Illicit drug use and cerebral microbleeds in stroke and transient ischemic attack patients

Background: Cerebral microbleeds (CMB) signal cerebral small vessel disease and are associated with ischemic stroke (IS) incidence, recurrence, and complications. While illicit drug use (IDU) is associated with cerebral small vessel disease, the association between CMB and IDU is understudied. We sought to delineate differences in vascular risk factors between IDU and CMB and determine the effect of this relationship on outcomes in IS/transient ischemic attack (TIA) patients. Methods: We included 2001 consecutive IS and TIA patients (years 2009-2018) with a readable T2*gradient-echo MRI sequence. CMB rating followed standardized guidelines and CMB were grouped topographically into lobar, deep or infratentorial. IDU data (history and/or urine toxicology) was available for 1746 patients. The adverse composite outcome included pneumonia, urinary tract infection, deep venous thrombosis or death during hospitalization. Good functional outcome was defined as modified Rankin scale score < 3 and ambulatory on discharge. Univariate analysis was used to assess vascular risk factors and multivariable logistic regression was used to characterize the IDU/CMB relationship on outcomes. Results: We observed IDU in 13.8 % (n=241), and CMB in 32.9% (n=575, 53.8% lobar, 27.3% deep and 18.8% infratentorial). Patients with IDU and at least one CMB were older (53.6±10.5 vs. 56.9±11.5, p=0.04), had a lower BMI (28.1±5.9 vs. 26.6±4.4, p=0.04), and were more likely to have had a previous IS/TIA (25.1% vs. 41.9%, p=0.01). IDU trended higher for those with severe CMB (10+) compared with those without CMB and 1-9 CMB (25% [n=9] vs 14.3% [n=1171] and 12.1% [n=65] respectively; p=0.07) without individual drug deviations from this pattern. Adverse and good functional outcomes were observed in 177 and 905 total patients, respectively. No significant interaction was observed between IDU and CMB with either adverse or functional composite outcomes. Conclusion: IDU prevalence was high in our urban study population, and showed a borderline association with increasing CMB burden. Patients with CMB and IDU history were older and more likely to have had a previous IS/TIA. Further studies are required to clarify the clinical consequences related to the relationship between IDU and CMB.Author Disclosures: B. Petrie: None. H. Lau: None. F. Cajiga-Pena: None. S. Abbas: None. B. Finn: None. K. Dam: None. A. Cervantes-Arslanian: None. T.N. Nguyen: None. H. Aparicio: None. D. Greer: None. J.R. Romero: Speakers' Bureau; Modest; Received speaker honoraria from Ferrer Group

Early Evidence for Using a Train-the-Trainer Program to Teach Debriefing for Meaningful Learning

Background Competent debriefers are essential to promote positive learner outcomes. While important, providing training to faculty may be difficult. The Train-The-Trainer (TTT) model is a successful approach for efficiently training large groups of individuals. Methods This study used a purposive, descriptive research design to test the feasibility and effectiveness of a TTT program for teaching debriefers how to implement and train others to use Debriefing for Meaningful Learning (DML). Results With training, assessment, and individualized feedback, trainers and trainees alike improved their ability to use DML, as well as self-assess their debriefing. Conclusion The TTT program was a successful, feasible, cost-effective way to provide DML training

The Effects of a Proprietary Fenugreek Extract on Strength & Body Composition

Fenugreek extract has been marketed in dozens of dietary products as having performance enhancing potential for resistance trained athletes. PURPOSE: The purpose of this study was to investigate the potential performance enhancing effects of a proprietary fenugreek extract in conjunction with a controlled resistance training program. METHODS: Thirty resistance trained male subjects were matched according to fat free mass and randomly assigned to ingest in a double-blind manner capsules containing 500mg of a placebo or fenugreek (Trigonella Foenun greacum) once per day for 8-weeks (Active: N = 17, 21 ± 2.8 yrs, 178 ± 5.8 cm, 85 ± 9.6 kg, 18.8 ± 4.8 BF%; Placebo: N = 13, 21 ± 3 yrs, 180 ± 6.4 cm, 84 ± 15 kg, 18.3 ± 6.8 BF%). Subjects were instructed to participate in a periodized 4-day per week resistance-training program split into two upper and two lower extremity workouts per week for a total of 8-weeks. Body composition was analyzed using hydrodensiometry and strength tests involved performing a one repetition max (1RM) on the isotonic bench press and leg press. Statistical analyses utilized a two-way ANOVA with repeated measures for all criterion variables (p \u3c 0.05). RESULTS: A significant (p \u3c 0.05) group x time interaction for body composition was observed indicating the Active (-1.8 ± 0.5 BF%) group decreased body fat percentage in comparison to Placebo (-0.05 ± 0.3 BF%) over the 8-week investigation period. In addition, there was a significant (p \u3c 0.05) main effect for time over the eight week period in lean muscle mass (Active: 2.4 ± 0.1 kg; Placebo: 1.0 ± 0.1 kg). No significant effects for group or time were observed for upper or lower body strength (p \u3e 0.05). CONCLUSION: In addition to a controlled resistance training program fenugreek had a significant impact on body composition in comparison to placebo. This study was funded by Indus Biotech

Verification of Casper in the Coq Proof Assistant

This report describes our effort to model and verify the Casper blockchain finality system in the Coq proof assistant. We outline the salient details on blockchain systems using Casper, describe previous verification efforts we used as a starting point, and give an overview of the formal definitions and properties proved. The Coq source files are available at: https://github.com/runtimeverification/casper-proofsOpe

The Comparison of High-Intensity Interval Exercise vs. Continuous Moderate-Intensity Exercise on C1q/TNF-Related Protein-9 Expression and Flow-Mediated Vasodilation in Obese Individuals

PURPOSE: A recent novel adipocytokine, C1q/TNF-related protein-9 (CTRP9), has been shown to increase activation of endothelial nitric oxide synthase and reduce vasoconstrictors (e.g., endothelin-1). In addition, CTRP9 may play a compensatory role in obesity-related endothelial dysfunction. Although there is limited information regarding exercise-mediated CTRP9, high-intensity interval exercise (HIIE) has been shown to be as or more effective than continuous moderate-intensity exercise (CME) in improving indicators of endothelial function (e.g., brachial artery flow-mediated dilation [BAFMD]). Therefore, the purpose of this study was to investigate the effect of acute HIIE vs. CME on serum CTRP9 and BAFMD responses in obese individuals. METHODS: Sixteen young male subjects (9 obese and 7 normal-weight) participated in a counterbalanced and caloric equated experiment: HIIE (30 minutes, 4 intervals of 4 minutes at 80-90% of VO2max with 3 minutes rest between intervals) and CME (38 minutes at 50-60% VO2max). Serum CTRP9 and BAFMD, were measured prior to, immediately following exercise, and 1 hour and 2 hours into recovery. RESULTS: The concentration of serum CTRP9 was significantly increased immediately following acute HIIE and CME in both obese and normal-weight groups (p = 0.003). Furthermore, both significant treatment by time and group by time interactions for BAFMD were observed following both exercise protocols (p = 0.018; p = 0.009; respectively), with a greater CME-induced BAFMD response at 2 hours into recovery in obese compared to normal-weight subjects. Additionally, a positive correlation in percent change (baseline to peak value) between CTRP9 and BAFMD was found following acute CME (r = 0.589, p = 0.016). CONCLUSIONS: Acute HIIE is as effective as CME to upregulate CTRP9 expression in both obese and normal-weight individuals, although CTRP9 may potentially improve CME-mediated BAFMD. The novel results from this study provide a foundation for additional examination of the mechanisms of exercise-mediated CTRP9 on endothelial function

Kinase-Impaired BTK Mutations Are Susceptible to Clinical-Stage BTK and IKZF1/3 Degrader NX-2127

INTRODUCTION: Bruton’s tyrosine kinase (BTK) is a nonreceptor kinase in the B cell receptor (BCR) signaling cascade critical for B cell survival. As such, chronic lymphocytic leukemia (CLL) and other B cell cancers are sensitive to inhibition of BTK. Covalent and noncovalent inhibitors of BTK have revolutionized the treatment of these cancers. Therefore, understanding mechanisms by which acquired mutation in BTK confer drug resistance and developing new therapies to overcome resistance are critically important. RATIONALE: We recently discovered BTK mutations that confer resistance across covalent and noncovalent BTK inhibitors. In this study, we found that a group of these mutants impair BTK kinase activity despite still enabling downstream BCR signaling. We therefore set out to understand the nonenzymatic functions of BTK and explored targeted protein degradation to overcome the oncogenic scaffold function of mutant BTK. This effort included evaluation of BTK degradation in patients with CLL treated in a phase 1 clinical trial of NX-2127, a first-in-class BTK degrader (NCT04830137). RESULTS: BTK enzymatic activity assays revealed that drug resistance mutations in BTK fall into two distinct groups: kinase proficient and kinase impaired. Immunoprecipitation mass spectrometry of kinase-impaired BTK L528W (Leu528→Trp) revealed a scaffold function of BTK with downstream signaling and survival dependent on surrogate kinases that bind to kinase-impaired BTK proteoforms. To target the nonenzymatic functions of BTK, we developed NX-2127, a heterobifunctional molecule that engages the ubiquitin-proteasome system to simultaneously bind both BTK and the cereblon E3 ubiquitin ligase complex, inducing polyubiquitination and proteasome-dependent degradation of IKZF1/3 and all recurrent drug-resistant forms of mutant BTK. The activity of NX-2127 on BTK degradation was further demonstrated in patients with CLL treated in a phase 1 clinical trial of NX-2127, where \u3e80% BTK degradation was achieved and clinical responses were also seen in 79% of evaluable patients, independent of mutant BTK genotypes. CONCLUSION: We identified that BTK inhibitor resistance mutations fall into two distinct functional categories. Kinase-impaired BTK mutants disable BTK kinase activity while promoting physical interactions with other kinases to sustain downstream BCR signaling. This scaffold function of BTK was disrupted by NX-2127, a potent BTK degrader, which showed promising responses for patients with relapsed and refractory CLL, independently of mutant BTK functional category

DU Undergraduate Showcase: Research, Scholarship, and Creative Works

DU Undergraduate Showcase: Research, Scholarship, and Creative Work

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe