Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: A prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial

Background: Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. 

Methods: In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. 

Findings: Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56-0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52-0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. 

Interpretation: Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. 

Funding: Algeta ASA and Bayer HealthCare Pharmaceuticals.

Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles:a stereo- and regio- selective study

The reactions of enantiopure cyclohexene epoxides and trans-1,2-bromoacetates, derived from the corresponding substituted benzene cis-dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2-aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms. Allylic trans-1,2-azidohydrins were prepared by Lewis acid-catalysed ring-opening of cyclic vinyl epoxides with sodium azide via an S(N)2 mechanism. On heating, these trans-1,2-azidohydrins isomerized to the corresponding trans-1,4-azidohydrins via a suprafacial allyl azide [3,3]-sigmatropic rearrangement mechanism. Conversion of a 1,2-azidohydrin to a 1,2-azidoacetate moved the equilibrium position in favour of the 1,4-substitution product. Allylic trans-1,2-bromoacetates reacted with sodium azide at room temperature to give C-2 and C-4 substituted products. A clean inversion of configuration at C-2 was found, as expected, from a concerted S(N)2-pathway. However, substitution at C-4 was not stereoselective and resulted in mixtures of 1,4-cis and 1,4-trans products. This observation can be rationalized in terms of competitive S(N)2 and S(N)2 reactions allied to a [3,3]-sigmatropic rearrangement. cis-1,2-Azidohydrins and cis-1,2-azidoacetates were much more prone to rearrange than the corresponding trans-isomers. Reaction of the softer tosamide nucleophile with trans-1,2-bromoacetates resulted, predominantly, in C-4 substitution via a syn-S(N)2 mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans-1,2-aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an S(N)2 mechanism. Copyright (c) 2013 John Wiley & Sons, Ltd.

Knowledge translation in men’s health research: development and delivery of content for use online

Background: Men can be hard to reach with face-to-face health-related information, while increasingly, research shows that they are seeking health information from online sources. Recognizing this trend, there is merit in developing innovative online knowledge translation (KT) strategies capable of translating research on men’s health into engaging health promotion materials. While the concept of KT has become a new mantra for researchers wishing to bridge the gap between research evidence and improved health outcomes, little is written about the process, necessary skills, and best practices by which researchers can develop online knowledge translation.
Objective: Our aim was to illustrate some of the processes and challenges involved in, and potential value of, developing research knowledge online to promote men’s health.

Methods: We present experiences of KT across two case studies of men’s health. First, we describe a study that uses interactive Web apps to translate knowledge relating to Canadian men’s depression. Through a range of mechanisms, study findings were repackaged with the explicit aim of raising awareness and reducing the stigma associated with men’s depression and/or help-seeking. Second, we describe an educational resource for teenage men about unintended pregnancy, developed for delivery in the formal Relationship and Sexuality Education school curricula of Ireland, Northern Ireland (United Kingdom), and South Australia. The intervention is based around a Web-based interactive film drama entitled “If I Were Jack”.

Results: For each case study, we describe the KT process and strategies that aided development of credible and well-received online content focused on men’s health promotion. In both case studies, the original research generated the inspiration for the interactive online content and the core development strategy was working with a multidisciplinary team to develop this material through arts-based approaches. In both cases also, there is an acknowledgment of the need for gender and culturally sensitive information. Both aimed to engage men by disrupting stereotypes about men, while simultaneously addressing men through authentic voices and faces. Finally, in both case studies we draw attention to the need to think beyond placement of content online to delivery to target audiences from the outset.

Conclusions: The case studies highlight some of the new skills required by academics in the emerging paradigm of translational research and contribute to the nascent literature on KT. Our approach to online KT was to go beyond dissemination and diffusion to actively repackage research knowledge through arts-based approaches (videos and film scripts) as health promotion tools, with optimal appeal, to target male audiences. Our findings highlight the importance of developing a multidisciplinary team to inform the design of content, the importance of adaptation to context, both in terms of the national implementation context and consideration of gender-specific needs, and an integrated implementation and evaluation framework in all KT work.

Effect of controlled periodic-based illumination on the photonic efficiency of photocatalytic degradation of methyl orange

The use of controlled periodic illumination with UV LEDs for enhancing photonic efficiency of photocatalytic decomposition processes in water has been investigated using methyl orange as a model compound. The impact of the length of light and dark time periods (T _ON/T _OFF times) on photodegradation and photonic efficiency using a UV LED-illuminated photoreactor has been studied. The results have shown an inverse dependency of the photonic efficiency on duty cycle and a very little effect on T _ON or T _OFF time periods, indicating no effect of rate-limiting steps through mass diffusion or adsorption/desorption in the reaction. For this reactor, the photonic efficiency under controlled periodic illumination (CPI) matches to that of continuous illumination, for the same average UV light intensities. Furthermore, under CPI conditions, the photonic efficiency is inversely related to the average UV light intensity in the reactor, in the millisecond time regime. This is the first study that has investigated the effect of controlled periodic illumination using ultra band gap UV LED light sources in the photocatalytic destruction of dye compounds using titanium dioxide. The results not only enhance the understanding of the effect of periodic illumination on photocatalytic processes but also provide a greater insight to the potential of these light sources in photocatalytic reactions. 

Evaluating early administration of the hydroxymethylglutaryl-CoA reductase inhibitor simvastatin in the prevention and treatment of delirium in critically ill ventilated patients (MoDUS trial): Study protocol for a randomized controlled trial

Background: The incidence of delirium in ventilated patients is estimated at up to 82%, and it is associated with longer intensive care and hospital stays, and long-term cognitive impairment and mortality. The pathophysiology of delirium has been linked with inflammation and neuronal apoptosis. Simvastatin has pleiotropic properties; it penetrates the brain and, as well as reducing cholesterol, reduces inflammation when used at clinically relevant doses over the short term. This is a single centre randomised, controlled trial which aims to test the hypothesis that treatment with simvastatin will modify delirium incidence and outcomes. 

Methods/Design: The ongoing study will include 142 adults admitted to the Watford General Hospital Intensive Care Unit who require mechanical ventilation in the first 72 hours of admission. The primary outcome is the number of delirium- and coma-free days in the first 14 days. Secondary outcomes include incidence of delirium, delirium- and coma-free days in the first 28 days, days in delirium and in coma at 14 and 28 days, number of ventilator-free days at 28 days, length of critical care and hospital stay, mortality, cognitive decline and healthcare resource use. Informed consent will be taken from patient's consultee before randomisation to receive either simvastatin (80 mg) or placebo once daily. Daily data will be recorded until day 28 after randomisation or until discharge from the ICU if sooner. Surviving patients will be followed up on at six months from discharge. Plasma and urine samples will be taken to investigate the biological effect of simvastatin on systemic markers of inflammation, as related to the number of delirium- and coma-free days, and the potential of cholinesterase activity and beta-amyloid as predictors of the risk of delirium and long-term cognitive impairment. 

Discussion: This trial will test the efficacy of simvastatin on reducing delirium in the critically ill. If patients receiving the statin show a reduced number of days in delirium compared with the placebo group, the inflammatory theory implicated in the pathogenesis of delirium will be strengthened. 

Selection and characterisation of geological materials for use as geopolymer precursors

Geopolymer binders are generally formed by reacting powdered aluminosilicate precursors with alkali silicate activators. Most research to date has concentrated on using either pulverised fuel ash or high purity dehydroxylated kaolin (metakaolin) in association with ground granulated blast furnace slag as the main precursor material. However, recently, attention has turned to alternative calcined clays that are abundant throughout the globe and have lower kaolinite contents than commercially available metakaolins. Due to the lack of clear and simple screening protocols enabling assessment of such geological resources for use as precursors in geopolymer systems, the present paper presents results from experimental work that was carried out to develop a functional binder using materials containing kaolinite taken from the Interbasaltic Formation of Northern Ireland. The influence of mineralogy has been examined, and a screening process, using three Interbasaltic materials as examples, that will assist in the rapid selection of suitable geopolymeric precursors from such materials is outlined.

Labour Law as Human Rights Law: A Critique of the Use of ‘Dignity’ by Freedland and Kountouris

In their recent book, The Legal Construction of Personal Work Relations, Mark Freedland and Nicola Kountouris present an ambitious study of the personal scope of (what they would not want to call) ‘employment’ law. The book does this within a broader argument that calls for the reconceptualization of labour law as a whole, and it is this broader argument on which I shall focus in this chapter. Their aim, in urging us to see labour law through the lens of ‘dignity’ is to bring labour law and human rights law into closer alignment than has sometimes been the case in the past. Increasingly, dignity is seen as providing a, sometimes the, foundation of human rights law, particularly in Europe. I shall suggest that whilst the aim of constructing a new set of foundations for labour law is a worthy and increasingly urgent task, the concepts on which Freedland and Kountouris seek to build their project pose significant difficulties. In particular, their espousal of ‘dignity’ presents problems that must be addressed if their reconceptualization is not to prove a blind alley.

Potential of hydrogel-forming and dissolving microneedles for use in paediatric populations

Development of formulations and drug delivery strategies for paediatric use is challenging, partially due to the age ranges within this population, resulting in varying requirements to achieve optimised patient outcomes. Although the oral route of drug delivery remains the preferred option, there are problematic issues, such as difficulty swallowing and palatability of medicines specific to this population. The parenteral route is not well accepted by children due to needle-related fear and pain. Accordingly, a plethora of alternative routes of drug administration have been investigated. Microneedles (MN) breach the stratum corneum (SC), the outermost layer of skin, increasing the number of drug substances amenable to transdermal delivery. This strategy involves the use of micron-sized needles to painlessly, and without drawing blood, create transient aqueous conduits in the SC. In this study, polymeric dissolving MN and hydrogel-forming MN were fabricated incorporating two model drugs commonly used in paediatric patients (caffeine and lidocaine hydrochloride). The potential efficacy of these MN for paediatric dosing was investigated via in vitro and in vivo studies. Views pertaining to MN technology were sought amongst school children in Northern Ireland, members of the UK general public and UK-based paediatricians, to determine perceived benefits, acceptance, barriers and concerns for adoption of this technology. In this study, polymeric MN were shown to substantially enhance skin permeability of the model therapeutic molecules in vitro and in vivo. In particular, hydrogel-forming MN led to a 6.1-fold increase in caffeine delivery whilst lidocaine HCl delivery was increased by 3.3-fold using dissolving MN in vitro. Application of caffeine-loaded MN led to a caffeine plasma concentration of 23.87μg/mL in rats at 24h. This research also highlighted a strong consensus regarding MN technology amongst schoolchildren, paediatricians and the general public, regarding potential use of MN in the paediatric population. Overall, 93.6% of general public respondents and 85.9% of paediatricians regarded the use of MN as a positive approach.