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We consider the initial value problem for the Navier-Stokes equations over R-3 x [0, T] with time T > 0 in the spatially periodic setting.
We prove that it induces open injective mappings A(s): B-1(s) -> B-2(s-1) where B-1(s), B-2(s-1) are elements from scales of specially constructed function spaces of Bochner-Sobolev typeparametrized with the smoothness index s is an element of N.
Finally, we prove that a map Asis surjective if and only if the inverse image A(s)(- 1) (K) of any pre compact set K from the range of the map Asis bounded in the Bochner space L-s([0, T], L-r(T-3))with the Ladyzhenskaya-Prodi-Serrin numbers s, r.
We consider Bayesian inference for large-scale inverse problems, where computational challenges arise from the need for repeated evaluations of an expensive forward model.
This renders most Markov chain Monte Carlo approaches infeasible, since they typically require O(10(4)) model runs, or more.
Moreover, the forward model is often given as a black box or is impractical to differentiate.
Therefore derivative-free algorithms are highly desirable. We propose a framework, which is built on Kalman methodology, to efficiently perform Bayesian inference in such inverse problems.
The basic method is based on an approximation of the filtering distribution of a novel mean-field dynamical system, into which the inverse problem is embedded as an observation operator.
Theoretical properties are established for linear inverse problems, demonstrating that the desired Bayesian posterior is given by the steady state of the law of the filtering distribution of the mean-field dynamical system, and proving exponential convergence to it.
This suggests that, for nonlinear problems which are close to Gaussian, sequentially computing this law provides the basis for efficient iterative methods to approximate the Bayesian posterior.
Ensemble methods are applied to obtain interacting particle system approximations of the filtering distribution of the mean-field model; and practical strategies to further reduce the computational and memory cost of the methodology are presented, including low-rank approximation and a bi-fidelity approach.
The effectiveness of the framework is demonstrated in several numerical experiments, including proof-of-concept linear/nonlinear examples and two large-scale applications: learning of permeability parameters in subsurface flow; and learning subgrid-scale parameters in a global climate model.
Moreover, the stochastic ensemble Kalman filter and various ensemble square-root Kalman filters are all employed and are compared numerically.
The results demonstrate that the proposed method, based on exponential convergence to the filtering distribution of a mean-field dynamical system, is competitive with pre-existing Kalman-based methods for inverse problems.
In this paper, we define a variant of Roe algebras for spaces with cylindrical ends and use this to study questions regarding existence and classification of metrics of positive scalar curvature on such manifolds which are collared on the cylindrical end.
We discuss how our constructions are related to relative higher index theory as developed by Chang, Weinberger, and Yu and use this relationship to define higher rho-invariants for positive scalar curvature metrics on manifolds with boundary.
This paves the way for the classification of these metrics.
Finally, we use the machinery developed here to give a concise proof of a result of Schick and the author, which relates the relative higher index with indices defined in the presence of positive scalar curvature on the boundary.
In this paper we consider surfaces which are critical points of the Willmore functional subject to constrained area.
In the case of small area we calculate the corrections to the intrinsic geometry induced by the ambient curvature.
These estimates together with the choice of an adapted geometric center of mass lead to refined position estimates in relation to the scalar curvature of the ambient manifold.
As the loop space of a Riemannian manifold is infinite-dimensional, it is a non-trivial problem to make sense of the "top degree component " of a differential form on it.
In this paper, we show that a formula from finite dimensions generalizes to assign a sensible "top degree component " to certain composite forms, obtained by wedging with the exponential (in the exterior algebra) of the canonical presymplectic 2-form on the loop space.
This construction is a crucial ingredient for the definition of the supersymmetric path integral on the loop space.
State space models enjoy wide popularity in mathematical and statistical modelling across disciplines and research fields. Frequent solutions to problems of estimation and forecasting of a latent signal such as the celebrated Kalman filter hereby rely on a set of strong assumptions such as linearity of system dynamics and Gaussianity of noise terms.
We investigate fallacy in mis-specification of the noise terms, that is signal noise
and observation noise, regarding heavy tailedness in that the true dynamic frequently produces observation outliers or abrupt jumps of the signal state due to realizations of these heavy tails not considered by the model. We propose a formalisation of observation noise mis-specification in terms of Huber’s ε-contamination as well as a computationally cheap solution via generalised Bayesian posteriors with a diffusion Stein divergence loss resulting in the diffusion score matching Kalman filter - a modified algorithm akin in complexity to the regular Kalman filter. For this new filter interpretations of novel terms, stability and an ensemble variant are discussed. Regarding signal noise mis-specification, we propose a formalisation in the frame work of change point detection and join ideas from the popular CUSUM algo-
rithm with ideas from Bayesian online change point detection to combine frequent reliability constraints and online inference resulting in a Gaussian mixture model variant of multiple Kalman filters. We hereby exploit open-end sequential probability ratio tests on the evidence of Kalman filters on observation sub-sequences for aggregated inference under notions of plausibility.
Both proposed methods are combined to investigate the double mis-specification problem and discussed regarding their capabilities in reliable and well-tuned uncertainty quantification. Each section provides an introduction to required terminology and tools as well as simulation experiments on the popular target tracking task and the non-linear, chaotic Lorenz-63 system to showcase practical performance of theoretical considerations.
Hardy inequalities on graphs
(2024)
The dissertation deals with a central inequality of non-linear potential theory, the Hardy inequality. It states that the non-linear energy functional can be estimated from below by a pth power of a weighted p-norm, p>1. The energy functional consists of a divergence part and an arbitrary potential part. Locally summable infinite graphs were chosen as the underlying space. Previous publications on Hardy inequalities on graphs have mainly considered the special case p=2, or locally finite graphs without a potential part.
Two fundamental questions now arise quite naturally: For which graphs is there a Hardy inequality at all? And, if it exists, is there a way to obtain an optimal weight? Answers to these questions are given in Theorem 10.1 and Theorem 12.1. Theorem 10.1 gives a number of characterizations; among others, there is a Hardy inequality on a graph if and only if there is a Green's function. Theorem 12.1 gives an explicit formula to compute optimal Hardy weights for locally finite graphs under some additional technical assumptions. Examples show that Green's functions are good candidates to be used in the formula.
Emphasis is also placed on illustrating the theory with examples. The focus is on natural numbers, Euclidean lattices, trees and star graphs. Finally, a non-linear version of the Heisenberg uncertainty principle and a Rellich inequality are derived from the Hardy inequality.
We present general existence and uniqueness results for marked models with pair interactions, exemplified through Gibbs point processes on path space.
More precisely, we study a class of infinite-dimensional diffusions under Gibbsian interactions, in the context of marked point configurations: the starting points belong to R-d, and the marks are the paths of Langevin diffusions.
We use the entropy method to prove existence of an infinite-volume Gibbs point process and use cluster expansion tools to provide an explicit activity domain in which uniqueness holds.
The Gutenberg-Richter (GR) and the Omori-Utsu (OU) law describe the earthquakes' energy release and temporal clustering and are thus of great importance for seismic hazard assessment. Motivated by experimental results, which indicate stress-dependent parameters, we consider a combined global data set of 127 main shock-aftershock sequences and perform a systematic study of the relationship between main shock-induced stress changes and associated seismicity patterns. For this purpose, we calculate space-dependent Coulomb Stress (& UDelta;CFS) and alternative receiver-independent stress metrics in the surrounding of the main shocks. Our results indicate a clear positive correlation between the GR b-value and the induced stress, contrasting expectations from laboratory experiments and suggesting a crucial role of structural heterogeneity and strength variations. Furthermore, we demonstrate that the aftershock productivity increases nonlinearly with stress, while the OU parameters c and p systematically decrease for increasing stress changes. Our partly unexpected findings can have an important impact on future estimations of the aftershock hazard.
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.
Deriving mechanism-based pharmacodynamic models by reducing quantitative systems pharmacology models
(2023)
Quantitative systems pharmacology (QSP) models integrate comprehensive qualitative and quantitative knowledge about pharmacologically relevant processes. We previously proposed a first approach to leverage the knowledge in QSP models to derive simpler, mechanism-based pharmacodynamic (PD) models. Their complexity, however, is typically still too large to be used in the population analysis of clinical data. Here, we extend the approach beyond state reduction to also include the simplification of reaction rates, elimination of reactions, and analytic solutions. We additionally ensure that the reduced model maintains a prespecified approximation quality not only for a reference individual but also for a diverse virtual population. We illustrate the extended approach for the warfarin effect on blood coagulation. Using the model-reduction approach, we derive a novel small-scale warfarin/international normalized ratio model and demonstrate its suitability for biomarker identification. Due to the systematic nature of the approach in comparison with empirical model building, the proposed model-reduction algorithm provides an improved rationale to build PD models also from QSP models in other applications.
Cell-level systems biology model to study inflammatory bowel diseases and their treatment options
(2023)
To help understand the complex and therapeutically challenging inflammatory bowel diseases (IBDs), we developed a systems biology model of the intestinal immune system that is able to describe main aspects of IBD and different treatment modalities thereof. The model, including key cell types and processes of the mucosal immune response, compiles a large amount of isolated experimental findings from literature into a larger context and allows for simulations of different inflammation scenarios based on the underlying data and assumptions. In the context of a large and diverse virtual IBD population, we characterized the patients based on their phenotype (in contrast to healthy individuals, they developed persistent inflammation after a trigger event) rather than on a priori assumptions on parameter differences to a healthy individual. This allowed to reproduce the enormous diversity of predispositions known to lead to IBD. Analyzing different treatment effects, the model provides insight into characteristics of individual drug therapy. We illustrate for anti-TNF-alpha therapy, how the model can be used (i) to decide for alternative treatments with best prospects in the case of nonresponse, and (ii) to identify promising combination therapies with other available treatment options.
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.
Introduction:
Hydrocortisone is the standard of care in cortisol replacement therapy for congenital adrenal hyperplasia patients. Challenges in mimicking cortisol circadian rhythm and dosing individualization can be overcome by the support of mathematical modelling. Previously, a non-linear mixed-effects (NLME) model was developed based on clinical hydrocortisone pharmacokinetic (PK) pediatric and adult data. Additionally, a physiologically-based pharmacokinetic (PBPK) model was developed for adults and a pediatric model was obtained using maturation functions for relevant processes. In this work, a middle-out approach was applied. The aim was to investigate whether PBPK-derived maturation functions could provide a better description of hydrocortisone PK inter-individual variability when implemented in the NLME framework, with the goal of providing better individual predictions towards precision dosing at the patient level.
Methods:
Hydrocortisone PK data from 24 adrenal insufficiency pediatric patients and 30 adult healthy volunteers were used for NLME model development, while the PBPK model and maturation functions of clearance and cortisol binding globulin (CBG) were developed based on previous studies published in the literature.
Results:
Clearance (CL) estimates from both approaches were similar for children older than 1 year (CL/F increasing from around 150 L/h to 500 L/h), while CBG concentrations differed across the whole age range (CBG(NLME) stable around 0.5 mu M vs. steady increase from 0.35 to 0.8 mu M for CBG (PBPK)). PBPK-derived maturation functions were subsequently included in the NLME model. After inclusion of the maturation functions, none, a part of, or all parameters were re-estimated. However, the inclusion of CL and/or CBG maturation functions in the NLME model did not result in improved model performance for the CL maturation function (& UDelta;OFV > -15.36) and the re-estimation of parameters using the CBG maturation function most often led to unstable models or individual CL prediction bias.
Discussion:
Three explanations for the observed discrepancies could be postulated, i) non-considered maturation of processes such as absorption or first-pass effect, ii) lack of patients between 1 and 12 months, iii) lack of correction of PBPK CL maturation functions derived from urinary concentration ratio data for the renal function relative to adults. These should be investigated in the future to determine how NLME and PBPK methods can work towards deriving insights into pediatric hydrocortisone PK.
The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %fT(>= MIC) (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC(0-24h)/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m(2)) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC <= 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of,130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement beta-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status.
The drug concentrations targeted in meropenem and piperacillin/tazobactam therapy also depend on the susceptibility of the pathogen. Yet, the pathogen is often unknown, and antibiotic therapy is guided by empirical targets. To reliably achieve the targeted concentrations, dosing needs to be adjusted for renal function. We aimed to evaluate a meropenem and piperacillin/tazobactam monitoring program in intensive care unit (ICU) patients by assessing (i) the adequacy of locally selected empirical targets, (ii) if dosing is adequately adjusted for renal function and individual target, and (iii) if dosing is adjusted in target attainment (TA) failure. In a prospective, observational clinical trial of drug concentrations, relevant patient characteristics and microbiological data (pathogen, minimum inhibitory concentration (MIC)) for patients receiving meropenem or piperacillin/tazobactam treatment were collected. If the MIC value was available, a target range of 1-5 x MIC was selected for minimum drug concentrations of both drugs. If the MIC value was not available, 8-40 mg/L and 16-80 mg/L were selected as empirical target ranges for meropenem and piperacillin, respectively. A total of 356 meropenem and 216 piperacillin samples were collected from 108 and 96 ICU patients, respectively. The vast majority of observed MIC values was lower than the empirical target (meropenem: 90.0%, piperacillin: 93.9%), suggesting empirical target value reductions. TA was found to be low (meropenem: 35.7%, piperacillin 50.5%) with the lowest TA for severely impaired renal function (meropenem: 13.9%, piperacillin: 29.2%), and observed drug concentrations did not significantly differ between patients with different targets, indicating dosing was not adequately adjusted for renal function or target. Dosing adjustments were rare for both drugs (meropenem: 6.13%, piperacillin: 4.78%) and for meropenem irrespective of TA, revealing that concentration monitoring alone was insufficient to guide dosing adjustment. Empirical targets should regularly be assessed and adjusted based on local susceptibility data. To improve TA, scientific knowledge should be translated into easy-to-use dosing strategies guiding antibiotic dosing.
The Levenberg–Marquardt regularization for the backward heat equation with fractional derivative
(2022)
The backward heat problem with time-fractional derivative in Caputo's sense is studied. The inverse problem is severely ill-posed in the case when the fractional order is close to unity. A Levenberg-Marquardt method with a new a posteriori stopping rule is investigated. We show that optimal order can be obtained for the proposed method under a Hölder-type source condition. Numerical examples for one and two dimensions are provided.
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.
In this article we prove upper bounds for the Laplace eigenvalues lambda(k) below the essential spectrum for strictly negatively curved Cartan-Hadamard manifolds. Our bound is given in terms of k(2) and specific geometric data of the manifold. This applies also to the particular case of non-compact manifolds whose sectional curvature tends to -infinity, where no essential spectrum is present due to a theorem of Donnelly/Li. The result stands in clear contrast to Laplacians on graphs where such a bound fails to be true in general.