Miracle-dz/UniFAR-FTUs huggingface dataset:
Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM

New drugs are needed for the treatment of relapsed acute lymphoblastic leukemia and preclinical evaluation of the MEK inhibitor, selumetinib, has shown that this drug has excellent activity in those leukemias with RAS pathway mutations. The proapoptotic protein, BIM is pivotal in the induction of cell death by both selumetinib and glucocorticoids, suggesting the potential for synergy. Thus, combination indices for dexamethasone and selumetinib were determined in RAS pathway-mutated acute lymphoblastic leukemia primagraft cells in vitro and were indicative of strong synergism (combination index <0.2; n=5). Associated pharmacodynamic assays were consistent with the hypothesis that the drug combination enhanced BIM upregulation over that achieved by a single drug alone. Dosing of dexamethasone and selumetinib singly and in combination in mice engrafted with primary-derived RAS pathway-mutated leukemia cells resulted in a marked reduction in spleen size which was significantly greater with the drug combination. Assessment of the central nervous system leukemia burden showed a significant reduction in the drug-treated mice, with no detectable leukemia in those treated with the drug combination. These data suggest that a selumetinib-dexamethasone combination may be highly effective in RAS pathway-mutated acute lymphoblastic leukemia. An international phase I/II clinical trial of dexamethasone and selumetinib (Seludex trial) is underway in children with multiply relapsed/refractory disease.
Population pharmacokinetics and dosage optimization of tacrolimus in pediatric patients with nephrotic syndrome .

OBJECTIVES The aims of this study were to investigate the population pharmacokinetic (PPK) characteristics of tacrolimus in Chinese children with nephrotic syndrome and to apply it in clinical practice. MATERIALS AND METHODS A total of 137 concentrations from 61 patients were collected from routine therapeutic drug monitoring data between 2011 and 2018. Population modeling was performed with the nonlinear mixed-effects model (NONMEM) program, using a one-compartment model with first-order absorption and elimination. The mean population estimate values of clearance (CL/F) and volume of distribution (V/F) were determined. Common demographic and clinical variables were tested for their influence on these parameters. External validation was conducted, and Monte Carlo simulation, based on the final model, was carried out to determine optimal dosage regimen. RESULTS Age and body weight were the covariates that displayed a significant influence on CL/F and V/F according to the final regression model. Goodness-of-fit plots, bootstrap outcomes, and external validation confirmed the relatively good stability and prediction capability of the model. The interindividual variability of CL/F was 31.10%, and the residual variability was 0.91 ng/mL. Mean prediction error (MPE, %) and Mean absolute prediction error (MAPE, %) were 10.3% and 16.6%, respectively. Monte Carlo simulation based on the final model was carried out to determine optimal dosage regimen. CONCLUSION A PPK model of tacrolimus in children with nephrotic syndrome was developed. Age and bodyweight could partly explain the interindividual variability in the CL/F and V/F of tacrolimus. The final model could be used to accurately predict tacrolimus individual pharmacokinetic parameters and assist in dosage optimization.
Outcomes After Use of Standard- and Low-Dose Non–Vitamin K Oral Anticoagulants in Asian Patients With Atrial Fibrillation

Background and Purpose— Limited data are available describing the relative effectiveness, safety, and optimal dosing of non–vitamin K antagonist oral anticoagulants (NOACs) for treatment of nonvalvular atrial fibrillation in East Asian patients. We tried to compare effectiveness and safety outcomes of standard- and low-dose NOACs and warfarin in this population. Methods— Using nationwide administrative claims-based datasets from the Korean National Health Insurance Service Database (July 1, 2015, to December 31, 2016), this study comprised 56 504 anticoagulation-naive nonvalvular atrial fibrillation patients with high thromboembolic risk (CHA2DS2-VASc score, ≥2) treated with oral anticoagulants. Main study outcomes included thromboembolic events (ischemic stroke or systemic embolism), major bleeding, and mortality. Results— Among the study patients, 10 409 (18.4%) received warfarin and 46 095 (81.6%) were treated with NOACs: dabigatran (n=12 593; 22.3%), rivaroxaban (n=21 000; 37.2%), and apixaban (n=12 502; 22.1%). Low-dose NOAC (75.1% dabigatran, 59.7% rivaroxaban, and 62.7% apixaban) was more frequently used than standard-dose NOAC. During median follow-up of 15.0 months, each NOAC was associated with significantly lower risk of thromboembolic events (hazard ratio [HR], 0.76; 95% CI, 0.75–0.81 for dabigatran; HR, 0.74; 95% CI, 0.65–0.83 for rivaroxaban; and HR, 0.68; 95% CI, 0.59–0.78 for apixaban). Regarding safety outcomes, dabigatran (HR, 0.81; CI, 0.69–0.95) and apixaban (HR, 0.67; CI, 0.56–0.79) were associated with lower risk of major bleeding but not with rivaroxaban (HR, 0.96; CI, 0.84–1.11). Among adults <75 years of age without chronic kidney disease, use of low-dose apixaban did not demonstrate clinical benefit over warfarin with respect to thromboembolic events (HR, 0.99; CI, 0.76–1.28) and mortality (HR, 0.85; CI, 0.62–1.16). Conclusions— In this cohort of East Asian patients with nonvalvular atrial fibrillation, NOACs were associated with better effectiveness and safety outcomes versus warfarin. Lower NOAC doses were more often used, but an unjustified underdosing of apixaban seems to result in lower clinical benefit.
Continuance of E-Textbook Use by Tertiary Students: A Qualitative Approach

ABSTRACT Textbooks are an important information resource for tertiary students. E-textbooks are now widely available and accessible to students offering them distinct advantages over print books at lower costs. However the uptake of e-textbooks has been slow and student preferences for either medium are not well understood. This study adopts a qualitative approach using an expectation-confirmation theory (ECT) lens and revealed causal mapping to understand from students participating in focus groups, their intentions to continue using e-textbooks. We extend ECT by including two new constructs: perceived quality and perceived value. The results assist in interpreting students’ behavior regarding intentions to continue using e-textbooks and the efficacy of the extended ECT model.
Genomic Landscape of Pancreatic Adenocarcinoma in Younger versus Older Patients: Does Age Matter?

Purpose: State-of-the-art genomic analyses of pancreatic adenocarcinoma (PDAC) have yielded insight into signaling pathways underlying carcinogenesis. PDAC is characterized by substantial genomic heterogeneity. We aimed to determine whether early-onset PDAC (EOPC; ≤55 years) displays a distinctive molecular landscape from average-age onset PDAC (AOPC; ≥70 years). Experimental Design: Three distinct datasets for PDAC were analyzed. In the first, patients undergoing treatment at Memorial Sloan Kettering (MSK) were consented for MSK-IMPACT next-generation sequencing. The second cohort analyzed was The Cancer Genome Atlas (TCGA) dataset for differences in somatic mutations, gene expression, and protein expression. The third dataset was an Australian cohort of PDAC. Clinical data were correlated with genomic analyses. Results: A total of 293 samples were analyzed, yielding 90 patients aged ≤55 years and 203 patients aged ≥70 years. Among the genes known to be associated with carcinogenesis, SMAD4 displayed higher mutation rates in younger patients. Comprehensive transcriptomic analysis of cellular pathways indicated that the TGFβ pathway has increased activation, and the expression levels of phospho-GSK3 were higher in EOPC. Survival outcomes revealed no differences between age groups. Conclusions: These exploratory analyses suggest that there may be somatic gene alterations within the population of patients with early-onset PDAC that involve unique cellular pathways compared with average-onset PDAC. Former studies imply these cellular pathways may play a role in smoking-related PDAC carcinogenesis. Larger genomic datasets are warranted for future evaluation to extend these observations.
Ethnic/Racial Identity—A Double-Edged Sword? Associations With Discrimination and Psychological Outcomes

Given the prominence of ethnicity/race in the United States, many youths construct an ethnic/racial identity (ERI). However, ERI development occurs against a backdrop of prejudice, oppression, and discrimination. This synthetic review explores (a) how identity and discrimination are related and (b) their association with psychological health. There is a reciprocal developmental association between ERI and discrimination, in which each informs the other. Although discrimination is detrimental for mental health, its impact depends on identity. In some cases, ERI confers protection from discrimination, and in others, it poses additional vulnerabilities. A strong sense of commitment to one’s identity confers protection against the negative effects of discrimination, while high levels of identity exploration are associated with increased vulnerability. However, the importance of ethnicity/race to one’s identity both protects from and increases vulnerabilities to discrimination. Suggestions for future research to help to disambiguate these associations are offered.
Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium

Noninvasive aerosol inhalation is an established method of drug delivery to the lung, and remains a desirable route for nucleic‐acid‐based therapeutics. In vitro transcribed (IVT) mRNA has broad therapeutic applicability as it permits temporal and dose‐dependent control of encoded protein expression. Inhaled delivery of IVT‐mRNA has not yet been demonstrated and requires development of safe and effective materials. To meet this need, hyperbranched poly(beta amino esters) (hPBAEs) are synthesized to enable nanoformulation of stable and concentrated polyplexes suitable for inhalation. This strategy achieves uniform distribution of luciferase mRNA throughout all five lobes of the lung and produces 101.2 ng g−1 of luciferase protein 24 h after inhalation of hPBAE polyplexes. Importantly, delivery is localized to the lung, and no luminescence is observed in other tissues. Furthermore, using an Ai14 reporter mouse model it is identified that 24.6% of the total lung epithelial cell population is transfected after a single dose. Repeat dosing of inhaled hPBAE‐mRNA generates consistent protein production in the lung, without local or systemic toxicity. The results indicate that nebulized delivery of IVT‐mRNA facilitated by hPBAE vectors may provide a clinically relevant delivery system to lung epithelium.
Meta-regression analysis of the effects of dietary cholesterol intake on LDL and HDL cholesterol.

Background Elevated low-density lipoprotein (LDL) cholesterol is a major risk factor for cardiovascular disease. Dietary guidance recommends reducing saturated fatty acid, trans fatty acid, and cholesterol intakes to reduce circulating LDL cholesterol. Cholesterol intake may also affect high-density lipoprotein (HDL)-cholesterol concentrations, but its impact has not been fully quantified. Objectives The aims of this study were to investigate the dose-response relation between changes in dietary cholesterol intake and changes in lipoprotein-cholesterol markers for cardiovascular disease risk and to provide a reference for clinicians on how changes in dietary cholesterol intake affect circulating cholesterol concentrations, after accounting for intakes of fatty acids. Methods We used a Bayesian approach to meta-regression analysis, which uses Markov chain Monte Carlo techniques, to assess the relation between the change in dietary cholesterol (adjusted for dietary fatty acids) and changes in LDL and HDL cholesterol based on the use of data from randomized dietary intervention trials. Results Fifty-five studies (2652 subjects) were included in the analysis. The nonlinear Michaelis-Menten (MM) and Hill models best described the data across the full spectrum of dietary cholesterol changes studied (0-1500 mg/d). Mean predicted changes in LDL cholesterol for an increase of 100 mg dietary cholesterol/d were 1.90, 4.46, and 4.58 mg/dL for the linear, nonlinear MM, and Hill models, respectively. Conclusions The change in dietary cholesterol was positively associated with the change in LDL-cholesterol concentration. The linear and MM models indicate that the change in dietary cholesterol is modestly inversely related to the change in circulating HDL-cholesterol concentrations in men but is positively related in women. The clinical implications of HDL-cholesterol changes associated with dietary cholesterol remain uncertain.
Genome-wide DNA methylation and transcriptomic profiles in the lifestyle strategies and asexual development of the forest fungal pathogen Heterobasidion parviporum

ABSTRACT Heterobasidion parviporum is the most devastating fungal pathogen of conifer forests in Northern Europe. The fungus has dual life strategies, necrotrophy on living trees and saprotrophy on dead woods. DNA cytosine methylation is an important epigenetic modification in eukaryotic organisms. Our presumption is that the lifestyle transition and asexual development in H. parviporum could be driven by epigenetic effects. Involvements of DNA methylation in the regulation of aforementioned processes have never been studied thus far. RNA-seq identified lists of highly induced genes enriched in carbohydrate-active enzymes during necrotrophic interaction with host trees and saprotrophic sawdust growth. It also highlighted signaling- and transcription factor-related genes potentially associated with the transition of saprotrophic to necrotrophic lifestyle and groups of primary cellular activities throughout asexual development. Whole-genome bisulfite sequencing revealed that DNA methylation displayed pronounced preference in CpG dinucleotide context across the genome and mostly targeted transposable element (TE)-rich regions. TE methylation level demonstrated a strong negative correlation with TE expression, reinforcing the protective function of DNA methylation in fungal genome stability. Small groups of genes putatively subject to methylation transcriptional regulation in response to saprotrophic and necrotrophic growth in comparison with free-living mycelia were also explored. Our study reported on the first methylome map of a forest pathogen. Analysis of transcriptome and methylome variations associated with asexual development and different lifestyle strategies provided further understanding of basic biological processes in H. parviporum. More importantly, our work raised additional potential roles of DNA methylation in fungi apart from controlling the proliferation of TEs.
Influence of Maternal Obesity on Labor Induction: A Systematic Review and Meta‐Analysis

INTRODUCTION Studies have shown that women with obesity have longer labors. The purpose of this systematic review and meta-analysis is to examine existing evidence regarding labor induction in women with obesity, including processes and outcomes. The primary outcome was cesarean birth following labor induction. Secondary outcomes were the timing and dosage of prostaglandins, the success of mechanical cervical ripening methods, and synthetic oxytocin dose and timing. METHODS Searches were performed in PubMed, MEDLINE, Embase, CINAHL, EBSCO, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Effects, Google Scholar, and ClinicalTrials.gov. Searches were limited to studies published in English after 1990. Ten studies published between 2009 and 2017 were included in this review. All were observational studies comparing processes and outcomes of induction of labor in relation to maternal body mass index. The primary outcome was cesarean birth following labor induction. We assessed heterogeneity using Cochran's Q test and tau-squared and I2 statistics. We also calculated fixed-effect models to estimate pooled relative risks and weighted mean differences. RESULTS Ten cohort studies met inclusion criteria; 8 studies had data available for a meta-analysis of the primary outcome. Cesarean birth was more common among women with obesity compared with women of normal weight following labor induction (Mantel-Haenszel fixed-effect odds ratio, 1.82; 95% CI, 1.55-2.12; P < .001). Maternal obesity was associated with a longer time to birth, higher doses of prostaglandins, less frequent success of cervical ripening methods, and higher dose of synthetic oxytocin, as well as a longer time to birth after oxytocin use. DISCUSSION Women with obesity are more likely than women with a normal weight to end labor induction with cesarean birth. Additionally, women with obesity require longer labor inductions involving larger, more frequent applications of both cervical ripening methods and synthetic oxytocin.
The Superior Hypophyseal Arteries: Anatomical Study with an Endoscopic Endonasal Perspective.

BACKGROUND The use of high-definition endoscopes in extended transsphenoidal approaches to the suprasellar area has significantly improved visualization of its vascularization. OBJECTIVE To systematically examine the superior hypophyseal arteries (SHAs) anatomy from an endonasal endoscopic perspective. METHODS The endoscopic endonasal transsphenoidal trans-tuberculum approach was performed in 19 adult, fresh and latex injected specimens. Dissections recordings were reviewed to analyze SHAs type, number, and branches, as well as internal carotid arteries (ICA) branches that vascularized optic nerves and chiasm. RESULTS Identification of SHAs was possible in all specimens (37/38 sides). The number of SHAs varied from 1 to 3 per side (mean: 1.7). The anterior superior hypophyseal artery was visible in almost all cases (35/37 sides) and originated at the level of the carotid cave in 18/35 specimens; number of branches ranged from 1 to 6 (mean: 3.5), directed to the optic nerve (86%), chiasm (57%), infundibulum (86%), and/or parallel to the pituitary stalk (74%). The 4 main branches and patterns, originally described by McConnell in 1953, were confirmed. The posterior superior hypophyseal artery was evident in 28/37 sides with number of branches ranging from 0 to 4 (mean: 2.1), directed to the optic chiasm (50%), optic tract (32%), infundibulum (79%), and/or pituitary stalk (36%). The surgical implications of this study, together with anatomical and clinical videos, are also briefly discussed. CONCLUSION SHAs constitute a complex of anterior and posterior branches that stem from the medial ICA with different patterns, vascularizing the optic apparatus and pituitary stalk.
Mass Azithromycin Distribution to Prevent Childhood Mortality: A Pooled Analysis of Cluster-Randomized Trials

Abstract. Mass drug administration (MDA) with azithromycin may reduce under-5 child mortality (U5M) in sub-Saharan Africa. Here, we conducted a pooled analysis of all published cluster-randomized trials evaluating the effect of azithromycin MDA on child mortality. We pooled data from cluster-randomized trials randomizing communities to azithromycin MDA versus control. We calculated mortality rates in the azithromycin and control arms in each study, and by country for multisite studies including multiple countries. We conducted a two-stage individual community data meta-analysis to estimate the effect of azithromycin for prevention of child mortality. Three randomized controlled trials in four countries (Ethiopia, Malawi, Niger, and Tanzania) were identified. The overall pooled mortality rate was 15.9 per 1,000 person-years (95% confidence interval [CI]: 15.5–16.3). The pooled mortality rate was lower in azithromycin-treated communities than in placebo-treated communities (14.7 deaths per 1,000 person-years, 95% CI: 14.2–15.3 versus 17.2 deaths per 1,000 person-years, 95% CI: 16.5–17.8). There was a 14.4% reduction in all-cause child mortality in communities receiving azithromycin MDA (95% CI: 6.3–21.7% reduction, P = 0.0007). All-cause U5M was lower in communities receiving azithromycin MDA than in control communities, suggesting that azithromycin MDA could be a new tool to reduce child mortality in sub-Saharan Africa. However, heterogeneity in effect estimates suggests that the magnitude of the effect may vary in time and space and is currently not predictable.
Reliability and validity of field-based fitness tests in youth soccer players

ABSTRACT This study aimed to establish between-day reliability and validity of commonly used field-based fitness tests in youth soccer players of varied age and playing standards, and to discriminate between players without (“unidentified”) or with (“identified”) a direct route to professional football through their existing club pathway. Three-hundred-and-seventy-three Scottish youth soccer players (U11–U17) from three different playing standards (amateur, development, performance) completed a battery of commonly used generic field-based fitness tests (grip dynamometry, standing broad jump, countermovement vertical jump, 505 (505COD) and T-Drill (T-Test) change of direction and 10/20 m sprint tests) on two separate occasions within 7–14 days. The majority of field-based fitness tests selected within this study proved to be reliable measures of physical performance (ICC = 0.83–0.97; p < .01). However, COD tests showed weaker reliability in younger participants (ICC = 0.57–0.79; p < .01). The field-based fitness testing battery significantly discriminated between the unidentified and identified players; χ2 (7) = 101.646, p < . 001, with 70.2% of players being correctly classified. We have shown field-based fitness tests to be reliable measures of physical performance in youth soccer players. However, results from the 505COD and T-Test change of direction tests may be more variable in younger players, potentially due to complex demands of these tests and the limited training age established by these players. While the testing battery selected in this study was able to discriminate between unidentified and identified players, findings were inconsistent when attempting to differentiate between individual playing standards within the “identified” player group (development vs. performance).
Evaluation of controlled-release triamcinolone acetonide-loaded mPEG-PLGA nanoparticles in treating experimental autoimmune uveitis

Uveitis is a recurrent, sight-threatening intraocular inflammatory disease and is treated with glucocorticoids in clinical practice. In the present study, methoxypoly(ethyleneglycol)-poly(dl-lactide-co-glycolic acid) (mPEG-PLGA) nanoparticles in combination with triamcinolone acetonide (TA) were fabricated using a modified double emulsification method. Further, we characterized the TA-loaded nanoparticles, and investigated the effects of TA-loaded nanoparticles on experimental autoimmune uveitis rats, including histopathological examination and the alterations in interleukin (IL)-17 and IL-10 at mRNA and protein levels in either aqueous humor or serum. As a result, the TA-loaded nanoparticles were a well-defined spherical shape with a mean particle size of 82 nm. The in vitro release profile showed that the TA-loaded nanoparticles could sustain for more than 45 days, and possessed higher anti-inflammatory effects compared to TA alone after pathological examination, resulting in decreased IL-17 and elevated IL-10 levels in both aqueous humor and serum. Based on these findings, it can be concluded that TA-loaded mPEG-PLGA nanoparticles can potentially provide a better anti-inflammatory effect in treating chronic and recurrent uveitis in clinical practice.