Thromboprophylaxis in atrial fibrillation and association with cognitive decline: systematic review

Objective:Atrial Fibrillation (AF) is associated with dementia. If AF-related cognitive decline is driven by cerebral embolic events, thromboprophylaxis may impact on this. This systematic review assessed the association between cognitive impairment and AF thromboprophylaxis. Methods:Two independent reviewers searched CINAHL, EMBASE, MEDLINE, PsycINFO, Web of Science Core Collection, and Cochrane Library from inception until 12th November 2014. Eligible studies compared AF thromboprophylaxis to control with an outcome measure of cognition or dementia. Where data allowed, meta-analyses describing between-group differences in cognitive test scores or rates of incident dementia were performed. Results:Nineteen studies were eligible. For two prospective studies (one RCT) comparing anticoagulation against antiplatelet therapy, change in Mini-Mental State Examination score from baseline to last follow-up (maximal duration:5.9 years) suggested a difference favouring anticoagulation (mean difference:0.90, 95% CI:0.29 to 1.51), in keeping with a trend seen in the single RCT (mean difference MMSE:0.80. 95% CI:-0.07 to 1.67). Pooled odds ratios suggested no association with incident dementia, comparing anticoagulant to antiplatelet therapy (two studies, OR:1.23, 95% CI:0.80 to 1.91) or no treatment (three studies, OR:0.89, 95%CI:0.47 to 1.69). Conclusions:Our analyses show no definitive evidence of cognitive benefit or harm from anticoagulation. We demonstrated a potential benefit of anticoagulation in comparison to antiplatelet over time. Larger-scale studies with longer follow-up are needed to determine the true cognitive impact of AF thromboprophylaxis

Mechanisms of Excitation and Remodeling of the Cardiac Action Potential in Two Model Systems.

Differences in cardiac ionic currents underlie action potential duration (APD) heterogeneity and alterations of any current may be arrhythmogenic. Biophysical analysis of ionic currents is crucial in understanding electrophysiological mechanisms of regional electrical heterogeneity and underlying factors that promote arrhythmogenicity. The first project presented in this dissertation characterized, for the first time, the electrophysiology of the Purkinje system of the murine heart. Current-clamp analysis of Purkinje cells (PCs) demonstrated pacemaker activity and a prolonged plateau phase compared to ventricular myocytes (VMs). We investigated, using voltage-clamp, the major ionic currents underlying the action potential and automaticity in PCs and VMs. We observed hyperpolarization activated currents, which contribute to automaticity in PCs, but not VMs. PCs demonstrated differences in transient outward potassium currents, sodium current and T-type calcium current, which was not present in VMs. A computational model of the mouse PC was developed and simulations determined that unlike VMs, in PCs the presence of T-type calcium current was capable of prolonging APD. The second project of this dissertation investigated the remodeling of action potentials in atrial cells by free fatty acids (FAs), which has not been investigated in large mammals. This project used an ovine model to serve as a better surrogate of human cardiac structure, electrophysiology and metabolism. Current-clamp analysis of ovine left atrial (LA) myocytes exposed to each of the major FAs showed that only stearic acid (SA) altered LA APD at all values measured. Voltage-clamp recordings showed a ~60% and ~30% reduction of ICaL and ITO in SA-treated cells. Integration of the experimental data into a computational model of the human atrial action potential showed reduction of ICaL was sufficient to remodel LA APD. Reduction in ICaL in SA-treated cells was accompanied by disruption of transverse (t)-tubules, a membrane compartment in which calcium channels are predominantly located into microdomains, thus providing a novel mechanism of cellular remodeling by fatty acids. These two studies provide insight into ionic remodeling and importance of calcium currents in heterogeneity and alterations of the cardiac action potential.PHDMolecular and Integrative PhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107266/1/oconnelr_1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/107266/2/oconnelr_2.pd

Orotracheal intubation in infants performed with a stylet versus without a stylet

Background: Neonatal endotracheal intubation is a common and potentially life-saving intervention. It is a mandatory skill for neonatal trainees, but one that is difficult to master and maintain. Intubation opportunities for trainees are decreasing and success rates are subsequently falling. Use of a stylet may aid intubation and improve success. However, the potential for associated harm must be considered. Objectives To compare the benefits and harms of neonatal orotracheal intubation with a stylet versus neonatal orotracheal intubation without a stylet. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE; Embase; the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and previous reviews. We also searched cross-references, contacted expert informants, handsearched journals, and looked at conference proceedings. We searched clinical trials registries for current and recently completed trials. We conducted our most recent search in April 2017. Selection criteria All randomised, quasi–randomised, and cluster-randomised controlled trials comparing use versus non-use of a stylet in neonatal orotracheal intubation. Data collection and analysis: Two review authors independently assessed results of searches against predetermined criteria for inclusion, assessed risk of bias, and extracted data. We used the standard methods of the Cochrane Collaboration, as documented in the Cochrane Handbook for Systemic Reviews of Interventions, and of the Cochrane Neonatal Review Group. Main results: We included a single-centre non-blinded randomised controlled trial that reported a total of 302 intubation attempts in 232 infants. The median gestational age of enrolled infants was 29 weeks. Paediatric residents and fellows performed the intubations. We judged the study to be at low risk of bias overall. Investigators compared success rates of first-attempt intubation with and without use of a stylet and reported success rates as similar between stylet and no-stylet groups (57% and 53%) (P = 0.47). Success rates did not differ between groups in subgroup analyses by provider level of training and infant weight. Results showed no differences in secondary review outcomes, including duration of intubation, number of attempts, participant instability during the procedure, and local airway trauma. Only 25% of all intubations took less than 30 seconds to perform. Study authors did not report neonatal morbidity nor mortality. We considered the quality of evidence as low on GRADE analysis, given that we identified only one unblinded study. Authors' conclusions: Current available evidence suggests that use of a stylet during neonatal orotracheal intubation does not significantly improve the success rate among paediatric trainees. However, only one brand of stylet and one brand of endotracheal tube have been tested, and researchers performed all intubations on infants in a hospital setting. Therefore, our results cannot be generalised beyond these limitations

Kant, Sade and the libertine enlightenment

The book chapter throws new light on the ways in which Kant and Sade question the tenets of mainstream Enlightenment thinking

An electrophysiological signal that precisely tracks the emergence of error awareness

Recent electrophysiological research has sought to elucidate the neural mechanisms necessary for the conscious awareness of action errors. Much of this work has focused on the error positivity (Pe), a neural signal that is specifically elicited by errors that have been consciously perceived. While awareness appears to be an essential prerequisite for eliciting the Pe, the precise functional role of this component has not been identified. Twenty-nine participants performed a novel variant of the Go/No-go Error Awareness Task (EAT) in which awareness of commission errors was indicated via a separate speeded manual response. Independent component analysis (ICA) was used to isolate the Pe from other stimulus- and response-evoked signals. Single-trial analysis revealed that Pe peak latency was highly correlated with the latency at which awareness was indicated. Furthermore, the Pe was more closely related to the timing of awareness than it was to the initial erroneous response. This finding was confirmed in a separate study which derived IC weights from a control condition in which no indication of awareness was required, thus ruling out motor confounds. A receiver-operating-characteristic (ROC) curve analysis showed that the Pe could reliably predict whether an error would be consciously perceived up to 400 ms before the average awareness response. Finally, Pe latency and amplitude were found to be significantly correlated with overall error awareness levels between subjects. Our data show for the first time that the temporal dynamics of the Pe trace the emergence of error awareness. These findings have important implications for interpreting the results of clinical EEG studies of error processing

Standardization is superior to traditional methods of teaching open vascular simulation

ObjectivesStandardizing surgical skills teaching has been proposed as a method to rapidly attain technical competence. This study compared acquisition of vascular skills by standardized vs traditional teaching methods.MethodsThe study randomized 18 first-year surgical residents to a standardized or traditional group. Participants were taught technical aspects of vascular anastomosis using femoral anastomosis simulation (Limbs & Things, Savannah, Ga), supplemented with factual information. One expert instructor taught a standardized anastomosis technique using the same method each time to one group over four sessions, while, similar to current vascular training, four different expert instructors each taught one session to the other (traditional) group. Knowledge and technical skill were assessed at study completion by an independent vascular expert using Objective Structured Assessment of Technical Skill (OSATS) performance metrics. Participants also provided a written evaluation of the study experience.ResultsThe standardized group had significantly higher mean overall technical (95.7% vs 75.8%; P = .038) and global skill scores (83.4% vs 67%; P = .006). Tissue handling, efficiency of motion, overall technical skill, and flow of operation were rated significantly higher in the standardized group (mean range, 88%-96% vs 67.6%-77.6%; P < .05). The standardized group trended to better cognitive knowledge (mean, 68.8% vs 60.7%; P = .182), creation of a secure knot at the toe of the anastomosis, fashioning an appropriate arteriotomy, better double-ended suture placement at the heel of the anastomosis (100% vs 62.7%; P = .07), and accurate suture placement (70% vs 25%; P = .153). Seventy-two percent of participant evaluations suggested a preference for a standardized approach.ConclusionsThis study demonstrates the feasibility of open vascular simulation to assess the effect of differing teaching methods on performance outcome. Findings from this report suggest that for simulation training, standardized may be more effective than traditional methods of teaching. Transferability of simulator-acquired skills to the clinical setting will be required before open simulation can be unequivocally recommended as a major component of resident technical skill training

Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue

Background: Transmitted HIV-1 clade B or C R5 viruses have been reported to infect macrophages inefficiently, while other studies have described R5 viruses in late disease with either an enhanced macrophage-tropism or carrying envelopes with an increased positive charge and fitness. In contrast, our previous data suggested that viruses carrying non-macrophage-tropic R5 envelopes were still predominant in immune tissue of AIDS patients. To further investigate the tropism and charge of HIV-1 viruses in late disease, we evaluated the properties of HIV-1 envelopes amplified from immune and brain tissues of AIDS patients with neurological complications. Results: Almost all envelopes amplified were R5. There was clear compartmentalization of envelope sequences for four of the five subjects. However, strong compartmentalization of macrophage-tropism in brain was observed even when brain and immune tissue envelope sequences were not segregated. R5 envelopes from immune tissue of four subjects carried a higher positive charge compared to brain envelopes. We also confirm a significant correlation between macrophage tropism and sensitivity to soluble CD4, a weak association with sensitivity to the CD4 binding site antibody, b12, but no clear relationship with maraviroc sensitivity. Conclusions: Our study shows that non-macrophage-tropic R5 envelopes carrying gp120s with an increased positive charge were predominant in immune tissue in late disease. However, highly macrophage-tropic variants with lower charged gp120s were nearly universal in the brain. These results are consistent with HIV-1 R5 envelopes evolving gp120s with an increased positive charge in immune tissue or sites outside the brain that likely reflect an adaptation for increased replication or fitness for CD4+ T-cells. Our data are consistent with the presence of powerful pressures in brain and in immune tissues selecting for R5 envelopes with very different properties; high macrophage-tropism, sCD4 sensitivity and low positive charge in brain and non-macrophage-tropism, sCD4 resistance and high positive charge in immune tissue