Preliminary clinical assessment of polyvinyl alcohol-tetrahydroxyborate hydrogels as potential topical formulations for local anesthesia of lacerations

The aim of this study was to assess a novel semisolid material as a potential topical drug delivery system for acute laceration. The objectives were to correlate physical characterization data using rheologic studies and to compare with clinical assessment of performance in an emergency department (ED).

Solid phase synthesis of Smac/DIABLO-derived peptides using a 'Safety-Catch' resin:Identification of potent XIAP BIR3 antagonists

The N-terminal sequence of the Smac/DIABLO protein is known to be involved in binding to the BIR3 domain of the anti-apoptotic proteins IAPs, antagonizing their action. Short peptides and peptide mimetics based on the first 4-residues of Smac/DIABLO have been demonstrated to re-sensitize resistant cancer cells, over-expressing IAPs, to apoptosis. Based on the well-defined structural basis for this interaction, a small focused library of C-terminal capped Smac/DIABLO-derived peptides was designed in silico using docking to the XIAP BIR3 domain. The top-ranked computational hits were conveniently synthesized employing Solid Phase Synthesis (SPS) on an alkane sulfonamide 'Safety-Catch' resin. This novel approach afforded the rapid synthesis of the target peptide library with high flexibility for the introduction of various C-terminal amide-capping groups. The library members were obtained in high yield (>65%) and purity (>85%), upon nucleophilic release from the activated resin by treatment with various amine nucleophiles. In vitro caspase-9 activity reconstitution assays of the peptides in the presence of the recombinant BIR3-domain of human XIAP (500nM) revealed N-methylalanyl-tertiarybutylglycinyl-4-(R)-phenoxyprolyl-N-biphenylmethyl carboxamide (11a) to be the most potent XIAP BIR3 antagonist of the series synthesized inducing 93% recovery of caspase-9 activity, when used at 1µM concentration. Compound (11a) also demonstrated moderate cytotoxicity against the breast cancer cell lines MDA-MB-231 and MCF-7, compared to the Smac/DIABLO-derived wild-type peptide sequences that were totally inactive in the same cell lines.

An Analysis of Soft Law Applicable to Humanitarian Assistance: Relative Normativity in Action?

There is limited binding international law specifically covering the provision of humanitarian assistance in response to natural and human-made disasters. Yet a variety of authoritative soft law texts have been developed in the past 20 years, including the UN Guiding Principles on Internal Displacement, the Red Cross Red Crescent Code of Conduct and the Sphere Project’s Humanitarian Charter and Minimum Standards in Disaster Response. While such ‘non-binding normative standards’ do not carry the weight of international law, they play an essential role in the provision of humanitarian assistance albeit subject to their limited enforceability vis-à-vis intended beneficiaries and to their voluntary application by humanitarian actors. Notwithstanding a lack of legal compulsion, certain non-binding normative standards may directly influence the actions of States and non-State actors, and so obtain a strongly persuasive character. Analysis of texts that influence the practice of humanitarian assistance advances our understanding of humanitarian principles and performance standards for disaster response. As the International Law Commission debates draft articles on the Protection of Persons in the Event of Disasters, such non-binding normative standards are crucial to the development of an internationally accepted legal framework to protect victims of disasters.

The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis

BACKGROUND: Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

RESULTS: Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

CONCLUSIONS: Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).

An Evaluation of the Drug and Alcohol Service User Network in NI

Objectives:
The process evaluation will consider the views of the appointed SUN workers and representatives from selected service user groups as regards the setting up and maintenance of the SUN network. This component of the evaluation will also examine the perceptions of stakeholders from a number of relevant organisations.

The outcome evaluation will assess the effectiveness of the SUN project in achieving the intended outcomes as outlined in the original Action Plans.
The following outcomes will be evaluated:
To ascertain the level to which the SUN has provided support, information and advice to existing service user groups.
To examine the SUN co-ordination of Trust and regional networks of service user groups.
To consider how the SUN assists organisations to establish and maintain service user groups.
To examine the level of current and future membership of service users on relevant groups, with a particular focus on engagement of hard to reach populations.
To gauge service user perceptions of the Service User Network.
To examine the levels of training provided and consider the efficacy of training.

Powers, liabilities and expertise in community safety: Comparative lessons for ‘urban security’ from the United Kingdom and the Republic of Ireland

This paper begins by outlining and critiquing what we term the dominant anglophone model of neo-liberal community safety and crime prevention. As an alternative to this influential but flawed model, a comparative analysis is provided of the different constitutional-legal settlements in each of the five jurisdictions across the UK and the Republic of Ireland (ROI), and their uneven institutionalization of community safety. In the light of this it is argued that the nature of the anglophone community safety enterprise is actually subject to significant variation. Summarizing the contours of this variation facilitates our articulation of some core dimensions of community safety. Then, making use of Colebatch’s (2002) deconstruction of policy activity into categories of authority and expertise, and Brunsson’s (2002) distinction between policy talk, decisions and action, we put forward a way of understanding policy activity that avoids the twin dangers of ‘false particularism’ and ‘false universalism’ (Edwards and Hughes, 2005); that indicates a path for further empirical enquiry to assess the ‘reality’ of policy convergence; and that enables the engagement of researchers with normative questions about where community safety should be heading.