bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Gp1ba-Cre transgenic mouse: a new model to delineate platelet and leukocyte functions
Authors: Nagy Zoltan , Vögtle Timo , Geer Mitchell J. , Mori Jun , Heising Silke , Di Nunzio Giada , Gareus Ralph , Tarakhovsky Alexander , Weiss Arthur , Neel Benjamin G. , Desanti Guillaume E. , Mazharian Alexandra , Senis Yotis A. 
Published: November 2018

AbstractConditional knockout (KO) mouse models are invaluable for elucidating the physiological roles of platelets. The Platelet factor 4-Cre recombinase (Pf4-Cre) transgenic mouse is the current model of choice for generating megakaryocyte/platelet-specific KO mice. Platelets and leukocytes work closely together in a wide range of disease settings, yet the specific contribution of platelets to these processes remains unclear. This is partially a result of the Pf4-Cre transgene being expressed in a variety of leukocyte populations. To overcome this issue, we developed a Gp1ba-Cre transgenic mouse strain in which Cre expression is driven by the endogenous Gp1ba locus. By crossing Gp1ba-Cre and Pf4-Cre mice to the mT/mG dual-fluorescence reporter mouse and performing a head-to-head comparison, we demonstrate more stringent megakaryocyte lineage-specific expression of the Gp1ba-Cre transgene. Broader tissue expression was observed with the Pf4-Cre transgene, leading to recombination in many hematopoietic lineages, including monocytes, macrophages, granulocytes, and dendritic and B and T cells. Direct comparison of phenotypes of Csk, Shp1, or CD148 conditional KO mice generated using either the Gp1ba-Cre or Pf4-Cre strains revealed similar platelet phenotypes. However, additional inflammatory and immunological anomalies were observed in Pf4-Cre-generated KO mice as a result of nonspecific deletion in other hematopoietic lineages. By excluding leukocyte contributions to phenotypes, the Gp1ba-Cre mouse will advance our understanding of the role of platelets in inflammation and other pathophysiological processes in which platelet-leukocyte interactions are involved.
Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma
Authors: Busse William W. , Brusselle Guy G. , Korn Stephanie , Kuna Piotr , Magnan Antoine , Cohen David , Bowen Karin , Piechowiak Teresa , Wang Millie M. , Colice Gene 
Published: November 2018

Long-term oral corticosteroid (OCS) use in patients with severe asthma is associated with significant adverse effects.This 40-week, randomised, double-blind trial evaluated the OCS-sparing potential of tralokinumab in patients with severe, uncontrolled asthma requiring maintenance OCS treatment plus inhaled corticosteroids/long-acting β2-agonists. Overall, 140 patients were randomised to tralokinumab 300 mg or placebo (n=70 in each group) administered subcutaneously every 2 weeks. The primary end-point was percentage change from baseline in average OCS dose at week 40, while maintaining asthma control. Secondary end-points included proportion of patients with a prescribed maintenance OCS dose of ≤5 mg, those with a ≥50% reduction in prescribed maintenance OCS dose and asthma exacerbation rate. Safety was also assessed.At week 40, the percentage reduction from baseline in the final daily average OCS dose was not significantly different between tralokinumab and placebo (37.62%versus29.85%; p=0.271). There were no significant between-treatment differences for any secondary end-point. Overall, reporting of adverse events and serious adverse events were similar for the tralokinumab and placebo groups. Although a greater proportion of tralokinumab-treated patients reported upper respiratory tract infections (35.7%versus14.3%), there were no reported cases of pneumonia.Overall, tralokinumab did not demonstrate an OCS-sparing effect in patients with severe asthma.
Antibiotic prophylaxis in foot and ankle surgery: a systematic review of the literature
Authors: Modha Mr Ravi Krishān , Morriss‐Roberts Chris , Smither Madeleine , Larholt Jonathan , Reilly Ian 
Published: November 2018

AbstractBackgroundWith the advent of bacterial resistance, it is important now more than ever to evaluate use of antibiotic chemoprophylaxis in foot and ankle surgery. Within this area of the body there may be less dissection, surgery time with smaller incisions and importantly smaller sizes of implanted fixation as compared to other bone and joint procedures. Our objective was to systematically evaluate the quality of evidence behind existing guidelines.MethodologyA systematic literature search was performed: MEDLINE, CINHAL, EMBASE and the Cochrane library from 1990 up to March 2018. To avoid omitting any studies on the subject, Google Scholar was also used. The inclusion criterion were studies exploring perioperative antibiotic use, postoperative infection rates in elective foot and ankle surgery and studies associated with this subject evaluating antibiotic use in clean elective foot and ankle surgery. The exclusion criterion being studies upon contaminated or dirty surgery or those which were inclusive of procedures proximal to the foot and ankle.ResultsOverall 11 studies met the inclusion criteria. From the grading of evidence, 2 level one and 4 level two studies were recognised. These studies ranked relatively highly in comparison to 5 studies that were graded as level three and level four tiers of evidence. Results of SSI rates found within this systematic review ranged from 0% to 9.4% of overall postoperative infections encountered after foot and ankle surgery in the studies analysed.ConclusionWhilst fragmented, aspects of antibiotic chemoprophylaxis are established fields in elective surgery with a growing body of evidence. Evidence for antibiotic use however, specifically within elective foot and ankle surgery, is lacking. This systematic review is a seminal paper which delivers an impression of the most influential literature within the field of foot and ankle surgery, with the aim being to entice conclusions and guide future research.
Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics
Authors: Okamura Ryosuke , Boichard Amélie , Kato Shumei , Sicklick Jason K. , Bazhenova Lyudmila , Kurzrock Razelle 
Published: November 2018

Purpose Fusions that involve neurotrophic-tropomyosin receptor kinase ( NTRK) genes are known drivers of oncogenesis. Therapies that target these ultra-rare, constitutionally active NTRK fusions have been remarkably effective. Herein, we analyze the prevalence of the full array of NTRK alterations—fusions, mutations, copy number alterations, and increased transcript expression—in diverse adult and pediatric tumor types to understand the landscape of NTRK aberrations in cancer. Methods We assessed 13,467 samples available from The Cancer Genome Atlas (adult tumors) and the St Jude PeCan database (pediatric tumors) for the prevalence of NTRK fusions, as well as associated genomic and transcriptomic co-aberrations in different tumor types. Results NTRK fusions were observed in 0.31% of adult tumors and in 0.34% of pediatric tumors. The most common gene partners were NTRK3 (0.16% of adult tumors) followed by NTRK1 (0.14% of pediatric tumors). NTRK fusions were found more commonly in pediatric melanoma (11.1% of samples), pediatric glioma (3.97%), and adult thyroid cancers (2.34%). Additional genomic and transcriptomic NTRK alterations—mutation, amplification, and mRNA overexpression—occurred in 14.2% of samples, whereas the frequency of alterations that implicated NTRK ligands and the NTRK co-receptor (p75NTR) ranged from 3.8% to 5.4%. Among 31 adult samples carrying NTRK fusions, co-alterations occurred often and usually involved the downstream phosphoinositide-3-kinase signaling pathway, cell-cycle machinery, other tyrosine-kinase receptors, and mitogen-activated protein kinase signals. Conclusion Whereas NTRK fusions are exceedingly rare, other NTRK abnormalities affect 14% of patients with cancer. Affecting these alterations has not yet been achievable in cancer. Genomic co-alterations occur frequently with NTRK fusions, but it is not known if co-targeting them can attenuate primary or secondary resistance to NTRK inhibitors.
Does evidence support the high expectations placed in precision medicine? A bibliographic review
Authors: Cortés Jordi , González José Antonio , Medina María Nuncia , Vogler Markus , Vilaró Marta , Elmore Matt , Senn Stephen John , Campbell Michael , Cobo Erik 
Published: November 2018

Background: Precision medicine is the Holy Grail of interventions that are tailored to a patient’s individual characteristics. However, conventional clinical trials are designed to find differences with the implicit assumption that the effect is the same in all patients within the eligibility criteria. If this were the case, then there would be no grounds for treating different patients differently. One consequence of the assumption is that the variance in the outcome variable would be the same in treated and control arms. We reviewed the literature to see if this were the case and so to see how often precision medicine would not be useful. Methods: We reviewed parallel trials with quantitative outcomes published in 2004, 2007, 2010 and 2013. We collected baseline and final standard deviations of the main outcome. We assessed homoscedasticity by comparing the variance of the primary endpoint between arms through the outcome variance ratio (treated to control group). Results: The review provided 208 articles with enough information to conduct the analysis. One out of seven studies (n = 30, 14.4%) had statistically different variances between groups, leading a non-constant-effect. The adjusted point estimate of the mean outcome variance ratio (treated to control group) is 0.89 (95% CI 0.81 to 0.97). Conclusions: We found that the outcome variance was more often smaller in the intervention group, suggesting that treated patients may end up pertaining more often to reference or “normality” values and thus would not require further precision medicine. However, this result may also be compatible with a reduced effect in some patients, which would require studying whether the effect merits enduring the side effects as well as the economic costs. We have shown that the comparison of variances is a useful but not definitive tool to asses if the design assumption of a constant effect holds.
Anti-hypercholesterolemic effect of Zingiber montanum extract
Authors: Paramita Swandari , Aminyoto Meiliati , Ismail Sjarif , Arung Enos Tangke 
Published: November 2018

Background: Hypercholesterolemia, high cholesterol levels in the blood, can contribute to many forms of disease, most notably cardiovascular disease. Anti-hypercholesterolemic agents generally used for those conditions have several side effects for patients. Zingiber montanum, known locally as “bangle”, belongs to the family Zingiberaceae and is a potential plants for alternative anti-hypercholesterolemic agents. This plant, from East Kalimantan, is used in traditional medicine for health problems caused by high cholesterol levels. The aim of this research was to find alternatives to anti-hypercholesterolemic agents, especially from natural sources. Methods: This study was an experimental study using 30 Wistar male white rats. Subjects were randomly divided into 6 groups (n=5): (1) normal control group; (2) high fat diet control group; (3) high fat diet with simvastatin; (4-6) high fat diet with Zingiber montanum extracts 100, 200, and 400 mg/kg. After 4 weeks of treatment, blood was collected from all groups, and plasma concentrations of triglycerides, total cholesterol, high density lipoproteins (HDL), and low density lipoproteins (LDL) were measured. Results: The results showed significant differences in total cholesterol (p=0.000), LDL (p=0.000) and triglycerides (p=0.001) in the high-fat diet group with Z. montanum extract, as compared to the high-fat diet control. Meanwhile, there were no significant differences in HDL levels (p=0.830) between the high-fat diet group and other groups. The results also showed significant differences in total cholesterol and LDLs for rats treated with Z. montanum extract, 100 mg/kg (p=0.000), 200 mg/kg (p=0.000), and 400 mg/kg (p=0.000) compared to the high-fat diet group. The result of Z. montanum 400 mg/kg also showed a significant reduction, not only for total cholesterol and LDLs, but also for triglycerides (p=0.030). Conclusion: It could be concluded that Z. montanum extracts have the potency to be further developed as a new natural source of the anti-hypercholesterolemic agents.
Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial
Authors: Jakola Asgeir Store , Werlenius Katja , Mudaisi Munila , Hylin Sofia , Kinhult Sara , Bartek Jr. Jiri , Salvesen Øyvind , Carlsen Sven Magnus , Strandéus Michael , Lindskog Magnus , Löfgren David , Rydenhag Bertil , Carstam Louise , Gulati Sasha , Solheim Ole , Bartek Jiri , Solheim Tora 
Published: November 2018

Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment. Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety. Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues. Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.
Relationships between variance in electroencephalography relative power and developmental status in infants with typical development and at risk for developmental disability: An observational study
Authors: Hooyman Andrew , Kayekjian David , Xiao Ran , Jiang Crystal , Vanderbilt Douglas L. , Smith Beth A. 
Published: November 2018

Background: Electroencephalography (EEG) is a non-invasive tool that has the potential to identify and quantify atypical brain development. We introduce a new measure here, variance of relative power of resting-state EEG. We sought to assess whether variance of relative power of resting-state EEG could predict i) classification of infants as typical development (TD) or at risk (AR) for developmental disability, and ii) Bayley developmental scores at the same visit or future visits. Methods: A total of 22 infants with TD participated, aged between 38 and 203 days. In addition, 11 infants broadly at risk participated (6 high-risk pre-term, 4 low-risk pre-term, 1 high-risk full-term), aged between 40 and 225 days of age (adjusted for prematurity). We used EEG to measure resting-state brain function across months. We calculated variance of relative power as the standard deviation of the relative power across each of the 32 EEG electrodes. The Bayley Scales of Infant Development (3rd edition) was used to measure developmental level. Infants were measured 1-6 times each, with 1 month between measurements. Results: Our main findings were: i) variance of relative power of resting state EEG can predict classification of infants as TD or AR, and ii) variance of relative power of resting state EEG can predict Bayley developmental scores at the same visit (Bayley raw fine motor, Bayley raw cognitive, Bayley total raw score, Bayley motor composite score) and at a future visit (Bayley raw fine motor). Conclusions: This was a preliminary, exploratory, small study. Our results support variance of relative power of resting state EEG as an area of interest for future study as a biomarker of neurodevelopmental status and as a potential outcome measure for early intervention.
Metabolic tracing reveals novel adaptations to skeletal muscle cell energy production pathways in response to NAD+ depletion
Authors: Oakey Lucy A. , Fletcher Rachel S. , Elhassan Yasir S. , Cartwright David M. , Doig Craig L. , Garten Antje , Thakker Alpesh , Maddocks Oliver D. K. , Zhang Tong , Tennant Daniel A. , Ludwig Christian , Lavery Gareth G. 
Published: November 2018

Background: Skeletal muscle is central to whole body metabolic homeostasis, with age and disease impairing its ability to function appropriately to maintain health. Inadequate NAD+ availability is proposed to contribute to pathophysiology by impairing metabolic energy pathway use. Despite the importance of NAD+ as a vital redox cofactor in energy production pathways being well-established, the wider impact of disrupted NAD+ homeostasis on these pathways is unknown. Methods: We utilised skeletal muscle myotube models to induce NAD+ depletion, repletion and excess and conducted metabolic tracing to provide comprehensive and detailed analysis of the consequences of altered NAD+ metabolism on central carbon metabolic pathways. We used stable isotope tracers, [1,2-13C] D-glucose and [U-13C] glutamine, and conducted combined 2D-1H,13C-heteronuclear single quantum coherence (HSQC) NMR spectroscopy and GC-MS analysis. Results: NAD+ excess driven by nicotinamide riboside (NR) supplementation within skeletal muscle cells results in enhanced nicotinamide clearance, but had no effect on energy homeostasis or central carbon metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) inhibition induced NAD+ depletion and resulted in equilibration of metabolites upstream of glyceraldehyde phosphate dehydrogenase (GAPDH). Aspartate production through glycolysis and TCA cycle activity is increased in response to low NAD+, which is rapidly reversed with repletion of the NAD+ pool using NR. NAD+ depletion reversibly inhibits cytosolic GAPDH activity, but retains mitochondrial oxidative metabolism, suggesting differential effects of this treatment on sub-cellular pyridine pools. When supplemented, NR efficiently reverses these metabolic consequences. However, the functional relevance of increased aspartate levels after NAD+ depletion remains unclear, and requires further investigation. Conclusions: These data highlight the need to consider carbon metabolism and clearance pathways when investigating NAD+ precursor usage in models of skeletal muscle physiology.
‘People are robots, too’: Expert gaming as autoplay
Authors: Taylor Nicholas , Elam Jessica 
Published: November 2018

Abstract
This article theorizes gaming expertise as a form of automated play (autoplay) by considering automation as a production of an arrangement of bodies and forces that solicits speed and accuracy in the processing of sensory, perceptual and cognitive events. Autoplay is not a property specific to technical machines, but to assemblages of machinic and organic bodies. In putting forward this notion of expertise as autoplay, we are not privileging either human bodies or technical components. Instead, resisting this dichotomy, we analyse the relations that constitute this assemblage, and the historical trajectories that shape and capture it – namely, the military–entertainment complex’s pursuit of seamless communicative circuits for threat detection and response. After operationalizing this framework through a look at expert players in League of Legends, this article concludes by drawing out some implications of what it means for particular subjects to play with(in) automation.
Narrativas de la enseñanza de la matemática y mestizaje civilizatorio en Colombia
Authors: Guerrero Recalde Néstor Fernando 
Published: November 2018

En este artículo se pretende mostrar como la enseñanza de las matemáticas durante la época de la independencia y con la formación de la Nueva Republica Neogranadina se instauró el proceso civilizatorio de los sujetos mestizos en el periodo comprendido entre 1821 a 1873.En las narrativas históricas se analiza como con la incorporación de los saberes matemáticos en la escuela cambiaron las costumbres, creencias y hábitos de la sociedad colombiana, especialmente de lo que se denominó ciudadano culto y letrado.Se hizo más notoria la división en clases sociales, se configuró el Estado Nación y la idea de una sociedad democrática igualitaria; un gobierno de una elite de criollos que con sus ideologías y valores éticos políticos separó a los dueños del proceso civilizatorio de la mayoría conformada por obreros, campesinos, negritudes y etnias. En este periodo encontramos un discurso orientado a la civilización de los rasgos aborígenes.
Fine-Scale Resolution of Runs of Homozygosity Reveal Patterns of Inbreeding and Substantial Overlap with Recessive Disease Genotypes in Domestic Dogs
Authors: Sams Aaron J , Boyko Adam R 
Published: November 2018

Abstract
Inbreeding leaves distinct genomic traces, most notably long genomic tracts that are identical by descent and completely homozygous. These runs of homozygosity (ROH) can contribute to inbreeding depression if they contain deleterious variants that are fully or partially recessive. Several lines of evidence have been used to show that long (&gt; 5 megabase) ROH are disproportionately likely to harbor deleterious variation, but the extent to which long vs. short tracts contribute to autozygosity at loci known to be deleterious and recessive has not been studied. In domestic dogs, nearly 200 mutations are known to cause recessive diseases, most of which can be efficiently assayed using SNP arrays. By examining genome-wide data from over 200,000 markers, including 150 recessive disease variants, we built high-resolution ROH density maps for nearly 2,500 dogs, recording ROH down to 500 kilobases. We observed over 678 homozygous deleterious recessive genotypes in the panel across 29 loci, 90% of which overlapped with ROH inferred by GERMLINE. Although most of these genotypes were contained in ROH over 5 Mb in length, 14% were contained in short (0.5 - 2.5 megabase) tracts, a significant enrichment compared to the genetic background, suggesting that even short tracts are useful for computing inbreeding metrics like the coefficient of inbreeding estimated from ROH (FROH). In our dataset, FROH differed significantly both within and among dog breeds. All breeds harbored some regions of reduced genetic diversity due to drift or selective sweeps, but the degree of inbreeding and the proportion of inbreeding caused by short vs. long tracts differed between breeds, reflecting their different population histories. Although only available for a few species, large genome-wide datasets including recessive disease variants hold particular promise not only for disentangling the genetic architecture of inbreeding depression, but also evaluating and improving upon current approaches for detecting ROH.