Moderating Readers and Reading Online

Despite the proliferation of online forums for the discussion of literary texts, very little has been written to date on the management of these spaces and how this helps frame the kinds of discussion and interpretative work that take place. This article draws on a series of interviews with moderators of online book-related sites, alongside close analysis of online interactions between moderators and users to consider issues of authority, hierarchy, power and control, asking how these act to structure or facilitate acts of interpretation taking place online. We begin by outlining the moderator's role before conducting a brief review of existing scholarship on offline reading groups and online communities, to identify how social infrastructures are established and negotiated. The main body of the article draws upon interviews with moderators of two online literary forums – The Republic of Pemberley and The Guardian’s online Reading Group – to explore the ways in which each of the respective moderators frames his or her role. This is accompanied by an in-depth exploration of how the forms of interpretation we find on the two sites are shaped and directed by the moderators. The article concludes by reflecting upon some of the issues raised by this study and its methodology, particularly with regards to digital dualism and the blurring of the boundaries between the public and the private in online spaces

Positive Art: Artistic Expression and Appreciation as an Exemplary Vehicle for Flourishing.

The relevance of the arts to wellbeing has been recognised within clinical fields, as reflected in therapeutic forms based on various art modalities, from music to drama therapy. However, there has hitherto been little appreciation in fields such as positive psychology of the broader potential of the arts as a vehicle for flourishing and fulfilment. As such, this paper proposes the creation of ‘positive art’ as a field encompassing theory and research concerning the wellbeing value of art. To show the scope and possibilities of this proposed field, the paper provides an indicative summary of literature pertaining to four major art forms: visual art, music, literature and drama. Moreover, the paper identifies five main positive outcomes that are consistently found in the literature across all these forms: sense-making, enriching experience, aesthetic appreciation, entertainment, and bonding. The paper aims to encourage a greater focus on the arts in fields like positive psychology, enabling science to more fully understand and appreciate the positive power of the arts

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10– ¹⁵) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65×10– ²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69×10– ¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

Germline selection shapes human mitochondrial DNA diversity.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.NIHR, Wellcome Trust, MRC, Genomics Englan

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson\u27s disease (PD MED): A large, open-label, pragmatic randomised trial

\ua9 2014 Elsevier Ltd. Background Whether initial treatment for Parkinson\u27s disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson\u27s disease. Methods In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson\u27s disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson\u27s disease questionnaire (PDQ-39) quality-of-life scale (range 0-100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316. Findings Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1\ub78 points (95% CI 0\ub75-3\ub70, p=0\ub7005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years\u27 observation. PDQ-39 mobility scores were 1\ub74 points (95% CI 0\ub70-2\ub79, p=0\ub705) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0\ub703 (95% CI 0\ub701-0\ub705; p=0\ub70002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0\ub781, 95% CI 0\ub761-1\ub708, p=0\ub714), admissions to institutions (0\ub786, 0\ub763-1\ub718; p=0\ub74), and death (0\ub785, 0\ub769-1\ub706, p=0\ub717) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p<0\ub70001). Interpretation Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy. MAOBI as initial levodopa-sparing therapy was at least as effective as dopamine agonists. Funding UK National Institute for Health Research Health Technology Assessment Programme and UK Department of Health