pinecone/core-2020-05-10-deduplication huggingface dataset:
Partner (dis)agreement on moving desires and the subsequent moving behaviour of couples

Residential mobility decisions are known to be made at the household level. However, most empirical analyses of residential mobility relate moving behaviour to the housing and neighbourhood satisfaction and pre-move thoughts of individuals. If partners in a couple do not share evaluations of dwelling or neighbourhood quality or do not agree on whether moving is (un)desirable, ignoring these disagreements will lead to an inaccurate assessment of the strength of the links between moving desires and actual moves. This study is one of the first to investigate disagreements in moving desires between partners and the subsequent consequences of such disagreements for moving behaviour. Drawing on British Household Panel Survey (BHPS) data, we find that disagreement about the desirability of moving is most likely where partners also disagree about the quality of their dwelling or neighbourhood. Panel logistic regression models show that the moving desires of both partners interact to affect the moving behaviour of couples. Only 7.6% of couples move if only the man desires to move, whereas 20.1% of shared moving desires lead to a subsequent move.This is the pre-peer reviewed version of the following article: Coulter, R., van Ham, M. and Feijten, P. 2012. Partner (dis)agreement on moving desires and the subsequent moving behaviour of couples. Population, Space and Place 18(1), pp. 16-30, which has been published in final form at http://dx.doi.org/10.1002/psp.700
Application of a systems pharmacology-based placebo population model to analyze long-term data of postmenopausal osteoporosis

Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed disease systems analysis model for osteoporosis could describe disease progression in a placebo-treated population from the Early Postmenopausal Intervention Cohort (EPIC) study. First, we qualified the model using a subset from the placebo arm of the EPIC study of 222 women who had similar demographic characteristics as the 149 women from the placebo arm of the original population. Second, we applied the model to all 470 women. Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population. This updated disease systems analysis placebo model describes the dynamics of all biomarkers in the corresponding datasets to a very good approximation; a good description of an individual placebo response will be valuable for evaluating treatments for osteoporosis
Quantitative Systems Pharmacology Approaches Applied to Microphysiological Systems (MPS): Data Interpretation and Multi-MPS Integration

Our goal in developing Microphysiological Systems (MPS) technology is to provide an improved approach for more predictive preclinical drug discovery via a highly integrated experimental/computational paradigm. Success will require quantitative characterization of MPSs and mechanistic analysis of experimental findings sufficient to translate resulting insights from in vitro to in vivo. We describe herein a systems pharmacology approach to MPS development and utilization that incorporates more mechanistic detail than traditional pharmacokinetic/pharmacodynamic (PK/PD) models. A series of studies illustrates diverse facets of our approach. First, we demonstrate two case studies: a PK data analysis and an inflammation response––focused on a single MPS, the liver/immune MPS. Building on the single MPS modeling, a theoretical investigation of a four-MPS interactome then provides a quantitative way to consider several pharmacological concepts such as absorption, distribution, metabolism, and excretion in the design of multi-MPS interactome operation and experiments.United States. Defense Advanced Research Projects Agency. Microphysiological Systems Program  (W911NF-12-2-0039)National Institutes of Health (U.S.) Microphysiological Systems Program  (4-UH3-TR000496-03)Massachusetts Institute of Technology. Center for Environmental Health Sciences (NIEHS Grant P30-ES002109
MatVPC: A User-Friendly MATLAB-Based Tool for the Simulation and Evaluation of Systems Pharmacology Models

International audienceQuantitative systems pharmacology (QSP) models are progressively entering the arena of contemporary pharmacology. The efficient implementation and evaluation of complex QSP models necessitates the development of flexible computational tools that are built into QSP mainstream software. To this end, we present MatVPC, a versatile MATLAB-based tool that accommodates QSP models of any complexity level. MatVPC executes Monte Carlo simulations as well as automatic construction of visual predictive checks (VPCs) and quantified VPCs (QVPCs). VPC is a model diagnostic tool that facilitates the evaluation of both the structural and the stochastic part of a model. It is constructed by superimposing the observations over the model simulations while accounting for both the interindivid-ual variability as well as the residual variability. 1 Once underutilized, 2 the VPC now is recognized as one of the most valuable model diagnostics in pharmacological model evaluation. 3–5 Its superiority over comparable diagnostic tools has been established 6 and reflected by the fact that regulatory agencies recommend it as one of the central model diagnostics.
Physiome-on-a-Chip: The Challenge of “Scaling” in Design, Operation, and Translation of Microphysiological Systems

Scaling of a microphysiological system (MPS) or physiome-on-a-chip is arguably two interrelated, modeling-based activities: on-platform scaling and in vitro-in vivo translation. This dual approach reduces the need to perfectly rescale and mimic in vivo physiology, an aspiration that is both extremely challenging and not substantively meaningful because of uncertain relevance of any specific physiological condition. Accordingly, this perspective offers a tractable approach for designing interacting MPSs and relating in vitro results to analogous context in vivo.United States. Defense Advanced Research Projects Agency. Microphysiological Systems Program (Grant W911NF-12-2-0039)National Institutes of Health (U.S.) Microphysiological Systems Program (Grant 4-UH3-TR000496-03)United States. Army Research Office (Institute for Collaborative Biotechnologies. Grant W911NF-09- 0001
Systematic Analysis of Quantitative Logic Model Ensembles Predicts Drug Combination Effects on Cell Signaling Networks

A major challenge in developing anticancer therapies is determining the efficacies of drugs and their combinations in physiologically relevant microenvironments. We describe here our application of “constrained fuzzy logic” (CFL) ensemble modeling of the intracellular signaling network for predicting inhibitor treatments that reduce the phospho-levels of key transcription factors downstream of growth factors and inflammatory cytokines representative of hepatocellular carcinoma (HCC) microenvironments. We observed that the CFL models successfully predicted the effects of several kinase inhibitor combinations. Furthermore, the ensemble predictions revealed ambiguous predictions that could be traced to a specific structural feature of these models, which we resolved with dedicated experiments, finding that IL-1α activates downstream signals through TAK1 and not MEKK1 in HepG2 cells. We conclude that CFL-Q2LM (Querying Quantitative Logic Models) is a promising approach for predicting effective anticancer drug combinations in cancer-relevant microenvironments.United States. Army Research Office (W911NF-09-0001
Disease Systems Analysis of Bone Mineral Density and Bone Turnover Markers in Response to Alendronate, Placebo, and Washout in Postmenopausal Women

A previously established mechanism-based disease systems model for osteoporosis that is based on a mathematically reduced version of a model describing the interactions between osteoclast (bone removing) and osteoblast (bone forming) cells in bone remodeling has been applied to clinical data from women (n=1,379) receiving different doses and treatment regimens of alendronate, placebo, and washout. The changes in the biomarkers, plasma bone-specific alkaline phosphatase activity (BSAP), urinary N-telopeptide (NTX), lumbar spine bone mineral density (BMD), and total hip BMD, were linked to the underlying mechanistic core of the model. The final model gave an accurate description of all four biomarkers for the different treatments. Simulations were used to visualize the dynamics of the underlying network and the natural disease progression upon alendronate treatment and discontinuation. These results complement the previous applications of this mechanism-based disease systems model to data from various treatments for osteoporosis
Population Pharmacokinetics of Bedaquiline and Metabolite M2 in Patients With Drug-Resistant Tuberculosis: The Effect of Time-Varying Weight and Albumin

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                  169463.pdf (publisher's version ) (Open Access)Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time. Bedaquiline and M2 disposition were well described by three and one-compartment models, respectively. Weight and albumin were correlated, typically increasing after the start of treatment, and significantly affected bedaquiline and M2 plasma disposition. Additionally, age and race were significant covariates, whereas concomitant human immunodeficiency virus (HIV) infection, sex, or having extensively drug-resistant TB was not. This is the first population model simultaneously characterizing bedaquiline and M2 PKs in its intended use population. The developed model will be used for efficacy and safety exposure-response analyses
Morphine Pharmacodynamics in Mechanically Ventilated Preterm Neonates Undergoing Endotracheal Suctioning

To date, morphine pharmacokinetics (PKs) are well quantified in neonates, but results about its efficacy are ambiguous. This work presents an analysis of a previously published study on pain measurements in mechanically ventilated preterm neonates who received either morphine or placebo to improve comfort during invasive ventilation. The research question was whether morphine reduces the pain associated with endotracheal or nasal suctioning before, during, and after suctioning. Because these neonates cannot verbalize their pain levels, pain was assessed on the basis of several validated pain measurement instruments (i.e., COMFORT-B, preterm infant pain profile [PIPP], Neonatal Infant Pain Scale (NIPS), and visual analogue scale (VAS)). The item response theory (IRT) was used to analyze the data in order for us to handle the data from multiple-item pain scores. The analysis showed an intra-individual relationship between morphine concentrations and pain reduction, as measured by COMFORT-B and VAS. However, the small magnitude of the morphine effect was not considered clinically relevant for this intervention in preterm neonates
Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer

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                  177889.pdf (publisher's version ) (Open Access)The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies
Commentary on the MID3 Good Practices Paper

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                  178217.pdf (publisher's version ) (Open Access)During the last 10 years the European Medicines Agency (EMA) organized a number of workshops on modeling and simulation, working towards greater integration of modeling and simulation (M&S) in the development and regulatory assessment of medicines. In the 2011 EMA - European Federation of Pharmaceutical Industries and Associations (EFPIA) Workshop on Modelling and Simulation, European regulators agreed to the necessity to build expertise to be able to review M&S data provided by companies in their dossier. This led to the establishment of the EMA Modelling and Simulation Working Group (MSWG). Also, there was agreement reached on the need for harmonization on good M&S practices and for continuing dialog across all parties. The MSWG acknowledges the initiative of the EFPIA Model-Informed Drug Discovery and Development (MID3) group in promoting greater consistency in practice, application, and documentation of M&S and considers the paper is an important contribution towards achieving this objective
Assessing Pharmacodynamic Interactions in Mice Using the Multistate Tuberculosis Pharmacometric and General Pharmacodynamic Interaction Models

The aim of this study was to investigate pharmacodynamic (PD) interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics (PKs), the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol, or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No PD interactions were observed against fast-multiplying bacteria. Interactions between rifampicin and isoniazid on killing slow and non-multiplying bacteria were identified, which led to an increase of 0.86 log10 colony-forming unit (CFU)/lungs at 28 days after treatment compared to expected additivity (i.e., antagonism). An interaction between rifampicin and ethambutol on killing non-multiplying bacteria was quantified, which led to a decrease of 2.84 log10 CFU/lungs at 28 days after treatment (i.e., synergism). These results show the value of pharmacometrics to quantitatively assess PD interactions in preclinical tuberculosis drug development
Translational Systems Pharmacology Studies in Pregnant Women

Pregnancy involves rapid physiological adaptation and complex interplay between mother and fetus. New analytic technologies provide large amounts of genomic, proteomic, and metabolomics data. The integration of these data through bioinformatics, statistical, and systems pharmacology techniques can improve our understanding of the mechanisms of normal maternal physiologic changes and fetal development. New insights into the mechanisms of pregnancy-related disorders, such as preterm birth (PTB), may lead to the development of new therapeutic interventions and novel biomarkers
Drugs Being Eliminated via the Same Pathway Will Not Always Require Similar Pediatric Dose Adjustments

For scaling drug plasma clearance (CLp) from adults to children, extrapolations of population pharmacokinetic (PopPK) covariate models between drugs sharing an elimination pathway have enabled accelerated development of pediatric models and dosing recommendations. This study aims at identifying conditions for which this approach consistently leads to accurate pathway specific CLp scaling from adults to children for drugs undergoing hepatic metabolism. A physiologically based pharmacokinetic (PBPK) simulation workflow utilizing mechanistic equations defining hepatic metabolism was developed. We found that drugs eliminated via the same pathway require similar pediatric dose adjustments only in specific cases, depending on drugs extraction ratio, unbound fraction, type of binding plasma protein, and the fraction metabolized by the isoenzyme pathway for which CLp is scaled. Overall, between-drug extrapolation of pediatric covariate functions for CLp is mostly applicable to low and intermediate extraction ratio drugs eliminated by one isoenzyme and binding to human serum albumin in children older than 1 month
Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations.

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                  191232.pdf (publisher's version ) (Open Access)The unmet medical need of providing evidence-based pharmacotherapy for pregnant women is recognized by the regulatory bodies. Physiologically based pharmacokinetic (PBPK) modeling offers an attractive platform to quantify anticipated changes in the pharmacokinetics (PKs) of drugs during pregnancy. Recent publications applying a pregnancy PBPK module to the prediction of maternal and fetal exposure of drugs are summarized. Future opportunities to use PBPK models to predict breast milk exposure and assess human fetotoxicity risks are presented.1 februari 201
Graphic Mining of High-Order Drug Interactions and Their Directional Effects on Myopathy Using Electronic Medical Records

We propose to study a novel pharmacovigilance problem for mining directional effects of high-order drug interactions on an adverse drug event (ADE). Our goal is to estimate each individual risk of adding a new drug to an existing drug combination. In this proof-of-concept study, we analyzed a large electronic medical records database and extracted myopathy-relevant case control drug co-occurrence data. We applied frequent itemset mining to discover frequent drug combinations within the extracted data, evaluated directional drug interactions related to these combinations, and identified directional drug interactions with large effect sizes. Furthermore, we developed a novel visualization method to organize multiple directional drug interaction effects depicted as a tree, to generate an intuitive graphical and visual representation of our data-mining results. This translational bioinformatics approach yields promising results, adds valuable and complementary information to the existing pharmacovigilance literature, and has the potential to impact clinical practice
Effect of Contact Interfaces on Quantum Conductance of Armchair
  Nanotubes

Effect of contact interfaces, between metallic single-wall carbon nanotubes
(SWCNT) and external electrodes made also of nanotubes, on the electrical
conductance is studied. A tight-binding model with both diagonal and
off-diagonal disorder, a recursive Green function technique as well as the
Landauer formalism are used. The studies are carried out within the coherent
transport regime and are focused on: (i) evolution from conductance
quantization to resonant tunneling, (ii) SWCNT's length effects and (iii)
magnetoresistance. It is shown that the so-called on-resonance devices, i.e.
nanotubes having a conductance peak at the Fermi energy, occur with a period of
3 carbon inter-ring spacings. Additionally, the present approach provides an
insight into magnetoresistance dependence of SWCNTs on conditions at the
contact interface.Comment: 9 pages, 3 figures. To appear in phys. stat. sol. (a
Effect of pelletization pressure on structural properties and critical current hysteresis of ceramic superconducting Bi1.7Pb0.3Sr2Ca2Cu3O y

The effect of pelletization pressures on structural properties and critical current hysteresis of Bi1.7Pb0.3Sr2Ca2Cu3Oy samples was investigated. The samples used in this study were prepared by classical solid-state reaction at the pressures from 100 up to 500 MPa. The obtained samples were characterized by resistance vs. temperature, (R-T), critical current density vs. applied magnetic field, (Jc-H), material density vs. pressure, (ρ-P), XRD, SEM, and ED AX. The results of this study showed that the quality of electrical and structural properties of Bi-2223 bulk superconductors strongly depends on the pelletization pressure. Pressing of bulk samples at 400 MPa produces textured grain alignment and associates micro- structural modifications in order to enhance flux pinning and thus increases current carrying capacities
Organic Single-Crystal Field-Effect Transistors

We present an overview of recent studies of the charge transport in the field
effect transistors on the surface of single crystals of organic
low-molecular-weight materials. We first discuss in detail the technological
progress that has made these investigations possible. Particular attention is
devoted to the growth and characterization of single crystals of organic
materials and to different techniques that have been developed for device
fabrication. We then concentrate on the measurements of the electrical
characteristics. In most cases, these characteristics are highly reproducible
and demonstrate the quality of the single crystal transistors. Particularly
noticeable are the small sub-threshold slope, the non-monotonic temperature
dependence of the mobility, and its weak dependence on the gate voltage. In the
best rubrene transistors, room-temperature values of $\mu$ as high as 15
cm$^2$/Vs have been observed. This represents an order-of-magnitude increase
with respect to the highest mobility previously reported for organic thin film
transistors. In addition, the highest-quality single-crystal devices exhibit a
significant anisotropy of the conduction properties with respect to the
crystallographic direction. These observations indicate that the field effect
transistors fabricated on single crystals are suitable for the study of the
\textit{intrinsic} electronic properties of organic molecular semiconductors.
We conclude by indicating some directions in which near-future work should
focus to progress further in this rapidly evolving area of research.Comment: Review article, to appear in special issue of Phys. Stat. Sol. on
  organic semiconductor
A new technique for the sp$^2$/sp$^3$ characterisation of carbon
  materials

We present a technique to determine the sp$^3$/sp$^2$ ratio of carbon
materials which is based on the electron energy-loss spectroscopy and which
uses the theoretical spectrum of graphite obtained from ab initio electronic
structure calculations. The method relies on the separation of the $\pi^*$ and
$\sigma^*$ components of the carbon K-edge of graphite. This $\pi^*$ spectrum
is adopted and assumed to be transferable to other carbon systems given an
appropriate parametrisation of the broadening. The method is applied on a
series of Monte-Carlo generated amorphous carbon structures and is shown to be
stable over a wide range of the energy windows for which spectral integration
is performed. The results are found to be in good agreement with the sp$^3$
fraction obtained from a microscopic scheme which uses the $\pi-$orbital axis
vector (POAV1) analysis. The technique was also applied on a series of
experimental spectra of amorphous carbon and was found to be in good agreement
with the results obtained from a functional fitting approach.Comment: 5 pages, 4 figures, two tables revtex4, Submitted for publication to
  Phys. Rev. Let