bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetics of ATR inhibitor berzosertib in phase I studies for different cancer types
Authors: Terranova Nadia , Jansen Mendel , Falk Martin , Hendriks Bart S. 
Published: November 2020

Abstract
Purpose
Berzosertib (formerly M6620) is the first-in-class inhibitor of ataxia–telangiectasia and Rad3-related protein, a key component of the DNA damage response, and being developed in combination with chemotherapy for the treatment of patients with advanced cancers. The objectives of this analysis were to characterize the pharmacokinetics (PK) of berzosertib across multiple studies and parts, estimate inter-individual variability, and identify covariates that could explain such variability.

Methods
A population PK analysis was performed using the combined dataset from two phase I clinical studies (NCT02157792, EudraCT 2013-005100-34) in patients with advanced cancers receiving an intravenous infusion of berzosertib alone or in combination with chemotherapy. The analysis included data from 240 patients across 11 dose levels (18–480 mg/m2). Plasma concentration data were modeled with a non-linear mixed-effect approach and clinical covariates were evaluated.

Results
PK data were best described by a two-compartment linear model. For a typical patient, the estimated clearance (CL) and intercompartmental CL were 65 L/h and 295 L/h, respectively, with central and peripheral volumes estimated to be 118 L and 1030 L, respectively. Several intrinsic factors were found to influence berzosertib PK, but none were considered clinically meaningful due to a very limited effect. Model simulations indicated that concentrations of berzosertib exceeded p-Chk1 (proximal pharmacodynamic biomarker) IC50 at recommended phase II doses in combination with carboplatin, cisplatin, and gemcitabine.

Conclusions
There was no evidence of a clinically significant PK interaction between berzosertib and evaluated chemo-combinations. The covariate analysis did not highlight any need for dosing adjustments in the population studied to date.

Clinical Trial information
NCT02157792, EudraCT 2013-005100-34
The prevalence and locations of bone metastases using whole-body MRI in treatment-naïve intermediate- and high-risk prostate cancer
Authors: Ottosson Fredrik , Baco Eduard , Lauritzen Peter M. , Rud Erik 
Published: November 2020

Abstract
Objective
The aim of this study was to assess the prevalence and distribution of bone metastases in treatment-naïve prostate cancer patients eligible for a metastatic workup using whole-body MRI, and to evaluate the results in light of current guidelines.

Methods
This single-institution, retrospective study included all patients with treatment-naïve prostate cancer referred to whole-body MRI during 2016 and 2017. All were eligible for a metastatic workup according to the guidelines: PSA > 20 ng/ml and/or Gleason grade group ≥ 3 and/or cT ≥ 2c and/or bone symptoms. The definition of a metastasis was descriptive and based on the original MRI reports. The anatomical location of metastases was registered.

Results
We included 161 patients with newly diagnosed prostate cancer of which 36 (22%) were intermediate-risk and 125 (78%) were high-risk. The median age and PSA were 71 years (IQR 64–76) and 13 ng/ml (IQR 8–28), respectively. Bone metastases were found in 12 patients (7%, 95% CI: 4–13), and all were high-risk with Gleason grade group ≥ 4. The pelvis was affected in 4 patients, and the spine + pelvis in the remaining 8. No patients demonstrated metastases to the spine without concomitant metastases in the pelvis. Limitations are the small number of metastases and retrospective design.

Conclusion
This study suggests that the overall prevalence of bone metastases using the current guidelines for screening is quite low. No metastases were seen in the case of Gleason grade group ≤ 3, and further studies should investigate if it necessary to screen non-high-risk patients.

Key Points
• The overall prevalence of bone metastases was 7% in the case of newly diagnosed intermediate- and high-risk prostate cancer.
• The prevalence in high-risk patients was 10%, and no metastases were seen in patients with Gleason grade group ≤ 3.
• The pelvic skeleton is the main site, and no metastases occurred in the spine without concomitant pelvic metastases.
Consciously processing balance leads to distorted perceptions of instability in older adults
Authors: Ellmers Toby J. , Kal Elmar C. , Young William R. 
Published: November 2020

Abstract
Background
Persistent dizziness without a clear cause is common in older adults. We explored whether an anxiety-driven preoccupation with consciously processing balance may underpin the distorted perceptions of unsteadiness that characterises ‘unexplained’ dizziness in older adults.

Methods
We experimentally induced anxiety about losing one’s balance (through a postural threat manipulation) in a cohort of asymptomatic older adults and evaluated associated changes in perceived stability, conscious movement processing and postural control. These outcomes were also assessed when performing a distracting cognitive task designed to prevent anxiety-related conscious movement processing, in addition to during baseline conditions (ground level).

Results
Despite a lack of increase in postural sway amplitude (p = 0.316), participants reported reductions in perceived stability during postural threat compared to baseline (p < 0.001). A multiple linear regression revealed that anxiety-related conscious movement processing independently predicted perceptions of instability during this condition (p = 0.006). These changes were accompanied by alterations in postural control previously associated with functional dizziness, namely high-frequency postural sway and disrupted interaction between open- and closed-loop postural control (ps < 0.014). While the distraction task successfully reduced conscious processing (p = 0.012), leading to greater perceived stability (p = 0.010), further increases in both postural sway frequency (p = 0.002) and dominance of closed-loop control (p = 0.029) were observed.

Conclusion
These findings implicate the role of conscious movement processing in the formation of distorted perceptions of unsteadiness, suggesting that such perceptions may be modifiable by reducing an over-reliance on conscious processes to regulate balance.
Spectral-domain OCT changes in retina and optic nerve in children with hypoxic–ischaemic encephalopathy
Authors: Grego L. , Pignatto S. , Busolini E. , Rassu N. , Samassa F. , Prosperi R. , Pittini C. , Cattarossi L. , Lanzetta Paolo 
Published: November 2020

Abstract
Purpose
To evaluate the effect of neonatal hypoxic–ischaemic injury on the retina and the optic nerve and to correlate ocular damage with systemic parameters, laboratory tests, neurological imaging and therapeutic hypothermia at birth.

Methods
Forty-one children with hypoxic–ischaemic encephalopathy (HIE) at birth (9.09 ± 3.78 years) and a control group of 38 healthy subjects (9.57 ± 3.47 years) were enrolled in a cohort study. The HIE population was divided into three subgroups, based on the degree of encephalopathy according to Sarnat score and the treatment with therapeutic hypothermia (TH): Sarnat score I not treated with hypothermia, Sarnat score II-III treated with TH and Sarnat score II-III not subjected to TH. Total macular thickness, individual retinal layers and peripapillary nerve fibre layer thickness were measured with spectral-domain optical coherence tomography. Clinical data of perinatal period of HIE children were collected: APGAR score, pH and base excess of funiculus blood at birth, apnoea duration, brain ultrasound, cerebral MRI ischaemic lesions and blood chemistry tests.

Results
Children with Sarnat score I did not show a reduction of peripapillary nerve fibres and ganglion cell layer compared to the control group (p = 0.387, p = 0.316). Peripapillary nerve fibre layer was 109.06 ± 7.79 μm in children with Sarnat score II-III treated with TH, 108.31 ± 7.83 μm in subjects with Sarnat score II-III not subjected to TH and 114.27 ± 6.81 μm in the control group (p = 0.028, p = 0.007). Ganglion cell layer was thinner in children with Sarnat score II-III treated with TH (50.31 ± 5.13 μm) compared to the control group (54.04 ± 2.81 μm) (p = 0.01). Inner retinal layers damage correlated with C-reactive protein and lactate dehydrogenase increase, while higher levels of total bilirubin were protective against retinal impairment (p < 0.05). Cerebral oedema was related to peripapillary nerve fibre layer damage (p = 0.046).

Conclusions
Thickness reduction of inner retinal layer and peripapillary nerve fibre impairment was related to encephalopathy severity. Ocular damage was associated with inflammation and cerebral oedema following hypoxic–ischaemic damage.
Neuronal tangential migration from Nkx2.1-positive hypothalamus
Authors: Murcia-Ramón Raquel , Company Verónica , Juárez-Leal Iris , Andreu-Cervera Abraham , Almagro-García Francisca , Martínez Salvador , Echevarría Diego , Puelles Eduardo 
Published: November 2020

AbstractDuring the development of the central nervous system, the immature neurons suffer different migration processes. It is well known thatNkx2.1-positive ventricular layer give rise to critical tangential migrations into different regions of the developing forebrain. Our aim was to study this phenomenon in the hypothalamic region. With this purpose, we used a transgenic mouse line that expresses thetdTomatoreporter driven by the promotor ofNkx2.1. Analysing theNkx2.1-positive derivatives at E18.5, we found neural contributions to the prethalamic region, mainly in the zona incerta and in the mes-diencephalic tegmental region. We studied the developing hypothalamus along the embryonic period. From E10.5 we detected that theNkx2.1expression domain was narrower than the reporter distribution. Therefore, theNkx2.1expression fades in a great number of the early-born neurons from theNkx2.1-positive territory. At the most caudal positive part, we detected a thin stream of positive neurons migrating caudally into the mes-diencephalic tegmental region using time-lapse experiments on open neural tube explants. Late in development, we found a second migratory stream into the prethalamic territory. All these tangentially migrated neurons developed a gabaergic phenotype. In summary, we have described the contribution of interneurons from theNkx2.1-positive hypothalamic territory into two different rostrocaudal territories: the mes-diencephalic reticular formation through a caudal tangential migration and the prethalamic zona incerta complex through a dorsocaudal tangential migration.
Reference values for N-terminal Pro-brain natriuretic peptide in premature infants during their first weeks of life
Authors: Fritz Agnes-Sophie , Keller Titus , Kribs Angela , Hünseler Christoph 
Published: November 2020

AbstractThe aim of our study was to observe the temporal distribution of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in premature infants of ≤ 31 weeks of gestational age (GA) during the first weeks of life. NT-proBNP values of 118 preterm infants born ≤ 31 weeks GA were determined during the first week of life, after 4 ± 1 weeks of life, and at a corrected GA of 36 ± 2 weeks. Infants were divided into two groups: those without relevant complications and those with complications related to prematurity. NT-proBNP values of infants without complications define our exploratory reference values. The Median NT-proBNP level of these infants was 1896 ng/l (n = 27, interquartile range (IQR): 1277–5200) during the first week of life, 463 ng/l (n = 26, IQR: 364–704) at 4 ± 1 weeks of life, and 824 ng/l (n = 33, IQR: 714–1233) at a corrected GA of 36 ± 2 weeks. Infants born < 28 + 0 weeks GA had significantly higher NT-proBNP values (n = 9, median: 5200, IQR: 1750–8972) than infants born ≥ 28 + 0–31 weeks GA (n = 18, median: 1528, IQR: 838–3052; p = 0.017). Growth restriction or PDA status could not account for the difference in NT-proBNP values between GA groups.Conclusions: The results of our observational and cross-sectional study describe exploratory reference values for NT-proBNP levels in preterm infants of ≤ 31 weeks GA according to postnatal age. NT-proBNP levels during the first week of life are high and widely distributed in preterm infants and decrease subsequently to reach a distinctly lower and stable plateau at around 1 month of life. Our results suggest an influence of GA on NT-proBNP values in the first week of life.

What is Known:• Several complications related to prematurity, e.g., hemodynamically significant PDA, pulmonary hypertension, bronchopulmonary dysplasia, and retinopathy of prematurity, have been associated with a temporary rise in NT-proBNP values in preterm infants during their first weeks of life.What is New:• This observational study provides reference values for NT-proBNP levels of very and extremely preterm infants during their first weeks of life.• In premature infants without complications, NT-proBNP values during their first week of life depend on gestational age at birth.
On incorporating warping effects due to transverse shear and torsion into the theories of straight elastic bars
Authors: Lewiński T. , Czarnecki S. 
Published: November 2020

AbstractBy endowing El Fatmi’s theories of bars with first-order warping functions due to torsion and shear, a family of theories of bars, of various applicability ranges, is effectively constructed. The theories thus formed concern bars of arbitrary cross-sections; they are reformulations of the mentioned theories by El Fatmi and theories by Kim and Kim, Librescu and Song, Vlasov and Timoshenko. The Vlasov-like theory thus developed is capable of describing the torsional buckling and lateral buckling phenomena of bars of both solid and thin-walled cross-sections, which reflects the non-trivial correspondence, noted by Wagner and Gruttmann, between the torsional St.Venant’s warping function and the contour-wise defined warping functions proposed by Vlasov. Moreover, the present paper delivers an explicit construction of the constitutive equations of Timoshenko’s theory; the equations linking transverse forces with the measures of transverse shear turn out to be coupled for all bars of asymmetric cross-sections. The modeling is hierarchical: the warping functions are numerically constructed by solving the three underlying 2D scalar elliptic problems, providing the effective characteristics for the 1D models of bars. The 2D and 1D problems are indissolubly bonded, thus forming a unified scientific tool, deeply rooted in the hitherto existing knowledge on elasticity of elastic straight bars.
Nonnegative forms with sublevel sets of minimal volume
Authors: Kozhasov Khazhgali , Lasserre Jean Bernard 
Published: November 2020

AbstractWe show that the Euclidean ball has the smallest volume among sublevel sets of nonnegative forms of bounded Bombieri norm as well as among sublevel sets of sum of squares forms whose Gram matrix has bounded Frobenius or nuclear (or, more generally, p-Schatten) norm. These volume-minimizing properties of the Euclidean ball with respect to its representation (as a sublevel set of a form of fixed even degree) complement its numerous intrinsic geometric properties. We also provide a probabilistic interpretation of the results.
Back to WHAT? The role of research ethics in pandemic times
Authors: Solbakk Jan Helge , Bentzen Heidi Beate , Holm Søren , Heggestad Anne Kari Tolo , Hofmann Bjørn , Robertsen Annette , Alnæs Anne Hambro , Cox Shereen , Pedersen Reidar , Bernabe Rose 
Published: November 2020

AbstractThe Covid-19 pandemic creates an unprecedented threatening situation worldwide with an urgent need for critical reflection and new knowledge production, but also a need for imminent action despite prevailing knowledge gaps and multilevel uncertainty. With regard to the role of research ethics in these pandemic times some argue in favor of exceptionalism, others, including the authors of this paper, emphasize the urgent need to remain committed to core ethical principles and fundamental human rights obligations all reflected in research regulations and guidelines carefully crafted over time. In this paper we disentangle some of the arguments put forward in the ongoing debate about Covid-19 human challenge studies (CHIs) and the concomitant role of health-related research ethics in pandemic times. We suggest it might be helpful to think through a lens differentiating between risk, strict uncertainty and ignorance. We provide some examples of lessons learned by harm done in the name of research in the past and discuss the relevance of this legacy in the current situation.
The two-stage interaction of Ebola virus VP40 with nucleoprotein results in a switch from viral RNA synthesis to virion assembly/budding
Authors: Wu Linjuan , Jin Dongning , Wang Dan , Jing Xuping , Gong Peng , Qin Yali , Chen Mingzhou 
Published: November 2020

AbstractEbola virus (EBOV) is an enveloped negative-sense RNA virus and a member of the filovirus family. Nucleoprotein (NP) expression alone leads to the formation of inclusion bodies (IBs), which are critical for viral RNA synthesis. The matrix protein, VP40, not only plays a critical role in virus assembly/budding, but also can regulate transcription and replication of the viral genome. However, the molecular mechanism by which VP40 regulates viral RNA synthesis and virion assembly/budding is unknown. Here, we show that within IBs the N-terminus of NP recruits VP40 and is required for VLP-containing NP release. Furthermore, we find four point mutations (L692A, P697A, P698A and W699A) within the C-terminal hydrophobic core of NP result in a stronger VP40–NP interaction within IBs, sequestering VP40 within IBs, reducing VP40–VLP egress, abolishing the incorporation of NC-like structures into VP40–VLP, and inhibiting viral RNA synthesis, suggesting that the interaction of N-terminus of NP with VP40 induces a conformational change in the C-terminus of NP. Consequently, the C-terminal hydrophobic core of NP is exposed and binds VP40, thereby inhibiting RNA synthesis and initiating virion assembly/budding.
Renal epithelial and stromal tumor with a multiple cystic lesion localized in the upper portion of the right kidney
Authors: Sawamura Masato , Sawa Naoki , Yamanouchi Masayuki , Ikuma Daisuke , Sekine Akinari , Mizuno Hiroki , Suwabe Tatsuya , Hoshino Junichi , Kono Kei , Kinowaki Keiichi , Ohashi Kenichi , Nagashima Yoji , Ubara Yoshifumi 
Published: November 2020

AbstractA 60-year-old Japanese woman was admitted because of the polycystic mass with right flank pain localized in the upper portion of the right kidney. Right nephrectomy was performed because the mass lesion had continuously increased in size over the past 10 years. A surgical specimen showed histology consistent with a mixed epithelial and stromal tumor, which is closely related to multilocular cystic nephroma, and was diagnosed by a defined capsule between the cystic mass lesion and normal renal tissue by CT and MRI, and histology. Localized renal cystic disease that does not have a capsule was excluded from differential diagnosis.
Ist mehr besser? Politische Implikationen der disparaten Daseinsvorsorge in Deutschland
Authors: Diermeier Matthias 
Published: November 2020

ZusammenfassungDie Covid-19-Krise verschärft die bereits lebhaft geführte Diskussion um regionale Disparitäten in der Daseinsvorsorge. Insbesondere im dünnbesiedelten, ländlichen Raum hatten viele Kommunen schon vor der aktuellen Ausnahmesituation Schwierigkeiten, attraktive medizinische Versorgung, Bildungsinfrastruktur, öffentlichen Personennahverkehr oder Breitbandinternet bereitzustellen. Während einerseits die weitere Stärkung urbaner Zentren zur Diskussion steht, wird den Menschen im ländlichen Raum andererseits ein Gefühl des Verlassenwerdens attestiert, das auf einen kulturellen Stadt-Land-Konflikt hinzudeuten scheint. Der vorliegende Beitrag bietet den Auftakt für die kleinräumige empirisch fundierte Debatte um Daseinsvorsorge und die Entfremdung von etablierten Parteien in Deutschland. Die Analyse beruht auf einem zu diesem Zweck aufgebauten Datensatz, der neben einem Index der Daseinsvorsorge auch eine Auswertung der Distanz zum nächstgelegenen Bahnhof und der Erreichbarkeit des nächstgelegenen Krankenhauses auf Gemeindeebene für die Bundestagswahl 2017 sowie die Europawahl 2019 erlaubt. Wie aus anderen westlichen Demokratien zu erwarten, geht auch in Deutschland ein besseres AfD-Ergebnis mit einer schwächeren Daseinsvorsorge einher. Ein Teil dieses Effektes ist jedoch schlicht auf die Divergenz zwischen ländlichem Raum und urbaner Agglomeration zurückzuführen und zeigt sich entgegen der Erwartungen weniger deutlich oder gar nicht zwischen kleineren ländlichen Gemeinden. Zudem steigt die Zustimmung zum Rechtspopulismus weder mit zunehmender Distanz zum nächstgelegenen Bahnhof noch mit einer höheren Kommunalverschuldung. Trotzdem deutet auch in den kleineren Gemeinden einiges auf Erfolge der AfD in Räumen politischer Entfremdung und wirtschaftlicher Schwierigkeiten hin. Robust schneidet die rechtspopulistische Partei umso besser ab desto geringer die vorherrschende Wahlbeteiligung desto stärker die Gemeinde von Abwanderung betroffen sowie desto angespannter der Arbeitsmarkt ist. Eine innovative Wirtschaft vor Ort hat hingegen das Potenzial, die Zustimmung zu den Rechtspopulisten abzumildern.
Dynamical incoherence for a large class of partially hyperbolic diffeomorphisms
Authors: BARTHELMÉ THOMAS , FENLEY SERGIO R. , FRANKEL STEVEN , POTRIE RAFAEL 
Published: November 2020

AbstractWe show that if a partially hyperbolic diffeomorphism of a Seifert manifold induces a map in the base which has a pseudo-Anosov component then it cannot be dynamically coherent. This extends [C. Bonatti, A. Gogolev, A. Hammerlindl and R. Potrie. Anomalous partially hyperbolic diffeomorphisms III: Abundance and incoherence.Geom. Topol., to appear] to the whole isotopy class. We relate the techniques to the study of certain partially hyperbolic diffeomorphisms in hyperbolic 3-manifolds performed in [T. Barthelmé, S. Fenley, S. Frankel and R. Potrie. Partially hyperbolic diffeomorphisms homotopic to the identity in dimension 3, part I: The dynamically coherent case.Preprint, 2019, arXiv:1908.06227; Partially hyperbolic diffeomorphisms homotopic to the identity in dimension 3, part II: Branching foliations.Preprint, 2020, arXiv: 2008.04871]. The appendix reviews some consequences of the Nielsen–Thurston classification of surface homeomorphisms for the dynamics of lifts of such maps to the universal cover.
Periodic point free homeomorphisms and irrational rotation factors
Authors: KOCSARD ALEJANDRO 
Published: November 2020

AbstractWe provide a complete characterization of periodic point free homeomorphisms of the

$2$
-torus admitting irrational circle rotations as topological factors. Given a homeomorphism of the

$2$
-torus without periodic points and exhibiting uniformly bounded rotational deviations with respect to a rational direction, we show that annularity and the geometry of its non-wandering set are the only possible obstructions for the existence of an irrational circle rotation as topological factor. Through a very precise study of the dynamics of the induced

$\rho $
-centralized skew-product, we extend and generalize considerably previous results of Jäger.