Anti-platelet therapy: ADP receptor antagonists.

The P2Y(12) receptor on platelets with which ADP interacts has an important role in promoting platelet function and thereby platelet involvement in both haemostasis and thrombosis. Agents that act as antagonists at this receptor are thus likely to provide effective antithrombotic therapy, provided that there are no adverse effects on haemostasis. Here we describe the ADP receptor antagonists that are available and in development. We also consider their mode of action and ask whether there are additional mechanisms through which they exert their inhibitory effects on platelet function

From sovereignty to modernity: revisiting the Colebrooke-Cameron Reforms – transforming the Buddhist and colonial imaginary in nineteenth century Ceylon

The Colebrooke-Cameron Reforms (1831) have been characterised by David Scott (1995) as marking the transformation of colonial Sri Lanka from one kind of political rationality – that of mercantile sovereignty – to another – that of colonial governmentality. Whilst consonant with the view that the Commission marked a moment when the colonial administration moved away from a strategic reliance on Asokan or Buddhist forms of authority in the earliest phase of British rule, we argue that there is a more nuanced genealogy to this transition. The Reforms, while directed to the administration, judicial and political institutions of the colony, also contemplated extensive commercial restructuring that inculcated a self improvement mode into ‘everyday life’. Drawing on colonial archives, we show how elements of a logic of governmentality, such as educational, land, and fiscal reform, were utilised at different times by the colonial administration to commence the modernisation of the colony well before 1832. It is also evident that the transformation was partial, and at points strongly resisted by local Buddhist communities. Instead of marking a clear point of transformation, the Colebrooke-Cameron Reforms gave legibility and a national imprimatur to a process already in train, while providing further impetus to a socio-political rationality that had begun to shift decades prior. The secular logic of the colonial State, however, was later to unleash a movement of Sinhalese Buddhist reform and cultural revaluation that generated, ‘a more modernised Sinhalese Buddhist nationalism to create expanding areas of social, cultural and religious life for the nationalist cause.

Crystal Viscoplastic Modeling of Single crystal and Directionally solidified Nickel-base Superalloys

Nickel-base superalloys (NBSAs) are widely used in engineering applications for many turbomachinery component designs. Superior material properties at high temperatures such as high tensile strength, superior fatigue strength, excellent resistance to thermal shocks, and strong corrosion resistance are primarily responsible for their extensive application. This proposal focuses on modeling generic single crystal (SX) and directionally solidified (DS) Ni-base superalloy. Compared to polycrystal superalloys, SX superalloys exhibit superior thermal fatigue and creep resistance which is attributed to the absence of grain boundaries in the SX crystalline structure. Directional solidification procedures enable the solidification structure of the materials to be comprised of columnar grains in aligned with the [001] direction. Grain boundaries are locations where failure is initiated hence the reduction of grain boundaries in comparison to polycrystals and the alignment of grain boundaries in the normal to stress axis increases the strength of the material at high temperatures. A physically based material model that can accurately simulate the cyclic deformation behavior is essential to facilitate component life predictions. A framework that combines theoretical mechanics, experimental mechanics, and numerical simulations are required to support the mechanical design process. For a method to be viable, it must capture material response for monotonic, low cycle fatigue (LCF), thermomechanical fatigue (TMF), and creep under a variety of conditions. At high temperatures, material deformation is mostly attributed to the evolution of the microstructure due to crystallographic slip along the crystallographic slip planes. A crystal viscoplastic (CVP) modeling framework is developed to simulate the physical characteristics to accurately model the material behavior. In doing so the approach presented in this dissertation establishes a framework to readily model any SX and DS material

Late gadolinium enhancement in Brugada syndrome: A marker for subtle underlying cardiomyopathy?

BACKGROUND: There is increasing evidence that the Brugada ECG pattern is a marker of subtle structural heart disease. OBJECTIVE: We characterised Brugada syndrome (BrS) patients using cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). METHODS: BrS was diagnosed according to international guidelines. 26% BrS patients carried SCN5A mutations. CMR data from 78 BrS patients were compared with 78 healthy controls (44±15 vs 42±14 years; p=0.434 and 64% vs 64% male; p=1.000). RESULTS: Right ventricular (RV) ejection fraction was slightly lower (61±8% vs 64±5%; p=0.004) and RV end-systolic volume slightly greater (31±10mL/m(2) vs 28±6mL/m(2); p=0.038) in BrS compared with controls. These values remained within the normal range. LGE was demonstrated in 8% BrS patients (left ventricular (LV) midwall LGE in 5%) but not in controls (p=0.028). In BrS patients with midwall LGE there were no other features of cardiomyopathy at the time of CMR but genetic testing and follow-up has revealed a desmoplakin mutation in one patient and evolution of T-wave inversion throughout all precordial ECG leads in another. Neither patient fulfils diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy. CONCLUSION: Some BrS patients have LV midwall LGE consistent with an underlying cardiomyopathic process. Even cases without LGE show greater RV volumes and reduced RV function. These findings lend further support to the presence of subtle structural abnormalities in BrS. The BrS pattern with LGE may serve as early markers for evolution of a cardiomyopathic phenotype over time. CMR is a potentially useful adjunct investigation in the clinical evaluation of BrS

Sudden death and cardiac arrest without phenotype: the utility of genetic testing.

Approximately 4% of sudden cardiac deaths are unexplained [the sudden arrhythmic death syndrome (SADS)], and up to 6-10% of survivors of cardiac arrest do not have an identifiable cardiac abnormality after comprehensive clinical evaluation [idiopathic ventricular fibrillation (IVF)]. Genetic testing may be able to play a role in diagnostics and can be targeted to an underlying phenotype present in family members following clinical evaluation. Alternatively, post-mortem genetic testing (the "molecular autopsy") may diagnose the underlying cause if a clearly pathogenic rare variant is found. Limitations include a modest yield, and the high probability of finding a variant of unknown significance (VUS) leading to a low signal-to-noise ratio. Next generation sequencing enables cost-efficient high throughput screening of a larger number of genes but at the expense of increased genetic noise. The yield from genetic testing is even lower in IVF in the absence of any suggestion of another phenotype in the index case or his/her family, and should be actively discouraged at this time. Future improvements in diagnostic utility include optimization of the use of variant-calling pipelines and shared databases as well as patient-specific models of disease to more accurately assign pathogenicity of variants. Studying "trios" of parents and the index case may better assess the yield of sporadic and recessive disease

Age of First Arrhythmic Event in Brugada Syndrome: Data From the SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) in 678 Patients.

BACKGROUND: Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE. METHODS AND RESULTS: A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter-defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27-84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±15.0 years; P<0.001). In adult patients (≥16 years), women experienced AE 6.5 years later than men (P=0.003). Whites and Asians exhibited their AE at the same median age (43 years). CONCLUSIONS: SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE

Profile of Brugada Syndrome Patients Presenting with Their First Documented Arrhythmic Event. Data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS).

BACKGROUND: Detailed information on the profile of Brugada syndrome (BrS) patients presenting their first arrhythmic event (AE) after prophylactic implantation of a cardioverter defibrillator (ICD) is limited. OBJECTIVES: 1) To compare clinical, electrocardiographic, electrophysiologic and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (CA) (group A) with those in whom the AE was documented after prophylactic ICD implantation (group B); 2) To characterize group B patients' profile using the Class II indications for ICD implantation established by HRS/EHRA/APHRS Expert Consensus Statement in 2013. METHODS: A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 BrS patients with AE (group A, n=426; group B, n=252). RESULTS: First AE occurred in group B patients 6.7 years later than in group A (46.1+ 13.3 vs. 39.4+15.1, P<0.001). Group B patients had a higher incidence of family history of sudden cardiac death (SCD) and SCN5A mutations. Of the 252 group B patients, 189 (75%) complied with the HRS/EHRA/APHRS indications whereas the remaining 63 (25%) did not. CONCLUSION: BrS patients with first AE documented after prophylactic ICD implantation exhibited their AE at a later age with a higher incidence of positive family history of SCD and SCN5A mutations compared to those presenting with an aborted CA. Only 75% of patients who suffered an AE after receiving a prophylactic ICD complied with the 2013 Class II indications, suggesting efforts are still required for improving risk stratification