Targeting the Substrate in Ablation of Persistent Atrial Fibrillation: Recent Lessons and Future Directions

While isolation of the pulmonary veins is firmly established as effective treatment for the majority of paroxysmal atrial fibrillation (AF) patients, there is recognition that patients with persistent AF have substrate for perpetuation of arrhythmia existing outside of the pulmonary veins. Various computational approaches have been used to identify targets for effective ablation of persistent AF. This paper aims to discuss the clinical aspects of computational approaches that aim to identify critical sites for treatment. Various analyses of electrogram characteristics have been performed with this aim. Leading techniques for electrogram analysis are Complex Fractionated Atrial Electrograms (CFAE) and Dominant Frequency (DF). These techniques have been the subject of clinical trials of which the results are discussed. Evaluation of the activation patterns of atria in AF has been another avenue of research. Focal Impulse and Rotor Modulation (FIRM) mapping and forms of Body Surface Mapping aim to characterize multiple atrial wavelets, macro-reentry and focal sources which have been proposed as basic mechanisms perpetuating AF. Both invasive and non-invasive activation mapping techniques are reviewed. The presence of atrial fibrosis causes non-uniform anisotropic impulse propagation. Therefore, identification of fibrosis by imaging techniques is an avenue of potential research. The leading contender for imaging-based techniques is Cardiac Magnetic Resonance (CMR). As this technology advances, improvements in resolution and scar identification have positioned CMR as the mode of choice for analysis of atrial structure. AF has been demonstrated to be associated with obesity, inactivity and diseases of modern life. An opportunity exists for detailed computational analysis of the impact of risk factor modification on atrial substrate. This ranges from microstructural investigation through to examination at a population level via registries and public health interventions. Computational analysis of atrial substrate has moved from basic science toward clinical application. Future directions and potential limitations of such analyses are examined in this review

Reverse Remodeling of the Atria After Treatment of Chronic Stretch in Humans Implications for the Atrial Fibrillation Substrate

ObjectivesThe aim of this report was to study the effect of chronic stretch reversal on the electrophysiological characteristics of the atria in humans.BackgroundAtrial stretch is an important determinant for atrial fibrillation. Whether relief of stretch reverses the substrate predisposed to atrial fibrillation is unknown.MethodsTwenty-one patients with mitral stenosis undergoing mitral commissurotomy (MC) were studied before and after intervention. Catheters were placed at multiple sites in the right atrium (RA) and sequentially within the left atrium (LA) to determine: effective refractory period (ERP) at 10 sites (600 and 450 ms) and P-wave duration (PWD). Bi-atrial electroanatomic maps determined conduction velocity (CV) and voltage. In 14 patients, RA studies were repeated ≥6 months after MC.ResultsImmediately after MC, there was significant increase in mitral valve area (2.1 ± 0.2 cm2, p < 0.0001) with decrease in LA (23 ± 7 mm Hg to 10 ± 4 mm Hg, p < 0.0001) and pulmonary arterial pressures (38 ± 16 mm Hg to 27 ± 12 mm Hg, p < 0.0001) and LA volume (75 ± 20 ml to 52 ± 18 ml, p < 0.0001). This was associated with reduction in PWD (139 ± 19 ms to 135 ± 20 ms, p = 0.047), increase in CV (LA: 1.3 ± 0.3 mm/ms to 1.7 ± 0.2 mm/ms, p = 0.006; and RA: 1.0 ± 0.1 mm/ms to 1.3 ± 0.3 mm/ms, p = 0.002) and voltage (LA: 1.7 ± 0.6 mV to 2.5 ± 1.0 mV, p = 0.005; and RA: 1.8 ± 0.6 mV to 2.2 ± 0.7 mV, p = 0.09), and no change in ERP. Late after MC, mitral valve area remained at 2.1 ± 0.3 cm2 (p = 0.7) but with further decrease in PWD (113 ± 19 ms, p = 0.04) and RA ERP (at 600 ms, p < 0.0001), with increase in CV (1.0 ± 0.1 mm/ms to 1.3 ± 0.2 mm/ms, p = 0.006) and voltage (1.8 ± 0.7 mV to 2.8 ± 0.6 mV, p = 0.002).ConclusionsThe atrial electrophysiologic and electroanatomic abnormalities that result from chronic stretch due to MS reverses after MC. These observations suggest that the substrate predisposing to atrial arrhythmias might be reversed

A theoretical analysis of Ballistic Electron Emission Microscopy: k-space distributions and spectroscopy

We analyze BEEM experiments. At low temperatures and low voltages, near the threshold value of the Schottky barrier, the BEEM current is dominated by the elastic component. Elastic scattering by the lattice results in the formation of focused beams and narrow lines in real space. To obtain the current injected in the semiconductor, we compute the current distribution in reciprocal space and, assuming energy and $k_{\parallel}$ conservation. Our results show an important focalization of the injected electron beam and explain the similarity between BEEM currents for Au/Si(111) and Au/Si(100).Comment: 17 pages, 5 figures (postscript), Latex, APS, http://www.icmm.csic.es/Pandres/pedro.htm. Appl. Surf. Sci. (in press

The Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction across a tunneling junction out of equilibrium

The Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction between two magnetic $s$-$d$ spin impurities across a tunneling junction is studied when the system is driven out of equilibrium through biasing the junction. The nonequilibrium situation is handled with the Keldysh time-loop perturbation formalism in conjunction with appropriate coupling methods for tunneling systems due to Caroli and Feuchtwang. We find that the presence of a nonequilibrium bias across the junction leads to an interference of several fundamental oscillations, such that in this tunneling geometry, it is possible to tune the interaction between ferromagnetic and antiferromagnetic coupling at a fixed impurity configuration, simply by changing the bias across the junction. Furthermore, it is shown that the range of the RKKY interaction is altered out of equilibrium, such that in particular the interaction energy between two slabs of spins scales extensively with the thickness of the slabs in the presence of an applied bias.Comment: 38 pages revtex preprint; 5 postscript figures; submitted to Phys. Rev.

A Machine Learning Aided Systematic Review and Meta-Analysis of the Relative Risk of Atrial Fibrillation in Patients With Diabetes Mellitus

Background: Meta-analysis is a widely used tool in which weighted information from multiple similar studies is aggregated to increase statistical power. However, the exponential growth of publications in key areas of medical science has rendered manual identification of relevant studies increasingly time-consuming. The aim of this work was to develop a machine learning technique capable of robust automatic study selection for meta-analysis. We have validated this approach with an up-to-date meta-analysis to investigate the association between diabetes mellitus (DM) and new-onset atrial fibrillation (AF).Methods: The PubMed online database was searched from 1960 to September 2017 where 4,177 publications that mentioned both DM and AF were identified. Relevant studies were selected as follows. First, publications were clustered based on common text features using an unsupervised K-means algorithm. Clusters that best matched the selected set of potentially relevant studies (a “training” set of 139 articles) were then identified by using maximum entropy classification. The 139 articles selected automatically on this basis were screened manually to identify potentially relevant studies. To determine the validity of the automated process, a parallel set of studies was also assembled by manually screening all initially searched publications. Finally, detailed manual selection was performed on the full texts of the studies in both sets using standard criteria. Quality assessment, meta-regression random-effects models, sensitivity analysis and publication bias assessment were then conducted.Results: Machine learning-assisted screening identified the same 29 studies for meta-analysis as those identified by using manual screening alone. Machine learning enabled more robust and efficient study selection, reducing the number of studies needed for manual screening from 4,177 to 556 articles. A pooled analysis using the most conservative estimates indicated that patients with DM had ~49% greater risk of developing AF compared with individuals without DM. After adjusting for three additional risk factors i.e., hypertension, obesity and heart disease, the relative risk was 23%. Using multivariate adjusted models, the risk for developing AF in patients with DM was similar for all DM subtypes. Women with DM were 24% more likely to develop AF than men with DM. The risk for new-onset AF in patients with DM has also increased over the years.Conclusions: We have developed a novel machine learning method to identify publications suitable for inclusion in meta-analysis.This approach has the capacity to provide for a more efficient and more objective study selection process for future such studies. We have used it to demonstrate that DM is a strong, independent risk factor for AF, particularly for women

'Ain't it a Ripping Night': Alcoholism and the Legacies of Empire in Salman Rushdie's Midnight's Children.

In the era of decolonisation that followed the Second World War, various authors sought to engage with India and the Empire’s past anew throughout their novels, identifying medicine and illness as key parts of Imperial authority and colonial experience. Salman Rushdie’s approach to the Raj in Midnight’s Children (1981) focused on the broad sweep of colonial life, juxtaposing the political and the personal. This article argues that Rushdie explores the history of colonial India by employing alcohol and alcoholism as lenses through which to explore the cultural, political and medical legacies of Empire. Through analysis of Midnight’s Children as well as a range of medical sources related to alcohol and inebriation, it will illustrate how drinking is central to Rushdie’s approach to secular and religious identities in newly independent India, as well as a means of satirising and undermining the supposed benefit that Empire presented to India and Indians

Spintronics: Fundamentals and applications

Spintronics, or spin electronics, involves the study of active control and manipulation of spin degrees of freedom in solid-state systems. This article reviews the current status of this subject, including both recent advances and well-established results. The primary focus is on the basic physical principles underlying the generation of carrier spin polarization, spin dynamics, and spin-polarized transport in semiconductors and metals. Spin transport differs from charge transport in that spin is a nonconserved quantity in solids due to spin-orbit and hyperfine coupling. The authors discuss in detail spin decoherence mechanisms in metals and semiconductors. Various theories of spin injection and spin-polarized transport are applied to hybrid structures relevant to spin-based devices and fundamental studies of materials properties. Experimental work is reviewed with the emphasis on projected applications, in which external electric and magnetic fields and illumination by light will be used to control spin and charge dynamics to create new functionalities not feasible or ineffective with conventional electronics.Comment: invited review, 36 figures, 900+ references; minor stylistic changes from the published versio

A Protective Role for ELR+ Chemokines during Acute Viral Encephalomyelitis

The functional role of ELR-positive CXC chemokines in host defense during acute viral-induced encephalomyelitis was determined. Inoculation of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice resulted in the rapid mobilization of PMNs expressing the chemokine receptor CXCR2 into the blood. Migration of PMNs to the CNS coincided with increased expression of transcripts specific for the CXCR2 ELR-positive chemokine ligands CXCL1, CXCL2, and CXCL5 within the brain. Treatment of JHMV-infected mice with anti-CXCR2 blocking antibody reduced PMN trafficking into the CNS by >95%, dampened MMP-9 activity, and abrogated blood-brain-barrier (BBB) breakdown. Correspondingly, CXCR2 neutralization resulted in diminished infiltration of virus-specific T cells, an inability to control viral replication within the brain, and 100% mortality. Blocking CXCR2 signaling did not impair the generation of virus-specific T cells, indicating that CXCR2 is not required to tailor anti-JHMV T cell responses. Evaluation of mice in which CXCR2 is genetically silenced (CXCR2−/− mice) confirmed that PMNs neither expressed CXCR2 nor migrated in response to ligands CXCL1, CXCL2, or CXCL5 in an in vitro chemotaxis assay. Moreover, JHMV infection of CXCR2−/− mice resulted in an approximate 60% reduction of PMN migration into the CNS, yet these mice survived infection and controlled viral replication within the brain. Treatment of JHMV-infected CXCR2−/− mice with anti-CXCR2 antibody did not modulate PMN migration nor alter viral clearance or mortality, indicating the existence of compensatory mechanisms that facilitate sufficient migration of PMNs into the CNS in the absence of CXCR2. Collectively, these findings highlight a previously unappreciated role for ELR-positive chemokines in enhancing host defense during acute viral infections of the CNS

The HELLP syndrome: Clinical issues and management. A Review

<p>Abstract</p> <p>Background</p> <p>The HELLP syndrome is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count occurring in 0.5 to 0.9% of all pregnancies and in 10–20% of cases with severe preeclampsia. The present review highlights occurrence, diagnosis, complications, surveillance, corticosteroid treatment, mode of delivery and risk of recurrence.</p> <p>Methods</p> <p>Clinical reports and reviews published between 2000 and 2008 were screened using Pub Med and Cochrane databases.</p> <p>Results and conclusion</p> <p>About 70% of the cases develop before delivery, the majority between the 27th and 37th gestational weeks; the remainder within 48 hours after delivery. The HELLP syndrome may be complete or incomplete. In the Tennessee Classification System diagnostic criteria for HELLP are haemolysis with increased LDH (> 600 U/L), AST (≥ 70 U/L), and platelets < 100·10⁹/L. The Mississippi Triple-class HELLP System further classifies the disorder by the nadir platelet counts. The syndrome is a progressive condition and serious complications are frequent. Conservative treatment (≥ 48 hours) is controversial but may be considered in selected cases < 34 weeks' gestation. Delivery is indicated if the HELLP syndrome occurs after the 34th gestational week or the foetal and/or maternal conditions deteriorate. Vaginal delivery is preferable. If the cervix is unfavourable, it is reasonable to induce cervical ripening and then labour. In gestational ages between 24 and 34 weeks most authors prefer a single course of corticosteroid therapy for foetal lung maturation, either 2 doses of 12 mg betamethasone 24 hours apart or 6 mg or dexamethasone 12 hours apart before delivery. Standard corticosteroid treatment is, however, of uncertain clinical value in the maternal HELLP syndrome. High-dose treatment and repeated doses should be avoided for fear of long-term adverse effects on the foetal brain. Before 34 weeks' gestation, delivery should be performed if the maternal condition worsens or signs of intrauterine foetal distress occur. Blood pressure should be kept below 155/105 mmHg. Close surveillance of the mother should be continued for at least 48 hours after delivery.</p