An observational cohort feasibility study to identify microvesicle and miRNA biomarkers of acute kidney injury following paediatric cardiac surgery

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Objectives: Micro-RNA, small noncoding RNA fragments involved in gene regulation, and microvesicles, membrane-bound particles less than 1 μm known to regulate cellular processes including responses to injury, may serve as disease-specific biomarkers of acute kidney injury. We evaluated the feasibility of measuring these signals as well as other known acute kidney injury biomarkers in a mixed pediatric cardiac surgery population. Design: Single center prospective cohort feasibility study. Setting: PICU. Patients: Twenty-four children (≤ 17 yr) undergoing cardiac surgery with cardiopulmonary bypass without preexisting inflammatory state, acute kidney injury, or extracorporeal life support. Interventions: None. Measurements and Main Results: Acute kidney injury was defined according to modified Kidney Diseases Improving Global Outcomes criteria. Blood and urine samples were collected preoperatively and at 6–12 and 24 hours. Microvesicles derivation was assessed using flow cytometry and NanoSight analysis. Micro-RNAs were isolated from plasma and analyzed by microarray and quantitative real-time polymerase chain reaction. Data completeness for the primary outcomes was 100%. Patients with acute kidney injury (n = 14/24) were younger, underwent longer cardiopulmonary bypass, and required greater inotrope support. Acute kidney injury subjects had different fractional content of platelets and endothelial-derived microvesicles before surgery. Platelets and endothelial microvesicles levels were higher in acute kidney injury patients. A number of micro-RNA species were differentially expressed in acute kidney injury patients. Pathway analysis of candidate target genes in the kidney suggested that the most often affected pathways were phosphatase and tensin homolog and signal transducer and activator of transcription 3 signaling. Conclusions: Microvesicles and micro-RNAs expression patterns in pediatric cardiac surgery patients can be measured in children and potentially serve as tools for stratification of patients at risk of acute kidney injury

Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-ß antibody in \u3ci\u3edb/db\u3c/i\u3e diabetic mice

Emerging evidence suggests that transforming growth factor-(TGF-β) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-antibody (αT) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-system mediates the functional and structural changes of the more advanced stages of nephropathy, we tested whether chronic administration of αT prevents renal insufficiency and glomerulosclerosis in the db/db mouse, model of type 2 diabetes that develops overt nephropathy. Diabetic db/db mice and nondiabetic db/m littermates were treated intraperitoneally with α or control IgG, 300 µg three times per week for 8 wk. Treatment with αT, but not with IgG, significantly decreased the plasma TGF-β1 concentration without decreasing the plasma glucose concentration. The IgG-treated db/db mice developed albuminuria, renal insufficiency, and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding α 1(IV) collagen and fibronectin. On the other hand, treatment with α completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factored for creatinine clearance was not significantly affected by α treatment. We conclude that chronic inhibition of the biologic actions of TGF-with neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type diabetes

Sketchtivity, an Intelligent Tutoring Software: Broadening Applications and Impact

Freehand sketching is an essential skill for engineers. Sketching enables designers to represent ideas rapidly and offload working memory. Sketches in the design process also correlate with positive design outcomes. Teaching sketching to engineers, however, presents many challenges in engineering curriculums. Sketching is most often taught in large entry-level courses where individualized feedback, which is vital to learning sketching, is not possible. Sketchtivity is an intelligent tutoring software designed to aid in the practice and feedback on freehand sketching skills. Sketchtivity teaches the basics of two-point perspective sketching providing lessons, feedback, and tips on how to improve. The goal of this project is to implement Sketchtivity at a broader range of universities, to expand on the software functionality, and to understand more about the implications of improving sketching skill. Sketchtivity is currently being implemented in classrooms at three diverse universities across the United States. Our research has shown that the tablet interface does not negatively impact students’ sketching skill development. We are currently conducting further experiments to better understand how students are learning from the feedback the software provides. Beyond measuring current impact, this project seeks to expand the functionality of Sketchtivity to offer lessons on more complex sketching tasks and more poignant feedback to learners. The main research goal is focused on improving sketching skills. The remaining goals turn outward toward the implications for improved sketching skill for engineers. It is essential to understand how to measure sketching skill effectively, and what role sketching skill plays in engineering design. Sketching skill has been measured in many different ways in many different fields and there seems to be no consensus on measurement strategy or validity. As a part of this project, we are conducting a systematic literature review of sketching evaluation. This literature review aims to compile the different methods of measurement to remove some of the ambiguity around evaluating sketching skill in engineering research and education. There has been much research on the role of sketching in engineering design, but the research around sketching skill has been limited. Essential to improving skill in any task is understanding how confidence in the skill is affected. Engineers’ self-efficacy can enable or limit their application of skills. We are also looking at how sketching skill is related to drawing self-efficacy. Sketching has the largest impact in the early stages of design. The final research goal of this project is to investigate the relationship between sketching and creativity in the early stages of design. Through experiments of idea generation and sketching abilities, we hope to better understand to what degree sketching enables creativity in design. To summarize, this project seeks to improve sketching skill through Sketchtivity. We are accomplishing this through expanding reach at multiple universities and expanding the capabilities of the software. It is also essential to understand the implications of improving sketching skill. This is being investigated through improved evaluation of sketching and investigations of sketching’s relationship to drawing self-efficacy and creativity

Impact of a sketch-based tutoring system at multiple universities

Large class sizes in engineering programs often prevent instructors from providing detailed and meaningful feedback to students on their homework problems. While the literature shows that frequent and immediate formative feedback has several benefits in terms of knowledge gain and academic motivation, several instructors struggle to provide any feedback. Motivated by this inability, a sketch-based virtual tutoring system, named Mechanix, has been developed and implemented. Mechanix lets the students to sketch their freebody diagram on a virtual interface and the process involved is very close to using a pencil and paper. The system provides real-time feedback on the accuracy of their Freebody diagrams and the solution to the problem. This paper reports the implementation of Mechanix at two large public universities in the United States - Georgia Institute of Technology and Texas State University. Mechanix is used to solve specific assignments from each school that involve the use of freebody diagrams. Pre- and post- concept inventories are used to measure the improvements in the conceptual understanding of the students. The results show that students who solve their homework using Mechanix outperform their peers who do not in one school, whereas the results are similar across the two groups in the second school. The evaluation of the concept inventories shows that the students who used Mechanix has the same level of improvement in their conceptual knowledge compared to the control group

Equation of state and high-pressure phase transitions in Mg2GeO4 olivine

Germanates are often used as structural analogs of planetary silicates. We have explored the high-pressure phase relations in Mg2GeO4 using diamond anvil cell experiments combined with synchrotron x-ray diffraction and computations based on density functional theory. Upon room temperature compression, forsterite remains stable up to 30 GPa. At higher pressures, a phase transition to a CmC21 structure was observed, which remained stable to the peak pressure of 105 GPa. Using a 3rd order Birch Murnaghan fit to the experimental data, we obtained V0 = 305.1 (3) A3, K0 = 124.6 (14) GPa and K' = 3.86 (fixed) for forsterite and V0 = 263.5 (15) A3, K0 = 175 (7) GPa and K' = 4.2 (fixed) for the CmC21 phase. In three separate runs, the forsterite sample was compressed to 26 GPa, 54 GPa and 105 GPa respectively and then laser-heated to ~2500 K. On laser heating, a mixture of perovskite MgGeO3 + MgO was found to be stable at the lower pressure conditions, whereas post-perovskite + MgO was observed at the highest pressure

Levonorgestrel-releasing intrauterine system vs. usual medical treatment for menorrhagia: An economic evaluation alongside a randomised controlled trial

Objective: To undertake an economic evaluation alongside the largest randomised controlled trial comparing Levonorgestrel-releasing intrauterine device ('LNG-IUS') and usual medical treatment for women with menorrhagia in primary care; and compare the cost-effectiveness findings using two alternative measures of quality of life. Methods: 571 women with menorrhagia from 63 UK centres were randomised between February 2005 and July 2009. Women were randomised to having a LNG-IUS fitted, or usual medical treatment, after discussing with their general practitioner their contraceptive needs or desire to avoid hormonal treatment. The treatment was specified prior to randomisation. For the economic evaluation we developed a state transition (Markov) model with a 24 month follow-up. The model structure was informed by the trial women's pathway and clinical experts. The economic evaluation adopted a UK National Health Service perspective and was based on an outcome of incremental cost per Quality Adjusted Life Year (QALY) estimated using both EQ-5D and SF-6D. Results: Using EQ-5D, LNG-IUS was the most cost-effective treatment for menorrhagia. LNG-IUS costs £100 more than usual medical treatment but generated 0.07 more QALYs. The incremental cost-effectiveness ratio for LNG-IUS compared to usual medical treatment was £1600 per additional QALY. Using SF-6D, usual medical treatment was the most cost-effective treatment. Usual medical treatment was both less costly (£100) and generated 0.002 more QALYs. Conclusion: Impact on quality of life is the primary indicator of treatment success in menorrhagia. However, the most costeffective treatment differs depending on the quality of life measure used to estimate the QALY. Under UK guidelines LNG-IUS would be the recommended treatment for menorrhagia. This study demonstrates that the appropriate valuation of outcomes in menorrhagia is crucial. Copyright: © 2014 Sanghera et al

Assessment of epicutaneous testing of a monovalent Influenza A (H1N1) 2009 vaccine in egg allergic patients

<p>Abstract</p> <p>Background</p> <p>H1N1 is responsible for the first influenza pandemic in 41 years. In the fall of 2009, an H1N1 vaccine became available in Canada with the hopes of reducing the overall effect of the pandemic. The purpose of this study was to assess the safety of administering 2 different doses of a monovalent split virus 2009 H1N1 vaccine in egg allergic patients.</p> <p>Methods</p> <p>Patients were skin tested to the H1N1 vaccine in the outpatient paediatric and adult allergy and immunology clinics of the Health Sciences Centre and Children's Hospital of Winnipeg, Manitoba Canada. Individuals <9 years of age were administered 1.88 μg's of hem-agglutinin antigen per 0.25 ml dose and individuals ≥9 years were administered 3.75 μg's of hemagglutinin antigen per 0.5 ml dose. Upon determination of a negative skin test, the vaccine was administered with a 30 minute observation period.</p> <p>Results</p> <p>A total of 61 patients with egg allergy (history of an allergic reaction to egg with either positive skin test &/or specific IgE to egg >0.35 Ku/L) were referred to our allergy clinics for skin testing to the H1N1 vaccine. 2 patients were excluded, one did not have a skin prick test to the H1N1 vaccine (only vaccine administration) and the other passed an egg challenge during the study period. Ages ranged from 1 to 27 years (mean 5.6 years). There were 41(69.5%) males and 18(30.5%) females. All but one patient with a history of egg allergy, positive skin test to egg and/or elevated specific IgE level to egg had negative skin tests to the H1N1 vaccine. The 58 patients with negative skin testing to the H1N1 vaccine were administered the vaccine and observed for 30 minutes post vaccination with no adverse results. The patient with the positive skin test to the H1N1 vaccine was also administered the vaccine intramuscularly with no adverse results.</p> <p>Conclusions</p> <p>Despite concern regarding possible anaphylaxis to the H1N1 vaccine in egg allergic patients, in our case series 1/59(1.7%) patients with sensitization to egg were also sensitized to the H1N1 vaccine. Administration of the H1N1 vaccine in egg allergic patients with negative H1N1 skin tests and observation is safe. Administering the vaccine in a 1 or 2 dose protocol without skin testing is a reasonable alternative as per the CSACI guidelines.</p

Current Fluctuations of the One Dimensional Symmetric Simple Exclusion Process with Step Initial Condition

For the symmetric simple exclusion process on an infinite line, we calculate exactly the fluctuations of the integrated current $Q_t$ during time $t$ through the origin when, in the initial condition, the sites are occupied with density $\rho_a$ on the negative axis and with density $\rho_b$ on the positive axis. All the cumulants of $Q_t$ grow like $\sqrt{t}$. In the range where $Q_t \sim \sqrt{t}$, the decay $\exp [-Q_t^3/t]$ of the distribution of $Q_t$ is non-Gaussian. Our results are obtained using the Bethe ansatz and several identities recently derived by Tracy and Widom for exclusion processes on the infinite line.Comment: 2 figure

Exploring the Use of Cost-Benefit Analysis to Compare Pharmaceutical Treatments for Menorrhagia

Background: The extra-welfarist theoretical framework tends to focus on health-related quality of life, whilst the welfarist framework captures a wider notion of well-being. EQ-5D and SF-6D are commonly used to value outcomes in chronic conditions with episodic symptoms, such as heavy menstrual bleeding (clinically termed menorrhagia). Because of their narrow-health focus and the condition’s periodic nature these measures may be unsuitable. A viable alternative measure is willingness to pay (WTP) from the welfarist framework. Objective: We explore the use of WTP in a preliminary cost-benefit analysis comparing pharmaceutical treatments for menorrhagia. Methods: A cost-benefit analysis was carried out based on an outcome of WTP. The analysis is based in the UK primary care setting over a 24-month time period, with a partial societal perspective. Ninety-nine women completed a WTP exercise from the ex-ante (pre-treatment/condition) perspective. Maximum average WTP values were elicited for two pharmaceutical treatments, levonorgestrel-releasing intrauterine system (LNG-IUS) and oral treatment. Cost data were offset against WTP and the net present value derived for treatment. Qualitative information explaining the WTP values was also collected. Results: Oral treatment was indicated to be the most cost-beneficial intervention costing £107 less than LNG-IUS and generating £7 more benefits. The mean incremental net present value for oral treatment compared with LNG-IUS was £113. The use of the WTP approach was acceptable as very few protests and non-responses were observed. Conclusion: The preliminary cost-benefit analysis results recommend oral treatment as the first-line treatment for menorrhagia. The WTP approach is a feasible alternative to the conventional EQ-5D/SF-6D approaches and offers advantages by capturing benefits beyond health, which is particularly relevant in menorrhagia

The medically managed patient with severe symptomatic aortic stenosis in the TAVR era: Patient characteristics, reasons for medical management, and quality of shared decision making at heart valve treatment centers

Background Little is known about patients with severe symptomatic aortic stenosis (AS) who receive medical management despite evaluation at a heart valve treatment center. Objective We identified patient characteristics associated with medical management, physician-reported reasons for selecting medical management, and patients’ perceptions of their involvement and satisfaction with treatment selection. Methods and results Of 454 patients evaluated for AS at 9 established heart valve treatment centers from December 12, 2013 to August 19, 2014, we included 407 with severe symptomatic AS. Information was collected using medical record review and survey of patients and treating physicians. Of 407 patients, 212 received transcatheter aortic valve replacement (TAVR), 124 received surgical aortic valve replacement (SAVR), and 71 received medical management (no SAVR/TAVR). Thirty-day predicted mortality was higher in patients receiving TAVR (8.7%) or medical management (9.8%) compared with SAVR (3.4%) (P<0.001). Physician-reported reasons for medical management included patient preference (31.0%), medical futility (19.7%), inoperability/anatomic infeasibility (11.3%), and inadequate vascular access (8.5%). Compared with patients receiving AVR, medically managed patients were less likely to report that they received enough information about the pros and cons of treatment options (P = 0.03), that their physicians involved them in treatment decisions (P<0.001), and that final decisions were the right ones (P<0.001). Conclusions Patient preference was the most common physician-reported reason for selecting non-invasive AS management, yet patients not undergoing AVR after valve center evaluation reported being less likely to receive sufficient education about treatment options and more likely to feel uncertain about final treatment decisions. Greater attention to shared decision making may improve the experience of care for this vulnerable group of patients