Transcatheter Implantation of the MONARC Coronary Sinus Device for Mitral Regurgitation 1-Year Results From the EVOLUTION Phase I Study (Clinical Evaluation of the Edwards Lifesciences Percutaneous Mitral Annuloplasty System for The Treatment of Mitral Regurgitation)

ObjectivesThis study sought to assess the safety and efficacy of transcatheter valve annuloplasty in patients with mitral regurgitation (MR).BackgroundMitral regurgitation is associated with a worsened prognosis in patients with dilated cardiomyopathy. Surgical mitral annuloplasty reduces the septal-lateral dimension of the mitral annulus resulting in improved leaflet coaptation with a reduction in regurgitation. Percutaneous annuloplasty with the MONARC device (Edwards Lifesciences, Irvine, California) implanted within the coronary sinus is designed to reduce mitral regurgitation through a similar mechanism.MethodsA total of 72 patients with MR grade ≥2 were enrolled at 8 participating centers in 4 countries. Clinical evaluation and transthoracic echocardiography were performed at baseline and at 3, 6, and 12 months. Multislice cardiac computed tomography and coronary angiography were performed at baseline and 3 months.ResultsThe MONARC device was implanted in 59 of 72 patients (82%). The primary safety end point (freedom from death, tamponade, or myocardial infarction at 30 days) was met in 91% of patients at 30 days and in 82% at 1 year. Computed tomography imaging documented passage of the great cardiac vein over an obtuse marginal artery in 55% of patients and was associated with angiographic coronary artery compression in 15 patients and myocardial infarction in 2 patients (3.4%). At 12 months, a reduction in MR by ≥1 grade was observed in 50.0% of 22 implanted patients with matched echocardiograms and in 85.7% of 7 patients with baseline MR grade ≥3.ConclusionsImplantation of the MONARC device in the coronary sinus is feasible and may reduce MR. However, coronary artery compression may occur in patients in whom the great cardiac vein passes over a coronary artery, necessitating strategies in future studies to avoid this occurrence

Estimation of Nuwiq® (simoctocog alfa) activity using one-stage and chromogenic assays-Results from an international comparative field study.

BACKGROUND Accurate determination of coagulation factor VIII activity (FVIII:C) is essential for effective and safe FVIII replacement therapy. FVIII C can be measured by one-stage and chromogenic substrate assays (OSAs and CSAs, respectively); however, there is significant interlaboratory and interassay variability. AIMS This international comparative field study characterized the behaviour of OSAs and CSAs used in routine laboratory practice to measure the activity of Nuwiq® (human-cl rhFVIII, simoctocog alfa), a fourth-generation recombinant human FVIII produced in a human cell line. METHODS FVIII-deficient plasma was spiked with Nuwiq® or Advate® at 1, 5, 30 and 100 international units (IU)/dL. Participating laboratories analysed the samples using their routine procedures and equipment. Accuracy, inter- and intralaboratory variation, CSA:OSA ratio and the impact of different OSA and CSA reagents were assessed. RESULTS Forty-nine laboratories from 9 countries provided results. Mean absolute FVIII:C was comparable for both products at all concentrations with both OSA and CSA, with interproduct ratios (Nuwiq® :Advate® ) of 1.02-1.13. Mean recoveries ranged from 97% to 191% for Nuwiq® , and from 93% to 172% for Advate® , with higher recoveries at lower concentrations. Subgroup analyses by OSA and CSA reagents showed minor variations depending on reagents, but no marked differences between the two products. CSA:OSA ratios based on overall means ranged from 0.99 to 1.17 for Nuwiq® and from 1.01 to 1.17 for Advate® . CONCLUSIONS Both OSAs and CSAs are suitable for the measurement of FVIII:C of Nuwiq® in routine laboratory practice, without the need for a product-specific reference standard

ECLAIRE: Effects of Climate Change on Air Pollution Impacts and Response Strategies for European Ecosystems. Project final report

The central goal of ECLAIRE is to assess how climate change will alter the extent to which air pollutants threaten terrestrial ecosystems. Particular attention has been given to nitrogen compounds, especially nitrogen oxides (NOx) and ammonia (NH3), as well as Biogenic Volatile Organic Compounds (BVOCs) in relation to tropospheric ozone (O3) formation, including their interactions with aerosol components. ECLAIRE has combined a broad program of field and laboratory experimentation and modelling of pollution fluxes and ecosystem impacts, advancing both mechanistic understanding and providing support to European policy makers. The central finding of ECLAIRE is that future climate change is expected to worsen the threat of air pollutants on Europe’s ecosystems. Firstly, climate warming is expected to increase the emissions of many trace gases, such as agricultural NH3, the soil component of NOx emissions and key BVOCs. Experimental data and numerical models show how these effects will tend to increase atmospheric N deposition in future. By contrast, the net effect on tropospheric O3 is less clear. This is because parallel increases in atmospheric CO2 concentrations will offset the temperature-driven increase for some BVOCs, such as isoprene. By contrast, there is currently insufficient evidence to be confident that CO2 will offset anticipated climate increases in monoterpene emissions. Secondly, climate warming is found to be likely to increase the vulnerability of ecosystems towards air pollutant exposure or atmospheric deposition. Such effects may occur as a consequence of combined perturbation, as well as through specific interactions, such as between drought, O3, N and aerosol exposure. These combined effects of climate change are expected to offset part of the benefit of current emissions control policies. Unless decisive mitigation actions are taken, it is anticipated that ongoing climate warming will increase agricultural and other biogenic emissions, posing a challenge for national emissions ceilings and air quality objectives related to nitrogen and ozone pollution. The O3 effects will be further worsened if progress is not made to curb increases in methane (CH4) emissions in the northern hemisphere. Other key findings of ECLAIRE are that: 1) N deposition and O3 have adverse synergistic effects. Exposure to ambient O3 concentrations was shown to reduce the Nitrogen Use Efficiency of plants, both decreasing agricultural production and posing an increased risk of other forms of nitrogen pollution, such as nitrate leaching (NO3-) and the greenhouse gas nitrous oxide (N2O); 2) within-canopy dynamics for volatile aerosol can increase dry deposition and shorten atmospheric lifetimes; 3) ambient aerosol levels reduce the ability of plants to conserve water under drought conditions; 4) low-resolution mapping studies tend to underestimate the extent of local critical loads exceedance; 5) new dose-response functions can be used to improve the assessment of costs, including estimation of the value of damage due to air pollution effects on ecosystems, 6) scenarios can be constructed that combine technical mitigation measures with dietary change options (reducing livestock products in food down to recommended levels for health criteria), with the balance between the two strategies being a matter for future societal discussion. ECLAIRE has supported the revision process for the National Emissions Ceilings Directive and will continue to deliver scientific underpinning into the future for the UNECE Convention on Long-range Transboundary Air Pollution

ECLAIRE third periodic report

The ÉCLAIRE project (Effects of Climate Change on Air Pollution Impacts and Response Strategies for European Ecosystems) is a four year (2011-2015) project funded by the EU's Seventh Framework Programme for Research and Technological Development (FP7)

The pathophysiology of self -injurious behavior in rhesus macaques

Some individually housed laboratory monkeys spontaneously develop self-injurious behavior (SIB). In rhesus macaques, this pathology usually takes the form of intense self-directed biting that, on occasion, can result in wounding severe enough to require veterinary treatment. Little is known about the underlying pathophysiology of SIB in socially reared monkeys. Most investigations of SIB have focused on monkeys that were reared in total social isolation, a form of deprivation that results in numerous abnormalities besides SIB. The objective of this dissertation was to characterize and identify the underlying pathophysiology of SIB in a group of socially reared, individually housed rhesus monkeys. Central monoamine systems, hypothalamic-pituitary-adrenal (HPA) and gonadal HPG) axes, and sympatho-adrenomedullary system (SAMS) activity were compared in monkeys with a veterinary record of self-inflicted wounding (SIB group) to that of control monkeys with similar rearing histories and ages (Control group). In addition to our focus on wounding, we examined the pathophysiology of SIB as it relates to the frequency of self-directed biting. Monkeys with SIB did not differ in their basal central monoamine activity from controls. Likewise, no group differences in basal gonadal or SAMS activity were found. However, monkeys with SIB did show persistently lower plasma cortisol levels following the stress of restraint and venipuncture, but not in 24-h urine samples collected under stress-free conditions. It was concluded that monkeys with SIB are hyporesponsive to the mild stress of blood sampling. Hypersensitivity in HPA negative feedback or reduced adrenocortical sensitivity were assessed as possible mechanisms for the observed attenuated stress response. Monkeys with SIB did not differ from controls in their response to a low dose of dexamethasone or to pharmacological challenge with ACTH. In contrast, when the relationship between HPA dysregulation and self-directed biting was assessed, significant negative correlations between self-biting and cortisol were found in post-stress blood samples and in response to ACTH, but not in 24-h urine samples. These data suggest that monkeys with high rates of self-biting show a blunted HPA response to stress. The role of early psychological and/or physical trauma as possible factors in the development of SUB and HPA dysregulation are discussed

Bioinspired Ether Cyclizations within a π-Basic Capsule Compared to Autocatalysis on π-Acidic Surfaces and Pnictogen-Bonding Catalysts

While the integration of supramolecular principles in catalysis attracts increasing attention, a direct comparative assessment of the resulting systems catalysts to work out distinct characteristics is often difficult. Herein is reported how the broad responsiveness of ether cyclizations to diverse inputs promises to fill this gap. Cyclizations in the confined, π-basic and Brønsted acidic interior of supramolecular capsules, for instance, are found to excel with speed (exceeding general Brønsted acid and hydrogen-bonding catalysts by far) and selective violations of the Baldwin rules (as extreme as the so far unique pnictogen-bonding catalysts). The complementary cyclization on π-acidic aromatic surfaces remains unique with regard to autocatalysis, which is shown to be chemo- and diastereoselective with regard to product-like co-catalysts but, so far, not enantioselective.ISSN:0947-6539ISSN:1521-376

Bioinspired Ether Cyclizations within a π‐Basic Capsule Compared to Autocatalysis on π‐Acidic Surfaces and Pnictogen‐Bonding Catalysts

While the integration of supramolecular principles in catalysis attracts increasing attention, a direct comparative assessment of the resulting systems catalysts to work out distinct characteristics is often difficult. Herein is reported how the broad responsiveness of ether cyclizations to diverse inputs promises to fill this gap. Cyclizations in the confined, π-basic and Brønsted acidic interior of supramolecular capsules, for instance, are found to excel with speed (exceeding general Brønsted acid and hydrogen-bonding catalysts by far) and selective violations of the Baldwin rules (as extreme as the so far unique pnictogen-bonding catalysts). The complementary cyclization on π-acidic aromatic surfaces remains unique with regard to autocatalysis, which is shown to be chemo- and diastereoselective with regard to product-like co-catalysts but, so far, not enantioselective.ISSN:0947-6539ISSN:1521-376

Decoded fingerprints of hyperresponsive, expanding product space: polyether cascade cyclizations as tools to elucidate supramolecular catalysis

Simple enough to be understood and complex enough to be revealing, cascade cyclizations of diepoxides are introduced as new tools to characterize supramolecular catalysis. Decoded product fingerprints are provided for a consistent set of substrate stereoisomers, and shown to report on chemo-, diastereo- and enantioselectivity, mechanism and even autocatalysis. Application of the new tool to representative supramolecular systems reveals, for instance, that pnictogen-bonding catalysis is not only best in breaking the Baldwin rules but also converts substrate diastereomers into completely different products. Within supramolecular capsules, new cyclic hemiacetals from House-Meinwald rearrangements are identified, and autocatalysis on anion-pi catalysts is found to be independent of substrate stereochemistry. Decoded product fingerprints further support that the involved epoxide-opening polyether cascade cyclizations are directional, racemization-free, and interconnected, at least partially. The discovery of unique characteristics for all catalysts tested would not have been possible without decoded cascade cyclization fingerprints, thus validating the existence and significance of privileged platforms to elucidate supramolecular catalysis. Once decoded, cascade cyclization fingerprints are easily and broadly applicable, ready for use in the community.ISSN:2041-6520ISSN:2041-653