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Objectives. Recent work suggests that a genetic variation associated with increased dopamine metabolism in the prefrontal cortex (catechol-O-methyltransferase Val158Met; COMT) amplifies age-related changes in working memory performance. Research on younger adults indicates that the influence of dopamine-related genetic polymorphisms on working memory performance increases when testing the cognitive limits through training. To date, this has not been studied in older adults. Method. Here we investigate the effect of COMT genotype on plasticity in working memory in a sample of 14 younger (aged 24-30 years) and 25 older (aged 60-75 years) healthy adults. Participants underwent adaptive training in the n-back working memory task over 12 sessions under increasing difficulty conditions. Results. Both younger and older adults exhibited sizeable behavioral plasticity through training (P < .001), which was larger in younger as compared to older adults (P < .001). Age-related differences were qualified by an interaction with COMT genotype (P < .001), and this interaction was due to decreased behavioral plasticity in older adults carrying the Val/Val genotype, while there was no effect of genotype in younger adults. Discussion. Our findings indicate that age-related changes in plasticity in working memory are critically affected by genetic variation in prefrontal dopamine metabolism.
Triaxial high temperature (900 °C) deformation experiments were conducted at constant strain rate in a Paterson-type deformation apparatus on cylinders of Carrara marble with two right or left stepping, non-overlapping weak inclusions of Solnhofen limestone, oriented at 45° to the cylinders’ longitudinal axes. Applying different values of confinement (30, 50, 100 and 300 MPa) we induced various amounts of brittle deformation in the marble matrix and investigated the effect of brittle precursors on the initiation and development of heterogeneity-induced high temperature shear zones.
Viscosity contrast between the matrix and the inclusions induces local stress concentration at the tips of these latter. The initial arrangement of the inclusions results in either an overpressured (contractional) or underpressured (extensional) domain in the step-over region of the sample. At low confinement (30 and 50 MPa) abundant brittle deformation is observed, but the spatial distribution of microfractures is dependent on the kinematics of the step-over region: microcracks occur either along the shearing plane between inclusions (in extensional bridge samples), or broadly distributed outside the step-over region (contractional bridge samples). Accordingly, ductile deformation localizes along the inclusions plane in the extensional bridge samples as opposed to distributing over large areas of the matrix in the contractional bridge samples. If microcracking is suppressed (high confinement), strain is accommodated by viscous creep and strain progressively de-localizes in extensional bridge samples. Our experiments demonstrate that brittle precursors enhance the degree of localization in the ductile deformation regime, but only if the interaction of pre-existing heterogeneities induces an extensional mean stress regime in between.
Background Uptake of self-testing and self-management of oral coagulation has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism.
Methods We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat.
Findings Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12 800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0.51; 95% CI 0.31-0.85) but not for major haemorrhagic events (0.88, 0.74-1.06) or death (0.82, 0.62-1.09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0.33, 95% CI 0.17-0.66), as did participants with mechanical heart valve (0.52, 0.35-0.77). Analysis of major outcomes in the very elderly (age >= 85 years, n=99) showed no significant adverse effects of the intervention for all outcomes.
Interpretation Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up.