A psychophysiological investigation of the interplay between orienting and executive control during stimulus conflict: A heart rate variability study.

BACKGROUND: It has been hypothesized that resting state cardiac vagal activity (CVA) - an indicator of parasympathetic nervous system activity - is a specific psychophysiological marker of executive control function. Here, we propose an alternative hypothesis - that CVA is associated with early stage attention orientation, promoting the flexible uptake of new information, on which the later operation of such executive control functions depends. We therefore predicted that CVA would predict the interaction between orienting and executive control. This was tested using the revised version of the Attention Network Test (ANT-R) that was developed to distinguish between orienting and executive attention during a stimulus conflict task. METHODS: Healthy adults (N = 48) performed the ANT-R and their resting CVA was measured over a 5 min period using ECG recordings. RESULTS: Multiple regression analyses indicated that, when other factors were controlled for, CVA was more strongly associated with the interaction between the orienting and executive control terms than with either factor individually. CONCLUSION: Higher levels of CVA are specifically implicated in the modulation of executive control by intrinsic orientation operating at early stages of conflict detection. These initial findings of higher CVA on orienting attention in conflict detection need to be replicated in larger samples.

Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab.

BACKGROUND: Ramucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of ramucirumab across a large patient population. MATERIALS AND METHODS: An individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials. RESULTS: A total of 4996 treated patients (N = 2748 in the ramucirumab arm and N = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5-1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5-1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5-1.1; high-grade, RR: 0.7, 95% CI 0.4-1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8-1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7-1.7) did not demonstrate a definite increased risk with ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1-2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the ramucirumab arm compared with the control arm. CONCLUSIONS: Ramucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs. Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).

Randomized phase II study of modified FOLFOX-6 in combination with ramucirumab or icrucumab as second-line therapy in patients with metastatic colorectal cancer after disease progression on first-line irinotecan-based therapy.

BACKGROUND: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind VEGF receptors 1 and 2 (VEGFR-1 and -2), respectively. This randomized phase II study evaluated the antitumor activity and safety of icrucumab and ramucirumab each in combination with mFOLFOX-6 in patients with metastatic colorectal cancer after disease progression on first-line therapy with a fluoropyrimidine and irinotecan. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive mFOLFOX-6 alone (mFOLFOX-6) or in combination with ramucirumab 8 mg/kg IV (RAM+mFOLFOX-6) or icrucumab 15 mg/kg IV (ICR+mFOLFOX-6) every 2 weeks. Randomization was stratified by prior bevacizumab therapy. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, safety, and PK. RESULTS: In total, 158 patients were randomized, but only 153 received treatment (49 on mFOLFOX-6, 52 on RAM+mFOLFOX-6, and 52 on ICR+mFOLFOX-6). Median PFS was 18.4 weeks on mFOLFOX-6, 21.4 weeks on RAM+mFOLFOX-6, and 15.9 weeks on ICR+mFOLFOX-6 (RAM+mFOLFOX-6 versus mFOLFOX-6, stratified hazard ratio [HR] 1.116 [95% CI 0.713-1.745], P = 0.623; ICR+mFOLFOX-6 versus mFOLFOX-6, stratified HR 1.603 [95% CI 1.011-2.543], P = 0.044). Median survival was 53.6 weeks on mFOLFOX-6, 41.7 weeks on RAM+mFOLFOX-6, and 42.0 weeks on ICR+mFOLFOX-6. The most frequent adverse events reported on the ramucirumab arm (RAM+mFOLFOX-6) were fatigue, nausea, and peripheral sensory neuropathy; those on the icrucumab arm (ICR+mFOLFOX-6) were fatigue, diarrhea, and peripheral sensory neuropathy. Grade ≥3 serious adverse events occurred at comparable frequency across arms. CONCLUSIONS: In this study population, combining ramucirumab or icrucumab with mFOLFOX-6 did not achieve the predetermined improvement in PFS. CLINICALTRIALSGOV: NCT01111604.

Simultaneous detection of ketamine, lorazepam, midazolam and sufentanil in human serum with liquid chromatography-tandem mass spectrometry for monitoring of analgosedation in critically ill patients.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the determination and quantification of four predominantly used analgosedatives in the intensive care unit: ketamine, lorazepam, midazolam and sufentanil in human serum. The extraction procedure consisted of protein precipitation of serum samples with acetonitrile and subsequent centrifugation. D5-fentanyl and D4-midazolam served as internal standards (ISTD). Separation of analytes was performed with a Hypersil C18 column and a mobile phase with acetonitrile and 0.1% formic acid (60/40, v/v) under isocratic conditions at a flow rate of 280µl/min. Analytes were simultaneously detected with a triple-stage quadrupole mass spectrometer (LC-MS/MS) in a selected reaction monitoring (SRM) mode with positive heated electrospray ionization (HESI) within a single 2-min run. Calibration curves were linear over a range of 50-2000 for ketamine, 10-1000 for lorazepam, 5-500 for midazolam and 1-100 for sufentanil (ng/ml). The limit of detection and the lower limit of quantification were 0.01 and 10.00 for ketamine, 0.005 and 10.00 for lorazepam, 0.018 and 5.00 for midazolam and 0.068 and 0.25 for sufentanil (ng/ml). Intra- and inter-day accuracies and precisions of all analytes were less than 15%. Bench stability with spiked serum samples was ensured after 12, 24 and 48h at room temperature, freeze- and thaw-stability after 3 cycles of thawing and freezing. The method was successfully established according to International Conference on Harmonization (ICH) guideline Q2 (R1) "Validation of Analytical Procedures" and applied in critically ill adult patients in the intensive care unit. We suggest its suitability for parallel quantification of the sedative analgesics ketamine, lorazepam, midazolam and sufentanil. The method serves as an instrumental tool for therapeutic drug monitoring (TDM) and pharmacokinetic studies [1].

Concomitant chemotherapy and radiation for the treatment of advanced-stage endometrial cancer.

INTRODUCTION: Ccombination chemotherapy and radiation therapy is used for adjuvant treatment of stage III-IV endometrial cancer. The goal of this study was to review the treatment duration, toxicity, and survival for patients treated with concomitant chemotherapy and radiation. METHODS: Women with stage III-IV endometrial cancer treated with concurrent chemotherapy and radiation between 2006 and 2013 were included. Toxicities were classified per CTCAE v3.0 and RTOG/EORTC late radiation morbidity scoring. Descriptive statistics were used to quantify treatment and toxicities. Kaplan-Meier method was used to estimate survival. RESULTS: Fifty-one patients met our inclusion criteria. Median age was 60 (range 33-85). Thirty-six patients (70.6%) had endometrioid histology, 13 patients (25.5%) had serous, clear cell, or mixed histology, and 2 women (3.9%) had carcinosarcoma. Forty-eight patients had stage III disease and three patients were stage IVB. Mean treatment duration was 107 ± 19 days. Forty-two patients received all planned chemotherapy, and 16 patients required a dose reduction. Thirty-four patients (66.7%) experienced grade 3-4 toxicities, the majority of which were hematologic. There were no deaths related to therapy. Eighty-six percent of patients received leukocyte growth factors, and 25% of patients received a blood transfusion. Seven late grade 3-4 complications occurred: four gastrointestinal and two genitourinary, and one patient had ongoing neuropathy. Median progression-free survival was 42.8 months (range 4.4-81.5 months) and median overall survival was 44.9 months (range 5.1-82.6 months). Three-year overall survival was 80%. CONCLUSION: Concomitant chemotherapy and radiation is an adequately tolerated treatment modality that allows for shorter treatment duration.

Rhythmic natural selection over intertidal and brackish water genotypes: simple formulations for testing hypothesis.

Tidal cycles at benthic habitats induce a set of periodic environmental changes in variables like salinity, temperature and sediment water content which are able to stress benthic organisms. Consequently, a natural selection temporally correlated with tides affects the fitness of genotypes (wi) depending on their adaptation degree. Classic population genetics demonstrate that (1) rhythmic wi is more restrictive than equivalent spatial variations to preserve genetic variance, and (2) mean fitness of the population (w¯) does not have to be enhanced by genetic variance (σ(2)w). The present study develops a simple replicator dynamics-based model of continuous selection, where wi of multiple asexual genotypes fluctuates as a sinusoid. The amplitude of w was set as 0.5 (1-wmin), whereas the ratio of tide period to generation time (h) was defined. Overall, the model shows that if h>1, then the success of an advantageous genotype is exposed to randomness, and w¯ may decrease over generations. In contrast, if h<1 the success is deterministic, is limiting co-dominance, and only depends on wmin. The amount of different genotypes buffers the decay of σ(2)w and hence increases cohesiveness. Finally, the reliability of the model is analyzed for a set of target intertidal and brackish water organisms.

Assessment of the bio-preparedness and of the training of the French hospital laboratories in the event of biological threat.

A national laboratory network 'Biotox-Piratox' was created in 2003 in France with the purpose of detecting, confirming and reporting potential biological and chemical threat agents. This network is divided into three levels: Level 1 is dedicated to the evaluation of risks (biological, chemical, radiological), to sampling and packing. Level 2 consists of university and military hospitals, who deal with biological specimens, and of environmental and veterinary laboratories, who deal with environmental and animal samples. Level 3 comprises national reference laboratories and the Jean Mérieux biosafety level (BSL)-4 laboratory in Lyon. This report presents the results of four bio-preparedness exercises to check critical points in the processing of samples. These exercises took place in 2007, 2009, 2010 and 2011. Each of them consisted of two parts. The first part was the identification of an unknown bacterial strain and its susceptibility to antibiotics used as a default in case of a bioterrorist event. The second part was the detection of Class III microorganisms, mainly by molecular techniques. The main lesson learnt in these exercises was that the key to successful detection of biological agents in case of a biological threat was standardisation and validation of the methods implemented by all the laboratories belonging to the network.

Entropy rate estimates from mutual information.

We show how to estimate the Kolmogorov-Sinai entropy rate for chaotic systems using the mutual information function, easily obtainable from experimental time series. We state the conditions under which the relationship is exact, and explore the usefulness of the approach for both maps and flows. We also explore refinements of the method, and study its convergence properties as a function of time series length.

Emergence of dengue virus serotype 3 on Mayotte Island, Indian Ocean.

A serosurvey carried out in 2006 in Mayotte, a French overseas collectivity in the Indian Ocean, confirmed previous circulation of dengue virus (DENV) on the island, but since the set up of a laboratory-based surveillance of dengue-like illness in 2007, no case of DENV has been confirmed. In response to an outbreak of DENV-3 on Comoros Islands in March 2010 surveillance of dengue-like illness in Mayotte was enhanced. By September 15, 76 confirmed and 31 probable cases of DENV have been identified in Mayotte. In urban and periurban settings on the island, Aedes albopictus is the predominant Aedes species, but Ae. aegyptii remains the most common species in rural areas. Given the epidemic potential of dengue virus in Mayotte, adequate monitoring including early detection of cases, timely investigation and sustained mosquito control actions remain essential.

Early immunomodulatory effects of linezolid in a human whole blood endotoxin model.

Gram-negative sepsis resulting in endotoxin triggered septic shock is one of the leading causes of death in critically ill patients. Because treatment options are limited, recent approaches focus on immunomodulatory effects of antimicrobials. Thus, we characterized the immunomodulatory effects of linezolid at mRNA and on cytokine levels in supernatants of an ex vivo model of endotoxemia. Whole blood from 10 healthy volunteers was incubated with 50 pg/ml LPS with or without 13 microg/ml linezolid (concentrations were chosen to reflect in vivo conditions) for 2 and 4 hours (h). Quantitative real-time PCR was performed from messenger RNA (mRNA) of IL-1beta;, IL-6, IL-8 or TNF-alpha;. Cytokine levels in the supernatant were measured by ELISA for IL-6, IL-8 and TNF-alpha;. Incubation of human whole blood with LPS increased mRNA levels of cytokines several thousand fold compared with baseline. The addition of linezolid significantly reduced mRNA levels of IL-1beta, IL-6, IL-8 and TNF-alpha; (p < 0.05) after 2 and 4 h. LPS stimulation also increased levels of IL-6, IL-8 and TNF-alpha between 100 and 1000-fold. However, in contrast to mRNA - except for IL-6 - no significant reduction at protein level was observed. These results indicate that immunosuppressive effects of linezolid on mRNA transcription are only partially reflected by cytokine release.

Geometry of repeated measurements in chaotic systems.

We use joint probability matrices for measurements at different times to describe chaotic systems. By coarse graining the range of the measured variable into uniformly sized bins we can generate matrices that contain both topological and metric information about the systems being studied. Armed with this tool we examine two extreme families of chaotic systems. In the case of one-dimensional piecewise linear maps, we can construct transfer matrices that depend on the map and partition used, and which allow us to generate the respective joint probability matrices for all times as well as the exact time evolution of the mutual information function. We find that the mutual information decays linearly or exponentially depending on whether the second-largest eigenvalue of the transfer matrix is zero or not. In the case of three-dimensional, continuous-time chaotic systems we generate the joint probability matrices directly from numerical data. We show that these matrices directly provide attractor reconstructions with information about the attractor's probability measure.

Determinism test for very short time series.

A test for determinism suitable for time series shorter than 100 points is presented, and applied to numerical and observed data. The method exploits the linear d(d(0)) dependence in the expression d(t) approximately d(0)e(lambda t) which describes the growth of small separations between trajectories in chaotic systems.

Unstable periodic orbits and discretization cycles.

Limit cycles that arise from discretizing the variable(s) of a nonlinear map are generally found to shadow individual unstable periodic orbits (UPOs) of the corresponding continuous map. In a few cases the discretization cycles can only be explained with other mechanisms, such as the near-occurrence of an UPO, or crossover between two or more UPOs.

Exploration of a rich variety of breather modes in Josephson ladders.

We report on systematic measurements of localized rotational modes in Josephson junction arrays. These modes, also known as rotobreathers, persist under the action of uniform bias force. In contrast to previous experiments, here we focus on systems with strong coupling between rotators. In ladders with either open or periodic boundary conditions, we observe a very rich variety of stable dynamic states including symmetric, asymmetric, combined, hybrid, coupled, and truncated modes. The switching scenarios between different states are discussed in detail.

Absence of determinism in El Niño Southern Oscillation.

We perform two direct determinism tests on the El Niño Southern Oscillation index monthly average series. The results indicate that, for timescales over 1 month, the series does not exhibit determinism, an essential feature of chaos.