Evidence of epistasis between Interleukin-1 and Selenoprotein-S with susceptibility to rheumatoid arthritis

Objective: Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently, promoter variants in the SELS gene were shown to be associated with plasma levels of interleukin (IL)6, IL1β and tumour necrosis factor (TNF). It was hypothesised that these variants could influence rheumatoid arthritis (RA) susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL1, IL6 and TNF. Methods: Genotyping was performed in 988 unrelated healthy controls and 965 patients with RA. Stratified analysis was used to test for interactions. Single gene effects and evidence of epistasis were investigated using the Mantel–Haenszel (M–H) test and the linkage disequilibrium (LD)-based statistic. Results: No association of SELS −105 genotype and RA susceptibility was detected. Stratification of SELS −105 genotypes by IL1 −511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS −105 locus) in individuals with the GG/AG genotype at the IL1β −511 locus was significantly lower than that in individuals having the AA genotype at the IL1β −511 locus (odds ratio (OR): 0.9 and 2.3, respectively; p = 0.004 by M–H test). Significant epistasis was also detected using the LD-based statistic (p = <0.001). No interaction was observed between SELS −105 and IL6 or TNF variants. Conclusion: Our results reveal evidence of strong epistasis in two genes in the IL1 production pathway and highlight the potential importance of gene–gene interactions in the pathogenesis of RA

Computing the symmetric ring of quotients

AbstractWe discuss and compute the symmetric Martindale ring of quotients for various classes of prime rings. In particular, we consider free algebras and group algebras

A Population-Based Study of the Risk of Diabetic Retinopathy in Patients With Type 1 Diabetes and Celiac Disease

Objective: Celiac disease (CD) is associated with type 1 diabetes (T1D). In the current study, we examined whether CD affects the risk of diabetic retinopathy (DRP) in patients with T1D. Research design and methods: This was a population-based cohort study. Through the Swedish National Patient Register, we identified 41,566 patients diagnosed with diabetes in 1964–2009 and who were ≤30 years of age at diagnosis. CD was defined as having villous atrophy (Marsh stage 3) according to small intestinal biopsies performed between 1969 and 2008, with biopsy reports obtained from Sweden’s 28 pathology departments. During follow-up, 947 T1D patients had a diagnosis of CD. We used Cox regression analysis with CD as a time-dependent covariate to estimate adjusted hazard ratios (aHRs) for DRP in patients with T1D and CD and compared them with patients with T1D but no CD. Results: Duration of CD correlated with the risk of DRP. When results were stratified by time since CD diagnosis, individuals with T1D and CD were at a lower risk of DRP in the first 5 years after CD diagnosis (aHR 0.57 [95% CI 0.36–0.91]), followed by a neutral risk in years 5 to <10 (1.03 [0.68–1.57]). With longer follow-up, coexisting CD was a risk factor for DRP (10 to <15 years of follow-up, aHR 2.83 [95% CI 1.95–4.11]; ≥15 years of follow-up, 3.01 [1.43–6.32]). Conclusions: Having a diagnosis of CD for >10 years is a risk factor for the development of DRP in T1D. Long-standing CD in patients with T1D merits intense monitoring of DRP

A rigorous evaluation of crossover and mutation in genetic programming

The role of crossover and mutation in Genetic Programming (GP) has been the subject of much debate since the emergence of the field. In this paper, we contribute new empirical evidence to this argument using a rigorous and principled experimental method applied to six problems common in the GP literature. The approach tunes the algorithm parameters to enable a fair and objective comparison of two different GP algorithms, the first using a combination of crossover and reproduction, and secondly using a combination of mutation and reproduction. We find that crossover does not significantly outperform mutation on most of the problems examined. In addition, we demonstrate that the use of a straightforward Design of Experiments methodology is effective at tuning GP algorithm parameters

Some extremal functions in Fourier analysis, III

We obtain the best approximation in $L^1(\R)$, by entire functions of exponential type, for a class of even functions that includes $e^{-\lambda|x|}$, where $\lambda >0$, $\log |x|$ and $|x|^{\alpha}$, where $-1 < \alpha < 1$. We also give periodic versions of these results where the approximating functions are trigonometric polynomials of bounded degree.Comment: 26 pages. Submitte

Which antidepressants have demonstrated superior efficacy? A review of the evidence

A review of published evidence of superior efficacy of a particular antidepressant in major depressive disorder may assist clinicians in making considered treatment choices. To identify such candidates, an international group of experts met to assess published evidence (identified through searches in Medline and Embase databases and discussions with experts in the field) from randomized, controlled trials and meta-analyses comparing two antidepressants under conditions of fair comparison. Criteria were defined to judge the strength of evidence. Two pivotal studies in moderate-to-severe major depressive disorder that demonstrate superiority on the primary efficacy measure, or alternatively one pivotal study supported by consistent results from meta-analyses, was considered to constitute evidence for definite superiority. Three antidepressants met these criteria: clomipramine, venlafaxine, and escitalopram. Three antidepressants were found to have probable superiority: milnacipran, duloxetine, and mirtazapine. Only escitalopram was found to have definite superiority in the treatment of severe depression; probable superiority was identified for venlafaxine and possible superiority for milnacipran and clomipramine. This review of published data found evidence that only a very few antidepressants are shown to be more effective than other

The problems with systematic reviews: a living systematic review

Objectives Systematic reviews and meta-analyses are proliferating as they are an important building block to inform evidence-based guidelines and decision-making. Enforcement of best practice in clinical trials is firmly on the research agenda of good clinical practice, but there is less clarity as to how evidence syntheses that combine these studies can be influenced by bad practice. Our aim was to conduct a living systematic review of articles that highlight flaws in published systematic reviews to formally document and understand these problems. Study Design and Setting We conducted a comprehensive assessment of all literature examining problems, which relate to published systematic reviews. Results The first iteration of our living systematic review (https://systematicreviewlution.com/) has found 485 articles documenting 67 discrete problems relating to the conduct and reporting of systematic reviews which can potentially jeopardize their reliability or validity. Conclusion Many hundreds of articles highlight that there are many flaws in the conduct, methods, and reporting of published systematic reviews, despite the existence and frequent application of guidelines. Considering the pivotal role that systematic reviews have in medical decision-making due to having apparently transparent, objective, and replicable processes, a failure to appreciate and regulate problems with these highly cited research designs is a threat to credible science

Demonstration of a novel technique to measure two-photon exchange effects in elastic e±pe^\pm p scattering

The discrepancy between proton electromagnetic form factors extracted using unpolarized and polarized scattering data is believed to be a consequence of two-photon exchange (TPE) effects. However, the calculations of TPE corrections have significant model dependence, and there is limited direct experimental evidence for such corrections. We present the results of a new experimental technique for making direct $e^\pm p$ comparisons, which has the potential to make precise measurements over a broad range in $Q^2$ and scattering angles. We use the Jefferson Lab electron beam and the Hall B photon tagger to generate a clean but untagged photon beam. The photon beam impinges on a converter foil to generate a mixed beam of electrons, positrons, and photons. A chicane is used to separate and recombine the electron and positron beams while the photon beam is stopped by a photon blocker. This provides a combined electron and positron beam, with energies from 0.5 to 3.2 GeV, which impinges on a liquid hydrogen target. The large acceptance CLAS detector is used to identify and reconstruct elastic scattering events, determining both the initial lepton energy and the sign of the scattered lepton. The data were collected in two days with a primary electron beam energy of only 3.3 GeV, limiting the data from this run to smaller values of $Q^2$ and scattering angle. Nonetheless, this measurement yields a data sample for $e^\pm p$ with statistics comparable to those of the best previous measurements. We have shown that we can cleanly identify elastic scattering events and correct for the difference in acceptance for electron and positron scattering. The final ratio of positron to electron scattering: $R=1.027\pm0.005\pm0.05$ for $=0.206$ GeV$^2$ and $0.830\leq \epsilon\leq 0.943$