TY - JOUR A1 - Khalil, Sara A1 - Schulze, Bert-Wolfgang T1 - Calculus on a Manifold with Edge and Boundary JF - Complex analysis and operator theory N2 - We study elements of the calculus of boundary value problems in a variant of Boutet de Monvel’s algebra (Acta Math 126:11–51, 1971) on a manifold N with edge and boundary. If the boundary is empty then the approach corresponds to Schulze (Symposium on partial differential equations (Holzhau, 1988), BSB Teubner, Leipzig, 1989) and other papers from the subsequent development. For non-trivial boundary we study Mellin-edge quantizations and compositions within the structure in terms a new Mellin-edge quantization, compared with a more traditional technique. Similar structures in the closed case have been studied in Gil et al. KW - algebra KW - Mellin quantization Y1 - 2019 U6 - https://doi.org/10.1007/s11785-018-0800-y SN - 1661-8254 SN - 1661-8262 VL - 13 IS - 6 SP - 2627 EP - 2670 PB - Springer CY - Basel ER - TY - JOUR A1 - Schulze, Bert-Wolfgang A1 - Seiler, Jörg T1 - Elliptic complexes on manifolds with boundary JF - The journal of geometric analysis N2 - We show that elliptic complexes of (pseudo) differential operators on smooth compact manifolds with boundary can always be complemented to a Fredholm problem by boundary conditions involving global pseudodifferential projections on the boundary (similarly as the spectral boundary conditions of Atiyah, Patodi, and Singer for a single operator). We prove that boundary conditions without projections can be chosen if, and only if, the topological Atiyah-Bott obstruction vanishes. These results make use of a Fredholm theory for complexes of operators in algebras of generalized pseudodifferential operators of Toeplitz type which we also develop in the present paper. KW - Elliptic complexes KW - Manifolds with boundary KW - Atiyah-Bott obstruction KW - Toeplitz-type pseudodifferential operators Y1 - 2018 U6 - https://doi.org/10.1007/s12220-018-0014-6 SN - 1050-6926 SN - 1559-002X VL - 29 IS - 1 SP - 656 EP - 706 PB - Springer CY - New York ER - TY - JOUR A1 - Zöller, Gert A1 - Hainzl, Sebastian A1 - Tilmann, Frederik A1 - Woith, Heiko A1 - Dahm, Torsten T1 - Comment on: Wikelski, Martin; Müller, Uschi; Scocco, Paola; Catorci, Andrea; Desinov, Lev V.; Belyaev, Mikhail Y.; Keim, Daniel A.; Pohlmeier, Winfried; Fechteler, Gerhard; Mai, Martin P. : Potential short-term earthquake forecasting by farm animal monitoring. - Ethology. - 126 (2020), 9. - S. 931 - 941. -ISSN 0179-1613. - eISSN 1439-0310. - doi 10.1111/eth.13078 JF - Ethology N2 - Based on an analysis of continuous monitoring of farm animal behavior in the region of the 2016 M6.6 Norcia earthquake in Italy, Wikelski et al., 2020; (Seismol Res Lett, 89, 2020, 1238) conclude that animal activity can be anticipated with subsequent seismic activity and that this finding might help to design a "short-term earthquake forecasting method." We show that this result is based on an incomplete analysis and misleading interpretations. Applying state-of-the-art methods of statistics, we demonstrate that the proposed anticipatory patterns cannot be distinguished from random patterns, and consequently, the observed anomalies in animal activity do not have any forecasting power. KW - animal behavior KW - earthquake precursor KW - error diagram KW - prediction KW - randomness KW - statistics Y1 - 2020 U6 - https://doi.org/10.1111/eth.13105 SN - 0179-1613 SN - 1439-0310 VL - 127 IS - 3 SP - 302 EP - 306 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Pohle, Jennifer A1 - Adam, Timo A1 - Beumer, Larissa T1 - Flexible estimation of the state dwell-time distribution in hidden semi-Markov models JF - Computational statistics & data analysis N2 - Hidden semi-Markov models generalise hidden Markov models by explicitly modelling the time spent in a given state, the so-called dwell time, using some distribution defined on the natural numbers. While the (shifted) Poisson and negative binomial distribution provide natural choices for such distributions, in practice, parametric distributions can lack the flexibility to adequately model the dwell times. To overcome this problem, a penalised maximum likelihood approach is proposed that allows for a flexible and data-driven estimation of the dwell-time distributions without the need to make any distributional assumption. This approach is suitable for direct modelling purposes or as an exploratory tool to investigate the latent state dynamics. The feasibility and potential of the suggested approach is illustrated in a simulation study and by modelling muskox movements in northeast Greenland using GPS tracking data. The proposed method is implemented in the R-package PHSMM which is available on CRAN. KW - Penalized likelihood KW - Smoothing KW - Time series KW - Animal movement modeling Y1 - 2022 U6 - https://doi.org/10.1016/j.csda.2022.107479 SN - 0167-9473 SN - 1872-7352 VL - 172 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Biskaborn, Boris A1 - Smith, Sharon L. A1 - Noetzli, Jeannette A1 - Matthes, Heidrun A1 - Vieira, Goncalo A1 - Streletskiy, Dmitry A. A1 - Schoeneich, Philippe A1 - Romanovsky, Vladimir E. A1 - Lewkowicz, Antoni G. A1 - Abramov, Andrey A1 - Allard, Michel A1 - Boike, Julia A1 - Cable, William L. A1 - Christiansen, Hanne H. A1 - Delaloye, Reynald A1 - Diekmann, Bernhard A1 - Drozdov, Dmitry A1 - Etzelmueller, Bernd A1 - Grosse, Guido A1 - Guglielmin, Mauro A1 - Ingeman-Nielsen, Thomas A1 - Isaksen, Ketil A1 - Ishikawa, Mamoru A1 - Johansson, Margareta A1 - Johannsson, Halldor A1 - Joo, Anseok A1 - Kaverin, Dmitry A1 - Kholodov, Alexander A1 - Konstantinov, Pavel A1 - Kroeger, Tim A1 - Lambiel, Christophe A1 - Lanckman, Jean-Pierre A1 - Luo, Dongliang A1 - Malkova, Galina A1 - Meiklejohn, Ian A1 - Moskalenko, Natalia A1 - Oliva, Marc A1 - Phillips, Marcia A1 - Ramos, Miguel A1 - Sannel, A. Britta K. A1 - Sergeev, Dmitrii A1 - Seybold, Cathy A1 - Skryabin, Pavel A1 - Vasiliev, Alexander A1 - Wu, Qingbai A1 - Yoshikawa, Kenji A1 - Zheleznyak, Mikhail A1 - Lantuit, Hugues T1 - Permafrost is warming at a global scale JF - Nature Communications N2 - Permafrost warming has the potential to amplify global climate change, because when frozen sediments thaw it unlocks soil organic carbon. Yet to date, no globally consistent assessment of permafrost temperature change has been compiled. Here we use a global data set of permafrost temperature time series from the Global Terrestrial Network for Permafrost to evaluate temperature change across permafrost regions for the period since the International Polar Year (2007-2009). During the reference decade between 2007 and 2016, ground temperature near the depth of zero annual amplitude in the continuous permafrost zone increased by 0.39 +/- 0.15 degrees C. Over the same period, discontinuous permafrost warmed by 0.20 +/- 0.10 degrees C. Permafrost in mountains warmed by 0.19 +/- 0.05 degrees C and in Antarctica by 0.37 +/- 0.10 degrees C. Globally, permafrost temperature increased by 0.29 +/- 0.12 degrees C. The observed trend follows the Arctic amplification of air temperature increase in the Northern Hemisphere. In the discontinuous zone, however, ground warming occurred due to increased snow thickness while air temperature remained statistically unchanged. Y1 - 2019 U6 - https://doi.org/10.1038/s41467-018-08240-4 SN - 2041-1723 VL - 10 PB - Nature Publ. Group CY - London ER - TY - BOOK ED - Kuzle, Ana ED - Rott, Benjamin ED - Gebel, Inga T1 - Implementation research on problem solving in school settings BT - Proceedings of the 2018 Joint Conference of ProMath and the GDM Working Group on Problem Solving T3 - Ars inveniendi et dejudicandi ; 13 Y1 - 2019 SN - 978-3-95987-116-7 SN - 978-3-95987-115-0 PB - WTM-Verlag CY - Münster ER - TY - GEN A1 - Krause, Andreas A1 - Kloft, Charlotte A1 - Huisinga, Wilhelm A1 - Karlsson, Mats A1 - Pinheiro, José A1 - Bies, Robert A1 - Rogers, James A1 - Mentré, France A1 - Musser, Bret J. T1 - Comment on Jaki et al., A proposal for a new PhD level curriculum on quantitative methods for drug development T2 - Pharmaceutical statistics : the journal of applied statistics in the pharmaceutical industry Y1 - 2019 SN - 1539-1604 SN - 1539-1612 VL - 18 IS - 3 SP - 278 EP - 281 PB - Wiley CY - Hoboken ER - TY - THES A1 - Seuring, Markus T1 - Output space compaction for testing and concurrent checking N2 - In der Dissertation werden neue Entwurfsmethoden für Kompaktoren für die Ausgänge von digitalen Schaltungen beschrieben, die die Anzahl der zu testenden Ausgänge drastisch verkleinern und dabei die Testbarkeit der Schaltungen nur wenig oder gar nicht verschlechtern. Der erste Teil der Arbeit behandelt für kombinatorische Schaltungen Methoden, die die Struktur der Schaltungen beim Entwurf der Kompaktoren berücksichtigen. Verschiedene Algorithmen zur Analyse von Schaltungsstrukturen werden zum ersten Mal vorgestellt und untersucht. Die Komplexität der vorgestellten Verfahren zur Erzeugung von Kompaktoren ist linear bezüglich der Anzahl der Gatter in der Schaltung und ist damit auf sehr große Schaltungen anwendbar. Im zweiten Teil wird erstmals ein solches Verfahren für sequentielle Schaltkreise beschrieben. Dieses Verfahren baut im wesentlichen auf das erste auf. Der dritte Teil beschreibt eine Entwurfsmethode, die keine Informationen über die interne Struktur der Schaltung oder über das zugrundeliegende Fehlermodell benötigt. Der Entwurf basiert alleine auf einem vorgegebenen Satz von Testvektoren und die dazugehörenden Testantworten der fehlerfreien Schaltung. Ein nach diesem Verfahren erzeugter Kompaktor maskiert keinen der Fehler, die durch das Testen mit den vorgegebenen Vektoren an den Ausgängen der Schaltung beobachtbar sind. N2 - The objective of this thesis is to provide new space compaction techniques for testing or concurrent checking of digital circuits. In particular, the work focuses on the design of space compactors that achieve high compaction ratio and minimal loss of testability of the circuits. In the first part, the compactors are designed for combinational circuits based on the knowledge of the circuit structure. Several algorithms for analyzing circuit structures are introduced and discussed for the first time. The complexity of each design procedure is linear with respect to the number of gates of the circuit. Thus, the procedures are applicable to large circuits. In the second part, the first structural approach for output compaction for sequential circuits is introduced. Essentially, it enhances the first part. For the approach introduced in the third part it is assumed that the structure of the circuit and the underlying fault model are unknown. The space compaction approach requires only the knowledge of the fault-free test responses for a precomputed test set. The proposed compactor design guarantees zero-aliasing with respect to the precomputed test set. KW - digital circuit KW - output space compaction KW - zero-aliasing KW - test KW - concurrent checking KW - propagation probability KW - IP core Y1 - 2000 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-0000165 ER - TY - JOUR A1 - Mueller-Schoell, Anna A1 - Groenland, Stefanie L. A1 - Scherf-Clavel, Oliver A1 - van Dyk, Madele A1 - Huisinga, Wilhelm A1 - Michelet, Robin A1 - Jaehde, Ulrich A1 - Steeghs, Neeltje A1 - Huitema, Alwin D. R. A1 - Kloft, Charlotte T1 - Therapeutic drug monitoring of oral targeted antineoplastic drugs JF - European journal of clinical pharmacology N2 - Purpose This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. Methods A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. Results OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. Conclusion Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window. KW - targeted antineoplastic drugs KW - tyrosine kinase inhibitors KW - therapeutic KW - drug monitoring KW - oral anticancer drugs KW - personalised medicine Y1 - 2020 U6 - https://doi.org/10.1007/s00228-020-03014-8 SN - 0031-6970 SN - 1432-1041 VL - 77 IS - 4 SP - 441 EP - 464 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Grisic, Ana-Marija A1 - Eser, Alexander A1 - Huisinga, Wilhelm A1 - Reinisch, Walter A1 - Kloft, Charlotte T1 - Quantitative relationship between infliximab exposure and inhibition of C-reactive protein synthesis to support inflammatory bowel disease management JF - British journal of clinical pharmacology N2 - Aim Quantitative and kinetic insights into the drug exposure-disease response relationship might enhance our knowledge on loss of response and support more effective monitoring of inflammatory activity by biomarkers in patients with inflammatory bowel disease (IBD) treated with infliximab (IFX). This study aimed to derive recommendations for dose adjustment and treatment optimisation based on mechanistic characterisation of the relationship between IFX serum concentration and C-reactive protein (CRP) concentration.
Methods Data from an investigator-initiated trial included 121 patients with IBD during IFX maintenance treatment. Serum concentrations of IFX, antidrug antibodies (ADA), CRP, and disease-related covariates were determined at the mid-term and end of a dosing interval. Data were analysed using a pharmacometric nonlinear mixed-effects modelling approach. An IFX exposure-CRP model was generated and applied to evaluate dosing regimens to achieve CRP remission.
Results The generated quantitative model showed that IFX has the potential to inhibit up to 72% (9% relative standard error [RSE]) of CRP synthesis in a patient. IFX concentration leading to 90% of the maximum CRP synthesis inhibition was 18.4 mu g/mL (43% RSE). Presence of ADA was the most influential factor on IFX exposure. With standard dosing strategy, >= 55% of ADA+ patients experienced CRP nonremission. Shortening the dosing interval and co-therapy with immunomodulators were found to be the most beneficial strategies to maintain CRP remission.
Conclusions With the generated model we could for the first time establish a robust relationship between IFX exposure and CRP synthesis inhibition, which could be utilised for treatment optimisation in IBD patients. KW - C‐ reactive protein remission KW - inflammatory bowel disease KW - infliximab dosing Y1 - 2020 U6 - https://doi.org/10.1111/bcp.14648 SN - 0306-5251 SN - 1365-2125 VL - 87 IS - 5 SP - 2374 EP - 2384 PB - Wiley CY - Hoboken ER -