Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene

AIMS/HYPOTHESIS: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study.

METHODS: Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot.

RESULTS: The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina.

CONCLUSIONS/INTERPRETATION: Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.

Reclaiming the Radical in Universal Human Rights: Universality as Universalisation

The universality of human rights has been a fiercely contested issue throughout their history. This article contributes to scholarly engagements with the universality of human rights by proposing a re-engagement with this concept in a way that is compatible with the aims of radical politics. Instead of a static attribute or characteristic of rights this article proposes that universality can be thought of as, drawing from Judith Butler, an ongoing process of universalisation. Universality accordingly emerges as a site of powerful contest between competing ideas of what human rights should mean, do or say, and universal concepts are continually reworked through political activity. This leads to a differing conception of rights politics than traditional liberal approaches but, moreover, challenges such approaches. This understanding of universality allows human rights to come into view as potentially of use in interrupting liberal regimes and, crucially, opens possibilities to reclaim the radical in rights.

Physical rehabilitation interventions for adult intensive care patients across the continuum of recovery (i.e. within the intensive care unit (ICU) and following ICU and hospital discharge): an overview of systematic reviews

Background
Patients admitted to the intensive care unit with critical illness often experience significant physical impairments, which typically persist for many years following resolution of the original illness. Physical rehabilitation interventions that enhance restoration of physical function have been evaluated across the continuum of recovery following critical illness including within the intensive care unit, following discharge to the ward and beyond hospital discharge. Multiple systematic reviews have been published appraising the expanding evidence investigating these physical rehabilitation interventions, although there appears to be variability in review methodology and quality. We aim to conduct an overview of existing systematic reviews of physical rehabilitation interventions for adult intensive care patients across the continuum of recovery.

Methods/design
This protocol has been developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines. We will search the Cochrane Systematic Review Database, Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials, MEDLINE, Excerpta Medica Database and Cumulative Index to Nursing and Allied Health Literature databases. We will include systematic reviews of randomised controlled trials of adult patients, admitted to the intensive care unit and who have received physical rehabilitation interventions at any time point during their recovery. Data extraction will include systematic review aims and rationale, study types, populations, interventions, comparators, outcomes and quality appraisal method. Primary outcomes of interest will focus on findings reflecting recovery of physical function. Quality of reporting and methodological quality will be appraised using the PRISMA checklist and the Assessment of Multiple Systematic Reviews tool.

Discussion
We anticipate the findings from this novel overview of systematic reviews will contribute to the synthesis and interpretation of existing evidence regarding physical rehabilitation interventions and physical recovery in post-critical illness patients across the continuum of recovery.

Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study

BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome.

METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone.

FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions.

INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.

PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy

PTEN loss is prognostic for patient relapse post-radiotherapy in prostate cancer (CaP). Infiltration of tumor-associated macrophages (TAMs) is associated with reduced disease-free survival following radical prostatectomy. However, the association between PTEN loss, TAM infiltration and radiotherapy response of CaP cells remains to be evaluated. Immunohistochemical and molecular analysis of surgically-resected Gleason 7 tumors confirmed that PTEN loss correlated with increased CXCL8 expression and macrophage infiltration. However PTEN status had no discernable correlation with expression of other inflammatory markers by CaP cells, including TNF-α. In vitro, exposure to conditioned media harvested from irradiated PTEN null CaP cells induced chemotaxis of macrophage-like THP-1 cells, a response partially attenuated by CXCL8 inhibition. Co-culture with THP-1 cells resulted in a modest reduction in the radio-sensitivity of DU145 cells. Cytokine profiling revealed constitutive secretion of TNF-α from CaP cells irrespective of PTEN status and IR-induced TNF-α secretion from THP-1 cells. THP-1-derived TNF-α increased NFκB pro-survival activity and elevated expression of anti-apoptotic proteins including cellular inhibitor of apoptosis protein-1 (cIAP-1) in CaP cells, which could be attenuated by pre-treatment with a TNF-α neutralizing antibody. Treatment with a novel IAP antagonist, AT-IAP, decreased basal and TNF-α-induced cIAP-1 expression in CaP cells, switched TNF-α signaling from pro-survival to pro-apoptotic and increased radiation sensitivity of CaP cells in co-culture with THP-1 cells. We conclude that targeting cIAP-1 can overcome apoptosis resistance of CaP cells and is an ideal approach to exploit high TNF-α signals within the TAM-rich microenvironment of PTEN-deficient CaP cells to enhance response to radiotherapy.

Peer Effects in Adolescent Cannabis Use: It's the Friends, Stupid

This paper examines peer effects in adolescent cannabis use from several different reference groups, exploiting survey data that have many desirable properties and have not previously been used for this purpose. Treating the school grade as the reference group, and using both neighbourhood fixed effects and IV for identification, we find evidence of large, positive, and statistically significant peer effects. Treating nominated friends as the reference group, and using both school fixed effects and IV for identification, we again find evidence of large, positive, and generally statistically significant peer effects. Our preferred IV approach exploits information about friends of friends – ‘friends once removed’, who are not themselves friends – to instrument for friends’ cannabis use. Finally, we examine whether the cannabis use of schoolmates who are not nominated as friends – ‘non-friends’ – influences
own cannabis use. Once again using neighbourhood fixed effects and IV for identification, the evidence suggests zero impact. In our data, schoolmates who are not also friends have no influence on adolescent cannabis use.

All the World's a Stage: Facilitating Discovery Science and Improved Cancer Care through the Global Alliance for Genomics and Health

The recent explosion of genetic and clinical data generated from tumor genome analysis presents an unparalleled opportunity to enhance our understanding of cancer, but this opportunity is compromised by the reluctance of many in the scientific community to share datasets and the lack of interoperability between different data platforms. The Global Alliance for Genomics and Health is addressing these barriers and challenges through a cooperative framework that encourages "team science" and responsible data sharing, complemented by the development of a series of application program interfaces that link different data platforms, thus breaking down traditional silos and liberating the data to enable new discoveries and ultimately benefit patients.

After the Critique of Rights: For a Radical Democratic Theory and Practice of Human Rights

The critique of human rights has proliferated in critical legal thinking over recent years, making it clear that we can no longer uncritically approach human rights in their liberal form. In this article I assert that after the critique of rights one way human rights may be productively re-engaged in radical politics is by drawing from the radical democratic tradition. Radical democratic thought provides plausible resources to rework the shortcomings of liberal human rights, and allows human rights to be brought within the purview of a wider political project adopting a critical approach to current relations of power. Building upon previous re-engagements with rights using radical democratic thought, I return to the work of Ernesto Laclau and Chantal Mouffe to explore how human rights may be thought as an antagonistic hegemonic activity within a critical relation to power, a concept which is fundamentally futural, and may emerge as one site for work towards radical and plural democracy. I also assert, via Judith Butler's model of cultural translation, that a radical democratic practice of human rights may be advanced which resonates with and builds upon already existing activism, thereby holding possibilities to persuade those who remain sceptical as to radical re-engagements with rights.

Assessing elements of a family approach to reduce adolescent drinking frequency: parent-adolescent relationship, knowledge management, and keeping secrets

AIMS: To estimate 1) the associations between parent-adolescent relationship, parental knowledge and subsequent adolescent drinking frequency and 2) the influence of alcohol use on parental knowledge.

DESIGN: Path analysis of school based cohort study with annual surveys SETTING: Post primary schools from urban and intermediate/rural areas in Northern Ireland PARTICIPANTS: 4,937 post primary school students aged around 11 years in 2000 followed until around age 16 in 2005.

MEASUREMENTS: Pupil reported measures of: frequency of alcohol use; parental-child relationship quality; sub-dimensions of parental monitoring: parental control, parental solicitation, child disclosure and child secrecy.

FINDINGS: Higher levels of parental control (Ordinal logistic OR 0.86 95% CI 0.78, 0.95) and lower levels of child secrecy (OR 0.83 95% CI 0.75 0.92) were associated with less frequent alcohol use subsequently. Parental solicitation and parent-child relationship quality were not associated with drinking frequency. Weekly alcohol drinking was associated with higher subsequent secrecy (Beta -0.42 95% CI -0.53, -0.32) and lower parental control (Beta -0.15 95% CI -0.26, -0.04). Secrecy was more strongly predictive of alcohol use at younger compared with older ages (P=0.02), and alcohol use was less strongly associated with parental control among families with poorer relationships (P=0.04).

CONCLUSIONS: Adolescent alcohol use appears to increase as parental control decreases and child secrecy increases. Greater parental control is associated with less frequent adolescent drinking subsequently, while parent-child attachment and parental solicitation have little influence on alcohol use. 

Adaptive utilitarianism, social enterprises and urban regeneration

Social enterprises have been placed at the centre of Big Society politics and an emphasis on the local as a site for experimentation and service delivery. Nationally, this has been supported by legislation in community transfer and procurement, social finance and new intermediaries to strengthen skills and loan readiness. This paper examines the role of social enterprises involved in urban development in Northern Ireland and highlights the multiple ethics, legitimation strategies and modalities that are necessary for sustainable forms of progressive regeneration. The paper concludes by stressing the possibilities of a more independent and reformist social economy and how this offers some practical alternatives to the enthusiasm for neoliberal policies in the local state.

Transfusion and Treatment of severe anaemia in African children (TRACT): a study protocol for a randomised controlled trial

BACKGROUND: In sub-Saharan Africa, where infectious diseases and nutritional deficiencies are common, severe anaemia is a common cause of paediatric hospital admission, yet the evidence to support current treatment recommendations is limited. To avert overuse of blood products, the World Health Organisation advocates a conservative transfusion policy and recommends iron, folate and anti-helminthics at discharge. Outcomes are unsatisfactory with high rates of in-hospital mortality (9-10 %), 6-month mortality and relapse (6 %). A definitive trial to establish best transfusion and treatment strategies to prevent both early and delayed mortality and relapse is warranted.

METHODS/DESIGN: TRACT is a multicentre randomised controlled trial of 3954 children aged 2 months to 12 years admitted to hospital with severe anaemia (haemoglobin < 6 g/dl). Children will be enrolled over 2 years in 4 centres in Uganda and Malawi and followed for 6 months. The trial will simultaneously evaluate (in a factorial trial with a 3 x 2 x 2 design) 3 ways to reduce short-term and longer-term mortality and morbidity following admission to hospital with severe anaemia in African children. The trial will compare: (i) R1: liberal transfusion (30 ml/kg whole blood) versus conservative transfusion (20 ml/kg) versus no transfusion (control). The control is only for children with uncomplicated severe anaemia (haemoglobin 4-6 g/dl); (ii) R2: post-discharge multi-vitamin multi-mineral supplementation (including folate and iron) versus routine care (folate and iron) for 3 months; (iii) R3: post-discharge cotrimoxazole prophylaxis for 3 months versus no prophylaxis. All randomisations are open. Enrolment to the trial started September 2014 and is currently ongoing. Primary outcome is cumulative mortality to 4 weeks for the transfusion strategy comparisons, and to 6 months for the nutritional support/antibiotic prophylaxis comparisons. Secondary outcomes include mortality, morbidity (haematological correction, nutritional and infectious), safety and cost-effectiveness.

DISCUSSION: If confirmed by the trial, a cheap and widely available 'bundle' of effective interventions, directed at immediate and downstream consequences of severe anaemia, could lead to substantial reductions in mortality in a substantial number of African children hospitalised with severe anaemia every year, if widely implemented.