Post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific survival: a nested case-control study in a breast cancer cohort from the UK Clinical Practice Research Datalink

INTRODUCTION: Recent observational studies indicate that post-diagnostic use of aspirin in breast cancer patients may protect against cancer progression perhaps by inhibiting cyclooxygenase-2 dependent mechanisms. Evidence also supports a crucial role for interactions between tumour cells and circulating platelets in cancer growth and dissemination, therefore, use of low-dose aspirin may reduce the risk of death from cancer in breast cancer patients.

METHODS: A cohort of newly diagnosed breast cancer patients (1998 to 2006) were identified in the UK Clinical Practice Research Datalink (and confirmed by cancer registry linkage). Cancer-specific deaths were identified up to 2011 from Office for National Statistics mortality data. A nested case-control analysis was conducted using conditional logistic regression to compare post-diagnostic aspirin exposure using General Practice prescription data in 1,435 cases (breast cancer deaths) with 5,697 controls (matched by age and year of diagnosis).

RESULTS: After breast cancer diagnosis, 18.3% of cancer-specific deaths and 18.5% of matched controls received at least one prescription for low-dose aspirin, corresponding to an odds ratio (OR) of 0.98 (95% CI 0.83, 1.15). Adjustment for potential confounders (including stage and grade) had little impact on this estimate. No dose response relationship was observed when the number of tablets was investigated and no associations were seen when analyses were stratified by receipt of prescriptions for aspirin in the pre-diagnostic period, by stage at diagnosis or by receipt of prescriptions for hormone therapy.

CONCLUSIONS: Overall, in this large population-based cohort of breast cancer patients, there was little evidence of an association between receipt of post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific death. However, information was not available on medication compliance or over-the-counter use of aspirin, which may have contributed to the null findings.

Electron-impact excitation of the astrophysically important singly ionized Fe-peak ions Sc and Ti

In this work we report on the evaluation of electron-impact collision strengths and Maxwellian averaged effective collision strengths for the lowly-ionized Fe-peak elements Sc II and Ti II using the parallel R-matrix package RMATRX II.

Observational Constraints on the Catastrophic Disruption Rate of Small Main Belt Asteroids

We have calculated 90% confidence limits on the steady-state rate of catastrophic disruptions of main belt asteroids in terms of the absolute magnitude at which one catastrophic disruption occurs per year  as a function of the post-disruption increase in brightness (Δm) and subsequent brightness decay rate (τ  ). The confidence limits were calculated using the brightest unknown main belt asteroid (V=18.5) detected with the Pan-STARRS1 (Pan-STARRS1) telescope. We measured the Pan-STARRS1’s catastrophic disruption detection efficiency over a 453-day interval using the Pan-STARRS moving object processing system (MOPS) and a simple model for the catastrophic disruption event’s photometric behavior in a small aperture centered on the catastrophic disruption event. We then calculated the  contours in the ranges from  and  encompassing measured values from known cratering and disruption events and our model’s predictions. Our simplistic catastrophic disruption model suggests that  and  which would imply that H_0≳28—strongly inconsistent withH_{0,B2005=23.26±0.02} predicted by Bottke et al. (Bottke, W.F., Durda, D.D., Nesvorný, D., Jedicke, R., Morbidelli, A., Vokrouhlický, D., Levison, H.F. [2005]. Icarus, 179, 63–94.) using purely collisional models. However, if we assume that H_0=H0,B2005 our results constrain , inconsistent with our simplistic impact-generated catastrophic disruption model. We postulate that the solution to the discrepancy is that >99% of main belt catastrophic disruptions in the size range to which this study was sensitive (∼100 m) are not impact-generated, but are instead due to fainter rotational breakups, of which the recent discoveries of disrupted asteroids P/2013 P5 and P/2013 R3 are probable examples. We estimate that current and upcoming asteroid surveys may discover up to 10 catastrophic disruptions/year brighter than V=18.5.

The EU Charter of Fundamental Rights in the case law of the European Court of Human Rights

The European Court of Human Rights has begun to refer to the EU Charter of Fundamental Rights in order to support its reasoning for interpreting the European Convention on Human Rights in a particular way. But the EU Charter does not yet have any special status in that regard, being treated by the Court as on a par with numerous other documents of international law. The Court’s use of the Charter began in connection with arts 8 and 12 of the Convention (the right to a family life and the right to marry) but in subsequent years it has been extended to many other Articles of the Convention. It is in relation to art.6 (the right to a fair trial) that the Charter’s influence has been most noticeable so far, the Court having changed its position on two important aspects of Article 6 partly because of the wording of the EU Charter. But the influence on art.3 (in relation to the rights of asylum seekers), art.7 (in relation to retroactive penal laws), art.9 (in relation to the right to conscientious objection) and art.11 (in relation to rights of trades unions) has also been significant. The potential for the Charter to have greater influence on the Court’s jurisprudence in years to come remains considerable.

A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD)

Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined P ADJ = 1.15 × 10(-6), OR 1.332 (1.187-1.496)]. This association was characterized by a highly significant sex difference (P diff = 0.0032) in that it was clearly confined to females with genome-wide significance [P ADJ = 2.62 × 10(-8), OR 1.541 (1.324-1.796); males: P ADJ = 0.382, OR 1.084 (0.905-1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMSaveD pathogenesis.

A new comparator account of auditory verbal hallucinations: how motor prediction can plausibly contribute to the sense of agency for inner speech

The comparator account holds that processes of motor prediction contribute to the sense of agency by attenuating incoming sensory information and that disruptions to this process contribute to misattributions of agency in schizophrenia. Over the last 25 years this simple and powerful model has gained widespread support not only as it relates to bodily actions but also as an account of misattributions of agency for inner speech, potentially explaining the etiology of auditory verbal hallucination (AVH). In this paper we provide a detailed analysis of the traditional comparator account for inner speech, pointing out serious problems with the specification of inner speech on which it is based and highlighting inconsistencies in the interpretation of the electrophysiological evidence commonly cited in its favor. In light of these analyses we propose a new comparator account of misattributed inner speech. The new account follows leading models of motor imagery in proposing that inner speech is not attenuated by motor prediction, but rather derived directly from it. We describe how failures of motor prediction would therefore directly affect the phenomenology of inner speech and trigger a mismatch in the comparison between motor prediction and motor intention, contributing to abnormal feelings of agency. We argue that the new account fits with the emerging phenomenological evidence that AVHs are both distinct from ordinary inner speech and heterogeneous. Finally, we explore the possibility that the new comparator account may extend to explain disruptions across a range of imagistic modalities, and outline avenues for future research.

Replication of the association of GLT6D1 with aggressive periodontitis in a Sudanese population

BACKGROUND: Susceptibility to aggressive periodontitis (AgP) is influenced by genetic as well as environmental factors. Studies linking gene variants to AgP have been mainly centred in developed countries with limited data from Africa.
AIM: To investigate whether previously reported candidate gene associations with AgP could be replicated in a population from Sudan.


METHODS: The investigation was a case-control design. Cases with AgP (n = 132) and controls (n = 136) were identified from patients attending the Periodontal Department in Khartoum Dental Hospital. Genotyping was performed using the Sequenom MassARRAY iPLEX platform. Analysis focused on gene variants with a minor allele frequency (MAF) > 25% in the Sudanese subjects that had previously been reported to be associated with AgP.


RESULTS: One candidate gene rs1537415 (GLT6D1) was significantly associated with AgP, OR = 1.50 (95% CI 1.04-2.17), p = 0.0295 (increasing to p = 0.09 after correction for multiple testing). The association strengthened to OR = 1.56 (95% CI 1.15-2.16), p = 0.0042 when the controls were supplemented with data from the Hap map for the Yoruba in Ibadan (n = 147) and remained significant (p = 0.013) after correction for multiple testing.


CONCLUSION: The study independently replicated the finding that rs1537415, a variant in glycosyl transferase gene GLT6D1, is associated with AgP and provided the first report of genetic associations with AgP in a Sudanese population.

Fluid balance, intradialytic hypotension, and outcomes in critically ill patients undergoing renal replacement therapy: a cohort study

Introduction: In this cohort study, we explored the relationship between fluid balance, intradialytic hypotension and outcomes in critically ill patients with acute kidney injury (AKI) who received renal replacement therapy (RRT).

Methods: We analysed prospectively collected registry data on patients older than 16 years who received RRT for at least two days in an intensive care unit at two university-affiliated hospitals. We used multivariable logistic regression to determine the relationship between mean daily fluid balance and intradialytic hypotension, both over seven days following RRT initiation, and the outcomes of hospital mortality and RRT dependence in survivors.

Results: In total, 492 patients were included (299 male (60.8%), mean (standard deviation (SD)) age 62.9 (16.3) years); 251 (51.0%) died in hospital. Independent risk factors for mortality were mean daily fluid balance (odds ratio (OR) 1.36 per 1000 mL positive (95% confidence interval (CI) 1.18 to 1.57), intradialytic hypotension (OR 1.14 per 10% increase in days with intradialytic hypotension (95% CI 1.06 to 1.23)), age (OR 1.15 per five-year increase (95% CI 1.07 to 1.25)), maximum sequential organ failure assessment score on days 1 to 7 (OR 1.21 (95% CI 1.13 to 1.29)), and Charlson comorbidity index (OR 1.28 (95% CI 1.14 to 1.44)); higher baseline creatinine (OR 0.98 per 10 mu mol/L (95% CI 0.97 to 0.996)) was associated with lower risk of death. Of 241 hospital survivors, 61 (25.3%) were RRT dependent at discharge. The only independent risk factor for RRT dependence was pre-existing heart failure (OR 3.13 (95% CI 1.46 to 6.74)). Neither mean daily fluid balance nor intradialytic hypotension was associated with RRT dependence in survivors. Associations between these exposures and mortality were similar in sensitivity analyses accounting for immortal time bias and dichotomising mean daily fluid balance as positive or negative. In the subgroup of patients with data on pre-RRT fluid balance, fluid overload at RRT initiation did not modify the association of mean daily fluid balance with mortality.

Conclusions: In this cohort of patients with AKI requiring RRT, a more positive mean daily fluid balance and intradialytic hypotension were associated with hospital mortality but not with RRT dependence at hospital discharge in survivors.

Lactobacilli possess inhibitory activity against dipeptidyl peptidase-4 (DPP-4)

Dipeptidyl peptidase 4 (DPP-4) enzymatically inactivates incretin hormones, and DPP-4 inhibitor drugs are clinically approved therapies for type 2 diabetes. The primary substrates of DPP-4 are produced in the intestinal lining and we therefore investigated whether lactobacilli colonizing the gut can inhibit this enzyme. Fifteen Lactobacillus strains (Lb 1-15) from human infant faecal samples were isolated, identified, extracted and screened for inhibitory activity against DPP-4. Activity was compared against Lactobacillus reference strains (Ref 1-7), a Gram positive control (Ctrl 1) and two Gram negative controls (Ctrl 2-3). A range of DPP-4 inhibitory activity was observed (10-32%; P<0.05-0.001). Strains of L. fabifermentans (25%), L. plantarum (12-24%) and L. fermentum (14%) had significant inhibitory activity. However, we also noted that E. coli (Ctrl 2) and S. Typhimurium (Ctrl 3) had the greatest inhibitory activity (30-32%). Contrastingly, some isolates (Lb 12-15) and reference cultures (Ref 1-4) instead of inhibiting DPP-4 actually enhanced it, perhaps indicating the presence of X-prolyl-dipeptidyl-amino-peptidase (PepX). This provides a future rationale for using probiotic bacteria or their components for management of type 2 diabetes via DPP-4 inhibition.

Energy levels and radiative rates for transitions in Ti X

We report calculations of energy levels, radiative rates, oscillator strengths and line strengths for transitions among the lowest 345 levels of Ti X. These include 146 levels of the n 3 configurations and 86 of 3s ²4ℓ, 3s²5ℓ and 3s3p4ℓ, plus some of the 3s²6ℓ, 3p²4ℓ and 3s3p5ℓ levels. The general-purpose relativistic atomic structure package and flexible atomic code are adopted for the calculations. Radiative rates, oscillator strengths and line strengths are provided for all electric dipole (E1), magnetic dipole (M1), electric quadrupole (E2) and magnetic quadrupole (M2) transitions among the 345 levels, although calculations have been performed for a much larger number of levels. Comparisons are made with existing results and the accuracy of the data is assessed. Additionally, lifetimes for all 345 levels are listed. Extensive comparisons of lifetimes are made for the lowest 40 levels, for which discrepancies with recent theoretical work are up to 30%. Discrepancies in lifetimes are even larger, up to a factor of four, for higher excited levels. Furthermore, the effect of large configuration interaction (CI) is found to be insignificant for both the energies and lifetimes for the lowest 40 levels of Ti X which belong to the 3s²3p, 3s3p², 3s²3d, 3p³ and 3s3p3d configurations. However, the contribution of CI is more appreciable for the energy levels and radiative rates among higher excited levels. Our listed energy levels are estimated to be accurate to better than 1% (within 0.1 Ryd), whereas results for other parameters are probably accurate to better than 20%. © 2013 The Royal Swedish Academy of Sciences.

Energy levels, radiative rates and electron impact excitation rates for transitions in Be-like Ti XIX

We report calculations of energy levels, radiative rates and electron impact excitation cross sections and rates for transitions in Be-like Ti XIX. The general-purpose relativistic atomic structure package is adopted for calculating energy levels and radiative rates. For determining the collision strengths and subsequently the excitation rates, the Dirac atomic R-matrix code (darc) is used. Oscillator strengths, radiative rates and line strengths are reported for all E1, E2, M1 and M2 transitions among the lowest 98 levels of the n≤ 4 configurations. Additionally, theoretical lifetimes are listed for all 98 levels. Collision strengths are averaged over a Maxwellian velocity distribution and the effective collision strengths obtained listed over a wide temperature range up to 10 ^7.7K. Comparisons are made with similar data obtained from the flexible atomic code (fac) to highlight the importance of resonances, included in calculations with darc, in the determination of effective collision strengths. Discrepancies between the collision strengths from darc and fac, particularly for forbidden transitions, are also discussed. 

Prostaglandin E2 as a regulator of germ cells during ovarian development

CONTEXT: The formation of primordial follicles occurs during fetal life yet is critical to the determination of adult female fertility. Prior to this stage, germ cells proliferate, enter meiosis, and associate with somatic cells. Growth and survival factors implicated in these processes include activin A (INHBA), the neurotrophins BDNF and NT4 (NTF5), and MCL1. The prostaglandins have pleiotrophic roles in reproduction, notably in ovulation and implantation, but there are no data regarding roles for prostaglandins in human fetal ovarian development.

OBJECTIVE: The aim of the study was to investigate a possible role for prostaglandin (PG) E(2) in human fetal ovary development.

DESIGN: In vitro analysis of ovarian development between 8 and 20 wk gestation was performed.

MAIN OUTCOME MEASURE(S): The expression patterns of PG synthesis enzymes and the PGE(2) receptors EP2 and EP4 in the ovary were assessed, and downstream effects of PGE(2) on gene expression were analyzed.

RESULTS: Ovarian germ cells express the PG synthetic enzymes COX2 and PTGES as well as the EP2 and EP4 receptors, whereas COX1 is expressed by ovarian somatic cells. Treatment in vitro with PGE(2) increased the expression of BDNF mRNA 1.7 +/- 0.16-fold (P = 0.004); INHBA mRNA, 2.1 +/- 0.51-fold (P = 0.04); and MCL1 mRNA, 1.15 +/- 0.06-fold (P = 0.04), but not that of OCT4, DAZL, VASA, NTF5, or SMAD3.

CONCLUSIONS: These data indicate novel roles for PGE(2) in the regulation of germ cell development in the human ovary and show that these effects may be mediated by the regulation of factors including BDNF, activin A, and MCL1.

Compressive behavior of steel fiber reinforced recycled aggregate concrete after exposure to elevated temperatures

For sustainability considerations, the use of recycled aggregate in concrete has attracted many interests in the research community. One of the main concerns for using such concrete in buildings is its spalling in fire. This may be alleviated by adding steel fibers to form steel fiber reinforced recycled aggregate concrete (SFRAC). This paper presents an experimental investigation into the compressive properties of SFRAC cylinders after exposure to elevated temperatures, including the compressive strength, Young's modulus (stiffness), stress-strain curve and energy absorption capacity (toughness). The effects of two parameters, namely steel fiber volume content (0%, 0.5%, 1%, 1.5%) and temperature (room temperature, 200 °C, 400 °C and 600 °C) on the compressive mechanical properties of concrete were investigated. The test results show that both compressive strength and stiffness of the concrete are significantly reduced after exposure to high temperatures. The addition of steel fibers is helpful in preventing spalling, and significantly improves the ductility and the cracking behavior of recycled aggregate concrete (RAC) after exposure to high temperatures, which is favorable for the application of RAC in building construction.