bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of the acute surgical assessment unit on the management of acute appendicitis: a single-centre review
Authors: Hannan Enda , El-Masry Sherif 
Published: July 2021

Abstract
Background
Acute surgical assessment units (ASAUs) aim to optimise management of surgical patients compared to the traditional ‘on-call’ emergency department (ED) system. Acute appendicitis (AA) is the most common acute surgical condition requiring emergency surgery.

Aim
We set out to assess if the ASAU improved care provided to patients with AA compared to those managed through the ED.

Methods
Patients admitted via the ED with AA in the 6 months prior to opening the ASAU were compared to those admitted via the ASAU in the first six months following its implementation. Relevant data was collected on key performance indicators from their charts.

Results
In the ASAU cohort, the mean time to be seen was one hour less than the ED cohort (21 min vs 74 min). The mean time to surgery was also 8.8 h shorter. Most patients in the ASAU group (78.6%) underwent surgery during the day, compared to 40.3% of ED patients. The ASAU patients also had a lower postoperative complication rate (0.9% vs 3.9%), as well as a lower negative appendicectomy rate (14.2% vs 18.6%) and lower conversion-to-open surgery rate. Greater consultant supervision and presence was observed.

Conclusions
The ASAU has resulted in better outcomes for patients with AA than those admitted via ED. More operations were performed in safer daytime hours with greater consultant presence, allowing for improved senior support for trainee surgeons. Our study supports the role of the ASAU in improving the quality and efficiency of emergency general surgery.
Can Autonomous Agents Without Phenomenal Consciousness Be Morally Responsible?
Authors: Bernáth László 
Published: July 2021

AbstractIt is an increasingly popular view among philosophers that moral responsibility can, in principle, be attributed to unconscious autonomous agents. This trend is already remarkable in itself, but it is even more interesting that most proponents of this view provide more or less the same argument to support their position. I argue that as it stands, the Extension Argument, as I call it, is not sufficient to establish the thesis that unconscious autonomous agents can be morally responsible. I attempt to show that the Extension Argument should overcome especially strong ethical considerations; moreover, its epistemological grounds are not too solid, partly because the justifications of its premises are in conflict.
Answers to burning questions for clinical allergologists related to the new COVID-19 vaccines
Authors: Altrichter Sabine , Wöhrl Stefan , Horak Fritz , Idzko Marco , Jordakieva Galateja , Untersmayr Eva , Szepfalusi Zsolt , Zieglmayer Petra , Jensen-Jarolim Erika , Wiedermann Ursula , Rosenkranz Alexander , Hötzenecker Wolfram 
Published: July 2021

Abstract
Background
Along with the newly approved vaccines against coronavirus disease 2019 (COVID-19), first reports of allergic or intolerance reactions were published. Subsequently, questions arose whether these vaccines pose an increased risk for intolerance reactions and whether allergic patients may be at higher risk for this.

Results
Allergic reactions following COVID-19 vaccinations have been reported, but mostly of mild severity and at normal (Moderna®) or only slightly increased frequency (BioNTech/Pfizer®) compared to established conventional vaccines. The risk of allergic reaction to the newly licensed vector vaccines (AstraZeneca®, Johnson&Johnson®) cannot be conclusively assessed yet, but also appears to be low. There is currently no evidence that patients with allergic diseases (atopic patients) react more frequently or more severely to these vaccines. It is currently assumed that intolerance reactions of the immediate-type are either type I allergic (IgE-mediated) reactions or occur via complement activation (CARPA, “complement activation-related pseudoallergy”). Polyethylene glycol (PEG) or polysorbate, which are present as stabilizers in the vaccines, are suspected as triggers for this.

Conclusion
The data available so far do not show a significantly increased risk of immediate-type allergic reactions in atopic persons. In almost all cases, atopic patients can be vaccinated without problems. Standardized follow-up tests after suspected allergic reactions or CARPA-mediated reactions are currently limited.
Wrong place, wrong time: Children’s sensitivity to present tense spelling conventions
Authors: de Bree Elise , van den Boer Madelon 
Published: July 2021

AbstractSpelling has been found to be influenced by the frequency with which certain orthographic patterns occur. We examined whether Grades 2–5 children were already sensitive to orthographic frequency in spelling present tense verb inflections that sound the same but are spelled differently. Children were asked to spell present tenses in two homophonous forms; both inflections are pronounced with final /t/ but are spelled with final -d (“ik vind,” I find) or -dt (“hij/zij vindt,” he/she finds). Previous research has shown that adolescents and adults make inflection errors based on the relative frequency within a pair; as “vind’ is more frequent than “vindt,” “vind” is often used incorrectly. The children showed low correct scores for third person singular spellings, and overall better performance for -d dominant verbs. Surprisingly, they did make errors related to homophone inflection but in the wrong place, marking the wrong time: homophone-based errors occurred in present tense non-homophone verbs and in past tenses. We take our findings to mean that the children were not sensitive to homophone dominance. Furthermore, the findings illustrate the importance of specific graphotactic patterns in literacy development and call for attention to these patterns in models and teaching of spelling.
Global Uptake of Atmospheric Methane by Soil From 1900 to 2100
Authors: Murguia‐Flores Fabiola , Ganesan Anita L. , Arndt Sandra , Hornibrook Edward R. C. 
Published: July 2021

AbstractSoil methanotrophy is the only biological process that removes methane (CH4) from the atmosphere. There is good agreement about the size of the global sink but great uncertainty about its interannual variability and regional responses to changes in key environmental drivers. We used the process‐based methanotrophy model Methanotrophy Model (MeMo) v1.0 and output from global climate models to simulate regional and global changes in soil uptake of atmospheric CH4 from 1900 to 2100. The annual global uptake doubled from 17.1 ± 2.4 to 37.2 ± 3.3 Tg yr−1 from 1900‐2015 and could increase further to 82.7 ± 4.4 Tg yr−1 by 2100 (RCP8.5), primarily due to enhanced diffusion of CH4 into soil as a result of increases in atmospheric CH4 mole fraction. We show that during the period 1980–2015 temperature became an important influence on the increasing rates of soil methanotrophy, particularly in the Northern Hemisphere. In RCP‐forced simulations the relative influence of temperature on changes in the uptake continues to increase, enhancing the soil sink through higher rates of methanotrophic metabolic activity, increases in the global area of active soil methanotrophy and length of active season. During the late 21st century under RCP6.0, temperature is predicted to become the dominant driver of changes in global mean soil uptake rates for the first time. Regionally, in Europe and Asia, nitrogen inputs dominate changes in soil methanotrophy, while soil moisture is the most important influence in tropical South America. These findings highlight that the soil sink could change in response to drivers other than atmospheric CH4 mole fraction.
cGAS-like receptors sense RNA and control 3′2′-cGAMP signalling in Drosophila
Authors: Slavik Kailey M. , Morehouse Benjamin R. , Ragucci Adelyn E. , Zhou Wen , Ai Xianlong , Chen Yuqiang , Li Lihua , Wei Ziming , Bähre Heike , König Martin , Seifert Roland , Lee Amy S. Y. , Cai Hua , Imler Jean-Luc , Kranzusch Philip J. 
Published: July 2021

AbstractCyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor that produces the second messenger cG[2′–5′]pA[3′–5′]p (2′3′-cGAMP) and controls activation of innate immunity in mammalian cells1–5. Animal genomes typically encode multiple proteins with predicted homology to cGAS6–10, but the function of these uncharacterized enzymes is unknown. Here we show that cGAS-like receptors (cGLRs) are innate immune sensors that are capable of recognizing divergent molecular patterns and catalysing synthesis of distinct nucleotide second messenger signals. Crystal structures of human and insect cGLRs reveal a nucleotidyltransferase signalling core shared with cGAS and a diversified primary ligand-binding surface modified with notable insertions and deletions. We demonstrate that surface remodelling of cGLRs enables altered ligand specificity and used a forward biochemical screen to identify cGLR1 as a double-stranded RNA sensor in the model organismDrosophila melanogaster. We show that RNA recognition activatesDrosophilacGLR1 to synthesize the novel product cG[3′–5′]pA[2′–5′]p (3′2′-cGAMP). A crystal structure ofDrosophilastimulator of interferon genes (dSTING) in complex with 3′2′-cGAMP explains selective isomer recognition, and 3′2′-cGAMP induces an enhanced antiviral state in vivo that protects from viral infection. Similar to radiation of Toll-like receptors in pathogen immunity, our results establish cGLRs as a diverse family of metazoan pattern recognition receptors.
CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis
Authors: Bae Daekwon , Lee Ji-Young , Ha Nina , Park Jinsol , Baek Jiyeon , Suh Donghyeon , Lim Hee Seon , Ko Soo Min , Kim Taehee , Som Jeong Da , Son Woo-chan 
Published: July 2021

AbstractDespite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35–55(MOG35–55)-induced experimental autoimmune encephalitis (EAE) under various treatment regimens. CKD-506 exerted prophylactic and therapeutic effects by regulating peripheral immune responses and maintaining blood–brain barrier (BBB) integrity. In MOG35–55-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-γ and IL-17A. CKD-506 downregulated the levels of pro-inflammatory cytokines in the blood of EAE mice. Additionally, CKD-506 decreased the leakage of intravenously administered Evans blue into the spinal cord; CD4+T cells and CD4−CD11b+CD45+macrophage/microglia in the spinal cord was also decreased. Moreover, CKD-506 exhibited therapeutic efficacy against MS, even when drug administration was discontinued from day 15 post-EAE induction. Disease exacerbation was not observed when fingolimod was changed to CKD-506 from day 15 post-EAE induction. CKD-506 alleviated depression-like behavior at the pre-symptomatic stage of EAE. In conclusion, CKD-506 exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity. Our results suggest that CKD-506 is a potential therapeutic agent for MS.
Identification of hub genes in colorectal cancer based on weighted gene co-expression network analysis and clinical data from The Cancer Genome Atlas
Authors: Zhang Yu , Luo Jia , Liu Zhe , Liu Xudong , Ma Ying , Zhang Bohang , Chen Yuxuan , Li Xiaofeng , Feng Zhiguo , Yang Ningning , Feng Dayun , Wang Lei , Song Xinqiang 
Published: July 2021

Abstract
Colorectal cancer (CRC) is one of the most common tumors worldwide and is associated with high mortality. Here we performed bioinformatics analysis, which we validated using immunohistochemistry in order to search for hub genes that might serve as biomarkers or therapeutic targets in CRC. Based on data from The Cancer Genome Atlas (TCGA), we identified 4832 genes differentially expressed between CRC and normal samples (1562 up-regulated and 3270 down-regulated in CRC). Gene ontology (GO) analysis showed that up-regulated genes were enriched mainly in organelle fission, cell cycle regulation, and DNA replication; down-regulated genes were enriched primarily in the regulation of ion transmembrane transport and ion homeostasis. Weighted gene co-expression network analysis (WGCNA) identified eight gene modules that were associated with clinical characteristics of CRC patients, including brown and blue modules that were associated with cancer onset. Analysis of the latter two hub modules revealed the following six hub genes: adhesion G protein-coupled receptor B3 (BAI3, also known as ADGRB3), cyclin F (CCNF), cytoskeleton-associated protein 2 like (CKAP2L), diaphanous-related formin 3 (DIAPH3), oxysterol binding protein-like 3 (OSBPL3), and RERG-like protein (RERGL). Expression levels of these hub genes were associated with prognosis, based on Kaplan–Meier survival analysis of data from the Gene Expression Profiling Interactive Analysis database. Immunohistochemistry of CRC tumor tissues confirmed that OSBPL3 is up-regulated in CRC. Our findings suggest that CCNF, DIAPH3, OSBPL3, and RERGL may be useful as therapeutic targets against CRC. BAI3 and CKAP2L may be novel biomarkers of the disease.
Hemostasis and Fibrinolysis following Aneurysmal Subarachnoid Hemorrhage: A Systematic Review on Additional Knowledge from Dynamic Assays and Potential Treatment Targets
Authors: Hvas Christine Lodberg , Hvas Anne-Mette 
Published: July 2021

AbstractMortality after aneurysmal subarachnoid hemorrhage (aSAH) is augmented by rebleeding and delayed cerebral ischemia (DCI). A range of assays evaluating the dynamic process of blood coagulation, from activation of clotting factors to fibrinolysis, has emerged and a comprehensive review of hemostasis and fibrinolysis following aSAH may reveal targets of treatment. We conducted a systematic review of existing literature assessing coagulation and fibrinolysis following aSAH, but prior to treatment. PubMed, Embase, and Web of Science were searched on November 18, 2020, without time boundaries. In total, 45 original studies were eventually incorporated into this systematic review, divided into studies presenting data only from conventional or quantitative assays (n = 22) and studies employing dynamic assays (n = 23). Data from conventional or quantitative assays indicated increased platelet activation, whereas dynamic assays detected platelet dysfunction possibly related to an increased risk of rebleeding. Secondary hemostasis was activated in conventional, quantitative, and dynamic assays and this was related to poor neurological outcome and mortality. Studies systematically investigating fibrinolysis were sparse. Measurements from conventional or quantitative assays, as well as dynamic fibrinolysis assays, revealed conflicting results with normal or increased lysis and changes were not associated with outcome. In conclusion, dynamic assays were able to detect reduced platelet function, not revealed by conventional or quantitative assays. Activation of secondary hemostasis was found in both dynamic and nondynamic assays, while changes in fibrinolysis were not convincingly demonstrable in either dynamic or conventional or quantitative assays. Hence, from a mechanistic point of view, desmopressin to prevent rebleeding and heparin to prevent DCI may hold potential as therapeutic options. As changes in fibrinolysis were not convincingly demonstrated and not related to outcome, the use of tranexamic acid prior to aneurysm closure is not supported by this review.
Sensitivity of movement features to fatigue during an exhaustive treadmill run
Authors: Chalitsios Christos , Nikodelis Thomas , Konstantakos Vasileios , Kollias Iraklis 
Published: July 2021

ABSTRACTThe objective of the present study was to examine the sensitivity of several movement variables during running to exhaustion adopting a cross‐sectional design. Thirteen recreational runners, that systematically trained and competed, performed an exhaustive running protocol on an instrumented treadmill. Respiratory data were collected to establish the ventilatory threshold in order to obtain a reference point regarding the gradual accumulation of fatigue. A machine learning approach was adopted to analyse a set of 29,650 data points (individual steps) of kinetic and kinematic data, using a random forest classifier for the region pre and post the ventilatory threshold. The overall accuracy of the model was 0.914 (95% CI: 0.907–0.919). The four most important variables, and more sensitive in predictive ability, as it was concluded from the variable importance procedure and the partial dependence (PD), were the angular range in AP axis of upper trunk C7, the maximum loading rate, the angular range in LT axis of the C7 and the maximum value of the ground reaction force. Two‐dimensional PD revealed considerable interactions for certain areas of the joint distributions between kinetic and kinematic data. These results provide a direction towards understanding the interconnections of kinetics and kinematics of the torso to maintain the coordinated running pattern under fatigue conditions.Highlights
Trunk frontal plane kinematics is the most sensitive parameter to fatigue. Practitioners should consider this finding during endurance training.
Kinetics exhibit a stable linear increase in mean values but a non‐linear increase in variance during an exhaustive incremental treadmill run. This may affect training at a submaximal fatigued state.
Specific areas in the joint distributions of kinetics and kinematics during treadmill running exhibit increased sensitivity in predicting fatigue state.
Management Decisions in Crohn’s Disease Are Changed by Knowledge of Proactive and Reactive Testing of Antitumor Necrosis Factor Drug Levels
Authors: Wu Yang , Wen Amy , Selvanderan Shane P , Xuan Wei , Andrews Jane M , Koo Jenn H , Williams Astrid-Jane , Ng Watson , Connor Susan 
Published: July 2021

Abstract

Background
There is controversy about the proactive clinical application of therapeutic drug monitoring (TDM) of biologic drugs in Crohn’s disease (CD). One way to practically assess this is to examine how TDM influences management decisions. We examined how knowledge of proactive and reactive antitumor necrosis factor (anti-TNF) drug levels changes management in a variety of clinical scenarios.

Methods
In this retrospective cohort study, all adults with CD having trough level infliximab or adalimumab measurements at Liverpool Hospital between June 2013 and July 2016 were included. Demographics, indications for testing, anti-TNF drug levels, and treatment details were collected along with subsequent management decisions. The decision made by the treating clinician after receiving the drug level was compared to a consensus decision from a panel of 3 gastroenterologists based on the clinical, laboratory, imaging, and/or endoscopic results without the drug level. When these 2 decisions were discrepant, the anti-TNF drug level was deemed to have changed management.

Results
One hundred and eighty-seven trough levels of infliximab or adalimumab from 108 patients were analyzed. Overall, assessment of anti-TNF levels affected management in 46.9% of the instances. Knowledge of the drug level was also more likely to result in management change when the test was performed for reactive TDM compared to proactive TDM (63% vs 36%, P = .001).

Conclusions
The addition of TDM of anti-TNF agents to routine investigations alters management decisions in adult CD patients on anti-TNF therapy in both proactive and reactive settings.
Cyclic GMP modulating drugs in cardiovascular diseases: mechanism-based network pharmacology
Authors: Petraina Alexandra , Nogales Cristian , Krahn Thomas , Mucke Hermann , Lüscher Thomas F , Fischmeister Rodolphe , Kass David A , Burnett John C , Hobbs Adrian J , Schmidt Harald H H W 
Published: July 2021

AbstractMechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3′-5′-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalized cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP-modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here, we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether.
Bcar1/p130Cas is essential for ventricular development and neural crest cell remodelling of the cardiac outflow tract
Authors: Mahmoud Marwa , Evans Ian , Wisniewski Laura , Tam Yuen , Walsh Claire , Walker-Samuel Simon , Frankel Paul , Scambler Peter , Zachary Ian 
Published: July 2021

AbstractAimsThe adapter protein p130Cas, encoded by the Bcar1 gene, is a key regulator of cell movement, adhesion, and cell cycle control in diverse cell types. Bcar1 constitutive knockout mice are embryonic lethal by embryonic days (E) 11.5–12.5, but the role of Bcar1 in embryonic development remains unclear. Here, we investigated the role of Bcar1 specifically in cardiovascular development and defined the cellular and molecular mechanisms disrupted following targeted Bcar1 deletions.Methods and resultsWe crossed Bcar1 floxed mice with Cre transgenic lines allowing for cell-specific knockout either in smooth muscle and early cardiac tissues (SM22-Cre), mature smooth muscle cells (smMHC-Cre), endothelial cells (Tie2-Cre), second heart field cells (Mef2c-Cre), or neural crest cells (NCC) (Pax3-Cre) and characterized these conditional knock outs using a combination of histological and molecular biology techniques. Conditional knockout of Bcar1 in SM22-expressing smooth muscle cells and cardiac tissues (Bcar1SM22KO) was embryonically lethal from E14.5–15.5 due to severe cardiovascular defects, including abnormal ventricular development and failure of outflow tract (OFT) septation leading to a single outflow vessel reminiscent of persistent truncus arteriosus. SM22-restricted loss of Bcar1 was associated with failure of OFT cushion cells to undergo differentiation to septal mesenchymal cells positive for SMC-specific α-actin, and disrupted expression of proteins and transcription factors involved in epithelial-to-mesenchymal transformation (EMT). Furthermore, knockout of Bcar1 specifically in NCC (Bcar1PAX3KO) recapitulated part of the OFT septation and aortic sac defects seen in the Bcar1SM22KO mutants, indicating a cell-specific requirement for Bcar1 in NCC essential for OFT septation. In contrast, conditional knockouts of Bcar1 in differentiated smooth muscle, endothelial cells, and second heart field cells survived to term and were phenotypically normal at birth and postnatally.ConclusionOur work reveals a cell-specific requirement for Bcar1 in NCC, early myogenic and cardiac cells, essential for OFT septation, myocardialization and EMT/cell cycle regulation and differentiation to myogenic lineages.