Primary task event-related potentials related to different aspects of information processing

The results of two studies which investigated the relationships between cognitive processing and components of transient event-related potentials (ERPs) are presented in a task in which mental workload was manipulated. The task involved the monitoring of an array of discrete readouts for values that went out of bounds, and was somewhat analogous to tasks performed in cockpits. The ERPs elicited by the changing readouts varied with the number of readouts being monitored, the number of monitored readouts that were close to going out of bounds, and whether or not the change took a monitored readout out of bounds. Moreover, different regions of the waveform differentially reflected these effects. The results confirm the sensitivity of scalp-recorded ERPs to the cognitive processes affected by mental workload and suggest the possibility of extracting useful ERP indices of primary task performance in a wide range of man-machine settings

Brain-wave measures of workload in advanced cockpits: The transition of technology from laboratory to cockpit simulator, phase 2

The present Phase 2 small business innovation research study was designed to address issues related to scalp-recorded event-related potential (ERP) indices of mental workload and to transition this technology from the laboratory to cockpit simulator environments for use as a systems engineering tool. The project involved five main tasks: (1) Two laboratory studies confirmed the generality of the ERP indices of workload obtained in the Phase 1 study and revealed two additional ERP components related to workload. (2) A task analysis' of flight scenarios and pilot tasks in the Advanced Concepts Flight Simulator (ACFS) defined cockpit events (i.e., displays, messages, alarms) that would be expected to elicit ERPs related to workload. (3) Software was developed to support ERP data analysis. An existing ARD-proprietary package of ERP data analysis routines was upgraded, new graphics routines were developed to enhance interactive data analysis, and routines were developed to compare alternative single-trial analysis techniques using simulated ERP data. (4) Working in conjunction with NASA Langley research scientists and simulator engineers, preparations were made for an ACFS validation study of ERP measures of workload. (5) A design specification was developed for a general purpose, computerized, workload assessment system that can function in simulators such as the ACFS

Cytosolic Phospholipase A2α and Eicosanoids Regulate Expression of Genes in Macrophages Involved in Host Defense and Inflammation

Acknowledgments: We thank Dr. Robert Barkley and Charis Uhlson for mass spectrometry analysis. Funding: This work was supported by grants from the National Institutes of Health HL34303 (to C.C.L., R.C.M. and D.L.B), DK54741 (to J.V.B.), GM5322 (to D.L.W.) and the Wellcome Trust (to N.A.R.G. and G.D.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS program

This study compared initiation of insulin and other AHAs with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs 16%), insulin (3% vs 9%;) or any non-insulin AHA (5% vs 12%; p<0.001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31,0.43; p<0.001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about two years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (p<0.001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes. Trial registration: ClinicalTrials.gov identifiers NCT01032629, NCT01989754. This article is protected by copyright. All rights reserved

Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories:Findings From the CANVAS Program

Rationale & Objective: Canagliflozin reduces the risk for cardiovascular and kidney outcomes in type 2 diabetes. This study aimed to assess the relative and absolute effects of canagliflozin on clinical outcomes across different KDIGO (Kidney Disease: Improving Global Outcomes) risk categories based on estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio. Study Design: Post hoc analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. Settings & Participants: The CANVAS Program randomly assigned 10,142 participants with type 2 diabetes at high cardiovascular risk and with eGFR ≥ 30 mL/min/1.73 m2 to treatment with canagliflozin or placebo. Intervention(s): Canagliflozin or matching placebo. Outcomes: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with a set of other cardiovascular and kidney prespecified outcomes. Results: Of 10,142 participants, 10,031 (98.9%) had available baseline eGFR and urinary albumin-creatinine ratio data. The proportion of participants in low-, moderate-, high-, and very high–risk KDIGO categories was 58.6%, 25.8%, 10.6%, and 5.0%, respectively. The relative effect of canagliflozin on the primary outcome (HR, 0.86; 95% CI, 0.75-0.97) was consistent across KDIGO risk categories (P trend = 0.2), with similar results for other cardiovascular and kidney outcomes. Absolute reductions in the primary outcome were greater within higher KDIGO risk categories (P trend = 0.03) with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure (P trend = 0.06) and for chronic eGFR slope (P trend = 0.04). Limitations: Predominantly a low kidney risk population, relatively few participants in higher KDIGO risk categories, and exclusion of individuals with eGFR < 30 mL/min/1.73 m2. Conclusions: Although the relative effects of canagliflozin are similar across KDIGO risk categories, absolute risk reductions are likely greater for individuals at higher KDIGO risk. The KDIGO classification system may be able to identify individuals who might derive greater benefits for end-organ protection from treatment with canagliflozin. Funding: This post hoc analysis was not specifically funded. The original CANVAS Program trials were funded by Janssen Research & Development, LLC and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical. Trial Registration: The original trials of the CANVAS Program were registered at ClinicalTrials.gov with study numbers NCT01032629 and NCT01989754

Co-occurrence of Fe and P stress in natural populations of the marine diazotroph Trichodesmium

Trichodesmium is a globally important marine microbe that provides fixed nitrogen (N) to otherwise N-limited ecosystems. In nature, nitrogen fixation is likely regulated by iron or phosphate availability, but the extent and interaction of these controls are unclear. From metaproteomics analyses using established protein biomarkers for nutrient stress, we found that iron–phosphate co-stress is the norm rather than the exception for Trichodesmium colonies in the North Atlantic Ocean. Counterintuitively, the nitrogenase enzyme was more abundant under co-stress as opposed to single nutrient stress. This is consistent with the idea that Trichodesmium has a specific physiological state during nutrient co-stress. Organic nitrogen uptake was observed and occurred simultaneously with nitrogen fixation. The quantification of the phosphate ABC transporter PstA combined with a cellular model of nutrient uptake suggested that Trichodesmium is generally confronted by the biophysical limits of membrane space and diffusion rates for iron and phosphate acquisition in the field. Colony formation may benefit nutrient acquisition from particulate and organic sources, alleviating these pressures. The results highlight that to predict the behavior of Trichodesmium, both Fe and P stress must be evaluated simultaneously

Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes:A Post Hoc Analysis from the CREDENCE Trial

Background The association between early changes in albuminuria and kidney and cardiovascular events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association occurs with sodium-glucose cotransporter 2 inhibition. Methods TheCanagliflozin and Renal Events inDiabeteswith EstablishedNephropathy Clinical Evaluation (CREDENCE) trial enrolled 4401 patients with type 2 diabetes and CKD (urinary albumin-creatinine ratio [UACR].300 mg/g). This post hoc analysis assessed canagliflozin's effect on albuminuria and how early change in albuminuria (baseline to week 26) is associated with the primary kidney outcome (ESKD, doubling of serum creatinine, or kidney death), major adverse cardiovascular events, and hospitalization for heart failure or cardiovascular death. Results Complete data for early change in albuminuria and other covariates were available for 3836 (87.2%) participants in the CREDENCE trial. Compared with placebo, canagliflozin lowered UACR by 31% (95% confidence interval [95% CI], 27% to 36%) at week 26, and significantly increased the likelihood of achieving a 30% reduction in UACR ( odds ratio, 2.69; 95% CI, 2.35 to 3.07). Each 30% decrease in UACR over the first 26 weeks was independently associated with a lower hazard for the primary kidney outcome (hazard ratio [HR], 0.71; 95% CI, 0.67 to 0.76; P,0.001), major adverse cardiovascular events (HR, 0.92; 95% CI, 0.88 to 0.96; P,0.001), and hospitalization for heart failure or cardiovascular death (HR, 0.86; 95% CI, 0.81 to 0.90; P,0.001). Residual albuminuria levels at week 26 remained a strong independent risk factor for kidney and cardiovascular events, overall and in each treatment arm. Conclusions In people with type 2 diabetes and CKD, use of canagliflozin results in early, sustained reductions in albuminuria, which were independently associated with long-term kidney and cardiovascular outcomes

Glycemic Control and Effects of Canagliflozin in Reducing Albuminuria and eGFR:A Post Hoc Analysis of the CREDENCE Trial

BACKGROUND: In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin improved kidney and cardiovascular outcomes and reduced the rate of estimated glomerular filtration decline (eGFR slope) in patients with type 2 diabetes and CKD. In other clinical trials of patients with CKD or heart failure, the protective effects of SGLT2 inhibitors on eGFR slope were greater in participants with versus participants without type 2 diabetes. This post hoc analysis of the CREDENCE trial assessed whether the effects of canagliflozin on eGFR slope varied according to patient subgroups by baseline glycated hemoglobin A1c (HbA1c).METHODS: CREDENCE ( ClinicalTrials.gov [ NCT02065791 ]) was a randomized controlled trial in adults with type 2 diabetes with an HbA1c of 6.5%-12.0%, an eGFR of 30-90 ml/min per 1.73 m 2 , and a urinary albumin-to-creatinine ratio of 300-5000 mg/g. Participants were randomly assigned to canagliflozin 100 mg once daily or placebo. We studied the effect of canagliflozin on eGFR slope using linear mixed-effects models.RESULTS: The annual difference in total eGFR slope was 1.52 ml/min per 1.73 m 2 (95% confidence interval [CI], 1.11 to 1.93) slower in participants randomized to canagliflozin compared with placebo. The rate of eGFR decline was faster in those with poorer baseline glycemic control. The mean difference in total eGFR slope between canagliflozin and placebo was greater in participants with poorer baseline glycemic control (difference in eGFR slope of 0.39, 1.36, 2.60, 1.63 ml/min per 1.73 m 2 for HbA1c subgroups 6.5%-7.0%, 7.0%-8.0%, 8.0%-10.0%, 10.0%-12.0%, respectively; Pinteraction = 0.010). The mean difference in change from baseline in urinary albumin-to-creatinine ratio between participants randomized to canagliflozin and placebo was smaller in patients with baseline HbA1c 6.5%-7.0% (-17% [95% CI, -28 to -5]) compared with those with an HbA1c of 7.0%-12% (-32% [95% CI, -40 to -28]; Pinteraction = 0.03).CONCLUSIONS: The effect of canagliflozin on eGFR slope in patients with type 2 diabetes and CKD was more pronounced in patients with higher baseline HbA1c, partly because of the more rapid decline in kidney function in these individuals.CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.</p