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Light in the Blood uses Ovid’s Metamorphoses as a starting point for a novel that features change, imagination and horror, and which, like Ovid’s original work, incorporates elements of several genres. Set in modern day Constanța in Romania, where Ovid was exiled by Augustus, it follows the experiences of five authors who are on retreat near the city and preparing for a debate on Ovid’s legacy. A storm at the beginning of the novel releases mysterious energies, after which a giant cockroach begins to haunt one of the writers, two of the writers are brought together as lovers who unknowingly re-enact versions of Ovid’s most famous love stories, and Ted Nowakow, the most famous of the authors, mutates into a wererhino. In his transformed state, Ted suffers from fugues in which the more savage side of his nature takes control. The first murder he commits in this fugue state prompts the police to come to the retreat, but they seem powerless to prevent further murders and are unwilling to believe that there could be a monster loose in the forest surrounding the retreat. As the novel progresses, the remaining authors begin to fear that something is hunting them down, and it becomes a question of which one of them will survive. Despite the novel’s several fantastical elements, it is deliberately located within a realistic world because part of my interest lies in exploring the relationship between reality, language and imagination, in the framework of both the late postmodern era of hyperreality and celebrity culture and the legacy of the Cold War. Although the novel features writers as its central characters, through the use of Ovidian echoes and motifs I hope to move it away from a simple consideration of the fate of fiction/writing in the twenty-first century and towards a renewed awareness of the power of creativity and the imagination, and its close relation to terror. The Language of Freedom: Narrative Form in E. L. Doctorow examines how Doctorow uses narrative form to subvert the discourse of what Raymond Williams terms ‘the dominant culture’. Moving beyond both the categorisation of Doctorow as a Leftist writer and the critical focus on his treatment of history, I consider the way in which his work resists monological representations of reality and instead promotes fiction as a democratic arena in which the novelist remains free to present alternative readings to those of the dominant culture. An integral part of this study is an examination of Doctorow’s potential intertextual relation to Herman Melville and the legacy of American Democratic Idealism. My first chapter focuses on encyclopaedic narrative forms in The Book ofDaniel and City of God. It includes a survey of the main theorists on encyclopaedic literature and a study of how Doctorow’s novels fulfil the categories they identify, but attempts to move beyond some of their critical strictures to consider how Doctorow’s use of this form destabilises claims to total knowledge on the part of the government and other institutions. My second chapter considers Doctorow’s use of genre fiction models in BillyBathgate and The Waterworks. I argue that these two books represent a return to genre writing that was inspired by Doctorow’s frustration with trying to write political fiction in the late Cold-War era. The chapter investigates the novels’ submerged political content and examines how they can be read as critiques of the Reagan and Bush Sr administrations, as well as meditations on the nature of democracy in the United States and of the role of the political writer within it. Throughout both chapters I make extensive use of E. L. Doctorow’s newly available archive in order to offer insights into the thinking behind the novels.

Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBβ in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.

BackgroundOne determinant of failure of atrial fibrillation (AF) ablation is the lack of transmural lesions. Contact force sensing (CFS) catheters enable real-time assessment of the amount of force applied at the catheter-tissue interface, with higher contact force associated with lesions of greater size. Previous meta-analyses have pooled results from randomized controlled trials (RCTs) and observational studies (OSs) and concluded that CFS catheters improve clinical outcomes. This meta-analysis sought to compare the efficacy and safety of CFS catheters with non-CFS catheters for AF radiofrequency ablation.MethodsA total of 28 studies were identified using Embase and Medline databases; 8 RCTs and 20 OSs. For the primary outcome of atrial tachyarrhythmia recurrence, data from RCTs and OSs were analysed according to study design. Secondary outcomes included ablation time and all procedure-related complications. Summary estimates for each variable were calculated using the random-effects model based on DerSimonian and Laird’s meta-analytic statistical method.ResultsIn the 8 RCTs there were a total of 844 patients (419 in CF group and 425 in non-CF group). In the 20 OS there were 3900 patients (1523 in CF group and 2377 in non-CF group). The median age of patients was 60.3 years (59.0 years in RCTs and 60.7 years in OSs). The majority were male (74.0% in RCTs and 69.6% in OSs). The median follow-up time post-AF ablation was 12 months in both RCTs and OSs.While CFS did not lead to a significant reduction in atrial tachyarrhythmia recurrence in RCTs (n=844, risk ratio (RR) 0.98, 95% confidence interval (CI) 0.80 to 1.19, p=0.81), a significant reduction was observed in OSs (n=2,259, RR 0.74, 95% CI 0.65 to 0.84, p<0.0001), both at a median follow-up of 12 months.Data on ablation time were available for 6 RCTs (n=751) and 14 OSs (n=3,152). The use of CFS catheters had no significant impact on ablation time in both RCTs (-0.36 minutes, 95% CI -3.32 to 2.59, p=0.81) and OSs (-3.68 minutes, 95% CI -7.91 to 0.55, p=0.09).For both RCTs (n=706) and OSs (n=3,427), the incidence of all procedure-related complications was similar in the CFS and non-CFS groups (RCTs, RR 0.99, 95% CI 0.55 to 1.78, p=0.97; OSs, RR 0.78, 95% CI 0.53 to 1.16, p=0.22).ConclusionAlthough OSs have demonstrated positive results, data from RCTs have failed to show any significant benefit from CFS catheters in terms of procedural success in AF ablation. The safety profile of CFS catheters was similar to non-CFS catheters in both RCTs and OSs.Conflict of InterestNo conflicts on interest

AimsDual-coil implantable cardioverter defibrillator (ICD) leads have traditionally been used over single-coil leads due to concerns regarding high defibrillation thresholds (DFT) and consequent poor shock efficacy. However, accumulating evidence suggests that this position may be unfounded and that dual-coil leads may also be associated with higher complication rates during lead extraction. This meta-analysis collates data comparing dual- and single-coil ICD leads.Methods and resultsElectronic databases were systematically searched for randomised controlled trials (RCT) and non-randomised studies comparing single-coil and dual-coil leads. The mean differences in DFT and summary estimates of the odds-ratio (OR) for first-shock efficacy and the hazard-ratio (HR) for all-cause mortality were calculated using random effects models. Eighteen studies including a total of 1 38 124 patients were identified. Dual-coil leads were associated with a lower DFT compared to single coil leads (mean difference –0.83J; 95% confidence interval [CI] –1.39–−0.27; p=0.004). There was no difference in the first-shock success rate with dual-coil compared to single-coil leads (OR 0.74; 95% CI 0.45–1.21; p=0.22). There was a significantly lower risk of all-cause mortality associated with single-coil leads (HR 0.91; 95% CI 0.86–0.95; p<0.0001).ConclusionThis meta-analysis suggests that single-coil leads have a marginally higher DFT but that this may be clinically insignificant as there appears to be no difference in first-shock efficacy when compared to dual-coil leads. The mortality benefit with single-coil leads most likely represents patient selection bias. Given the increased risk and complexity of extracting dual-coil leads, centres should strongly consider single-coil ICD leads as the lead of choice for routine new left-sided ICD implants.

BackgroundWith subcutaneous ICDs (S-ICD) not offering the same range of pacing therapies as transvenous systems (T-ICD), it is unclear how many ICD recipients may be suitable for a S-ICD. In addition, the benefit from ICD therapy is dependent on non-sudden cardiac death (SCD) risk. The study aims were to [1] establish how many ICD recipients may be suitable for S-ICD implantation based on a range of selection policies, and [2] determine the impact of S-ICD use on the risk of non-SCD.MethodsWe performed a retrospective study of all ICD implants over 5 years (2009–2013). We evaluated how widely the S-ICD could be utilised using the following indications: (a) Least liberal use – S-ICD used only in patients with inherited channelopathies and idiopathic ventricular fibrillation; (b) Intermediate use – S-ICD also used for SCD primary prevention in hypertrophic cardiomyopathy; (c) Most liberal use – S-ICD also used for SCD primary prevention in coronary artery disease (CAD) and non-ischaemic dilated cardiomyopathy (DCM) who have a narrow QRS complex (120msec). Given the potential impact of age on the benefit from S-ICDs, we stratified our results by implant age (70, 60 and 50 years). Non-SCD risk was quantified using the MADIT-II risk score (score 0–5, 5 (highest risk)). Mann-Whitney U testing was used to compare risk scores.ResultsOver the 5 years, there were 402 implants (79% male, age 70±13 years). After exclusion of patients implanted with a CRT-D device or with a pacing indication, 219 remained for consideration of a S-ICD. Using our definition of least liberal use, intermediate use, and most liberal use, the number of patients considered suitable for a S-ICD was 18 (4.5%), 30 (7.5%) and 77 (19.2%), respectively. Age as a discriminator had a significant impact on the proportion of patients considered suitable for a S-ICD. This was predominantly due to a reduction in the number of patients with CAD and DCM being considered for a prophylactic device. Using the most liberal definition, the number of potential S-ICD candidates dropped from 52 (12.9%) in those 70 years old at implant, to 34 (8.5%) for 60 years, to 20 (5%) using 50 years as the cut-off.The MADIT-II score was 0.22±0.1, 0.47±0.1 and 0.96±0.1, in the least liberal, intermediate and most liberal use S-ICD groups, respectively. The score was 2.07±0.1, 2.11±0.1 and 2.24±0.1 in the respective T-ICD groups. The mean MADIT-II score in the S-ICD group was significantly lower than that in the respective T-ICD group (p<0.0001, for all three selection policies).ConclusionsWhile up to one-fifth of patients currently receiving ICDs may be suitable for a S-ICD, this result is dependent on both which patient groups the S-ICD is used in and whether an age cut-off is applied. The cohort of patients suitable for a S-ICD also have a lower risk of non-SCD compared to those receiving conventional T-ICDs.

AimsRandomised trials have shown that empiric ICD programming, using long detection times and high detection zones, reduces device therapy in ICD recipients. However, there is less data on its effectiveness in a “real-world” setting, especially secondary prevention patients. Our aim was to evaluate the introduction of a standardised programming protocol in a “real-world” setting of unselected ICD recipients.MethodsWe analysed 270 consecutive ICD recipients implanted in a single centre – 135 implanted prior to protocol implementation (Physician-Led group) and 135 after (Standardised group). The protocol included long arrhythmia detection times (30/40 or equivalent) and high rate detection zones (primary prevention lower treatment zone 200 bpm). Programming in the Physician-Led group was at the discretion of the implanter. The primary endpoint was time-to-any therapy (ATP or shocks). Secondary endpoints were time-to-inappropriate therapy and time-to-appropriate therapy. The safety endpoints were syncopal episodes, hospital admissions, and death.ResultsAt 12 months follow-up, 47 patients had received any ICD therapy (Physician-Led group, n = 31 vs. Standardised group, n = 16). There was a 47% risk reduction in any device therapy (p = 0.04) and an 86% risk reduction in inappropriate therapy (p = 0.009) in the Standardised compared to the Physician-led group. Results were consistent across primary and secondary prevention patients. There were no significant differences in the rates of syncope, hospitalization and death.ConclusionsIn unselected patients in a “real-world” setting introduction of a standardised programming protocol, using long detection times and high detection zones, significantly reduces the burden of ICD therapy without an increase in adverse outcomes.Abstract 51 Figure 1Kaplan-Meier curves for survival from any-therapy. Physician-Led (dotted) vs. Standardised (black)Abstract 51 Figure 2Kaplan-Meier curves for survival from inappropriate therapy. Physician-led (dotted) vs. Standardised (black)

BackgroundImplantable cardiac defibrillator (ICD) therapy reduces mortality in selected patients at high risk of sudden cardiac death. However, patients at high risk of non-sudden cardiac death, whose risk of short-term mortality following device implantation is high, may gain no significant benefit from an ICD. A number of approaches have been proposed to identify these high-risk patients, including single clinical markers and more complex scoring systems. The aims of this study were to use the proposed scoring systems to: (1) establish how many current ICD recipients may be too high risk to derive significant benefit from ICD therapy and (2) evaluate how well the proposed scoring systems predict short-term mortality in an unselected cohort of ICD recipients.MethodsWe performed asingle-centre retrospective observational study of all new ICD implants over 5years (2009–2013). We used 3 published scoring systems (Kramer et al 1; Barsheshet et al 2; Parkash et al 3) to identify new ICDrecipients whose short-term risk of death following ICD implantation waspredicted to be high. We then evaluated how well the scoring systems predicteddeath during follow-up.ResultsOver 5 years there were 406 new implants (79% male, age 67 ± 13 years). The majority (58%) were primary prevention implants and 45% were cardiac resynchronisation therapy-defibrillator devices. During a mean follow-up of 936 ± 560 days, 77 patients died.Using the published scoring systems, the proportion of ICD recipients predicted to be at high risk of short-term mortality were 4% (Kramer), 36% (Barsheshet) and 23% (Parkash). Three-year mortality rates in these high-risk groups were 76%, 32% and 36% respectively; in the overall study population 3-year mortality was 20%.In univariate Cox regression analyses, all 3 scoring systems predicted death (p < 0.001 for each model). However, using multivariate analysis, only the Kramer model remained predictive once serum urea was included in the analysis (p < 0.001). The ROC scores for the prediction of death for the 3 scoring systems and urea were 0.73 (Kramer), 0.69 (Barsheshet), 0.65 (Parkash) and 0.70 (urea).ConclusionsUsing published scoring systems, a significant proportion of current ICD recipients are at high risk of short-term mortality following device implantation. Although all 3 scoring systems predicted mortality during follow-up, only the Kramer model added predictive accuracy compared to renal function alone.RENCESKramer DB, Friedman PA, Kallinen LM, Morrison TB, Crusan DJ, Hodge DO, Reynolds MR, Hauser RG. Development and validation of a risk score to predict early mortality in recipients of implantable cardioverter-defibrillators. Heart Rhythm 2012;9:42–6Barsheshet A, Moss AJ, Huang DT, McNitt S, Zareba W, Goldenberg I. Applicability of a risk score for prediction of the long-term (8-year) benefit of the implantable cardioverter-defibrillator. J Am Coll Cardiol 2012;59:2075–9Parkash R, Stevenson WG, Epstein LM, Maisel WH. Predicting early mortality after implantable defibrillator implantation: a clinical risk score for optimal patient selection. Am Heart J 2006;151:397–403

BackgroundImplantable cardiac defibrillator (ICD) therapy reduces mortality in selected patients at high risk of sudden cardiac death. However, patients at high risk of non-sudden cardiac death, whose risk of short-term mortality following device implantation is high, may gain no significant benefit from an ICD. A number of approaches have been proposed to identify these high-risk patients, including single clinical markers and more complex scoring systems. The aims of this study were to use the proposed scoring systems to: (1) establish how many current ICD recipients may be too high risk to derive significant benefit from ICD therapy and (2) evaluate how well the proposed scoring systems predict short-term mortality in an unselected cohort of ICD recipients.MethodsWe performed asingle-centre retrospective observational study of all new ICD implants over 5years (2009-2013). We used 3 published scoring systems (Kramer et al 1; Barsheshet et al 2; Parkash et al 3) to identify new ICDrecipients whose short-term risk of death following ICD implantation waspredicted to be high. We then evaluated how well the scoring systems predicteddeath during follow-up.ResultsOver 5 years there were 406 new implants (79% male, age 67 plus or minus 13 years). The majority (58%) were primary prevention implants and 45% were cardiac resynchronisation therapy-defibrillator devices. During a mean follow-up of 936 plus or minus 560 days, 77 patients died.Using the published scoring systems, the proportion of ICD recipients predicted to be at high risk of short-term mortality were 4% (Kramer), 36% (Barsheshet) and 23% (Parkash). Three-year mortality rates in these high-risk groups were 76%, 32% and 36% respectively; in the overall study population 3-year mortality was 20%.In univariate Cox regression analyses, all 3 scoring systems predicted death (p < 0.001 for each model). However, using multivariate analysis, only the Kramer model remained predictive once serum urea was included in the analysis (p < 0.001). The ROC scores for the prediction of death for the 3 scoring systems and urea were 0.73 (Kramer), 0.69 (Barsheshet), 0.65 (Parkash) and 0.70 (urea).ConclusionsUsing published scoring systems, a significant proportion of current ICD recipients are at high risk of short-term mortality following device implantation. Although all 3 scoring systems predicted mortality during follow-up, only the Kramer model added predictive accuracy compared to renal function alone.RENCESKramer DB, Friedman PA, Kallinen LM, Morrison TB, Crusan DJ, Hodge DO, Reynolds MR, Hauser RG. Development and validation of a risk score to predict early mortality in recipients of implantable cardioverter-defibrillators. Heart Rhythm 2012; 9:42-6Barsheshet A, Moss AJ, Huang DT, McNitt S, Zareba W, Goldenberg I. Applicability of a risk score for prediction of the long-term (8-year) benefit of the implantable cardioverter-defibrillator. J Am Coll Cardiol 2012; 59:2075-9Parkash R, Stevenson WG, Epstein LM, Maisel WH. Predicting early mortality after implantable defibrillator implantation: a clinical risk score for optimal patient selection. Am Heart J 2006; 151:397-403

Purpose Patients at high non-sudden cardiac death risk may gain no significant benefit from implantable cardioverter-defibrillator (ICD) therapy. A number of approaches have been proposed to identify these patients, including single clinical markers and more complex scoring systems. The aims of this study were to use the proposed scoring systems to (1) establish how many current ICD recipients may be too high risk to derive significant benefit from ICD therapy and (2) evaluate how well the scoring systems predict short-term mortality in an unselected ICD cohort. Methods We performed a single-centre retrospective observational study of all new ICD implants over 5 years (2009–2013). We used four published scoring systems (Bilchick, Goldenberg, Kramer and Parkash) and serum urea to identify new ICD recipients whose short-term predicted mortality risk was high. We evaluated how well the scoring systems predicted death. Results Over 5 years, there were 406 new implants (79% male, mean age 70 (60–76), 58% primary prevention). During a follow-up of 936 ± 560 days, 96 patients died. Using the scoring systems, the proportion of ICD recipients predicted to be at high short-term mortality risk were 5.9% (Bilchick), 34.7% (Goldenberg), 7.4% (Kramer), 21.4% (Parkash) and 25% (urea, cut-off of >9.28 mM). All four risk scores predicted mortality ( P  < 0.0001); however, none outperformed urea for the prediction of 1- or 3-year mortality. Conclusions Using published scoring systems, a significant proportion of current ICD recipients are at high short-term mortality risk. Although all four scoring systems predicted mortality during follow-up, none significantly outperformed serum urea.