bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol for Isolation and Culture of Mouse Hepatocytes (HCs), Kupffer Cells (KCs), and Liver Sinusoidal Endothelial Cells (LSECs) in Analyses of Hepatic Drug Distribution
Authors: Elvevold Kjetil , Kyrrestad Ingelin , Smedsrød Bård 
Published: February 2022

AbstractDevelopment of the new generation of drugs (e.g., oligo- and polynucleotides administered intravascularly either as free compounds or as nano-formulations) frequently encounters major challenges such as lack of control of targeting and/or delivery. Uncontrolled or unwanted clearance by the liver is a well-known and particularly important hurdle in this respect. Hence, reliable techniques are needed to identify the type(s) of liver cells, receptors, and metabolic mechanisms that are responsible for unwanted clearance of these compounds.We describe here a method for the isolation and culture of the major cell types from mouseliver: hepatocytes (HCs), Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs). The presently described protocol employs perfusion of the liver with a collagenase-based enzyme preparation to effectively transform the intact liver to a single cell suspension. From this initial cell suspension HCs are isolated by specified centrifugation schemes, yielding highly pure HC preparations, and KCs and LSECs are isolated by employing magnetic-activated cell sorting (MACS). The MACS protocol makes use of magnetic microbeads conjugated with specific antibodies that bind unique surface antigens on either KCs or LSECs. In this way the two cell types are specifically and separately pulled out of the initial liver cell suspension by applying a magnetic field, resulting in high purity, yield, and viability of the two cell types, allowing functional studies of the cells.If the drug compound in question is to be studied with respect to liver cell distribution of intravascularly administered drug compounds the isolated cells can be analyzed directly after isolation. Detailed studies of receptor-ligand interactions and/or dynamics of intracellular metabolism of the compound can be conducted in primary surface cultures of HCs, LSECs, and KCs established by seeding the isolated cells on specified growth substrates.
Patent Considerations When Embarking on New Antisense Drug Programs
Authors: Gainey Laurence D. S. 
Published: February 2022

AbstractThe aim of this chapter is to provide some key information on patents and the patent system to assist someone embarking on the design, development, and commercialization of new antisense drugs.Here I outline certain key topics such as what is a patent? why patent? how do I protect my molecule with a patent? confidentiality, searching for the same or similar molecules in the prior art, data requirements, the patenting timeline and freedom to operate.
Design of Bifunctional Antisense Oligonucleotides for Exon Inclusion
Authors: Zhou Haiyan 
Published: February 2022

AbstractBifunctional antisense oligonucleotide (AON) is a specially designed AON to regulate pre-messenger RNA (pre-mRNA) splicing of a target gene. It is composed of two domains. The antisense domain contains sequences complementary to the target gene. The tail domain includes RNA sequences that recruit RNA binding proteins which may act positively or negatively in pre-mRNA splicing. This approach can be designed as targeted oligonucleotide enhancers of splicing, named TOES, for exon inclusion; or as targeted oligonucleotide silencers of splicing, named TOSS, for exon skipping. Here, we provide detailed methods for the design of TOES for exon inclusion, using SMN2 exon 7 splicing as an example. A number of annealing sites and the tail sequences previously published are listed. We also present methodology of assessing the effects of TOES on exon inclusion in fibroblasts cultured from a SMA patient. The effects of TOES on SMN2 exon 7 splicing were validated at RNA level by PCR and quantitative real-time PCR, and at protein level by western blotting.
Securitization, Emergency and the Rediscovery of Responsibility in Times of Pandemic: Analyzing Political Discourses from the European South
Authors: Boukala Salomi , Serafis Dimitris 
Published: February 2022

AbstractThis chapter intends to provide an argumentative perspective on the justification of securitization by Southern EU’s political leaders in times of a public health crisis and the COVID-19 pandemic by examining instances of public discourses, specifically addresses to the nation of four EU leaders with different ideological positioning, in different social settings of the European South. Based on the theory of securitization, we perceive public debate as a polylogical phenomenon where multiple actors, from multiple (ideological) positions, in multiple times and spaces interact, creating a complex network of public communication while expressing and supporting their claims. Through this prism, our aim is to shed light on argumentative polylogues by unveiling whether and how the state of emergency has been justified. We employ the frame of the Discourse-Historical Approach (DHA) to Critical Discourse Studies (CDS) (Reisigl & Wodak, 2016) to study the socio-historically conditions against which established endoxical premises are (re)constructed by the political leadership and how these interrelate with specific argumentation strategies (topoi) in the social settings under scrutiny. We then draw on the quasi-Y structure provided by the Argumentum Model of Topics (AMT) (Rigotti & Greco, 2019) to scrutinize the interplay of topical and endoxical premises in the development of single standpoint-argument couplings.
Staying Up to Date with Fact and Reason Checking: An Argumentative Analysis of Outdated News
Authors: Musi Elena , Rocci Andrea 
Published: February 2022

AbstractThis paper tackles outdated news about COVID-19 as a type of misinformation from an argumentative perspective, focusing on the fact-checker Snopes. In rapidly changing information environments the circulation of outdated news can be highly detrimental causing risky behaviors. Such type of misinformation is difficult to pin down through fact-checking since encompassing different types of contents, motivations and channels. To fully understand this phenomenon we deem necessary to move away from a naïve view of fact checking to an argumentative one. But what are the argumentative configurations of outdated statements in the context of the current information ecosystem? To answer this question we rely on the distinction between upstream and downstream argumentation to anchor the kind of issues put forward by outdated statements. We then take as a sample all the news that have been rated as “outdated” and “miscaptioned” by Snopes during the pandemic and analyse the type of source, the semantic type of news claim and the argumentative role played by the outdated information. We come up with an argumentative taxonomy of outdated news where the presence of multimodal information as well as the semantic-argumentative role played by outdated statements pattern with the spread of mis- and disinformation.
Good and Ought in Argumentation: COVID-19 as a Case Study
Authors: Soria-Ruiz Andrés , Maldonado Mora , Stojanovic Isidora 
Published: February 2022

AbstractThe present chapter concerns arguments whose conclusions take the form of a prescription such asyou ought to do such-and-such, which have driven much public discussion and policy since the beginning of the COVID-19 pandemic. We aim to tackle a hitherto under-explored characteristic of many such normative arguments, namely, the relationship between evaluative and deontic propositions, depending on whether they occur as premises or conclusions in such arguments. In order to investigate how willing people are to argue from what is good to what one ought to do, and the other way round, we conducted an Inferential Judgment Experiment. Participants were presented with arguments involving deontic and evaluative propositions, and had to judge whether they could infer conclusion from premise. The stimuli that we used are tightly related to the argumentation surrounding the pandemic, regarding the measures of preventing the spread of COVID-19. The results of the study show that there is a robust inferential connection between evaluatives and deontics, but at the same time, a significant asymmetry as well. We explore several theoretical approaches to the relationship between the deontic and the evaluative realm, and test their predictions against the results of our study.
Pressure: The Bernoulli Principle and Flow Energy Conservation
Authors: Decher Reiner 
Published: February 2022

AbstractThe relation between descriptive variables of flowing air, pressure and the like, and the dynamic field, speeds or velocities, are often invoked for their understanding. Such relationships depend on whether the flow is compressible or not. When it is, physical work done by air elements on one another, become important. This chapter, virtually devoid of illuminating images, nevertheless sheds light on how to think about air flows in general and how to deduce the local pressures from knowledge of the flow field.
Pressure, Pressure, It’s All About Pressure!
Authors: Decher Reiner 
Published: February 2022

AbstractThe airplane or wing designer seeks to harness the pressure forces associated with the motion of air. These have important consequences for the operation of an airplane in flight because the forces on it must be balanced and flight should be stable. We examine the various descriptive pressures that are relevant and look at airfoil and wing data that is displayed as clean and compact. We introduce yet another consequence of the nature of vorticity associated with lift, namely drag that is associated with the trailing vortex system. The discussion is concluded with thoughts about how the pilot of an airplane thinks about speed.
Putting It All Together
Authors: Decher Reiner 
Published: February 2022

AbstractWe examine the lift and drag characteristics of wings as these are affected by the two physical aspects of flight: friction effects and for higher speed, air compressibility. We encounter the phenomenon of stall, shock waves, and visible condensation. These make flight phenomena interesting and challenging. Friction effects in supersonic flight are shown to be an almost negligibly small part of the heating of aircraft skin surfaces.
Propulsion for Flight: Power or Thrust?
Authors: Decher Reiner 
Published: February 2022

AbstractAn engine is required to provide the power necessary for overcoming the drag of flight. There are not many engine types available to perform that important function: they all have advantages and limitations. They share common features and are different in fundamental ways. The histories of their development paced the history of man’s ability to fly and the modern gas turbine engine is the climax of that progression toward today’s state of aviation. In this chapter we focus on the salient features of engines as they relate to flight.
A reverse Hölder inequality for the gradient of solutions to Trudinger’s equation
Authors: Saari Olli , Schwarzacher Sebastian 
Published: February 2022

AbstractWe provide a higher integrability result for the gradient of positive solutions to Trudinger’s equation (also known as the doubly non-linear equation) for the range $$p\in [2,\infty )$$

p
∈
[
2
,
∞
)

. The estimate is achieved by refining a construction of intrinsic cylinders from the vectorial setting by incorporating estimates that are only available in the scalar case.
Hand dominance and experience improve bimanual performance on arthroscopic simulator task
Authors: Feeley Aoife A. , Gibbons John P. , Feeley Iain H. , Fitzgerald Eilis , Merghani Khalid , Sheehan Eoin 
Published: February 2022

Abstract
Purpose
The aim of this study was to identify if experience in arthroscopy confers ambidexterity to the operator and the role of baseline characteristics in arthroscopic simulator performance.

Methods
A prospective comparative study was carried out across four regional Orthopaedic training centres. Participants were divided into novice, intermediate or experienced groups based on arthroscopic experience. Baseline demographics including age, sex, handedness, and gaming history were also collected. Following familiarisation with the procedure, participants were asked to complete a simulated task requiring bimanual control consisting of visualisation with camera control and manipulation of highlighted objects using a grasping instrument. One attempt using camera control and grasping accuracy per hand was performed by each participant, with scores for each hand collected for analysis. Performance scores for camera alignment, camera path length, grasper path length and grasping efficiency were collected. Time taken to completion was also noted for each attempt.

Results
Fifty-six participants were recruited to the study. A significant difference in grasping efficiency between groups in the dominant hand was demonstrated (p = 0.013). Novices demonstrated laterality with superior performance in grasping efficiency in the dominant hand (p = 0.001). No significant difference was noted between dominant and non-dominant hand performance in the experienced group.

Conclusion
Arthroscopic simulation-based training is a valuable learning tool for orthopaedic training. This study demonstrated that experienced orthopaedic surgeons have a greater degree of ambidexterity than intermediate or novice groups, hypothesised by authors to be conferred through conventional orthopaedic training. Dedicated bimanual control tasks to reduce laterality in trainees should be incorporated in simulated surgical curricula.

Level of evidence
III.
Interaction of childhood abuse and depressive symptoms on cortical thickness: a general population study
Authors: Voss Sara , Frenzel Stefan , Klinger-König Johanna , Janowitz Deborah , Wittfeld Katharina , Bülow Robin , Völzke Henry , Grabe Hans J. 
Published: February 2022

AbstractChildhood abuse was inconsistently related to whole-brain cortical thickness in former studies. However, both childhood abuse and cortical thickness have been associated with depressive symptoms. We hypothesised that childhood abuse moderates the association between depressive symptoms and cortical thickness. In 1551 individuals of the general population, associations between whole-brain cortical thickness and the interaction of childhood abuse (emotional, physical, and sexual) and depressive symptoms were analysed using an ANCOVA. Linear regression analyses were used to estimate the same effect on the cortical thickness of 34 separate regions (Desikan-Killiany-atlas). A significant interaction effect of childhood abuse and depressive symptoms was observed for whole-brain cortical thickness (F(2, 1534) = 5.28, p = 0.007). A thinner cortex was associated with depressive symptoms in abused (t value = 2.78, p = 0.025) but not in non-abused participants (t value = − 1.50, p = 0.224). Focussing on non-depressed participants, a thicker whole-brain cortex was found in abused compared to non-abused participants (t value = − 2.79, p = 0.025). Similar interaction effects were observed in 12 out of 34 cortical regions. Our results suggest that childhood abuse is associated with reduced cortical thickness in subjects with depressive symptoms. In abused subjects without depressive symptoms, larger cortical thickness might act compensatory and thus reflect resilience against depressive symptoms.
Combining vestibular rehabilitation with noisy galvanic vestibular stimulation for treatment of bilateral vestibulopathy
Authors: Eder Josefine , Kellerer Silvy , Amberger Tamara , Keywan Aram , Dlugaiczyk Julia , Wuehr Max , Jahn Klaus 
Published: February 2022

Abstract
Objective
Noisy galvanic vestibular stimulation (nGVS) has been shown to partly restore vestibular function and to stabilize stance and gait in patients with incomplete bilateral vestibulopathy (BVP). Here, we examined potential synergistic effects of nGVS when combined with standardized vestibular rehabilitation training (VRT).

Methods
23 patients with confirmed BVP received a 30-min vestibular rehabilitation training (VRT) program three times a week for 2 weeks. The intervention group (n = 12) was stimulated with nGVS (at individually determined optimal amplitudes) during training, whereas the control group (n = 11) received zero-amplitude nGVS (sham stimulation) during training. Outcome measurements assessed at baseline, after 2 weeks of training, and at 2-week follow-up included quantitative posturography, instrumented gait analysis, Timed Up and Go Test (TUG), Functional Gait Assessment (FGA), and clinical scores related to quality of life and balance confidence.

Results
After 2 weeks of VRT, all patients showed moderate improvement in balance. Irrespective of nGVS treatment, performance improved in the TUG (p < 0.013), and in the FGA (p < 0.040). Furthermore, base of support when walking with closed eyes was reduced after 2-week training (p < 0.003). Postural sway did not change. There was no difference between groups and thereby no evidence for an additional influence of nGVS on the VRT treatment effects.

Conclusion
nGVS does not induce synergistic treatment effects in combination with VRT in patients with BVP when applied during treatment sessions. Hence, rather than being applied in parallel, nGVS and VRT might be complementary therapeutic options with nGVS being used during postural activities in daily life, e.g., walking.
UEG and EAES rapid guideline: Systematic review, meta-analysis, GRADE assessment and evidence-informed European recommendations on TaTME for rectal cancer
Authors: Milone Marco , Adamina Michel , Arezzo Alberto , Bejinariu Nona , Boni Luigi , Bouvy Nicole , de Lacy F Borja , Dresen Raphaëla , Ferentinos Konstantinos , Francis Nader K. , Mahaffey Joe , Penna Marta , Theodoropoulos George , Kontouli Katerina Maria , Mavridis Dimitris , Vandvik Per Olav , Antoniou Stavros A. 
Published: February 2022

Abstract
Background
Evidence and practice recommendations on the use of transanal total mesorectal excision (TaTME) for rectal cancer are conflicting.

Objective
We aimed to summarize best evidence and develop a rapid guideline using transparent, trustworthy, and standardized methodology.

Methods
We developed a rapid guideline in accordance with GRADE, G-I-N, and AGREE II standards. The steering group consisted of general surgeons, members of the EAES Research Committee/Guidelines Subcommittee with expertise and experience in guideline development, advanced medical statistics and evidence synthesis, biostatisticians, and a guideline methodologist. The guideline panel consisted of four general surgeons practicing colorectal surgery, a radiologist with expertise in rectal cancer, a radiation oncologist, a pathologist, and a patient representative. We conducted a systematic review and the results of evidence synthesis by means of meta-analyses were summarized in evidence tables. Recommendations were authored and published through an online authoring and publication platform (MAGICapp), with the guideline panel making use of an evidence-to-decision framework and a Delphi process to arrive at consensus.

Results
This rapid guideline provides a weak recommendation for the use of TaTME over laparoscopic or robotic TME for low rectal cancer when expertise is available. Furthermore, it details evidence gaps to be addressed by future research and discusses policy considerations. The guideline, with recommendations, evidence summaries, and decision aids in user-friendly formats can also be accessed in MAGICapp: https://app.magicapp.org/#/guideline/4494.

Conclusions
This rapid guideline provides evidence-informed trustworthy recommendations on the use of TaTME for rectal cancer.
Haben Patient*innen die moralische Pflicht, ihre klinischen Daten für Forschung bereitzustellen? Eine kritische Prüfung möglicher Gründe
Authors: Jungkunz Martin , Köngeter Anja , Mehlis Katja , Spitz Markus , Winkler Eva C. , Schickhardt Christoph 
Published: February 2022

ZusammenfassungDie Sekundärnutzung klinischer Daten für Forschungs- und Lernaktivitäten hat das Potenzial, medizinisches Wissen und klinische Versorgung erheblich zu verbessern. Zur Realisierung dieses Potenzials bedarf es einer ethischen und rechtlichen Grundlage für die Datennutzung, vorzugsweise in Form der Einwilligung von Patient*innen. Damit stellt sich die grundsätzliche Frage: Haben Patient*innen eine moralische Pflicht, ihre klinischen Daten für Forschungs- und Lernaktivitäten zur Verfügung zu stellen?Auf Basis eines ethischen Ansatzes, der als „sorgender Liberalismus“ bezeichnet werden kann, werden folgende Argumente zur Begründung einer Pflicht von Patient*innen zur Bereitstellung ihrer klinischen Daten für Forschungs- und Lernaktivitäten auf Plausibilität und moralisches Gewicht untersucht: die allgemeine Hilfspflicht; Solidarität; die Pflicht zu gemeinwohlförderlichem Handeln; das Trittbrettfahrerargument; transgenerationale Gerechtigkeit; das Prinzip des Zurückgebens; das Prinzip des Nicht-Schädigens; die Forschungsfreiheit und der Wert der Wissenschaft.Die allgemeine Hilfspflicht und die Pflicht zu gemeinwohlförderlichem Handeln sind gewichtige Gründe für eine moralische Pflicht von Patient*innen zur Bereitstellung ihrer klinischen Daten für Forschungs- und Lernaktivitäten. Das Argument der transgenerationalen Gerechtigkeit und das Prinzip des Zurückgebens sind ethisch schwache Gründe für eine solche Pflicht, können jedoch eine motivationale Rolle spielen. Die anderen Gründe sind nicht geeignet, eine Pflicht zu begründen. Das Ergebnis ist in mehrfacher Hinsicht relevant: für Patient*innen, die um die Einwilligung in die Sekundärnutzung ihrer klinischen Daten gebeten werden; für die ethische Diskussion der Frage, ob und inwieweit Abstriche von der klassischen spezifischen Einwilligung unter bestimmten Bedingungen ethisch akzeptabel sind; für die rechtwissenschaftliche Diskussion der Bedingungen für eine juristisch verhältnismäßige Sekundärnutzung klinischer Daten für Forschungs- und Lernaktivitäten.
Being Overweight or Obese Is Associated with an Increased Platelet Reactivity Despite Dual Antiplatelet Therapy with Aspirin and Clopidogrel
Authors: Puccini Marianna , Rauch Christian , Jakobs Kai , Friebel Julian , Hassanein Adel , Landmesser Ulf , Rauch Ursula 
Published: February 2022

Abstract
Purpose
Obese patients exhibit an overall increased platelet reactivity and a reduced sensitivity to antiplatelet therapy. The aim of this study is to evaluate the platelet reactivity measured by impedance aggregometry in overweight and obese patients and chronic coronary syndrome (CCS) that were treated with dual antiplatelet therapy (DAPT).

Methods
Platelet aggregation was assessed by impedance aggregometry in patients with CCS receiving DAPT (aspirin plus clopidogrel). We compared the platelet reactivity in patients with a normal weight versus overweight or obese patients. Furthermore, the correlation between the body mass index (BMI) and adenosine diphosphate- (ADP-) or thrombin receptor-activating peptide- (TRAP-) dependent platelet aggregation was analyzed.

Results
64 patients were included in the study of which 35.9% were patients with normal weight. A higher ADP- and TRAP-dependent platelet reactivity was observed in overweight and obese patients (ADP: median 27 units (U) [IQR 13–39.5] vs. 7 U [6–15], p < 0.001 and TRAP: 97 U [73–118.5] vs. 85 U [36–103], p = 0.035). Significant positive correlations were observed between agonist-induced platelet reactivity and BMI.

Conclusion
Despite the use of DAPT, a higher platelet reactivity was found in overweight and obese patients with CCS. If these patients will benefit from treatment with more potent platelet inhibitors, it needs to be evaluated in future clinical trials.