bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural Basis of Vitamin K Antagonism
Authors: Li Weikai , Liu Shixuan , Li Shuang 
Published: February 2020

The vitamin K cycle supports blood coagulation, bone mineralization, and vascular calcium homeostasis. A key enzyme in this cycle, vitamin K epoxide reductase (VKOR), is the target of vitamin K antagonists (VKAs). Despite their extensive clinical use, the dose of VKAs (e.g., warfarin) is hard to regulate and overdose can lead to fatal bleeding. Improving the dose regulation requires understanding how VKAs inhibit VKOR, which is a membrane-embedded enzyme difficult to characterize with structural and biochemical studies. Here we achieve a long-standing goal of obtaining crystal structures of human VKOR with warfarin, which represents coumarin-based VKAs; with phenindione, which represents indandione-based VKAs; with superwarfarins, the most commonly used rodenticides; and with vitamin K epoxide in a reaction intermediate state. We have also solved structures of a VKOR-like homolog with warfarin, with vitamin K substrates, and without ligand. These structures show that human VKOR adopts an overall fold with four transmembrane helices (TM) and a large ER-luminal region. VKAs are bound at the active site of HsVKOR, which is formed by the surrounding four-TM bundle and a cap domain on top. The cap domain is stabilized by a linked anchor domain that interacts with the membrane surface. VKOR binds specifically to VKAs through hydrogen bonding to their diketone groups. Mutating VKOR residues recognizing the diketones render strong warfarin resistance. Except the hydrogen bonds, the binding pocket is largely hydrophobic. This pocket is incompatible with warfarin metabolite, explaining the inactivation of warfarin through CYP2C9 metabolism; CYP2C9 and VKOR genotypes can explain 30-50% of the patient variability in warfarin dose. In addition, the high potency of superwarfarins is due to the interaction of their side group with a tunnel where the isoprenyl chain of vitamin K is bound. For VKOR catalysis, the same residues affording the VKA-binding specificity also facilitate substrate reduction Initiation of the catalysis requires a reactive cysteine to form a substrate adduct. Interactions from this stably bound adduct induces a closed conformation, thereby triggering electron transfer to reduce the substrate. Importantly, the open to closed conformational change during catalysis similar to that induced by the binding of VKAs. Taken together, VKAs achieve inhibition through mimicking key interactions and conformational changes required for VKOR catalytic cycle. Understanding of these mechanisms will enable improved strategy to regulate warfarin dose and have a broad impact on thromboembolic diseases and bone disorders.

Disclosures
No relevant conflicts of interest to declare.
Prothrombin R541W Mutation Impairs Protein C Activation and Constitutes a New Genetic Risk Factor for Venous Thrombosis
Authors: WU XI , Jing Dai , Li Fang , Xu Qin , Chen Changming , Ding Qiulan , Wang Xuefeng , WU Wenman 
Published: February 2020

Defective protein C (PC) pathway predisposes patients to venous thromboembolism (VTE)and is mostly, but not exclusively, attributed tohereditary PC or protein S (PS) deficiencies and activated PC resistance caused by factor V Leiden mutation. In a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the three pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased. In conclusion, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin's procoagulant activity over anticoagulant function.
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Disclosures
Ding: Shanghai General Hospital affiliated to Shanghai Jiao Tong University, Shanghai: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work.. Wang:Ruijin Hospital, Shanghai Jiao Tong University School of Medicine: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work.. WU:Ruijin Hospital, Shanghai Jiao Tong University School of Medicine: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work..
Regulation of eIF4E Guides a Unique Translational Program to Steer Erythroid Maturation
Authors: Forester Craig M , Woo-Byeon Gun , Oses-Prieto Juan , Burlingame Al , Barna Maria , Ruggero Davide M 
Published: February 2020

Erythropoiesis is an intricately orchestrated process responsible for rapidly responding to an array of signaling cues to direct cell fates. While gene expression during erythropoiesis has mainly been studied at the transcription level, regulation of gene expression at the level of translation is still poorly understood. As translational control is one of the fastest steps to regulate protein abundance in the cell, we hypothesize that this mechanism plays an important role to rapidly control protein levels in response to extracellular cues during erythroid differentiation. However, outstanding questions remain on how translational control regulates specific gene programs in early erythroid states including 1.) how mRNA are selected for translation in normal erythropoiesis and 2.) how components of the translational machinery are regulated by upstream signaling pathways to orchestrate the translational landscape. In addressing these questions, we have nuncovered a dynamic interplay between Eukaryotic Initiation Factor 4E (eIF4E), the major mRNA cap binding protein that controls translation initiation and its repressor protein, 4EBP1 in erythropoiesis. Specifically, using in vivo phospho-flow cytometry analysis of the eIF4E-4EBP1 axis, eIF4E activity is high in early erythroid phases and is repressed by 4EBP1 in order to allow erythroid maturation. Surprisingly, high eIF4E activity in early erythroid precursors occurs without an increase in global protein synthesis. Utilizing a model of CD34+ human cord blood cells (HUDEP-2), we show that constitutive overexpression of eIF4E impaired erythropoietic maturation. To capture the specific proteins potentially regulated by eIF4E activity during erythropoiesis, we performed quantitative TMT mass spectrometry during HUDEP-2 erythroid differentiation. Our results revealed that eIF4E controls a specific key network of genes necessary for maintenance of early erythroid precursors. By analyzing the 5' untranslated region (5'UTR) of the eIF4E-dependent mRNA network, we identify a highly conserved, CT-rich motif which is required for these mRNAs to be more efficiently translated with increasing eIF4E levels. These results demonstrate wide-spread translational control of CT-rich mRNAs by eIF4E during early erythropoiesis. We are currently employing DMS-MaPseq to understand whether these motifs are also part of structured RNA elements that confer sensitivity to eIF4E levels. We have further extended these findings to a novel transgenic mouse model we have developed that allows in vivo assessment of increased eIF4E temporally at concise phases of erythroid maturation. Understanding this balance of eIF4E activity provides a novel insight into how of translational control dictates gene expression to determine phases of maturation in a crucial differentiation process.

Disclosures
No relevant conflicts of interest to declare.
Patients’ experiences of seeking help for emotional concerns in primary care: doctor as drug, detective and collaborator
Authors: Parker Daisy , Byng Richard , Dickens Chris , McCabe Rose 
Published: February 2020

Abstract
Background
NICE guidelines for the management of emotional concerns in primary care emphasise the importance of communication and a trusting relationship, which is difficult to operationalise in practice. Current pressures in the NHS mean that it is important to understand care from a patient perspective. This study aimed to explore patients’ experiences of primary care consultations for emotional concerns and what patients valued when seeking care from their GP.

Methods
Eighteen adults with experience of consulting a GP for emotional concerns participated in 4 focus groups. Data were analysed thematically.

Results
(1) Doctor as Drug: Patients’ relationship with their GP was considered therapeutic with continuity particularly valued. (2) Doctor as Detective and Validator: Patients were often puzzled by their symptoms, not recognising their emotional concerns. GPs needed to play the role of detective by exploring not just symptoms, but the person and their life circumstances. GPs were crucial in helping patients understand and validate their emotional concerns. (3) Doctor as Collaborator: Patients prefer a collaborative partnership, but often need to relinquish involvement because they are too unwell, or take a more active role because they feel GPs are ill-equipped or under too much pressure to help. Patients valued: GPs booking their follow up appointments; acknowledgement of stressful life circumstances; not relying solely on medication.

Conclusions
Seeking help for emotional concerns is challenging due to stigma and unfamiliar symptoms. GPs can support disclosure and understanding of emotional concerns by fully exploring and validating patients’ concerns, taking into account patients’ life contexts. This process of exploration and validation forms the foundation of a curative, trusting GP-patient relationship. A trusting relationship, with an emphasis on empathy and understanding, can make patients more able to share involvement in their care with GPs. This process is cyclical, as patients feel that their GP is caring, interested, and treating them as a person, further strengthening their relationship. NICE guidance should acknowledge the importance of empathy and validation when building an effective GP-patient partnership, and the role this has in supporting patients’ involvement in their care.
Information needs and information seeking behaviour of people with dementia and their non-professional caregivers: a scoping review
Authors: Soong Aijia , Au Shu Ting , Kyaw Bhone Myint , Theng Yin Leng , Tudor Car Lorainne 
Published: February 2020

Abstract
Background
People with dementia often require full-time caregivers especially in the later stages of their condition. People with dementia and caregivers’ access to reliable information on dementia is essential as it may have an important impact on patient care and quality of life. This study aims to provide an overview of the information needs and information seeking behaviour of people with dementia and their non-professional caregivers.

Methods
We conducted a scoping review of the literature and searched four electronic databases for eligible studies published up to August 2018. Two reviewers independently screened studies and extracted data. Information needs were classified according to emerging themes in the literature, and information seeking behaviour was categorized using Wilson’s model of information behaviour.

Results
Twenty studies with a total of 4140 participants, were included in this review. Reported information needs focused on: (i) disease; (ii) patient care provision; (iii) healthcare services; and (iv) caregiver self-care. The most commonly reported information need was on healthcare service-related information. Characteristics found to influence information needs were the severity of dementia as well as patient and caregiver status. People with dementia and non-professional caregivers mainly displayed active searching, information seeking behaviour and preferred using electronic sources to obtain health information.

Conclusion
Current dementia information sources available in English are extensive in the information they offer, but more emphasis needs to be placed on healthcare service-related information. All studies originated from high income countries and focused on information needs of non-professional caregivers only. The only variables found to be associated to information needs were severity of dementia condition as well as patient/caregiver status. The information needs identified in this review can be used to inform development and design of future dementia resources for people with dementia and their non-professional caregivers.
Nasogastric tube feeding versus assisted hand feeding in-home healthcare older adults with severe dementia in Taiwan: a prognosis comparison
Authors: Chou Hsiao-Hui , Tsou Meng-Ting , Hwang Lee-Ching 
Published: February 2020

Abstract
Background
All individuals with severe dementia should be offered careful hand feeding. However, under certain circumstances, people with severe dementia have a feeding tube placed. In Taiwan, tube feeding rate in demented older home care residents is increasing; however, the benefits of tube feeding in this population remain unknown. We compared the clinical prognosis and mortality of older patients with severe dementia receiving nasogastric tube feeding (NGF) or assisted hand feeding (AHF).

Methods
Data from the in-home healthcare system between January 1 and December 31, 2017 were analyzed to identify 169 participants over 60 years of age in this retrospective longitudinal study. All subjects with severe dementia and complete functional dependence suffered from difficulty in oral intake and required either AHF or NGF. Data were collected from both groups to analyze pneumonia, hospitalization, and mortality rates.

Results
A total of 169 subjects (56 males and 113 females, aged 85.9 ± 7.5 years) were analyzed. 39 required AHF and 130 NGF. All subjects were bedridden; 129 (76%) showed Barthel index < 10. Pneumonia risk was higher in the NGF group (48%) than in the AHF group (26%, p = 0.015). After adjusting for multiple factors in the regression model, the risk of pneumonia was not significantly higher in the NGF group compared with the AHF group. One-year mortality rates in the AHF and NGF groups were 8 and 15%, respectively, and no significant difference was observed after adjustment with logistic regression (aOR = 2.38; 95% CI, 0.58–9.70). There were no significant differences in hospitalization rate and duration.

Conclusions
For older patients with dementia requiring in-home healthcare, NGF is not associated with a significantly lower risk of pneumonia than AHF. Additionally, neither mortality nor hospitalization rates decreased with NGF. On the contrary, a nonsignificant trend of increased risk of pneumonia was observed in NGF group. Therefore, the benefits of NGF are debatable in older patients with severe dementia requiring in-home healthcare. Continued careful hand feeding could be an alternative to NG feeding in patients with severe dementia. Furthermore, large-scale studies on in-home healthcare would be required to support these results.
A post-market, multi-vessel evaluation of the imaging of peripheral arteries for diagnostic purposeS comparing optical Coherence tomogrApy and iNtravascular ultrasound imaging (SCAN)
Authors: Pavillard Edward , Sewall Luke 
Published: February 2020

AbstractBackgroundIntravascular imaging plays an important part in diagnosis of vascular conditions and providing insight for treatment strategy. Two main imaging modalities are intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The objective of this study was to prove non-inferiority of OCT imaging to IVUS images in matched segments of peripheral vessels in patients with suspected peripheral vascular disease.MethodsThe SCAN study was a prospective, non-inferiority clinical study of matched IVUS and OCT images collected along defined segments of peripheral vessels from twelve subjects (mean age 68 ± 10.3 years; 10 men) displaying symptoms of vascular disease. Luminal diameters were measured by both imaging systems at the distal, middle, and proximal points of the defined segments. Three blinded interventional radiologists evaluated the quality of both imaging modalities in identifying layered structures (3-point grading), plaque (5-point grading), calcification (5-point grading), stent structure (3-point grading), and artifacts (3-point grading) from 240 randomly ordered images. Mean grading scores and luminal diameters were calculated and analyzed with Student’s t-Test and Mann-Whitney-Wilcoxon testing. Intrareader reproducibility was calculated by intraclass correlation (ICC) analysis.ResultsThe mean scoring of plaque, calcification, and vascular stent struts by the three readers was significant better in terms of image quality for OCT than IVUS (p < 0.001,p = 0.001,p = 0.004, respectively). The mean scores of vessel wall component visibility and artifacts generated by the two imaging systems were not significantly different (p = 0.19,p = 0.07, respectively). Mean vessel luminal diameter and area at three specific locations within the vessels were not significantly different between the two imaging modalities. No patient injury, adverse effect or device malfunction were noted during the study.ConclusionsImaging by OCT provides the physician with better visualization of some vessel and plaque chacteristics, but both IVUS and OCT imaging are safe and effective methods of examining peripheral vessels in order to perform diagnostic assessment of peripheral vessels and provide information necessary for the treatment strategy of peripheral artery disease.Trial registrationNCT03480685registered on 29 March 2018.
Low dose of flurbiprofen axetil decrease the rate of acute kidney injury after operation: a retrospective clinical data analysis of 9915 cases
Authors: Wang Dong , Yang Shi-Kun , Zhao Meng-Xi , Tang Yong-Zhong , OU-Yang Wen , Zhang Hao , Liao Qin 
Published: February 2020

AbstractBackgroundFlurbiprofen axetil (FA) is a commonly prescribed agent to relieve perioperative pain, but the relationship between FA and postoperative acute kidney injury (AKI) remains unclear. This study attempted to evaluate the effects of different dose of perioperative FA on postoperative AKI.MethodsA total of 9915 patients were enrolled for this retrospective study. The clinical characteristics and the prevalence of postoperative AKI among patients non-using, using low dose (50-100 mg), middle dose (100-250 mg) and large dose (≧250 mg) of FA were analyzed respectively. The impact of different dose of FA on postoperative AKI was analyzed using univariable and multivariate logistic regression analysis.ResultsThe prevalence of postoperative AKI was 6.7% in the overall subjects and 5.1% in 2446 cases who used FA. The incidence of AKI in low dose group was significantly less than that of non use group (4.5% vs 7.2%,P < 0.001), but the incidence of AKI in large dose group was significantly higher than that in the non-use group (18.8% vs 7.2%,P < 0.001). However, there was no significant difference between patients without using FA and subjects using middle dose of FA (7.2% vs 5.6%,p = 0.355). Multivariate logistic regression analysis showed that low dose of FA was a protective factor for postoperative AKI (OR = 0.75,p = 0.0188), and large dose of FA was a risk factor for postoperative AKI (OR = 4.8,p < 0.0001).ConclusionsThe impact of FA on postoperative AKI was dose-dependent, using of low dose FA (50-100 mg) perioperatively may effectively reduce the incidence of postoperative AKI.
Capacity and patient flow planning in post-term pregnancy outpatient clinics: a computer simulation modelling study
Authors: Viana Joe , Simonsen Tone Breines , Faraas Hildegunn E. , Schmidt Nina , Dahl Fredrik A. , Flo Kari 
Published: February 2020

AbstractBackgroundThe demand for a large Norwegian hospital’s post-term pregnancy outpatient clinic has increased substantially over the last 10 years due to changes in the hospital’s catchment area and to clinical guidelines. Planning the clinic is further complicated due to the high did not attend rates as a result of women giving birth. The aim of this study is to determine the maximum number of women specified clinic configurations, combination of specified clinic resources, can feasibly serve within clinic opening times.MethodsA hybrid agent based discrete event simulation model of the clinic was used to evaluate alternative configurations to gain insight into clinic planning and to support decision making. Clinic configurations consisted of six factors: X0: Arrivals. X1: Arrival pattern. X2: Order of midwife and doctor consultations. X3: Number of midwives. X4: Number of doctors. X5: Number of cardiotocography (CTGs) machines. A full factorial experimental design of the six factors generated 608 configurations.ResultsEach configuration was evaluated using the following measures: Y1: Arrivals. Y2: Time last woman checks out. Y3: Women’s length of stay (LoS). Y4: Clinic overrun time. Y5: Midwife waiting time (WT). Y6: Doctor WT. Y7: CTG connection WT. Optimisation was used to maximise X0 with respect to the 32 combinations of X1-X5. Configuration 0a, the base case Y1 = 7 women and Y3 = 102.97 [0.21] mins. Changing the arrival pattern (X1) and the order of the midwife and doctor consultations (X2) configuration 0d, where X3, X4, X5 = 0a, Y1 = 8 woman and Y3 86.06 [0.10] mins.ConclusionsThe simulation model identified the availability of CTG machines as a bottleneck in the clinic, indicated by the WT for CTG connection effect on LoS. One additional CTG machine improved clinic performance to the same degree as an extra midwife and an extra doctor. The simulation model demonstrated significant reductions to LoS can be achieved without additional resources, by changing the clinic pathway and scheduling of appointments. A more general finding is that a simulation model can be used to identify bottlenecks, and efficient ways of restructuring an outpatient clinic.