text:
The score was calculated by adding the number of risk alleles. One point is awarded for each copy of the risk alleles CYP2C19*2 and ABCB1 3435 TT. One point is awarded when a copy of protective alleles CYP2C19*17 or ITGB3 PLA2 is absent. A homozygous carrier of both the CYP2C19*2 (2 points) and the ABCB1 3435 TT (2 points) variants who has no copies of either the CYP2C19*17 (2 points) or the ITGB3PLA2 (2 points) alleles will score an 8, the highest score. Conversely, a patient with no copies of either the CYP2C19*2 (0 points) or the ABCB1 3435 CC (0 points) variants who carries 1 copy of the CYP2C19*17 (1 point) and 2 copies of the protective ITGB3PLA2 allele (0 points) will score 1, the lowest score. aFor 2 participants, information on a genotype was missing and the score could not be calculated.
The clinical model is based on nongenetic factors (type C lesion, proton pump inhibitor use, diabetes mellitus, left ventricular dysfunction <40%, percutaneous coronary intervention in acute setting, and clopidogrel loading dose), with sensitivity of 60% and specificity of 70%, for a positive likelihood ratio of 2.1 (area under the curve, 0.73; 95% CI, 0.67-0.78; P <.001).The genetic model contains CYP2C19 metabolic status, ABCB1 3435 TT genotype, and ITGB3 PLA2 polymorphism, with a sensitivity of 48% and specificity of 78%, for a positive likelihood ratio of 2.0 (area under the curve, 0.68; 95% CI, 0.62-0.74; P <.001). The combined model contains all clinical, angiographic, and genetic predictors, with a sensitivity of 67% and specificity of 79%, for a positive likelihood ratio of 3.4 (area under the curve, 0.78; 95% CI, 0.73-0.83; P <.001). The diagonal dotted line is the expected receiver operating characteristic curve for a totally random classifier.
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Cayla G, Hulot J, O’Connor SA, et al. Clinical, Angiographic, and Genetic Factors Associated With Early Coronary Stent Thrombosis. JAMA. 2011;306(16):1765–1774. doi:10.1001/jama.2011.1529
Author Affiliations: Institut de Cardiologie, INSERM Unité Mixte de Recherche (UMR)_S 937, Pitié-Salpêtrière Hospital (Drs Cayla, O’Connor, Silvain, Vignalou, Beygui, Barthélémy, Montalescot, and Collet) and Université Pierre et Marie Curie (Paris 6), UMR_S 956 (Dr Hulot and Mr Allanic), Paris, France; Department of Cardiology, Centre Hospitalo-Universitaire (CHU) Nîmes, Nîmes, France (Dr Cayla); Faculté de Médecine, Université Montpellier 1 (Drs Cayla and Huerre), and Department of Cardiology, CHU Montpellier (Dr Huerre), Montpellier, France; Cardiovascular Research Center (Dr Hulot) and Department of Genetics and Genomic Sciences (Dr Scott), Mount Sinai School of Medicine, New York, New York; Laboratoire de Pharmacologie Médicale et Clinique, INSERM U1048, Faculté de Médecine, Université de Toulouse, and Service de Cardiologie, CHU Rangueil, Toulouse, France (Dr Pathak); and Department of Hematology-Hemostasis, Centre National de La Recherche Scientifique, UMR 6239, and Department of Cardiology (Dr de la Briolle), CHU Tours, and Faculté de Médecine, Université Francois Rabelais (Drs Gruel and de la Briolle), Tours, France.
Context Despite dual antiplatelet therapy, stent thrombosis remains a devastating and unpredictable complication of percutaneous coronary intervention (PCI).
Objective To perform a sequential analysis of clinical and genetic factors associated with definite early stent thrombosis.
Design, Setting, and Participants Case-control study conducted in 10 centers in France between January 2007 and May 2010 among 123 patients undergoing PCI who had definite early stent thrombosis and DNA samples available, matched on age and sex with 246 stent thrombosis–free controls.
Main Outcome Measure Accuracy of early stent thrombosis prediction by 23 genetic variants.
Results Among the 23 genetic variants investigated in 15 different genes, the significant determinants of early stent thrombosis were CYP2C19 metabolic status (adjusted odds ratio [OR], 1.99; 95% CI, 1.47-2.69), ABCB1 3435 TT genotype (adjusted OR, 2.16; 95% CI, 1.21-3.88), and ITGB3 PLA2 carriage (adjusted OR, 0.52; 95% CI, 0.28-0.95). Nongenetic independent correlates were acuteness of PCI (adjusted OR, 3.05; 95% CI, 1.54-6.07), complex lesions (American College of Cardiology/American Heart Association type C) (adjusted OR, 2.33; 95% CI, 1.40-3.89), left ventricular function less than 40% (adjusted OR, 2.25; 95% CI, 1.09-4.70), diabetes mellitus (adjusted OR, 1.82; 95% CI, 1.02-3.24), use of proton pump inhibitors (adjusted OR, 2.19; 95% CI, 1.29-3.75), and higher clopidogrel loading doses (adjusted OR, 0.73; 95% CI, 0.57-0.93). The discriminative accuracy of the clinical-only model was similar to that of a genetic-only model (area under the curve, 0.73 [95% CI, 0.67-0.78] vs 0.68 [95% CI, 0.62-0.74], respectively; P = .34). A combined clinical and genetic model led to a statistically significant increase in the discriminatory power of the model compared with the clinical-only model (area under the curve, 0.78 [95% CI, 0.73-0.83] vs 0.73 [95% CI, 0.67-0.78]; P = .004).
Conclusions This case-control study identified 3 genes (CYP2C19, ABCB1, and ITGB3) and 2 clopidogrel-related factors (loading dose and proton pump inhibitors) that were independently associated with early stent thrombosis. Future studies are needed to validate the prognostic accuracy of these risk factors in prospective cohorts.
Percutaneous coronary intervention (PCI) with stent implantation has become the standard of care for myocardial revascularization, especially in the setting of unstable coronary artery disease.1 Despite the use of dual antiplatelet therapy (DAPT; ie, aspirin and clopidogrel), which reduces cardiovascular events after PCI by more than 80%, definite stent thrombosis remains a concern. Although it is a rare complication, occurring in 0.5% to 4% of patients within the first year of PCI,2 the majority of stent thromboses occur in the first month and are defined as early stent thrombosis. It is a devastating complication, with a mortality rate up to 40% and large myocardial infarction in roughly 80% of survivors who remain exposed to frequent recurrence.2,3 Clinical and angiographic correlates of stent thrombosis have been well described, of which premature interruption of DAPT is the most important risk factor for early stent thrombosis.2,4 In addition, comorbidities, the initial clinical presentation, diabetes, stent undersizing or underexpansion, complex and/or bifurcation lesions, and coronary dissection have been associated with stent thrombosis.2
Much attention recently has been focused on patient response to clopidogrel, with a strong relationship between high on-clopidogrel platelet reactivity and stent thrombosis despite stringent adherence to DAPT.5 Clopidogrel is a prodrug that requires metabolic activation to generate its active thiol metabolite. It repeatedly has been shown that variable or insufficient clopidogrel active metabolite generation is the primary explanation for poor responsiveness to clopidogrel.5 The reduced-function genetic variants in the hepatic cytochrome P450 2C19 (CYP2C19) gene have been identified as the most prominent contributors to this variability.6 There is a strong link among CYP2C19 genetic polymorphisms, decreased clopidogrel responsiveness as measured by platelet function assays, and adverse clinical outcomes.7-10 Other genes also might influence clopidogrel absorption and metabolism,11-13 but their relative contribution to the occurrence of stent thrombosis has been rarely explored. Additionally, a number of variants in genes encoding key factors of the coagulation/fibrinolytic systems and platelet receptor function have been associated with a higher risk of arterial thrombotic events, but their relation to stent thrombosis remains unknown.14-17
Our goal was to perform a case-control study using a candidate gene approach, testing all genetic variants previously associated with clopidogrel pharmacogenetics and arterial thrombosis to determine their relative contribution to definite early stent thrombosis in addition to classic clinical and angiographic factors.
The Online Assistance for Stent Thrombosis (ONASSIST) project is a French nationwide Web registry of patients with definite stent thrombosis following stent implantation. This online interactive approach allows submission of clinical cases from any hospital followed by medical expert review.18 In each participating center, a cardiologist is responsible for the collection and submission of all stent thrombosis cases. Accuracy of case ascertainment is obtained by review of each Web-based case record by 3 interventional cardiologists who pay particular attention to discontinuation of aspirin or clopidogrel. Only data on definite stent thromboses not related to drug interruption are collected. This investigator-initiated registry is led and partially supported by a nonprofit academic research organization, ACTION (Allies in Cardiovascular Trials, Initiatives and Organized Networks), at Pitié-Salpêtrière Hospital, Paris. The workflow of the Web site is customized to provide online assistance with regard to on-treatment platelet reactivity and pharmacogenetic profiles. A total of 10 centers performing about 18 500 PCIs participated between January 2007 and May 2010. The protocol was approved by the Pitié-Salpêtrière University Hospital Ethics Committee and the study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.
Patients aged 18 years or older with an angiographically documented stent thrombosis according to Academic Research Consortium definitions19 were enrolled. Angiographic definite stent thrombosis consisted of partial or complete occlusion within a previously implanted stent and evidence of new thrombus (in the stent or in the 5 mm proximal or distal to the stent) associated with at least 1 of the following: ischemic symptoms, ischemic electrocardiographic changes, or elevation of biomarkers. Among early stent thromboses (≤30 days), acute stent thrombosis occurred within 24 hours after stent implantation and subacute stent thrombosis occurred more than 24 hours but no more than 30 days after stent implantation. Control participants were recruited in the same participating centers, were identified in the local PCI database, had to be receiving DAPT, had at least 6 weeks of follow-up without history of stent thrombosis, and had available genetic samples. For the case-control comparison, a ratio of 1 stent thrombosis case to 2 age- and sex-matched controls was used.
Baseline clinical, angiographic, and procedural characteristics of case and control participants were collected. Ancestry and region of birth were self-identified. Coronary angiograms of both case and control participants were reviewed by 2 independent interventional cardiologists (G.C., J.S.H., J.S., F.B., O.B., or G.M.). In addition, a dedicated questionnaire allowing an accurate description of the use of antiplatelet therapy within the 6 weeks prior to the occurrence of stent thrombosis was used. Partial antiplatelet therapy interruption was defined as clopidogrel or aspirin cessation for at least 3 consecutive days within 14 days prior to stent thrombosis. Complete interruption was defined as cessation of both aspirin and clopidogrel for at least 3 consecutive days within 14 days prior to stent thrombosis. No biological analyses were attempted if there was any evidence of treatment discontinuation. Definite stent thrombosis cases that occurred after partial or complete interruption of DAPT were excluded from the current analysis.
Genomic DNA of case and control participants was extracted from peripheral blood leukocytes by standard procedures (Puregene DNA isolation kit, Merck Eurolab). Genotyping was performed using TaqMan Validated SNP assays with the 7900HT Sequence Detection System (Applied Biosystems). All participants had genotyping for the common CYP2C19*2 (rs4244285) loss-of-function allele as well as CYP2C19*3 (rs4986893), CYP2C19*4 (rs28399504), CYP2C19*5 (rs56337013), CYP2C19*6 (rs72552267), CYP2C19*17 (rs12248560), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), CYP2B6*5 (rs3211371), CYP2B6*9 (rs3745274), CYP3A5*3 (rs776746), POR*28 (rs1057868), PON1 Q192R (rs662), PON1 L55M (rs854560), ABCB1 C3435T (rs1045642), P2Y12 (rs2046934), ITGB3 (rs5918), MTHFR (rs1801133), PAI1 (rs1799889), factor V (rs6025), prothrombin G20210A (rs1799963), fibrinogen beta chain (rs1800790), and VKORC1 (rs2359612), as previously described.7
CYP2C19, CYP2C9, and CYP2B6 metabolic status was determined for cases and controls based on identified polymorphisms and their effect on enzymatic function20,21 (eTable 1).
All analyses were performed with SAS software, version 9.1 (SAS Institute Inc). All single-nucleotide polymorphisms were tested for deviation from Hardy-Weinberg equilibrium with the χ2 test. Continuous variables were expressed as means and standard deviations unless otherwise indicated and categorical variables as frequencies and percentages. P values were 2-sided with a level of statistical significance of P <.05.
The sample size calculation was based on the hypothesis of a 2-fold increase in the CYP2C19*2 allelic frequency in patients with stent thrombosis compared with controls. From our previous studies, the CYP2C19*2 allelic frequency was expected to be 17% in controls. We estimated that 120 cases matched with 2 controls each would be required to detect such a difference with a type I error risk of .05 and power of 80% (Quanto software, version 1.1, University of California, Santa Cruz).
Baseline characteristics and genotype distribution were compared between cases and controls using conditional logistic regression analyses. A univariate logistic model was used to compare all characteristics (clinical, angiographic, and genetic). Comparisons are expressed as univariate odds ratios (ORs) with 95% confidence intervals. A multivariable logistic regression analysis was then used to identify independent variables associated with the occurrence of early stent thrombosis. The following variables were considered for inclusion in the comprehensive model: baseline demographic (age, sex, body mass index, smoking, and ancestry), clinical (hypertension, diabetes mellitus, previous myocardial infarction, creatinine clearance <60 mL/min, left ventricular ejection fraction <40%, clopidogrel loading dose, and use of proton pump inhibitors [PPIs] and calcium channel blockers), and angiographic (American College of Cardiology/American Heart Association [ACC/AHA] type C lesion, number of vessels with disease, minimum stent diameter, acuteness of PCI, and post-PCI dissection) characteristics; predicted metabolic status (CYP2C19, CYP2C9, and CYP2B6); and genetic variants (CYP3A5*3, POR*28, PON1 Q192R and L55M, ABCB1 C3435T, P2Y12 H1/H2, ITGB3 T1565C, MTHFR C677T, PAI1 5G/4G, factor V G1691A, prothrombin G20210A, fibrinogen G455A, and VKORC1). Loading doses were classified as no loading dose, 150 to 300 mg, 300 to 600 mg, and more than 600 mg. CYP2C19 metabolic status was defined as rapid, extensive, intermediate, or poor according to a recent consensus definition22 (eTable 1). Inclusion in the final model was determined by a backward-stepwise technique evaluating all potential univariate variables (P < .20) to create a multivariable model containing variables with P < .05. We performed several sensitivity analyses that confirmed the models' consistency (eg, modeling using forward selection of variables, interaction analyses, and rejection of colinearity). We tested for interactions between clopidogrel loading dose and significant genotypes in all models. The main analyses were age- and sex-adjusted. Additional analyses were also restricted to the predominant ethnicity. The clinical and genetic models were built according to the same procedure. Baseline demographic, clinical, and angiographic characteristics were considered for the clinical-only model, whereas predicted metabolic status and genetic variants were considered for the genetic-only model.
For each model, the regression parameter estimates of the independent variables were calculated and used to derive 3 different weighted equations corresponding to the clinical-only, genetic-only, and comprehensive models, respectively. Nonparametric receiver operating characteristic curves were used to assess the discriminatory power of the 3 prediction algorithms to distinguish cases and controls. Pairwise comparisons of the area under the curve (AUC) were performed according to DeLong et al.23 For each model, the best cutoff that maximized the sensitivity + specificity sum was determined and gives an indication of the optimal model's sensitivity and specificity. Finally, individual scores were calculated for both cases and controls using the 3 equations. We divided the distribution of the resulting clinical-only, genetic-only, and comprehensive scores into tertiles and compared the risk of early stent thrombosis according to the tertiles for each model.
Among the 233 PCI patients with definite stent thrombosis who were referred to the ONASSIST registry between January 2007 and May 2010, 31 instances of stent thrombosis occurred after complete or partial interruption of DAPT and 33 occurred during antiplatelet monotherapy and were not considered in the analyses (Figure 1). Among the remaining 169 cases, 123 were identified as early stent thrombosis and matched according to age and sex with 246 controls.
Cases were more frequently found to be diabetic and to have impaired left ventricular function and less frequently had hypercholesterolemia (Table 1). They also presented more frequently with complex lesions (ACC/AHA type C) and acute coronary syndromes in comparison with controls. In addition, cases received significantly lower clopidogrel loading doses than controls and were more frequently receiving PPIs.
Carriage of the CYP2C19*2 loss-of-function allele was more frequent in cases than in controls (48.8% [n = 60] vs 27.4% [n = 67], respectively; unadjusted OR, 2.53; 95% CI, 1.61-3.97) (Table 2, Table 3, and Table 4), including a 7-fold higher prevalence of *2/*2 homozygotes (16.3% [n = 20] vs 2.5% [n = 6]; unadjusted OR, 7.73; 95% CI, 3.02-19.82). Of note, carriage of the CYP2C19*17 gain-of-function allele was significantly less frequent in cases than in controls (20.4% [n = 25] vs 32.7% [n = 80]; unadjusted OR, 0.53; 95% CI, 0.31-0.88). Consequently, the CYP2C19 metabolic status distribution was significantly different between cases and controls (eFigure 1).
Of interest, cases were more frequently ABCB1 3435 TT homozygotes vs CT/CC (31.7% ([n = 39] vs 18.8% [n = 46]; unadjusted OR, 2.01; 95% CI, 1.22-3.30) and less frequently carriers of the ITGB3 PLA2 polymorphism (16.4% [n = 20] vs 28.2% [n = 69]; unadjusted OR, 0.50; 95% CI, 0.29-0.87) than controls. None of the other genetic variants that have been shown to interfere with clopidogrel pharmacology (CYP2B6, CYP2C9, CYP3A5, POR, PON1, and P2Y12) or with thrombotic disorders (MTHFR, PAI1, factor V, prothrombin, fibrinogen beta chain, and VKORC1) were associated with stent thrombosis.
To further evaluate the association between early stent thrombosis and combination of genetic determinants, a risk allele count score was developed to determine whether there was a gene-dose effect in CYP2C19, ABCB1, or ITGB3 variant allele carriers. As shown in Figure 2, we identified a gradual increase in the risk of early stent thrombosis according to the number of risk alleles carried by patients.
Multivariable logistic regression analyses were performed to identify which clinical, angiographic, and genetic variables were independently associated with the occurrence of early stent thrombosis (Table 5). Nongenetic independent correlates of early stent thrombosis were acuteness of PCI (adjusted OR, 3.05; 95% CI, 1.54-6.07), complex lesions (ACC/AHA type C) (adjusted OR, 2.33; 95% CI, 1.40-3.89), left ventricular function less than 40% (adjusted OR, 2.25; 95% CI, 1.09-4.70), diabetes mellitus (adjusted OR, 1.82; 95% CI, 1.02-3.24), use of PPIs (adjusted OR, 2.19; 95% CI, 1.29-3.75), and higher clopidogrel loading doses (adjusted OR, 0.73; 95% CI, 0.57-0.93). Among the genetic factors, predicted CYP2C19 metabolic status (rapid, extensive, intermediate, or poor) was a major determinant of early stent thrombosis (adjusted OR, 1.99; 95% CI, 1.47-2.69), along with ABCB1 3435 TT genotype (adjusted OR, 2.16; 95% CI, 1.21-3.88) and ITGB3 PLA2 carriage (adjusted OR, 0.52; 95% CI, 0.28-0.95). There was a gradual risk increase according to CYP2C19 metabolic status, the lowest being associated with rapid metabolic and the highest with poor metabolic status.
Similar results were found when restricting the analyses to white individuals, the overwhelming majority in our study population. No significant interactions were identified between the genetic variants and each of the independent clinical and angiographic factors. Notably, we did not find any significant interactions between clopidogrel loading doses and CYP2C19, ABCB1, or ITGB3 (P = .46, P = .84, and P = .63 for interaction, respectively). There were also no significant interactions in the CYP2C19, ABCB1, and ITGB3 genetic variants.
In addition to the combined (clinical and genetic) model, a model including only clinical and angiographic characteristics (clinical-only model) and a model including CYP2C19 metabolic status and ABCB1 (TT vs CC or CT) and ITGB3 genotypes (genetic-only model) were built using multivariable logistic regression analyses. The regression parameter estimates of the independent variables were used to derive 3 different weighted equations as defined in eTable 2. We then compared the predictive performance of these models by receiver operating characteristic curve analyses.
We found that the clinical-only and genetic-only models were able to similarly discriminate between early stent thrombosis and controls (AUC, 0.73 [95% CI, 0.67-0.78] vs 0.68 [95% CI, 0.62-0.74], respectively; P = .34) (Figure 3). The combined clinical and genetic model, however, had significantly greater power to discriminate early stent thrombosis than the clinical-only model (AUC, 0.78 [95% CI, 0.73-0.83] vs 0.73 [95% CI, 0.67-0.78]; P = .004). Moreover, it had greater sensitivity and specificity (67% and 79%, respectively) than the clinical-only (60% and 70%, respectively) or genetic-only (48% and 78%, respectively) models. Therefore, the positive likelihood ratio (LR) was highest with the combined clinical and genetic model (LR, 3.4) vs with the clinical-only (LR, 2.1) or genetic-only (LR, 2.0) models. Patients in the highest tertile of risk using the combined clinical and genetic model had a 7-fold increased risk of early stent thrombosis vs patients in the lowest tertile (OR, 7.63; 95% CI, 4.18-13.91) (eFigure 2).
Stent thrombosis is a serious complication of coronary stenting but its low incidence makes it difficult to study in a comprehensive manner. Registry studies have identified a certain number of risk factors that may or may not be connected to each other, but, to our knowledge, no study has evaluated a range of clinical, drug, angiographic, procedural, and genetic factors of stent thrombosis. Our multicenter study suggests that a combination of 3 genotypes related to clopidogrel metabolism and platelet function (CYP2C19, ABCB1, and ITGB3) is an independent risk factor for early stent thrombosis beyond clinical and angiographic factors. We also identified 2 potentially modifiable factors of early stent thrombosis: clopidogrel loading dose and clopidogrel interaction with PPIs.
Our study adds to the understanding of the genetic profile of patients treated with clopidogrel who are at risk of early stent thrombosis. Of the 23 preselected genetic variants, 4 were found to be independently associated with the occurrence of early stent thrombosis. These nonmodifiable risk factors are highly prevalent. All variants except 1 have been shown to directly interfere with clopidogrel metabolism and are significantly associated with on-clopidogrel platelet reactivity. Notably and contrasting with a recent report,11 we found no significant association between carriage of the PON1 Q192R allele and stent thrombosis. Together with the recent demonstration that the fate of 2-oxo-clopidogrel in vivo, the clopidogrel intermediate metabolism, depends mainly on CYP enzymes and only to a minor extent on esterases such as PON1,24 this further supports the lack of association between PON1 Q192R and clinical events recently reported by other groups.25-27 In contrast, the CYP2C19*2 allele was independently associated with a high risk of stent thrombosis, and the prevalence of homozygotes was impressively high in patients with stent thrombosis and was 7-fold higher than in controls. In addition, CYP2C19*17 gain-of-function allele carriers were at lower risk of early stent thrombosis, a variant associated with higher on-treatment platelet inhibition and more bleeding complications28 and less ischemic events in the CHARISMA study.29 This further strengthens the current evidence on the predominant role of CYP2C19 in clopidogrel metabolism.
The current study confirms a significant association between carriage of the ABCB1 3435 TT (vs CC or CT) genotype and early stent thrombosis. This gene encodes a drug efflux transporter, P-glycoprotein, that modulates clopidogrel absorption. It has been previously associated with reduced clopidogrel response,13,30 but with variable clinical consequences.10,13,31 One explanation for the discrepancy may be that ABCB1 C3435T is a synonymous variant (p.Ile1145Ile) that affects protein conformation and substrate specificity,32 which may vary according to clopidogrel dosing strategies as recently shown by a greater effect of this variant at the time of clopidogrel loading vs during the maintenance phase.33 Our finding that ABCB1 C3435T carriage and low clopidogrel loading dose were independent correlates of early stent thrombosis and the lack of saturable clopidogrel intestinal absorption demonstrated by previous investigation of the effects of different loading dose strategies on clopidogrel response34-36 are not supportive of such a hypothesis. Of note, assessment of both ABCB1 C3435T and CYP2C19 shows that the 2 genes offer complementary information, and nearly three-fourths of patients with stent thrombosis had an increased genetic risk profile defined by the number of alleles at risk. Our regression models also indicate that in patients with a low clinical likelihood of stent thrombosis, the influence of genetic factors was important in predicting stent thrombosis.
The ITGB3 gene encodes for the integrin β3, a component of the glycoprotein IIb/IIIa platelet receptor, which mediates the final pathway of platelet aggregation. It is highly polymorphic, with 2 common allelic isoforms, PLA1 and PLA2. The relation of PLA2 (p.Leu59Pro) with the occurrence of acute coronary syndromes has been controversial, with a trend toward an increased risk.37 There is also consistent evidence of lower platelet inhibition in response to clopidogrel among carriers of the PLA2 allele.38-40 Our investigation shows that the PLA2 polymorphism was less frequent in patients with stent thrombosis than in controls. This appears to be a new finding contradictory with previous investigations performed in another setting. Although it may add to the accuracy of our predictive model, replication is needed.
The procedure-related independent correlates of early stent thrombosis were expected and could not be altered. We found that the only 2 potentially modifiable correlates of early stent thrombosis (clopidogrel dose and PPI use) are also major determinants of high on-clopidogrel platelet reactivity. Several studies have shown that increasing the clopidogrel dose regimen results in higher clopidogrel active metabolite isomer H4,41 overcomes high on-clopidogrel platelet reactivity,34,36,41 and reduces the risk of early stent thrombosis.42 Although the clinical effect of concomitant PPI use in clopidogrel-treated patients is more controversial, consistent evidence exists of a significant pharmacological interaction between omeprazole and clopidogrel, with a decrease in clopidogrel metabolite formation,43 leading possibly to an increase in cardiovascular risk, especially in high-risk populations, as in patients with previous stent thrombosis.8 Whether the effect of PPIs was driven by an interaction with the CYP2C19 pathway could not be evaluated because the type of PPI was not recorded. Altogether, clopidogrel dose, PPI use, and presence of CYP2C19 and ABCB1 genetic variants suggest that the level of P2Y12 antagonism achieved through clopidogrel active metabolite generation is the key factor influencing the risk of early stent thrombosis in patients receiving clopidogrel and adherent to treatment.
The overlap between the clinical and genetic regression models appears limited and no significant interaction was found. Obviously, genetic information cannot be captured by clinical or procedural characteristics. The lack of variation in the OR values of early stent thrombosis clinical predictors before and after consideration of the genetic correlates and their similar absolute values to those of clinical and angiographic correlates further suggest a similar extent of the predicted risk and a lack of correlation.
The case-control design of our investigation may have underestimated some potential confounding factors and represents a limitation per se, although it is the only suitable design to evaluate rare events like stent thrombosis and we undertook thorough data collection on all variables. Additionally, we had a limited sample size to develop our predictive models and, thus, may have overestimated the models' predictive accuracy in independent cohorts. Skewed inclusions may have occurred within our Web base case selection because we could not ensure an exhaustive selection of patients. However, we estimated that 18 500 patients underwent stent implantation in the participant centers during the study period, corresponding to a stent thrombosis prevalence of 1.26% (0.6% for early stent thrombosis), concordant with the recent literature. We acknowledge that the score now should be prospectively validated in a new independent cohort of patients. Another limitation of this type of study is that only early stent thrombosis survivors could be studied, and the genotype-phenotype relation is not known for the most severe cases, who died soon after stent thrombosis. However, we may have also underestimated the weight of the identified variants by missing the most severe cases. We also acknowledge that the last generation of drug-eluting stents, with less thrombogenic platforms, represented less than 10% of the cases. This might have potentially biased our findings, although the benefit of these new platforms is mainly driven by a reduction in late and very late stent thrombosis, issues that were beyond the scope of the current investigation.44 Stent malapposition or underexpansions are other important factors associated with stent thrombosis that were not evaluated. Platelet reactivity was not included in the stent thrombosis prediction model because it could not be systematically measured at the time of the event. Moreover, platelet function testing has its own limitations and is difficult to use on admission for emergent cases such as the stent thrombosis cases in the current multicenter study. Finally, our findings apply to white individuals, who were dominantly represented in our cohort, and the effects of different genes according to different ethnic groups may warrant dedicated studies.
In conclusion, in addition to established clinical and angiographic factors, 3 genes involved in clopidogrel metabolism and platelet receptor function (CYP2C19, ABCB1, and ITGB3) and 2 clopidogrel-related factors (loading dose and PPI use) were independently associated with early stent thrombosis. Combining genetic factors with clinical factors improved risk stratification for stent thrombosis. Whether treatment adjustment on the basis of such global risk stratification can improve the prognosis of patients undergoing PCI will require future validation in independent cohorts.
Corresponding Author: Gilles Montalescot, MD, PhD, Institut de Cardiologie, Bureau 236, Pitié-Salpêtrière Hospital, 47 Bd de l’Hôpital, 75013 Paris, France (email@example.com).
Author Contributions: Drs Hulot and Collet had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Cayla and Hulot contributed equally to this work and are considered first coauthors.
Study concept and design: Cayla, Hulot, Montalescot, Collet.
Acquisition of data: Cayla, O’Connor, Pathak, Gruel, Silvain, Vignalou, Huerre, de la Briolle, Allanic, Barthélémy, Montalescot, Collet.
Analysis and interpretation of data: Cayla, Hulot, O’Connor, Scott, Silvain, Beygui, Beygui, Barthélémy, Montalescot, Collet.
Drafting of the manuscript: Cayla, Hulot, Scott, Montalescot, Collet.
Critical revision of the manuscript for important intellectual content: Hulot, O’Connor, Pathak, Scott, Gruel, Silvain, Vignalou, Huerre, de la Briolle, Allanic, Beygui, Beygui, Barthélémy, Collet.
Statistical analysis: Cayla, Hulot, Beygui, Beygui.
Obtained funding: Montalescot, Collet.
Administrative, technical, or material support: Pathak, Scott, Gruel, Vignalou, Allanic, Montalescot, Collet.
Study supervision: Hulot, Montalescot, Collet.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Cayla reports receiving a research grant from la Fédération Française de Cardiologie; consultant fees from Abbott Vascular, AstraZeneca, CLS Behring, Daiichi Sankyo, and Eli Lilly; and lecture fees from Abbott Vascular, AstraZeneca, Biotronik, CLS Behring, Daiichi Sankyo, Eli Lilly, and Iroko Cardio. Dr Hulot reports receiving research grant support from Fondation de France, INSERM, Federation Francaise de Cardiologie, Biotronik, and Medco Research Institute; consulting fees from Biotronik and Medco Health Solutions; and lecture fees from sanofi-aventis, Daiichi Sankyo, and Eli Lilly. Dr Pathak reports receiving honoraria from BMS, AstraZeneca, and Daiichi. Dr Silvain reports that he has received research grants (to his institution) from sanofi-aventis, Daiichi Sankyo, Eli Lilly, Brahms, INSERM, Fédération Française de Cardiologie, and Société Française de Cardiologie; has served as a consultant to Daiichi Sankyo and Eli Lilly; and has received lecture fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, Iroko Cardio, and Servier. Dr Montalescot reports receiving grant support from Abbott Vascular, Boston Scientific, Cordis, Eli Lilly, Fédération Française de Cardiologie, Fondation de France, Guerbet Medical, INSERM, ITC Edison, Medtronic, Pfizer, sanofi-aventis, Société Française de Cardiologie, and Stago and consulting or board fees and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cardiovascular Research Foundation, Cleveland Clinic Research Foundation, Daiichi Sankyo, Duke Institute, Eli Lilly, Europa, Lead-up, GlaxoSmithKline, Institut de Cardiologie de Montreal, Menarini, Nanospheres, Novartis, Pfizer, Portola, sanofi-aventis, the Medicines Company, and the TIMI Study Group. Dr Collet reports receiving research grants from Bristol-Myers Squibb, sanofi-aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Fondation de France, INSERM, Fédération Française de Cardiologie, and Société Française de Cardiologie; consulting fees from sanofi-aventis, Eli Lilly, and Bristol-Myers Squibb; and lecture fees from Bristol-Myers Squibb, sanofi-aventis, Eli Lilly and AstraZeneca. No other disclosures were reported.
Funding/Support: This study was funded by ACTION, the Société Française de Cardiologie, the Fédération Française de Cardiologie, and INSERM. The ONASSIST program was also partially supported by an unrestricted grant from Eli Lilly and by a grant from the SGAM Foundation.
Role of the Sponsor: The sponsors were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Additional Contributions: We thank Elodie Blicq, MD, University of Tours, for her contribution to data management. Dr Blicq did not receive compensation in association with her work on this article.


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2Edit – Tropicalia (Torro Torro Remix) + Neoteric & Wax Motif – Go Deep (Torro Torro remix) : Must Hear Unique Electro Remixes [FREE DOWNLOAD]Posted in Bangin by nick | Tags: Electro House, Moombahton, Remix, Torro torro
Here are two amazing tracks from a group I haven’t featured nearly enough of. It’s Torro Torro, the talented electro / moombahton duo paving their way out of Toronto who are starting to gain international attention. The first song included is their remix to “Go Deep” by Neoteric & Wax Motif, which has been getting played out by countless big name Dj’s like the likes of Steve Aoki and Zeds Dead just naming a few. The song packs such a funky bass infused punch that is sure to get you moving around. The song is for sale through Beatport here, but to make the post even better we also have the free download on their remix of “Tropicalia” by 2Edit. It has a fresh jungle-esque vibe powered by crushing bass. We’ll be eagerlly awaiting the next Torro Torro track. Enjoy!
Neoteric & Wax Motif – Go Deep (Torro Torro remix) | Purchase
2Edit – Tropicalia (Torro Torro Remix) | Direct Download
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My story has changed quite a lot since moving to Boulder, Colorado and starting Thissongissick back in 2010. My name is Nick Guarino and this is Thissongissick.com. We have grown a lot since, but the original goal has stayed the same, making it easier for you to discover sick new music you have never heard before. In high school I would make mix cd's for my friends to show them all the new music I was discovering. Now through Thissongissick, we work with musicians and record labels from all over the world to showcase a variety of freshest electronic, hip-hop, indie, and other fresh genres to a worldwide following that now reaches millions of music lovers over 110+ countries, every single month. Make yourself at home, enjoy countless amazing musicians from a variety of genres and let the sick sounds fill your ears.Enjoy!

domain: entertainment


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Oh boy, this leftover salad was delicious! With so many flavors going on, it’s a feast of a salad. Let’s see: A savory sautéed chicken breast. A sweet and aromatic roasted rutabaga and carrots with currants, maple syrup and ras el hanout (a mild, fragrant North African curry powder). A reliable bed of lettuce, baby kale, grape tomatoes and scallion. Then everything gets a coat of bright, earthy, garlicky lime garlic tahini dressing. The combination was 100% spot-on and satisfying.
I made the salad using the curry-spiced rutabaga and carrots that I already had roasted, but you can of course start from roasting the root vegetables. Recipe for roasting is right here. You can save time by using pre-sauteed (or even better, pre-grilled) chicken breast as well. Then it’ll be a matter of assembling everything–perfect for a weeknight DASH diet dinner.
DASH diet considerations: This curry roasted root vegetable salad with lime garlic tahini dressing is an all-A student of the DASH diet realm. It packs about 4 servings of different vegetables (full of fiber and potassium); tahini helps it go light on oil while providing an incredibly earthy depth to the dressing; and simply cooked chicken breast provides lean protein.
The wide range of flavors, from bright, earthy tahini dressing to sweetly aromatic curry roasted vegetables, as well as the different textures really jazzes up the salad without a lot of sodium or oil. Give it a try! We skipped grains, but a pita would go perfectly with this Middle Eastern-inspired salad.
DASH diet servings:
4 vegetables & fruits
2 meats & fish
½ fat & oil
¼ nuts & beans
In a saute pan, heat 2 tsp olive oil on medium high and add the chicken breast. Saute until the chicken is cooked through, about 7-8 minutes, flipping once to brown both sides. Set aside in a wam place.
While the chicken breast cooks, make the dressing. Mix the tahini, extra virgin olive oil, lime juice and grated garlic in a bowl large enough to toss the lettuce and kale comfortably. Add water, 1 tsp at a time, to thin the dressing to a pourable consistency. Season with salt and pepper.
To the bowl of the dressing, add the lettuce, baby kale, grape tomatoes and scallion. Toss to coat evenly.
Slice the chicken breast into strips.
Place the lettuce-kale mixture in two plates or bowls. Top with the roasted rutabaga and carrots, as well as the chicken breast strips.
Sprinkle some za’atar on top, if you like, before serving.
It’s winter, and winter calls for a chowder. Which is awesome, because I love chowder. With miso soup, chowder is tied at the absolute top of my favorite soup list.
Sunday evening, after spending a few hours wandering around on a windswept beach with beautiful golden grass and elegant sand dunes, I needed something warm and hearty but not too heavy. The temperature was in the upper 40s at the beach, but fog was rolling in. The dampness cut through, and I needed to warm up. Chowder to the rescue! I had Ecuadorian chorizo and a couple of poblano chiles on hand, so I decided to make a vaguely Latin American chowder using those. Instead of regular potatoes, I used sweet potatoes. It was a choice based entirely on convenience, but added an interesting bit of sweetness to the hearty, otherwise savory chowder.
I roasted the poblano chiles in the toaster oven. This extra step does add a smoky, roasty flavor to the chowder, but it isn’t absolutely necessary. Unless you can roast the poblano chiles on a charcoal grill, that is–if you have access to that luxury (an envy of all NYC apartment dwellers, let me tell you :P), definitely roast the chiles. They’ll take on the flame-grilled awesomeness and add another dimension to the chowder.
Poblano chiles can be a Russian roulette. I roasted three chiles, and tasted each before adding them to the pot. One was super-duper spicy, way too hot to put the entire thing in the chowder. The other two were completely mild. I set the spicy one aside for another use and used the two milder ones in the chowder. You might want to taste yours and decide how much to put in, depending on how spicy you like your chowder to be.
Sweet Potato, Chorizo, Roasted Poblano & Kale Chowder
DASH diet considerations: The sweet potato, chorizo, roasted poblano and kale chowder is a hearty winter soup with zesty Latin American flavors. A tiny bit of chorizo per serving (about one DASH diet serving of meat) is enough to give the soup a savory, faintly spicy backbone. Both sweet potatoes and kale are a good source of potassium; overall, it’s a veggie-filled soup of 3 vegetable servings.
As is the case with many soups, it can be on the high side for sodium. I used Better Than Bouillon for chicken stock, and with that option, this chowder has about 460 mg of sodium (from the soup base, salt and chorizo). For a complete DASH diet meal, pair it with a crusty whole wheat bread.
3 vegetables & fruits
1 meats & fish
¼ fat & oil
460 mg sodium
While the peppers roast, heat olive oil in a large pot over medium heat. Add the garlic and onion. Cook, stirring occasionally, for 2-3 minutes until the onions are slightly translucent and soft.
Add the chorizo and break it up into small chunks with a spoon or a spatula. Cook, stirring frequently, until the chorizo pieces start to brown, for about 3 minutes.
Add the sweet potatoes and cook briefly, stirring to coat everything in the oil. Season with salt and pepper.
Add the chicken stock to the pot. Cover and bring it to a boil. Once boiling, turn the heat down to a simmer. Cook for 12-15 minutes, or until the sweet potatoes are cooked through.
Remove the poblano chiles from the oven. Once cool enough to handle, remove the stem and seeds, then dice. Set aside. (You might want to check the spiciness level of the chiles here and adjust how much of the diced poblano chiles you add to the soup.)
When the sweet potatoes can be pierced easily through, add the kale and cook for an additional 2-3 minutes, until the kale is wilted.
Add the milk, sour cream and roasted poblano chilies. Cook for 3-4 minutes, until everything is heated and the flavors are melded together.

domain: food


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Office of Civil Rights Compliance (Title IX and Equity)
Goodwin University is committed to providing an educational environment and workplace that is free from discrimination, harassment, sexual misconduct, and retaliation.
Non-Discrimination Statement and Acts of Intolerance Policy
Goodwin University is an affirmative action/equal opportunity educator and employer, fully committed to the goal of providing equal opportunity and full participation in its educational programs, activities, and employment without discrimination because of race, color, religious creed, sex, age, national origin, political affiliation, marital status, veteran status, sexual orientation, gender identity or expression, disability, HIV/AIDS or other communicable disease status, or any other consideration not directly and substantively related to effective performance. This policy implements Federal and State laws, regulations, and executive orders.
The staff, faculty, student body, and administration of Goodwin University form a diverse community and the University maintains that activities, programs, and everyday interactions are enriched by acceptance of one another in an environment of positive engagement and mutual respect. Acts of discrimination, intolerance, or harassment directed against individuals or specific groups of individuals will not be tolerated and will be dealt with according to employee and student grievance and disciplinary procedures.
To file a discrimination complaint, or for inquiries concerning Goodwin University’s Non-discrimination Policy, Title IX and the Rehabilitation Act of 1973, and the Americans with Disabilities Act, contact .

domain: sociology


We assume the ongoing responsibility for 24X7 monitoring, managing and/or problem resolution for our customers’ IT infrastructure. Keeping an IT environment operational and running smoothly requires the constant attention of highly skilled staff. We provide support to customers who are overwhelmed by rapidly changing business demands and the need to retain proper IT resources.
Our help desk support personnel respond to any IT issues our customers face, big or small, routine or critical, with the greatest care:
WTI offers superior services with outstanding results. Our team has extensive experience providing expert IT consulting and an impressive range of IT solutions and services that will fulfill most business requirements. We listen closely to what our customers need for their specific business operations so that we can offer comprehensive, personalized solutions that ensure each of those needs is met. Our team helps businesses achieve their IT goals efficiently, effectively, and securely.
Our network infrastructure services consolidate software and hardware resources to optimize connectivity, communication, operations and management within our customers’ networks. We ensure and enhance communication paths between users, processes, applications, services and external networks (e.g., the internet).
Organizations cannot always avoid disasters, but with careful planning the effects of a disaster can be minimized. Given increasing dependency on information technology to run operations, a disaster recovery plan can minimize data loss as well as downtime. Disaster recovery and contingency plans comprise processes and procedures to protect and recover the IT infrastructure of an organization in the event of a disaster, whether man-made, environmental or natural. Utilizing an effective disaster recovery and contingency plan, our team can protect your organization in the event that all or some of your computer services and/or operations are compromised or rendered unusable.
Using leading technologies, we design, develop and deploy data centers capable of offering virtualization and cloud computing platforms to our customers. Our process incorporates an extensive range of tools and technologies, allowing physical data centers to provide services based on virtualized applications, servers, storage and networks. In essence, we create data centers that are capable of hosting virtual and cloud environments. These data centers, as a result, are then enabled for hosting a multitude of services running on the same infrastructure – creating multi-tenant environments for use by various organizations and applications simultaneously.
Two mainstream products that we utilize for virtualization technology are “Hyper-V” (developed by Microsoft Corporation), which utilizes hypervisor-based emulations when providing IT managed services, and “VCenter Server” (developed by VMWare), which centralizes resources provisioning, management and operation, and evaluation of the performance of virtual machines.
With the power of cloud computing, we help make computer system resources, especially data storage and computing power, available to our customers from anywhere in the world. The services come in three standard options to suit the needs of your business:
Public Cloud: With this option, cloud services and infrastructure are owned and operated by a third-party cloud service provider, delivered over the internet, and shared by all customers. Public Cloud offers the economies of scalability and reliability.
Private Cloud: Running from your data center, this completely on-premises, private cloud offers versatility and convenience, while enabling a business to focus on management, control and security.
Hybrid Cloud: This model combines the elements of both public and private clouds. With hybrid cloud, a business can maximize its efficiencies by running mission-critical workloads or sensitive applications on the private cloud, while utilizing the public cloud for non-sensitive operations.
For any of the cloud environment options described above, cloud services can be conceptualized as a pyramid with three layers: Infrastructure-as-a-Service (IaaS) sits at the base of the pyramid, Platform-as-a-Service (PaaS) is the middle layer, and Software as-a-Service (SaaS) sits at the top of the pyramid. The amount of control over the virtualized IT resources decreases as the customer ascends the pyramid.
Infrastructure-as-a -Service (IaaS) offers highly scalable resources, including virtualized server spaces, storage spaces, network connections and IP addresses, and is typically hosted by a third-party provider.
Platform-as-a-Service (PaaS) is an environment where providers host development tools in the infrastructures, such that developers can build applications over the internet.
Software-as-a-Service (SaaS) is probably the most common model known to most information system users, in which the platform is used as part of the software delivery model, facilitating software applications to be hosted on the cloud and made available to customers over the internet.
Our services offerings for cloud platforms are below:
Assessment and Planning
We carefully evaluate our customer’s existing infrastructure, suggest areas for improvement and develop a migration plan.
Having a clear understanding of the customer’s needs and a set of objectives for their cloud requirements, we build an environment per the specification, deploy systems and applications, migrate databases, and verify the stability and reliability of the infrastructure.
Our experts make sure that our customers reach the highest efficiency with their cloud computing environment and convert their applications to utilize native features of cloud (i.e., services packaged in containers, deployed as microservices and managed using the elastic infrastructure).
We help our customers understand all the modulation of the cloud topology and train them to employ the new infrastructure efficiently and effectively.
Our monitoring and disaster recovery solutions ensure the high availability and superior performance of our customers’ cloud infrastructure.


As Australia celebrates International Women's Day this March 8, local and international voices continue to condemn the lack of basic human rights for Indigenous women. Kirstie Parker is the co-chair of the National Congress of Australia's First Peoples. She told VICE that she felt the work being done was failing to make a real impact. "Our women are way behind the eight-ball if you're talking about health, housing, education, safety and freedom from violence," she said. And despite efforts to cut the disparity, Parker is less than satisfied, saying "We're not seeing the sort of progress that we're going to need to see if we're going to close that gap."
According to data from the Australian Bureau of Statistics, one in three Australian women are victims of domestic or sexual violence, while male violence is the biggest health risk for women between the ages of 15 and 44. As high as those figures are, the 2011 Universal Periodic Review found Aboriginal and Torres Strait Islander women are 45 times more likely to be victims of domestic and family violence.
The concern was in that year's United Nations Human Rights Council review of Australia's human rights protection. It recommended the Commonwealth consolidate its anti-discrimination laws on human rights, sex, race, age and disability to address citizens experiencing multiple forms of discrimination. They highlighted Indigenous women who encounter racial and sexual discrimination, and called for better anti-discrimination legislation to protect them.
While Australia accepted this recommendation, four years later it's yet to be implemented.
"There is currently no remedy for intersecting and compounding forms of discrimination that Aboriginal and Torres Strait Islander women face," said Shannon Williams from the Indigenous Women's Legal Program of Women's Legal Services NSW.
Williams is concerned about multiple discriminations these women are up against. "They may also face further discrimination on the basis of age, disability, sexual orientation, gender identity and intersex status," she told VICE. "Challenging and trying to do something to stop discrimination is a task for all of us every day of the year."
The Australian Women Against Violence Alliance reported in its pre-budget submission in 2015-2016 that the cost of domestic violence on Australia's economy is around $13.6 billion and estimated to rise to $15.6 billion by 2021-22. At that time, it's estimated violence in Indigenous communities will constitute $2.2 billion of that figure if more assertive action isn't taken.
But Parker reports that change can only happen when Indigenous women's voices are adequately represented in the management of their lives. "We need to see much more Aboriginal and Torres Strait Islander women taking part in the design and delivery of the support services for our women," she said. Adding that if the women affected were involved in support and preventive services they might start to see a change. Although she added, "that change is taking a long time to come."
A 2009 Australian Human Rights Commission inquiry into Indigenous people's access to justice showed between 2000 and 2008, the imprisonment rate of Indigenous women has increased by 46 percent. It dwarfed the 27 percent increase for Indigenous men.
Although the statistics show the need for legal services, a 2002 National Aboriginal and Torres Strait Islander Social Survey showed only 20 percent of Indigenous people had used legal services. The commission expressed concern that Indigenous women faced bigger difficulties in gaining legal representation. It said offenders were more eligible for legal aid through the Aboriginal and Torres Strait Islander Legal Services because they came to the attention of the services program faster. Thus occupying them with the offenders and not the victim.
Ms Williams reiterates the breakdown saying, "The experience of the legal system for many Aboriginal and Torres Strait Islander women has been a negative, confusing and disempowering one."
She continues that it is vital that Aboriginal and Torres Strait Islander women not only know their rights, but also that they have access to culturally safe, trauma informed services that provide ongoing holistic support.
Parker reiterates the need for Indigenous women to get involved in creating such services. However, according to her, that still seems a long way away, saying "It's only when our backs are to the wall, truly to the wall, that you start to see the kernels of the society that we could become."
Follow Andrew on Twitter: @andreasbooth


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The former CEO of Motorola, Rick Osterloh, is coming to lead Google’s new hardware division, per our confirmation with a Google spokesperson and re/code’s report. It’s the first time Google has unified all of its product lines under one roof, with one leader to boot.
Osterloh’s new responsibilities will include oversight of the Nexus program, Chromecast, the Pixel line, OnHub routers, ATAP (the experimental lab responsible for Project Ara) and finally, Google Glass.
The previously noted divisions now report to Osterloh, who left his head position at Lenovo-owned Motorola last month, and will operate together as Google’s united hardware front.
From an industry perspective, it makes sense to have all of Google hardware offerings under one set of watchful eyes. The move makes it more straightforward to deal with partners, and simplifies the organization overall.

domain: news


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No one ever really knows what happens in anyone's house but her own.
A handful of my friends, some who've been together for decades, some for far less time but with seemingly no less depth of commitment, are splitting up. Gay and straight. Married or simply cohabiting. Some of them the kind of couple -- you know the type -- that cause a sharp intake of breath and the Really? They're splitting? Jeeeez response from those of us who'd like to think there are a few models out there, a few folks we can point to and say: Wow, those people found life partners. They're making it work.
It makes us feel better about ourselves when we see such couples. Like there's less reason to worry about our own lives, because someone, for God's sake, got it right. Like there's a reason to think, despite growing up with that crazy divorce rate hanging over our heads and dozens of adultery scandals and endless heartbreak, that there's a Right Way To Do It. "It" being long-term commitment. Marriage, if that's your bag. Babies and rings. Life markers. Holding hands like that annoying old couple in the diamond commercials who step aside for the fast-moving younger couple -- who are also going to stay together that long.
But if there is any take-away from the latest string of high-profile divorce and separation news -- most recently, the depressing example that Karenna Gore Schiff
and husband Drew Schiff have been taking a break for the last few months, and the elder Gores, who are also separating, have been helping Karenna out with the kids while the couple seek counseling and debate Next Steps -- it's that it's impossible to know what's happening in another person's home. But they seemed so storybook perfect
doesn't mean much.
In the case of the younger generation Gore family, they had managed to avoid the klieg lights. But, perhaps because Al and Tipper are pulling apart as well, the news was released. It all just seems sad, rather than prurient. This was the same Karenna who married, worked on her father's presidential campaign, finished law school and gave birth, seemingly all in one breath. As one friend told U.S. News & World Report that year
, "I sometimes look at Karenna as this über-woman." Except she wasn't.
There's much less schadenfreude than often accompanies such announcements.
For that, see also that Shania Twain
this week finalized her divorce from Robert "Mutt" Lange (rumored cause of the breakup: his infidelity with her former best friend and assistant) and the disturbing made-for-TV drama of Heidi Montag and Spencer Pratt
(who seemed to split up to prep for a reality show about their splitting up).
Do you care? Thought not. (Well, maybe Shania Twain makes you feel kind of sad.) But it seems almost awful to group these couples into one category. News of celebrities breaking up -- other than Sandra Bullock -- somehow doesn't have the resonance of it happening in a family like the Gores, genuine do-gooders (who called themselves the Griswolds, f
or God's sake), who never seemed to lord it over us that they were so young and beautiful and blond. (Okay, when the Gore girls were young and Chelsea was in her mocked-on-"SNL"
phase, that wasn't the best moment for them. But they were teenagers then.)
But after a brief star turn during her father's run for president in 2000, Karenna stepped off the national stage. She's a Columbia-trained lawyer and was working on a documentary, but she's also got three young kids and for the most part is just "being a mom," as one of her friends said. Not the best phase of life to lose your partner, in any capacity.
As much as my generation grew up suspicious of marriage, skeptical of fairy tale romance and storybook endings, we were also told that we should not, by any means, settle -- the underlying message being that there is someone out there for us, someone "right." That we should find a partner who "completes" us. A soul mate, as Stanford law professor Ralph Richard Banks
wrote in the New York Times this week. All of which meant, ostensibly, that we wouldn't shack up until we'd figured it all out.
Pretty much as a nation, we wanted to think that the Gores, older and younger, hadn't settled. That they'd found love either in high school (Al and Tipper) or later (Karenna and Drew). The Gore kids seemed almost Kennedy-esque, Karenna marrying in the National Cathedral (in a Vera Wang dress later highlighted in a book about weddings), the same spot her parents had wed 27 years earlier.
With Al and Tipper, Rebecca Traister
pointed out on Salon last week, the universal response was "You get through forty years -- of ill-behaved children and ill-behaved bosses and stolen elections -- and then you split? This is precisely the kind of mysterious and inexplicable narrative of marriage thing that scares the bejesus out of people who are newly or not yet married. Forty years?"
But as my friend Michelle Cottle points out in the New Republic
, regarding los padres, "It is disappointing, of course, that the Gores didn't turn out to be the till-death-do-us-part romance that we, from the looks of the public response, so desperately needed them to be. (Perhaps no one craves marital idols more than we who spend our days watching self-important pols chase tail and discard wives like used Kleenex.) But still I can't bring myself to join in the chorus of Why now, after everything?
Al and Tipper are clearly thinking not in terms of the years behind but the years ahead. For them, there is still a whole lot of 'everything' to come. It may not be the fairy tale, but it is a classically American tale, with its themes of hope and promise and new beginnings."
And maybe they weren't all that happy. Maybe Karenna didn't want to wait until she was 61 to find a better path.
Time to turn back to our own houses and clean up our own messes.


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AISI 304 Grade Stainless Steel. AISI 304 stainless steel is the most commonly used material in stainless steels, and is usually purchased in an annealed or cold worked state. Because SS 304 contains 18% chromium (Cr) and 8% nickel (Ni), it is also known as 18/8 stainless steel.
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A blast of cold is going to hit Michigan this week. The cold won't be like anything already experienced this winter. This cold will be more severe, last longer and focus heavy lake effect in a different area.
Most of the heavy lake effect this winter has come on a northwest wind. The lake effect this week will be brought by a more northerly wind. So the lake effect will fall closer to the Lake Michigan shoreline. The heaviest snow will likely fall in the far southwest corner of Lower Michigan from St. Joseph to Michigan City, IN and South Bend, IN. Also heavy lake effect should fall from Traverse City, Leelanau County and southward to just west of Cadillac.
The heaviest areas of lake effect snow should easily have 6" of snow, with spots getting up to a foot of snow.
Travel Tip: If you have to drive to Chicago, taking I-80/I-90 will probably have a shorter stretch of heavy snow than I-94.
Of course with this kind of cold, the Upper Peninsula snow belts will have plenty of snow.
The rest of Michigan will have only 1" to 3" of total snow this week. The farther south and east, the lighter the snow will be.
No area will escape the deep cold. This cold snap won't be like the other cold snaps this winter that only lasted a few days. This cold snap will start Tuesday and gradually get colder each day into next weekend.
By the time temperatures bottom out this weekend, we'll freeze with highs in the teens and low temperatures in the single digits above or below zero.
The wind will push wind chill temperatures down to -10deg to -20deg at times in the second half of the week.
For those of you hoping this cold doesn't last into March, the eight to 14 day forecast calls for a warmup.
I will say one thing. For the health of Michigan's fruit crop, staying cold into March would be the best weather. If we get warm too early, fruit blossoms too early and likely would get frozen.
If you have any weather questions, please ask below.
MLive Chief Meteorologist Mark Torregrossa has been forecasting Michigan weather for more than 25 years. He's been chief meteorologist at three television news stations in Michigan, and he's an avid gardener and hunter. Email him at email@example.com and find him on Facebook at facebook.com/mark.torregrossa and Twitter @weathermanmark


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A new study found that online dating websites make people have a higher standard when shopping for a lifetime partener. The study being published in the February issue of Psychological Science in the Public Interest finds out the truth in the billion dollar industry of online dating. Reseachers analyzed more than 400 studies done about online dating.
Those online dating services offer a matchmaking algorithm to help you find your lifetime partner. In the study, they say those scientific algorithms aren’t any more acurate than meeting a stranger. Study author Dr. Eli Finkel, associate professor of social psychology at Northwestern University wrote, “To date, there is no compelling evidence that any online dating matching algorithm actually works. If dating sites want to claim that their matching algorithm is scientifically valid, they need to adhere to the standards of science, which is something they have uniformly failed to do. In fact, our report concludes that it is unlikely that their algorithms can work, even in principle, given the limitations of the sorts of matching procedures that these sites use.”
While online dating sites have become the second form of matchmaking in the United States next to meeting someone through a mutual friend. In a study, scientists found that in April 2011, there were almost 25 million users on the online dating sites. Study co-author Harry Reis, professor of psychology at the university, said in a written statement, “Online dating is definitely a new and much needed twist on relationships. Studies in behavioral economics show that the dating market in Western society is grossly inefficient, particularly once people leave high school or college. The Internet holds great promise for helping adults form healthy and supportive romantic partnerships, and those relationships are one of the best predictors of emotional and physical health.”
Men and women behave differently on the sites for dating. A 2010 study of 6,485 users of a major online dating site found that men viewed three times more profiles than women did (597,169 to 196,363). Men were approximately 40 percent more likely to initiate contact with a woman after viewing her profile than women were after viewing a man’s profile (12.5 to 9 percent).
Online dating sites can also lead people to disappointment. Having so many profiles to sift through and “shop” for a mate leads to people feeling overwhelmed and less satisfied. In the study scientists compare this to an experiment done with chocolate. “No studies in the romantic domain have examined satisfaction with choices after selecting from larger versus small choice sets of potential partners, but research outside the romantic domain suggests that people are likely to be less satisfied when choosing from a larger choice set. For example, people who selected a chocolate from an array of 6 chocolates thought the chocolate tasted significantly better than did participants who selected their chocolate from an array of 30, and they chose to be compensated for their research participation in chocolate rather than in cash four times more frequently (48% vs. 12%; Iyengar & Lepper, 2000). Analogously, online daters choosing from relatively large (vs. small) choice sets may be less satisfied with the potential partners they select from those choice set.”
Photo Credit: rochester.edu


354 Franklin Avenue
4 stories 55 feet
Scarano & Associates Architects
Dev-Kanovsky Donny Partner
6 units 8,579 Sq. Ft
The intersection of two streets provides a pale context for this modernist icon. In an area that is home to a mix of residential and industrial buildings, the development seeks to provide a striking composition with austere and elegant design. The large expanses of glass are framed by a ribbon of stone that undulates around the main fa e like a snake through a garden. This stone feature provides both relief and tension as it moves up and around the facade.
With only six units the development is small but every unit is packed with amenities which include individual parking garages, cellar storage spaces and recreation rooms, outdoor terraces and balconies, and multi-height living and sleeping areas. The second and third floor apartments have mezzanine spaces which create an additional multipurpose space for the owner. Direct access to rooftop gardens for the third floor apartments provide a triplex feel to the units, while the second floor has direct access to both the first and cellar levels and outdoor space.
In today's competitive real estate market interesting facade designs and dynamic interior spaces are a sure way to sell apartments at premium prices per square foot.


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India strike over petrol price increase announced
India's main opposition parties have announced a nationwide strike on 31 May to protest against a sharp increase in petrol prices.
State-run oil firms raised petrol prices by more than 11% or 7.54 rupees (13 cents) a litre, the steepest single increase in a decade.
The increase in fuel prices is likely to fuel inflation.
The oil firms said they were forced to increase prices because the falling rupee had made imports costlier.
On Thursday, the Indian currency fell to 56.4 rupees against the US dollar, from 55.82 on Wednesday. The slide comes amid concerns that slowing growth and a high rate of inflation may hurt India's economy.
"The decision has been taken, petrol is a deregulated commodity," Finance Minister Pranab Mukherjee was quoted as saying by the NDTV news channel before the increase in prices took place at midnight on Wednesday.
A spokesman for the main opposition National Democratic Alliance (NDA), led by the Bharatiya Janata Party (BJP), said it was talking to other parties to garner support for the strike.
"The government has washed its hands clean on price hike, but in reality, it happens only when the government wants it to happen. The government will also increase prices of diesel and cooking gas after the presidential elections get over," Sharad Yadav said.
BJP spokesman Prakash Javadekar said the price increase should be rolled back.
"We condemn the price hike. We won't allow it. A strong democratic agitation is on the cards," he said.
Mamata Banerjee, leader of the Trinamul Congress, an ally of the Congress-led government, said the price increase would be an "additional burden on people who are anyway reeling under price hikes".
"We are not pulling out of the government but that does not foreclose our options of protesting against such a hike, or the manner in which it is being brought about - in a unilateral manner," she said.
In 2010, the government allowed state-run oil firms to fix the price of petrol but it continues to control the prices of diesel, kerosene and cooking gas to protect the poor and to keep a check on inflation.


Wonder Woman has no FearMarch 8, 2021
“We do this together.”
Woman Woman revisits her ancient homeland, Themyscira, perhaps mournfully reflecting on the past. We don’t yet know what happens to the Amazons in the #SnyderCut, but based on Wonder Woman’s appearance, and Steppenwolf’s quote, “I watched your island burn,” it’s safe to assume it’s not good.
“You said the age of heroes would never come again.”
— Zack Snyder's Justice League (@snydercut) March 8, 2021


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What challenges exist in a sick child's upbringing
Especially difficult is necessary in this lifeparents of sick children. Besides the usual concerns associated with the development and upbringing of a child, they have a responsibility to care for a sick baby. At the same time, special attention and care require children suffering from serious diseases such as cerebral palsy, anemia, cancer, epilepsy or other.
Some of the parents, exhausted everyday,endless work and constant fatigue concerns about the education of a sick child, experiencing feelings of guilt, anger and bitterness. And sometimes, unfortunately, we vent them on our children. Naturally, this adversely affects our relations with them during their education and increases the barrier of misunderstanding between us and the children.
In such difficult situations, we would recommend that parents turn to a psychologist in order to defuse conflict and to help develop a more robust position in relation to the child and his illness.
Sick children often develop more slowly thana normal healthy child, and therefore need special methods of education and training. They also need special and psychological support of parents and teachers, which helped to create a positive attitude toward their future life.
Sometimes adults, too protecting their children,applied to them thus more harm than benefit, since it limits the possibility of the child poznavatokruzhayuschy world and narrow the boundaries of his social intercourse. If the patient also observed and any irregularities in the development, it is very alarming and protecting the behavior of his parents can these problems even develop child.
Even with such a widespread disease as aasthma varies considerably throughout the normal life of the family. Nobody is able to predict the onset of the next attack, and this leads to the fact that the whole family is in a state of constant expectation, tension and fear.
It limits the ability of the child's diseaseparents in work, career development, as well as personal and intimate life. Mother of sick child said that she was forced to take care of him for 5 years and all these years not to work because of the frequent attacks of asthma in the child.
Sick child in their behavior can bevery stubborn, whiny, demanding, closed and secretive. Mothers of these children often complain of chronic fatigue, pain in the head, sleep problems and lack of appetite.
Children themselves while so get used to the increased attention that sometimes even pretend painful condition.
Currently, a number of studies foundthat, with the same source data in a variety of cases, the disease is largely dependent on the psychological climate in the family and the more mutual assistance and support between the family and to the patient, the less symptoms of the disease and the more successful his upbringing and subsequent development. Therefore, along with the patient's recommended treatment medikomentoznym sessions with a psychologist for the whole family.

domain: medical


Triumph has announced that two all-new models featuring a single-cylinder, 4-valve, liquid-cooled engine will join the company’s Modern Classics lineup for 2024. The 2024 Triumph Speed 400 joins the larger Speed Twin 900 and Speed Twin 1200, while the 2024 Triumph Scrambler 400 X takes its design cues from the Scrambler 900 and Scrambler 1200, with an off-road pedigree that goes back to the first factory scramblers of the 1950s.
Triumph says the new bikes are designed to deliver a “fun, agile, and confidence-inspiring ride for riders of all ages and experience levels.”
James Wood, Triumph’s global product marketing manager, said when unveiling the Speed 400 and Scrambler 400 X that the company’s ambition with creating the small-bore bikes was to give a “whole new generation of riders the opportunity to own a Triumph.”
“This means that the brief we stepped out to deliver on was all about creating a new 400cc capacity choice for our iconic Speed and Scrambler lineups,” he said. “These would, of course, need to be genuine Triumphs but even more accessible.”
The New TR-Series Engine
The new TR-Series engine is a fuel-injected, liquid-cooled 398cc single-cylinder engine making a claimed 39.5 hp at 8,000 rpm and 27.7 lb-ft of torque at 6,500 rpm and mated to a 6-speed gearbox, a slip/assist clutch, and chain final drive.
Wood said the “TR-Series” name was chosen to celebrate Triumph racing singles of the early 20th century: “Six Day Trial-winning machines that went on to inspire the TR-trophy racing bloodline of Singles and Twins that followed.”
Technical highlights include a 4-valve, DOHC cylinder head and a crankshaft that has been weighted and balanced to optimize inertia for low-speed rideability, as well as a finger-follower valvetrain with a low reciprocating mass and DLC coatings that reduce friction.
Triumph says the new engine delivers “responsive, fun, and characterful power delivery along with an evocative, rich, and distinctive exhaust note.”
2024 Triumph Speed 400 and Scrambler 400 X
Wood said a key part of the company’s planning with the new range was to “really understand what riders want and value in this world.”
“What riders have told us is that style matters a great deal to them, thereby it must be beautiful, but it also must be authentic,” he said. “They want something that’s very easy to maneuver, with a height that they feel comfortable on and in control of, and to have a ride that is unintimidating and fun but that also comes with a responsive, usable plan for power delivery, plus a great sound. On top of all that, they demand a very high level of quality and reliability, preferably from a brand with credibility and desirability, and of course, all for a price that represents genuine value for money.”
Beyond the new TR-Series engine, the Speed 400 and Scrambler 400 X share some of the latest rider-focused technology tailored to suit each model, including throttle-by-wire, switchable traction control, and Bosch dual-channel ABS, which can be deactivated on the Scrambler 400 X when riding off-road.
Dual format instruments feature a large analog speedometer and an integrated LCD screen that includes a digital tachometer, fuel range remaining, and a gear indicator. The display is also pre-enabled to show the status of accessory heated grips, if fitted, and there is a USB-C charging port.
Both the Triumph Speed 400 and Scrambler 400 X benefit from a slim standover with an accessible seat height of 31 inches on the Speed 400 and 32.9 inches on the Scrambler 400 X and low weights of 375 lb and 395 lb, respectively. Both models also have their own model-specific chassis, with a new frame, bolt-on rear subframe, and cast-aluminum swingarm paired with suspension set-ups tailored to each use.
The Speed 400 features a 43mm inverted fork offering 5.5 inches of travel, a monoshock rear suspension unit giving 5.1 inches of travel, lightweight 17-inch wheels, and roadster-specific geometry and wheelbase, all of which Triumph says offer “an engaging and intuitive ride along with a comfortable, neutral riding position that inspires confidence for riders of all sizes and skill levels.” Stopping power comes from a 4-piston radial front brake caliper with a 300mm front disc and braided lines and a floating caliper and 230mm disc in the rear.
The Scrambler 400 X features a longer wheelbase than the Speed 400 (55.8 inches vs. 54.2 inches), longer travel suspension (5.9 inches front and rear), and a larger 320mm front brake disc. A larger 19-inch front wheel and a wide handlebar provide greater stability and control when riding on loose surfaces. It also has a more upright riding position, and the larger cast steel brake pedal and high-grip footpegs are positioned lower and wider for a more natural standing riding position when riding off-road.
Triumph Design DNA with Contemporary Poise
Stuart Wood, Triumph’s chief engineer, said at the unveiling that it was more than just the specifications. “We’ve put our heart and soul into setting these bikes up to give you all the character and performance you expect from us,” he said. “So they’re really fun bikes, really great response, a little bit more power than the others as well. They really are fun to ride.”
However, Triumph says that both bikes are still “instantly recognizable.” Traditional touches, like the distinctive finned cylinder head and traditional exhaust header clamps, combine with contemporary details like the upswept silencer, graphics, and “sensitively incorporated technology,” such as concealed liquid-cooling and a flowing exhaust with a hidden primary silencer. They also feature the trademark black powder-coated engine casings, tough gold anodized forks, and high-quality paint and logo detailing.
The Scrambler 400 X’s all-road attitude is accentuated by protection for the headlight, radiator, and sump, as well as handguards, a handlebar brace with pad, and a longer front fender.
The 2024 Triumph Speed 400 will be offered with three two-tone paint schemes – Carnival Red, Caspian Blue, and Phantom Black – each featuring a prominent Triumph tank graphic.
The Scrambler 400 X is also available in three color schemes, each featuring Triumph’s distinctive Scrambler tank stripe and triangle badge: Matte Khaki Green and Fusion White, Carnival Red and Phantom Black, and Phantom Black and Silver Ice options.
James Wood said the bikes are the result of a “major five-year collaboration” with Bajaj Auto in India.
“Based on Triumph’s concept and design, Bajaj has worked hand-in-hand with our engineering team here in Italy to add that expertise in large-scale efficient and cost-effective manufacturing to our leading engineering and design capabilities.”
Wood added that the bikes will be built by Triumph factories in Thailand and Brazil, as well as Bajaj Auto in India, where both models will launch starting in July 2023. They will be on sale in all other markets in early 2024.
The 2024 Triumph Speed 400 will be priced at $4,995 for all colors, and the 2024 Triumph Scrambler 400 X will be priced at $5,595 for all colors.
For more information, visit the Triumph website.


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Initially, Orthokeratology attracted the interest of adults who wanted to enter certain careers such as pilots, police officers and the military. Many adults simply want to be able to see more clearly, both for distance and for near. Some people want to be able to see unencumbered by eyeglasses or daytime contact lenses. Soft lenses can feel dry after several hours of wear, particularly for individuals that spend considerable time on computer.
Ortho-K is particularly appealing for people who work in dusty, dirty environments that can make contact lens wear difficult. Others want to be able to play sports such as skiing, tennis or baseball without having to wear eyeglasses. Many people don’t want to take the risks associated with LASIK or are not good candidates for LASIK because their corneas are thin or they have large pupils.
Ortho-K has the advantage that it can be discontinued at any time without permanent change to the eye. If modifications are needed to enable clearer reading, that is possible too. People of any age can benefit from the procedure, as long as their eyes are healthy.
Some Advantages to Orthokeratology over Contact Lenses or Glasses
- Wearing Sunglasses is easy, and your eyes aren’t extra sensitive from lenses.
- Athletes see clearly whether on the field, on the court, or even in the pool.
- Driving for Long Distances can be difficult with eyeglasses or contact lenses, especially when faced with dry eyes. OrthoK makes it safer.
- Healthy & Comfortable Eyes – Your eyes will get the right amount of oxygen during the day without any interference from eyewear like contact lenses.
Multifocal Orthokeratology is another advance in Ortho-K treatment. Beginning at about 40, people find they can see at distance through their eyeglasses or contact lenses, but have difficulty at near, for example reading or working on computer. Most eye doctors in East Brunswick, NJ will then recommend a bifocal or progressive eyeglass lens. Multifocal Ortho-K enables people to wear special lenses at night while sleeping, and they are then able to see clearly at both distance (i.e. driving) and near(i.e. reading), without the risks associated with LASIK.
OrthoK is safe and FDA approved for both adults and children.
For more information on Orthokeratology, contact Dr. Roth today for full details.


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| This article or section is a Stub about Lore. You can help AoCWiki out by expanding it.
The Mark of Acheron is a magic seal, born of the evil kingdom of Acheron. The cursed mark is employed with use of an ancient ritual, infesting the flesh of mortal men with hell-bound Acheronian souls. It is rare for those who carry the mark to have shed the evil they unwittingly carried, but it is rumoured an artifact known as the The Phoenix Medallion exists which can repel the Acheronian magic. Should the mark's power be countered without use of the medallion, however, it is unlikely the bearer will ever regain memories of their former life.

domain: literature


Actress Ellen Page took to Twitter this weekend to address a message she received from an anti-gay pastor regarding her sexuality.
Ellen Page was nominated for an Oscar for her work in Juno (2007). Pic/Getty Images
Though the alleged message itself isn't available, Page tweeted out her hilarious response to the pastor to her almost 900k followers on Saturday.
She posted, "2 da Pastor who wrote me-Being gay isn't a belief. My soul isnt struggling & I don't want arms of Heavenly Father around me. A girl's arms? Yes."
Page publicly came out of the closet in mid-February through an incredible and compelling speech at The Human Rights Campaign's Time To Thrive conference.
At the time, the actress told the crowd, "I'm here today because I am gay... and because maybe I can make a difference. To help others have an easier and more hopeful time."
This summer, the 27-year-old will reprise her role as the mutant Kitty Pryde in the upcoming installment of the popular X-Men franchise.
Photos: Varun, Taapsee, Jacqueline promote 'Judwaa 2' on 'Dance Plus 3'
Photos: This is how Chitrangda Singh looks without make-up
Photos: Malaika Arora parties wearing see-through lace dress
When exes Ranveer Singh and Anushka Sharma met at GQ Awards 2017
Photos: Mira Rajput visits a clinic in Bandra


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It’s Tuesday again which means that PlayStation Plus subscribers will be able to download another free game. That game is Arc System Works’ BlazBlue Continuum Shift, a traditional 2D fighting title developed by the people behind the Guilty Gear series.
Additionally, PS Plus members can try Fuse and Sly Cooper: Thieves in Time for free. In terms of discounts, Hamilton’s Great Adventure is $2.50, Draw Slasher is $4.19 and Germinator is $5.99. The latter is also available as part of a bundle: the PS3 and PS Vita Germinator bundle costs $5.99.
Later today, when the PlayStation Store updates, we’ll have access to a bunch of new releases, PSN titles, bundles and discounts. As usual, I’ll be writing an article compiling some of the best titles on the digital distribution service, so look forward to that. I also hope PlayStation Plus members enjoy BlazBlue Continuum Shift.
Source: PlayStation Blog