Association Testing of Previously Reported Variants in a Large Case-Control Meta-analysis of Diabetic Nephropathy

We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10-9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

Psychosocial factors in GP work:the effects of taking a GP position or leaving GP work

BACKGROUND: We examined the effects of leaving public sector general practitioner (GP) work and of taking a GP position on changes in work-related psychosocial factors, such as time pressure, patient-related stress, distress and work interference with family. In addition, we examined whether changes in time pressure and patient-related stress mediated the association of employment change with changes of distress and work interference with family. METHODS: Participants were 1705 Finnish physicians (60% women) who responded to surveys in 2006 and 2010. Analyses of covariance were conducted to examine the effect of employment change to outcome changes adjusted for gender, age and response format. Mediational effects were tested following the procedures outlined by Baron and Kenny. RESULTS: Employment change was significantly associated with all the outcomes. Leaving public sector GP work was associated with substantially decreased time pressure, patient-related stress, distress and work interference with family. In contrast, taking a position as a public sector GP was associated with an increase in these factors. Mediation tests suggested that the associations of employment change with distress change and work interference with family change were partially explained by the changes in time pressure and patient-related stress. CONCLUSIONS: Our results showed that leaving public sector GP work is associated with favourable outcomes, whereas taking a GP position in the public sector is associated with adverse effects. Primary health-care organizations should pay more attention to the working conditions of their GPs, in particular, to time pressure and patient-related stress.

Donepezil and memantine for moderate-to-severe Alzheimer's disease

Background: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. Methods: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS.
Results: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P = 0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone.
Conclusions: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035).

The influence of evidence-based medicine training on decision-making in relation to over-the-counter medicines: a qualitative study

Objectives
To explore the role of evidence of effectiveness when making decisions about over-the-counter (OTC) medication and to ascertain whether evidence-based medicine training raised awareness in decision-making. Additionally, this work aimed to complement the findings of a previous study because all participants in this current study had received training in evidence-based medicine (unlike the previous participants).

Methods
Following ethical approval and an e-mailed invitation, face-to-face, semi-structured interviews were conducted with newly registered pharmacists (who had received training in evidence-based medicine as part of their MPharm degree) to discuss the role of evidence of effectiveness with OTC medicines. Interviews were recorded and transcribed verbatim. Following transcription, all data were entered into the NVivo software package (version 8). Data were coded and analysed using a constant comparison approach.

Key findings
Twenty-five pharmacists (7 males and 18 females; registered for less than 4 months) were recruited and all participated in the study. Their primary focus with OTC medicines was safety; sales of products (including those that lack evidence of effectiveness) were justified provided they did no harm. Meeting patient expectation was also an important consideration and often superseded evidence. Despite knowledge of the concept, and an awareness of ethical requirements, an evidence-based approach was not routinely implemented by these pharmacists. Pharmacists did not routinely utilize evidence-based resources when making decisions about OTC medicines and some felt uncomfortable discussing the evidence-base for OTC products with patients.

Conclusions
The evidence-based medicine training that these pharmacists received appeared to have limited influence on OTC decision-making. More work could be conducted to ensure that an evidence-based approach is routinely implemented in practice

Diachronic Change in Verbal Agreement Patterns with Majorité

This article is concerned with the description of data relating to a case of morphosyntactic variation and change in French: verbal agreement patterns with the noun majorité (‘majority’). Quantitative analysis of apparent-time data from cloze (‘gap-fill’) tests suggests that plural agreement with this noun is increasing; data from a diachronic corpus study confirm that this is the case. A number of factors are found to constrain this variation and change, including most importantly the presence and number of a post-modifying noun phrase (e.g. la majorité des hommes). The implications of these findings for the definition of collective nouns in French are discussed.

Are power laws that estimate fractal dimension a good descriptor of soil structure and its link to soil biological properties?

The study of interrelationships between soil structure and its functional properties is complicated by the fact that the quantitative description of soil structure is challenging. Soil scientists have tackled this challenge by taking advantage of approaches such as fractal geometry, which describes soil architectural complexity through a scaling exponent (D) relating mass and numbers of particles/aggregates to particle/aggregate size. Typically, soil biologists use empirical indices such as mean weight diameters (MWD) and percent of water stable aggregates (WSA), or the entire size distribution, and they have successfully related these indices to key soil features such as C and N dynamics and biological promoters of soil structure. Here, we focused on D, WSA and MWD and we tested whether: D estimated by the exponent of the power law of number-size distributions is a good and consistent correlate of MWD and WSA; D carries information that differs from MWD and WSA; the fraction of variation in D that is uncorrelated with MWD and WSA is related to soil chemical and biological properties that are thought to establish interdependence with soil structure (e.g., organic C, N, arbuscular mycorrhizal fungi). We analysed observational data from a broad scale field study and results from a greenhouse experiment where arbuscular mycorrhizal fungi (AMF) and collembola altered soil structure. We were able to develop empirical models that account for a highly significant and large portion of the correlation observed between WSA and MWD but we did not uncover the mechanisms that underlie this correlation. We conclude that most of the covariance between D and soil biotic (AMF, plant roots) and abiotic (C. N) properties can be accounted for by WSA and MWD. This result implies that the ecological effects of the fragmentation properties described by D and generally discussed under the framework of fractal models can be interpreted under the intuitive perspective of simpler indices and we suggest that the biotic components mostly impacted the largest size fractions, which dominate MWD, WSA and the scaling exponent ruling number-size distributions. (C) 2010 Elsevier Ltd. All rights reserved.

Pan-genome analysis of the emerging foodborne pathogen Cronobacter spp. suggests a species-level bidirectional divergence driven by niche adaptation

Background: Members of the genus Cronobacter are causes of rare but severe illness in neonates and preterm infants following the ingestion of contaminated infant formula. Seven species have been described and two of the species genomes were subsequently published. In this study, we performed comparative genomics on eight strains of Cronobacter, including six that we sequenced (representing six of the seven species) and two previously published, closed genomes.

Results: We identified and characterized the features associated with the core and pan genome of the genus Cronobacter in an attempt to understand the evolution of these bacteria and the genetic content of each species. We identified 84 genomic regions that are present in two or more Cronobacter genomes, along with 45 unique genomic regions. Many potentially horizontally transferred genes, such as lysogenic prophages, were also identified. Most notable among these were several type six secretion system gene clusters, transposons that carried tellurium, copper and/or silver resistance genes, and a novel integrative conjugative element.

Conclusions: Cronobacter have diverged into two clusters, one consisting of C. dublinensis and C. muytjensii (Cdub-Cmuy) and the other comprised of C. sakazakii, C. malonaticus, C. universalis, and C. turicensis, (Csak-Cmal-Cuni-Ctur) from the most recent common ancestral species. While several genetic determinants for plant-association and human virulence could be found in the core genome of Cronobacter, the four Cdub-Cmuy clade genomes contained several accessory genomic regions important for survival in a plant-associated environmental niche, while the Csak-Cmal-Cuni-Ctur clade genomes harbored numerous virulence-related genetic traits.

DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease

Genetic risk factors for chronic kidney disease (CKD) are being identified through international collaborations. By comparison, epigenetic risk factors for CKD have only recently been considered using population-based approaches. DNA methylation is a major epigenetic modification that is associated with complex diseases, so we investigated methylome-wide loci for association with CKD. A total of 485,577 unique features were evaluated in 255 individuals with CKD (cases) and 152 individuals without evidence of renal disease (controls). Following stringent quality control, raw data were quantile normalized and β values calculated to reflect the methylation status at each site. The difference in methylation status was evaluated between cases and controls with resultant P values adjusted for multiple testing. Genes with significantly increased and decreased levels of DNA methylation were considered for biological relevance by functional enrichment analysis using KEGG pathways in Partek Genomics Suite. Twenty-three genes, where more than one CpG per loci was identified with Padjusted < 10−8, demonstrated significant methylation changes associated with CKD and additional support for these associated loci was sought from published literature. Strong biological candidates for CKD that showed statistically significant differential methylation include CUX1, ELMO1, FKBP5, INHBA-AS1, PTPRN2, and PRKAG2 genes; several genes are differentially methylated in kidney tissue and RNA-seq supports a functional role for differential methylation in ELMO1 and PRKAG2 genes. This study reports the largest, most comprehensive, genome-wide quantitative evaluation of DNA methylation for association with CKD. Evidence confirming methylation sites influence development of CKD would stimulate research to identify epigenetic therapies that might be clinically useful for CKD.

Effects of the mycotoxin patulin at the level of nuclear receptor transcriptional activity and steroidogenesis in vitro

Patulin (PAT) is a mycotoxin produced by various species of fungi, with Penicillium expansum being the most commonly occurring. Apples and apple products are the main sources of PAT contamination. This mycotoxin has been shown to induce toxic effects in animals, a few of which include reproductive toxicity and interference with the endocrine system. Here the endocrine disrupting potential of PAT has been investigated in vitro to identify disruption at the level of oestrogen, androgen, progestagen and glucocorticoid nuclear receptor transcriptional activity, and to assess interferences in estradiol, testosterone and progesterone steroid hormone production. At the receptor level, 0.5-5000ng/ml (0.0032-32μM) PAT did not appear to induce any specific (ant) agonistic responses in reporter gene assays (RGAs); however, nuclear transcriptional activity was affected. A >6 fold increase in the glucocorticoid receptor transcriptional activity was observed following treatment with 5000ng/ml PAT in the presence of cortisol. At the hormone production level, despite cytotoxicity being observed after treatment with 5000ng/ml PAT, estradiol levels had increased >2 fold. At 500ng/ml PAT treatment, an increase in progesterone and a decrease in testosterone production were observed. The findings of this study could be considered in assessing the health risks following exposure to PAT.

Varieties of Economic Crisis, Varieties of Ideational Change: How and Why Macroeconomic Policy and Financial Regulation Differ

One of the principal tasks facing post-crash academic political economy is to analyse patterns of ideational change and the conditions that produce such change. What has been missing from the existing literature on ideational change at times of crises however, is a sense of how processes of persuasive struggle, and how the success of those ‘norm entrepreneurs’ arguing for ideational change is shaped by two contextual variables: the most immediate material symptoms and problems that a crisis displays (the variety of crisis); and the institutional character of the policy subsystem that agents have to operate within to affect change. Introducing these two variables into our accounts of persuasive struggle and ideational change enables us to deepen our understanding of the dynamics of ideational change at times of crisis. The article identifies that a quite rapid and radical intellectual change has been evident in the field of financial regulation in the form of an embrace of a macroprudential frame. In contrast in the field of macroeconomic policy - both monetary and fiscal policy, many pre-crash beliefs remain prominent, there is evidence of ideational stickiness and inertia, and despite some policy experimentation, overarching policy frameworks and their rationales have not been overhauled. The article applies Peter Hall’s framework of three orders of policy changes to help illuminate and explain the variation in patterns of change in the fields of financial regulation and macroeconomic policy since the financial crash of 2008. The different patterns of ideational change in macroeconomic policy and financial regulation in the post-crash period can be explained by timing and variety of crisis; sequencing of policy change; and institutional political differences between micro policy sub systems and macro policy systems.