@unpublished{NazaikinskiiSavinSchulzeetal.2002,
  author    = {Nazaikinskii, Vladimir and Savin, Anton and Schulze, Bert-Wolfgang and Sternin, Boris},
  title     = {Elliptic theory on manifolds with nonisolated singularities : I. The index of families of cone-degenerate operators},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26327},
  year      = {2002},
  abstract  = {We study the index problem for families of elliptic operators on manifolds with conical singularities. The relative index theorem concerning changes of the weight line is obtained. AN index theorem for families whose conormal symbols satisfy some symmetry conditions is derived.},
  language  = {en}
}
@unpublished{EgorovKondratievSchulze2001,
  author    = {Egorov, Yu. and Kondratiev, V. and Schulze, Bert-Wolfgang},
  title     = {On completeness of eigenfunctions of an elliptic operator on a manifold with conical points},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-25937},
  year      = {2001},
  abstract  = {Contents: 1 Introduction 2 Definitions 3 Rays of minimal growth 4 Completeness of root functions},
  language  = {en}
}
@unpublished{FladSchneiderSchulze2007,
  author    = {Flad, Heinz-J{\"u}rgen and Schneider, Reinhold and Schulze, Bert-Wolfgang},
  title     = {Asymptotic regularity of solutions of Hartree-Fock equations with coulomb potential},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-30268},
  year      = {2007},
  abstract  = {We study the asymptotic regularity of solutions of Hartree-Fock equations for Coulomb systems. In order to deal with singular Coulomb potentials, Fock operators are discussed within the calculus of pseudo-differential operators on conical manifolds. First, the non-self-consistent-field case is considered which means that the functions that enter into the nonlinear terms are not the eigenfunctions of the Fock operator itself. We introduce asymptotic regularity conditions on the functions that build up the Fock operator which guarantee ellipticity for the local part of the Fock operator on the open stretched cone R+ × S². This proves existence of a parametrix with a corresponding smoothing remainder from which it follows, via a bootstrap argument, that the eigenfunctions of the Fock operator again satisfy asymptotic regularity conditions. Using a fixed-point approach based on Cances and Le Bris analysis of the level-shifting algorithm, we show via another bootstrap argument, that the corresponding self-consistent-field solutions of the Hartree-Fock equation have the same type of asymptotic regularity.},
  language  = {en}
}
@unpublished{SchulzeTarkhanov2000,
  author    = {Schulze, Bert-Wolfgang and Tarkhanov, Nikolai Nikolaevich},
  title     = {Asymptotics of solutions to elliptic equatons on manifolds with corners},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-25716},
  year      = {2000},
  abstract  = {We show an explicit link between the nature of a singular point and behaviour of the coefficients of the equation, under which formal asymptotic expansions are still available.},
  language  = {en}
}
@unpublished{Schulze1999,
  author    = {Schulze, Bert-Wolfgang},
  title     = {Operator algebras with symbol hierarchies on manifolds with singularities},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-25647},
  year      = {1999},
  abstract  = {Problems for elliptic partial differential equations on manifolds M with singularities M' (here with piece-wise smooth geometry)are studied in terms of pseudo-differential algebras with hierarchies of symbols that consist of scalar and operator-valued components. Classical boundary value problems (with or without the transmission property) belong to the examples. They are a model for operator algebras on manifolds M with higher "polyhedral" singularities. The operators are block matrices that have upper left corners containing the pseudo-differential operators on the regular M\M' (plus certain Mellin and Green summands) and are degenerate (in streched coordinates) in a typical way near M'. By definition M' is again a manifold with singularities. The same is true of M'', and so on. The block matrices consist of trace, potential and Mellin and Green operators, acting between weighted Sobolev spaces on M(j) and M(k), with 0 ≤ j, k ≤ ord M; here M(0) denotes M, M(1) denotes M', etc. We generate these algebras, including their symbol hierarchies, by iterating so-called "edgifications" and "conifications" os algebras that have already been constructed, and we study ellipicity, parametrics and Fredholm property within these algebras.},
  language  = {en}
}
@unpublished{Schulze1999,
  author    = {Schulze, Bert-Wolfgang},
  title     = {An algebra of boundary value problems not requiring Shapiro-Lopatinskil conditions},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-25596},
  year      = {1999},
  abstract  = {We construct an algebra of pseudo-differential boundary value problems that contains the classical Shapiro-Lopatinskij elliptic problems as well as all differential elliptic problems of Dirac type with APS boundary conditions, together with their parametrices. Global pseudo-differential projections on the boundary are used to define ellipticity and to show the Fredholm property in suitable scales of spaces.},
  language  = {en}
}
@unpublished{KapanadzeSchulzeWitt2000,
  author    = {Kapanadze, David and Schulze, Bert-Wolfgang and Witt, Ingo},
  title     = {Coordinate invariance of the cone algebra with asymptotics},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-25671},
  year      = {2000},
  abstract  = {The cone algebra with discrete asymptotics on a manifold with conical singularities is shown to be invariant under natural coordinate changes, where the symbol structure (i.e., the Fuchsian interior symbol, conormal symbols of all orders) follows a corresponding transformation rule.},
  language  = {en}
}
@unpublished{NazaikinskiiSchulzeSternin2000,
  author    = {Nazaikinskii, Vladimir and Schulze, Bert-Wolfgang and Sternin, Boris},
  title     = {Quantization methods in differential equations : Part II: Quantization by the method of ordered operators (Noncommutative Analysis) : Chapter 1: Noncommutative Analysis: Main Ideas, Definitions, and Theorems},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-25762},
  year      = {2000},
  abstract  = {Content: 0.1 Preliminary Remarks Chapter 1: Noncommutative Analysis: Main Ideas, Definitions, and Theorems 1.1 Functions of One Operator (Functional Calculi) 1.2 Functions of Several Operators 1.3 Main Formulas of Operator Calculus 1.4 Main Tools of Noncommutative Analysis 1.5 Composition Laws and Ordered Representations},
  language  = {en}
}
@unpublished{RabinovichSchulzeTarkhanov1999,
  author    = {Rabinovich, Vladimir and Schulze, Bert-Wolfgang and Tarkhanov, Nikolai Nikolaevich},
  title     = {Boundary value problems in domains with corners},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-25552},
  year      = {1999},
  abstract  = {We describe Fredholm boundary value problems for differential equations in domains with intersecting cuspidal edges on the boundary.},
  language  = {en}
}
@unpublished{NazaikinskiiSchulzeSternin1999,
  author    = {Nazaikinskii, Vladimir E. and Schulze, Bert-Wolfgang and Sternin, Boris},
  title     = {Quantization methods in differential equations : Chapter 2: Quantization of Lagrangian modules},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-25582},
  year      = {1999},
  abstract  = {In this chapter we use the wave packet transform described in Chapter 1 to quantize extended classical states represented by so-called Lagrangian sumbanifolds of the phase space. Functions on a Lagrangian manifold form a module over the ring of classical Hamiltonian functions on the phase space (with respect to pointwise multiplication). The quantization procedure intertwines this multiplication with the action of the corresponding quantum Hamiltonians; hence we speak of quantization of Lagrangian modules. The semiclassical states obtained by this quantization procedure provide asymptotic solutions to differential equations with a small parameter. Locally, such solutions can be represented by WKB elements. Global solutions are given by Maslov's canonical operator [2]; also see, e.g., [3] and the references therein. Here the canonical operator is obtained in the framework of the universal quantization procedure provided by the wave packet transform. This procedure was suggested in [4] (see also the references there) and further developed in [5]; our exposition is in the spirit of these papers. Some further bibliographical remarks can be found in the beginning of Chapter 1.},
  language  = {en}
}
@unpublished{SavinSchulzeSternin2000,
  author    = {Savin, Anton and Schulze, Bert-Wolfgang and Sternin, Boris},
  title     = {Elliptic operators in subspaces},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-25701},
  year      = {2000},
  abstract  = {We construct elliptic theory in the subspaces, determined by pseudodifferential projections. The finiteness theorem as well as index formula are obtained for elliptic operators acting in the subspaces. Topological (K-theoretic) aspects of the theory are studied in detail.},
  language  = {en}
}
@unpublished{SchulzeSterninSavin1999,
  author    = {Schulze, Bert-Wolfgang and Sternin, Boris and Savin, Anton},
  title     = {The homotopy classification and the index of boundary value problems for general elliptic operators},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-25568},
  year      = {1999},
  abstract  = {We give the homotopy classification and compute the index of boundary value problems for elliptic equations. The classical case of operators that satisfy the Atiyah-Bott condition is studied first. We also consider the general case of boundary value problems for operators that do not necessarily satisfy the Atiyah-Bott condition.},
  language  = {en}
}
@unpublished{ManicciaSchulze2002,
  author    = {Maniccia, L. and Schulze, Bert-Wolfgang},
  title     = {An algebra of meromorphic corner symbols},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26360},
  year      = {2002},
  abstract  = {Operators on manifolds with corners that have base configurations with geometric singularities can be analysed in the frame of a conormal symbolic structure which is in spirit similar to the one for conical singularities of Kondrat'ev's work. Solvability of elliptic equations and asymptotics of solutions are determined by meromorphic conormal symbols. We study the case when the base has edge singularities which is a natural assumption in a number of applications. There are new phenomena, caused by a specific kind of higher degeneracy of the underlying symbols. We introduce an algebra of meromorphic edge operators that depend on complex parameters and investigate meromorphic inverses in the parameter-dependent elliptic case. Among the examples are resolvents of elliptic differential operators on manifolds with edges.},
  language  = {en}
}
@unpublished{OliaroSchulze2002,
  author    = {Oliaro, Alessandro and Schulze, Bert-Wolfgang},
  title     = {Parameter-dependent boundary value problems on manifolds with edges},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26424},
  year      = {2002},
  abstract  = {As is known from Kondratyev's work, boundary value problems for elliptic operators on a manifold with conical singularities and boundary are controlled by a principal symbolic hierarchy, where the conormal symbols belong to the typical new components, compared with the smooth case, with interior and boundary symbols. A similar picture may be expected on manifolds with corners when the base of the cone itself is a manifold with conical or edge singularities. This is a natural situation in a number of applications, though with essential new difficulties. We investigate here corresponding conormal symbols in terms of a calculus of holomorphic parameter-dependent edge boundary value problems on the base. We show that a certain kernel cut-off procedure generates all such holomorphic families, modulo smoothing elements, and we establish conormal symbols as an algebra as is necessary for a parametrix constructions in the elliptic case.},
  language  = {en}
}
@unpublished{CoriascoSchulze2002,
  author    = {Coriasco, Sandro and Schulze, Bert-Wolfgang},
  title     = {Edge problems on configurations with model cones of different dimensions},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26438},
  year      = {2002},
  abstract  = {Elliptic equations on configurations W = W1 ∪ ... ∪ Wn with edge Y and components Wj of different dimension can be treated in the frame of pseudo-differential analysis on manifolds with geometric singularities, here, edges. Starting from edge-degenerate operators on Wj, j = 1, ..., N, we construct an algebra with extra "transmission" conditions on Y that satisfy an analogue of the Shapiro-Lopatinskij condition. Ellipticity refers to a two-component symbolic hierarchy with an interior and an edge part; the latter one is operator-valued, operating on the union of different dimensional model cones. We construct parametrices within our calculus, where exchange of information between the various components is encoded in Green and Mellin operators that are smoothing on W\Y. Moreover, we obtain regularity of solutions in weighted edge spaces with asymptotics.},
  language  = {en}
}
@unpublished{SchulzeSeiler2002,
  author    = {Schulze, Bert-Wolfgang and Seiler, J{\"o}rg},
  title     = {Pseudodifferential boundary value problems with global projection conditions},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26233},
  year      = {2002},
  abstract  = {Contents: Introduction 1 Operators with the transmission property 1.1 Operators on a manifold with boundary 1.2 Conditions with pseudodifferential projections 1.3 Projections and Fredholm families 2 Boundary value problems not requiring the transmission property 2.1 Interior operators 2.2 Edge amplitude functions 2.3 Boundary value problems 3 Operators with global projection conditions 3.1 Construction for boundary symbols 3.2 Ellipticity of boundary value problems with projection data 3.3 Operators of order zero},
  language  = {en}
}
@unpublished{NazaikinskiiSchulzeSternin2001,
  author    = {Nazaikinskii, Vladimir and Schulze, Bert-Wolfgang and Sternin, Boris},
  title     = {Localization problem in index theory of elliptic operators},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26175},
  year      = {2001},
  abstract  = {This is a survey of recent results concerning the general index locality principle, associated surgery, and their applications to elliptic operators on smooth manifolds and manifolds with singularities as well as boundary value problems. The full version of the paper is submitted for publication in Russian Mathematical Surveys.},
  language  = {en}
}
@unpublished{NazaikinskiiSavinSchulzeetal.2002,
  author    = {Nazaikinskii, Vladimir and Savin, Anton and Schulze, Bert-Wolfgang and Sternin, Boris},
  title     = {Elliptic theory on manifolds with nonisolated singularities : III. The spectral flow of families of conormal symbols},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26386},
  year      = {2002},
  abstract  = {When studyind elliptic operators on manifolds with nonisolated singularities one naturally encounters families of conormal symbols (i.e. operators elliptic with parameter p ∈ IR in the sense of Agranovich-Vishik) parametrized by the set of singular points. For homotopies of such families we define the notion of spectral flow, which in this case is an element of the K-group of the parameter space. We prove that the spectral flow is equal to the index of some family of operators on the infinite cone.},
  language  = {en}
}
@unpublished{HarutjunjanSchulze2002,
  author    = {Harutjunjan, G. and Schulze, Bert-Wolfgang},
  title     = {Reduction of orders in boundary value problems without the transmission property},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26220},
  year      = {2002},
  abstract  = {Given an algebra of pseudo-differential operators on a manifold, an elliptic element is said to be a reduction of orders, if it induces isomorphisms of Sobolev spaces with a corresponding shift of smoothness. Reductions of orders on a manifold with boundary refer to boundary value problems. We consider smooth symbols and ellipticity without additional boundary conditions which is the relevant case on a manifold with boundary. Starting from a class of symbols that has been investigated before for integer orders in boundary value problems with the transmission property we study operators of arbitrary real orders that play a similar role for operators without the transmission property. Moreover, we show that order reducing symbols have the Volterra property and are parabolic of anisotropy 1; analogous relations are formulated for arbitrary anisotropies. We finally investigate parameter-dependent operators, apply a kernel cut-off construction with respect to the parameter and show that corresponding holomorphic operator-valued Mellin symbols reduce orders in weighted Sobolev spaces on a cone with boundary.},
  language  = {en}
}
@unpublished{NazaikinskiiSavinSchulzeetal.2002,
  author    = {Nazaikinskii, Vladimir and Savin, Anton and Schulze, Bert-Wolfgang and Sternin, Boris},
  title     = {Elliptic theory on manifolds with nonisolated singularities : IV. Obstructions to elliptic problems on manifolds with edges},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26415},
  year      = {2002},
  abstract  = {The obstruction to the existence of Fredholm problems for elliptic differentail operators on manifolds with edges is a topological invariant of the operator. We give an explicit general formula for this invariant. As an application we compute this obstruction for geometric operators.},
  language  = {en}
}
@unpublished{NazaikinskiiSavinSchulzeetal.2002,
  author    = {Nazaikinskii, Vladimir and Savin, Anton and Schulze, Bert-Wolfgang and Sternin, Boris},
  title     = {Elliptic theory on manifolds with nonisolated singularities : II. Products in elliptic theory on manifolds with edges},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26335},
  year      = {2002},
  abstract  = {Exterior tensor products of elliptic operators on smooth manifolds and manifolds with conical singularities are used to obtain examples of elliptic operators on manifolds with edges that do not admit well-posed edge boundary and coboundary conditions.},
  language  = {en}
}
@unpublished{NazaikinskiiSavinSchulzeetal.2003,
  author    = {Nazaikinskii, Vladimir and Savin, Anton and Schulze, Bert-Wolfgang and Sternin, Boris},
  title     = {Differential operators on manifolds with singularities : analysis and topology : Chapter 5: Manifolds with isolated singularities},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26659},
  year      = {2003},
  abstract  = {Contents: Chapter 5: Manifolds with Isolated Singularities 5.1. Differential Operators and the Geometry of Singularities 5.1.1. How do isolated singularities arise? Examples 5.1.2. Definition and methods for the description of manifolds with isolated singularities 5.1.3. Bundles. The cotangent bundle 5.2. Asymptotics of Solutions, Function Spaces,Conormal Symbols 5.2.1. Conical singularities 5.2.2. Cuspidal singularities 5.3. A Universal Representation of Degenerate Operators and the Finiteness Theorem 5.3.1. The cylindrical representation 5.3.2. Continuity and compactness 5.3.3. Ellipticity and the finiteness theorem 5.4. Calculus of ΨDO 5.4.1. General ΨDO 5.4.2. The subalgebra of stabilizing ΨDO 5.4.3. Ellipticity and the finiteness theorem},
  language  = {en}
}
@unpublished{DinesSchulze2003,
  author    = {Dines, Nicoleta and Schulze, Bert-Wolfgang},
  title     = {Mellin-edge representations of elliptic operators},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26627},
  year      = {2003},
  abstract  = {We construct a class of elliptic operators in the edge algebra on a manifold M with an embedded submanifold Y interpreted as an edge. The ellipticity refers to a principal symbolic structure consisting of the standard interior symbol and an operator-valued edge symbol. Given a differential operator A on M for every (sufficiently large) s we construct an associated operator As in the edge calculus. We show that ellipticity of A in the usual sense entails ellipticity of As as an edge operator (up to a discrete set of reals s). Parametrices P of A then correspond to parametrices Ps of As, interpreted as Mellin-edge representations of P.},
  language  = {en}
}
@unpublished{KrainerSchulze2004,
  author    = {Krainer, Thomas and Schulze, Bert-Wolfgang},
  title     = {The conormal symbolic structure of corner boundary value problems},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26662},
  year      = {2004},
  abstract  = {Ellipticity of operators on manifolds with conical singularities or parabolicity on space-time cylinders are known to be linked to parameter-dependent operators (conormal symbols) on a corresponding base manifold. We introduce the conormal symbolic structure for the case of corner manifolds, where the base itself is a manifold with edges and boundary. The specific nature of parameter-dependence requires a systematic approach in terms of meromorphic functions with values in edge-boundary value problems. We develop here a corresponding calculus, and we construct inverses of elliptic elements.},
  language  = {en}
}
@unpublished{NazaikinskiiSavinSchulzeetal.2004,
  author    = {Nazaikinskii, Vladimir and Savin, Anton and Schulze, Bert-Wolfgang and Sternin, Boris},
  title     = {Differential operators on manifolds with singularities : analysis and topology : Chapter 7: The index problem on manifolds with singularities},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26700},
  year      = {2004},
  abstract  = {Contents: Chapter 7: The Index Problemon Manifolds with Singularities Preface 7.1. The Simplest Index Formulas 7.1.1. General properties of the index 7.1.2. The index of invariant operators on the cylinder 7.1.3. Relative index formulas 7.1.4. The index of general operators on the cylinder 7.1.5. The index of operators of the form 1 + G with a Green operator G 7.1.6. The index of operators of the form 1 + G on manifolds with edges 7.1.7. The index on bundles with smooth base and fiber having conical points 7.2. The Index Problem for Manifolds with Isolated Singularities 7.2.1. Statement of the index splitting problem 7.2.2. The obstruction to the index splitting 7.2.3. Computation of the obstruction in topological terms 7.2.4. Examples. Operators with symmetries 7.3. The Index Problem for Manifolds with Edges 7.3.1. The index excision property 7.3.2. The obstruction to the index splitting 7.4. Bibliographical Remarks},
  language  = {en}
}
@unpublished{HarutjunjanSchulze2004,
  author    = {Harutjunjan, Gohar and Schulze, Bert-Wolfgang},
  title     = {Boundary problems with meromorphic symbols in cylindrical domains},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-26735},
  year      = {2004},
  abstract  = {We show relative index formulas for boundary value problems in cylindrical domains and Sobolev spaces with different weigths at ±∞. The amplitude functions are meromorphic in the axial covariable and take values in the space of boundary value problems on the cross section of the cylinder.},
  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}
}
@article{RodriguezZuluagaStolleYamazakietal.2021,
  author    = {Rodr{\´i}guez Zuluaga, Juan and Stolle, Claudia and Yamazaki, Yosuke and Xiong, Chao and England, Scott L.},
  title     = {A synoptic-scale wavelike structure in the nighttime equatorial ionization anomaly},
  series = {Earth and Space Science : ESS},
  volume    = {8},
  journal   = {Earth and Space Science : ESS},
  number    = {2},
  publisher = {American Geophysical Union},
  address   = {Malden, Mass.},
  issn      = {2333-5084},
  doi       = {10.1029/2020EA001529},
  pages     = {10},
  year      = {2021},
  abstract  = {Both ground- and satellite-based airglow imaging have significantly contributed to understanding the low-latitude ionosphere, especially the morphology and dynamics of the equatorial ionization anomaly (EIA). The NASA Global-scale Observations of the Limb and Disk (GOLD) mission focuses on far-ultraviolet airglow images from a geostationary orbit at 47.5 degrees W. This region is of particular interest at low magnetic latitudes because of the high magnetic declination (i.e., about -20 degrees) and proximity of the South Atlantic magnetic anomaly. In this study, we characterize an exciting feature of the nighttime EIA using GOLD observations from October 5, 2018 to June 30, 2020. It consists of a wavelike structure of a few thousand kilometers seen as poleward and equatorward displacements of the EIA-crests. Initial analyses show that the synoptic-scale structure is symmetric about the dip equator and appears nearly stationary with time over the night. In quasi-dipole coordinates, maxima poleward displacements of the EIA-crests are seen at about +/- 12 degrees latitude and around 20 and 60 degrees longitude (i.e., in geographic longitude at the dip equator, about 53 degrees W and 14 degrees W). The wavelike structure presents typical zonal wavelengths of about 6.7 x 10(3) km and 3.3 x 10(3) km. The structure's occurrence and wavelength are highly variable on a day-to-day basis with no apparent dependence on geomagnetic activity. In addition, a cluster or quasi-periodic wave train of equatorial plasma depletions (EPDs) is often detected within the synoptic-scale structure. We further outline the difference in observing these EPDs from FUV images and in situ measurements during a GOLD and Swarm mission conjunction.},
  language  = {en}
}
@article{YenvonSpechtLinetal.2022,
  author    = {Yen, Ming-Hsuan and von Specht, Sebastian and Lin, Yen-Yu and Cotton, Fabrice and Ma, Kuo-Fong},
  title     = {Within- and between-event variabilities of strong-velocity pulses of moderate earthquakes within dense seismic arrays},
  series = {Bulletin of the Seismological Society of America},
  volume    = {112},
  journal   = {Bulletin of the Seismological Society of America},
  number    = {1},
  publisher = {Seismological Society of America},
  address   = {El Cerito, Calif.},
  issn      = {0037-1106},
  doi       = {10.1785/0120200376},
  pages     = {361 -- 380},
  year      = {2022},
  abstract  = {Ground motion with strong-velocity pulses can cause significant damage to buildings and structures at certain periods; hence, knowing the period and velocity amplitude of such pulses is critical for earthquake structural engineering. However, the physical factors relating the scaling of pulse periods with magnitude are poorly understood. In this study, we investigate moderate but damaging earthquakes (M-w 6-7) and characterize ground- motion pulses using the method of Shahi and Baker (2014) while considering the potential static-offset effects. We confirm that the within-event variability of the pulses is large. The identified pulses in this study are mostly from strike-slip-like earthquakes. We further perform simulations using the freq uency-wavenumber algorithm to investigate the causes of the variability of the pulse periods within and between events for moderate strike-slip earthquakes. We test the effect of fault dips, and the impact of the asperity locations and sizes. The simulations reveal that the asperity properties have a high impact on the pulse periods and amplitudes at nearby stations. Our results emphasize the importance of asperity characteristics, in addition to earthquake magnitudes for the occurrence and properties of pulses produced by the forward directivity effect. We finally quantify and discuss within- and between-event variabilities of pulse properties at short distances.},
  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}
}
@article{SchindlerMoldenhawerStangeetal.2021,
  author    = {Schindler, Daniel and Moldenhawer, Ted and Stange, Maike and Lepro, Valentino and Beta, Carsten and Holschneider, Matthias and Huisinga, Wilhelm},
  title     = {Analysis of protrusion dynamics in amoeboid cell motility by means of regularized contour flows},
  series = {PLoS Computational Biology : a new community journal},
  volume    = {17},
  journal   = {PLoS Computational Biology : a new community journal},
  number    = {8},
  publisher = {PLoS},
  address   = {San Fransisco},
  issn      = {1553-734X},
  doi       = {10.1371/journal.pcbi.1009268},
  pages     = {33},
  year      = {2021},
  abstract  = {Amoeboid cell motility is essential for a wide range of biological processes including wound healing, embryonic morphogenesis, and cancer metastasis. It relies on complex dynamical patterns of cell shape changes that pose long-standing challenges to mathematical modeling and raise a need for automated and reproducible approaches to extract quantitative morphological features from image sequences. Here, we introduce a theoretical framework and a computational method for obtaining smooth representations of the spatiotemporal contour dynamics from stacks of segmented microscopy images. Based on a Gaussian process regression we propose a one-parameter family of regularized contour flows that allows us to continuously track reference points (virtual markers) between successive cell contours. We use this approach to define a coordinate system on the moving cell boundary and to represent different local geometric quantities in this frame of reference. In particular, we introduce the local marker dispersion as a measure to identify localized membrane expansions and provide a fully automated way to extract the properties of such expansions, including their area and growth time. The methods are available as an open-source software package called AmoePy, a Python-based toolbox for analyzing amoeboid cell motility (based on time-lapse microscopy data), including a graphical user interface and detailed documentation. Due to the mathematical rigor of our framework, we envision it to be of use for the development of novel cell motility models. We mainly use experimental data of the social amoeba Dictyostelium discoideum to illustrate and validate our approach. <br /> Author summary Amoeboid motion is a crawling-like cell migration that plays an important key role in multiple biological processes such as wound healing and cancer metastasis. This type of cell motility results from expanding and simultaneously contracting parts of the cell membrane. From fluorescence images, we obtain a sequence of points, representing the cell membrane, for each time step. By using regression analysis on these sequences, we derive smooth representations, so-called contours, of the membrane. Since the number of measurements is discrete and often limited, the question is raised of how to link consecutive contours with each other. In this work, we present a novel mathematical framework in which these links are described by regularized flows allowing a certain degree of concentration or stretching of neighboring reference points on the same contour. This stretching rate, the so-called local dispersion, is used to identify expansions and contractions of the cell membrane providing a fully automated way of extracting properties of these cell shape changes. We applied our methods to time-lapse microscopy data of the social amoeba Dictyostelium discoideum.},
  language  = {en}
}
@article{KretschmerCoumouDongesetal.2016,
  author    = {Kretschmer, Marlene and Coumou, Dim and Donges, Jonathan and Runge, Jakob},
  title     = {Using Causal Effect Networks to Analyze Different Arctic Drivers of Midlatitude Winter Circulation},
  series = {Journal of climate},
  volume    = {29},
  journal   = {Journal of climate},
  publisher = {American Meteorological Soc.},
  address   = {Boston},
  issn      = {0894-8755},
  doi       = {10.1175/JCLI-D-15-0654.1},
  pages     = {4069 -- 4081},
  year      = {2016},
  abstract  = {In recent years, the Northern Hemisphere midlatitudes have suffered from severe winters like the extreme 2012/13 winter in the eastern United States. These cold spells were linked to a meandering upper-tropospheric jet stream pattern and a negative Arctic Oscillation index (AO). However, the nature of the drivers behind these circulation patterns remains controversial. Various studies have proposed different mechanisms related to changes in the Arctic, most of them related to a reduction in sea ice concentrations or increasing Eurasian snow cover. Here, a novel type of time series analysis, called causal effect networks (CEN), based on graphical models is introduced to assess causal relationships and their time delays between different processes. The effect of different Arctic actors on winter circulation on weekly to monthly time scales is studied, and robust network patterns are found. Barents and Kara sea ice concentrations are detected to be important external drivers of the midlatitude circulation, influencing winter AO via tropospheric mechanisms and through processes involving the stratosphere. Eurasia snow cover is also detected to have a causal effect on sea level pressure in Asia, but its exact role on AO remains unclear. The CEN approach presented in this study overcomes some difficulties in interpreting correlation analyses, complements model experiments for testing hypotheses involving teleconnections, and can be used to assess their validity. The findings confirm that sea ice concentrations in autumn in the Barents and Kara Seas are an important driver of winter circulation in the midlatitudes.},
  language  = {en}
}
@article{MaierWiljesHartungetal.2022,
  author    = {Maier, Corinna Sabrina and Wiljes, Jana de and Hartung, Niklas and Kloft, Charlotte and Huisinga, Wilhelm},
  title     = {A continued learning approach for model-informed precision dosing},
  series = {CPT: pharmacometrics \& systems pharmacology},
  volume    = {11},
  journal   = {CPT: pharmacometrics \& systems pharmacology},
  number    = {2},
  publisher = {London},
  address   = {Nature Publ. Group},
  issn      = {2163-8306},
  doi       = {10.1002/psp4.12745},
  pages     = {185 -- 198},
  year      = {2022},
  abstract  = {Model-informed precision dosing (MIPD) is a quantitative dosing framework that combines prior knowledge on the drug-disease-patient system with patient data from therapeutic drug/ biomarker monitoring (TDM) to support individualized dosing in ongoing treatment. Structural models and prior parameter distributions used in MIPD approaches typically build on prior clinical trials that involve only a limited number of patients selected according to some exclusion/inclusion criteria. Compared to the prior clinical trial population, the patient population in clinical practice can be expected to also include altered behavior and/or increased interindividual variability, the extent of which, however, is typically unknown. Here, we address the question of how to adapt and refine models on the level of the model parameters to better reflect this real-world diversity. We propose an approach for continued learning across patients during MIPD using a sequential hierarchical Bayesian framework. The approach builds on two stages to separate the update of the individual patient parameters from updating the population parameters. Consequently, it enables continued learning across hospitals or study centers, because only summary patient data (on the level of model parameters) need to be shared, but no individual TDM data. We illustrate this continued learning approach with neutrophil-guided dosing of paclitaxel. The present study constitutes an important step toward building confidence in MIPD and eventually establishing MIPD increasingly in everyday therapeutic use.},
  language  = {en}
}
@article{HartungWahlRastogietal.2021,
  author    = {Hartung, Niklas and Wahl, Martin and Rastogi, Abhishake and Huisinga, Wilhelm},
  title     = {Nonparametric goodness-of-fit testing for parametric covariate models in pharmacometric analyses},
  series = {CPT: pharmacometrics \& systems pharmacology},
  volume    = {10},
  journal   = {CPT: pharmacometrics \& systems pharmacology},
  number    = {6},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2163-8306},
  doi       = {10.1002/psp4.12614},
  pages     = {564 -- 576},
  year      = {2021},
  abstract  = {The characterization of covariate effects on model parameters is a crucial step during pharmacokinetic/pharmacodynamic analyses. Although covariate selection criteria have been studied extensively, the choice of the functional relationship between covariates and parameters, however, has received much less attention. Often, a simple particular class of covariate-to-parameter relationships (linear, exponential, etc.) is chosen ad hoc or based on domain knowledge, and a statistical evaluation is limited to the comparison of a small number of such classes. Goodness-of-fit testing against a nonparametric alternative provides a more rigorous approach to covariate model evaluation, but no such test has been proposed so far. In this manuscript, we derive and evaluate nonparametric goodness-of-fit tests for parametric covariate models, the null hypothesis, against a kernelized Tikhonov regularized alternative, transferring concepts from statistical learning to the pharmacological setting. The approach is evaluated in a simulation study on the estimation of the age-dependent maturation effect on the clearance of a monoclonal antibody. Scenarios of varying data sparsity and residual error are considered. The goodness-of-fit test correctly identified misspecified parametric models with high power for relevant scenarios. The case study provides proof-of-concept of the feasibility of the proposed approach, which is envisioned to be beneficial for applications that lack well-founded covariate models.},
  language  = {en}
}
@article{DemarisWidigsonIlvemarketal.2022,
  author    = {D{\´e}maris, Alix and Widigson, Ella S. K. and Ilvemark, Johan F. K. F. and Steenholdt, Casper and Seidelin, Jakob B. and Huisinga, Wilhelm and Michelet, Robin and Aulin, Linda B. S. and Kloft, Charlotte},
  title     = {Ulcerative colitis and acute severe ulcerative colitis patients are overlooked in infliximab population pharmacokinetic models},
  series = {Pharmaceutics / Molecular Diversity Preservation International},
  volume    = {14},
  journal   = {Pharmaceutics / Molecular Diversity Preservation International},
  number    = {10},
  publisher = {MDPI},
  address   = {Basel},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics14102095},
  pages     = {32},
  year      = {2022},
  abstract  = {Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis alpha monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.},
  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{GrisicHuisingaReinischetal.2017,
  author    = {Grisic, Ana-Marija and Huisinga, Wilhelm and Reinisch, W. and Kloft, Charlotte},
  title     = {P485 Dosing infliximab in Crohn's disease},
  series = {Journal of Crohn's and Colitis},
  volume    = {11},
  journal   = {Journal of Crohn's and Colitis},
  number    = {1},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {1873-9946},
  doi       = {10.1093/ecco-jcc/jjx002.609},
  pages     = {S325 -- S326},
  year      = {2017},
  abstract  = {Background: Infliximab (IFX), an anti-TNF monoclonal antibody approved for the treatment of inflammatory bowel disease, is dosed per kg body weight (BW). However, the rationale for body size adjustment has not been unequivocally demonstrated [1], and first attempts to improve IFX therapy have been undertaken [2]. The aim of our study was to assess the impact of different dosing strategies (i.e. body size-adjusted and fixed dosing) on drug exposure and pharmacokinetic (PK) target attainment. For this purpose, a comprehensive simulation study was performed, using patient characteristics (n=116) from an in-house clinical database. Methods: IFX concentration-time profiles of 1000 virtual, clinically representative patients were generated using a previously published PK model for IFX in patients with Crohn's disease [3]. For each patient 1000 profiles accounting for PK variability were considered. The IFX exposure during maintenance treatment after the following dosing strategies was compared: i) fixed dose, and per ii) BW, iii) lean BW (LBW), iv) body surface area (BSA), v) height (HT), vi) body mass index (BMI) and vii) fat-free mass (FFM)). For each dosing strategy the variability in maximum concentration Cmax, minimum concentration Cmin (= C8weeks) and area under the concentration-time curve (AUC), as well as percent of patients achieving the PK target, Cmin=3 μg/mL [4] were assessed. Results: For all dosing strategies the variability of Cmin (CV ≈110\%) was highest, compared to Cmax and AUC, and was of similar extent regardless of dosing strategy. The proportion of patients reaching the PK target (≈⅓ was approximately equal for all dosing strategies.},
  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{MelinParraGuillenHartungetal.2018,
  author    = {Melin, Johanna and Parra-Guillen, Zinnia Patricia and Hartung, Niklas and Huisinga, Wilhelm and Ross, Richard J. and Whitaker, Martin J. and Kloft, Charlotte},
  title     = {Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults},
  series = {Clinical Pharmacokinetics},
  volume    = {57},
  journal   = {Clinical Pharmacokinetics},
  number    = {4},
  publisher = {Springer},
  address   = {Northcote},
  issn      = {0312-5963},
  doi       = {10.1007/s40262-017-0575-8},
  pages     = {515 -- 527},
  year      = {2018},
  abstract  = {Background and objective Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort (R) oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency. Methods Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort (R) or 20 mg of Infacort (R)/hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model. Results Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline (cort),15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing < 20 kg. Conclusions Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing < 20 kg.},
  language  = {en}
}