Anomalous Dimensions and Non-Gaussianity

We analyze the signatures of inflationary models that are coupled to strongly interacting field theories, a basic class of multifield models also motivated by their role in providing dynamically small scales. Near the squeezed limit of the bispectrum, we find a simple scaling behavior determined by operator dimensions, which are constrained by the appropriate unitarity bounds. Specifically, we analyze two simple and calculable classes of examples: conformal field theories (CFTs), and large-N CFTs deformed by relevant time-dependent double-trace operators. Together these two classes of examples exhibit a wide range of scalings and shapes of the bispectrum, including nearly equilateral, orthogonal and local non-Gaussianity in different regimes. Along the way, we compare and contrast the shape and amplitude with previous results on weakly coupled fields coupled to inflation. This signature provides a precision test for strongly coupled sectors coupled to inflation via irrelevant operators suppressed by a high mass scale up to 1000 times the inflationary Hubble scale.Comment: 40 pages, 10 figure

Effects and Detectability of Quasi-Single Field Inflation in the Large-Scale Structure and Cosmic Microwave Background

Quasi-single field inflation predicts a peculiar momentum dependence in the squeezed limit of the primordial bispectrum which smoothly interpolates between the local and equilateral models. This dependence is directly related to the mass of the isocurvatons in the theory which is determined by the supersymmetry. Therefore, in the event of detection of a non-zero primordial bispectrum, additional constraints on the parameter controlling the momentum-dependence in the squeezed limit becomes an important question. We explore the effects of these non-Gaussian initial conditions on large-scale structure and the cosmic microwave background, with particular attention to the galaxy power spectrum at large scales and scale-dependence corrections to galaxy bias. We determine the simultaneous constraints on the two parameters describing the QSF bispectrum that we can expect from upcoming large-scale structure and cosmic microwave background observations. We find that for relatively large values of the non-Gaussian amplitude parameters, but still well within current uncertainties, galaxy power spectrum measurements will be able to distinguish the QSF scenario from the predictions of the local model. A CMB likelihood analysis, as well as Fisher matrix analysis, shows that there is also a range of parameter values for which Planck data may be able distinguish between QSF models and the related local and equilateral shapes. Given the different observational weightings of the CMB and LSS results, degeneracies can be significantly reduced in a joint analysis.Comment: 27 pages, 14 figure

Transport equations for the inflationary trispectrum

We use transport techniques to calculate the trispectrum produced in multiple-field inflationary models with canonical kinetic terms. Our method allows the time evolution of the local trispectrum parameters, tauNL and gNL, to be tracked throughout the inflationary phase. We illustrate our approach using examples. We give a simplified method to calculate the superhorizon part of the relation between field fluctuations on spatially flat hypersurfaces and the curvature perturbation on uniform density slices, and obtain its third-order part for the first time. We clarify how the 'backwards' formalism of Yokoyama et al. relates to our analysis and other recent work. We supply explicit formulae which enable each inflationary observable to be computed in any canonical model of interest, using a suitable first-order ODE solver.Comment: 24 pages, plus references and appendix. v2: matches version published in JCAP; typo fixed in Eq. (54

Cardiac arrhythmias and conduction defects in systemic sclerosis

Signs and symptoms of arrhythmias or conduction defects are frequently reported in patients with SSc. These rhythm disorders may have several origins (i.e. related to primary heart involvement, pericardial disease, valvular regurgitation or pulmonary arterial hypertension) and may negatively affect the overall prognosis of these patients. It is therefore important to identify patients at high risk for cardiac arrhythmias with a complete cardiological evaluation and to identify the underlying heart disease, including SSc-related myocardial involvement. In addition, some therapeutic options in SSc patients may differ from those recommended in other population

S.8.1 An immunochip-based interrogation of scleroderma susceptibility variants

Introduction. Understanding the genetic architecture of scleroderma (SSc) susceptibility is vital both in gene discovery and in determining the influence of previously identified susceptibility variants. It is particularly important in understanding disease mechanism in a disease with few therapies and great morbidity and mortality. Methods. We selected 557 cases from the Australian Scleroderma Cohort Study (ASCS), for genotyping with the Immunochip, a custom Illumina Infinium genotyping array containing 196 524 rare and common variants shown to be important in a wide variety of autoimmune disorders. A total of 4537 controls were taken from the 1958 British Birth cohort. Genotype data were analysed with PLINK. Samples and SNPs with low call rates were excluded, as were SNPs in Hardy-Weinberg disequilibrium or with less than two occurrences of the minor allele. Eigenstrat was used to analyse population structure. The final data set consisted of 505 cases, 4491 controls and 146 867 SNPs. Allelic association analyses were conducted using Fisher's exact test. Genotype clusters were manually examined for all associations of P < 10−5 since calling is difficult for some rare variants. Results. Significant and suggestive associations were detected at seven loci. Several of these have been previously implicated in scleroderma susceptibility (HLA-DRB1 and STAT4) and several are novel associations, including SNPs near PXK (P = 4.4 × 10−6) and CFDP1(P = 2.6 × 10−6). The strongest associations were with SNPs in the Class II region of the MHC. One of the most strongly associated SNPs [rs4639334; P = 1.6 × 10−8; odds ratio (OR) = 1.8] is in linkage disequilibrium (r2 = 0.46) with the Class II allele HLA-DRB1*11:01. This allele has been associated with SSc. Another strongly associated SNP is rs2857130 (P = 1.6 × 10−8; OR = 0.67), which lies in the promoter region of HLA-DRB1, but is not in LD with any classical MHC alleles. Outside the MHC, there were six regions of association with P < 10−5,including the confirmed SSc locus at STAT4. Several SNPs implicate a locus at PXK, which has been previously associated with SLE but not with SSc. The remaining associations are novel for both SSc and SLE and require replication. Of particular interest is a rare variant located within a non-coding RNA on chromosome 6q21 which was ∼20 times more frequent in cases than controls. We are currently dissecting the potential biological implications of this locus. Conclusions. This pilot study has confirmed previously reported SSc associations, revealed further genetic overlap between SSc and SLE, and identified putative novel SSc susceptibility loci including a rare allele with major effect siz

Constraining the WMAP9 bispectrum and trispectrum with needlets

We develop a needlet approach to estimate the amplitude of general (including non-separable) bispectra and trispectra in the cosmic microwave background, and apply this to the WMAP 9-year data. We obtain estimates for the `orthogonal' bispectrum mode, yielding results which are consistent with the WMAP 7-year data. We do not observe the frequency-dependence suggested by the WMAP team's analysis of the 9-year data. We present 1-$\sigma$ constraints on the `local' trispectrum shape \gnl/10^5= -4.1\pm 2.3, the `$c1$' equilateral model \gnl^{c_1}/10^6= -0.8\pm 2.9, and the constant model \gnl^{\rm{const}}/10^6= -0.2\pm 1.8, together with a $95\%$ confidence-level upper bound on the multifield local parameter \taunl<22000. We estimate the bias on these parameters produced by point sources. The techniques developed in this paper should prove useful for other datasets such as Planck.Comment: 21 pages - matches published versio

The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34×10&lt;sup&gt;−8&lt;/sup&gt;, OR = 1.22, CI 95% = 1.14–1.30; rs2004640: P = 4.60×10&lt;sup&gt;−7&lt;/sup&gt;, OR = 0.84, CI 95% = 0.78–0.90; rs10488631: P = 7.53×10&lt;sup&gt;−20&lt;/sup&gt;, OR = 1.63, CI 95% = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04×10&lt;sup&gt;−22&lt;/sup&gt;, OR = 1.75, CI 95% = 1.56–1.97) better explained the observed association (likelihood P-value = 1.48×10&lt;sup&gt;−4&lt;/sup&gt;), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific

S.11.1 Influence of digital ulcer healing on disability and daily activity limitations in SSc

Objective. We previously showed that DU significantly increased global and hand disability with a significant impact on activities of daily living (ADLs) and work disability. This study aims to evaluate the impact of digital ulcer (DU) healing on disability and daily activity limitations in SSc. Methods. From January 2008 and June 2009, we prospectively evaluated 189 SSc patients for DU history, disability, employment and occupational status during meetings of the French SSc Patient Association (n = 86, 45.5%) or during hospitalization (n = 103, 54.5%)1. Among the 60 patients with at least one active DU at baseline (M0), 40 patients were followed longitudinally over 6 (3) months. These patients were evaluated for DU history, global and hand disability, health-related quality of life (HRQoL), daily activity limitation and employment status. Results. The median (IQR) age was 57.5 (43.5-68) years and the median (IQR) disease duration was 8.3 (3-16.5) years. Twenty-two (55%) patients had diffuse SSc and 34 (85%) were females. At baseline, a mean of 2.9 (2.8) DU per patient was reported. Thirty-three (82.5%) patients had ischaemic DU, 7 (17.5%) patients had >1 DU associated with calcinosis and 13 (32.5%) patients had mechanical DU. Thirteen (32.5%) patients had >4 DU at baseline. Among the 40 patients, 16 (40%) patients showed complete ulcer healing. In these patients with DU, the presence of calcinosis was associated with a lower probability of healing (P = 0.03). Comparison between healed and no-healed DU patients showed an improvement of hand disability provided by an improvement of the Cochin Hand Function score (P = 0.05)) and a trend towards HAQ domain dressing and grooming (P = 0.06) between M0 and M6 (3) visit in healed patients but not in no-healed patients. Concerning HRQoL, there were no difference for Mental and Physical component Scores of SF-36 but significant improvement of Bodily Pain score (P = 0.04) and Physical Role score (P = 0.05) between M0 and M6 (3) visit in patients with healed DU. The absence of healing was associated with significantly decreased work productivity (P = 0.05), whereas the performance in ADL was not significantly decreased (P = 0.15). Patients who were on sick-leave and who received some help for household tasks at the time of active DU were more likely to heal. Conclusion. For the first time, we provide prospective data with evidence that DU healing is associated with an improvement in hand function. Sick leave was associated with better healing of D

The Scleroderma Patient-centered Intervention Network (SPIN) Cohort : protocol for a cohort multiple randomised controlled trial (cmRCT) design to support trials of psychosocial and rehabilitation interventions in a rare disease context

Introduction: Psychosocial and rehabilitation interventions are increasingly used to attenuate disability and improve health-related quality of life (HRQL) in chronic diseases, but are typically not available for patients with rare diseases. Conducting rigorous, adequately powered trials of these interventions for patients with rare diseases is difficult. The Scleroderma Patient-centered Intervention Network (SPIN) is an international collaboration of patient organisations, clinicians and researchers. The aim of SPIN is to develop a research infrastructure to test accessible, low-cost self-guided online interventions to reduce disability and improve HRQL for people living with the rare disease systemic sclerosis (SSc or scleroderma). Once tested, effective interventions will be made accessible through patient organisations partnering with SPIN. Methods and analysis: SPIN will employ the cohort multiple randomised controlled trial (cmRCT) design, in which patients consent to participate in a cohort for ongoing data collection. The aim is to recruit 1500– 2000 patients from centres across the world within a period of 5 years (2013–2018). Eligible participants are persons ≥18 years of age with a diagnosis of SSc. In addition to baseline medical data, participants will complete patient-reported outcome measures every 3 months. Upon enrolment in the cohort, patients will consent to be contacted in the future to participate in intervention research and to allow their data to be used for comparison purposes for interventions tested with other cohort participants. Once nterventions are developed, patients from the cohort will be randomly selected and offered interventions as part of pragmatic RCTs. Outcomes from patients offered interventions will be compared with outcomes from trial-eligible patients who are not offered the interventions. Ethics and dissemination: The use of the cmRCT design, the development of self-guided online interventions and partnerships with patient organisations will allow SPIN to develop, rigourously test and effectively disseminate psychosocial and rehabilitation interventions for people with SSc.(undefined