bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broad spectrum of regorafenib activity on mutant KIT and absence of clonal selection in gastrointestinal stromal tumor (GIST): correlative analysis from the GRID trial
Authors: Jeffers Michael , Kappeler Christian , Kuss Iris , Beckmann Georg , Mehnert Daniel H. , Fredebohm Johannes , Teufel Michael 
Published: January 2022

Abstract
Background
In the phase 3 GRID trial, regorafenib improved progression-free survival (PFS) independent of KIT mutations in exons 9 and 11. In this retrospective, exploratory analysis of the GRID trial, we investigated whether a more comprehensive KIT mutation analysis could identify mutations that impact treatment outcome with regorafenib and a regorafenib-induced mutation pattern.

Methods
Archived tumor samples, collected at any time prior to enrollment in GRID, were analyzed by Sanger sequencing (n = 102) and next-generation sequencing (FoundationONE; n = 47). Plasma samples collected at baseline were analyzed by BEAMing (n = 163) and SafeSEQ (n = 96).

Results
In archived tumor samples, 67% (68/102) had a KIT mutation; 61% (62/102) had primary KIT mutations (exons 9 and 11) and 12% (12/102) had secondary mutations (exons 13, 14, 17, and 18). At baseline, 81% of samples (78/96) had KIT mutations by SafeSEQ, including the M541L polymorphism (sole event in 6 patients). Coexisting mutations in other oncogenes were rare, as were mutations in PDGFR, KRAS, and BRAF. Regorafenib showed PFS benefit across all primary and secondary KIT mutational subgroups examined. Available patient-matched samples taken at baseline and end of treatment (n = 41; SafeSEQ), revealed heterogeneous KIT mutational changes with no specific mutation pattern emerging upon regorafenib treatment.

Conclusion
These data support the results of the GRID trial, and suggest that patients may benefit from regorafenib in the presence of KIT mutations and without the selection of particular mutation patterns that confer resistance. The study was not powered to address biomarker-related questions, and the results are exploratory and hypothesis-generating.
Lawson schemes for highly oscillatory stochastic differential equations and conservation of invariants
Authors: Debrabant Kristian , Kværnø Anne , Mattsson Nicky Cordua 
Published: January 2022

AbstractIn this paper, we consider a class of stochastic midpoint and trapezoidal Lawson schemes for the numerical discretization of highly oscillatory stochastic differential equations. These Lawson schemes incorporate both the linear drift and diffusion terms in the exponential operator. We prove that the midpoint Lawson schemes preserve quadratic invariants and discuss this property as well for the trapezoidal Lawson scheme. Numerical experiments demonstrate that the integration error for highly oscillatory problems is smaller than that of some standard methods.
Direct Inference and Probabilistic Accounts of Induction
Authors: Williamson Jon 
Published: January 2022

AbstractSchurz (2019, ch. 4) argues that probabilistic accounts of induction fail. In particular, he criticises probabilistic accounts of induction that appeal to direct inference principles, including subjective Bayesian approaches (e.g., Howson 2000) and objective Bayesian approaches (see, e.g., Williamson 2017). In this paper, I argue that Schurz’ preferred direct inference principle, namely Reichenbach’s Principle of the Narrowest Reference Class, faces formidable problems in a standard probabilistic setting. Furthermore, the main alternative direct inference principle, Lewis’ Principal Principle, is also hard to reconcile with standard probabilism. So, I argue, standard probabilistic approaches cannot appeal to direct inference to explicate the logic of induction. However, I go on to defend a non-standard objective Bayesian account of induction: I argue that this approach can both accommodate direct inference and provide a viable account of the logic of induction. I then defend this account against Schurz’ criticisms.
Hidden champions: a review of the literature & future research avenues
Authors: Schenkenhofer Julian 
Published: January 2022

AbstractSubstantial efforts have contributed to overcome the scarcity of research on hidden champions. Nevertheless, literature has yet missed to compile a comprehensive review. Drawing on the insights of 112 publications, four strands of literature could be distinguished to unravel the essence of hidden champions. Research on hidden champions studies their (1) internationalization strategies, (2) R&D and innovation strategies, the (3) worldwide and regional geographic distribution of hidden champions and finally (4) other research that could not be assigned to one of the first three strands. A hand-collected sample of 1372 German hidden champions exemplifies the key insights from the reviewed research articles. Discussing the findings of the different literature strands aims at drawing a conclusion on their main results and analytical pitfalls to eventually unfold and motivate future research avenues.
The underconfidence-with-practice effect in action memory: The contribution of retrieval practice to metacognitive monitoring
Authors: Kubik Veit , Jemstedt Andreas , Eshratabadi Hassan Mahjub , Schwartz Bennett L. , Jönsson Fredrik U. 
Published: January 2022

AbstractWhen making memory predictions (judgments of learning; JOLs), people typically underestimate the recall gain across multiple study–test cycles, termed the underconfidence-with-practice (UWP) effect. This is usually studied with verbal materials, but little is known about how people repeatedly learn and monitor their own actions and to what extent retrieval practice via interim tests influence the progression of JOLs across cycles. Using action phrases (i.e.,squeeze the lemon) as learning material, we demonstrated the UWP effect after both verbal and enactive encoding, although we did not get first-cycle overconfidence. As predicted, participants exhibited underconfidence in Cycles 2 and 3, as an error of calibrations. However, people’s resolution of JOLs (i.e., ability to discriminate recalled from unrecalled items) increased across study–test cycles. Importantly, JOLs for study–test (relative to study–study) items increased faster across cycles suggesting that repeated study–test practice not only produces underconfidence across cycles, but also reduces underconfidence relative to study–study practice. We discuss these findings in terms of current explanations of the underconfidence-with-practice effect.
Prävention von demenzbedingten Versorgungskrisen im hausarztbasierten Setting – das Projekt DemStepCare als innovative Versorgungsform
Authors: Wangler Julian , Geschke Katharina , Wuttke-Linnemann Alexandra , Fellgiebel Andreas , Jansky Michael 
Published: January 2022

ZusammenfassungHintergrundIn Deutschland mangelt es im Bereich der Demenzversorgung an multiprofessionellen, sektorenübergreifenden Strukturen, die Hausärzt*innen unterstützen und es ermöglichen, auf individuelle Bedürfnisse von Patient*innen und Angehörigen einzugehen. Infolgedessen ereignen sich häufig Versorgungskrisen, die zu Krankenhaus- und Pflegeheimeinweisungen führen.Ziel der ArbeitDer Beitrag thematisiert das Innovationsfonds-geförderte Modellprojekt zur ambulanten medizinisch-pflegerischen DemenzversorgungDemStepCare. Hierzu werden Hintergründe, Zielsetzungen und Status quo des Projekts vorgestellt sowie Herausforderungen bei der Rekrutierung angesprochen.Material und MethodenIm Mittelpunkt vonDemStepCaresteht die gezielte Unterstützung der hausärztlichen Versorgung mittels eines bedarfsadaptiert tätigen, ambulanten Case Managements sowie einer von Pflegeexpert*innen geführten Krisenambulanz. Darüber hinaus soll das Modellprojekt zu einer stärkeren Demenzkompetenz der einbezogenen Hausärzt*innen beitragen.ErgebnisseTrotz erlebter Rekrutierungsproblematiken zeigt sich bereits eine gute Realisierbarkeit des Modells im ambulanten Setting. Befragungen von Case Manager*innen, Mitarbeiter*innen der Krisenambulanz und Hausärzt*innen belegen eine wahrgenommene Wirksamkeit, wenn es um die Prävention von Versorgungskrisen geht. Hausärzt*innen bestätigen eine höhere Sicherheit im Umgang mit Demenzerkrankungen.DiskussionDemStepCarebietet das Potenzial, eine Versorgungslücke zu schließen, indem Hausärzt*innen effektive ambulante Unterstützungsinstrumente zur konsequenten Demenzversorgung und Risikoprävention an die Hand gegeben werden. Weitere Anstrengungen zur Stärkung einer hausarztbasierten, sektorenübergreifenden Demenzversorgung sollten angestrebt werden.
Double-Win Properties Response of Mechanical and Hydrogen Absorption in Melt-Spun Ti-Zr-Ni-Cr Amorphous Metals
Authors: Huang Shuiming , Song Huihui , Hu Yuhu , Xu Kai , Zhou Chao , Hou Xueling 
Published: January 2022

AbstractThe effect of spinning rates on mechanical properties and hydrogen absorption/desorption properties of Ti47Zr31Ni14Cr8 amorphous ribbons have been investigated in the present work. A fully amorphous structure was confirmed by x-ray diffraction (XRD) and transmission electron microscopy (TEM) analysis of the ribbons obtained from spinning rates of 30 m s−1 to 45 m s−1. The uniformity of amorphous ribbons and their mechanical properties were improved with the increase in the spinning rate. Scanning electron microscopy (SEM) revealed that the fracture surface of amorphous ribbons had a cleavage feature and vein-like pattern when the spinning rates were 30 m s−1 and 45 m s−1, respectively. Because of the influence of flow units on the kinetic process of hydrogen absorption, the hydrogenation kinetics and hydrogen desorption capacity of amorphous ribbons were enhanced with the increased spinning rates. After the amorphous ribbons absorbed a large amount of hydrogen, ZrH2, TiH2, and (ZrTi)2Ni7 crystalline phases were formed from the amorphous matrix. Hydrogen promotes amorphous phase decomposition and the crystallinity of the new phases led to deterioration of the mechanical properties.
Value creation and value capture for AI business model innovation: a three-phase process framework
Authors: Åström Josef , Reim Wiebke , Parida Vinit 
Published: January 2022

AbstractThe rise of AI technologies is generating novel opportunities for companies to create additional value for their customers by applying a proactive approach, managing uncertainty, and thus improving cost efficiency and increasing revenue. However, AI technology capabilities are not enough—companies need to understand how the technology can be commercialized through appropriate AI business model innovation. When emerging technologies are introduced, business-model concepts often need to be significantly altered. This is necessary to fully capitalize on disruptive technologies because it is just as important to innovate the business model as it is to build advanced technology solutions. Therefore, the purpose of this study is to explain how AI providers align value-creation and value-capture dimensions in order to develop commercially viable AI business models. To fulfill our stated purpose, this study has adopted an inductive and exploratory single case-study approach centered on a market-leading provider of AI-related services. The findings are consolidated into a process framework that explicitly illustrates the key activities that companies need to perform concerning value creation and value capture for AI business model innovation and commercialization. The framework explains that AI providers need to follow three phases—namely, identifying prerequisites for AI value creation, matching value capture mechanisms, and developing AI business model offer. We also find that AI providers need to test and develop multiple AI business models and operate them simultaneously to ensure commercial success.
Neonatal Seizures—Perspective in Low-and Middle-Income Countries
Authors: Vegda Hemadri , Krishnan Vaisakh , Variane Gabriel , Bagayi Vaishnavi , Ivain Phoebe , Pressler Ronit M. 
Published: January 2022

AbstractNeonatal seizures are the commonest neurological emergency and are associated with poor neurodevelopmental outcome. While they are generally difficult to diagnose and treat, they pose a significant clinical challenge for physicians in low- and middle-income countries (LMIC). They are mostly provoked seizures caused by an acute brain insult such as hypoxic–ischemic encephalopathy (HIE), ischemic stroke, intracranial hemorrhage, infections of the central nervous system, or acute metabolic disturbances. Early onset epilepsy syndromes are less common. Clinical diagnosis of seizures in the neonatal period are frequently inaccurate, as clinical manifestations are difficult to distinguish from nonseizure behavior. Additionally, a high proportion of seizures are electrographic-only without any clinical manifestations, making diagnosis with EEG or aEEG a necessity. Only focal clonic and focal tonic seizures can be diagnosed clinically with adequate diagnostic certainty. Prompt diagnosis and timely treatment are important, with evidence suggesting that early treatment improves the response to antiseizure medication. The vast majority of published studies are from high-income countries, making extrapolation to LMIC impossible, thus highlighting the urgent need for a better understanding of the etiologies, comorbidities, and drug trials evaluating safety and efficacy in LMIC. In this review paper, the authors present the latest data on etiology, diagnosis, classification, and guidelines for the management of neonates with the emphasis on low-resource settings.
The Equivalence Problem in Analytic Dynamics for 1-Resonance
Authors: Rousseau Christiane 
Published: January 2022

AbstractWhen are two germs of analytic systems conjugate or orbitally equivalent under an analytic change of coordinates in a neighborhood of a singular point? The present paper, of a survey nature, presents a research program around this question. A way to answer is to use normal forms. However, there are large classes of dynamical systems for which the change of coordinates to a normal form diverges. In this paper, we discuss the case of singularities for which the normalizing transformation is k-summable, thus allowing to provide moduli spaces. We explain the common geometric features of these singularities, and show that the study of their unfoldings allows understanding both the singularities themselves, and the geometric obstructions to convergence of the normalizing transformations. We also present some moduli spaces for generic k-parameter families unfolding such singularities.
The Moral Superiority of Bioengineered Wombs and Ectogenesis for Absolute Uterine Factor Infertility
Authors: Kendal Evie , Koplin Julian J. 
Published: January 2022

AbstractThis paper argues that uterine transplants are a potentially dangerous distraction from the development of alternative methods of providing reproductive options for women with absolute uterine factor infertility (AUFI). We consider two alternatives in particular: the bioengineering of wombs using stem cells (which would carry fewer risks than uterine transplants) and ectogenesis (which would not require surgical intervention for either the prospective mother with AUFI or a womb donor). Whether biologically or mechanically engineered, these womb replacements could provide a way for women to have children, including genetically related offspring for those who would value this possibility. Most importantly, this alternative would avoid the challenge of sourcing wombs for transplant, a practice that we argue would likely be exploitative and unethical. Continued research into bioengineering and ectogenesis will therefore remain morally important despite the recent development of uterine transplantation, even if the procedure reaches routine clinical application.
Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2
Authors: El-Shennawy Lamiaa , Hoffmann Andrew D. , Dashzeveg Nurmaa Khund , McAndrews Kathleen M. , Mehl Paul J. , Cornish Daphne , Yu Zihao , Tokars Valerie L. , Nicolaescu Vlad , Tomatsidou Anastasia , Mao Chengsheng , Felicelli Christopher J. , Tsai Chia-Feng , Ostiguin Carolina , Jia Yuzhi , Li Lin , Furlong Kevin , Wysocki Jan , Luo Xin , Ruivo Carolina F. , Batlle Daniel , Hope Thomas J. , Shen Yang , Chae Young Kwang , Zhang Hui , LeBleu Valerie S. , Shi Tujin , Swaminathan Suchitra , Luo Yuan , Missiakas Dominique , Randall Glenn C. , Demonbreun Alexis R. , Ison Michael G. , Kalluri Raghu , Fang Deyu , Liu Huiping 
Published: January 2022

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of the coronavirus induced disease 2019 (COVID-19) with evolving variants of concern. It remains urgent to identify novel approaches against broad strains of SARS-CoV-2, which infect host cells via the entry receptor angiotensin-converting enzyme 2 (ACE2). Herein, we report an increase in circulating extracellular vesicles (EVs) that express ACE2 (evACE2) in plasma of COVID-19 patients, which levels are associated with severe pathogenesis. Importantly, evACE2 isolated from human plasma or cells neutralizes SARS-CoV-2 infection by competing with cellular ACE2. Compared to vesicle-free recombinant human ACE2 (rhACE2), evACE2 shows a 135-fold higher potency in blocking the binding of the viral spike protein RBD, and a 60- to 80-fold higher efficacy in preventing infections by both pseudotyped and authentic SARS-CoV-2. Consistently, evACE2 protects the hACE2 transgenic mice from SARS-CoV-2-induced lung injury and mortality. Furthermore, evACE2 inhibits the infection of SARS-CoV-2 variants (α, β, and δ) with equal or higher potency than for the wildtype strain, supporting a broad-spectrum antiviral mechanism of evACE2 for therapeutic development to block the infection of existing and future coronaviruses that use the ACE2 receptor.
Resolving the conflict between antibiotic production and rapid growth by recognition of peptidoglycan of susceptible competitors
Authors: Maan Harsh , Itkin Maxim , Malitsky Sergey , Friedman Jonathan , Kolodkin-Gal Ilana 
Published: January 2022

AbstractMicrobial communities employ a variety of complex strategies to compete successfully against competitors sharing their niche, with antibiotic production being a common strategy of aggression. Here, by systematic evaluation of four non-ribosomal peptides/polyketide (NRPs/PKS) antibiotics produced by Bacillus subtilis clade, we revealed that they acted synergistically to effectively eliminate phylogenetically distinct competitors. The production of these antibiotics came with a fitness cost manifested in growth inhibition, rendering their synthesis uneconomical when growing in proximity to a phylogenetically close species, carrying resistance against the same antibiotics. To resolve this conflict and ease the fitness cost, antibiotic production was only induced by the presence of a peptidoglycan cue from a sensitive competitor, a response mediated by the global regulator of cellular competence, ComA. These results experimentally demonstrate a general ecological concept – closely related communities are favoured during competition, due to compatibility in attack and defence mechanisms.
A bioactivated in vivo assembly nanotechnology fabricated NIR probe for small pancreatic tumor intraoperative imaging
Authors: Ren Han , Zeng Xiang-Zhong , Zhao Xiao-Xiao , Hou Da-yong , Yao Haodong , Yaseen Muhammad , Zhao Lina , Xu Wan-hai , Wang Hao , Li Li-Li 
Published: January 2022

AbstractReal-time imaging of the tumour boundary is important during surgery to ensure that sufficient tumour tissue has been removed. However, the current fluorescence probes for bioimaging suffer from poor tumour specificity and narrow application of the imaging window used. Here, we report a bioactivated in vivo assembly (BIVA) nanotechnology, demonstrating a general optical probe with enhanced tumour accumulation and prolonged imaging window. The BIVA probe exhibits active targeting and assembly induced retention effect, which improves selectivity to tumours. The surface specific nanofiber assembly on the tumour surface increases the accumulation of probe at the boundary of the tumor. The blood circulation time of the BIVA probe is prolonged by 110 min compared to idocyanine green. The assembly induced metabolic stability broaden the difference between the tumor and background, obtaining a delayed imaging window between 8–96 h with better signal-to-background contrast (>9 folds). The fabricated BIVA probe permits precise imaging of small sized (<2 mm) orthotopic pancreatic tumors in vivo. The high specificity and sensitivity of the BIVA probe may further benefit the intraoperative imaging in a clinical setting.
Cu-catalyzed asymmetric addition of alcohols to β,γ-alkynyl-α-imino esters for the construction of linear chiral N,O-ketals
Authors: Sheng Cheng , Ling Zheng , Luo Yicong , Zhang Wanbin 
Published: January 2022

AbstractN,O-acetals are part of many synthetic intermediates and important skeletons of numerous natural products and pharmaceutical drugs. The most straightforward method of the synthesis of N,O-acetals is the enantioselective addition of O-nucleophiles to imines. However, using this method for the synthesis of linear chiral N,O-ketals still remains challenging due to the instability of raw materials under acidic or basic conditions. Herein, we developed a Cu-catalyzed asymmetric addition of alcohols to β,γ-alkynyl-α-imino esters under mild conditions, providing the corresponding linear chiral N,O-ketals with up to 96% ee. The method tolerates some variation in the β,γ-alkynyl-α-imino ester and alcohol scope, including some glucose and natural amino acid derivatives. Computational results indicate that the Boc group of the substrates assist in the extraction of hydrogen atoms from the alcohols to promote the addition reactions. These products could be synthesized on a gram-scale and can be used in several transformations. This asymmetric addition system provides an efficient, mild, gram-scale, and transition-metal-catalyzed synthesis of linear chiral N,O-ketals.
Theory of the Kitaev model in a [111] magnetic field
Authors: Zhang Shang-Shun , Halász Gábor B. , Batista Cristian D. 
Published: January 2022

AbstractRecent numerical studies indicate that the antiferromagnetic Kitaev honeycomb lattice model undergoes a magnetic-field-induced quantum phase transition into a new spin-liquid phase. This intermediate-field phase has been previously characterized as a gapless spin liquid. By implementing a recently developed variational approach based on the exact fractionalized excitations of the zero-field model, we demonstrate that the field-induced spin liquid is gapped and belongs to Kitaev’s 16-fold way. Specifically, the low-field non-Abelian liquid with Chern number C = ±1 transitions into an Abelian liquid with C = ±4. The critical field and the field-dependent behaviors of key physical quantities are in good quantitative agreement with published numerical results. Furthermore, we derive an effective field theory for the field-induced critical point which readily explains the ostensibly gapless nature of the intermediate-field spin liquid.