bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smart pumps improve medication safety but increase alert burden in neonatal care
Authors: Melton Kristin R. , Timmons Kristen , Walsh Kathleen E. , Meinzen-Derr Jareen K. , Kirkendall Eric 
Published: November 2019

Abstract

Background
Smart pumps have been widely adopted but there is limited evidence to understand and support their use in pediatric populations. Our objective was to assess whether smart pumps are effective at reducing medication errors in the neonatal population and determine whether they are a source of alert burden and alert fatigue in an intensive care environment.

Methods
Using smart pump records, over 370,000 infusion starts for continuously infused medications used in neonates and infants hospitalized in a level IV NICU from 2014 to 2016 were evaluated. Attempts to exceed preset soft and hard maximum limits, percent variance from those limits, and pump alert frequency, patterns and salience were evaluated.

Results
Smart pumps prevented 160 attempts to exceed the hard maximum limit for doses that were as high as 7–29 times the maximum dose and resulted in the reprogramming or cancellation of 2093 infusions after soft maximum alerts. While the overall alert burden from smart pumps for continuous infusions was not high, alerts clustered around specific patients and medications, and a small portion (17%) of infusions generated the majority of alerts. Soft maximum alerts were often overridden (79%), consistent with low alert salience.

Conclusions
Smart pumps have the ability to improve neonatal medication safety when compliance with dose error reducing software is high. Numerous attempts to administer high doses were intercepted by dosing alerts. Clustered alerts may generate a high alert burden and limit safety benefit by desensitizing providers to alerts. Future efforts should address ways to improve alert salience.
Workload and influencing factors in non-emergency medical transfers: a multiple linear regression analysis of a cross-sectional questionnaire study
Authors: Keunecke Johann Georg , Gall Christine , Birkholz Torsten , Moritz Andreas , Eiche Christian , Prottengeier Johannes 
Published: November 2019

Abstract

Background
Human workload is a key factor for system performance, but data on emergency medical services (EMS) are scarce. We investigated paramedics’ workload and the influencing factors for non-emergency medical transfers. These missions make up a major part of EMS activities in Germany and are growing steadily in number.

Methods
Paramedics rated missions retrospectively through an online questionnaire. We used the NASA-Task Load Index (TLX) to quantify workload and asked about a variety of medical and procedural aspects for each mission. Teamwork was assessed by the Weller teamwork measurement tool (TMT). With a multiple linear regression model, we identified a set of factors leading to relevant increases or decreases in workload.

Results
A total of 194 non-emergency missions were analysed. Global workload was rated low (Mean = 27/100). In summary, 42.8% of missions were rated with a TLX under 20/100. TLX subscales revealed low task demands but a very positive self-perception of performance (Mean = 15/100). Teamwork gained high ratings (Mean TMT = 5.8/7), and good teamwork led to decreases in workload. Aggression events originating from patients and bystanders occurred frequently (n = 25, 12.9%) and increased workload significantly. Other factors affecting workload were the patient’s body weight and the transfer of patients with transmittable pathogens.

Conclusion
The workload during non-emergency medical transfers was low to very low, but performance perception was very positive, and no indicators of task underload were found. We identified several factors that led to workload increases. Future measures should attempt to better train paramedics for aggression incidents, to explore the usefulness of further technical aids in the transfer of obese patients and to reconsider standard operating procedures for missions with transmittable pathogens.
5-Aminolevulinic acid fermentation using engineered Saccharomyces cerevisiae
Authors: Hara Kiyotaka Y. , Saito Masaru , Kato Hiroko , Morikawa Kana , Kikukawa Hiroshi , Nomura Hironari , Fujimoto Takanori , Hirono-Hara Yoko , Watanabe Shigeyuki , Kanamaru Kengo , Kondo Akihiko 
Published: November 2019

Abstract

Background
5′-Aminolevulinic acid (ALA) is widely used in the pharmaceutical industry, healthcare, and food production, and is a substrate for the biosynthesis of heme, which is required for respiration and photosynthesis. Enhancement of ALA biosynthesis has never been developed in Saccharomyces cerevisiae, which is a well-known model microorganism used for bioproduction of many value-added compounds.

Results
We demonstrated that metabolic engineering significantly improved ALA production in S. cerevisiae. First, we found that overexpression of HEM1, which encodes ALA synthetase, increased ALA production. Furthermore, addition of an optimal amount of glycine, a substrate for ALA biosynthesis, or levulinic acid, an inhibitor of ALA dehydrogenase, effectively increased ALA production. Next, we developed an assay for multiple metabolites including ALA and found that aconitase, encoded by ACO1 and ACO2, is the rate-limiting enzyme of ALA biosynthesis when sufficient glycine is supplied. Overexpression of ACO2 further enhanced ALA production in S. cerevisiae overexpressing HEM1.

Conclusions
In this study, ALA production in S. cerevisiae was enhanced by metabolic engineering. This study also shows a strategy to identify the rate-limiting step of a target synthetic pathway by assay for multiple metabolites alongside the target product. This strategy can be applied to improve production of other valuable products in the well-studied and well-industrialized microorganism S. cerevisiae.
High production of valencene in Saccharomyces cerevisiae through metabolic engineering
Authors: Chen Hefeng , Zhu Chaoyi , Zhu Muzi , Xiong Jinghui , Ma Hao , Zhuo Min , Li Shuang 
Published: November 2019

AbstractBackgroundThe biological synthesis of high value compounds in industry through metabolically engineered microorganism factories has received increasing attention in recent years. Valencene is a high value ingredient in the flavor and fragrance industry, but the low concentration in nature and high cost of extraction limits its application.Saccharomyces cerevisiae, generally recognized as safe, is one of the most commonly used gene expression hosts. Construction ofS. cerevisiaecell factory to achieve high production of valencene will be attractive.ResultsValencene was successfully biosynthesized after introducing valencene synthase intoS. cerevisiaeBJ5464. A significant increase in valencene yield was observed after down-regulation or knock-out of squalene synthesis and other inhibiting factors (such aserg9,rox1) in mevalonate (MVA) pathway using a recyclable CRISPR/Cas9 system constructed in this study through the introduction of Cre/loxP. To increase the supplement of the precursor farnesyl pyrophosphate (FPP), all the genes of FPP upstream in MVA pathway were overexpressed in yeast genome. Furthermore, valencene expression cassettes containing different promoters and terminators were compared, and PHXT7-VS-TTPI1was found to have excellent performance in valencene production. Finally, after fed-batch fermentation in 3 L bioreactor, valencene production titer reached 539.3 mg/L with about 160-fold improvement compared to the initial titer, which is the highest reported valencene yield.ConclusionsThis study achieved high production of valencene inS. cerevisiaethrough metabolic engineering and optimization of expression cassette, providing good example of microbial overproduction of valuable chemical products. The construction of recyclable plasmid was useful for multiple gene editing as well.
Exosomal microRNA-205 is involved in proliferation, migration, invasion, and apoptosis of ovarian cancer cells via regulating VEGFA
Authors: Wang Lijun , Zhao Fei , Xiao Zhongqing , Yao Liang 
Published: November 2019

Abstract

Background
Recently, the impact of microRNAs (miRNAs) and exosome on ovarian cancer has been assessed in many studies. We aim to explore the mechanism of exosomes transferring miR-205 in ovarian cancer, and confirm its diagnostic value in ovarian cancer.

Methods
The expression of miR-205 of ovarian cancer patients and healthy people was detected by RT-qPCR, and the diagnostic value of miR-205 was evaluated. The exosomes derived from SKOV3 cells were identified. Ovarian cancer SKOV3 donor cells and receptor cells were used to measure the proliferation, migration, invasion, apoptosis and cell cycle by a series of experiments. The binding site between miR-205 and vascular endothelial growth factor A (VEGFA) was evaluated by bioinformatics tool and dual-luciferase reporter gene assay.

Results
MiR-205 was up-regulated in ovarian cancer, and up-regulated miR-205 could enhance the risk of ovarian cancer and was one of its risk factors. After SKOV3 cells-derived exosomes were transiently introduced with miR-205 mimics, the cell proliferation, migration and invasion in ovarian cancer were elevated, the apoptosis of ovarian cancer cells was attenuated, and the epithelial–mesenchymal transition (EMT) protein E-cadherin was down-regulated, while Vimentin was elevated. VEGFA was identified to be a target gene of miR-205.

Conclusion
This study suggests that exosomes from donor ovarian cancer cell SKOV3 shuttled miR-205 could participate in the regulation of the proliferation, migration, invasion, apoptosis as well as EMT progression of receptor SKOV3 cells by targeting VEGFA.
ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis
Authors: Lin Qiushi , Chen Xuesong , Meng Fanzheng , Ogawa Kosuke , Li Min , Song Ruipeng , Zhang Shugeng , Zhang Ziran , Kong Xianglu , Xu Qinggang , He Fuliang , Bai Xuewei , Sun Bei , Hung Mien-Chie , Liu Lianxin , Wands Jack , Dong Xiaoqun 
Published: November 2019

Abstract

Background
Aspartate β-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer.

Methods
Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied.

Results
Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH’s β-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis.

Conclusions
ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH’s pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.
Serum and follicular fluid thyroid hormone levels and assisted reproductive technology outcomes
Authors: Cai Yun Ying , Lin Na , Zhong Lan Ping , Duan Hui Juan , Dong Yun Hua , Wu Ze , Su Heng 
Published: November 2019

AbstractObjectiveThe objective ofthis study was to assess the association between thyroid hormone (TH) levels in follicular fluid (FF) and serum and to determine whether THs impact assisted reproductive technology (ART) outcomes.MethodsThis study enrolled 299 women undergoing ART. Blood samples were drawn on the day of human chorionic gonadotrophin (HCG) administrationand analysed for thyroid-stimulating hormone (TSH), thyroxine(T4), triiodothyronine(T3),free T4 (fT4),free T3(fT3), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) levels. FF was obtained on the oocyte pick up (OPU) day and analysed forTSH, T4, T3, fT4, fT3, TPOAb, TgAb and estradiol levels.Results(1) There were significant positive correlations between serum and FF TH and thyroid autoantibody levels. Statistically significant differences were discovered in serum and FF levels of TSH (p ≤ 0.001), T4 (p ≤ 0.001), T3 (p ≤ 0.001), TPOAbs (p ≤ 0.001) and TGAbs (p = 0.021).(2) Serum T4 levels [121.9(104.8,140.8) vs 114.1(98.6,130.6) nmol/l,p = 0.026], serum fT4 levels[(19.0(17.7,21.8) vs 18.6(17.0,20.1) pmol/l,p = 0.026], serum T4/T3 ratios [62.5 (55.7, 66.2) vs 59.4 (53.4, 64.9),p = 0.029], FF fT4 levels [19.0(17.5,21.3) vs 18.1(16.8,19.9) pmol/l,p = 0.009] and FF T4/T3 ratios [52.6 (46.4, 57.3) vs 50.0 (43.7, 53.1),p = 0.004] were significantly higher in the successful pregnancy group than the implantation failure group.(3) Spearman’s rank correlation analysis revealed positive associations of both the FF T4/T3 ratio and serum TSH levels with the numbers of retrieved oocytes (total or MII) and embryos (fertilized, cleavage, and good quality).ConclusionsTH levels in FF are strongly correlated with those in serum on the HCG day, and THs on the HCG day may affect ART outcomes.
Platelets promote breast cancer cell MCF-7 metastasis by direct interaction: surface integrin α2β1-contacting-mediated activation of Wnt-β-catenin pathway
Authors: Zuo Xiao-xiao , Yang Ya , Zhang Yue , Zhang Zhi-gang , Wang Xiao-fei , Shi Yong-gang 
Published: November 2019

Abstract

Background
Integrin-mediated platelet-tumor cell contacting plays an important role in promoting epithelial-mesenchymal transition (EMT) transformation of tumor cells and cancer metastasis, but whether it occurs in breast cancer cells is not completely clear.

Objective
The purpose of this study was to investigate the role of integrin α2β1 in platelet contacting to human breast cancer cell line MCF-7 and its effect on the EMT and the invasion of MCF-7 cells.

Methods
Human platelets were activated by thrombin, and separated into pellets and releasates before the co-incubation with MCF-7 cells. Cell invasion was evaluated by transwell assay. The surface integrins on pellets and MCF-7 cells were inhibited by antibodies. The effect of integrin α2β1 on Wnt-β-catenin pathway was assessed by integrin α2β1-silencing and Wnt-β-catenin inhibitor XAV. The therapeutic effect of integrin α2β1-silencing was confirmed in the xenograft mouse model.

Results
Pellets promote the invasion and EMT of MCF-7 cells via direct contacting of surface integrin α2β1. The integrin α2β1 contacting activates Wnt-β-catenin pathway and promotes the expression of EMT proteins in MCF-7 cells. The activated Wnt-β-catenin pathway also promotes the autocrine of TGF-β1 in MCF-7 cells. Both Wnt-β-catenin and TGF-β1/pSmad3 pathways promote the expression of EMT proteins. Integrin α2β1-silencing inhibits breast cancer metastasis in vivo.

Conclusions
The direct interaction between platelets and tumor cells exerts its pro-metastatic function via surface integrin α2β1 contacting and Wnt-β-catenin activation. Integrin α2β1-silencing has the potential effect of inhibiting breast cancer metastasis.
Changes in cytokine and chemokine profiles in mouse serum and brain, and in human neural cells, upon tick-borne encephalitis virus infection
Authors: Pokorna Formanova Petra , Palus Martin , Salat Jiri , Hönig Vaclav , Stefanik Michal , Svoboda Pavel , Ruzek Daniel 
Published: November 2019

Abstract

Background
Tick-borne encephalitis (TBE) is a severe neuropathological disorder caused by tick-borne encephalitis virus (TBEV). Brain TBEV infection is characterized by extensive pathological neuroinflammation. The mechanism by which TBEV causes CNS destruction remains unclear, but growing evidence suggests that it involves both direct neuronal damage by the virus infection and indirect damage caused by the immune response. Here, we aimed to examine the TBEV-infection-induced innate immune response in mice and in human neural cells. We also compared cytokine/chemokine communication between naïve and infected neuronal cells and astrocytes.

Methods
We used a multiplexed Luminex system to measure multiple cytokines/chemokines and growth factors in mouse serum samples and brain tissue, and in human neuroblastoma cells (SK-N-SH) and primary cortical astrocytes (HBCA), which were infected with the highly pathogenic TBEV strain Hypr. We also investigated changes in cytokine/chemokine production in naïve HBCA cells treated with virus-free supernatants from TBEV-infected SK-N-SH cells and in naïve SK-N-SH cells treated with virus-free supernatants from TBEV-infected HBCA cells. Additionally, a plaque assay was performed to assess how cytokine/chemokine treatment influenced viral growth following TBEV infection.

Results
TBEV-infected mice exhibited time-dependent increases in serum and brain tissue concentrations of multiple cytokines/chemokines (mainly CXCL10/IP-10, and also CXCL1, G-CSF, IL-6, and others). TBEV-infected SK-N-SH cells exhibited increased production of IL-8 and RANTES and downregulated MCP-1 and HGF. TBEV infection of HBCA cells activated production of a broad spectrum of pro-inflammatory cytokines, chemokines, and growth factors (mainly IL-6, IL-8, CXCL10, RANTES, and G-CSF) and downregulated the expression of VEGF. Treatment of SK-N-SH with supernatants from infected HBCA induced expression of a variety of chemokines and pro-inflammatory cytokines, reduced SK-N-SH mortality after TBEV infection, and decreased virus growth in these cells. Treatment of HBCA with supernatants from infected SK-N-SH had little effect on cytokine/chemokine/growth factor expression but reduced TBEV growth in these cells after infection.

Conclusions
Our results indicated that both neurons and astrocytes are potential sources of pro-inflammatory cytokines in TBEV-infected brain tissue. Infected/activated astrocytes produce cytokines/chemokines that stimulate the innate neuronal immune response, limiting virus replication, and increasing survival of infected neurons.
Quercetin prevents necroptosis of oligodendrocytes by inhibiting macrophages/microglia polarization to M1 phenotype after spinal cord injury in rats
Authors: Fan Hong , Tang Hai-Bin , Shan Le-Qun , Liu Shi-Chang , Huang Da-Geng , Chen Xun , Chen Zhe , Yang Ming , Yin Xin-Hua , Yang Hao , Hao Ding-Jun 
Published: November 2019

Abstract

Background
Oligodendrocytes (OLs) death after spinal cord injury (SCI) contributes to demyelination, even leading to a permanent neurological deficit. Besides apoptosis, our previous study demonstrated that OLs underwent receptor-interacting serine-threonine kinase 3(RIP3)/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. Considering that necroptosis is always accompanied with pro-inflammatory response and quercetin has long been used as anti-inflammatory agent, in the present study we investigated whether quercetin could inhibit necroptosis of OLs and suppress the M1 macrophages/microglia-mediated immune response after SCI as well as the possible mechanism.

Methods
In this study, we applied quercetin, an important flavonoid component of various herbs, to treat rats with SCI and rats injected with saline were employed as the control group. Locomotor functional recovery was evaluated using Basso-Beattie-Bresnahan (BBB) scoring and rump-height Index (RHI) assay. In vivo, the necroptosis, apoptosis, and regeneration of OLs were detected by immunohistochemistry, 5′-bromo-2′-deoxyuridine (BrdU) incorporation. The loss of myelin and axons after SCI were evaluated by Luxol fast blue (LFB) staining, immunohistochemistry, and electron microscopic study. The polarization of macrophages/microglia after SCI and the underlying mechanisms were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. In vitro, the ATP and reactive oxygen species (ROS) level examination, propidium iodide (PI) labeling, and Western blotting were used to analyze the necroptosis of cultured OLs, while the signaling pathways-mediated polarization of cultured macrophages/microglia was detected by qRT-PCR and Western blotting.

Results
We demonstrated that quercetin treatment improved functional recovery in rats after SCI. We then found that quercetin significantly reduced necroptosis of OLs after SCI without influencing apoptosis and regeneration of OLs. Meanwhile, myelin loss and axon loss were also significantly reduced in quercetin-treated rats, as compared to SCI + saline control. Further, we revealed that quercetin could suppress macrophages/microglia polarized to M1 phenotype through inhibition of STAT1 and NF-κB pathway in vivo and in vitro, which contributes to the decreased necroptosis of OLs.

Conclusions
Quercetin treatment alleviated necroptosis of OLs partially by inhibiting M1 macrophages/microglia polarization after SCI. Our findings suggest that necroptosis of OLs may be a potential therapeutic target for clinical SCI.
Patient with severe fever with thrombocytopenia syndrome virus infection and central nervous system disturbance in Dongyang, Zhejiang Province, China, 2017
Authors: Sun Yi , Guo Bin , Yan Hao , Wu Ai Lan , Yao Wen Wu , Chen Kang , Pan Jun Hang , Li Zhao Xia , Mao Hai Yan , Zhang Yan Jun 
Published: November 2019

Abstract

Background
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever that was first described in China in 2011. We report a patient who died of Severe fever with thrombocytopenia syndrome virus (SFTSV) infection, with a rapidly progressive central nervous system (CNS) disturbance, in Dongyang, Zhejiang Province, China, in 2017.

Case presentation
A 64-year-old man was admitted to hospital after 4 days of fever. SFTSV was detected 1 day after the patient was admitted to hospital. The patient presented with CNS disturbance and died 4 days after admission. Detailed clinical and epidemiological investigations and laboratory tests were conducted. Reduced platelet, white blood cell, lymphocyte, and neutrophil counts, elevated lactate dehydrogenase, creatine kinase, aspartate aminotransferaseand alanine aminotransferase concentrations, and an increased activated partial thromboplastin time were observed. In a phylogenetic analysis, the isolate clustered close to a strain derived from South Korea.
Conclusions: This is the first case of SFTSV infection with CNS disturbance in Dongyang, Zhejiang Province, China. The surveillance of suspected cases of SFTS is important in SFTSV endemic regions.