SummaryBackgroundLowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients.MethodsThis randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607.Findings4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74–0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76–1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60–0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68–0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13).InterpretationReduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.FundingMerck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.

Brothers volcano, which is part of the active Kermadec arc, northeast of New Zealand, forms an elongate edifice 13 km long by 8 km across that strikes northwest-southeast. The volcano has a caldera with a basal diameter of ~3 km and a floor at 1,850 m below sea level, surrounded by 290-to 530-m-high walls. A volcanic cone of dacite rises 350 m from the caldera floor and partially coalesces with the southern caldera wall. Three hydrothermal sites have been located: on the northwest caldera wall, on the southeast caldera wall, and on the dacite cone. Multiple hydrothermal plumes rise ~750 m through the water column upward from the caldera floor, originating from the northwest caldera walls and atop the cone, itself host to three separate vent fields (summit, upper flank, northeast flank). In 1999, the cone site had plumes with relatively high concentrations of gas with a ∆pH of-0.27 relative to seawater (proxy for CO2 + S gases), dissolved H2S up to 4,250 nM, high concentrations of particulate Cu (up to 3.4 nM), total dissolvable Fe (up to 4,720 nM), total dissolvable Mn (up to 260 nM) and Fe/Mn values of 4.4 to 18.2. By 2002, plumes from the summit vent field had much lower particulate Cu (0.3 nM), total dissolvable Fe (175 nM), and Fe/Mn values of 0.8 but similar ∆pH (-0.22) and higher H2S (7,000 nM). The 1999 plume results are consistent with a magmatic fluid component with the concentration of Fe suggesting direct exsolution of a liquid brine, whereas the much lower concentrations of metals but higher overall gas contents in the 2002 plumes likely reflect subsea-floor phase separation. Plumes above the northwest caldera site are chemically distinct, and their compositions have not changed over the same 3-year interval. They have less CO2 (∆pH of-0.09), no detectable H2S, total dissolved Fe of 955 nM, total dissolved Mn of 150 nM, and Fe/Mn of 6.4. An overall increase in 3 He/ 4 He values in the plumes from R/RA = 6.1 in 1999 to 7.2 in 2002 is further consistent with a magmatic pulse perturbing the system. The northwest caldera site is host to at least two large areas (~600 m by at least 50 m) of chimneys and subcropping massive sulfide. One deposit is partially buried by sediment near the caldera rim at ~1,450 m, whereas the other crops out along narrow, fault-bounded ledges between ~1,600 and 1,650 m. Camera tows imaged active 1-to 2-m-high black smoker chimneys in the deeper zone together with numerous 1-to 5-m-high inactive spires, abundant sulfide talus, partially buried massive sulfides, and hydrothermally altered volcanic rocks. 210 Pb/ 226 Ra dating of one chimney gives an age of 27 ± 6 years; 226 Ra/Ba dating of other mineralization indicates ages up to 1,200 years. Formation temperatures derived from ∆ 34 Ssulfate-sulfide mineral pairs are 245°to 295°for the northwest caldera site, 225°to 260°C for the southeast caldera and ~260°to 305°C for the cone. Fluid inclusion gas data suggest subsea-floor phase separation occurred at the northwest caldera site. Alteration minerals identified include silicates, ...

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BackgroundDespite the problem of inadequate recruitment to randomised trials, there is little evidence to guide researchers on decisions about how people are effectively recruited to take part in trials. The PRioRiTy study aimed to identify and prioritise important unanswered trial recruitment questions for research. The PRioRiTy study - Priority Setting Partnership (PSP) included members of the public approached to take part in a randomised trial or who have represented participants on randomised trial steering committees, health professionals and research staff with experience of recruiting to randomised trials, people who have designed, conducted, analysed or reported on randomised trials and people with experience of randomised trials methodology.MethodsThis partnership was aided by the James Lind Alliance and involved eight stages: (i) identifying a unique, relevant prioritisation area within trial methodology; (ii) establishing a steering group (iii) identifying and engaging with partners and stakeholders; (iv) formulating an initial list of uncertainties; (v) collating the uncertainties into research questions; (vi) confirming that the questions for research are a current recruitment challenge; (vii) shortlisting questions and (viii) final prioritisation through a face-to-face workshop.ResultsA total of 790 survey respondents yielded 1693 open-text answers to 6 questions, from which 1880 potential questions for research were identified. After merging duplicates, the number of questions was reduced to 496. Questions were combined further, and those that were submitted by fewer than 15 people and/or fewer than 6 of the 7 stakeholder groups were excluded from the next round of prioritisation resulting in 31 unique questions for research. All 31 questions were confirmed as being unanswered after checking relevant, up-to-date research evidence. The 10 highest priority questions were ranked at a face-to-face workshop. The number 1 ranked question was “How can randomised trials become part of routine care and best utilise current clinical care pathways?” The top 10 research questions can be viewed at www.priorityresearch.ie.ConclusionThe prioritised questions call for a collective focus on normalising trials as part of clinical care, enhancing communication, addressing barriers, enablers and motivators around participation and exploring greater public involvement in the research process.

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A variety of mineralogical, textural and geochemical evidence shows that igneous rocks in giant layered intrusions containing platinum-group element (PGE) deposits such as the Bushveld Complex, South Africa, the Stillwater Complex, USA, and the Skaergaard Intrusion, East Greenland were recrystallized and chemically modified by magmatic

Data from regional and mine-scale mapping, alteration zonation, and ore mineral paragenesis studies are given for eight mafic-ultramafic, shear zone-hosted, gold-bearing quartz vein deposits within the 3.1-to 3.5-Ga Barberton greenstone belt, South Africa. Fluid properties and light stable isotope geochemistry of the ore-bearing fluid are also discussed.The studied deposits occur mostly in an arc near the Kaap Valley tonalite-greenstone belt contact, over a distance of •60 km. Each deposit is structurally controlled, typified by host D s (deformation) shear zones that are either located within, or in close proximity to, major De and/or Ds tectonic breaks, inferred to be thrust faults. The deposits have a distinctly similar structural style and alteration zonation with a noticeable correlation between alteration type and proximity to the mineralized Ds shear(s). From the least to the most intensely deformed rocks, the following alteration assemblages are recorded: talc-carbonate, quartz-carbonate, fuchsite-quartz-carbonate _ sulfides, and sericite-quartz-sulfides _ carbonate -fuchsite. Gold appears late in the overall alteration sequence, although it is relatively early within the sulfide paragenetic sequence. Gold has been introduced syndeformationally, during a period of intense shear development. U-Pb analyses of zircon and rutile show that gold mineralization is bracketed between 3126 _ 21 and 3084 _ 18 Ma, i.e., •100 to 140 m.y. after the intrusion of the nearby Kaap Valley tonalitc (3227 _ i Ma). The Kaap Valley tonalitc may thus have acted as a relatively impermeable barrier to the hydrothermal fluid. The gold-bearing fluid(s) also postdate the main thrusting event in the north-central part of the greenstone belt by 100 to 140 m.y. but utilized the De (3229-3227 Ma) and later Ds (•3164 Ma) thrusts as zones of weakness for fluid flow. Fluid inclusions and light stable isotopes show evidence for fluid homogeneity over a minimum scale of •60 x 10 km and for phase separation on a local (mine) scale. Evidence for phase separation is noted by spatially related, primary, H20-CO2 inclusions having variable H20/COe ratios (type I), coexisting with monophase, primary, COe-rich (type III) inclusions. Wt percent NaC1 equiv values for the dominant type I inclusions are typically in the 5 to 6 percent range for all the mines studied. Variable COe densities are noted which are also ascribed to phase separation. Fluid inclusion homogenization temperatures for type I inclusions are 230 ø to 310øC, with 290 ø to 310øC considered representative for the main-stage fluid. The confining pressure for type I inclusions is •890 bars which can be converted to a minimum depth of formation of •3,400 m. Fluid inclusion volatiles, from heated crushing-gas chromatographic analysis, show dominant HeO (•90 mole %) and CO2 (•10 mole %) with minor CH 4 (•0.06 mole %) and Ne (•0.04 mole %) and traces of COS, Cell6, CsHs, and other hydrocarbons. A combined HeO-COe-NaC1 "average" fluid for the gold deposits studied is -•88.5 mole percent H20, •...