@article{HarutyunyanSchulze2006,
  author    = {Harutyunyan, Gohar and Schulze, Bert-Wolfgang},
  title     = {The Zaremba problem with singular interfaces as a corner boundary value problem},
  series = {Potential analysis : an international journal devoted to the interactions between potential theory, probability theory, geometry and functional analysis},
  volume    = {25},
  journal   = {Potential analysis : an international journal devoted to the interactions between potential theory, probability theory, geometry and functional analysis},
  publisher = {Springer},
  address   = {Dordrecht},
  issn      = {0926-2601},
  doi       = {10.1007/s11118-006-9020-6},
  pages     = {327 -- 369},
  year      = {2006},
  abstract  = {We study mixed boundary value problems for an elliptic operator A on a manifold X with boundary Y, i.e., Au = f in int X, T (+/-) u = g(+/-) on int Y+/-, where Y is subdivided into subsets Y+/- with an interface Z and boundary conditions T+/- on Y+/- that are Shapiro-Lopatinskij elliptic up to Z from the respective sides. We assume that Z subset of Y is a manifold with conical singularity v. As an example we consider the Zaremba problem, where A is the Laplacian and T- Dirichlet, T+ Neumann conditions. The problem is treated as a corner boundary value problem near v which is the new point and the main difficulty in this paper. Outside v the problem belongs to the edge calculus as is shown in Bull. Sci. Math. ( to appear). With a mixed problem we associate Fredholm operators in weighted corner Sobolev spaces with double weights, under suitable edge conditions along Z {v} of trace and potential type. We construct parametrices within the calculus and establish the regularity of solutions.},
  language  = {en}
}
@article{HedayatMahmoudiSchulze2018,
  author    = {Hedayat Mahmoudi, Mahdi and Schulze, Bert-Wolfgang},
  title     = {A new approach to the second order edge calculus},
  series = {Journal of pseudo-differential operators and applications},
  volume    = {9},
  journal   = {Journal of pseudo-differential operators and applications},
  number    = {2},
  publisher = {Springer},
  address   = {Basel},
  issn      = {1662-9981},
  doi       = {10.1007/s11868-017-0191-2},
  pages     = {265 -- 300},
  year      = {2018},
  abstract  = {We establish essential steps of an iterative approach to operator algebras, ellipticity and Fredholm property on stratified spaces with singularities of second order. We cover, in particular, corner-degenerate differential operators. Our constructions are focused on the case where no additional conditions of trace and potential type are posed, but this case works well and will be considered in a forthcoming paper as a conclusion of the present calculus.},
  language  = {en}
}
@article{KhalilSchulze2019,
  author    = {Khalil, Sara and Schulze, Bert-Wolfgang},
  title     = {Calculus on a Manifold with Edge and Boundary},
  series = {Complex analysis and operator theory},
  volume    = {13},
  journal   = {Complex analysis and operator theory},
  number    = {6},
  publisher = {Springer},
  address   = {Basel},
  issn      = {1661-8254},
  doi       = {10.1007/s11785-018-0800-y},
  pages     = {2627 -- 2670},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}
@article{SchulzeSeiler2019,
  author    = {Schulze, Bert-Wolfgang and Seiler, J{\"o}rg},
  title     = {Elliptic complexes on manifolds with boundary},
  series = {The journal of geometric analysis},
  volume    = {29},
  journal   = {The journal of geometric analysis},
  number    = {1},
  publisher = {Springer},
  address   = {New York},
  issn      = {1050-6926},
  doi       = {10.1007/s12220-018-0014-6},
  pages     = {656 -- 706},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}
@article{ZoellerHainzlTilmannetal.2020,
  author    = {Z{\"o}ller, Gert and Hainzl, Sebastian and Tilmann, Frederik and Woith, Heiko and Dahm, Torsten},
  title     = {Comment on: Wikelski, Martin; M{\"u}ller, 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},
  series = {Ethology},
  volume    = {127},
  journal   = {Ethology},
  number    = {3},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0179-1613},
  doi       = {10.1111/eth.13105},
  pages     = {302 -- 306},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{PohleAdamBeumer2022,
  author    = {Pohle, Jennifer and Adam, Timo and Beumer, Larissa},
  title     = {Flexible estimation of the state dwell-time distribution in hidden semi-Markov models},
  series = {Computational statistics \& data analysis},
  volume    = {172},
  journal   = {Computational statistics \& data analysis},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0167-9473},
  doi       = {10.1016/j.csda.2022.107479},
  pages     = {15},
  year      = {2022},
  abstract  = {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.},
  language  = {en}
}
@article{BiskabornSmithNoetzlietal.2019,
  author    = {Biskaborn, Boris and Smith, Sharon L. and Noetzli, Jeannette and Matthes, Heidrun and Vieira, Goncalo and Streletskiy, Dmitry A. and Schoeneich, Philippe and Romanovsky, Vladimir E. and Lewkowicz, Antoni G. and Abramov, Andrey and Allard, Michel and Boike, Julia and Cable, William L. and Christiansen, Hanne H. and Delaloye, Reynald and Diekmann, Bernhard and Drozdov, Dmitry and Etzelmueller, Bernd and Grosse, Guido and Guglielmin, Mauro and Ingeman-Nielsen, Thomas and Isaksen, Ketil and Ishikawa, Mamoru and Johansson, Margareta and Johannsson, Halldor and Joo, Anseok and Kaverin, Dmitry and Kholodov, Alexander and Konstantinov, Pavel and Kroeger, Tim and Lambiel, Christophe and Lanckman, Jean-Pierre and Luo, Dongliang and Malkova, Galina and Meiklejohn, Ian and Moskalenko, Natalia and Oliva, Marc and Phillips, Marcia and Ramos, Miguel and Sannel, A. Britta K. and Sergeev, Dmitrii and Seybold, Cathy and Skryabin, Pavel and Vasiliev, Alexander and Wu, Qingbai and Yoshikawa, Kenji and Zheleznyak, Mikhail and Lantuit, Hugues},
  title     = {Permafrost is warming at a global scale},
  series = {Nature Communications},
  volume    = {10},
  journal   = {Nature Communications},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2041-1723},
  doi       = {10.1038/s41467-018-08240-4},
  pages     = {11},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}
@book{OPUS4-43561,
  title     = {Implementation research on problem solving in school settings},
  series = {Ars inveniendi et dejudicandi ; 13},
  journal   = {Ars inveniendi et dejudicandi ; 13},
  editor    = {Kuzle, Ana and Rott, Benjamin and Gebel, Inga},
  publisher = {WTM-Verlag},
  address   = {M{\"u}nster},
  isbn      = {978-3-95987-116-7},
  pages     = {IV, 220},
  year      = {2019},
  language  = {en}
}
@misc{KrauseKloftHuisingaetal.2019,
  author    = {Krause, Andreas and Kloft, Charlotte and Huisinga, Wilhelm and Karlsson, Mats and Pinheiro, Jos{\´e} and Bies, Robert and Rogers, James and Mentr{\´e}, France and Musser, Bret J.},
  title     = {Comment on Jaki et al., A proposal for a new PhD level curriculum on quantitative methods for drug development},
  series = {Pharmaceutical statistics : the journal of applied statistics in the pharmaceutical industry},
  volume    = {18},
  journal   = {Pharmaceutical statistics : the journal of applied statistics in the pharmaceutical industry},
  number    = {3},
  publisher = {Wiley},
  address   = {Hoboken},
  organization    = {ASA Special Interest Grp Stat Phar ASA Special Interest Grp Stat Phar},
  issn      = {1539-1604},
  pages     = {278 -- 281},
  year      = {2019},
  language  = {en}
}
@phdthesis{Seuring2000,
  author    = {Seuring, Markus},
  title     = {Output space compaction for testing and concurrent checking},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-0000165},
  school      = {Universit{\"a}t Potsdam},
  year      = {2000},
  abstract  = {In der Dissertation werden neue Entwurfsmethoden f{\"u}r Kompaktoren f{\"u}r die Ausg{\"a}nge von digitalen Schaltungen beschrieben, die die Anzahl der zu testenden Ausg{\"a}nge drastisch verkleinern und dabei die Testbarkeit der Schaltungen nur wenig oder gar nicht verschlechtern. Der erste Teil der Arbeit behandelt f{\"u}r kombinatorische Schaltungen Methoden, die die Struktur der Schaltungen beim Entwurf der Kompaktoren ber{\"u}cksichtigen. Verschiedene Algorithmen zur Analyse von Schaltungsstrukturen werden zum ersten Mal vorgestellt und untersucht. Die Komplexit{\"a}t der vorgestellten Verfahren zur Erzeugung von Kompaktoren ist linear bez{\"u}glich der Anzahl der Gatter in der Schaltung und ist damit auf sehr große Schaltungen anwendbar. Im zweiten Teil wird erstmals ein solches Verfahren f{\"u}r sequentielle Schaltkreise beschrieben. Dieses Verfahren baut im wesentlichen auf das erste auf. Der dritte Teil beschreibt eine Entwurfsmethode, die keine Informationen {\"u}ber die interne Struktur der Schaltung oder {\"u}ber das zugrundeliegende Fehlermodell ben{\"o}tigt. Der Entwurf basiert alleine auf einem vorgegebenen Satz von Testvektoren und die dazugeh{\"o}renden Testantworten der fehlerfreien Schaltung. Ein nach diesem Verfahren erzeugter Kompaktor maskiert keinen der Fehler, die durch das Testen mit den vorgegebenen Vektoren an den Ausg{\"a}ngen der Schaltung beobachtbar sind.},
  language  = {en}
}
@article{MuellerSchoellGroenlandScherfClaveletal.2020,
  author    = {Mueller-Schoell, Anna and Groenland, Stefanie L. and Scherf-Clavel, Oliver and van Dyk, Madele and Huisinga, Wilhelm and Michelet, Robin and Jaehde, Ulrich and Steeghs, Neeltje and Huitema, Alwin D. R. and Kloft, Charlotte},
  title     = {Therapeutic drug monitoring of oral targeted antineoplastic drugs},
  series = {European journal of clinical pharmacology},
  volume    = {77},
  journal   = {European journal of clinical pharmacology},
  number    = {4},
  publisher = {Springer},
  address   = {Heidelberg},
  issn      = {0031-6970},
  doi       = {10.1007/s00228-020-03014-8},
  pages     = {441 -- 464},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{GrisicEserHuisingaetal.2020,
  author    = {Grisic, Ana-Marija and Eser, Alexander and Huisinga, Wilhelm and Reinisch, Walter and Kloft, Charlotte},
  title     = {Quantitative relationship between infliximab exposure and inhibition of C-reactive protein synthesis to support inflammatory bowel disease management},
  series = {British journal of clinical pharmacology},
  volume    = {87},
  journal   = {British journal of clinical pharmacology},
  number    = {5},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0306-5251},
  doi       = {10.1111/bcp.14648},
  pages     = {2374 -- 2384},
  year      = {2020},
  abstract  = {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. <br /> 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. <br /> 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. <br /> 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.},
  language  = {en}
}
@article{KluweMicheletMuellerSchoelletal.2020,
  author    = {Kluwe, Franziska and Michelet, Robin and M{\"u}ller-Sch{\"o}ll, Anna and Maier, Corinna and Klopp-Schulze, Lena and van Dyk, Madele and Mikus, Gerd and Huisinga, Wilhelm and Kloft, Charlotte},
  title     = {Perspectives on model-informed precision dosing in the digital health era},
  series = {Clinical pharmacology \& therapeutics},
  volume    = {109},
  journal   = {Clinical pharmacology \& therapeutics},
  number    = {1},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0009-9236},
  doi       = {10.1002/cpt.2049},
  pages     = {29 -- 36},
  year      = {2020},
  language  = {en}
}
@article{NassarHohmannMicheletetal.2022,
  author    = {Nassar, Yomna M. and Hohmann, Nicolas and Michelet, Robin and Gottwalt, Katharina and Meid, Andreas D. and Burhenne, J{\"u}rgen and Huisinga, Wilhelm and Haefeli, Walter E. and Mikus, Gerd and Kloft, Charlotte},
  title     = {Quantification of the Time Course of CYP3A Inhibition, Activation, and Induction Using a Population Pharmacokinetic Model of Microdosed Midazolam Continuous Infusion},
  series = {Clinical Pharmacokinetics},
  volume    = {61},
  journal   = {Clinical Pharmacokinetics},
  number    = {11},
  publisher = {Springer},
  address   = {Northcote},
  issn      = {0312-5963},
  doi       = {10.1007/s40262-022-01175-6},
  pages     = {1595 -- 1607},
  year      = {2022},
  abstract  = {Background Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice. Objective We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity. Methods Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1'-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM (R). CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm. Results Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2-3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28-30 h followed by a steep drop to almost baseline within 1-2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1\%, +46.7\%, -70.6\%, and -61.1\% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively. Conclusions We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected.},
  language  = {en}
}
@misc{WeisserStueblerMatheisetal.2017,
  author    = {Weisser, Karin and St{\"u}bler, Sabine and Matheis, Walter and Huisinga, Wilhelm},
  title     = {Towards toxicokinetic modelling of aluminium exposure from adjuvants in medicinal products},
  series = {Regulatory toxicology and pharmacology : official journal of the International Society for Regulatory Toxicology and Pharmacology},
  volume    = {88},
  journal   = {Regulatory toxicology and pharmacology : official journal of the International Society for Regulatory Toxicology and Pharmacology},
  publisher = {Elsevier},
  address   = {San Diego},
  issn      = {0273-2300},
  doi       = {10.1016/j.yrtph.2017.02.018},
  pages     = {310 -- 321},
  year      = {2017},
  abstract  = {As a potentially toxic agent on nervous system and bone, the safety of aluminium exposure from adjuvants in vaccines and subcutaneous immune therapy (SCIT) products has to be continuously reevaluated, especially regarding concomitant administrations. For this purpose, knowledge on absorption and disposition of aluminium in plasma and tissues is essential. Pharmacokinetic data after vaccination in humans, however, are not available, and for methodological and ethical reasons difficult to obtain. To overcome these limitations, we discuss the possibility of an in vitro-in silico approach combining a toxicokinetic model for aluminium disposition with biorelevant kinetic absorption parameters from adjuvants. We critically review available kinetic aluminium-26 data for model building and, on the basis of a reparameterized toxicokinetic model (Nolte et al., 2001), we identify main modelling gaps. The potential of in vitro dissolution experiments for the prediction of intramuscular absorption kinetics of aluminium after vaccination is explored. It becomes apparent that there is need for detailed in vitro dissolution and in vivo absorption data to establish an in vitro-in vivo correlation (IVIVC) for aluminium adjuvants. We conclude that a combination of new experimental data and further refinement of the Nolte model has the potential to fill a gap in aluminium risk assessment. (C) 2017 Elsevier Inc. All rights reserved.},
  language  = {en}
}
@article{WichaHuisingaKloft2017,
  author    = {Wicha, Sebastian G. and Huisinga, Wilhelm and Kloft, Charlotte},
  title     = {Translational pharmacometric evaluation of typical antibiotic broad-spectrum combination therapies against staphylococcus aureus exploiting in vitro information},
  series = {CPT: pharmacometrics \& systems pharmacology},
  volume    = {6},
  journal   = {CPT: pharmacometrics \& systems pharmacology},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {2163-8306},
  doi       = {10.1002/psp4.12197},
  pages     = {512 -- 522},
  year      = {2017},
  abstract  = {Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER.},
  language  = {en}
}
@article{EdlundGrisicSteenholdtetal.2019,
  author    = {Edlund, Helena and Grisic, Ana-Marija and Steenholdt, Casper and Ainsworth, Mark Andrew and Brynskov, Torn and Huisinga, Wilhelm and Kloft, Charlotte},
  title     = {Absence of Relationship Between Crohn's Disease Activity Index or C-Reactive Protein and Infliximab Exposure Calls for Objective Crohn's Disease Activity Measures for the Evaluation of Treatment Effects at Treatment Failure},
  series = {Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology},
  volume    = {41},
  journal   = {Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology},
  number    = {2},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  issn      = {0163-4356},
  doi       = {10.1097/FTD.0000000000000590},
  pages     = {235 -- 242},
  year      = {2019},
  abstract  = {Background: Circulating infliximab (IFX) concentrations correlate with clinical outcomes, forming the basis of the IFX concentration monitoring in patients with Crohn's disease. This study aims to investigate and refine the exposure-response relationship by linking the disease activity markers "Crohn's disease activity index" (CDAI) and C-reactive protein (CRP) to IFX exposure. In addition, we aim to explore the correlations between different disease markers and exposure metrics. Methods: Data from 47 Crohn's disease patients of a randomized controlled trial were analyzed post hoc. All patients had secondary treatment failure at inclusion and had received intensified IFX of 5 mg/kg every 4 weeks for up to 20 weeks. Graphical analyses were performed to explore exposure-response relationships. Metrics of exposure included area under the concentration-time curve (AUC) and trough concentrations (Cmin). Disease activity was measured by CDAI and CRP values, their change from baseline/last visit, and response/remission outcomes at week 12. Results: Although trends toward lower Cmin and lower AUC in nonresponders were observed, neither CDAI nor CRP showed consistent trends of lower disease activity with higher IFX exposure across the 30 evaluated relationships. As can be expected, Cmin and AUC were strongly correlated with each other. Contrarily, the disease activity markers were only weakly correlated with each other. Conclusions: No significant relationship between disease activity, as evaluated by CDAI or CRP, and IFX exposure was identified. AUC did not add benefit compared with Cmin. These findings support the continued use of Cmin and call for stringent objective disease activity (bio-)markers (eg, endoscopy) to form the basis of personalized IFX therapy for Crohn's disease patients with IFX treatment failure.},
  language  = {en}
}
@article{KnoechelKloftHuisinga2018,
  author    = {Kn{\"o}chel, Jane and Kloft, Charlotte and Huisinga, Wilhelm},
  title     = {Understanding and reducing complex systems pharmacology models based on a novel input-response index},
  series = {Journal of pharmacokinetics and pharmacodynamics},
  volume    = {45},
  journal   = {Journal of pharmacokinetics and pharmacodynamics},
  number    = {1},
  publisher = {Springer Science + Business Media B.V.},
  address   = {New York},
  issn      = {1567-567X},
  doi       = {10.1007/s10928-017-9561-x},
  pages     = {139 -- 157},
  year      = {2018},
  abstract  = {A growing understanding of complex processes in biology has led to large-scale mechanistic models of pharmacologically relevant processes. These models are increasingly used to study the response of the system to a given input or stimulus, e.g., after drug administration. Understanding the input-response relationship, however, is often a challenging task due to the complexity of the interactions between its constituents as well as the size of the models. An approach that quantifies the importance of the different constituents for a given input-output relationship and allows to reduce the dynamics to its essential features is therefore highly desirable. In this article, we present a novel state- and time-dependent quantity called the input-response index that quantifies the importance of state variables for a given input-response relationship at a particular time. It is based on the concept of time-bounded controllability and observability, and defined with respect to a reference dynamics. In application to the brown snake venom-fibrinogen (Fg) network, the input-response indices give insight into the coordinated action of specific coagulation factors and about those factors that contribute only little to the response. We demonstrate how the indices can be used to reduce large-scale models in a two-step procedure: (i) elimination of states whose dynamics have only minor impact on the input-response relationship, and (ii) proper lumping of the remaining (lower order) model. In application to the brown snake venom-fibrinogen network, this resulted in a reduction from 62 to 8 state variables in the first step, and a further reduction to 5 state variables in the second step. We further illustrate that the sequence, in which a recursive algorithm eliminates and/or lumps state variables, has an impact on the final reduced model. The input-response indices are particularly suited to determine an informed sequence, since they are based on the dynamics of the original system. In summary, the novel measure of importance provides a powerful tool for analysing the complex dynamics of large-scale systems and a means for very efficient model order reduction of nonlinear systems.},
  language  = {en}
}
@phdthesis{Knoechel2019,
  author    = {Kn{\"o}chel, Jane},
  title     = {Model reduction of mechanism-based pharmacodynamic models and its link to classical drug effect models},
  doi       = {10.25932/publishup-44059},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-440598},
  school      = {Universit{\"a}t Potsdam},
  pages     = {vii, 147},
  year      = {2019},
  abstract  = {Continuous insight into biological processes has led to the development of large-scale, mechanistic systems biology models of pharmacologically relevant networks. While these models are typically designed to study the impact of diverse stimuli or perturbations on multiple system variables, the focus in pharmacological research is often on a specific input, e.g., the dose of a drug, and a specific output related to the drug effect or response in terms of some surrogate marker. To study a chosen input-output pair, the complexity of the interactions as well as the size of the models hinders easy access and understanding of the details of the input-output relationship. The objective of this thesis is the development of a mathematical approach, in specific a model reduction technique, that allows (i) to quantify the importance of the different state variables for a given input-output relationship, and (ii) to reduce the dynamics to its essential features -- allowing for a physiological interpretation of state variables as well as parameter estimation in the statistical analysis of clinical data. We develop a model reduction technique using a control theoretic setting by first defining a novel type of time-limited controllability and observability gramians for nonlinear systems. We then show the superiority of the time-limited generalised gramians for nonlinear systems in the context of balanced truncation for a benchmark system from control theory. The concept of time-limited controllability and observability gramians is subsequently used to introduce a state and time-dependent quantity called the input-response (ir) index that quantifies the importance of state variables for a given input-response relationship at a particular time. We subsequently link our approach to sensitivity analysis, thus, enabling for the first time the use of sensitivity coefficients for state space reduction. The sensitivity based ir-indices are given as a product of two sensitivity coefficients. This allows not only for a computational more efficient calculation but also for a clear distinction of the extent to which the input impacts a state variable and the extent to which a state variable impacts the output. The ir-indices give insight into the coordinated action of specific state variables for a chosen input-response relationship. Our developed model reduction technique results in reduced models that still allow for a mechanistic interpretation in terms of the quantities/state variables of the original system, which is a key requirement in the field of systems pharmacology and systems biology and distinguished the reduced models from so-called empirical drug effect models. The ir-indices are explicitly defined with respect to a reference trajectory and thereby dependent on the initial state (this is an important feature of the measure). This is demonstrated for an example from the field of systems pharmacology, showing that the reduced models are very informative in their ability to detect (genetic) deficiencies in certain physiological entities. Comparing our novel model reduction technique to the already existing techniques shows its superiority. The novel input-response index as a measure of the importance of state variables provides a powerful tool for understanding the complex dynamics of large-scale systems in the context of a specific drug-response relationship. Furthermore, the indices provide a means for a very efficient model order reduction and, thus, an important step towards translating insight from biological processes incorporated in detailed systems pharmacology models into the population analysis of clinical data.},
  language  = {en}
}
@phdthesis{Solms2017,
  author    = {Solms, Alexander Maximilian},
  title     = {Integrating nonlinear mixed effects and physiologically-based modeling approaches for the analysis of repeated measurement studies},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-397070},
  school      = {Universit{\"a}t Potsdam},
  pages     = {x, 141},
  year      = {2017},
  abstract  = {During the drug discovery \& development process, several phases encompassing a number of preclinical and clinical studies have to be successfully passed to demonstrate safety and efficacy of a new drug candidate. As part of these studies, the characterization of the drug's pharmacokinetics (PK) is an important aspect, since the PK is assumed to strongly impact safety and efficacy. To this end, drug concentrations are measured repeatedly over time in a study population. The objectives of such studies are to describe the typical PK time-course and the associated variability between subjects. Furthermore, underlying sources significantly contributing to this variability, e.g. the use of comedication, should be identified. The most commonly used statistical framework to analyse repeated measurement data is the nonlinear mixed effect (NLME) approach. At the same time, ample knowledge about the drug's properties already exists and has been accumulating during the discovery \& development process: Before any drug is tested in humans, detailed knowledge about the PK in different animal species has to be collected. This drug-specific knowledge and general knowledge about the species' physiology is exploited in mechanistic physiological based PK (PBPK) modeling approaches -it is, however, ignored in the classical NLME modeling approach. Mechanistic physiological based models aim to incorporate relevant and known physiological processes which contribute to the overlying process of interest. In comparison to data--driven models they are usually more complex from a mathematical perspective. For example, in many situations, the number of model parameters outrange the number of measurements and thus reliable parameter estimation becomes more complex and partly impossible. As a consequence, the integration of powerful mathematical estimation approaches like the NLME modeling approach -which is widely used in data-driven modeling -and the mechanistic modeling approach is not well established; the observed data is rather used as a confirming instead of a model informing and building input. Another aggravating circumstance of an integrated approach is the inaccessibility to the details of the NLME methodology so that these approaches can be adapted to the specifics and needs of mechanistic modeling. Despite the fact that the NLME modeling approach exists for several decades, details of the mathematical methodology is scattered around a wide range of literature and a comprehensive, rigorous derivation is lacking. Available literature usually only covers selected parts of the mathematical methodology. Sometimes, important steps are not described or are only heuristically motivated, e.g. the iterative algorithm to finally determine the parameter estimates. Thus, in the present thesis the mathematical methodology of NLME modeling is systemically described and complemented to a comprehensive description, comprising the common theme from ideas and motivation to the final parameter estimation. Therein, new insights for the interpretation of different approximation methods used in the context of the NLME modeling approach are given and illustrated; furthermore, similarities and differences between them are outlined. Based on these findings, an expectation-maximization (EM) algorithm to determine estimates of a NLME model is described. Using the EM algorithm and the lumping methodology by Pilari2010, a new approach on how PBPK and NLME modeling can be combined is presented and exemplified for the antibiotic levofloxacin. Therein, the lumping identifies which processes are informed by the available data and the respective model reduction improves the robustness in parameter estimation. Furthermore, it is shown how apriori known factors influencing the variability and apriori known unexplained variability is incorporated to further mechanistically drive the model development. Concludingly, correlation between parameters and between covariates is automatically accounted for due to the mechanistic derivation of the lumping and the covariate relationships. A useful feature of PBPK models compared to classical data-driven PK models is in the possibility to predict drug concentration within all organs and tissue in the body. Thus, the resulting PBPK model for levofloxacin is used to predict drug concentrations and their variability within soft tissues which are the site of action for levofloxacin. These predictions are compared with data of muscle and adipose tissue obtained by microdialysis, which is an invasive technique to measure a proportion of drug in the tissue, allowing to approximate the concentrations in the interstitial fluid of tissues. Because, so far, comparing human in vivo tissue PK and PBPK predictions are not established, a new conceptual framework is derived. The comparison of PBPK model predictions and microdialysis measurements shows an adequate agreement and reveals further strengths of the presented new approach. We demonstrated how mechanistic PBPK models, which are usually developed in the early stage of drug development, can be used as basis for model building in the analysis of later stages, i.e. in clinical studies. As a consequence, the extensively collected and accumulated knowledge about species and drug are utilized and updated with specific volunteer or patient data. The NLME approach combined with mechanistic modeling reveals new insights for the mechanistic model, for example identification and quantification of variability in mechanistic processes. This represents a further contribution to the learn \& confirm paradigm across different stages of drug development. Finally, the applicability of mechanism--driven model development is demonstrated on an example from the field of Quantitative Psycholinguistics to analyse repeated eye movement data. Our approach gives new insight into the interpretation of these experiments and the processes behind.},
  language  = {en}
}
@phdthesis{Gopalakrishnan2016,
  author    = {Gopalakrishnan, Sathej},
  title     = {Mathematical modelling of host-disease-drug interactions in HIV disease},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-100100},
  school      = {Universit{\"a}t Potsdam},
  pages     = {121},
  year      = {2016},
  abstract  = {The human immunodeficiency virus (HIV) has resisted nearly three decades of efforts targeting a cure. Sustained suppression of the virus has remained a challenge, mainly due to the remarkable evolutionary adaptation that the virus exhibits by the accumulation of drug-resistant mutations in its genome. Current therapeutic strategies aim at achieving and maintaining a low viral burden and typically involve multiple drugs. The choice of optimal combinations of these drugs is crucial, particularly in the background of treatment failure having occurred previously with certain other drugs. An understanding of the dynamics of viral mutant genotypes aids in the assessment of treatment failure with a certain drug combination, and exploring potential salvage treatment regimens. Mathematical models of viral dynamics have proved invaluable in understanding the viral life cycle and the impact of antiretroviral drugs. However, such models typically use simplified and coarse-grained mutation schemes, that curbs the extent of their application to drug-specific clinical mutation data, in order to assess potential next-line therapies. Statistical models of mutation accumulation have served well in dissecting mechanisms of resistance evolution by reconstructing mutation pathways under different drug-environments. While these models perform well in predicting treatment outcomes by statistical learning, they do not incorporate drug effect mechanistically. Additionally, due to an inherent lack of temporal features in such models, they are less informative on aspects such as predicting mutational abundance at treatment failure. This limits their application in analyzing the pharmacology of antiretroviral drugs, in particular, time-dependent characteristics of HIV therapy such as pharmacokinetics and pharmacodynamics, and also in understanding the impact of drug efficacy on mutation dynamics. In this thesis, we develop an integrated model of in vivo viral dynamics incorporating drug-specific mutation schemes learned from clinical data. Our combined modelling approach enables us to study the dynamics of different mutant genotypes and assess mutational abundance at virological failure. As an application of our model, we estimate in vivo fitness characteristics of viral mutants under different drug environments. Our approach also extends naturally to multiple-drug therapies. Further, we demonstrate the versatility of our model by showing how it can be modified to incorporate recently elucidated mechanisms of drug action including molecules that target host factors. Additionally, we address another important aspect in the clinical management of HIV disease, namely drug pharmacokinetics. It is clear that time-dependent changes in in vivo drug concentration could have an impact on the antiviral effect, and also influence decisions on dosing intervals. We present a framework that provides an integrated understanding of key characteristics of multiple-dosing regimens including drug accumulation ratios and half-lifes, and then explore the impact of drug pharmacokinetics on viral suppression. Finally, parameter identifiability in such nonlinear models of viral dynamics is always a concern, and we investigate techniques that alleviate this issue in our setting.},
  language  = {en}
}
@article{StachanowNeumannBlankensteinetal.2022,
  author    = {Stachanow, Viktoria and Neumann, Uta and Blankenstein, Oliver and Bindellini, Davide and Melin, Johanna and Ross, Richard and Whitaker, Martin J. J. and Huisinga, Wilhelm and Michelet, Robin and Kloft, Charlotte},
  title     = {Exploring dried blood spot cortisol concentrations as an alternative for monitoring pediatric adrenal insufficiency patients},
  series = {Frontiers in pharmacology},
  volume    = {13},
  journal   = {Frontiers in pharmacology},
  publisher = {Frontiers Media},
  address   = {Lausanne},
  issn      = {1663-9812},
  doi       = {10.3389/fphar.2022.819590},
  pages     = {8},
  year      = {2022},
  abstract  = {Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling. Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations. In addition to previously characterized binding of cortisol to albumin (linear process) and corticosteroid-binding globulin (CBG; saturable process), DBS data enabled the characterization of a linear cortisol association with RBCs, and thereby providing a quantitative link between DBS and plasma cortisol concentrations. The ratio between the observed cortisol plasma and DBS concentrations varies highly from 2 to 8. Deterministic simulations of the different cortisol binding/association fractions demonstrated that with higher blood cortisol concentrations, saturation of cortisol binding to CBG was observed, leading to an increase in all other cortisol binding fractions. In conclusion, a mathematical PK model was developed which links DBS measurements to plasma exposure and thus allows for quantitative interpretation of measurements of DBS samples.},
  language  = {en}
}
@phdthesis{Schindler2023,
  author    = {Schindler, Daniel},
  title     = {Mathematical modeling and simulation of protrusion-driven cell dynamics},
  doi       = {10.25932/publishup-61327},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-613275},
  school      = {Universit{\"a}t Potsdam},
  pages     = {VI, 161},
  year      = {2023},
  abstract  = {Amoeboid cell motility takes place in a variety of biomedical processes such as cancer metastasis, embryonic morphogenesis, and wound healing. In contrast to other forms of cell motility, it is mainly driven by substantial cell shape changes. Based on the interplay of explorative membrane protrusions at the front and a slower-acting membrane retraction at the rear, the cell moves in a crawling kind of way. Underlying these protrusions and retractions are multiple physiological processes resulting in changes of the cytoskeleton, a meshwork of different multi-functional proteins. The complexity and versatility of amoeboid cell motility raise the need for novel computational models based on a profound theoretical framework to analyze and simulate the dynamics of the cell shape. The objective of this thesis is the development of (i) a mathematical framework to describe contour dynamics in time and space, (ii) a computational model to infer expansion and retraction characteristics of individual cell tracks and to produce realistic contour dynamics, (iii) and a complementing Open Science approach to make the above methods fully accessible and easy to use. In this work, we mainly used single-cell recordings of the model organism Dictyostelium discoideum. Based on stacks of segmented microscopy images, we apply a Bayesian approach to obtain smooth representations of the cell membrane, so-called cell contours. We introduce a one-parameter family of regularized contour flows to track reference points on the contour (virtual markers) in time and space. This way, we define a coordinate system to visualize local geometric and dynamic quantities of individual contour dynamics in so-called kymograph plots. In particular, we introduce the local marker dispersion as a measure to identify membrane protrusions and retractions in a fully automated way. This mathematical framework is the basis of a novel contour dynamics model, which consists of three biophysiologically motivated components: one stochastic term, accounting for membrane protrusions, and two deterministic terms to control the shape and area of the contour, which account for membrane retractions. Our model provides a fully automated approach to infer protrusion and retraction characteristics from experimental cell tracks while being also capable of simulating realistic and qualitatively different contour dynamics. Furthermore, the model is used to classify two different locomotion types: the amoeboid and a so-called fan-shaped type. With the complementing Open Science approach, we ensure a high standard regarding the usability of our methods and the reproducibility of our research. In this context, we introduce our software publication named AmoePy, an open-source Python package to segment, analyze, and simulate amoeboid cell motility. Furthermore, we describe measures to improve its usability and extensibility, e.g., by detailed run instructions and an automatically generated source code documentation, and to ensure its functionality and stability, e.g., by automatic software tests, data validation, and a hierarchical package structure. The mathematical approaches of this work provide substantial improvements regarding the modeling and analysis of amoeboid cell motility. We deem the above methods, due to their generalized nature, to be of greater value for other scientific applications, e.g., varying organisms and experimental setups or the transition from unicellular to multicellular movement. Furthermore, we enable other researchers from different fields, i.e., mathematics, biophysics, and medicine, to apply our mathematical methods. By following Open Science standards, this work is of greater value for the cell migration community and a potential role model for other Open Science contributions.},
  language  = {en}
}
@article{HijaziFreitagLandwehr2023,
  author    = {Hijazi, Saddam and Freitag, Melina A. and Landwehr, Niels},
  title     = {POD-Galerkin reduced order models and physics-informed neural networks for solving inverse problems for the Navier-Stokes equations},
  series = {Advanced modeling and simulation in engineering sciences : AMSES},
  volume    = {10},
  journal   = {Advanced modeling and simulation in engineering sciences : AMSES},
  number    = {1},
  publisher = {SpringerOpen},
  address   = {Berlin},
  issn      = {2213-7467},
  doi       = {10.1186/s40323-023-00242-2},
  pages     = {38},
  year      = {2023},
  abstract  = {We present a Reduced Order Model (ROM) which exploits recent developments in Physics Informed Neural Networks (PINNs) for solving inverse problems for the Navier-Stokes equations (NSE). In the proposed approach, the presence of simulated data for the fluid dynamics fields is assumed. A POD-Galerkin ROM is then constructed by applying POD on the snapshots matrices of the fluid fields and performing a Galerkin projection of the NSE (or the modified equations in case of turbulence modeling) onto the POD reduced basis. A POD-Galerkin PINN ROM is then derived by introducing deep neural networks which approximate the reduced outputs with the input being time and/or parameters of the model. The neural networks incorporate the physical equations (the POD-Galerkin reduced equations) into their structure as part of the loss function. Using this approach, the reduced model is able to approximate unknown parameters such as physical constants or the boundary conditions. A demonstration of the applicability of the proposed ROM is illustrated by three cases which are the steady flow around a backward step, the flow around a circular cylinder and the unsteady turbulent flow around a surface mounted cubic obstacle.},
  language  = {en}
}
@article{MolkenthinDonnerReichetal.2022,
  author    = {Molkenthin, Christian and Donner, Christian and Reich, Sebastian and Z{\"o}ller, Gert and Hainzl, Sebastian and Holschneider, Matthias and Opper, Manfred},
  title     = {GP-ETAS: semiparametric Bayesian inference for the spatio-temporal epidemic type aftershock sequence model},
  series = {Statistics and Computing},
  volume    = {32},
  journal   = {Statistics and Computing},
  number    = {2},
  publisher = {Springer},
  address   = {Dordrecht},
  issn      = {0960-3174},
  doi       = {10.1007/s11222-022-10085-3},
  pages     = {25},
  year      = {2022},
  abstract  = {The spatio-temporal epidemic type aftershock sequence (ETAS) model is widely used to describe the self-exciting nature of earthquake occurrences. While traditional inference methods provide only point estimates of the model parameters, we aim at a fully Bayesian treatment of model inference, allowing naturally to incorporate prior knowledge and uncertainty quantification of the resulting estimates. Therefore, we introduce a highly flexible, non-parametric representation for the spatially varying ETAS background intensity through a Gaussian process (GP) prior. Combined with classical triggering functions this results in a new model formulation, namely the GP-ETAS model. We enable tractable and efficient Gibbs sampling by deriving an augmented form of the GP-ETAS inference problem. This novel sampling approach allows us to assess the posterior model variables conditioned on observed earthquake catalogues, i.e., the spatial background intensity and the parameters of the triggering function. Empirical results on two synthetic data sets indicate that GP-ETAS outperforms standard models and thus demonstrate the predictive power for observed earthquake catalogues including uncertainty quantification for the estimated parameters. Finally, a case study for the l'Aquila region, Italy, with the devastating event on 6 April 2009, is presented.},
  language  = {en}
}
@article{KucharskiErgintavAhmadetal.2019,
  author    = {Kucharski, Maciej and Ergintav, Arzu and Ahmad, Wael Abdullah and Krstić, Miloš and Ng, Herman Jalli and Kissinger, Dietmar},
  title     = {A Scalable 79-GHz Radar Platform Based on Single-Channel Transceivers},
  series = {IEEE Transactions on Microwave Theory and Techniques},
  volume    = {67},
  journal   = {IEEE Transactions on Microwave Theory and Techniques},
  number    = {9},
  publisher = {Inst. of Electr. and Electronics Engineers},
  address   = {Piscataway},
  issn      = {0018-9480},
  doi       = {10.1109/TMTT.2019.2914104},
  pages     = {3882 -- 3896},
  year      = {2019},
  abstract  = {This paper presents a scalable E-band radar platform based on single-channel fully integrated transceivers (TRX) manufactured using 130-nm silicon-germanium (SiGe) BiCMOS technology. The TRX is suitable for flexible radar systems exploiting massive multiple-input-multipleoutput (MIMO) techniques for multidimensional sensing. A fully integrated fractional-N phase-locked loop (PLL) comprising a 39.5-GHz voltage-controlled oscillator is used to generate wideband frequency-modulated continuous-wave (FMCW) chirp for E-band radar front ends. The TRX is equipped with a vector modulator (VM) for high-speed carrier modulation and beam-forming techniques. A single TRX achieves 19.2-dBm maximum output power and 27.5-dB total conversion gain with input-referred 1-dB compression point of -10 dBm. It consumes 220 mA from 3.3-V supply and occupies 3.96 mm(2) silicon area. A two-channel radar platform based on full-custom TRXs and PLL was fabricated to demonstrate high-precision and high-resolution FMCW sensing. The radar enables up to 10-GHz frequency ramp generation in 74-84-GHz range, which results in 1.5-cm spatial resolution. Due to high output power, thus high signal-to-noise ratio (SNR), a ranging precision of 7.5 mu m for a target at 2 m was achieved. The proposed architecture supports scalable multichannel applications for automotive FMCW using a single local oscillator (LO).},
  language  = {en}
}
@article{SharmaHainzlZoelleretal.2020,
  author    = {Sharma, Shubham and Hainzl, Sebastian and Z{\"o}ller, Gert and Holschneider, Matthias},
  title     = {Is Coulomb stress the best choice for aftershock forecasting?},
  series = {Journal of geophysical research : Solid earth},
  volume    = {125},
  journal   = {Journal of geophysical research : Solid earth},
  number    = {9},
  publisher = {American Geophysical Union},
  address   = {Washington},
  issn      = {2169-9313},
  doi       = {10.1029/2020JB019553},
  pages     = {12},
  year      = {2020},
  abstract  = {The Coulomb failure stress (CFS) criterion is the most commonly used method for predicting spatial distributions of aftershocks following large earthquakes. However, large uncertainties are always associated with the calculation of Coulomb stress change. The uncertainties mainly arise due to nonunique slip inversions and unknown receiver faults; especially for the latter, results are highly dependent on the choice of the assumed receiver mechanism. Based on binary tests (aftershocks yes/no), recent studies suggest that alternative stress quantities, a distance-slip probabilistic model as well as deep neural network (DNN) approaches, all are superior to CFS with predefined receiver mechanism. To challenge this conclusion, which might have large implications, we use 289 slip inversions from SRCMOD database to calculate more realistic CFS values for a layered half-space and variable receiver mechanisms. We also analyze the effect of the magnitude cutoff, grid size variation, and aftershock duration to verify the use of receiver operating characteristic (ROC) analysis for the ranking of stress metrics. The observations suggest that introducing a layered half-space does not improve the stress maps and ROC curves. However, results significantly improve for larger aftershocks and shorter time periods but without changing the ranking. We also go beyond binary testing and apply alternative statistics to test the ability to estimate aftershock numbers, which confirm that simple stress metrics perform better than the classic Coulomb failure stress calculations and are also better than the distance-slip probabilistic model.},
  language  = {en}
}
@article{EngbertRabeKliegletal.2021,
  author    = {Engbert, Ralf and Rabe, Maximilian Michael and Kliegl, Reinhold and Reich, Sebastian},
  title     = {Sequential data assimilation of the stochastic SEIR epidemic model for regional COVID-19 dynamics},
  series = {Bulletin of mathematical biology : official journal of the Society for Mathematical Biology},
  volume    = {83},
  journal   = {Bulletin of mathematical biology : official journal of the Society for Mathematical Biology},
  number    = {1},
  publisher = {Springer},
  address   = {New York},
  issn      = {0092-8240},
  doi       = {10.1007/s11538-020-00834-8},
  pages     = {16},
  year      = {2021},
  abstract  = {Newly emerging pandemics like COVID-19 call for predictive models to implement precisely tuned responses to limit their deep impact on society. Standard epidemic models provide a theoretically well-founded dynamical description of disease incidence. For COVID-19 with infectiousness peaking before and at symptom onset, the SEIR model explains the hidden build-up of exposed individuals which creates challenges for containment strategies. However, spatial heterogeneity raises questions about the adequacy of modeling epidemic outbreaks on the level of a whole country. Here, we show that by applying sequential data assimilation to the stochastic SEIR epidemic model, we can capture the dynamic behavior of outbreaks on a regional level. Regional modeling, with relatively low numbers of infected and demographic noise, accounts for both spatial heterogeneity and stochasticity. Based on adapted models, short-term predictions can be achieved. Thus, with the help of these sequential data assimilation methods, more realistic epidemic models are within reach.},
  language  = {en}
}
@phdthesis{Sareeto2024,
  author    = {Sareeto, Apatsara},
  title     = {Algebraic properties of a subsemigroup of the symmetric inverse semigroup},
  school      = {Universit{\"a}t Potsdam},
  pages     = {92},
  year      = {2024},
  language  = {en}
}
@article{GerlachGlueck2017,
  author    = {Gerlach, Moritz Reinhardt and Gl{\"u}ck, Jochen},
  title     = {On a convergence theorem for semigroups of positive integral operators},
  series = {Comptes Rendus Mathematique},
  volume    = {355},
  journal   = {Comptes Rendus Mathematique},
  publisher = {Elsevier},
  address   = {Paris},
  issn      = {1631-073X},
  doi       = {10.1016/j.crma.2017.07.017},
  pages     = {973 -- 976},
  year      = {2017},
  abstract  = {We give a new and very short proof of a theorem of Greiner asserting that a positive and contractive -semigroup on an -space is strongly convergent in case it has a strictly positive fixed point and contains an integral operator. Our proof is a streamlined version of a much more general approach to the asymptotic theory of positive semigroups developed recently by the authors. Under the assumptions of Greiner's theorem, this approach becomes particularly elegant and simple. We also give an outlook on several generalisations of this result.},
  language  = {en}
}
@article{Gerlach2018,
  author    = {Gerlach, Moritz Reinhardt},
  title     = {Convergence of dynamics and the Perron-Frobenius operator},
  series = {Israel Journal of Mathematics},
  volume    = {225},
  journal   = {Israel Journal of Mathematics},
  number    = {1},
  publisher = {Hebrew univ magnes press},
  address   = {Jerusalem},
  issn      = {0021-2172},
  doi       = {10.1007/s11856-018-1671-7},
  pages     = {451 -- 463},
  year      = {2018},
  abstract  = {We complete the picture how the asymptotic behavior of a dynamical system is reflected by properties of the associated Perron-Frobenius operator. Our main result states that strong convergence of the powers of the Perron-Frobenius operator is equivalent to setwise convergence of the underlying dynamic in the measure algebra. This situation is furthermore characterized by uniform mixing-like properties of the system.},
  language  = {en}
}
@article{GerlachGlueck2019,
  author    = {Gerlach, Moritz Reinhardt and Gl{\"u}ck, Jochen},
  title     = {Convergence of positive operator semigroups},
  series = {Transactions of the American Mathematical Society},
  volume    = {372},
  journal   = {Transactions of the American Mathematical Society},
  number    = {9},
  publisher = {American Mathematical Soc.},
  address   = {Providence},
  issn      = {0002-9947},
  doi       = {10.1090/tran/7836},
  pages     = {6603 -- 6627},
  year      = {2019},
  abstract  = {We present new conditions for semigroups of positive operators to converge strongly as time tends to infinity. Our proofs are based on a novel approach combining the well-known splitting theorem by Jacobs, de Leeuw, and Glicksberg with a purely algebraic result about positive group representations. Thus, we obtain convergence theorems not only for one-parameter semigroups but also for a much larger class of semigroup representations. Our results allow for a unified treatment of various theorems from the literature that, under technical assumptions, a bounded positive C-0-semigroup containing or dominating a kernel operator converges strongly as t ->infinity. We gain new insights into the structure theoretical background of those theorems and generalize them in several respects; especially we drop any kind of continuity or regularity assumption with respect to the time parameter.},
  language  = {en}
}
@article{EdekoGerlachKuehner2019,
  author    = {Edeko, Nikolai and Gerlach, Moritz Reinhardt and K{\"u}hner, Viktoria},
  title     = {Measure-preserving semiflows and one-parameter Koopman semigroups},
  series = {Semigroup forum},
  volume    = {98},
  journal   = {Semigroup forum},
  number    = {1},
  publisher = {Springer},
  address   = {New York},
  issn      = {0037-1912},
  doi       = {10.1007/s00233-018-9960-3},
  pages     = {48 -- 63},
  year      = {2019},
  abstract  = {For a finite measure space X, we characterize strongly continuous Markov lattice semigroups on Lp(X) by showing that their generator A acts as a derivation on the dense subspace D(A)L(X). We then use this to characterize Koopman semigroups on Lp(X) if X is a standard probability space. In addition, we show that every measurable and measure-preserving flow on a standard probability space is isomorphic to a continuous flow on a compact Borel probability space.},
  language  = {en}
}
@article{GerlachGlueck2018,
  author    = {Gerlach, Moritz Reinhardt and Gl{\"u}ck, Jochen},
  title     = {Lower bounds and the asymptotic behaviour of positive operator semigroups},
  series = {Ergodic theory and dynamical systems},
  volume    = {38},
  journal   = {Ergodic theory and dynamical systems},
  publisher = {Cambridge Univ. Press},
  address   = {New York},
  issn      = {0143-3857},
  doi       = {10.1017/etds.2017.9},
  pages     = {3012 -- 3041},
  year      = {2018},
  abstract  = {If (T-t) is a semigroup of Markov operators on an L-1-space that admits a nontrivial lower bound, then a well-known theorem of Lasota and Yorke asserts that the semigroup is strongly convergent as t -> infinity. In this article we generalize and improve this result in several respects. First, we give a new and very simple proof for the fact that the same conclusion also holds if the semigroup is merely assumed to be bounded instead of Markov. As a main result, we then prove a version of this theorem for semigroups which only admit certain individual lower bounds. Moreover, we generalize a theorem of Ding on semigroups of Frobenius-Perron operators. We also demonstrate how our results can be adapted to the setting of general Banach lattices and we give some counterexamples to show optimality of our results. Our methods combine some rather concrete estimates and approximation arguments with abstract functional analytical tools. One of these tools is a theorem which relates the convergence of a time-continuous operator semigroup to the convergence of embedded discrete semigroups.},
  language  = {en}
}
@article{GerlachGlueck2019,
  author    = {Gerlach, Moritz Reinhardt and Gl{\"u}ck, Jochen},
  title     = {Mean ergodicity vs weak almost periodicity},
  series = {Studia mathematica},
  volume    = {248},
  journal   = {Studia mathematica},
  number    = {1},
  publisher = {Polska Akademia Nauk, Instytut Matematyczny},
  address   = {Warszawa},
  issn      = {0039-3223},
  doi       = {10.4064/sm170918-20-3},
  pages     = {45 -- 56},
  year      = {2019},
  abstract  = {We provide explicit examples of positive and power-bounded operators on c(0) and l(infinity) which are mean ergodic but not weakly almost periodic. As a consequence we prove that a countably order complete Banach lattice on which every positive and power-bounded mean ergodic operator is weakly almost periodic is necessarily a KB-space. This answers several open questions from the literature. Finally, we prove that if T is a positive mean ergodic operator with zero fixed space on an arbitrary Banach lattice, then so is every power of T .},
  language  = {en}
}
@article{GerlachGlueckKunze2023,
  author    = {Gerlach, Moritz and Gl{\"u}ck, Jochen and Kunze, Markus},
  title     = {Stability of transition semigroups and applications to parabolic equations},
  series = {Transactions of the American Mathematical Society},
  volume    = {376},
  journal   = {Transactions of the American Mathematical Society},
  number    = {1},
  publisher = {American Mathematical Soc.},
  address   = {Providence},
  issn      = {0002-9947},
  doi       = {10.1090/tran/8620},
  pages     = {153 -- 180},
  year      = {2023},
  abstract  = {This paper deals with the long-term behavior of positive operator semigroups on spaces of bounded functions and of signed measures, which have applications to parabolic equations with unbounded coefficients and to stochas-tic analysis. The main results are a Tauberian type theorem characterizing the convergence to equilibrium of strongly Feller semigroups and a generalization of a classical convergence theorem of Doob. None of these results requires any kind of time regularity of the semigroup.},
  language  = {en}
}
@article{DimitrovaKoppitz2022,
  author    = {Dimitrova, Ilinka and Koppitz, J{\"o}rg},
  title     = {On relative ranks of the semigroup of orientation-preserving transformations on infinite chain with restricted range},
  series = {Communications in algebra},
  volume    = {50},
  journal   = {Communications in algebra},
  number    = {5},
  publisher = {Taylor \& Francis Group},
  address   = {Philadelphia},
  issn      = {0092-7872},
  doi       = {10.1080/00927872.2021.2000998},
  pages     = {2157 -- 2168},
  year      = {2022},
  abstract  = {Let X be an infinite linearly ordered set and let Y be a nonempty subset of X. We calculate the relative rank of the semigroup OP(X,Y) of all orientation-preserving transformations on X with restricted range Y modulo the semigroup O(X,Y) of all order-preserving transformations on X with restricted range Y. For Y = X, we characterize the relative generating sets of minimal size.},
  language  = {en}
}
@article{DimitrovaKoppitz2020,
  author    = {Dimitrova, Ilinka and Koppitz, J{\"o}rg},
  title     = {On relative ranks of the semigroup of orientation-preserving transformations on infinite chains},
  series = {Asian-European journal of mathematics},
  volume    = {14},
  journal   = {Asian-European journal of mathematics},
  number    = {08},
  publisher = {World Scientific},
  address   = {Singapore},
  issn      = {1793-5571},
  doi       = {10.1142/S1793557121501461},
  pages     = {15},
  year      = {2020},
  abstract  = {In this paper, we determine the relative rank of the semigroup OP(X) of all orientation-preserving transformations on infinite chains modulo the semigroup O(X) of all order-preserving transformations.},
  language  = {en}
}
@article{KretzschmarAshbyFearonetal.2022,
  author    = {Kretzschmar, Mirjam E. and Ashby, Ben and Fearon, Elizabeth and Overton, Christopher E. and Panovska-Griffiths, Jasmina and Pellis, Lorenzo and Quaife, Matthew and Rozhnova, Ganna and Scarabel, Francesca and Stage, Helena B. and Swallow, Ben and Thompson, Robin N. and Tildesley, Michael J. and Villela, Daniel Campos},
  title     = {Challenges for modelling interventions for future pandemics},
  series = {Epidemics},
  volume    = {38},
  journal   = {Epidemics},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {1755-4365},
  doi       = {10.1016/j.epidem.2022.100546},
  pages     = {13},
  year      = {2022},
  abstract  = {Mathematical modelling and statistical inference provide a framework to evaluate different non-pharmaceutical and pharmaceutical interventions for the control of epidemics that has been widely used during the COVID-19 pandemic. In this paper, lessons learned from this and previous epidemics are used to highlight the challenges for future pandemic control. We consider the availability and use of data, as well as the need for correct parameterisation and calibration for different model frameworks. We discuss challenges that arise in describing and distinguishing between different interventions, within different modelling structures, and allowing both within and between host dynamics. We also highlight challenges in modelling the health economic and political aspects of interventions. Given the diversity of these challenges, a broad variety of interdisciplinary expertise is needed to address them, combining mathematical knowledge with biological and social insights, and including health economics and communication skills. Addressing these challenges for the future requires strong cross disciplinary collaboration together with close communication between scientists and policy makers.},
  language  = {en}
}