Premature ovarian insufficiency: the need for evidence on the effectiveness of hormonal therapy

Premature ovarian insufficiency (POI) – the loss of ovarian function before the age of 40 years, a decade before natural menopause – is a life-changing diagnosis for women. POI causes significant short-term and long-term morbidity related to estrogen deficiency. The condition is managed by providing exogenous estrogen replacement, usually as the oral contraceptive pill or hormone therapy. These preparations have different estrogen formulations and may have differing benefits and risks. At present, there are no robust data to inform clinical recommendations and women’s decision-making about treatment that they may be taking for many years. The POISE study (Premature Ovarian Insufficiency Study of Effectiveness of hormonal therapy) has been designed to determine whether hormone therapy is superior to combined oral contraceptives on important clinical outcomes and patient-reported symptoms, based on the hypothesis that hormone therapy provides more physiological continuous hormone supplementation with natural estrogens. The study is an open and pragmatic, parallel, randomized controlled trial. The primary outcome is absolute bone mineral density assessed by dual-energy X-ray absorptiometry of the lumbar spine after 2 years of treatment. The study will also investigate cardiovascular markers, symptom relief and acceptability of treatment, and will continue to collect long-term data on fractures and cardiovascular events. Results will inform future guidance on management of POI

Neutralisation treatment of AMD at affordable cost

Acid mine drainage (AMD) has for many years been a major environmental challenge associated with the mining industry, especially in the Eastern, Central and Western mining basins of Gauteng. The aims of this article are to: (i) demonstrate the suitability of the sequencing batch reactor (SBR) system for both neutralisation of free acid and removal of iron(II), often the main component in AMD, using limestone, the cheapest alkali, followed by lime treatment for removal of heavy metals, and partial sulphate removal through gypsum crystallisation; (ii) compare the alkali cost of the alternative SBR system where limestone and lime are used for treatment, with conventional lime treatment, and (iii) present the capital cost of the SBR system.The conclusions of this study are that: (i) precipitated calcium carbonate can be used for complete removal of iron(II) in an SBR system within 90 min reaction time; (ii) lime can be used for complete removal of heavy metals after pre-treatment with precipitated calcium carbonate; (iii) the alkali cost for treatment of AMD from the Western Basin will amount to R2.80/m3 in the case of limestone/lime treatment compared to R5.83/m3 if only lime is used; (iv) the alkali cost for treatment of 85 Mℓ/d acid mine water from both the Western and Central Basins will amount to R60 m./a in the case of limestone/lime treatment compared to R136.9 m./a if only lime is used; and (v) the capital cost for the SBR system amounts to R3.5 m. per Mℓ/d.Keywords: Acid mine drainage, sequencing batch reactor, neutralisation, limeston

Electromechanical Response of Polycrystalline Barium Titanate Resolved at the Grain Scale

Ferroic materials are critical components in many modern devices. Polycrystalline states of these materials dominate the market due to their cost effectiveness and ease of production. Studying the coupling of ferroic properties across grain boundaries and within clusters of grains is therefore critical for understanding bulk polycrystalline ferroic behavior. Here, three-dimensional X-ray diffraction is used to reconstruct a 3D grain map (grain orientations and neighborhoods) of a polycrystalline barium titanate sample and track the grain-scale non-180° ferroelectric domain switching strains of 139 individual grains in situ under an applied electric field. The map shows that each grain is located in a very unique local environment in terms of intergranular misorientations, leading to local strain heterogeneity in the as-processed state of the sample. While primarily dependent on the crystallographic orientation relative to the field directions, the response of individual grains is also heterogeneous. These unique experimental results are of critical importance both when building the starting conditions and considering the validity of grain-scale modeling efforts, and provide additional considerations in the design of novel ferroic materials

Levonorgestrel-releasing intrauterine system vs. usual medical treatment for menorrhagia: An economic evaluation alongside a randomised controlled trial

Objective: To undertake an economic evaluation alongside the largest randomised controlled trial comparing Levonorgestrel-releasing intrauterine device ('LNG-IUS') and usual medical treatment for women with menorrhagia in primary care; and compare the cost-effectiveness findings using two alternative measures of quality of life. Methods: 571 women with menorrhagia from 63 UK centres were randomised between February 2005 and July 2009. Women were randomised to having a LNG-IUS fitted, or usual medical treatment, after discussing with their general practitioner their contraceptive needs or desire to avoid hormonal treatment. The treatment was specified prior to randomisation. For the economic evaluation we developed a state transition (Markov) model with a 24 month follow-up. The model structure was informed by the trial women's pathway and clinical experts. The economic evaluation adopted a UK National Health Service perspective and was based on an outcome of incremental cost per Quality Adjusted Life Year (QALY) estimated using both EQ-5D and SF-6D. Results: Using EQ-5D, LNG-IUS was the most cost-effective treatment for menorrhagia. LNG-IUS costs £100 more than usual medical treatment but generated 0.07 more QALYs. The incremental cost-effectiveness ratio for LNG-IUS compared to usual medical treatment was £1600 per additional QALY. Using SF-6D, usual medical treatment was the most cost-effective treatment. Usual medical treatment was both less costly (£100) and generated 0.002 more QALYs. Conclusion: Impact on quality of life is the primary indicator of treatment success in menorrhagia. However, the most costeffective treatment differs depending on the quality of life measure used to estimate the QALY. Under UK guidelines LNG-IUS would be the recommended treatment for menorrhagia. This study demonstrates that the appropriate valuation of outcomes in menorrhagia is crucial. Copyright: © 2014 Sanghera et al

Public health equity in refugee situations

Addressing increasing concerns about public health equity in the context of violent conflict and the consequent forced displacement of populations is complex. Important operational questions now faced by humanitarian agencies can to some extent be clarified by reference to relevant ethical theory. Priorities of service delivery, the allocation choices, and the processes by which they are arrived at are now coming under renewed scrutiny in the light of the estimated two million refugees who fled from Iraq since 2003

What guidance are researchers given on how to present network meta-analyses to end-users such as policymakers and clinicians? A systematic review

© 2014 Sullivan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Introduction: Network meta-analyses (NMAs) are complex methodological approaches that may be challenging for non-technical end-users, such as policymakers and clinicians, to understand. Consideration should be given to identifying optimal approaches to presenting NMAs that help clarify analyses. It is unclear what guidance researchers currently have on how to present and tailor NMAs to different end-users. Methods: A systematic review of NMA guidelines was conducted to identify guidance on how to present NMAs. Electronic databases and supplementary sources were searched for NMA guidelines. Presentation format details related to sample formats, target audiences, data sources, analysis methods and results were extracted and frequencies tabulated. Guideline quality was assessed following criteria developed for clinical practice guidelines. Results: Seven guidelines were included. Current guidelines focus on how to conduct NMAs but provide limited guidance to researchers on how to best present analyses to different end-users. None of the guidelines provided reporting templates. Few guidelines provided advice on tailoring presentations to different end-users, such as policymakers. Available guidance on presentation formats focused on evidence networks, characteristics of individual trials, comparisons between direct and indirect estimates and assumptions of heterogeneity and/or inconsistency. Some guidelines also provided examples of figures and tables that could be used to present information. Conclusions: Limited guidance exists for researchers on how best to present NMAs in an accessible format, especially for non-technical end-users such as policymakers and clinicians. NMA guidelines may require further integration with end-users' needs, when NMAs are used to support healthcare policy and practice decisions. Developing presentation formats that enhance understanding and accessibility of NMAs could also enhance the transparency and legitimacy of decisions informed by NMAs.The Canadian Institute of Health Research (CIHR) Drug Safety and Effectiveness Network (Funding reference number – 116573)

Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND: Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy. METHODS: We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930. FINDINGS: Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group. INTERPRETATION: In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. FUNDING: National Institute of Health Research

Rapid simulation of spatial epidemics : a spectral method

Spatial structure and hence the spatial position of host populations plays a vital role in the spread of infection. In the majority of situations, it is only possible to predict the spatial spread of infection using simulation models, which can be computationally demanding especially for large population sizes. Here we develop an approximation method that vastly reduces this computational burden. We assume that the transmission rates between individuals or sub-populations are determined by a spatial transmission kernel. This kernel is assumed to be isotropic, such that the transmission rate is simply a function of the distance between susceptible and infectious individuals; as such this provides the ideal mechanism for modelling localised transmission in a spatial environment. We show that the spatial force of infection acting on all susceptibles can be represented as a spatial convolution between the transmission kernel and a spatially extended ‘image’ of the infection state. This representation allows the rapid calculation of stochastic rates of infection using fast-Fourier transform (FFT) routines, which greatly improves the computational efficiency of spatial simulations. We demonstrate the efficiency and accuracy of this fast spectral rate recalculation (FSR) method with two examples: an idealised scenario simulating an SIR-type epidemic outbreak amongst N habitats distributed across a two-dimensional plane; the spread of infection between US cattle farms, illustrating that the FSR method makes continental-scale outbreak forecasting feasible with desktop processing power. The latter model demonstrates which areas of the US are at consistently high risk for cattle-infections, although predictions of epidemic size are highly dependent on assumptions about the tail of the transmission kernel

Central odontogenic fibroma: a case report with long-term follow-up

An osteolytic tumour of the mandible with prominent expansive growth on the alveolar ridge and displacement of the involved teeth is described in a 28-year-old man. The lesion was diagnosed as a central odontogenic fibroma, an uncommon benign neoplasm derived from dental apparatus, and was removed by curettage. The patient remains asymptomatic after thirteen years of follow-up, which supports the claimed indolent behavior of this poorly documented disease and the adequacy of a conservative surgical treatment