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Leigh MacConell,1 Kate Gurney,2 Jaret Malloy,1 Ming Zhou,3 Orville Kolterman4 1Clinical Development, Bristol-Myers Squibb, San Diego, CA, USA; 2Medical Writing, Bristol-Myers Squibb, San Diego, CA, USA; 3Biostatistics, Bristol-Myers Squibb, Princeton, NJ, 4Safety, Bristol-Myers Squibb, San Diego, CA, USA Background: Exenatide once weekly (QW) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of type 2 diabetes. Safety and tolerability are key considerations in treatment selection. This analysis examines the safety and tolerability profile of exenatide QW, other approved GLP-1RAs (exenatide twice daily and liraglutide once daily), and a pooled population of commonly used non-GLP-1RA treatments. Methods: Intent-to-treat populations from eight randomized Phase III trials with 24-week and 30-week comparator-controlled periods were analyzed. Data were pooled for exenatide QW, exenatide twice daily, and non-GLP-1RA comparator groups; comparisons between exenatide QW and liraglutide were analyzed separately to better match study groups. The incidence of treatment-emergent adverse events with 95% confidence intervals and exposure-adjusted incidence were calculated. Duration and recurrence were analyzed for gastrointestinal adverse events and adverse events of special interest. Results: Incidences of serious adverse events did not differ between treatments. Discontinuations due to adverse events occurred numerically less frequently with exenatide QW than with other GLP-1RAs but numerically more frequently than with non-GLP-1RA comparators. The most frequent adverse events in the GLP-1RA groups were gastrointestinal and generally mild, with decreasing incidence over time. Gastrointestinal adverse event incidences appeared lower with exenatide QW versus other GLP-1RAs and greater than with non-GLP-1RA comparators. Injection site-related adverse events seemed highest with exenatide QW, but generally did not lead to withdrawal and abated over time. Hypoglycemia was infrequent overall, but occurred numerically more frequently in the non-GLP-1RA comparator group and increased with concomitant sulfonylurea use. Pancreatitis, thyroid cancer, renal failure, and gallbladder disease were rarely reported. Conclusion: The overall safety and tolerability profile of exenatide QW was similar to that of other GLP-1RAs, with improved gastrointestinal tolerability. The safety and tolerability profile of exenatide QW compared with non-GLP-1RA comparators was similar overall, with the exception of a lower incidence of hypoglycemia and anticipated differences in gastrointestinal and injection site-related adverse events. Keywords: glucagon-like peptide-1 receptor agonist, hyperglycemia, adverse events, hypoglycemia

Jaret Malloy, Kate Gurney, Kevin Shan, Ping Yan, Steve ChenAmylin Pharmaceuticals LLC, San Diego, CABackground: Recent studies have demonstrated an increased incidence of pancreatitis in patients with type 2 diabetes compared with obese nondiabetic individuals. Serum lipase and pancreatic amylase concentrations are used in conjunction with clinical findings to diagnose pancreatitis.Methods: In two large clinical trials of overweight/obese nondiabetic and type 2 diabetic subjects, lipase and pancreatic amylase were measured at screening and 2–5 weeks later at baseline (prior to treatment with study medication).Results: Lipase and pancreatic amylase concentrations were above the upper limit of normal (ULN) in 13% and 6% of type 2 diabetic subjects, respectively, and were approximately three-fold (3 ×) higher than the proportion of nondiabetic subjects with levels above ULN. Elevations exceeding ULN were seen in many subjects asymptomatic for pancreatitis; however, elevations >2 × ULN and >3 × ULN were uncommon, and elevations >3 × ULN were often associated with a history of dyslipidemia, hyperlipidemia, and gastrointestinal disorders. Additionally, enzyme concentrations varied within this 2–5-week screening period, including shifts between elevated and normal levels.Conclusion: Results from this post hoc analysis suggest that, although pancreatic enzymes can be a useful marker for pancreatitis within the proper clinical context, diagnosis of pancreatitis may be confounded in populations known to have asymptomatic elevations associated with disease, such as type 2 diabetes. Further effort is needed to clarify the etiology and epidemiology of pancreatic enzyme elevations in type 2 diabetes.Keywords: diabetes, pancreatitis, amylase, lipase

Leigh MacConell, Carl Brown, Kate Gurney, Jenny HanAmylin Pharmaceuticals, Inc. San Diego, CA, USABackground: Exenatide twice daily is a first-in-class glucagon-like peptide receptor agonist approved for the treatment of type 2 diabetes. The objective of this analysis was to evaluate the safety profile of exenatide twice daily and to compare its profile with that of a pooled comparator (placebo and insulin) in patients with type 2 diabetes.Methods: Data from 19 completed, randomized, controlled clinical trials of exenatide twice daily (5 µg and 10 µg) were pooled and analyzed; the pooled data included 5594 intent-to-treat patients who were followed for 12–52 weeks. Incidence rates, exposure-adjusted incidence rates, and 95% confidence intervals around risk differences between groups were calculated.Results: Baseline demographics and exposure time were comparable between groups (exenatide, N = 3261; pooled comparator, N = 2333; mean exposure time 166–171 days). Transient, mild-to-moderate nausea was the most frequent adverse event with exenatide (36.9% versus 8.3% in the pooled comparator). The incidence of hypoglycemia (minor or major) with concomitant sulfonylurea (exenatide 26.5%, pooled comparator 20.7%) was higher than that without sulfonylurea (exenatide 3.1%, pooled comparator 2.7%) in all groups. Serious adverse events, discontinuations due to serious adverse events, and deaths were reported with similar frequency in the exenatide and pooled comparator groups. Composite exposure-adjusted incidence rates were not statistically different between groups for pancreatitis, renal impairment, or major adverse cardiac events; there was a difference in incidence rates for benign thyroid neoplasm (0.3% versus 0%).Conclusion: Overall, this analysis, representing over 1500 patient-years of exposure, demonstrated that exenatide twice daily was safe and generally well tolerated in patients with type 2 diabetes. The incidence of most adverse events, including serious adverse events, was similar in both exenatide-treated and comparator-treated patients. The most distinct differences between groups were in gastrointestinal-related adverse events, which is consistent with other therapies within the glucagon-like peptide class.Keywords: exenatide, safety, adverse events, risk difference

Efforts to control climate change require the stabilization of atmospheric CO 2 concentrations. This can only be achieved through a drastic reduction of global CO 2 emissions. Yet fossil fuel emissions increased by 29% between 2000 and 2008, in conjunction with increased contributions from emerging economies, from the production and international trade of goods and services, and from the use of coal as a fuel source. In contrast, emissions from land-use changes were nearly constant. Between 1959 and 2008, 43% of each year's CO 2 emissions remained in the atmosphere on average; the rest was absorbed by carbon sinks on land and in the oceans. In the past 50 years, the fraction of CO 2 emissions that remains in the atmosphere each year has likely increased, from about 40% to 45%, and models suggest that this trend was caused by a decrease in the uptake of CO 2 by the carbon sinks in response to climate change and variability. Changes in the CO 2 sinks are highly uncertain, but they could have a significant influence on future atmospheric CO 2 levels. It is therefore crucial to reduce the uncertainties. © 2009 Macmillan Publishers Limited. All rights reserved.

Vegetation composition at high latitudes plays a critical role in the climate and, in turn, is strongly affected by the climate. The increased frequency of fires expected as a result of climate warming at high latitudes will feedback positively to further warming by releasing carbon to the atmosphere, but will also feedback negatively by increasing the surface albedo. The net effect is complex because the severity of fire affects the trajectory of both carbon stocks and albedo change following a fire, and these are likely to differ between high latitude ecosystems in North America and northern Eurasia. Here we use growth trajectories, productivity trends and regional carbon fluxes to characterize these fire- and climate-driven changes.

Monthly CO2 fluxes are estimated across 1988–2003 for 22 emission regions using data from 78 CO2 measurement sites. The same inversion (method, priors, data) is performed with 13 different atmospheric transport models, and the spread in the results is taken as a measure of transport model error. Interannual variability (IAV) in the winds is not modeled, so any IAV in the measurements is attributed to IAV in the fluxes. When both this transport error and the random estimation errors are considered, the flux IAV obtained is statistically significant at P ≤ 0.05 when the fluxes are grouped into land and ocean components for three broad latitude bands, but is much less so when grouped into continents and basins. The transport errors have the largest impact in the extratropical northern latitudes. A third of the 22 emission regions have significant IAV, including the Tropical East Pacific (with physically plausible uptake/release across the 1997–2000 El Niño/La Niña) and Tropical Asia (with strong release in 1997/1998 coinciding with large-scale fires there). Most of the global IAV is attributed robustly to the tropical/southern land biosphere, including both the large release during the 1997/1998 El Niño and the post-Pinatubo uptake.

In TransCom-3 (Level 1), atmospheric CO2 measurements from 76 monitoring stations for the period 1992–1996 and 16 atmospheric transport models were used to constrain annual mean CO2 fluxes over 11 land and 11 ocean regions. The tower measurements of atmospheric CO2 from Fraserdale, a continental site in northern Ontario, Canada are now available and processed for use in the TransCom-3 inverse modelling framework. In this short study, we show that by including this set of continental CO2 data, the estimated flux for the North American boreal region becomes nearly zero, a reduction of about 0.26 Pg C yr−1 from the previous estimate. The uncertainty of the estimated flux for this region is also reduced by ∼30%. All transport models show negative changes for boreal North America, with the strongest responses (∼−0.5 Pg C yr−1) shown by NIRE, NIES, CSU and SKYHI. Furthermore, models showing a strong response in boreal North America tend to show strong sensitivity in middle- and high-latitude Asian regions.

This paper explores various sources of error in atmospheric CO2 synthesis inversions using global circulation models. The estimation of prior, observation, model transport, and representation errors is described, and the latter two error sources are explored in more detail. Not accounting for these errors will act as a hard constraint on the inversion and will produce incorrect solutions to the problem as is shown in some example inversions. The magnitude of these errors falls generally between about 10% and 100% in the retrieved fluxes but can be even larger. This makes it highly desirable to avoid hard constraints and apply any prior information we have about the surface fluxes as a weak constraint to the inversion problem.

In this paper, we present two versions of a hardware processing architecture for modeling large networks of leaky-integrate-and-fire (LIF) neurons; the second version provides performance enhancing features relative to the first. Both versions of the architecture use fixed-point arithmetic and have been implemented using a single field-programmable gate array (FPGA). They have successfully simulated networks of over 1000 neurons configured using biologically plausible models of mammalian neural systems. The neuroprocessor has been designed to be employed primarily for use on mobile robotic vehicles, allowing bio-inspired neural processing models to be integrated directly into real-world control environments. When a neuroprocessor has been designed to act as part of the closed-loop system of a feedback controller, it is imperative to maintain strict real-time performance at all times, in order to maintain integrity of the control system. This resulted in the reevaluation of some of the architectural features of existing hardware for biologically plausible neural networks (NNs). In addition, we describe a development system for rapidly porting an underlying model (based on floating-point arithmetic) to the fixed-point representation of the FPGA-based neuroprocessor, thereby allowing validation of the hardware architecture. The developmental system environment facilitates the cooperation of computational neuroscientists and engineers working on embodied (robotic) systems with neural controllers, as demonstrated by our own experience on the Whiskerbot project, in which we developed models of the rodent whisker sensory system. Index Terms--Field-programmable gate array (FPGA), integrate and fire, neuronal networks (NNs), real time, robotics.