Comparison of a Novel Insulin Bolus-Patch with Pen/Syringe Injection to Deliver Mealtime Insulin for Efficacy, Preference, and Quality of Life in Adults with Diabetes: A Randomized, Crossover, Multicenter Study

Objective: This study compared the efficacy, safety, device satisfaction, and quality of life (QOL) in people with diabetes using an insulin bolus-patch versus current devices (pen/syringe) to deliver mealtime insulin. Research Design and Methods: Thirty-eight subjects with diabetes (26 with type 1 and 12 with type 2) were randomized to bolus-patch or current injection device (55% pen and 45% syringe) to deliver mealtime insulin in a multicenter, 6-week crossover study. Efficacy was assessed by equivalence in mean daily seven-point blood glucose (MDBG). Safety assessments included severe hypoglycemia episodes, adverse device effects (ADEs), and adverse events (AEs). Device satisfaction was determined by the validated Insulin Delivery System Rating Questionnaire (IDSRQ) and QOL by the validated Diabetes Specific QOL Scale (DSQOLS). Results: Using bolus-patch, MDBG (mean•SE) was equivalent to that using pen/syringe (8.61+/-0.28 vs. 9.02+/-0.26-mmol/L; P=0.098). SD of the seven-point blood glucose measurements was lower using bolus-patch (3.18+/-0.18 vs. 3.63+/-0.17 mmol/L; P=0.004), as was the coefficient of variation (CV) (37.2+/-1.7 vs. 40.3+/-1.7%; P=0.046). Hemoglobin A1c, 1,5-anhydroglucitol, fructosamine, and insulin use were similar between groups. There were no severe hypoglycemia episodes or serious ADEs. Between-device AEs were comparable. Subjects scored better on six of seven subscales on the DSQOLS and five of six subscales on the IDSRQ while using bolus-patch versus pen/syringe. At study completion, 76% of subjects would choose to switch to bolus-patch (P=0.001). Conclusions: Delivery of mealtime insulin with bolus-patch compared with pen/syringe resulted in equivalent MDBG, lower SD and CV of seven-point blood glucose measurements, good safety, significant device satisfaction, and improved QOL.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90477/1/dia-2E2011-2E0047.pd

Restoring native forest understory: The influence of ferns and light in a hawaiian experiment

Ecological restoration is an increasingly important component of sustainable land management. We explore potential facilitative relationships for enhancing the cost-effectiveness of restoring native forest understory, focusing on two factors: (1) overstory shade and (2) possible facilitation by a fern (Dryopteris wallichiana), one of few native colonists of pasture in our montane Hawai\u27i study system. We planted 720 understory tree seedlings and over 4000 seeds of six species under six planting treatments: a full factorial combination of low, medium and high light, situating plantings in either the presence or absence of a mature fern. After three years, 75% of outplanted seedlings survived. Seedling survivorship was significantly higher in the presence of a fern (79% vs. 71% without a fern) and in medium and low light conditions (81% vs. 64% in high light). Relative height was highest at low to medium light levels. After 2.2 years, 2.8% of the planted seeds germinated. We observed no significant differences in seed germination relative to light level or fern presence. Analyzing several approaches, we found nursery germination of seeds followed by outplanting ca. 20% less costly than direct seeding in the field. This study opens new questions about facilitation mechanisms that have the potential to increase the extent and effectiveness of restoration efforts. © 2013 by the authors

The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study

Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Increasing extracellular H2O2 produces a bi-phasic response in intracellular H2O2, with peroxiredoxin hyperoxidation only triggered once the cellular H2O2-buffering capacity is overwhelmed

Reactive oxygen species, such as H2O2, can damage cells but also promote fundamental processes, including growth, differentiation and migration. The mechanisms allowing cells to differentially respond to toxic or signaling H2O2 levels are poorly defined. Here we reveal that increasing external H2O2 produces a bi-phasic response in intracellular H2O2. Peroxiredoxins (Prx) are abundant peroxidases which protect against genome instability, ageing and cancer. We have developed a dynamic model simulating in vivo changes in Prx oxidation. Remarkably, we show that the thioredoxin peroxidase activity of Prx does not provide any significant protection against external rises in H2O2. Instead, our model and experimental data are consistent with low levels of extracellular H2O2 being efficiently buffered by other thioredoxin-dependent activities, including H2O2-reactive cysteines in the thiol-proteome. We show that when extracellular H2O2 levels overwhelm this buffering capacity, the consequent rise in intracellular H2O2 triggers hyperoxidation of Prx to thioredoxin-resistant, peroxidase-inactive form/s. Accordingly, Prx hyperoxidation signals that H2O2 defenses are breached, diverting thioredoxin to repair damage

Activity Levels and Body Mass Index of Children in the US, Sweden and Australia

Purpose: Assess the physical activity and body mass index (BMI) levels of children in the United States, Sweden, and Australia. Methods: A total of 1954 children, 6-12 yr old (711 American, 563 Australian, and 680 Swedish) wore sealed pedometers for four consecutive days. Height and weight measures were obtained. Results: Descriptive data for step counts and BMI by sex, age, and country were calculated to determine activity levels and BMI. Three-way multivariate ANOVA for step counts and BMI between countries at each age and sex found that, in general, the Swedish children were significantly more active than the Australian and American children, and the American children were significantly heavier than the Australian and Swedish children. For boys, the mean step counts ranged from 15,673 to 18,346 for Sweden, 13,864 to 15,023 for Australia, and 12,554 to 13,872 for America. For girls, the mean step Counts ranged from 12,041 to 14,825 for Sweden, 11,221 to 12,322 for Australia, and 10,661 to 11,383 for America. The activity curve is somewhat level during the preadolescent years. The rate of increase in BMI with age is much greater in the American children than in the Swedish or Australian children. The percent of American, Swedish, and Australian boys classified as overweight/obese was 33.5, 16.6, and 15.8, respectively. The percent of American, Swedish, and Australian girls classified as overweight/obese was 35.6, 16.8, and 14.4, respectively. Correlation analysis found few significant negative relationships between step counts and BMI. Conclusions: American children tend to be the least active and heaviest with the greatest rate of increase in BMI. The Swedish children are the most active group followed by Australia. Swedish and Australian children maintain lower BMI throughout their prepubescent years than do the American children who have a greater percentage who are classified as overweight

Genetic, physical and functional interactions between the double-stranded RNA-dependent protein kinase PKR and the tumor suppressor p53

The tumor suppressor p53 is a multifunctional protein that plays a critical role in modulating cellular responses such as cell cycle arrest and apoptosis upon DNA damage or other stresses. These functions of p53 can be regulated by protein-protein interactions and by phosphorylation. The interferon (IFN)-inducible, double-stranded RNA activated protein kinase PKR is a serine/threonine kinase that mediates the antiviral and antigrowth effects of IFNs by inhibiting protein synthesis through the phosphorylation of the translation initiation factor eIF-2alpha. Both PKR and p53 have the capacity to inhibit cell growth and to modulate gene expression at both the transcriptional and translational level. However, the exact molecular mechanism(s) behind the regulation of cell growth by PKR are not-well understood. Based on previous reports demonstrating a cross talk between other IFN-inducible proteins and p53, it was of interest to examine whether and how PKR might modulate p53 function to explain the ability of PKR to regulate cell growth. This study demonstrates that PKR can physically, functionally and genetically interact with p53. PKR and p53 physically interact both in vivo and in vitro, and the interaction of PKR with p53 is a functional one since PKR can directly phosphorylate p53 on serine392 in vitro. Furthermore, studies using PKR+/+ and PKR-/- cells treated with adriamycin or expressing a temperature sensitive mutant of p53, showed that p53-mediated gene expression and G0/G 1 arrest was inhibited in PKR-/- cells. The phosphorylation levels of serine18 of p53, which plays a role in p53 function in vivo, was inhibited in PKR+/+ cells expressing temperature sensitive p53 compared to PKR-/- cells. Induction of serine18 phosphorylation was inhibited in PKR-/- cells in response to gamma-radiation and adriamycin but not ultraviolet radiation. While PKR does not directly phosphorylate serine18 of p53 in vitro, the specific phosphatidylinositol-3 (PI-3) kinase inhibi

BMI-Referenced Standards for Recommended Pedometer-Determined Steps/Day in Children

Background: Recommended levels of youth physical activity (PA) should emerge from data related to important health outcomes. The purpose of the present study was to establish criterion-referenced standards for PA (using pedometer-assessed steps/day) related to healthy body composition. Methods: This is a secondary analysis of an existing data set (including pedometer-assessed PA and objectively measured BMI) of 1,954 children (995 girls, 959 boys; ages 6-12 years) from the USA, Australia, and Sweden. The contrasting groups method [M.J. Sarif, Introduction to Measurement in Physical Education and Exercise Science, St. Louis, MO: Mosby College Publishing; 1986] for establishing criterion-referenced cut points was used to identify optimal age- and sex-specific standards for steps/day related to international BMI cut points for normal weight and overweight/obesity. Results: The selected cut points for steps/day for 6-12 year olds were 12,000 steps/day for girls and 15,000 steps/day for boys. Conclusions: The analytical process undertaken in this study illuminated the difference in previously used norm-referenced standards vs. criterion-referenced standards based on BMI categories. The steps/day cut points established herein, using an international sample, are higher than previously suggested normative standards but are not inconsistent with recent advances in our understanding of PA needs in youth. This analysis provides the foundation for cross-validation and evaluation of these BMI-referenced steps/day cut points in independent samples and with longitudinal study designs