Simple de Sitter Solutions

We present a framework for de Sitter model building in type IIA string theory, illustrated with specific examples. We find metastable dS minima of the potential for moduli obtained from a compactification on a product of two Nil three-manifolds (which have negative scalar curvature) combined with orientifolds, branes, fractional Chern-Simons forms, and fluxes. As a discrete quantum number is taken large, the curvature, field strengths, inverse volume, and four dimensional string coupling become parametrically small, and the de Sitter Hubble scale can be tuned parametrically smaller than the scales of the moduli, KK, and winding mode masses. A subtle point in the construction is that although the curvature remains consistently weak, the circle fibers of the nilmanifolds become very small in this limit (though this is avoided in illustrative solutions at modest values of the parameters). In the simplest version of the construction, the heaviest moduli masses are parametrically of the same order as the lightest KK and winding masses. However, we provide a method for separating these marginally overlapping scales, and more generally the underlying supersymmetry of the model protects against large corrections to the low-energy moduli potential.Comment: 37 pages, harvmac big, 4 figures. v3: small correction

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

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

Gender Differences in Patients with Brugada Syndrome and Arrhythmic Events: Data from a Survey on Arrhythmic Events in 678 Patients.

BACKGROUND: There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs). OBJECTIVES: To compare clinical, electrocardiographic (ECG), electrophysiologic (EP) and genetic characteristics between males and females in BrS-patients with their first AE. METHODS: The multicenter Survey on AE in BrS (SABRUS) collected data on first AE in 678 BrS-patients including 619 (91.3%) males and 59 (8.7%) females aged 0.27 to 84 (mean 42.5±14.1) years at the time of AE. RESULTS: After excluding pediatric patients, females were older than males (49.5±14.4 vs. 43±12.7 years, respectively, P=0.001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, male/female ratio of AE was ≈9-fold higher compared to Caucasians. Spontaneous type 1 BrS-ECG was associated with earlier onset of AE in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS-ECG was present in males and females above age of 60 years. Females less frequently showed a spontaneous type-1 BrS-ECG (31% vs. 59%, P<0.001) or arrhythmia-inducibility at EP study (34% vs. 64%, P<0.001). An SCN5A mutation was more frequently found in females (47.6% vs. 27.8% in males, P=0.007). CONCLUSIONS: This study confirms that female BrS-patients are much rarer, display less type 1 Brugada-ECG and exhibit lower inducibility rates than males. It shows for the first time that BrS females with AE have higher SCN5A mutation rates as well as the relationship between gender vs. age at onset of AE and ethnicity

Fever-related arrhythmic events in the multicenter Survey on Arrhythmic Events in Brugada Syndrome

BACKGROUND: The literature on fever related arrhythmic events (AE) in Brugada syndrome (BrS) is currently limited to few case reports and small series. OBJECTIVE: The current study aims to describe the characteristics of fever-related AE in a large cohort of BrS patients. METHODS: SABRUS is a multicenter study on 678 BrS patients with first AE documented at time of aborted cardiac arrest (ACA) (n=426) or after prophylactic ICD implantation (n=252). RESULTS: In 35(6%) of the 588 patients with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%) and proband (70%). Age at time of AE was 29±24 (range 0.3-76) years. Most patients (80%) presented with ACA and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope and spontaneous type 1 Brugada-ECG were noted in 17%, 40% and 66% of patients, respectively. VF was induced at EPS in 9/19(47%) patients. An SCN5A mutation was found in 14/28(50%) patients. The highest proportion of fever-related AE was observed in the pediatric population (age <16), with disproportionally higher event rate in the very young (0-5 years old) (65%). Males were involved in all age groups and females only in the pediatric and elderly groups. Fever-related AE affected 17 Caucasians aged<24 years, but no Asians aged <24 years. CONCLUSIONS: The risk of fever-related AE in BrS markedly varies according to age group, gender and ethnicity. Taking these factors into account could help the clinical management of BrS patients with fever

Time-to-first appropriate shock in patients implanted prophylactically with an implantable cardioverter-defibrillator: data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS).

Aims: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce. Methods and results: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P < 0.05), those with syncope (P = 0.001), and those with Class IIa indication for ICD (P = 0.001). A longer time was associated with a positive family history of sudden cardiac death (P < 0.05). Multivariate Cox regression revealed shorter time-to-ICD therapy in patients with syncope [odds ratio (OR) 1.65, P = 0.001]. In 193 patients (76.6%), therapy was delivered during the first 5 years. Factors associated with this time were syncope (OR 0.36, P = 0.001), spontaneous Type 1 Brugada electrocardiogram (ECG) (OR 0.5, P < 0.05), and Class IIa indication (OR 0.38, P < 0.01) as opposed to Class IIb (OR 2.41, P < 0.01). A near-significant trend for female gender was also noted (OR 0.13, P = 0.052). Two score models for prediction of <5 years to shock were built. Conclusion: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy

An International Multi-Center Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multi-center collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (JLNS2, N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc > 460ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 JLNS2 patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9 ± 38.6ms) compared to genotype positive family members (441.8 ± 30.9ms, p<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR]: 11.6, 95% confidence interval [CI]: 2.6-52.2; p=0.001). Event incidence did not differ significantly for JLNS2 patients relative to the overall heterozygous cohort (10.5% [2/19]; HR: 1.7, 95% CI: 0.3-10.8, p=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database (gnomAD), which is a human database of exome and genome sequencing data from now over 140,000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs. 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT-prolongation, however the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for JLNS2 patients

Chemokine receptor co-expression reveals aberrantly distributed T-H effector memory cells in GPA patients

Linear regression analysis for percentages of CD4 + TEM cells, TEM1, and TEM17 cells between r-GPA patients and HCs. (PDF 208 kb

Prevalence of optic disc haemorrhages in an elderly UK Caucasian population and possible association with reticular pseudodrusen—the Bridlington Eye Assessment Project (BEAP): a cross-sectional study (2002–2006)

Aims: To determine disc haemorrhages (DH) prevalence in an elderly UK population-the Bridlington Eye Assessment Project (BEAP).Methods: Thirty-degree (30°) fundus photographs (3549 participants ≥65 years) were graded for DH/macula changes. Glaucoma evaluation included Goldmann tonometry, 26-point suprathreshold visual-fields and mydriatic slit-lamp assessment for glaucomatous optic neuropathy.Results: 3548 participants with photographs in at least one eye. DH were present in 53 subjects (1.49%), increasing from 1.17% (65-69-year age-group) to 2.19% (80-84-year age53 group), p=0.06. DH was found in 9/96 (9.38%) right eyes (RE) with open angle glaucoma (OAG). Two of twelve RE (16.67%) with normal tension glaucoma (NTG) had DH. Prevalence in eyes without glaucoma was lower (32/3452, [0.93%]). Reticular pseudodrusen (RPD) occurred in 170/3212 (5.29%) subjects without DH, and 8/131 subjects (6.11%) with OAG. Twenty (20) eyes had normal tension glaucoma (NTG), 2 of whom had RPD (10%) (p=0.264). Within a logistic regression model, DH was associated with glaucoma (OR 10.2, 95% CI 5.32 - 19.72) and increasing age (OR 1.05, 95% CI 1.00-1.10, p=0.03). DH was associated with RPD (p=0.05) with univariate analysis but this was not statistically significant in the final adjusted model. There was no significant association with gender, diabetes mellitus (DM), hypertension treatment or AMD grade.Conclusion: DH prevalence is 1.5% in those over 65 years old and significantly associated with glaucoma and increasing age. There appears to be increased RPD prevalence in eyes with DH and NTG with age acting as a confounding factor. Larger studies are required to fully assess the relationship and investigate a possible shared aetiology of choroidal ischaemia

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac