bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance Mechanisms
Authors: Ferng Timothy T. , Terada Daisuke , Ando Makoto , Tarver Theodore C. , Chaudhary Fihr , Lin Kimberly C. , Logan Aaron C. , Smith Catherine C. 
Published: April 2022

Abstract
Small-molecule FLT3 inhibitors have recently improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML) after many years of development, but resistance remains an important clinical problem. FF-10101 is the first irreversible, covalent inhibitor of FLT3 which has previously shown activity against FLT3 tyrosine kinase inhibitor resistance–causing FLT3 F691L and D835 mutations. We report that FF-10101 is also active against an expanded panel of clinically identified FLT3 mutations associated with resistance to other FLT3 inhibitors. We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.
KRAS Mutants Upregulate Integrin β4 to Promote Invasion and Metastasis in Colorectal Cancer
Authors: Choi Seo-Hyun , Kim Jin K. , Chen Chin-Tung , Wu Chao , Marco Michael R. , Barriga Francisco M. , O'Rourke Kevin , Pelossof Raphael , Qu Xuan , Chang Qing , de Stanchina Elisa , Shia Jinru , Smith J. Joshua , Sanchez-Vega Francisco , Garcia-Aguilar Julio 
Published: April 2022

Abstract

KRAS mutation in colorectal cancer is associated with aggressive tumor behavior through increased invasiveness and higher rates of lung metastases, but the biological mechanisms behind these features are not fully understood. In this study, we show that KRAS-mutant colorectal cancer upregulates integrin α6β4 through ERK/MEK signaling. Knocking-out integrin β4 (ITGB4) specifically depleted the expression of integrin α6β4 and this resulted in a reduction in the invasion and migration ability of the cancer cells. We also observed a reduction in the number and area of lung metastatic foci in mice that were injected with ITGB4 knockout KRAS-mutant colorectal cancer cells compared with the mice injected with ITGB4 wild-type KRAS-mutant colorectal cancer cells, while no difference was observed in liver metastases. Inhibiting integrin α6β4 in KRAS-mutant colorectal cancer could be a potential therapeutic target to diminish the KRAS-invasive phenotype and associated pulmonary metastasis rate.

Implications:
Knocking-out ITGB4, which is overexpressed in KRAS-mutant colorectal cancer and promotes tumor aggressiveness, diminishes local invasiveness and rates of pulmonary metastasis.
Is Being a Genus? Syrianus’ Criticism of Aristotle
Authors: Granieri Roberto 
Published: April 2022

Abstract
In Metaphysics B 3 Aristotle sets out a famous argument for the thesis that being is not a genus. In his commentary on Metaphysics B, Syrianus criticizes this argument and explains in what sense being is to be regarded as a genus. I reconstruct both Syrianus’ criticisms and his own view. I bring out ways in which they can help us rethink key assumptions of Aristotle’s ontology and shed light both on Syrianus’ critical attitude towards Aristotle and on some of Syrianus’ main views in metaphysics.
Neo-Triple Helix Model of Innovation Ecosystems: Integrating Triple, Quadruple and Quintuple Helix Models
Authors: Cai Yuzhuo 
Published: April 2022

Abstract
This article proposes the neo-Triple Helix model of innovation ecosystems by integrating the Triple, Quadruple and Quintuple Helix models, inspired by Lewontin’s gene, organism and environment Triple Helix metaphor. The model considers innovation ecosystems evolved through interactions between 1) innovation dynamics (or innovation genes), 2) social structures and 3) the natural environment. The systems include two-layer triple helix interactions (or triads): university, industry and government at the gene level, and innovation genes, social structures and the natural environment at the system level. Innovation dynamics are conceptualised by integrating the neo-institutional and neo-evolutionary perspectives of the Triple Helix model. The dialectical relationships between innovation genes, social structures and the natural environment are primarily explained using aspects of the Quadruple and Quintuple Helix models. The neo-Triple Helix model clarifies debates on different helix innovation models, advances helical approaches through synergy building and can guide empirical research and policy design on innovation ecosystems.
Is the Universe Moral?
Authors: Large William 
Published: April 2022

Abstract
Kant argues against the ontological argument for the existence of God but replaces it with a moral theism. This article analyses Kant’s moral proof with emphasis on the Critique of the Power of Judgement, and his historical and political writings. It argues that at the heart of this argument is the idea of progress. The concrete content of the moral law is the idea of a just world. Such a just world would be impossible without the idea of God, since there would be no harmony between nature and freedom. It contrasts Kant’s concept of time and history with Heidegger’s. The difference between them is a reversal of modality. For Kant, actuality determines possibility. If I cannot imagine a just word as actual, then I would fall into moral despair. The idea of God grounds this actuality. For Heidegger, possibility is higher than actuality. Since history has no teleology, then no idea of God is required.
Unmasking the Confounder: The Inherent Physiologic Variability of Swine During an Automated Experimental Model of Ischemia-Reperfusion Injury
Authors: Martin Symonne C. , Hauser Nathaniel , Renaldo Antonio C. , Lane Magan , Jordan James E. , Qadri Hisham I. , Mouser Nicholas , Rahbar Elaheh , Williams Timothy K. , Neff Lucas P. 
Published: April 2022

Background We sought to determine the magnitude of the inherent inter-animal physiologic variability by automating a porcine Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) protocol to minimize external influences that might alter physiology and confound experimental results. Methods Swine (n = 42) underwent a controlled 30% blood volume hemorrhage followed by 30 minutes of REBOA (ie, ischemic phase). The animals were weaned from REBOA autonomously over 15 minutes, beginning the reperfusion phase, while continuing to provide partial flow balloon support to maintain a target proximal mean arterial pressure (pMAP) of 65 mmHg. Simultaneously, shed blood was re-transfused as part of the resuscitation efforts. Physiologic data were continuously recorded, and serum samples were serially collected. Baseline characteristics, variance in vital signs, and 8-isoprostane levels were quantified during hemorrhage, REBOA, and reperfusion phases. Results There was no significant difference in baseline physiology across animals ( P > .05). Hemodynamic variability was highest for pMAP during the ischemic phase ( P = .001) and for distal mean arterial pressure (dMAP) during the weaning/reperfusion phase ( P = .001). The latter finding indicated the variable physiologic response to ischemia-reperfusion injury, as the automated balloon support required by each animal to maintain pMAP was highly variable. Circulating 8-isoprostane variance was significantly higher following the start of reperfusion compared to baseline levels ( P = .001). Discussion Despite subjecting animals to a highly consistent ischemia-reperfusion injury through automation, we noted significant variability in the hemodynamic and biochemical response. These findings illustrate the inherent physiologic variability and potential limitations of porcine large animal models for the study of shock.
Changes in Injury Patterns Associated With Elevated Blood Alcohol Level
Authors: Rhodes Heather X. , Moncada Isabella , Biswas Saptarshi 
Published: April 2022

Introduction This study aims to improve public health outreach in a high-risk population. Methods This is a single center study of Trauma Registry data, inclusive years January 1, 2016 to March 30, 2021. The study population was stratified into two groups: ETOH ≥ 80 mg/dL and ETOH <80 mg/dL. A total of 1141 were included. Results Those above the legal drinking limit had a significantly higher mean ETOH (231 mg/dL; P <.01) and were typically younger men that arrived by ground ambulance. The significant injury patterns of those above the legal limit included full activation and consults who fell from stairs and fell from other or unknown. A higher proportion of intoxicated fall trauma patients above the legal limit were diagnosed with a concussion. Conclusions Excess alcohol consumption, particularly during a pandemic year, may lead to a higher incidence of fall from stairs trauma in men who are more likely to be diagnosed with a concussion.
Movement Disorders Secondary to Novel Antiseizure Medications in Pediatric Populations: A Systematic Review and Meta-analysis of Risk
Authors: Peacock Dakota J. S. J. , Yoneda Joshua R. K. , Siever Jodi E. , Vis-Dunbar Mathew , Boelman Cyrus 
Published: April 2022

Novel antiseizure medications are thought to be safer than their conventional counterparts, though no dedicated analysis of movement disorder risk among pediatric populations using novel antiseizure medications has been completed. We report a systematic review with meta-analysis describing the relationship between novel antiseizure medications and movement disorders in pediatrics. MEDLINE, EMBASE, and the World Health Organization’s International Clinical Trials Registry Platform were searched up to October 2020 for randomized controlled trials investigating novel antiseizure medications in pediatric populations. Antiseizure medications included lacosamide, perampanel, eslicarbazepine, rufinamide, fenfluramine, cannabidiol, and brivaracetam. Outcomes were pooled using random effects models; risk difference (RD) and 95% confidence intervals (CIs) were calculated. Twenty-three studies were selected from 1690 nonredundant manuscripts (n = 1912 total). There was a significantly increased risk of movement disorders associated with perampanel (RD 0.07, 95% CI 0.01-0.13; n = 133), though only 1 relevant trial was found. No increased risk of movement disorders was found with other antiseizure medications. Our findings indicate most novel antiseizure medications are safe to use in pediatric populations with respect to movement disorders. However, findings were limited by quality of adverse event reporting.
Potential Reporters of Suspected Child Maltreatment are Sensitive to the Amount of Evidence and the Potential Consequences of Reporting
Authors: Price Heather L. , Kehn Andre 
Published: April 2022

The context of suspected maltreatment cases is likely to influence the decision of whether or not to make a formal report. Across one pilot study ( N = 368) and two experiments (Exp. 1 N = 444; Exp. 2 N =416), undergraduate students and online community participants reported their anticipated actions and beliefs when confronted with evidence of child maltreatment. Participants reviewed case dossiers built from real-world child neglect cases in which increasing levels of evidence were presented and the consequences of reporting, or not reporting, the maltreatment were made salient to the adult or child. The experiments revealed a clear difficulty in deciding whether or not to report suspected maltreatment. Highlighting the impact on either the child or the adult by describing potential consequences moved participants either closer to (child-salient) or farther from (adult-salient) a formal report. Participants were also sensitive to the amount of evidence to support a suspicion of abuse, which influenced the likelihood of a formal report. This work suggests that increasing the salience of maltreatment consequences to child victims may increase the likelihood that suspected maltreatment will be reported.
Burden of kidney disease among patients with peritoneal dialysis versus conventional in-centre haemodialysis: A randomised, non-inferiority trial
Authors: Fan Li , Yang Xiao , Chen Qinkai , Zhang Hao , Wang Jianqin , Chen Menghua , Peng Hui , Ni Zhaohui , Wan Jianxin , Yang Hongtao , Li Yun , Wang Li , Peng Ai , Lin Hongli , Zhang Jinyuan , Shen Huaying , Xiong Fei , He Yongcheng , Zha Yan , Xie Minyan , Jiao Jundong , Jiang Gengru , Zheng Xunhuan , Xiao Jun , Rong Rong , Qian Jiaqi , Yu Xueqing 
Published: April 2022

Background: Little is known about the impact of haemodialysis (HD) and peritoneal dialysis (PD) on health-related quality of life (HRQoL). We compared HRQoL between conventional in-centre HD and home-based PD in 1082 newly diagnosed kidney failure patients. Methods: This was an open-label, randomised, non-inferiority trial of adult patients with a diagnosis of end-stage kidney disease (estimated glomerular filtration rate ≤ 15 mL/min/1.73 m2) requiring maintenance dialysis from 36 sites in China randomised 1:1 to receive PD or conventional in-centre HD. The primary outcome was the ‘Burden of Kidney Disease’ assessed using the Kidney Disease Quality of Life-Short Form (KDQoL-SF) survey over 48 weeks and the main secondary outcomes were the remaining scales of KDQoL-SF and all-cause mortality. The effect of PD versus HD on the primary outcome was compared by their geometric mean (GM) ratio, and non-inferiority was defined by the lower bound of a one-sided 95% confidence interval (CI) >0.9. Results: A total of 725 subjects completed the trial per protocol (395 PD and 330 HD, mean age 49.8 (standard deviation (SD) 14.4) years, 41.4% women). For the primary outcome, the mean (SD) change in ‘Burden of Kidney Disease’ over 48 weeks was 2.61 (1.27) in PD group and 2.58 (1.35) in HD group, and the GM ratio (95% CI) was 1.059 (0.908–1.234), exceeding the limit for non-inferiority. For the secondary outcomes, the PD and HD groups were similar in all scales. There were 17 and 31 deaths in PD and HD groups, respectively. Patients receiving PD had more adverse events, adverse event leading to hospitalisation and serious adverse events compared to those allocated to HD, but adverse events leading to death and discontinuation of the trial were not different between PD and HD. Conclusions: In this trial, PD may be non-inferior to HD on the ‘Burden of Kidney Disease’ among Chinese kidney failure patients who are of younger age and have lower comorbidity after 48 weeks’ follow-up.
Human rights and the political: Assessing the allegation of human rights overreach in migration matters
Authors: Farahat Anuscheh 
Published: April 2022

Europe's external borders have been the site of intense human rights struggles over the last decade. While States are inventing ever new practices to circumvent their human rights responsibility by not responding to rescue calls or using private actors as proxies for refoulement, human rights activists seek to expand State jurisdiction to effectively hold European governments responsible for human rights violations at their borders and on the high seas. At the same time, the rise of populist movements and increasing xenophobia have made expansive human rights interpretation to the benefit of migrants increasingly suspicious in public discourse. The question therefore arises: Does the expansion of migrants’ human rights and State responsibility bear features of ‘human rights overreach’ in the sense that human rights encroach too much on State sovereignty, which may ultimately decrease the acceptance of human rights themselves? Or is it a necessary ‘outreach’ of human rights, that is, an adaptation of human rights to new practices of border protection in order to ensure human rights’ effectiveness? This paper addresses these questions in three steps. It first briefly presents current struggles about migrants’ human rights in the Mediterranean. It then deals with the increasing critique of human rights overreach in migration matters and assesses judicial practice in reaction to increasing State pressure. The core argument finally developed in this paper is that we should respond to the allegation of overreach by advancing a more political understanding of human rights, which acknowledges the methodological limits of regressive human rights interpretation and defends the idea of human rights as a concrete utopia. The paper develops this argument with a view to the concrete case law on migration issues and suggests how courts and migration law scholars should deal with the challenges of human rights struggles regarding migration.
A randomised trial of intracavitary electrocardiography versus surface landmark measurement for central venous access device placement
Authors: Alexandrou Evan , Mifflin Nicholas , McManus Craig , Sou Vanno , Frost Steven A , Sanghavi Ritesh , Doss David , Pillay Sugendran , Lawson Kenny , Aneman Anders , Konstantinou Evangelos , Rickard Claire M 
Published: April 2022

Background: Malpositioned central venous access devices (CVADs) can lead to significant patient injury including central vein thrombosis and dysrhythmias. Intra-cavitary electrocardiography (IC ECG) has been recommended by peak professional bodies as an accurate alternative for bedside CVAD insertion, to reduce risk of malposition and allowing immediate use of the device. Our objective was to compare the effect of IC ECG on CVAD malposition compared to traditional institutional practice for CVAD placement. Methods: Randomised controlled trial of IC ECG CVAD insertion verses traditional CVAD insertion (surface landmark measurement with post insertion x ray). Patient recruitment was from December 2016 to July 2018. The setting was a 900-bed tertiary referral hospital based in South Western Sydney, Australia. Three hundred and forty-four adult patients requiring CVAD insertion for intravenous therapy, were enrolled and randomly allocated (1:1 ratio) to either IC-ECG ( n = 172) or traditional ( n = 172) CVAD insertion. Our primary outcome of interest was the rate of catheters not requiring repositioning after insertion (ready for use). Secondary outcomes were comparison of procedure time and cost. Results: Of the 172 patients allocated to the IC ECG method, 170 (99%) were ready for use immediately compared to 139 of the 172 (81%) in the traditional insertion group (difference, 95% confidence interval (CI): 18%, 11.9–24.1%). The total procedure time was mean 15 min (SD 8 min) for IC ECG and mean 36 min (SD 17 min) for traditional CVAD insertion (difference–19.9 min (95% CI–14.6 to −34.4). IC ECG guided CVAD insertion had a cost reduction of AUD $62.00 per procedure. Conclusions: Using IC-ECG resulted in nearly no requirement for post-insertion repositioning of CVADs resulting in savings in time and cost and virtually eliminating the need for radiographic confirmation. Trial registration: This trial is registered at the Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au ). The registration number is ACTRN12620000919910.
Media use in gynecological and obstetric care and women’s perceived level of education received of lifestyle-related risks: A cross-sectional study
Authors: Bombana Manuela , Wensing Michel , Müller Gerhard , Ullrich Charlotte , Heinzel-Gutenbrunner Monika , Wittek Maren 
Published: April 2022

Objective: The application of media on lifestyle-related risk factors (LRRFs) by healthcare providers to educate women may improve women’s adherence, health literacy, and awareness of LRRFs, as well as offspring’s health outcomes. This study investigated whether exposure to media-based education in gynecological and obstetric care is associated with LRRFs perceived levels of education received during pregnancy and lactation. Methods: We conducted a cross-sectional, observational study across 14 randomly generated sample points in the 12 most populated cities in Baden-Württemberg, southwest Germany. Women were recruited from gynecological and obstetric institutions. Participants were 219 women who met our inclusion criteria and completed the quantitative questionnaire. We applied ordinal logistic regression analyses to calculate odds ratios (ORs) and 95% confidence intervals (CIs) of women’s perceived level of education received related to healthcare providers’ exposure to media-based education. Results: Media-based education on LRRFs during pregnancy through gynecologists and/or midwives were significantly associated with women’s perceived level of education received (gynecologists: OR = 4.26 (95% CI: 2.04, 8.90; p < .001); midwives: OR = 3.86 (95% CI: 1.66, 8.98; p = .002)). Similar results were found for media-based education through gynecologists and/or midwives on LRRFs during lactation and its association with women’s self-assessed level of perceived level of education received (gynecologists: OR = 4.76 (95% CI: 2.15, 10.56; p < .001); midwives: OR = 7.61 (95% CI: 3.13, 18.53; p < .001)). Conclusions: This study suggests that the exposure to media-based education in gynecological and obstetric care increases women’s perceived level of education received of LRRFs during pregnancy and lactation. Therefore, it is recommendable to apply media in gynecological and obstetric care settings.
Design of the DAVOS Study: Diabetes Smartphone App, a Fully Automatic Transmission of Data From the Blood Glucose Meter and Insulin Pens Using Wireless Technology to Enhance Diabetes Self-Management—A Study Protocol for a Randomized Controlled Trial
Authors: Grosser Franziska , Herrmann Sandra , Bretschneider Maxi , Timpel Patrick , Schildt Janko , Bentrup Markus , Schwarz Peter E. H. 
Published: April 2022

Background: In the treatment of diabetes mellitus, the challenge is to integrate adequate self-management into clinical care. Customization including goal setting, monitoring, and feedback could be achieved through digitization. Digital linking between different devices could simplify and promote self-management. The aim of this study is to evaluate the outcome of diabetes treatment assisted by a digital health application compared with standard diabetes therapy. Methods: The DAVOS study is a 6-month-period prospective, multicentric, randomized controlled trial. In total, 154 diabetes patients (age ≥18; treated with insulin) will be recruited and randomized into control group or intervention group. Both groups will receive standard diabetes care. The intervention group will additionally use a diabetes app. HbA1c value will be monitored on three separate defined visits. Primary endpoint is the overall reduction of HbA1c value. Secondary endpoints (eg, usability of the app) will be determined through patient-reported outcome questionnaires. Discussion: Through enhanced interaction of health care professionals, providers of the app, and patients, the study aims to demonstrate improvement in the self-management of diabetes. As part of the closure management, all patients will be invited to use the examined application after completion of the study. The DAVOS study will be conducted in accordance with the valid version of the present study protocol and the internationally recognized International Conference on Harmonization–Good Clinical Practice (ICH-GCP) Guidelines. Special attention will be paid to European, national, and regional requirements for the approval, provision, and use of medical devices. The study was registered in the German Register of Clinical Trials (DRKS) with number DRKS00025996.