Characterisation and modelling of the thermorheological properties of pharmaceutical polymers and their blends using capillary rheometry: Implications for hot melt processing of dosage forms.

Given the growing interest in thermal processing methods, this study describes the use of an advanced rheological technique, capillary rheometry, to accurately determine the thermorheological properties of two pharmaceutical polymers, Eudragit E100 (E100) and hydroxypropylcellulose JF (HPC) and their blends, both in the presence and absence of a model therapeutic agent (quinine, as the base and hydrochloride salt). Furthermore, the glass transition temperatures (Tg) of the cooled extrudates produced using capillary rheometry were characterised using Dynamic Mechanical Thermal Analysis (DMTA) thereby enabling correlations to be drawn between the information derived from capillary rheometry and the glass transition properties of the extrudates. The shear viscosities of E100 and HPC (and their blends) decreased as functions of increasing temperature and shear rates, with the shear viscosity of E100 being significantly greater than that of HPC at all temperatures and shear rates. All platforms were readily processed at shear rates relevant to extrusion (approximately 200–300 s−1) and injection moulding (approximately 900 s−1). Quinine base was observed to lower the shear viscosities of E100 and E100/HPC blends during processing and the Tg of extrudates, indicative of plasticisation at processing temperatures and when cooled (i.e. in the solid state). Quinine hydrochloride (20% w/w) increased the shear viscosities of E100 and HPC and their blends during processing and did not affect the Tg of the parent polymer. However, the shear viscosities of these systems were not prohibitive to processing at shear rates relevant to extrusion and injection moulding. As the ratio of E100:HPC increased within the polymer blends the effects of quinine base on the lowering of both shear viscosity and Tg of the polymer blends increased, reflecting the greater solubility of quinine within E100. In conclusion, this study has highlighted the importance of capillary rheometry in identifying processing conditions, polymer miscibility and plasticisation phenomena.

Recruiting schools, adolescents and parents to a sexual-health trial: experiences, challenges and lessons learned from the Jack Trial

Background
Recruitment to school-based randomised trials is challenging; even more so when the focus of the study is a sensitive issue such as sexual health. The Jack Feasibility Trial aims to determine the facilitators and barriers to recruitment and retention to a school-based sexual health trial and identify optimal multi-level strategies for a full trial.
Method
The Jack Trial is an NIHR-funded feasibility study of a film-based sexual health intervention, recruiting over 800 adolescents from 8 post-primary schools in Northern Ireland. In order to examine the feasibility of piloted recruitment and retention methods and assess acceptability of participation across the range of schools and individuals approached, we analysed qualitative data from triangulated sources including a parents’ survey and semi-structured interviews with principals, vice-principals, teachers and parents recruited to the study.
Results
With reference to Social Learning Theory, we identified a number of individual, behavioural and environmental level factors which influenced recruitment and retention. Commonly identified facilitators included the perceived relevance and potential benefit of the intervention to adolescents, the credibility of the organisation running the study, support offered by trial staff, and financial incentives. Key barriers were prior commitment to other research, lack of time and resources, and perceptions that the intervention was incompatible with adolescent needs or school ethos.
Conclusion
This study highlights pertinent general and trial-specific facilitators and barriers to recruitment to a sexual health trial in a school setting, which will prove useful for successful conduct of future trials with schools, adolescents and parents.

Genome wide interactions of wild-type and activator bypass forms of σ54

Enhancer-dependent transcription involving the promoter specificity factor σ54 is widely distributed amongst bacteria and commonly associated with cell envelope function. For transcription initiation, σ54-RNA polymerase yields open promoter complexes through its remodelling by cognate AAA+ ATPase activators. Since activators can be bypassed in vitro, bypass transcription in vivo could be a source of emergent gene expression along evolutionary pathways yielding new control networks and transcription patterns. At a single test promoter in vivo bypass transcription was not observed. We now use genome-wide transcription profiling, genome-wide mutagenesis and gene over-expression strategies in Escherichia coli, to (i) scope the range of bypass transcription in vivo and (ii) identify genes which might alter bypass transcription in vivo. We find little evidence for pervasive bypass transcription in vivo with only a small subset of σ54 promoters functioning without activators. Results also suggest no one gene limits bypass transcription in vivo, arguing bypass transcription is strongly kept in check. Promoter sequences subject to repression by σ54 were evident, indicating loss of rpoN (encoding σ54) rather than creating rpoN bypass alleles would be one evolutionary route for new gene expression patterns. Finally, cold-shock promoters showed unusual σ54-dependence in vivo not readily correlated with conventional σ54 binding-sites.

Speaking Out Online:The Benefits and Risks of Speaking About Sexual Violence for Young People

Speaking out about sexual violence has been a fundamental part of feminist politics since the 1970s. The practice of narrating experiences of violence, either publicly or to friends and family aims to combat the culture of silence and stigmatisation that surrounds sexual violence while also helping individuals to gain a sense of empowerment and connect with other survivors. However, speaking out also contains inherent risks, especially for young people. Survivors may meet with stigmatising or disbelieving responses, and they may lose control over who knows their story and the way in which it is told and retold.
These risks and benefits are altered, and potentially exacerbated, in an online environment. While social media may increase survivors’ ability to contact and connect with others with similar experiences it also makes it harder to control when and how their story is shared. The disjuncture between online and offline environments may also increase feelings of stigmatisation and isolation.
There is a need to explore the specific risks and benefits of speaking out online given both young people’s extensive use of social media for social interactions and the increasing tendency for support and educational services targeted at young people to make use of social media and online environments. This paper draws on literature and some preliminary research to consider both risks and benefits of speaking out online and to open a conversation about the creation of supportive spaces and mechanisms for young people to speak about sexual violence in online environments.

Perspectives on social citizenship in the EU – from status positivus to status socialis activus via two forms of transnational solidarity

Ever since the inauguration of EU citizenship, elements of social citizenship have been on the agenda of European integration. European level social benefits were proposed early on, and demands for collective labour rights have followed suit. This chapter uses the theoretical umbrella of transnational social citizenship in order to link transnational access to social benefits and collective labour rights. It promotes transnational rights as the best way to conceptualise EU social citizenship as an institution enabling the enjoyment of EU integration without being forced to forego social rights at other levels. Such a perspective sits well in a collection on EU citizenship and federalism, since it simultaneously challenges demands of renationalisation of social rights in the EU and pleas to reduce EU-level citizenship rights to a merely liberal dimension. Social citizenship as promoted here requires an interactive conceptualisation of regulatory and judicial powers at different levels of government as typical for federal systems.
In linking citizenship with human rights the chapter highlights different statuses of citizens. It argues that the rights constituted by social citizenship derive from a status positivus and a status socialis activus, expanding the time-honoured categories of Jellinek. This concept is developed further by linking the notions of receptive solidarity to the status positivus and the notion of participative solidarity to the status socialis activus. In relation to European Union citizenship it promotes a sustainable transnational social citizenship catering for receptive and participative solidarity.
These ideas contrast with most current discourses on EU citizenship. The stress on social citizenship takes issue with a retreat to mere liberalist notions of EU-level citizenship, and the stress on rights takes issue with conceptualising EU citizenship as a community bond with obligations, downplaying the empowering potential of rights. The difficulty of conceptualising transnational social citizenship is to avoid, on the one hand, taking up the tune of populist discourses imagining those moving beyond state borders as a threat to national social citizenship and, on the other hand, to reject the legitimate fears of those remaining at home of creating rupture in the social fabric of Europe’s society. Promoting transnational social citizenship rights based on receptive and participative solidarity the present chapter aims to contribute to avoiding these pitfalls.

Young People, Peer-to-Peer Grooming and Sexual Offending: Understanding and Responding to Harmful Sexual Behaviour within a Social Media Society

There is ample evidence that young people engage in grooming and harmful sexual behaviour (HSB) using social media with enough frequency to make those behaviours important con-cerns for both society and care providers. This article provides a critical overview of the con-ceptual and empirical foundations of peer-to-peer grooming and the use of social media with-in the context of HSB. Based on this learning, it ultimately introduces a new model of inter-vention and of professional practice, which provides the standards for micro-level decision-making about goals, methods and assessment tailored to this specific offending context.

Pan-retinal photocoagulation and other forms of laser treatment and drug therapies for non-proliferative diabetic retinopathy: systematic review and economic evaluation

BACKGROUND: Diabetic retinopathy is an important cause of visual loss. Laser photocoagulation preserves vision in diabetic retinopathy but is currently used at the stage of proliferative diabetic retinopathy (PDR).

OBJECTIVES: The primary aim was to assess the clinical effectiveness and cost-effectiveness of pan-retinal photocoagulation (PRP) given at the non-proliferative stage of diabetic retinopathy (NPDR) compared with waiting until the high-risk PDR (HR-PDR) stage was reached. There have been recent advances in laser photocoagulation techniques, and in the use of laser treatments combined with anti-vascular endothelial growth factor (VEGF) drugs or injected steroids. Our secondary questions were: (1) If PRP were to be used in NPDR, which form of laser treatment should be used? and (2) Is adjuvant therapy with intravitreal drugs clinically effective and cost-effective in PRP?

ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) for efficacy but other designs also used.

REVIEW METHODS: Systematic review and economic modelling.

RESULTS: The Early Treatment Diabetic Retinopathy Study (ETDRS), published in 1991, was the only trial designed to determine the best time to initiate PRP. It randomised one eye of 3711 patients with mild-to-severe NPDR or early PDR to early photocoagulation, and the other to deferral of PRP until HR-PDR developed. The risk of severe visual loss after 5 years for eyes assigned to PRP for NPDR or early PDR compared with deferral of PRP was reduced by 23% (relative risk 0.77, 99% confidence interval 0.56 to 1.06). However, the ETDRS did not provide results separately for NPDR and early PDR. In economic modelling, the base case found that early PRP could be more effective and less costly than deferred PRP. Sensitivity analyses gave similar results, with early PRP continuing to dominate or having low incremental cost-effectiveness ratio. However, there are substantial uncertainties. For our secondary aims we found 12 trials of lasers in DR, with 982 patients in total, ranging from 40 to 150. Most were in PDR but five included some patients with severe NPDR. Three compared multi-spot pattern lasers against argon laser. RCTs comparing laser applied in a lighter manner (less-intensive burns) with conventional methods (more intense burns) reported little difference in efficacy but fewer adverse effects. One RCT suggested that selective laser treatment targeting only ischaemic areas was effective. Observational studies showed that the most important adverse effect of PRP was macular oedema (MO), which can cause visual impairment, usually temporary. Ten trials of laser and anti-VEGF or steroid drug combinations were consistent in reporting a reduction in risk of PRP-induced MO.

LIMITATION: The current evidence is insufficient to recommend PRP for severe NPDR.

CONCLUSIONS: There is, as yet, no convincing evidence that modern laser systems are more effective than the argon laser used in ETDRS, but they appear to have fewer adverse effects. We recommend a trial of PRP for severe NPDR and early PDR compared with deferring PRP till the HR-PDR stage. The trial would use modern laser technologies, and investigate the value adjuvant prophylactic anti-VEGF or steroid drugs.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005408.

FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Lost in Transition? Emerging forms of residential architecture in Kathmandu

Kathmandu has been the last few cities in the world which retained its medieval urban culture up until twentieth century. Various Hindu and Buddhist religious practices shaped the arrangement of houses, roads and urban spaces giving the city a distinctive physical form, character and a unique oriental nativeness. In recent decades, the urban culture of the city has been changing with the forces of urbanisation and globalisation and the demand for new buildings and spaces. New residential design is increasingly dominated by distinctive patterns of Western suburban ideal comprising detached or semi-detached homes and high rise tower blocks. This architectural iconoclasm can be construed as a rather crude response to the indigenous spaces and builtform. The paper attempts to dismantle the current tension between traditional and contemporary 'culture' (and hence society) and housing (or builtform) in Kathmandu by engaging in a discussion that cuts across space, time and meaning of building. The paper concludes that residential architecture in Kathmandu today stands disoriented and lost in the transition.