A randomised controlled trial of the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia:the ECLIPSE trial

BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem, yet evidence to inform decisions about initial medical treatment is limited. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena(®), Bayer) compared with usual medical treatment, with exploration of women's perspectives on treatment. DESIGN: A pragmatic, multicentre randomised trial with an economic evaluation and a longitudinal qualitative study. SETTING: Women who presented in primary care. PARTICIPANTS: A total of 571 women with HMB. A purposeful sample of 27 women who were randomised or ineligible owing to treatment preference participated in semistructured face-to-face interviews around 2 and 12 months after commencing treatment. INTERVENTIONS: LNG-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progesterone alone). Women could subsequently swap or cease their allocated treatment. OUTCOME MEASURES: The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period and then again at 5 years. Secondary outcomes included general quality of life (QoL), sexual activity, surgical intervention and safety. Data were analysed using iterative constant comparison. A state transition model-based cost-utility analysis was undertaken alongside the randomised trial. Quality-adjusted life-years (QALYs) were derived from the European Quality of Life-5 Dimensions (EQ-5D) and the Short Form questionnaire-6 Dimensions (SF-6D). The intention-to-treat analyses were reported as cost per QALY gained. Uncertainty was explored by conducting both deterministic and probabilistic sensitivity analyses. RESULTS: The MMAS total scores improved significantly in both groups at all time points, but were significantly greater for the LNG-IUS than for usual treatment [mean difference over 2 years was 13.4 points, 95% confidence interval (CI) 9.9 to 16.9 points; p < 0.001]. However, this difference between groups was reduced and no longer significant by 5 years (mean difference in scores 3.9 points, 95% CI -0.6 to 8.3 points; p = 0.09). By 5 years, only 47% of women had a LNG-IUS in place and 15% were still taking usual medical treatment. Five-year surgery rates were low, at 20%, and were similar, irrespective of initial treatments. There were no significant differences in serious adverse events between groups. Using the EQ-5D, at 2 years, the relative cost-effectiveness of the LNG-IUS compared with usual medical treatment was £1600 per QALY, which by 5 years was reduced to £114 per QALY. Using the SF-6D, usual medical treatment dominates the LNG-IUS. The qualitative findings show that women's experiences and expectations of medical treatments for HMB vary considerably and change over time. Women had high expectations of a prompt effect from medical treatments. CONCLUSIONS: The LNG-IUS, compared with usual medical therapies, resulted in greater improvement over 2 years in women's assessments of the effect of HMB on their daily routine, including work, social and family life, and psychological and physical well-being. At 5 years, the differences were no longer significant. A similar low proportion of women required surgical intervention in both groups. The LNG-IUS is cost-effective in both the short and medium term, using the method generally recommended by the National Institute for Health and Care Excellence. Using the alternative measures to value QoL will have a considerable impact on cost-effectiveness decisions. It will be important to explore the clinical and health-care trajectories of the ECLIPSE (clinical effectiveness and cost-effectiveness of levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia) trial participants to 10 years, by which time half of the cohort will have reached menopause. TRIAL REGISTRATION: Current Controlled Trials ISRCTN86566246. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 88. See the NIHR Journals Library website for further project information.

Penetration of chlorhexidine into human skin

This study evaluated a model of skin permeation to determine the depth of delivery of chlorhexidine into full-thickness excised human skin following topical application of 2% (wt/vol) aqueous chlorhexidine digluconate. Skin permeation studies were performed on full-thickness human skin using Franz diffusion cells with exposure to chlorhexidine for 2 min, 30 min, and 24 h. The concentration of chlorhexidine extracted from skin sections was determined to a depth of 1,500 µm following serial sectioning of the skin using a microtome and analysis by high-performance liquid chromatography. Poor penetration of chlorhexidine into skin following 2-min and 30-min exposures to chlorhexidine was observed (0.157 ± 0.047 and 0.077 ± 0.015 µg/mg tissue within the top 100 µm), and levels of chlorhexidine were minimal at deeper skin depths (less than 0.002 µg/mg tissue below 300 µm). After 24 h of exposure, there was more chlorhexidine within the upper 100-µm sections (7.88 ± 1.37 µg/mg tissue); however, the levels remained low (less than 1 µg/mg tissue) at depths below 300 µm. There was no detectable penetration through the full-thickness skin. The model presented in this study can be used to assess the permeation of antiseptic agents through various layers of skin in vitro. Aqueous chlorhexidine demonstrated poor permeation into the deeper layers of the skin, which may restrict the efficacy of skin antisepsis with this agent. This study lays the foundation for further research in adopting alternative strategies for enhanced skin antisepsis in clinical practice.

Design and construction of an ultrasonic probe for use in a Cryo-Magnet NMR Spectrometer

SINNMR (Sonically Induced Narrowing of the Nuclear Magnetic Resonance spectra of solids), is a novel technique that is being developed to enable the routine study of solids by nuclear magnetic resonance spectroscopy. SINNMR aims to narrow the broad resonances that are characteristic of solid state NMR by inducing rapid incoherent motion of solid particles suspended in a support medium, using high frequency ultrasound in the range 2-10 MHz. The width of the normal broad resonances from solids are due to incomplete averaging of several components of the total spin Hamiltonian caused by restrictions placed on molecular motion within a solid. At present Magic Angle Spinning (MAS) NMR is the classical solid state technique used to reduce line broadening, but: this has associated problems, not least of which is the appearance of many spinning side bands which confuse the spectra. It is hoped that SlNNMR will offer a simple alternative, particularly as it does not reveal spinning sidebands The fundamental question concerning whether the use of ultrasound within a cryo-magnet will cause quenching has been investigated with success, as even under the most extreme conditions of power, frequency and irradiator time, the magnet does not quench. The objective of this work is to design and construct a SINNMR probe for use in a super conducting cryo-magnet NMR spectrometer. A cell for such a probe has been constructed and incorporated into an adapted high resolution broadband probe. It has been proved that the cell is capable of causing cavitation, up to 10 MHz, by running a series of ultrasonic reactions within it and observing the reaction products. It was found that the ultrasound was causing the sample to be heated to unacceptable temperatures and this necessitated the incorporation of temperature stabilisation devices. Work has been performed on the investigation of the narrowing of the solid state 23Na spectrum of tri-sodium phosphate using high frequency ultrasound. Work has also been completed on the signal enhancement and T1 reduction of a liquid mixture and a pure compound using ultrasound. Some preliminary "bench" experiments have been completed on a novel ultrasonic device designed to help minimise sample heating. The concept involves passing the ultrasound through a temperature stabilised, liquid filled funnel that has a drum skin on the end that will enable the passage of ultrasound into the sample. Bench experiments have proved that acoustic attenuation is low and that cavitation in the liquid beyond the device is still possible.

Design, modeling and construction of a novel ablative fast pyrolysis reactor and product collection system

The objective of this work was to design, construct and commission a new ablative pyrolysis reactor and a high efficiency product collection system. The reactor was to have a nominal throughput of 10 kg/11r of dry biomass and be inherently scalable up to an industrial scale application of 10 tones/hr. The whole process consists of a bladed ablative pyrolysis reactor, two high efficiency cyclones for char removal and a disk and doughnut quench column combined with a wet walled electrostatic precipitator, which is directly mounted on top, for liquids collection. In order to aid design and scale-up calculations, detailed mathematical modelling was undertaken of the reaction system enabling sizes, efficiencies and operating conditions to be determined. Specifically, a modular approach was taken due to the iterative nature of some of the design methodologies, with the output from one module being the input to the next. Separate modules were developed for the determination of the biomass ablation rate, specification of the reactor capacity, cyclone design, quench column design and electrostatic precipitator design. These models enabled a rigorous design protocol to be developed capable of specifying the required reactor and product collection system size for specified biomass throughputs, operating conditions and collection efficiencies. The reactor proved capable of generating an ablation rate of 0.63 mm/s for pine wood at a temperature of 525 'DC with a relative velocity between the heated surface and reacting biomass particle of 12.1 m/s. The reactor achieved a maximum throughput of 2.3 kg/hr, which was the maximum the biomass feeder could supply. The reactor is capable of being operated at a far higher throughput but this would require a new feeder and drive motor to be purchased. Modelling showed that the reactor is capable of achieving a reactor throughput of approximately 30 kg/hr. This is an area that should be considered for the future as the reactor is currently operating well below its theoretical maximum. Calculations show that the current product collection system could operate efficiently up to a maximum feed rate of 10 kg/Fir, provided the inert gas supply was adjusted accordingly to keep the vapour residence time in the electrostatic precipitator above one second. Operation above 10 kg/hr would require some modifications to the product collection system. Eight experimental runs were documented and considered successful, more were attempted but due to equipment failure had to be abandoned. This does not detract from the fact that the reactor and product collection system design was extremely efficient. The maximum total liquid yield was 64.9 % liquid yields on a dry wood fed basis. It is considered that the liquid yield would have been higher had there been sufficient development time to overcome certain operational difficulties and if longer operating runs had been attempted to offset product losses occurring due to the difficulties in collecting all available product from a large scale collection unit. The liquids collection system was highly efficient and modeling determined a liquid collection efficiency of above 99% on a mass basis. This was validated due to the fact that a dry ice/acetone condenser and a cotton wool filter downstream of the collection unit enabled mass measurements of the amount of condensable product exiting the product collection unit. This showed that the collection efficiency was in excess of 99% on a mass basis.

Using secondary knowledge to support decision tree classification of retrospective clinical data

Retrospective clinical data presents many challenges for data mining and machine learning. The transcription of patient records from paper charts and subsequent manipulation of data often results in high volumes of noise as well as a loss of other important information. In addition, such datasets often fail to represent expert medical knowledge and reasoning in any explicit manner. In this research we describe applying data mining methods to retrospective clinical data to build a prediction model for asthma exacerbation severity for pediatric patients in the emergency department. Difficulties in building such a model forced us to investigate alternative strategies for analyzing and processing retrospective data. This paper describes this process together with an approach to mining retrospective clinical data by incorporating formalized external expert knowledge (secondary knowledge sources) into the classification task. This knowledge is used to partition the data into a number of coherent sets, where each set is explicitly described in terms of the secondary knowledge source. Instances from each set are then classified in a manner appropriate for the characteristics of the particular set. We present our methodology and outline a set of experiential results that demonstrate some advantages and some limitations of our approach. © 2008 Springer-Verlag Berlin Heidelberg.

Toward the atomistic simulation of T cell epitopes automated construction of MHC:peptide structures for free energy calculations

Epitopes mediated by T cells lie at the heart of the adaptive immune response and form the essential nucleus of anti-tumour peptide or epitope-based vaccines. Antigenic T cell epitopes are mediated by major histocompatibility complex (MHC) molecules, which present them to T cell receptors. Calculating the affinity between a given MHC molecule and an antigenic peptide using experimental approaches is both difficult and time consuming, thus various computational methods have been developed for this purpose. A server has been developed to allow a structural approach to the problem by generating specific MHC:peptide complex structures and providing configuration files to run molecular modelling simulations upon them. A system has been produced which allows the automated construction of MHC:peptide structure files and the corresponding configuration files required to execute a molecular dynamics simulation using NAMD. The system has been made available through a web-based front end and stand-alone scripts. Previous attempts at structural prediction of MHC:peptide affinity have been limited due to the paucity of structures and the computational expense in running large scale molecular dynamics simulations. The MHCsim server (http://igrid-ext.cryst.bbk.ac.uk/MHCsim) allows the user to rapidly generate any desired MHC:peptide complex and will facilitate molecular modelling simulation of MHC complexes on an unprecedented scale.

The construction of masculinities and femininities in the Church of England:the case of the male clergy spouse

The ordination of women to the priesthood in the Church of England in 1994 signified great change. The impact of the new priests was well documented, and their integration became the focus of much research in the following years. One important area of change was the altered dynamics of gender identity. New roles had opened up for women, but new identities had also emerged for men. While women priests were a new historical emergence, so too were clergy husbands. This paper will consider the historical construction of masculinities and femininities within the church and will go on to look at this in the context of clergy spouses, specifically focusing on men occupying this role. Some provisional findings, acting as work in progress, will be considered.

The political control of orthodoxy in the construction of the Romanian State, 1859-1918

This article analyses the relationship between Orthodoxy and state from the unification of the Principalities of Moldavia and Wallachia in 1859 to the creation of Greater Romania in 1918. Examining the attitudes of political leaders towards the dominant religion, this article argues that during the reigns of Prince Cuza and King Carol I the Church became a state institution closely connected to the development of political regimes. It is suggested that by claiming doctrinal religious connections with Constantinople and independence from foreign intervention in the Church’s affairs, religious and political leaders from 1859 to 1918 amplified the construction of Romanian national mythology which contributed towards the political unity of the state.

France and the construction of Europe, 1944-2007:the geopolitical imperative

In the second half of the twentieth century France played the greatest role - even greater than Germany’s - in shaping what eventually became the European Union. By the early twenty-first century, however, in a hugely transformed Europe, this era had patently come to an end. This comprehensive history shows how France coupled the pursuit of power and the furtherance of European integration over a sixty-year period, from the close of the Second World War to the hesitation caused by the French electorate’s referendum rejection of the European Union’s constitutional treaty in 2005.

Semi-supervised construction of general visualization hierarchies

We have recently developed a principled approach to interactive non-linear hierarchical visualization [8] based on the Generative Topographic Mapping (GTM). Hierarchical plots are needed when a single visualization plot is not sufficient (e.g. when dealing with large quantities of data). In this paper we extend our system by giving the user a choice of initializing the child plots of the current plot in either interactive, or automatic mode. In the interactive mode the user interactively selects ``regions of interest'' as in [8], whereas in the automatic mode an unsupervised minimum message length (MML)-driven construction of a mixture of GTMs is used. The latter is particularly useful when the plots are covered with dense clusters of highly overlapping data projections, making it difficult to use the interactive mode. Such a situation often arises when visualizing large data sets. We illustrate our approach on a data set of 2300 18-dimensional points and mention extension of our system to accommodate discrete data types.

The social construction of sleep and work in the British print news media

This article presents a sociological study of sleep issues in the British print news media, with particular focus on the relationship between sleep, work and the changing demands of ‘flexible capitalism’. Drawing on over 1000 newspaper articles from 1984 to 2005, we explore how and why sleep is framed or constructed in terms of continuity and change (in British working life and work cultures) and, equally, viewed as a neglected component of our social lives which is too easily sacrificed to the demands of the 24/7 society, long hours culture and the struggle to create a harmonious work-life balance. This is particularly the case for certain British work cultures in which sleep has conflicting and contrasting associations. Finally, we reflect on the broader class-based discourses and debates that arise from certain workers having their sleep patterns increasingly scrutinized and regulated, and the role of the media in any ensuing sleep/work ‘crisis’.

Medicalisation and beyond: the social construction of insomnia and snoring in the news

What role do the media play in the medicalization of sleep problems? This article, based on a British Academy funded project, uses qualitative textual analysis to examine representations of insomnia and snoring in a large representative sample of newspaper articles taken from the UK national press from the mid-1980s to the present day. Constructed as ‘common problems’ in the population at large, insomnia and snoring we show are differentially located in terms of medicalizing—healthicizing discourses and debates. Our findings also suggest important differences in the gendered construction of these problems and in terms of tabloid and ‘broadsheet’ newspaper coverage of these issues. Newspaper constructions of sleep, it is concluded, are complex, depending on both the ‘problem’ and the paper in question.

Who are you sleeping with? The construction of heteronormativity in stories about sleep in British newspapers

In popular British understanding the terms 'sleeping' or 'slept' are often used to mean sex, and (hetero)sex is seen as crucial to sustaining intimate relationships. This study of UK newspapers coverage shows that stories about sieep and sleeping arrangements can be seen to (re)produce heteronormativity through focusing on the (heterosexual) 'marital bed'. The 'marital bed' is constructed as both the physical and symbolic centre of successful heterosexual relationships. Moreover, the maintenance of this symbolic space is gendered with women given primary responsibility. The focus on the 'marital bed' helps to exclude non-heterosexuals from the idea of intimate relationships, by effectively silencing their experiences of sleep and sleeping arrangements. Normative ideas about male and female (hetero)sexualities are drawn on to undermine women's right to refuse sex within the martial bed. In addition, the term 'sleep-sex' is used to reconceptualise stories of rape, minimising the victim's experiences and absolve the perpetrator from full responsibility for the assault. By exploring these articles we can see both how the representation of the organisation of sleep is produced through heteronormativity, as well as how heteronormativity determines whose accounts of sleeping are prioritised. © Sociological Research Online.

Problematising the construction of journal quality:an engagement with the mainstream

Journal ranking studies have generally adopted citation techniques or academic perceptions as the basis for assessing journal quality. They have traditionally been a source of information about potential research outlets, new journals, and an aid to developing a consensus about the relative merit of publications for promotion decisions. The aim of our research is to address specific shortcomings in the conventional literature and construct an alternative view of how we might more appropriately assess journal ‘quality’. We attempt to engage with the conventional literature by applying an approach that does not privilege either citation techniques or academic perceptions. We have adopted from Zeff (1996) an objective measure of academic journal library holdings, which Zeff describes as a ‘market test’. Our construct provides evidence of an important difference in journal holdings for the Australasian region that could significantly influence further research on journal quality. The method itself is entirely mundane but may be considered to reflect a complex of historic and more contemporary variables which impact on academic and administrative decisions, influencing the makeup of academic library holdings and providing a proxy for journal ‘quality’.

Methodology choices and the construction of facts:some implications from the sociology of scientific knowledge

This paper has two objectives: first, to provide a brief review of developments in the sociology of scientific knowledge (SSK); second to apply an aspect of SSK theorising which is concerned with the construction of scientific knowledge. The paper offers a review of the streams of thought which can be identified within SSK and then proceeds to illustrate the theoretic constructs introduced in the earlier discussion by analysing a particular contribution to the literature on research methodology in accounting and organisations studies. The paper chosen for analysis is titled “Middle Range Thinking”. The objective of this paper is not to argue that the approach used in this paper is invalid, but to seek to expose the rhetorical nature of the argumentation which is used by the author of the paper.