Gender-Specific Modulation of the Response to Arterial Injury by Soluble Guanylate Cyclase α1

Objective: Soluble guanylate cyclase (sGC), a heterodimer composed of α and β subunits, synthesizes cGMP in response to nitric oxide (NO). NO modulates vascular tone and structure but the relative contributions of cGMP-dependent versus cGMP-independent mechanisms remain uncertain. We studied the response to vascular injury in male (M) and female (F) mice with targeted deletion of exon 6 of the sGCα1 subunit (sGCα1-/-), resulting in a non-functional heterodimer. Methods: We measured aortic cGMP levels and mRNA transcripts encoding sGC α1, α2, and β1 subunits in wild type (WT) and sGCa1-/- mice. To study the response to vascular injury, BrdU-incorporation and neointima formation (maximum intima to media (I/M) ratio) were determined 5 and 28 days after carotid artery ligation, respectively. Results: Aortic cGMP levels were 4-fold higher in F than in M mice in both genotypes, and, within each gender, 4-fold higher in WT than in sGCa1-/-. In contrast, sGCα1, sGCα2, and sGCβ1 mRNA expression did not differ between groups. 3H-thymidine incorporation in cultured sGCa1-/- smooth muscle cells (SMC) was 27%±12% lower than in WT SMC and BrdU-incorporation in carotid arteries 5 days after ligation was significantly less in sGCa1-/- M than in WT M. Neointima area and I/M 28 days after ligation were 65% and 62% lower in sGCa1-/- M than in WT M mice (p<0,05 for both) but were not different in F mice. Conclusion: Functional deletion of sGCa1 resulted in reduced cGMP levels in male sGCa1-/- mice and a gender-specific effect on the adaptive response to vascular injury

Report of the Working Group on Commercial Catches (WGCATCH)

The Working Group on Commercial Catches (WGCATCH), chaired by Mike Arm- strong (UK) and Hans Gerritsen (Ireland), met in ICES HQ, Copenhagen, Denmark, 10–14 November 2014. The meeting was attended by 34 experts from 21 laboratories or organizations, covering 16 countries. Currently, an important task for WGCATCH is to improve and review sampling sur- vey designs for commercial fisheries, particularly those for estimating quantities and size or age compositions of landings and discards and providing data quality indica- tors. However, the scope of WGCATCH is broader than this, covering many other aspects of collection and analysis of data on fishing activities and catches. This will be end-user driven, and coordinated with the work of other ICES data EGs such as the Working Group on Biological Parameters (WGBIOP), the Planning Group on Data Needs for Assessments and Advice (PGDATA) and the Working Group on Recrea- tional Fisheries Surveys (WGRFS) to ensure synergy and efficiency. The report of the meeting commences with background information on the formation of WGCATCH and its overall role. The remainder of the report provides the out- comes for each of the Terms of Reference (ToRs) and responses to external requests, the proposed future work plan and the ToRs for the 2015 meeting. The group formed two large subgroups to deal with the two major terms of reference which are the development of guidelines for carrying out sampling of catches on shore and the provision of advice on adapting sampling programmes to deal with the landing obligation. In order to evaluate methods and develop guidelines for best practice in carrying out sampling of commercial sampling of commercial fish catches onshore, a question- naire was circulated before the meeting. This questionnaire was structured around guidelines developed by the ICES Workshop on Practical Implementation of Statisti- cally Sound Catch Sampling Programmes (WKPICS) for best practice at each stage of the sampling process, and asked for a description of current practices at each of these stages. Based on these questionnaires, common and specific problems were cata- logued and potential solutions were identified. At the same time, the discussion of the questionnaires provided a form of peer-review of the sampling designs and iden- tified where improvements could be made. WGCATCH provided guidelines for de- signing a sampling survey and summarized earlier guidelines provided by the 2010 Workshop on methods for merging métiers for fishery based sampling (WKMERGE) The other main subject addressed by WGCATCH concerns the provision of advice on adapting sampling protocols to deal with the impact of the introduction of the land- ing obligation, which will alter discarding practices and result in additional catego- ries of catch being landed. A second questionnaire was circulated before the meeting to allow the group to identify the fleets that will be affected and possible issues that are anticipated, as well as to propose solutions to adapt existing monitoring and sampling schemes and to quantify bias resulting from the introduction of this regula- tion. WGCATCH outlined a range of likely scenarios and the expected effects of these on fishery sampling programmes, and developed guidelines for adapting sam- pling schemes. The group also explored a range of analyses that could be conducted in order to quantify bias resulting from the introduction of the landing obligation. Finally a number of pilot studies/case studies were summarized, highlighting the practical issues involve

Report of the Regional Co-ordination Meeting for the North Sea and Eastern Arctic (RCM NS&EA) 2014

Report of the Regional Co-ordination Meeting for the North Sea and Eastern Arctic (RCM NS&EA) 2014 Swedish University of Agriculture Sciences (SLU Aqua) Lysekil, Sweden 08-12 September 2014The RCM NS&EA met in Lysekil (Sweden) between 8-12 September 2014. The main purpose of the RCM is coordinate the National Programmes (NP) of the Member States (MS) in the North Sea region for 2015

Report of the Regional Co-ordination Meeting for the North Sea and Eastern Arctic (RCM NS&EA) 2013

Report of the Regional Co-ordination Meeting for the North Sea and Eastern Arctic (RCM NS&EA) 2013 final report European Fisheries Control Agency (EFCA) Vigo, Spain 09/09/2013-13/09/2013The Regional Coordination Meeting for the North Sea & Eastern Arctic (RCM NS&EA) was held in September 2013 in Vigo (Spain). The main task of the RCM’s is to coordinate the National Programmes (NP), which propose the national data collection to be carried out by the Member States (MS) under the EU Data Collection Framework (DCF). It was envisaged that, from 2104 onwards, data collection by the MS would be carried out under a new framework (DC-MAP). However, the legislation for this framework is not ready yet. Therefore the Commission has decided to extend the present DCF for the time being and the most recent NPs have been adopted for 2014. Since these NP have been adopted without any changes, there is no need for major coordinatio

Report of the Regional Co-ordination Meeting for the North Sea and Eastern Arctic (RCM NS&EA) 2015

The RCM NS&EA met 31st August - 4th September 2015 at den Haag, Netherlands with 27 participants form 11 member states and autonomous regions attending, including representatives of ICES and the Commission. National correspondents from Spain, UK, Denmark, Lithuania, Germany, Sweden and the Netherlands were present. The meeting was co-chaired by Katja Ringdahl (Sweden) and Alastair Pout (Scotland). The RCM N&SEA considered the recommendations from the 11th Liasion meeting and summaries were presented of the work of expert groups and end users for the 2014-15 period to the plenary session of the meeting. The expert groups included WGCATCH, PGDATA, WKISCON2, WKRDB 2014-01, RDB–SC, STECF and the Zagreb meeting on transversal variables. ICES, as a main end user, provided feedback. A summary was presented of the progress in the regional coordination project (fishPi). This project involves over 40 participants from 12 members states from NS&EA, NA and Baltic regions, two external statistical experts, and ICES. The project has a wide scope of regional cooperation issues including sampling designs, data formats, code lists, PETS, stomach sampling, small scale and recreational sampling, and data quality software production. It has a budget of €400,000, and a one year time line and with a planned completion date of April 2016. A project with identical aims is running in paralleled in the Mediterranean and Black Sea regions The majority of the ToRs of the RCM NS&EA were addressed by three subgroups: one concerned with data analysis, one with the landing obligation, and one with issues particularly related to role and work of national correspondents

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Numerical Methods for Dynamic Optimization of (Bio)Chemical Processes under Stochastic Parametric Uncertainty

Sustainable design and operation are key requirements for the current chemical process industry. To achieve these, mathematical process models and computer aided process engineering are key tools. Mathematical models are however only an approximation of the process under study and uncertainty is inherently present due to: (i) structural or parametric model uncertainty, (ii) exogenous disturbances or (iii) process variability. Consequently, this uncertainty is also present when model-based optimization techniques are used. Not accounting for this uncertainty can lead to erroneous model predictions. Using these erroneous model predictions potentially results in an overestimation of the actual process performance or unsafe process operation. The overall goal of this PhD research is to study how stochastic parametric uncertainty can be accounted for in an efficient manner in model-based optimization approaches to enable a more sustainable process operation. The assumption of stochastic parametric uncertainty entails that the uncertainty is modeled in the model parameters, i.e., parametric uncertainty, and it is considered that the parametric uncertainty can be described by a known probability distribution (i.e., stochastic) which is obtained from a previous identification procedure. To achieve this overall goal, three model-based approaches have been studied: (i) model-based experiment design, (ii) model-based optimization/simulation for achieving a better process understanding and (iii) multi-objective optimization and decision making. Four contributions have been made with respect to these three aspects. The first two contributions are related to accounting for uncertainty in model-based experiment design (OED). Firstly a sampling-based stochastic OED formulation based on non-intrusive polynomial chaos expansion has been presented. This approach has been compared with a sigma points approach for a benchmark Williams-Otto reactor case study. As a second contribution, the earlier presented formulation has been compared with an approximate robust sensitivities based OED formulation. Two case studies have been implemented: (i) a Lotka Volterra fishing problem in which the focus was on robustness with respect to information content and (ii) a jacketed tubular plug flow reactor in which the emphasis was on robustness with respect to constraint satisfaction. As a conclusion guidelines have been presented on which approach to use for OED under uncertainty. The third contribution is related to dynamic optimization of biological networks under parametric uncertainty. It has been investigated how three stochastic uncertainty propagation techniques, the linearization, sigma points and polynomial chaos expansion approaches, can be used in the frame of predicting the regulation of metabolic pathways in biological networks under stochastic parametric uncertainty. A critical comparison of these three techniques has been made and two biological network case studies have been investigated: (i) the minimization of intermediate metabolite accumulation in a basic three-step linear pathway model and (ii) the multiobjective optimization (i.e., the minimization) of the final time and enzymatic cost in a glycolysis inspired network model. The results are discussed from both a mathematical and a physical/biological point of view, showing that each of the studied uncertainty propagation strategies offered a reduction in constraint violations and consistent performance predictions. The fourth and final contribution of this PhD dissertation addresses the need for efficient algorithms for multi-objective optimization under parametric uncertainty. The computational cost of multi-objective optimization problems increases with the number of Pareto points to be computed and accounting for uncertainty increases this computational cost even further. An algorithm is presented that constructs Pareto ellipsoids from the variance and expected value approximations on the objective functions computed with state-of-the-art stochastic parametric uncertainty propagation techniques: linearization, sigma points and polynomial chaos expansion. These Pareto ellipsoids comprise the actual values the objective functions can take in practice. The trade-off between Pareto points is now extended to a trade-off between Pareto ellipsoids and is used in a divide and conquer strategy for multiobjective optimization. The novel algorithm has been applied to the bi-objective optimization of the batch fermentation of glucose to gluconic acid by Pseudomonas ovalis and the tri-objective optimization of a plug flow reactor in which a state constraint on the reactor temperature has to be satisfied. As a lower number of Pareto points (or better: Pareto ellipsoids) are computed, the computational cost is also reduced when compared with standard NBI (normal boundary intersection, a standard scalarization based multi-objective optimization method that doesn't account for uncertainty on the Pareto points) and a divide and conquer algorithm that does not account for uncertainty on the Pareto points.status: publishe