HMW) dissolved organic matter (DOM) in seawater : chemical structure, dources and cycling." Thesis, Massachusetts Institute of Technology, 1999. http://hdl.handle.net/1721.1/53038.
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Thesis (Ph. D.)--Joint Program in Chemical Oceanography (Massachusetts Institute of Technology, Dept. of Earth, Atmospheric and Planetary Sciences; and the Woods Hole Oceanographic Institution), 1999.Includes bibliographical references.
The goal of this thesis was to use high resolution analytical techniques coupled with molecular level analyses to chemically characterize high molecular weight (> 1 k Da (HMW)) dissolved organic matter (DOM) isolated from seawater in an attempt to provide new insights in to the cycling of DOM in the ocean. While a variety of sites spanning different environments (fluvial, coastal and oceanic) and ocean basins were examined, the chemical structure of the isolated HMW DOM varied little at both the polymer and monomer levels. All samples show similar ratios of carbohydrate:acetate:lipid carbon (80±4:10±2:9±4) indicating that these biochemicals are present within a family of related polymers. The carbohydrate fraction shows a characteristic distribution of seven major neutral monosaccharides: rhamnose, fucose, arabinose, xylose, mannose, glucose and galactose; and additionally contains Nacetylated amino sugars as seen by Nuclear Magnetic Resonance Spectroscopy (NMR). This family of compounds, consisting of a specifically linked polysaccharide backbone that is acylated at several positions, has been termed acylated polysaccharides (APS) by our laboratory. APS accounts for 50% of the carbon in HMW DOM isolated from the surface ocean and 20% of the carbon in HMW DOM isolated from the deep ocean. In order to identify a possible source for APS three species of phytoplankton, Thalassiossira weissflogii, Emiliania huxleyi and Phaeocystis, were cultured in seawater and their HMW DOM exudates examined by variety of analytical techniques. Both the T. weissflogii and E. huxleyi exudates contain compounds that resemble APS indicating that phytoplankton are indeed a source of APS to the marine environment. Furthermore, the degradation of the T. weissflogii exudate by a natural assemblage of microorganisms indicates that the component resembling APS is more resistant to microbial degradation compared to other polysaccharides present in the culture. Molecular level analyses show the distribution of monosaccharides to be conservative in surface and deep waters suggesting that APS is present throughout the water column. In order to determine the mechanism by which APS is delivered to the deep ocean the [delta]14C value of APS in the deep ocean was compared to the A14C value of the dissolved inorganic carbon (DIC) at the same depth. If the formation of deep water is the dominant mode of transport then both the DIC and APS will have similar [delta]14C values. However, if APS is injected into the deep ocean from particles or marine snow then the [delta]14C value of APS will be higher than the DIC at the same depth. Our results indicate that APS in the deep Pacific Ocean carries a modem [delta]14C value and is substantially enriched in 14C relative to the total HMW DOM and the DIC at that depth. Thus, particle dissolution appears to be the most important pathway for the delivery of APS to the deep ocean.
by Lihini I. Aluwihare.
Ph.D.
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Quaresma, Joana Rita de Jesus. "Estudo da evolução da cor no processo de refinação de ramas de cana-de-açucar." Master's thesis, ISA/UL, 2019. http://hdl.handle.net/10400.5/18397.
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Mestrado em Engenharia Alimentar - Instituto Superior de Agronomia / ULA cor da rama, matéria-prima nas refinarias de açúcar, é uma das características fun-damentais; quando acentuada pode afetar o bom funcionamento deste tipo de indústria. A descoloração do licor, remoção dos compostos de cor que estão originalmente na rama da cana-de-açúcar e os que se formam durante o processo de refinação, é uma das fases mais importantes numa refinaria uma vez que no final se pretende produzir açúcar branco. Nos últimos anos a refinaria SIDUL, onde se realizou o presente trabalho, recebeu ra-mas com intensidades de cores bastante elevadas, o que causou um aumento na cor do licor bruto e consequentemente do licor filtrado que segue para descoloração nas resinas. Uma vez que estas não foram dimensionadas para cores de entrada tão altas, a sua performance diminuiu. Como resultado a cor do licor branco aumentou, o que levou ao interesse pela pro-cura de agentes descolorantes que pudessem melhorar estes parâmetros. Numa primeira fase deste trabalho, estudou-se o desempenho de diferentes tipos de polímeros catiónicos, Amber (2009, 2006 e 2001 HMW), tendo o Amber 2001 HMW apresen-tado a melhor relação percentagem de descoloração/preço. Este produto foi de seguida utili-zado nos estudos de descoloração a nível industrial, sendo verificado que esta aplicação era vantajosa, sob os pontos de vista tecnológico e económico, para cores de licor bruto a partir de 2000 UI. Uma vez que a evaporação é a etapa após a descoloração em que pode ocorrer a for-mação de compostos de cor, sendo por isso importante minimizar esta ocorrência, foi ainda estudado o eventual aumento de cor do licor no evaporador com a variação da pressão do vapor de aquecimento (115 kPa, 120 kPa e 125 kPa). Contrariamente ao esperado, não houve elevação expressiva da temperatura do licor, resultando na ausência de um aumento significativo de cor
N/A
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Atanassova, Vessela. "Les prêtres Hmw-ntr du culte divin (de l’époque thinite à la fin de l’Ancien Empire)." Thesis, Paris 4, 2015. http://www.theses.fr/2015PA040226.
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Les prêtres sont une partie indissociable de l’organisation et du fonctionnement de la société égyptienne. Parmi eux les prophètes avaient une grande importance dans le clergé égyptien. Leur étude nous permet non seulement une meilleure compréhension du sacerdoce égyptien, mais aussi une meilleure connaissance de la religion égyptienne. Concentrée sur l’époque thinite et l’Ancien Empire, notre recherche a fait l’examen exhaustif des titulaires des prêtrises divines afin de comprendre les mécanismes de l’obtention de celle-ci et les fonctions déléguées aux prophètes. L’examen de sources nous a parmi d’attester une relation entre fonction civile et prêtrise divine qui est étudiée en détail. Nous discuterons la chronologie des prêtrises, les divinités concernées et la nature de ses titulaires. Nous interrogeons sur l’obtention et la transmission de la prêtrise divine. Enfin, nous poserons la question sur les lieux d’exercice de la fonction sacerdotale, ainsi que sur ce que celle-ci devait êtreThe priests were an inseparable part of the organisation and functioning of the Egyptian society. Among them the prophets were one of the most important for the Egyptian clergy. The study of them allows us not only a better comprehension ofthe Egyptian priesthood but also a better knowledge of the Egyptian religion. Focused on the Early dynastic period and the Old Kingdom our research examinedthe holders of the divine priesthoods in order to understand the ways of having andobtaining it. The study of the sources allowed us to attest a relation between the civil service and the divine priesthood. We discussed the priesthood’s chronology, the mentioned gods and its holders. We question about its obtainment and transmission. At last, we focused on finding the place of exercise of the priesthood and its significance
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Liao, Siyun. "The Role of Fibroblast Growth Factor-2 Isoforms in Ischemia-reperfusion Injury and Cardioprotection." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1203690695.
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Pierucci, Valquiria Resende Malaspina. "An investigation of the effects of high molecular weight glutenin subunits on wheat tortilla quality." Thesis, Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/750.
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Schmid, Markus Josef Anton [Verfasser], Peter [Akademischer Betreuer] Köhler, Peter [Gutachter] Köhler, and Stephan [Gutachter] Sieber. "Isolation and proteinchemical characterization of HMW-gliadins from wheat flour / Markus Josef Anton Schmid ; Gutachter: Peter Köhler, Stephan Sieber ; Betreuer: Peter Köhler." München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1164590987/34.
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Wurster, Elena [Verfasser]. "Vergleichende Genexpressionsanalyse in viszeralem Fettgewebe von Patienten mit Colorektalen Karzinomen und Adipositas sowie Nachweis der Expression von HMW- Adiponektin im Serum / Elena Wurster." Ulm : Universität Ulm. Medizinische Fakultät, 2015. http://d-nb.info/1071629255/34.
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Echeverri, Christophe de Jesus. "A comparative study of high and low molecular weight microtubule-associated protein 2 (HMW-MAP2 and MAP2c) in differentiating neurons and transfected fibroblasts cells." Thesis, University of Ottawa (Canada), 1993. http://hdl.handle.net/10393/6823.
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Microtubule-associated protein 2 (MAP2) is the most abundant MAP in vertebrate brain tissues, and the best studied of all structural MAPs. In adult brain, it is present as one or two high-molecular weight polypeptides (HMW-MAP2, $\sim$280kDa by SDS-PAGE) which segregate to the somato-dendritic compartments of neurons. Apart from its ontogeny and sequence, little is known about MAP2c biochemistry, although sequence similarities with HMW-MAP2 suggest that the smaller isoform should also bind to MTs, promote their assembly, stabilize them, and possibly induce bundling. This thesis aimed to examine these questions about MAP2c by studying it in parallel with HMW-MAP2 both in differentiating neurons, and in transfected fibroblasts. Neuronal differentiation was examined in retinoic acid-induced P19 embryonal carcinoma cells, using an anti-$\beta$III-tubulin antibody to identify neurons. Expression of MAP2 was examined using three monoclonal antibodies, two of which (HM2 and AP18) recognized all forms of MAP2, while the third (AP14) was specific for HMW-MAP2. Onset of detectable expression of MAP2 was found to coincide with initial neurite outgrowth of P19 EC-derived neurons. The HM2 antibody stained almost all visible neurons, while AP18 stained a smaller subset, and AP14, the smallest. Only the HM2 antibody stained filopodia on some cell bodies and neurite shafts, as well as some growth cones. It is proposed that MAP2 is present as two or more subpopulations which sort differently within the cell. Transient transfections into 3T3 fibroblasts confirmed that MAP2c binds to MTs, stabilizes them against colchicine-induced depolymerization, and induces the formation of MT bundles. It is proposed that MAP2-induced bundles initially arise through the funnelling of MTOC-based MTs into thin cytoplasmic extensions which are eventually resorbed into the cell body. MT bundles are then released from the MTOC, and their stability is slightly decreased as a result. (Abstract shortened by UMI.)
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Bröder, Lisa-Marie. "Transport, degradation and burial of organic matter released from permafrost to the East Siberian Arctic Shelf." Doctoral thesis, Stockholms universitet, Institutionen för miljövetenskap och analytisk kemi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-136380.
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Permafrost soils in the Arctic store large quantities of organic matter, roughly twice the amount of carbon that was present in the atmosphere before the industrial revolution. This freeze-locked carbon pool is susceptible to thawing caused by amplified global warming at high latitudes. The remobilization of old permafrost carbon facilitates its degradation to carbon dioxide and methane, thereby providing a positive feedback to climate change. Accelerating coastal erosion in addition to projected rising river discharge with enhancing sediment loads are anticipated to transport increasing amounts of land-derived organic carbon (OC) to the Arctic Ocean. On its shallow continental shelves, this material may be remineralized in the water column or in the sediments, transported without being altered off shelf towards the deep sea of the Arctic Interior or buried in marine sediments and hence sequestered from the contemporary carbon cycle. The fate of terrigenous material in the marine environment, though offering potentially important mechanisms to either strengthen or attenuate the permafrost-carbon climate feedback, is so far insufficiently understood. In this doctoral thesis, sediments from the wide East Siberian Arctic Shelf, the world’s largest shelf-sea system, were used to investigate some of the key processes for OC cycling. A range of bulk sediment properties, carbon isotopes and molecular markers were employed to elucidate the relative importance of different organic matter sources, the role of cross-shelf transport and the relevance of degradation during transport and after burial. Overall, OC released from thawing permafrost constitutes a significant proportion of the sedimentary organic matter on the East Siberian Arctic Shelf. Two sediment cores from the inner and outer East Siberian Sea recorded no substantial changes in source material or clear trends in degradation status for the last century. With increasing distance from the coast, however, strong gradients were detected towards lower concentrations of increasingly reworked land-derived OC. The time spent during cross-shelf transport was consequently found to exert first-order control on degradation. Compound-specific radiocarbon dating on terrigenous biomarkers revealed a net transport time of ~4 000 years across the 600 km wide Laptev Sea shelf, yielding degradation rate constants for bulk terrigenous OC and specific biomarkers on the order of 2-4 kyr-1. From these results, the carbon flux released by degradation of terrigenous OC in surface sediments was estimated to be ~1.7 Gg yr-1, several orders of magnitude lower than what had been quantified earlier for dissolved and particulate OC in the water column. Lower oxygen availability and close associations with the mineral matrix may protect sedimentary OC from remineralization and thereby weaken the permafrost-carbon feedback to present climate change.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Submitted. Paper 4: Manuscript.
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Pierce, Kyle C., and Michael H. Stone. "Children and Sport – How Hard Should Children Be Trained?" Digital Commons @ East Tennessee State University, 2017. https://doi.org/10.7707/hmj.730.
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The participation of children and early and late adolescents in resistance training activities, including training for sport, appears to continually be on the rise. The involvement of youth in the sport of weightlifting and the use of weightlifting methods as part of training for sport performance also appears to be growing. The increased acceptance of these activities is evidenced by the number of both lay and scientific articles, specialized magazines and publications devoted to the different types of resistance training. It is also indicated by simple observation of fitness centres and sports training facilities. The use of resistance training appears to be growing in popularity despite poorly supported position statements, anecdotal reports and speculation concerning the potential for injury. Children and adolescents participating in resistance training programs can make noticeable increases in strength and power as well as physiological parameters associated with both health and sport performance. Although the number of children and adolescents (aged 8–18 years) involved in some form of resistance training is increasing and evidenced-based reviews that support these activities have been published, controversy still exists. There are still those who insist that training with free weights, particularly the sport of weightlifting, should not take place until a person is fully developed, even though there is not much objective evidence to support such a position. More recently published scientific data support the notion that properly supervised resistance training programs can improve sport performance, reduce injury potential and enhance healthy facets of children and early and late adolescents.
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Steyrer, Johannes, Michael Schiffinger, Huber Clemens, Andreas Valentin, and Guido Strunk. "Attitude is everything? The impact of workload, safety climate, and safety tools on medical errors: A study of intensive care units." Lippincott Williams & Wilkins, 2013. http://dx.doi.org/10.1097/HMR.0b013e318272935a.
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Background: Hospitals face an increasing pressure towards efficiency and cost reduction while ensuring patient safety. This warrants a closer examination of the trade-off between production and protection posited in the literature for a high-risk hospital setting (intensive care).
Purposes: Based on extant literature and concepts on both safety management and organizational/safety culture, this study investigates to which extent production pressure (i.e., increased staff workload and capacity utilization) and safety culture (consisting of safety climate among staff and safety tools implemented by management) influence the occurrence of medical errors and if/how safety climate and safety tools interact.
Methodology / Approach: A prospective, observational, 48-hour cross-sectional study was conducted in 57 intensive care units. The dependent variable is the incidence of errors affecting those 378 patients treated throughout the entire observation period. Capacity utilization and workload were measured by indicators such as unit occupancy, nurse-/physician-to-patient ratios, levels of care, or NEMS scores. The safety tools considered include Critical Incidence Reporting Systems, audits, training, mission statements, SOPs/checklists and the use of barcodes. Safety climate was assessed using a psychometrically validated four-dimensional questionnaire. Linear regression was employed to identify the effects of the predictor variables on error rate, as well as interaction effects between safety tools and safety climate.
Findings: Higher workload has a detrimental effect on safety while safety climate - unlike the examined safety tools - has a virtually equal opposite effect. Correlations between safety tools and safety climate as well as their interaction effects on error rate are mostly nonsignificant.
Practice Implications: Increased workload and capacity utilization increase the occurrence of medical error; an effect that can be offset by a positive safety climate but not by formally implemented safety procedures and policies. (authors' abstract)
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Freitag, Walburga. "Contergan eine genealogische Studie des Zusammenhangs wissenschaftlicher Diskurse und biographischer Erfahrungen." Münster New York München Berlin Waxmann, 2003. http://www.waxmann.com/kat/1503.hml.
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Golz, Sebastian, and Thomas Naumann. "Bautechnische Überflutungsvorsorge für Wohngebäude und kleingewerblich genutzte Gebäude." Hochschule für Technik und Wirtschaft, 2020. https://htw-dresden.qucosa.de/id/qucosa%3A71416.
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Durch die Umsetzung gezielter Maßnahmen der objektspezifischen Bauvorsorge lassen sich überflutungsinduzierte Schäden sowohl an bestehenden als auch an neu zu errichtenden Gebäuden in teils erheblichem Umfang mindern. Der vorliegende Ergebnisbericht des Forschungs- und Entwicklungsvorhabens „Bautechnische Überflutungsvorsorge für Wohngebäude und kleingewerblich genutzte Gebäude“ verdichtet das Wissen über wirksame Handlungsoptionen der Bauvorsorge und unterstützt somit die Praxis bei der Planung robuster Konstruktionen gegenüber Überflutung.
Als zentrales Ergebnis des Projekts fungiert ein Bauteilkatalog, der im Sinne einer Beispiel-sammlung typische Ausführungsvarianten von Außenwand- sowie von Decken- und Fußbodenkonstruktionen enthält, die bei Überflutungsereignissen häufig betroffen sind. Für mehrere baupraktisch relevante Bauteilvarianten empfiehlt der Katalog konkrete Maßnahmen, welche zur wirksamen Minderung der Schadensanfälligkeit bei Überflutungsbeanspruchungen beitragen.
Der Bauteilkatalog ermöglicht den direkten Vergleich der Schadensanfälligkeit zwischen der „unangepassten“ Ausgangskonstruktion und der „angepassten“ Zielkonstruktion. Die Beurteilung der Schadensanfälligkeit basiert hierbei auf insgesamt acht Kriterien, die das Verhalten der Bauteile bei Überflutungsbeanspruchungen charakterisieren. Der Bauteilkatalog enthält die zeichnerische Darstellung aller Beispielkonstruktionen, um die empfohlenen Veränderungen in den Schichtenfolgen sichtbar zu machen.It is evident, that the implementation of flood resilient measures on building scale provide a considerable potential to reduce flood damage to both existing and new buildings. The report of the research and development project 'Constructional flood protection for residential build-ings and small commercial buildings' condenses the knowledge of effective options for enhancing flood resilience and thus supports practice in the planning of robust constructions against flooding. The central result of the project is a compendium of building constructions, which contains typical design variants of exterior wall, ceiling and floor constructions that are often affected by flood events. The compendium recommends specific measures for building constructions that contribute to the effective reduction of their physical flood vulnerability. The compendium enables a direct comparison of the flood vulnerability between the 'unadapted' initial construction and the 'adapted' target construction. The flood vulnerability assessment bases on a total of eight criteria that characterize the behaviour of the components in the event of flooding. The compendium contains the graphic representation of all sample constructions to visualise the recommended changes in the layer sequences.
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Miersch, Sören, Ralph Schubert, Thomas Schuhmann, Uwe Schuffenhauer, Markus Buddenbohm, Markus Beyreuther, Jeannette Kuhn, Mathias Lindner, Bernd Cebulski, and Jakob Jung. "Ceramic-like Composite Systems for Winding Insulation of Electrical Machines." IEEE, 2020. https://htw-dresden.qucosa.de/id/qucosa%3A74384.
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Insulating sheets, impregnants and encapsulation materials commonly used for winding insulation offer low thermal conductivities. This leads to an increased heating of the winding of electrical machines and to the existence of hotspots. The electromagnetical utilization of the machine has to be reduced with respect to the allowed maximum winding temperature. In this paper, the development and experimental investigation of novel polysiloxane composites with ceramic fillers are presented. The materials are tested by means of impregnated and encapsulated samples of a round-wire winding as well as the main insulation of electrical steel sheets and laminated cores. Numerical models are implemented for determining the equivalent thermal conductivity of the winding compound comprising the enameled wire and the impregnant. Based on the example of a permanent-magnet synchronous machine with outer-rotor in modular construction, the potential for increasing the electromagnetical utilization is shown.
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Lehmann, Rüdiger. "Improved critical values for extreme normalized and studentized residuals in Gauss-Markov models." Springer Verlag, 2012. https://htw-dresden.qucosa.de/id/qucosa%3A23275.
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We investigate extreme studentized and normalized residuals as test statistics for outlier detection in the Gauss-Markov model possibly not of full rank. We show how critical values (quantile values) of such test statistics are derived from the probability distribution of a single studentized or normalized residual by dividing the level of error probability by the number of residuals. This derivation neglects dependencies between the residuals. We suggest improving this by a procedure based on the Monte Carlo method for the numerical computation of such critical values up to arbitrary precision. Results for free leveling networks reveal significant differences to the values used so far. We also show how to compute those critical values for non‐normal error distributions. The results prove that the critical values are very sensitive to the type of error distribution.Wir untersuchen extreme studentisierte und normierte Verbesserungen als Teststatistik für die Ausreißererkennung im Gauß-Markov-Modell von möglicherweise nicht vollem Rang. Wir zeigen, wie kritische Werte (Quantilwerte) solcher Teststatistiken von der Wahrscheinlichkeitsverteilung einer einzelnen studentisierten oder normierten Verbesserung abgeleitet werden, indem die Irrtumswahrscheinlichkeit durch die Anzahl der Verbesserungen dividiert wird. Diese Ableitung vernachlässigt Abhängigkeiten zwischen den Verbesserungen. Wir schlagen vor, diese Prozedur durch Einsatz der Monte-Carlo-Methode zur Berechnung solcher kritischen Werte bis zu beliebiger Genauigkeit zu verbessern. Ergebnisse für freie Höhennetze zeigen signifikante Differenzen zu den bisher benutzten Werten. Wir zeigen auch, wie man solche Werte für nicht-normale Fehlerverteilungen berechnet. Die Ergebnisse zeigen, dass die kritischen Werte sehr empfindlich auf den Typ der Fehlerverteilung reagieren.
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Lehmann, Rüdiger. "Im Schwerpunkt der Anschlusspunkte – Zur Genauigkeit geodätischer Koordinatentransformationen." Hochschule für Technik und Wirtschaft Dresden, 2010. https://htw-dresden.qucosa.de/id/qucosa%3A23283.
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Eine in der Geoda¨sie bekannte Regel besagt, dass die Genauigkeit zu transformierender Neupunkte im Schwerpunkt der Anschlusspunkte am höchsten ist. Weniger bekannt ist, unter welchen Voraussetzungen dies generell gilt. Allgemein unbekannt ist bisher, auf welche Koordinatentransformationen man diese Regel ausdehnen kann. Wir zeigen dies auf und untersuchen einen Fall, in dem diese Regel nicht gilt. Es stellt sich heraus, dass der am genauesten transformierbare Neupunkt theoretisch sogar außerhalb der konvexen Hülle der Anschlusspunkte liegen kann.A rule well-known in Geodesy states that the accuracy of points to be transformed is best in the centre of gravity of the control points. Less well- known is, under which conditions this rule gen- erally applies. The exact set of coordinate transforms, to which we can extend the validity of this rule, is widelyunknown. We demonstrate this and investigate a case, in which this rule does not apply. It turns out that the most accurately transformable point be even be located outside the convex hull of the control points.
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Lösler, Michael, Torsten Lossin, Alexander Neidhardt, and Rüdiger Lehmann. "Untersuchung zur automatisierten Bestimmung des IVS-Referenzpunktes am TWIN Radioteleskop Wettzell." Hochschule für Technik und Wirtschaft Dresden, 2014. https://htw-dresden.qucosa.de/id/qucosa%3A23284.
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Die Verknüpfung von geodätischen Raumtechniken wie GNSS, DORIS, SLR oder VLBI zur Ableitung eines geodätischen Referenzrahmens wie dem ITRF gelingt erst durch sogenannte Kolokationsstationen. Die geometrischen Beziehungen zwischen den betriebenen Raumtechniken sind dabei aus präzisen lokalen Vermessungen abzuleiten. Es wird ein Konzept zur automatisierten Bestimmung des IVS-Referenzpunktes am TWIN Radioteleskop Wettzell vorgestellt. Erste Untersuchungsergebnisse werden präsentiert.
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Lehmann, Rüdiger. "Observation error model selection by information criteria vs. normality testing." Hochschule für Technik und Wirtschaft Dresden, 2015. https://htw-dresden.qucosa.de/id/qucosa%3A23301.
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To extract the best possible information from geodetic and geophysical observations, it is necessary to select a model of the observation errors, mostly the family of Gaussian normal distributions. However, there are alternatives, typically chosen in the framework of robust M-estimation. We give a synopsis of well-known and less well-known models for observation errors and propose to select a model based on information criteria. In this contribution we compare the Akaike information criterion (AIC) and the Anderson Darling (AD) test and apply them to the test problem of fitting a straight line. The comparison is facilitated by a Monte Carlo approach. It turns out that the model selection by AIC has some advantages over the AD test.
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Lehmann, Rüdiger, and Michael Lösler. "Multiple Outlier Detection: Hypothesis Tests versus Model Selection by Information Criteria." Hochschule für Technik und Wirtschaft Dresden, 2016. https://htw-dresden.qucosa.de/id/qucosa%3A23307.
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The detection of multiple outliers can be interpreted as a model selection problem. Models that can be selected are the null model, which indicates an outlier free set of observations, or a class of alternative models, which contain a set of additional bias parameters. A common way to select the right model is by using a statistical hypothesis test. In geodesy data snooping is most popular. Another approach arises from information theory. Here, the Akaike information criterion (AIC) is used to select an appropriate model for a given set of observations. The AIC is based on the Kullback-Leibler divergence, which describes the discrepancy between the model candidates. Both approaches are discussed and applied to test problems: the fitting of a straight line and a geodetic network. Some relationships between data snooping and information criteria are discussed. When compared, it turns out that the information criteria approach is more simple and elegant. Along with AIC there are many alternative information criteria for selecting different outliers, and it is not clear which one is optimal.
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Böhme, Hans-Joachim, Sven Hellbach, Zdeněk Míkovec, Pavel Slavík, and Markus Wacker. "Proceedings of the 20th Bilateral Student Workshop CTU Prague: Dresden (Germany) 2016." Hochschule für Technik und Wirtschaft Dresden, 2017. https://htw-dresden.qucosa.de/id/qucosa%3A23309.
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This technical report publishes the proceedings of the 20th Prague Workshop, which was held from 25th to 26th November 2016 The workshop offers a possibility for young scientists to present their current research work in the fields of computer graphics, human-computer-interaction, robotics and usability.
The works is meant as a platform to bring together researchers from both the Czech Technical University in Prague (CTU) and the University of Applied Sciences Dresden (HTW). The German Academic Exchange Service offers its financial support to allow student participants the bilateral exchange between Prague and Dresden.
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Böhme, Hans-Joachim, Sven Hellbach, Zdeněk Míkovec, Pavel Slavík, and Markus Wacker. "Proceedings of the 21th Bilateral Student Workshop CTU Prague: Dresden (Germany) 2017." Hochschule für Technik und Wirtschaft Dresden, 2018. https://htw-dresden.qucosa.de/id/qucosa%3A23315.
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This technical report publishes the proceedings of the 21th Prague Workshop, which was held from 25th to 26th December 2017. The workshop offers a possibility for young scientists to present their current research work in the fields of computer graphics, human-computer-interaction, robotics and usability.
The works is meant as a platform to bring together researchers from both the Czech Technical University in Prague (CTU) and the University of Applied Sciences Dresden (HTW). The German Academic Exchange Service offers its financial support to allow student participants the bilateral exchange between Prague and Dresden.
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Lehmann, Rüdiger. "On the formulation of the alternative hypothesis for geodetic outlier detection." Springer Verlag, 2013. https://htw-dresden.qucosa.de/id/qucosa%3A23274.
Full textAbstract:
The concept of outlier detection by statistical hypothesis testing in geodesy is briefly reviewed. The performance of such tests can only be measured or optimized with respect to a proper alternative hypothesis. Firstly, we discuss the important question whether gross errors should be treated as non-random quantities or as random variables. In the first case, the alternative hypothesis must be based on the common mean shift model, while in the second case, the variance inflation model is appropriate. Secondly, we review possible formulations of alternative hypotheses (inherent, deterministic, slippage, mixture) and discuss their implications. As measures of optimality of an outlier detection, we propose the premium and protection, which are briefly reviewed. Finally, we work out a practical example: the fit of a straight line. It demonstrates the impact of the choice of an alternative hypothesis for outlier detection.Das Konzept der Ausreißererkennung durch statistische Hypothesentests in der Geodäsie wird kurz überblickt. Die Leistungsfähigkeit solch eines Tests kann nur gemessen oder optimiert werden in Bezug auf eine geeignete Alternativhypothese. Als erstes diskutieren wir die wichtige Frage, ob grobe Fehler als nicht-zufällige oder zufällige Größen behandelt werden sollten. Im ersten Fall muss die Alternativhypothese auf das Mean-Shift-Modell gegründet werden, im zweiten Fall ist das Variance-Inflation-Modell passend. Als zweites stellen wir mögliche Formulierungen von Alternativhypothesen zusammen und diskutieren ihre Implikationen. Als Optimalitätsmaß schlagen wir das Premium-Protection-Maß vor, welches kurz überblickt wird. Schließlich arbeiten wir ein praktisches Beispiel aus: Die Anpassung einer ausgleichenden Gerade. Es zeigt die Auswirkung der Wahl einer Alternativhypothese für die Ausreißererkennung.
24
Lehmann, Rüdiger. "The 3σ-rule for outlier detection from the viewpoint of geodetic adjustment." American Society of Civil Engineers, 2013. https://htw-dresden.qucosa.de/id/qucosa%3A23281.
Full textAbstract:
The so-called 3σ-rule is a simple and widely used heuristic for outlier detection. This term is a generic term of some statistical hypothesis tests whose test statistics are known as normalized or studentized residuals. The conditions, under which this rule is statistically substantiated, were analyzed, and the extent it applies to geodetic least-squares adjustment was investigated. Then, the efficiency or non-efficiency of this method was analyzed and demonstrated on the example of repeated observations.Die sogenannte 3σ-Regel ist eine einfache und weit verbreitete Heuristik für die Ausreißererkennung. Sie ist ein Oberbegriff für einige statistische Hypothesentests, deren Teststatistiken als normierte oder studentisierte Verbesserungen bezeichnet werden. Die Bedingungen, unter denen diese Regel statistisch begründet ist, werden analysiert. Es wird untersucht, inwieweit diese Regel auf geodätische Ausgleichungsprobleme anwendbar ist. Die Effizienz oder Nichteffizienz dieser Methode wird analysiert und demonstriert am Beispiel von Wiederholungsmessungen.
25
Lehmann, Rüdiger. "Geodätische Fehlerrechnung mit der skalenkontaminierten Normalverteilung." Hochschule für Technik und Wirtschaft Dresden, 2012. https://htw-dresden.qucosa.de/id/qucosa%3A23282.
Full textAbstract:
Geodätische Messabweichungen werden oft gut durch Wahrscheinlichkeitsverteilungen beschrieben, die steilgipfliger als die Gaußsche Normalverteilung sind. Das gilt besonders, wenn grobe Messabweichungen nicht völlig ausgeschlossen werden können. Neben einigen in der Geodäsie bisher verwendeten Verteilungen (verallgemeinerte Normalverteilung, Hubers Verteilung) diskutieren wir hier die skalenkontaminierte Normalverteilung, die für die praktische Rechnung einige Vorteile bietet.Geodetic measurement errors are frequently well described by probability distributions, which are more peak-shaped than the Gaussian normal distribution. This is especially true when gross errors cannot be excluded. Besides some distributions used so far in geodesy (generalized normal distribution, Huber’s distribution) we discuss the scale contaminated normal distribution, which offers some advantages in practical calculations.
26
Lehmann, Rüdiger. "Transformation model selection by multiple hypotheses testing." Hochschule für Technik und Wirtschaft Dresden, 2014. https://htw-dresden.qucosa.de/id/qucosa%3A23299.
Full textAbstract:
Transformations between different geodetic reference frames are often performed such that first the transformation parameters are determined from control points. If in the first place we do not know which of the numerous transformation models is appropriate then we can set up a multiple hypotheses test. The paper extends the common method of testing transformation parameters for significance, to the case that also constraints for such parameters are tested. This provides more flexibility when setting up such a test. One can formulate a general model with a maximum number of transformation parameters and specialize it by adding constraints to those parameters, which need to be tested. The proper test statistic in a multiple test is shown to be either the extreme normalized or the extreme studentized Lagrange multiplier. They are shown to perform superior to the more intuitive test statistics derived from misclosures. It is shown how model selection by multiple hypotheses testing relates to the use of information criteria like AICc and Mallows’ Cp, which are based on an information theoretic approach. Nevertheless, whenever comparable, the results of an exemplary computation almost coincide.
27
Böhme, Hans-Joachim, Sven Hellbach, Zdeněk Míkovec, Pavel Slavík, and Markus Wacker. "Proceedings of the 19th Bilateral Student Workshop CTU Prague: Dresden (Germany) 2015." Hochschule für Technik und Wirtschaft Dresden, 2017. https://htw-dresden.qucosa.de/id/qucosa%3A23308.
Full textAbstract:
This technical report publishes the proceedings of the 19th Prague Workshop, which was held from 27th to 28. November 2015. The workshop offers a possibility for young scientists to present their current research work in the fields of computer graphics, human-computer-interaction, robotics and usability.
The works is meant as a platform to bring together researchers from both the Czech Technical University in Prague (CTU) and the University of Applied Sciences Dresden (HTW). The German Academic Exchange Service offers its financial support to allow student participants the bilateral exchange between Prague and Dresden.
28
Lehmann, Rüdiger, and Frank Neitzel. "Testing the compatibility of constraints for parameters of a geodetic adjustment model." Springer Verlag, 2013. https://htw-dresden.qucosa.de/id/qucosa%3A23273.
Full textAbstract:
Geodetic adjustment models are often set up in a way that the model parameters need to fulfil certain constraints.
The normalized Lagrange multipliers have been used as a measure of the strength of constraint in such a way that
if one of them exceeds in magnitude a certain threshold then the corresponding constraint is likely to be incompatible with
the observations and the rest of the constraints. We show that these and similar measures can be deduced as test statistics of
a likelihood ratio test of the statistical hypothesis that some constraints are incompatible in the same sense. This has been
done before only for special constraints (Teunissen in Optimization and Design of Geodetic Networks, pp. 526–547,
1985). We start from the simplest case, that the full set of constraints is to be tested, and arrive at the advanced case,
that each constraint is to be tested individually. Every test is worked out both for a known as well as for an unknown
prior variance factor. The corresponding distributions under null and alternative hypotheses are derived. The theory is
illustrated by the example of a double levelled line.Geodätische Ausgleichungsmodelle werden oft auf eine Weise formuliert, bei der die Modellparameter bestimmte Bedingungsgleichungen zu erfüllen haben. Die normierten Lagrange-Multiplikatoren wurden bisher als Maß für den ausgeübten Zwang verwendet, und zwar so, dass wenn einer von ihnen betragsmäßig eine bestimmte Schwelle übersteigt, dann ist davon auszugehen, dass die zugehörige Bedingungsgleichung nicht mit den Beobachtungen und den restlichen Bedingungsgleichungen kompatibel ist. Wir zeigen, dass diese und ähnliche Maße als Teststatistiken eines Likelihood-Quotiententests der statistischen Hypothese, dass einige Bedingungsgleichungen in diesem Sinne inkompatibel sind, abgeleitet werden können. Das wurde bisher nur für spezielle Bedingungsgleichungen getan (Teunissen in Optimization and Design of Geodetic Networks, pp. 526–547, 1985). Wir starten vom einfachsten Fall, dass die gesamte Menge der Bedingungsgleichungen getestet werden muss, und gelangen zu dem fortgeschrittenen Problem, dass jede Bedingungsgleichung individuell zu testen ist. Jeder Test wird sowohl für bekannte, wie auch für unbekannte a priori Varianzfaktoren ausgearbeitet. Die zugehörigen Verteilungen werden sowohl unter der Null- wie auch unter der Alternativhypthese abgeleitet. Die Theorie wird am Beispiel einer Doppelnivellementlinie illustriert.
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Kunath, Maxi. "Erfassung und Bewertung von Quellen im Forstrevier Ottomühle zur Erarbeitung von Handlungsempfehlungen für die Renaturierung oder zukünftige Pflege der Quellbereiche und die forstliche Bewirtschaftung im Umfeld." Bachelor's thesis, Hochschule für Technik und Wirtschaft, 2020. https://htw-dresden.qucosa.de/id/qucosa%3A73113.
Full textAbstract:
Ziel der vorliegenden Bachelorarbeit war es, die Grundwasseraustritte im Forstrevier Ottomühle zu erfassen und zu bewerten, um Handlungsempfehlungen für die Renaturierung oder zukünftige Pflege der Quellbereiche und die forstliche Bewirtschaftung im Umfeld erarbeiten zu können.
Zwischen März und Juni 2020 konnten insgesamt 19 Quellen im Forstrevier Ottomühle auf Grundlage einer Handlungsanleitung des Bayrischen Landesamtes für Umwelt erfasst und nach ihrer Naturnähe bewertet werden. Die vorgefundenen Beeinträchtigungen waren in absteigender Häufigkeit (Anzahl der betroffenen Quellen):
• Nicht standortgerechter Baumbestand (12)
• Kronenmaterial oder Schlagabraum (9)
• Trittschäden (8)
• Aufstau (5)
• Kahlschlag (3)
• Oberflächen- oder Drainagewassereinleitung (3)
• Uferverbau oder Sohlenverbau (3)
• Verrohrung (3)
• Totalverbau (2)
• Umleitung oder Verlegung (2)
Auf Basis aktueller Literatur wurde anschließend für jede Quelle eine Handlungsempfehlung erarbeitet. Sie beinhaltet Maßnahmenvorschläge, Renaturierungsempfehlungen sowie Pflege- und Bewirtschaftungshinweise für den Quellbereich und das nähere Umfeld.:1 EINLEITUNG
2 MATERIAL UND METHODEN
2.1 UNTERSUCHUNGSGEBIET
2.2 SYSTEMATIK DER QUELLEN
2.3 DATENAUFNAHME IM FREILAND
2.3.1 Basis-Bogen
2.3.2 Detail-Bogen
2.4 QUELLENBEWERTUNG
2.5 ERARBEITUNG DER HANDLUNGSEMPFEHLUNG
3 ERGEBNISSE
3.1 ALLGEMEINE AUSWERTUNG
3.2 EINZELQUELLEN
3.2.1 „Wegquelle“ (ID 00001)
3.2.2 Zehrborn (ID 00002)
3.2.3 „Sumpfquelle“ (ID00003)
3.2.4 „Eisenquelle“ (ID 00004)
3.2.5 „Flurquelle“ (ID 00005)
3.2.6 Singeborn (ID 00006)
3.2.7 „Turmquelle“ (ID 00007/00008)
3.2.8 „Wildquelle“ (ID 00009)
3.2.9 „Teichquelle“ (ID 00010)
3.2.10 „Kapuzinerquelle“ (ID 00011)
3.2.11 Herkulesquelle (ID 00012)
3.2.12 „Johannisquelle“ (ID 00013)
3.2.13 „Kachequelle“ (ID 00015)
3.2.14 „Fichtenquelle“ (ID 00016)
3.2.15 „Jägerquelle“ (ID 00017)
3.2.16 „Brennnesselquelle“ (ID 00018)
3.2.17 „Fallenquelle“ (ID 00019)
3.2.18 „Dornquelle“ (ID 00020)
3.2.19 „Hainquelle“ (ID 00021)
4 DISKUSSION
5 FAZIT
ANHANGThe aim of this bachelor thesis was to register and evaluate the current state of coldwater springs in the forest district „Ottomühle“. The gathered data was used to develop recommendations for action, which include renaturation processes, future maintenance of the springs and forest management in the surrounding areas. From March to June 2020 a total of 19 springs were registered in the district. The collection of needed parameters and the proximate assessment according to a springs natural state followed the instruction manual of the Bavarian State Office for the Environment (Bayrisches Landesamtes für Umwelt). The impairments found were in decreasing frequency (number of affected springs): • Non-natural tree population (12) • Branch material or low-grade timber (9) • Soil damage by trampling or vehicles (8) • Water impoundment (5) • Forest clearance (3) • Waterinput from surface or drainage water (3) • Piping (3) • Obstruction of riverbanks or riverbed sheeting (3) • Complete obstruction (2) • Bypass or relocation (2) The recommendations for further action in relation to impairments are presented in this paper.:1 EINLEITUNG 2 MATERIAL UND METHODEN 2.1 UNTERSUCHUNGSGEBIET 2.2 SYSTEMATIK DER QUELLEN 2.3 DATENAUFNAHME IM FREILAND 2.3.1 Basis-Bogen 2.3.2 Detail-Bogen 2.4 QUELLENBEWERTUNG 2.5 ERARBEITUNG DER HANDLUNGSEMPFEHLUNG 3 ERGEBNISSE 3.1 ALLGEMEINE AUSWERTUNG 3.2 EINZELQUELLEN 3.2.1 „Wegquelle“ (ID 00001) 3.2.2 Zehrborn (ID 00002) 3.2.3 „Sumpfquelle“ (ID00003) 3.2.4 „Eisenquelle“ (ID 00004) 3.2.5 „Flurquelle“ (ID 00005) 3.2.6 Singeborn (ID 00006) 3.2.7 „Turmquelle“ (ID 00007/00008) 3.2.8 „Wildquelle“ (ID 00009) 3.2.9 „Teichquelle“ (ID 00010) 3.2.10 „Kapuzinerquelle“ (ID 00011) 3.2.11 Herkulesquelle (ID 00012) 3.2.12 „Johannisquelle“ (ID 00013) 3.2.13 „Kachequelle“ (ID 00015) 3.2.14 „Fichtenquelle“ (ID 00016) 3.2.15 „Jägerquelle“ (ID 00017) 3.2.16 „Brennnesselquelle“ (ID 00018) 3.2.17 „Fallenquelle“ (ID 00019) 3.2.18 „Dornquelle“ (ID 00020) 3.2.19 „Hainquelle“ (ID 00021) 4 DISKUSSION 5 FAZIT ANHANG
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Bielefeld, Malte. "Übertragung von Prinzipien der Ameisenkolonieoptimierung auf eine sich selbst organisierende Produktion." Bachelor's thesis, Hochschule für Technik und Wirtschaft, 2019. https://htw-dresden.qucosa.de/id/qucosa%3A34517.
Full textAbstract:
Die Bachelorarbeit behandelt die Themen der Selbstorganisation in Produktionssystemen im Kontext von Industrie 4.0. Dabei wird gezeigt, wie man mithilfe von einer Ameisenkolonieoptimierung die Reihenfolgeplanung organisieren kann.:Abbildungsverzeichnis
Tabellenverzeichnis
Formelverzeichnis
1. Einleitung
1.1. Motivation
1.2. Ziele
1.3. Vorgehensweise
2. Sich selbst organisierende Produktionen
2.1. Begriffserklärung
2.2. Stand der Technik
2.3. Reihenfolgeplanung als ein Problem der Selbstorganisation
2.3.1. Begriffserklärung
2.3.2. Stand der Technik
2.3.3. Umsetzung in einer Selbstorganisation
3. Ameisenkolonieoptimierung
3.1. Begriffserklärung
3.2. Allgemeine Umsetzung
3.3. Konkrete Umsetzungen
3.4. Vor- und Nachteile
3.5. Anwendungsbeispiele
4. Entwicklung einer Ameisenkolonieoptimierung für ein sich selbst organisierendes Produktionssystem
4.1. Analyse des gegebenen sich selbst organisierenden Produktionssystems
4.1.1. Grobanalyse des Systems
4.1.2. Feinanalyse der bisherigen Reihenfolgeplanung
4.2. Entwurf der Reihenfolgeplanung durch Prinzipien der Ameisenkolonieoptimierung
4.3. Implementierung der Prinzipien der Ameisenkolonieoptimierung
5. Empirische Untersuchung der implementierten Ameisenkolonieoptimierung
5.1. Beschreibung der gegebenen Produktionsdaten
5.2. Szenarienuntersuchung zur Funktionsfähigkeit
5.2.1. Schichtwechselszenario
5.2.2. Abnutzungs- und Wartungsszenario
5.2.3. Vergleichsszenario
5.3. Untersuchung hinsichtlich der Laufzeit und des Speicherbedarfs
5.3.1. Laufzeit
5.3.2. Speicherbedarf
6. Zusammenfassung und Ausblick
6.1. Zusammenfassung
6.2. Ausblick
QuellenverzeichnisThe bachelor thesis is about self organization in production systems in the context of Industry 4.0. Its about ant colony optimization for scheduling in the production planning.:Abbildungsverzeichnis Tabellenverzeichnis Formelverzeichnis 1. Einleitung 1.1. Motivation 1.2. Ziele 1.3. Vorgehensweise 2. Sich selbst organisierende Produktionen 2.1. Begriffserklärung 2.2. Stand der Technik 2.3. Reihenfolgeplanung als ein Problem der Selbstorganisation 2.3.1. Begriffserklärung 2.3.2. Stand der Technik 2.3.3. Umsetzung in einer Selbstorganisation 3. Ameisenkolonieoptimierung 3.1. Begriffserklärung 3.2. Allgemeine Umsetzung 3.3. Konkrete Umsetzungen 3.4. Vor- und Nachteile 3.5. Anwendungsbeispiele 4. Entwicklung einer Ameisenkolonieoptimierung für ein sich selbst organisierendes Produktionssystem 4.1. Analyse des gegebenen sich selbst organisierenden Produktionssystems 4.1.1. Grobanalyse des Systems 4.1.2. Feinanalyse der bisherigen Reihenfolgeplanung 4.2. Entwurf der Reihenfolgeplanung durch Prinzipien der Ameisenkolonieoptimierung 4.3. Implementierung der Prinzipien der Ameisenkolonieoptimierung 5. Empirische Untersuchung der implementierten Ameisenkolonieoptimierung 5.1. Beschreibung der gegebenen Produktionsdaten 5.2. Szenarienuntersuchung zur Funktionsfähigkeit 5.2.1. Schichtwechselszenario 5.2.2. Abnutzungs- und Wartungsszenario 5.2.3. Vergleichsszenario 5.3. Untersuchung hinsichtlich der Laufzeit und des Speicherbedarfs 5.3.1. Laufzeit 5.3.2. Speicherbedarf 6. Zusammenfassung und Ausblick 6.1. Zusammenfassung 6.2. Ausblick Quellenverzeichnis
31
Lehmann, Rüdiger. "Ebene Geodätische Berechnungen: Internes Manuskript." Hochschule für Technik und Wirtschaft, 2018. https://htw-dresden.qucosa.de/id/qucosa%3A31824.
Full textAbstract:
Dieses Manuskript entstand aus Vorlesungen über Geodätische Berechnungen an der Hochschule für Technik und Wirtschaft Dresden. Da diese Lehrveranstaltung im ersten oder zweiten Semester stattfindet, werden noch keine Methoden der höheren Mathematik benutzt. Das Themenspektrum beschränkt sich deshalb weitgehend auf elementare Berechnungen in der Ebene.:0 Vorwort
1 Ebene Trigonometrie
1.1 Winkelfunktionen
1.2 Berechnung schiefwinkliger ebener Dreiecke
1.3 Berechnung schiefwinkliger ebener Vierecke
2 Ebene Koordinatenrechnung
2.1 Kartesische und Polarkoordinaten
2.2 Erste Geodätische Grundaufgabe
2.3 Zweite Geodätische Grundaufgabe
3 Flächenberechnung und Flächenteilung
3.1 Flächenberechnung aus Maßzahlen.
3.2 Flächenberechnung aus Koordinaten
3.3 Absteckung und Teilung gegebener Dreiecksflächen
3.4 Absteckung und Teilung gegebener Vierecksflächen
4 Kreis und Ellipse
4.1 Kreisbogen und Kreissegment
4.2 Näherungsformeln für flache Kreisbögen
4.3 Sehnen-Tangenten-Verfahren
4.4 Grundlegendes über Ellipsen
4.5 Abplattung und Exzentrizitäten
4.6 Die Meridianellipse der Erde
4.7 Flächeninhalt und Bogenlängen
5 Ebene Einschneideverfahren
5.1 Bogenschnitt
5.2 Vorwärtsschnitt
5.3 Anwendung: Geradenschnitt
5.4 Anwendung: Kreis durch drei Punkte
5.5 Schnitt Gerade ⎼ Kreis oder Strahl ⎼ Kreis
5.6 Rückwärtsschnitt
5.7 Anwendung: Rechteck durch fünf Punkte
6 Ebene Koordinatentransformationen
6.1 Elementare Transformationsschritte
6.2 Rotation und Translation.
6.3 Rotation, Skalierung und Translation
6.4 Ähnlichkeitstransformation mit zwei identischen Punkten
6.5 Anwendung: Hansensche Aufgabe
6.6 Anwendung: Kleinpunktberechnung
6.7 Anwendung: Rechteck durch fünf Punkte
6.8 Ebene Helmert-Transformation
6.9 Bestimmung der Parameter bei Rotation und Translation
6.10 Ebene Affintransformation
7 LösungenThis manuscript evolved from lectures on Geodetic Computations at the University of Applied Sciences Dresden (Germany). Since this lecture is given in the first or second semester, no advanced mathematical methods are used. The range of topics is limited to elementary computations in the plane.:0 Vorwort 1 Ebene Trigonometrie 1.1 Winkelfunktionen 1.2 Berechnung schiefwinkliger ebener Dreiecke 1.3 Berechnung schiefwinkliger ebener Vierecke 2 Ebene Koordinatenrechnung 2.1 Kartesische und Polarkoordinaten 2.2 Erste Geodätische Grundaufgabe 2.3 Zweite Geodätische Grundaufgabe 3 Flächenberechnung und Flächenteilung 3.1 Flächenberechnung aus Maßzahlen. 3.2 Flächenberechnung aus Koordinaten 3.3 Absteckung und Teilung gegebener Dreiecksflächen 3.4 Absteckung und Teilung gegebener Vierecksflächen 4 Kreis und Ellipse 4.1 Kreisbogen und Kreissegment 4.2 Näherungsformeln für flache Kreisbögen 4.3 Sehnen-Tangenten-Verfahren 4.4 Grundlegendes über Ellipsen 4.5 Abplattung und Exzentrizitäten 4.6 Die Meridianellipse der Erde 4.7 Flächeninhalt und Bogenlängen 5 Ebene Einschneideverfahren 5.1 Bogenschnitt 5.2 Vorwärtsschnitt 5.3 Anwendung: Geradenschnitt 5.4 Anwendung: Kreis durch drei Punkte 5.5 Schnitt Gerade ⎼ Kreis oder Strahl ⎼ Kreis 5.6 Rückwärtsschnitt 5.7 Anwendung: Rechteck durch fünf Punkte 6 Ebene Koordinatentransformationen 6.1 Elementare Transformationsschritte 6.2 Rotation und Translation. 6.3 Rotation, Skalierung und Translation 6.4 Ähnlichkeitstransformation mit zwei identischen Punkten 6.5 Anwendung: Hansensche Aufgabe 6.6 Anwendung: Kleinpunktberechnung 6.7 Anwendung: Rechteck durch fünf Punkte 6.8 Ebene Helmert-Transformation 6.9 Bestimmung der Parameter bei Rotation und Translation 6.10 Ebene Affintransformation 7 Lösungen
32
Böhme, Hans Joachim, Markus Wacker, Pavel Slavík, and Zdeněk Míkovec. "Proceedings of the 22th Bilateral Student Workshop CTU Prague: Dresden (Germany) 2018." Hochschule für Technik und Wirtschaft, 2019. https://htw-dresden.qucosa.de/id/qucosa%3A36112.
Full textAbstract:
This technical report publishes the proceedings of the 22th Prague Workshop, which was held from 30th November to 1st December 2018. The workshop offers a possibility for young scientists to present their current research work in the fields of computer graphics, human-computer-interaction, robotics and usability. The works is meant as a platform to bring together researchers from both the Czech Technical University in Prague (CTU) and the University of Applied Sciences Dresden (HTW). The German Academic Exchange Service offers its financial support to allow student participants the bilateral exchange between Prague and Dresden.:1) An approach to a self-organizing production in com-
parison to a centrally planned production 4
2) Tactile symbols for visually impaired older adults 9
3) Design of Olfactory Cues for Approximate Spatial Self-
Localization 11
4) Shape To Muscle: A Model for estimating Muscle
Activation from Skin Deformation 13
5) Model of a Conversational System for Controlling Sec-
ondary Tasks while Driving 19
6) Tools for Art and Architectural Research with His-
toric Media Repositories 22
7) Direct Labels: Real-time External Labeling Without
Leader Lines 25
8) Seamless Cloning with Poisson Image Editing 29
9) Multimodal user interaction for human behavior mod-
eling in adaptation and personalization 32
10) Objective Feature Selection using GMLVQ with Di-
rectly Incorporated L1-Regularization 35
11) How to Call a Robot in an Emergency Situation 37
12) Development of a Collaborative Computer Game for
Elderly with Dementia 39
33
Hesse, Elfi, Juliane Baier, and Knut Schmidtke. "FDM-Handbuch für HAW: Handlungshilfe für aktives Forschungsdatenmanagement an Hochschulen für angewandte Wissenschaften." Hochschule für Technik und Wirtschaft, 2019. https://htw-dresden.qucosa.de/id/qucosa%3A36556.
Full textAbstract:
Das hier vorliegende Handbuch ist im Rahmen des Projektes „Vernetztes Forschungsdatenmanagement an Hochschulen für angewandte Wissenschaften am Beispiel der HTW Dresden – FoDaMa-HTWD“ entstanden.1 Es stellt eine kurze und übersichtliche Zusammenfassung der wichtigsten Erkenntnisse dar, welche während der Projektlaufzeit an der Hochschule für Technik und Wirtschaft Dresden (HTWD) zum Forschungsdatenmanagement (FDM) gewonnen wurden. Die Autor/innen möchten mit diesem Handbuch andere Hochschulen für angewandte Wissenschaften (HAW) bei der Strategieentwicklung und dem notwendigen FDM-Strukturaufbau unterstützen. Es richtet sich demnach vorrangig an Personen, die sich an Hochschulen mit der strategischen Weiterentwicklung im Bereich Forschung beschäftigen und sich vielleicht die Frage stellen, welche unterstützenden
FDM-Services und Maßnahmen ergriffen werden sollten, damit die Forschenden der eigenen Institution der zunehmenden Forderung nach offener und nachhaltiger Arbeitsweise im Umgang mit Forschungsdaten gerecht werden können.This handbook was developed within the project ' Vernetztes Forschungsdatenmanagement an Hochschulen für angewandte Wissenschaften am Beispiel der HTW Dresden – FoDaMa-HTWD '. It is a short and clear summary of the most important findings, which were gained during the project at the University of Applied Sciences Dresden (HTWD) on research data management (FDM). With this handbook, the authors would like to support other Universities of Applied Sciences (HAW) in developing strategies and the necessary FDM structure. It is therefore primarily aimed at people who are involved in the strategic development of research at universities and who may ask themselves the question of which supporting FDM services and measures should be taken to ensure that the researchers of their own institution are able to meet the increasing demand for open and sustainable working methods in dealing with research data.
34
Griebsch, Anne. "Untersuchungen zur Klauengesundheit in einem Sächsischen Milchviehbetrieb." Hochschule für Technik und Wirtschaft, 2016. https://htw-dresden.qucosa.de/id/qucosa%3A70549.
Full textAbstract:
Die Abschlussarbeit beschäftigt sich mit der Klauengesundheit von Deutschen Holsteins Kühen in einem Sächsischen Milchviehbetrieb. Ziel war die Erfassung und Bewertung der Klauenmaße und Klauengesundheit bei unterschiedlicher Laufflächengestaltung. Aufgrund einer hohen Prävalenz von 89,1 % im Bereich Klauen und Gliedmaßen und der starken Abnutzung des vorhandenen Gussasphaltes im Laufstall, wurde nach der Ist-Aufnahme (Klauenschnitt, Erfassung von Klauenkrankheiten und –maßen) im Mai 2016 eine Stallhälfte am Futtertisch komplett mit Gummiboden (Kraiburg Kura P) ausgelegt und zwei Versuchsgruppen (N=178) gebildet. Während der 93-tägigen Versuchsphase wurden Daten zum Locomotion Score, Hygienescore, Anzahl aktiver Kühe, Gruppenstärke sowie Klimadaten erhoben. Am Ende der Beobachtungsphase wurden alle Versuchstiere einer weiteren Klauenpflege unterzogen, die Klauenmaße und eventuelle Klauenerkrankungen erfasst. Im Ergebnis konnte gezeigt werden, dass sich die Klauengesundheit der Versuchsgruppe, auf einer Kombination von Gummiboden und Gussasphalt, im Vergleich zur Kontrolle, bei der nur Gussasphalt berücksichtigt wurde, verbessert hatte. Zudem konnte verdeutlicht werden, dass Klauenerkrankungen multifaktoriell sind. Der Einbau von Gummiboden kann gesundheitsfördernd wirken, z. B. durch geringere Belastung und besseres Wohlbefinden, aber das Management hat einen essentiellen Anteil der Klauen- und Gliedmaßengesundheit. Als Empfehlung wird eine Kombination aus weichen und abrasiven Laufflächen als sinnvoll angesehen. Jedoch wird eine Analyse des gesamten Managements und der Haltungsumwelt der Tiere unerlässlich, da der Mensch der wichtigste Einflussfaktor auf die Klauen- und Gliedmaßengesundheit ist.:Inhalt
Abkürzungsverzeichnis V
Abbildungsverzeichnis VI
Tabellenverzeichnis VIII
1. Einleitung 1
2. Literaturteil 2
2.1 Physiologische Grundlagen der Hornqualität und des Hornwachstums 2
2.1.1 Anatomie der Klaue und der Klauenhaut 2
2.1.2 Hornqualität 5
2.1.3 Messung der Klauenhornhärte zur Darstellung der Hornqualität 6
2.1.4 Erfassung der Klauenmaße zur Überprüfung des Hornschuhs 9
2.2 Übersicht zu den wichtigsten Klauenerkrankungen 12
2.3 Faktorenkrankheit Dermatitis Digitalis 17
2.4 Bewertung des Gangverhaltens mittels Locomotion Score 20
2.5 Bewertung der Stallhygiene mittels Hygienescore 23
2.6 Liegeflächenmanagement und Liegeverhalten 26
2.7 Gussasphalt vs. Gummibelag, Vor- und Nachteile der dargestellten Bodenbeläge 30
2.8 Stallklima 34
2.9 Management der Klauen- und Gliedmaßengesundheit 36
3. Material und Methoden 39
3.1 Tierbestand und betriebliche Gegebenheiten 39
3. 2 Versuchsaufbau 41
3.3 Datenerfassung 46
3.3.1 Bestimmung der Klauenmaße 46
3.3.2 Erfassung der Klauenbefunde 48
3.3.3 Erfassung Locomotion Score 49
3.3.4 Erfassung Hygienescore 50
3.3.5 Erfassung weiterer Parameter für die Beurteilung Klauengesundheit 50
3.3.6 Bestimmung Klimadaten 51
3.4 Datenauswertung 52
4. Ergebnisse 53
4.1 Prävalenz 53
4.1.1 Auswertung aller Klauenerkrankungen 53
4.1.2 Auswertung Dermatitis Digitalis 56
4.2 Klauendaten 57
4.3 Locomotion Score 59
4.4 Hygienescore 61
4.5 Auswertung weiterer Parameter für die Beurteilung der Klauengesundheit 62
4.6 Klimadaten 67
5. Diskussion und Schlussfolgerungen 69
5.1 Ist-Situation der Klauengesundheit in Bezug auf die gesamte Herde 69
5.2 Entwicklung der Klauengesundheit und Klauenmaße in den Untersuchungsgruppen 70
5.3 Weitere Einflussfaktoren auf die Klauengesundheit 75
5.4 Locomotion Score 79
5.5 Hygienescore 80
5.6 Schlussfolgerungen für die Praxis 81
6. Zusammenfassung 83
Literaturverzeichnis 85
Anhang 97The current work focuses on claw health within a herd of German Holsteins on a Saxon dairy farm. The aim was to record and evaluate the claw dimensions and claw health on different flooring systems. Due to a high prevalence of 89.1% in the area of the claws and limbs and the heavy wear of the existing mastic asphalt in the playpen, the operational management decided to carry out a partial renovation of the flooring system. Thus, after recording the actual condition (claw cut, recording of claw diseases and dimensions) in May 2016, one half of the stable at the feeding table was completely covered with rubber flooring (Kura P by Kraiburg) and two test groups (N=178) were formed. During the 93-day trial period, data were collected on locomotion score, hygiene score, number of active cows, group strength and climate data. At the end of the observation phase, all test animals were subjected to further claw care, claw dimensions and possible claw diseases were recorded. As a result, it was shown that the claw health of the experimental group had improved on a combination of rubber flooring and mastic asphalt compared to the control that only considered mastic asphalt. In addition, it could be shown that claw diseases are multifactorial. The installation of rubber flooring can have a health-promoting effect, e.g. by reducing stress and improving well-being, but management plays a major role in claw and limb health. A combination of soft and abrasive treads is considered reasonable. However, an analysis of the overall management and housing environment of the animals becomes essential as humans are the most important factor influencing claw and limb health.:Inhalt Abkürzungsverzeichnis V Abbildungsverzeichnis VI Tabellenverzeichnis VIII 1. Einleitung 1 2. Literaturteil 2 2.1 Physiologische Grundlagen der Hornqualität und des Hornwachstums 2 2.1.1 Anatomie der Klaue und der Klauenhaut 2 2.1.2 Hornqualität 5 2.1.3 Messung der Klauenhornhärte zur Darstellung der Hornqualität 6 2.1.4 Erfassung der Klauenmaße zur Überprüfung des Hornschuhs 9 2.2 Übersicht zu den wichtigsten Klauenerkrankungen 12 2.3 Faktorenkrankheit Dermatitis Digitalis 17 2.4 Bewertung des Gangverhaltens mittels Locomotion Score 20 2.5 Bewertung der Stallhygiene mittels Hygienescore 23 2.6 Liegeflächenmanagement und Liegeverhalten 26 2.7 Gussasphalt vs. Gummibelag, Vor- und Nachteile der dargestellten Bodenbeläge 30 2.8 Stallklima 34 2.9 Management der Klauen- und Gliedmaßengesundheit 36 3. Material und Methoden 39 3.1 Tierbestand und betriebliche Gegebenheiten 39 3. 2 Versuchsaufbau 41 3.3 Datenerfassung 46 3.3.1 Bestimmung der Klauenmaße 46 3.3.2 Erfassung der Klauenbefunde 48 3.3.3 Erfassung Locomotion Score 49 3.3.4 Erfassung Hygienescore 50 3.3.5 Erfassung weiterer Parameter für die Beurteilung Klauengesundheit 50 3.3.6 Bestimmung Klimadaten 51 3.4 Datenauswertung 52 4. Ergebnisse 53 4.1 Prävalenz 53 4.1.1 Auswertung aller Klauenerkrankungen 53 4.1.2 Auswertung Dermatitis Digitalis 56 4.2 Klauendaten 57 4.3 Locomotion Score 59 4.4 Hygienescore 61 4.5 Auswertung weiterer Parameter für die Beurteilung der Klauengesundheit 62 4.6 Klimadaten 67 5. Diskussion und Schlussfolgerungen 69 5.1 Ist-Situation der Klauengesundheit in Bezug auf die gesamte Herde 69 5.2 Entwicklung der Klauengesundheit und Klauenmaße in den Untersuchungsgruppen 70 5.3 Weitere Einflussfaktoren auf die Klauengesundheit 75 5.4 Locomotion Score 79 5.5 Hygienescore 80 5.6 Schlussfolgerungen für die Praxis 81 6. Zusammenfassung 83 Literaturverzeichnis 85 Anhang 97
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Lehmann, Rüdiger. "A universal and robust computation procedure for geometric observations." Hochschule für Technik und Wirtschaft, 2017. https://htw-dresden.qucosa.de/id/qucosa%3A31843.
Full textAbstract:
This contribution describes an automatic and robust method, which can be applied to all classical geodetic computation problems. Starting from given input quantities (e.g. coordinates of known points, observations) computation opportunities for all other relevant quantities are found. For redundant input quantities there exists a multitude of different computation opportunities from different minimal subsets of input quantities, which are all found automatically, and their results are computed and compared. If the computation is non-unique, but only a finite number of solutions exist, then all solutions are found and computed. By comparison of the different computation results we may detect outliers in the input quantities and produce a robust final result. The method does not work stochastically, such that no stochastic model of the observations is required. The description of the algorithm is illustrated for a practical case. It is implemented on a webserver and is available for free via internet.Der Beitrag beschreibt ein automatisches und robustes Verfahren, welches auf alle klassischen geodätischen Berechnungsprobleme angewendet werden kann. Ausgehend von vorgelegten Eingabegrößen (z.B. Koordinaten bekannter Punkte, Beobachtungen) werden Berechnungsmöglichkeiten für alle anderen relevanten Größen gefunden. Bei redundanten Eingabegrößen existiert eine Vielzahl von verschiedenen Berechnungsmöglichkeiten aus verschiedenen minimalen Untermengen von Eingabegrößen, die alle automatisch gefunden und deren Ergebnisse berechnet und verglichen werden. Wenn die Berechnung nicht eindeutig ist, aber nur eine endliche Anzahl von Lösungen existiert, dann werden alle Lösungen gefunden und berechnet. Durch den Vergleich verschiedener Berechnungsergebnisse können Ausreißer in den Eingabegrößen aufgedeckt werden und ein robustes Endergebnis wird erhalten. Das Verfahren arbeitet nicht stochastisch, so dass kein stochastisches Modell der Beobachtungen erforderlich ist. Die Beschreibung des Algorithmus wird an einem praktischen Fall illustriert. Er ist auf einem Webserver installiert und über das Internet frei verfügbar.
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Aland, Sebastian, Sabine Egerer, John Lowengrub, and Axel Voigt. "Diffuse interface models of locally inextensible vesicles in a viscous fluid." Elsevier, 2014. https://htw-dresden.qucosa.de/id/qucosa%3A32307.
Full textAbstract:
We present a new diffuse interface model for the dynamics of inextensible vesicles in a viscous fluid with inertial forces. A new feature of this work is the implementation of the local inextensibility condition in the diffuse interface context. Local inextensibility is enforced by using a local Lagrange multiplier, which provides the necessary tension force at the interface. We introduce a new equation for the local Lagrange multiplier whose solution essentially provides a harmonic extension of the multiplier off the interface while maintaining the local inextensibility constraint near the interface. We also develop a local relaxation scheme that dynamically corrects local stretching/compression errors thereby preventing their accumulation. Asymptotic analysis is presented that shows that our new system converges to a relaxed version of the inextensible sharp interface model. This is also verified numerically. To solve the equations, we use an adaptive finite element method with implicit coupling between the Navier-Stokes and the diffuse interface inextensibility equations. Numerical simulations of a single vesicle in a shear flow at different Reynolds numbers demonstrate that errors in enforcing local inextensibility may accumulate and lead to large differences in the dynamics in the tumbling regime and smaller differences in the inclination angle of vesicles in the tank-treading regime. The local relaxation algorithm is shown to prevent the accumulation of stretching and compression errors very effectively. Simulations of two vesicles in an extensional flow show that local inextensibility plays an important role when vesicles are in close proximity by inhibiting fluid drainage in the near contact region.
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Lehmann, Rüdiger, and Anja Voß-Böhme. "On the statistical power of Baarda’s outlier test and some alternative." Hochschule für Technik und Wirtschaft, 2017. https://htw-dresden.qucosa.de/id/qucosa%3A31756.
Full textAbstract:
Baarda’s outlier test is one of the best established
theories in geodetic practice. The optimal test statistic of
the local model test for a single outlier is known as the normalized
residual. Also other model disturbances can be
detected and identified with this test. It enjoys the property
of being a uniformly most powerful invariant (UMPI) test,
but is not a uniformly most powerful (UMP) test. In this
contribution we will prove that in the class of test statistics
following a common central or non-central chi2 distribution,
Baarda’s solution is also uniformly most powerful,
i.e. UMPchi2 for short. It turns out that UMPchi2 is identical to
UMPI, such that this proof can be seen as another proof of
the UMPI property of the test. We demonstrate by an example
that by means of the Monte Carlo method it is even
possible to construct test statistics, which are regionally
more powerful than Baarda’s solution. They follow a socalled
generalized chi2 distribution. Due to high computational
costs we do not yet propose this as a ”new outlier
detection method”, but only as a proof that it is in principle
possible to outperform the statistical power of Baarda’s
test.Der Ausreißertest nach Baarda ist eine der am besten etablierten Theorien in der geodätischen Praxis. Die optimale Teststatistik des lokalen Modelltests für einen einzelnen Ausreißer wird als normierte Verbesserung bezeichnet. Auch andere Modellabweichungen können mit diesem Test aufgedeckt und identifiziert werden. Er hat die Eigenschaft, der gleichmäßig stärkste invariante (uniformly most powerful invariant, UMPI) Test zu sein, aber er ist kein gleichmäßig stärkster (uniformly most powerful, UMP) Test. In diesem Beitrag werden wir beweisen, dass in der Klasse der Teststatistiken mit einer gewöhnlichen zentralen oder nichtzentralen chi2 Verteilung die Baardaschen Lösung auch gleichmäßig stärkster Test ist, abgekürzt UMPchi2. Es stellt sich heraus, dass UMPchi2 gleichwertig mit UMPI ist, so dass dieser Beweis als ein weiterer Beweis der UMPI-Eigenschaft des Testes angesehen werden kann. Wir zeigen an einem Beispiel, dass es mittels der Monte Carlo Methode sogar möglich ist, Teststatistiken zu konstruieren, die regional stärker ist, als die Baardasche Lösung. Diese weisen eine sogenannte verallgemeinerte chi2 Verteilung auf. Wegen der hohen Rechenkosten schlagen wir das noch nicht als neue Ausreißererkennungsmethode vor, sondern nur als Beweis, dass es im Prinzip möglich ist, die Teststärke des Ausreißertests nach Baarda zu übertreffen.
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Johnson, Kara. "A Functional Polymorphism in the Epidermal Growth Factor Gene Independently Predicts Clinical Decompensation in HCV-Related Cirrhosis." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/43.
Full textAbstract:
Background and Aims: Several single nucleotide polymorphisms (SNPs), including rs4444903 in the epidermal growth factor (EGF) gene, rs12979860 near the interleukin-28B (IL28B) gene, and rs738409 in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, have been linked to treatment response, steatosis, fibrosis, and development of hepatocellular carcinoma (HCC) in chronic hepatitis C (HCV). No study has comprehensively examined the effects of these SNPs on the natural history of HCV-related cirrhosis.
Methods: We performed a retrospective cohort study of 169 subjects with chronic HCV and biopsy-proven cirrhosis who had long term followup for clinical events. Formalin-fixed, paraffin-embedded liver biopsy specimens were genotyped for EGF, IL28B, and PNPLA3 using a TaqMan assay with commercial probes and primers. Cox proportional hazards modeling was used to determine the hazard ratio for clinical decompensation, defined as the development of ascites, encephalopathy, variceal hemorrhage, HCC, or cirrhosis-related death.
Results: During a median followup of 6.6 years, 66 patients (39%) experienced clinical decompensation. On univariate analysis, EGF non-A/A, PNPLA3 non-C/C, and IL28B non-C/C genotypes were each associated with increased risk of decompensation. In multivariable Cox regression modeling, EGF non-A/A genotype was independently associated with an increased rate of clinical decompensation (HR = 3.00, p = 0.005).
Conclusions: HCV cirrhotics with the EGF A/G and G/G genotypes at rs4444903, a functional polymorphism associated with higher intrahepatic EGF levels, have an increased risk of clinical decompensation. Further study of the predictive value of EGF genotyping in patients with earlier stages and other etiologies of liver disease is warranted.
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Song, Zirui. "Payment Reform in Massachusetts: Health Care Spending and Quality in Accountable Care Organizations Four Years into Global Payment." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/44.
Full textAbstract:
Background: The United States health care system faces two fundamental challenges: a high growth rate of health care spending and deficiencies in quality of care. The growth rate of health care spending is the dominant driver of our nation’s long-term federal debt, while the inconsistent quality of care hinders the ability of the health care system to maximize value for patients. To address both of these challenges, public and private payers are increasingly changing the way they pay providers—moving away from fee-for-service towards global payment contracts for groups of providers coming together as accountable care organizations. This thesis evaluates the change in health care spending and in quality of care associated with moving to global payment for accountable care organizations in Massachusetts in the first 4 years. This thesis studies the Blue Cross Blue Shield of Massachusetts Alternative Quality Contract (AQC), a global payment contract that provider organizations in Massachusetts began to enter in 2009. The AQC pays provider organizations a risk-adjusted global budget for the entire continuum of care for a defined population of enrollees insured by Blue Cross Blue Shield of Massachusetts. It also awards substantial pay-for-performance incentives for organizations meeting performance thresholds on quality measures. This work assesses its effect on spending and quality through the first 4 years of the contract. Methods: Enrollee-level claims data from 2006-2012 were used with a difference-in-differences design to evaluate the changes in spending and quality associated with the Alternative Quality Contract over the first 4 years. The study population consisted of enrollees in Blue Cross Blue Shield of Massachusetts plans (intervention group) and enrollees in commercial employer-sponsored plans across 5 comparison states (control group). Unadjusted and adjusted results are reported for each comparison between intervention and control. Changes in spending for all 4 AQC cohorts relative to control were evaluated. In adjusted analyses of spending, I used a multivariate linear model at the enrollee-quarter level, controlling for age, sex, risk score, indicators for intervention, quarters of the study period, the post-intervention period, and the appropriate interactions. For analyses of quality, an analogous model at the enrollee-year level was used. Process and outcome quality were evaluated. Results: Seven provider organizations joined the AQC in 2009, with a total of 490,167 individuals who were enrolled for at least 1 calendar year in the study period. The control group had 966,813 unique individuals enrolled for at least 1 year during the study period. Average age, sex, and risk scores before and after the AQC were similar between the two groups. In the 2009 cohort, claims spending grew on average $62.21 per enrollee per quarter less than control over 4 years (p<0.001), a 6.8% savings. Analogously, the 2010, 2011, and 2012 cohorts had average savings of 8.8% (p<0.001), 9.1% (p<0.001), and 5.8% (p=0.04), respectively, by the end of 2012. Savings on claims were concentrated in the outpatient facility setting, specifically procedures, imaging, and tests (8.7%, 10.9%, and 9.7%, respectively, p<0.001). Organizations with and without risk-contracting experience saw similar average savings of 6.3% and 7.7%, respectively, over 4 years (p<0.001). About 40% of savings were explained by lower volume. Pre-intervention trends were not statistically different between intervention and control (-$4.57, p=0.86), suggesting savings were not driven by inherently different trajectories of spending. No differences in coding intensity were found. In sensitivity analyses, estimates were robust to alterations in the model, variables, and sample. Notably, claims savings were exceeded by incentive payments to providers (shared savings and quality bonuses) in 2009-2011, but exceeded incentives payments in 2012, generating net savings. Improvements in quality among intervention cohorts generally exceeded New England and national comparisons. Quality performance on chronic care measures increased from 79.6% pre-intervention to 84.5% post-intervention in the 2009 cohort, compared to 79.8% to 80.8% for the HEDIS national average, a 3.9 percentage-point relative increase over the 4 years. Analogously, preventive care and pediatric care measures increased 2.7 and 2.4 percentage points relative to control, respectively. On outcome measures, achievement of hemoglobin A1c, LDL cholesterol, and blood pressure control grew by 2.1 percentage points per year in the 2009 cohort after the AQC, while HEDIS averages remained largely unchanged (Figure). Conclusion: After 4 years, physician organizations in the AQC had lower spending growth relative to control and generally outperformed national averages on quality measures. Shared savings coupled with quality bonuses can exceed savings on claims in initial years, but over time, savings on claims may outgrow incentive payments. Incentive payments themselves may serve meaningful purposes, as quality measures may protect against stinting and shared savings may help ease providers into risk contracts. Changes in utilization suggest that this payment model can help modify underlying care patterns, a likely prerequisite for sustainable reform. The AQC experience may be useful to policymakers, insurers, and providers embarking on payment reform. Combining global budgets with pay-for- performance may encourage organizations to embark on the delivery system reforms necessary to slow spending and improve quality.
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Lewis, William. "Changes in Language Pathways in Tuberous Sclerosis Complex Patients with Autism." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/45.
Full textAbstract:
Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disease caused by loss of the TSC1 (encoding hamartin) or TSC2 (encoding tuberin) genes. Neurologic symptoms are common and varied in TSC and include epilepsy and behavioral conditions like autism spectrum disorders (ASD). Between 17 and 61% of children with TSC exhibit symptoms of ASD.
The purpose of this study was to investigate a potential correlate of poor neurological outcome in TSC by assessing the integrity of brain language pathways and the relationship to ASD.
42 patients with TSC and 42 age-matched control subjects were scanned with advanced diffusion-weighted MRI. White matter language pathways were identified with a validated automatic method and analyzed for microstructural characteristics, including fractional anisotropy (FA) and mean diffusivity (MD). Well-defined white matter pathways in the brain are characterized by high FA and low MD. During normal development, brain white matter pathways increase in FA and decrease in MD.
Out of 42 patients with TSC, 12 had ASD (29%). After controlling for age, TSC patients without ASD showed a small decrease in FA of the arcuate fasciculus compared to control subjects, and TSC patients with ASD had much lower FA than both control subjects and TSC patients without ASD. Similarly, while TSC patients without ASD had only a small increase in MD compared to control subjects in the arcuate fasciculus, TSC patients with ASD had much higher MD than control subjects and TSC patients without ASD.
A new method for assessing the microstructure of young patients showed similar results with decreased compactness in language pathways of TSC patients with ASD. Another new method designed to better analyze regions with crossing pathways showed modifications in language pathway microstructure that correlated with ASD diagnosis in the TSC patients. Preliminary analysis of neuropsychiatric data also showed a trend toward an association of arcuate fasciculus MD with verbal IQ, although the result was not significant after multiple comparisons correction.
It remains unclear why some patients with TSC develop ASD, while others have better language outcomes. Our results suggest that aberrant development of language pathways may act as a marker for poor neurological outcome in TSC patients. The impaired microstructure in language pathways of TSC patients may be responsible for the development of ASD, although prospective studies examining the development of language pathways and subsequent ASD diagnosis in this patient population remain essential. It is also possible that a primary problem with language leads to decreased use and subsequent poor development of language pathways. Early diagnosis of ASD is crucial for improving the outcomes of affected children.
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Parikh, Ravi B. "DEFINITIVE PRIMARY THERAPY IN PATIENTS PRESENTING WITH OLIGOMETASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/47.
Full textAbstract:
Background: Although palliative chemotherapy is the standard of care for patients diagnosed with stage IV NSCLC, patients with a small metastatic burden, “oligometastatic” disease, may benefit from definitive local therapy.
Methods: We identified 186 patients (26% of Stage IV patients) prospectively enrolled in our institutional database from 2002-2012 with oligometastatic disease, which we defined as five or fewer distant metastatic lesions at diagnosis. Univariable and multivariable Cox proportional hazards models were used to identify patient and disease factors associated with improved survival. Using propensity score methods, we investigated the effect of definitive local therapy to the primary site on overall survival.
Results: Median age at diagnosis was 61 years, 51% of patients were female, 12% had squamous histology, and 33% had N0-1 disease. On multivariable analysis, ECOG performance status ≥2 (hazard ratio [HR] 2.43), nodal status N2-3 (HR 2.16), squamous pathology, and metastases to multiple organs (HR 2.11) were associated with a greater hazard of death (all p<0.01). Number of metastatic lesions and size of primary were not significantly associated with overall survival. Definitive local therapy to the primary tumor was associated with prolonged survival (HR 0.65, p=0.043).
Conclusions: Definitive local therapy to the primary tumor appears to be associated with improved survival in patients with oligometastatic NSCLC. Select patient and tumor characteristics, including good performance status, non-squamous histology, and limited nodal disease, may predict for improved survival in these patients.
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Reidler, Jay S. "Modulation of Pain with Transcranial Direct Current Stimulation and Diffuse Noxious Inhibitory Controls." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/48.
Full textAbstract:
Background: While pain is essential for physiological functioning, chronic or pathologic pain is responsible for a major burden of disease in society. Novel approaches to treating acute and chronic pain have employed neuromodulatory tools to target the central and peripheral neural structures that mediate pain. Transcranial direct current stimulation (tDCS), for example, is a safe, non-invasive brain stimulation technique that has been shown in preliminary studies to reduce chronic pain when applied to the primary motor cortex. In contrast to this exogenous neuromodulatory approach, diffuse noxious inhibitory controls (DNIC) refers to endogenous pain regulatory mechanisms that decrease pain following introduction of heterotopic noxious stimuli. This thesis explores whether combining these exogenous and endogenous pain modulation approaches synergistically increases the threshold at which pain is perceived.
Methods: We conducted a double-blinded, randomized, placebo-controlled trial with a crossover design to investigate the effects of tDCS and DNIC on pain thresholds in 15 healthy human subjects. Pain thresholds were assessed prior to and following administration of active tDCS, sham tDCS, cold-water-induced DNIC, and combined active tDCS and DNIC. Using magnetic resonance spectroscopy, we examined whether baseline concentrations of brain metabolites such as N-acetylaspartate in pain-related regions of interest were associated with responses to the varying neuromodulatory conditions.
Results: Pain thresholds significantly increased following both active tDCS and the DNIC paradigm. These modulatory approaches appeared to have additive effects when combined. Pain threshold increases after active tDCS were positively correlated with baseline levels of N-acetylaspartate, a marker of good neural function, in the anterior cingulate cortex and negatively correlated with baseline levels of glutamine in the thalamus.
Conclusions: Combining endogenous pain regulatory mechanisms with exogenous stimulation of the motor cortex can more effectively increase pain thresholds in healthy humans. Future studies should examine whether existing pain therapies may be enhanced with noninvasive brain stimulation and activation of DNIC. They should also assess whether brain metabolite levels can be utilized to predict clinical response to therapeutic interventions.
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Mattos, David. "PROPHYLACTIC MASTECTOMIES: OCCULT HISTOLOGY AND FISCAL IMPACTS OF SURVEILLANCE VS. SURGERY." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/51.
Full textAbstract:
Introduction:
During the last decade, our institution saw a 260% increase in bilateral breast reconstruction cases, consistent with national trends. We reported a drop in average age of prophylactic mastectomy from 57 to 51 years. There is limited data on the likelihood of histological abnormalities in this population. This study measures the prevalence of occult histological findings in prophylactic mastectomy patients. Given the current healthcare reform climate, we estimate the lifetime cost implications of prophylactic mastectomy with immediate reconstruction vs. surveillance.
Methods:
A retrospective database of breast reconstructions at the Massachusetts General Hospital was searched from 2004 to 2011 for prophylactic mastectomy patients. Breasts with prior biopsy-proven LCIS, DCIS, or cancer were excluded. Patient demographics, risk factors, and pathology reports were collected. Lifetime treatment reimbursements were estimated with 2013 rates from the Center for Medicare and Medicaid Services using Medicare billing codes. Reimbursements were estimated for 45-year-old patients undergoing contralateral prophylactic mastectomy and 40-year-old patients undergoing bilateral prophylactic mastectomies, and then were compared to women opting for surveillance. Conversion rates to cancer in these patients were used to estimate the percentage patients in the surveillance groups that would need therapeutic mastectomy. Sensitivity analyses were done to test the robustness of the models.
Results:
495 prophylactic mastectomy specimens were identified, of which 2.0% had invasive cancer, 4.4% had ductal carcinoma in situ (DCIS), and 10.9% had lobular carcinoma in situ (LCIS) as the highest-risk lesion. Only age group was predictive of finding DCIS or cancer (P=0.02). The likelihood of finding LCIS, DCIS, or cancer increased with age group (P<0.001) and decreased with prior bilateral salpingo-oophorectomy (BSO)(P=0.02). In almost all scenarios, lifetime reimbursements were lower for pursuing either contralateral or bilateral prophylactic mastectomy, with immediate single-stage implant, expander, or abdominal perforator free flap (DIEP) reconstruction, as compared to surveillance.
Conclusions:
Prophylactic mastectomy patients have a significant rate of occult histological findings, increasing with age group and decreasing with prior BSO. Lifetime cost estimates suggest a cost-saving role in bilateral and contralateral prophylactic mastectomies. Ultimately, such a critical decision needs to be made individually, but should not be hindered by cost concerns. This study addresses a gap in knowledge with broad interest, contributing evidence of oncologic risk and cost to help guide decision-making in prophylactic mastectomy.
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Xu, Wenxin. "Optimal Systolic Blood Pressure Target, Time-to-Intensification and Time-to-Follow-up in the Treatment of Hypertension." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/55.
Full textAbstract:
Objective:
I sought to determine the systolic intensification threshold, time-to-intensification and time-to-follow-up associated with the lowest risk of cardiovascular events or death in primary care patients with hypertension.
Methods:
A retrospective cohort study of 88,756 patients was performed. Systolic intensification threshold, time-to-intensification and time-to-follow-up were analyzed with respect to risk of acute cardiovascular event or death. The Cox model was adjusted for age, sex, smoking status, socioeconomic deprivation, history of diabetes, cardiovascular disease or CKD, Charlson Comorbidity Index, BMI, medication possession ratio, and baseline blood pressure.
Results:
During median follow-up of 37.4 months, 9,985 participants experienced acute cardiovascular event or death (11.3%). Systolic intensification thresholds of 130-150 mmHg were associated with no difference in risk, while higher thresholds were associated with progressively greater risk. Risk increased progressively from the lowest (0-1.4 months) to the highest quintile of time to medication intensification. The highest quintile of time to-follow-up (>2.7 months) was also associated with increased risk.
Conclusions:
Systolic intensification threshold higher than 150 mmHg, delays of greater than 1.4 months before medication intensification following systolic blood pressure elevation, and delays of greater than 2.7 months before blood pressure follow-up following medication intensification were associated with increased risk for acute cardiovascular events or death.
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Swaminathan, Swarup Sai. "The Role of SPARC in Aqueous Humor Outflow and TGFß2-mediated Ocular Hypertension in a Murine Model." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/56.
Full textAbstract:
Glaucoma is the leading cause of irreversible blindness worldwide, and is a major cause of blindness in the United States. It affects approximately 5% of Caucasians and 10% of African- Americans over the age of 60 years. Elevated intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma. Impaired outflow of aqueous humor from the eye is thought to be the cause of pathologically elevated IOP. However, the etiology of outflow impairment is unknown. Anatomically, the aqueous humor drains into the iridocorneal angle of the eye, where the iris inserts at the transition between the cornea and sclera. In humans, approximately 80-90% of the aqueous traverses through the trabecular meshwork (TM), juxtacanalicular connective tissue (JCT), Schlemm’s canal, collector channels and empties into episcleral veins. Abnormalities at these sites are thought to cause impaired outflow. Abnormal accumulation of extracellular matrix (ECM) in the TM or JCT, abnormal endothelial function in Schlemm’s canal, or a combination of these components have been strongly implicated. Our laboratory has focused on the role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in regulating outflow. SPARC is the prototypical matricellular protein that mediates ECM organization and turnover in numerous human tissues. Our lab was first to demonstrate that SPARC is highly expressed in the TM and JCT regions of the eye, and that the SPARC knockout (KO) mouse has a significant decrease in IOP of 15-20%. SPARC may affect the degree of segmental flow, a theory that states that variable aqueous outflow occurs around the circumference of the eye; only certain portions of the TM are thought to display active outflow at any particular moment. The cytokine transforming growth factor-ß2 (TGFß2) has been shown to modulate multiple ECM proteins, including SPARC. TGFß2 is significantly upregulated by 2 to 3-fold in the aqueous humor of glaucoma patients compared to controls. In addition, when TGFß2 is overexpressed in rodent eyes, increased ECM deposition is observed within the trabecular meshwork leading to IOP elevation. SPARC is one of the most highly upregulated proteins by TGFß2, and is downstream of TGFß2. We hypothesized that wild-type (WT) mice would demonstrate segmental flow, while SPARC KO mice would display a more continuous pattern of outflow around the eye. We also believed that IOP would be inversely correlated with outflow area. We also hypothesized that SPARC is essential to the process of TGFß2-mediated ocular hypertension, and that the lack of SPARC would impair IOP elevation.
We conducted a tracer study utilizing fluorescent microbeads to determine the location of outflow circumferentially around the mouse TM. Microbeads were injected intracamerally into the eyes of WT and KO mice. After a 45-minute incubation period, the mice were euthanized and eyes were processed for confocal, light, and electron microscopy. During the second group of experiments, empty or TGFß2-containing adenovirus was injected intravitreally into WT and SPARC KO mice and IOP was measured for 2 weeks. Immunohistochemistry was completed on all tissues to assess for changes in major ECM proteins.
Percentage effective filtration length (PEFL), or area of the TM labeled by tracer, was significantly increased in SPARC KO mice (70.61% ± 11.36%, p<0.005; N=11) compared to WT mice (54.68% ± 9.95%; N=11). In addition, the pressures between the two sets of eyes were significantly different with mean pressures of 16.3 mm Hg in WT mice and 12.6 mm Hg in KO mice (p<0.005, N=11 pairs). In addition, PEFL and IOP were inversely correlated with R2 = 0.72 (N=10 pairs); in eyes with higher IOP, PEFL was reduced. Electron microscopy demonstrated that high-tracer TM areas had a greater separation between trabecular beams. Collagen fibril diameter was found to be smaller in the KO (28.272 nm) compared to WT (34.961 nm; p<0.0005, N=3 pairs). These data provided structural correlations to the functional data regarding segmental flow.
In the second set of experiments, IOP was found to be significantly elevated in TGFß2- injected WT mice compared to empty vector-injected WT mice during days 4-11 (p<0.05, N=8). However, IOP was not significantly elevated in TGFß2-injected KO mice compared to controls. Immunohistochemistry demonstrated that TGFß2 increased expression of collagen IV, fibronectin, plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor (CTGF), and SPARC within the TM of WT mice, but only PAI-1 and CTGF in KO mice (p<0.05, N=3 pairs).
These data support our hypotheses, indicating that SPARC plays an integral role in the modulation of aqueous humor outflow. In addition, it appears as though SPARC is essential to the regulation of TGFß2-mediated ocular hypertension. Aside from providing further evidence of the importance of ECM in IOP regulation, our work presents the novel discovery of segmental flow in the mouse. Given the potential role of SPARC in TGFß2-mediated ocular hypertension, SPARC may not only play an integral role in ECM homeostasis within the trabecular meshwork, but may be a valuable target for pharmacologic therapy in treating primary open-angle glaucoma.
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Sethi, Rosh Kumar Viasha. "Technology Adoption in the United States: The Impact of Hospital Market Competition." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/57.
Full textAbstract:
Objectives: Technological innovation in medicine is a significant driver of healthcare spending growth in the United States. Factors driving adoption and utilization of new technology is poorly understood, however market forces may play a significant role. Vascular surgery has experienced a surge in development of new devices and serves as an ideal case study. Specifically, the share of total abdominal aortic aneurysm (AAA) repairs performed by endovascular aneurysm repair (EVAR) increased rapidly from 32% in 2001 to 65% in 2006 with considerable variation between states. This paper hypothesizes that that hospitals in competitive markets were early EVAR adopters and had improved AAA repair outcomes.
Methods: The Nationwide Inpatient Sample (NIS) and linked Hospital Market Structure (HMS) data was queried for patients who underwent repair for non-ruptured AAA in 2003. In HMS the Herfindahl Hirschman Index (HHI, range 0-1) is a validated and widely accepted economic measure of competition. Hospital markets were defined using a variable geographic radius that encompassed 90% of discharged patients. Bivariable and multivariable linear and logistic regression analyses were performed for the dependent variable of EVAR use. A propensity score-adjusted multivariate logistic regression model was used to control for treatment bias in the assessment of competition on AAA-repair outcomes.
Results: A weighted total of 21,600 patients was included in the analyses. Patients at more competitive hospitals (lower HHI) were at increased odds of undergoing EVAR vs. open repair (Odds Ratio 1.127 per 0.1 decrease in HHI, P<0.0127) after adjusting for patient demographics, co-morbidities and hospital level factors (bed size, teaching status, AAA repair volume and ownership). Competition was not associated with differences in in-hospital mortality or vascular, neurologic or other minor post-operative complications.
Conclusion: Greater hospital competition is significantly associated with increased EVAR adoption at a time when diffusion of this technology passed its tipping point. Hospital competition does not influence post-AAA repair outcomes. These results suggest that adoption of novel technology is not solely driven by clinical indications, but may also be influenced by market forces.
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Messmer, Sarah Elizabeth. "A Pilot Study on Women's Health Education in Rural Guatemala: Impact on Beliefs and Behaviors." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/60.
Full textAbstract:
Great disparities exist in women’s health outcomes in rural indigenous communities in Guatemala; indigenous women are less likely to utilize family planning and cervical cancer screening services. This pilot study assessed baseline women’s health knowledge and the effects of a comprehensive women’s health course on women’s health knowledge and behaviors. From February to November 2013, 61 participants in a seven-week language-appropriate women’s health curriculum were evaluated before and after the course using a 10-item knowledge assessment. Cervical cancer screening and contraceptive utilization rates were assessed by self-report before and after the course. Several women’s health knowledge deficits were noted: belief that contraception causes cancer, inability to name symptoms of STIs, lack of understanding of pap smears, and lack of familiarity with condoms. The average pre-test score was 54.6%; increasing to 83.7% on the post-test (p<0.0001). 79% had received a pap smear prior to the course; this increased to 92% at the post-test (p=0.013). 53% had utilized contraception prior to the course; at the time of the post-test the percentage was 54% (p=1). This study reveals important patterns in women’s health beliefs in rural Guatemala, and shows that a seven-week curriculum was effective in improving scores on a knowledge assessment.
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Lin, ChieYu. "Characterization and Optimization of the CRISPR/Cas System for Applications in Genome Engineering." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/61.
Full textAbstract:
The ability to precisely manipulate the genome in a targeted manner is fundamental to driving both basic science research and development of medical therapeutics. Until recently, this has been primarily achieved through coupling of a nuclease domain with customizable protein modules that recognize DNA in a sequence-specific manner such as zinc finger or transcription activator-like effector domains. Though these approaches have allowed unprecedented precision in manipulating the genome, in practice they have been limited by the reproducibility, predictability, and specificity of targeted cleavage, all of which are partially attributable to the nature of protein-mediated DNA sequence recognition. It has been recently shown that the microbial CRISPR-Cas system can be adapted for eukaryotic genome editing. Cas9, an RNA-guided DNA endonuclease, is directed by a 20-nt guide sequence via Watson-Crick base-pairing to its genomic target. Cas9 subsequently induces a double-stranded DNA break that results in targeted gene disruption through non-homologous end-joining repair or gene replacement via homologous recombination. Finally, the RNA guide and protein nuclease dual component system allows simultaneous delivery of multiple guide RNAs (sgRNA) to achieve multiplex genome editing with ease and efficiency.
The potential effects of off-target genomic modification represent a significant caveat to genome editing approaches in both research and therapeutic applications. Prior work from our lab and others has shown that Cas9 can tolerate some degree of mismatch with the guide RNA to target DNA base pairing. To increase substrate specificity, we devised a technique that uses a Cas9 nickase mutant with appropriately paired guide RNAs to efficiently inducing double-stranded breaks via simultaneous nicks on both strands of target DNA. As single-stranded nicks are repaired with high fidelity, targeted genome modification only occurs when the two opposite-strand nicks are closely spaced. This double nickase approach allows for marked reduction of off-target genome modification while maintaining robust on-target cleavage efficiency, making a significant step towards addressing one of the primary concerns regarding the use of genome editing technologies.
The ability to multiplex genome engineering by simply co-delivering multiple sgRNAs is a versatile property unique to the CRISPR-Cas system. While co-transfection of multiple guides is readily feasible in tissue culture, many in vivo and therapeutic applications would benefit from a compact, single vector system that would allow robust and reproducible multiplex editing. To achieve this, we first generated and functionally validated alternate sgRNA architectures to characterize the structure-function relationship of the Cas9 protein with the sgRNA in DNA recognition and cleavage. We then applied this knowledge towards the development and optimization of a tandem synthetic guide RNA (tsgRNA) scaffold that allows for a single promoter to drive expression of a single RNA transcript encoding two sgRNAs, which are subsequently processed into individual active sgRNAs.
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Vallurupalli, Mounica. "Identifying Targetable Liabilities in Ewing Sarcoma." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/62.
Full textAbstract:
Background: Despite multi-modality therapy, the majority of patients with metastatic or recurrent Ewing sarcoma (ES), the second most common pediatric bone malignancy, will die of their disease. ES tumors express aberrantly activated ETS transcription factors through translocations that fuse the EWS gene to ETS family genes FLI1 or ERG. The aberrant activation of ETS transcription factors promotes malignant transformation and proliferation. While, FLI1 or ERG cannot be readily targeted, there is an opportunity to deploy functional genomics screens, to develop novel therapeutic approaches by identifying targetable liabilities in EWS/FLI1 dependent tumors.
Materials and Methods: We performed a near whole-genome pooled shRNA screen in a panel of five EWS/FLI1 dependent Ewing sarcoma cell lines and one EWS/ERG cell line to identify essential genes. Essential genes were defined as those genes whose loss resulted in reduced viability selectively in ES cells compared to non-Ewing cancer cell lines. Essential hits were subsequently validated with genomic knockdown and chemical inhibition in vitro, followed by validation of the on-target effect of chemical inhibition. Next, we determined the in vivo effects of small-molecule inhibition on survival and tumor growth in NOD scid gamma (NSG) mice with established subcutaneous ES xenografts.
Results: Top hits in our screen that could be readily targeted by small-molecule inhibitors, and thus have potential for rapid clinical validation, were selected for further investigation. These hits included IKBKE, CCND1 and CDK4. IKBKΕ, a non-canonical IKK with an oncogenic role in breast cancer, was one of the top kinase hits in the screen. IKBKΕ shares significant homology to TBK1, another non-canonical IKK that is essential in k-RAS dependent lung cancer. We validated IKBKE through small-molecule inhibition of IKBKE/TBK1 and shRNA based knockdown. Ewing sarcoma cell lines are sensitive to low micromolar concentrations of two IKBKE/TBK1 inhibitors (CYT387 and MRT67307). Additionally, in a panel of ES cell lines, knockdown of IKBKE resulted in decreased growth and impaired colony formation. These observations, paired with impairment of NF-κB nuclear localization following CYT387 treatment suggests that non-canonical IKK mediated signaling may be essential in Ewing sarcoma. We further validated these results through inhibition of IKBKE/TBK1 in in vivo xenograft models treated with 100 mg/kg/day of CYT387. Treatment over the course of twenty-nine days resulted in a significant increase in survival (p-value = 0.0231) and a significant decrease (p-value = 0.036) in tumor size after fifteen days of treatment.
CDK4 and CCND1 are highly expressed in Ewing sarcoma as compared to other tumor types. shRNA mediated knockdown of CDK4 and CCND1 resulted in impaired viability and anchorage independent growth. Furthermore, treatment of Ewing sarcoma cell lines with a highly selective CDK4/6 inhibitor, LEE011, resulted in decreased viability (IC50 range of 0.26-18.06 μM), potent G1 arrest in six of eight EWS/FLI1 containing Ewing sarcoma lines tested and apoptosis in a panel of four highly sensitive lines. Administration of 75 mg/kg/day and 250 mg/kg/day of LEE011 in NSG mice with Ewing xenografts resulted in significant impairment of tumor growth, (p-value <0.001 for both treatment arms), as compared to vehicle control.
Conclusions: These studies suggest a role for the targeting of IKBKE and CDK 4/6 in Ewing sarcoma, findings with immediate clinical relevance for patients with this malignancy, because small-molecule inhibitors of these proteins have already entered clinical trial for other disease indications.
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Rahman, Rifaquat M. "Magnetic Resonance Imaging for Prediction and Assessment of Treatment Response in Bevacizumab-Treated Recurrent Glioblastoma." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/65.
Full textAbstract:
Glioblastoma is the most common primary brain tumor in adults, and it is associated with a dismal prognosis with a median survival of 15 months. Despite treatment with chemotherapy, radiation therapy and surgery, patients inevitably have disease recurrence. Bevacizumab is a monoclonal humanized antibody that inhibits vascular endothelial growth factor signaling, and it has been shown to be effective in recurrent glioblastoma with respect to prolonging progression-free survival (PFS). The use of bevacizumab and other anti-angiogenic agents in recurrent glioblastoma have created novel challenges in interpreting magnetic resonance imaging (MRI) of patients. Furthermore, since only some patients appear to have a durable benefit from bevacizumab, there is a need for imaging biomarkers that can reliably identify this subgroup of patients.
Partly due to the challenges created by anti-angiogenic agents, the Response Assessment in Neuro-Oncology (RANO) was proposed to address some of the limitations with traditional response assessment criteria. In the first part of this project, we attempted to validate the RANO criteria by performing a comparative analysis of the RANO criteria vs. the Macdonald criteria using imaging from the phase II BRAIN trial. As we hypothesized, the RANO criteria yielded a significantly decreased PFS by identifying a subset of patients who had progression of nonenhancing tumor evident on T2-weighted imaging. Additionally, response and progression as defined by the RANO criteria correlated with subsequent overall survival (OS) in landmark analyses. While this supports the implementation of RANO criteria for response assessment in glioma clinical trials, future research will be necessary to further improve response assessment by incorporating advanced techniques such as volumetric anatomic assessment, perfusion-weighted MR (PWI-MR), diffusion-weighted MR (DWI-MR), MR spectroscopy (MRS) and positron emission tomography (PET).
Advanced imaging techniques are becoming increasingly recognized for their ability to provide objective, non-invasive assessment of treatment response but also to serve as predictive and prognostic biomarkers allowing for stratification of patient subgroups with better treatment outcome. In the second part of the project, we attempted to perform volumetric analysis of tumor size based on conventional MRI, as well as a histogram analysis of apparent diffusion coefficients (ADC) derived from diffusion-weighted MRI, to evaluate imaging parameters as predictors for PFS and OS in a single institution database of recurrent glioblastoma patients initiated on bevacizumab. Volumetric percentage change and absolute early post-treatment volume (3-6 weeks after initiation) of enhancing tumor can stratify survival for patients with recurrent glioblastoma receiving bevacizumab therapy. ADC histogram analysis using a multi-component curve-fitting technique within both enhancing and nonenhancing components of tumor prior to the initiation of bevacizumab can also be used to stratify OS in recurrent glioblastoma patients. While prospective studies are necessary to validate findings, future studies will increasingly incorporate multiparametric approaches to elucidate biomarkers that combine the value of conventional MRI with advanced techniques such as DWI-MR, PWI-MR, MRS and PET to obtain better predictors for PFS and OS in recurrent glioblastoma.