The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial

BACKGROUND: At the time of feasibility work and final design of the trial there was no randomised control trial evidence for the long-term risks and benefits of hormone replacement therapy. Observational studies had suggested that long term use of estrogen was likely to be associated, amongst other things, with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer. Concomitant use of progestogens had been shown to protect against endometrial cancer, but there were few data showing how progestogen might affect estrogen actions on other conditions. Disease specific risks from observational studies suggested that, overall, long-term HRT was likely to be beneficial. Several studies showed that mortality from all causes was lower in HRT users than in non-users. Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women. The WISDOM trial was designed to compare combined estrogen and progestogen versus placebo, and estrogen alone versus combined estrogen and progestogen. During the development of WISDOM the Women's Health Initiative trial was designed, funded and started in the US. DESIGN: Randomised, placebo, controlled, trial. METHODS: The trial was set in general practices in the UK (384), Australia (94), and New Zealand (24). In these practices 284175 women aged 50–69 years were registered with 226282 potentially eligible. We sought to randomise 22300 postmenopausal women aged 50 – 69 and treat for ten years. The interventions were: conjugated equine estrogens, 0.625 mg orally daily; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily; matched placebo. Primary outcome measures were: major cardiovascular disease, osteoporotic fractures, breast cancer and dementia. Secondary outcomes were: other cancers, all cause death, venous thromboembolism and cerebro-vascular disease. RESULTS: The trial was prematurely closed during recruitment following publication of early results from the Women's Health Initiative. At the time of closure, 56583 had been screened, 8980 entered run-in, and 5694 (26% of target of 22,300) randomised. Those women randomised had received a mean of one year of therapy, mean age was 62.8 years and total follow-up time was 6491 person years. DISCUSSION: The WISDOM experience leads to some simple messages. The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery. When a trial is very costly and beyond the resources of one country, funders and investigators should make every effort to develop international collaboration with joint funding

Craniofacial fibrous dysplasia: clinical characteristics and long-term outcomes

Aim: To present the clinical features and management outcomes in a large longitudinal series of patients with craniofacial fibrous dysplasia (CFD). Methods: Retrospective interventional consecutive case series. Main outcome measures included signs and symptoms, radiographic findings, long-term outcomes, and postoperative complications. Results: A total of 42 patients with CFD were identified. The mean age at presentation was 16.7 years; mean follow-up was 12.6 years. Out of these 42 patients, 37 (88.1%) had unilateral involvement and 5 (11.9%) had bilateral involvement, of which 3 (7.1%) had McCune–Albright syndrome. The commonest presenting symptom was facial asymmetry (36 cases, 86%). The frontal bone was the most commonly involved (27 cases, 64.3%), zfollowed by the sphenoid (24 cases, 57.1%). The most common pattern of bone involvement was monostotic (32 cases, 76.2%). Radiological optic canal involvement occurred in 18 eyes of 15 (37.5%) patients, with optic atrophy in 9 eyes (18.8%) of 7 patients (16.7%). Surgical intervention was performed in 30 (71.4%) cases for both functional and reconstructive reasons. Optic canal decompression was performed in three cases, in all of which stabilization of vision was achieved; no patient lost vision as a result of surgery. Conclusions: In this large longitudinal series of CFD, visual loss was not uncommon and occurred insidiously. The presenting clinical and radiological features, surgical interventions, and outcomes are discussed.AMA Rahman, SN Madge, K Billing, PJ Anderson, I Leibovitch, D Selva and D Davidhttp://www.nature.com/eye/journal/v23/n12/abs/eye20096a.htm

Endonasal dacryocystorhinostomy for nasolacrimal duct obstruction in patients with sarcoidosis

PurposeTo evaluate the outcomes of endonasal dacryocystorhinostomy (EN-DCR) surgery in patients with sarcoidosis.MethodsRetrospective chart review of all patients with sarcoidosis undergoing EN-DCR in 6 practices from 1999-2011.ResultsWe included 18 procedures in 14 patients (8 female, 6 male) who underwent EN-DCR for acquired NLDO secondary to sarcoidosis. The mean age was 53.7 (range 38-82). The presenting symptom in all cases was epiphora. Eight patients (57%) complained of having additional nasal congestion. Surgery was performed using endoscopic powered-type DCR with flaps in 12/18 (67%) and non-endoscopic mechanical EN-DCR in 6/18 (33%). In 15 (83%) cases the lacrimal sac and nasal mucosa appeared abnormally yellowish, crusty, oedematous and friable. Five patients were treated with pre-operative oral steroid and overall 8 patients had oral prednisolone post operatively, 30-60 mg tapered within 10 days-8 weeks. One patient had difficulties in tapering down the oral steroids at 6 months of follow-up. All patients were free of epiphora and patent to syringing, with nasal endoscopy revealing free flow of fluorescein through the ostium at a mean follow-up of 11.3 months (median follow-up 9 months).ConclusionsAll 18 cases of acquired nasolacrimal duct obstruction secondary to sarcoidosis were treated successfully with EN-DCR. An abnormal appearance of the nasal mucosa is an important sign. Nasal congestion is a frequent sign. A successful outcome may not depend on intensive long-term therapy with local or systemic steroids. Mechanical or powered EN-DCR for nasolacrimal duct obstruction secondary to sarcoidosis achieves encouraging medium-term outcomes.Inbal Avisar, Alan A. McNab, Peter J. Dolman, Bhupendra Patel, Jean-Louis deSousa, Dinesh Selva, and Raman Malhotr

The nature of upper mantle upwelling during initiation of seafloor spreading in the southern Red Sea

The response of the mantle and specifically melt generation during the progression from continental to oceanic rifting is poorly understood due to an absence of direct observations. Specifically, it is unclear when during the rifting process the segmented nature of magma supply typical of seafloor spreading initiates. We have imaged the mantle beneath the southern Red Sea, Afar and the Main Ethiopian rift using Rayleigh-wave tomography. From this we have generated a high-resolution absolute 3-dimensional shear-wave velocity model of the upper 250 kilometres imaging the mantle response during the progression from continental rifting to seafloor spreading. We interpret segmented partial melt beneath the rifts based on observations of low seismic velocities and rift parallel anisotropy. The low velocities are likely formed by focusing of partial melt along the base of the lithosphere in addition to buoyancy driven active upwelling. The segmented anomalies are consistent in scale from the oceanic southern Red Sea rift to the continental Main Ethiopian, suggesting that mantle segmentation beneath oceanic rifts initiates early during continental rifting. The similarity between the observed mantle segmentation and mantle segmentation observed at oceanic rifts worldwide indicates that these interpretations may apply globally