bluuebunny/crossref_metadata_2025_split huggingface dataset:
A cell-based high-throughput screen identifies drugs that cause bleeding disorders by off-targeting the vitamin K cycle
Authors: Chen Xuejie , Li Caihong , Jin Da-Yun , Ingram Brian , Hao Zhenyu , Bai Xue , Stafford Darrel W. , Hu Keping , Tie Jian-Ke 
Published: May 2020

AbstractDrug-induced bleeding disorders contribute to substantial morbidity and mortality. Antithrombotic agents that cause unintended bleeding of obvious cause are relatively easy to control. However, the mechanisms of most drug-induced bleeding disorders are poorly understood, which makes intervention more difficult. As most bleeding disorders are associated with the dysfunction of coagulation factors, we adapted our recently established cell-based assay to identify drugs that affect the biosynthesis of active vitamin K–dependent (VKD) coagulation factors with possible adverse off-target results. The National Institutes of Health (NIH) Clinical Collection (NCC) library containing 727 drugs was screened, and 9 drugs were identified, including the most commonly prescribed anticoagulant warfarin. Bleeding complications associated with most of these drugs have been clinically reported, but the pathogenic mechanisms remain unclear. Further characterization of the 9 top-hit drugs on the inhibition of VKD carboxylation suggests that warfarin, lansoprazole, and nitazoxanide mainly target vitamin K epoxide reductase (VKOR), whereas idebenone, clofazimine, and AM404 mainly target vitamin K reductase (VKR) in vitamin K redox cycling. The other 3 drugs mainly affect vitamin K availability within the cells. The molecular mechanisms underlying the inactivation of VKOR and VKR by these drugs are clarified. Results from both cell-based and animal model studies suggest that the anticoagulation effect of drugs that target VKOR, but not VKR, can be rescued by the administration of vitamin K. These findings provide insights into the prevention and management of drug-induced bleeding disorders. The established cell-based, high-throughput screening approach provides a powerful tool for identifying new vitamin K antagonists that function as anticoagulants.
Added prognostic value of secondary AML-like gene mutations in ELN intermediate-risk older AML: ALFA-1200 study results
Authors: Gardin Claude , Pautas Cécile , Fournier Elise , Itzykson Raphaël , Lemasle Emilie , Bourhis Jean-Henri , Adès Lionel , Marolleau Jean-Pierre , Malfuson Jean-Valère , Gastaud Lauris , Raffoux Emmanuel , Lambert Juliette , Braun Thorsten , Thomas Xavier , Chantepie Sylvain , Cluzeau Thomas , de Botton Stéphane , Berthon Céline , Boissel Nicolas , Duployez Nicolas , Terré Christine , Peffault de Latour Régis , Michallet Mauricette , Celli-Lebras Karine , Preudhomme Claude , Dombret Hervé 
Published: May 2020

AbstractIn this study, we aimed to refine prognostication of older with acute myeloid leukemia (AML) after intensive chemotherapy. Five hundred and nine patients aged 60 years or older (median age, 68 years) were prospectively enrolled in the intensive Acute Leukemia French Association (ALFA)-1200 trial between 2012 and 2016, and 471 patient samples were submitted to multigene analysis. Mutations in any of 8 genes frequently altered in myelodysplastic syndromes (MDS), including ASXL1, SRSF2, STAG2, BCOR, U2AF1, EZH2, SF3B1, and ZRSR2, defined a secondary AML (sAML)-like disease, as reported. Of the samples analyzed, 48% included sAML-like gene mutations. These mutations were associated with a shorter event-free survival, both overall (hazard ratio, 1.46; 95% confidence interval, 1.19-1.79; P &lt; .001) and within the European LeukemiaNet (ELN)-2017 intermediate-risk subgroup (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28; P = .044), which excludes ASXL1-mutated cases by definition. We therefore included patients with intermediate-risk AML carrying sAML-like mutations in a single high-risk patients group together with adverse-risk patients with AML, whereas other intermediate-risk patients were included in a standard-risk group together with favorable-risk patients (high-risk/standard-risk patient ratio, 1.00). Using this 2-class risk assessment, we observed that transplantation prolonged overall survival from remission in patients with high-risk AML only, not in patients with standard-risk AML. Routine analysis of sAML-like gene mutations may thus improve the definition of high-risk older patients with AML, and better identify the half of older patients who clearly derive survival benefit from allogeneic transplantation in first remission. This trial was registered at www.clinicaltrials.gov as #NCT01966497.
Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML
Authors: Choe Sung , Wang Hongfang , DiNardo Courtney D. , Stein Eytan M. , de Botton Stéphane , Roboz Gail J. , Altman Jessica K. , Mims Alice S. , Watts Justin M. , Pollyea Daniel A. , Fathi Amir T. , Tallman Martin S. , Kantarjian Hagop M. , Stone Richard M. , Quek Lynn , Konteatis Zenon , Dang Lenny , Nicolay Brandon , Nejad Parham , Liu Guowen , Zhang Vickie , Liu Hua , Goldwasser Meredith , Liu Wei , Marks Kevin , Bowden Chris , Biller Scott A. , Attar Eyal C. , Wu Bin 
Published: May 2020

Abstract
Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed mIDH1 R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG–restoring mutations (second-site IDH1 mutations, IDH2 mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at www.clinicaltrials.gov as #NCT02074839
A randomised trial of high-flow nasal cannula in infants with moderate bronchiolitis
Authors: Durand Philippe , Guiddir Tamazoust , Kyheng Christèle , Blanc Florence , Vignaud Olivier , Epaud Ralph , Dugelay Frédéric , Breant Isabelle , Badier Isabelle , Degas-Bussière Vanessa , Phan Florence , Soussan-Banini Valérie , Lehnert Agnès , Mbamba Célestin , Barrey Catherine , Tahiri Cédric , Decobert Marion , Saunier-Pernaudet Marie , Craiu Irina , Taveira Mélanie , Gajdos Vincent 
Published: May 2020

BackgroundThe objective was to determine whether high-flow nasal cannula (HFNC), a promising respiratory support in infant bronchiolitis, could reduce the proportion of treatment failure requiring escalation of care.MethodsIn this randomised controlled trial, we assigned infants aged <6 months who had moderate bronchiolitis to receive either HFNC at 3 L·kg−1·min−1or standard oxygen therapy. Crossover was not allowed. The primary outcome was the proportion of patients in treatment failure requiring escalation of care (mostly noninvasive ventilation) within 7 days following randomisation. Secondary outcomes included rates of transfer to the paediatric intensive care unit (PICU), oxygen, number of artificial nutritional support-free days and adverse events.ResultsThe analyses included 268 patients among the 2621 infants assessed for inclusion during two consecutive seasons in 17 French paediatric emergency departments. The percentage of infants in treatment failure was 14% (19 out of 133) in the study group, compared to 20% (27 out of 135) in the control group (OR 0.66, 95% CI 0.35–1.26; p=0.21). HFNC did not reduce the risk of admission to PICU (21 (15%) out of 133 in the study groupversus26 (19%) out of 135 in the control group) (OR 0.78, 95% CI 0.41–1.41; p=0.45). The main reason for treatment failure was the worsening of modified Wood clinical asthma score (m-WCAS). Short-term assessment of respiratory status showed a significant difference for m-WCAS and respiratory rate in favour of HFNC. Three pneumothoraces were reported in the study group.ConclusionsIn patients with moderate bronchiolitis, there was no evidence of lower rate of escalating respiratory support among those receiving HFNC therapy.
Self-analysis of repeat proteins reveals evolutionarily conserved patterns
Authors: Merski Matthew , Młynarczyk Krzysztof , Ludwiczak Jan , Skrzeczkowski Jakub , Dunin-Horkawicz Stanisław , Górna Maria W. 
Published: May 2020

Abstract
Background
Protein repeats can confound sequence analyses because the repetitiveness of their amino acid sequences lead to difficulties in identifying whether similar repeats are due to convergent or divergent evolution. We noted that the patterns derived from traditional “dot plot” protein sequence self-similarity analysis tended to be conserved in sets of related repeat proteins and this conservation could be quantitated using a Jaccard metric.

Results
Comparison of these dot plots obviated the issues due to sequence similarity for analysis of repeat proteins. A high Jaccard similarity score was suggestive of a conserved relationship between closely related repeat proteins. The dot plot patterns decayed quickly in the absence of selective pressure with an expected loss of 50% of Jaccard similarity due to a loss of 8.2% sequence identity. To perform method testing, we assembled a standard set of 79 repeat proteins representing all the subgroups in RepeatsDB. Comparison of known repeat and non-repeat proteins from the PDB suggested that the information content in dot plots could be used to identify repeat proteins from pure sequence with no requirement for structural information. Analysis of the UniRef90 database suggested that 16.9% of all known proteins could be classified as repeat proteins. These 13.3 million putative repeat protein chains were clustered and a significant amount (82.9%) of clusters containing between 5 and 200 members were of a single functional type.

Conclusions
Dot plot analysis of repeat proteins attempts to obviate issues that arise due to the sequence degeneracy of repeat proteins. These results show that this kind of analysis can efficiently be applied to analyze repeat proteins on a large scale.
Cloning, molecular and functional characterization by overexpression in Arabidopsis of MAPKK genes from grapevine (Vitis vinifera)
Authors: Wang Gang , Liang Ying-hai , Zhang Ji-yu , Cheng Zong-Ming 
Published: May 2020

Abstract
Background
The mitogen-activated protein kinases (MAPKs), as a part of the MAPKKK-MAPKK-MAPK cascade, play crucial roles in plant development as an intracellular signal transduction pathway to respond various environmental signals. However, few MAPKK have been functionally characterized in grapevine.

Results
In the study, five MAPKK (MKK) members were identified in grapevine (cultivar ‘Pinot Noir’), cloned and designated as VvMKK1-VvMKK5. A phylogenetic analysis grouped them into four sub-families based on the similarity of their conserved motifs and gene structure to Arabidopsis MAPKK members. qRT-PCR results indicated that the expression of VvMKK1, VvMKK2, VvMKK4, and VvMKK5 were up-regulated in mature leaf and young blades, and roots, but exhibited low expression in leaf petioles. VvMKK2, VvMKK3, and VvMKK5 genes were differentially up-regulated when grapevine leaves were inoculated with spores of Erisyphe necator, or treated with salicylic acid (SA), ethylene (ETH), H2O2, or exposed to drought, indicating that these genes may be involved in a variety of signaling pathways. Over expression of VvMKK2 and VvMKK4 genes in transgenic Arabidopsis plants resulted in the production of seeds with a significantly higher germination and survival rate, and better seedling growth under stress conditions than wild-type plants. Overexpression of VvMKK2 in Arabidopsis improved salt and drought stress tolerance while overexpression of VvMKK4 only improved salt stress tolerance.

Conclusions
Results of the present investigation provide a better understanding of the interaction and function of MAPKKK-MAPKK-MAPK genes at the transcriptional level in grapevine and led to the identification of candidate genes for drought and salt stress in grapes.
Transcriptomic and physiological analyses of rice seedlings under different nitrogen supplies provide insight into the regulation involved in axillary bud outgrowth
Authors: Wang Rongna , Qian Junjie , Fang Zhongming , Tang Jihua 
Published: May 2020

Abstract
Background
N is an important macronutrient required for plant development and significantly influences axillary bud outgrowth, which affects tillering and grain yield of rice. However, how different N concentrations affect axillary bud growth at the molecular and transcriptional levels remains unclear.

Results
In this study, morphological changes in the axillary bud growth of rice seedlings under different N concentrations ranging from low to high levels were systematically observed. To investigate the expression of N-induced genes involved in axillary bud growth, we used RNA-seq technology to generate mRNA transcriptomic data from two tissue types, basal parts and axillary buds, of plants grown under six different N concentrations. In total, 10,221 and 12,180 DEGs induced by LN or HN supplies were identified in the basal parts and axillary buds, respectively, via comparisons to expression levels under NN level. Analysis of the coexpression modules from the DEGs of the basal parts and axillary buds revealed an abundance of related biological processes underlying the axillary bud growth of plants under N treatments. Among these processes, the activity of cell division and expansion was positively correlated with the growth rate of axillary buds of plants grown under different N supplies. Additionally, TFs and phytohormones were shown to play roles in determining the axillary bud growth of plants grown under different N concentrations. We have validated the functions of OsGS1;2 and OsGS2 through the rice transgenic plants with altered tiller numbers, illustrating the important valve of our transcriptomic data.

Conclusion
These results indicate that different N concentrations affect the axillary bud growth rate, and our study show comprehensive expression profiles of genes that respond to different N concentrations, providing an important resource for future studies attempting to determine how axillary bud growth is controlled by different N supplies.
Psychometric properties of measures of substance use: a systematic review and meta-analysis of reliability, validity and diagnostic test accuracy
Authors: Santos Glenn-Milo , Strathdee Steffanie A. , El-Bassel Nabila , Patel Poonam , Subramanian Divya , Horyniak Danielle , Cook Ryan R. , McCullagh Charlotte , Marotta Phillip , Choksi Foram , Kang Brian , Allen Isabel , Shoptaw Steven 
Published: May 2020

Abstract
Background
Synthesis of psychometric properties of substance use measures to identify patterns of use and substance use disorders remains limited. To address this gap, we sought to systematically evaluate the psychometric properties of measures to detect substance use and misuse.

Methods
We conducted a systematic review and meta-analysis of literature on measures of substance classes associated with HIV risk (heroin, methamphetamine, cocaine, ecstasy, alcohol) that were published in English before June 2016 that reported at least one of the following psychometric outcomes of interest: internal consistency (alpha), test-retest/inter-rater reliability (kappa), sensitivity, specificity, positive predictive value, and negative predictive value. We used meta-analytic techniques to generate pooled summary estimates for these outcomes using random effects and hierarchical logistic regression models.

Results
Findings across 387 paper revealed that overall, 65% of pooled estimates for alpha were in the range of fair-to-excellent; 44% of estimates for kappa were in the range of fair-to-excellent. In addition, 69, 97, 37 and 96% of pooled estimates for sensitivity, specificity, positive predictive value, and negative predictive value, respectively, were in the range of moderate-to-excellent.

Conclusion
We conclude that many substance use measures had pooled summary estimates that were at the fair/moderate-to-excellent range across different psychometric outcomes. Most scales were conducted in English, within the United States, highlighting the need to test and validate these measures in more diverse settings. Additionally, the majority of studies had high risk of bias, indicating a need for more studies with higher methodological quality.
Association between antipsychotic drug dose and length of clinical notes: a proxy of disease severity?
Authors: Sørup Freja Karuna Hemmingsen , Brunak Søren , Eriksson Robert 
Published: May 2020

Abstract
Background
Most structured clinical data, such as diagnosis codes, are not sufficient to obtain precise phenotypes and assess disease burden. Text mining of clinical notes could provide a basis for detailed profiles of phenotypic traits. The objective of the current study was to determine whether drug dose, regardless of polypharmacy, is associated with the length of clinical notes, and to determine the frequency of adverse events per word in clinical notes.

Methods
In this observational study, we utilized restricted-access data from an electronic patient record system. Using three methods (defined daily dose, olanzapine equivalents, and chlorpromazine equivalents) we calculated antipsychotic dose equivalents and compared these with the number of words recorded per treatment day. For each normalization method, the frequencies of adverse events per word in manually curated samples were compared to dose intervals.

Results
The length of clinical notes per treatment day was positively associated with the prescribed dose for all normalization methods. The number of adverse events per word was stable over the analyzed dose spectrum.

Conclusions
Assuming that drug dose increases with the severity of disease, the length of clinical notes can serve as a proxy for disease severity. Due to the near-linear relationship, correction of daily word count is unnecessary when text mining for potential adverse drug reactions.
An assessment of the quality of current clinical meta-analyses
Authors: Hameed Irbaz , Demetres Michelle , Tam Derrick Y. , Rahouma Mohamed , Khan Faiza M. , Wright Drew N. , Mages Keith , DeRosa Antonio P. , Baltich Nelson Becky , Pain Kevin , Delgado Diana , Girardi Leonard N. , Fremes Stephen E. , Gaudino Mario 
Published: May 2020

Abstract
Background
The objective of this study was to assess the overall quality of study-level meta-analyses in high-ranking journals using commonly employed guidelines and standards for systematic reviews and meta-analyses.

Methods
100 randomly selected study-level meta-analyses published in ten highest-ranking clinical journals in 2016–2017 were evaluated by medical librarians against 4 assessments using a scale of 0–100: the Peer Review of Electronic Search Strategies (PRESS), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Institute of Medicine’s (IOM) Standards for Systematic Reviews, and quality items from the Cochrane Handbook. Multiple regression was performed to assess meta-analyses characteristics’ associated with quality scores.

Results
The overall median (interquartile range) scores were: PRESS 62.5(45.8–75.0), PRISMA 92.6(88.9–96.3), IOM 81.3(76.6–85.9), and Cochrane 66.7(50.0–83.3). Involvement of librarians was associated with higher PRESS and IOM scores on multiple regression. Compliance with journal guidelines was associated with higher PRISMA and IOM scores.

Conclusion
This study raises concerns regarding the reporting and methodological quality of published MAs in high impact journals Early involvement of information specialists, stipulation of detailed author guidelines, and strict adherence to them may improve quality of published meta-analyses.
Tuberculosis and its association with CD4+ T cell count among adult HIV positive patients in Ethiopian settings: a systematic review and meta-analysis
Authors: Geremew Demeke , Melku Mulugeta , Endalamaw Aklilu , Woldu Berhanu , Fasil Alebachew , Negash Markos , Baynes Habtamu Wondifraw , Geremew Habtamu , Teklu Takele , Deressa Tekalign , Tessema Belay , Sack Ulrich 
Published: May 2020

Abstract
Background
Tuberculosis (TB) and HV have been intertwined and makeup a deadly human syndemic worldwide, especially in developing countries like Ethiopia. Previous studies have reported different TB incidences and its association with CD4+ T cell counts among HIV positive patients in Ethiopia. Thus, the goal of this meta-analysis was, first, to determine pooled incident TB among adult HIV positive patients, and second, to assess the association between incident TB and baseline CD4+ T cell count strata’s.

Methods
We searched PubMed, Cochrane library, Science Direct and Google scholar databases from June 1 to 30, 2018. The I2 statistics and Egger’s regression test was used to determine heterogeneity and publication bias among included studies respectively. A random effects model was used to estimate pooled incident TB and odds ratio with the respective 95% confidence intervals using Stata version 11.0 statistical software.

Results
A total of 403 research articles were identified, and 10 studies were included in the meta-analysis. The pooled incident TB among adult HIV infected patients in Ethiopia was 16.58% (95% CI; 13.25–19.91%). Specifically, TB incidence in Pre-ART and ART was 17.16% (95% CI; 7.95–26.37%) and 16.24% (95% CI; 12.63–19.84%) respectively. Moreover, incident TB among ART receiving patients with baseline CD4+ T cell count < and > 200 cells/mm3 was 28.86% (95% CI; 18.73–38.98%) and 13.7% (95% CI; 1.41–25.98%) correspondingly. The odds of getting incident TB was 2.88 (95% CI; 1.55–5.35%) for patients with baseline CD4+ T cell count < 200 cells/mm3 compared to patients with baseline CD4+ T cell count > 200 cells/mm3.

Conclusion
High incident TB among adult HIV positive patients was estimated, especially in patients with CD4+ T cell count < 200 cells/mm3. Therefore, Early HIV screening and ART initiation, as well as strict compliance with ART and increasing the coverage of TB preventive therapy to more risky groups are important to prevent the problem.

Trial registration
Study protocol registration: CRD42018090802.
A clinical case report of brain abscess caused by Nocardia brasiliensis in a non-immunocompromised patient and a relevant literature review
Authors: Zhu Jian-Wei , Zhou Hui , Jia Wei-Qiang , You Jian , Xu Ru-Xiang 
Published: May 2020

Abstract
Background
Brain abscess due to the Nocardia genus is rare and usually found in immunocompromised patients. The most common subtype implicated is Nocardia farcinica while brain abscess due to Nocardia brasiliensis is comparatively rare. Diagnosis of brain abscess is based mainly on bacteriological culture from pus collected at the site of infection, and brain imaging. Stereotaxic aspiration or surgical resection combined with adequate duration of treatment with antibiotics to which the bacteria are sensitive represent effective treatment strategies.

Case presentation
We report a rare case of brain abscess caused by Nocardia brasiliensis in a non-immunocompromised patient. He admitted to our hospital twice with a headache. Stereotaxic aspiration was performed at the patient’s first appointment at the hospital, and a craniotomy was used to excise the lesion during subsequent abscess recurrence.

Conclusion
Early diagnosis, reasonable surgical intervention, and adequate duration of treatment with effective antibiotics are critical for treating brain abscess.