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

Atrial natriuretic factor increases splenic microvascular pressure and fluid extravasation in the rat

The spleen is an important site of atrial natriuretic factor (ANF)-induced fluid extravasation into the systemic lymphatic system. The mechanism underlying this process was studied in a blood-perfused (1 ml min−1) rat spleen using the double occlusion technique. To ensure that our observations were spleen specific, a similar protocol was repeated in the hindquarters.Rat ANF(1-28), infused into the splenic artery of anaesthetized male rats, caused a dose-dependent (0.3-59 pmol min−1) increase in microvascular pressure from 11.3 ± 0.7 to 14.9 ± 0.5 mmHg and in post-capillary resistance from 7.2 ± 0.6 to 10.1 ± 1.1 mmHg ml−1. ANF elicited no change in splenic pre-capillary resistance or in hindquarter haemodynamics.Intrasplenic ANF (6.5 pmol min−1) caused a sustained increase in intrasplenic fluid efflux from 0.1 ± 0.1 to 0.3 ± 0.1 ml min−1, and in capillary filtration coefficient (Kf) from 1.2 ± 0.5 to 2.4 ± 0.6 ml mmHg−1 min−1 (100 g tissue)−1.Mechanical elevation of splenic intravascular pressure (from 11.3 ± 0.7 to 22.4 ± 0.2 mmHg) significantly increased intrasplenic fluid extravasation (from 0.4 ± 0.3 to 1.4 ± 0.3 ml min−1).The natriuretic peptide receptor-C (NPRC)-specific agonist C-ANF(4-23) (12.5 and 125 pmol min−1) did not alter splenic intravascular pressure or pre-/post-capillary resistance.The ANF antagonist A71915 (8.3 and 83 pmol min−1), which blocks ANF-stimulated cGMP production via natriuretic peptide receptor-A (NPRA), inhibited the ANF-induced changes in splenic microvascular pressure and post-capillary resistance.It is concluded that ANF enhances the extravasation of isoncotic fluid from the splenic vasculature both by raising intrasplenic microvascular pressure (increased post-capillary resistance) and by increasing filtration area. The constrictive activity of ANF on the splenic vasculature is mediated through NPRA

On dynamical genetic programming: Random boolean networks in learning classifier systems

Abstract. Many representations have been presented to enable the effective evolution of computer programs. Turing was perhaps the first to present a general scheme by which to achieve this end. Significantly, Turing proposed a form of discrete dynamical system and yet dynamical representations remain almost unexplored within genetic programming. This paper presents results from an initial investigation into using a simple dynamical genetic programming representation within a Learning Classifier System. It is shown possible to evolve ensembles of dynamical Boolean function networks to solve versions of the well-known multiplexer problem. Both synchronous and asynchronous systems are considered. 1

The effect of interactive cognitive-motor training in reducing fall risk in older people: a systematic review

Background: It is well-known physical exercise programs can reduce falls in older people. Recently, several studies have evaluated interactive cognitive-motor training that combines cognitive and gross motor physical exercise components. The aim of this systematic review was to determine the effects of these interactive cognitive-motor interventions on fall risk in older people. Methods: Studies were identified with searches of the PubMed, EMBASE, and Cochrane CENTRAL databases from their inception up to 31 December 2013. Criteria for inclusion were a) at least one treatment arm that contained an interactive cognitive-motor intervention component; b) a minimum age of 60 or a mean age of 65 years; c) reported falls or at least one physical, psychological or cognitive fall risk factor as an outcome measure; d) published in Dutch, English or German. Single case studies and robot-assisted training interventions were excluded. Due to the diversity of populations included, outcome measures and heterogeneity in study designs, no meta-analyses were conducted. Results: Thirty-seven studies fulfilled the inclusion criteria. Reporting and methodological quality were often poor and sample sizes were mostly small. One pilot study found balance board training reduced falls and most studies reported training improved physical (e.g. balance and strength) and cognitive (e.g. attention, executive function) measures. Inconsistent results were found for psychological measures related to falls-efficacy. Very few between-group differences were evident when interactive cognitive-motor interventions were compared to traditional training programs. Conclusions: The review findings provide preliminary evidence that interactive cognitive-motor interventions can improve physical and cognitive fall risk factors in older people, but that the effect of such interventions on falls has not been definitively demonstrated. Interactive cognitive-motor interventions appear to be of equivalent efficacy in ameliorating fall risk as traditional training programs. However, as most studies have methodological limitations, larger, high-quality trials are needed