bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the horizon—the value and promise of the global pipeline of Alzheimer's disease therapeutics
Authors: Cole Michael A. , Seabrook Guy R. 
Published: May 2020

AbstractIntroductionThe recent failure of several late‐stage Alzheimer's disease (AD) clinical trials focused on amyloid beta (Aβ) highlights the challenges of finding effective disease‐modifying therapeutics. Despite major advances in our understanding of the genetic risk factors of disease and the development of clinical biomarkers, and that not all Aβ‐based approaches are equivalent, these failures may engender skepticism regarding the value of the AD pipeline.MethodsTo investigate these concerns, we compiled a database of current Phase 2 and 3 trials based on disease‐modifying targets through a query of the National Institutes of Health's ClinicalTrials.gov. We then assessed the financial value of the pipeline. Financial modeling utilized risk‐adjusted net present value (rNPV) measurements and included sensitivity analyses to help inform the drug development process.ResultsResults indicate that the preponderance of current Phase 3 trials were indeed targeting Aβ, with only 15% addressing other targets. In contrast, the pipeline of Phase 2 trials was more diverse. The estimated rNPV of Phase 2 and 3 therapeutics was estimated to be $338 billion over 10 years. This figure increased to a theoretical cumulative value of $788 billion when incorporating the assumption that diagnostics will be developed to identify individuals at high risk for developing AD. Results from model sensitivity analyses showed that speed of market penetration and patient access contributed the most weight to financial value. In contrast, decreasing drug development costs had minimal impact on rNPV.DiscussionThese findings argue in favor of conducting thorough biomarker‐driven Phase 2 proof of concept studies to avoid prematurely advancing assets into Phase 3. Insights from these analyses are also discussed in the context of the financial ecosystem needed to maintain a healthy AD pipeline.
A review of applications of fractional advection–dispersion equations for anomalous solute transport in surface and subsurface water
Authors: Sun Liwei , Qiu Han , Wu Chuanhao , Niu Jie , Hu Bill X. 
Published: May 2020

AbstractFractional advection–dispersion equations (FADEs) have been widely used in hydrological research to simulate the anomalous solute transport in surface and subsurface water. However, a large gap still exists between real‐world application (i.e., being a prediction tool) and theoretical FADEs. To better understand this disparity, the FADEs are firstly reviewed from the perspective of fractional‐in‐time and fractional‐in‐space, as well as the anomalous characteristics described by those functions. Then, challenges for the application of FADEs are summarized, including the theoretical gap of FADEs that needs multidisciplinary efforts to fill, extensive requirements for computation techniques and mathematical knowledge to apply the FADEs, the poor predictability for most parameters in the FADEs, and the limitations for collecting geologic information of flow fields. Then, some suggestions are given for future work, such as developing excellent code sets and mature simulation software with a friendly interface. This kind of work would alleviate the computation workload of hydrologists, especially those without coding expertise. Summarizing and determining the value ranges of the important parameters are needed (e.g., the order of the fractional derivative), through the extensive field, laboratory, and numerical experiments rather than blindly using their mathematical ranges. It is also needed to perform global sensitivity analysis for the FADEs. Meanwhile, comprehensive comparison work is necessary for suggesting a model suitable for a specific problem. Last but not least, further research is clearly needed to establish a link between nonlocal parameters and the heterogeneity property to develop more efficient fractional order partial differential equations.This article is categorized under:
Science of Water > Methods
Science of Water > Water Quality
Die „historische Studie“ SOLIDARITY als Antwort der Forschung auf die Sars-CoV-2 Pandemie
Authors: Gadebusch Bondio Mariacarla , Marloth Maria 
Published: May 2020

ZusammenfassungDieser Beitrag ist Teil des Forums COVID-19: Perspektiven in den Geistes- und Sozialwissenschaften. Das neuartige Coronavirus (Sars-CoV-2) stellt die Weltgemeinschaft vor eine große Herausforderung. Das Wissen über das Virus und seine Eigenschaften ist lückenhaft, aber der Bedarf, politische und medizinische Entscheidungen an wissenschaftlicher Erkenntnis auszurichten ist groß. Diese Lage führt zu einer Dynamisierung der Forschung. Ein prominentes Beispiel ist die WHO-Studie SOLIDARITY. Die epistemologischen Besonderheiten und die daraus resultierenden ethischen Implikationen werden in diesem Beitrag näher beleuchtet.
Testing and unpacking the effects of digital fake news: on presidential candidate evaluations and voter support
Authors: Leyva Rodolfo , Beckett Charlie 
Published: May 2020

AbstractThere is growing worldwide concern that the rampant spread of digital fake news (DFN) via new media technologies is detrimentally impacting Democratic elections. However, the actual influence of this recent Internet phenomenon on electoral decisions has not been directly examined. Accordingly, this study tested the effects of attention to DFN on readers’ Presidential candidate preferences via an experimental web-survey administered to a cross-sectional American sample (N = 552). Results showed no main effect of exposure to DFN on participants’ candidate evaluations or vote choice. However, the perceived believability of DFN about the Democratic candidate negatively mediated evaluations of that candidate—especially amongst far-right ideologues. These results suggest that DFN may at worst reinforce the partisan dispositions of mostly politically conservative Internet users, but does not cause or induce conversions in these dispositions. Overall, this study contributes novel experimental evidence, indicating that the potential electoral impact of DFN, although concerning, is strongly conditional on a reciprocal interaction between message receptibility and a pre-existing right-wing ideological orientation. The said impact is, therefore, likely narrow in scope.
Beneficial switch from aflibercept to ranibizumab for the treatment of refractory neovascular age-related macular degeneration
Authors: Marquis Liza-Marie , Mantel Irmela 
Published: May 2020

Abstract
Purpose
The aim of this study was to evaluate the effects of switching to ranibizumab in patients with neovascular age-related macular degeneration (nAMD) refractory to aflibercept treatment and to identify predictive factors for switch response.

Methods
A retrospective chart review was conducted including 32 eyes from 26 patients with refractory nAMD, who switched from monthly intravitreal aflibercept treatment (≥ 6 months) to ranibizumab. Outcome measures included changes in visual acuity (VA), intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED), and central retinal thickness (CRT), evaluated at 6 months before switch (T1), at the time of switch (T2), and 3 months post-switch (T3).

Results
There was an increase in CRT from T1 to T2, which decreased after switch from T2 to T3. Regression analysis of the changes per month observed between time points showed significant differences in PED height (p = 0.02), SRF (p = 0.01), and neuroretinal thickness as a measure for IRF (p = 0.03). No significant change was found for VA. Predictive factors for better switch response included an exacerbation between T1 and T2, thicker measurements at T2, male sex, shorter treatment duration before switch, and fewer preceding injections. No association with preceding switch was found.

Conclusion
Patients with nAMD refractory to aflibercept benefit from switching to ranibizumab, particularly those whose condition worsened prior to the switch. This may be explained by drug tolerance to aflibercept. Our findings may facilitate making appropriate treatment decisions, potentially improving patient outcomes.
Stochastic quasi-gradient methods: variance reduction via Jacobian sketching
Authors: Gower Robert M. , Richtárik Peter , Bach Francis 
Published: May 2020

AbstractWe develop a new family of variance reduced stochastic gradient descent methods for minimizing the average of a very large number of smooth functions. Our method—JacSketch—is motivated by novel developments in randomized numerical linear algebra, and operates by maintaining a stochastic estimate of a Jacobian matrix composed of the gradients of individual functions. In each iteration, JacSketch efficiently updates the Jacobian matrix by first obtaining a random linear measurement of the true Jacobian through (cheap) sketching, and then projecting the previous estimate onto the solution space of a linear matrix equation whose solutions are consistent with the measurement. The Jacobian estimate is then used to compute a variance-reduced unbiased estimator of the gradient. Our strategy is analogous to the way quasi-Newton methods maintain an estimate of the Hessian, and hence our method can be seen as a stochastic quasi-gradient method. Our method can also be seen as stochastic gradient descent applied to a controlled stochastic optimization reformulation of the original problem, where the control comes from the Jacobian estimates. We prove that for smooth and strongly convex functions, JacSketch converges linearly with a meaningful rate dictated by a single convergence theorem which applies to general sketches. We also provide a refined convergence theorem which applies to a smaller class of sketches, featuring a novel proof technique based on a stochastic Lyapunov function. This enables us to obtain sharper complexity results for variants of JacSketch with importance sampling. By specializing our general approach to specific sketching strategies, JacSketch reduces to the celebrated stochastic average gradient (SAGA) method, and its several existing and many new minibatch, reduced memory, and importance sampling variants. Our rate for SAGA with importance sampling is the current best-known rate for this method, resolving a conjecture by Schmidt et al. (Proceedings of the eighteenth international conference on artificial intelligence and statistics, AISTATS 2015, San Diego, California, 2015). The rates we obtain for minibatch SAGA are also superior to existing rates and are sufficiently tight as to show a decrease in total complexity as the minibatch size increases. Moreover, we obtain the first minibatch SAGA method with importance sampling.
The OGS-Eclipse code for simulation of coupled multiphase flow and geomechanical processes in the subsurface
Authors: Benisch Katharina , Wang Wenqing , Delfs Jens-Olaf , Bauer Sebastian 
Published: May 2020

AbstractThis paper presents a numerical simulation tool for the analysis of coupled processes related to subsurface operations. The tool combines the open-source scientific code OpenGeoSys with the reservoir simulator Eclipse enabling the coupling of thermal, hydraulic, mechanical and geochemical processes. While the coupling of multiphase flow with heat and reactive geochemical component transport has been already implemented, OpenGeoSys-Eclipse is now extended for the coupling of multiphase flow and deformation. By this, OpenGeoSys-Eclipse is capable of addressing the impact of pore pressure changes on rock stability and deformation as well as the feedback effects of geomechanical processes on multiphase flow via pore volume coupling and porosity and permeability update. The coupling is verified by several test cases of gas storage scenarios and compared with reference simulations of OpenGeoSys. The results are in good agreement regarding the general effects of geomechanical feedback on pore pressure as well as porosity and permeability changes. Differences in the results are only observed for the pore volume coupling arising from the different implementation of rock compressibility models in the two simulators. The simulations are furthermore used to investigate the relevance of addressing geomechanical feedback in numerical scenario simulations for the assessment of subsurface operations. The results show clearly, that, depending on the given storage site conditions and rock types, the feedback of deformation on pore pressure can be significant and should therefore be accounted for in the assessment.
Judicial perspectives on the sentencing of minor drug offenders in Indonesia: discretionary practice and compassionate approaches
Authors: Mustafa Cecep , Malloch Margaret , Hamilton Smith Niall 
Published: May 2020

AbstractThis paper explores the perceptions of Indonesian Judges in sentencing minor drug offenders. The Judge holds a central role in the administration of justice and, because of the significance of judicial discretion, it is essential to understand how judges come to their sentencing decisions. To develop an understanding of what judges are trying to achieve when sentencing minor drug offenders, a total of 31 judges were interviewed: 28 participants came from District Courts in Urban and Rural jurisdictions in Indonesia (17 from Urban Courts and 11 from Rural Courts) and three were Supreme Court judges. The findings highlight that the process of justice involves not merely the application of the rule of the law or relevant legal codes; rather, how the judiciary balance and interpret the law is a central part of court sentencing practice.
Primary cilia-dependent signaling is involved in regulating mesenchymal stem cell proliferation and pluripotency maintenance
Authors: Ma Zhourui , Qin Mingde , Liang Hansi , Chen Ruihua , Cai Shizhong , Huang Zhijian , Tai Guangping 
Published: May 2020

AbstractUsing a large-scale quantitative mesenchymal stem cells (MSCs) membrane proteomics analysis, we identified a large group of ciliary proteins in the MSCs membrane fraction, which prompted us to examine the cilia, intricate organelles that were originally discovered approximately 100 years ago. Here we characterize their primary structure and function in MSCs. We first characterized the primary cilia on undifferentiated human MSCs by immunostaining and verified these observation with scanning and 3D electronic microscopy. To investigate the function of the primary cilia of the MSCs we induced loss of function by means of siRNA knockdown (targeted to two known ciliary proteins: IFT172 and KIF3A). After either of these two proteins was knocked down by the respective siRNA, the MSCs showed fewer and shortened primary cilia. The MSCs proliferation assays showed increased cell proliferative activity under confluent conditions after the siRNA knockdown of IFT172 or KIF3A; among these MSCs, the proportion in S phase was increased in the IFT172 siRNA knockdown group. The expression of stem cell markers on the MSCs, namely, Oct4, Nanog and Sox2, were downregulated after the siRNA-induced knockdown of IFT172 or KIF3A, and the gene expression upregulation of ectoderm lineage markers was notable. Furthermore, manipulation of the primary cilia-dependent Shh pathway, using the Shh activator SAG (smoothened agonist), upregulated the gene expression of pluripotency markers, including Nanog and Oct4, and transcriptional target genes in the Shh pathway. This study confirms that MSCs have primary cilia and provides evidence that primary cilia-dependent signaling pathways play functional roles in MSCs proliferation and stemness maintenance.
Dynamics of a neuron–glia system: the occurrence of seizures and the influence of electroconvulsive stimuli
Authors: Erhardt André H. , Mardal Kent-Andre , Schreiner Jakob E. 
Published: May 2020

AbstractIn this paper, we investigate the dynamics of a neuron–glia cell system and the underlying mechanism for the occurrence of seizures. For our mathematical and numerical investigation of the cell model we will use bifurcation analysis and some computational methods. It turns out that an increase of the potassium concentration in the reservoir is one trigger for seizures and is related to a torus bifurcation. In addition, we will study potassium dynamics of the model by considering a reduced version and we will show how both mechanisms are linked to each other. Moreover, the reduction of the potassium leak current will also induce seizures. Our study will show that an enhancement of the extracellular potassium concentration, which influences the Nernst potential of the potassium current, may lead to seizures. Furthermore, we will show that an external forcing term (e.g. electroshocks as unidirectional rectangular pulses also known as electroconvulsive therapy) will establish seizures similar to the unforced system with the increased extracellular potassium concentration. To this end, we describe the unidirectional rectangular pulses as an autonomous system of ordinary differential equations. These approaches will explain the appearance of seizures in the cellular model. Moreover, seizures, as they are measured by electroencephalography (EEG), spread on the macro–scale (cm). Therefore, we extend the cell model with a suitable homogenised monodomain model, propose a set of (numerical) experiment to complement the bifurcation analysis performed on the single–cell model. Based on these experiments, we introduce a bidomain model for a more realistic modelling of white and grey matter of the brain. Performing similar (numerical) experiment as for the monodomain model leads to a suitable comparison of both models. The individual cell model, with its seizures explained in terms of a torus bifurcation, extends directly to corresponding results in both the monodomain and bidomain models where the neural firing spreads almost synchronous through the domain as fast traveling waves, for physiologically relevant paramenters.
Learning Design: European Approaches
Authors: Wasson Barbara , Kirschner Paul A. 
Published: May 2020

AbstractResearch on instructional and learning design is ‘booming’ in Europe, although there has been a move from a focus on content and the way to present it in a formal educational context (i.e., instruction), to a focus on complex learning, learning environments including the workplace, and access to learner data available in these environments. We even see the term ‘learning experience design’ (Neelen and Kirschner 2020) to describe the field. Furthermore, there is an effort to empower teachers (and even students) as designers of learning (including environments and new pedagogies), and to support their reflection on their own practice as part of their professional development (Hansen and Wasson 2016; Luckin et al. 2016; Wasson et al. 2016). While instructional design is an often heard term in the United States and refers to “translating principles of learning and instruction into plans for instructional materials, activities, information resources, and evaluation” (Smith and Ragan 1999), Europe tends to lean more towards learning design as the key for providing efficient, effective, and enjoyable learning experiences. This is not a switch from an instructivist to a constructivist view nor from a teacher-centred to a student-centred paradigm. It is, rather, a different mind-set where the emphasis is on the goal (i.e., learning) rather than the approach (i.e., instruction). Designing learning opportunities in a technology enhanced world builds on theories of human learning and cognition, opportunities provided by technology, and principles of instructional design. New technology both expands and challenges some instructional design principles by opening up new opportunities for distance collaboration, intelligent tutoring and support, seamless and ubiquitous learning and assessment technologies, and tools for thinking and thought. In this article, the authors give an account of their own and other research related to instructional and learning design, highlight related European research, and point to future research directions.
Feedback im Anfangsunterricht der Grundschule – Eine Videostudie zum Feedbackverhalten von Lehrpersonen in der Domäne Schreiben
Authors: Pohlmann-Rother Sanna , Kürzinger Anja , Lipowsky Frank 
Published: May 2020

ZusammenfassungIm Beitrag wird das Feedbackverhalten von Grundschullehrkräften als Merkmal der Tiefenstruktur des Unterrichts in der ersten Jahrgangsstufe analysiert. Es wird der Frage nachgegangen, wie häufig und in welcher Form Lehrkräfte während einer Schülerarbeitsphase beim Schreiben (Texte verfassen) Rückmeldungen geben und wie sie diese auf die Schülerinnen und Schüler verteilen. Im Anschluss werden Zusammenhänge zwischen einzelnen Feedbackformen und der Qualität der Schülertexte analysiert. Die vorliegenden Analysen stammen aus dem DFG-Projekt NaSch1 („Narrative Schreibkompetenz in Klasse 1“) und stützen sich auf 47 ca. 90-minütige videografierte Unterrichtseinheiten mit 540 Lernenden aus der PERLE-Videostudie. Die Ergebnisse zeigen deutliche Unterschiede im Rückmeldeverhalten der Lehrpersonen. Elaborierte Feedbackformen (z. B. tutorielles Feedback) treten seltener auf als einfache Formen. Tendenziell erhalten Jungen häufiger ein Feedback, wobei die Initiative zur Erteilung eines Feedbacks eher von den Lernenden als von den Lehrkräften ausgeht. In den Mehrebenenanalysen lassen sich keine signifikanten Zusammenhänge zwischen einfachen bzw. elaborierten Rückmeldeformen und der Textqualität nachweisen. Dagegen zeigt sich ein negativer Zusammenhang zwischen inhaltsbezogenem Feedback und der sprachsystematischen Dimension der Textqualität.
Strongyloides stercoralis Hyper infection Syndrome
Authors: Karanam L Sampath Kumar , Basavraj Gopi Krishna , Papireddy Chaitanya Kumar Reddy 
Published: May 2020

AbstractStrongyloides stercoralis is a helminth, widely distributed in tropical and subtropical countries. Its infestation in humans usually does not produce symptoms. However, in some patients, severe and life-threatening forms of this infection can occur, especially in immunocompromised individuals. Severe parasitic infection is triggered by any imbalance in the host’s immunity favouring the auto-infective cycle. This results in an increase in the intraluminal parasitic burden. In addition, tissue infestation is also very common. Clinical presentation is variable, and it is very difficult to diagnose clinically. Diagnosis requires a high index of suspicion. In some cases, the diagnosis is established only on histopathological examination of the excised tissue by the pathologist. Here, the authors report a case of an elderly male diabetic patient, who presented to the emergency department with the features of acute abdomen. On exploratory laparotomy, he was found to have the features suggestive of gangrene of small bowel. Resection of the gangrenous bowel was done, and end-to-end anastomosis was done as the rest of the bowel appeared to be normal. However, the patient died of multi-organ failure and septicaemia on the second postoperative day. The resected intestine showed tissue infestation of Strongyloides stercoralis on histopathological examination. In this review article, the authors summarize a case of hyper infection syndrome of strongyloidiasis and discuss the various aspects of Strongyloides stercoralis infection with emphasis on life cycle of the parasite and different clinical features of the disease.