Schizophrenia spectrum disorders and dissociative disorders:The blurry boundaries between categorical diagnoses

In lijn met de onderzoektrend die afstand neemt van categorische modellen van psychopathologie, wordt in dit proefschrift onderzocht in hoeverre schizofrenie spectrum stoornissen en dissociatieve stoornissen categorisch verschillende aandoeningen zijn. Het proefschrift begint met een overzicht van de literatuur gevolgd door nieuw onderzoek dat de uniekheid en de overlap van deze twee diagnostische clusters toetst. Verschillende benaderingen worden hierbij gebruikt, zo wordt er bijvoorbeeld door middel van netwerk analyse specifiek gekeken naar dissociatieve symptomen, die bij beide diagnoses voorkomen. Een andere studie is gericht op het experimenteel induceren van derealisatie, onafhankelijk van schizotypische ervaringen. Hoewel er verschillen zijn tussen schizofrenie spectrum stoornissen en dissociatieve stoornissen, blijkt uit dit proefschrift dat de grenzen tussen deze diagnoses niet zo duidelijk zijn als categorische modellen van psychopathologie, zoals het DSM-5, impliceren. De bevindingen van het proefschrift worden besproken in relatie tot veelbelovende projecten zoals RDoC, HiTOP en het netwerkmodel van psychopathologie

Understanding predictive uncertainty in hydrologic modeling: The challenge of identifying input and structural errors

Meaningful quantification of data and structural uncertainties in conceptual rainfall-runoff modeling is a major scientific and engineering challenge. This paper focuses on the total predictive uncertainty and its decomposition into input and structural components under different inference scenarios. Several Bayesian inference schemes are investigated, differing in the treatment of rainfall and structural uncertainties, and in the precision of the priors describing rainfall uncertainty. Compared with traditional lumped additive error approaches, the quantification of the total predictive uncertainty in the runoff is improved when rainfall and/or structural errors are characterized explicitly. However, the decomposition of the total uncertainty into individual sources is more challenging. In particular, poor identifiability may arise when the inference scheme represents rainfall and structural errors using separate probabilistic models. The inference becomes ill‐posed unless sufficiently precise prior knowledge of data uncertainty is supplied; this ill‐posedness can often be detected from the behavior of the Monte Carlo sampling algorithm. Moreover, the priors on the data quality must also be sufficiently accurate if the inference is to be reliable and support meaningful uncertainty decomposition. Our findings highlight the inherent limitations of inferring inaccurate hydrologic models using rainfall‐runoff data with large unknown errors. Bayesian total error analysis can overcome these problems using independent prior information. The need for deriving independent descriptions of the uncertainties in the input and output data is clearly demonstrated.Benjamin Renard, Dmitri Kavetski, George Kuczera, Mark Thyer, and Stewart W. Frank

Visualizing Kinetically Robust (Co4L6)-L-III Assemblies in Vivo: SPECT Imaging of the Encapsulated [Tc-99m]TcO4- Anion

© 2018 American Chemical Society. Noncovalent encapsulation is an attractive approach for modifying the efficacy and physiochemical properties of both therapeutic and diagnostic species. Abiotic self-assembled constructs have shown promise, yet many hurdles between in vitro and (pre)clinical studies remain, not least the challenges associated with maintaining the macromolecular, hollow structure under nonequilibrium conditions. Using a kinetically robust CoIII4L6 tetrahedron we now show the feasibility of encapsulating the most widely used precursor in clinical nuclear diagnostic imaging, the I-emitting [99mTc]TcO4- anion, under conditions compatible with in vivo administration. Subsequent single-photon emission computed tomography imaging of the caged-anion reveals a marked change in the biodistribution compared to the thyroid-accumulating free oxo-anion, thus moving clinical applications of (metallo)supramolecular species a step closer

Synthesis of a porphyrin with histidine-like chelate: an efficient path towards molecular PDT/SPECT theranostics

© The Royal Society of Chemistry 2020. The goal of “personalised” medicine has seen a growing interest in the development of theranostic agents. Bifunctional, and targeted-trifunctional, theranostic water-soluble porphyrins with a histidine-like chelating group have been synthesisedviacopper-catalysed azide-alkyne cycloaddition (CuAAC) “click” chemistry in high yield and purity. They are capable of photodynamic treatment and [99mTc(CO)3]+complexation for single-photon emission computed tomography (SPECT) imaging, with a radiochemical yield of >95%. The toxicity and phototoxicity were evaluated on HT-29 cells, DU145, and DU145-PSMA cell lines, with the targeted theranostic showing more potent phototoxicity towards DU145-PSMA expressing cells

A limited memory acceleration strategy for MCMC sampling in hierarchical Bayesian calibration of hydrological models

Hydrological calibration and prediction using conceptual models is affected by forcing/response data uncertainty and structural model error. The Bayesian Total Error Analysis methodology uses a hierarchical representation of individual sources of uncertainty. However, it is shown that standard multiblock “Metropolis-within-Gibbs” Markov chain Monte Carlo (MCMC) samplers commonly used in Bayesian hierarchical inference are exceedingly computationally expensive when applied to hydrologic models, which use recursive numerical solutions of coupled nonlinear differential equations to describe the evolution of catchment states such as soil and groundwater storages. This note develops a “limited-memory” algorithm for accelerating multiblock MCMC sampling from the posterior distributions of such models using low-dimensional jump distributions. The new algorithm exploits the decaying memory of hydrological systems to provide accurate tolerance-based approximations of traditional “full-memory” MCMC methods and is orders of magnitude more efficient than the latter.George Kuczera, Dmitri Kavetski, Benjamin Renard and Mark Thye

64Cu PET Imaging of the CXCR4 Chemokine Receptor Using a Cross-Bridged Cyclam Bis-Tetraazamacrocyclic Antagonist

© 2020 by the Society of Nuclear Medicine and Molecular Imaging. Expression of the chemokine receptor chemokine C-X-C motif receptor 4 (CXCR4) plays an important role in cancer metastasis, in autoimmune diseases, and during stem cell-based repair processes after stroke and myocardial infarction. Previously reported PET imaging agents targeting CXCR4 suffer from either high nonspecific uptake or bind only to the human form of the receptor. The objective of this study was to develop a high-stability 64Cu-labeled small-molecule PET agent for imaging both human and murine CXCR4 chemokine receptors. Methods: Synthesis, radiochemistry, stability and radioligand binding assays were performed for the novel tracer 64Cu-CuCB-bicyclam. In vivo dynamic PET studies were performed on mice bearing U87 (CXCR4 low-expressing) and U87.CXCR4 (human-CXCR4 high-expressing) tumors. Biodistribution and receptor blocking studies were performed on CD1-IGS immunocompetent mice. CXCR4 expression on tumor and liver disaggregates was confirmed using a combination of immunohistochemistry, quantitative polymerase chain reaction, and Western blot. Results:64Cu-CuCB-bicyclam has a high affinity for both the human and the murine variants of the CXCR4 receptor (half-maximal inhibitory concentration, 8 nM [human]/2 nM [murine]) and can be obtained from the parent chelator that has low affinity. In vitro and in vivo studies demonstrate specific uptake in CXCR4-expressing cells that can be blocked by more than 90% using a higher-affinity antagonist, with limited uptake in non-CXCR4-expressing organs and high in vivo stability. The tracer was also able to selectively displace the CXCR4 antagonists AMD3100 and AMD3465 from the liver. Conclusion: The tetraazamacrocyclic small molecule 64Cu-CuCB-bicyclam has been shown to be an imaging agent for the CXCR4 receptor that is likely to be applicable across a range of species. It has high affinity and stability and is suitable for preclinical research in immunocompetent murine models

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology.

Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future