bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetic and exploratory exposure–response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study
Authors: Wang Bei , Deng Rong , Hennig Stefanie , Badovinac Crnjevic Tanja , Kaewphluk Monika , Kågedal Matts , Quartino Angelica L. , Girish Sandhya , Li Chunze , Kirschbrown Whitney P. 
Published: June 2021

Abstract
Purpose
To characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure–response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure–efficacy and –safety relationships and support the approved SC dosing regimen.

Methods
Population pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression.

Results
SC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest.

Conclusion
The approved PH FDC SC dose [loading: 1200/600 mg pertuzumab/trastuzumab (15 mL); maintenance: 600 mg pertuzumab/trastuzumab (10 mL) and 2000 U/mL recombinant human hyaluronidase every 3 weeks] provides a positive benefit–risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab.
Pre-contrast T1-weighted imaging of the spinal cord may be unnecessary in patients with multiple sclerosis
Authors: Riederer Isabelle , Mühlau Mark , Zimmer Claus , Gutbrod-Fernandez Magaly , Sollmann Nico , Kirschke Jan S 
Published: June 2021

Abstract
Objectives
Multiple sclerosis (MS) is an inflammatory disease frequently involving the spinal cord, which can be assessed by magnetic resonance imaging (MRI). Here, we hypothesize that pre-contrast T1-w imaging does not add diagnostic value to routine spinal MRI for the follow-up of patients with MS.

Methods
3-T MRI scans including pre- and post-contrast T1-w as well as T2-w images of 265 consecutive patients (mean age: 40 ± 13 years, 169 women) with (suspected) MS were analyzed retrospectively. Images were assessed in two separate reading sessions, first excluding and second including pre-contrast T1-w images. Two independent neuroradiologists rated the number of contrast-enhancing (ce) lesions as well as diagnostic confidence (1 = unlikely to 5 = very high), overall image quality, and artifacts. Results were compared using Wilcoxon matched-pairs signed-rank tests and weighted Cohen’s kappa (κ).

Results
Fifty-six ce lesions were found in 43 patients. There were no significant differences in diagnostic confidence between both readings for both readers (reader 1: p = 0.058; reader 2: p = 0.317). Inter-rater concordance was both moderate regarding artifacts (κ = 0.418) and overall image quality (κ = 0.504). Thirty-one black holes were found in 25 patients with high diagnostic confidence (reader 1: 4.04 ± 0.81; reader 2: 3.80 ± 0.92) and substantial inter-rater concordance (κ = 0.700).

Conclusions
Availability of pre-contrast T1-w images did not significantly increase diagnostic confidence or detection rate of ce lesions in the spinal cord in patients with MS. Thus, pre-contrast T1-w sequences might be omitted in routine spinal MRI for follow-up exams, however not in special unclear clinical situations in which certainty on contrast enhancement is required.

Key Points

Availability of pre-contrast T1-w images does not increase diagnostic confidence or detection rate of contrast-enhancing lesions in the spinal cord of MS patients.

Excluding pre-contrast T1-w sequences reduces scan time, thus providing more time for other sequences or increasing the patients’ compliance.
Can preoperative results predict the need for future reintervention following injection laryngoplasty for unilateral vocal fold paralysis?
Authors: Miaśkiewicz Beata , Panasiewicz Aleksandra , Gos Elżbieta , Krasnodębska Paulina , Skarżyński Piotr H. , Szkiełkowska Agata 
Published: June 2021

Abstract
Purpose
The objective was to investigate whether a patient’s preoperative test results can predict the need for future reoperation in unilateral vocal fold paralysis (UVFP).

Methods
A single-centre retrospective study was performed. The study group consisted of 18 patients with UVFP who had been treated with injection laryngoplasty but who required further treatment and were augmentated again within 36 months. The control group consisted of 33 injected patients who had not required reintervention up to 36 months later.

Results
Only glottal gap was associated with a relative risk for reinjection. Glottal gap was found to be severe in 77.8% of the patients from the study group compared to 42.4% of the controls, and the difference was statistically significant. The kind of injected material (calcium hydroxylapatite or hyaluronic acid), age, and voice assessment (perceptual, objective, or subjective) did not seem to affect the likelihood of reoperation being needed. There were no between-group statistically significant differences in individual aspects of the GRBAS scale. The global score was slightly higher in the study group, but it did not reach statistical significance (U = 198.5; p = 0.09). A comparison of VHI scores did not yield statistically significant differences between the study and control groups. No significant differences in objective acoustic voice parameters were observed between the groups.

Conclusion
Only glottal gap occurred to be associated with a relative risk for reinjection. A kind of injected material (CaHA or HA), age, perceptual, objective and subjective voice assessment do not seem to impact the likelihood of reoperation in patients with UVFP.
A continuum mechanical framework for modeling tumor growth and treatment in two- and three-phase systems
Authors: Miller Cass T. , Gray William G. , Schrefler Bernhard A. 
Published: June 2021

AbstractThe growth and treatment of tumors is an important problem to society that involves the manifestation of cellular phenomena at length scales on the order of centimeters. Continuum mechanical approaches are being increasingly used to model tumors at the largest length scales of concern. The issue of how to best connect such descriptions to smaller-scale descriptions remains open. We formulate a framework to derive macroscale models of tumor behavior using the thermodynamically constrained averaging theory (TCAT), which provides a firm connection with the microscale and constraints on permissible forms of closure relations. We build on developments in the porous medium mechanics literature to formulate fundamental entropy inequality expressions for a general class of three-phase, compositional models at the macroscale. We use the general framework derived to formulate two classes of models, a two-phase model and a three-phase model. The general TCAT framework derived forms the basis for a wide range of potential models of varying sophistication, which can be derived, approximated, and applied to understand not only tumor growth but also the effectiveness of various treatment modalities.
Influence of morphology on the effective hygro-elastic properties of softwood (spruce) and hardwood (balsa)
Authors: Livani M. A. , Bosco E. , Suiker A. S. J. 
Published: June 2021

AbstractWood materials are characterized by complex, hierarchical material structures spanning across various length scales. The present work aims at establishing a relation between the hygro-elastic properties at the mesoscopic cellular level and the effective material response at the macroscopic level, both for softwood (spruce) and hardwood (balsa). The particular aim is to explore the influence on the effective hygro-elastic properties under variations in the meso-scale morphology. The multi-scale framework applied for this purpose uses the method of asymptotic homogenization, which allows to accurately and efficiently obtain the effective response of heterogeneous materials characterized by complex meso-structural geometries. The meso-structural model considered for softwood is based on a periodic, two-dimensional statistically representative volume element that is generated by a spatial repetition of tracheid cells. The tracheid cells are modeled as hexagonal elements characterized by a certain geometrical irregularity. The hardwood meso-structure consists of a region composed of hexagonal cellular fibers with large vessels embedded, which is connected to a ray region that is constructed of ray cells. The hardwood fibers are modeled as hexagonal cellular elements, similar to softwood tracheids. The rays are represented by quadrilateral cells oriented along the radial direction, whereby different arrangements are considered, i.e., the ray cells are either regularly stacked or organized as a staggered configuration. The interface between the fiber and ray regions may also be characterized by a regular or a staggered arrangement. The meso-structural models for softwood and hardwood are discretized by means of plane-strain, finite element models, which describe the hygro-elastic response of the wood material in the radial–tangential plane. For softwood, the sensitivity of the effective elastic and hygro-expansive properties is explored as a function of the geometrical irregularity of the tracheids. For hardwood, the effective properties are studied under a variation of the ray cell arrangement, the type of interface between ray and fiber regions, and the vessel volume fraction. The modeling results agree well with results obtained from other numerical homogenization studies and show to be in reasonable agreement with experimental data taken from the literature.
Group membership does not modulate automatic imitation
Authors: Genschow Oliver , Westfal Mareike , Cracco Emiel , Crusius Jan 
Published: June 2021

AbstractIndividuals have the automatic tendency to imitate each other. A key prediction of different theories explaining automatic imitation is that individuals imitate in-group members more strongly than out-group members. However, the empirical basis for this prediction is rather inconclusive. Only a few experiments have investigated the influence of group membership using classic automatic imitation paradigms and these experiments led to mixed results. To put the group membership prediction to a critical test, we carried out six high-powered experiments (total N = 1538) in which we assessed imitation with the imitation-inhibition task and manipulated group membership in different ways. Evidence across all experiments indicates that group membership does not modulate automatic imitation. Moreover, we do not find support for the idea that feelings of affiliation or perceived similarity moderate the effect of group membership on automatic imitation. These results have important implications for theories explaining automatic imitation and contribute to the current discussion of whether automatic imitation can be socially modulated.
Fronto-parietal homotopy in resting-state functional connectivity predicts task-switching performance
Authors: Vallesi Antonino , Visalli Antonino , Gracia-Tabuenca Zeus , Tarantino Vincenza , Capizzi Mariagrazia , Alcauter Sarael , Mantini Dante , Pini Lorenzo 
Published: June 2021

AbstractHomotopic functional connectivity reflects the degree of synchrony in spontaneous activity between homologous voxels in the two hemispheres. Previous studies have associated increased brain homotopy and decreased white matter integrity with performance decrements on different cognitive tasks across the life-span. Here, we correlated functional homotopy, both at the whole-brain level and specifically in fronto-parietal network nodes, with task-switching performance in young adults. Cue-to-target intervals (CTI: 300 vs. 1200 ms) were manipulated on a trial-by-trial basis to modulate cognitive demands and strategic control. We found that mixing costs, a measure of task-set maintenance and monitoring, were significantly correlated to homotopy in different nodes of the fronto-parietal network depending on CTI. In particular, mixing costs for short CTI trials were smaller with lower homotopy in the superior frontal gyrus, whereas mixing costs for long CTI trials were smaller with lower homotopy in the supramarginal gyrus. These results were specific to the fronto-parietal network, as similar voxel-wise analyses within a control language network did not yield significant correlations with behavior. These findings extend previous literature on the relationship between homotopy and cognitive performance to task-switching, and show a dissociable role of homotopy in different fronto-parietal nodes depending on task demands.
Phase transitions for spatially extended pinning
Authors: Caravenna Francesco , den Hollander Frank 
Published: June 2021

AbstractWe consider a directed polymer of lengthNinteracting with a linear interface. The monomers carry i.i.d. random charges$$(\omega _i)_{i=1}^N$$(ωi)i=1Ntaking values in$${\mathbb {R}}$$Rwith mean zero and variance one. Each monomericontributes an energy$$(\beta \omega _i-h)\varphi (S_i)$$(βωi-h)φ(Si)to the interaction Hamiltonian, where$$S_i \in {\mathbb {Z}}$$Si∈Zis the height of monomeriwith respect to the interface,$$\varphi :\,{\mathbb {Z}}\rightarrow [0,\infty )$$φ:Z→[0,∞)is the interaction potential,$$\beta \in [0,\infty )$$β∈[0,∞)is the inverse temperature, and$$h \in {\mathbb {R}}$$h∈Ris the charge bias parameter. The configurations of the polymer are weighted according to the Gibbs measure associated with the interaction Hamiltonian, where the reference measure is given by a Markov chain on$${\mathbb {Z}}$$Z. We study both thequenchedand theannealedfree energy per monomer in the limit as$$N\rightarrow \infty $$N→∞. We show that each exhibits a phase transition along a critical curve in the$$(\beta ,h)$$(β,h)-plane, separating alocalized phase(where the polymer stays close to the interface) from adelocalized phase(where the polymer wanders away from the interface). We derive variational formulas for the critical curves and we obtain upper and lower bounds on the quenched critical curve in terms of the annealed critical curve. In addition, for the special case where the reference measure is given by aBessel random walk, we derive the scaling limit of the annealed free energy as$$\beta ,h \downarrow 0$$β,h↓0inthree different regimesfor the tail exponent of$$\varphi $$φ.
Erweiterung von Kosten-Nutzen-Analysen im Hochwassermanagement durch Berücksichtigung sozialer und psychologischer Verwundbarkeit
Authors: Thaler Thomas , Seebauer Sebastian , Rogger Magdalena , Dworak Thomas , Winkler Claudia 
Published: June 2021

ZusammenfassungKosten-Nutzen-Analysen im Hochwassermanagement verwenden zur Beurteilung von Schutzkonzepten meist den physischen Schaden als Hauptkriterium. Dies kann zu einer ungleichen räumlichen Entwicklung führen, da in strukturschwachen Gemeinden meist weit geringere monetäre Werte gefährdet sind als in verdichteten Siedlungszentren. Der folgende Beitrag zeigt den Zusammenhang zwischen sozialer Gerechtigkeit und Kosten-Nutzen-Analyse und schlägt vor, wie strukturschwache Gemeinden besser in einem neuen Konzept der Kosten-Nutzen-Analyse abgebildet werden könnten, indem im Entscheidungsprozess soziale und psychologische Merkmale der Betroffenen mitberücksichtigt werden. Diese Erweiterung führt dazu, dass insbesondere Gemeinden in strukturschwachen Gebieten die Möglichkeit haben, einen Hochwasserschutz rascher umzusetzen. Mit diesem Beitrag möchten wir nicht nur die Bedeutung der sozialen und psychologischen Indikatoren im Hochwassermanagement aufzeigen, sondern auch, wie der Entscheidungsprozess in Zukunft gerechter gestaltet werden kann.
An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease
Authors: Biagioni Francesca , Ferese Rosangela , Giorgi Filippo Sean , Modugno Nicola , Olivola Enrica , Lenzi Paola , Gambardella Stefano , Centonze Diego , Ruggieri Stefano , Fornai Francesco 
Published: June 2021

AbstractPeripheral markers in Parkinson’s disease (PD) represent a hot issue to provide early diagnosis and assess disease progression. The gold standard marker of PD should feature the same reliability as the pathogenic alteration, which produces the disease itself. PD is foremost a movement disorder produced by a loss of nigrostriatal dopamine innervation, in which striatal dopamine terminals are always markedly reduced in PD patients to an extent, which never overlaps with controls. Similarly, a reliable marker of PD should possess such a non-overlapping feature when compared with controls. In the present study, we provide a novel pathological hallmark, the autophagosome, which in each PD patient was always suppressed compared with each control subject. Autophagosomes were counted as microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive vacuoles at ultrastructural morphometry within peripheral (blood) blood mononuclear cells (PBMC). This also provides the gold standard to assess the autophagy status. Since autophagy may play a role in the pathogenesis of PD, autophagosomes may be a disease marker, while participating in the biology of the disease. Stoichiometric measurement of α-synuclein despite significantly increased in PD patients, overlapped between PD and control patients. Although the study need to be validated in large populations, the number of autophagy vacuoles is neither related with therapy (the amount was similarly suppressed in a few de novo patients), nor the age in PD or controls.
Efficacy of resin infiltration to mask post-orthodontic or non-post-orthodontic white spot lesions or fluorosis — a systematic review and meta-analysis
Authors: Bourouni S. , Dritsas K. , Kloukos D. , Wierichs R. J. 
Published: June 2021

Abstract
Objective
The present review systematically analyzed clinical studies investigating the efficacy of resin infiltration on post-orthodontic or non-post-orthodontic, white spot lesions (WSL), or fluorosis.

Materials
Five electronic databases (Central, PubMed, Ovid MEDLINE, Ovid EMBASE, LILACS) were screened. Article selection and data abstraction were done in duplicate. No language or time restrictions were applied. Outcomes were visual-tactile or DIAGNOdent measurements.

Results
Eleven studies with 1834 teeth being affected in 413 patients were included. Nine studies were randomized control trials, one a prospective cohort study, and one had an unclear study design. Meta-analysis could be performed for “resin infiltration vs. untreated control,” “resin infiltration vs. fluoride varnish,” and “resin infiltration without bleaching vs. resin infiltration with bleaching.” WSL being treated with resin infiltration showed a significantly higher optical improvement than WSL without any treatment (standard mean difference (SMD) [95% CI] = 1.24 [0.59, 1.88], moderate level of evidence [visual-tactile assessment]) and with fluoride varnish application (mean difference (MD) [95% CI] = 4.76 [0.74, 8.78], moderate level of evidence [DIAGNOdent reading]). In patients with fluorosis, bleaching prior to resin infiltration showed no difference in the masking effect compared to infiltration alone (MD [95% CI] = − 0.30 [− 0.98, 0.39], moderate level of evidence).

Conclusion
Resin infiltration has a significantly higher masking effect than natural remineralization or regular application of fluoride varnishes. However, although the evidence was graded as moderate, this conclusion is based on only very few well-conducted RCTs.

Clinical relevance
Resin infiltration seems to be a viable option to esthetically mask enamel white spot lesions and fluorosis.
Optimized location of light sources to cover a rectangular region
Authors: Kovács Kristóf , Tóth Boglárka 
Published: June 2021

AbstractThe problem we considered was proposed by an industrial partner. The aim is to locate light sources around a rectangular field such that the areas these illuminate cover the whole field. We assume these illuminated areas to be rectangular as well, parallel to the field. Covering an area with multiple lights is allowed. There are several types of light sources, priced differently with different sizes of their illuminated area. We aim to minimize the cost of the cover. We propose a constraint generation approach for solving this covering problem. We formulate a MIP model to locate the light sources such that a finite number of predetermined points have to be covered. The result does not necessarily solve the original problem, i.e. it does not cover the whole field. Therefore, a constraint generation model is built to calculate a non-covered point such that the first model has to improve its previous solution to cover this new point as well. If no uncovered point is found, the result is an optimal covering, thus we stop. We have also designed some set of additional constraints to exclude symmetrical solutions, to speed up the algorithm. We analyze the efficiency of the additional constraints and report some computational results in realistic settings.
Multi-paradigm modelling for cyber–physical systems: a descriptive framework
Authors: Amrani Moussa , Blouin Dominique , Heinrich Robert , Rensink Arend , Vangheluwe Hans , Wortmann Andreas 
Published: June 2021

AbstractThe complexity of cyber–physical systems (CPSs) is commonly addressed through complex workflows, involving models in a plethora of different formalisms, each with their own methods, techniques, and tools. Some workflow patterns, combined with particular types of formalisms and operations on models in these formalisms, are used successfully in engineering practice. To identify and reuse them, we refer to these combinations of workflow and formalism patterns as modelling paradigms. This paper proposes a unifying (Descriptive) Framework to describe these paradigms, as well as their combinations. This work is set in the context of Multi-Paradigm Modelling (MPM), which is based on the principle to model every part and aspect of a system explicitly, at the most appropriate level(s) of abstraction, using the most appropriate modelling formalism(s) and workflows. The purpose of the Descriptive Framework presented in this paper is to serve as a basis to reason about these formalisms, workflows, and their combinations. One crucial part of the framework is the ability to capture the structural essence of a paradigm through the concept of a paradigmatic structure. This is illustrated informally by means of two example paradigms commonly used in CPS: Discrete Event Dynamic Systems and Synchronous Data Flow. The presented framework also identifies the need to establish whether a paradigm candidate follows, or qualifies as, a (given) paradigm. To illustrate the ability of the framework to support combining paradigms, the paper shows examples of both workflow and formalism combinations. The presented framework is intended as a basis for characterisation and classification of paradigms, as a starting point for a rigorous formalisation of the framework (allowing formal analyses), and as a foundation for MPM tool development.