bluuebunny/crossref_metadata_2025_split huggingface dataset:
The scientific basis of rational prescribing. A guide to precision clinical pharmacology based on the WHO 6-step method
Authors:   On behalf of the EACPT research working group, Rongen G. A. , Marquet P. , van Gerven J. M. A. 
Published: November 2020

Abstract
Background and methods
This opinion paper expanded on the WHO “six-step approach to optimal pharmacotherapy,” by detailed exploration of the underlying pharmacological and pathophysiological principles. This exercise led to the identification of a large number of domains of research that should be addressed to make clinical pharmacology progress toward “precision clinical pharmacology,” as a prerequisite for precision medicine.

Result
In order to improve clinical efficacy and safety in patient groups (to guide drug development) as well as in individuals (to guide therapeutic options and optimize clinical outcome), developments in clinical pharmacology should at least tackle the following: (1) molecular diagnostic assays to guide drug design and development and allow physicians to identify the optimal targets for therapy in the individual patient in a quick and precise manner (to guide selection of the right drug for the right patient); (2) the setting up and validation of biomarkers of target engagement and modification as predictors of clinical efficacy and safety; (3) integration of physiological PK/PD models and intermediate markers of pharmacological effects with the natural evolution of the disease to predict the drug dose that most effectively improves clinical outcome in patient groups and individuals, making use of advanced modeling technologies (building on deterministic models, machine-learning, and deep learning algorithms); (4) methodology to validate human or humanized in vitro, ex vivo, and in vivo models for their ability to predict clinical outcome with investigational therapies, including nucleic acids or recombinant genes together with vectors (including viruses or nanoparticles), cell therapy, or therapeutic vaccines; (5) methodological complements to the gold-standard, large Phase 3 randomized clinical trial to provide clinically relevant and reliable data on the efficacy and safety of all treatment options at the population level (pragmatic clinical trials), as well as in small groups of patients (as low as n = 1); (6) regulatory science, so as to optimize the ethical review process, documentation, and monitoring of clinical trials, improve efficiency, and reduce costs of clinical drug development; (7) interventions to effectively improve patient compliance and to rationalize polypharmacy for the reduction of adverse effects and the enhancement of therapeutic interactions; and (8) appraisal of the ecological and societal impact of drug use to safeguard against environmental hazards (following the “One Health” concept) and to reduce drug resistance.

Discussion and conclusion
As can be seen, precision clinical pharmacology aims at being highly translational, which will require very large panels of complementary skills. Interdisciplinary collaborations, including non-clinical pharmacologists, will be key to achieve such an ambitious program.
Phosphatidylglyerol Lipid Binding at the Active Site of an Intramembrane Protease
Authors: Bondar Ana-Nicoleta 
Published: November 2020

AbstractTransmembrane substrate cleavage by the smallEscherichia colirhomboid protease GlpG informs on mechanisms by which lipid interactions shape reaction coordinates of membrane-embedded enzymes. Here, I review and discuss new work on the molecular picture of protein–lipid interactions that might govern the formation of the substrate–enzyme complex in fluid lipid membranes. Negatively charged PG-type lipids are of particular interest, because they are a major component of bacterial membranes. Atomistic computer simulations indicate POPG and DOPG lipids bridge remote parts of GlpG and might pre-occupy the substrate-docking site. Inhibition of catalytic activity by PG lipids could arise from ligand-like lipid binding at the active site, which could delay or prevent substrate docking. Dynamic protein–lipid H-bond networks, water access to the active site, and fluctuations in the orientation of GlpG suggest that GlpG has lipid-coupled dynamics that could shape the energy landscape of transmembrane substrate docking.Graphic Abstract
Morphological comparison of internal auditory canal diverticula in the presence and absence of otospongiosis on computed tomography and their impact on patterns of hearing loss
Authors: Burd Christian , Pai Irumee , Pinto Melisha , Dudau Cristina , Connor Steve 
Published: November 2020

Abstract
Purpose
The association of internal auditory canal (IAC) fundal diverticula with otospongiosis (OS) and their clinical significance remain unclear. We explored whether isolated IAC diverticula were morphologically different from those with additional CT features of OS, and whether IAC diverticula morphology influenced patterns of hearing loss.

Methods
Consecutive temporal bone CT studies with (n = 978) and without (n = 306) features of OS were retrospectively assessed. Two independent observers evaluated the presence of IAC diverticula morphological features (depth, neck:depth ratio, definition of contour and angulation of shape), and these were correlated with the presence of fenestral and pericochlear OS. Audiometric profiles were analysed for the isolated IAC diverticula and those with fenestral OS alone. Continuous data was compared using Wilcoxon rank sum tests and categorical data with chi-squared and Fisher’s exact tests.

Results
Ninety-five isolated IAC diverticula were demonstrated in 54/978 patients (5.5%) without CT evidence of OS (31M, 23F, mean age 46), and 119 IAC diverticula were demonstrated in 71/306 patients (23%) with CT evidence of OS (23M, 48F, mean age 55). Reduced neck:depth ratio, ill definition and angulation were all significantly associated with the presence of pericochlear OS (p < 0.001), whilst only ill definition was associated with the presence of fenestral OS alone (p < 0.05). No morphological feature was associated with conductive hearing loss in isolated diverticula or with sensorineural hearing loss in diverticula with fenestral OS alone.

Conclusion
IAC diverticula associated with pericochlear OS demonstrate different morphological features from isolated IAC diverticula. There are no clear audiometric implications of these morphological features.
What is the Best Therapeutic Strategy for Metachronous Resectable Colorectal Liver Metastases After Adjuvant Oxaliplatin‐Based Chemotherapy? A Multidisciplinary Inter‐Group Survey
Authors: Nassar Alexandra , Phelip Jean Marc , Goéré Diane , Loriau Jérôme , Gallois Claire , Michel Pierre , Penna Christophe , Taieb Julien , Brouquet Antoine , Benoist Stéphane 
Published: November 2020

AbstractBackgroundTo report the current clinical practice of French physicians for metachronous resectable liver metastasis (LM) occurring after a FOLFOX adjuvant chemotherapy for primary cancer.MethodsTwenty four clinical situations were proposed to a panel of experts via 4 learned societies. Clinical situations varied according time of recurrence (early between 6 and 12 month or > 12 month), extension of LM (limited ≤ 2 or extended > 2 lesions), presence of a neuropathy or not, and of a RAS or BRAF mutation.ResultsA total of 157 physicians participated in this study. A consensus was reached in 17 (71%) clinical situations. For an early limited recurrence, whatever presence of neuropathy, the preferred therapeutic approach (45%) was upfront surgery. For an early extended recurrence, whatever presence of neuropathy, there was a consensus (64%) for a preoperative chemotherapy by FOLFIRI + biologic agent. For a late recurrence without neuropathy, there was a consensus (50%) for a preoperative FOLFOX chemotherapy, whatever the extension of LM. For a late recurrence with neuropathy, upfront surgery was chosen (52%) for limited LM, and preoperative chemotherapy by FOLFIRI + biologic agent (73%) for extended LM. No response was influenced by the RAS mutation status. There was a strong consensus for intensified preoperative chemotherapy in all clinical situations for BRAF‐mutated LM.ConclusionsThis national survey provides an overview of the practice patterns in the treatment of LM occurring after adjuvant FOLFOX for primary. It could be a basis to establish expert's recommendations for the clinical practice.
Electrical conductivity of HCl-bearing aqueous fluids to 700 ºC and 1 GPa
Authors: Klumbach Steffen , Keppler Hans 
Published: November 2020

AbstractSubsurface magmatic–hydrothermal systems are often associated with elevated electrical conductivities in the Earthʼs crust. To facilitate the interpretation of these data and to allow distinguishing between the effects of silicate melts and fluids, the electrical conductivity of aqueous fluids in the system H2O–HCl was measured in an externally heated diamond anvil cell. Data were collected to 700 °C and 1 GPa, for HCl concentrations equivalent to 0.01, 0.1, and 1 mol/l at ambient conditions. The data, therefore, more than double the pressure range of previous measurements and extend them to geologically realistic HCl concentrations. The conductivities $$\sigma$$
σ
(in S/m) are well reproduced by a numerical model log $$\sigma$$
σ
= −2.032 + 205.8 T−1 + 0.895 log c + 3.888 log $$\rho$$
ρ
+ log$$\Lambda_{0}$$

Λ
0

(T,$$\rho$$
ρ
), where T is the temperature in K, c is the HCl concentration in wt. %, and $$\rho$$
ρ
is the density of pure water at the corresponding pressure and temperature conditions. $$\Lambda_{0}$$

Λ
0

(T,$$\rho$$
ρ
) is the limiting molar conductivity (in S cm2 mol−1) at infinite dilution, $$\Lambda_{0}$$

Λ
0

(T,$$\rho$$
ρ
) = 2550.14 − 505.10$$\rho$$
ρ
− 429,437 T−1. A regression fit of more than 800 data points to this model yielded R2 = 0.95. Conductivities increase with pressure and fluid densities due to an enhanced dissociation of HCl. However, at constant pressures, conductivities decrease with temperature because of reduced dissociation. This effect is particularly strong at shallow crustal pressures of 100–200 MPa and can reduce conductivities by two orders of magnitude. We, therefore, suggest that the low conductivities sometimes observed at shallow depths below the volcanic centers in magmatic–hydrothermal systems may simply reflect elevated temperatures. The strong negative temperature effect on fluid conductivities may offer a possibility for the remote sensing of temperature variations in such systems and may allow distinguishing the effects of magma intrusions from changes in hydrothermal circulation. The generally very high conductivities of HCl–NaCl–H2O fluids at deep crustal pressures (500 MPa–1 GPa) imply that electrical conductors in the deep crust, as in the Altiplano magmatic province and elsewhere, may at least partially be due to hydrothermal activity.
Selective retina therapy (SRT) in patients with therapy refractory persistent acute central serous chorioretinopathy (CSC): 3 months functional and morphological results
Authors:   on behalf of the SRT Study Group, Büttner Maximilian , Luger Benjamin , Abou Moulig Wasim , Junker Bernd , Framme Carsten , Jacobsen Christina , Knoll Katharina , Pielen Amelie 
Published: November 2020

Abstract
Purpose
Central serous chorioretinopathy (CSC) is a disease presenting with detachment of the neurosensory retina and characteristic focal leakage on fluorescein angiography. The spontaneous remission rate is 84% within 6 months. In this study, the efficacy of selective retina therapy (SRT) was examined in patients with therapy refractory persistent acute CSC defined by symptoms for at least 6 months and persistent subretinal fluid (SRF) despite eplerenone therapy.

Material and methods
This is a prospective, monocentric observational study in 17 eyes (16 patients, mean age 42 years, 2 female). SRT was performed with the approved R:GEN laser (Lutronic, South Korea), a micropulsed 527-nm Nd:YLF laser device, with a train of 30 pulses of 1.7 μs at 100-Hz repetition rate at the point of focal leakage determined by fluorescein angiography (FA) at baseline (BSL). Visits on BSL, week 4 (wk4), and week 12 (wk12) included best corrected visual acuity (BCVA, logMar), central retinal thickness (CRT) on spectral domain optical coherence tomography (SD-OCT), and FA. Statistical analysis was performed by pair-by-pair comparisons of multiple observations in each case with Bonferroni correction for multiple testing. (IBM SPSS Statistics 25®).

Results
Mean CRT at BSL was 387.69 ± 110.4 μm. CRT significantly decreased by 106.31 μm in wk4 (95%-KI: 21.42–191.2; p = 0.01), by 133.63 μm in wk12 (95%-KI: 50.22–217.03; p = 0.001) and by 133.81 μm (95%-KI: 48.88–218.75; p = 0.001) compared to BSL. Treatment success defined as complete resolution of SRF occurred at wk4 in 7/17 eyes (35.3%) and at wk12 in 10/17 eyes (58.8%). Re-SRT was performed in 7/17 eyes (41.2%) after an average of 107.14 ± 96.59 days. Treatment success after Re-SRT was observed in 4/6 eyes (66.6%, 12 weeks after Re-SRT). Mean BCVA did not change significantly from BSL to any later timepoint after adjusting for multiple testing. Notably, eyes with treatment success showed better BCVA at all timepoints and gained more letters compared to failures.

Conclusion
Single or repetitive SRT may be an effective and safe treatment in 2 of 3 patients suffering from acute persistent CSC after 6 months of symptoms or more. We observed complete resolution of SRF in around 60% of eyes 12 weeks after first SRT treatment and also 12 weeks after Re-SRT treatment in eyes with persistent or recurrent SRF. Results on the long-term course after SRT are still pending.
A distributional solution framework for linear hyperbolic PDEs coupled to switched DAEs
Authors: Borsche R. , Kocoglu D. , Trenn S. 
Published: November 2020

AbstractA distributional solution framework is developed for systems consisting of linear hyperbolic partial differential equations and switched differential-algebraic equations (DAEs) which are coupled via boundary conditions. The unique solvability is then characterize in terms of a switched delay DAE. The theory is illustrated with an example of electric power lines modelled by the telegraph equations which are coupled via a switching transformer where simulations confirm the predicted impulsive solutions.
Phytohormones and volatile organic compounds, like geosmin, in the ectomycorrhiza of Tricholoma vaccinum and Norway spruce (Picea abies)
Authors: Abdulsalam Oluwatosin , Wagner Katharina , Wirth Sophia , Kunert Maritta , David Anja , Kallenbach Mario , Boland Wilhelm , Kothe Erika , Krause Katrin 
Published: November 2020

AbstractThe ectomycorrhizospheric habitat contains a diverse pool of organisms, including the host plant, mycorrhizal fungi, and other rhizospheric microorganisms. Different signaling molecules may influence the ectomycorrhizal symbiosis. Here, we investigated the potential of the basidiomyceteTricholoma vaccinumto produce communication molecules for the interaction with its coniferous host, Norway spruce (Picea abies). We focused on the production of volatile organic compounds and phytohormones in axenicT. vaccinumcultures, identified the potential biosynthesis genes, and investigated their expression by RNA-Seq analyses.T. vaccinumreleased volatiles not usually associated with fungi, like limonene and β-barbatene, and geosmin. Using stable isotope labeling, the biosynthesis of geosmin was elucidated. The geosmin biosynthesis geneges1ofT. vaccinumwas identified, and up-regulation was scored during mycorrhiza, while a different regulation was seen with mycorrhizosphere bacteria. The fungus also released the volatile phytohormone ethylene and excreted salicylic and abscisic acid as well as jasmonates into the medium. The tree excreted the auxin, indole-3-acetic acid, and its biosynthesis intermediate, indole-3-acetamide, as well as salicylic acid with its root exudates. These compounds could be shown for the first time in exudates as well as in soil of a natural ectomycorrhizospheric habitat. The effects of phytohormones present in the mycorrhizosphere on hyphal branching ofT. vaccinumwere assessed. Salicylic and abscisic acid changed hyphal branching in a concentration-dependent manner. Since extensive branching is important for mycorrhiza establishment, a well-balanced level of mycorrhizospheric phytohormones is necessary. The regulation thus can be expected to contribute to an interkingdom language.
Combining Molecular Spintronics with Electron Paramagnetic Resonance: The Path Towards Single-Molecule Pulsed Spin Spectroscopy
Authors: Slota Michael , Bogani Lapo 
Published: November 2020

AbstractWe provide a perspective on how single-molecule magnets can offer a platform to combine quantum transport and paramagnetic spectroscopy, so as to deliver time-resolved electron paramagnetic resonance at the single-molecule level. To this aim, we first review the main principles and recent developments of molecular spintronics, together with the possibilities and limitations offered by current approaches, where interactions between leads and single-molecule magnets are important. We then review progress on the electron quantum coherence on devices based on molecular magnets, and the pulse sequences and techniques necessary for their characterization, which might find implementation at the single-molecule level. Finally, we highlight how some of the concepts can also be implemented by including all elements into a single molecule and we propose an analogy between donor–acceptor triads, where a spin center is sandwiched between a donor and an acceptor, and quantum transport systems. We eventually discuss the possibility of probing spin coherence during or immediately after the passage of an electron transfer, based on examples of transient electron paramagnetic resonance spectroscopy on molecular materials.
The employment and wage effects of export VAT rebates: evidence from China
Authors: Gao Bo , Ma Jing , Wang Zheng 
Published: November 2020

AbstractThis paper studies the employment and wage effects of VAT rebates to exporters with comprehensive firm-product-level data of China. It is found that the adjustments in VAT rebates significantly and positively affect firm’s employment but have no statistically significant effect on firm’s wage. Moreover, this paper finds that the employment effect of VAT rebates is heterogeneous across firms. In particular, low-productivity firms are more sensitive to the adjustments of VAT rebates than high-productivity firms, suggesting that an increase of VAT rebates may cause mis-reallocation of resources.
Sliding mode synchronization between uncertain Watts-Strogatz small-world spatiotemporal networks
Authors: Liu Shuang , Zhang Runze , Wang Qingyun , He Xiaoyan 
Published: November 2020

AbstractBased on the topological characteristics of small-world networks, a nonlinear sliding mode controller is designed to minimize the effects of internal parameter uncertainties. To qualify the effects of uncertain parameters in the response networks, some effective recognition rates are designed so as to achieve a steady value in the extremely fast simulation time period. Meanwhile, the Fisher-Kolmogorov and Burgers spatiotemporal chaotic systems are selected as the network nodes for constructing a drive and a response network, respectively. The simulation results confirm that the developed sliding mode could realize the effective synchronization problem between the spatiotemporal networks, and the outer synchronization is still achieved timely even when the connection probability of the small-world networks changes.
The Effect of Personal Finance Education on The Financial Knowledge, Attitudes and Behaviour of University Students in Indonesia
Authors: Johan Irni , Rowlingson Karen , Appleyard Lindsey 
Published: November 2020

AbstractThere is much debate about the impact of personal finance education on financial knowledge, attitudes and behaviour, particularly based on studies in the United Kingdom (UK) and United States of America (US). This paper makes a contribution to this debate, drawing on analysis of a survey of 521 undergraduate students at Bogor Agricultural University (IPB) in Indonesia in 2015. As part of that study, we measured the impact of a 14-week personal finance education course on financial knowledge, attitudes and behaviour. Our findings show that, when controlling for other factors, the personal finance course did, indeed, have a positive and statistically significant impact on financial knowledge. However, there was no statistically significant impact of the course on financial attitudes or behaviour. Our analysis also shows that family financial socialisation was an important driver of financial knowledge, attitudesandbehaviour while other drivers of financial behaviour included income, work experience, year/field of study and discussing money with friends. We do not argue here that formal financial education is unimportant but that its role in changing attitudes and behaviour should be considered carefully if this is, indeed, its aim.
One-exact approximate Pareto sets
Authors: Herzel Arne , Bazgan Cristina , Ruzika Stefan , Thielen Clemens , Vanderpooten Daniel 
Published: November 2020

AbstractPapadimitriou and Yannakakis (Proceedings of the 41st annual IEEE symposium on the Foundations of Computer Science (FOCS), pp 86–92, 2000) show that the polynomial-time solvability of a certain auxiliary problem determines the class of multiobjective optimization problems that admit a polynomial-time computable $$(1+\varepsilon , \dots , 1+\varepsilon )$$

(
1
+
ε
,
⋯
,
1
+
ε
)

-approximate Pareto set (also called an $$\varepsilon $$
ε
-Pareto set). Similarly, in this article, we characterize the class of multiobjective optimization problems having a polynomial-time computable approximate $$\varepsilon $$
ε
-Pareto set that is exact in one objective by the efficient solvability of an appropriate auxiliary problem. This class includes important problems such as multiobjective shortest path and spanning tree, and the approximation guarantee we provide is, in general, best possible. Furthermore, for biobjective optimization problems from this class, we provide an algorithm that computes a one-exact $$\varepsilon $$
ε
-Pareto set of cardinality at most twice the cardinality of a smallest such set and show that this factor of 2 is best possible. For three or more objective functions, however, we prove that no constant-factor approximation on the cardinality of the set can be obtained efficiently.
The Questioning Turing Test
Authors: Damassino Nicola 
Published: November 2020

AbstractThe Turing Test (TT) is best regarded as a model to test for intelligence, where an entity’s intelligence is inferred from its ability to be attributed with ‘human-likeness’ during a text-based conversation. The problem with this model, however, is that it does not care if or how well an entity produces a meaningful conversation, as long as its interactions are humanlike enough. As a consequence, the TT attracts projects that concentrate on how best to fool the judges. In light of this, I propose a new version of the TT: the Questioning Turing Test (QTT). Here, the entity has to produce an enquiry rather than a conversation; and it is parametrised along two further dimensions in addition to ‘human-likeness’: ‘correctness’, evaluating if the entity accomplishes the enquiry; and ‘strategicness’, evaluating how well the entity accomplishes the enquiry, in terms of the number of questions asked (the fewer, the better).