Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial

Background: Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint. Methods: In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560. Findings: Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference -1·37 letters, 95% CI -3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1·63 letters, -4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 [6%] of 314 participants) and bevacizumab (12 [4%] of 296; odds ratio [OR] 1·69, 95% CI 0·80-3·57; p=0·16), or those given continuous (12 [4%] of 308) and discontinuous treatment (20 [7%] of 302; 0·56, 0·27-1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22-1·03; p=0·05), but did not differ by drug group (0·96, 0·46-2·02; p=0·91). Interpretation: Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought.

Processing the Peace:An Interview with Teya Sepinuck

In this interview, Teya Sepinuck, the Artistic Director of Theatre of Witness reflects not only on her first two projects in Northern Ireland, but also vividly illustrates her way of working by evoking seminal moments in her previous practice. Although, she has resisted attempts to systematise the Theatre of Witness process, preferring to see it as a set of principles rather than a fixed methodology, these principles have given rise to clear guidelines that have come to govern the process through which she works. As the interview illustrates, Sepinuck, a Jewish Buddhist, has no hesitation in explaining her approach within the framework of a humanist ‘spirituality’ that explicitly deploys Judeo-Christian terminology. She invites discussion of each participant's ‘prayer-life’ and positions herself primarily as a listener rather than an interlocutor. The introduction to the interview contextualises Sepinuck's practice in relation to her previous work and other drama-based interventions in Northern Ireland. Concerns that the lack of critical distance between the tellers and their stories inhibits those who see it from freely engaging with it as they might with a fictionalised account, are also critiqued. In the interview, Sepinuck directly addresses the risk of the commodification of her work, explaining the safeguards in place to protect the participants, who have repeatedly asserted how beneficial they have found their involvement in the work to be. The sense of autonomy and empowerment that emerges from these responses represent a persuasive challenge to concerns that they are passive instruments of the Theatre of Witness process.

Investigation of moisture condition and Autoclam sensitivity on air permeability measurements for both normal concrete and high performance concrete

While on site measurement of air permeability provides a useful approach for assessing the likely long term durability of concrete structures, no existing test method is capable of effectively determining the relative permeability of high performance concrete (HPC). Lack of instrument sensitivity and the influence of concrete moisture are proposed as two key reasons for this phenomenon. With limited systematic research carried out in this area to date, the aim if this study was to investigate the influence of instrument sensitivity and moisture condition on air permeability measurements for both normal concrete and HPC. To achieve a range of moisture conditions, samples were dried initially for between one and 5 weeks and then sealed in polythene sheeting and stored in an oven at 50 C to internally distribute moisture evenly. Moisture distribution was determined throughout using relative humidity probe and electrical resistance measurements. Concrete air permeability was subsequently measured using standardised air permeability (Autoclam) and water penetration (BS EN: 12390-8) tests to assess differences between the HPCs tested in this study. It was found that for both normal and high performance concrete, the influence of moisture on Autoclam air permeability results could be eliminated by pre-drying (50 ± 1 C, RH 35%) specimens for 3 weeks. While drying for 5 weeks alone was found not to result in uniform internal moisture distributions, this state was achieved by exposing specimens to a further 3 weeks of sealed pre-conditioning at 50 ± 1 C. While the Autoclam test was not able to accurately identify relative HPC quality due to low sensitivity at associated performance levels, an effective preconditioning procedure to obtain reliable air permeability of HPC concretes was identified. © 2013 The Authors

Partisanship and Public Reason

In the large body of literature concerning John Rawls’s Political Liberalism (1993) and his conception of public reason, little attention has been paid to the implications that the constraints of public reason have for partisans, i.e. citizens who participate in politics through political parties. This paper argues that even on the basis of a ‘mild’ understanding of Rawls’s conception of the constraints of public reason, which takes into account the various stipulations Rawls provided throughout his later work, when applied to partisans the constraints of public reason lose none or little of their hindering force. This seriously undermines the contribution that parties and partisans can provide to the change and the varieties of public reason that Rawls himself advocates as a response to social change and, therefore, to political justification and legitimacy. Parties articulate, coordinate and enhance societal demands which, without their support, may remain unheard and fail to change the acceptable terms of public reason and political justification. If the political speech of partisans is restrained, this potential for change (and, therefore, its contribution to political legitimacy) is seriously undermined.

Elements of A New Framework for the principle of Equal Treatment of persons in EC Law

In June and November 2000, the European Parliament and the Council adopted two Directives referring to ‘the principle of equal treatment irrespective of’ in their title, one relating to racial and ethnic origin, the other to disability, age, religion and belief or sexual orientation. A thorough reform of Directive 76/207/EEC on the principle of equal treatment for women and men in employment matters is pending between the European Parliament's second reading and adoption while this is written. Community secondary legislation on equal treatment of persons has thus expanded in scope and number of reasons which must not serve as starting points for differentiation. Does this signify progress in legal protection against personal discrimination? While not providing a ready answer, this article proposes an analytical framework to answer this question, concentrating on conceptions of equality in general and in particular on the problems multi-dimensional discrimination might pose for the law.

Falls prevention and support:: translating research, integrating services and promoting the contribution of service users for quality and innovative programmes of care

Falls are a significant threat to the safety, health and independence of older citizens. Despite the substantial evidence that is available around effective falls prevention programmes and interventions, their translation into falls reduction programmes and policies has yet to be fully realised. While hip fracture rates are decreasing, the number and incidence of fall-related hospital admissions among older people continue to rise. Given the demographic trends that highlight increasing numbers of older people in the UK, which is broadly reflected internationally, there is a financial and social imperative to minimise the rate of falls and associated injuries. Falling is closely aligned to growing older (Slips, Trips and Falls Update: From Acute and Community Hospitals and Mental Health Units in England and Wales, Department of Health, HMSO, London, 2010). According to the World Health Organization, around 30% of older people aged over 65 and 50% of those over 80 will fall each year (Falls Fact Sheet Number 344, WHO, Geneva, 2010). Falls happen as a result of many reasons and can have harmful consequences, including loss of mobility and independence, confidence and in many cases even death (Cochrane Database Syst Rev 15, 2009, 146; Slips, Trips and Falls Update: From Acute and Community Hospitals and Mental Health Units in England and Wales, Department of Health, HMSO, London, 2010; Falling Standards, Broken Promises: Report of the National
Audit of Falls and Bone Health in Older People 2010, Health Care Quality
Improvement Partnership, London, 2011). What is neither fair nor correct is the
common belief by old and young alike that falls are just another inconvenience to put up with. The available evidence justifiably supports the view that well-organised services, based upon national standards and expert guidance, can prevent future falls among older people and reduce death and disability from fractures. This paper will draw from the UK, as an exemplar for policy and practice, to discuss the strategic direction of falls prevention programmes for older people and the partnerships that need to exist between researchers, service providers and users of services to translate evidence to the clinical setting. Second, it will propose some mechanisms for disseminating evidence to healthcare professionals and other stakeholders, to improve the quality and capacity of the clinical workforce.

Dimensionality, Reliability and Validity of the InterRAI Depression Rating Scale in a Canadian Palliative Care Population

A reliable and valid instrument is needed to screen for depression in palliative patients. The interRAI Depression Rating Scale (DRS) is based on seven items in the interRAI Palliative Care instrument. This study is the first to explore the dimensionality, reliability and validity of the DRS in a palliative population. Palliative home care patients (n = 5,175) residing in Ontario (Canada) were assessed with the interRAI Palliative Care instrument. Exploratory factor analysis and Mokken scale analysis were used to identify candidate conceptual models and evaluate scale homogeneity/performance. Confirmatory factor analysis compared models using standard goodness-of-fit indices. Convergent and divergent validity were investigated by examining polychoric correlations between the DRS and other items. The “known groups” test determined if the DRS meaningfully distinguished among client subgroups. The non-hierarchical two factor model showed acceptable fit with the data, and ordinal alpha coefficients of 0.83 and 0.82 were observed for the two DRS subscales. Omega hierarchical (ωh) was 0.78 for the bifactor model, with the general factor explaining three quarters of the common variance. Despite the multidimensionality evident in the factor analyses, bifactor modelling and the Mokken homogeneity coefficient (0.34) suggest that the DRS is a coherent scale that captures important information on sub-constructs of depression (e.g., somatic symptoms). Higher correlations were seen between the DRS and mood and psychosocial well-being items, and lower correlations with functional status and demographic variables. The DRS distinguished in the expected manner for known risk factors (e.g., social support, pain). The results suggest that the DRS is primarily unidimensional and reliable for use in screening for depression in palliative care patients.

A realist literature review of transition to adult services by young people with life-limiting conditions in ireland.

Background As a result of improvements in care and treatment more young people with life-limiting conditions are now living beyond childhood, meaning they must make the transition from children's to adult services. The loss of long-standing relationships with providers of children's services combines with poor co-ordination of services to make this a daunting prospect for young people and their families. However, there is little evidence on transition services for young people with life limiting conditions, with few models of good practice in the literature.


Aims The purpose of this review was to determine the factors that promote or hinder the transition to adult services for young adults with life limiting conditions, and identify gaps to be addressed.


Methods A comprehensive search of the literature was undertaken using key terms, of the following databases; MEDLINE and the Cochrane Database of Systematic Reviews. 314 articles were sourced and inclusion and exclusion criteria were applied to highlight the most relevant literature.


Results Studies were reviewed using a realist review approach and three themes emerged from the literature. Barriers and facilitators to the transition process were identified associated with: 1. The patient 2. Parents/carers 3. The organisation.


Conclusion It is unclear from the literature what the specific factors are that promote or hinder the transition process for young adults with life limiting conditions who go through the transition from children's to adult services, therefore, research is required to identify the factors that promote and hinder the transition process in Ireland. This research is currently being carried out by the author as part of Doctoral studies. The three year full time Doctoral study commenced in January 2013 and is funded by the All Ireland Institute of Hospice and Palliative Care.

A comparison of two informative SNP-based strategies for typing Pseudomonas aeruginosa isolates from patients with cystic fibrosis

BACKGROUND: Molecular typing is integral for identifying Pseudomonas aeruginosa strains that may be shared between patients with cystic fibrosis (CF). We conducted a side-by-side comparison of two P. aeruginosa genotyping methods utilising informative-single nucleotide polymorphism (SNP) methods; one targeting 10 P. aeruginosa SNPs and using real-time polymerase chain reaction technology (HRM10SNP) and the other targeting 20 SNPs and based on the Sequenom MassARRAY platform (iPLEX20SNP).

METHODS: An in-silico analysis of the 20 SNPs used for the iPLEX20SNP method was initially conducted using sequence type (ST) data on the P. aeruginosa PubMLST website. A total of 506 clinical isolates collected from patients attending 11 CF centres throughout Australia were then tested by both the HRM10SNP and iPLEX20SNP assays. Type-ability and discriminatory power of the methods, as well as their ability to identify commonly shared P. aeruginosa strains, were compared.

RESULTS: The in-silico analyses showed that the 1401 STs available on the PubMLST website could be divided into 927 different 20-SNP profiles (D-value = 0.999), and that most STs of national or international importance in CF could be distinguished either individually or as belonging to closely related single- or double-locus variant groups. When applied to the 506 clinical isolates, the iPLEX20SNP provided better discrimination over the HRM10SNP method with 147 different 20-SNP and 92 different 10-SNP profiles observed, respectively. For detecting the three most commonly shared Australian P. aeruginosa strains AUST-01, AUST-02 and AUST-06, the two methods were in agreement for 80/81 (98.8%), 48/49 (97.8%) and 11/12 (91.7%) isolates, respectively.

CONCLUSIONS: The iPLEX20SNP is a superior new method for broader SNP-based MLST-style investigations of P. aeruginosa. However, because of convenience and availability, the HRM10SNP method remains better suited for clinical microbiology laboratories that only utilise real-time PCR technology and where the main interest is detection of the most highly-prevalent P. aeruginosa CF strains within Australian clinics.

Proportioning variability in the dispensation of hand-mixed dental cements

Objectives: The purpose of this investigation was to determine for dispensed multiples (1 through 4) of powder (P) and liquid (L) in hand-mixed dental cement whether: (1) the mean (P/L) ratio (m/m) and (2) the maximum difference in (P/L) ratio is dependent on the number of multiples dispensed. The Null hypotheses were: (a) mean (P/L) ratio is independent of the number of multiples dispensed and (b) maximum difference in (P/L) ratio is independent of the number of multiples dispensed.
Methods: The materials investigated are listed in the Table. The masses of dispensed aliquots of powder and liquid were measured by a single operator (n=10, for multiples 1 through 4) on a 4-place analytical balance. All measurements were made independently and all possible (P/L) ratios calculated for each sample. The effect of multiple dispensations on (P/L) ratios and maximum (P/L) differences was by one-way ANOVA and linear regression, respectively, with the Tukey post-hoc correction for multiple comparisons.MULTIPLE DISPENSEDDISPENSED MU(x1)(x2)(x3)(x4)Zinc phosphateHeraeus12.271(0.691)a13.051(1.269)b13.215(0.824)b13.118(1.149)bFuji IXGC4.209(0.373)a4.085(0.275)b4.095(0.226)b4.095(0.217)bIRMDentsply7.933(0.767)a7.430(0.451)b7.977(0.729)a8.186(0.929)aKetac-Cem3M Espe9.6206(0.613)a9.714(0.523)a9.298(0.314)b9.321(0.292)bMean (SD) powder/liquid ratio (m/m). Superscript letters represent significances (α = 0.05) within each material
Results: Mean (SD) (P/L) ratios are presented in the Table. Null hypothesis (a) is rejected: either (x1) or (x2) dispensation yields a different (P/L) ratio to (x3) or (x4) (p < 0.05). Null hypothesis (b) is rejected: a negative correlation is observed in max (P/L) ratio difference with dispensed multiple for Ketac Cem (p = 0.029).
Conclusion: For hand-mixed dental cements: (1) more consistent (P/L) ratios may be observed with multiple dispensations of powder & liquid; (2) maximum differences in (P/L) ratio may be negatively correlated with dispensation multiple in some materials.

Using Comparative Constitutionalism in Human Rights Discourse:Ireland’s Past and Scotland’s Future

The article considers the use of comparisons in constitutional development, specifically the use of comparative reasoning in the context of debates about human rights in newly emerging independent states, using the examples of Ireland and Scotland.

Symposium - Organisational transformation in policing: Leadership and change in extreme contexts

Nearly 4000 people died in Northern Ireland’s long running conflict, 314 of them police officers (Brewer and Magee 1991, Brewer 1996, Hennessey 1999, Guelke and Milton-Edwards 2000). The republican and loyalist ceasefires of 1994 were the first significant signal that NI society was moving beyond the ‘troubles’ and towards a normalised political environment. The Belfast (Good Friday) Agreement of 1998 cemented that movement (Hennessey 1999). Policing was a key and seemingly unresolvable element of the conflict, seen as unrepresentative and partisan. Its reform or ‘recasting’ in a new dispensation was an integral part of the conflict transformation endeavour(Ellison 2010). As one of the most controversial elements of the conflicted past, it had remained outside the Agreement and was subject to a specific commission of interest (1999), generally known as the Patten Commission. The Commission’s far reaching proposals included a change of name, badge and uniform, the introduction of 50/50 recruitment (50% Roman Catholic and 50% other), a new focus on human rights, a new district command and headquarter structure, a review of ‘Special Branch’ and covert techniques, a concern for ‘policing with the community’ and a significant voluntary severance process to make room for new recruits, unconnected with the past history of the organisation(Murphy 2013).

This paper reflects upon the first data collection phase of a long term processual study of organisational change within the Royal Ulster Constabulary / Police Service of Northern Ireland. This phase (1996-2002) covers early organisational change initiation (including the pre-change period) and implementation including the instigation of symbolic changes (name, badge, and crest) and structural changes (new HQ structure and District Command structure). It utilises internal documentation including messages from the organisations leaders, interviews with forty key informants (identified through a combination of snow-balling from referrals by initial contacts, and key interviews with significant individuals), as well as external documentation and commentary on public perceptions of the change. Using a processual lens (Langley, Smallman et al. 2013) it seeks to understand this initial change phase and its relative success in a highly politicised environment.

By engaging key individuals internally and externally, setting up a dedicated change team, adopting a non normative, non urgent, calming approach to dissent, communicating in orthodox and unorthodox ways with members, acknowledging the huge emotional strain of letting go of the organisation’s name and all it embodied, and re-emphasising the role of officers as ‘police first’, rather than ‘RUC first’, the organisations leadership remained in control of a volatile and unhappy organisational body and succeeded in moving it on through this initial phase, even while much of the political establishment lambasted them externally. Three years into this change process the organisation had a new name, a new crest, new structures, procedures and was deeply engaged in embedding the joint principles of human rights and community policing within its re-woven fabric. While significant problems remained, the new Police Service of Northern Ireland had successfully begun a long journey to full community acceptance in a post conflict context.

This case illustrates the significant challenges of leading change under political pressure, with external oversight and no space for failure(Hannah, Uhl-Bien et al. 2009). It empirically reflects the reality of change implementation as messy, disruptive and unpredictable and highlights the significance of political skill and contextual understanding to success in the early stages(Buchanan and Boddy 1992). The implications of this for change theory and the practice of change implementation are explored (Eisenhardt and Graebner 2007) and some conclusions drawn about what such an extreme case tells us about change generally and change implementation under pressure.

Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer

A fluorescence in situ hybridisation (FISH) assay has been used to screen for ETV1 gene rearrangements in a cohort of 429 prostate cancers from patients who had been diagnosed by trans-urethral resection of the prostate. The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.001), PSA level at diagnosis (P=<0.0001) and clinical stage (P=0.017) but was not linked to poorer survival. We found that the six previously characterised translocation partners of ETV1 only accounted for 34% of ETV1 re-arrangements (eight out of 23) in this series, with fusion to the androgen-repressed gene C15orf21 representing the commonest event (four out of 23). In 5'-RACE experiments on RNA extracted from formalin-fixed tissue we identified the androgen-upregulated gene ACSL3 as a new 5'-translocation partner of ETV1. These studies report a novel fusion partner for ETV1 and highlight the considerable heterogeneity of ETV1 gene rearrangements in human prostate cancer.

Three-dimensional porous carbon nanofiber networks decorated with cobalt-based nanoparticles: A robust electrocatalyst for efficient water oxidation

Electrochemical water splitting used for generating hydrogen has attracted increasingly attention due to energy and environmental issues. It is a major challenge to design an efficient, robust and inexpensive electrocatalyst to achieve preferable catalytic performance. Herein, a novel three-dimensional (3D) electrocatalyst was prepared by decorating nanostructured biological material-derived carbon nanofibers with in situ generated cobalt-based nanospheres (denoted as CNF@Co) through a facile approach. The interconnected porous 3D networks of the resulting CNF@Co catalyst provide abundant channels and interfaces, which remarkably favor both mass transfer and oxygen evolution. The as-prepared CNF@Co shows excellent electrocatalytic activity towards the oxygen evolution reactions with an onset potential of about 0.445 V vs. Ag/AgCl. It only needs a low overpotential of 314 mV to achieve a current density of 10 mA/cm² in 1.0 M KOH. Furthermore, the CNF@Co catalyst exhibits excellent stability towards water oxidation, even outperforming commercial IrO<inf>2</inf> and RuO<inf>2</inf> catalysts.