Saxagliptin clinical trials: evaluation of CV risk

Diabetes is Australia's fastest growing chronic disease with approximately 890,000 patients currently diagnosed with diabetes. 1 By 2031 it is predicted that 3.3 million Australians will have type 2 diabetes mellitus, 2 thus increasing the demand for treatment. However, several diabetes, obesity, and lipid drug trials have had unexpected and unfavourable cardiovascular (CV) results. The saxagliptin (SAXA) phase 2b/3 program enrolled a range of patients with diabetes and included a controlled, long-term safety extension phase. SAXA is a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor. In the SAXA clinical data, the primary endpoint, major adverse cardiovascular events (MACE; stroke, myocardial infarction or CV death, analysed post hoc) and acute cardiovascular events (ACE; acute, clinically significant events, including cardiac revascularisation procedures) were identified using selected MedDRA Preferred Terms. CV events were analysed in a comprehensive dataset: 8 randomised, double-blind, phase 2b/3 trials, which included 4607 patients (3206 randomised to SAXA 2.5, 5, or 10 mg; 150 randomised to SAXA 20, 40, or 100 mg; and 1251 randomised to placebo, metformin, or up-titrated glyburide). Overall exposure was 3758 patient-years on SAXA and 1293 patient-years on comparators. Within the SAXA population, 81% had at least 1 CV risk factor in addition to diabetes, with hypertension (52%), dyslipidaemia (44%), or history of smoking (39%) the most common; 12% had known prior CV disease. Comparator group had similar proportions. Numbers of patients with events are shown in Table. The Cox proportional hazard ratio for MACE was 0.44 (95% CI: 0.24–0.82) and for ACE was 0.59 (95% CI: 0.35–1.00). A series of sensitivity analyses using related endpoints and alternative analytic methods produced consistent results. Based on a >5000 patient-year clinical trial experience, there was no evidence of increased CV risk with SAXA treatment ― as monotherapy or in combination with other oral antidiabetic agents. These data raise the hypothesis of a cardioprotective effect of SAXA, which will be studied in the SAVOR trial

Building a data sharing model for global genomic research

Data sharing models designed to facilitate global business provide insights for improving transborder genomic data sharing. We argue that a flexible, externally endorsed, multilateral arrangement , combined with an objective third-party assurance mechanism, can effectively balance privacy with the need to share genomic data globally

Ozone loss derived from balloon-borne tracer measurements and the SLIMCAT CTM

Balloon-borne measurements of CFC-11 (on flights of the DIRAC in situ gas chromatograph and the DESCARTES grab sampler), ClO and O3 were made during the 1999/2000 winter as part of the SOLVE-THESEO 2000 campaign. Here we present the CFC-11 data from nine flights and compare them first with data from other instruments which flew during the campaign and then with the vertical distributions calculated by the SLIMCAT 3-D CTM. We calculate ozone loss inside the Arctic vortex between late January and early March using the relation between CFC-11 and O3 measured on the flights, the peak ozone loss (1200 ppbv) occurs in the 440–470 K region in early March in reasonable agreement with other published empirical estimates. There is also a good agreement between ozone losses derived from three independent balloon tracer data sets used here. The magnitude and vertical distribution of the loss derived from the measurements is in good agreement with the loss calculated from SLIMCAT over Kiruna for the same days

Campaign Finance Reform: The Unfinished Agenda

In 1974, following the Watergate scandal, Congress enacted major campaign finance reform legislation. The legislation created a revolutionary new public financing system for our presidential campaigns, but it left congressional campaigns to be financed totally by private money. The presidential public financing system has worked well. Despite some incremental problems, the system has accomplished its basic goal of allowing individuals to run for the presidency without becoming dependent on their financial backers. The system for financing congressional cam paigns, on the other hand, is out of control and in need of fundamental reform. The inappropriate role of special interest political action commit tees (PACs) in influencing congressional elections and congressional decisions is the single biggest problem facing the political process. Congress needs to complete the unfinished campaign finance reform agenda of the 1970s by enacting public financing for congressional campaigns and establishing new restrictions on the total amount that PACs may give to a congressional candidate.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67356/2/10.1177_000271628648600107.pd

Improved Malaria Case Management through the Implementation of a Health Facility-Based Sentinel Site Surveillance System in Uganda

Heath facility-based sentinel site surveillance has been proposed as a means of monitoring trends in malaria morbidity but may also provide an opportunity to improve malaria case management. Here we described the impact of a sentinel site malaria surveillance system on promoting laboratory testing and rational antimalarial drug use.Sentinel site malaria surveillance was established at six health facilities in Uganda between September 2006 and January 2007. Data were collected from all patients presenting to the outpatient departments including demographics, laboratory results, diagnoses, and treatments prescribed. Between the start of surveillance and March 2010, a total 424,701 patients were seen of which 229,375 (54%) were suspected of having malaria. Comparing the first three months with the last three months of surveillance, the proportion of patients with suspected malaria who underwent diagnostic testing increased from 39% to 97% (p<0.001). The proportion of patients with an appropriate decision to prescribe antimalarial therapy (positive test result prescribed, negative test result not prescribed) increased from 64% to 95% (p<0.001). The proportion of patients appropriately prescribed antimalarial therapy who were prescribed the recommended first-line regimen artemether-lumefantrine increased from 48% to 69% (p<0.001).The establishment of a sentinel site malaria surveillance system in Uganda achieved almost universal utilization of diagnostic testing in patients with suspected malaria and appropriate decisions to prescribed antimalarial based on test results. Less success was achieved in promoting prescribing practice for the recommended first-line therapy. This system could provide a model for improving malaria case management in other health facilities in Africa

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC

Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2 x 10(-4) after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation

Geodetic and seismic constraints on some seismogenic zone processes in Costa Rica

New seismic and geodetic data from Costa Rica provide insight into seismogenic zone processes in Central America, where the Cocos and Caribbean plates converge. Seismic data are from combined land and ocean bottom deployments in the Nicoya peninsula in northern Costa Rica and near the Osa peninsula in southern Costa Rica. In Nicoya, inversion of GPS data suggests two locked patches centered at 14 ± 2 and 39 ± 6 km depth. Interplate microseismicity is concentrated in the more freely slipping intermediate zone, suggesting that small interseismic earthquakes may not accurately outline the updip limit of the seismogenic zone, the rupture zone for future large earthquakes, at least over the short (∼1 year) observation period. We also estimate northwest motion of a coastal “sliver block” at 8 ± 3 mm/yr, probably related to oblique convergence. In the Osa region to the south, convergence is orthogonal to the trench. Cocos-Caribbean relative motion is partitioned here, with ∼8 cm/yr on the Cocos-Panama block boundary (including a component of permanent shortening across the Fila Costeña fold and thrust belt) and ∼1 cm/yr on the Panama block–Caribbean boundary. The GPS data suggest that the Cocos plate–Panama block boundary is completely locked from ∼10–50 km depth. This large locked zone, as well as associated forearc and back-arc deformation, may be related to subduction of the shallow Cocos Ridge and/or younger lithosphere compared to Nicoya, with consequent higher coupling and compressive stress in the direction of plate convergence